Tuberculosis

TUBERCULOSIS

Springer Berlin Heidelberg New York Hong Kong London Milan Paris Tokyo

M. Monir Madkour (Editor) A. Al Saif . M. Al Shahed . K. R. Al Moutaery A. Al Kudwah (Associate Editors)

Tuberculosis Foreword by

David A. Warrell

With 444 Figures in 846 Separate Illustrations, 139 in Color and 89 Tables

Springer

Editor: M. MONIR MADKOUR

Department of Medicine Armed Forces Hospital Riyadh 11159 Saudi Arabia

Associate Editors: ABDULAZIZ AL SAIF

MONA AL SHAHED

Department of Medicine Armed Forces Hospital Riyadh 11159 Saudi Arabia

Department of Radiology Armed Forces Hospital Riyadh 11159 Saudi Arabia

KALAF AL MOUTAERY

AIDA AL KUDWAH

Department of Neurosurgery Armed Forces Hospital Riyadh 11159 Saudi Arabia

Department of Dermatology Armed Forces Hospital Riyadh 11159 Saudi Arabia

ISBN 3-540-01441-1 Springer-Verlag Berlin Heidelberg Library of Congress Cataloging-in-Publication Data Tuberculosis I M. Monir Madkour, ed p.cm. Includes bibliographical references and index. ISBN 3-540-01441-1 (alk. paper) 1. Tuberculosis. 1. Madkour, M. Monir. RC311.T4172003 616.9'95--dc22

2003059067

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitations, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer-Verlag is part of Springer Science+Business Media httpllwww.springeronline.com © Springer-Verlag Berlin Heidelberg 2004 Printed in Germany The use of general descriptive names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every case the user must check such information by consulting the relevant literature. Cover-Design: Erich Kirchner, Heidelberg Typesetting: Verlagsservice Teichmann, Mauer 2113150xq - 5432 1 0 - Printed on acid-free paper

Foreword

It was through his superb monograph on brucellosis, first published in 1989, that I came to know Dr. M. Monir Madkour and later to meet him in Riyadh. From this introduction, I was quick to enlist his help as an author of the Oxford Textbook ofMedicine. He has now turned his considerable talents as physician, author and editor to a disease at least as interesting but even more important, tuberculosis. Considered against the background of a large literature on this subject, Dr. Madkour's monumental monograph is distinctive in several respects. As he emphasises in his preface, his book, unlike most others published on tuberculosis in English, has not been written by western experts whose experience of the disease is based in developed countries. The Kingdom of Saudi Arabia has afforded the unusual combination of an abundance of clinical material with state-ofthe-art facilities for laboratory diagnosis, investigation, imaging and medical and surgical management. Dr. Madkour and his four associate editors, all from the prestigious Riyadh Armed Forces Hospital, have assembled a distinguished international cast of 64 authors; 29 from the Kingdom of Saudi Arabia, 16 from Europe, 12 from North America, five from Asia and two from Africa. The result is an exciting, comprehensive and original work incorporating a wide range of clinical and scientific skills and experience and carrying enormous authority. Tuberculosis is the most prevalent of all bacterial infections, existing actively or in latent form in a third of the world's population. In the developing world, almost everyone is infected and the tubercle bacillus might almost be regarded as part of the normal human condition. It is not surprising that the disease has played such an important role in the political, social, industrial, artistic and scientific history of mankind. This commanding historical perspective is clearly identified in the two opening chapters. I was fascinated by Dr. Saleh A. Bedeir's review of tuberculosis in Ancient Egypt, although the examples of Pott's disease in remains from the predynastic period may be antedated by neolithic finds near Heidelberg, Germany (5000 B.C.) and Liguria, Italy (4000 B.C.) (Formicola et al. 1987). So was it Europe that gave the world tuberculosis? In Chap. 2 ("Historical aspects of tuberculosis"), Dr. Madkour and colleagues include an important section on the achievements of Arabian medicine during the period 500-1500 A.D., usually regarded as the "Dark Ages" in Europe. The roles of the Baghdad and Cairo Schools during this era, and notably the contributions of Ibn an-Nafis, Rhazes, Avicenna and Albucasis, have certainly been neglected. Understandably, this account does not dwell on the enormous impact of tuberculosis on the arts, literature and science in Europe, especially during the nineteenth century, when this disease determined the creative life of many outstanding authors, artists and composers and supplied many fictional heroes, heroines and story lines. In Chap. 3 ("Global epidemiology of tuberculosis"), Marcos Espinal and Mario Raviglione of WHO Geneva, provide compelling evidence of the current worldwide crisis in tuberculosis control. An annual incidence of some 8 million new cases, with 2 million deaths and a case notification rate of around 50 per 100,000, shows no evidence of decline

despite the availability of effective anti-tuberculosis chemotherapy. The most chilling evidence for a failure of implementation of chemotherapy, the impact of the HIV-AIDS epidemic and emerging multi-drug resistant disease, is given in their Fig. 3.5, which predicts an increase to 10 million new cases in 2010. The epidemiological situation in the Kingdom of Saudi Arabia (Chap. 4) is complicated by the large influx of pilgrims from all over the world during the Hajj. Molecular fingerprinting of Mycobacterium tuberculosis (Chap. 5) has provided fascinating insights into the epidemiology, history and geographical origins of the pathogen, for example into the Cape coloured population of Cape Town (van HeIden 2002). Tuberculosis has become a major occupational health concern for medical personnel and others who work in high-risk communities. This important area is covered by Jaime Esteban in Chap. 7 ("Tuberculosis in Special Groups and Occupational Hazards"). There is a strong section on the microbiology, immunology, pathogenesis and pathology of tuberculosis, including a substantial review of immunology and pathogenesis by Graham Rook (Chap. 9). Pathological changes in the central nervous system are often dominated by secondary effects of obstructive or communicating hydrocephalus or the involvement of major blood vessels or cranial nerves at the base of the brain (Chap. 10). Environmental and other non-tuberculous mycobacteria, many of which have been regarded as virtually non-pathogenic in immunocompetent people, have caused lifethreatening infections in those with subtle immune deficits, for example in the IL-12dependent interferon-gamma pathway (Lammas et al. 2000; Fieschi et al. 2003) (Chap. 11). These rare deficiency syndromes provide insights into normal immune defence mechanisms, as does reactivation of latent tuberculosis by corticsteroids, anti-TNF antibodies and other agents. The section on diagnosis (Chaps. 12-15) covers conventional and newer methods, including PCR. The last decade has witnessed increasing investment in basic science research into the cell biology, genetics and immunology of tuberculosis. A landmark achievement has been the sequencing of the M. tuberculosis genome. However, these advances in the understanding of the biology of the bacillus and the host response have not yet resulted in any tangible improvements in diagnosis and management of tuberculosis patients and their contacts. One area in which recent scientific advances are beginning to make an impact on clinical practice is the diagnosis of latent tuberculosis infection. Until very recently, this relied upon the century-old tuberculin skin test, introduced by Robert Koch (Chap. 15). Blood tests measuring interferon-gamma secretion in response to purified protein derivative (PPD) may offer a more rapid and convenient approach to detecting latent infection. Cellular immune responses to PPD may, however, cross-react with BCG vaccination, just as with the delayed type hypersensitivity response to PPD detected by skin testing, resulting in poor specificity. Comparative mycobacterial genomics has identified a stretch of DNA (region of difference I, RD1) that is present in M. tuberculosis but absent from all strains of BCG vaccine. The antigens encoded by RD 1 genes thus offer the opportunity to develop more specific tests for M. tuberculosis infection. Two of these antigens, ESAT-6 and CFP10, have now been incorporated into a rapid, sensitive blood test that enumerates individual interferon-gamma-secreting T cells, the enzyme-linked immunospot (ELISPOT) assay. In active tuberculosis, EllSPOT appears to have a higher sensitivity and specificity than the tuberculin skin test (Lalvani et al. 2001). In latent infection, the absence of a gold standard reference test makes evaluation of any new test difficult, but recent studies indicate that ELISPOT successfully distinguishes latent infection from BCG vaccination and thus has a higher specificity than skin testing, while the observation that ELISPOT correlates more

closely with M. tuberculosis exposure than skin testing suggests that it may also have a higher sensitivity (Lalvani et al. 2001; Ewer et al. 2003). From the clinical point of view, tuberculosis is the most protean of all diseases, demanding inclusion in the differential diagnosis of almost every symptom, sign and abnormal result of investigation. The organ-related chapters of the book provide a thorough coverage of disease manifestations in the different age groups (Chaps. 16-18), during pregnancy (Chap. 19), in the face of immunosuppression (Chap. 29) and in the various sytems, organs and tissues (Chaps. 20-43). A great strength of the book is its inclusion of a rich variety of high-resolution pictures of clinical cases (see, for example, Chap. 36 on skin manifestations, and Chap. 40 on the eye). The clinical suspicion that allows the crucial early diagnosis of tuberculous meningitis (Chaps. 32 and 33) is particularly subtle, but the diagnosis may be difficult to confirm in the developing world. I have seen too many patients undergoing inappropriate therapeutic trials of antituberculosis chemotherapy for this condition. Tuberculous meningitis is a prevalent and commonly misdiagnosed condition that deserves a far more detailed and lengthy discussion. Compliance to the necessarily prolonged treatment regimens has been improved by the "DOTS" (directly observed treatment) strategy (Chap. 45). Once the correct treatment has been implemented, its efficacy must be monitored (Chap. 47), as the greatest threat to successful cure is drug resistance. Peter Davies provides an authoritative review of this, the most challenging obstacle to cure and control (Chap. 46). Of the many suggested ancillary treatments, corticosteroids are becoming less controversial for pericardial and pleural effusions and for tuberculous meningitis. It is to be hoped that the current large randomised controlled trial of corticosteroids in tuberculous meningitis, being conducted by The Centre for Tropical Diseases in Ho Chi Minh City, Vietnam, will finally provide decisive evidence in this long-running debate. I congratulate Dr. Madkour and his expert team of contributors for producing a timely, thorough, scholarly and truly fascinating account of one of the world's most important and complex diseases. Their book deserves to be consulted by all medical practitioners and to be read in its entirety by all infectious diseases specialists. It will surely become a classic in the literature of this disease. Oxford, UK

DAVID

A. WARRELL

References Ewer K, Deeks J, Alvarez L et al (2003) Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 361: 1168-1173 Fieschi C, Dupuis S, Catherinot E et al (2003) Low penetrance, broad resistance, and favorable outcome of interleukin-12 receptor beta-l deficiency: medical and immunological implications. J Exp Med 197:527-535 Formicola V, Milanesi Q, Scarsini C (1987) Evidence of spinal tuberculosis at the beginning of the fourth millennium B.C. from Arene Candide Cave (Liguria, Italy). American J Physical Anthropology 72:1-6 Van HeIden PD (2002) Molecular epidemiology of TB: challenging dogmas and asking new questions. IUBMB Life 53:219-223 Lalvani A, Pathan AA, McShane H et al (2001) Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Medicine 163:824-828 Lammas DA, Casanova J-L, Kumararatne DS (2000) Immunodeficiency review. Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin Exp Immunol 121:417-425

Preface

In 1993, the World Health Organization declared tuberculosis a global emergency. Yet, the incidence of tuberculosis continues to rise. It is not clear, however, whether the rising incidence can be attributed to failure of control strategies, the recent impact of the HIV pandemic or the increasing problem of multidrug resistance. At present, it is estimated that one-third of the world population is infected with Mycobacterium tuberculosis, with over 8 million new cases of active disease detected every year and almost 2 million annual deaths. The impact of the present situation and the current inadequate efforts necessitates the development of a novel and alternative approach to the control and therapy measures. It is interesting to note that while the incidence of tuberculosis is generally low in developed countries, most of the authoritative textbooks on tuberculosis in the English language have been written by western experts. As an expatriate, working in Saudi Arabia, I found a rare opportunity to work in an endemic area yet enjoy the diagnostic and therapeutic facilities of developed countries. Such a combination of circumstances is rarely present in developing or developed countries. The rich clinical material is clearly reflected in this book in the form of "evidence-based" clinical practice enriched with vast numbers of images of various body organs and systems as well as by a thorough survey of all the relevant literature. The numerous figures that are present in a lot of chapters, many in colour, give a vivid picture of what is seen in clinical practice and comprise a special feature of this textbook. Separate imaging chapters were compiled whenever the inclusion with the text would have rendered the corresponding chapter unwieldy. Some of the world's most distinguished medical scientists from North America, South-East Asia, the Far East, South Africa and many European countries have contributed chapters on global epidemiology, molecular epidemiology, the molecular epidemiology of Mycobacterium bovis, polymerase chain reaction (PCR), serological methods, latent tuberculosis, prevention and control, directly observed therapy (DOT), multidrug-resistant tuberculosis, HIV and tuberculosis, thoracic surgery, new vaccines and many other clinical topics. Animal tuberculosis, which may contribute to human disease, is included in a separate chapter. The main goal of this book is to present a clear account of all aspects of tuberculosis as seen and practiced both in developing and developed countries. All authors took this into consideration while writing their chapters. Recent advances in diagnosis, prevention and control measures, and treatment are also addressed. I am humbled by the honour that was given to me by Professor David A. Warrell, Founding Director of the Centre for Tropical Medicine (Emeritus), University of Oxford and editor of the Oxford Textbook of Medicine, in agreeing to write the foreword in this book, and I am most grateful to him. Riyadh

M. MONIR MADKouR

This work is dedicated to: The renaissance of the ancient glorious Library of Alexandria, Egypt, and to those who contributed to its resurrection over the original site. Alexandria was the chief cultural and commercial center of its time, and when the Library was built in approximately 332 Be it attracted manuscripts and scholars from the entire Hellenistic world. It contained over 700,000 rolls of the work of Socrates, Plato, Aristotle, Hippocrates and all the writing of the known world, but was destroyed by a great fire. Virtual images of the ancient Library are available at UNESCO. The inauguration ceremony of the "new--ancient" Library of Alexandria in September 2002 was attended by heads of state, scientists, artists and dignitaries from all over the world. The World Health Organization, for its enormous, determined and unyielding efforts to control tuberculosis, particularly in endemic, poorly resourced, and developing countries.

Acknowledgements: I am indebted to Gen. Dr. S.M. Al Deeb and the Hospital Management Board for providing the facilities I required for this project. I am grateful to our medical library staff: R. Ahtashemuddi, S.Z. Khan, Y.S. AI-Zharani, M.A. Khushi, S.M. AI-Rakaf, S. Al-Salafi, R. AI-Sous, and A. AI-Sultan; our medical record staff: J. Al Anazi, A. Al Humaid and T. Al Shuriti; and our medical illustration staff: S. Nally, T. Michalak, D. Hargreaves, K. Jefferson, N. Morgan, R. Ponmbath, M. Horaib. Support from our colleagues from the department of microbiology, Dr. S. Bakheshwain and Dr. N. EI-Khizzi, is highly appreciated. I would like to thank Dr. M. Sofi and Dr. S.A. AI-Mohaimeed for their support. My colleagues from the department of medicine helped and supported this project, including Drs. T. AI-Tassan, B. AI-Dosary, S. AI-Faraj, A. AI-Zaid, N. AI-Qahtani and many others, and I am grateful. I would like to thank our secretaries for typing the manuscripts of my chapters and for their secretarial help: I. Andries, J. Misquith, E. Sabbagh. I would like to thank my son Amr Madkour, pre-medical student at Austin, Texas for helping me with his experience in the Internet and other computer facilities for this project during his summer vacations. My other children, Rasha, Monir and Reem, helped with typing and sending correspondence bye-mail and with MedLine searches. Without their help, my handicap in computer technology would have been insurmountable. I am most grateful to Dr. Julia Heidelmann, Dr. Ute Heilmann, Ms. Wilma McHugh and the staff at Springer-Verlag for their meticulous care and efforts in the production of this book. Despite the help I have received from others, I alone stand responsible for any shortcomings this book may contain. M. MONIR MADKouR

Contents

Historical Background

.

Tuberculosis in Ancient Egypt SALEH A. BEDEIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Historical Aspects of Tuberculosis M. MONIR MADKOUR, KITAB E. AL-OTAIBI, R. AL SWAILEM

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 15

31

3 Global Epidemiology of Tuberculosis MARCOS A. ESPINAL and MARIO C. RAVIGLIONE

33

4 Epidemiology of Tuberculosis in Saudi Arabia ABDULRAHMAN A.ALRAJHI and ALI M.AL-BARRAK

45

5 The Molecular Epidemiology of Tuberculosis KATHRYN DERIEMER and CHARLES L DALEY

57

6 Molecular Epidemiology of Mycobacterium bovis ROBIN A SKUCE and SYDNEY D NEILL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

7 Tuberculosis in Special Groups and Occupational Hazards JAIME ESTEBAN

93

Microbiology, Immunology, Pathogenesis and Pathology

113

8 Microbiology of Tuberculosis A OLU OSOBA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 115 9 The Immunology and Pathogenesis of Tuberculosis GRAHAM A. W. ROOK

133

10 Pathology of Tuberculosis MOHAMMED AKHTAR and HADEEL AL MANA

153

11 Nontuberculous Mycobacteria JAE-JOON YIM and STEVEN M. HOLLAND

163

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 185 12 Serologic Testing for Tuberculosis CHAKHRADHAR KOTARU and EDWARD D. CHAN. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187

XIV

Contents

13 PCR and Diagnosis of Tuberculosis DIANA LWILLIAMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 199 14 Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients GORGON AKPEK

213

15 Immunodiagnostics for Latent Tuberculosis Infection ROHIT K. KATIAL

231

Organ-related Chapters

241

General 16 Childhood Tuberculosis PETER R. DONALD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 243 17 Primary Tuberculosis in Adults M. MONIR MADKOUR

265

18 Miliary/Disseminated Tuberculosis M. MONIR MADKOUR

273

19 Tuberculosis and Pregnancy M. MONIR MADKOUR

301

Thorax 20 Post-primary Pulmonary Tuberculosis M. MONIR MADKOUR, Y. ABUSABAAH, ALI BEN MOUSA, ALI AL MASOUD . . . . . . . .. 313 21 Endobronchial Tuberculosis HEE SOON CHUNG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 329 22 Pleural Tuberculosis M. MONIR MADKOUR, MAJDY IDREEs, M. AL SHAHED

349

23 Radiology of Pulmonary Tuberculosis MONA AL SHAHED, MOHAMMED ABD EL BAGI, M. MONIR MADKOUR . . . . . . . . . . .. 359 24 Pulmonary Function Test and Tuberculosis MAJDY M. IDREES, SIRAJ O. WALl, ABDULLA AL-AMOUDI

385

25 Thoracic Surgery for Tuberculosis YUJI SHIRAISHI

395

26 Radionuclides in Pulmonary and Extra-Pulmonary Tuberculosis DAVID HAMILTON and JAWDA AL-NABULSI

411

27 Tuberculosis of the Heart and Pericardium ERNESTO E SALCEDO and AHMAD S OMRAN

431

Contents

xv

Immune System 28 Mycobacterial Lymphadenitis

M. MONIR MADKOUR and RASHID AL KUHAYMI 29 Tuberculosis and Co-infection with the Human Immunodeficiency Virus ALIMUDDIN ZUMLA and JOHN M GRANGE

445 455

eNS

30 Spinal Tuberculosis M. MONIR MADKOUR, M. WASEF AL SEBAI, KHALAF R. AL MOUTAERY .. . . . . . . . .. 481 31 Surgical Management of Spinal Tuberculosis M. WASEF AL SEBAI, M. MONIR MADKOUR, KAHLAF R. AL MOUTAERY . . . . . . . . . .. 493 32 Tuberculosis of the Central Nervous System M. ZUHEIR AL-KAWI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 535 33 Imaging of Brain and Spinal Cord Tuberculosis FRANCIS MCGUINNESS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 547

Musculo-Skeletal and Soft Tissue 34 Extraspinal Musculoskeletal Tuberculosis M. MONIR MADKOUR, AIDA J. AL-KUDWAH, MOHAMMED ABD EL BAGI

587

35 Imaging of Musculoskeletal Tuberculosis MOHAMMED ABD EL BAGI, MONA AL SHAHED, M. MONIR MADKOUR . . . . . . . . . . .. 605 36 Tuberculosis of the Skin AIDA J. AL KUDWAH

627

Gastrointestinal 37 Abdominal Tuberculosis MOHAMMAD SULTAN KHUROO and NAIRA SULTAN KHUROO

659

38 Imaging of Gastrointestinal Tuberculosis MONA AL SHAHED and MOHAMMED ABD EL BAGI

679

Genitourinary 39 Genitourinary Tuberculosis M. MONIR MADKOUR

699

Head 40 Ocular Manifestations of Tuberculosis SHWU-JIUAN SHEU

731

41 Otorhinolaryngeal Aspects of Tuberculosis SUJATA MURANJAN

741

XVI

Contents

Endocrine 42 Endocrine and Metabolic Manifestations of Tuberculosis SOHAIL INAM and MONA AL-SHAHED

751

Vascular 43 Tuberculous Vasculitis and Mycotic Aneurysms M. MONIR MADKOUR

771

Treatment

779

44 Treatment of Tuberculosis DEAN E SCHRAUFNAGEL

781

45 Directly Observed Treatment for Tuberculosis Control ZHANG LI-XING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 801 46 Multi-Drug-Resistant Tuberculosis PETER D. O. DAVIES

809

47 Monitoring Treatment Efficiacy P. H. LAGRANGE, N. SIMONNEY, A. O. SOUSA, A. WARGNIER, J. L. HERRMANN

839

Control and Prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 853 48 Tuberculosis Control in Developing and Developed Countries KEVIN SCHWARTZMAN .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 855 49 BCG and New Tuberculosis Vaccines ZHOU XING

881

50 Tuberculosis in Animals P. L. NICOLETTI

893

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 903 About the Editor

930

List of Contributors

ABD EL BAGI MOHAMMED, MB, BCh, DMRD, FSRRCSI Department of Radiology Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-KuDWAH AIDA J, MD, DD, FRCP (Ed) Consultant Dermatologist, Department of Dermatology Riyadh Armed Forces Hospital P.O. Box 7897, C-117 Riyadh 11159 Saudi Arabia

ABUSABAAH Y, ABIM Fellow, Respiratory Medicine Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL KUHAYMI RASHID, FRCS Director of Surgery Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AKHTAR MOHAMMED, MD, FCAP, FRCPA, FRCPath Chairman, Department of Pathology and Laboratory Medicine King Faisal Specialist Hospital and Research Centre P.O. Box 3354, MBCI0 Riyadh 11211 Saudi Arabia

AL MANA HADEEL, MD Fellow, Department of Pathology ad Laboratory Medicine King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia

AKPEK GORGON, MD Assistant Professor of Medicine Greenebaum Cancer Center at University of Maryland School of Medicine 22 South Greene Street Baltimore MD 21201 USA

AL MAsouD ALI, MD Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-AMOUDI ABDULLA, MD, FRCP (C) Deputy Head, Department of Medicine King Faisal Specialist Hospital & Research Center Jeddah Saudi Arabia

AL MOUTAERY KHALAF R, MD, FRCS (Ed), FACS Head of Neurosurgery Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-BARRAK ALI M, AmBIM, DTM & H, FRCP (C) Consultant Infectious Diseases Unit Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-NABULsI JAWDA, DMRD, MSc NM Nuclear Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

AL-KAwI M. ZUHEIR, MD, FACP Senior Consultant Neurologist & Deputy Chairman Department of Neurosciences King Faisal Specialist Hospital and Research Center P.O. Box 3354 Riyadh 11211 Saudi Arabia

AL-OTAIBI KITAB E, Facharzt (Urology), MD, FRCS (Edin) Director General of Medical Services Department Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia

XVIII ALRAJHI ABDULRAHMAN A, MD, MPH, FIDSA Consultant and Head, Section of Infectious Diseases, Chairman, Department of Medicine (MBC #46), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia AL SAIF A, MD, PhD, FCCP, FRCP (Lon) Consultant Respiratory Medicine Director of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 1159 Saudi Arabia AL SEBAI M WASEF, FRCS. FFCS Consultant Spinal Surgeon Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia AL SHAHED MONA, MBBS, FRCR Consultant Radiologist Department of Radiology Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia AL SWAILEM R, MRCP (UK), ABIM Consultant Rheumatologist Department of Medicine Director of Postgraduate and Academic Affairs Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia BEDEIR SALEH A, MD Dean, Faculty of Medicine Cairo University Kasr El-Aini Hospitals Cairo Egypt BEN MOUSA ALI, MD Department of Medicine, Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia CHAN EDWARD D, MD Associate Professor of Medicine K613e Goodman Bldg. National Jewish Medical and Research Center, Denver, CO 1400 Jackson St Denver, CO 80206 USA

List of Contributors CHUNG HEE SOON, MD, FCCP Associate Professor of Medicine Seoul National University College of Medicine and Seoul Municipal Boramae Hospital affiliated to Seoul National University Hospital # 395 Shindaebang - 2 Dong Dongjak-Gu, Seoul, 156-707 Korea DALEY CHARLES L, MD Associate Professor of Medicine Division of Pulmonary and Critical Care Medicine San Francisco General Hospital Room 5K-l 1001 Potrero Ave San Francisco, CA 94110 USA DAVIES PETER D 0, DM, FRCP Director, Tuberculosis Research Unit Cardiothoracic Centre Liverpool Ll4 3PE UK DERIEMER KATHRYN, PhD Senior Research Scientist Division of Infectious Diseases and Geographic Medicine Stanford Medical Center, Stanford California, USA DONALD PETER R, MD Department of Paediatrics and Child Health Faculty of Health Sciences University of Stellenbosch P.O. Box 19063 7505, Tygerberg, South Africa ESPINAL MARCOS A, MD World Health Organization Stop TB Department Tuberculosis Strategy & Operations Ave Appia # 22 1211 Geneva Switzerland ESTEBAN JAIME, MD Department of Medical Microbiology Fundaci6n Jimenez Diaz Av. Reyes Cat6licos 2 28040 Madrid Spain GRANGE JOHN M, MSc, MD (Lon) Visiting Prof, Centre for Infectious Diseases & International Health Royal Free and University College Medical School Windeyer Institute of Medical Sciences 46 Cleveland St London WIP 6DB UK

XIX

List of Contributors HAMILTON DAVID, PhD, FIPEM Department of Nuclear Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia HERRMANN J L, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France HOLLAND STEVEN M, MD Immunopathogenesis Unit Building 10, Room llN103 10 Center Dr. MSC 1886 Bethesda, MD 20892 1886 USA IDREES MAJDY M, MD, FRCP (C), FCCP Head, Pulmonary Function Laboratory Division of Pulmonary Medicine Department of Medicine Riyadh Armed Forces Hospital ClIO, P.O. Box 7897 Riyadh 11159 Saudi Arabia INAM SOHAIL, MBBS, FRCP (Edin), FRCP Head of Endocrinology Division Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897 Riyadh 11159 Saudi Arabia KATIAL ROHIT K, MD Associate Professor of Medicine National Jewish Medical and Research Center Denver 1400 Jackson St. Denver, CO 80206 USA KHUROO MOHAMMAD SULTAN, MD, DM, FRCP (Edin), MACP Professor, Consultant Gastroenterologist Department of Medicine - MBC 46 King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia KHUROO NAIRA SULTAN, MBBS Department of Radiology King Faisal Specialist Hospital and Research Centre P.O. Box 3354 Riyadh 11211 Saudi Arabia

KOTARU CHAKRADHAR, MD Department of Medicine and Program in Cell Biology National Jewish Medical and Research Center Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, and Denver Veteran Administration Medical Center K613e, Goodman Building 1400 Jackson Street Denver, CO 80206 USA LAGRANGE P H, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France LI-XING ZHANG, MD Vice President & Secretary General Chinese Anti-Tuberculosis Association 5, Dong Gang Hu-Tong Beijing 100035 China MADKOUR M MONIR, MD, DM, FRCP (London) Consultant Department of Medicine Riyadh Armed Forces Hospital P.O. Box 7897, C-119 Riyadh 11159 Saudi Arabia MCGUINESS FRANCIS, MD Apt. 169, Al Haurin EI Grande 2912 Malaga Spain MURANJAN SUJATA, MS (ENT), DNB, DORL Consultant ENT Suman Apptartment, 3rd Floor 16B Naushir Bharucha Road Tardeo Mumbai 400007 India NEILL SYDNEY D., BSc, PhD Veterinary Sciences Division Department of Agriculture and Rural Development Stoney Road Stormont, Bellfast BT4 3SD UK NICOLETTI P L, DVM, MS College of Veterinary Medicine Department of Veterinary Pathology P.O. Box 110880 Gainseville Florida 32611 0880 USA

xx Ow OSOBA A, MD, FRCPath (UK), FFPath (Ireland), FWACP Consultant & Head of Microbiology

King Khalid National Guard Hospital P.O. Box 9515 Jeddah 2143 Saudi Arabia OMRAN AHMAD S, MD Consultant Cardiologist King Abdulaziz Cardiac Center, King Abdulaziz Medical City, National Guard, Riyadh, Saudi Arabia P.O. Box 22490 Riyadh 11426 Saudi Arabia RAVIGLIONE MARIO C, MD World Health Organization Stop TB Department Ave Appia # 22 1211 Geneva Switzerland ROOK GRAHAM A.W, BA, MB Bchir, MD Professor, Department Medical Microbiology Royal Free and University College Medical School Windeyer Institute of Medical Sciences 46 Cleveland Street London WIT 4JF UK SALCEDO ERNESTO E, MD Department of Cardiology King Abdulaziz Cardiac Center National Guard Hospital P.O. Box 22490 Riyadh 11426 Saudi Arabia SCHRAUFNAGEL DEAN E, MD Department of Medicine M/C 787 University of Illinois at Chicago 840 S. Wood St Chicago, IL 60612 7323 USA SCHWARTZMAN KEVIN, MD, MPH, FRCPC Assistant Professor Department of Medicine and Epidemiology And Biostatistics Respiratory & Epidemiology Unit McGill University 1110 Pine Avenue West Montreal, Quebec Canada H3A lA3 SHEU SHWU-JIUAN, MD Department of Ophthalmology Kaohsiung Veterans General Hospital 386 Ta-Chung 1st Road, Kaohsiung Taiwan 813

List of Contributors SHIRAISHI YUJI, MD Head, Section of Chest Surgery Fukujuji Hospital 3-1-24 Matsuyama Kiyose Tokyo 204 8522 Japan SIMONNEY N, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux, 75475 Paris France SKUCE ROBIN A, BSc, PhD Veterinary Sciences Division Stoney Road Stormont Belfast, BT4 3SD Northern Ireland

SOUSA A O,MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France

WALl SIRAJ 0, MD, FRCP (C), FCCP Head, Division of Pulmonary Medicine Department of Medicine King Khalid Hospital National Guard Jeddah Saudi Arabia

WARGNIER A, MD Service de Microbiologie H6pital Saint Louis Assistance Publique-H6pitaux de Paris Universite Denis Diderot 1, avenue Claude Vellefaux 75475 Paris France

WILLIAMS DIANA L, PhD Molecular Biology Research Department Laboratory Research Branch National Hansen's Disease Programs At LSU-SVM, Rm 3517W Skip Bertman Dr., Baton Rouge, LA 70803 USA

List of Contributors XING ZHOU, MD Associate Prof. Pathology & Molecular Medidine Head, Division of Infectious Diseases Centre of Gene Therapeutics McMaster University Health Sciences 1200 Main Street W Hamilton, Ontario L8N 3Z5 Canada

MD Respiratory and Critical Care Medicine Seoul Natinal University College of Medicine Seoul South Korea 110744

YIM JAE-JOON,

XXI ZUMLA ALIMUDDIN, BSc, MBChB, MSc, PhD, FRCP (Lon), FRCP (Edin) Professor of Infectious Diseases and International Health Director, Centre for Infectious Diseases and International Health Royal Free & University College Medical School Windeyer Institute of Medical Sciences Room G41 46 Cleveland St London WIP 6DB UK

Historical Background

1

Tuberculosis in Ancient Egypt SALEH

A. BEDEIR

CONTENTS 1.1 1.2 1.2.1 1.2.1.1 1.2.1.2 1.2.1.3 1.2.2 1.2.3 1.2.3.1 1.3

1.4 1.5 1.6 1.7 1.8 1.8.1 1.8.1.1 1.8.1.2 1.8.1.3 1.8.1.4 1.8.1.5 1.8.1.6 1.8.1.7 1.9 1.10

Introduction 3 Predynastic Period 3 The Foundation of Egypt 4 Predynastic Period 4 Archaic Period 4 Old Kingdom 4 Development of Egyptian Language 4 A Chronology of Literature 5 From Alexander to Napoleon 5 Ancient Egyptian Art 5 Paleopathology 6 Differential Diagnosis 7 The Author's Case 7 Pulmonary and Osseous Tuberculosis in Ancient Egyptian Mummies 8 PCR and the Diagnosis of Tuberculosis in Ancient Egyptian Population 8 Environment 9 The Nile 9 Climate 9 Housing 9 Diet 9 Religion 10 Sports and Recreation 10 Physique 10 The Medical Papyri 10 Sanatorial Treatment 11 References 12

1.1 Introduction In all probability, tuberculosis is older than the human race, and different species in the genus Mycobacterium may have caused the disease in mammals, birds, reptiles and fish (Breed et al. 1957). Tuberculosis in man and other animals, both warm-blooded and cold-blooded, may have arisen from a common Mycobacterium ancestor many millions of years ago (Cockburn and Cockburn 1980). Other authors believe that tuberculosis in man may be of much more recent origin. The earliest report on presumptive tuberculosis in ancient Old World human remains is an article by Bartels (1907) on a Neolithic skeleton found near Heidelberg, Germany. The fourth and fifth thoracic vertebrae have collapsed and fused with the sixth vertebra, creating an angulation often seen in spinal tuberculosis (Ortner and Putschar 1981).

1.2 Predynastic Period Tuberculosis has existed for thousands of years in Egypt and Nubia, as shown by art forms and skeletal material. The ancient Egyptian obtained his first tuberculosis bacillus from the close contact with livestock that occurred after the Neolithic revolution, as early as 3300 B.C., during the initial herding period of Fayoum (Filer 1995). One of the earliest examples of spinal tuberculosis has been found at excavations at the predynastic site of Adaima, 8 km south of Esna. The chronological order of Ancient Egyptian Dynasties are given here according to:

S. A. BEDEIR, MD Dean, Faculty of Medicine, Cairo University, Kasr El-Aini Hospital, Cairo, Egypt

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

a. b. c. d.

Foundation of Egypt Development of Egyptian Language A Chronology of Literature From Alexander to Napoleon

S.A. Bedeir

4

1.2.1 The Foundation of Egypt 1.2.1.1

Predynastic Period Badarian Period

Naqada I Period

Naqada II Period

Naqada III Period

5000-4000 B.C. First evidence for

4000-3500 B.C. Development of pottery in Egypt

3500-3150 B.C. First major towns culture

3150-3000 B.C. First hieroglyphs

1.2.1.2

Archaic Period Dynasty I

Dynasty II

3050-2815 B.C. Unification of Egypt; royal tombs at Abydos

2815-2600 B.C. Royal tombs at Saqqara

1.2.1.3 Old Kingdom Dynasty III

Dynasty IV

2660-2600 B.C. First pyramids

2600-2470 B.C. Great pyramids at Giza

1.2.2 Development of Egyptian Language Archaic Period

Old Kingdom

First Intermediate Period

Dynasties I-II 3050-2660 B.C. Earliest script

Dynasties III-IV 2660-2200 B.C. Old Egyptian

Dynasties VII-XIa 2200-2070 B.C. Transition to Middle Egyptian, which lasts through the Middle Kingdom, dynasties Xlb-XIII

Second Intermediate Period

New Kingdom

Third Intermediate Period

Dynasties XIV-XVII 1650-1550 B.C. Middle Egyptian

Dynasties XVIII-XX 1550-1070 B.C. Middle Egyptian transition to Late Egyptian

Dynasties XXI-XXV 1070-664 B.C. Late Egyptian Demotic

Late Period

Graeco-Roman Period

Coptic Period

Dynasties XXVII-XXXI 664-332 B.C. Late Egyptian

Dynasties XVIII-XX Ptolemies 332-30 B.C. Demotic

Romans Byzantines 30 B.C.-A.D. 395 A.D. 395-640 Demotic Coptic Demotic

5

Tuberculosis in Ancient Egypt

1.2.3 A Chronology of Literature Archaic Period

Old Kingdom

First Intermediate Period

Middle Kingdom

Dynasties I-II 3050-2660 B.C. Labels; short inscriptions only

Dynasties III-IV 2660-2200 B.C. Pyramid texts, first biographies

Dynasties VII-XIa 2200-2070 B.C. Decrees, biographies

Dynasties XIb-XIII 2070-1650 B.C. Coffin texts, stories, wisdom texts

New Kingdom

Third Intermediate Period

Graeco-Roman Period

Dynasties XVIII-XX 1550-1070 B.C. Book of the Dead; "Historical" texts

Dynasties XXI-XXV 1070-664 B.C. Major mythological texts: continue through Later Period, Dynasties XXVI-XXXI

Ptolemies Romans 332-30 B.C. 30 B.C.-A.D. 395 Increasing Greek influence

1.2.3.1 From Alexander to Napoleon Coptic Period

Ptolemaic Period

Roman Period

332-30 B.C. Egypt ruled by heirs of Alexander the Great

30 B.C.-A.D. 395 A.D. 395-640 Egypt made a Egypt part of Roman province the Eastern Empite, based on Constantinople

Arab Period

Ottoman Period

A.D. 640-1517 GeneralAmr conquers Egypt for the Caliphs

A.D. 1517-1805 The Turkish Sultan Selim I invades and incorporates the country into his empire

Spinal tuberculosis, or Pott's disease, is more likely to be found in an archaeological context. Evidence for pulmonary tuberculosis is less tenable, as the bacilli disappear soon after the death of the victim. The discovery of lung collapse or pleuritic adhesions in some mummies has been mentioned as evidence of its existence, but other conditions may cause these complications.

1.3

Ancient Egyptian Art Pott's disease is well presented in both ancient Egyptian art and human remains. Several clay statuettes of men, dating to the Predynastic period, have been considered to be cases of Pott's disease. The men are depicted with humped spines and an emaciated look that suggests tuberculosis. Yet some of the figures are in large clay bowls, which may reflect a style of burial (Filer 1995). A wooden figurine in the Brussels Museum, probably Predynastic period, shows an angular deformity of the spine and chest, strongly suggesting Pott's disease. A gardening scene from the tomb of Ipwy of the 19th dynasty shows a

gardener with a humped back denoting Pott's disease (Fig. 1.1). In the Cairo Museum, there is an Old Kingdom statue with a humped spine and a concomitant deformity of the chest (Fig. 1.2). A false door from a mastaba tomb of Ankh-my-was of the Old Kingdom (4th to 5th dynasty), now preserved in Glyptotek Ny Carlsberg, Copenhagen, represents the deceased with a deformed upper part of the torso, indicating Pott's disease (Cave 1939). The tomb of Seshen Nufer I from the 4th dynasty near the Giza pyramids compromises the scene of a humped-back serving maid clearly suffering from Pott's disease (Mahmoud 1998). Ruffer (1921) described two drawings denoting tuberculosis of the spine. The first, in Beny Hassan, shows affection of the lower cervical and upper dorsal spine. The other, in Tel EI-Amarna, dates back to the 18th dynasty and shows the kyphosis is in the lower dorsal and upper lumbar region. There are many representations of humped-back servants in the tomb chapels, but it is difficult to distinguish between Pott's disease, Porter's hump, ankylosing spondylitis and simply poor posture. In Pott's disease, the deformity is localized and the angulation is usually in the form of a gibbus. The chest wall may show a corresponding deformity.

6

S.A. Bedeir

Fig. 1.1. A scene from the tomb of Ipwy, 19th dynasty, Deir el-Medinah. A gardener irrigating a garden with a "shadouf". His spine appears to have Pott's disease

Fig. 1.2. An Old Kingdom statue with a humped back and chest deformity denoting Pott's disease

1.4

A 4- to 6-year-old girl from the Ptolemaic period, whose mummy is in the Bolton Museum, appears to have Pott's disease. Lines of growth arrest (Harris line) are shown at the ends of the long bones due to the long period of disease and stress (Filer 1995). When the tomb of Iurudef at Saqqara was excavated in 1991, an intrusive burial of a non-royal female was found to have

Paleopathology There are several reports of lesions attributed to tuberculosis in Egyptian skeletal materials and mummies. The classic, and perhaps the most convincing case of skeletal tuberculosis, comes from the 21st dynasty, or about 1000 B.C. It is the mummy of Nespaheran, a 25 to 30-year-old Egyptian priest of Amun, near Thebes. It was found among a cache of 44 priests of Amun. The spine is acutely angulated due to destruction of the lower thoracic and upper lumbar vertebrae. A huge abscess cavity is present in the sheath of the right psoas muscle (Ruffer 1910, 1921; Cave 1939; Reyad 1960; Kamal 1964; Filer 1995; Nunn 1997). The drawing, by Mrs. Cecil M. Firth, was first introduced by Ruffer in 1910 and is now a classic (Fig. 1.3). Most of the known possible cases from the Predynastic to the 21st dynasty were reviewed by Morse et al. (1964). Buikstra et al. (1993) added new cases. Flinders Petrie and Quibell collected 13 specimens with tuberculosis affection from 2000 graves in Naqada (Nunn 1997). Derry (1938) reported nine cases. The Nubian collection of the Royal College of Surgeons of England contained many cases of skeletal tuberculosis, but many were lost together with their records during an air raid in 1941. Morse et al. (1964) described a single case of a mummy with a collapsed lung and pleural adhesions, which are common complications of tuberculosis.

Fig. 1.3. Nespaheran, a priest of Amun from the 21st dynasty. The side view shows marked kyphosis of the spine and, in the front view, a large cold abscess cavity is seen in the right psoas major muscle. The anterior abdominal wall is removed

Tuberculosis in Ancient Egypt

7

severe degeneration of the spine with marked angulation and a possible paravertebral abscess. Iurudef was a high Memphite official in the household of Princess Tia, sister of Rameses II of the 19th dynasty. It is believed that the woman, who died at approximately the age of 20 years, had lived her life as an invalid and only survived through family care (Walker 1991). It is interesting to note that one of the possible causes of the early death of Tutankhamen is tuberculosis (Reyad 1960).

1.5 Differential Diagnosis Although there is very little doubt that tuberculosis was the cause of the pathological findings in most of the reported cases, it is sometimes difficult to exclude compression fractures of the spine, osteomyelitis, spinal metastasis degenerative spondylosis, fungal infection and bone cysts.

Fig. 1.4. Tuberculosis of the right iliac bone and right sacroiliac joint, of a male aged 35-39 years old at time of death. Giza necropolis. There is ankylosis of the sacroiliac joint, erosion of the iliac bone and the sacrum and a round defect in the iliac bone

1.6 The Author's Case I was privileged to have the opportunity to examine the Giza collection of disarticulated skeletons, which should be considered one of the most important materials in the history of archaeology and archaeopathology. The material belongs to a very important period, the Old Kingdom, which was when the great pyramids were built. The United Nations Educational, Scientific and Cultural Organization (UNESCO) had added the entire archaeological area of Giza to its list of world heritage, as it is the oldest and most famous necropolis in the world. The material includes the skeletal remains of two different classes that lived in the same country during the same period of the third millennium B.C. The high officials and the dignitaries were buried in the western cemetery and the workmen and artisans were buried in the southeast cemetery. The excavations were headed by Reisner in 1942 and Hawass in 1994. Skeleton number 1932 (male) is one of the high officials buried in the western cemetery. His age at the time of death was between 35 years and 39 years. The right iliac bone and the adjoining right side of the sacrum are markedly affected by a chronic infective condition (Fig. 1.4). There is complete bony ankylosis of the right sacroiliac bone (Fig. 1.5). The outer part

Fig. 1.5. Radiograph of the specimen in Fig. 1.4

of the bone is markedly eroded, with bone buildup at the iliac crest and parts of the iliac bone and sacrum. The greater trochanter of right femur shows exuberant bone formation (Fig. 1.6). It seems that the tuberculous cold abscess trickled down along the gluteal muscle to involve the trochanter in the tuberculous process. The sacroiliac joint is the most common site of the pelvis that is affected by tuberculosis (Ortner and Putschar 1981) and chronic tuberculous affection of the greater trochanter is a characteristic lesion that affects young adults more than children. The spine and the hip joints do not show obvious pathological or radiological changes. The differential diagnosis of this case is pyogenic osteomyelitis, which is very rare in ancient Egyptian

8

S.A. Bedeir

1.7 Pulmonary and Osseous Tuberculosis in Ancient Egyptian Mummies

Fig. 1.6. Chronic tuberculosis of the greater trochanter of the right femur. Same case as in Fig. 1.4. There is erosion of the bone and exuberant bone buildup denoting a good healing reaction. There is no involvement of the femoral head

skeletal remains (Wood-Jones 1910). Patients with hematogenous osteomyelitis were expected to die from toxemia and pyemia before the inflammation produced manifested bone changes. The skeletal response to the tubercle bacilli is dependent on the virulence of the organism and the host response. If the host had little ability to defend himself, then tuberculosis could cause a progressive type of acute disease and early death. If the host's resistance was considerable, it is presumed that the disease then would be chronic, with the possibility of extensive healing and exuberant bone reaction. In our case, we believe that the patient's resistance was good, as manifested by the complete bony fusion of the right sacroiliac joint, the marked bone healing reaction of the iliac bone and the excessive bony build-up of the greater trochanter. The patient was one of the high dignitaries of the king. He most likely enjoyed eating a good, nutritive diet and lived in an appropriate house. It is interesting to comment on the presence of three healed fractures of both ulnae and left fibula. Fracture of the ulna is usually considered a "parry" injury, in which the patient tried to fend off a blow using the forearm. These injuries, which were in different stages of healing, indicate that our patient was active and aggressive during his life.

Pulmonary tuberculosis has been suspected by many authors to have occurred in ancient Egyptian populations (Cockburn et al.1975). The first to prove its occurrence, with microscopic confirmation of the presence of Mycobacterium tuberculosis bacilli, was Zimmerman (1979) from Michigan, USA. This author reported his anatomical and microscopic finding on the mummy of an ancient Egyptian child of five years of age belonging to Dra-Abu-el-Naga, found on the road to the Valley of the Kings, the tombs of the officials of 19th and 20th dynasties (1314-1085 B.C.). The author described the anatomical features that suggested pulmonary and osseous tuberculosis with recurrent and finally fatal pulmonary hemorrhage. Ziehl-Neelsen stain of a bone specimen showed scattered acid-fast bacilli. In a more recent report, pulmonary tuberculosis in an ancient Egyptian mummy was diagnosed and confirmed by polymerase chain reaction (PCR) (Nerlich et al. 1997). These German authors described their excavation findings at the tombs of the Nobles at Thebes-West in Upper Egypt. They reported a mummy of 35-year-old male dated from the New Kingdom (1550-1080 B.C.). These authors noted residue of the affected right lung with extensive pleural adhesions while the pleura of the left lung were normal. They also found two lumbar vertebral bodies severely affected anteriorly with lytic lesions and new bone formation. Specimens from both lungs were examined using PCR-amplification ofmycobacterial DNA. A specific positive band was identified from right lung specimens but not from the left unaffected lung. This was probably the first confirmed case of pulmonary tuberculosis using PCR in an ancient Egyptian mummy (Nerlich et al. 1997).

1.8 peR and the Diagnosis of Tuberculosis in Ancient Egyptian Population Many authors have tried to use the relatively recently acquired knowledge and development of DNA molecular technology for various purposes (Leek 1979; Harrison and Connolly 1969, David 1997). Svante Piiiibo (1985) used this technology, aiming at studying the descent and relationship of the ancient pharaonic families, individual relationships between members of these families and population in the Nile Valley. The author sampled 23 mummies from various

Tuberculosis in Ancient Egypt

dynasties between the 6th dynasty (2370-2160 B.C.) up to the Roman times. The ages ofthese mummies ranged between one-year-old boys to older ages, as estimated by the radiocarbon age technique of accelerator mass spectroscopy. Blunt-ended extract material was mixed with E. coli DNA polymerase with labeled radioactive nucleotides. The author concluded that recombinant DNA techniques could allow the study of the descent of the ancient Egyptian pharaonic families and their individual relationships. However, this author failed to recognize what would become the much wider use of this technique-detecting diseases in ancient Egyptian pharaonic population and families. The molecular approaches to DNA probe analysis using a nucleic acid-base methodology was originally described in early 1980s. It has been used extensively and has begun to have a major influence on current clinical management of various diseases. Several methods of PCR assays have been developed and IS6110 PCR can be done with a turnaround time of 24-36 h. It is a rapid and reliable molecular approach that can detect Mycobacterium tuberculosis DNA directly from clinical specimens. Such advances in investigative techniques have been exploited by many scientists and researchers who aim to trace diseases to an ancient time. In a large series of ancient Egyptian cadavers, Zink and colleagues (2001) from Munich, Germany, collected 41 skeletal specimens. Four were from Abydos (3000 B.C.) and thirty-seven were from Thebes-West, Upper Egypt (2120-500 B.C.). Three had typical macromorphological evidence of skeletal tuberculosis, 17 showed probable disease and 21 were without morphological skeletal changes. DNA was extracted from bone specimens and amplified by PCR with a primer pair that recognized the Mycobacterium tuberculosis complex insertion sequence IS611O. Nine of these cases were positive for Mycobacterium tuberculosis DNA. Two of the three cadavers with typical macromorphology of osseous tuberculosis had positive results for Mycobacterium tuberculosis DNA. Five of those with probable and two of those without morphological changes had positive results for Mycobacterium tuberculosis DNA. The authors concluded that their findings confirmed the relatively frequent occurrence of tuberculosis in ancient Egypt, dating back to 3000 B.C.

1.8.1 Environment

The lives of ancient Egyptians were shaped by their environment. The geography of Egypt was, and is still, like that of no other country. The Nile valley

9

was enclosed by deserts that protected Egypt against invasion, which resulted in long periods of stability. 1.8.1.1 The Nile

The Nile played a central role in daily life. Between July and October of each year, the Nile flooded its banks, depositing a rich and fertile layer of alluvial slit on the land. Inundation saved an enormous labor in the transportation of water and renewed the fertility of the land. 1.8.1.2

Climate Herodotus stated that the good health of the ancient Egyptians was due to the lack of variability in the weather. The Egyptian sky was blue almost all year round. The sun's rays nourished the Egyptians'bodies with vitamin D, and decreased the incidence of rickets. The dry, hot climate of Egypt is better suited to the preservation of human remains than that of any other country in the world. However, heat encourages flies, which were responsible for the spread of infections, especially eye infections and diarrhea. The Sahara (Khamasin) winds blew up dust storms and sand particles, resulting in chest infection, pneumoconiosis, laryngitis and sinusitis. 1.8.1.3 Housing The hot and dry climate influenced the design of ancient Egyptian housing. Houses varied from the large, villa-like houses of the top members of society to the small, crowded houses, with limited amount of light and space, of the poor people. In Amarna, smoke-blackened roof timbers indicated a heavy passage of soot. Tuberculosis thrived in such conditions of ill-housing and bad ventilation. 1.8.1.4

Diet Egyptians were already enjoying reasonably healthy and varied diets. Food production was not a major problem in Egypt, provided that the inundation of the Nile occurred every year. The main cereal crops were barley and emmer, with wheat being introduced only in the late period. Barley was used to make loaves and beer. Vegetables and fruits were grown on a large scale. Many of the familiar varieties were known: grapes, figs,

S.A. Bedeir

10

dates,pomegranates, melons, onions, leeks, cucumbers, lettuce, garlic, lentils and chickpeas. These provided many of the vitamins essential for good health. The ancient Egyptians consumed a wide variety of animal products, including cattle, sheep, goats and pigs. They kept sheep for producing wool, milk, cheese and meat. They ate ducks, geese, pigeons and quails. Hens were known only during the Ptolemaic period. The ancient Egyptians consumed fish that was fresh or dried and salted. Pure salt has been found from the sixth dynasty, but the method of preparation is unknown. Dates or honey was used for sweetening. Bee keeping was actively practiced, and honey was used to prepare medicines. The funerary offerings for King Unas of the fifth dynasty included: • Milk, three kinds of beer, five kinds of wine, ten loaves, four of bread, ten cakes, fruit cakes, four meats, different cuts, joints, roast, spleen, limb, breast, tail, goose, pigeon, figs, ten other fruits, three kinds of corn, barley, spelt, five kinds of oil and fresh plants (Nunn 1997). 1.8.1.5 Religion

Religion had a beneficial effect on the general health of the ancient Egyptians. Sacred holidays allowed them to rest and go to the temples to see the King. The poor people took their shares from the offerings. Vacations and ceremonial activities had the effect of raising the morale of the people. They had to take baths using running water and natron to clean their bodies. Men would shave their hair and women removed their unwanted hair. The ancient Egyptians believed that diseases were caused by excessive food, thus they used drugs and suppositories to evacuate their stomachs and bowels three times every month. 1.8.1.6 Sports and Recreation

Athletic sports were an ancient Egyptian invention. The ancient Egyptians were skilled in wrestling, stick combat, gymnastics, ball games, hunting, fishing and bull fighting. Families played cup games and board games (senet). They also enjoyed music, singing, and dancing. 1.8.1.7 Physique

The ancient Egyptians were small; the mean height of the males was 1.67 cm and the females 1.53 cm.

The arithmetic mean age at death was 36 years in the dynastic period. There are very few burials of people over the age of 60 years (Sarry EI-Din 1995). Pepi II and Rameses II survived to well in their eighties.

1.9 The Medical Papyri Although there can be no doubt of the existence of tuberculosis in ancient Egypt, many authors believe that nothing in the medical papyri can be directly related to the disease. The medical papyri do not contain any clear descriptions of tuberculosis (Ortner and Putschar 1981; Steinbock 1976). However, Ebbell (1937) and Kamal (1964) believe that the Ebers Papyrus (Ebers 1875) contains the description of two cases with tuberculosis of the cervical lymph nodes. The first case is described in section 860, column 195; Ebbell entitled the section "Soft Tuberculosis Gland". The section is translated as follows: \'Jl "Information about enlarged cystic node in his neck" - Examination: if you examine a man having an enlarged cystic node in his neck, and you find it like the thymus(?) gland because of its softness at palpation and its white discharge ... (empty space). - Diagnosis: you shall then say concerning him he has enlargement of the cystic node in his neck. An ailment I will treat by surgery to protect the vessels. - Treatment: you shall prepare medicines to treat him by a bandage that makes the cyst open through the skin: acacia seyal, pea, fruit, animal blood, insect's blood, honey, common salt (and other things). Grind. Mix together and bandage. «I The second case, section 861, reads as follows: - Title: information about enlarged infected node in the neck of a man. - Examination: if you examine an enlarged infected node in the neck of a man. After it is enlarged and removed the skin that covered it, and caused suppurating granulation for many years and months. It discharges a secretion like the seminal fluid of synodontis (a type of fish). - Diagnosis: you shall then say concerning him he has an enlarged infected node. An ailment I will treat. - Treatment: you shall prepare the medicines for him: wax or fat, As(?), ink, salt, goose fat, fruit(?) Galena. Heat and bandage the neck (Fig. 1.8),

Tuberculosis in Ancient Egypt

11

Fig.I.7. Healed fractures of the right ulna and left fibula of the same case as in Fig. 1.4

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Serologic Testing for Tuberculosis

12.2.2 A60Antigen

The A60 antigen, a thermostable component of PPD, has also been used in the serodiagnosis ofTB (Charpin et al. 1990; Cocito 1991; Fadda et al. 1992; Luh et al. 1996; Yu et al.1992; Zou et al.1994). Unfortunately, this molecule is not specific for mycobacteria because it is also present in Nocardia and Corynebacterium species. In 83 patients with smear-negative but culture-positive pulmonary TB, measurement of both IgM and IgG in an ELISA revealed a sensitivity of 68% and specificity of 100% (Charpin et al. 1990). Similarly, an ELISA revealed a sensitivity of 76.2% for patients with active pulmonary TB and 59% for patients with extrapulmonary TB (Luh et al. 1996). In 153 individuals with inactive tuberculous infection, the specificity was only 81.7%, and in over 500 patients with nontuberculous infection, the specificity was 91.3%. Thus, the positive predictive value was only 67.9% (Luh et al. 1996). In a study of 560 Chinese patients with pulmonary and extrapulmonary TB and over 700 controls, the measurement of IgM appeared to be sensitive (80%) for active primary TB and specific (100%) for latent TB (Zou et al. 1994). On the other hand, IgG against the A60 antigen was more predictive of active postprimary TB (sensitivity of 89%). Among 529 healthy persons most of whom were vaccinated with BCG, including 287 who were PPD positive, there was less than 1% false-positives. Anuradha et al. (2001) evaluated the utility of detecting antibodies to A60 for the diagnosis of extrapulmonary TB. In 72 patients with neuro-TB, antibodies were detected in the serum and/ or CSF in almost 80%. The diagnosis of other forms of extrapulmonary TB by anti-A60 antibodies could be made in about 60% of the cases.

12.2.3 30 kDa Antigen

Using a 30 kDa antigen purified from culture filtrates of M. tuberculosis, McDonough and colleagues (1992) compared a dot EIA with the standard ELISA assay on patients with active TB using control patients who had no clinical evidence of TB but whose PPD status was not known. The specificity for dot EIA and plate ELISA were 92% and 97%, respectively; the sensitivity rate for hospitalized patients with TB was 69% and 78%, respectively. Interestingly, the sensitivity rate was -48% for both methods in ambulatory patients with active TB, while in 26 HIV-positive patients with TB, both immunoassays showed extremely poor sensitiv-

189

ity (12% for the plate ELISA and 0% for the dot EIA). In assessing the lymphocyte proliferative and humoral responses to patients with active pulmonary TB and of healthy household contacts, the group with active disease had a strong humoral response to the 30 kDa antigen but a poor proliferative response (Torres et al. 1994); the opposite pattern was seen in the exposed control patients. Thus, a humoral response to tuberculous antigen may not only signify active infection but may also indicate a nonprotective immune response. In a study that measured the presence of the 30 kDa antigen in 25 African patients with smear-positive TB using a monoclonal antibody, 20 of them tested positive (sensitivity 80%) (Ng et al. 1995).

12.2.4 Antigen p90

Arikan and co-workers (1997) showed that in 51 patients with active TB, the sensitivity of anti-Kp90 IgA in either sera or body fluids was 82%, while in 71 control patients, the specificity was 90%. In another study of 88 TB patients, comprised of 32 smear-positive and 56 smear-negative individuals, the overall sensitivity was 70% (Alifano et al. 1997). In a control group of 87 individuals with either nontuberculous lung disease, healed TB, or healthy volunteers, the specificity was 92%.

12.2.5 19 kDa Antigen

Although previously promlsmg, antibody titers to the 19 kDa antigen were found to have poor sensitivity (8%) in Indian patients with active TB, but it was higher in patients from the UK (55%-57%) (Bothamley et al. 1992).

12.2.6 16 kDa Antigen

Using a recombinant 16 kDa antigen of M. tuberculosis, Imaz et al. (2001) compared the seroresponse using EIA to detect IgG, IgM, and IgA in 74 children with active TB, in 149 with nonmycobacterial disease, and in 49 healthy contacts. The average levels of antibodies were higher in the healthy contacts when compared with children with nonmycobacterial disease, making it a potentially useful test for predicting patients who require prophylaxis against latent infection; however,

C. Kotaru and E. D. Chan

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the low overall sensitivity (34%, 19%,3%, and 43% for IgG, IgA, IgM, and combined IgG IlgM, respectively) prevented the test being useful in the diagnosis of active childhood TB.

controls who were all skin test-positive (Maekura et al. 1993). Interestingly, the cord factor antibody titers declined to normal levels with antituberculous chemotherapy.

12.2.7 45/47 kDa Antigen Complex

12.2.10 Glycolipid Antigens

In a study that evaluated the IgG response to the 451 47 kDa secreted protein ofM. tuberculosis, the specificity of the test was >98% in control subjects, comprised of healthy volunteers who were either PPD-positive or PPD-negative (Diagbouga et al. 1997). However, the sensitivity of the test was only 40% even in smearpositive TB patients.

Detection of IgG against M. tuberculosis glycolipid antigen in 57 patients (27 smear-positive and 30 smear-negative) revealed that the overall sensitivity was 96% and specificity 91 % (Dogan and Aksu 1997). Escamilla and colleagues (1996) used glycolipids from M. fortuitum (di- and tri-O-acylated trehaloses) to detect an antibody response and found the sensitivity for active TB was >80% and the specificity 98%. In a large multicenter study from Japan, Maekura et al. (2001) described the utility of an ELISA for antituberculous glycolipid (anti-TBGL) in the serodiagnosis of TB. Using a cut-off of anti-TBGL antibody titer >2 Ulml, the assay had a sensitivity of 81 % and specificity of 96% in 318 patients with active pulmonary TB (216 smear-positive andlor culture-positive and 102 smear- and culture-negative, but clinically diagnosed). Subgroup analysis revealed greater sensitivity (90%) in patients with smear- and culture-positive TB, as opposed to culture-positive only (70%) or smear- and culture-negative, clinically diagnosed patients (73%). This suggests a correlation between the positivity of the test and the mycobacterial burden. Another interesting observation that has potential implications in judging the response to therapy was the decline in titers in a subgroup of patients with initially high titers (> 10 U/ml) at the beginning of treatment. The test performance characteristics of ELISA to detect antibodies against M. tuberculosis antigenic glycolipids was evaluated in 142 patients with extrapulmonary TB compared with 578 patients with nontuberculous disease (Niculescu et al.1999). The sensitivity and specificity were 82 and 92%, respectively. Simmoney and co-workers (1996) compared the diagnostic utility of ELISA in detecting antibodies against glycolipid to those against A60 antigen in 46 HIV-positive and 50 HIV-negative patients with documented TB. Overall, antibody to A60 was detected in only 37% of the cases, while 85% of the patients had a positive antibody response to glycolipid antigens. When the data were analyzed in the context of HIV status and the associated level of immunosuppression, HIV-positive patients with lower CD4 counts were more likely to have negative antibody responses to A60 than to glycolipids.

12.2.8 P32Antigen

The serological response to purified protein of M. bovis BCG (known as P32 antigen) was also evaluated in patients with active TB (Turneer et al. 1988). Although there was a statistically significant difference in mean IgG and IgA antibody levels between active TB patients and healthy control subjects, the combined sensitivity rate for both immunoglobulin classes was only 47%. Interestingly, neither naturally acquired tuberculin hypersensitivity nor BCG vaccination affected the positive frequencies in healthy subjects. This same group of investigators also utilized a dot-blot assay with BCG cellular extract and found a good correlation between their ELISA assay and the dot-blot assay (van Vooren et al. 1988).

12.2.9 Cord Factor

The IgG antibody response to M. tuberculosis cord factor (trehalose-6,6'-dimycolate) was examined in a group of 99 patients with mycobacterial infection (42 with culture-positive TB, 46 with a clinical diagnosis of TB, and 11 patients with atypical mycobacterial infection), 5 patients with lung cancer, and 100 healthy controls. The overall sensitivity of patients with any bacterial or clinical diagnosis of a mycobacterial infection was 83%, and the specificity was 100% (He et al. 1991). The antibody response to M. tuberculosis cord factor was tested in an ELISA for patients with active TB and produced a sensitivity of 81 % and a specificity of 96% compared with healthy

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Serologic Testing for Tuberculosis

that of M. avium complex (the predominant atypical mycobacteria), the fine structural differences between the LAMs (e.g., degree and configuration The cell walls of mycobacterial organisms contain of mannose capping) have not been fully elucidated. complex macromolecules such as lipoarabinoman- Therefore, despite the relatively good specificity rate nan (LAM) (Fig. 12.1). LAM is a lipoglycan known to reported, the degree of antibody cross-reactivity have a number of immunomodulatory effects. LAM is against LAM of M. tuberculosis vs that of atypical comprised of a linear series of ringed mannose sugar mycobacteria remains to be determined. Second, there was a wide range of sensitivity of residues, with occasional branches of single mannose residues. At the proximal end of LAM, a phosphati- anti-LAM IgG among HIV-negative patients with dylinositol group anchors it to the plasma membrane. active TB, while the sensitivity was generally poor Distal to the mannose residues, a series of arabinose in HIV-positive patients. For example, in HIV-negasugar residues is attached. In M. tuberculosis, these tive patients, the sensitivity ranged from 21.5% to arabinose residues are further 'capped' with mannose 89% (del Prete et al. 1998; Julian et al. 1997; Lawn residues. Thus, the LAM of M. tuberculosis is called et al. 1997; Ratanasuwan et al. 1997; Sada et al. 1992, 'ManLAM'. In relatively recent reports, the detection 1999) but was between 7% and 40% in HIV-positive of anti-LAM antibodies has shown great promise in patients (Boggian et al. 1996; Julian et al. 1997; Lawn the serological diagnosis of active TB (Boggian et al. et al. 1997; Ratanasuwan et al. 1997; Sada et al. 1992, 1996; del Prete et al. 1998; Julian et al. 1997; Lawn et 1999). In HIV-negative patients, the sensitivity of the al. 1997; Ratanasuwan et al. 1997; Sada et al. 1990, MycoDot antiLAM IgG test in Tanzania, Ghana, and 1992; Somi et al. 1999). Thailand was 33%,56%, and 63%, respectively (Lawn In general, three important points can be taken et al. 1997; Ratanasuwan et al. 1997; Somi et al.I999). Third, as with most other types of serological tests, from these studies. First, the specificity of the test was excellent, ranging from 84% to 100%. Moreover, the sensitivity of the test fell with negative smears, Julian and co-workers (1997) tested 14 patients with a finding generally attributed to the lower burden atypical mycobacteria, and anti-LAM IgG could not of organisms in smear-negative cases and/or to the be detected in any of them although it is not clear how greater incidence of smear-negativity in patients comany of these patients were co-infected with HIV. infected with HIV. We recently tested the accuracy of Boggian et al. (1996) tested 104 patients with atypical a simplified, visually detectable, colloidal gold-based mycobacteria for anti-LAM IgG, and only 2 patients serological assay to qualitatively detect IgG directed were weakly positive; however, all the patients tested against LAM in a population of individuals largely were HIV-positive. Although the basic structure of comprised of immigrants to the USA from areas with LAM associated with M. tuberculosis is similar to a high prevalence of TB infection (Chan et al. 2000).

12.2.11

Lipoarabinomannan

ManLAM

Fig. 12.1. Cell wall of M. tuberculosis showing the various macromolecules that comprise the complex structure, including the plasma membrane, peptidoglycan, lipoprotein ,and various Iipoglycans such as mannose-capped Iipoarabinomannan, mycolic acid-arabinogaJactan peptidoglycan complexes (mAGP), Iipomannan (LM), and phosphatidylinositol dimannose (PIM z). The fatty acid chains (acyl groups) are attached to the plasma membrane

lipoproteins

mycolic acids

• 0- mannose-p • D-arabinose-f • galaetose-f '

phosphatidylinositol (palmitate, tuberculostearate)

192

In patients with active TB, the sensitivity of anti-LAM IgG was 85%-93%. Importantly, in five patients with active TB who were smear-negative, all tested positive for anti-LAM IgG. The specificity of the test depended on the presence of tuberculous infection. In a group of US citizens comprised of young healthy adults and rheumatology patients, the specificity was 100%. In a population at risk for TB infection who were either tuberculin skin test-negative or -positive, the specificity of the test for active TB was 89%. The negative and positive predictive values of the test were 98% and 52%, respectively. The overall accuracy of the test was 81 %. The high negative predictive value of the test in a population at risk for tuberculous infection makes it a potentially valuable screening test for active TE.

12.2.12 ICT Tuberculosis Test

The ICT tuberculosis test is a card test based on the detection of IgG antibodies directed against five M. tuberculosis secreted antigens, using an anti-human IgG labeled with colloidal gold (Rasolofo et al. 2000), a method similar to the one we employed in the antiLAM IgG dot-blot assay (Chan et al. 2000). Rasolofo and colleagues (2000) showed that the ICT test had a sensitivity of only 68.2% for smear-positive TB and 65.2% for extrapulmonary TB in a group of patients from Madagascar. The specificity was 83.3%. Overall, the ICT assay is not sufficiently predictive for clinical application. The choice of a diagnostic test depends on the pretest probability of a positive response, and therefore the prevalence of disease in the population being tested. Such factors are especially important when decisions regarding health care policy and screening of large populations are being considered. McConkey et al. (2002) illustrated this point well by testing the diagnostic yield of a rapid antibody card test in areas of high prevalence of the disease (Cairo, Egypt) and of low prevalence(St. Louis, Missouri, USA). In Egypt, the antibody test was highly sensitive (87%) for smear-positive and -negative pulmonary TB; the specificity was 82%. The sensitivity and specificity in St. Louis were 29% and 79%, respectively.

12.2.13 Dermal Response to MPB64 Antigen

Although not a serological assay, Nakamura and colleagues (1998) recently reported that the MPB64

C. Kotaru and E. D. Chan

mycobacterial antigen delivered transdermally by the patch test method was highly accurate for diagnosing active TB. In this promising study, 52 of 53 patients (98%) with active TB showed a positive reaction to MPB64, while none of the 43 PPD-positive controls were positive. This resulted in an overall sensitivity of the test for active TB of 98.1%, a specificity of 100%, and an accuracy of 98.9%.

12.2.14 Integral Membrane Antigens of M. habana TMC 5135

Chaturvedi and Gupta (2002) evaluated the usefulness of detecting antimycobacterial antibodies to antigens that belong to the integral compartment of the plasma membrane of M. habana in serum and body fluids of patients with mainly extrapulmonary TB (only 4 of 42 patients had exclusively pulmonary TB). The presence of antibodies against M. habana integral membrane antigens (IMAs) was detected in 36 patients, for an overall positivity rate of 86% (36/42). Anti-M. tuberculosis H37RA antibodies were also found in 29 out of 36 anti-M. habana IMA antibody-positive patients.

12.2.15 Lipopolysaccharide Antigen

Meena and co-workers (2002) recently reported the isolation of an immunodominant lipopolysaccharide (LPS) antigen from M. tuberculosis H37Rv for the serodiagnosis of TB. Serum samples obtained from 59 Indian patients (19 patients with active pulmonary TB, 20 with extrapulmonary TB, and 20 with nontuberculous pulmonary disease) and 20 healthy adults were tested for LPS and three other commercially available antigen assays. The presence of IgG against LPS was highly sensitive and specific (84 and 97%, respectively), similar to the test characteristics of A60 IgG and superior to the assays for antibodies to 38 kDa or p90 antigens.

12.3 Specific Targeted Populations In certain individuals, the diagnosis of active TB is particularly challenging. Such persons include young children, the elderly, HIV-positive individuals, and patients with extrapulmonary TE. This is due to the

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Serologic Testing for Tuberculosis

greater difficulty in obtaining a sputum sample, the lower incidence of acid-fast bacilli in respiratory samples, and/or the indolent or atypical presentation of TB in such groups of people.

12.3.1 Childhood TB Although childhood TB represents a small percentage of all cases, infected children are a reservoir for many adult cases (Khan and Starke 1995). The bacteriologic diagnosis of TB is particularly difficult in young children because of the greater incidence of disseminated disease and because children often do not produce an adequate amount of sputum. Thus, serological methods to diagnose childhood TB have great potential and relevance. For children with clinical TB, the detection of IgG and IgM against A60 antigen is comparable to that seen in adults. In a study that examined the utility of detecting specific IgM, IgA, and IgG antibodies to A60 antigen in childhood TB on the Indian subcontinent, the overall sensitivity and specificity of the test with combined IgA and IgM testing were 76% and 92%, respectively (Gupta et al. 1997). In children who were acid-fast positive, the sensitivity rose to 95%. For 150 children with extrapulmonary TB, the overall sensitivity was 77%. In a study to detect IgG against an autoclaved suspension of H37Rv in 132 clinical cases of childhood TB, the sensitivity of the test in the culture-positive group (n=35) was 69% (Hussey et al. 1991). Interestingly, there was a positive correlation between the titer level and increasing age. Prior BCG did not affect the ELISA result. However, in another study that examined IgM and/or IgG against A60 antigen in primary TB or TB adenitis in children, the authors concluded that the test was not diagnostically useful (Turneer et al.1994). Levels of antiglycolipid IgG were found to be higher in children with active TB than in nontuberculous controls, leading the authors to conclude that the detection of IgG antibodies against glycolipids was useful as a complementary technique in the serodiagnosis of pulmonary TB in children (Simonneyet al. 2000).

patterns of primary infection in the elderly compared with young adults may lower the health care provider's suspicion ofTB (Morris 1989). In adults, the incidence of active TB cases is higher in the elderly (Dorken et al. 1987). Miliary TB, often presenting without localizing signs or symptoms, is also more common in the elderly person than in young adults, although the diagnosis is frequently not made until autopsy (Korzeniewska et al. 1994). Reactivation is associated with co-morbid diseases that result in waning cell-mediated immunity, disclosed by reduced skin test positivity to PPD with increasing age. For example, in men, PPD reactivity drops from 50% at age 65-74 years to 10% at age 95+, and in women from 40% to about 5%, respectively (Dorken et al. 1987). Because of the high rate of conversion in the absence of symptoms in nursing home residents, a two-step skin test is recommended for residents on admission to the nursing home: an initial test and, if negative or equivocal, a repeat test 1-2 weeks later. A positive booster effect is defined as an increase of 6 mm or more from an induration 64 Ilg/ml) (Williams et al. 1998a).

13.4

PCR-SSCP. PCR single-strand conformation polymor-

Knowledge of the specific mechanisms that result in the development of antituberculosis drug resistance

phism analysis assays have been developed and used to detect drug-resistant mutants of M. tuberculosis directly from patient specimens or clinical isolates (Telenti et al. 1993a,b; Kim et al. 2001) (Table 13.2).

peR Detection of Drug Resistance

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PCR and Diagnosis of Tuberculosis

This is accomplished using the same basic approach taken to produce PCR arnplicons for DNA sequencing for gene targets. These double-stranded amplicons are then dissociated into single strands by heat denaturation and separated very slowly by gel electrophoresis under stringently controlled temperature conditions. Gels are stained to observe ssDNA fragment mobility patterns called SSCP profiles. A schematic representation of the SSCP assay is shown in Fig. 13.2. DNA strands from a RMp R strain demonstrate a unique mobility pattern compared with RMPS, reflecting the change in nucleotide composition. Numerous studies have used this analysis to study drug resistance in M. tuberculosis (Table 13.2).

affect the mobility of the resultant DNA fragments (Fig. 13.3). Therefore, when the heteroduplexes are separated by gel electrophoresis on polyacrylamide gels and stained with ethidium bromide, unique heteroduplex profiles are observed for susceptible and resistant genotypes (Williams et al. 1998b). The PCR-UHG requires approximately 6 h to complete and uses precast minigels and a nonradioactive detection format.

RRDR rpoB PCR amplieon RMP,Strain

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PCR-HDA. PCR heteroduplex assay is another gel electrophoresis-based assay which has been developed to detect simultaneously the presence of M. tuberculosis and its susceptibility to RMP directly from clinical isolates (Williams et al.1994). This assay has been modified to reduce the time taken and technical complexity and can be used directly on clinical specimens with the use of a universal heteroduplex generator (UHG) (Williams et al. 1996, 1998a). The UHG contains several base pair mismatches, insertions, and deletions within the RRDR region of M. tuberculosis rpoB (Williams et al. 1996). When the UHG is heat-denatured and slowly annealed to these denatured amplicons, it provides enhanced mutation detection. Enhanced mutation detection occurs because large areas of unmatched nucleotides (bubbles) in the newly formed duplexes greatly

RRDR rpoB PCR amplieon RMP.Strain

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RMP.

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Profiles

Fig. 13.2. Schematic representation of the PCR single-strand conformation polymorphism (PCR-SSCP) assay for detection of rifampin susceptibility of M. tuberculosis

Universal Heteroduplex Generator

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Fig. 13.3. Schematic representation of the PCR universal heteroduplex generator (PCR-UHG-Rif) assay for detection of rifampin susceptibility of M. tuberculosis

206

D. L. Williams

PCR-LiPA. The line probe assay is a PeR-based reverse hybridization assay that has been developed for the rapid detection of RMP susceptibility of M. tuberculosis (de Beenhouwer et al. 1995; Rossau et al. 1997). LiPA uses PCR to amplify the RRDR region of rpoB and, at the same time, label the fragment with biotin. Denatured PCR amplicons are hybridized with a set of DNA probes immobilized on a membrane strip at specific sites (Fig. 13.4). The immobilized probes are small DNA fragments that are either homologous with short segments of the RRDR of rpoB from a RMp s strain or contain mutations in the RRDR associated with RMp R M. tuberculosis mutants. The stringency of the hybridization reaction is designed so that the single-stranded PCR amplicons will bind only to probes with 100% sequence homology. The resultant hybrids are detected by immunoenzymatic staining, and the results are read visually. An example of LiPA for RMP susceptibility testing is shown in Fig. 13.4. The genotype of the test organism is determined by which lines test positive. Therefore, the presence or absence of a RMp R strain of M. tuberculosis can be determined from the pattern obtained. This assay is commercially available in certain areas of the world (Rossau et al. 1997).

probes contain homologous sequences to either the susceptible or resistant genotype. In addition, they contain a fluorophore on one end and a molecule that quenches fluorescence when it is in close proximity to a fluorophore on the other end. When no PCR amplicons are present, the probe remains in its hairpin shape, and the fluorescence is quenched. However, after these probes bind to their intended targets, they undergo a conformational change that restores thefiuorescence of the internally quenched fluorophore. Therefore, the more amplicons produced, the more fluorescence. The specificity for drug resistance detection is in the short sequence that binds to the amplicon. In summary, there are several PCR-based mutational detection assays to identify drug-resistant mutants of M. tuberculosis. These assays can be performed within days of specimen acquisition or isolation of strains from specimens and, therefore, can be useful for the early detection of drug-resistant tuberculosis. Early detection of drug-resistant tuberculosis can potentially improve patient care and reduce the transmission of drug-resistant tuberculosis by effective isolation of infected individuals.

Molecular Beacons. PCR molecular beacon sequence

13.5 Impact of PCR Diagnosis on Patient Care

analysis has been developed to detect mutations in the rpoB that are associated with RMP resistance (Piatek et al. 1998,2000; EI-Hajj et al. 2001) and INH resistance (Piatek et al. 2000) in M. tuberculosis. Molecular beacons are small hairpin-shaped DNA probes that report the presence of specific nucleic acids (Fig. 13.5). These

BiotioylatedRRDR rpoD PCR Amplicoo RMP.

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Because of the specificity of PCR assays for the detection of M. tuberculosis, a smear-positive, PCR-positive specimen would indicate that the acid-fast bacilli in the sputum of a particular patient are M. tuber-

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207

peR and Diagnosis of Tuberculosis

~+ Qumched Targd DNA Molecular Beaooo (ss AqJIicoo)

Fig. 13.5. Schematic representation of molecular beacon sequence analysis. The black circle represent the quenching molecule. The open circle represents the fluorophore

developed to monitor drug therapy (DesJardin et al. 1996; Hellyer et al. 1999a) and has been shown to be very useful for rapidly determining the efficacy of therapeutic regimens directly from sputum specimens (DesJardin et al.1996; Hellyer et al. 1999a,b).

13.6

Summary

culosis (Kaul 2001). Therefore, the patient should be appropriately retained in isolation and treated until their sputum becomes smear-negative. A PCR-negative specimen would indicate the presence of a nontuberculosis mycobacterial infection, and the patient could be released from isolation and treated more appropriately. In addition, because of the availability of PCR-based assays for the detection of mutations associated with antituberculosis drug resistance, a smear-positive, PCR-resistant specimen would indicate that this patient is also harboring drug-resistant tuberculosis. Therefore, the patient should be appropriately retained in isolation and treated with additional drug therapy until their sputum becomes smear-negative. The immediate impact on patient care, the reduction of transmission of tuberculosis, and cost of providing care is very apparent. Because of the high specificity of these assays, they cannot identify the presence of other mycobacteria in mixed infections. It is, therefore, recommended that PCR should be augmented by culture to determine if other nontuberculosis mycobacteria are present in specimens. This is especially important in areas of the world where HIV infection is highly endemic and other nontuberculosis mycobacteria present problems for the differential diagnosis of tuberculosis. Recently, newer multiplex PCR assays have been developed which can be used for the detection of M. tuberculosis complex and nontuberculous mycobacteria. These assays are currently being characterized for the identification of mixed infections (Ahmed 1999; Yeboah-Manu et al. 2001). Most M. tuberculosis PCR assays are based on the detection of DNA or ribosomal RNA targets. Although beneficial for the initial diagnosis, such assays have proven unsuitable for rapidly monitoring therapeutic efficacy owing to the persistence of these nucleic acid targets long after the conversion of smears and cultures to negative (DesJardin et al. 1998; Hellyer et al. 1999a). It has recently been ascertained that the presence of mRNA is a good indicator for determining the viability of M. tuberculosis from sputum specimens. Using mRNA, an assay has been

Methodologies developed over 30 years ago for the detection of tuberculosis and drug susceptibility testing are cumbersome and require protracted periods of time to obtain results. The resurgence of tuberculosis and drug-resistant tuberculosis has promoted the development of a number of new options for the rapid laboratory diagnosis of M. tuberculosis. One of the most promising and exciting methodologies has been the introduction of assays employing PCR amplification technology to detect M. tuberculosis directly from clinical specimens. PCR-based assays for the diagnosis of tuberculosis and identification of drug-resistant strains are configured to yield results in a few hours to days because these assays can detect the presence of M. tuberculosis and/or mutations present in its genome that are associated with the development of drug resistance directly from crude biological specimens. This represents a major step forward in the ability to rapidly identify tuberculosis patients and patients harboring drug-resistant tuberculosis. Therefore, the implementation of these assays has the potential to improve patient care and provide substantial savings in the overall cost of patient care compared with conventional smear, culture, and speciation alone. In addition, since rapid detection allows for the rapid isolation of tuberculosis patients, the nosocomial or environmental spread of tuberculosis and drug-resistant-tuberculosis to susceptible individuals will most likely be reduced. However, the major drawbacks for the implementation of many of these assays in clinical laboratories in developing countries are the cost of the reagents used and the need for expensive equipment and trained individuals to perform the analysis. This review has attempted to describe many of the current molecular aspects of the detection of tuberculosis using PCR, the modes of action, the resistance mechanisms of the major drugs used to treat tuberculosis, and the current molecular assays for detecting drug resistance in M. tuberculosis. Although amplification assays hold significant promise to improve the laboratory diagnosis of tuberculosis,

208

the decision to perform these assays is complicated because most assays have decreased sensitivity with specimens that are AFB smear-negative. In addition, many other factors, such as cost, assay performance, and technical difficulty must be considered in order to facilitate the decision-making process about whether an amplification assay would be appropriate in a particular laboratory setting. As nucleic acid-based tests evolve, it is anticipated that they will become cheaper and simpler to perform. This is extremely important in developing countries, where resources are limited, and tuberculosis is highly endemic and often complicated by HIV infection. Therefore, research continues to be conducted to automate and simplify sample preparation, amplification, and amplicon detection procedures, thus making them easier to implement in clinical laboratories within both developed and developing countries. This will assist tuberculosis control programs with their overall goals of providing better patient care, reducing the transmission of tuberculosis, and providing the capability to monitor trends in drug resistance at the regional and local levels.

References Ahmed YH (1999) Detection of Mycobacterium tuberculosis complex and non-tuberculous mycobacteria by multiplex polymerase chain reactions. East Mediterr Health J 5:831 Almeda J et al (2000) Clinical evaluation of an in-house IS6110 polymerase chain reaction for diagnosis of tuberculosis. Eur J Clin Microbiol Infect Dis 19:859-867 Banerjee A et al (1994) InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227-230 Bartfai Z et al (2001) Molecular characterization of rifampinresistant isolates of Mycobacterium tuberculosis from Hungary by DNA sequencing and the line probe assay. J Clin MicrobioI39:3736-3739 Bennedsen J et al (1996) Utility of PCR in diagnosing pulmonary tuberculosis. J Clin MicrobioI34:1407-1411 Bergmann JS, Woods GL (1996) Clinical evaluation of the Roche AMPLICOR@ PCR Mycobacterium tuberculosis test for detection of M. tuberculosis in respiratory specimens. J Clin MicrobioI34:1083-1085 Blanchard JS (1996) Molecular mechanisms of drug resistance in Mycobacterium tuberculosis. Annu Rev Biochem 65:215-239 Boddinghaus B et al (1990) Detection and identification of mycobacteria by amplification of rRNA. J Clin Microbiol 28:1751-1759 Bogard M et al (2001) Multicenter study of a commercial, automated polymerase chain reaction system for the rapid detection of Mycobacterium tuberculosis in respiratory specimens in routine clinical practice. Eur J Clin Microbiol Infect Dis 20:724-731

D. 1. Williams Borun M et al (2001) Detection of Mycobacterium tuberculosis in clinical samples using insertion sequences IS6110 and IS990. Tuberculosis (Edinb) 81:271-278 Bottger EC (1989) Rapid determination of bacterial ribosomal RNA sequences by direct sequencing of enzymatically amplified DNA. FEMS Microbiol Lett 53:171-176 Bradford WZ et al (1996) The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 348:928-931 Brisson-Noel A et al (1991) Diagnosis of tuberculosis by DNA amplification in clinical practice evaluation. Lancet 338: 364-366 Butler WR, Kilburn JO (1983) Susceptibility of Mycobacterium tuberculosis to pyrazinamide and its relationship to pyrazinamidase activity. Antimicrob Agents Chemother 24:600-601 Cambau E et al (1994) Selection of a gyrA mutant of Mycobacterium tuberculosis resistant to fluoroquinolones during treatment with ofloxacin. J Infect Dis 170: 1351 Cave MD et al (1991) IS611O: conservation of sequence in the Mycobacterium tuberculosis complex and its utilization in DNA fingerprinting. Mol Cell Probes 5:73-80 Clarridge JE III et al (1993) Large-scale use of polymerase chain reaction for detection of Mycobacterium tuberculosis in a routine mycobacteriology laboratory. J Clin Microbiol 31:2049-2056 Cockerill FR III (1999) Minireview: genetic methods for assessing antimicrobial resistance. Antimicrob Agents Chemother 43:199-212 Cohn DL, Bustreo F, Faviglione MC (1997) Drug-resistant tuberculosis: review of the worldwide situation and the WHO/IUATLD global surveillance project. International Union against Tuberculosis and Lung Disease. Clin Infect Dis 24:S121-S130 Cousins DV et al. (1992) Use of polymerase chain reaction for the rapid diagnosis of tuberculosis. J Clin Microbiol 30:255-258 Dalovisio JR et al (1996) Comparison of the amplified Mycobacterium tuberculosis (MTB) direct test, Amplicor@ MTB PCR, and IS61l0-PCR for detection of MTB in respiratory specimens. Clin Infect Dis 23:1099-1108 De Beenhouwer H et al (1995) Rapid detection of rifampicin resistance in sputum and biopsy specimens from tuberculosis patients by PCR and line probe assay. Tuber Lung Dis 76:425-430 Delgado M, Telenti A (1996) Detection of fluoroquinolone resistance mutations in Mycobacterium tuberculosis. In: Persing D (ed) PCR protocols for emerging infectious diseases. ASM Press, Washington DC, pp 138-143 Del Portillo P, Murillo LA, Patarroyo ME (1991) Amplification of a species-specific DNA fragment of Mycobacterium tuberculosis and its possible used in diagnosis. J Clin MicrobioI29:2163-2168 DesJardin LE et al (1996) Alkaline decontamination of sputum specimens adversely affects stability of mycobacterial mRNA. J Clin MicrobioI34:2435-2439 DesJardin LE et al (1998) Comparison of the ABI 7700 (TaqMan) and competitive PCR for quantification of IS6110 DNA in sputum during treatment of tuberculosis. J Clin Microbiol 36:1964-1968 Douglass J, Steyn LM (1993) A ribosomal gene mutation in streptomycin-resistant Mycobacterium tuberculosis isolates. J Infect Dis 167:1505-1506

PCR and Diagnosis of Tuberculosis Eing BR et al (1998) Comparison of Roche COBAS AMPLICORiZ> Mycobacterium tuberculosis assay with in-house PCR and culture for detection of M. tuberculosis. J Clin MicrobioI36:2023-2029 Eisenach KD et al. (1990) Polymerase chain reaction amplification of a repetitive DNA sequence specific for Mycobacterium tuberculosis. J Infect Dis 161:977-981 Eisenach KD et al (1991) Detection of Mycobacterium tuberculosis in sputum samples using a polymerase chain reaction. Am Rev Respir Dis 144:1160-1163 El-Hajj HH et al (2001) Detection of rifampin resistance in Mycobacterium tuberculosis in a single tube with molecular beacons. J Clin MicrobioI39:4131-4137 Felmlee TA et al (1995) Genotypic detection of Mycobacterium tuberculosis rifampin resistance: comparison of single-strand conformation polymorphism and dideoxy fingerprinting. J Clin MicrobioI33:1617-1623 Finken M et al (1993) Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alterations of the ribosomal protein S12 gene and point mutations within a functional16S ribosomal RNA pseudoknot. Mol MicrobioI9:1239-1246 Forbes BA (1997) Critical assessment of gene amplification approaches on the diagnosis of tuberculosis. Immunol Invest 26:105-116 Frieden TR et al (1993) The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 328:521-526 Gomez-Pastrana D et al (2001) Comparison of Amplicor, inhouse polymerase chain reaction, and conventional culture for the diagnosis of tuberculosis in children. Clin Infect Dis 32:17-22 Heifets LB (l991) Antituberculosis drugs: antimicrobial activity in vitro. In: Heifets LB (ed) Drug susceptibility in the chemotherapy of mycobacterial infections. CRC Press, Boca Raton, pp 14-57 Hellyer TJ et al (l999a) Quantitative analysis of mRNA as a marker for viability of Mycobacterium tuberculosis. J Clin Microbiol 37:290-295 Hellyer TJ et al (l999b) Detection of viable Mycobacterium tuberculosis by reverse transcriptase-strand displacement amplification of mRNA. J Clin MicrobioI37:518-523 Heym B et al (l995) Missense mutations in the catalase-peroxidase gene, katG, are associated with isoniazid resistance in Mycobacterium tuberculosis. Mol MicrobioI15:235-245 Hooper DC, Wolfson JS (1989) Mechanism of action and resistance. In: Hooper DC, Wolfson JS (eds) Quinolone antimicrobial agents. American Society of Microbiology Press, Washington DC, pp 5-34 lovannisci DM, Winn-Deen ES (l993) Ligation amplification and fluorescence detection of Mycobacterium tuberculosis DNA. Mol Cell Probes 7:35-43 Jonas V et al (1993) Detection and identification of Mycobacterium tubercuosis directly from sputum sediments by amplification of rRNA. J Clin MicrobioI31:2410-2416 Kaul KL (2001) Molecular detection of Mycobacterium tuberculosis: impact on patient care. Clin Chern 47:1553-1558 Kapur V et al (1994) Characterization by automated DNA sequencing of mutations in the gene (rpoB) encoding the RNA polymerase beta subunit in rifampin-resistant Mycobacterium tuberculosis strains from New York City and Texas. J Clin MicrobioI32:1095-1098 Kapur Vet al (l995) Rapid Mycobacterium species assignment and unambiguous identification of mutations associated with antimicrobial resistance in Mycobacterium tubercu-

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losis by automated DNA sequencing. Arch Pathol Lab Med 119:131-138 Kent L et al (1996) Demonstration of homology between IS6110 of Mycobacterium tuberculosis and DNAs of other Mycobacterium spp.? J Clin Microbiol 33:2290-2293 Kent P, Kubica G (1985) Public health mycobacteriology: a guide for the Level III laboratory. US Department of Health and Human Services, Public Heath Service, CDC, Atlanta, pp 31-56 Kim BJ et al (2001) Detection of rifampin-resistant Mycobacterium tuberculosis in sputa by nested PCR-linked singlestrand conformation polymorphism and DNA sequencing. J Clin MicrobioI39:2610-2617 Kirschner P et al (1993) Genotypic identification of mycobacteria by nucleic acid sequence determination: report of a 2-year experience in a clinical laboratory. J Clin Microbiol 31:2882-2889 Konno K, Feldmann FM, McDermott W (l967) Pyrazinamide susceptibility and amidase activity of tubercle bacilli. Am Rev Respir Dis 95:461-469 Marttila HJ et al (1996) katG mutations in isoniazid-resistant Mycobacterium tuberculosis isolates recovered from Finnish patients. Antimicrob Agents Chemother 40:2187-2189 Mitarai S et al (2001) Potential use of Amplicor PCR kit in diagnosing pulmonary tuberculosis from gastric aspirate. J Microbiol Methods 47:339-344 Moore M et al (1997) Trends in drug-resistant tuberculosis in the United States. J Am Med Assoc 278:833-837 Mulcahy GM et al (1996) IS611O-based PCR methods for the detection of Mycobacterium tuberculosis. J Clin Microbiol 34:1348-1349 Mullis KB, Faloona FA (l987) Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol 155:335-350 Musser JM (l995) Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev 8:496-514 Musser JM et al (1996) Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. J Infect Dis 173: 196-202 Nachamkin I, Kang C, Weinstein MP (l997) Detection of resistance to isoniazid, rifampin, and streptomycin in clinical isolates of Mycobacterium tuberculosis by molecular methods. Clin Infect Dis 24:894-900 Nolte FS et al (1993) Direct detection of Mycobacterium tuberculosis in sputum by polymerase chain reaction and DNA hybridization. J Clin MicrobioI31:1777-1782 Oh EJ et al (2001) Improved detection and differentiation of mycobacteria with combination of Mycobacterium Growth Indicator Tube and Roche COBAS AMPLICORiZ> System in conjunction with Duplex PCR. J Microbiol Methods 46: 29-36 Otal I et al (1997) Use of a PCR method based on IS611 0 polymorphism for typing Mycobacterium tuberculosis strains from BACTEC cultures. J Clin Microbiol 35:273-277 Piatek AS et al (1998) Molecular beacon sequence analysis for detecting drug resistance in Mycobacterium tuberculosis. Nat BiotechnoI16:359-363 Piatek AS et al (2000) Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular

210 beacons: implications for rapid susceptibility testing. Antimicrob Agents Chemother 44:103-110 Plikaytis BB et al (1993) Rapid, amplification-based fingerprinting of Mycobacterium tuberculosis. J Gen Microbiol 139:1537-1542 Poa CC et al (1990) Direct detection and identification of Mycobacterium tuberculosis by DNA amplification. J Clin MicrobioI28:1877-1880 Ramaswamy S, Musser JM (1998) Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuberc Lung Dis 79:3-29 Rossau R et al (1997) Evaluation of the INNO-LiPA Rif. TB assay, a reverse hybridization assay for the simultaneous detection of Mycobacterium tuberculosis complex and its resistance to rifampin. Antimicrob Agents Chemother 41:2093-2098 Rouse DA et al (1995) Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob Agents Chemother 39: 2472-2477 Selvakumar N et al (1997) Single strand conformation polymorphism profiles with biotinylated PCR products to detect mutation in rpoB gene of Mycobacterium tuberculosis. Curr Sci 73:774-777 Shalwar R et al (1993) Detection of Mycobacterium tuberculosis in clinical samples by amplification of DNA. J Clin MicrobioI29:712-717 Shah J et al (1995) Q-beta replicase-amplified assay for detection of Mycobacterium tuberculosis directly from clinical specimens. J Clin MicrobioI33:1435-1441 Shinnick TM, Jonas V (1994) Molecular approaches to the diagnosis of tuberculosis. In: Bloom B (ed) Tuberculosis: pathogenesis, protection and control. American Society for Microbiology Press, Washington DC, pp 517-530 Soini H et al (1992) Detection and identification of mycobacteria by amplification of a segment of the gene coding for the 32-kilodalton protein. J Clin MicrobioI30:2025-2028 Soini H et al (1996) Comparison of AMPLICOR® and 32-kilodalton PCR for detection of Mycobacterium tuberculosis from sputum specimens. J Clin MicrobioI34:1829-1830 Sougakoff W et al (1997) Nonradioactive single-strand conformation polymorphism analysis for detection of fluoroquinolone resistance in mycobacteria. Eur J Clin Microbiol Infect Dis 16:395-398 Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Bioi 98:503-517 Sreevatsan S et al (1996) Characterization of rpsL and rrs mutations in streptomycin-resistant Mycobacterium tuberculosis isolates from diverse geographical localities. Antimicrob Agents Chemother 40:1024-1 026 Sreevatsan S et al (1997a) Mutations associated by pyrazinamide resistance in pncA of Mycobacterium tuberculosis complex organisms. Antimicrob Agents Chemother 41:636-640 Sreevatsan S et al (1997b) Ethambutol resistance in mycobacterium tuberculosis: critical role of embB mutations. Antimicrob Agents Chemother 41:1677-1681 Sreevatsan S et al. (1997c) Analysis of the oxyR-ahpC region in isoniazid-resistant and -susceptible Mycobacterium tuberculosis complex organisms recovered from diseased humans and animals in diverse localities. Antimicrob Agents Chemother 41:600-606 Stratton MA, Reed MT (1986) Short-course drug therapy for tuberculosis. Clin Pharm 5:977-987

D. 1. Williams Sullivan EA et al (1995) Emergence of fluoroquinolone-resistant tuberculosis in New York City. Lancet 345:1148-1150 Takayama K, Kilburn JO (1989) Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother 33:1493-1499 Takayama K et al (1979) Inhibition by ethambutol of mycolic acid transfer into the cell wall of Mycobacterium smegmatis. Antimicrob Agents Chemother 16:240-242 Takiff HE et al (1994) Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother 38:773-780 Telenti A et al (1993a) Detection of rifampin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647-650 Telenti Aet al (1993b) Direct, automated detection of rifampinresistant Mycobacterium tuberculosis by polymerase chain reaction and single-strand conformation polymorphism analysis. Antimicrob Agents Chemother 37:2054-2058 Telenti A et al (1997a) Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level. J Clin Microbiol 35:719-723 Telenti A et al (1997b) The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med 3:567-570 Temesgen Z et al (1997) Use of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis to detect a point mutation in the catalase-peroxidase gene (katG) of Mycobacterium tuberculosis. Mol Cell Probes 11 :59-63 Thierry D et al (1990) IS6110, an IS-like element of Mycobacterium tuberculosis complex. Nucleic Acids Res 18:188 Thomas GA, Williams DL, Soper SA (2001) Capillary electrophoresis-based heteroduplex analysis with a universal heteroduplex generator for detection of point mutations associated with rifampin resistance in tuberculosis. Clin Chern 47:1195-1203 van Embden JD et al (1993) Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 31: 406-409 van Soolingen D et al (1994) DNA fingerprinting of Mycobacterium tuberculosis. Methods EnzymoI235:196-205 Victor TC et al (1996) katG mutations in isoniazid-resistant strains of Mycobacterium tuberculosis are not infrequent. Antimicrob Agents Chemother 40:1572 Walker GT et al (1992) Strand displacement amplification-an isothermal, in vitro DNA amplification technique. Nucleic Acids Res 20:1691-1696 Whelen A et al (1995) Direct genotypic detection of Mycobacterium tuberculosis rifampin resistance in clinical specimens by using single-tube heminested PCR. J Clin Microbiol 33:556-561 Williams DL et al (1994) Characterization of rifampin resistance in pathogenic mycobacteria. Antimicrob Agents Chemother 38:2380-2386 Williams DL, Gillis TP, Dupree WG (1995) Ethanol fixation of sputum sediments for DNA-based detection of Mycobacterium tuberculosis. J Clin MicrobioI33:1558-1561 Williams DL et al (1996) PCR-heteroduplex detection of rifampin-resistant Mycobacterium tuberculosis. In: Persing D (ed) PCR protocols for emerging infectious diseases. ASM Press, Washington DC, pp 122-129

PCR and Diagnosis of Tuberculosis Williams DL et al (l998a) Contribution of rpoR mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 42:1853-1857 Williams DL et al (l998b) Evaluation of a polymerase chain reaction-based universal heteroduplex generator assay for direct detection of rifampin-susceptibility of Mycobacterium tuberculosis directly from sputum specimens. Clin Infect Dis 26:446-450 Winder FG, Collins PB, Whelan D (1971) Effects of ethionamide and isoxyl on mycolic acid synthesis in Mycobacterium tuberculosis BCG. J Gen MicrobioI66:379-380 Winder FG (1982) Mode of action of the antimycobacterial

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agents and associated aspects of the molecular biology of the mycobacteria. In: Ratledge C, Stanford J (eds) The biology of the mycobacteria, vol 1. Academic Press, London, pp 353-438 Woods GL (2001) Molecular techniques in mycobacterial detection. Arch Pathol Lab Med 125:122-126 Yeboah-Manu D, Yates MD, Wilson SM (2001) Application of a simple multiplex PCR to aid in routine work of the mycobacterium reference laboratory. J Clin MicrobioI39:4166-4168 Zhang Y et al (1992) The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature 358:591-593

14 Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients GORGUN AKPEK

CONTENTS 14.1

Introduction

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14.1.1 Mycobacterium Tuberculosis 214 14.2 14.2.1 14.2.2 14.2.3 14.2.4 14.2.5 14.2.6 14.2.7 14.3

14.3.1

14.3.2 14.3.3 14.3.4 14.3.5 14.3.6 14.3.7 14.3.8 14.3.9 14.4 14.4.1 14.4.2 14.4.3 14.5

Hematologic Findings in Tuberculosis 215 Anemia 216 White Blood Cell Abnormalities 216 Thrombocytopenia 216 Pancytopenia 216 Possible Mechanisms of Hematologic Findings in Tuberculosis 217 Prognostic Significance of Hematologic Abnormalities. 219 Tuberculosis-Induced Lymphopenia and Immunosuppression 219 Hematologic Abnormalities Associated with Mycobacterial Infections in Imrnunocompromised Hosts 220 Hematologic Complications of HIV Infection and AIDS 220 Mycobacterium avium Complex in HIV-Infected Patients 220 Anemia Associated with MAC in HIV-Infected Patients 220 Other Cytopenias Associated with MAC in HIV-Infected Patients 222 MAC Infections in Other Immunocompromised Hosts 222 Hemophagocytic Syndrome Associated with MAC 223 Miliary/Disseminated Tuberculosis in AIDS 223 Diagnostic Yield of Bone Marrow Aspiration/Biopsy for Mycobacterial Infections in Patients with HIV Infection 224 Other Mycobacterial Infections Associated with Hematologic Disorders 226 Coagulation Abnormalities Associated with Mycobacterial Infections and Clinical Presentations 226 Disseminated Intravascular Coagulation 226 Deep Vein Thrombosis Associated with Tuberculosis 226 Thrombotic Thrombocytopenic Purpura Associated with Mycobacterial Infections 227 Conclusion 227 References 227

G.AKPEK,MD Greenebaum Cancer Center at University of Maryland School of Medicine, 22 South Greene Street, Baltimore MD 21201, USA

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

14.1 Introduction The relationship between hematologic abnormalities and mycobacterial infections dates back to the beginning of the 20th century. Flinn and his colleagues suggested at that time that the change in hematologic parameters is the earliest finding of tuberculosis (TB) (Flinn and Finn 1929). The authors said,'In connection with the above studies we have formed the impression that an extension of the pathologic process in a tuberculosis lung usually manifests itself first in the blood picture, later by physical signs and x-ray, and often last of all by symptoms: Before embarking upon a general discussion of hematologic manifestations of mycobacterial infections, I would like to present two cases that were previously discussed at the Medical Staff Conference in the University of San Francisco, California, USA, in 1967. These cases have certain features of the history and clinical findings of TB, in particular, the striking difference in the hematological manifestations between the two cases. A brief summary about the demographics and clinical presentation of Mycobacterium TB infection is included thereafter.

Case 1. The first patient is a 50-year-old white man who came in for evaluation of a fever of about 7 months' duration. His symptoms began with multiple episodes of severe pain in the left upper quadrant of the abdomen and nausea. These symptoms were followed in a few days by fever and generalized malaise. According to the patient's description, the febrile episodes would last for approximately 1 week and recurred at approximately 4-week intervals with temperatures in the range of 38.3°C-40.6°C (lOI°F105°F). He was noted to have axillary and inguinal adenopathy 2 months later when seen by a physician because of persistent symptoms. Laboratory data included hemoglobin of 12.2 gm/dl, markedly elevated erythrocyte sedimentation rate, increased concentration of serum gammaglobulin, and a positive tuberculin test. Two months later, the patient underwent surgery for the repair of an incarcer-

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ated incisional hernia. An exploratory laparotomy performed at that time revealed no intraabdominal pathology. Two months later, the patient's fever recurred and was associated with night sweats and 13 pounds (6 kg) of weight loss since the onset of his symptoms. At that time no history could be obtained of cough, pleuritic chest pain, hemoptysis, or production of sputum. The family history was negative. The patient had been a heavy smoker for 20 years. On physical examination, the only abnormalities were slight adenopathy in the inguinal and axillary regions, hepatomegaly, and questionable splenomegaly. Body temperature was 38.3°C (101°F). Hemoglobin content was 8.7 g/dl, WBC of 3400/mm3, with 30% neutrophils, 65% lymphocytes, 3% monocytes, and 2% basophils. The platelet count was 301,000/mm 3, with reticulocytes forming 2.1 % of the total. Additional hematologic data included normal haptoglobulin, leukocyte alkaline phosphatase, coagulation parameters, and serum iron and iron-binding capacity. The bone marrow at that time showed generalized hyperplasia, predominantly of the erythroid series. Skin test was positive with PPD. A chest X-ray showed fibrocalcific densities. There was no active pulmonary disease, but there was evidence of old granulomatous disease. There were granulomas in the right upper lung field and some scattered granulomas in the right mid-lung field. All other work-up for fever of unknown origin was negative. A scalene lymph node biopsy showed multiple confluent and epithelioid caseous granulomas. The patient improved on an anti-TB regimen. Cultures of the scalene lymph node specimen grew acid-fast organisms.

Case 2. The second patient is a 62-year-old man with a chief complaint of tenderness in the left upper quadrant of the abdomen, with weight loss and weakness of 5 months' duration. A mass in the left upper quadrant was noted on routine physical examination. Four months later, the patient first noticed anorexia, weight loss, and weakness. Three months later, he developed anemia and was admitted to the hospital. The patient has had regular chest X-rays taken every 6 months for the past 2 years. These films have shown stable apical infiltrates. He was also known to have a positive PPD skin test. He had been a heavy smoker for the past 45 years; he has had chronic nonproductive cough and a history of acute upper gastrointestinal bleeding, which responded to medical management. On physical examination, the patient was pale and cachectic. Body temperature was 38°C (101 OF). He had several small lymphadenopathies. Lung expansion was decreased bilaterally, and the anteroposterior diam-

G.Akpek

eter of the chest was increased. There was dullness and increased fremitus on the right. Peristaltic movement was visible beneath a thin abdominal wall. The spleen, which was large and rock-hard, extended 8 cm below the left costal margin, and there was a tender nodule, 2x3 cm, at the anterior margin. The liver edge was felt 4 cm below the right costal margin. It was not tender and firm. Early clubbing of the fingers and severe muscular wasting of the extremities were noted. Leukocyte numbered 16,000/mm3 , with 60% neutrophils, many immature myeloid cells, 10% basophils, and 10% eosinophils. Hematocrit was 19%, reticulocyte count 2.5% of the total, and platelet count 80,000/mm 3• Normoblasts were present in the peripheral blood. Xray examination revealed dense bones. Patchy apical infiltrates, which had increased since the previous examination, were noted on chest X-ray. There was a large right pleural effusion. A skin test with PPD was positive. Thoracentesis and pleural biopsy were performed. The latter revealed caseating granulomas. No intrabronchiallesions were seen at bronchoscopy. A bone biopsy was performed since three previous marrow taps had been dry. The bone biopsy revealed sclerotic bone and myelofibrosis. Triple anti-TB therapy was begun. Subsequently, cultures of both sputum and pleural fluid grew acid-fast bacilli.

14.1.1

Mycobacterium Tuberculosis Currently, more than one-third of the world's population is infected with Mycobacterium TB: 8 million new cases and approximately 2 million deaths are reported each year (Dye et al. 1999). Although the lung is the primary site of disease in 80%-84% of cases of TB in the USA (Center for Disease Control and Prevention 2000), extrapulmonary TB has become more common with the advent of HIV infection, and the risk of TB increases as the immunosuppression progresses (Moore et al.1997; Jones et al.1993; Iseman 2000). The most common extrapulmonary sites of disease are the lymph nodes, pleura, and bones or joints (Center for Disease Control and Prevention 2000). Lymphatic TB is usually seen in children and young adults; more commonly in women (especially Asian and Indian women). It presents with unilateral, painless, cervical adenopathy, which is connected to the skin by sinus tracts late in the course of disease. Excisional biopsy with culture yields the diagnosis of TB lymphadenitis. PPD is usually positive. It may respond slowly to medication and rarely may require excision (Mandel et al. 2000).

Hematologic Findings in Mycobacterial Infections Among Immunosuppressed and Immunocompetent Patients

Clinical presentations ofTB have changed dramatically since the introduction of anti-TB agents. In the pre-antibiotic era, late generalized TB was often the primary disease, occurring mainly in young adults and frequently associated with pulmonary symptoms. In the antibiotic era, TB commonly occurs together with and is frequently obscured by other diseases. It often afflicts the elderly and is much less frequently accompanied by pulmonary symptoms (Slavin et al. 1980). Disseminated TB involving the lung, liver, spleen, bone marrow, and lymph nodes can occur occasionally in an immunocompetent host and is usually associated with hematologic abnormalities and poor outcome (Charfi et al.1998). Splenomegaly associated with fever is another clinical sign of disseminated TB (O'Reilly 1998). The histologic appearance in this rare form of disseminated hematogenous TB (nonreactive TB) shows nonspecific necrosis containing disintegrating polymorphonuclear leukocytes and enormous numbers of tubercle bacilli (O'Brien 1954). In a typical case, granulomas and epithelioid cells are lacking, although intermediate cases have areas more typical for T8. The gross pathologic findings are minute soft abscesses up to 1 cm, which always involve the liver and spleen, usually the marrow, commonly the lungs and kidneys, but almost never the meninges. The clinical picture may be overwhelming sepsis, with splenomegaly and often an inconspicuous diffuse mottling on the chest X-ray. Major hematologic abnormalities are common. Whether the lesions are typical or not, it is necessary to have bacteriologic confirmation of TB. Near these lesions, the bone marrow cellularity is often raised or lowered, reticular fibers are often increased, and sometimes reticulin fibrosis is marked (Tulliez 1976). In the following sections, common types of mycobacterial infections that are associated with various hematologic findings are discussed.

14.2 Hematologic Findings in Tuberculosis While most patients with TB do not manifest major hematologic abnormalities, some patients with late generalized or chronic hematogenous TB and most with nonreactive TB have serious hematologic abnormalities, including leukopenia, thrombocytopenia, anemia, leukemoid reactions, myelofibrosis, and polycythemia (Cameron 1974). Leukemoid reactions may suggest acute leukemia, although most patients in whom hematogenous TB coexists with the clinical picture ofleukemia have both diseases. Slavin and his

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colleagues reviewed the medical records of a community-based university teaching hospital over a lO-year period (1978 to 1987) to determine the clinical and laboratory characteristics, diagnostic methods, and prognostic variables in adults treated for miliary TB in the rifampicin era. They identified a total of 109 patients including 12 who did not have miliary nodules on the chest X-ray (all of whom were shown to have hematogenous dissemination). Hematologic abnormalities were common: leukopenia (less than 4xlO(9)/I) was present in 16 of 107 patients (15%), thrombocytopenia (less than 150x10(9)/L) in 24 of 104 (23%), and lymphopenia (less than 1.5X10(9)/L) in 82 of 94 (87%). Pancytopenia was found in 6 patients, 3 of whom recovered. Disseminated intravascular coagulation occurred in 4 patients, all of whom died (Slavin et al. 1980). In a recent study, investigators from India compared peripheral blood and bone marrow findings in patients with disseminated/miliary TB (DTB/MTB) as well as pulmonary TB (PTB) (Singh et al. 2001). They also assessed the effect of anti-TB therapy on the occurrence of hematologic abnormalities. Thirty-two patients with DTB/MTB and 23 patients with PTB were prospectively studied. All patients received standard anti-TB treatment. They were subjected to a hemogram including a peripheral blood examination, which was repeated on completion of the anti-TB therapy. Bone marrow aspiration and biopsy were also done in all patients before starting the treatment. Normocytic normochromic anemia was the most common abnormality observed in all groups and subgroups (DTB/MTB 84%, PTB 86%). Other hematological abnormalities of the white blood cells include leukopenia (DTB/MTB 25%, PTB 0%; p12 mm the incidence of disease was 380/100,000. In another study, Palmer et al. (1959) evaluated skin-test reactivity in Pakistani children and again demonstrated a bimodal distribution with peaks at 2-5 mm and 17 mm. They concluded that the first peak was due to NTM, and the larger size peak represented true TB reactors. The reactions from NTM tend to be smaller than from MTB. Thus, increasing the cut-off for a positive reaction increases the specificity but reduces the sensitivity. In the USA, this has been the rationale for a 15 mm cut-off, since the prevalence of NTM is high (particularly in the southern USA) and of MTB low. A value of 15 mm is also close to the peak of reactivity described by the WHO in true reactors. In groups at high risk for TB, the cut-off is lowered in order to improve the sensitivity; immunocompromised groups, in particular, may have smaller size reactions or become anergic due to immune dysregulation, and thus the cut-off has been reduced to 5 mm.

15.8 Booster Although the PPD skin-test reactivity can persist throughout life, occasionally there is a diminution or absence in the DTH response to PPD over time. In such individuals, a return in response may be seen if tested sequentially over several weeks. This phenomenon of accentuation of response after repeat testing is commonly known as the booster effect and must not be interpreted as a new skin test conversion. Boostering most often occurs in persons older than age 55 years in whom cellular immunity may wane. Health care institutions where repeat TB testing is performed use an initial screening two-step test (two PPD skin tests about 3 weeks apart) to establish a baseline reactivity, in order to avoid falsely classifying a repeat test at a later time as a new conversion.

15.9 Adverse Reactions to PPD Testing Generally, adverse reactions to TB skin testing are rare; however, immediate hypersensitivity reactions have been reported and are in no way correlated to underlying TB infection (Tarlo et al. 1977; Wright et al. 1989). Individuals may also develop vesicular or ulcerating lesions at the site of PPD injection. These severe reactions occur in a small percentage ofpositive reactors; however, a previous positive does not predict an increased likelihood of developing a severe cutaneous reaction (Reichman and O'Day 1977). Health care providers use topical corticosteroid creams to treat these local reactions, but one controlled study using hydrocortisone did not demonstrate efficacy, although the use of a more potent steroid may have shown benefit (Hanson and Comstock 1968).

15.10 New Trends in Diagnosing Latent TB Infection The immune response to mycobacterial infection is predominantly cellular (Kaufmann 2001). The PPD skin test has been a convenient, cost-effective method for assessing cell-mediated immune responses to mycobacterial-derived proteins. Although the test is reasonably priced, there continue to be multiple factors challenging the accuracy of the PPD skin test (ST) in different settings. These factors include (but are not limited to) variability in operator placement and reading, cross-reactivity among mycobacterial species (including M. avium and BeG), the need for the patient to return in 48-72 h for a reading, and the modulation of the skin response due to underlying illness or immunosuppression. Clearly, there is a need for another more sensitive and specific test that would overcome the limitations of the skin test. In addition, the tools used to diagnose active disease are currently different from the skin test, which is used to detect exposure. The major immunodiagnostic advances to date have centered on more sensitive and rapid testing to determine the presence of active disease, but progress in the area of detecting exposure in healthy individuals has been slower. Recent work has shifted to identifying recombinant and purified antigens that may be used for skin testing and in immunoassays with greater sensitivity. One of the first tuberculosis complex-specific antigens discovered was MPT64, a

R. K. Katial

236

24 kDa protein. More recently, other antigens have been purified, including 38 kDa (antigen b), 10 kDa, 18 kDa, MPT59 (Ag85B), and ESAT-6 (Gennaro 2000). MPT64 has produced disappointing results when used as a skin-test reagent. Only 6% of PPD-reactive TB-positive patients responded to MPT64 in comparison with a 50% reactivity with MPT59 (Wilcke et al. 1966). Antigen b has been shown to be very antigenic and, when studied in guinea pigs, elicited a positive skin test in MTB-vaccinated animals but not in those exposed to other strains. The antigen appears to be more specific than PPD (Haslov et al. 1990). Vordermeier et al. (1992), using an epitope located near the 38 kDa antigen of MTB, elicited a DTH reaction in PPD-positive individuals but not in negative ones. These antigens may find a role in immunoassays and possibly in skin testing by providing the ability to detect newly exposed individuals with greater specificity as well as to differentiate those vaccinated from those infected. The immune response to MTB is highly dependent upon IFN-y production by macrophages and antigen-specific T-cells; over the past decade, there has been an increasing interest in the development and application of in vitro culture assays measuring IFN-y production in response to tuberculin antigen stimulation as a substitute diagnostic screening test for the classic PPD skin test (Lein and von Reyn 1997). Initially using peripheral blood mononuclear cells, the methodology evolved to a whole blood culture technique that was first validated in Australian cattle. These studies demonstrated that the IFN-y test had greater diagnostic sensitivity, lower cost, and rapid results for cattle TB screening (Rothel et al. 1992; Wood et al. 1991; Wood and RotheI1994). This method was developed for human TB testing using human PPD, avian PPD, and the mitogen phytohemagglutinin (PHA). A standardized diagnostic kit with a specifically defined data analysis procedure has been marketed by CSL in Australia (now Cellestis, Australia): QuantiFERON-TB or Q-IFN. In various studies comparing the Q-IFN assay with PPD-ST, the agreement ranges from 40% to 100% when looking at subjects without active disease or a history of active disease (Table 15.2). Agreement has been lower in those with active disease. Streeton et al. (1998) reported a sensitivity and specificity of 90.5% and 98%, respectively, for diagnosing MTB exposure in human subjects. In their study, the gold standard for diagnosis was the PPD-ST, and the study subjects were stratified according to their skin test induration and risk of exposure to tuberculosis. Kimura et al. (1998) and

Table 15.2. Agreement between Q-1FN and SKT for latent TB infection in various studies Reference

Skin test classification

Agreement between Q-1FN test and SKT

(Q-1FN/SKT)a N (HIV-) 68% P (HIV-) 70% 700/0 Overall, H1VN (H1V+) 85% 40% P (H1V+) 61% Overall, H1V+ 40% N (H1V -) Converse et aI. (1997) P (H1V - ) 100% Overall, H1V72% N (H1V+) 73% P(H1V+) 92% Overall, H1V+ 79% 100% Desem and Jones N 90% (1998) P 95% Overall 80% KatiaI et aI. N (2001) 80% P Overall 80% 500/0 N (H1V-) Kimura et aI. (1998) P (H1V -) 89% 59% Overall, HIV 85% N (H1V+) 56% P (H1V +) 82% OveraIl, H1V + 900/0 Mazurek et aI. N 65% (2001) P 85% Overall Pottumarthy et aI. N (high-risk country) 89% (1999) P (high-risk country) 64% N(HCW) 81% P (HCW) 67% 79% OveraIl 88% N Streeton et aI. (1998) 900/0 P 88% Overall Bellete et aI. (2002)

(43/63) (921131) (135/194) (22126) (ll/28) (33/54) (6115) (17117) (23/32) (16122) (ll/12) (27/34) (10/10) (9/10) (19/20) (16/20) (16/20) (32/40) (115/229) (63171) (178/300) (128/151) (9/16) (137/167) (738/818) (1471227) (885/1045) (135/151) (55/86) (64179) (32/48) (286/364) (480/545) (163/182) (643/727)

With ~15% = positive Q-1FN, excluding those with active disease or past history of active disease N =negative skin test defined at various cut-offs depending on risk; P =positive skin test defined at various cut-offs depending on risk; Hew = health care worker

a

Converse et al.(1997) used Q-IFN in studies comparing the IFN release assay with PPD-ST in populations at risk for MTB exposure (intravenous drug users with or without HIV infection). They found that the Q-IFN assay detected more reactors than PPD-ST. Agreement between the two tests was weak. We studied 40 patients and found good agreement between PPD-ST and the Q-IFN kit (kappa=0.73). We evaluated the agreement between in vivo and in vitro tests and did not refer to sensitivity and specificity because they assume comparison to an adequate gold standard, which we feel does not exist

237

Immunodiagnostics for Latent Tuberculosis Infection

(Katial et al. 2001). Recently, Mazurek and colleagues (2001) evaluated 1226 volunteers and found overall 83% agreement between the IFN-y assay and skin test in individuals at both low and high risk for latent TB infection. However, only 68% agreement was noted in the positive PPD-ST group. A similar study by Bellete et al. (2002) reported an overall agreement in a USA cohort of 79% (in Baltimore), but lower agreement (68%) was seen in Ethiopia, an endemic TB area. In addition, the authors found poor reproducibility in the in vitro results from one test to another. One significant drawback of both the skin test and the Q-IFN test is the nonspecific response to PPD because of cross-reactivity between tuberculin and other mycobacterial species. Although the Q-IFN test does distinguish M. avium from MTB reactivity, it does not differentiate between responses from MTB and other mycobacterial species such as M. kansasii, M. marum, and M. africanum. The false-positivity in the PPD skin testing due to BCG vaccination is well documented. However, the in vitro IFN-yproduction by BCG-vaccinated individuals in response to PPD may also be influenced by cross-reacting mycobacterial antigens. Streeton et al. (1998) included BCG vaccinees in their study but were unable to discern the effects of BCG on the assay results. Therefore, additional studies are needed to delineate the diagnostic value of the Q-IFN kit in this population. The in vitro diagnostic system affords a distinct advantage over PPD-ST in that one can test for tuberculin-specific proteins without unnecessarily exposing the patient. The low-molecular-weight antigen ESAT-6 (6 kDa) has been shown to differentiate between MTB and BCG strains and thus may serve as an additional stimulant to determine the effect of BCG. Recently, ESAT-6 was evaluated in the Q-IFN assay and found to differentiate those infected with TB from controls, with high sensitivity and specificity (Johnson et al. 1999). We studied low-molecular-weight culture filtrate proteins, culture filtrate proteins minus lipoarabinomannan, soluble cell wall proteins, and cytosolic proteins in whole blood culture, and none of the subfractions performed any better than the whole PPD (Katial et al. 2001). However, the crude preparations used in this study did stimulate IFN-y production in sensitized individuals and should be further purified and studied in the whole blood system. The immune response to TB is complex and directed to a heterogeneous mixture of antigens rather than anyone protein. Therefore, studying a cocktail of native or recombinant antigens may prove to be more specific and sensitive in diagnosing TB than anyone immunodominant protein. The advantages of the

blood test include the absence of any reading or placement variability and the need for only one office visit. The current disadvantages are the need for stringent laboratory requirements dealing with blood handling, cell culture, and ELISA testing. The areas needing clarification include defining the performance characteristics and lower cut-off limit for the enzyme immunoassay. Data are needed on temporal measurements to determine if the time of day or different days have any impact on the whole blood stimulation response. Finally, the cut-offs differentiating a positive from a negative response suggested in the Q-IFN kit need to be verified based on the prevalence of disease in different populations as has been done with PPD-ST. These issues should be addressed and followed up by large-scale trials to assess the true sensitivity, specificity, and positive predictive value of the Q-IFN kit, prior to Widespread use for clinical MTB testing. The assessment of IFN-y production by TB-specific lymphocytes is also being studied by more sensitive techniques such as flow cytometry and Elispot assays. Tilley and Menon (2000) demonstrated the correlation between intracellular staining of IFN-y in TB-specific lymphocytes with the extracellular secretion of IFN-y as measured by the Elispot assay. The authors were also able to conclude that the IFNy response as measured by the intracellular staining correlated directly with the Mantoux skin test. As the data in TB patients using these techniques increase, the understanding of the underlying TB immune response will become clear, and some combination of tests may become the new standard of care for the diagnosis of latent TB infection.

References Ahmed AR, Blose DA (1983) Delayed type hypersensitivity skin testing: a review. Arch DermatoI119:934-945 American Thoracic Society and Centers for Disease Control and Prevention (2000) Diagnostic standards and classification of tuberculosis in adults and children. Am J Crit Care Med 161:1376-1395 Bates JH, Stead WW (1993) The history of tuberculosis as a global epidemic. Med Clin North Am 77:1205-1217 Betiete B et al (2002) Evaluation of a whole-blood interferon-y release assay for the detection of Mycobacterium tuberculosis infection in 2 study populations. Clin Infect Dis 34: 1449-1456 Bouros D et al (1991) Palpation vs pen method for the measurement of skin tuberculin reaction (Mantoux test). Chest 99:416 Bouros D et al (1992) The role of inexperience in measuring tuberculin skin reaction (Mantoux test) by the pen or palpation technique. Respir Med 86:219-223

238 Centers for Disease Control (1994) Core curriculum on tuberculosis, 3rd edn. Centers for Disease Control, Atlanta, p 9 Collins H, Kaufmann S (2001) The many faces of host responses to tuberculosis. Immunology 103:1-9 Converse PJ et al (1997) Comparison of a tuberculin skin test in high-risk adults of human immunodeficiency virus infection. J Infect Dis 176:144-150 Daniel T (1980) The immunology tuberculosis. Clin Chest Med 1:189-201 Daniel TM, Boom WH, Ellner JJ (2000) Immunology of tuberculosis. In: Reichman L, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, 2nd edn. Dekker, New York, pp 187-214 Davis AL (2000) A historical perspective on tuberculosis and its control. In: Reichman L, Hershfield ES (eds) Tuberculosis: a comprehensive international approach, 2nd edn. Dekker, New York, pp 3-54 Desem N, Jones SL (1998) Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin Diagn Lab Immunol 5: 531-536 Edwards LB et al (1969) An atlas of sensitivity to tuberculin, PPD-B and histoplasmin in the United States. Am Rev Respir Dis 99:1-132 Ellner JJ (1997) The immune response in human tuberculosis-implications for tuberculosis control. JID 176: 1351-1359 Gennaro ML (2000) Immunologic diagnosis of tuberculosis. Clin Infect Dis 30:s243-s246 Gryzbowski S, Brown MT, Stothard D (1969) Infections with atypical mycobacteria in British Columbia. CMAJ 100: 896-900 Hagan WA (1931) The no lesion case problem in the tuberculosis eradication campaign. Cornell Vet 21:163-171 Hanson ML, Comstock GW (1968) Efficacy of hydrocortisone ointment in the treatment of local reactions to tuberculin. Am Rev Respir Dis 97:472-473 Haslov K et al (1990) Comparison of the immunological activity of five defined antigens from mycobacterium tuberculosis in seven inbred guinea pig strains. The 38 kDa antigen is immunodominant. Scand J ImmunoI31:503-514 Hershey J, Engler RJ, Katial RK (2001) Tuberculin skin tests: to measure or not to measure in two directions? JACI 107: s254 Hirsch CS et al (1996) Cross-modulation by transforming growth factor b in human tuberculosis: suppression of antigen-driven blastogenesis and interferon g production. Proc Natl Acad Sci USA 93:3193-3198 Hirsch CS et al (1999) Depressed T-cell interferon-y responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. JID 180:2069-2073 Howard T, Solomon DA (1988) Reading the tuberculin skin test: Who, when and how. Arch Intern Med 148:2457-2459 Iseman M (1999) Immunity and pathogenesis. In: A clinician's guide to tuberculosis. Lippincott Williams and Wilkins, Philadelphia, pp 63-96 Johnson PDR et al (1999) Tuberculin-purified protein derivative, MPT-64, and ESAT-6 stimulated gamma interferon responses in medical students before and after mycobacterium bovis BCG vaccination and in patients with tuberculosis. Clin Diagn Lab Immunol 6:934-937 Jordon T et al (1987) Tuberculin reaction size measurement by

R. K. Katial the pen method compared to traditional palpation. Chest 92:234-236 Katial RK et al (2001) Cell mediated immune response to tuberculosis purified protein derivative: comparison of TB skin testing to in-vitro g-interferon production in whole blood culture. Clin Diagn Lab Immunol 8:339-345 Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nature Rev Immunol1:20-30 Kimura M et al(1998) Comparison between a whole blood interferon-gamma release assay and tuberculin skin testing for the detection of tuberculosis infection among patients at risk for tuberculosis exposure. J Infect Dis 179: 1297-1300 Kiple KF (ed) (1993) The Cambridge world history of human disease. Cambridge University Press, Cambridge Koch R (1890) Ober bacterilogische Forschung. Dtsch Med Wochenschr 16:756 Koch R (1891) Fortsetzung der Mitteilungen tiber ein Heilmittel gegen Tuberculose. Dtsch Med Wochenschr 891:17-101 Lein D, von Reyn F (1997) In vitro cellular and cytokine responses to mycobacterial antigens: application to diagnosis of tuberculosis infection and assessment of response to mycobacterial vaccines. Am J Med Sci 313:364-371 Longfield J et al (1984) Interobserver and method variability in tuberculin testing. Pediatr Infect Dis 3:323-326 Lunn JA (1980) Reasons for variable response to tine test. Br Med J 280:223 Mazurek GH et al (2001) Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 286:1740-1747 Murtagh K (1980) Unreliability of the Mantoux test using 1 TU PPD in excluding childhood tuberculosis in Papua New Guinea. Arch Dis Child 55:795-799 Grme I, Cooper A (1999) Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 20:307-312 Palmer CE (1945) Nontuberculous pulmonary calcification and sensitivity to histoplasmin. Public Health Rep 60,513-520 Palmer CE et al (1959) Experimental and epidemiologic basis for the interpretation of tuberculin sensitivity. J Pediatr 55:413-428 Pearson L (1892) Tuberculin as a diagnostic agent. Med News 60:358-359 Pouchot J et al (1997) Reliability of tuberculin skin test measurement. Ann Intern Med 126:210-214 Pottumarthy S et al (1999) Evaluation of the tuberculin gamma interferon assay: potential to replace the Mantoux skin test. J Clin Microbiol 37:3229-3232 Reichman LB, G'Day R (1977) The influence of a history of a previous test on the prevalence ands size of reactions to tuberculin. Am Rev Respir Dis 115:737-741 Research Committee of the British Thoracic Association (1982) Reproducibility of the tine tuberculin test. Br J Dis Chest 76:75-78 Rothel JS et al (1992) The gamma-interferon assay for diagnosis of bovine tuberculosis in cattle: conditions affecting the production of gamma-interferon in whole blood culture. Aust Vet J 69: 1-4 Seibert FB, Glenn JT (1941) Tuberculin purified protein derivative: preparation and analysis of a large quantity for standard. Am Rev Tuberc 44:9-25 Snider D (1982) The tuberculin skin test. Am Rev Respir Dis 125:s108-s118

Immunodiagnostics for Latent Tuberculosis Infection Sokal JE (1975) Measurement of delayed skin test responses. N Engl J Med 293:501-502 Streeton JA,Desem N, Jones SL (1998) Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection. Int J Tuberc Lung Dis 2:443-445 Tarlo SM et al (1977) Immediate hypersensitivity to tuberculin in in-vivo and in-vitro studies. Chest 71:33-37 Tilley PAG, Menon IN (2000) Detection of Mycobacteriumspecific interferon-gamma-producing human T lymphocytes by flow cytometry. APMIS 108:57-66 Tsuyuguchi I (1996) Regulation of the human immune response in tuberculosis. Infect Agents Dis 5:82-97 Villarino ML et al (1999) Comparable specificity of 2 commercial tuberculin reagents in persons at low risk for tuberculous infection. JAMA 281:169-171

239 Vordermeier HM et al (1992) M. tuberculosis-complex specific T-cell stimulation and DTH reactions induced with a peptide from the 38-kDa protein. Scand J Immunol 35: 11-718 Wilcke JT et al (1966) Clinical evaluation of MPT-64 and MPT59, two proteins secreted from mycobacterium tuberculosis, for skin test reagents. Tuber Lung Dis 77:250-256 Wood PR, Rothel JS (1994) In vitro immunodiagnostic assay for bovine tuberculosis. Vet MicrobioI40:125-135 Wood PR et al (1991) Field comparison of the interferongamma assay and the intradermal tuberculin test for the diagnosis of bovine tuberculosis. Aust Vet J 68:286-290 Wright DN, Ledford DK, Lockey RF (1989) Systemic and local allergic reactions to the tine test purified protein derivative. JAMA 262:2999-3000

Organ-related Chapters

16 Childhood Tuberculosis PETER R.

DONALD

CONTENTS Introduction 243 Epidemiology of Childhood Tuberculosis 243 Pathogenesis and Clinical Manifestations of Childhood Tuberculosis 245 Central Nervous System Tuberculosis 248 16.4 Intracranial Tuberculomata 250 16.5 16.6 Childhood Tuberculosis and HIV/AIDS 251 16.7 Diagnosis of Tuberculosis in Childhood 251 Tuberculosis in Infancy 254 16.8 Tuberculosis During Adolescence 255 16.9 16.10 Treatment of Tuberculosis in Childhood 256 16.11 Drug-resistant Tuberculosis in Childhood 257 16.12 Prevention and Control of Tuberculosis in Childhood 258 References 261

16.1 16.2 16.3

tion. It is of considerable interest that the frequency with which these various features are seen varies with age and therefore probably reflects changes in the immune response to tuberculosis infection. Perhaps because of this wide spectrum of pathology, childhood tuberculosis will be looked upon by some as a relatively benign manifestation of tuberculosis infection and regarded by others as a major child health problem, particularly in developing countries. This chapter will describe the epidemiology of tuberculosis in childhood, the most important clinical features of childhood tuberculosis, the interaction of childhood tuberculosis and HIV/AIDS, and the diagnosis and management of childhood tuberculosis.

16.1 Introduction

16.2 Epidemiology of Childhood Tuberculosis

Childhood tuberculosis refers to a wide spectrum of manifestations of tuberculosis seen in children from birth to adolescence. At one extreme, particularly in the very young, are life-threatening disseminated forms of tuberculosis, such as tuberculous meningitis and miliary tuberculosis. At the other extreme, enlargement of the mediastinal lymph nodes may pass entirely unnoticed, and the development of a positive tuberculin test will be the only sign that tuberculosis infection has occurred. As the children enter adolescence, "adult-type" pulmonary tuberculosis will be seen with increasing frequency, characterized by the development of cavitation involving mainly the apices of the lungs. Also at this age, large pleural effusions with straw-coloured fluid become more common as a manifestation of primary infec-

The incidence of childhood tuberculosis will be determined by the frequency of exposure to a source of infection, which will nearly always be an adult with sputum microscopy smear-positive, cavitating pulmonary tuberculosis. In developed communities, tuberculosis has become mainly a disease of the elderly, with a male predominance, occurring amongst the economically deprived, living on the fringes of society. Small foci of disease may also be found amongst disadvantaged groups such as immigrants. Children will thus not often be exposed to the risk of infection and disease. In developing communities, tuberculosis will be a disease of young adults, often with a female predominance. Children aged 15 years or less may constitute 40% or more of the population, and it is therefore not surprising that the incidence of childhood tuberculosis is far higher in a developing community than a developed community and that children make up a far greater portion of the tuberculosis case load. Thus, not only are there more young children in these communities, but they will be exposed to tuberculosis infection at a much

P. R. DONALD, MD, FRCP (Edin), FCP (SA), DCH (Glasgow), DTM&H (London) Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, P.O. Box 19063, 7505, Tygerberg, South Africa M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

244

younger age than would be the case in a developed community. Because more serious forms of tuberculosis such as miliary tuberculosis and tuberculous meningitis tend to occur in younger children, these potentially deadly forms of tuberculosis will occur more frequently in developing communities. During the last decade tuberculosis has been acknowledged as a worldwide threat to health, and in 1993 the World Health Organization declared the tuberculosis situation in the world a global emergency. Although considerable effort has since been expended in promoting the diagnosis of adult pulmonary tuberculosis by sputum smear microscopy and curing patients with directly observed short course treatment (DOTS), the burden of childhood tuberculosis frequently goes unrecognized. In developed countries, this is understandable as children may constitute less than 5% of the tuberculosis case load; in developing countries, however, this percentage may rise to 20% or even 40% in certain high-incidence countries and communities. Because of the difficulty of diagnosing tuberculosis in childhood, estimates of the global burden of childhood tuberculosis are at best an educated guess. In an often quoted estimate, the number of cases of childhood tuberculosis occurring in 1990 was put at 1.3 million, leading to 450,000 deaths (Kochi 1991). In other estimates, an arbitrary figure of 10% appears to have been used to calculate the portion of the tuberculosis burden attributable to children. Thus, it was predicted that during 2000 just over 1,000,000 cases of childhood tuberculosis would occur in the world. In the African region, however, under the influence of HIV/AIDS, 447,000 children would make up 20% of the tuberculosis burden, in contrast to the 1990 estimate of 90,000 cases of childhood tuberculosis for the region (Dolin et al. 1994). That such a dramatic increase has in fact occurred is suggested by data from several sources. In Malawi, for example, the number of children 0-14 years of age with tuberculosis managed at the Queen Elizabeth Central Hospital increased from 64 in 1986 to 507 in 1995. In 1995 and 1996,64% of children being treated for tuberculosis were mY-seropositive (Harries et al. 1997). In contrast to the above estimates, which must be open to considerable doubt, the risk of infection to which children are exposed can be objectively quantified by determining the annual risk of tuberculosis infection (ART!). ART! is determined by tuberculin testing a representative group of children at regular intervals to detect the incidence of infection and is considered one of the most objective ways to evaluate the tuberculosis situation in any community (Bleiker

P. R. Donald

1991). While ART! in most developed countries will be in the region of 0.01 %, it may rise as high as 2% or 3% in developing countries, implying that between a third and a half of the population will be infected by 15 years of age. From this figure it then becomes possible to predict more accurately the number of cases of childhood tuberculosis that are likely to arise in a particular community. It is disturbing that several recent studies from the developing world have shown no fall in ART! over long periods. In the Chingleput district of south India, for example, ART! has remained at 2% since observations started in 1968 (Tuberculosis Research Centre 2001). In Tanzania, ART! was 1.0% during 1988-1992 and 0.9% during 1993-1998. In this instance, the relatively constant ART! is reason for a certain amount of optimism, in that adult tuberculosis notifications have doubled under the influence of mY/AIDS during this same period (Tanzania Tuberculin Survey Collaboration 2001). This "success" is ascribed to the early adoption and implementation of the DOTS strategy by Tanzania. Figure 16.1 illustrates the age- and sex-related incidence of tuberculosis up to the age of 20 years in a developing community. There are several noteworthy features. Firstly, there is a very high incidence of tuberculosis in a developing community in early childhood, with a slight but consistent male predominance in the first year of life. This susceptibility of the young infant to tuberculosis is even more striking when considered as a proportion of the infected population, and very high rates of disease following infection of 5,000 to 6,000/100,000 population have been calculated for infected infants (Rich 1951; Bentley et al. 1954). Not only are the very young more susceptible to tuberculosis disease, but the disease is c:

o

~::>

250

Co

8. 8o 200 o o....

g 150

Tuberculous meningitis Miliary tuberculosis Lymphobronchial tuberculosis 'Adult type' tuberculosis

C1l

"t:l

'0

.5

'" 100

.~

~ 2 ~

501....&........- -......- _ - -.....-__.--_

Fig. 16.1. Age- and sex-related incidence of tuberculosis up to the age of 20 years in a typical developing community

245

Childhood Tuberculosis

likely to be more serious, disseminated and to take the form of tuberculous meningitis or miliary tuberculosis. With increasing age both the frequency and severity of disease decline until a nadir is reached between 5 and 10 years of age, the so-called "safe school age" of the old German authors. As adolescence is entered, the incidence of disease rises again, "adult-type" pulmonary tuberculosis with apical cavitation becomes the norm, and large pleural effusions with a straw-coloured exudate are frequently encountered.

16.3 Pathogenesis and Clinical Manifestations of Childhood Tuberculosis Following infection, the clinical manifestations of tuberculosis will develop in a certain pattern, which was described as the "time-table of tuberculosis" by the great Swedish paediatrician, Arvid Wallgren (1948). As a generalization it is usually stated that disease will occur in approximately 10% of individuals following infection and that the greatest risk for most manifestations of disease is in the 3-12 months following upon infection, although a lifetime risk of disease does remain. In some communities disease may follow infection in as many as 15% or 20% of individuals. The "timetable of tuberculosis" is summarized in Fig. 16.2. Within 3-8 weeks of infection, the majority of infected individuals will become tuberculin-positive

Time after primary infection

and experience an unobtrusive ,fever of onset' (Wallgren 1928). By 1 month later, the features of primary tuberculosis will start to be seen, and by the end of one year after infection, most cases of tuberculous meningitis, miliary tuberculosis and pleural effusion will have occurred. In contrast, although many cases of osteoarticular tuberculosis will develop within a year ofinfection, they will continue to occur for several years after infection. Interestingly' although haematuria will often be detected shortly after infection and M. tuberculosis can be cultured from the urine, renal tuberculosis will seldom be seen sooner than 5 years after infection (Munro 1944). Following upon infection, two events playa major role in determining the clinical manifestations of childhood tuberculosis. Firstly, before the establishment of cellular immunity to M. tuberculosis, lymphohaematogenous dissemination of organisms occurs and will distribute small numbers of organisms throughout the body, but particularly to sites with a good blood supply. In addition to reaching the bone ends, meninges and kidneys, bacilli also again reach the lungs and in the form of Simon foci may later give rise to adult tuberculosis. Should exceptionally large numbers of organisms be liberated into the blood by erosion into a blood vessel within a lymph node or following the establishment of tubercles within a blood vessel, a tuberculous septicaemia ensues, and small tubercles will develop throughout the body. In the lungs, these give rise to small, uniformly sized nodules the size of millet seeds on chest radiography, and hence the name miliary tuberculosis (Fig. 16.3). The second important factor in the pathogenesis of childhood tuberculosis is the role of the medias-

Clinical Manifestation Fever ofOnset

2 - 3 months Tuberculin Test Positive

Primary puhnonary TB TB Meningitis Miliary TB TB Pleural effusion

3 - 12 months

I

I

ttl

oS

is ~

isc.. 0

§'"

f I ()

0

.3.

~

~:

r;;'

6 - 24 months

II

Osteo-articular TB

> 5 years

II

RenalTB

Fig. 16.2. The timetable of tuberculosis

Fig.16.3. Massive haematogenous dissemination of bacilli leading to multiple small nodules less than 2 mm in diameter evenly distributed throughout the lungs

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tinal nodes which form part of the primary or Ghon complex in the lungs. Following inhalation of a small droplet 5-10 flm in diameter containing a very small number of M. tuberculosis organisms, a tuberculous focus becomes established in the lungs. From the primary or Ghon focus organisms spread via the lymph ducts to the regional lymph nodes. Most often, only the nodes, either hilar (Fig.16.4) or paratracheal (Fig. 16.5} or both, are seen on a chest radiograph. Occasionally, the primary focus is visible or more commonly it may become visible some 6-9 months later as calcification develops. In a majority of cases, there is only a single primary focus, but in approxi-

P. R. Donald

mately 20% of individuals two or more primary foci may be seen, as illustrated in Fig. 16.6. Enlargement of the hilar nodes with or without ulceration gives rise to a spectrum of pathological changes including segmental or lobar collapse or hyperinflation, collapse consolidation, and segmental or lobar expansile consolidation with or without cavitation. With complete obstruction, collapse of a lobe or segment will develop (Fig. 16.7}. With partial obstruction and a ball-valve effect, hyperinflation of a lobe or segment or a whole lung may develop (Fig. 16.8). Ulceration of a node and discharge of its contents into the relevant bronchus may lead to collapse consolidation or in the absence of obstruction to a lobar or segmental opacification or the appearance of an expansile pneumonia. The histology of these lesions may vary according to the immune response and the numbers of organisms present in the lesion (Seal and Thomas 1956). At one extreme, a benign ,tuberculin' response may be seen with a good prognosis and clearing within 2-3 months. At the other extreme, caseation with cavity formation may develop and lead to bronchiectasis and permanent lung damage (Fig. 16.9}. Should partial obstruction also be present, a grossly enlarged tension cyst may be formed. This course of events is summarized in Fig. 16.10. In the past, these usually well defined lesions were referred to as epituberculosis, segmental tuberculosis, or endobronchial tuberculosis. They are perhaps best grouped together

Fig. 16.4. Enlargement of the hilar nodes in a child 2 years of age with a Mantoux test giving an induration of 20 mm and the gastric aspirate positive on culture for M. tuberculosis

Fig. 16.5. Enlargement of the right paratracheal nodes in a 5year-old child. Sputum positive on culture for M. tuberculosis

Fig. 16.6. Right-sided paratracheal enlargement with calcification appearing in the nodes and in three right-sided primary foci in a 3-year-old child. Gastric aspirate positive on culture for M. tuberculosis

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Fig. 16.7. Collapse of the right middle lobe in a 2-year-old child who presented with persistent cough and wheeze. Gastric aspirate positive on culture for M. tuberculosis. A Mantoux test gave an induration of 18 mm

b

Fig. 16.8. Enlargement of the paratracheal nodes with hyperinflation of the right lung in a 2-year-old child with gastric aspirate positive on culture for M. tuberculosis

Fig. 16.9. Consolidation of the left upper lobe with several cavities enlarged by pressure inflation. A fine nodularity is also present in the right lung, which may indicate bronchogenic dissemination and a small left-sided pleural reaction. Gastric aspirate positive on culture for M. tuberculosis

as lymphobronchial tuberculosis, thus emphasizing the role of both lymph node enlargement and bronchial disease in determining the varied features of these lesions which, none the less, have a common origin. Any primary tuberculosis infection will be accompanied by a greater or lesser degree of lympho-hae-

matogenous dissemination of organisms throughout the body. These have a predilection for certain organ systems where they may establish themselves and give rise to disease if not controlled by the individual's immune response. The most important site where extrapulmonary disease may arise in childhood is the central nervous system.

P. R. Donald

248

Benign "Tuberculin Response"

Fig.16.10. Lymphobronchial tuberculosis: the spectrum of possible consequences of tuberculous involvement of the mediastinal nodes during primary tuberculosis

16.4

Central Nervous System Tuberculosis Tuberculous meningitis (TBM) is the most serious complication of childhood tuberculosis and has its highest incidence between the ages of 2 and 3 years. At this age it is often associated with miliary tuberculosis, and if untreated a majority of children with miliary tuberculosis will die of TBM. In both developed and developing countries the diagnosis of TBM is frequently delayed, with disastrous consequences for the patient as the prognosis is closely linked to the stage of the disease at the time of diagnosis. A classification of the stage of TBM developed by the British Medical Research Council in 1948 is still useful. Patients with early signs of meningeal irritation but no other focal signs are at stage I TBM. Patients diagnosed at this point should recover fully. When focal neurological signs appear or the patient is mentally confused, the disease is considered to be at stage II. Although the majority of patients presenting at stage II will survive, they are likely to do so with a physicalor intellectual deficit. By stage III, the patient is comatose, unable to localise pain, and may have a complete hemiplegia or rarely a quadriplegia. A third of these patients may die, and the great majority of survivors will have severe physical and mental handicaps (Medical Research Council 1948). Although TBM may occur at any time following primary infection, it occurs most often approximately 3 months after primary infection as result of the rupture of a parenchymal focus, or less often a

meningeal focus into the cerebrospinal fluid (CSF). This release of antigens into the CSF elicits a severe inflammatory response, which gives rise to a thick gelatinous exudate. This exudate envelops the base of the brain and the adjacent structures. This in turn leads to cranial nerve palsies, vasculitis, and raised intracranial pressure due to obstruction to the flow of CSF. The vasculitis affects the larger blood vessels such as the middle cerebral artery and the smaller blood vessels of the basal ganglia and will often lead to infarctions and irreversible brain damage. TBM usually has an insidious onset lasting a week or more marked by increasing lassitude, loss of appetite and irritability. Occasionally, a more acute onset may be seen resembling that of other forms of bacterial meningitis. Many children will experience a preceding loss of weight. Common presenting complaints include vomiting, cough, fever, apathy and headache; this last complaint being seen mainly in children older than 3 years. Because of the non-specific nature of these features, a high index of suspicion is necessary when these complaints persist. A tuberculin test, a chest radiograph or enquiry as to household contact with an adult with ,smear-positive' pulmonary tuberculosis may lead to the early diagnosis of TBM or to the prevention of TBM in some instances by the early prescription of antituberculosis treatment. In any case where doubt is present, a lumbar puncture should be done. The CSF in TBM will typically be clear with a mean cell count of approximately 100Xl06/L, predominantly lymphocytes, a mean protein of 1.5 giL, and a mean glucose of 1.8 mmollL. It is very important to note that this is a typical picture. In 5%-10% of cases, a cell count of >500x106 /L with a predominance of polymorphonuclear leucocytes may be found; CSF protein levels may be normal or between 0.45 giL and 0.8 giL in close to 20% of cases; the CSF glucose may be >2.2 mmollL in as many as 30%-40% of cases (Donald et al. 1991). There is thus ample room for mistakes to be made. In any case of doubt, it is better to initiate antituberculosis treatment and review the diagnostic evidence later. The diagnosis of TBM is confirmed by a culture of M. tuberculosis from the CSF. This is, however, positive in only a minority of cases. This is probably due to the relatively small amounts of CSF that are submitted for culture from children. Support for the diagnosis is provided by culture of M. tuberculosis from another source such as gastric aspirate or lymph node biopsy, a chest radiograph suggestive of tuberculosis, a positive Mantoux test, or a history of close contact with an adult with sputum "smear-positive" tuberculosis.

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A chest radiograph may show evidence of respira- raised CSF white cell count or protein concentration tory tuberculosis in up to 70% of children with in such cases would provide sound support for a deciTBM, while a Mantoux test should be positive in a sion to continue antituberculosis treatment. The management of TBM involves three aspects: majority of children. It must be emphasized, however, that a negative Mantoux test does not exclude TBM. the elimination of viable M. tuberculosis from the Approximately 50% of children with TBM will have lesions, the control of raised intracranial pressure a history of contact with an adult with pulmonary and the prevention of further brain damage related tuberculosis, and in many cases this will be a family to the presence of the basal exudate, and the associated hypersensitivity and vasculitis. member, often the mother or a grandparent. There are almost no controlled trials evaluating Cranial computed tomography or magnetic resonance imaging, if available, may also assist and show different regimens for treating TBM. Consequently, hydrocephalus associated with the basal enhance- a variety of recommendations can be found in the literature and various official documents. Standard ment and possibly cerebral infarctions (Fig. 16.11). Other diagnostic aids include CSF polymerase short course regimens given for 6 months and all chain reaction, the detection of tuberculostearic acid containing rifampicin for the full 6 months have been in the CSF, CSF adenosine deaminase concentrations, reported to be successful by several groups (Biddulph CSF lactate or lactate dehydrogenase concentrations, 1990; Jacobs et al. 1992). Our own preference is for a and the bromide partition test. None of these tests at 6-month regimen of isoniazid, rifampicin, pyrazinpresent has a totally satisfactory sensitivity or speci- amide and ethionamide, with isoniazid and rifampificity, and while they may be valuable in individual cin given in a dose of 20 mg/kg body weight. In our patients, the final decision as to whether to treat a region there is an overall incidence of isoniazid resispatient remains a clinical one assisted mainly by the tance of 10%. Approximately half of these isolates are resistant at isoniazid concentrations of Th2 switch and loss of CD4 cells in chronic infections: an immunoendocrinological hypothesis not exclusive to HIV, Immunol Today 14:568-569 Romanus V (1987) Bacillus Calmette-Guerin-immunized and unimmunized children in Sweden: a ten-year evaluation following the cessation of general Bacillus Calmette Guerin immunization of the newborn in 1975. Pediatr Infect Dis J 6:272-280 Rutherfoord GS, Hewlett RH (1994) Atlas of correlative surgical and neuropathology and imaging (Gresham GA, ed). Kluwer Academic, Dordrecht, pp 47-74 Schaaf HS, Nel ED (1992) Tuberculosis presenting as cholestatic jaundice in early infancy. J Pediatr Gastroenterol Nutr 15:437-439 Schaaf HS, Smith J, Donald PR, Stockland B (1989) Tuberculosis presenting in the neonatal period. Clin Pediatr 28: 474-475 SchaafHS, Donald PR, Scott F (1991) Maternal chest radiography as supporting evidence for the diagnosis of tuberculosis in childhood. J Trop Pediatr 37:223-225 Schaaf HS, Gie RP, Beyers N, Smuts, Donald PR (1993) Tuberculosis in infants less than 3 months of age. Arch Dis Child 69:371-374 Schaaf HS, Geldenhuys A, Gie RP, Cotton MF (1998) Culturepositive tuberculosis in human immunodeficiency virus type I-infected children. Pediatr Infect Dis J 17:599-604 Schaaf HS, Vermeulen HAS, Gie RP, Beyers N, Donald PR (1999) Evaluation of young children in household contact with adult multidrug-resistant pulmonary tuberculosis cases. Pediatr Infect Dis J 18:494-500 Schaaf HS, Gie RP, Beyers N, Sirgel FA, de Klerk, Donald PR. (2000a) Primary drug-resistant tuberculosis in children. Int J Tuberc Lung Dis 4:1149-1155 SchaafHS,Van Rie A, Gie RP et al (2000b) Transmission of multidrug-resistant tuberculosis. Pediatr Infect Dis J 19:695-699 Seifart HI, Parkin DP, Donald PR (1991) The stability of isoniazid, rifampicin and pyrazinamide suspensions used for the treatment of tuberculosis in children. Pediatr Infect Dis J 10:827-831 Shaw JB, Wynn-Williams N (1954) Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 69:724-732 Sirgel FA, Botha FJH, Parkin DP et al (1993) The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts - a new method of drug assessment. J Antimicrob Chemother 32: 867-875

264 Small PM, Schafer RW, Hopewell PC et al (1993) Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 328:1137-1144 Smith KC, Starke JR, Eisenach K, Ong LT, Denby M (1996) Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction. Pediatrics 97:155-160 Smith MHD (1967) Tuberculosis in adolescence. Characteristics, recognition, management. Clin Pediatr 6:9-15 Snider DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO (1985) Infection and disease among contacts of tuberculosis cases with drug-resistant and drug susceptible bacilli. Am Rev Respir Dis 132:125-132 Snider DE, Caras GJ, Koplan JP (1986) Preventive therapy with isoniazid. Cost effectiveness of different durations of therapy. J Am Med Assoc 255:1579-1583 Steiner P, Rao M, Mitchell M, Steiner M (1985) Primary drug resistant tuberculosis in children. Am J Dis Child 139:780-782 Tanzania Tuberculin Survey Collaboration (2001) Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983- I998. Int J Tuberc Lung Dis 5:103-112 Talbot EA, Perkins MD, Fagundes S et al (1997) Disseminated Bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis 24:1139-1146 Te Water Naude JM, Donald PR, Hussey GD et al (2000) Twice weekly vs.daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 19:405-410 Thomas P, Bornschlegel K, Singh TP et al (2000) Tuberculosis in human immunodeficiency virus-infected and human immunodeficiency virus-exposed children in New York City. Pediatr Infect Dis J 19:700-706 Tripathy SP,Menon NK, Mitchison DA et al (1969) Response to

P. R. Donald treatment with isoniazid plus PAS of tuberculosis patients with primary isoniazid resistance. Tubercle 50:257-268 Udani PM (1983) Tuberculosis on children in India. A major health hazard! Pediatr Clin India 18: 11-42 Vallejo JG, Ong LT, Starke JR (1994) Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 94: 1-7 Van Eden W, De Vries RR, Stanford JL et al (1983) HLA-DR3 associated genetic control of response to multiple skin tests with new tuberculins. J Immunogenet 10:107-114 Van Geuns HA, Meijer J, Styblo K (1975) Results of contact investigation in Rotterdam, 1967-1969. Bull Int Union Against Tuberc 50:107-121 Wallgren A (1928) Initial fever in tuberculosis. Am J Dis Child 36:1341-1345 Wallgren A (1938) Pulmonary tuberculosis. Relation of childhood infection to disease in adults. Lancet 1:417-420 Wallgren A (1948) The ,time-table' of tuberculosis. Tubercle 29:245-251 Weber HC, Beyers N, Gie RP, Schaaf HS, Fish T, Donald PR (2000) The clinical and radiological features of tuberculosis in adolescents. Ann Trop Paediatr 20:5-10 Weyer K, Groenewald P, Zwarenstein M, Lombard CJ (1995) Tuberculosis drug resistance in the Western Cape. South Afr Med J 85:499-504 Wilcox WD, Laufer S (1994) Tuberculosis in adolescents. Clin Pediatr 33:258-262 World Health Organization (1989) Provisional guidelines for the diagnosis and classification of the EPI target diseases for primary health care, surveillance and special studies. EPIIGEN/83/4 Zar HJ, Tannenbaum E, Appoles P, Roux P, Hanslo D, Hussey G (2000) Sputum induction for the diagnosis of pulmonary tuberculosis in infants and young children in an urban setting in South Africa. Arch Dis Child 82:305-308

17 Primary Tuberculosis in Adults M. MONIR MADKOUR

CONTENTS 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10 17.11 17.12

Epidemiology of Primary Tuberculosis in Adults 265 Pathogenesis of Primary Pulmonary Tuberculosis 266 Culture Yield of Bacilli from Primary Lesion and Primary Complex 267 Groups at Risk of Primary Tuberculosis 267 Clinical Features and Diagnosis of Primary Tuberculosis in Adults 268 Lung Infiltrates and Consolidation 268 Lymphadenopathy 269 Pleural Effusion 269 Miliary Tuberculosis 269 Microbiological Confirmation 269 Treatment and Possible Paradoxical Transient Worsening 270 Conclusion 270 References 270

Traditionally, primary tuberculosis is a disease of childhood (Beyers 1979). This remains true in poor, developing countries where tuberculosis is endemic, and infections commonly start during childhood (see Chap. 16). This tradition, however, has been modified in rich, developed and industrialized countries that adopted successful tuberculosis control programs starting in the nineteenth century. Developed industrialized countries at present harbor only 5% of the world burden of tuberculosis, and the population group most infected is over 65 years of age (Alexander et al. 1979) (see Chap. 3). In these developed countries, exposure to the infection occurs mostly in the elderly population, leading to primary pulmonary tuberculosis. During the current epidemic of HIV, co-infection of adults with primary tuberculosis has been increasingly reported, leading to its dissemination (Pitchenik and Rubinson 1985; Wasser et al. 1988). This shift towards the presentation of primary tuberculosis in the elderly and among HIV-infected patients appears M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

to be related to decreasing childhood exposure in the developed, industrialized countries (Khan et al. 1977; Miller and MacGregor 1978; Woodring et al. 1986; Choyke et al. 1983; Hulnick et al.I983). As a consequence of this shift of primary tuberculosis to the adult population, some authors from developed countries suggested that the term 'childhood tuberculosis' and 'adult tuberculosis' be abandoned (Berger and Granada 1974; Choyke et al.I983). We reviewed the medical records of 10 adult patients with primary tuberculosis who attended our hospital from 1990 through 2000. Their clinical features will be discussed in this chapter. The imaging features of these patients, including the follow-up radiograph findings during treatment and after its completion, are clearly described in our separate chapter specially devoted to the radiology of pulmonary tuberculosis. Imaging figures on primary pulmonary tuberculosis are numbers: 23.3,23.4,23.8,23.9,23.10,23.12,23.16, 23.17 and 23.18.

17.1 Epidemiology of Primary Tuberculosis in Adults Since the shift of patient care from long-term sanatorium management into general hospitals, the clinicians' awareness of primary tuberculosis has decreased. This is because tuberculous patients are no longer managed by clinicians with a special interest in the disease, along with the decline in the incidence of the disease in the populations of developed countries (Ellersten 1959; Khan et al. 1977; Varkey and Politis 1981; Choyke et al. 1983). The incidence of primary tuberculosis has been reported to range between 10% and 34% (Stead et al. 1968; Khan et al. 1977; Miller and MacGregor 1978; Woodring et al. 1986; Buckner et al. 1990; Miller et al. 1993; Miller 1994; McAdams et al. 1995). Most of the epidemiological data on primary tuberculosis in adults are reported from the USA and Europe.

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The criteria adopted to determine the incidence of adult primary tuberculosis in various reported series vary slightly among different authors. The criteria for diagnosis basically rested upon the conversion of PPD skin testing as well as imaging features (Chiba and Kurihara 1979; Choyke et al. 1983). Choyke and colleagues from Duke and Yale Universities reviewed 103 patients with adult-onset primary pulmonary tuberculosis seen over a period of 6 years. Their criteria included recent PPD skin test conversion with adenopathy or pleural effusion in a patient with no history of tuberculosis and previously normal chest radiographs. Black male predominance was noted in approximately 60%, and 73.8% was aged 40 years or more. These authors reported that the incidence of active primary tuberculosis in adult is approximately 10%-20%. Miller and Miller (1993) considered a recent conversion of the PPD skin test with isolated pleural effusion, lymphadenopathy, isolated middle and lower lobe infiltration, and most cases of miliary tuberculosis as diagnostic of primary tuberculosis. These authors estimated the incidence of primary tuberculosis in adults as ranging from 23% to 34%. In Norway, Heldal and colleagues (2000) reviewed the cases of Norwegian-born patients with pulmonary tuberculosis. They found that most cases in their series were due to endogenous reactivation of the disease. The incidence of adult primary pulmonary tuberculosis in these patients was reported to be 10% in 1975,19% in 1985, and 16% in 1995.

17.2 Pathogenesis of Primary Pulmonary Tuberculosis Primary pulmonary tuberculosis is transmitted by inhalation of air-borne Mycobacterium tuberculosis present in the cough particles from the sputum of a smear-positive patient. The inhaled bacilli usually deposit in the middle or lower lung field. The exact mechanisms of the protective immunity response against the development of the disease in humans have not been totally clarified (Ellner 1997). M. tuberculosis lipoproteins and glycolipids induce activation of macrophage, T-cell, and cytokine expression (Wallis and Johnson 2001). Alveolar macrophages phagocytose the bacilli, and activation of the cell-mediated immune response (CMI) plays an essential role in combating infection (Reddy and Hayworth 2002; Garcia et al. 2002). The bacilli may

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survive, especially within nonactivated monocytel macrophages that enter the alveoli from the bloodstream (Dannenberg 2001). Early in the primary infection (within a few hours), the bacilli are transported by macrophages to the hilar and/or paratracheal lymph nodes (Milburn 2001). Tissue-damaging delayed hypersensitivity (DTH) develops, and the bacilli-laden macrophages are killed. Key factors in this process include monocyte-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-oc as well as T-cell-derived IL-2 and interferon (IFN)-y. These cytokines playa crucial role in the induction of macrophage-mediated elimination of mycobacteria (Vanham et al. 1997; Garcia et al. 2002). During active pulmonary tuberculosis, signs of both immune depression and immune activation are concomitantly present (Vanham et al.1997). The balance of cytokines produced by lymphocytes in response to infection is believed to have a profound effect on the clinical outcome. Depression of peripheral blood T-cell and cytokine production has been demonstrated during active tuberculosis disease (Garcia et al. 2002). As the infection progresses, local areas of inflammation with granuloma formation and cellular infiltrates occur in the middle or lower zones of the lung. This is the pulmonary component of the primary Ghon focus and, in combination with hilar and/or paratracheallymphadenitis, forms the primary complex. Tuberculin conversion may occur 3-6 weeks after the initial infection (Milburn 2001). The outcome of the infection depends on the interaction between the host immune system response and the bacilli. In patients with strong and competent cellular immunity, the Ghon focus and regional lymphadenitis heal with fibrosis and calcifications within weeks or months. However, the primary complex lesion may progress into lung parenchymal or lymph node infection or both in what is known as progressive primary tuberculosis. Many tuberculosis specialists adopted the use of the term 'progressive primary tuberculosis' if it occurs within 3-8 months after tuberculin conversion. About 10% of all cases of primary tuberculosis progress to a chronic form indistinguishable from reactivation disease (Goppert and Left 1979). Within the first year of primary pulmonary infection, the incidence of clinically significant disease is approximately 1.5%, and the cumulative risk during the first 5 years is 5%-10% (Chiba and Kurihara 1979). Balasubramanian and colleagues (1994) from Wisconsin, USA, extensively reviewed the published work of other investigators which dealt with the pathogenesis of tuberculosis. Particular emphasis was laid on the infective dose, the yield of bacilli from the pri-

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mary lesion, predominant locations, and the argument regarding the endogenous versus exogenous pathway leading to post-primary tuberculosis. The following paragraphs include some personal abstracts as well as the investigators' views and schools of thought on the issues of the pathogenesis of primary pulmonary tuberculosis. The size of the infective dose has been debated among investigators in a review article. On the one hand, some investigators indicated that a large infectious dose occurred more frequently in household contacts of sputum-positive cases. The infective dose includes the number of bacilli per infectious particles inhaled during anyone period of exposure. Other investigators indicated that the infectious dose in tuberculosis was very small. The size of a droplet nucleus disseminated during a cough by a sputum-positive tuberculosis patient is 5.0 ~m in diameter. It is estimated that the number of bacilli in a droplet nucleus is 1-10. Accordingly, these observations suggest that the infectious dose in tuberculosis is very low. The location of the primary complex was noted by Medlar (1948) in his series of 105 individuals found during autopsies performed on 1225 bodies. The single primary complex was located within 1 cm of the pleural surface in 85%, and in the lower half of the lung field in 66%, while only 12% were supraclavicular; he ascribed this pattern of lung lesion distribution to the direction of the airflow. The primary focus is the initial lesion produced by tubercle bacilli in any tissue. The primary or Ghon complex includes both the primary focus and homologous lesions in the draining lymph nodes. The primary complex most commonly occurs in the lung, but may also develop in the skin, intestines, genital tract, and tonsils. A mucous membrane primary focus may not incite a typical tuberculous healing reaction, so that only fibrocalcific lymph nodes may remain as indicators of a primary infection in these tissues. Therefore, fibrocalcific lesions in the lung or lymph nodes of a patient with organ and miliary tuberculosis may be taken to represent evidence of a prior primary infection (Slavin et al. 1980).

17.3 Culture Yield of Bacilli from Primary Lesion and Primary Complex Canetti (1972) suggested 'that tubercle bacilli do not survive indefinitely in tuberculous foci'. Work on guinea-pigs with inoculations of the component

of the primary complex (before the era of chemotherapy) indicated that no live bacilli could be cultured in 85% of calcified lesions and in 50% in the encapsulated stage. This review explored as well the work and school of thought of other investigators on how a calcified primary focus can be a source of reactivation of the disease when live bacilli no longer exist. Theories of alternative locations created during the primary disease by the progeny of bacilli from the primary lesion which had been disseminated hematogenously have been postulated. Other aspects of pathogenesis including the postprimary tuberculosis and the specified pathways (endogenous versus exogenous) by which the disease may occur later in life have already been elaborated.

17.4 Groups at Risk of Primary Tuberculosis Adults and the elderly in developed countries with diseases that affect the integrity of their immune system will increase the chances for the development of primary tuberculosis infection (Alexander et al. 1979; Ikejoe et al. 1992). Young adults with preexisting HIV infection are particularly susceptible to co-infection with primary pulmonary tuberculosis. Patients on chemotherapy or steroids for cancer and other diseases are particularly vulnerable to the development of primary tuberculosis. Drug abusers, the homeless, and the elderly residing in nursing homes are susceptible to the development of adult primary pulmonary tuberculosis. Traveling to endemic areas or a long airplane flight has been reported as risk factors for the transmission of tuberculosis. Kenyon and colleagues (1996) from the USA reported the transmission of tuberculosis during a long flight (8.75 hours) from a 32-year-old Korean woman tourist to four passengers on the same flight in April 1994. The patient was traveling from Chicago to Honolulu, and she had been on antituberculous treatment for the past 2 years. She was coughing during the flight and had fever. Eventually, she became very sick and was admitted to hospital and died 1 week later with massive hemoptysis. The sputum smear was highly positive, and culture was positive for M. tuberculosis. The CDC was involved in the investigation that included notifications to the passengers of that flight. Careful and thorough epidemiological screening was conducted including all risk factors and previous PPD skin test history. Four patients who were known

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tuberculin skin test-negative had initial testing after exposure which was negative and had a final test repeated 12 weeks later that showed conversion to positive results. In the Netherlands, Cobelens et al. (2000) investigated Dutch long-term travelers to countries of high tuberculosis endemicity. PPD skin testing was done before traveling and 2-4 months after their return. The results of 656 individuals were reported: there were 12 with M. tuberculosis infection, and 2 had active disease (1.8%). The overall incidence rate was estimated as 3.5 per 1000 person-months of travel and 2.8 per 1000 person-months of travel after the exclusion of health-care workers. The inclusion criteria for this study were over 15 years of age, not yet received BCG vaccination, and intended to travel for 3-12 months to these highly endemic countries. Exclusion criteria were history of tuberculosis or positive skin test, diabetes mellitus, HIV, or history of immunosuppressive therapy.

17.5 Clinical Features and Diagnosis of Primary Tuberculosis in Adults Primary pulmonary tuberculosis in adults may present with constitutional symptoms as well as cough, fever, hemoptysis, or weight loss that are often misdiagnosed initially as bacterial pneumonia. It is only because of the atypical clinical features in association with the so-called 'unusual' radiographic findings (Segarra et al. 1963; Parmar 1967; Dodd et al. 1978; Palmer 1979; Hadlock et al. 1980; Stead 1981; Lee et al. 1993) or the adoption of 'routine' microbiological examination of the sputum by smear staining and culture for acid-fast bacilli that an accurate diagnosis can be achieved (Choyke et al. 1983). A high index of suspicion by the attending clinician is essential for an early diagnosis. Failure in considering tuberculosis as a possible cause in these patients will delay the initiation of appropriate chemotherapy. The disease may progress, and serious dissemination to other body organs or systems may occur. Guidelines and criteria were used by several authors to identify and classify patients as having adult primary pulmonary tuberculosis (Stead et al. 1968; Khan et al. 1977; Choyke et al. 1983). Khan and colleagues (1977) classified adult patients with tuberculosis in the lower lung field as having primary pulmonary tuberculosis if one or more of the following criteria were also present: (1) known recent tuberculin conversion, (2) tuberculous pleural effusions

M. M. Madkour

without roentgenographic evidence of post-primary disease, (3) hilar adenopathy with or without parenchymal infiltration. These authors found 12 patients with adult primary pulmonary tuberculosis in their large series of 88 adult patients with newly proven diagnosis of active pulmonary tuberculosis who fulfilled these criteria. They were seen over a 12-month period and attended two hospitals in Boston, USA. Ten patients were young adults (19-38 years old), and 2 were in their 60s. Choyke and colleagues (1983) from the USA adopted the same criteria and reported their own series of 103 adult patients with primary pulmonary tuberculosis with positive M. tuberculosis cultures from at least one source. In our own series of 10 adult patients with primary pulmonary tuberculosis, the criteria for the classification depended mainly on radiographic findings. Recent PPD skin test conversion or the status of a previous tuberculin test is unknown in many of our patients. Choyke and colleagues (1983) from the USA stated: 'The diagnosis of primary tuberculosis rests upon tuberculin skin test (PPD) conversion.' However, they reported that there was inadequate documentation of the PPD skin test in their own series. Symptoms lasting a few days or weeks at the time of presentation are commonly reported in 84% by Khan et al. (1977) and Choyke et al. (1983). These included constitutional symptoms, fever, cough, and hemoptysis. The initial diagnosis of tuberculosis on admission was only made in 10%, and 70% were initially diagnosed to have 'bacterial pneumonia', and diagnosis was delayed for up to 6 weeks as reported in Choyke's series of 103 patients.

17.6 Lung Infiltrates and Consolidation Plain radiographs of the chest may look normal, and lung infiltrates may only be depicted on CT. Segmental or lobar consolidation of the right middle or lower lobe is the most common pattern of distribution in primary tuberculosis in adults as we noted in 6 of our patients (60%) (Figs. 23.3,23.9,23.16, and 23.18). Consolidation in the upper lobe may also occur, but it is rare. Associated hilar or right paratracheal lymphadenopathy with consolidation was noted in these 6 patients as well. Cavitation (Dahl 1952) in primary tuberculous consolidation was noted in 1 of our patients (Fig. 23.4). In the series of 12 patients reported by Khan et al. (1977), consolidations in the lower and middle lobes

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Primary Tuberculosis in Adults

were noted in 6 patients (50%) and in the upper lobe, in 1 patient. In Choyke and colleagues' (1983) series of 103 patients, they reported consolidations in the lower and middle lobes in 77 patients (75%) and in the upper lobe in 36 patients (35%), bilateral in 13 (13%), cavitations in 8 (8%), and normal radiographs in 10 patients (10%). In Belgium, van den Brande and colleagues (1998) reported the incidence of adult pulmonary tuberculosis in a low prevalence area. They reviewed the chest radiographs of patients who had bacteriologically proven pulmonary tuberculosis over two periods (1981-1985 and 1986-1990). They found 114 and 105 patients, respectively. Approximately 50% of these patients were aged 65 years and over. Radiological features were classified as 'usual' or 'unusual' presentation.'Unusual' radiological features were defined as solitary pleural effusion, isolated hilar or mediastinal lymphadenopathies, normal chest xray, lower lung field tuberculosis, nodular lesions, diffuse infiltration, and atelectasis. The usual imaging features of pulmonary tuberculosis were present in 76% and 68%, respectively. Unusual imaging features of pulmonary tuberculosis were present in 24% and 35%, respectively. The authors noted the shift in the incidence of tuberculosis to elderly subjects who had never been infected before. They also noted that their 'unusual' imaging features resemble those observed in childhood primary pulmonary tuberculosis. They concluded that there is a recent trend towards a more 'unusual' presentation of primary pulmonary tuberculosis in the elderly.

17.7 Lymphadenopathy Unilateral or bilateral hilar lymphadenopathy and/or right paratracheal lymph node enlargement are the hallmarks of primary tuberculosis. They were noted in 9 patients with adult primary pulmonary tuberculosis (90%) in our own series, and their imaging features are illustrated in our chapter on radiography of pulmonary tuberculosis (Figs. 23.3, 23.4, 23.6, 23.7, 23.8,23.9,23.12,23.16, and 23.18). Hilar and/or paratracheal tuberculous lymphadenopathy in primary tuberculosis is more commonly reported in children than adults (McAdams et al. 1995; Woodring et al. 1986; Leung et al. 1992). Caseation and necrosis of tuberculous hilar or paratracheal lymph nodes may occur (Fig.23.8). Enlarged lymph nodes may obstruct the airway and may lead to atelectasis. It may invade the surrounding structures, particularly

the esophagus, phrenic nerve, recurrent laryngeal nerve, superior vena cava, or pericardium (Figs. 23.10 and 23.11). Other authors reported the incidence of tuberculous hilar lymphadenopathy as 15%-50% in their series (Khan et al. 1977; Choyke et al. 1983).

17.8 Pleural Effusion Pleural effusion in primary tuberculosis in an adult may occur in 29%-70% of patients (Roper and Waring 1955; Stead et al. 1968; Miller and MacGregor 1978; Khan et al. 1977; Choyke et al. 1983; Epstein et al. 1987). It is often unilateral, but bilateral effusion may rarely occur (Fig. 23.12). Associated parenchymal lesions and hilar lymphadenopathy may be present but not depicted on plain radiographs. Computed tomography is more sensitive in depicting such an association. Pleural effusion due to primary tuberculosis in adults was noted in one patient from our series (Fig. 23.12).

17.9 Miliary Tuberculosis Miliary tuberculosis may occur in both primary and reactivation tuberculosis (Munt 1972; Gelb et al.1973; Sahn and Neff 1974; Grieco and Chmel 1974). It is increasingly reported in immunosuppressed adults, particularly with HIV co-infection, in up to 13% (Choyke et al. 1983; Lee and 1m 1995). The plain radiograph may initially look normal, and CT is more sensitive in depicting the miliary lung shadowing.

17.10 Microbiological Confirmation Microbiological confirmation of the diagnosis in adult primary pulmonary tuberculosis may be difficult. The sputum smear and culture with positive yield were reported in as many as 60%-70% (Khan et al. 1977; Choyke et al. 1983). Bronchoscopy to obtain samples was performed in 34 patients, and in 27, the cultures were positive as reported by Choyke et al. (1983). Pleural fluid and biopsies were positive with yield of the bacilli in 10 out of 26 cases reported by the

270

same authors. Other sources reported about pathological specimens obtained by open lung biopsies and thoracotomy in difficult-to-diagnose cases.

17.11

Treatment and Possible Paradoxical Transient Worsening The treatment of primary tuberculosis in adults does not differ from the treatment of reactivation disease. Directly observed therapy (DOT) is the most appropriate therapeutic regimen for primary pulmonary tuberculosis in adults. It is usually given on an outpatient basis for 6 months. In the initia12-month phase, four drugs are used (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by a 4-month continuation phase of rifampicin and isoniazid. Treatment is usually given daily but can be given thrice weekly (see Chap. 44). During the initial 3 months of chemotherapy, paradoxical transient worsening of the original radiographic findings or development of new lesions may occur, as reported by many authors (Weber et al. 1968; Matthay et al. 1974; Campbell and Dyson 1977; Amodio et al. 1986; Lamont et al. 1986; Akira et al. 2000). The mechanisms and pathogenesis of this paradoxical response remain unclear. Enhanced immune responses to a sudden destruction and release of tubercular antigens or even a drug reaction has been postulated by several authors (Onwubalili et al. 1986; Marshall and Chambers 1988; Akira et al. 2000). Paradoxical transient worsening should be differentiated from true worsening of tuberculous lesions due to co-infection with HIY, other bacteria, or fungi. In our series, worsening of the original parenchymal shadowing as well as the development of new ipsilateral or contralateral consolidations were noted in two patients (Fig. 23.16 and 23.17). Radiological evaluation should be done at 2-3 months after initiation of chemotherapy (Bass et al. 1986).

17.12

Conclusion Primary pulmonary tuberculosis in adults is rarely reported in endemic developing countries, where it is mostly reported in children. The recent PPD skin test conversions, considered as important criteria for the diagnosis in developed countries, are difficult to

M. M. Madkour

document in most patients in endemic, resourcepoor countries. In developed, industrialized countries where the tuberculosis control program has been applied for many years, with a low incidence of the disease in the population, primary pulmonary tuberculosis has shifted to adults and the elderly population. The criteria for classification of primary pulmonary tuberculosis in adults, particularly, the recent PPD skin test conversions, can be applicable. The clinical and imaging features of adult primary pulmonary tuberculosis are no longer considered as 'usual' because of the shift of the disease to adults in developed countries. The clinical, imaging, and other investigations to confirm the diagnosis are discussed. Our own experiences with 10 patients with adult primary pulmonary tuberculosis have been discussed, and the imaging features of these patients can be seen in our separate chapter, Imaging of Pulmonary Tuberculosis, Figs. 23.3, 23.4, 23.8, 23.9, 23.10, 23.12, 23.16,23.17, and 23.18. Paradoxical transient worsening of radiology features during the early phase of chemotherapy is also documented.

References Akira M, Sakatani M, Ishikawa H (2000) Transient radiographic progression during initial treatment of pulmonary tuberculosis: CT findings. J Comput Assist Tomogr 24:426-43 I Alexander WJ, Avent CK et al (1979) Simple primary tuberculosis in an elderly woman. J Am Geriatr Soc 27:123-125 Amodio J, Abramson S, Berdon W (1986) Primary pulmonary tuberculosis in infancy: a resurgent disease in urban United States. Paediatr RadioI16:185-189 Balasubramanian V et al (1994) Pathogenesis of tuberculosis: pathway to apical localization. Tuberc Lung Dis 75: 168-178 Bass JB, Farer LS, Hopewell PC et al (1986) Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 134:355-363 Berger HW, Granada MG (1974) Lower lung field tuberculosis. Chest 65:522-526 Beyers JA (1979) The radiological features of primary pulmonary tuberculosis. S Afr Med J 55:994-997 Buckner CB, Walker CW et al (1990) Radiologic manifestations of adult tuberculosis. J Thorac Imaging 5:28-37 Campbell lA, Dyson AJ (1977) Lymphnode tuberculosis: a comparison of various methods of treatment. Tuberculosis 58:171-179 Canetti G (1972) Endogenous reactivation and exogenous reinfection. Their relative importance with regard to the development of non-primary tuberculosis. Bull Int Union Tuberc 47:116-122 Chiba Y, Kurihara T (1979) Development of pulmonary tuberculosis with special reference to the time interval after tuberculin conversion. Bull Int Union Tuberc 54:263-264

Primary Tuberculosis in Adults Choyke PL,Sostman HD et al (1983) Adult onset of pulmonary tuberculosis. Radiology 148:357-362 Cobelens FGJ, Deutekom HV et al (2000) Risk of infection with Mycobacterium tuberculosis in travelers to areas of high tuberculosis endemicity. Lancet 356:461-465 Dahl RV (1952) The first appearance of a pulmonary cavity after primary infection with relation to time and age. Acta Tuberc Scand 27:140 Dannenberg Am Jr (2001) Pathogenesis of pulmonary Mycobacterium bovis infection: basic principles established by the rabbit model. Tuberculosis 81:87-96 Dodd GD, Capitanio MA et al (1978) Case 11 (primary tuberculosis). In: Film interpretation session. Radiological Society of North America, 64th scientific assembly and annual meeting, Nov 1978. Summary of discussion and diagnoses. Radiology 129:831 Ellertsen E (1959) Epidemics of primary tuberculosis and their significance. Acta Tuberc Scand 37:203 Ellner JJ (1997) Regulation of the human immune response during tuberculosis. J Lab Clin Med 130:469-475 Epstein DM, Kline LR et al (1987) Tuberculous pleural effusions. Chest 91: 106 Garcia M, Vargas A, Castej6n R et al (2002) Flow-cytometric assessment of lymphocyte cytokine production in tuberculosis. Tuberculosis 82:37-41 Gelb AF, Lefler C et al (1973) Miliary tuberculosis. Am Rev Respir Dis 108:1327 Goppert EF, Left A (1979) The pathogenesis of pulmonary and military tuberculosis. Arch Intern Med 139: 1381-1383 Grieco MH, Chmel H (1974) Acute disseminated tuberculosis as a diagnostic problem. Am Rev Respir Dis 109:554 Hadlock FP, Park SK et al (1980) Unusual radiographic findings in adult pulmonary tuberculosis. AJR 134:1015-1018 Heldal E et al (2000) Pulmonary tuberculosis in Norwegian patients. The role of reactivation, re-infection and primary infection is assessed by previous mass screening data and restriction fragment length polymprphism analysis. Int J Tuberc Lung Dis 4:300-307 Hulnick DH, Naidich DP, McCauley Dr (1983) Pleural tuberculosis evaluated by computed tomography. Radiology 149: 759-765 Ikejoe J, Kakeuchi N et al (1992) CT appearance of pulmonary tuberculosis in diabetic and immunocompromised patients: comparison with patients who had no underlying disease. AJR 159:1175-1179 Kenyon TA, Valway SE et al (1996) Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 334:933-938 Khan MA, Kovnat DM et al (1977) Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 62:31-38 Lamont AC, Cremin BJ, Pelleret RM (1986) Radiological patterns of pulmonary tuberculosis in paediatric age group. Pediatr RadioI16:2-7 Lee KS, 1m JG (1995) CT in adults with tuberculosis of the chest: characteristic findings and role in management AJR 164:1361-1367 Lee KS, Song KS et al (1993) Adult-onset pulmonary tuberculosis: findings on chest radiographs and CT scans. AJR 160:753-758 Leung AN, Muller NL, Pineda PR et al (1992) Primary tuberculosis in childhood. Radiographic manifestations. Radiology 182:87-91

271 Marshall BG, Chambers MA (1988) Central nervous system tuberculosis: the paradox of host immune response. J Infect 36:3-4 Matthay RA, Neff TA, Iseman MD (1974) Tuberculous pleural effusion developing during chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 109:469-472 McAdams HP, Erasmus J, Winter JA (1995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 Medlar EM (1948) The pathogenesis of minimal pulmonary tuberculosis: a study of 1225 necropsies in cases of sudden and unexpected death. Am Rev Tuberc 58:583-611 Milburn HJ (2001) Primary tuberculosis. Curr Opin Pul Med 7:133-141 Miller WT (1994) Tuberculosis in the 1990s. Radiol Clin North Am 32:649-661 Miller WT, MacGregor RR (1978) Tuberculosis: the frequency of unusual radiographic findings. AJR Am J Roentgenol 130:867-875 Miller WT, Miller WT Jr (1993) Tuberculosis in the normal host: Radiological findings. Semin RoentgenoI28:109-118 Munt RW (1972) Miliary tuberculosis in the chemotherapy era: with a clinical review in 69 American adults. Medicine (Baltimore) 51:139 Onwubalili JK, Scott GM, Smith H (1986) Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis. A study of two cases and review of the literature. OJ Med 59:599-610 Palmer PES (1979) Pulmonary tuberculosis - usual and unusual radiographic presentations. Semin RoentgenoI14:204-243 Parmar MS (1967) Lower lung field tuberculosis. Am Rev Respir Dis 96:310 Pitchenik AE, Rubinson HA (1985) The radiographic appearance of tuberculosis in patients with the acquired immunodeficiency syndrome (AIDS) and pre-AIDS. Am Rev Respir Dis 131:393-396 Reddy VM, Hayworth DA (2002) Interaction of Mycobacterium tuberculosis with human respiratory epithelial cells (Hep-2). Tuberculosis 82:31-36 Roper WH, Waring JJ (1955) Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 71:616 Sahn S, Neff TA (1974) Miliary tuberculosis. Am J Med 56:495 Segarra F, Sherman DS et al (1963) Lower lung field tuberculosis. Am Rev Respir Dis 87:37-40 Slavin RE, Walsh TJ et al (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59: 352-366 Stead WW, Kerby GR et al (1968) The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 68:731-745 Stead WW (1981) Tuberculosis among elderly persons: an outbreak in a nursing horne. Ann Intern Med 94:606 Van den Brande PV, Dockx S et al (1998) Pulmonary tuberculosis in the adult in a low prevalence area: is the radiological presentation changing? Int J Tuberc Lung Dis 2:904-908 Vanham G, Toossi Z, Hirsch CS et al (1997) Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. Tuberc Lung Dis 78:145-158 Varkey B, Politis J (1981) Pulmonary tuberculosis. A multifaceted disease. Postgrad Med 69:117-121, 124-126, 129

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Wallis RS, Johnson JL (2001) Adult tuberculosis in the 21st century: pathogenesis, clinical features and management. CUff Opin Pul Med 7:124-132 Wasser LS et al (1988) Endobronchial tuberculosis in the acquired immunodeficiency syndrome. Chest 94:1240-1244

M. M. Madkour Weber AL, Bird KT, Janower ML (1968). Primary tuberculosis in children with particular emphasis on changes affecting the tracheobronchial tree: AJR 103:123-132 Woodring JH, Vandiviere H et al (1986) The radiographic features of pulmonary tuberculosis. AJR 146:497-506

18 Miliary/Disseminated Tuberculosis M. MONIR MADKOUR

mary tuberculosis, immediately after the post-primary period, or at a time far remote from the post-primary 18.1 Introduction 273 period as late generalized tuberculosis (LGT) (Slavin 18.2 Epidemiology of MiliarylDisseminated et al. 1980). A wide spectrum of pathological features Tuberculosis 274 occurs as a result of hematogenous dissemination of 18.3 Pathology and Pathogenesis the bacilli. This spectrum of pathology is determined of Miliary/Disseminated Tuberculosis 275 18.4 Clinical Features of Miliary/Disseminated by the size of the bacillary inoculum load, the viruTuberculosis 277 lence of the bacilli, and the status of the host immune 18.5 Meningitis and Tuberculomas response. It ranges from a rare but acute fulminating in Miliary/Disseminated Tuberculosis 277 form due to the release of massive myriads of caseous 18.5.1 Case Illustration 1 279 18.5.2 Case Illustration 2 283 and necrotic tubercles into the blood with a nonreac18.5.3 Case Illustration 3 288 tive and an anergic response, very low count of CD4+ 18.5.4 Case Illustration 4 290 T-cells with scanty or absent granuloma formation; 18.5.5 Case Illustration 5 292 that form of the disease is only diagnosed at autopsy. 18.6 Adult Respiratory Distress Syndrome If, on the other hand, tuberculous bacteremia is slight and Disseminated Intravascular Coagulation in Miliary Tuberculosis 292 with the formation of few tubercles, this discrete type of 18.7 Pneumothorax in Miliary/Disseminated generalized dissemination is usually without immediTuberculosis 293 ate clinical significance, although these tubercles serve 18.8 Diagnosis of MiliarylDisseminated as 'seed beds' for the later development of organ tuberTuberculosis 293 culosis or LGT (Slavin et al. 1980). Between these two 18.9 High Resolution CT 296 18.10 Laboratory Diagnosis of Miliary pathological and clinical extremes lies a spectrum of Tuberculosis 296 pathology that varies in severity. The more common 18.10.1 Polymerase Chain Reaction 297 classic miliary tuberculosis resembles the fulminating 18.11 Treatment of MiliarylDisseminated form (Prout et al. 1980). Miliary tuberculosis is defined Tuberculosis 297 as a hematogenous dissemination of the bacilli resultReferences 298 ing in widespread, active, visceral, caseous tubercle formations measuring 1-3 mm in diameter (the size of millet seeds) with radiologic or pathologic evidence of pulmonary micronodules (Sahn and Neff 1974; Slavin et al. 1980; Penner et al. 1995). Disseminated tubercu18.1 losis is defined as a hematogenous transmission of the Introduction bacilli with active caseous tubercle formation in two Miliary/disseminated tuberculosis signifies the wide- or more extrapulmonary sites and with no pulmonary spread occurrence of caseating visceral tuberculosis miliary nodular shadowing on chest radiography that occurs by hematogenous dissemination of the (Penner et al. 1995; Sahn and Neff 1974). Proudfoot bacilli from an active caseous focus or foci located in the et al. (1969) described the fulminating dissemination lung or extrapulmonary sites. Hematogenous dissemi- form of tuberculosis in patients with other co-existing nation of the bacilli may occur during the course of pri- underlying disease that may lead to a clinical presentation with atypical features due to an impaired cellmediated immune response and the absence of miliary lung shadowing as 'cryptic disseminated tuberculosis', M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces which is usually diagnosed at autopsy. Disseminated tuberculosis is a diagnostic challenge even in endemic Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

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M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

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areas when the attending clinician has a high index of suspicion. Chest radiography is usually the initial diagnostic investigation for miliary tuberculosis. The sensitivity of chest radiography was found to range from 59% to 69% in a study based on population and group control subject (Kwong et al. 1996). ARDS may occur as a complication of miliary tuberculosis, and chest radiography may be difficult to interpret since the miliary nodules are superimposed on a more diffuse ground (Armstrong et al. 1995). Fatal consequences if undiagnosed and untreated at an early stage may affect 21 %-64% of patients with disseminated tuberculosis (Monie et al. 1983; Al-Jahdali et al. 2000; Prout et al. 1980; Bobrowitz 1982). Miliary/disseminated tuberculosis has increased in incidence in the USA, particularly among HIV co-infected patients (Rieder et al. 1991; Hill 1991; FitzGerald et al. 1991; Korzeniewska-Kosela et al. 1992). Iatrogenic miliary/disseminated tuberculosis due to Mycobacterium bovis, induced by intravesical BCG immunotherapy for the treatment of urinary bladder cancer, has been increasingly reported (Foster 1997; McParland et al. 1992; Palayew et al. 1993).

18.2 Epidemiology of Miliary/Disseminated Tuberculosis The incidence of miliary/disseminated tuberculosis is difficult to determine in either developing or developed countries (Vijayan 2000). Many patients were undiagnosed in life, and it is only at autopsy that the disease may be found (JuuI1977; Bobrowitz 1982; Slavin et al. 1980; Prout et al. 1980). In the USA, Slavin et al. (1980) from Johns Hopkins reviewed the records of 120 autopsies performed between May 1937 and December 1959. They excluded 20 cases due to missed records. The remaining 100 autopsies had microbiologically proven TB, histopathological features, and evidence of hematogenous spread involving the spleen, liver, lung, bone marrow, kidney, adrenal glands, and other organs. The total number of autopsies performed during these 22 years was 14,224, and LGT was found in 120 (0.8%). Sixty of the 100 patients lived in the pre-antibiotic era (mid-1948) and 40 in the antibiotic period. Male predominance was noted in 61 (61 %), of whom 44% were black. There were 39 women, 28% of whom were black. The total number of black patients was 72 and white patients, 28. The authors estimated that 1 case of LGT was found in every 142 autopsies.

M. M. Madkour

In Canada, Long et al. (1997) reviewed the records of 2013 patients with active tuberculosis between January 1, 1979, and December 31,1993, to determine the clinical-pathologic-radiologic correlation in disseminated tuberculosis with and without a miliary pattern on radiography. All patients came from Manitoba, with a low seroprevalence of HIV in that area. They adopted a rigorously defined; radiographic or histopathologic evidence of hematogenous dissemination and found 56 patients (3%) (42 miliary and 14 nonmiliary). Women were 2.4 times more likely to be affected than men in this series. The mean age for both sexes was 50±26 years. Fourteen patients died, of whom 5 (12%) had miliary and 9 (64%) had nonmiliary disseminated tuberculosis. In Glasgow, Scotland, Monie et al. (1983) reviewed the records of 1000 patients with tuberculosis reported during a 3-year period (1976-1978) and found 28 (2.8%) patients with miliary tuberculosis. Seventeen (61%) had miliary shadowing, 7 (25%) had other radiological changes consistent with active or previous pulmonary tuberculosis, and 4 (14%) had no radiological changes suggesting pulmonary tuberculosis. About 50% of patients were over 60 years of age, and 23% were non-European in origin. These authors reported fatalities in 9 (32%) of the 28 patients with miliary tuberculosis. Ormerod and Horsfield (1995) from Blackburn, UK, reviewed notified cases of tuberculosis in the Blackburn, Hyndburn and Ribble Valley District Health Authority (DHA), an area of high prevalence for tuberculosis. They found 39 cases of miliary tuberculosis over 16 years (1978-1993 inclusive). Fourteen patients had miliary TB, and 25 had cryptic miliary TB. The authors noted ethnic differences with regard to the number of cases and the age at onset. The mean age among Caucasian patients was 51.3 years, while among Indian subcontinent (ISC) patients, it was 37 years. The incidence of miliary tuberculosis in Blackburn was approximately 0.25/100,000 in the Caucasian ethnic group and 7.99/100,000 in the ISC ethnic group. These authors reported the death rate due to miliary tuberculosis as 10%. In Denmark, Juul (1977) reported on clinically undiagnosed, active tuberculosis in 895 autopsies. They found active tuberculosis undiagnosed in life in 86 (0.1 %) patients. Miliary tuberculosis found in 38 (44.2%). The mean age of these patients was 70.7 years, with a female predominance. In NewYork,Bobrowitz (1982) reported 21 patients in whom tuberculosis was not diagnosed in life. At autopsy, 10 had suffered miliary tuberculosis and 11, pulmonary tuberculosis. Fifteen were male and

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6 female, and 13 were white, 6 black, and 2 Hispanic. Over 70% of the patients were more than 60 years of age. The main diagnosis of the 10 patients with miliary tuberculosis on admission was pneumonia, malignancy, or sepsis. The authors explained the failure to discover tuberculosis in these patients as due to combinations of other diseases and conditions. The incidence of miliary tuberculosis in developing countries is more difficult to determine (Prout et al. 1980). Lack of notification of miliary tuberculosis is due to failure to make the diagnosis while alive in countries like South Africa, which has a high incidence of tuberculosis (Prout et al. 1980). These authors reviewed the computerized records of medical diagnoses over a 6year period and found 64 cases of miliary or disseminated tuberculosis. Thirty-seven cases fulfilled the inclusion criteria: miliary lung shadowing, detection of the bacilli by stain or culture, caseating granulomas from liver or bone marrow biopsies, and involvement of two or more organs. These authors also reviewed the autopsies of 2,200 patients who died between 1973 and 1978 and found a further 34 cases (of them 9 fell into both groups and were excluded). A total number of 62 cases (live and autopsies) was reviewed. Eight (12.9%) were white, 20 (32.3%) colored, and 34 (54.8%) black. Thirty-six (58.1%) were male and 26 (41.9%) female. Over 72% of men and 42% of women were over 40 years of age. Alcoholism, malnutrition, diabetes, cytotoxicity or radiotherapy for malignancies were concomitantly present in 25 patients (40.3%). Forty patients (64%) died, and 31 deaths were directly attributed to disseminated tuberculosis. In Saudi Arabia, AI-Jahdali et al. (2000) reported 780 cases of tuberculosis seen over a period of 7 years. Miliary tuberculosis was found in 47 (6%) patients, and 68% were over 60 years of age. A male predominance was noted (n=30), and the mean age was 61 years for both sexes. Risk factors such as diabetes, prior tuberculosis, chronic liver disease, renal failure, immunosuppressive drugs, and malignancies were present in over 50% of these patients. Ten patients died (21 %), all were due to miliary tuberculosis. In our own hospital in Riyadh, computerized records of medical diagnoses for patients admitted during the period from 1983-2000 inclusive (using ICD-9 code description) revealed a total number of 2,484 tuberculosis patients, with miliary tuberculosis reported in 79 patients (3.18%). Since the HIV epidemic in 1980s, the incidence of miliary/disseminated tuberculosis in HIV co-infected patients in the USA has increased. The incidence of miliary/disseminated tuberculosis has therefore increased from 1.3% of all reported cases of tuber-

culosis to 8%-10% among HIV co-infected patients (Rieder et al. 1991; Hill 1991; Schaefer et alI991).

18.3 Pathology and Pathogenesis of Miliary/Disseminated Tuberculosis Acute miliary/cryptic disseminated tuberculosis is part of a broad spectrum of hematogenous spread of Mycobacterium tuberculosis with various and variable degrees of clinical manifestation and severity. It is most commonly encountered in children and young adults in developing countries. It may occur during primary disease or within 6-8 months of primary disease (progressive primary). In endemic areas, hematogenous spread may occur in neonates, infants, and children or in immunocompromised patients, leading to primary miliary or disseminated tuberculosis. In developed countries, adults particularly those co-infected with HIV may develop primary miliary/disseminated tuberculosis via hematogenous transmission of the infection. Miliary/disseminated tuberculosis may occur in post-primary disease, either due to endogenous reactivation or exogenous re-infection (Auerbach 1944,1959). Hematogenous spread of the bacilli from a focus or foci located in the lung or extrapulmonary sites is the source of infection. Transmission of the organisms via the lymphatics to the blood circulation or direct invasion of the blood vessels by liquefied caseous material may occur due to a rupture or erosion of a contiguous focus or foci (Geppert and Leff 1979; Yu et al. 1986; Murray et al. 1978; Prout et al. 1980). Slavin et al. (1980) used the term late generalized tuberculosis (LGT) to describe generalized hematogenous spread occurring at a time far remote from the post-primary period. If tuberculous bacteremia is slight, a discrete type of generalization is usually without immediate clinical significance, although these 'seed beds' may serve later in the development of organ tuberculosis and LGT. However, if the generalization of the tuberculous bacteremia is massive, necrotizing tubercles are formed in various organs, and this is known as acute miliary tuberculosis. In postprimary disease, it is often believed that a single focus at the pulmonary or extrapulmonary site is considered the source of hematogenous spread of the bacilli. Clinical and pathological studies reported by several authors indicated that more than one focus located at different unrelated anatomical sites in various body organs may be reactivated simultaneously, discharg-

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ing an enormous quantity of mycobacterial inoculum into the bloodstream. Slavin et al. (1980) stated that 'Late Generalized Tuberculosis (LGT) derived from a single extrapulmonary focus was very infrequent (7%); whereas in more than half of the cases, the origin of dissemination appears to have been derived from large foci present in a variety of organs'. This may occur intermittently, episodically, or continuously in 54% of cases (Pagel et al. 1964; Saye 1936; Slavin et al. 1980; Jacques and Sloan 1970). Evidence of intermittent or episodic hematogenous spread of infection was noted at autopsy. Soft exudative tuberculous lesions were mixed with other lesions showing partial or complete healing with fibrosis, calcifications, and ossifications (Slavin et al. 1980; Saye 1936; Jacques and Sloan 1970). It has been debated by some authors whether the lung is the main source of focal active caseous spread via the hematogenous route to other body organs; they believe that an extrapulmonary focus or foci are the most common source of hematogenous spread of infection. Slavin et al. (1980) reported that 'in the antibiotic era, chronic pulmonary tuberculosis and late generalized tuberculosis (LGT) coexisted far less commonly than they did prior to the advent of chemotherapy'. They reviewed the clinical and autopsy findings of 100 patients with LGT in two eras (pre-antibiotic and antibiotic periods) and concluded,'thus, both clinical and autopsy findings in the antibiotic period support Biehl's statement - that only a minority of cases of miliary tuberculosis arise from patients with pulmonary tuberculosis'. Hematogenous release of large quantities of necrotic caseous material of uniform size spread via the blood will cause embolization of the capillaries of most organs, particularly those with the richest vascular supply such as the liver, spleen, bone marrow, brain, and lungs. It is generally fatal if undetected and not treated early. At the other end of the spectrum of the hematogenous bacteremia, few bacilli may be discretely seeded into these body organs without immediate clinical manifestation. At a later stage, these hematogenous 'seed beds' may be reactivated in an organ or in all organs, with the development of miliary tuberculosis. They may also remain nonprogressive and well localized and cause few or no clinical symptoms. The course of the disease may take the form of 'chronic miliary tuberculosis', which is slowly progressive and not fatal (Pagel et al. 1964; Saye 1936). Fatal cases due to late generalized miliary tuberculosis do occur, but some clinicians consider these as representative of the terminal event of long-standing pulmonary or extrapulmonary disease (Yu et al.1986; Slavin et al. 1980). Factors determining the pattern of

M. M. Madkour

the disease presentation will depend on the size of the bacilli inoculum, its virulence, and the host immune response. In its severe acute fulminating form, septicemia may occur with extensive tissue damage and necrosis with very little evidence of a cell-mediated immune response. The diagnosis of this form is mostly missed in life because of the absence of the typical miliary lung shadowing seen on chest radiography, and the diagnosis is only made at autopsy (Chapman and Whorton 1946; Biehl 1958; Treip and Meyers 1959; Proudfoot et al.1969; Munt 1972; Prout et al.1980). Proudfoot et al. (1969) described this form of the disease as 'cryptic disseminated tuberculosis', Patients with cryptic disseminated tuberculosis may have a co-existing underlying disease that may present with atypical features and also cause impairment of the cell-mediated immunity such as alcoholism, cirrhosis, malnutrition, diabetes mellitus, connective tissue diseases, HIV, or may be taking immunosuppressive chemotherapy, and the diagnosis is then missed in life, with an absence of miliary lung shadowing, and is usually made at autopsy (Millar and Horn 1979; Bobrowitz 1982; Yu et al. 1986; Crump 1998). Patients in the late stage of AIDS with disseminated tuberculosis have a very low count of CD4+ T-cells and an anergic response with scanty or absent granuloma formation as reported by Zumla and Grange (see Chap. 29). In immunocompetent patients, the cell-mediated immune response (CM!) and tissue-damaging delayed hypersensitivity (DTH) responses will be activated. The bacilli cell wall antigens will activate the macrophages, CD4+ T cell, increased production of cytokines, TNF-a, IFN -y, IL-12 to combat the infection. The bacilli may survive, and during these responses concomitant immune depression and immune activation occur at the same time (Dannenbergh 2001; Vanham et al. 1997; Ellner 1997). The infection may overcome the immune system responses, and the disease progresses. At sites of the capillary bed seeded with bacilli, granuloma formation with central caseation and necrosis may occur simultaneously in all affected body organs. Adult respiratory distress syndrome (ARDS) is known as a complication of miliary/disseminated tuberculosis; it requires mechanical ventilation and has a high mortality rate ranging from 40% to 60% (Mohan et al. 1996; Dyer and Potgieter 1984; Murray et al. 1978; Dyer et al. 1985; Dee et al. 1980). The exact pathogenetic mechanisms by which miliary tuberculosis causes ARDS is not clearly understood. Penner et aI. (1995) suggested that the immunological aspects and pathogenesis of ARDS caused by miliary tuberculosis are similar to those caused by Gram-negative sepsis. In

MiliarylDisseminated Tuberculosis

277

miliary tuberculosis, a massive release of mycobacteria including fever, sweating, loss of appetite, weight lipoarabino-mannan cell wall antigens causes wide- loss, and weakness. Respiratory symptoms may spread perifocal inflammatory responses, injury to the include dry or productive cough, hemoptysis, shortalveolocapillary membrane, interstitial granulomatous ness of breath, and pleuritic chest pain. Neurological infiltration, obliterative endarteritis, increased capillary symptoms such as headaches, confusion, disorientaendothelial cell susceptibility to the toxic effect of the tion, cranial nerve palsies, or even coma may be the released TNF-a and ICAM-l (Penner et al.1995; Sutton presenting features. A history of tuberculosis may be et al. 1974; Petty and Ashburgh 1971; Massaro and Katz present in 10%-20% of patients (Slavin et al. 1980). 1964; Ashburgh et al.1967; McClement et al.1951). Fever is the most common symptom and may be The alveoli will be filled with inflammatory exu- the only presenting feature (pyrexia of unknown dative edema due to increased local vascularity, with origin). Other symptoms of tuberculosis related to vasculitis leading to pulmonary edema which is the other body systems or organs such as musculoskhallmark of ARDS (So and Yu 1981; Penner et al. eletal, genitourinary tract, or the abdomen are less 1995; Dee et al. 1980). The alveolar exudate mate- frequently encountered at the time of presentation. rial includes mostly polymorphonuclear leukocytes, Concomitant chronic illnesses such as diabetes melerythrocytes, fibrin, as well as caseating granulomas. litus, alcoholism, connective tissue diseases, chronic This will lead to mismatching of ventilation and per- renal failure, silicosis, HIV, or immunosuppressive fusion and an impaired diffusion capacity (Mohan et chemotherapy may be found in patients with miliary/ al.1996; William and Yoo 1973). disseminated tuberculosis. The physical signs may be Acute miliary/disseminated tuberculosis may few, including tachypnea, wasting, lymphadenopathy, also be caused by Mycobacterium bovis. Miliary M. hepatic and splenic enlargement, cutaneous lesions, bovis induced by intravesical BCG immunotherapy or features of meningitis (Ray et al. 2002; Sharma used for the treatment of bladder cancer has been et al. 1981; Pasculle et al. 1980; Bateman et al. 1980; reported (Deresiewicz et al. 1990; Rawls et al. 1990; K6ylii et al.1997; Shibolet et al.1979; Prout et al.1980; Kesten et al. 1990; Gupta et al. 1988; McParland et al. Evans et al. 1998; Long et al. 1997). The frequency of 1992; Iantorno et al. 1998; Palayew et al. 1993; Foster symptoms and signs of miliary/disseminated tuber1997; Jasmer et al. 1996; Rabe et al. 1999; Soloway culosis as reported by some authors are shown in 1988). The mechanism by which BCG induces mili- Tables 18.1 and 18.2. ary tuberculosis has been debated among authors (Lotte et al. 1984; de Hertogh et al. 1989; Orihvela et al. 1987). Some authors suggested that it is a hypersensitivity reaction in response to BCG, particularly 18.5 when they failed to grow the organisms. Other Meningitis and Tuberculomas authors explained the widespread lung shadowing in Miliary/Disseminated Tuberculosis as due to hematogenous dissemination of the bacilli which were isolated from various pathological fluid Miliary/disseminated tuberculosis may involve the and tissue biopsy specimens. Other nontuberculous central nervous system with evidence of meningitis Mycobacterium species may cause miliary and dis- or tuberculomas in up to 30% of patients (Slavin et seminated diseases similar to those caused by M. al.1980; Biehl 1958; Maartens et al.1990). Headaches, tuberculosis. These nontuberculous mycobacteria are hemiplegia, seizures, and coma may indicate involveparticularly found in patients with HIV. Mycobacte- ment by meningitis and/or tuberculoma, as noted in rium avium-intracellulare, M. kansasii, and M. fortui- our case no. 3 (Fig. 18.3f,g). However, the patients may tum are the ones most frequently reported (Bone and have no symptoms that are related to the central nerStableforth 1981; Longdale et al. 1992). vous system, and cerebral tuberculoma may only be depicted by MRI. The cerebrospinal fluid (CSF) may be either clear or turbid with lymphocytic pheocytosis, raised protein concentration, with a low level of 18.4 glucose (Gelb et al. 1973). Cerebrospinal fluid smear Clinical Features of Miliary/Disseminated is rarely positive for acid-fast bacilli, and culture may Tuberculosis yield the bacilli in up to 20% of patients (Hill 1991). The prognosis may be poor if undiagnosed and not The clinical symptoms at the time of presentation of treated early, with the development of hydrocephalus, miliary/disseminated TB may only be constitutional coma, and death.

54

109

21 26

59

67

62

63

Long et al. (1997)

Maartens et al. (1990)

Bobrowitz (1982) Stenius-Aarniala (1979)

Prout et al. (1980)

Munt (1972)

Biehl (1958)

Chapman and Whorton (1946)

79

62

84

44

95 88

92

82

72

Fever (%)

82

63

65

63

43 15

72

59

60

Cough (%)

-

-

-

37

-

19

72

26

30

Expectorant (%)

64

23

1

37

33 31

72

30

34

Dyspnea (%)

-

-

-

15

-

72

11

-

84

69

63

Munt (1972)

Biehl (1958)

62

72 82 96 44

60

-

33

-

62

67

-

-

62

6

6

8.5

15

-

13

Pleural effusion 8 46 36 57

30

-

12

15 12

52 62

72 53

35

13 36

-

4 20 21 28

9

14

-

-

85

61

95

59

33 38

92

62

30

Hemoptysis Weight loss (%) (%)

-

-

38 16

Epididymo-orchitis, subcutaneous abscess arthritis 13

Others

Fatigue - 49 Sweating - 45 Sweating - 37 Weakness - 70 Abdominal pain - 21 Musculoskeletal - 13 Disorientation and confusion - 52 Abdominal pain - 35 Fatigue - 35 Nausea & vomiting - 23 Anorexia - 51 Weakness - 42 Abdominal pain - 30 Confusion - 17 Abdominal pain - 7 Weakness - 93 Anorexia - 91 Weakness - 65 Anorexia - 42 Abdominal pain - 10 Anorexia - 90

Others

Neck stiffness 26 Pericardial effusion 8 Choroidal TB 7 -

20 -

7

18

10

17

12

25

-

-

Headaches (%)

Hepato- Spleno- Ascites CNS megaly megaly

Chest pain (%)

No. of Fever Tachypnea Wasting Lympha- Chest signs denopathy cases

Al-Jahdali et al. (2000) 47 Long et al. (1997) 54 Maartens et al. (1990) 109 Prout et al. (1980) 62

Reference

Table 18.2. Most common signs of miliary/disseminated tuberculosis

47

No. of cases

Al-Jahdali et al. (2000)

Reference

Table 18.1. Most common symptoms of miliary/disseminated tuberculosis

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MiliarylDisseminated Tuberculosis

18.5.1 Case Illustration 1

A 39-year-old male clerk working in our hospital presented to me on 8 September 1999 with a I-month history of right knee pain which was mild and associated with swelling. Symptoms were progressive. He was in good health before presentation and denied a history of trauma. He was always overweight and did not notice any recent weight loss, and had no fever or sweating. Musculoskeletal system investigation was otherwise normal. He was using analgesics as self-medication, which were controlling his knee pain. There was no low-back pain or other systemic symptoms that could be related to connective tissue diseases. He was treated in the ophthalmology clinic for dryness of the eyes but that lasted only for a few months before resolving. He denied a history of drinking raw milk or consumption of raw liver or meat or contact with animals. Other systemic enquiries were normal. On physical examination he looked well, apyrexial, not in pain and not pale. The right knee was swollen with effusion but not tender or warm and had a full range of movement. There was no thigh or leg muscle wasting. Other joint examinations were normal. Other systematic physical examination showed no lymphadenopathy, and other systems were normal. Synovial fluid aspiration was obtained, and other investigations included hemogram, ESR, biochemical profiles including serum urate, blood culture, and Brucella agglutinins, plain radiography of the knees and chest. He was referred to our orthopedic surgeon for arthroscopy, but he refused this investigation. The hemoglobin was 13.2 gldl with normal white cell count, but the ESR was raised 50 mm/h. Biochemical parameters were normal apart from slightly raised serum urate at 467 f.lmolll (normal range 210-430 f.lmolll). Chest and knee radiography results were normal (Fig. 18.1a,b). Synovial fluid white cell count was normal, and culture was negative. Plain radiography and MRI of the right knee showed two small defects in the joint's surface on the medial condyle of the femur, one measured 7 mm and the second 3-4 mm in diameter. This was interpreted as osteonecrosis but could also be due to an inflammatory process (Fig. 18.1c-f, j). Arthroscopy was refused again by the patient. He was taking Diclofenac retard 100 mg once daily orally and was controlling his mild knee pain, and the swelling resolved. Four months later he presented to the emergency room with a 1O-day history of fever, rigor, night sweating, and 4-day history of cough with whitish sputum, left pleuritic chest pain, and shortness of breath. He also had a history of diarrhea for 3 days before presentation. He was anorexic

279

with occasional vomiting, and although he was on a weight-reducing diet, he did not notice faster weight reduction. On physical examination in the emergency room, he looked unwell, tachypnea, feverish 40°C, pale, and had lost 5 kg of weight since last weighed 4 months earlier. There was no lymphadenopathy, no positive abnormal sounds heard over the lung, and no pleural rub. Abdominal examination revealed an enlarged, tender liver extending 4 cm below the costal margin and enlarged spleen extending 3 cm below the costal margin, but there was no ascites or other palpable masses. The right knee was swollen with mild knee effusion. Chest radiograph looked normal, but the hemoglobin decreased to ILl gldl with normal blood film, and there was evidence of malaria, while the white cell count was normal. Blood culture was done, and the blood biochemical parameters were normal. When I reviewed the patient the following day, a softer chest radiograph was done which showed faint reticular lung shadowing at both lung bases (Fig. 18.lg). Miliary tuberculosis was the presumptive admission diagnosis, and he was started on four-drug chemotherapy. Other investigations were carried out during admission. The sedimentation rate (ESR) was 90 mm/h, negative blood and sputum cultures. Brucella serology was repeated, autoimmune screenings were all negative. Liver enzymes were abnormal; ALT 79 U/l (normal range 2-40 U/I); alkaline phosphatase 1151 U/I (normal range 98-279 U/I), albumin 33 gil (normal range 38-51 gil), urate 467 f.lmolll (normal range 210-430 Ilmolll), and total bilirubin was normal 12 f.lmolll (normal range 2-22 f.lillolll). The tuberculin test was negative; it had been done twice, once at the initial visit 4 months earlier and during the current admission. MRI of the chest showed diffuse confluent miliary lung shadowing widely spread over both lung fields with small areas of nonhomogeneous consolidation in the lateral segment of the right middle lobe (Fig. 18.1h,i). Ultrasound of the right knee showed significant synovial thickening but no effusion. Ultrasound of the abdomen showed an enlarged spleen with a span of 16 cm but without focal lesions in it; the liver was enlarged, but no focal lesions were depicted; and there was no definite para-aortic lymphadenopathy. The other abdominal organs were normal. The nonsteroidal anti-inflammatory medication was discontinued, and the patient remained on antituberculous medication. Bronchoscopy was done which showed an inflamed bronchial mucosa but no endobronchial lesions, and bronchoalveolar lavage (BAL) was performed. BAL was sent for cytology, AFB smear, and culture - post-bronchoscopy sputum specimens were sent for microbiological examination.

280

M. M. Madkour

a

b

[>

c Fig. 18.1 a Frontal radiograph of the right knee at the initial presentation with monoarthritis. This was interpreted as showing no bony abnormalities. b Chest radiograph at the initial presentation with right knee monoarthritis, showing no abnormal imaging features. c, d MRI of the right knee: sagittal Tl-weighted images demonstrate presence of effusion (arrow) and two osteochondral lesions (arrowheads) at the medial femoral condyle appearing as central areas of increased signal intensity surrounded by signal void rim. Appearances are typical of osteochondritis dissecans, but an infective pathology is also possible. e, f MRI of the right knee: sagittal T2-weighted images at the same level demonstrates joint effusion better (arrow) and the osteochondral defect as high signal intensity indicating activity (arrowheads). g Chest radiograph during acute presentation demonstrates numerous fine discrete nodules bilaterally (arrowheads) consistent with miliary tuberculosis. h Axial CT scan with lung windowing demonstrates generalized increase in parenchymal density with ill-defined fine nodular pattern in a random distribution (arrowheads). i Axial CT scan at a caudal level demonstrates air-space consolidation in the left lower lobe (arrowheads). j Frontal radiograph of the right knee during the acute miliary tuberculosis presentation demonstrates evidence of periarticular osteoporosis (arrowheads) and subchondral erosions (arrows). Note preservation of joint space (*). k Isotope bone scan (99mTc) demonstrates marked tracer uptake in the right knee (arrowheads). I Isotope bone scan demonstrates tracer uptake in 010 vertebral body (arrowheads). m Axial CT of the lung with mediastinal windowing demonstrates destruction of the lower dorsal vertebral body with associated paravertebral abscess (arrows). n Sagittal gadolinium-enhanced Tl-weighted MR image of the spine demonstrates destruction of the vertebral body (arrows), paraspinal abscess (large arrowheads) with subligamentous spread (small arrowheads) causing compression of the spinal cord (*).0 Axial gadolinium-enhanced Tl-weighted MR image with fat saturation demonstrates paraspinal abscess with wall enhancement (arrows)

281

Miliary/Disseminated Tuberculosis

e

f

[>

282

M. M. Madkour

k

n

m

o

Fig. 18.1 (Continued) k-o

MiliarylDisseminated Tuberculosis

283

The patient agreed to arthroscopy, which showed a cough, expectoration, loss of appetite, and weight hemorrhagic hypertrophic synoviurn with grade II loss. The swelling in the forehead was painless, and degenerative changes at the medial femoral condyle. she denied any history of head trauma. She had low Debridement, synovial tissue biopsies, and wash-out back pain and amenorrhea for the same duration. She were sent for histopathological and microbiological was in perfect health before the present illness. Other examination. Bone marrow biopsy was performed. systemic reviews were noncontributory, but she gave The patient responded to the antituberculous treat- a history of contact with a housemaid who had pulment, and the fever and dyspnea began to improve monary tuberculosis 6 years before the onset of the within 1 week of hospitalization. However, he com- current illness. She had no family history of tubercuplained of back pain, and there was tenderness over losis. She was a high school student and single. She T9-1O. He later admitted that he had had occasional was initially diagnosed to have tuberculosis a few back pain before, but it was so mild that it was relieved days before her presentation to our hospital. She initially presented to our satellite military hoswith the nonsteroidal anti-inflammatory treatment he used for his knee. Isotope bone scan and MRI of the pital in Al-Kharj (80 km south of Riyadh) and was spine and other joints were performed. MRI showed diagnosed as having tuberculosis and was referred to destruction of T9 with collapse of the vertebral body, our hospital a few days after initiating her on antitugibbus deformity, and para-spinal abscess with exten- berculous antibiotics. On physical examination, the sion into the epidural space (Fig. 18.1m-o). Isotope patient was unwell, pale, underweight (38 kg) with bone scan showed increased uptake at T9-1O and in forehead cystic swelling measuring 3.0x2.0 cm in the right knee (Fig. 18.1k,1). Histopathological results diameter. It was not tender or hot or red, and there of the bone marrow showed multiple areas of granulo- was no discharge from it. She had fever with a temmatous lesions with central caseation, but bacilli were perature of 39SC and tachycardia of llO/min. She not seen, and the culture was later reported as negative. had no peripheral lymphadenopathy. Cardiovascular, The histopathological findings of the synovial tissue respiratory, abdominal, and central nervous system and debridement specimen showed multiple granulo- examinations showed no abnormalities. Joint examimatous synovitis with central caseation. BAL culture nations were normal; she had localized tenderness and post-bronchoscopy sputum grew M. tuberculosis on percussion over multiple areas of the spine, but that was sensitive to isoniazid, rifampicin, pyrazin- there were no deformities or kyphosis. The hemoamide, and ethambutol. The temperature settled after gram showed WBC 5.3X109, hemoglobin 8.1 g/dl, and 9 days of antituberculous medication. The difficulties ESR 90 mm/h. Clinical chemistry parameters were in the diagnosis of this patient were due to several normal. Chest radiograph showed normal cardiac factors: the mild nature of the right knee symptoms size and clear lung fields. There were two ill-defined, with absence of constitutional symptoms, the refusal soft-tissue mediastinal masses on the right lateral of exploratory arthroscopy as an important diagnos- border and upper left border of the cardiac shadow tic means of investigation, the use of nonsteroidal with no calcification. Frontal and lateral dorsolumbar anti-inflammatory medication that masked back pain spine radiographs showed loss of height of L2 and despite the enquiry into spinal symptoms, the initially reduced bone density ofL! and L3 (Fig. 18.2a). Sagitnormal-appearing chest radiograph was done in the tal CT showed destruction of L2 (Fig. 18.2b). MRI of emergency room when he presented with acute chest the lumbar spine showed destruction of the body of and constitutional symptoms, the multiplicity of skel- L2 with compression of the dural space by a paraetal foci that were the most likely source of hematog- spinal abscess (Fig. 18.2c-e). Postcontrast CT of the enous dissemination rather than a single focus. The abdomen showed anterior subligamentous abscess patient responded well and continued antituberculous with a large right psoas muscle abscess (Fig. 18.2f,g). medication for 12 months. He has been followed up MRI of the abdomen at the same level showed a for over 2 years with no evidence of recurrence or any large right psoas abscess displacing the right kidney neurological or other complications. (Fig. 18.2h). Drainage of the right psoas abscess was performed in the prone position (Fig. 18.2i). The dorsal spine MRI showed another lesion 18.5.2 affecting the mid-dorsal region (Fig. 18.2j,k). Chest Case Illustration 2 CT with contrast of lung and mediastinal windows depicted a small lung parenchymal granuloma A 16-year-old Kuwaiti girl presented on 29 July 2000 and caseating lymph nodes in the retrosternal with a 6-month history of forehead swelling, fever, carina, subcarinal region, and prevascular groups

284

M. M. Madkour

a

b

c

d[> Fig. IS.2a-s. A 16-year-old girl presented with painless, soft-tissue swelling of the forehead, fever, cough, and low-back pain. a Frontal and lateral radiographs of the dorsolumbar spine demonstrate loss of height of L2 vertebral body (arrow) due to destructive lesion demonstrated better on the lateral view (arrowheads). There is also reduced bone density of the vertebral body of L1 and L3 and narrowing of disc spaces (D). b Sagittal reformatted CT image demonstrates destruction of the body of L2 with sclerosis of the remaining part (arrowhead). c MRI of the lumbar spine: sagittal post-enhanced Tl-weighted image demonstrates destruction of the body of L2 with large tuberculous cavity (arrow). Note posterior comparison on the dural space (open arrow). d Right para-sagittal image demonstrates anterior subligamentous tuberculous abscess (arrows) which had a tract to form right paraspinal abscess (A) in a. e Sagittal T2-weighted image with fat suppression demonstrates the paraspinal abscess as high signal intensity mass (A), the subligamentous abscess (long arrows), diffused increased signal intensity of the body of L2 and to lesser extent the body of L1 (open arrowheads). Note abscess cavity in L2 (arrow). f Post-enhanced CT of the abdomen at the level of L2 demonstrates destruction of the vertebral body (black arrow), anterior subligamentous abscess (arrowhead), and a large right psoas muscle abscess. g Post-enhanced axial CT at a caudal level demonstrates further destruction of L2 vertebral body (black arrow), tracking of the anterior subligamentous abscess (open black arrow), into a large right psoas muscle abscess (A). h MRI of the abdomen at same level as f: post-enhanced Tl-weighted image demonstrates destruction of

MiliarylDisseminated Tuberculosis

285

e

f

g

h the body of L2 (black arrow) and a large psoas muscle abscess (A), note the enhancing thick wall of the abscess (small arrows). The abscess is displacing the right kidney (thick black arrow). i Axial CT of the abdomen demonstrates percutaneous insertion of drainage catheter at the site of psoas abscess (arrow) (the examination is performed in the prone position). j Sagittal MRI of the dorsal spine: T2-weighted image with fat suppression demonstrates large anterolateral abscess appearing as diffuse high signal intensity anterior and to the right of mid-dorsal region (arrows). No associated bone or disc lesion is seen. k, I MRI of the same patient. Post-enhanced II-weighted sagittal (k) and axial (I) images demonstrate the abscess (A) as low signal intensity surrounded by thick enhancing wall (arrows). m, n CT of the chest: post-enhanced CT at the level of aortic arch. m Lung window demonstrates narrow lung parenchyma separate from small granuloma (arrow). n Mediastinal window demonstrates caseating lymph node with characteristic ring enhancement in the retrosternal and prevascular group (arrows). 0, p Post-enhanced axial CT at the level above the carina (0) and subcarinal (p) demonstrates appearance characteristic of subcarinal region. Note ring enhancement of the wall (arrow). q, r Frontal and lateral skull radiographs demonstrate focal area of bone destruction in the frontal bone. Note loss of the outer table of the skull bone on the lateral radiograph (white arrows) and focal ill-defined radiolucency due to bone destruction (black arrows). s Axial CT of the brain demonstrates bone destruction of the frontal bone (curved arrow) and associated soft-tissue mass due to abscess formation (white arrow)

l>

286

Fig. 18.2 (Continued) i-m

M. M. Madkour

m[>

MiliarylDisseminated Tuberculosis

287

n

o

q

p

s r

Fig. 18.2 (Continued) n-s

288

(Fig. 18.2m-p). Plain radiograph of the skull depicted a focal area of bone destruction in the frontal bone (Fig. 18.2q,r). Axial CT of the brain showed a softtissue abscess associated with frontal bone destruction (Fig. 18.2s). Ultrasound of the abdomen showed no evidence of hepatic or splenic involvement, and CT showed no intra-abdominal free fluid or other abdominal organ involvement. Culture of psoas abscess drainage yielded M. tuberculosis after 14 days incubation and was sensitive to all antituberculous agents. The forehead abscess was drained by our neurosurgeon, and tissue biopsies were obtained. Histopathological examination of the forehead abscess showed caseating granulomas, and culture yielded M. tuberculosis. The patient was treated with isoniazid 300 mg, rifampicin 450 mg, pyrazinamide IG, ethambutol 800 mg, and pyridoxine 25 mg as single oral daily dosing for 2 months and continued on isoniazid and rifampicin for a further 10 months. She responded well to treatment while in hospital, and her temperature settled with weight gain. She remained in hospital for 2 months and was discharged in September 2000. She stayed in Riyadh with members of her family and was followed up in the outpatient clinic regularly. She made a full recovery with no sequelae. This patient had disseminated tuberculosis with spinal disease at multiple levels, mediastinallymph node abscesses, psoas abscess, and forehead abscess. Although there was no lung parenchymal active disease depicted on plain chest radiography, CT showed small parenchymal lung granuloma. This patient did not have HIV or other diseases and was not on any medication that could have contributed to such severe disseminated tuberculosis.

M. M. Madkour

18.5.3 Case Illustration 3

A 27-year-old man transferred to our infectious disease unit isolation room with advanced AIDS, multidrug-resistant pulmonary tuberculosis, left hemiplegia due to tuberculous abscess of the brain, and recurrent seizures. This patient was diagnosed in another hospital in Riyadh with pulmonary tuberculosis and HIV co-infection in 1997. His pulmonary tuberculosis relapsed in 1999 due to poor compliance with medication. He was moved from one hospital to another and finally came to our hospital on 29 April 2001 until his death on 3 November 2001 due to disseminated multidrug-resistant tuberculosis. On arrival at our hospital, he was cachectic, pale, dyspneic, had oral thrush, and looked very ill. The hemogram showed low WBC 2.8109, and CD4 count ranged between 14 and 30/111, hemoglobin was 8.2 g/dl, and ESR was 84 mm/h. The HIV viral load was 75,000 COP/ml in 1999. Sputum culture yielded M. tuberculosis resistant to rifampicin and isoniazid. He was already on AZT, lamuvidine, rifampicin, clarithromycin, co-trimoxazole, fluconazole, phenytoin, and pyridoxine. Chest radiograph showed paratracheal and hilar lymphadenopathy and fibronodular infiltrative left upper lobe lesions with thin-walled cavities (Fig. 18.3a). Axial CT of the chest showed evidence of endobronchial tuberculosis with caseating hilar lymphadenopathy (Fig. 18.3b-d). In June 2001, the patient developed abdominal pain, vomiting, abdominal distension, and constipation for 2 days. The abdomen was tender all over with absent bowel sounds. Abdominal radiograph and axial CT showed

Fig. 18.3a. Plain chest radiograph demonstrates paratracheal and hilar adenopathy (arrows) and fibronodular infiltrative changes in the left upper lobe (curved arrow) with thin-walled cavities (arrowheads). b Axial CT of the chest with lung windowing demonstrates nodular and branching opacities of endobronchial tuberculosis (arrowheads) in both upper lobes, dilated bronchi (arrows). c Axial CT at caudal level, lung windowing demonstrates multiple thin cavities (arrows). d Axial post-enhanced CT of the chest at the level of carina demonstrates enlarged lymph nodes with typical ring enhancement and caseating center (arrows). e Axial post-enhanced CT of the abdomen demonstrates significantly dilated small-bowel loops (B) and caseating mesenteric lymph node (curved arrow). There was no ascites (dry type). At surgery, 20 cc of pus were aspirated from the mesenteric abscess. f MRI of the brain: post-enhanced TI-weighted image demonstrates tuberculoma and tuberculous abscess in the left parietal lobe. Note the enhancement of the tuberculoma (arrowhead) and the irregular enhancing wall of the tuberculous abscess (arrow). g MRI post-enhanced fast spin-echo inversion recovery image (FSEIR) at the same level demonstrates surrounding edema (arrowheads)

a

l>

Miliary/Disseminated Tuberculosis

dilated small-bowel loops and caseating mesenteric lymphadenopathy. Exploratory laparotomy after taking all precautionary measures in the theatre was performed. A massively distended small bowel was noted with mild changes in color. There was a large inflammatory mass in the root of the mesentery of

289

the small bowel. Thick pus was freely present in the abdominal cavity, and 20 cc was aspirated and sent to the Microbiology Department. Bowel adhesions were noted and released. It was decided to close with interrupted sutures, and the patient tolerated the procedure. In October 2001, he went into a coma,

b

c

d

e

f

g

290

and brain MRI showed enlargement of the tuberculoma of the brain with development of left parietal lobe brain abscess (Fig. 18.3f,g). The patient died 1 month later.

18.5.4 Case Illustration 4 A 21-year-old married female patient presented to the surgical department with a right iliopsoas mass. She had a history of abdominal pain lasting 6 months associated with fever, profuse night sweating, loss of appetite, and weight loss. She was well before that time and had no previous illnesses. She noted a swelling in the right inguinal region which was associated with a gradual but progressive pain that increased with flexion of the right hip and was relieved by extension of the leg. The pain became worse 2 months before presentation, and the swelling became larger, and she noted a loss of 13 kg in weight. She had an associated history of dysuria and dribbling of urine during the 2 months before presentation. She had no hematuria but had loin pain on both sides. Other systematic reviews were noncontributory. She was using pain-killers to relieve her pain during that time which had been provided by a private clinic. She was also given several courses of antibiotics for a period

M. M. Madkour

of 2-3 months before presentation to our hospital. There was no past history of any illnesses. She had married at the age of 18 years and had one healthy boy. She had a history of vaginal discharge which was yellowish after IUCD insertion 1 year before presentation, and it was subsequently removed. On physical examination, she was underweight, and blood pressure was 92/66 mmHg. There was a cystic swelling at the right inguinal area. Chest examination showed dextrocardia and situs inversus. There were positive clinical findings in the lungs including crepitations and bronchial breathing in the left upper zone. The heart was otherwise normal. Abdominal examination revealed soft lax abdomen with no masses or organomegaly. The right iliac fossa was tender with vague fullness but no definite masses felt. She was pale and feverish, with a temperature of 38.5°C. The patient felt pain during examinations of her hip joint and resisted manipulation. Other systemic examinations were normal. The hemogram showed normal white cell count, hemoglobin 8.8 gldl, and ESR 90 mml h. Biochemical parameters were normal. Chest radiograph showed dextrocardia and pneumonic consolidation in the left mid-zone (Fig. 18.4a). Axial CT of the chest showed airspace consolidation with air bronchogram (Fig. 18.4b). Axial CT of the chest postcontrast showed an abscess in the left erector spinae muscle (Fig. 18.4c,d).

a Fig. 18.4a-h. A 21-year-old woman with situs inversus and dextrocardia presented with rigor, fever, night sweating, loss of weight, and right hip pain. She was found to have a right iliopsoas mass. a Chest radiograph demonstrates pneumonic consolidation in the left mid-zone (arrow) (figure should read situs inversus). b Axial CT of the chest with lung windowing demonstrates air space consolidation with air bronchogram (arrowheads). There is minimal para-pneumonic effusion (open arrow). c, d Axial post-enhanced CT of the patient at the thoraco-abdominal region demonstrates abscess cavity in the left erector spinae muscle (arrows). Note the situs inversus with the liver on the left (arrowhead) and dextrocardia. e, fAxial CT of the pelvis: nonenhanced (e) and post-contrast-enhanced (0 axial images at the same level demonstrate multiple pelvic abscesses (A). Note enhancement of the walls of the abscesses (arrows; B). g, h Axial CT at the level of the hip joints: nonenhanced (g) and post-contrast-enhanced (h) axial images demonstrate right inguinal abscess

Miliary/Disseminated Tuberculosis

Axial CT of the pelvis pre- and post-enhancement showed large multiple pelvic abscesses with wall enhancement (Fig. 18.4e,f). Axial CT at the level of the hip joints showed right inguinal abscess with ring enhancement after contrast (Fig. 18.4g,h). Percutaneous drainage of the right inguinal abscess and other pelvic abscesses was performed under CT guidance.

291

Other sputum cultures and cultures of the abscess contents yielded M. tuberculosis that was sensitive to all antituberculous drugs. Histopathology of the inguinal abscess wall showed granulomas. The patient had negative testing for HIV and no evidence of any underlying diseases. She responded well to antituberculous treatment without any sequelae.

c

e

f

g

h

292 18.5.5 Case Illustration 5

A 26-year-old man was referred from Al-Kharj (80 kIn south of Riyadh) with a 6-month history of fever, sweating, dry cough, left-sided chest pain, dyspnea on mild exertion, weakness, loss of appetite, weight loss, and back pain. He had a strong family history of tuberculosis. He was initially treated with antibiotics and analgesics, but his symptoms gradually progressed. He was healthy previously and was not on any medication prior to the presenting illness. Other systemic reviews were normal. On physical examination, he looked unwell, pale, underweight, and his temperature was 38.5°C. There was no palpable peripherallymphadenopathy. Chest examination revealed features of leftsided pleural effusion. Cardiovascular system examination was normal. The abdomen was soft, but there was a splenomegaly with tenderness on palpation. There was no other organ enlargement and no ascites. The spine showed no deformities, but tenderness was elicited at different areas on percussion, mostly at the mid-thoracic and lumbar spine. There was no evidence of neurological deficit, and the fundi were normal. The hemogram showed a normal white cell count, hemoglobin 8.3 g/dl, and ESR 94 mm/h. All biochemical parameters were normal. Chest radiograph showed left-sided, encysted pleural effusion, and a paraspinal shadow was noted, consistent with a paraspinal abscess (Fig. 18.5a). Plain radiograph of the thoracolumbar spine depicted a paraspinal abscess with narrowing of the disc space at TlO-ll {Fig. 18.5d). Ultrasound of the abdomen showed a poorly defined, hypoechoic lesion in the spleen consistent with a splenic abscess (Fig. 18.5j). Axial CT of the chest showed a large, encysted, left pleural effusion with pleural thickening {Fig. 18.5b). MRI of the dorsolumbar spine showed several lesions affecting the vertebral bodies at multiple levels in the thoracic and lumbar vertebrae with paraspinal abscess formation {Fig. 18.5c,f,h,i). Pleural aspiration and biopsy were performed for histopathological and microbiological investigations. Pleural biopsy showed multiple areas of granulomas consistent with tuberculosis. The patient was seen by the spinal surgeon, and surgery was planned after initiating antituberculous treatment. Paraspinal abscess drainage and bone fusion for stabilization of the spine were performed {Fig. 18.5e). Culture of the granulation tissue and abscess content were positive for M. tuberculosis which was sensitive to all antituberculous drugs. Histopathology of spinal granulation tissue showed caseating granulomas. Serological testing

M. M. Madkour

for HIV was negative. The patient responded well to treatment. His antituberculous treatment was extended to 16 months because of the multiplicity of spinal lesions. He made a full recovery and had no spinal deformities or late neurological deficits.

18.6 Adult Respiratory Distress Syndrome and Disseminated Intravascular Coagulation in Miliary Tuberculosis ARDS is an uncommon but serious complication of miliary tuberculosis with a high hospital mortality rate of up to 69%, similar to that of other etiologies such as Gram-negative sepsis (Penner et al. 1995). It has no pathognomonic clinical or imaging features that could differentiate a tuberculous from a nontuberculous etiology. Goldfine et al. (1969) were the first to describe respiratory failure in patients with miliary tuberculosis, and Agarwal et al. (1977) were the first to use mechanical ventilation for such patients. The criteria for diagnosing ARDS is based on the American-European Consensus Conference (Bernard et al. 1994) which includes: 1. The ratio of partial pressure of arterial oxygen (Pa02) to the fraction of inspired oxygen (Fi0 2) is ::;200. 2. Chest radiographic features of bilateral lung infiltrates. 3. A pulmonary artery occlusion pressure ::;18 mmHg. 4. Or absence of clinical or imaging evidence of raised left atrial pressure. The onset of ARDS due to miliary tuberculosis is often preceded by fever and chest symptoms for a few weeks, but may occur acutely over a few days with intense dyspnea (Mohan et al.1996; Murray et al. 1978; So and Yu 1981; Dyer et al. 1985). A high index of suspicion by the treating clinician and willingness to consider tuberculosis as a possible cause of ARDS of unknown origin are essential and may reduce the mortality. Tachypnea and bilateral inspiratory crackles over both lungs may be found. Other physical examination results may detect splenomegaly, hepatomegaly, and signs of meningitis. Some authors have suggested that ARDS due to miliary tuberculosis may have a longer duration of symptoms than 1 week, while Gram-negative septicemia and viral pneumonia produce symptoms much faster. Hypotension is uncommon (7%) in ARDS due to miliary tuberculosis, while it is more frequent in ARDS due

Miliary/Disseminated Tuberculosis

293

to sepsis (Dyer et al. 1985). Disseminated intravascu- TB is not clear, but disseminated emphysematous lar coagulation (DIC), acute renal failure, hepatitis, tuberculosis, rupture of a pleural bleb, or rupture of and intercurrent infections are common features a subpleural caseous miliary nodule may be the cause (up to 87.5%) in ARDS due to miliary tuberculosis (Mert et al. 2001). There are only a few single case and Gram-negative septicemia (Murray et al. 1978; reports on such complications in the literature. Mert Piqueras et al. 1987; Dyer et al. 1985; Mohan et al. el al. (2001) found eight cases in the English literature 1996). Death may occur with 1-7 days of the onset between 1974 and 1999 and reported one case of their of ARDS (Murray et al. 1978), and early diagnosis own. These authors reported their own series of 38 and initiation of antituberculous chemotherapy may patients with miliary tuberculosis, only 1 of whom reduce the mortality (Mohan et al.1996). had pneumothorax while on antituberculous treatThe etiological diagnosis of ARDS due to miliary ment. The size of the pneumothorax as noted by other tuberculosis may be achieved in up to 35% of patients authors ranged from small up to 80%. Pneumothorax by sputum smear and in 20% by urine sediment smear in these rare cases was mostly unilateral. Graf-Deuel showing the bacilli. The chest radiograph may be and Knoblauch (1994) described 12 patients with bilatstrongly suggestive of miliary tuberculosis in 15% eral pneumothorax due to various causes and reviewed of patients (Dyer et al. 1985). Other investigations the literature and found 56 published cases including in smear-negative patients should include bron- 3 patients due to miliary tuberculosis. Chandra et al. choscopy with brushing, transbronchial lung biopsy, (1988) described an 18-year-old woman with miliary bone marrow trephine, and liver biopsies as well as tuberculosis. She was given antituberculous chemolumbar puncture if features of meningitis are present. therapy, but on the 20th day of admission, she develThe hemogram often shows normal white cell count, oped bilateral simultaneous pneumothorax that was anemia, or pancytopenia. Patients with ARDS due to aspirated by needle and tube drainage and improved. miliary tuberculosis may develop disseminated intra- Two weeks later, recurrent right-sided pneumothorax vascular coagulation (Die). The pathogenesis and was followed by left-sided pneumothorax and a bronfactors contributing to DIC occurrence are not clear. chopleural fistula that required surgery and responded Tuberculous vasculitis may possibly be a contributing well to treatment. Severe chest pain and breathlessness factor to the initiation oflocal consumption of clotting may occur at the onset of pneumothorax, even while factors leading to Die. Subclinical coagulopathy may the patient is on chemotherapy. It may respond to possibly occur as indicated by the presence of micro- needle aspiration, tube drainage, or may require thothrombi in the biopsy specimen from these patients. racotomy if a bronchopleural fistula develops. The development of DIC may be noted with clinically overt bleeding or the results of laboratory tests consistent with its occurrence (Murray et al. 1980; Dyers et al. 1985; Maartens et al. 1990). The development 18.8 of DIC in such cases is often fatal (Rosenberg and Diagnosis of Miliary/Disseminated . Rumans 1978). In endemic areas or when clinical and Tuberculosis imaging features are suggestive of miliary tuberculosis as a possible cause of ARDS, empirical antituberculous The chest radiograph is the most important initial treatment should be commenced while the diagnosis diagnostic tool for patients with miliary tuberculosis is actively pursued. (Berger and Samortin 1970). However, most authors reported a wide range in the incidence of depicting miliary lung nodularity: from 30% to 93% of patients. The diagnostic accuracy of the chest radiograph was 18.7 determined with a high specificity and good interobPneumothorax in Miliary/Disseminated server agreement by Kwong and colleagues (1996) from Vancouver, Canada. These authors reviewed all Tuberculosis cases with miliary TB diagnosed over a lO-year period Pneumothorax as a complication of miliary tuberculo- (1982-1992), with inclusion of a group of control subsis is extremely rare (Mert et al. 2001; Graf-Deuel and jects and interpretation by three independent blinded Knoblauch 1994; Chandra et al. 1988). Pneumothorax observers. They identified miliary nodular lung shadin cavitary pulmonary tuberculosis may occur due to owing with a sensitivity ranging from 59% to 69%, rupture of the subpleural cavity into the pleural space. higher in those with HIV (71 %-85%), and lower when The possible mechanism of pneumothorax in miliary the diagnosis was made only at autopsy (30%-60%).

294

M. M. Madkour

b a

c

e

!:.id.... f

[>

MiliarylDisseminated Tuberculosis

295

h

g

Fig.18.5a-j. A 26-year-old male patient presented with chest pain, fever, rigor, abdominal and back pain. a Chest X-ray demonstrates large, left-sided, encysted, pleural effusion (arrowhead). Note paraspinal shadow consistent with abscess formation (open arrows). b Axial post-contrast-enhanced CT demonstrates collapsed left upper lobe (black arrowhead) and a large pleural effusion (open arrow). Note thickening of the parietal pleura (small arrows). c MRI of the spine: post-enhanced II-weighted image demonstrating lesion in the vertebral body of Dll (large white arrow); note dural enhancement (small arrowheads). Note also enhancement of the thickened visceral and parietal pleura (small white arrows) around the pleural effusion (large arrowhead). d Frontal X-ray of the dorsolumbar spine demonstrates paraspinal abscess (curved arrow). Narrowing of the disc at DlO-ll level (open arrows). e Postsurgical frontal radiograph of dorsolumbar spine demonstrates resolution of the paraspinal abscess (drained surgically). Bone fusion for stabilization has been performed (long arrows). f Sagittal post-enhanced II-weighted image demonstrates multiple spinal involvement by tuberculous foci (arrows). Note large intraspinal abscess involving two adjacent vertebral bodies and crossing the intervening disc space (open arrow). Abscess is also tracking anteriorly along the anterior spinal ligament (long arrows). Note enhancement of the dura (arrowheads). g MRI of the spine after surgery: sagittal proton-density and T2-weighted image demonstrate marked improvement with resolution of the osteomyelitis and paraspinal abscess. Bone graft (arrow) has been performed for stabilization. h Sagittal post-enhanced II-weighted image demonstrates enhancement of the last two lumbar vertebral bodies (arrows) and a small intravertebral abscess (arrowhead). i Sagittal proton and T2-weighted images at the same level demonstrates the abscess cavity at L5 (arrows). j Same patient, ultrasound examination of the spleen demonstrates poorly defined, hypoechoic lesion in the spleen consistent with splenic abscess (arrows)

296

The interobserver agreement of the three independent radiologists was 90%. The chest radiography features of miliary tuberculosis characteristically consist of widespread, bilateral, nodular lung opacities in the upper and lower zones often measuring 1-3 mm in diameter in 90% of patients and greater than 3 mm in 10% (Kwong et al. 1996). Areas of consolidation may be noted in up to 30% of patients (Fig. 18.1i) and are depicted better by CT of the chest. Parenchymal lung cavities may be seen in 3%-11.9% of patients with miliary tuberculosis (Kwong et al. 1996; Long et al. 1997; Hong et al. 1998). An associated mediastinal and/or hilar lymphadenopathy may be noted in about 15% of patients (Kwong et al. 1996). Other additional radiographic findings may include pleural effusion and calcified granulomas (Fig. 23.14a, b).

18.9

High Resolution (T HRCT of the chest findings in patients with miliary tuberculosis has been reported in only a few articles with a relatively small number of patients (Oh et al. 1994; Optican et al. 1992; McGuinness et al.1992). These reports suggested that HRCT is more specific and observed the following imaging findings in patients with miliary tuberculosis, miliary nodules, groundglass opacities (GGOs), reticulation, and interlobular septal thickening. Oh et al. (1994) described the GGOs as multiple microscopic granulomas with acid-fast bacilli after obtaining transbronchiallung biopsies of these areas. The GGOs appear as random patchy opacities and are the second most common (miliary nodules being the first) HRCT feature of miliary tuberculosis. A large retrospective study on HRCT findings of miliary tuberculosis was reported by Hong et al. (1998) from Seoul, Korea. They reviewed 25 patients with microbiologically andlor histopathologically proven miliary tuberculosis who had undergone HRCT. Miliary nodules that are uniformly distributed throughout both lung fields, mostly ranging from 1-3 mm in diameter and sharply defined, were the most common findings in 24 of the 25 patients (96%). Larger nodules up to 5 mm in diameter due to coalescence or enlargement of granulomas were noted in 5%-10% of all nodules. GGOs occurred in 23 (92%) of these patients and are considered the second most common CT finding. These authors observed that in two of their patients with severe dyspnea and impending ARDS due to miliary TB, extensive GGOs were depicted by HRCT. Interlobar reticulation and interlobar septal thicken-

M. M. Madkour

ing were found in 44% each. The authors also reported other HRCT findings including pre-existing TB lesions in 44%, lymphadenopathy in 32%, pleural effusion in 16%, and bronchogenic spread in 16%. Diverse diseases may cause a similar miliary lung shadowing including hematogenous dissemination of infectious diseases, sarcoidosis, metastatic malignancy, histoplasmosis, pneumoconiosis, and interstitial fibrosis (Curull et al.1985; Willcox et al.1986). Centrilobular (core) and paraseptal (peripheral) nodules may be identified with HRCT. Similar additional findings in chest radiography such as pleural effusion, lung cavities, and lymphadenopathy may also be noted (Hong et al. 1998). The imaging features of miliary tuberculosis are not pathognomonic of the disease (McGuinness et al.1992; Chugh and Agarwal 1997; Miyake et al. 1997).

18.10

Laboratory Diagnosis of Miliary Tuberculosis A rapid and specific laboratory diagnosis is the most pressing need in confirming the diagnosis of miliary tuberculosis. The many weeks that are required for culture yield in patients with miliary tuberculosis cannot be used as a means of confirming the diagnosis before starting chemotherapy. A rapid confirmatory laboratory investigation may not always be easy to achieve. A chest radiograph showing miliary nodular lung shadowing in the presence of clinical Table 18.3. Rapid diagnosis by Ziehl-Neelsen stain: number of patients and percentage of positive AFB Body fluid

Prout et aI. (1980)

39 (31%) Sputum 17 (18%) Urine 31 (3%) CSF Bronchial lavage 3 (100%)

Maartens et aI. (1990) 64 22 24 51

(33%) (14%) (8%) (27%)

Table 18.4. Rapid diagnosis by tissue biopsies: number of patients and percentage of positive granulomata Biopsy site

Al-Jahdali et al. (2000)

Maartens et aI. (1990)

Prout et al. (1980)

Liver Bone marrow TransbronchiaI Lymph nodes

16 (88%) 11 (73%) 10 (70%) 2 (100%)

11 (100%) 22 (82%) 48 (63%) 9 (100%)

12 (92%) 15 (71%) 2 (100%)

297

Miliary/Disseminated Tuberculosis

features that suggest miliary tuberculosis may be the only available clues for the attending clinician. Maartens et al. (1990) reported on 109 patients with miliary tuberculosis, and in 7 patients, the diagnosis was based on clinical grounds and classical miliary nodules on chest radiography; they were treated with chemotherapy with a good response. Rapid confirmation of the diagnosis of miliary tuberculosis may be achieved in up to 83% of patients by means of ZieW-Neelsen stain and by the finding of granulomata in tissue biopsies or by fine-needle aspiration (AI BWa12001; Maartens et al. 1990; Prout et al. 1980; Al-Jahdali et al. 2000). The most common body fluids used for Ziehl-Neelsen stain include sputum, gastric fluid aspirate, urine, CSF, bronchial lavage and brushings, and pleural fluid (Sharma et al. 1988) (Table 18.3). Common sites of tissue biopsies to detect granulomata in patients with miliary TB include transbronchial lung tissue, bone marrow trephine, liver, pleura and lymph nodes (Stallworth et al. 1980; Steiner et al.1976) (Table 18.4). Sputum culture in patients with miliary tuberculosis may be positive in 30%-60% (Prout et al. 1980; Monie et al. 1983; Maartens et al. 1990; Al-Jahdali et al. 2000).

18.10.1 Polymerase Chain Reaction PCR assays are a rapid, specific, and noninvasive method of confirming the diagnosis of tuberculosis. PCR using the IS6110 method can be used in identifying the DNA fingerprinting of M. tuberculosis in the sputum, urine, bronchial lavage, gastric aspirate, blood, and tissue biopsies. It has a specificity of 100% and sensitivity of 95% with a turnaround time of 2436 h (Clarridge et al. 1993; Shalwar et al. 1993; Nolte et al. 1993). This rapid and specific diagnostic tool is very useful in confirming the diagnosis of miliary tuberculosis when it is available. Penner et al. (1995) used PCR to determine the strain of Mycobacterium. Tuberculosis was found in 6 of their 13 patients (46%) with miliary tuberculosis, pulmonary and disseminated disease with respiratory failure that required mechanical ventilation. In disseminated tuberculosis, extrapulmonary systems and organs affected can be diagnosed with other investigations appropriate to the site of involvement. These may include various imaging modalities with guided tissue biopsies, sur- . gical drainage of abscesses as demonstrated in the five case illustrations from our own patients. Other investigations should include serological testing for

HIV and PPD skin test. The hemogram may show pancytopenia or 10wWBC (Cassim et al.1993). Tuberculin skin test may be positive in 25%-75% of patients with miliary/disseminated tuberculosis, as reported in various series, but is low among those co-infected with HIV (Hill 1991; Maartens et al. 1990; Gelb et al. 1973; Grieco and Chmel1974; Munt 1972).

18.11 Treatment of Miliary/Disseminated Tuberculosis The treatment of miliary/disseminated tuberculosis is similar to that used for pulmonary and extrapulmonary disease. In miliary tuberculosis, the four-drug regimen includes isoniazid, rifampicin, pyrazinamide, and ethambutol which is used for 2 months and is followed by isoniazid and rifampicin for a further 4-6 months. Drug susceptibility and resistance should be determined. In patients co-infected with HIY, the duration of treatment should be extended to at least 9 months. In disseminated tuberculosis, the duration of treatment may be extended to at least 12 months, particularly when the bone is involved. Surgical intervention may be required to stabilize the spine, release abdominal adhesions if intestinal obstruction arises, drain abdominal, paraspinal, inguinal abscesses, or treat other pulmonary or extrapulmonary complication (see case illustrations). The use of corticosteroids as a modulator of the inflammatory process in miliary tuberculosis with ARDS, meningitis, or pericarditis has been reported by many authors and debated by others (Dyer and Potgieter 1984; So and Yu 1981). Penner et al. (1995) used steroids in 8 of their 13 patients (61.5%) with miliary and pulmonary tuberculosis with ARDS and respiratory failure; they required mechanical ventilation. The median time interval between hospitalization and commencement of treatment was 2 days (range 1-36 days) (Maartens et al.1990). Fever resolved in approximately 7 days (range 1-55 days). Death occurred in 25% of patients within 1-2 weeks of receiving treatment. The most important single factor in the mortality of patients with miliary tuberculosis is a delay in the diagnosis (Maartens et al. 1990). Other factors that contribute to mortality include old age, lymphopenia, hypoalbuminemia, elevated liver transaminases, and delay in early commencement of treatment. Other underlying chronic illnesses may contribute to mortality. The development of complications such as ARDS, DIC, Addison's

298

disease, acute renal or multiorgan failure also contributes to the raised rate of mortality. The mortality rate among patients with miliary tuberculosis is approximately 70%, and 77% among those requiring mechanical ventilation due to ARDS, DIe leading to respiratory failure. Mortality rates reported in large series ranged between 20% and 80% of patients (Maartens et al. 1990; Prout et al. 1980; AI-Jahdali et a1.2000; Monie et al.1983; Stenius-Aarniala and Tukiainen 1979; Dahmash et al. 1995; Evans et al. 1998; Mohan et al.1996; Ormerod and Horsfield 1995).

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299 distress syndrome associated with miliary tuberculosis. Chest 73:37-43 Myers JA (1970) Miliary tuberculosis in the elderly. Br Med J 1:565 Nolte FS et al (1993) Direct detection of Mycobacterium tuberculosis in sputum by polymerase chain reaction and DNA hybridization. J Clin MicrobioI31:1777-1782 Oh YU, Kim YH et al (1994) High-resolution CT appearance of miliary tuberculosis. J Comput Assist Tomogr 18:862-866 Optican RJ, Ost A et al (1992) High-resolution computed tomography in the diagnosis of miliary tuberculosis. Chest 102:941-943 Orihuela E, Herr HW, Pinsky CM et al (1987) Toxicity of intravesical BCG and its management in patients with superficial bladder tumors. Cancer 60:326-333 Ormerod LP, Horsfield N (1995) Miliary tuberculosis in a high prevalence area of the UK: Blackburn 1978-1993. Resp Med 89:555-557 Pagel W, Simmonds FAH et al (1964) Pulmonary tuberculosis, 4th edn. Oxford University Press, London . Palayew M, Briedis D et al (1993) Disseminated infection after intravesical BCG immunotherapy. Chest 104:307-309 Pasculle AW, Kapadia SB et al (1980) Tuberculous bacillemia, hyperpyrexia, and rapid death. Arch Intern Med 140:426-427 Penner C, Roberts D et al (1995) Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 151:867-872 Petty TL, Ashburg DG (1971) The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 60:233-239 Piqueras AR, Marruecos L et al (1987) Miliary tuberculosis and adult respiratory distress syndrome. Intensive Care Med 13:175-182 Pitchenik AE, Fertel D, Bloch AB (1988) Mycobacterial disease: epidemiology, diagnosis, treatment,and prevention. Clin Chest Med 9:425-441 Proudfoot AT, Asktan A, Douglas AC et al (1969) Miliary tuberculosis in adults. Br Med J 2:273-276 Prout S, Benatar SR et al (1980) Disseminated tuberculosis. S Afr Med J 58:835-842 Rabe J, Neff KW et al (1999) Miliary tuberculosis after intravesical bacilli Calmette-Guerin immunotherapy for carcinoma of the bladder. Am J Roentgenoll72:748-750 Rawls WH, Lamm DL et al (1990) Fatal sepsis following intravesical bacillus Calmette Guerin administration for bladder cancer. J UroI144:1328-1330 Ray M, Kataria S et al (2002) Unusual presentation of disseminated tuberculosis. Indian Pediatr 39:88-91 Rieder HL, Kelly GD, Bloch AB et al (1991) Tuberculosis diagnosed at death in the United States. Chest 100:678-681 Rosenberg MJ, Rumans LW (1978) Survival of a patient with pancytopenia and disseminated coagulation associated with miliary tuberculosis. Chest 73:536-539 Sahn SA, Neff TA (1974) Miliary tuberculosis. Am J Med 56: 495-505 Saye L (1936) Tuberculosis miliar cronica. Rev Med Barcelona 25:387-423 Shafer RW, Kim DS et al (1991) Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine 70:384-397 Shalwar R et al (1993) Detection of Mycobacterium tuberculosis in clinical samples by amplification of DNA. J Clin MicrobioI29:712-717

300 Sharma SK, Shamim SQ et al (1981) Disseminated tuberculosis presenting as massive hepatosplenomegaly and hepatic failure. Am J Gastroenterol 76:153-156 Sharma SK,Pande IN et al (1988) Bronchoalveolar lavage (Bal) in miliary tuberculosis. Tubercle 69:175-178 Sharma SK, Pande IN et al (1992) Pulmonary function and immunologic abnormalities in miliary tuberculosis. Am Rev Respir Dis 145:1167-1171 Shibolet A, Dan M et al (1979) Recurrent miliary tuberculosis secondary to infected ventriculoatrial shunt. Chest 76:328-330 Slavin RE, Walsh TJ et al (1980) Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras. Medicine 59:352-366 So SY, Yu D (1981) The adult respiratory distress syndrome associated with miliary tuberculosis. Tubercle 62:49-53 Soloway MS (1988) Intravesical therapy for bladder cancer. Urol Clin North Am 15:661-669 Stallworth JR, Brasfield DM et al (1980) Congenital miliary tuberculosis proved by open lung biopsy specimen and successfully treated. Am J Dis Child 134:320-321 Steiner P,Rao M et al (1976) Miliary tuberculosis in two infants

M. M. Madkour after nursery exposure: epidemiologic, clinical, and laboratory findings. Am Rev Respir Dis 113:267-271 Stenius-Aarniala BS, Tukiainen P (1979) Miliary tuberculosis. Acta Med Scand 206:417-422 Sutton FD, Hudson LD et al (1974) Recognition and management of the adult respiratory distress syndrome. Chest 66:34S-36S Treip C, Meyers D (1959) Fatal tuberculosis in a general hospital. A diagnostic problem. Lancet 1:164-1'67 Vanham G, Toossi Z, Hirsch CS et al (1997) Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. Tubercle Lung Dis 78:145-158 Vijayan VK (2000) Disseminated tuberculosis. J Indian Med Assoc 98:107-109 Willcox PA, Potgieter PD et al (1986) Rapid diagnosis of sputum negative miliary tuberculosis using the flexible fibreoptic bronchoscope. Thorax 41:681-684 Williams MH, Yoo OH (1973) Pulmonary function in miliary tuberculosis. Am Rev Respir Dis 107:858 Yu YL, Chow WH et al (1986) Cryptic miliary tuberculosis. Q J Med 59:421-428

19 Tuberculosis and Pregnancy M. MONIR MADKOUR

risk factor for the development of tuberculosis has never been proven, as suggested in the past (Snider 19.1 Introduction 301 1984; Espinal et al. 1996). Pregnancy has no effect 19.2 Epidemiology 301 on the incidence or prognosis of tuberculosis. The 19.3 Pathogenesis 302 effect of tuberculosis on the outcome of pregnancy, 19.4 Pregnancy-Tuberculosis: Interrelations 303 the fetus, and the neonate has lost most of its 19.5 Clinical Features 303 19.6 Personal Series 303 importance due to the existence of effective anti19.6.1 Case Illustration 1 304 tuberculous agents. However, a delay in diagnosing 19.6.2 Case Illustration 2 304 active tuberculosis poses a real risk to the pregnant 19.6.3 Case Illustration 3 306 woman, fetus, and infant. Tuberculosis in pregnant 19.7 Diagnosis 306 19.8 PPD Skin Test 306 women may be asymptomatic, particularly when 19.9 Chest Radiography 307 it invades extrapulmonary sites in the body, and 19.10 Microbiology and Other therefore presents a great risk of neonatal morbidAdvanced Laboratory Tests 307 ity and mortality. Symptoms related to tuberculosis 19.11 Breast-Feeding and Its Contraindications 307 may be mild and mimic those caused by normal 19.12 Treatment of Active TB During Pregnancy 308 19.13 Treatment of Multidrug-Resistant TB pregnancy such as dyspnea and fatigue (Gogus et al. During Pregnancy 309 1993; Machin et al. 1992). The disease may first pres19.14 Preventive Treatment During Pregnancy 309 ent in the neonate, and acute tuberculosis may later References 311 be discovered in the mother. Hageman et al. (1980) reported that tuberculosis was initially presented and diagnosed in neonates in 15 of 26 cases, and subsequent investigations of their mothers detected 19.1 active disease. Congenital and neonatal tuberculosis Introduction associated with undiagnosed and untreated mothers carries an infant mortality rate of 50% (Nemir The prevalence of tuberculosis in women of child- and O'Hare 1985). Antenatal screening of pregnant bearing age and during pregnancy is increasing women in endemic areas should include plain chest both in developing countries and among ethnic radiography if pulmonary tuberculosis is suspected, immigrants in urban areas of developed countries with proper shielding of the abdomen. (Centers for Disease Control and Prevention 1994, The outcome of pregnancy for the tuberculous 1995; Ahmed et al. 1999; Hageman 1998). The mor- woman, fetus, and neonate who are treated promptly bidity and mortality among pregnant women with with antituberculous drugs is similar to that for pregtuberculosis, the fetus, and the neonate have also nant women without tuberculosis. increased, particularly among those co-infected with HIV (Adhikari et al.1997).A high index of suspicion by attending clinicians and effective measures during the prenatal period are essential for reducing these 19.2 risks (Starke 1997). Pregnancy as a predisposing or Epidemiology

CONTENTS

M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Specific epidemiological data on the incidence of tuberculosis during pregnancy at present is unknown even in developed countries such as the USA. Available data from the 1970s, based on hospitalized

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pregnant women with tuberculosis in a New York hospital, was estimated by Schaefer et al. (l975) as ranging from 0.6% to 1% and was higher (3.2%) among those with pulmonary disease. These data were equivalent to those from nonpregnant women with tuberculosis of comparable age. In the late 1980s and 1990s, the incidence of tuberculosis in the USA has increased in young adults and children, which implies that tuberculosis during pregnancy may be more prevalent. Such a rise was attributed to the HIV epidemic as the most important risk factor, immigrants of different ethic origin coming from countries where tuberculosis is endemic, decline in public health services, and increased transmission in congregate settings. Tuberculosis among foreign-born persons has increased from 22% in 1986 to 35% in 1995 in the USA (McKenna et al.1995). The epidemiology of tuberculosis in England and Wales has changed its pattern since 1988 (Ormerod 2001). During the 1980s, white ethnic women over the age of 50 contributed 50% of the cases, and only a minority of patients were of child-bearing age (Medical Research Council 1992). In 1998, over 56% of cases were foreign-born immigrants from the Indian subcontinent and of African ethnic origin. The median age of these immigrants was under 30 years, while among the white ethnic women, tuberculosis declined to 37% with a minority of child-bearing age (Rose et al. 2001). In developing countries, poverty compounded by HIV infection form closely associated risk factors and contributed to an estimated 70% mortality due to tuberculosis in the age group 15-40 years including women of child-bearing age (Connolly and Nunn 1996). In Africa, there are no data on the number of women of child-bearing age co-infected with HIV and tuberculosis. The World Health Organization (WHO) estimated that about 50% of women of childbearing age living in sub-Saharan Africa has been infected with M. tuberculosis (Connolly and Nunn 1996). In South Africa, the incidence of tuberculosis is 311 per 100,000 population, and the prevalence rate of HIV infection at an antenatal clinic was reported as 7.6% (Epidemiology Comments, Department of Health, Pretoria 1996). In developing countries, the maternal mortality attributed to tuberculosis is high. Ahmed and colleagues (l999) from Zambia reported hospital-based, nonobstetric maternal mortality among pregnant women with tuberculosis. These authors analyzed 251 maternal deaths over a 2-year period (1996-1997) in Lusaka University Hospital.

A total of 106 (42%) maternal deaths was due to direct obstetric causes, and 145 (58%) were due to nonobstetric causes. Tuberculosis, a nonobstetric cause of maternal death, was associated with 25% of pregnant women. Other reports from Zambia indicated that 25% of antenatal women were infected with HIV, and a rate of 1 woman in 8 was presumed to be co-infected with HIV and TB. The risk of developing overt tuberculosis is expected at 8% annually (Fylkesnes et al. 1997; Dolin et al. 1994). Neonatal tuberculosis is rare, and there are no reports of a recent increase in incidence from countries with a high incidence of HIV infection. Adhikari et al. (l997) from South Africa reported a hospitalbased incidence of neonatal tuberculosis. Eleven neonates with culture-confirmed tuberculosis were reported from King Edward VIII Hospital in Natal, seen in a I-year period (l996-1997). The mothers of six of these neonates were co-infected with TB and HIV. One neonate and two mothers died within the first 3 months. These data suggest that the increase in the co-infections of pregnant women in endemic areas for both diseases was associated with an increased incidence of neonatal TB.

19.3 Pathogenesis The pathogenesis of tuberculosis during pregnancy is similar to that in nonpregnant women. Mycobacterium tuberculosis enters the body commonly by inhalation. The bacilli are ingested by the alveolar macrophages. A few weeks later two responses take place: tissuedamage response (delayed-type hypersensitivity-specific humoral response) and macrophages-activating response (cell-mediated immunity). Cytokines produced by alveolar macrophages and T-Iymphocytes (CD4+) take an active role in the host defense. Subsequently, granuloma formation occurs in the lungs. Granulomas may heal with fibrosis and scarring, but some bacilli may remain viable and reactivate if the patient's immunity is suppressed. Hematogenous spread of the bacilli to the placenta from pulmonary or extrapulmonary disease is the most common route of transmission. Rarely, transmission by direct spread and extension of the disease from pre-existing genital tuberculosis may occur (Hallum and Thomas 1995; Kaplan et al. 1980; BazazMalik et al. 1983). The organisms are transmitted to the placenta and may infect the chorionic villi, amniotic fluid, and decidua. The bacilli may be transmit-

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ted to the fetus via the umbilical vein, infecting the liver first, and may pass through the main circulation, leading to lung disease. Fetal ingestion or aspiration of infected amniotic fluid may also be another mode of transmission of tuberculosis to the fetus in utero or the time of birth (Vallejo and Starke 1992). Transmission of infection in the neonatal period may also occur via inhalation if the mother is not diagnosed or treated.

19.4 Pregnancy-Tuberculosis: Interrelations "For the virgin, no marriage; For the married, no pregnancy; For the pregnant, no confinement; For the mother, no suckling." In an excellent comprehensive review on the interrelationships between tuberculosis and pregnancy, Miller and Miller (1996) abstracted these statements from archaic reports reflecting the opinions and advice of scientists and clinicians in various medical eras. The influence of pregnancy as a risk factor for the development of tuberculosis, altering the course of the disease and prognosis, has intrigued clinicians for centuries since the days of Hippocrates through the early 1920s. The pendulum of opinion swung widely from the beneficial value of pregnancy on tuberculosis to the detrimental effect on the patient as it worsened the course of the disease, and abortion was even advised. Even before the discovery of antituberculous treatment, pregnancy was reported not to worsen the course of the disease (Hill 1928, cited by Miller and Miller 1996). Shortly after the introduction of antituberculous drugs, many reports in the early 1950s, 1960s, and 1970s confirmed that there was no significant difference between the patients who improved and those whose tuberculosis progressed during pregnancy or after delivery (Cohen et al.1952; Hedvalll953; Schaefer et al.1975; Espinal et al.1996). There is no evidence that pregnancy increases the risk of tuberculosis in the postpartum period in HIVinfected or uninfected women (Espinal et al. 1996). The effect of tuberculosis on the course of pregnancy, fetus, and neonate is similar to that in nontuberculous pregnant women. Untreated active tuberculosis poses a real great risk to the pregnant woman, fetus, and neonate. Women with active tuberculosis have a significantly

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higher incidence of spontaneous abortion, congenital malformations of the fetus, and neonatal disease (Bjerkedal et al. 1975).

19.5 Clinical Features Tuberculosis may present initially with symptoms mimicking those physiologically related to normal pregnancy such as dyspnea, fatigue, and lack of energy. The attending clinician has to have a high index of suspicion and make diligent efforts to diagnose the disease in order to prevent fetal and neonatal infection, particularly in endemic areas and among groups at risk (HIV, alcoholics, drug addicts, the homeless). Pregnancy does not alter the mode of onset or the presentation of initial symptoms. However, one-half to one-third of pregnant women with tuberculosis are asymptomatic and unaware of the disease, and the diagnosis may be missed (Wilson et al. 1973; Schaefer et al. 1975; Carter and Mates 1994). However, the clinical features of tuberculosis during pregnancy are similar to those in nonpregnant women.

19.6 Personal Series In our series, review of the medical records of pregnant women with active tuberculosis who attended the Military Hospital in Riyadh were analyzed. Between 1985 and 2000, there were 39 patients with active tuberculosis during their pregnancy. Their age ranged between 16 and 42 years (average 19.7 years). We found a past history of tuberculosis (treated or partially treated) in 13 patients (33.3%). History of contact and a family history of tuberculosis were found in 9 patients (23%). Pulmonary tuberculosis was the most common site of infection and found in 23 of these pregnant women (59%). Extrapulmonary localizations of active tuberculosis were found in 16 (41 %). Cough, fever, easy fatigability, shortness of breath, and weight loss were the most common presenting features and found in 23 patients (59%). Accidental discovery of cervical lymph adenopathy during antenatal screening was noted in 9 patients (23%). Four women were aware of the cervical lymphadenopathy, while the other 5 women were unaware of

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its presence. None of the pregnant women with tuberculous lymphadenitis were symptomatic at the time of the antenatal screening. The 4 women who were aware of lymph node enlargement did not notice any recent changes in size. Two of these women with TB lymphadenitis presented with pancytopenia or thrombocytopenic purpura (see case illustrations). The mean gestational age at the time of clinical presentation or suspicion during antenatal screening was 24.6 weeks, with a range of 1-35 weeks. Tuberculous pleural effusion was found in 3 patients (7.7%). One patient had a vulval swelling that was biopsied and found to be tuberculous by culture and histopathology findings (2.6%). One patient had military tuberculosis (2.6%). One patient had tuberculosis of the knee (2.6%). One patient had cold abscess in the right thigh (see case illustration) (2.6%). All 39 patients had positive tuberculin skin tests. Pulmonary tuberculosis was diagnosed in 23 pregnant women by plain chest radiography findings and confirmed by cultures from sputum, early morning gastric aspiration, and urine, identifying M. tuberculosis. None of the 39 patients in our series had HIV co-infection, drug-resistant tuberculosis, or nontuberculous mycobacterial disease. In New York, the incidence of tuberculosis during pregnancy has increased in association with the HIV epidemic. Margono et al. (1994) reviewed the computerized records of 16 pregnant women with active tuberculosis attending two hospitals. In a 6year period (1985-1991) they found 5 cases, while they found 11 cases in the following 2-year period (1991-1992). A HIV test was positive in 7 among 11 tested pregnant women with tuberculosis. Pulmonary tuberculosis was the most common site (10 cases, 62.5%), and extrapulmonary sites were found in 6 cases (37.5). Tuberculous lymphadenitis was the least common site of extrapulmonary localization reported by these authors in contrast to our own series where the lymph node was the most common location. Early reports on tuberculosis during pregnancy in the USA mostly involved pulmonary localizations (Good et al. 1981). In Great Britain, pregnant women with tuberculosis mostly had an extrapulmonary site of the disease. In a prospective study carried out in Northwick Park District General Hospital, Llewelyn et al. (2000) reported 13 pregnant women with active tuberculosis seen prospectively over a 30-month period (1995-1998). Extrapulmonary sites of localization of tuberculosis were present in 9 patients (69.2%). All patients in this recent study were immigrants to Britain.

M. M. Madkour

19.6.1 Case Illustration 1 A 36-year-old Saudi woman in the 24th week of pregnancy presented with a swelling in the middle third of the right thigh. The swelling started as a small area but increased in size over the following 3 months before presentation, when it became painful. There was no history of trauma or discharge. The patient had fever, sweating, and loss of appetite over the same period. She had never been ill before, and other systematic enquiries were negative. The patient was not acutely ill or in distress. A large soft-tissue swelling extending through the anterolateral aspect of the proximal third of the right thigh was seen. The skin over it was normal, and it was slightly tender. The uterus size corresponded with 24 weeks' gestation. The hemogram, coagulation profile, and biochemical values were normal. ESR was 40 mm/h. Ultrasound of the right thigh depicted a large, soft-tissue, cystic swelling with thick mobile fluid, which could be an abscess or hematoma. It measured 16 cm in length and contained about 800 ml of fluid (Fig. 19.1a). MRI of the right thigh was done, axial T1 and T2 slices obtained through both upper femora and the lower pelvis. The post-gadolinium images were not diagnostic due to the patient's movement. MRI depicted a huge, well-defined, elliptical mass in the right rectus femoris muscle extending from its attachment down to the distal thigh (Fig.1b,c). Similar masses were also noted in the right iliopsoas muscle and right pectineus muscle. These masses showed low T1 and high T2 signal intensity, most probably indicating pus caused by tuberculous abscesses. No bone involvement was seen, and MRI of the thoracolumbar spine showed no evidence of spinal involvement (Fig. 19.1b,c). Aspiration of 200 ml of yellowish purulent pus was obtained and sent for microbiological examination and culture for tuberculosis. The culture yielded M. tuberculosis that was sensitive to all antituberculous drugs. Rifampicin, INH, and ethambutol were given to this patient, and she responded well to treatment. A normal, spontaneous, full-term delivery of a healthy infant was the result in this patient.

19.6.2 Case Illustration 2 A 33-year-old woman presented to my clinic with a 2-month history of fever, sweating, and drug cough.

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a

c Fig.19.1a-d. A 36-year-old pregnant woman presented with a swelling of her right thigh. a Ultrasound shows a well-defined cystic mass with relatively thick wall (curved arrow) consistent with localized abscess. TI-weighted (b) and T2-weighted (c) MRI of the same patient show the abscess in the right vastus lateralis muscle as low signal intensity lesion on TI and as homogeneous high signal intensity on T2 (arrowheads). d MRI of lower pelvis demonstrated a gravid uterus with gestational sac (arrowheads). This was done in an attempt to trace the source of this tuberculous abscess and avoid missing abdominal or pelvic pathology (the safety of MRI in pregnancy is not yet clear). Patient completed the treatment and delivered a normal healthy boy

She had lost 21 kg in weight over that period. She cough, and weight loss. She looked pale, feverish, but was 95 kg in weight before the illness and 74 kg at there was no change in the size of the left supraclathe time of presentation. She had a past history of vicular lymph nodes. There were no other clinical two swellings on the left side of the neck for the past findings. There were purpura and petechiae over the 17 years with no recent changes in their size. She had lower limbs. Repeat chest radiograph, with shield five healthy children. The patient looked pale, her tem- over the abdomen, remained normal. The hemoperature was 38.3°C. There were two enlarged lymph gram showed pancytopenia with Hb 10.9 G/dl, WBC nodes in the left supraclavicular region but no other 2.400/mm3, platelets 31,OOO/mm 3, and the blood film clinical findings. The hemogram showed Hb 1O.9G/dl, showed microcytic hypochromic features. Her serum WBC 9000/mm 3 , platelets 211,OOO/mm 3, and the blood iron and other biochemical parameters were otherfilm showed hypochromic microcytic anemia. wise normal. Coombs test was negative. Bone marrow Biochemical parameters were normal, but the aspiration and biopsy showed hypercellularity in the Mantoux test was positive. The patient refused lymph myeloid and erythroid series with normal maturanode biopsy and discharged herself against medical tion and increased number of megakaryocytes. advice. Two months later she presented to me with a The marrow iron store was normal. Ultrasound of 3-day history of hematuria and skin petechiae over the abdomen was normal. Lymph node biopsy was her legs. She was pregnant with gestational age of performed and showed granulomas with caseation. 9 weeks. She continued to have fever, sweating, dry The biopsy culture yielded M. tuberculosis 4 weeks

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later. She responded well to antituberculous treatment, and the hemogram returned to normal after 3 months. She subsequently had a normal, spontaneous delivery of a healthy baby.

19.6.3 Case Illustration 3 A 30-year-old woman from AI-Qurayyat, northern Saudi Arabia, was referred to our hematologist because of thrombocytopenia, anemia, and convulsions 5 days after a normal delivery. The patient was well during her antenatal follow-up until the last month of her pregnancy when she presented with epistaxis and melena. At that time, her hemoglobin was only 5.8 Gldl, low platelet of 12,OOO/mm3 with normal white cell count. The bleeding time was prolonged, and bone marrow aspiration could not be done at the referring hospital. She was suspected to have idiopathic thrombocytopenic purpura and was started on prednisolone 60 mg oral daily. She was given 5 units of blood and 4 units of platelets and vitamin K. Five days prior to her transfer to our hospital, she delivered a healthy girl. After delivery, she developed headache and recurrent attacks of convulsions. Brain CT scan with contrast was normal. Her fits were controlled with phenytoin. She was admitted on arrival to our general intensive care unit (GICU). She gave a history of easy bruising for the past few years and had not been investigated for this complaint. She had delivered a baby boy 4 years ago with fetal abnormalities, the exact nature of which was not known, who died 3 months after birth. Her history included pulmonary tuberculosis while pregnant with that congenitally deformed boy 4 years ago. She discontinued her antituberculous medication after 2 months when she discovered that she was pregnant. She decided herself to discontinue taking the antituberculous drugs for fear of taking medication during pregnancy. The patient looked ill, emaciated, with bruises all over her body, particularly in the upper limbs. She was not jaundiced and had no lymphadenopathy. Fine apical crepitations were heard over the right lung. Other systemic examinations were normal. The hemogram showed features of severe iron deficiency anemia with low platelets of 18,OOO/mm3 and normal white cell count. Biochemical parameters were normal. Plain chest radiography showed multiple cavitating lesions in the right upper lobe compatible with active tuberculosis. Abdominal cT showed no abnormalities. Bone

M. M. Madkour

marrow aspiration and trephine showed marked hypercellular marrow with hyperactive myeloid and erythroid series with normal maturation and an increased number of megakaryocytes. The iron store was normal. EEG and MRI of the brain were normal. Lumber puncture showed normal CSF. She was seen by our pulmonologist and started on four antituberculous antibiotics. The prednisolone dosage was gradually reduced and stopped. The patient's platelets and hemoglobin returned to normal. She had no further convulsions or bruises. Her follow-up at the chest and hematology clinic was satisfactory, and the patient had a full recovery.

19.7 Diagnosis Prenatal health care screening may help in identifying pregnant women with active pulmonary or extrapulmonary tuberculosis. Early detection of active disease may help in preventing serious consequences to the mother, fetus, and neonate. A high index of suspicion by the attending clinician is essential' particularly in endemic areas and among women at high risk for tuberculosis infection. Detailed history and clinical examination and screening investigations are required to achieve this goal. Investigations may include microbiological methods, plain chest radiography, tuberculin skin testing, and other laboratory tests as appropriate to each patient.

19.8 PPD Skin Test Earlier concepts suggested that a false-negative tuberculin skin testing might occur as a result of the suppression of cell-mediated immunity due to pregnancy (Finn et al. 1972). Pregnancy is found by controlled studies to have no demonstrable effect on tuberculin skin testing, and the test is valid at any time during pregnancy (Snider 1984; Present and Comstock 1975; Huebner et al. 1993). In endemic areas, a positive tuberculin skin test identifies individuals with previous infection by M. tuberculosis but does not indicate the state of disease activity, and a negative response may be noted in patients with active disease. HIV-infected pregnant women react to tuberculin skin testing in a similar way to nonpregnant women with HIV infection with

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similar rates of anergy. Anergy is not more frequent as a result of pregnancy among women with HIV infection (Mofenson et al.1995). In the USA, the recommendations of the Advisory Committee at the Center for Disease Control (CDC 1990) with regard to performing the tuberculin test for screening individuals at high risk are as follows: (a) pregnant woman with clinical features suggestive of tuberculosis, (b) women with known or suspected exposure to tuberculosis, (c) women at high risk of developing tuberculosis. A skin reaction of 15 mm in low-risk patient and 5-10 mm in immunocompromised patients is considered positive and should lead to the inclusion of chest radiography as part of the screening (Division of Tuberculosis Elimination, CDC 1991). The interpretation of the tuberculin skin test and the rationale of using various induration size measurements as a positive indication among different populations at variable risk have been the subject of debates in many recent publications. In populations at high risk of developing tuberculosis, contact with active tuberculosis patients, those with clinical or imaging evidence of tuberculosis, or patients with HIV or immunocompromised individuals, induration of at least 5 mm is considered positive and indicating infection with M. tuberculosis. For children in contact with high-risk adults, immunesuppressed patients due to other medical illness, and foreign-born persons, an induration of at least 10 mm is considered positive. In populations at low risk for tuberculosis, an induration of at least 15 mm is considered positive. There has been no classification scheme study of tuberculin induration measurements for pregnant women with or without HIV infection, nevertheless, the tuberculin skin test reaction during pregnancy is not different from that for nonpregnant women (American Academy of Pediatrics 1992; American Thoracic Society 1993; Centers for Disease Control and Prevention 1995).

19.9 Chest Radiography In the past, routine chest radiography was performed as part of screening investigations for all pregnant women (Freth 1952). This routine was found to be potentially hazardous due to irradiation of the fetus, particularly during the first trimester (Bonebrake et al. 1978). However, chest radiography can be per-

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formed for pregnant women if active pulmonary tuberculosis is suspected particularly in endemic areas and among women at high risk. In nonendemic areas, a positive tuberculin skin test in pregnant women is an indication for chest radiography. Appropriate shielding of the abdomen will reduce irradiation to 50 millirads, which is a less hazardous dose for the fetus, and chest radiography is preferably done after the first trimester. Women with chest symptoms even with a negative tuberculin skin test should have a chest radiograph done (Swartz and Reichling 1978; Brent 1989).

19.10 Microbiology and Other Advanced Laboratory Tests The diagnosis of active tuberculosis during pregnancy may be difficult, particularly when conventional sputum smear staining is negative. Specimens from sputum, gastric or bronchial aspirates, urine and other body fluids, or tissue biopsies should be sent for culturing. Recent advances in automated culture systems such as BACTEC (Becton Dickson Diagnostic Instrument Systems, Towson, MD, USA) are now widely used in many laboratories. Immunological tests and PCR are useful tools that can be used, when available, for the diagnosis of tuberculosis during pregnancy.

19.11 Breast-Feeding and Its Contraindications Breast-feeding by mothers with newly discovered active tuberculosis, before initiating treatment, has been a subject of debate among authors in developed and developing countries. Authors from developed countries, where alternative feeding of infants is readily available, have their own views. Authors from poor, developing countries where feeding substitutes are not easily available have different views as well. To make matters worse, co-infection with HIV complicates the issue of breast-feeding in these poor countries. Transmission of HIV via breast milk to infants is a real threat, and starvation and infant death follow if breast-feeding is contraindicated in such circumstances. This issue is clearly defined in developed countries as a contraindication to breastfeeding (Oxtoby 1988).

308

Nursing mothers with active tuberculosis who are receiving antituberculous treatment should be encouraged to breast-feed their infants. Concerns about the side-effects of antituberculous drugs secreted in the mother's milk have been investigated by many authors. Rifampicin, INH, and streptomycin concentrations in breast milk have been measured after the administration of 600 mg, 300 mg, and 1 g of these drugs, respectively. Peak milk concentrations ranged between 10 and 30 mg!l when rifampicin was given in a dose of 600 mg. A concentration level of 16.6 mg!l was found 3 h after INH injection at a dose of 300 mg, while streptomycin 30 min after intramuscular injection of 1 g dose reached a concentration of 1.3 mg!I. These concentrations of antituberculous drugs in breast milk have no toxic effect on the infant (Lawrence and Lawrence 2001; Berlin and Lee 1979; Vorherr 1974; Fugimoritt and Imais 1957; Snider and Powell 1984). These antituberculous medications have been used directly and safely in infants (Snider 1984). Tuberculosis infection and active tuberculosis are considered two separate issues with regard to breastfeeding. Breast-feeding is not contraindicated in women with previous tuberculosis infection. In women with active tuberculosis, the American Academy Committee has indicated that respiratory contact puts these infants in jeopardy. Breast milk in such patients does not contain tubercle bacilli and can be pumped into bottles and fed to these infants until medication has commenced, and the mother is no longer considered infective. The committee also recommended that active tuberculosis is an indication for temporary isolation of the mother until she has received about 2 weeks of antituberculous therapy. Mothers with TB mastitis should have the milk pumped and discarded until the breast lesion has completely healed (American Academy of Pediatrics 1992). The presence of concomitant HIV and active tuberculosis in mothers living in developed countries is an absolute contraindication to breast-feeding. The rate of HIV transmission to infants via breast milk is estimated to range between 5% and 20% or higher (Lawrence 1997; Lawrence and Lawrence 2001; Oxtoby 1988). Data on freezing or heating breast milk to destroy HIV type I are sparse and insufficient (Ando et aI. 1989). In developing countries where alternative affordable infant feeding, sanitary measures, and medical resources are not available to prevent the transmission of HIV to infants, the World Health Organization, UNICEF, and the United Nations AIDS program recommend the following measures: (l) If

M. M. Madkour

an adequate and safe milk substitute is available, then breast-feeding should not be used. (2) If substitutes are not available, then women who are HIV-positive should be offered the choice of what is appropriate for their circumstances and supported in their choice (WHO 1998).

19.12 Treatment of Active T8 During Pregnancy Pregnant women with active pulmonary or extrapulmonary tuberculosis should be treated without delay. Delay in treatment poses a real threat to the pregnant women, her fetus, and the contact. Treatment should not be interrupted in women with active tuberculosis if pregnancy is discovered while she is on antituberculous medication. The only exception is streptomycin, which may cause fetal ototoxicity and should be replaced unless no alternative drugs are available (Hamadeh and Glassroth 1992). Concerns about the teratogenic effect of antituberculous drugs have been extensively studied by many authors in recent years. Isoniazid, rifampicin, ethambutol, and pyrazinamide are the most widely used and carefully evaluated drugs with no evidence of increased teratogenicity (Steen and Seainton-Ellis 1977; Snider et al. 1980; Starke 1997; Czeizel et aI. 2001). The human teratogenic potential of isoniazid, rifampicin, ethambutol, pyrazinamide, ethionamide, prothionamide, and cycloserine during pregnancy was carefully studied by Czeizel from Hungary and his colleagues from Denmark (Czeizel et al. 2001). These authors surveyed case-controlled, populationbased, congenital abnormalities from the Hungarian National Birth Registry between 1980 and 1996, regarding the safety of 7 oral antituberculous drugs used during pregnancy. These drugs were used during the second and third months of gestation to treat pregnant women with active tuberculosis (critical period for most major congenital abnormalities). The authors reported their findings as shown in their table (Table 19.1). They found no detectable teratogenic risk to the fetus; however, the number of pregnant women who were treated with these drugs during the critical period was limited (6 cases vs 21 controls). The guidelines and recommendations with regard to the choice of the antituberculous drug regimen are subject to revisions and updating depending on drug sensitivity and resistance tests. The most commonly used regimen at present involves the use of two to four or more oral drugs including isoniazid, rifam-

309

Tuberculosis and Pregnancy Table 19.1 Characteristics of the antituberculosis drugs studied, in addition to the number of cases and controls during the study period between 1980 and 1996 (reproduced with permission from Czeizel et al. 2001) Antituberculosis drugs Isoniazid Rifampicin Ethambutol Pyrazinamide Ethionamide Prothionamide Cycloserine Total

Table dose (mg) 50 150,300 250 500 250 250 250

Recommended daily treatment (mg) 50-300 450-600 15-15 mglbwkg 35 mglbw kg (1000-2000) 750-1000 500-1000 750-1000

Cases

Controls for all CAs

Crude POR

(n=22865) n (0/0)

(n=38151) n (0/0)

POR (950/0CI)

6 (0.03) 0(0.00) 4 (0.02) 0(0.00) 0(0.00) 0(0.00) 1 (0.00) 11 (0.05)

17 (0.04) 1 (0.00) 6 (0.02) 3 (0.01) 1 (0.00) 1 (0.00) 0(0.00) 29 (0.08)

0.6 (0.2-1.5) 0.6 (0.0-13.7) 1.1 (0.3-13.7) 0.2 (0.0-4.6) 0.6 (0/0-13.7) 0.6 (0.0-13.7) 5.0 (0.2-122.9) 0.6 (0.3-1.3)

POR, prevalence odds ratio; CA, congenital abnormality; CI, confidence interval; bw, body weight

picin, ethambutol, and pyrazinamide. The duration of treatment may range between 6 and 9 months. Ethambutol should be added in the first 2 months to INH and rifampicin. Alternatively, pyrazinamide can be used in the first 2 months with INH and rifampicin. Pyridoxine 50 mg daily should be added to prevent seizure in the newborn when INH is used. The dosages of these drugs are similar to those used in nonpregnant women. Streptomycin should be avoided unless no alternative antituberculous drug is available. Kanamycin and capreomycin share the same potential for producing ototoxicity as streptomycin. Successful treatment of active tuberculosis during pregnancy depends on the identification of the organisms by culture and sensitivity, the use of multiple drugs to which the organisms are sensitive, and close follow-up of the patient for treatment compliance.

19.13 Treatment of Multidrug-Resistant T8 During Pregnancy Single or multiple drug-resistant tuberculosis during pregnancy is increasing. Isoniazid-resistant tuberculosis during pregnancy can be treated with rifampicin and ethambutol for 18 months (Vallejo and Starke 1992). However, the management of pregnant women with multidrug-resistant tuberculosis is a real dilemma. Iseman recommended the use of 5-6 drugs in areas of known multidrug-resistant tuberculosis until drug sensitivity patterns are identified. This makes the treatment of pregnant women with multidrug-resistant tuberculosis extremely difficult, because some of these medications may

be contraindicated or of unknown teratogenic effect (Iseman 1993). There are no clear recommendations or guidelines to this problem because of possible serious consequences to the fetus. Good and colleagues reported their views and stated: 'it is reasonable to consider therapeutic abortion in this setting' (Good et al. 1981). Nitta and Milligan (1999) from the MDR tuberculosis unit in Los Angeles reported their experience of management of four pregnant women with multidrug-resistant pulmonary tuberculosis. MDR tuberculosis was acquired due to their nonadherence to previous regimens of antituberculous treatment. One of them chose termination of her pregnancy. In one, treatment was withheld, and only rifampicin and INH were given to prevent TB progression; another patient was allowed to continue self-administered medication during her pregnancy. Yet another patient was not treated during pregnancy. All three women who carried their gestation to full term had healthy infants. Retreatment of all four women was done using 5-6 drugs including ethambutol, cycloserine, para-aminosalicylic acid (PAS), capreomycin, ofloxacin, and clofazimine given as daily DOT for 17-24 months. The authors concluded that individualized treatment is considered according to each patient's medical and psychosocial needs. They also demonstrated that MDR tuberculosis during pregnancy can be managed safely and successfully.

19.14 Preventive Treatment During Pregnancy Pregnant women infected with tuberculosis with a positive tuberculin skin test but who are asymptomatic form

M. M. Madkour

310

a controversial issue (Vallejo and Starke 1992). Should they receive preventive treatment, and what are the guidelines in developed and developing countries? Authors from developed countries do not adopt the same policy or guidelines with regard to preventative therapy during pregnancy. Not all infected, pregnant women in developed countries have the same chance of developing active tuberculosis. In the USA, the incidence of tuberculosis infection (not disease) in the general population is approximately 7% (MedchillI999). Individuals who have a positive tuberculin test have a 5% chance of developing active tuberculosis within the first 1-2 years after exposure and can gain an additional 5% chance over the rest of their lives (Barnes and Barrows 1993). As pregnancy has no effect on the development of active tuberculosis, some clinicians may delay initiating preventive therapy until after delivery (Hamadeh et al. 1992). Starke (1997) has debated the value of initiating isoniazid treatment during pregnancy for such individuals particularly those with poor compliance to treatment. However, he structured an algorithm to serve as a guideline for clinicians in the USA to help identify those who will need treatment and when to start it (Fig. 19.2).

Starke recommended the initiation of preventive therapy to those co-infected with HIV. The cost-effectiveness of preventive therapy was reported in the USA by Medchill from Phoenix in 1999. His study was based on the data about the chance of development of active TB among those with a positive tuberculin test and found preventive therapy to be cost-effective. Isoniazid is given as a single daily dose of 300 mg for 6-12 months. Hepatotoxicity should be monitored at least monthly (Hamadeh and Glassroth 1992). In Great Britain, preventive therapy is less widely used in asymptomatic women with a positive tuberculin test but may be recommended for refugees and new immigrants (Ormerod 2001). In developing countries, preventive treatment during pregnancy is not an adopted policy as tuberculosis is highly endemic, and the prevalence of a positive tuberculin test is high. In a large study from Chile, 840 pregnant women in the third trimester were assessed by tuberculin test. Over 50% of them had a positive tuberculin test, none developed symptoms of tuberculosis during pregnancy, and 93% were followed up for 1 year with no evidence of active disease. The Chilean Ministry of Health policy is 'not to perform tuberculin testing as a means of

Positive Mantoux Sj Test During Pregnancy Chest Radiograph (abdominal shield) I Abnonnal

Nonnal

Recent High risk Exposure for progression to disease

y

Start isoniazid and monitor carefully

Consistent with "Older" infection Calcified or likely fibrotic lesion active (not active) and tuberculosis no symptoms or symptoms

I.

'd . Start Isom8Z1 After delivery

Start isoniazid after delivery if repeat chest radiograph is nonnal

I

Three sputum AFB smears and cultures

I

Start multidrug therapy (isoniazid, rifampin, ethambutol, usually pyrazinamide)

Fig. 19.2. Evaluation and treatment of a pregnant woman with a positive Mantoux skin test. AFB, acid-fast bacilli (Starke's algorithm, Starke 1997, from Clinics in Perinatology; with permission from Dr. Stark)

Tuberculosis and Pregnancy

identifying infected women and not to treat asymptomatic tuberculin-positive individuals' (Sepulveda et al. 1995).

References Adhikari M et al (1997) Tuberculosis in the newborn: an emerging disease. Pediatr Infect Dis J 16:1108-1112 Ahmed Yet al (1999) A study of maternal mortality at the university teaching hospital, Lusaka, Zambia: the emergence of tuberculosis as a major non-obstetric cause of maternal death. Int J Tuberc Lung Dis 3:675-680 American Academy of Paediatrics (1992) Committee on infectious diseases: screening for tuberculosis in infants and children. Pediatrics 93:313 American Thoracic Society (1993) Control of tuberculosis in the United States. Am Rev Respir Dis 146:1623 Ando Y et al (1989) Effect of freeze thawing breast milk on vertical HTLV-l transmission from seropositive mothers to children. Jpn J Cancer Res 80:405 Barnes PF, Barrows SA (1993) Tuberculosis in the 1990's. Ann Intern Med 19:400-410 Bazaz-Malik G et al (1983) Tuberculosis endometritis. A clinicopathological study of 1000 cases. Br J Obstet Gynaecol 90:84-88 Berlin C, Lee C (1979) Isonizid and acetylisoniazid disposition in human milk, saliva and plasma. Fed Proc 38:426 Bjerkedal T et al (1975) Course and outcome of pregnancy in women with pulmonary tuberculosis. Scand J Respir Dis 56:245-250 Bonebrake CR et al (1978) Routine chest roentgenography in pregnancy. JAMA 240:2747-2748 Brent RL (1989) The effect of embryonic and fetal exposure to x-ray, microwaves and ultrasound: counseling the pregnant and non-pregnant patient about these risks. Semin Oncol 16:346-368 Carter EJ, Mates S (1994) Tuberculosis during pregnancy: the Rhode Island experience, 1987 to 1991. Chest 106: 1466-1470 Centers for Disease Control (1990) Screening for tuberculosis and tuberculosis infection in high-risk populations. Recommendations of the Advisory Committee for Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 39:1-7 Centers for Disease Control and Prevention (1994) COR Curriculum on tuberculosis, what the clinician should know, 3rd edn. Department of Health and Human Services, Atlanta, pp 6-7 Centers for Disease Control and Prevention (1995) Screening for tuberculosis and tuberculosis infection in high-risk populations. MMWR Morb Mortal Weekly Rep 44:19 Cohen JD et al (1952) The tuberculous mother. Am Rev Respir Dis 65:1-23 Connolly M, Nunn P (1996) Women and tuberculosis. World Health Statist Quart 49:115-119 Czeizel AE et al (2001) A population-based case-control study of the safety of oral anti-tuberculous drug treatment during pregnancy. Int J Tuberc Lung Dis 5:564-568 Division of Tuberculosis Elimination, Center for Prevention Services (1991) Center for Disease Control and American

311 Thoracic Society: core corriculum on tuberculosis. US Public Health Services, New York Dolin PJ et al (1994) Global tuberculosis incidence and mortality during 1990-2000. Bull WHO 72:213-220 Epidemiology Comments (1996) Report of the review of the tuberculosis control programme of South Africa, June 10 to 25, 1996: Department of Health, Pretoria, South Africa, vol 23, pp 2-20 Espinal MA et al (1996) The effect of pregnancy on the risk of developing active tuberculosis. J Infect Dis 173:488-491 Finn R, Hill CA et al (1972) Immunological responses in pregnancy and survival of foetal hemograft. Br Med J 3: 150-152 Freth A (1952) Routine x-ray examination of the chest at an antenatal clinic. Lancet 1:287-288 Fujimori H, Imais (1957) Studies on dihydrostreptomycin administered to the pregnant and transferred to their fetuses. Jpn Obstet Gynecol Soc 4:133-149 Fylkesnes K et al (1997) The HIV epidemic in Zambia: sociodemographic prevalence patterns and indications of trends among childbearing women. AIDS 11:339-345 Gogus S et al (1993) Neonatal tuberculosis. Pediatr Pathol13: 299-304 Good JT et al (1981) Tuberculosis in association with pregnancy. Am J Obstet GynecoI140:492-498 Hageman J (1998) Congenital and perinatal tuberculosis: discussion of difficult issues in diagnosis of difficult in diagnosis and management. J Perinatal 18:389-394 Hageman J et al (1980) Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Paediatrics 66:980-984 Hallum JL, Thomas HE (1995) Full-term pregnancy after proved endometrial tuberculosis. J Obstet Gyaecol Br Emp 62:548 Hamadeh MA, Glassroth J (1992) Tuberculosis and pregnancy. Chest 101:1114-1120 Hedvall E (1953) Pregnancy and tuberculosis. Acta Med Scand 147:1-101 Huebner RE et al (1993) The tuberculin skin test. Clin Infect Dis 17:968-975 Iseman MD (1993) Treatment of multi-drug-resistant tuberculosis. N Engl JMed 329:784-791 Kaplan C et al (1980) Placental tuberculosis in early and late pregnancy. Am J Obstet Gynecol137:858-860 Lawrence RA (1997) A review of the medical benefits and contraindications to breast-feeding in the United States. Maternal and Child Health Technical Information Bulletin. National Center for Education in Maternal and Child Health, Arlington Lawrence RM, Lawrence RA (2001) Given the benefits of breast-feeding, what contraindications exist? Pediatr Clin North Am 48:235-251 Llewelyn M et al (2000) Tuberculosis diagnosed during pregnancy: a prospective study from London. Thorax 55: 129-132 Machin GA et al (1992) Perinatally acquired neonatal tuberculosis: report of two cases. Peadiatr PathoI12:707-716 Margono F, Mroueh J, Garely A et al (1994) Resurgence of active tuberculosis among pregnant women. Obstet Gynecol 83:911-914 McKenna MT et al (1995) The epidemiology of tuberculosis among foreign-born persons in the United States, 1986 to 1993. N Engl JMed 332:1071

312 Medchill MT (1999) Prenatal purified protein derivative skin testing in a teaching clinic with a large Hispanic population. Am J Obstet GynecoI180:1579-1583 Medical Research Council Cardiothoracic Epidemiology Group (1992) National Survey of Notifications of Tuberculosis in England and Wales in 1988. Thorax 47:770-775 Miller KS, Miller JM Jr (1996) Tuberculosis in pregnancy: Interactions, diagnosis and management. Clin Obstet GynecoI39:120-142 Mofenson et al (1995) Mycobacterium tuberculosis infection in pregnant and non-pregnant women infected with HIV in the women and infants transmission study. Arch Intern Med 155:1066-1072 Nemir RL, O'Hare D (1985) Congenital tuberculosis. Am J Dis Child 139:284-287 Nitta AT, Milligan D (1999) Management of four pregnant women with multi-drug-resistant tuberculosis. Clin Infect Dis 28:1298-1304 Ormerod P (2001) Tuberculosis in pregnancy and puerperium. Thorax 56:494-499 Oxtoby MJ (1988) Human immunodeficiency virus and other viroses in human milk: placing the issue in broader perspective. Pediatr Infect Dis J 7:825-835 Present PA, Comstock GW (1975) Tuberculosis sensitivity in pregnancy. Am Rev Respir Dis 112:413-416 Rose AMC et al (2001) Tuberculosis at the end of the 20th century in England and Wales: results of a national survey in1998. Thorax 56:173-179

M. M. Madkour Schaefer G et al (1975) Pregnancy and pulmonary tuberculosis. Obstet GynaecoI46:706-715 Sepulveda RL et al (1995) The influence of BCG immunization on tuberculin reactivity in healthy Chilean women in the third trimester of pregnancy. Tuberc Lung Dis 76:28-34 Snider D (1984) Pregnancy and tuberculosis. Chest 86: 105-135 Snider DE, Powell K (1984) Should women taking anti-tuberculosis drugs breastfeed? Arch Intern Med 144:589-590 Snider DE et al (1980) Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 122:65-79 Starke JR (1997) Tuberculosis, an old disease but a new threat to the mother, fetus and neonate. Clin Perinatol 24: 107-127 Steen JSM, Seainton-Ellis DM (1977) Rafampicin in pregnancy. Lancet ii:604-605 Swartz HM, Reichling BA (1978) Hazards of radiation exposure for pregnant women. JAMA 239:1907-1908 Vallejo JG, Starke JR (1992) Tuberculosis and pregnancy. Clin Chest Med 13:693-707 Vorherr H (1974). Drug excretion in breast milk. Postgrad Med J 56:97-104 Wilson EA et al (1973) Tuberculosis complicated by pregnancy. Am J Obstet GynecoI115:526-529 World Health Organization (1998) HIV and infant feeding: guidelines for healthcare managers and supervisors. World Health Organization, Geneva. Publication WHO/FRH/NUT 98.2, UNAIDS/98.4, UNICEF/PD/NUT/(J) 98.2

20 Post-primary Pulmonary Tuberculosis M. MONIR MADKOUR, Y. ABusABAAH, ALI BEN MOUSA, ALI AL MASOUD

CONTENTS 20.1 20.2 20.2.1 20.2.2 20.2.3 20.2.4 20.2.5 20.2.6 20.2.7 20.2.8 20.2.9 20.2.10 20.2.11 20.2.12 20.3 20.3.1 20.3.2 20.3.3 20.3.4 20.3.5 20.4 20.4.1

Pathogenesis and Pathology 313 Clinical Features and Complications 315 Hemoptysis in Pulmonary Tuberculosis 316 Massive Hemoptysis in Tuberculosis 316 Rasmussen Aneurysm 317 Endobronchial Tuberculosis 318 Bronchiectasis as a Complication of Post-primary Pulmonary TB 318 Pneumothorax as Complication of Post-primary Pulmonary TB 318 ARDS and Tuberculosis 319 Tuberculous Bronchopleural Fistula 319 Aspergilloma (Mycetoma) 319 Tuberculomas 320 Tuberculous Pulmonary Gangrene 320 Tuberculosis, Lung Cancer and Other Neoplasia 320 Diagnosis of Post-primary Pulmonary TB 320 Imaging Features of Post-primary Pulmonary TB 320 Microbiology of the Sputum and Bronchial Aspirate 321 Bronchoscopic Diagnosis 321 Tuberculin Skin Test 322 Other Diagnostic Investigations 322 Treatment of Post-primary Pulmonary TB 322 Response to Treatment 324 References 324

M. M. MADKouR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia Y. ABusABAAH, ABIM Fellow, Respiratory Medicine, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia A. BEN MousA, MD Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia A. AL MAsouD, MD Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Post-primary pulmonary tuberculosis is a chronic disease commonly caused by either endogenous reactivation of a latent infection or exogenous re-infection by Mycobacterium tuberculosis. It has other synonyms derived mostly from the route of transmission of the infection or from the age of the patient at the onset of the disease, including endogenous reactivation primary tuberculosis, exogenous re-infection pulmonary tuberculosis, or adult-onset pulmonary tuberculosis. The term being used here is 'post-primary pulmonary tuberculosis'to include both re-infection and reactivation forms. The clinical features of the disease are not specific, and the imaging features are suggestive but can simulate other diseases. The definitive diagnosis depends on the identification of M. tuberculosis bacilli, using conventional microbiological methods of sputum smear and culture or radiometric culture methods such as BACTEC or DNA probe PCR-based assays which can identify drug-resistant strains as well. Sputum smear and culture remain the most important investigative methods. Smear-negative sputum may delay the diagnosis for 4-8 weeks or longer if the culture is also negative. A presumptive diagnosis based on the clinical and radiographic features should be made with initiation of treatment after the exclusion of other possible causes of the radiographic findings. Infection with HIV is a great risk for the development of either endogenous reactivation or exogenous re-infection pulmonary disease (Millar and Horne 1979; Barnes et al. 1991; Heyderman et al. 1998). The development of drug-resistant pulmonary tuberculosis is a real global concern that indicates a failure of the tuberculosis control program. The current treatment is both toxic and expensive, and new drug development is sparse at present.

20.1 Pathogenesis and Pathology The development of post-primary pulmonary tuberculosis as a result of endogenous reactivation or exog-

314

enous re-infection in low-risk and high-risk areas has been debated for many years among authors (Glynn et al. 2001). Balasubramanian and colleagues reviewed the world literature on these issues and added their own views (Balasubramanian et al. 1994). Schools of thought adopted by those researchers based on microbiological studies of tissue specimens from the lung and lymph nodes of the primary complex. Some authors quoted by reviewers suggested that the primary complex is sterile within 5 years, while other authors suggest that virulent bacilli lie dormant in a metastatic site seeded hematogenously within the vulnerable region. Cultures of apical lung lesions yielded viable bacilli in 25%-76% as reported by some of the quoted authors, and transmission via the bloodstream was suggested. Other researchers examined the sputum and urine cultures in patients living in Bangalore, India, and compared the bacilli virulence, INH sensitivity, and phage typing of the isolates and drew conclusions about the biological evidence of exogenous re-infection in that study. Epidemiologists have noted that high- or lowrisk incidence rates of infection in different areas of the world played an important role (in exogenous reinfection or endogenous reactivation). In areas with a risk greater than 1% of developing countries, with the likelihood of repeated episodes of droplet infection via the airway, the disease is more likely to be due to exogenous re-infection. In areas of low-risk (less than 0.05%), as in developed countries, endogenous reactivation is more likely to be the cause of the disease. Some other authors gave evidence of the contributions of both exogenous re-infection as well as endogenous reactivation. Balasubramanian et al. hypothesized that the implantation of the vulnerable region is directly transmitted via the airway (exogenous re-infection). They also concluded that more studies using genetic fingerprinting of Mycobacterium bacilli isolates would help in the future in disease control in endemic areas and in the development of new vaccines. Immune suppression resulting from HIV infection leads to higher rates of co-infection with tuberculosis. Recent molecular epidemiological studies have indicated that up to 40% of newly diagnosed tuberculous patients and over 70% of recurrences may be due to exogenous re-infection (Stead and Bates 2000; Bates et al. 2001). Among the immunosuppressed patients due to HIV, exogenous re-infection was the leading mechanism. Endogenous reactivation contributed to only 16% of patients in a low-risk area in developed countries and more than 70% in a high-risk area in developing countries (Alland et al. 1994; Brande et al. 1998; Small et

M. M. Madkour et aI.

al. 1994; van Rie et al. 1999; McDonough et al. 2000; Rook and Zumla 2001; Caminero et al. 2001; Bandera et al. 2001; Wallis and Johnson 2001). Caminero and colleagues (2001) reported 912 patients with culture-proved pulmonary tuberculosis between 1991 and 1996 on a Spanish island with a moderate risk rate of incidence. They were treated and followed up for at least 12 months after completing chemotherapy and were culture-negative. Twentythree patients (2.5%) became culture positive again. DNA fingerprinting results were available from 18 patients with recurrence of the disease. DNA fingerprinting was available of pretreatment and recurrent isolates and was reviewed. In 8 patients (44%), the genotype of the recurrent isolate showed a different pattern to the pretreatment isolate. These authors concluded that in 8 patients, 2 of them HIV-positive, exogenous re-infection was the cause of the recurrent pulmonary tuberculosis. Immune suppression or reduction of immune responses may also occur in certain diseases such as silicosis, diabetes mellitus, or with corticosteroid and other immunosuppressive drugs used for malignancies or connective tissue diseases. Regardless of the mode of infection (exogenous or endogenous), the apex of the lung (apical-posterior segments) is the most common site of post-primary pulmonary tuberculosis. Specific factors permitting the progression of tuberculosis in most cases are not yet known (Wallis and Johnson 2001). The host immune response and the role of the cellmediated immunity of activated macrophages and T-cells and the expression of cytokines (Garcia et al. 2002) in response to M. tuberculosis glycolipids and lipoproteins have been discussed in the pathogenesis of primary pulmonary tuberculosis in Chap. 17. Post-primary pulmonary tuberculosis commonly affects the apical and posterior segments of the upper lobe or the superior segment of a lower lobe. After its localization, inflammatory granulomatous nodular formations with cellular infiltrates, fibrosis, central necrosis, and caseation may take place. Hilar and paratracheal lymphadenitis (Woodring 1986) in post-primary tuberculosis is a rare occurrence and reported in approximately 5% of patients (see Figs. 23.18, 23.20, 23.21, 23.22, 23.39, 23.40b). Healing with fibrosis and calcification (Fig. z.25) of lung parenchymal lesion may occur, leading to traction of the trachea (Fig. 23.21, 23.22, 23.23), and in late advanced stages when the lung is destroyed and replaced by extensive fibrosis, displacement of the mediastinum may occur (Fig. 23.24). The initial upper lobe infiltration may form a pneumonic consolidation, and cavitation often

Post-primary Pulmonary Tuberculosis

315

occurs in 40%-80% of patients (Fig. 23.20, 23.26a, b) sheep with udder tuberculosis. It can also be transmit(Rohenberg and Shaw 1996). Tuberculous consolida- ted to humans from cows as an airborne infection tion with cavity formation may expand and form a (Geppert and Leff 1979; Liesegang and Cameron 1980; lung abscess discharging large numbers of the bacilli Sauret et al. 1992). The incidence ofM. bovis in humans in the sputum as was noted in one of our patients is higher in rural areas with infected herds (Moda et al. (Fig. 23.26d). Tuberculous cavities with areas of 1996). Ingestion of contaminated milk, particularly by necrosis and caseation may rupture into the pleura, young children living in developing countries, leads to leading to empyema (Fig. 23.34b) or a bronchopleu- establishment in the cervical and less frequently in the raj fistula (Fig. 23.36). Rupture of a tuberculous cavity axillary lymph nodes (scrofula). The bacilli may also into the trachea or bronchi is a common complica- affect the intestine, kidney, bones, and central nervous tion and occurs in up to 40% of patients (Rohenberg system in endemic areas with a similar pathogenicity and Shaw 1996). Bronchogenic spread of necrotic and to M. tuberculosis (Moda et al. 1996). HIV patients caseous tissue loaded with the bacilli to other parts of co-infected with M. bovis have been reported in San the lung fields on the same side or opposite lung may Diego, USA, near the border with Mexico (Dankner occur (Figs. 23.19,23.20, 23.27b,c, 23.28b,c). Infection et al.1993). Nontuberculous mycobacterial organisms starts at the newly seeded sites with nodular infiltrate may also cause a similar pulmonary infection (see bronchopneumonia or similar tissue destruction and Chap. 11). fibrosis to the lung parenchyma (Figs. 23.25, 23.26a, z.27b, c, 23.28b). A severe form of transbronchial spread of infection takes the form of dissemination in both lungs (Fig. 23.28c). 20.2 Endobronchial involvement of the bronchial wall is Clinical Features and Complications common, leading to scarring and luminal narrowing and post-stenotic emphysema (Figs. 23.22b, 23.30a, b, Post-primary tuberculosis often presents with a 23.25, 23.31b), atelectasis, and cystic or tubular bron- gradual onset of symptoms that may be tolerated by chiectasis due to traction or endobronchial fibrosis as the patient. The duration of symptoms before prea common complication of the tuberculous disease sentation may vary widely, from 3 days to 23 months process. It is often located in the upper lobes but can (Dahmash et al. 1995; Maartens and Beyers 2002). occur at any other site (Figs. 23.30a, b, 23.31a, b). Post- The presenting features may initially be related to the tuberculous bronchiectasis, although often asymp- respiratory system or present as constitutional symptomatic, may cause hemoptysis in these patients. toms or both. Cough is the most frequently reported A tuberculous cavity larger than 25 mm in diameter presenting feature. Initially, it is dry but later becomes may persist long after successful antibiotic treatment. productive. The sputum may be mucoid, muco-puruColonization with fungi forming a ball of mycetoma lent, blood-stained, or with massive hemoptysis. Chest may rarely occur (Fig. 23.26b, 23.37a,b), and hemopty- pain due to associated pleurisy or pneumothorax may sis may rarely be a presenting complaint. be a presenting symptom. Dyspnea due to tuberculous Tuberculous granulomatous tissue nodules may pneumonia or bilateral fibrocavitary disease may be be encapsulated with connective tissue during vari- the presenting symptom. Fever with sweating and able stages of disease healing and activity, leading chills are common, particularly at night. Other constito tuberculomas found in 3%-6% of patients. It may tutional symptoms including weakness, anorexia, and be single or multiple with a central area of necrosis weight loss, which are nonspecific, may also be present or calcification (Figs. 23.32a-d). Tuberculomas may (Dunlap et al. 2000; Johnson and Ellner 2000). occur in both primary and post-primary pulmonary Symptoms related to extrapulmonary tuberculotuberculosis. sis such as tuberculous monoarthritis, Pott's disease, In bovine tuberculosis, the M. bovis bacilli are genitourinary symptoms, or other organ involvebacteriologically distinctive from M. tuberculosis but ment might accompany the respiratory symptoms at otherwise cause identical pathogenesis, lung lesions, the time of presentation. We retrospectively reviewed and clinical disease. In humans, M. bovis is a zoonotic the records of 176 adult patients with post-primary disease that has been virtually eliminated in developed pulmonary tuberculosis who had a positive sputum countries and other developing countries that practice culture for M. tuberculosis. They attended our hospipasteurization of milk and immunization of dairy tal between 1998 and 2000. The frequency of history/ herds (Grange et al. 1994; Dannenberg 2001). The symptoms, physical findings, and imaging features of organism is excreted in the milk from cows, goats, and these patients are presented in Table 20.1.

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Table 20.1. Clinical features of 176 patients with culture-positive post-primary pubnonary tuberculosis No. of patients

Percentage

166 128 40 135 80 98 76 58

94.3 72.7 23.0 76.7 45.4 55.7 43.2 32.9

105 Crackles Localized wheezes 23 Bronchial sound 55 Diminished sound 66 20 Clubbing 16 Extrapulmonary 28 Bronchoscopy

59.6 13.0 31.2 37.5 11.4 9.0 16.0

Clinical features

Symptoms: Cough Expectoration Hemoptysis Fever Sweating Weight loss Dyspnea Chest pain

Signs:

The frequency of these symptoms may vary, being more intense among those co-infected with HIV (Corbett et al. 2000). The frequency of symptoms was also reported from a large tuberculosis center in Riyadh for 1566 hospitalized patients with pulmonary tuberculosis during 1983-1987. Fever and constitutional symptoms were reported in 77.7%, cough with or without expectoration in 94.3%, and hemoptysis in 40.7% (AlHajjaj et al. 1991). In another series from the south of Saudi Arabia, Al Wabel et al. (1995) reported on 190 patients with post-primary pulmonary tuberculosis who were hospitalized over a 2.5-year period. Cough was noted in 84%, expectoration in 65%, hemoptysis in 23%, fever and constitutional symptoms in over 40% of patients. Pulmonary tuberculosis in elderly patients with underlying and concomitant other chronic illnesses in 80 patients were reported from Riyadh (Dahmash et al. 1995). These patients had diabetes mellitus or malignancies, and some were on steroids, and these illnesses occurred in 86% of them, but none had HIY. Cough was noted in 85%, expectoration in 60%, fever in 66%, hemoptysis in 17.5%, anorexia, weight loss, and other constitutional symptoms in over 50%. Choyke and colleagues (1983) reported on 103 patients with adult-onset pulmonary tuberculosis: 85% were symptomatic, with fever in 40%, cough in 37%, weight loss in 23.6%, and hemoptysis in 8%. Physical examination of the chest may be normal despite the presence of pulmonary infiltrations depicted by chest radiography. Displacement of the trachea due to lung fibrosis and collapse may

be found (Fig. 23.21). Chest wall retraction due to fibrosis or prominence due to associated pleural effusion may be found. Features of consolidations with crepitation and bronchial breathing may be detected. Localized wheezes may be present, indicating endobronchial disease. Other systemic features including pallor, rarely clubbing of the fingers and toes in chronic cases, weight loss, dyspnea, and other extrapulmonary involvement may be found on physical examination. Patients with post-primary pulmonary tuberculosis may present with clinical features similar to those of community-acquired pneumonia. Al-Zeer and colleagues (1998) reported a series of 64 patients admitted to hospital during the pilgrimage season to Mecca in 1994 with an initial diagnosis of community-acquired pneumonia. All patients came from developing countries. Microbiologically proven M. tuberculosis was found in 13 patients (20.3%) and was the most common cause of pneumonia among this group.

20.2.1 Hemoptysis in Pulmonary Tuberculosis Hemoptysis is often an alarming presenting symptom in patients with tuberculosis. It may vary in severity from a slight tinge of blood mixed with the sputum, to mild, moderate, or severe, massive, lifethreatening hemoptysis. In our series of 176 patients with microbiologically proved pulmonary tuberculosis, 28 patients (16%) had slight to mild hemoptysis that was managed with chemotherapy and conservative treatment. Active pulmonary tuberculosis with or without cavitation or post-tuberculous bronchiectasis is the most common cause among these patients. Rarely, the development of bronchial carcinoma in these patients as well or mycetoma or other unrelated illnesses could be the cause of hemoptysis in tuberculous patients (Stebbings and Lim 1999; Hirshberg et al. 1997).

20.2.2 Massive Hemoptysis in Tuberculosis Life-threatening massive hemoptysis due to active tuberculosis or post-tuberculous bronchiectasis has been reported as 'common in comparison to other causes listed in many publications', as reported by Hsiao et al. (2001) from the USA. Life-threatening, massive hemoptysis is defined by most authors as

Post-primary Pulmonary Tuberculosis

expectoration of at least 200 ml of blood in 24 h, significant drop of hemoglobin requiring blood transfusion, or failure to respond to conservative treatment such as oxygen supplement, morphine, and antibiotics (Wong et al. 2002; Abal et al. 2001; Lee et al. 2000; Hsiao et al. 2001; Conlan et al. 1983). In South Africa, Conlan et al. (1983) reviewed 123 patients with massive hemoptysis due to different causes. Tuberculosis was by far the most common cause, either due to culture-proved active disease or bronchiectasis as a sequela to tuberculosis. These authors reported that active pulmonary tuberculosis as a cause of massive hemoptysis was found in 47 patients (38%),24 men and 23 women aged between 19 and 60 years. Thirty-seven patients had bronchiectasis, and 17 (45.9%) had bilateral upper lobe bronchiectasis secondary to former tuberculosis. The total number of patients with massive hemoptysis with or who had tuberculosis was 64 (52%). The remaining causes were chronic narcotizing pneumonitis in II, lung abscess in 6, lung cancer in 6, primary fungal pneumonia in 4, bronchovascular fistula in 5, and miscellaneous causes in 7 patients. In France, Mal and colleagues (1999) reported the intermediate and long-term outcome of bronchial artery embolization (BAE) performed on 46 patients with massive hemoptysis. Tuberculosis (active or sequela) was found in 23 patients (50%) as a cause of the massive hemoptysis. Idiopathic in 10, bronchiectasis in 4, lung cancer in 2, and 1 patient each due to other various causes. The outcome of BAE was favorable with an immediately successful result in stopping the bleeding, but complications were also frequent. Revascularization may occur with recurrence of hemoptysis, technical failure in BAE, spinal cord injury related to invisible anastomotic connections between the bronchial circulation and the anterior spinal artery. The authors recommended that BAE should be avoided in patients with minor hemoptysis. In the USA, Hsiao et al. (2001) from Stanford reported the assessment of modalities of investigations used for the localization of the site of bleeding in patients with massive hemoptysis. They reviewed the records of 28 patients seen between 1988 and 2000 who presented with massive hemoptysis. They found 16 patients with tuberculosis (57%), 14 with tuberculous bronchiectasis, and 2 with active disease, bronchogenic carcinoma in 2, and other causes had 1 patient each. These authors noted, 'Contrary to the statistics reported in many recent series, tuberculous bronchiectasis is the most common underlying etiology for massive hemoptysis in our patients'.

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The authors also indicated that the overall mortality of patients with massive hemoptysis was 7%-80% and operative mortality was 30%-40% as they found from reviewing the literature on the subject. These authors reported, 'The angiographic signs in hemoptysis include hyperplasia of the bronchial artery trunk and branches, bronchopulmonary anastomoses, and bronchial arterial aneurysms', which were seen on angiography of these patients. They concluded that fibroptic bronchoscopy before BAE is unnecessary in patients with hemoptysis of known origin. In Kuwait, Abal et al. (2001) prospectively studied 52 hospitalized patients with hemoptysis of variable degrees of severity over a period of 1 year. Twenty had blood-stained sputum, and 32 had frank hemoptysis including 16 with massive blood expectoration. They found that pulmonary tuberculosis (active or old) was the most common cause, found in 17 patients (32.7%). Other causes included carcinoma in 5, bronchitis in 3, 1 patient each due to other causes, and unknown cause in 13 patients. These authors managed 80.8% of their patients conservatively, and only 19% required BAE or surgery. Recurrent hemoptysis occurred in 12% at the I-year follow-up in this series. In a retrospective study of BAE for massive hemoptysis, Wong et al. (2002) from South Africa reported on 165 patients, and bilateral post-tuberculous bronchiectasis was the most common cause (75%). The short-term outcome of BAE was satisfactory in controlling hemoptysis in all patients. Thoracic aortography was done during the initial assessment, and they noted pathologic enlargement of the bronchial arteries and the presence of nonbronchial systemic collaterals with arteriovenous shunting including intercostal arteries. One patient had transient paraparesis, and the authors noted that the presence of spinal arteries was not considered a contraindication to embolization.

20.2.3 Rasmussen Aneurysm This is a rare phenomenon that can cause massive, life-threatening hemoptysis. It involves invasion of a peripheral pulmonary artery located within a tuberculous cavity often in the upper lobe. Invasion of the arterial wall by tuberculous granulation tissue leads to granulomatous vasculitis with replacement of the adventitia and media with fibrin during the process of healing. This will lead to weakening of the arterial wall with mycotic pseudoaneurysmal formation in one or more locations (see Chapter 43). Rupture of

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the aneurysm will lead to massive, life-threatening hemoptysis as reported in 5% of postmortem cases (Winer-Muram and Rubin 1990; Kim et al. 2001).

20.2.4 Endobronchial Tuberculosis Endobronchial tuberculosis is a common complication of post-primary pulmonary tuberculosis. It may occur in up to 40% of patients, and the most common source of bronchial wall infection is a contiguous tuberculous cavity (Rohenberg and Shaw 1996). Rarely, the bronchial wall may be affected by a hilar or paratracheal tuberculous caseating lymphadenitis. Hematogenous or lymphatic spread of infection to the bronchial wall may occur (Buckner and Walker 1990). The role of the bronchial tree in the spread of tuberculosis to other parenchymal segments or lobes on the same or opposite side by transbronchial spread of caseous material leading to bronchopneumonia is well recognized (1m et al.1993). Hoarseness ofvoice due to laryngeal involvement and localized wheezes due to bronchial disease in the chest are common clinical features. The imaging features of plain radiography and CT may show multiple nodular opacities, bronchial wall thickening, post-stenotic dilatation, lobar hyperinflation, pulmonary collapse, and atelectasis (Figs. 23.27 and 23.28). Endobronchial tuberculosis, its definition, epidemiology, pathogenesis and pathology, classification, clinical features, diagnosis, the role of bronchoscopy in the diagnosis and management, and the treatment are considered in a separate chapter (see Chap. 21).

20.2.5 Bronchiectasis as a Complication of Post-primary PulmonaryTB Bronchiectasis is a common sequela of pulmonary tuberculosis (primary and post-primary). It may occur primarily as a result of endobronchial tuberculosis with irreversible bronchial wall dilatation (Lee et al. 1991). Secondary tuberculous bronchiectasis occurs as a result of lung parenchymal destruction with fibrosis (traction bronchiectasis). Based on high-resolution CT, bronchiectasis was found in 27% of patients with pulmonary tuberculosis, and the upper lobes were the most common site (Cartier et al. 1999). In our series of 176 patients with pulmonary tuberculosis, 17 (9.6%, see Table 20.2) had imaging features of tuberculous bronchiectasis (Figs. 23.9, 23.27c, 23.28c, 23.29, 23.30, and 23.31). Typically, the

M. M. Madkour et al. Table 20.2. Imaging features of 176 patients with culture-positive post-primary pulmonary tuberculosis Imaging features

No. of patients Percentage

Unilateral-parenchymal 119 Bilateral-parenchymal 57 Infiltrates and consolidation 144 Cavities 61 Bronchiectasis 17 Destroyed lungs 2 Calcifications 22 (LN, parenchymal and pleural) Pneumothorax 8 Lymphadenopathy 19 (hilar and paratracheal) Lung infiltrates with pleural 46 effusion Mycetoma 2 Tuberculomas 3 Bronchopleural fistula 1

67.6 32.3 81.8 34.6 9.6 1.1

12.5 4.5 10.8 26.1 1.1 1.7 0.5

apical and posterior segments of the upper lobes are the most common sites of tuberculous bronchiectasis (Fig. 23.27c). Chest radiography may show ring shadows with occasional fluid levels (Figs. 23.9 and 23.29). Features on CT and HRCT will show the details of the bronchial wall changes (Figs. 23.28c, 23.30, and 23.31) (McAdams et al. 1995). Tuberculous bronchiectasis may also occur in the lower lobes of the lung. It is usually asymptomatic, but secondary bacterial infection or hemoptysis may be a presenting feature.

20.2.6 Pneumothorax as Complication of Post-primary PulmonaryTB Pneumothorax may occur during active post-primary pulmonary tuberculosis. Rupture of a tuberculous cavity contiguous to the pleura may result in pneumothorax. The incidence has been reported as low, ranging from 0.6% to 1% in hospitalized tuberculous patients (Wilder et al.1962; Ihm et al.I972). In our own series of 176 patients (see Table 20.2), pneumothoraxoccurred in 8 (4.5%). In 1 patient,pneumothorax failed to respond to antituberculous treatment and chest tube insertion, and a bronchopleural fistula was suspected. A fistulogram confirmed the presence of a bronchopleural fistula and active tuberculosis in the apical segment of the left upper lobe (Fig. 23.36). Pneumothorax may also occur in treated and healed pulmonary tuberculosis (Lambert 1956).

Post-primary Pulmonary Tuberculosis

20.2.7 ARDS and Tuberculosis

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20.2.8 Tuberculous Bronchopleural Fistula

Acute respiratory distress may occur in patients with Tuberculous bronchopleural fistula is rarely reported bilateral chronic cavitary or bronchogenic pulmo- nowadays with the recent advances in chemotherapy. nary tuberculosis with a high hospital mortality rate Most recent reports are on patients with late complicaof up to 47%. Dyer and Potgieter (1984) described tions of collapse therapy for pulmonary tuberculosis three adult patients from South Africa with adult that was done in the past (Johnson et al. 1973; Iseman respiratory distress syndrome (ARDS) due to pul- and Madsen 1991; Uchida et al. 1999; Weissberg and monary tuberculosis (nonmiliary). Weissberg 2001). It may develop after lung resection A 31-year-old woman with cough, fever, and for pulmonary tuberculosis. The lung parenchymal dyspnea lasting 2 months had bilateral pulmonary tuberculous cavity may rupture into the pleural space tuberculosis, and because of the severe dyspnea and with pneumothorax, and the diagnosis can be made the abnormal arterial blood gases, she was mechani- by fistulography (Fig. 23.36 radiology of pulmonary cally ventilated. The diagnosis of tuberculosis was TB chapter). A tract may form between the bronchus made by sputum-positive direct smear. Antituber- contiguous to the tuberculous cavity and the pleura, culous treatment was started, but the patient died. producing a bronchopleural fistula. It is estimated that Postmortem examination showed left upper and a bronchopleural fistula can occur in patients with right lower lobe cavitary tuberculosis. The second active extensive pulmonary parenchymal tuberculosis patient was a 22-year-old woman with a similar pre- in less than 1% (Miller 1981; Woodring 1986; Winersentation who died in the ICU with postmortem evi- Muram and Rubin 1990). Patients are usually sympdence of bilateral tuberculous bronchopneumonia tomatic, and sputum production may increase. Plain with a left bronchopleural fistula. The third patient chest radiography may show air in the pleural space, had a similar presentation but did not require a changing air-fluid level, and contralateral spread of ventilation and responded well to antituberculous tuberculous infiltration. CT may depict the sites of the treatment. bronchopleural fistula (Kim et al. 2001). Levy and colleagues (1987) from South Africa The management of these patients is usually reported a retrospective study of 15 patients admit- difficult. Patients with a susceptible organism may ted to the ICU between January 1982 and June 1985 respond to antituberculous treatment and intercoswith a confirmed diagnosis of pulmonary tuberculo- tal tube drainage. Patients with multidrug-resistant sis. These patients required ICU admission for respi- tuberculosis are treated with chemotherapy and ratory failure. They comprised 1.5% of 933 patients lobectomy or pneumonectomy and pleural decortiwith pulmonary tuberculosis hospitalized in Hillbow cation unless found to have respiratory insufficiency Hospital. Eleven patients required ventilation, and 5 (Iseman and Madsen 1991). Endobronchial occlusion died. Miliary tuberculosis was found in 6 patients, by coils has been found to be an effective method tuberculous bronchopneumonia in 5 patients, lobar (Uchida et al. 1999). pneumonia in 3 patients, bilateral lung parenchymal destructive disease in 2. Penner and colleagues (1995) from Canada 20.2.9 reviewed the records of 13 patients with confirmed Aspergilloma (Mycetoma) pulmonary tuberculosis (7 women and 6 men) from 1984 to 1993, and all had respiratory failure requir- A chronic tuberculous cavity may be colonized by ing mechanical ventilation. Seven patients had mili- the spores of Aspergillus fumigatus to form a fungal ary or disseminated tuberculosis and 6, tuberculous ball (Aderaye and Jajaw 1996). It may occur in 11% of pneumonia. Nine patients died, and only 4 survived. patients with a chronic tuberculous cavity, and approxM. tuberculosis was isolated in all patients from imately 25%-55% of patients with aspergilloma have respiratory or nonrespiratory sites. These authors a history of the disease (Kim et al. 2001). Patients with also quoted the work of Agarwal and colleagues aspergilloma are often asymptomatic but may present (1977) regarding 16 patients with respiratory fail- with hemoptysis (Kaestel et al. 1999). Plain radiography ure due to tuberculous pneumonia who required of the chest may depict a mobile, rounded mass with mechanical ventilation. air-crescent ring (Fig.23.26b and 23.37a,b). Surgical resection is essential if associated with hemoptysis and systemic antifungal treatment is ineffective.

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20.2.10 Tuberculomas

Solitary or multiple, round or oval, tuberculous pulmonary mass lesions may be noted on the chest radiographs in approximately 5% of patients (Kim et al. 2001; Winer-Muram and Rubin 1990). They may be the only radiographic manifestation of primary or post-primary pulmonary tuberculosis. Their diameter may range between 0.5 and 4.0 cm or larger with a smooth or sharply defined margin. Central caseation or calcifications may be found in 20%-30% of tuberculomas. Satellite lesions may be seen in up to 80% of these lesions.

20.2.11 Tuberculous Pulmonary Gangrene

An extremely rare but fatal complication of tuberculous cavitary lesion is the involvement of adjacent vessels and the development of arterial and venous vasculitis with thrombosis, leading to pulmonary gangrene (Reich 1993). Khan and colleagues (1980) from New York reported on 4 patients with pulmonary gangrene due to pulmonary tuberculosis, and only 1 survived. The first patient was a 55-year-old man who presented with fever, cough, and hemoptysis lasting 3 months. Chest radiography showed bilateral upper lobe infiltrate with cavitation and intracavitary mass. The sputum smear was positive for the bacilli. Chemotherapy was started, but the patient developed pneumothorax and died. Autopsy showed tuberculous pneumonia with extensive tuberculous arteritis and occlusion of the lumen by thrombosis. The second patient died before establishing the diagnosis, and subsequent sputum culture taken on admission grew M. tuberculosis. Autopsy showed pulmonary vasculitis in arteries and veins contiguous with the tuberculous cavity. The third patient was known to be tuberculous before and had undergone lobectomy, and now presented with fever and a large pulmonary cavity with an intracavitary mass in the right upper lobe. The sputum smear was positive, and culture grew M. tuberculosis. She responded well to chemotherapy. The fourth patient had a similar chest radiographic cavity with intracavitary mass and died. The bacilli were found at autopsy as well as lung parenchymal cavities, tuberculous granulomatous vasculitis with thrombosis of the pulmonary arteries and veins. We reviewed the world literature and found 18 previously reported patients with pulmonary gangrene mostly due to Klebsiella pneumonia and other

organisms but not due to M. tuberculosis. Lopez-Contreras et al. (1994) reported a 61-year-old alcoholic man with a 4-month history of cough, fever, and weight loss. Sputum smear and culture were positive for M. tuberculosis. Chest radiography showed a large cavity with air-fluid level and a free-floating mass. The patient died, and autopsy was denied.

20.2.12 Tuberculosis, Lung Cancer and Other Neoplasia

The relationship between pulmonary tuberculous and lung cancer has been frequently debated. Such a relationship was raised by Greenberg and colleagues (1964), indicating the co-existence of carcinoma and tuberculosis of the lung. The co-existence between bronchogenic carcinoma and tuberculosis creates a difficult diagnostic problem for radiologists as the radiographic changes may be misinterpreted as progression of tuberculosis (Kim et al. 2001; WinerMuram and Rubin 1990). Brown and Almenoff (1992) reviewed the literature of various retrospective studies on this co-existence. They reviewed other malignancies including leukemia, lymphoma, myelofibrosis, head and neck malignancies, as well as the use of immunosuppressive chemotherapy, and their relationship with the development of tuberculosis. They noted that tuberculosis was 6-9 times more common among patients with Hodgkin's disease, lung cancer, and non-Hodgkin's lymphoma than those with other malignancies. These authors noted, 'Tuberculosis was more likely to be diagnosed at the time of tumor diagnosis in patients with lung, head and neck malignancies, and disease in these patients was predominantly confined to the lungs'. Profound suppression of the cell-mediated immune response caused by malignant diseases or as a result of severe immunosuppressive chemotherapy is the most likely cause of the high risk of developing tuberculosis among these patients (Brown and Almenoff 1992).

20.3 Diagnosis of Post-primary Pulmonary T8 20.3.1 Imaging Features of Post-primary PulmonaryTB Various imaging modalities are used for the depiction of features of post-primary pulmonary

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Post-primary Pulmonary Tuberculosis

tuberculosis. The imaging features of post-primary pulmonary tuberculosis can be broadly classified as lung parenchymal disease with cavitation, endobronchial tuberculosis, pleural extension of the disease, and other complications such as tuberculoma and mycetoma. Conventional plain chest radiography is the mainstay imaging modality in depicting pulmonary features of the disease. However, a normal chest radiograph does not exclude pulmonary tuberculosis and has been reported in approximately 10%-20% of immunocompetent and immunocompromised patients, respectively (Fitzgerald et a1.1991; Miller and Miller 1993; Greenberg et al.1994; Lee and 1m 1995). Computed tomography (CT) is useful in depicting cavitation and in patients with pleural effusion that may be masking lung parenchymal involvement on the same side (Kuhlman et aI.1990). CT is more sensitive than chest radiography (Hulnick et al. 1983; Lee et a1.1996) in depicting mediastinal and paratracheal lymphadenopathy, endobronchial tuberculosis, and dissemination to the lung parenchyma and other rare complications (Hatipoglu et al. 1996). Bronchography, now replaced by CT, is still used as the investigation of choice for the detection of bronchiectasis in poor-recourse countries of endemic areas (Fig. 23.29). Arteriography for diagnostic or therapeutic methods of bronchial artery embolization (BAE) is used for these rare but life-threatening massive hemoptysis cases. Imaging features of post-primary pulmonary tuberculosis, although suggestive, are not characteristic as they can simulate other diseases (Lee and 1m 1995). Upper lobe infiltration or consolidation should always be suspected as tuberculous. Cavitation may occur in approximately 40%, and the diagnosis of tuberculosis is usually not difficult if it is present in the upper lobe and associated with bronchogenic spread to other parts of the lung (Miller and Miller 1993). In some instances, upper lobe consolidation should always be considered to be tuberculosis until proven otherwise. The presence of lung parenchymal scarring, fibronodular or calcific changes should not be assumed as inactive, and follow-up is essential. We retrospectively reviewed the radiological records of 176 adult patients with post-primary pulmonary tuberculosis who had positive sputum culture for M. tuberculosis. They attended our hospital between 1998 and 2000, and their imaging features and frequencies are presented in Table 20.2. The imaging features of post-primary pulmonary tuberculosis have been reported by us in a separate chapter (Chap. 23).

20.3.2 Microbiology of the Sputum and Bronchial Aspirate Sputum microscopy for the detection of acid-fast bacilli by the Ziehl-Nielsen stain remains the cornerstone of rapid diagnosis of pulmonary tuberculosis (Maartens 2002). In HIV patient's sputum, microscopy is positive less often. At least 3 single specimens of sputum should be initially collected from patients with productive cough. In those who have difficulty in providing sputum, an aerosol inhalation of sterile hypertonic saline can be used to stimulate sputum production. Morning gastric aspiration, bronchoalveolar lavage, or transbronchoscopic brush or biopsies may be required. At least 5,000 to 10,000 bacilli per milliliter of sputum must be present to enable the detection of the organism by stained smear (Hobby et al. 1973). Sputum culture will require 10 to 100 bacilli to yield a positive result (Yeager et al. 1967). The American Thoracic Society (2000) reported on the diagnostic standards and classifications of tuberculosis in adult and children, and indicated that 50%-80% of patients with pulmonary tuberculosis will have positive sputum smears. Traditional culture media required 4-8 weeks to yield the bacilli, while radiometric culture methods (BACTEC) combined with a DNA probe allow identification of M. tuberculosis in 1-3 weeks. Currently, PCR-based assays for the diagnosis of tuberculosis and identification of drug-resistant strains are configured to yield results in a few hours to days (see Chapter PCR and Diagnosis of Tuberculosis by Dr. Diana L. Williams).

20.3.3 Bronchoscopic Diagnosis The use of bronchoscopy to obtain diagnostic specimens for patients with a chest radiograph suggesting tuberculosis but with negative sputum specimen has been reported (Willcox et al. 1982). Willcox and colleagues reported on 275 patients seen from 1976 to 1980, with imaging features of suspected tuberculosis and negative sputum smear. Specimens collected by bronchoscopy included bronchial brushings in 83, transbronchiallung biopsies in 18,and post-bronchoscopy sputum. Positive brushing yield was 67.5%, and transbronchial biopsies were positive in 50%. They also reported the co-existence of tuberculosis and bronchial carcinoma in 4 of their patients (4%).

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In our series of 176 patients, bronchoscopy was done on 27 patients with a chest radiograph suggesting pulmonary tuberculosis but with negative direct smear. Tuberculosis was confirmed by positive culture of bronchoscopic specimens, and no bronchial carcinoma was found. Tuberculous infection after bronchoscopy may be transmitted from patient to patient. Molecular epidemiological studies by molecular typing of DNA supported the transmission of M. tuberculosis isolates to other patients via bronchoscopic contamination (Michele et al. 1997; Argeton et al. 1997). It is recommended that the instrument be cleaned prior to its immersion in 2% aqueous solutions of glutaraldehyde for 45-min exposure times (Food and Drug Administration 1992).

20.3.4 Tuberculin Skin Test The tuberculin skin test is still widely used to identify infection with M. tuberculosis. Antigenic extracts of culture 'PPD' produces a delayed-type hypersensitivity reaction. Intradermal injection of 0.1 mg/0.1 ml of the standard 5-tuberculin unit (TU) dose (Mantoux method) is done into the volar or dorsal surface of the forearm (American Thoracic Society 2000). The test should be read between 48 and 72 h after injection. Three cut-off points have been recommended for defining a positive PPD test. A cut-off point of 2:5 mm of induration using the ballpoint pen method of Sokal is considered positive in a person with recent contact or in the presence of abnormal chest radiographs consistent with tuberculosis. A cut-off point of 2:10 mm is suggested for individuals who have normal or mildly impaired immunity and a high likelihood of being infected with the disease but without other risk factors. A cut-off point of2:15 mm for individuals with no risk factors for tuberculosis is considered positive (American Thoracic Society 2000). Tuberculin tests have several limitations including difficult administration, anergy, poor specificity, and the need for repeated testing to detect boosting (Maartens 2002).A comparative study between skin tests with PPD and measurement of the response by in-vitro culture assays measuring IFN-y production in response to tuberculin antigen stimulation is described in detail in a separate chapter. Dr. Rohit Katial has demonstrated the superiority of these assays and compared it with the PPD skin test (see Chap. 15).

20.3.5 Other Diagnostic Investigations Ultrasound or CT-guided, transthoracic, percutaneous, fine-needle aspiration (FNA) cytology may be useful in diagnosing pulmonary tuberculosis in patients initially suspected of having malignancies. Das et al. (1995) reported the use of FNA to diagnose tuberculosis in 29 patients in their series of 190 patients with malignancies and other causes. Serological tests for antimycobacterial antibodies in the serum using an ELISA immunoassay may be positive in up to 88% (Barnes et al. 1993). DNA fingerprinting PCR-based assays provide a noninvasive method of diagnosing M. tuberculosis as well as identifying drug-resistant strains, with results ready in a few hours or days (see Chap. 13). Pulmonary function tests may be required in tuberculous patients, particularly when lung surgery is required. Radionuclide studies in pulmonary tuberculosis are useful imaging tools in assessment of the disease (see Chap. 24 and 26).

20.4 Treatment of Post-primary Pulmonary T8 The history of the management of tuberculosis has been called 'the story of medical failure' (Holme 1998). 'The patients have been blamed for non-compliance with the therapeutic regimen, but sociologic studies have shown that, in most cases, the providers of health care are at fault' (Grange and Zumla 2000). The infectivity of tuberculous patients for close contacts after starting chemotherapy has been studied by several authors. Riley et al. (1962) reported that the effluent air from the rooms of patients receiving chemotherapy became noninfectious for guinea-pigs within 2 weeks. Other authors found the rapid reduction in the number of viable bacilli by 1-2 logarithmic counts within 2 weeks (Yeager et a1.1967; Hobby et al. 1973; Jindani et al. 1980). An editorial (1980) reviewed the issue of isolation of infectious patients with pulmonary tuberculosis, indicating that admission to a sanatorium was justified for supervised treatment, considering its toxicity and to safeguard their close contacts. It also referred to the work of Jenkinson et al. (1979) who found viable bacilli in the sputum of 15 patients who had received 6 weeks of treatment, and active disease was produced when injected into guinea-pigs. Studies on the duration of antituberculous treatment for patients with a positive

Post-primary Pulmonary Tuberculosis

sputum smear to achieve three consecutive negative results has been carefully studied prospectively by Telzak and colleagues (1997) from the South Bronx in New York. The study started from April 1993 to March 1995 of all patients with culture-confirmed tuberculosis. Data included the results of smears, cultures, and drug susceptibility, HIV status, CD4 cell count (for HIV-positive patients). The main objective of the study was to identify the time duration between initiating antituberculous treatment to the first of three consecutive negative sputum smears and the first of three consecutive negative sputum cultures. During the period of the study, 199 patients with culture-positive tuberculosis were diagnosed, 75% had lung parenchymal disease alone, 2% had lung and pleural abscess, 14% had pulmonary and extrapulmonary TB, 3% had only pleural disease, and 7% had extrapulmonary disease alone. They had complete information on 100 of the sputum smearpositive patients (85%). They found that the mean number of days before the first of three consecutive negative sputum smears was 33, and the median was 23 days. The mean number of days until the first of three consecutive negative sputum cultures was 32, and the median was 26 days. These authors noted that the following factors were associated with an increased number of days to achieve their objective: the high number of AFB on initial smear, the presence of cavitary disease, and no previous history of tuberculosis. They noted that HIV had no effect on the duration of treatment before achieving the study objectives. HIV-positive patients are less likely to have cavitary disease, and therefore more likely to produce few AFB. In conclusion, patients with smearpositive sputum require hospitalization and must be isolated for a mean duration of 32 days after initiating appropriate treatment or longer if the initial AFB count was high in the presence ofcavitary disease and if the patient had no prior history of tuberculosis. The aim of the appropriate chemotherapy is to use drugs to which the bacilli are susceptible, with bactericidal activity to cure the patient, reduce infectivity to contacts, and prevent the emergence of drug resistance (Centers for Disease Control 1994). Clinicians are often required to take the decision of either to initiate the treatment of smear-negative patients with a presumptive diagnosis of pulmonary tuberculosis based on the presence of clinical and imaging features, or to wait for the sputum culture results that may require 4-8 weeks to obtain and may not yield the bacilli. In a prospective study of 139 patients with a presumptive diagnosis of pulmonary tuberculosis, Gordin et al. (1989) reported their findings. The

323

study was carried out in San Francisco between mid1981 to the end of 1982. The presumptive diagnosis in this series was based on the presence of clinical and radiological features suggestive of pulmonary tuberculosis with negative sputum smear. Treatment with isoniazid, rifampicin, and ethambutol was given to all patients. Positive culture was reported later in 16 patients. Among the culture-negative patients, 43 showed radiographic improvement after 3 months of initiating the treatment, clinical improvement in 7, and bronchoscopic confirmation of the diagnosis in 1 patient. There were 72 individuals with radiological stability who were considered as having inactive previous tuberculosis. The authors concluded that the treatment was appropriate in 66 of 139 (48%) of patients. The British Medical Research Council (BMRC) recommended the initiation of antituberculous treatment for such patients after other causes for abnormal chest radiography findings have been excluded (Dutt and Stead 1994; Fox et al. 1999). The modern short course of antituberculous chemotherapy, Directly Observed Therapy (DOT), is the best strategy for the treatment of post-primary pulmonary tuberculosis to achieve the three goals, that is, cure the patient, reduce infectivity to contacts, and prevent the emergence of drug resistance if appropriately adhered to. DOT is usually given as an outpatient treatment and supervised by nurses. Such visits to the outpatient facility may be difficult as it involves traveling and may be costly for patients in developing countries. Training of a family member or a community lay person to supervise the administration of DOT may be more practical in developing countries (Wilkinson 1994). WHO indicated that for the DOT strategy to be effective, it requires government commitment, the availability of microscopic and other diagnostic facilities, a continuous supply of high-quality medication, direct observation of treatment administration, and recording the response to treatment (Netto et al. 1999). DOT consists of an initial2-month phase of intensive treatment using four drugs (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by a 4-month continuation phase of rifampicin and isoniazid. These drugs are usually given as daily treatment but can be given thrice weekly, either throughout or during the continuation phase, to facilitate the supervision of treatment. The isoniazid daily dose is 5 mg/kg orally or intramuscularly (maximum 300 mg), rifampicin daily dose is 10 mg/kg orally (maximum 600 mg), pyrazinamide daily dose is 15-30 mg/kg orally (maximum 2 g),

324

streptomycin daily dose is 15 mg/kg intramuscularly (maximum 1 g) for persons below the age of 60 years and 10 mg/kg intramuscularly (maximum 750 mg) for persons above 60 years, ethambutol daily dose is 15-25 mg/kg orally (maximum 2-5 g). The cure rate of drug-susceptible disease when the patient completes the course of treatment is up to 98%. HIV co-infected patients have a similar outcome of tuberculosis treatment success rate (Grange and Zumla 2000). Although DOT has been successful in some countries, endemic areas with HIV and MDR tuberculosis have not achieved the WHO targets for disease control (Netto et al. 1999). Multidrug-resistant tuberculosis is a much more serious problem to treat. Drugs used for treatment are more toxic, more expensive, and require a prolonged period of up to 24 months, and surgery may be considered to decrease the load of the organisms during chemotherapy (Iseman 1993; Iseman et al.1990).

20.4.1 Response to Treatment Appropriate chemotherapy is usually associated with clinical and radiological improvements. Clinical improvement with resolution of fever occurred in 92% of patients 4 weeks after starting treatment (Teklu and AI-Wabel 1994; Vanham et al. 1997). Radiological improvement is noticed after 3 months (Gordin et al. 1989). Paradoxical worsening of the clinical and imaging responses to treatment may occur particularly in the first few weeks or months. HIV co-infected patients are more prone to paradoxical worsening after starting antituberculous treatment, and this is reported to occur in 36% (Wendel et al. 2001). In tuberculous patients without HIV, paradoxical worsening may occur in 16% (AI-Majed 1996). Paradoxical worsening after antituberculous treatment is defined as worsening of fever, cough, shortness of breath or even development of ARDS, enlargement of lymph nodes or other extrapulmonary site of the disease during appropriate treatment (Smith 1987; AI-Majed 1996; Rodriguez-Bano et al. 1997; Hung and Chang 1999; Wendel et al. 2001). Radiological worsening of the pre-existing pulmonary infiltrates, development of new lesions on the same or apposite lung, enlargement of hilar or paratracheal lymph nodes were noted in our series (Figs.23.16a-c and 23.17a-c). The pathogenesis of paradoxical worsening is not yet clear. It is believed that it may be due to enhanced immune responses (immunological rebound) with increased proliferation of

M. M. Madkour et al.

mononuclear cells and IFN-y production in response to M. tuberculosis antigens (Wendel et al. 2001). Corticosteroid therapy has been used to modify the intensity of symptoms (Rodriguez-Bano et al. 1997). There have been no controlled trials on the management of these paradoxical worsening responses.

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325 assessment of lymphocyte cytokine production in tuberculosis. Tuberculosis 82:37-41 Geppert EF, Leff A (1979) The pathogenesis of pulmonary and miliary tuberculosis. Arch Intern Med 139:1381-1383 Glynn JR, Shearer S, Kambashi B, Godfrey-Fausett P (2001) HIV-I and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort in South African mineworkers. Lancet 358:1687-1693 Gordin FM, Slutkin G, Schecter G et al (1989) Presumptive diagnosis and treatment of pulmonary tuberculosis based on radiographic findings. Am Rev Respir Dis 139:1090-1093 Grange JM, Zurnla A (2000) Advances in the management of tuberculosis: clinical trials and beyond. Curr Opin Pul Med 6:193-197 Grange JM, Daborn C, Cosivi 0 (1994) HIV-related tuberculosis due to Mycobacterium bovis. Eur Respir J 7:1564-1566 Greenberg SD, Jenkins DE, Bahar D (1964) Coexistence of carcinoma and tuberculosis of the lung. Am Rev Respir Dis 90:67-76 Greenberg SD, Frager D, Suster B et al (1994) Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 193:115-119 Hatipoglu ON, Osma E, Manisali M et al (1996) High resolution computed tomographic findings in pulmonary tuberculosis. Thorax 1996:397-402 Heyderman RS, Goyal M, Roberts P et al (1998) Pulmonary tuberculosis in Harare, Zimbabwe: analysis by spoligotyping. Thorax 53:346-350 Hirshberg B, Biran I, Glazer M et al (1997) Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital. Chest 112:440-444 Hobby G, Holman A, Iseman M et al (1973) Enumeration of tubercle bacilli in sputum of patients with pulmonary tuberculosis. Antimicrob Agents Chemother 4:94-104 Holme C (1998) Tuberculosis: story of medical failure. Br Med J 317:1260 Hsiao EI, Kirsch CM, Kagawa FT et al (2001) Utility of fiberoptic bronchoscopy before bronchial artery embolization for massive hemoptysis. AJR Am J Roentgenoll77:861-867 Hulnick DH, Naidich DP, McCauley DL (1983) Pleural tuberculosis evaluated by computed tomography. Radiology 149: 759-765 Hung SC, Chang SC (1999) New pulmonary lesions during therapy for extrapulmonary tuberculosis. Chest 116:1794-1797 Ihm HJ, Hankins JR et al (1972) Pneumothorax associated with pulmonary tuberculosis. J Thorac Cardiovasc Surg 64:211-219 1m JG, Itoh H, Shim YS (1993) Pulmonary tuberculosis: CT findings-early active disease and sequential change with antituberculous therapy. Radiology 186:653-660 Iseman MD (1993) Treatment of multidrug-resistant tuberculosis. N Engl J Med 329:784-791 Iseman MD, Madsen LA (1991) Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance. Chest 100:124-127 Iseman MD, Madsen L, Goble M et al (1990) Surgical intervention in the treatment of pulmonary disease caused by drug-resistant Mycobacterium tuberculosis. Am Rev Respir Dis 141:623-625 Jindani A, Aber V, Edwards E et al (1980) The early bacterial activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 121:939-949

326 Johnson JL, Ellner 11 (2000) Adult tuberculosis overview: African versus Western perspectives. Curr Opin Pulm Med 6:180-186 Johnson TM, McCann et al (l973) Tuberculous bronchopleural fistula. Am Rev Respir Dis 107:30-41 Kaestel M, Meyer W, Mittelmeier HO et al (1999) Pulmonary aspergilloma - clinical findings and surgical treatment. Thorac Cardiovasc Surg 47:340-345 Khan FA, Rehman M et al (l980) Pulmonary gangrene occurring as a complication of pulmonary tuberculosis. Chest 77:76-80 Kim HY,Song KS et al (2001) Thoracic sequelae and complications of tuberculosis. Radiographics 21:839-860 Kuhlman JE et al (1990) CT features of thoracic mycobacterial disease. Radiographics 10:413-431 Lambert HP (1956) Spontaneous pneumothorax and pulmonary tuberculosis. Tubercle 37:207-209 Lee KS,Im JG (l995) CT in adult with tuberculosis of the chest: Characteristic findings and role of management. AJR 164: 1361-1367 Lee KS, Kim YH, Kim WS et al (l99l) Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 15:424-428 Lee KS, Hwang JW, Chung MP et al (l996) Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 110:977-984 Lee TW, Wan S, Choy DK et al (2000) Management of massive hemoptysis: a single institution experience. Ann Thorac Cardiovasc Surg 6:232-235 Levy H, Kallenbach JM, Feldman C et al (l987) Acute respiratory failure in active tuberculosis. Crit Care Med 15: 221-225 Liesegang TJ, Cameron Douglas (l980) Mycobacterium bovis infection of the conjunctiva. Arch Ophtalmol 98:1764-1766 Lopez-Contreras JL, Ris J et al (1994) Tuberculous pulmonary gangrene: report of a case and review. Clin Infect Dis 18: 243-245 Maartens G (2002) Advances in adult pulmonary tuberculosis. Curr Opin Pulm Med 8:172-177 Maartens G, Beyers N (2002) Tuberculosis in the tropics. Clin Chest Med 23:341-350 Mal H, Rullon I, Mellot F (1999) Immediate and long-term results of bronchial artery embolization for life-threatening hemoptysis. Chest 115:996-1001 McAdams HP, Erasmus J et al (l995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33:655-678 McDonough KA, Florczyk MA, Kress Y (2000) Intracellular passage within macrophages affects the trafficking of virulent tubercle bacilli upon reinfection of other macrophages in a serum-dependent manner. Tuberc Lung Dis 80:259-271 Michele TM, Cronin WA, Graham NMH et al (l997) Transmission of Mycobacterium tuberculosis by a fiberoptic bronchoscope: identification by DNA fingerprinting. JAMA 278: 1093-1095 Millar JW, Horne NW (l979) Tuberculosis in immunosuppressed patients. Lancet 1:1176-1178 Miller WT (l981) Tuberculosis in the adult. Postgrad Radiol 1:147-167 Miller WT, Miller WT (l993) Tuberculosis in the normal host: radiological findings. Semin Roentgenol 28:109-118 Moda G, Daborn q, Grange JM et al (l996) The zoonotic importance of Mycobacterium bovis. Tuberc Lung Dis 77:103-108

M. M. Madkour et al. Netto EM, Dye C, Raviglione MC (l999) Progress in global tuberculosis control 1995-1996, with emphasis on 22-highincidence countries. Global Monitoring and Surveillance Project. Int J Tuberc Lung Dis 3:310-320 Penner C, Roberts D, Kunimoto D et al (l995) Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation. Am J Respir Crit Care Med 151:867-872 Reich JM (l993) Pulmonary gangrene and the air crescent sign. Thorax 48:70-74 Riley R, Mills C, O'Grady F et al (l962) Infectiousness of air from a tuberculosis ward. Ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 85:511-525 Rodriguez-BaflO JR et al (l997) Systemic paradoxical response to antituberculous drugs: resolution with corticosteroid therapy. Clin Infect Dis 24:517-519 Rohenberg GT, Shaw P (l996) Radiology of pulmonary tuberculosis. Br J Hosp Med 56:195-199 Rook GAW,Zumla A (2001) Advances in the immunopathogenesis of pulmonary tuberculosis. Curr Opin Pulm Med 7:116-123 Sauret J,Jolis R,Ausina Vet al (l992) Human tuberculosis due to Mycobacterium bovis: report of 10 cases. Tuberc Lung Dis 73:388-391 Small PM, Hopewell PC, Singh SP et al (l994) The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 330:1703-1709 Smith H (1987) Paradoxical responses during the chemotherapy of tuberculosis. J Infect 15:1-3 Sokal JE (1975) Measurement of delayed skin-test responses. N Engl J Med 293:501-502 Stead WW, Bates JH (2000) Recurrent tuberculosis due to exogenous reinfection. N Engl J Med 341:1050 Stebbings AE, Lim TK (l999) Cause, treatment and outcome of patients with life-threatening haemoptysis. Singapore Med J 40:67-69 Teklu B, Al-Wabel AH (l994) Resolution of fever in patients on chemotherapy for pulmonary tuberculosis. Ann Saudi Med 14:392-395 Telzak EE, Fazal BA, Pollard CL et al (1997) Factors influencing time to sputum conversion among patients with smearpositive tuberculosis. Clin Infect Dis 25:666-670 Uchida T, Wada M, Sakamoto J et al (l999) Treatment for empyema with bronchopleural fistulas using endobronchial occlusion coils: report of a case. Jpn J Surg 29:186-189 Van Rie A, Warren R, Richardson M et al (1999) Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341: 1174-1179 Vanham G, Toossi Z, Hirsch CS et al (l997) Examining a paradox in the pathogenesis of human pulmonary tuberculosis: immune activation and suppression/anergy. Tuberc Lung Dis 78: 145-158 Wallis RS, Johnson JL (2001) Adult tuberculosis in the 21st century: pathogenesis, clinical features, and management. Curr Opin Pulm Med 7:124-133 Weissberg D, Weissberg D (2001) Late complications of collapse therapy for pulmonary tuberculosis. Chest 120:847-851 Wendel KA, Alwood KS, Gachuhi R et al (2001) Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 120:193-197 Wilder RJ, Beacham EG et al (1962) Spontaneous pneumothorax complicating cabitary tuberculosis. J Thorac Cardiovase Surg 43:561-573

Post-primary Pulmonary Tuberculosis Wilkinson D (1994) High-compliance tuberculosis treatment program in a rural community. Lancet 343:647-648 Willcox PA, Benatar SR, Potgieter (1982) Use of the flexible fibreoptic bronchoscope in diagnosis of sputum-negative pulmonary tuberculosis. Thorax 37:598-601 Winer-Muram HT, Rubin SA (1990) Thoracic complications of tuberculosis. J Thorac Imag 5:46-63

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Wong ML, Szkup P, Hopley MJ (2002) Percutaneous embolotherapy for life-threatening hemoptysis. Chest 121:95-102 Woodring JH (1986) Update: the radiographic features of pulmonary tuberculosis. AJR 146:497-506 Yeager HJ, Lacy J, Smith L et al (1967) Quantitative studies on mycobacterial populations in sputum and saliva. Am Rev Respir Dis 95:998-1004

21 Endobronchial Tuberculosis HEE SOON CHUNG

21.15.1.1 Interventional Management 343 21.15.1.2 Tracheobronchial Stent 344 21.15.1.3 Endobronchial Electrosurgery vs Laser Photoresection 346 21.15.1.4 Surgical Management 346 21.15.2 Bronchiectasis 346 21.15.3 Broncholith 346 References 347

CONTENTS 21.1 21.2 21.3 21.4 21.5 21.6 21.7

Introduction 329 Definition 330 Epidemiology 330 Pathogenesis 330 Pathology 331 Classification 332 Characteristics of the Each Subtype of Endobronchial Tuberculosis 333 21.7.1 Actively Caseating Type 333 21.7.2 Edematous-Hyperemic Type 333 21.7.3 Fibrostenotic Type 334 21.7.4 Tumorous Type 334 21.7.5 Granular Type 335 21.7.6 Ulcerative Type 335 21.7.7 Nonspecific Bronchitic Type 336 21.8 Location of Bronchial Involvement 336 21.9 Natural Course of Endobronchial Tuberculosis 21.10 Endobronchial Tuberculosis in HIV-Infected Patients 337 21.11 Clinical Features 338 21.12 Diagnosis 338 21.12.1 Clinical History 338 21.12.2 Physical Examination 339 21.12.3 Laboratory Testing 339 21.12.4 Bacteriology 339 21.12.5 Tuberculin Testing 340 21.12.6 Pulmonary Function Test 340 21.12.7 Radiology 340 21.12.7.1 Simple Roentgenograms 340 21.12.7.2 Computerized Tomography 340 21.12.8 Bronchoscopy 341 21.13 Differential Diagnosis 341 21.13.1 Pneumonia 341 21.13.2 Fungal Infection and Actinomycosis 342 21.13.3 Lung Cancer 342 21.13.4 Bronchial Asthma 342 21.14 Treatment 342 21.14.1 Anti-Tuberculosis Chemotherapy 342 21.14.2 Corticosteroid Treatment 343 21.15 Complications and Their Management 343 21.15.1 Bronchostenosis 343

21.1 Introduction

337

H. S. CHUNG, MD, FCCP Associate Professor of Medicine, Seoul National University College of Medicine and Seoul Municipal Boramae Hospital affiliated to Seoul National University Hospital, # 395 Shindaebang-2-Dong, Dongjak-Gu, Seoul, 156-707, Korea

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

Endobronchial tuberculosis is a specific form or a significant complication of pulmonary tuberculosis. It is important to remember that endobronchial tuberculosis has the following pitfalls: (1) its diagnosis is frequently delayed, since the decreased incidence itself diminishes the suspicion of tuberculosis (Greenbaum et al. 1980; Chung et al. 1991a); (2) bronchostenosis may develop as a serious complication despite efficacious antituberculosis chemotherapy (Albert and Petty 1976; Hoheisel et al. 1994; Park et al. 1997); and (3) it is often misdiagnosed as bronchial asthma (Watson and Ayres 1988; Williams et al.1988; Park et al.1995) or lung cancer (Matthews et al.1984; Smith et al. 1987). Recently there has been an unprecedented resurgence of tuberculosis, which is related to the human immunodeficiency virus (HIV) epidemic, multidrugresistant strains, poverty and homelessness, immigration, and failures in the treatment system (Millard et al. 1994; Glynn 1998; Lerner 1999). The HIV epidemic may be associated with a higher incidence of endobronchial tuberculosis (Judson and Sahn 1994; Calpe et al.1995). Therefore, endobronchial tuberculosis continues to be a health problem, though the incidence of tuberculosis affecting respiratory organs including the trachea and bronchi has been greatly reduced (Shulutko et al. 1979). Endobronchial tuberculosis should be borne in mind when patients are young female adults or adolescents who present with symptoms suggestive of asthma and/or with unusual roentgenographic patterns, or in patients with HlV infection.

330

21.2 Definition Endobronchial tuberculosis was first described by Richard Morton in 1694 (Jenks 1940), and is defined as a specific inflammation of the trachea or major bronchi caused by tubercle bacilli. Active disease can be diagnosed when certain endobronchial lesions, such as whitish gelatinous material, ulcer, tumor, stenosis or inflammation, exist on bronchoscopy and tuberculosis is proven by bronchoscopic biopsy of these lesions. Bronchial anthracofibrosis is defined as a luminal narrowing associated with anthracotic pigmentation on bronchoscopy, without a relevant history of pneumoconiosis or smoking, and may be a sign of active endobronchial tuberculosis (Chung et al. 1998; Kim et al. 2000), but histologic confirmation is necessary for definitive diagnosis (Garimella 2001). Bronchial fibrostenosis is sometimes a surprise finding in patients with a previous history of tuberculosis, which must be the presumed cause of stenosis. Since the sequela of endobronchial tuberculosis and reactivated pulmonary tuberculosis can be present coincidently, fibrotic stenosis of bronchi may be inactive lesions resulting from prior endobronchial tuberculosis even though sputum examination for acid-fast bacilli is positive. Therefore, it is necessary to obtain histologic proof of tuberculosis for a definite diagnosis of endobronchial tuberculosis. Localized tuberculous bronchitis in segmental bronchi communicating with diseased portions of lung is common in pulmonary tuberculosis (Daniel 1994). Resected lung specimens frequently show either ulceration or stenosis of the draining bronchioles or bronchi, and the same endobronchial processes may result in bronchiectasis due to destruction of the bronchial wall (Rossman and Oner-Eyuboglu 1998). Since these endobronchial lesions distal to lobar bronchi do not have clinical significance, they should be included in the disease entity of pulmonary tuberculosis rather than that of endobronchial tuberculosis.

21.3 Epidemiology Tuberculosis is still a common disease despite its great decline in recent years. In high-prevalence areas, tuberculosis afflicts chiefly young adults. In countries where HIV infection is endemic, tuberculosis is one of the most important causes of morbid-

H. S. Chung

ity and mortality in acquired immune deficiency syndrome (AIDS) patients (Daniel 1994). The incidence of endobronchial tuberculosis among tuberculous postmortem specimens was as high as 40% prior to the chemotherapy era (Wolinsky 1989). With modern treatment, endobronchial tuberculosis has been reported in about 10% of cases of pulmonary tuberculosis, when fiberoptic bronchoscopy is routinely performed (Jokinen et al. 1977). In my previous study, the incidence of endobronchial tuberculosis in pulmonary tuberculosis was 5.88 percent. However, it should be borne in mind that the actual incidence is somewhat higher than this, because bronchoscopy was not performed routinely in all tuberculosis patients but only when an endobronchial lesion was highly suspected. Endobronchial tuberculosis shows a marked preference for female patients, and the male-to-female ratio is approximately 1:5. The disease is usually detected in the third decade. The reason why endobronchial tuberculosis is more common in young females is not clear. One of the possible reasons is that organism implantation from infected sputum may occur more easily in females, especially in teenagers and those in their twenties, because they do not expectorate sputum, for sociocultural and cosmetic reasons (Chung and Lee 2000). In addition, it is well recognized that endobronchial tuberculosis frequently occurs as a part of primary pulmonary tuberculosis in young adults (Smith et al. 1987).

21.4

Pathogenesis

First infection with the tubercle bacillus is known as primary tuberculosis, and usually includes the involvement of the draining lymph nodes in addition to the initial lesion. The combination of the primary or Ghon focus and draining lymph nodes is termed the primary complex. Although primary tuberculosis was formerly relatively common in intestines or tonsils, due to infection from milk, and may occur in various other unusual sites, in the vast majority of cases the route of infection is by inhalation and, consequently, the primary lesion is pulmonary. All other tuberculous lesions are regarded as post-primary. Multiple terms have been used to describe this stage of tuberculosis - for example, chronic tuberculous postprimary disease, reinfection or recrudescent tuberculosis, adult-type progressive tuberculosis, endogenous reinfection and reactivation tubercu-

331

Endobronchial Tuberculosis

losis (Garay 1996). Regardless of the nomenclature, these tuberculous lesions are not accompanied by major involvement of the draining lymph nodes. In primary pulmonary tuberculosis, the first focus of exudative inflammation may occur in any bronchopulmonary segment, more often near the periphery in the middle or lower lung, i.e. that portion of the lung receiving the greatest ventilation, and this is where bacilli within droplet nuclei tend to be implanted. Tubercle bacilli multiply in the exudates and may be carried into some of the very abundant pulmonary lymphatics, and then to the regional lymph nodes. Hematogenous seeding to the distant organs then probably occurs with considerable frequency, either by way of lymphatic channels or more directly from smaller pulmonary veins within the exudate. However, lesions of clinical magnitude do not develop by hematogenous seeding unless native resistance is low or the number of bacilli is great. Regional lymph node involvement is a fairly consistent characteristic of primary pulmonary tuberculosis. The hilar lymph node is most commonly involved, but the paratracheal node is also frequently enlarged, and a substantial minority of cases show enlargement of both the hilar and paratracheal nodes. These nodes develop an intense cellular inflammatory response and may become so large that they compress the major bronchi, with obstructive atelectasis or obstructive pneumonitis. This phenomenon was formerly called epituberculosis. Caseation often follows in the nodes, but healing by partial resorption of the caseum, and the calcification of the lesion in the lung and lymph nodes, is the rule. However, such nodes occasionally rupture or protrude into bronchi. In children especially, rupture of the caseous glands into the trachea or major bronchi causes collapse of the lung or even sudden death by suffocation in young children. In adults, the lung component of the primary complex is usually more obvious and the nodal component may not be seen, whereas in children often only an enlarged hilar or paratracheal node is apparent (Seaton et al.1989). In post-primary tuberculosis, lymph node involvement is seldom extensive and pulmonary lesions on chest roentgenograms are usually located in the apical or subapical areas of the upper lobe. The predilection for the upper lung probably relates to the high oxygen tensions at the lung apex (Riley 1960). Even though the pathogenesis of endobronchial tuberculosis is not yet fully established, sources of endobronchial tuberculosis may include direct implantation of tubercle bacilli into the bronchus from an adjacent pulmonary parenchymal lesion,

direct airway infiltration from an adjacent tuberculous mediastinal lymph node, erosion and protrusion of an intrathoracic tuberculous lymph node into the bronchus, hematogenous spread and extension to the peribronchial region by lymphatic drainage (Myerson 1944; Smart 1951; Matthews et al. 1984; Smith et al.1987; Lee et al. 1992; Kim et al.1993). Endobronchial tuberculosis, before the era of chemotherapy, was considered a complication of advanced post-primary disease. Effective antituberculosis chemotherapy and preventive measures have reduced childhood tuberculosis exposure, which has resulted in an increase in adult primary tuberculosis with unusual clinical and roentgenographic presentations. In the 1970s and early 1980s, a number of reports concerning the so-called unusual radiographic manifestations of adult tuberculosis were published. Up to one-third of adult cases were reported to have atypical findings, such as mediastinal adenopathy, lower lung consolidation and miliary disease. However, these "unusual manifestations" are the usual manifestations of primary tuberculosis. The only unusual aspect is the increasing incidence of primary tuberculosis in adults (McAdams et al.1995). In the modern drug era, endobronchial tuberculosis is more likely to be discovered in adults with primary tuberculosis (Smith et al. 1987), whereas post-primary disease is by far the most common type of pulmonary tuberculosis.

21.5

Pathology

The pathologic changes that occur in the involved bronchi differ in primary tuberculosis from those of post-primary tuberculosis. The involvement of the trachea and bronchi in primary tuberculosis usually results from the pressure created by the enlarged lymph nodes, which may cause partial or complete bronchial obstruction, necrosis and ulceration of the bronchial wall, often in association with the rupture of caseous nodes into the bronchi. In post-primary tuberculosis, the pathogenesis differs, and bronchial lesions are usually secondary to repeated implantation of tubercle bacilli from a sloughing parenchymal source distal to the lesion (Medlar 1955). The earliest lesions often are lymphocytic infiltrations of the mucosa with or without congestion or edema. These usually clear when the parenchymal focus ceases to slough. However, bronchial lesions may progress to tubercle formation in the mucosa and submucosa. Rarely, necrosis with ulceration and sloughing may involve

332

portions of the bronchial wall, and it is this type of lesion that causes bronchial narrowing and stenosis, distal to which further bronchial inflammation may lead to obstructive pneumonitis or bronchiectasis. The healing of more extensive lesions is frequently accompanied by cicatricial stenosis (Wolinsky 1989).

21.6

Classification The clinical course of endobronchial tuberculosis is variable, not only because there are several possible pathogenetic mechanisms, but also because the interactions between the effects of mycobacteria, host immunity and antituberculous drugs is complex, and any variation in these three factors may result in an altered course (Chan and Pang 1989). Therefore, it is an oversimplification to view cases of endobronchial tuberculosis as a homogeneous group, and endobronchial tuberculosis is probably better divided into subtypes. Over the past five decades, many classifications of endobronchial tuberculosis have been published. Judd (l947) classified endobronchial tuberculosis into intrabronchial and extrabronchial types on the basis of their pathogenetic mechanisms. In 1957, the Sixth All-Union Congress of Phthisiologists adopted a classification which categorized endobronchial tuberculosis into four forms: infiltrative, ulcerative, cicatricial and fistulous (or glandular). After the introduction of the flexible bronchoscope, Oho and Amemiya (l984) suggested that endobronchial tuberculosis be classified as edematous-hyperemic, infiltrative-proliferative, ulcerative-granulative and fibrostenotic. In 1991, my colleagues and I suggested a classification of endobronchial tuberculosis which considered the above-mentioned classifications and bronchoscopic features. This classification categorized endobronchial tuberculosis into seven forms: actively caseating, stenotic without fibrosis, stenotic with fibrosis, tumorous, granular, ulcerative and nonspecific bronchitic (Chung et al. 1991a), and was partially reported at the Sixth World Congress for Bronchology (Han et al. 1989). However, the terms "stenotic without fibrosis" and "stenotic with fibrosis" were later renamed "edematous-hyperemic" and "fibrostenotic:' respectively, due to the fact that gross bronchoscopic findings cannot reflect the presence of fibrosis. As a result, the forms of endobronchial tuberculosis were classified into seven subtypes by bronchoscopic findings: actively caseating, edematous-hyperemic,

H. S. Chung

fibrostenotic, tumorous, granular, ulcerative and nonspecific bronchitic (Chung and Lee 2000). The actively caseating, edematous-hyperemic, fibrostenotic and tumorous forms of endobronchial tuberculosis have varying degrees of bronchostenosis proximal to the segmental bronchi, whereas the granular, ulcerative and nonspecific bronchitic forms do not have luminal narrowing of the bronchi. This new classification is valuable for predicting the therapeutic outcome of endobronchial tuberculosis, because it is closely related to the extent of disease progression (Chung and Lee 2000). Pathologically, the initial lesion, which presents as simple erythema and edema of the mucosa with lymphocytic infiltration of the submucosa (Medlar 1955; Shulutko et al.1979),corresponds to nonspecific bronchitic endobronchial tuberculosis. This lesion is followed by submucosal tubercle formation, which produces the erythema and granularity seen at bronchoscopy (Myerson 1944), and partial bronchial stenosis, which is caused by considerable congestion and edema of the mucosa (Medlar 1955). These are the granular and edematous-hyperemic types, respectively. At this point, the development of caseous necrosis, with the formation of tuberculous granuloma, can be found at the mucosal surface (Medlar 1955), which constitutes actively caseating endobronchial tuberculosis. However, when the inflammation erupts through the mucosa, an ulcer is seen, which may be covered by caseous material (Myerson 1944), and the disease is considered to be of the ulcerative type. Finally, the bronchial mucosal ulcer evolves into hyperplastic inflammatory polyps, and the endobronchial tuberculous lesion heals by fibrostenosis (Salkin et al. 1943; Smith et al. 1987). During this process, the lesion has moved through either the tumorous or fibrostenotic type. In addition, tumorous endobronchial tuberculosis can develop via a pathway involving erosion and later protrusion of an intrathoracic tuberculous lymph node into the bronchus (Shulutko et al.1979; Judson and Sahn 1994). This may be the principal mechanism oftumorous endobronchial tuberculosis, given that computed tomography usually reveals an endobronchial mass, as well as enlarged lymph nodes adjacent to the bronchus, and anthracotic pigment is frequently seen in biopsy specimens (Yee et al. 1985; Smith et al.1987). Interestingly, endobronchial tuberculosis in patients with HIV infection shows such bronchoscopic and computed tomography findings (Judson and Sahn 1994; Alame et al. 1995; Calpe et al. 1995; Saadoun et al.1998). In my previous study (Chung and Lee 2000), the actively caseating type was the most common form, the edematous-hyperemic, fibrostenotic, tumorous and granular types were relatively common, the non-

333

Endobronchial Tuberculosis

specific bronchitic type occurred less frequently and the ulcerative type was the rarest form (Table 21.1).

21.7 Characteristics of the Each Subtype of Endobronchial Tuberculosis

In my previous study, about a third of the cases of the edematous-hyperemic type became of the nonspecific bronchitic type and healed within three months of treatment. The remaining two-thirds became fibrostenotic within three months of drug treatment, and complete obstruction of the bronchial lumen often occurred. The prognosis of edematoushyperemic endobronchial tuberculosis is poor.

21.7.1 Actively Caseating Type Actively caseating endobronchial tuberculosis is diagnosed when the bronchial mucosa is swollen, hyperemic and diffusely covered with a whitish cheese-like material. This form is usually accompanied by luminal narrowing at diagnosis, whether granulation tissue is present or not (Fig. 21.1). In my previous study, approximately one-third of the cases of actively caseating endobronchial tuberculosis healed via the edematous-hyperemic, granular or nonspecific bronchitic types without complication. The remaining two-thirds transformed into the fibrostenotic type within three months of antituberculosis and corticosteroid treatment. The formation of granulation tissue is a poor prognostic factor, because all cases that showed granulation tissue on follow-up bronchoscopy changed into the fibrostenotic type. The prognosis of actively caseating endobronchial tuberculosis is poor.

Fig.21.1. Bronchoscopic finding of actively caseating endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.7.2 Edematous-Hyperemic Type In cases of edematous-hyperemic endobronchial tuberculosis, the bronchial lumen is narrowed due to severe mucosal swelling with surrounding hyperemia. However, neither caseous material nor fibrous contracture is found at diagnosis (Fig. 21.2). Table 21.1. Classification of 114 endobronchial tuberculoses by Bronchoscopic Features Type

Cases

%

Actively caseating type Edematous-Hyperemic type Fibrostenotic type Tumorous type Granular type Nonspecific bronchitic type Ulcerative type

49 16 12 12 13 9 3

43.0 14.0 10.5 10.5 11.4 7.9 2.7

From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig. 21.2. Bronchoscopic finding of edematous-hyperemic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

334

21.7.3 Fibrostenotic Type

H. S. Chung

Tumorous endobronchial tuberculosis is characterized by an endobronchial mass that has a surface often cov-

ered with caseous material, and which nearly totally occludes the bronchial lumen (Fig. 21.4). This form of endobronchial tuberculosis is frequently mistaken for lung cancer because of its bronchoscopic appearance and the fact that the computerized tomography findings mimic those of lung cancer. Anthracotic pigmentation or anthracofibrosis can appear after the endobronchial lesion has been successfully treated. If the lymph nodes caseate, they may point towards and discharge intrabronchially. Following discharge, the resultant fistulae usually heal slowly, leaving small, sometimes pigmented, pitted scars in the bronchial wall. These can be visualized as hard, depressed, black plaques by bronchoscopy, and have been observed to follow the intrabronchial perforations of tuberculous lymph nodes. The black pigment derives from the anthracotic material present in the tuberculous nodes, which is subsequently incorporated into scarred areas. In my previous study, the evolution of tumorous endobronchial tuberculosis was very complicated and unpredictable. Approximately 70% of cases eventually changed into the fibrostenotic type, which included the complete obstruction of the bronchial lumen with fibrosis. Six months after treatment, another 20% were found to exhibit impending obstruction of the left main bronchus due to a re-growing mass, although this were successfully corrected by bronchoscopic electrocautery. In 20% of cases, new tumorous lesions appeared five or six months after treatment, and anthracofibrosis or anthracotic pigmentation was

Fig.21.3. Bronchoscopic finding of fibrostenotic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig.21.4. Bronchoscopic finding of tumorous endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fibrostenotic endobronchial tuberculosis presents as a marked narrowing of the bronchial lumen with fibrosis. Usually) endobronchial tuberculous lesions do not encircle the bronchial mucosa and normal mucosa is partly spared, and the stenotic bronchial lumen becomes a crushed waterdrop-shape, as shown in Fig. 21.3. In some cases, the bronchial lumen is completely occluded. The edges of this stricture are avascular and pale because of dense fibrosis, and it is impossible to biopsy due to its very hard consistency. However, active tuberculosis can be diagnosed by bronchoscopic biopsy of the chronic inflamed mucosa at the periphery of the lesion, which is usually swollen and reddened. In my previous study, all cases remained in a fibrostenotic state inspite of drug therapy. In addition, roughly half of the cases showed progressive fibrostenosis and this resulted in complete obstruction of the bronchial lumen two or three months after treatment. The prognosis of fibrostenotic endobronchial tuberculosis is very poor.

21.7.4 Tumorous Type

335

Endobronchial Tuberculosis

observed in 30% of cases. The prognosis of tumorous endobronchial tuberculosis is grave. It is very difficult to analyze the evolution of tumorous endobronchial tuberculosis; this is due to the fact that the disease exhibits diverse progress and unexpected changes. However, the observations of Shulutko and coworkers (l979) are extremely valuable. In bronchoglandular tuberculosis, which is equivalent to tumorous endobronchial tuberculosis, bronchoglandular fistulas occur when the necrotic foci of tuberculous lymph nodes rupture into the bronchial lumen, extruding the lymph node contents. During this stage, bronchial stenosis is often temporary, and the bronchoglandular fistula usually heals, leaving a thin tender scar that neither deforms the wall nor narrows the lumen of the bronchus, provided endobronchial treatment (removal of caseous masses and granulations, cauterization of the fistulous opening or peribronchial blockades) is performed. However, if scarring of the bronchoglandular fistula continues, the bronchial lumen may be permanently narrowed by persistent cicatricial stenosis, or it may even be completely obliterated. Most cicatricial stenoses of endobronchial tuberculosis appear to be the sequelae of tumorous bronchadenitis, and occasionally more lymphoglandular fistulas arise near the first fistula. When the insights of Shulutko et al. were applied to my previous series, unexpected changes were no longer unexpected, but probable. In order to maintain bronchial patency, early diagnosis and efficacious treatment, including interventional

modalities (Smith et al.1987; Watson and Ayres 1988; Chung et al. 1991a), are very important in tumorous endobronchial tuberculosis.

Fig.21.5. Bronchoscopic finding of granular endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

Fig.21.6. Bronchoscopic finding of ulcerative endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.7.5 Granular Type Granular endobronchial tuberculosis appears macroscopically like scattered grains of boiled rice, and the underlying bronchial mucosa shows severe inflammatory change (Fig. 21.5). In my previous study, roughly 20% of the cases showed fibrostenosis of the bronchial lumen two months after treatment, and the other 80% of cases healed without endobronchial sequelae three or four months after treatment. The prognosis of granular endobronchial tuberculosis is good.

21.7.6 Ulcerative Type The appearance of the bronchial ulcer in ulcerative endobronchial tuberculosis is very similar to that of a peptic ulcer (Fig. 21.6), and it can result from the submucosal lymphatic spread of organisms from adjacent parenchymal disease or implantation. In my previous study, the prognosis of ulcerative endobronchial tuberculosis was excellent, as all cases were completely resolved within three months of

336

H. S. Chung

treatment commencement. However, the number of cases involved was too small to serve as a basis for evaluating prognosis.

21.7.7 Nonspecific Bronchitic Type In nonspecific bronchitic endobronchial tuberculosis, only mild mucosal swelling and/or hyperemia are evident by bronchoscopy (Fig. 21.7). Tuberculosis is proven by bronchoscopic biopsy of the lesions. As my previous investigation indicated, all cases of nonspecific bronchitic endobronchial tuberculosis that were studied healed within two months of treatment, suggesting that the prognosis for this disease is excellent.

Fig. 21.7. Bronchoscopic finding of nonspecific bronchitic endobronchial tuberculosis. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

21.8 Location of Bronchial Involvement As pulmonary tuberculosis shows a right-sided predominance in most series (McAdams et al. 1995), so endobronchial tuberculosis may occur more frequently in the right side (Garay 1996). In my previous study (Chung et al. 1991a), endobronchial tuberculosis showed a mild right-sided predominance, whereas luminal narrowing of the bronchi was more frequently observed in the left. Moreover, tracheal involvement was not rare. Interestingly, the

Trachea: 17.3

Rt main B: 6.1

Cas' 48.6 E-H . 37.1 Fs : 8.6 NsB. 5.7

Cas: 56.2 E-H :18.7 Fs : 12.5 Tum: 6.3 Gra . 6.3

Lt Main B: 18.4 E-H : 35.6 Cas: 26.7 Fs : 24.4 Tum: 8.9 Gra : 4.4

Rt upper B: 17.9 Cas : 40.0 E-H : 29.3 Fs . 17.3 NsB : 6.7 Ulcer: 6.7 Rt lower B : 15.1 NsB : 55.6 E-H : 18.5 Fs : 18.5 Cas. 7.4

most common site of endobronchial tuberculous lesions was found to be the left mainstem bronchus. Lowet al. (2001) confirmed this finding. Endobronchial tuberculosis of both lower lobe bronchi and the right middle lobe bronchus was found to be mainly of the nonspecific bronchitic type, and tumorous endobronchial tuberculosis was found to occur mainly in the left mainstern bronchus. The distributions of involved sites and their types are illustrated in Fig. 21.8.

Lt upper B: 4.8 Fs : 37.5 Cas: 37.5 E-H : 25.0 Upper div: 5.8

E-H : 50.0 Cas: 25.0 Tum: 25.0 Rt middle B : 3.7 NsB Fs E-H Tum

42.8 28.6 14.3 14.3

Cas: E-H : Fs : Tum:

30.8 30.8 23.0 15.4

Lingular div: 1.2 Fs: 100.0

Lt lower B: 7.6 NsB : 84.6 Tum: 15.4

Fig. 21.8. Distributions of involved sites and their types versus their relative frequencies (%) in endobronchial tuberculosis. *Rt right, Lt left, Interm intermediate, B bronchus, div division. Cas actively caseating type, E-H edematous-hyperemic type, Fs fibrostenotic type, Tum tumorous type, era granular type, Ulcer ulcerative type, NsB nonspecific bronchitic type

337

Endobronchial Tuberculosis

21.9 Natural Course of Endobronchial Tuberculosis

21.10 Endobronchial Tuberculosis in HIV-Infected Patients

The presumptive natural course of endobronchial tuberculous lesions (Fig. 21.9, dashed arrow) can be deduced by observing the healing process (Fig. 21.9, solid arrow). The desired end result of endobronchial tuberculosis is healing without significant sequelae; the other possibility is fibrostenosis. All subtypes of endobronchial tuberculosis are situated between these two conclusions, and they can transform into other subtypes during treatment. However, there is a critical point between these two extremes, the position of which is mainly determined by the extent of disease progression (Kim et al. 1993) and the formation of granulation tissue (Shulutko et al. 1979; Smith et al. 1987). Bronchial stenosis is inevitable (Albert and Petty 1976; Caligiuri et al. 1984) if the disease progresses beyond this critical point. Therefore, prompt diagnosis and efficacious treatment are of paramount importance in cases of endobronchial tuberculosis in order to minimize the resultant bronchial stenosis (Park et al. 1997). To alleviate bronchostenosis that has already developed, aggressive therapeutic modalities should be considered before dense fibrosis progresses or complete obstruction of the bronchus occurs.

In a normal host the immunologic response to infection by the tubercle bacillus provides a degree of protection against additional tubercle bacilli that may be subsequently inhaled in droplet nuclei. The likelihood of reinfection is a function of the risk of re-exposure, the intensity of such exposure, and the integrity of the host's immune system. In developed countries the risk of re-exposure to an infectious case is low. Furthermore, in the otherwise healthy, but previously infected person, any organisms deposited in the alveoli are likely to be killed by cell-mediated immune response. Mycobacterial infections have been commonly observed in patients infected with HIV. These individuals are 200 times more likely to contract tuberculosis than HIV-negative individuals (Broughton and Bass 1999). In contrast to tuberculosis infections in normal adults, tuberculosis in AIDS patients cannot be readily identified by clinical or radiological criteria. It has become apparent that infection with HIV, because of its profound suppression of normal immune response, predisposes the individual to much more severe forms of tuberculosis. In HIVinfected persons with tuberculosis, dissemination of the tubercle bacilli and a variety of extrapulmonary manifestations are common. Thus, unusual clinical

Observed Healing Protess HEALING WITHOUT SEQUELAE

• I

.....- - - - -

ULCERATIVE TYPE

,I ,,

Critical Point

.--------.-

TUMOROUS TYPE

,, ,, ,, ,, ,, ,, ,, ,, ,

I I

:,

\\\\

/:/'/

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I I I

,,, ,,

\\

l

- - - . . BRONCHIAL STENOSIS

,,'

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NONSPECIFIC • - - - - - - - - - - .- EDEMATOUS· - - - - - - - - - . Formation of - - - - . FIBROSTENOTIC BRONCHITIC TYPE .. HYPEREMIC TYPE .. Granulation Tissue TYPE

t \\\

/// \\\

Bro"chiolln\lO!vement " , ' ofTuberculosis \ ,

•

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+ NORMAL BRONCHUS

•

Presumptive Natural Course

- - - - - -- -- -- -- - -.-

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I ----------.

BRONCHIAL StENOSIS

Fig. 21.9. A scheme summarizing the observed healing process (solid arrow) and the presumptive natural course (dashed arrow) of endobronchial tuberculous lesions. From Chung and Lee (2000). Reproduced, with permission, from Chest 117:385

338

H. S. Chung

presentations of tuberculosis in HIV-infected persons present a special diagnostic challenge (American Thoracic Society 1990). Tuberculosis in HIV-infected patients may have the radiographic characteristics of primary disease. Infiltrates may appear in any lung zone, cavitation is uncommon, and mediastinal or hilar lymphadenopathy is often present (Mangura and Reichman 1989). The tumorous type of endobronchial tuberculosis predominates in patients with HIV infection, and the condition may be the result of the erosion and protrusion of a tuberculous lymph node into the bronchus, a pathogenetic mechanism of primary tuberculosis. The diagnosis of endobronchial tuberculosis in HIV patients should always be considered, since it may be more frequent than suspected (Calpe et al. 1995). Consequently, a more liberal indication of bronchoscopy helps in the early detection of endobronchial tuberculosis in patients with AIDS (Alame et al. 1995). Even if no endobronchial lesion is apparent by bronchoscopy, bronchoalveolar lavage and transbronchial biopsy are particularly useful for diagnosing HIV-related pulmonary tuberculosis, since only two-thirds to three-quarters of the patients have a positive acid-fast smear, and the tuberculin skin test is less sensitive in these patients (Rossman and Oner-Eyuboglu 1998).

A cough is the most common symptom, which has an almost imperceptible onset. Coughs slowly progress over weeks or months and become more frequent; they may be nonproductive at first, but occasionally may be associated from the onset with mucopurulent sputum or blood, and later, the expectoration of sputum usually appears. Shortness of breath frequently occurs, and may be associated with localized wheezes, stridors or the absence of a breathing sound. Fever is frequently associated with the disease, and though low-grade at the onset it may become marked as the disease progresses. Characteristically, the fever develops in the late afternoon and may not be accompanied by pronounced symptoms. With defervescence, usually during sleep, sweating occurs - the classic «night sweats." In more extensive disease, hemoptysis may occur but is seldom massive. The clinical features of endobronchial tuberculosis as detailed in several reports are summarized in Table 21.2. Symptoms are usually nonspecific and are caused mainly by the coexisting pulmonary tuberculosis. In contrast to uncomplicated pulmonary tuberculosis, hemoptysis was less frequent and dyspnea was much more common in my previous study.

21.12 Diagnosis 21.11 Clinical Features

21.12.1 Clinical History

The clinical features of endobronchial tuberculosis vary widely, depending on the site(s) and the extent of involvement, and endobronchial tuberculosis may occur in the absence of recognized symptoms.

When endobronchial tuberculosis is suspected, inquiries concerning patient exposure to a person with an open case of pulmonary tuberculosis may be helpful, especially if this contact is long-standing and close. A

Table 21.2. Clinical features of endobronchial tuberculosis as detailed in several reports Symptom and sign (%)

Song et al. (1985)

Chung et al. (1991)

Ip et al. (1986)

Hoheisel et al. (1994)

Low et al. (2001)

Cough Sputum Dyspnea Hemoptysis Chest pain Fever Absence of a BS Wheezing/Stridor Rhonchi Weight loss None

87.5 75 24 17.5 45 35 27.5 27.5

75.3 68.7 33.1 1.2

100 95 35 25 15 50

87 89

86

BS breathing sound

26.5 28.3 27.7 14.5

15

57 8 15 87 19 9 12

24 19 29

35

Endobronchial Tuberculosis

past diagnosis of pneumonia that has recurred from time to time should always arouse suspicion regarding endobronchial tuberculosis. All previous chest films should be obtained. Medical conditions that increase the risk of tuberculosis (i.e. diabetes mellitus, gastrectomy, drug abuse, etc) should also be reported.

21.12.2 Physical Examination Acomplete physical examination should be performed, although an examination of the chest will usually furnish the main clues. Wheezing is frequently heard on auscultation. Persistent unilateral wheezing is more indicative of endobronchial tuberculosis, while transient wheezing due to bronchial secretions usually clears with cough. Stridor may occur with an ulceration and cicatrix of the trachea or larynx. It is nearly impossible to differentiate wheezing and stridor heard in endobronchial tuberculosis from that heard in bronchial asthma. Decreased breathing or the absence of a breathing sound is another frequent finding. When tuberculosis involves the larynx, hoarseness is usually present and is often accompanied by severe pain.

21.12.3 Laboratory Testing Routine laboratory examinations are rarely helpful in establishing or suggesting a diagnosis. A broad range of hematologic manifestations has been reported in endobronchial tuberculosis. The most common of these are increases in peripheral blood leukocyte counts and modest anemia, each of which occurs in approximately 10% of patients. WBC counts of over 20,000/f.lL suggest another infectious process, and the erythrocyte sedimentation rate is usually elevated. With endobronchial tuberculosis, HIV testing is recommended in patients who have known or suspected risk factors for the acquisition of HIV infection.

21.12.4 Bacteriology Endobronchial tuberculosis, especially the extensive form, is usually higWy infectious. In my previous study, the sputum smear for acid-fast bacilli was positive in about half of the patients, and the sputum culture for tubercle bacilli was positive in 70% or more.

339

Conversely, some recent studies have found a low yield on sputum acid-fast bacilli smears. The explanation given was that the expectoration of sputum is difficult because of mucus entrapment by proximal bronchial granulation tissue (Ip et al. 1986; Lee et al. 1992; van den Brande et al. 1990). It should not be surprising that large differences are observed in the positive rates of acid-fast bacilli, because culture yield, like microscopic examination, is affected by the clinical status of patients. Sputum examination for acid-fast bacilli is much more important, since patients with endobronchial tuberculosis occasionally present with apparent acute pneumonia. In fact, the diagnosis of tuberculosis is made only on routine sputum examination or because of a failure of clinical or radiological resolution using broad-spectrum antibiotics. However, it should be noted that a positive acid-fast smear is not specific for Mycobacterium tuberculosis. Other mycobacteria, both saprophytes and potential pathogens, can be acid-fast. Thus, the only absolute way of confirming a diagnosis of M tuberculosis is by culture. FresWy expectorated sputum is the best sample to stain and culture for M tuberculosis. Twenty-four hour old sputum samples are frequently overgrown with mouth flora and are much less useful. If a patient is not producing sputum spontaneously, induced sputum is the next best specimen for study. When a patient cannot provide a spontaneous sputum sample, a gastric aspirate to obtain swallowed sputum may be useful. This sample must be obtained in the morning before the patient arises or eats. Bronchoscopy is preferable to gastric aspiration, since bronchial secretions are readily available for acid-fast smear and culture, as well as for cytologic study, and a careful evaluation of the tracheobronchial tree can be carried out at the same time. Specimens for culture should be obtained using a minimal amount of anesthesia, because the local anesthetics used for fiberoptic bronchoscopy may be lethal to M tuberculosis. The portion of the biopsy specimen to be used for culture should not be placed in formalin. Post-bronchoscopy sputum can be another valuable source of diagnostic material, and bronchoscopy may cause the patient to continue producing sputum for several days. These later specimens should also be collected and examined, as they may reveal tubercle bacilli absent from the sample taken on the day of the bronchoscopy. Newer technologies, such as radiometric technology (the BACTEC system), polymerase chain reaction and genetic probes, immunoassay of mycobacterial antigens, and the detection of biologic compounds,

H. s. Chung

340

can allow an early diagnosis or improve our ability to isolate mycobacteria from clinical specimens (Glassroth 1993).

21.12.5 Tuberculin Testing The tuberculin skin test is used as an indicator of M. tuberculosis infection, and relies on a cell-mediated immune response. However, a positive delayed hypersensitivity reaction to tuberculin indicates only the occurrence of a prior primary infection and not the presence of clinically active disease. Very large reactions (greater than 25 mm of induration) are more frequently associated with active tuberculosis. However, a negative reaction to tuberculin does not rule out the diagnosis, because the patient may be anergic or have a specific anergy to tuberculin (Rossman and Oner-Eyuboglu 1998). Nevertheless, the absence of skin reactivity to tuberculin makes the possibility of tuberculosis unlikely in most situations.

21.12.6 Pulmonary Function Test Bronchial disease and pulmonary parenchymal lesions coexist in endobronchial tuberculosis. Although this may have an influence on pulmonary function, no pathognomonic pattern of physiologic disturbance exists in endobronchial tuberculosis. Nevertheless, the usual pattern is that of a predominantly restrictive ventilatory defect. The reason why endobronchial tuberculosis shows this restrictive pattern may be due to organic obstruction of the bronchial tree and chronic inflammatory or bronchiectatic changes of the lung parenchyme. The pulmonary function test may be helpful in the differential diagnosis of endobronchial tuberculosis and bronchial asthma. The results of pulmonary function testing in my previous study are illustrated in Fig. 21.10.

Pulmonary function testing is useful for the followup of endobronchial tuberculosis. Changes in pulmonary function during treatment in endobronchial tuberculosis are significantly correlated with changed bronchoscopic findings, although the indices of pulmonary function testing at diagnosis do not correlate significantly with the gross bronchoscopic findings of endobronchial tuberculosis (Chung and Lee 1996).

21.12.7 Radiology 21.12.7.1 Simple Roentgenograms

Despite the fact that roentgenographic examination itself is not diagnostic of endobronchial tuberculosis, it is a necessary procedure. A lateral chest film should be a part of every roentgenographic inquiry, since approximately 25 percent of the lung fields cannot be visualized on the conventional posteroanterior film. Endobronchial tuberculosis, as well as pulmonary tuberculosis, may produce almost any form of pulmonary radiographic abnormality. However, endobronchial tuberculosis frequently presents with unusual roentgenographic findings, such as pneumonic consolidation, lobar or segmental collapse, a mass-like lesion or hilar or paratracheal adenopathy. A normal chest radiograph cannot completely exclude endobronchial tuberculosis, because roughly 10% of patients show normal chest roentgenograms. Radiologic findings of endobronchial tuberculosis in my previous study are shown in Table 21.3. 21.12.7.2 Computerized Tomography

Special imaging techniques, such as computerized tomography and magnetic resonance imaging, may be of particular value in defining nodules, cavities, cysts, Table 21.3. Radiologic findings of 166 endobronchial tuberculoses Characteristics

Fig.21.10. The results of pulmonary function testing in 85 cases of endobronchial tuberculosis

Cases

Pneumonic patchy infiltration 42 Atelectasis or Collapse 33 Fibrostreaky densities 27 Cavitary lesion 23 Mass-like lesion 12 Bronchiectatic change 7 18 Mediastinal widening No active lesion 21

%

25.3 19.9

16.3 13.9

7.2 4.2 10.8 12.7

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calcifications, the contours oflarge bronchi and vascular details in lung parenchyma. Moreover, since the length of bronchial involvement, the thickness of bronchial wall and mediastinal lymph node enlargement can be evaluated noninvasively, computerized tomography is a useful adjunct to direct endoscopic visualization, particularly when performed at a 5-mm intervals with 5-mm slice collimation through the hila. The technique accurately depicts bronchial abnormality in 93 to 100% of all cases (McAdams et al. 1995), and it can also reconstruct three-dimensional images of the trachea and of the major bronchi (Choi et al. 2002). Computerized tomography findings of endobronchial tuberculosis include: isolated long segment bronchial narrowing with concentric wall thickening, complete endobronchial obstruction, extrinsic compression by adjacent adenopathy and even direct bronchial invasion of a caseous node. The erosion of calcified lymph nodes into adjacent bronchi, known as broncholithiasis, can also be observed, along with the resultant segmental collapse or overinflation. Computerized tomographic scans of the central airways usually show active endobronchial tuberculosis as an irregular narrowing of the airways with marked wall thickening; the scans also frequently show mediastinal lymph node enlargement, whereas fibrotic tuberculosis shows as a rather smooth narrowing of the airways with minimal wall thickening (Kim et al.1997; Moon et al.1997).

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essential that aggressive therapy be performed before the disease progresses too far and bronchostenosis becomes inevitable. Therefore, the bronchoscopic approach is mandatory not only for the prompt diagnosis of endobronchial tuberculosis, but also for the prevention of further bronchostenosis. The suspicion of endobronchial tuberculosis provides an important indication for bronchoscopy. The presence of a wheeze or of a persistent and uncontrollable cough, or the presence of tubercle bacilli in the sputum without an obvious source in the lung parenchyma, provides sufficient reason for the procedure. Roentgenographic findings of atelectasis or selective segmental or lobar collapse, unexplained shadows near the hilum, the sudden or gradual appearance of localized obstructive over-distention or ballooning cavities should also be investigated by bronchoscopy. A ballooning cavity is often referred to as the tension cavity, regardless of whether or not the intracavitary pressure is known. Ballooning cavities are frequently secondary to the involvement of bronchi in tuberculosis (Wolinsky 1989). Tuberculosis produces two main bronchoscopically visible changes: endobronchial inflammation and distortion due to extrabronchial lymph-node enlargement. One may see inflamed, swollen mucosa and purulent secretions or blood; alternatively, one may sometimes see fibrous masses ofwhite-pink color resembling cauliflower and simulating a cancerous tumor, or even ulceration, in the bronchial draining 21.12.8 lobes or segments afflicted with active tuberculosis. Bronchoscopy Acute inflammatory changes can respond rapidly to chemotherapeutic treatment, leaving normal bronBronchoscopy is the single most useful modality chi, but healing may lead to bronchial scarring and in the diagnosis of endobronchial tuberculosis, sometimes to marked contractive stenosis. whereas the chest radiograph is the most important In summary, the diagnostic use of bronchoscopy for suggesting a diagnosis of pulmonary tuberculo- in obtaining a biopsy from an area of bronchial sis. Bronchoscopy is necessary not only to make the ulceration or obstruction can clinch the diagnosis of diagnosis of endobronchial tuberculosis, but also endobronchial tuberculosis. to exclude bronchogenic carcinoma. Bronchoscopy has a unique value in the management of endobronchial tuberculosis. When the different forms of endobronchial tuberculosis are classified into seven 21.13 subtypes (actively caseating, edematous-hyperemic, Differential Diagnosis fibrostenotic, tumorous, granular, ulcerative and nonspecific bronchitic), the therapeutic outcome of 21.13.1 each subtype, except the tumorous type, can be pre- Pneumonia dicted by follow-up bronchoscopy during the initial two to three months of treatment. However, in the In contrast to endobronchial tuberculosis, in which case of tumorous endobronchial tuberculosis, close symptoms are nonspecific, the acute pneumonic and long-term follow-up is advisable, given that the patient usually has typical symptoms of fairly recent evolution of lesions during treatment is very compli- onset. If the patient is symptomatic, an oral antibicated and bronchial stenosis may develop later. It is otic should be prescribed, and if the radiographic

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opacities do not clear or improve in 2 to 3 weeks, then tuberculosis is a possibility. If the pneumonia is refractory to standard treatment, especially if the white count is normal, then repeated sputum specimens should be examined for acid-fast bacilli.

21.13.2 Fungal Infection and Actinomycosis Polesky et al. (1999) presented data on 38 cases of coccidioidomycosis of the airways, which included 6 cases detailed from their own experience and 32 from the literature. In histoplasmosis, regional lymph node involvement is invariable during the initial infection. The extrinsic pressure of enlarged nodes on the airways may cause obstruction and distal infection or atelectasis. Complications of histoplasmosis are similar to those of primary pulmonary tuberculosis (Fraser et al. 1994). In 1999, Lee et al. reported a case of biopsy-proven endobronchial actinomycosis. The bronchoscopic findings of this disease are very similar to those of endobronchial tuberculosis.

21.13.3 Lung Cancer This differential diagnosis occurs primarily in the middle-aged and elderly age groups. Consolidation distal to a proximal carcinoma may be cavitated and closely mimic tuberculosis. Moreover, carcinoma of the lung and tuberculosis may be present simultaneously; in fact, the frequency of coexistent lung cancer and tuberculosis is as high as 5% (McAdams et al. 1995). In cases with a simultaneous presentation of carcinoma and tuberculosis, the diagnosis of tuberculosis is frequently made first, and the carcinoma diagnosis is often delayed for several months. Thus, if the radiographic and clinical findings suggest carcinoma, but the sputum has acid-fast bacilli, further procedures to diagnose carcinoma may still be indicated (Rossman and Mayock 1988). On bronchoscopy, tuberculous granulation tissue may be observed to erupt through the bronchial mucosa to form a tumor-like mass. The caseous tracheobronchial lymph nodes can produce ominous, irregular swellings into the main bronchi or trachea that suggest the malignant invasion of lymph nodes (Stradling 1981). Bronchoscopic biopsy will reveal the true situation.

21.13.4 Bronchial Asthma Some patients with endobronchial tuberculosis show wheezing on physical examination but have normal chest films, which mimics bronchial asthma. One should always consider the possibility of endobronchial tuberculosis during the differential diagnosis of bronchial asthma if patients with wheezing show normal airway responsiveness (Park et al. 1995) or a poor response to bronchodilation (Williams et al. 1988).

21.14 Treatment 21.14.1 Anti-Tuberculosis Chemotherapy In principle, the short-course regimens are the regimens of choice for patients with endobronchial tuberculosis. Many short-course regimens have been investigated and proposed for pulmonary tuberculosis, and these can also be applied in endobronchial tuberculosis. A 6-month regimen consisting of isoniazid, rifampin and pyrazinamide for 2 months, followed by isoniazid and rifampin for 4 months, is the preferred treatment for patients with fully susceptible organisms and who can adhere to treatment. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results ofdrug susceptibility studies are available, unless there is only a small possibility of drug resistance (i.e. if there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance and has no known exposure to a drug-resistant case). The four-drug,6-month regimen is effective even when the infecting organism is resistant to isoniazid. This recommendation applies for both HIV-infected and uninfected persons. However, in the presence of HIV infection, it is critically important to comprehensively assess the clinical and bacteriologic response. Any problem with the response to treatment indicates that the usual evaluation should be undertaken and the therapy possibly prolonged. Consideration should be given to treating all patients with directly observed therapy, and the duration of treatment should total at least 6 months and 3 months beyond culture conversion. Children should be managed in essentially the same ways as adults by using appropriately adjusted

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doses of the drugs. In multidrug-resistant tuberculosis (i.e. resistance to at least isoniazid and rifampin), treatment must be based on susceptibility studies (American Thoracic Society 1994). With endobronchial tuberculosis, therapy needs to be prolonged as decided on a case-by-case basis and should be individualized after considering the clinical, bacteriologic and bronchoscopic response, especially if the dominant form is of the tumorous type or if interventional management is performed.

loon dilatation, which tends to be only a temporary measure, Nd-YAG laser resection and surgical reconstructive procedures, which are generally considered to be the gold standard, although some patients will have contraindications to surgery. Stent placement, in contrast, is a new therapeutic modality. For select patients, a multidisciplinary approach, whereby pulmonologists, otolaryngologists and thoracic surgeons decide on the most appropriate use of laser resection, stent placement and surgical techniques has been advocated (Dineen et al. 2002).

21.14.2 Corticosteroid Treatment

21.15.1.1 Interventional Management

The use of corticosteroids has been and remains controversial. Nevertheless, under certain conditions corticosteroids are of benefit in patients with endobronchial tuberculosis. It appears that steroids are effective in rapidly reducing the mass effects of mediastinallymphadenopathy in patients with primary tuberculosis. Steroids may, therefore, decrease the severity of local obstructive complications (Nemir et al. 1963). Corticosteroids are more likely to be beneficial in the earlier stages of endobronchial tuberculosis, when hypersensitivity is the predominant mechanism (Dooleyet al. 1997), and they are unlikely to be helpful in more advanced cases when extensive fibrosis is present. Therefore, corticosteroids can be cautiously prescribed for actively caseating and edematous-hyperemic endobronchial tuberculosis (which occur in the earlier stages of the disease) and for tumorous endobronchial tuberculosis, which may be derived from primary tuberculosi~. The usual dose required is 40-60 mg of prednisone (or approximately 1 mg/kg ofbody weight) orally daily for 4-6 weeks, with gradual tapering over the next few weeks. It should be emphasized that before corticosteroids are prescribed, one must be confident that adequate antituberculosis chemotherapy is being given. Prompt treatment upon early diagnosis, before the formation of dense fibrosis, is a prerequisite for the prevention and amelioration of bronchostenosis (Park et al.1997).

Since bronchostenosis develops despite adequate antituberculosis therapy and/or corticosteroid treatment, more aggressive interventional management may be indicated to restore the patency of the involved bronchus in selected cases of endobronchial tuberculosis. In tumorous endobronchial tuberculosis, because the prognosis is grave if the condition is not treated aggressively, the endobronchial tumorous lesion itself should be removed by laser resection or electrosurgery to prevent further bronchostenosis. The fibrous membrane can simply be resected by laser photoresection or electrocautery (in the fibrostenotic type of endobronchial tuberculosis), if the membrane has a concentric web-like stricture (Becker et al. 1991). In cases where the fibrostenosis is relatively long, an endobronchial stent can be placed after dilatation with a high-pressure balloon catheter. Some, but not all, patients with tuberculous bronchostenosis may be provided with long-term control of their disease process by stent placement. Restenosis by granulation tissue formation can develop, but it may be successfully treated by laser ablation or electrosurgery. The therapeutic results of stent placement have been very poor in actively caseating, edematoushyperemic and tumorous endobronchial tuberculosis, which have active severe inflammation of the involved bronchus. Thus, appropriate antituberculosis chemotherapy and/or corticosteroid treatment should be administered prior to stent placement, until active inflammation disappears. This may take up to 5 months, after which, the endobronchial tuberculosis is usually of the fibrostenotic type, which is the main indication of stent placement. During drug therapy, repeated balloon dilatation may be needed to prevent complete obstruction and to maintain the patency of the narrowed bronchus (an example is shown in Figs. 21.11 and 21.12). Once active inflammation has been ameliorated by drug treatment, a

21.15 Complications and Their Management 21.15.1 Bronchostenosis Traditional strategies for repairing benign tracheobronchial stenosis include repeated endoscopic bal-

344

tracheobronchial stent can be placed, if necessary (Figs. 21.13-15}. Further chemotherapy should be given for a minimum of 3 months after the procedure to prevent recurrence. The stent may be successfully removed one year after placement, and the success rate of stenting is roughly 50% (Kim, personal communication). Granular, ulcerative and nonspecific bronchitic endobronchial tuberculosis do not indicate stent placement, because they do not involve significant bronchostenosis. 27.75.7.2

TracheobronchialStent The ideal tracheobronchial stent should possess several vital characteristics. It should be capable of establishing and maintaining airway patency; it should be easy and safe to place and (if necessary) remove;

H. S. Chung

it should be biocompatible; and, it should be flexible enough to fit appropriately in irregular anatomy. In addition, it should not cause mucosal injury or granulation tissue formation, hamper the ability to clear secretions, migrate from its desired position or obstruct otherwise patent lumens (Jantz and Silvestri 2000). As of yet, no such stent has been developed. Essentially, five types of stent have been developed and used for tracheobronchial obstructions. The earliest types were of silicone, most notably the Dumon or Endoxane stent. The next stents used were of uncovered stainless steel, such as the Gianturco Z and the Palmaz stents, which were the first stents capable of being deployed by flexible bronchoscopy. The third type were the second generation of metal stents as represented by the Wallstent and the Ultraflex. These stents are alloy-based mesh or interwoven loop stents and are also available with a polyurethane covering.

Fig. 21.11a-d. Repeated balloon dilatation of the left mainstem bronchus in a case with endobronchial tuberculosis. a At diagnosis. b At 1 month of treatment. c At 2 months of treatment; d At 3 months of treatment

Fig. 21.12a, b. Three-dimensional images of central airways in the case illustrated in Fig. 21.11. a At diagnosis. b At 2 months of treatment

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Fig. 21.13a-d. Stent placement for endotracheal tuberculosis. a Before stenting. b After stenting. c Just after stent-removal. d At 4 months after stent-removal

Fig. 21.14a, b. Three-dimensional images of the trachea in the case illustrated in Fig. 21.13. a Before stenting. b After stenting

Fig.21.15a, b. Stent placement for mainstem endobronchial tuberculosis. a Before stenting. b Just after stenting

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The polymer coating prevents the ingrowth of tumor or granulation tissue through the stent mesh framework. The fourth type of stent, the bifurcated Y-stent, was designed specifically to deal with the anatomic complexities of the central airways and the carina, and the fifth type of stent was constructed from a variety of different materials, such as polyester/silicone and nitinollsilicone. Generally, the most common complications associated with stents are stent migration, secretion retention and granulation tissue formation. Refinements in stent designs are required to improve biocompatibility and reduce migration and granulation tissue formation (Dineen et al. 2002). Overall, silicone stents have been very successful in treating benign airway obstructing lesions and may well be the gold standard for years to come. Recently, animal model trials have been reported with a bioabsorbable stent (Korpela et al. 1999). In the future, bioabsorbable stents may have a role in the management of benign airway stenoses. 21.15.1.3 Endobronchial Electrosurgery vs Laser Photoresection

Nd-YAG laser photoresection is the most effective therapy for treating tracheobronchial obstructions from benign or malignant lesions. However, the widespread use of this technique is limited by the perceived need for rigid bronchoscopy, expensive equipment and special training and fear of major complications. Advances in flexible bronchoscopy have allowed developments in other techniques directed at alleviating airway obstruction, including cryotherapy, brachytherapy and photodynamic therapy. Although costeffective, their effects are delayed and they may require repeated treatments (Coulter and Mehta 2000). Labeled "the poor man's laser:' electrosurgery offers equivalent laser-like tissue effects at a fraction of the cost. The ability to perform endobronchial electrosurgery in the outpatient setting is more accommodating for patients and time-saving for physicians, and it offers Significant cost savings. The lesions found to be most amenable to endobronchial electrosurgery are polypoid in morphology and attached to the airway by a stalk. Flat or sessile lesions can be treated by fulguration with the coagulation probe (Coulter and Mehta 2000). Endobronchial lesions in the tumorous type of endobronchial tuberculosis are good candidates for electrosurgery, because they usually present as polypoid masses or sessile lesions. Although the number of cases was small, my previous study found that electrosurgery produced successful results in this

H. S. Chung

type of endobronchial tuberculosis (Chung and Lee 2000). Granulation tissue caused by metallic stents can also be removed by endobronchial electrosurgery. Special care must be taken not to touch the wires when ablating these lesions, since electrical conduction may occur through the wire mesh. The circumferential treatment of endobronchial lesions should be avoided in endobronchial electrosurgery, as this may lead to cartilaginous damage, fibrosis and subsequent stenosis. 21.15.1.4 Surgical Management

Severe bronchostenosis with poor response to medical treatment and intervention usually requires later resection. Bronchoscopy and computed tomography are the treatments of choice in the accurate diagnosis of bronchial involvement and the assessment of surgical indications (Watanabe et al. 1997). To preserve lung function, bronchoplastic surgery is essential, especially for bronchial stricture of the trachea or larger bronchi, and appropriate antituberculosis chemotherapy should be given for 9 to 12 months perioperatively to prevent recurrence and restenosis (Hsu et al. 1997).

21.15.2 Bronchiectasis Distention by mucus, caseous tissue or secondary infection beyond a bronchial stenosis may result in bronchiectasis, especially following lobar or segmental lesions. (Seaton et al. 1989). The incidence of bronchiectasis is reduced by prompt antituberculosis chemotherapy.

21.15.3 Broncholith In primary tuberculosis, gross tracheobronchial lymph-node enlargement may take place. In many cases, these caseous nodes do not rupture but instead inspissate, contract and calcify, and occasionally such calcifications may later begin to ulcerate through the bronchial wall to produce repeated hemoptysis and eventually be extruded into a bronchus as a "broncholith:' A partially protruded broncholith can sometimes be removed bronchoscopically if not expectorated by the patient. However, attempts to remove broncholiths bronchoscopically can lead to profuse hemorrhage and, therefore, are best avoided (Stradling 1981).

Endobronchial Tuberculosis

Acknowledgements. I am very grateful to Dr. Ho Joong Kim, and Miss Jin Ha Park for their generous contribution.

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22 Pleural Tuberculosis M. MONIR MADKOUR, MAJDY IDREES, MONA

CONTENTS 22.1 22.2 22.3 22.4 22.5 22.5.1 22.5.2 22.5.3 22.5.4 22.5.5 22.5.6 22.5.7

Introduction 349 Epidemiology 349 Pathogenesis of Tuberculous Pleural Effusion 350 Clinical Features 351 Diagnosis of Tuberculous Pleural Effusion 352 Diagnosis 352 Pleural Fluid Examination 352 Pleural Biopsy 353 Thoracoscopy in Tuberculous Patients 354 Tuberculin Skin Test (PPD) 354 Imaging Features of Pleural Tuberculosis 355 Treatment 355 References 356

22.1 Introduction Tuberculous pleurisy is a common disease in developing countries and its incidence is increasing in developed countries. It is considered an extrapulmonary manifestation of tuberculosis despite its intimate anatomical relationship with the lung parenchyma. In the United States, because of the recent increase in the incidence of tuberculosis due to the HIV epidemic and immigrants from developing endemic countries, the incidence of pleural tuberculosis has increased in parallel with, and has been found in 20% of, AIDS patients (Ankobiah et al. 1990). Although tuberculous pleural effusion is associated with parenchymal infiltrates and cavitation in approximately 50% of patients, isolated pleural effusion without lung parenchymal disease can present M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia M. IDREES, MD, FRCP (C), FCCP Head, Pulmonary Function Laboratory, Division of Pulmonary Medicine, Department of Medicine, Riyadh Armed Forces Hospital, ClIO, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. AL SHAHED, MBBS, FRCR Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

AL SHAH ED

a diagnostic challenge; malignancy is of particular concern (Hunlnick et al. 1983; Hirsch et al. 1979). It is estimated that between 15 to 20% of patients with exudative pleural effusion in general are difficult to diagnose. In developing countries with poor resources, conventional methods of diagnosis by pleural fluid culture may only be positive in 25-50% of patients (Idell 1994). Presumptive diagnoses of tuberculous origin in exudative pleural effusion, based on clinical features, radiography and response to antituberculous chemotherapy in endemic countries are still adopted by many clinicians. Patients who are not treated for tuberculous pleural effusion often develop reactivation pulmonary disease (Palmer 1979). In developed countries, due to recent advances in investigative facilities, particularly in the field of molecular biology assays, the diagnosis can be made in few hours or days if other investigations are not helpful (Takagi et al.1998; Querol et al.1995; Lassence et al. 1992).

22.2 Epidemiology Pleural tuberculosis is the second commonest form of extra pulmonary parenchymal disease, after the tuberculous lymphadenitis. Pleural tuberculosis is also more common in patients that are co-infected with AIDS (11%) than among those without AIDS (6%). Other reports indicating a higher incidence of pleural tuberculosis (20%) in AIDS patients have found it to be the most common cause of pleural effusion in this patient population (Modilevsky et al. 1989; Shivaram et al.1989;Ankobiah et aI.1990). In developed countries, pleural tuberculosis is more commonly caused by post-primary disease than by primary infection. Reactivation of the disease was the cause of tuberculous pleural effusion in 64% of patients seen in Scotland and reported by Moudgil et al. (1994). Primary pleural tuberculosis was noted in 7% of patients with active pulmonary disease (Aktogu

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et al. 1996). In young adults with HIV who are coinfected with tuberculosis, the primary disease as a cause of pleural tuberculosis was more common than reactivation (post-primary) (Sudre et al.1992; Batungwanayo et al.1993; Richter et al.1994). Seibert et al. (1991) from Alabama, USA, reviewed the medical records of 1,738 patients with tuberculosis seen between 1968 and 1988, to determine the age distribution, pleural fluid culture and frequency of pleural effusion among those with parenchymal disease, as well as the prevalence of positive tuberculin test. Pleural tuberculosis was found in 70 patients (4.0%) of all forms of the disease. The mean age was 47±17.7 years, with male predominance and pulmonary parenchymal involvement noted in 50% of patients. In Spain, two large studies of patients with pleural effusion were undertaken to determine the causes. The first series was a retrospective study of 414 patients with pleural effusion of unknown cause, who were seen between 1979 and 1986. Tuberculous cause was identified in 107 patients (28.5%) (Bueno et al. 1990). Male predominance was noted and the average age was 55 years. In the second series, 642 patients with pleural effusion were seen between 1989 and 1993. Tuberculous pleural effusion was found in 25% of these patients, similar to the earlier series, and the average age was also similar (57.1±21.1 years) with male predominance as well (Valdes et al.I996b). In Australia, Christopher et al. (1998) reported a prospective study of 27 patients with plural effusion that were hospitalized for the purpose of etiological diagnosis. Tuberculosis was found in 16 patients (59%) and was considered as the single most common cause of exudative pleural effusion in that series. In the United States, the incidence of tuberculosis as a cause of pleural effusion in AIDS patients was found to be increased. In New York, Relkin and colleagues (1994) retrospectively studied pleural tuberculosis in HIV-positive patients and found it to occur at a younger age. They found 70 patients with tuberculosis pleural effusion, including 43 HIV-positive (mean age 38±1 years) and 27 HIV-negative (mean age 52±3 years). They also confirmed previous observations that pleural tuberculosis in HIV-negative patients occurs more frequently in the older age group. In developing countries, such as some sub-Saharan African countries, the prevalence of tuberculosis has increased as a result of the HIV epidemic and the incidence of pleural tuberculosis has also increased in parallel. Richter and colleagues from Tanzania (Richter et al. 1991) prospectively studied 127 patients with pleural effusion. Tuberculosis was the

M. M. Madkour et al.

most common cause (70%) in this series. The authors also found that among the 89 patients with tuberculous pleurisy 57 (64%) were HIV-positive. In Zimbabwe where HIV is endemic, tuberculosis has become the single most likely cause of opportunistic infection (Heyderman et al. 1998). The prevalence of HIV among male factory workers was 19.4% and in females was over 30% (Mbizvo et al. 1996). In 1995, Harare provided an annual report of the incidence of tuberculosis, which was 195 cases per 100,000 population, with over 40% of the TB cases co-infected with HIV. In our series of 176 patients with culture positive sputum for M. tuberculosis, 46 patients had pleural effusion (26.1 %) - see Table 2 in the chapter on postprimary tuberculosis. The average age group was 40 years, with male predominance (75%). The majority of the patients were from the central (57%) and southern (29%) provinces of Saudi Arabia. Unlike the situation in the sub-Saharan African countries, HIV was not found to be a contributing factor for the development of tuberculous pleural effusion.

22.3 Pathogenesis of Tuberculous Pleural Effusion Tuberculous pleurisy has been described by an immunologist as an excellent model for studying the immune response in vivo. The mode of transmission of M. tuberculosis to the pleura may be hematogenous spread, as in primary tuberculosis, or it may be secondary to the direct invasion from adjacent tuberculous lymphadenitis or the rupture of subpleural tuberculous lung parenchymal cavity; it may also result from extrapulmonary disease such as spinal tuberculosis (Sahn 1988; Stevenson 1955; Mohammed et al. 1998; Maeda et al. 1993; Wallis 1996; Zhang et al. 1994; Morehead 1998). The pleura respond to the mycobacterial antigens with an extensive infiltration of mononuclear phagocytic cells and increased production of cytokines; however, the mechanisms by which these cells are recruited to the pleural space remains unclear. Several recent immunological studies have suggested that activated macrophages and CD4 lymphocytes play the most important role in cell-mediated immunity with granuloma formation against M. tuberculosis. Antigens from the wall of the bacilli have a potent stimulant effect and lead to the excessive production of cytokines (TNF-a and IFN-y) from these inflammatory cells, which in turn contribute to

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the formation of granuloma and to the defense mechanism against infection (Epstein et al. 1987; Shimokata et al. 1986; Barnes et al. 1989, 1990; Lorgat et al. 1992; Kunkel et al. 1989; Willis et al. 1990; Zhang et al. 1994; Wallis 1996). Several observations have suggested that a vigorous in-situ or "compartmentalized" intrapleural immune response with activation of cell-mediated immunity (CMI) and delayed type hypersensitivity (DTH) with cytokine production in response to the bacilli cell-wall antigens take place (Barnes et al. 1989). Mycobacterium tuberculosis bacilli contain multiple antigens, including polysaccharides (arabinogalactan and arabinomannan) and proteins (mainly glycolipids and lipoproteins). Polysaccharides from the bacilli generally do not elicit delayed type hypersensitivity (DTH) (Chaparas et al. 1971; Yamamura et al. 1968; Barnes et al. 1993). Lipoprotein and glycolipids antigens elicit DTH and stimulate T lymphocyte and cytokine production, which can be detected in high concentration in the pleural fluid. Pleural mesothelial cells are the first cells to respond to bacilli invading the pleural space. These cells are metabolically active and likely initiate and propagate an inflammatory reaction (Mohammed et al. 1998). Mesothelial cells have been found to initiate inflammation in response to various agonists by the production and release of chemokines (Boylan et al. 1992; Goodman et al. 1992; Jonjic et al. 1992).lnterleukin 12 (IL-12) cytokine has been found in high concentration in the pleural fluid of patients with tuberculous pleurisy (Zhang et al. 1994). Zhang and colleagues from California found that IL-12 play an important role in the immune response by enhancing the production of interferon-y, facilitating development of Thl cells and augmenting cytotoxicity of antigen-specific T-cells and natural killer cells. IL-12 enhances natural killer cell-mediated cytotoxicity and augments antigen-dependant proliferation by CD8+ cytotoxic T lymphocytes (Zhang et al. 1994). It has also been suggested that IL12 enhances cytotoxicity by activating CD4 + T cells against the bacilli loaded phagocytic macrophages, leading to its apoptosis and the destruction of the bacilli within it. Evidence for the excessive production ofantigen-reactive T lymphocytes,IFN-y, TNF-u and IL-12 is provided by the elevated levels of these cytokines in the pleural fluid of tuberculous patients. There is evidence that IL-12 is produced locally in the pleura in response to M. tuberculosis antigens, and that when IL-12 is experimentally suppressed, the bacilli proliferate again. These findings suggest that IL-12 contributes to lymphocyte recognition of M. tuberculosis antigens, probably by enhancing proliferation of activated T cells. The high concentration

of IFN-y and TNF-u (both have anti-mycobacterial activity) in the pleural fluid are a likely indication that they playa role in immune resistance. TNF-u augments the macrophages' capacity to phagocytose and kill the bacilli (Zhang et al. 1994). The authors conclude that IL-12 contribute to the immune response against M. tuberculosis by enhancing production of IFN-y, the T cells and orchestrating antigen-specific cytolytic mechanisms. CD4 T cells also playa critical role in the immune response to M. tuberculosis antigens. In 1996, Wallis (from Ohio), studied the response of T-cells to alpha antigen, a major protein from the wall of the bacilli, and reported the increased IFN-yproduction. As a result of the immune response and the outcome of the infection, inflammatory cellular infiltrates and granulomata formations may occur. As the infection progresses, inflammatory responses and cytokines release will lead to increased vascular permeability of the local capillaries. Subsequently, plasma protein exude fluid into the pleural space forming pleural effusion (Ellner et al. 1988). In postprimary pleural effusion, the disease may be complicated by empyema, lung parenchymal spread or bronchopleural fistula. Pleural fibrosis and calcification may occur in chronic tuberculous empyema.

22.4 Clinical Features Pleural effusion due to tuberculosis most commonly occurs 3 to 12 months, or even more, after the primary infection in adolescents and young adults, but it may occur at any time during the course of the disease (Gedde-Dhal 1952; Berger and Mejia 1973; Sahn 1988; Ansari and Idell 1998). Pleural tuberculosis, due to reactivation of the disease, may be noted in up to 50% of patients with post-primary lung parenchymal involvement, particularly with cavitations (Seibert et al. 1991). The onset of symptoms is acute in about 70% of patients with cough, fever and chest pain. Gradual onset may be noted in about 30% with dyspnea, weight-loss and weakness. The frequency of these symptoms may vary from one series to another. The presence or absence of co-infection with HIV does not change the frequency of symptoms, but non-HIV patients are more symptomatic (See Table 22.1). Non-symptomatic pleural effusion may occur in HIV co-infected patients and was reported in 4 of 21

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Table 22.1. Symptoms

Our Own Hong Kong USA Zimbabwe series (Chang et al. 1991) (Ankobiah et al. 1990) (Heyderman et al. 1998) No HIV No HIV ±HIV ±HIV

Cough 0/0 Dyspnea 0/0 Fever 0/0 Weight loss 0/0 Chest pain 0/0

63

77 86.5 90 44

71 48 71 55 53

60 38 72 59 44

HIV patients (20%) by Ankobiah et al. (1990) from New York. Clinically, sharp pain with pleural rub during deep inspiration on the affected side may be noted. The clinical features of pleural effusion may depend on its size, and are manifested as decreased chest movement, dullness of percussion, decreased breath sound or retraction of chest wall due to extensive pleural fibrosis. These features are not characteristic of tuberculous pleurisy. Pleural tuberculosis is most commonly unilateral but may be bilateral in 5% of patients (Chan et al.1991; Heyderman et al.1998). In our experience with 46 patients with proven pleural tuberculosis, 44 (96%) had unilateral pleural effusion. One patient (2%) had transudative effusion based on Light's criteria. Thirty patients (65%) had moderate effusions and 11 (24%) had massive effusions. Loculated effusion was reported in 9 patients (20%) and pleural calcification in 7 (15%).

97 82 73 51 73

cell count and bloodstained exudative effusion were the best discriminating functions in the screening for pleural tuberculosis. The diagnosis, however, can only be confirmed by the presence of M. tuberculosis determined by direct staining or by culture. The diagnosis of pleural tuberculosis has been defined for the purpose of clinical studies by several authors when one or more of the following were confirmed: (1) positive microbiological findings (smear or culture) in pleural fluid or biopsy; (2) histopathological evidence of granulomatous pleuritis with clinical andlor radiological response to anti-tuberculous treatment; (3) positive skin testing, recent conversion in young patient with a lymphocytic, exudative effusion (Ankobiah et al. 1990; Seibert et al. 1991; Morehead 1998).

22.5.2 Pleural Fluid Examination

22.5

Diagnosis of Tuberculous Pleural Effusion

22.5.1 Diagnosis The diagnosis of pleural tuberculosis begins with a high index of suspicion, clinical features, PPD skin test, imaging features and a culture of all potentially diagnostic specimens (body fluids or tissue biopsies). Screening methods used to differentiate tuberculous from non-tuberculous pleural effusion have been evaluated to identify the discriminate power of each investigative parameter. In a recent report from Spain, Carrion-Valero and Perpina-Tordera (2001) screened tuberculous pleural effusion by discriminant analysis of 189 patients. In this retrospective study, the discriminating power of routine imagining features and laboratory parameters was reviewed. Using the backward elimination method, the authors found that age, the tuberculin skin test, pleural white

Pleural fluid examination remains an important tool in the of investigation of tuberculous pleurisy. Tuberculous pleural fluid is an exudate which may be cloudy (turbid), yellow, serosanguineous or hemorrhagic in appearance. The PH usually ranges between 7.30 and 7.40 or lower, particularly among those co-infected with HIV (George et al. 1985; Pablo et al. 1997). Total WBC may range from 5,000 to 10,000/mm3, with more than 50% lymphocytes; however, polymorphs may be seen early after the onset of symptoms. Red cell count may be raised to a variable degree in the pleural fluid. Mesothelial cell count is usually less than 5% of the pleural fluid white cell count. Raised mesothelial count above 5% is considered by many authors to argue against tuberculous pleurisy (Spriggs and Boddington 1960). However, some authors have reported mesothelial cell counts above 5% in patients with tuberculous pleurisy (Hirsch et al. 1979; Lau 1989; Santos-Santre et al. 1990). Pleural fluid protein is usually greater than 3.0 Gldl, and glucose may be decreased. Pleural fluid

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lactic dehydrogenase (LDH) is usually above 200 LU.I L. Pleural fluid adenosine deaminase (ADA) measurement has been used as a biochemical parameter in an attempt to differentiate between tuberculous and other exudative non-tuberculous pleural effusions (Valdes et al. 1996). In a prospective study from India, Sharma et al. (2001) reported the diagnostic value of ADA as a marker for tuberculous pleurisy. Seventy-five patients with exudative pleural effusion were assessed. Pleural fluid ADA, as well as serum ADA, levels were significantly higher in tuberculous pleurisy compared with non-tuberculous effusions. The authors reported the sensitivity and specificity of pleural ADA at two cut-off points, 35 lUlL and 100 lUlL. At 100 lUlL, the sensitivity of ADA was 40% and the specificity was 100%. The authors suggested that using 100 lUlL pleural ADA level may spare as many as 40% of patients from having a pleural biopsy. However, ADA level estimation is complicated by false-positive and false-negative results (Yamada et al. 2001). Maartens and Bateman (1990) from South Africa found in their prospective study of 111 patients with pleural effusion that ADA did not provide a valuable diagnostic test of pleural tuberculosis as has been suggested. In recent years, the use of pleural fluid cytokines as parameters for the diagnosis of tuberculous pleurisy has been reported (Yamada et al. 2001; Pablo et al. 1997; Xirouchaki et al. 2002). In a comparative study between raised pleural levels of ADA and cytokines, interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y), Yamada et al. reported their findings. The study involved samples of pleural fluid obtained from 21 tuberculous, 21 inflammatoryand 18 malignancy cases. The authors indicated that IFN-y was a "very reliable marker" of tuberculous pleurisy. Xirouchaki and colleagues (2002) indicated that the measurement of pleural fluid cytokines might be helpful in differentiating malignancy from tubercu10sis in exudative pleural effusion. Methods for measuring antigens and antibodies to M. tuberculosis in the pleural fluid have been reported by many authors. It has further been reported that the sensitivity of these tests are only about 50% (Murante et al.1990; Hara et al. 1992; Caminero et al.1993). See chapter on Immunological Tests for Tuberculosis. Molecular biology techniques utilizing various PCR protocols have been developed for detecting the M. tuberculosis genome in pleural and other body fluid samples, as well as in tissue biopsies. The reported sensitivity and specificity has varied from one technique to another. Querol and colleagues (1995) from Spain reported 107 patients with pleural effusion

between 1991 and 1993. Twenty-one patients had proven tuberculosis and 86 non-tuberculous (cancer, parapneumonia, cirrhosis, heart failure, emphysema, lymphoma, SLE and non-specific pleuritis). The PCR assay was based on the detection of a 123-bp DNA segment belonging to the insertion sequence IS6100, specific for M. tuberculosis. The diagnoses of twentyone tuberculous patients were confirmed by clinical, PPD skin test, pleural ADA, cytology, microbiology and histopathology of pleural biopsies. Positive pleural biopsy with granuloma formation was found in 72%, positive culture in 67% and raised ADA activity in 86%. PCR sensitivity and specificity were found to be 81% and 100%, respectively. Other authors applied PCR to detect DNA (IS 6110) in pleural biopsy specimens (Takagi et al.1998). These authors reported PCR sensitivity and specificity of 89% and 100%, respectively, of patients, which was similar to the results of Querol and colleagues. These two studies demonstrate the excellent sensitivity and specificity of PCR using either pleural fluid or pleural tissue for rapidly diagnosing pleural tuberculosis. Pleural fluid microbiological examination (smear and culture) for M. tuberculosis may detect only 25% to 50% of patients (Idell 1994). In patients coinfected with HIV, pleural fluid cultures are more often positive than in non-HIV patients. Parenchymal lung infiltrates are more severe and depicted by various imaging modalities in HIV positive patients, suggesting more mycobacterial extension from the lung into the pleural space, in contrast to HIV negative individuals (Luzze et al. 2001). In a prospective study of 111 patients with pleural effusion, and from an area with a high prevalence of tuberculosis in South Africa, radiometric cultures using BACTEC and conventional cultures were compared (Maartens and Bateman 1990). Tuberculosis was confirmed by histopathology, microbiology or both in 62 patients (56%). Positive pleural fluid culture was found in 47%, while histology and tissue culture were positive in 84% and 71%, respectively. BACTEC was faster than conventional mycobacterial culturing, and the yield appeared after 18 versus 33 days. The incidence of a positive pleural fluid culture as reported in some series is shown in Table 22.2.

22.5.3 Pleural Biopsy Closed needle biopsy of the pleura should be considered for further evaluation if clinical features, PPD skin test, imaging findings and pleural fluid

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Table 22.2. Pleural tuberculosis in some recent reports: diagnostic procedures, % yield Series Year

Fluid culture % positive

Biopsy culture % positive

Biopsy histology % positive

PPD % positive

Maartens and Bateman (l990) Ankobiah et al. (l990) Seibert et al. (1991) Chang et al. (l991) Relkin et al. (1994) Kitinya et al. (1994) Heyderman et al. (1998) Our Own Series

47 57 58 23 83.3 28 14b (smear) 23

71 45.6 66.7 40 65.5 45.6 40 65

84 80.7 84.6 97 80 100 60 80

78 60 93 77 56 74 30' 76

'Had problem with PPD reading compliance bCulture was not reported

biochemical parameters and culture do not provide a definitive diagnosis. It is an invasive procedure with significant discomfort and potential complications (Ansari and IdellI998). Good quality single pleural biopsy sampling is sufficient to diagnose pleural tuberculosis, in contrast to the increased diagnostic yield with multiple biopsies for malignancy (Jimenez et al. 2002). Positive pleural biopsy culture was found to be higher than pleural fluid (39% versus 13%) by Bueno and colleagues (1990). Histopathological findings of granuloma in pleural biopsy may be found in up to 80% of cases. PCR of pleural tissue biopsy for M. tuberculosis was found to be rapid, sensitive and specific in 89-100% of cases for diagnosing pleural tuberculosis (Takagi et al. 1998). An audit to value the routine practice of pleural fluid aspiration and biopsy for the investigation of pleural effusion has been reported by Walshe and colleagues (1992). The authors reviewed the investigative results of pleural fluid and biopsy procedures of 112 patients. They reported that the protein content of pleural fluid was of little value as a diagnostic indicator, as it overlapped substantially between various other diagnostic groups. A low positive yield for microbiological findings was of significance. Pleural biopsy was performed only in 30% in this series. The authors, however, indicated that the practical difficulties regarding pleural biopsy included the lack of experience among junior staff, lack of pleural biopsy needles and inadequate or poor quality samples. The authors reported the rate of complications (pneumothorax and emphysema) as 2% for aspiration alone and 4% for aspiration combined with biopsy. The incidence of pleural tissue biopsies, positive cultures and the presence of granulomata on histopathological examination in different series are shown in Table 22.2.

22.5.4 Thoracoscopy in Tuberculous Patients

Thoracoscopic examination was first described by Professor Hans Christian Jabobaeus from Sweden in 1910. He inserted a cystoscope into the pleural space of two patients with exudative pleuritis (Thomas 1994). He reported his observations of patients with pulmonary tuberculosis that had been treated with pneumothorax in which there was no pleuritis. He also explored the therapeutic application of thoracoscopy in breaking adhesions in patients with pulmonary tuberculosis that were selected for lung collapse therapy. He noted the complications of thoracoscopy, including haemorrhage, pleural effusion and subcutaneous emphysema. At present, the role of thoracoscopy in obtaining pleural tissue biopsies in the diagnosis of pleural tuberculosis is restricted, as a closed-needle pleural biopsy is the most reasonable method of initially obtaining a diagnostic tissue specimen.

22.5.5 Tuberculin Skin Test (PPD)

The use ofPPD skin testing is valuable in the diagnosis of patients with pleural tuberculosis. In patients with recent conversion, pleural tuberculosis will be classified as primary tuberculous pleurisy. Patients with a past history of positive PPD or active tuberculosis will be classified as secondary (Ankobiah et al. 1990). The PPD skin test is considered positive when the induration measurement is over 9 mm, and it is found in 60 to 90% of patients with pleural tuberculosis as reported in several series (See Table 22.2). A negative PPD skin test is more frequently reported in patients with tuberculous pleurisy co-infected with

Pleural Tuberculosis

HIV than in those with negative HIV. Ankobiah and colleagues (1990) from New York found positive PPD reaction in only 12% of AIDS patients and 80% in non-AIDS patients. Relkin et al. (1994) found a similar low incidence of positive PPD in their patients with tuberculous pleurisy co-infected with HIV. compared with HIV negative ones (41 versus 76%). The high frequency of negative PPD skin tests among those co-infected with HIV reflects the alternation of delayed hypersensitivity due to HIV.

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sion (Fig.22b in chapter 23). Bronchopleural fistula may be depicted by CT or fistulograrn (see Fig. 36 in chapter 23). Fibrothorax with diffuse pleural thickening but without effusion may be seen on CT. Ultrasonography (US) may play a role in the investigation of tuberculous pleural effusions. It may help in detecting pleural thickening, nodularity and in obtaining US-guided closed-needle pleural biopsy (Chang et al. 1991; Akhan et al. 1992). The imaging features of various modalities for pleural tuberculosis are non-specific, but may help in distinguishing tuberculous from non-tuberculous pleural disease.

22.5.6 Imaging Features of Pleural Tuberculosis 22.5.7 The imaging modalities most commonly used in Treatment tuberculous pleural disease are plain chest radiography, CT and ultrasonography. Rarely, a fistulogram Treatment of pleural tuberculosis is similar to treatfor bronchopleural fistula is used when CT localiza- ment of pulmonary disease. Full assessment is essention of the tract is not clear. CT is more sensitive tial, particularly in regard to prior treatment for TB, and useful than plain radiography in the evaluation drug susceptibility or resistance. The co-infection of pleural disease. It may show unrecognized small with HIV has to be determined. Detection of comsubpleural cavities, parenchymal lung involvement, plicated pleural effusion is essential, as it may lead lymphadenitis or rib involvement (see Figs. 36a, bin to therapeutic failure if medical treatment is used chapter on "Radiology of Pulmonary Tuberculosis") alone without surgical intervention. If left untreated, (Moon et al. 1999; Yilmaz et al. 1998; Winer-Muram pleural tuberculosis will develop into active pulmonary or extra-pulmonary disease within 5 years in at and Rubin 1990; Hunlnick et al. 1983). Unilateral, moderate or large pleural effusion can least 65% of immunocompetent patients (Roper and easily be depicted by plain radiography (see Figs. 12a, Waring 1955). Uncomplicated, HIV negative tuberculous pleub, 34b in the chapter on "Radiology of Pulmonary Tuberculosis"). Bilateral small or moderate pleural risy can be treated with a short course of 6-9 months effusions may be depicted by plain radiography and of anti-tuberculous chemotherapy. CT (see Fig. 12c in chapter 23). Imaging features of Six months of anti-tuberculous chemotherapy contiguous subpleural tuberculous cavities in the lung using two drugs for pleural tuberculosis was reported parenchyma as localized empyema may be seen on by Dutt et al. (1992). The authors used isoniazid 300 mg plain radiography or CT (see Figs. 22b, 26 in chapter 23) and rifampicin 600 mg daily for one month, followed (Seibert et al. 1991). Other imaging features of lung by twice weekly treatment with isoniazid 900 mg and parenchymal disease with bronchiectasis may be rifampicin 600 mg for five more months. This regimen noted in patients with tuberculous pleural effusion used by Dutt and colleagues on 161 patients with TB (see Fig. 30b in chapter 23). Features of large empy- pleurisy and follow-up for about 4-6 months revealed ema with increased thickness of the pleura may be no relapses. In areas with high risk for HIV infection found on plain radiography and CT (see Fig.34b in or with high incidence of drug-resistant mycobacteria, chapter 23). Tuberculous pleural empyema may be initial treatment should include at least four drugs localized with thick, calcified wall better depicted on until drug susceptibility testing is available. CT than plain chest radiography (see Figs. 13, 22b, 23, Immunosuppressed patients with pleural tuber34a, 35a in chapter 23). CT may depict focal pleural culosis should be treated for a much longer period, thickness with calcifications in the absence of fluid at least 12 months. Patients with multi-drug resistant collection (see Figs. 23, 32d in chapter 23). An asso- tuberculosis should be treated with 5-6 drugs. ciated destruction of adjacent ribs with cold abscess Complicated tuberculous pleural effusion may formation and empyema may be depicted better by CT be due to the development of loculated chronic (35a, b in chapter 23). Other calcifications in the lung empyema, drug resistance or bronchopleural fistula. parenchyma or mediastinal lymph nodes may also be Medical treatment alone will not be sufficient in such depicted in association with tuberculous pleural effu- patients and surgical intervention will be required

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(Brown and Pomerantz 1995; Iseman et al. 1991). Surgical treatment is discussed in detail in a separate chapter (see chapter XX). In a recent report from India, Lahiri et al. (1998) analyzed the surgical procedures for thoracic tuberculosis in 1655 cases seen over a 20-year period. These procedures were needed in only 2.2% of the patients, including tuberculous empyema with or without broncho-pleural fistula. Intercostal drainage with irrigation, thoracostoma and chest wall tube drainage were the most frequent minor procedures. Major procedures were less frequently required and included decortication and thoracoplasty.

References Akhan 0 et al (1992) Tuberculous pleural effusions: ultrasonic diagnosis. J Clin Ultrasound 20:461-465 Aktogu S et al (1996) Clinical spectrum of pulmonary and pleural tuberculosis: a report of 4, 480 cases. Eur Respir J 9:2031-2035 Ankobiah WA, Finch P Powell S et al (1990) Pleural tuberculosis in patients with and without AIDS. J Assoc Acad Minor Phy 1:20-23 Ansari T, Idell S (1998) Management of undiagnosed persistent pleural effusions. Clin Chest Med 19:407-417 Barnes PF, Mistry SD, Cooper CL et al (1989) Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleurisy. J ImmunoI142:1114-1119 Barnes PF, Fong S-J, Brennan PJ et al (1990) Local production of tumor necrosis factor and IFN-'Yin tuberculous pleurisy. J ImmunoI145:149-154 Barnes P et al (1993) Cytokine production at the site of disease in human tuberculosis. Infect Immun 61:3482-3489 Batungwanayo J et al (1993) Pleural effusion, tuberculosis and HIV-l infection in Kigali, Rwanda. AIDS 7:73-79 Berger H, Mejia E (1973) Tuberculous pleurisy. Chest 63:88-92 Boylan AM, Ruegg C, Kim KJ et al (1992) Evidence of a role for mesothelial cell derived interleukin-8 in the pathogenesis of asbestos-induced pleurisy in rabbits. J Clin Invest 89: 1257-1267 Brown J, Pomerantz M (1995) Extrapleural pneumonectomy for tuberculosis. Chest Surg Clin North Am 5:289-296 Bueno CE et al (1990) Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope's needle. Arch Intern Med 150:1190-1994 Caminero JA et al (1993) Diagnosis of tuberculosis by detection of specific IgG antigen 60 in serum and pleural fluid. Respiration 60:58-62 Carrion-Valero F, Perpina-Tordera M (2001) Screening tuberculous pleural effusion by discriminant analysis. Int J Tuberc Lung Dis 5:673-679 Chang DB et al (1991) Ultrasound-guided pleural biopsy with tru-cut needle. Chest 100:132-133 Chaparas SD, Thor DE, Hedrick SR (1971) Comparison oflymphocyte transformation, inhibition of macrophage migration and skin tests using dialyzable and nondialyzable tuberculin fractions from Mycobacterium bovis (BCG). J

M. M. Madkour et al. Immunol107:149-153 Christopher DJ, Peter JV, Cherian AM (1998) Blind pleural biop~y using a tru-cut needle in moderate to large pleural effUSIOn - an experience. Singapore Med J 39:196-199 Dutt AK et al (1992) Tuberculous pleural effusion: 6-month therapy with isoniazid and rifampicin. Am Rev Respir Dis 145:1429-1432 Ellner JJ et al (1988) The immunology of tuberculous pleurisy. Semin Respir Infect 3:335-342 Epstein DM et al (1987) Tuberculosis pleural effusions. Chest 91:106-109 Gedde-Dahl T (1952) Tuberculosis infection in the light of tuberculin maticuolation. Am J Hyg 56:139-214 George RB et al (1985) Mycobacterial, fungal, actinomycotic and nocardial infection of the pleura. Clin Chest Med 6:63-75 Goodman RB, Wood RG, Martin TR et al (1992) Cytokinestimulated human mesothelial cells produce chemotactic activity for neutrophils including NAP-lIlL-8. J Immunol 148:457-465 Hara N et al (1992) Pleural SC56-9 in differential diagnosis of tuberculous, malignant and other effusions. Chest 102: 1060-1064 Heyderman RS,Makunike R,Muza T et al (1998) Pleural tuberculosis in Harare, Zimbabwe: the relationship between human immunodeficiency virus, CD4 lymphocyte count, granuloma formation and disseminated disease. Trop Med Int Health 3:14-20 Hirsch A et al (1979) Pleural effusion: laboratory test in 300 cases. Thorax 34:106-112 Hunlnick D et al (1983) Pleural tuberculosis evaluated by computed tomography. RadioI149:759-765 Idell S (1994) Evaluation of perplexing pleural effusion. Contemp Intern Med 6:31-39 Iseman MD et al (1991) Chronic tuberculous empyema with bronchopleural fistula resulting in treatment failure and progressive drug resistance. Thorax 100:124-127 Jimenez D et al (2002) Determining the optimal number of specimens to obtain with needle biopsy of the pleura. Respir Med 96:14-17 Jonjic N, Peri G, Bernasconi S et al (1992) Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J Exp Med 176:1165-1174 Kitinya IN, Richter C, Perenboom R et al (1994) Influence pf HIV status on pathological changes in tuberculous pleuritis. Tuberc Lung Dis 75:195-198 Kunkel SL, Chensue SW, Strieter RM et al (1989) Cellular and molecular aspects of granulomatous inflammation. Am J Respir Cell Mol Bioi 1:439-447 Lassence AD et al (1992) Detection of mycobacterial DNA in pleural fluid from patients with tuberculous pleurisy by means of the polymerase chain reaction: comparison of two protocols. Thorax 47:265-269 Lau KY (1989) Numerous mesothelial cells in tuberculous pleural effusion. Chest 96:438-439 Lorgat F et al (1992) Evidence for in vitro generation of cytotoxic T-cells. PPD-stimulated lymphocytes from tuberculous effusion demonstrate enhanced cytotoxicity with accelerated kinetics of induction. Am Rev Respir Dis 145:418-423 Luzze H etal (2001) Evaluation ofsuspected tuberculous pleurisy: clinical and diagnostic findings in HIV-positive and HIV-negative adults in Uganda. Int J Tuberc Lung Dis 5:745-755 Maartens G, Bateman ED (1990) Tuberculous pleural effusion: increased culture yield with bedside inoculation of pleural

Pleural Tuberculosis fluid and poor diagnostic value of adenosine deaminase. Thorax 46:96-99 Maeda J, Ueki N, Ohkawa T et al (1993) Local production and localization of transforming growth factor-beta in tuberculous pleurisy. Clin Exp Immunol 92:32-38 Mbizvo MT et al (1996) HIV seroincidence and correlates of seroconversion in a cohort of male factory-workers in Harare, Zimbabwe. AIDS 10:895-901 Modilevsky T et al (1989) Mycobacterial disease in patients with human immunodeficiency virus infection. Arch Intern Med 147:2201-2205 Mohammed KA, Nasreen N, Ward MJ et al (1998) Mycobacterium-mediated chemokine expression in pleural mesothelial cells: role of C-C chemokines in tuberculous pleurisy. J Infect Dis 178:1450-1456 Moon WK et al (1999) Complicated pleural tuberculosis in children: CT evaluation. Pediatr RadioI29:153-157 Morehead RS (1998) Tuberculosis of the pleura. South Med J 91:630-636 Moudgil H et al (1994) Reactivation disease: the commonest form of tuberculous pleural effusion in Edinburgh. Respir Med 88:301-304 Murante T et al (1990) Antipurified protein-derivative antibody in tuberculous pleural effusion. Chest 97:670-673 Pablo AD et al (1997) Are pleural fluid parameters related to the development of residual pleural thickening in tuberculosis? Chest 112:1293-1297 Palmer PES (1979) Thoracic tuberculosis. Semin Roentegenol 14:204-243 Querol JM et al (1995) Rapid diagnosis of pleural tuberculosis by polymerase chain reaction. Am J Respir Crit Care Med 152:1977-1981 Relkin F,Aranda CP,Garay SM et al (1994) Pleural tuberculosis and HIV infection. Chest 105:1338-1341 Richter C et al (1991a) Extrapulmonary tuberculosis - a simple diagnosis? A retrospective study in Dar es Salam. Trop Geog Med 43:375-378 Richter C et al (1991b) Pleural effusion aetiology, diagnosis and clinical picture in HIV-positive and negative patients. A prospective study in Dar es Salam. Proceedings of the VIth international congress on AIDS in Africa, Dakar, Senegal, Dec 1991; WA.220 Richter C et al (1994) Clinical features ofHIV-seropositive and HIV-seronegative patients with tuberculous pleural effusion in Dar es Salam, Tanzania. Chest 106:1471-1476 Roper WH, Waring JJ (1955) Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 71:616-635 Sahn SA (1988) State of the art - the pleura. Am Rev Respir Dis 138:184-234 Santos-Sastre et al (1990) Mesothelial cells and tuberculous pleuritis. Chest 98:518 Seibert AF et al (1991) Tuberculous pleural effusion. Twentyfive year experience. Chest 99:883-887

357 Sharma SK et al (2001) A prospective study of sensitivity and specificity of adenosine deaminase estimation in the diagnosis of tuberculous pleural effusion. Indian J Chest Dis Allied Sci 43:149-155 Shimokata K, Kishimoto H, Takagi E et al (1986) Determination of the T-cell subunit producing g-interferon in tuberculous pleural effusion. Microbiol Immunol 30:353-361 Shivaram I et al (1989) Pleural effusion in AIDS/ARC. Chest 96:2215 Spriggs AL, Boddington MM (1960) Absence of Mesothelial cells from tuberculous pleural effusions. Thorax 15:169-171 Stevenson F (1955) The natural history of pleural effusion and orthopaedic tuberculosis. J Bone Joint Surg Br 37:80-91 Sudre P et al (1992) Tuberculosis: a global overview of the situation today. Bull WHO 70:149-159 Takagi N et al (1998) Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2:338-341 Takagi N, Hasegawa Y,Ichiyama S et al (1998) Polymerase chain reaction of pleural biopsy specimens for rapid diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2:338-341 Thomas PA (1994) A thoracoscopic peak: what did Jacobaeus see? Ann Thorac Surg 57:770-771 Valdes L et al (1996a) Adinosine deaminase (ADA) isoenzyme analysis in pleural effusion: diagnostic role and relevance to the origin of increased ADA in tuberculous pleurisy. Eur Respir J 9:747-751 Valdes L et al (1996b) The etiology of pleural effusion in an area with high incidence of tuberculosis. Chest 109:158-162 Wallis RS (1996) New approaches to identification of antigens of Mycobacterium tuberculosis. Infect Agents Dis 5: 119-125 Walshe AD, Douglas JG, Kerr KM et al (1992) An audit of the clinical investigation of pleural effusion. Thorax 47:734-737 Willis RS, Amiy-Tahmasseb M, Ellner JJ (1990) Induction of interleukin-l and tumor necrosis factor by mycobacterial proteins: the monocyte Western blot. Proc Nat! Acad Sci USA 87:3348-3352 Winer-Muram HT, Rubin SA (1990) Thoracic complications of tuberculosis. J Thorac Imag 5:46-63 Xirouchaki N et al (2002) Diagnostic value of interleukin-lalpha, interleukin-6 and tumor necrosis factor in pleural effusion. Chest 121:815-820 Yamada Yet al (2001) Cytokines in pleural liquid for diagnosis of tuberculous pleurisy. Respir Med 95:577-581 Yamamura Y, Onoue K, Azuma I (1968) Biology of the mycobacterioses. Chemical and immunological studies on peptides and polysaccharides from tubercle bacilli. Ann NY Acad Sci 154:88-97 Yilmaz MU et al (1998) Computed tomography findings of tuberculous pleurisy. Int J Tuberc Lung Dis 2:164-167 Zhang M, Gately MK, Wang E et al (1994) Interleukin 12 at the site of disease in tuberculosis. J Clin Invest 93: 1733-1739

23 Radiology of Pulmonary Tuberculosis MONA AL SHAHED, MOHAMMED ABD EL BAGI, M. MONIR MADKOUR

CONTENTS 23.1 23.2 23.2.1 23.2.2 23.2.3 23.2.4 23.2.5 23.3 23.3.1 23.3.1.1 23.3.1.2 23.3.1.3 23.3.1.4 23.3.2 23.3.3 23.3.3.1 23.3.3.2 23.3.3.3 23.3.3.4 23.3.3.5 23.3.3.6 23.4 23.5 23.6 23.6.1 23.6.2 23.6.3 23.6.3.1 23.6.3.2 23.6.3.3 23.6.3.4

Introduction 359 Imaging 359 Conventional Radiography 359 Computed Tomography (CT) 360 High Resolution Computed Tomography 360 Bronchography 360 Arteriography 360 Classification and Radiological Presentation 360 Primary Tuberculosis 360 Parenchymal Disease 361 Lymphadenopathy 362 Pleural Disease in Primary Tuberculosis 364 Miliary TB 365 Paradoxical Transient Worsening Phenomenon 366 Post Primary Tuberculosis 368 Parenchymal Disease 369 Cavitation 370 Endobronchial Disease 371 Tuberculoma 374 Pleural Disease in Post-primary Tuberculosis 375 Mycetoma Formation 378 Assessment of Activity of Pulmonary TB 379 Non-tuberculous Mycobacteria 379 Mycobaqerial Infection and Human Immunocompromised Virus (HIV) 379 Background 379 Mycobacterial Tuberculosis 380 Non-Tuberculous Infections 380 Mycobacterial Avium-intercellular Complex (MAl) 380 Mycobacterial Kansasii 381 Other Non-Tuberculous Infections 381 Non-Tuberculous Bacteria in Immunodeficiency States Other than HIV 382 References 382

M. AL SHAHED, MBBS, FRCR Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. ABD EL BAGI, MB BCh, DMRD, FSRRCSI Senior Consultant Radiologist, Department of Radiology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia M. M. MADKOUR, MD, DM, FRCP Consultant, Department of Medicine, Riyadh Armed Forces Hospital, P.O. Box 7897, C-119, Riyadh 11159, Saudi Arabia

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

23.1

Introduction

Tuberculosis (TB) is a disease caused by infection with Mycobacterium tuberculosis and accounts for more than 95% of pulmonary mycobacterial infection. Other non-tuberculous mycobacteria, e.g. M. Kansasii, M. avium-intercellular complex and others, account for the remainder. Tuberculosis (TB) can affect virtually any organ system in the body. It is a topic of universal concern due to the recent resurgence of (TB) in both immunocompetent and immunocompromised individuals (Davis et al. 1993). Much of this increase has been ascribed to human immunocompromised virus infection (HIV), poverty and homelessness. The radiology of pulmonary (TB) reflects, and is influenced by, the immune status of the host, the virulence of the organisms, the presence of delayed hypersensitivity due to mycobacterium tuberculosis and the method of spread. Pulmonary (TB) is classically divided into primary and post primary (reactivation) disease. There is considerable overlap in the radiological manifestation of these two entities. Should primary (TB) pass into the post primary form without a break, the term progressive primary tuberculosis is used.

23.2

Imaging

23.2.1 Conventional Radiography Conventional chest radiography is the mainstay in the detection and follow up examination of patients with pulmonary TB. Good quality chest radiographs are essential and remain the first line of investigation. Normal radiographs do not exclude tuberculosis and have been reported in up to 10% of immunocompetent patients and in up to 20% of immunocompromised patients (Fitzgerald et al. 1991; Greenberg et al. 1994).

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23.2.2

23.2.4

Computed Tomography (CT)

Bronchography

Recently, conventional Computerized Tomography (CT) has been used in selected cases. It is required in many circumstances such as in the detection of cavitation and in the evaluation of the route of spread (Kuhlman et al. 1990). CT is most useful in assessing pleural disease and in patients with extensive opacification on the conventional radiographs because of the marked destruction of the lung by the disease process. CT has proven to be more sensitive than conventional radiography in detecting adenopathy, parenchymal shadowing, particularly in miliary disease, and in detecting bronchogenic dissemination. CT is used in the evaluation of complications that might occur in the process of the disease, including bronchopleural fistula formation and extension into chest wall. CT is also used to guide percutaneous intervention procedures and pre-surgical planning.

Bronchography was once the tool of choice for the detection of bronchiectasis, but it has now been replaced by HRCT.

23.2.3 High Resolution Computed Tomography High resolution CT (HRCT) is extremely useful in understanding the pathological process of the disease and route of spread; it is also useful in the evaluation of disease activity (1m et al. 1993).

23.2.5 Arteriography

Bronchial artery angiography is currently performed for therapeutic reasons in the treatment of lifethreatening haemoptysis, which is not a common presentation of bronchiectasis due to tuberculosis.

23.3 Classification and Radiological Presentation 23.3.1 Primary Tuberculosis Primary (TB) is a term used when the infected individual has not been previously exposed to M. tuberculous and lacks hypersensitivity to tuberculoprotein. Initially, primary TB was described in infants and children, in whom it remains the most common

b

a

Fig. 23.1. a Primary TB. Chest x-ray of 7 year old showing ill-defined air space consolidation (arrowheads). b CT the same patient showing dense air space consolidation with air bronchogram (arrowhead)

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form (Miller and Miller 1993; Lamont et al. 1986). Increasingly, however, it has been encountered in adult population, and it is now estimated to account for 23-34% of all adult cases (Buckner et al. 1990; McAdams et al. 1995; Miller and Miller 1993; Miller 1994; Woodring et al. 1986). Radiologically, primary pulmonary TB typically manifests in four major ways, singly or in aggregate: (l) parenchymal disease; (2) lymphadenopathy; (3) pleural effusion; and (4) miliary disease (Agrons et al. 1993; 1m et al. 1995; Leung et al. 1992; Palmer 1979; Stansberry 1990). Ten percent (lO%) of all cases of primary TB progress directly into the chronic form, which is indistinguishable from reactivation (Gepport and Left 1979). Moreover, the result of a chest radiograph may be normal in 15-50% of cases (McAdams et al. 1995; Miller and Miller 1993; Woodring et al.1986). 23.3.7.7

ParenchYn1alDisease By radiological examination, parenchymal shadowing is commonly manifested as homogenously dense air space consolidation with ill-defined margins, frequently segmental or lobar in distribution (Fig. 23.1a). Expansion of a consolidated lobe may occur (Fig. 23.2). The focal parenchymal lesion may be mass-like, and in adults it may be confused with neoplasia (Fig. 23.3). It is usually unilateral and single, but multilobar consolidation can be seen in up to 25% of cases (Leung et al. 1992; Woodring et al. 1986). A tendency to favor the right lung has

Fig. 23.2. Chest x-ray demonstrating dense air space consolidation with expansion of right upper lobe in 10 years old child with primary tuberculosis.

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emerged in several series (Lamont et al. 1986; Leung et al. 1992; Weber et al. 1968). This was also noted in our patients. No consensus has been reached as to regional preference within the lung. Upper lobe predominance (Weber et al. 1968; Nagakura 1960; Joffe 1960; Choyke et al. 1983), mid and lower lobes predominance (Woodring et al. 1986; Choyke et al. 1983) and no anatomic bias (Lamont et al.1986) have each been reported. Cavitation may occur in primary TB (Fig. 23.4). The incidence varies from 10% (Choyke et al. 1983) to 30% (Woodring et al. 1986). It is more common in infants and children raised in communities in which TB has been introduced comparatively recently (Weizman et al. 1980). At Computed Tomography (CT), primary TB typically manifests as dense hemogenous air space consolidation with well-defined margins (Harishigani et al. 2000) (Fig. 23.1b). Parenchymal shadowing usually resolves with no radiological sequelae over 6-24 months. Some may be left with residual scarring or a calcified focus (Ghon focus). This is seen in up to 20% of patient (Fig. 23.5). Occasionally during the first three months of treatment, worsening of parenchymal shadowing occurs despite appropriate therapy, a phenomenon referred to as paradoxical transient worsening (see below). Single or multiple tuberculomas may develop in primary TB, but they are seen much less frequently than in post primary TB.

Fig.23.3. Chest x-ray of a 35-year old female with primary tuberculosis presenting with a focal lung lesion (arrow), right paratracheal and left hilar lymph adenopathy (arrowhead)

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b

a Fig. 23.4. a Chest x-ray showing cavitation within tuberculous consolidation in the right upper lobe. b The lesion has resolved with minimal residual scaring after the completion of antituberculous treatment

Fig.23.5. Chest x-ray showing foci of the calcification in the right perihilar region (arrowhead) a stigma or previous tuberculous infection

23.3.1.2 Lymphadenopathy

Lymphadenopathy is the hallmark of primary TB, with or without concomitant parenchymal abnormality. Age stratification qas been identified in many series (Lamont et al. 1986; Leung et al. 1992; Weber et al. 1968), with a higher prevalence of lymphadenopathy in children under 3 years of age than in

older children and adults with primary tuberculosis (McAdams et al.1995; Woodring et al.1986). It can be the only manifestation in young children (Campbell and Dyson 1977). Any lymph node group may be involved, but the patterns commonly seen are unilateral hilar, unilateral hilar plus right paratracheal or isolated right paratracheal adenopathy (Fig. 23.6). Right paratracheal nodal involvement predominates in our experience, similar to the experience of others (Amorosa et al. 1978; Rottenberg and Shaw 1996; Weber et al.1968). Bilateral adenopathy has also been described in up to 32% of cases (Leung et al. 1992); when present, it is almost always asymmetrical and can be strikingly extensive, resembling lymphoma, metastatic disease and sarcoidosis (Fig. 23.7). CT demonstrates lymphadenopathymore accuratelythan chest radiographs. Characteristically, on post-contrast studies the nodes larger than 2 cm in diameter consistently display a low density center, 40-50 HU, with enhancing peripheral rims (Harishigani et al. 2000) (Fig. 23.8), and hence citing dissimilarity to lymphoma, sarcoidosis or histoplasmosis. Lymphadenopathy usually resolves at a slower rate than parenchymal lesions. Nodal calcification occurs 6 months or more after infection and is more frequently seen than parenchymal calcification; it is encountered in up to 35% of all cases (Weber et al. 1968; Leung et al. 1992). There are significant differences in the distribution and pattern of calcification of lymph nodes in TB and sarcoidosis, which can be explained by the route of lymphatic drainage and the

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a Fig.23.6. Primary tuberculous presenting with isolated right paratracheallymphadenopathy in 12-year old male patient

b

Fig. 23.8. Post contrast CT of the chest demonstrating characteristic appearance of tuberculous lymphadenopathy with low density centre and enhancing peripheral rim (arrowheads)

Fig. 23.7. a Frontal and lateral. Chest x-ray of primary tuberculosis presenting with extensive lymphadenopathy resembling lymphoma. Note large hilar (arrow) and bilateral paratracheal (arrowhead) lymph node involvement. b Lateral x-ray of the same patient demonstrating hilar adenopathy (arrows)

caseating nature of tuberculous granulomas. When hilar node calcification is present, it is more likely to be unilateral in TB and bilateral in sarcoidosis. A focal pattern of calcification is more common in sarcoidosis, while complete nodal calcification is common in TB (Fig. 23.9). Nodal pressure and/or erosion into adjacent structures may lead to the following complications: (1) Obstruction of airways leading to over-inflation and/or segmental/lobar collapse, usually in the anterior segment of the right middle lobe; (2) Perforation into an airway, leading to Widespread bronchogenic dissemination. The healing of these

lesions, though occasionally without sequelae, often results in various combinations of bronchostenosis, bronchiectasis, parenchymal fibrosis and loss of lung volume; (3) Haematogenous spread from infected nodes, which can lead to "metastatic" lesions such as soft tissue abscesses. These "metastatic" foci may lie dormant for years before they become active, manifesting as bone, joint or renal TB; (4) Erosion of the node into the pericardium, leading to tuberculous pericarditis. Pericarditis can also be a complication of miliary TB. Involvement of the pericardium can present in the form of pericardial effusion (Fig. 23.10) or

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Fig. 23.10. Chest x-ray demonstrating cardiac enlargement due to pericardial effusion caused by tuberculous pericarditis Fig.23.9. Chest x-ray demonstrating complete lymph node calcification typical of tuberculosis (arrowhead). Note extensive cystic bronchiectasis changes in the right middle and lower lobes (arrows), some showing air fluid level (small arrows). Also node calcined granuloma in the left mid zone (short arrow)

in the form of constrictive pericarditis, with or without calcification (Fig. 23.11). Other complications of nodal involvement include erosion into oesophagus, phrenic and recurrent laryngeal nerve paresis, superior vena cava obstruction and fistula formation. 23.3.1.3 Pleural Disease in Primary Tuberculosis

Pleural effusion is fairly common, occurring in up to 25% of cases. Unlike lymphadenopathy, it is seen more in adults than in children (Weber et al. 1968; Stead et al. 1968; Derham 1956). The effusions are generally unilateral, the exception being when the disease is a complication of miliary TB. Associated pulmonary parenchymal lesions or adenopathy may be radiologically occult. Tuberculosis should be considered in any young patient with moderate size or large unilateral pleural effusion in the absence of demonstrable pulmonary disease (Fig. 23.12a, b). Pleural effusion in primary tuberculosis can be self-limiting, or it can lead to serious disease years later. The effusions are usually painless and can be very large at presentation. The majority of these effusions are reactive in nature, rather than due to direct pleural involvement

Fig. 23.11. Lateral chest x-ray showing pericardial calcification as sequelae to tuberculous pericarditis (arrowheads)

by tuberculosis. Therefore, mycobacterium bacilli are rarely isolated from culture of the pleural fluid. The diagnosis is best established by pleural biopsy. CT is more sensitive than plain radiographs in depicting associated pulmonary infiltrate and adenopathy in addition to pleural fluid (Fig. 23.12c, d). CT will also demonstrate evenly thickened parietal pleura, which will enhance when contrast material is used. Com-

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a

b

c

d Fig. 23.12. a Chest x-ray demonstrating left sided pleural effusion with no visible parenchymal lesion or adenopathy in a young patient presenting with fever, night sweat, loss of weight and high ESR. Pleural biopsy confirms the diagnosis. b Post enhanced CT of the chest of the same patient demonstrating right sided simple effusion (arrow). c Thoracic post-enhanced CT of another patient presented with fever and weight loss showing thin bilateral pleural effusion (arrowheads) and lymph nodes (arrows). d CT scan of the same patient at lower level showing posterior mediastinal adenopathy. No parenchymal lesions were seen Bronchial aspirate was positive for tuberculosis

plete resolution is the usual sequelae to antituberculous treatment. Incompletely resolved effusions will commonly develop into secondary disease (Palmer 1979). Tuberculous empyema is a less common form of pleural disease in primary tuberculosis, resulting from discharge of mycobacterium bacilli into pleural space (Fig. 23.13). It is usually seen in post primary cases (see below). 23.3.7.4 Miliary 18

Miliary TB results from haematogenous dissemination of the organisms and is seen in both primary and reactivation tuberculosis. It is increasingly encountered in adults, particularly the immunosuppressed, in whom it has been reported in up to 13% of cases

(Lee and 1m 1995). It is associated with a very high mortality if untreated, respiratory failure being the major cause of death. The characteristic radiologiCal appearance consists of Widespread nodular shadows measuring 2-3 mm in diameter and randomly distributed throughout the parenchyma (Fig. 23.14). In approximately 50% of cases the initial radiographs appear normal. Ill-defined haze can be an early manifestation before the characteristic miliary pattern became discernable. High resolution CT (HRCT) can detect diffuse lung changes where the initial radiographic appearance is normal or undetermined (Fraser et al. 1989). Miliary TB at HRCT manifests as numerous fine, discrete nodular or reticulonodular shadows. An associated nodular appearance of the interlobular septa and vessels may also be seen (McGuinness et al. 1992) (Fig. 23.15). Miliary tuber-

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culosis differs from bronchogenic spread in its even distribution throughout the lung and its uniform size. Diseases which have a similar appearances to that of miliary TB are varicella pneumonia, sarcoidosis, histoplasmosis, metastasis, pneumoconiosis and haemosiderosis. The resolution of these nodules is

Fig. 23.13. Tuberculous empyema as a complication of pleural disease. Note the presence of irregular pleural calcification (arrowheads)

a

usually slow and complete, with no residual calcification after treatment. Radiological improvement can be seen within 3 weeks of starting therapy.

23.3.2 Paradoxical Transient Worsening Phenomenon Paradoxical transient worsening of the radiographic findings, both parenchymal and extraparenchymal, is common in the first three months following the initiation of therapy (Akira et al. 2000; Amodio et al. 1986; Bobrowitz 1980; Campbell and Dyson 1977; Lamont et al. 1986; Matthay et al. 1974; Weber et al. 1968). Paradoxical response refers to progression of the original lesions or development of new ones during apparently adequate antituberculous treatment (Bobrowitz 1980), usually regresses without a change in the initial drug regimen. As we and others have observed (Akira et al. 2000), progression often manifests as enlargement of the original parenchymal shadowing. Areas of ground glass opacities, new areas of consolidations ipsilateral or contralateral to the initial lesion and new macronodules in the ipsilateral site were also encountered; none were with cavitations (Figs. 23.16, 23.17). It is important to recognize this transient benign phenomenon to avoid unnecessary invasive procedures or changes of appropriate therapy. The mechanisms of these clinically and radiologically impressive changes remain unclear. Several hypotheses have been considered,

Fig. 23.14. a Chest x-ray of a child presenting with miliary tubeculosis. Note widespread nodular shadowing involving both lung fields. b Miliary tuberculosis in another child presenting with massive mediastinal adenopathy (arrowheads) and superadded consolidation in the right middle lobe (arrow)

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a Fig. 23.15. a CT scan of the chest demonstrating numerous fine discrete nodular shadow. Note the nodular appearance of the interlobular septa (arrows). b CT scan of same patient more caudally showing the miliary pattern of tuberculosis. Note the nodular irregular outline of the blood vessels (arrows)

b

a

Fig. 23.16. a Paradoxical transient worsening: A young female patient presented with malaise, fever, weight loss and night sweats. Chest x-ray showed right paratracheal adenopathy (arrow) and ill-defined consolidation in the right perihilar region (arrowhead). Tuberculosis was diagnosed based on positive bronchial aspirates and was started on antituberculous treatment. b Chest x-ray 8 weeks after initiation of antituberculous treatment showed progression of the parenchymal lesion with development of new macronodular lesions (arrowheads). Note significant regression of the right paratracheal adenopathy. c Chest x-ray demonstrates complete resolution after completion of antituberculous treatment

c

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Fig.23.17. a Paradoxical transient worsening: A middle aged male patient with positive bronchial aspirate. Initial chest x-ray showed patchy infiltrates in the right lower lobe. b Six weeks after initiation of antituberculous treatment a new lesion with thick wall developed in the right upper lobe (arrowhead). Note resolution of the initial changes. c Chest x-ray 6 months after initiation of treatment showing almost complete resolution

a

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including enhanced focal immune responses (Iwai et al. 1979; Marshall and Chambers 1988), local hypersensitivity to sudden destruction of the bacilli and tuberculoprotein (Onwubalili et al. 1986) and local hypersensitivity to drug reaction (Akira et al. 2000). Interestingly, new pulmonary lesions during therapy for extrapulmonary TB have been reported by Sze-chunhung et al. (Hung and Chang 1999). Transient paradoxical worsening should be differentiated from true worsening of tuberculous lesions, complication by bacterial and fungal infection and drug reaction. Thin-cut CT in this aspect may playa role. In a study by (Akira et al. 2000), the dominant CT findings of transient progressions were ground glass opacities and/or consolidation, whereas the dominant CT findings of true worsening of TB were macronodules and centrilobular nodules, often with cavitations. Currently, the American Thoracic Society

and Centers for Disease Control recommend a radiographic evaluation at 2-3 months after initiation of therapy (Bass et al. 1986). Parenchymal abnormalities can then be evaluated every 2-3 months until they clear, and lymphadenopathy at yearly intervals until radiographically stable (Abernathy 1989).

23.3.3 Post Primary Tuberculosis The term post-primary TB is used to describe tuberculosis in patients who have acquired tubercula protein hypersensitivity from a previous infection or BCG vaccination. Other terminology used include: reactivation, secondary, reinfection or adult tuberculosis. Postprimary disease results from reactivation of a previously dormant primary infection in 90% of

Radiology of Pulmonary Tuberculosis

cases, and as extension of primary TB in 10% of cases (Woodring et al. 1986). It is a disease of adolescence and adulthood characterized by its chronicity, strong site preference, cavitation and fibrosis. Radiologic features of postprimary TB can be broadly classified as lung parenchymal disease with cavitation, endobronchial airway disease, tuberculoma, pleural extension and other complications. 23.3.3.1

ParenchYlnalDisease The earliest radiological manifestation is the development of exudative lesions of patchy ill-defined segmental or subsegmental infiltrations in typical anatomic regions: apical and posterior segments of an upper lobe or a superior segment of a lower lobe in 95% of patients. This site of preference has been attributed to the oxygen tension being relatively high, and to lymphatic drainage being relatively ineffective in these areas. The lesions consist of peripheral consolidation, often patchy and frequently associated with accentuated bronchovascular markings, extending to the ipsilateral hilar region (Fig. 23.18). Widespread bronchopneumonia is usually a result of endobronchial seeding (Spencer et al. 1990). Despite this strong site preference, no portion of the lung is immune; isolated anterior and basal involvement have been reported (Woodring et al. 1986). Pulmonary TB presenting as segmental consolidation has similar radiological appearances as non-tuberculous segmental pneumonia. Park et al. (1999) have shown

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that CT findings of fluid-bronchogram, in an area of consolidation, bronchial dilatation and proximal bronchial wall thickening is significantly more prominent in tuberculous pneumonia than in nontuberculous, non obstructive pneumonia (Fig. 23.19, 23.24b). Hilar and mediastinal lymph node involvement is veryrare,being reported in only5% ofcases (Woodring et al. 1986) (Fig. 23.20). The initial exudative infiltrates will be replaced by a more sharply defined nodular pattern (acinar nodules), interspersed with reticular opacities of fibroproductive lesions (Fig. 23.21). The

Fig. 23.19. CT chest demonstrating dense consolidation with fluid-bronchogram (arrowheads), and evidence of endobronchial spread (small arrows). The posterior mass (large arrows) is due to enlarged lymph nodes

a

b Fig. 23.18. a Chest x-ray of an adult female showing patchy consolidation with element of collapse in the right upper lobe. Note bilateral hilar calcification as evidence of previous tuberculous infection (arrowheads). b Chest x-ray of an adult male showing consolidation in the apical segment of both upper lobes. Note calcification of the hilar lymph nodes (arrows)

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Fig.23.20. Chest x-ray of 40 year old male presented with fever and malaise, chest x-ray showed upper lobe and lower lobe consolidation with associated paratracheal adenopathy

(arrowheads)

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Fig.23.21. Post primary TB. Chest x-ray demonstrating noduloreticular opacities in the apical segment of the right upper lobe with element of fibrosis. Note shifting of the trachea to the ipsilateral site

majority of patients show both patterns. Marked tissue destruction may occur at this stage, with cavitation and necrosis. Healing may occur by fibrosis, resulting in cicatrization, considerable loss of lung volume, traction bronchiectasis and atelectasis. Scattered calcification may also be seen (Fig.23.22) (Lee et al. 1991). Secondarily, compensatory signs include elevation of ipsilateral hilum, over-infiltration of adjacent lung tissue and bullate formation (Figs. 23.23, 23.24). Extensive fibrosis and bullae formation with scattered

Fig. 23.22. a Post primary TB. Chest x-ray demonstrating fibrotic changes with cicatrization, deviation of trachea to the right indicating loss of lung volume in the right upper lobe (black arrowheads). Bronchial distortion is also present (white arrowhead). b CT of different patient with post primary TB showing evidence of fibrosis and thickened septi in the left upper lobe and scattered calcific densities (arrows). Patchy emphysematous changes (white arrowhead) and thickened pleura (black arrowheads). Note complete calcification of lymph nodes (large black

arrowhead)

macronodular shadows are seen in end-stage pulmonary tuberculosis (Fig. 23.25). 23.3.3.2 Cavitation Cavitation is a distinct feature of postprimary TB and is of considerable diagnostic significance, since it indicates the likelihood of activity (1m et al. 1993). It is seen in up to 40-80% of patients with postpri-

Radiology of Pulmonary Tuberculosis

Fig. 23.23. Post primary TB. Chest x-ray demonstrating fibrotic changes with considerable loss of lung volume of the right upper lobe. Note deviation of trachea to the ipsilateral site, elevation of right hilum, (small arrow) and compensatory hyperinflation of right lower lobe (large arrow). Pleural thickening and calcification (arrowheads)

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Fig. 23.24. Post primary TB chest x-ray demonstrate end stage tuberculous changes involving the right lung with extensive fibrosis, loss of lung volume, deviation of the mediastinum, bullae formation (arrowheads) and hyperinflation of the left lung

mary TB (Rottenberg and Shaw 1996). Cavities tend to occur in the areas of consolidation. They have no diagnostic features and may be single or multiple, small or large, thin or thick-walled (McAdams et al. 1995). Air fluid level may be present, but it is uncommon and usually indicates superadded infection (Fig. 23.26). Spontaneous pneumothorax may be seen (Woodring et al. 1986). A residual tuberculous cavity may lead to endobronchial spread or become a site for the development of mycetoma. Rasmussen aneurysm is a rare but a life-threatening complication of cavitary lesion involving the wall of the pulmonary artery, and may lead to massive haemoptysis if ruptured. 23.3.3.3

Endobronchial Disease Endobronchial disease is a common complication seen in up to 40% of patients with active TB. The source of bronchogenic spread is usually from an adjacent tuberculous cavity or tuberculous lymph node containing liquefied materials rich in tuberculous bacilli (Smith and Schillaci 1987; McLoud and Naidich 1992). The spread through peribronchial lymphatic channels or directly via infected sputum are less common routes (Collins et al. 1998; Rottenberg and Shaw 1996). Rarely, the airways can be involved through a haematogenous route via bronchial arteries (Auerbacho 1949; Buckner and Walker

Fig.23.25. Post primary TB. Chest x-ray showing end stage tuberculous changes with extensive fibrosis, macro noduloreticular shadows, hyperinflation and bullae formation involving both lung fields. Note scattered calcifications

(arrowheads)

1990). Bronchogenic spread can be ipsilateral or contralateral, and bilateral dissemination can also occur. (see chapter 21, Endobronchial Tuberculosis) The radiological manifestations of bronchogenic spread include multiple small nodular opacities that

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a

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c Fig. 23.26. a Post-primary TE. Chest x-ray demonstrating a large thick wall cavity in a consolidated left upper lobe with an air fluid levels (arrow). Patchy infiltrate with macronodular shadows in the right lower lobe (small arrowheads) indicating bronchogenic spread. Note two nodular opacities in the left midzone representing tuberculous granuloma (open arrows). b CT chest of a different patient demonstrating thick-walled subpleural tuberculous cavity with air fluid level. Note localized empyema as a complication (arrowheads). c Tomography of the chest demonstrates a thin-wall tuberculous cavity (arrow). d Tuberculous abscess. Chest x-ray of a female patient with bilateral thin wall cavities demonstrating air fluid level (arrowheads)

may later become confluent (Fig. 23.27). Bronchial wall thickening, post-stenotic dilatation, lobar hyperinflation, persistent pulmonary collapse, obstructive pneumonia and mucoid impaction are other radiological features of bronchogenic disease. HRCT is more sensitive than conventional radiographs in demonstrating early endobronchial spread. The most common findings are the formation of 2-4 mm centrilobular nodules and branching linear structures ((tree-on bud" appearance), which represent caseation necrosis within and around the bronchioles. The centrilobular nodules are well defined and of high attenuation, a finding which is unusual in other

causes of bronchopneumonias (1m et al. 1993, 1995) (Fig. 23.28). Other findings include ill defined 8 mm centrilobular nodules, lobular consolidation, thickened interlobular septa and long segment narrowing with acentric wall thickening of the bronchi (1m et al. 1993; Lee et al.I993). Bronchiectasis is a common complication of endobronchial TB (Lee et al. 1991). It is defined as the irreversible dilatation of a bronchial tree. It is typically secondary to pulmonary destruction and fibrosis (traction bronchiectasis). It may also result from central bronchostenosis (Fig. 23.27c). Since the vast majority of post primary TB affects apical and

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Fig. 23.27. a Endobronchial tuberculosis: chest x-ray showing multiple small nodular opacities (arrows). b Endobronchial TE. Chest x-ray showing consolidation of the left upper lobe with large cavity with irregular outline and an intracavitary mass, mycetoma (arrowheads). Multiple macronodular shadows are seen bilaterally (arrows) indicating bronchogenic spread. Note hyperinflation of the right upper lobe and the paraspinal tuberculous abscess (curved arrows). c Endobronchial tuberculosis: chest x-ray demonstrates extensive bronchiectasis and cavitation in the right upper lobe with multiple bilateral basal nodular and bronchial linear shadows of indicating bronchogenic spread (arrows)

posterior segments of the upper lobes, facilitating bronchial drainage, bronchiectasis is usually asymptomatic. Chest radiographic findings include tram line opacities (dilated thickened wall bronchi with loss of normal tapering) and ring shadows, occasionally with air-fluid levels (Fig. 23.9). Bronchography was until recently the investigation of choice for the diagnosis of bronchiectasis (Fig. 23.29). CT, particularly HRCT, has replaced bronchography in the diagnosis of bronchiectasis in the recent years (Park et al.1999), with sensitivity up to 82-97% (Munroe et al. 1990; Grenier et al. 1986). Features on HRCT include uniform bronchial dilatation extending to the lung periphery without tapering (Fig. 23.28a), bronchial wall thickening and ring shadows representing markedly dilated bronchi (Fig. 23.30). HRCT is able to demonstrate the lobular distribution of airway abnormalities in early bronchiectasis

not seen using conventional x-ray or conventional CT. Features include subpleural nodules and branching linear structures ("tree-on-bud" appearance) corresponding to impacted bronchioles (Fig. 23.28c) (Davis et al. 1993; Moon et al. 1997). Hypertrophy of bronchial arteries, secondary to bronchiectasis, is demonstrated on contrast enhanced CT. With effective treatment, most of the changes of endobronchial spread resolve over time; residual fibrosis, bronchiectasis and emphysematous changes are invariably seen. The latter is believed to result from traction by adjacent fibrosis, from paracicatricial emphysema, and from bronchial stricture (1m et al. 1993). CT after treatment will demonstrate the residual changes of fibrosis, bronchiectasis and emphysema. Lobular emphysematous changes will give rise to a mosaic pattern (Fig. 23.31) (Eber et al. 1993; Martin et al. 1986).

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Fig.23.28. a Endobronchial tuberculosis: HRCT scan showing irregular bronchial wall thickening, loss of tapering (long arrow), multiple scattered linear branching densities, tree-on-bud (small arrow), and macronodular shadows. b CT of the same patient at lower level showing widespread macronodular and linear branching shadows of endobronchial spread (arrowheads). Note solid consolidation in the left lower lobe and massive adenopathy (arrow). c CT scan of the same patient at lung bases demonstrating impaction of the peripheral bronchioles with infective material resulting in extensive linear and nodular shadows (arrowheads)

c

23.3.3.4 Tuberculoma

Fig.23.29. Bronchogram demonstrating both cystic (arrowheads) and tubular (arrows) dilatation of the lower lobe bronchial tree

A tuberculoma is a focus of acid-fast bacilli that is encapsulated by connective tissue. It can be a manifestation of either primary or secondary TB, and it is believed to represent localized parenchymal disease that alternately activates and heals. Tuberculoma always carry a potential risk of cavitation and dissemination. They are seen in 3-6 % of cases, can be multiple and may be associated with satellite nodules (Leung 1999). Tuberculoma, by radiographic investigation, appears as a well-defined, round or oval masslike lesion (Fig. 23.32a). Most tuberculoma are 200 cell/mm\ radiological findings are typical of post primary TB, especially apical cavitary disease and bronchogenic spread. Skin testing to tuberculin is usually positive at this stage. With a greater degree of immunocompromise (CD 4 count

a Fig.31.5. This is a 13-year-old girl who presented with back pain, deformity and progressive paraplegia. She was referred as a case of congenital kyphoscoliosis with neurological complication. a, b Plain radiographic examination demonstrates kyphoscoliosis with L" looks like a hemivertebra (black arrowhead). Note that the pedicle and posterior elements are not seen on one side (white arrowhead) with obliteration of the disc space between T12 and L,.

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h c, d, e Magnetic resonance imaging (MRI) study indicates diminished signal in the body of L[ on n (arrow), and increased signal intensity on T2 (arrowhead). On post-gadolinium n, MRI, there is enhancement of the remaining destroyed body, there is extensive anterior spinal abscess (arrow) and cord compression by epidural abscess (arrowhead). fAxial scan demonstrates affection of posterior and anterior columns of L[ (arrowheads). g, h Post-operative x-ray films following two-stage operation shows correction of deformity and fusion

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c Fig. 31.6. This is a 25-year-old lady who presented with abdominal pain and fever. Investigations revealed incomplete intestinal obstruction and destructive lesion in the lower thoracic spine causing lower extremities weakness. Lumbar spine was noticed to be minimally affected. She was operated on by two-stage operation for the lower thoracic lesion 2 weeks after start of antituberculous treatment. Patient continued to have constitutional symptoms and lymphopenia. Lumbar spine lesion continued to deteriorate and necessitated radical debridement after extension of the fixation and fusion of the lumbar spine. a Lateral plain radiograph shows severe destruction of TIO with localized kyphosis (arrowhead) as well as early lesion at L3 (arrowhead) with intact disc spaces between L2> 3 and L3> 4' b Non-contrast computed tomography (CT) demonstrating

l>

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severe destruction of TID, 11 including costovertebral junction and the pedicle on left side (arrowhead). There is a big anterior and posterior abscess. c Non-contrast CT of the lumbar spine shows marginal anterior osteolytic lesion (arrowhead) with anterior abscess. d Lateral view x-ray, 4 months following two-stage operation of the thoracic spine and correction of its deformity. Note the complete collapse of L3 with localized kyphosis (arrowhead). e Non-contrast CT demonstrates fragmentary lesion of L3 (arrowhead) with bilateral psoas abscess. Note the left-sided lesion at Ls (open arrow). f Post-operative plain radiograph, 18 months following extension of fixation and fusion to the lumbar spine and radical debridement and fusion between L2 and L4

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d Fig. 31.7. This is a 60-year-old lady who presented with back pain, girdle pain and paraparesis with signs of upper motor neuron disease. a Lateral radiograph demonstrates collapse of T6 with obliteration of the disc space between T5 and T6 vertebrae (arrow). b,c T1 and T2 weighted, sagittal scans demonstrate destruction of T6 with intraosseous abscess at T5. Note: the unusual high intensity signals in the bodies of T5 and T6 on T1 scali (thick arrow). There is also diffused lesion behind the cord with increased signal intensity on both T1 and T2 imaging indicating fat (lipomatosis) (thin arrow). d, e T1 and T2 weighted, axial

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scans demonstrate the cord is compressed between the anterior destructive lesion (arrow) and the posterior lipomatosis (arrowhead). f Lateral view of the lumbosacral spine in the same patient, shows destructive lesion at L4, 5 and the sacrum (arrow). g Sagittal T1 weighted magnetic resonance imaging. Tuberculous spondylitis of L4,5 and the sacrum with diffuse anterior abscess (arrow). h Lateral plain radiograph of the thoracic spine following radical debridement and fusion between T4 and T6

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Fig. 31.8. This is a 21-year-old male admitted by the thoracic surgeon because of tuberculous mediastinal abscess. Evaluation of the spine preoperatively did not show major spinal affection. While the patient was walking 5 days following chest drainage, he fell down paraplegic. a Plain chest radiography shows huge mediastinal mass (arrows). b, c Plain radiographs of the thoracic spine show haziness of vertebral bodies with reduction of the disc spaces (open arrows) with no gross collapse or instability. d Computed tomography reveals the huge mediastinal shadow (A) surrounding the spine without destruction. Note: also bilateral pleural effusion (arrows). e Five days following drainage anterior-posterior radiograph shows translation of vertebrae at the level of T6, 7 (arrowhead). Myelography shows total blockage at the T8 level. f Post-contrast computed tomography demonstrates translation of vertebrae with shearing at the pedicles (arrowhead) and cord transection. g. Anterior-posterior radiography, 4 years following surgery shows fusion at translation site

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Fig. 31.9. This is a 60-year-old male, presented with severe low back pain, left sciatica and inability to walk. a, b Plain anterior posterior and lateral radiographs show severe destruction of L4 , less severe destruction of L3, localized kyphosis and surrounding calcification. Note: the destruction of facet joints at L3, L4 level (arrow). c, d Tl and T2 weighted studies reveal loss of the Lr L4 disc, (thin arrow) with extensive destruction of L4 vertebrae (thick arrow). e, f Post-gadolinium sagittal and axial scans demonstrate total destruction of L4 body, enhancing L3 and Ls (arrowhead) and low-intensity signals represents caseating material (arrow). Note: also on axial cut, the nerve root is surrounded by granulation tissue (curved arrow) and severe thecal compression (arrowhead). g Post-operative lateral radiograph shows anterior fusion and posterior fixation. Note: the correction of kyphosis

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c Fig. 31.10. a, b Plain radiograph in a 45-year-old lady shows L2-L 3 disc space narrowing, unilateral and anterior osteophytes (arrowheads) with destruction of L3 upper and plate. Serological tests for Brucellosis were negative. c Post-contrast computed tomography demonstrates anterior-marginal bone destruction (arrowhead in the upper cut) and multi-loculated abscess with surrounding enhancement (arrowhead in the lower cut). d Lateral plain radiograph shows anterior debridement and fusion 3 months post-operative

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Fig.31.11. a Lateral radiograph of a 40-year-old lady who presented with back pain, shows no obvious abnormality. b Anterior-posterior radiograph reveals destruction of the lower half of the spinous process of L4 (arrows). c Non-contrast computed tomography shows destruction of the spinous process (arrow) with surrounding paraspinal and subcutaneous abscess (A). d Lateral radiograph 2 years after debridement shows no further changes

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Fig. 31.12. This is a 60-year-old lady who presented with back pain and complete paraplegia diagnosed as a metastatic disease of the spine a Plain radiographic examination demonstrates vertebra plana at T5 (arrow). b The conventional myelogram demonstrates the vertebral-body lesion (arrow) with compression of the spinal canal contents (open arrow). c Post-contrast computed tomography shows fragmentation lesion with small soft-tissue shadow (arrow). Note: also cord compression (arrowhead) d Lateral radiograph after combined operation of posterior decompression, fusion and fixation followed by anterior radical debridement and fusion

Fig. 31.13. This is a 30-year-old male who presented with neck pain, back pain and inability to walk because of weakness of the lower limbs and painful left hip joint. a, b Plain radiograph shows destructive lesion C6, C7 and T1 and kyphotic deformity with huge retropharyngeal abscess (long arrow). There is subluxation C6, C7 on lateral radiograph (thick arrow) and cervicothoracic scoliosis because of unilateral destruction of C7 as shown on anterior-posterior radiograph (arrow). c, d plain radiographs of the thoracic spine shows another lesion affecting mainly T8 (vertebra plana) (arrow). e Computed tomographs of the cervicothoracic region revealed affection of C7 mainly, including the right pedicle and transverse process (arrowhead). fThoracic computed tomographs show destruction of the anterior and posterior elements ofT8 (arrow) with cord compression by an epidural abscess (arrowhead). g Computed tomographs of the left hip show soft-tissue shadow (arrow) and decreased bone density (open arrow). h Lateral radiograph of the cervical spine following combined operation shows correction of deformity. i Thoracic spine lateral radiography after combined operation demonstrates correction of deformity, posterior fixation and anterior fusion

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d Fig.31.14. This is a 45-year-old lady who presented with back pain, inability to walk and incomplete paraplegia. a Lateral radiograph shows a lesion involving two vertebra. The disc space is obliterated and the upper vertebra is dipped into the lower one. b Diagram shows the bifacetal dislocation Tll-Tl2. c Non-contrast computed tomography shows TIl body inside lower part of TI2 in the upper scan and bare facet sign in the lower scan because of dislocation (arrows). d Sagittal reformat of the computed tomography show the facet dislocation posteriorly (arrow). e Radiography 10 months after combined operation shows fusion and reduction of dislocation

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d Fig. 31.15. a Radiography of a 40-year-old lady with chronic back pain and deformity of six years duration. Severe destruction of the lumbar spine with kyphosis and shortness of the trunk. b Anterior-posterior radiograph demonstrates the disorganization of the facet joints and calcification. c The conventional myelogram demonstrates the thecal indentation. d Post-contrast computed tomography show the destruction of the vertebrae TI2 and all lumbar vertebrae. e Lateral radiography following debridement and fibular graft fusion between TIl and the sacrum

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31.3.2 Conventional Tomography Conventional tomography remains as an important imaging modality particularly in countries where TB is common in poor underdeveloped parts of the world with lack of CT and MRI facilities. It also has the advantage of the absence of overshadowing of overlying structures. However, the loss of densities between various tissues limits its value (Fig. 31.16). It is of considerable value in the occipito-cervical junction as it shows the extent of bone destruction and subluxation between the first and second cervical vertebrae (Fig. 31.17). Conventional tomography is also useful in depicting TB infection at the cervico-thoracic junction and the dorsal spine (Figs. 31.16,31.17).

31.3.3 Myelography Water-soluble contrast myelography is still used in poor underdeveloped countries with endemic TB. However, it has been superseded by CT, CT-myelography or MRI in rich industrialized countries. Its value is limited to certain groups of patients with posterior subligamentous abscesses or extradural tuberculous granulomatous masses protruding in the spinal canal that are not depicted by plain radiography or conventional tomography. An extradural space-occupying lesion change appears as displacement of the contrast column or even total spinal blockage (Fig. 31.2).

31.3.4 CT Features Axial CT scanning is ideal for showing the extent of bone involvement in TB but is less efficient in soft tissue mass lesions, particularly extradural granulomatous encroaching on the spinal canal. Another disadvantage of CT is the difficulty in the detection of skip distant spinal lesions that may occur and are not included in the site of imaging. Some recent advances in the development of soft and hardware may help in soft tissue involvement but are not as cost effective. Early changes characteristically appear as rarefaction, homogenous focal low-density lesions with regular boundaries. Clarification appears as the disease advances with subsequent abscess formation (Fig. 31.9).

Destruction of the cortical bone and intervertebral disc occur as the disease advances and these can be clearly depicted by axial and sagittal CT (Fig. 31.2). Loss of clarity in the fat planes surrounding the vertebra is an early feature that indicates paravertebral extension of the infection. In advanced tuberculous vertebral osteomyelitis, loss of normal bone architecture, extensive fragmentation, kyphosis, multiloculated paravertebral abscesses and subligamentous spread of infection are characteristic findings (Fig. 31.10). Spinal canal encroachment by extradural inflammatory tissue granulomas and abscess formation may enhance with contrast media if pus is present (Fig. 31.4). The four distinctive patterns of vertebral body destruction have been described by Jain et al. in 1993 as fragmentary, osteolytic, subperiosteal and localized sclerotic. The fragmentary type is the most common and is described by most authors and noted in 47% of patients (Fig. 31.18). CT-guided needle biopsy and aspiration is an important tool for diagnosing TB of the spine. CT with intrathecal injection of a small volume of low concentration metrizamide has been used to evaluate extradural encroachment of the spinal cord (Bront et al. 1983; McGraham and Dublin 1985). However, it is an invasive procedure and carries the risk of further spread of infection (AI Arabi et al.1992).

31.3.5 MRI Features MRI imaging modality is the investigation of choice for spinal infection. It has good tissue differentiation, bone marrow visualization, as well as excellent depiction of the spinal canal, its content and the paravertebral soft tissue. It does not expose the patient to ionizing radiation. However, it has a poor definition of bone and calcified tissue than CT modality. At the time of presentation, MRI may show vertebral end-plate destruction, loss of disc space height and paraspinal abscess. However, early changes of tuberculous spondylitis may only appear in a single vertebral body, which may simulate neoplastic disease. A Tl-weighted image may show an area of a homogeneous low signal of intensity at the infected area (commonly the anterior inferior part of the vertebral end-plate). The T2-weighted images may show an increased signal in the infected area of the vertebral body. Occasionally, posterior areas of the vertebral body may show similar changes. As the disease advances, a vertebral abscess may appear as a

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Fig. 31.16. a Conventional tomography in a young man presented with progressive paraplegia. There is destruction of the upper thoracic vertebrae with kyphosis. b, c Pre and post-gadolinium II scans of II to TS tuberculous spondylitis. There is obliteration of the disc spaces and big anterior collection (arrow). Note: the extensive epidural abscess pressing the cord. (Small arrow in Tl and arrowhead in enhanced Tl). d T2 weighted imaging show high signal intensity in the bodies, in the disc spaces and the abscesses. Note: prevertebral abscess (arrow) and epidural abscess (arrowhead). e Conventional tomography done 6 weeks after debridement and fusion shows correction of kyphosis

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Fig. 31.17. This is an 8-year-old girl who presented with painful torticollis, inability to support her head and paraparesis. a Lateral radiograph shows invagination of the odontoid process (arrowhead) and retropharyngeal collection, (arrow), and subluxation Cl>~' b Anterior-posterior radiograph demonstrates upper mediastinal shadow (arrow) and decreased intervertebral disc spaces at the cervicothoracic region. c Non-contrast computed tomographs of the craniocervicaljunction reveal destructive lesion of the occipital condyles, CI and C2 (thin arrows). There is distortion of the anatomy of the region with invagination of the odontoid process (thick arrows). d Non-contrast computed tomographs of the cervicothoracic junction reveal destruction of the vertebrae with fragmentation and cord compression (arrow). e Conventional tomography was useful in this case to show the severe kyphosis in the upper thoracic spine and subluxation ofTl-T2. (curved arrow). Note: also invagination of odontoid process (arrow). fA sagittal Tl and T2 scans show anterior medulla compression by the tip of odontoid process (arrowhead) and prevertebral abscess with increased signal intensity in both Tl and T2 because of proteinaceous material. There is destruction of the upper thoracic vertebrae with severe cord compression (arrow). g Post-operative radiography show reduction of craniocervical as well as CI, C2 subluxation. This was treated by traction and brace. The thoracic spine demonstrates the correction of kyphosis following combined operation

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Fig. 31.18. This is a 39-year-old lady who was transferred from another hospital 3 months following laminectomy. She had back pain and inability to walk because of neurological deterioration following laminectomy. a, b Plain radiographs show destructive lesion affecting T9, 10 and 11 with extensive destruction of TlO (arrow) and kyphosis. There is absence of posterior elements of TlO and II because oflaminectomy (arrowheads). c Post-contrast computed tomographs show extensive destruction of TlO with fragmentation (small arrow) and cord compression (arrow) in spite oflaminectomy (arrowhead). d Post-operative lateral radiograph shows correction of deformity and fusion following two-stage operation

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low-intensity signal with rim enhancement by gadolinium contrast (Fig. 31.9). Early changes of the disc in Tl-images, do not show signal changes or may show blurring of the disc-space margins. In T2-irnages, high-signal intensity in the disc is uncommon, unlike early disc involvement in pyogenic infection. Subligamentous spread, anterior or posterior, is depicted better on Sagittal Tl-imaging (Fig. 31.5) as isointense with other structures. In Tl-images, high intensity signal beneath the anterior longitudinal ligament may appear with margins enhancement by gadolinium. Multiloculated large paravertebral abscesses may show isointensity or low intensity signals on Tlweighted images. T2-weighted images will show a high signal as well as the size and extent of the abscesses.

31.3.6 Scintigraphy Please refer to Chap. 30.

31.4 Treatment of T8 Spine The goals of treatment are to eradicate the infection and to treat neurological deficit and spinal deformity. The best method of treatment should produce rapid fusion, prevent late recurrence after clinical healing and prevent the development of progressive and severe deformity. The traditional treatment of Pott's disease prior to the discovery of effective chemotherapy was prolonged immobilization, utilizing prolonged bed rest and/or body casts (Dobson 1951). Although many of the patients did remarkably well, mortality was in the range of 20% and 20-30% of the patients suffered recurrence of infection (Dobson 1951). The clinical availability of streptomycin in 1944, para-amino salicylic acid in 1950 and isoniazid in 1951 ushered in a new area in the management of Pott's disease. In 1962, Konstam and Blesovsky reported the management results of 207 patients with Pott's disease who were treated with chemotherapy and allowed to walk without bracing (Konstam and Konstam 1958). Only 27 patients underwent operations for abscess drainage and 86% made complete recoveries. One hundred patients had to be withdrawn from the study because of

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poor drug compliance and only 35 patients were monitored for longer than 2 years. This was the first study to show that chemotherapy without long-term immobilization would be used to treat Pott's disease successfully.

31.5 Antibiotics With or Without Surgery (MRC Trials> The multinational prospective study on the efficiency of conservative chemotherapy and surgical treatment coordinated by the Medical Research Council (MRC) has just completed a final IS-year follow up report. They conducted a series of randomized clinical trials of the following treatment modalities: (1) chemotherapy with immobilization via either strict bed rest or body cast, (2) outpatient chemotherapy with mobilization, (3) chemotherapy and debridement of obviously infected bone without fusion, (4) radical operation of anterior resection and debridement with autologous bone-strut grafting (Medical Research Council Working Party 1973a, b, 1974a, b, 1976, 1978a, b, 1982, 1985, 1986, 1989). The first two modalities of non-operative treatment regimens resulted in a favorable outcome (return to normal activity without pain or neurological deficit) in 85% and 86%, respectively, with radiographic evidence of fusion in 36% and 67%, respectively. Operative debridement resulted in no better outcome, although patients who were debrided tended to have an earlier resolution of abscesses. Overall, the patients treated without radical debridement experienced an increase in kyphosis of II°,30% had an increase in kyphosis of II° to 30° and 10% had an increase of up to 50°. Although it appears from these studies that conservative treatment is as effective as surgical intervention for earlier and milder diseases, there are still reservations on the effect of such treatment for more severe diseases (Luk 1999). The optimal duration of anti-tuberculous chemotherapy required for complete recovery is still debated. The duration currently recommended by most experts is 12 months (Moon 1997; Pertuiset 1999). Shorter durations of 6-9 months have been advocated in adults. These trials failed to resolve this issue because of methodological inadequacies regarding sample size and statistical analysis (Pertuiset 1999).

Surgical Management of Spinal Tuberculosis

31.6

Operative Treatment Active surgical intervention of the diseased area in the care of Pott's disease was begun even before the introduction of specific anti-tuberculous chemotherapy, even though most of the authors considered chemotherapy as the mainstay treatment for TB. Still, lesions could be safely treated without surgery to be defined (Boachie-Adjei and Squillante 1996).

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3. Unresponsiveness to medical therapy as manifested by development or progression of neurological deficits, spinal deformity, intractable pain and progression of disease 4. Non-compliance with medications 5. Non-diagnostic biopsy

Tuli described a middle-path regimen of selective operative treatment (Tuli 1975). He considered surgery for cases with neurological deficits that failed to improve during the initial trial of chemotherapy. All other patients received chemotherapy with surgery reserved for posterior lesions, persistent active infection, instability, doubtful diagnosis or recurrence 31.7 of neurological deficit. Lifeso, from Saudi Arabia, Indications for Surgical Intervention modified surgical indications (Lifeso et a1.1985). The Hodgson and Stock proposed that the operation, in authors indicated the need for immediate anterior combination with chemotherapy, be done as early as decompression and fusion for complete paralysis, possible after the diagnosis for the following reasons profound neurological deficits due to cervical or (Hodgson and Stock 1956): upper thoracic lesion and gross destruction of the 1. Diseased material may be obtained for a definitive cervical spine or any severe kyphosis associated with active disease. They recommended that patients diagnosis 2. The patient's general condition improves dra- who have slight or no neurological deficit and slight matically immediately after the evacuation of the kyphosis can be safely treated with medical therapy alone, and close observation should then be the rule. abscess In our own series we separated the cases into three 3. In the thoracic spine, especially in children, early decompression of the abscess is necessary, as the groups: (1) Early cases with no or minimal bony affecabscess tends to extend up and down the spine tion are treated conservatively. Drugs to be continued for 12 months, with four drugs in the first 2 months rapidly 4. Bone sequestra, sequestrated intervertebral discs, and two drugs for the remaining 10 months. (2) Cases caseous material and avascular bone may be with bony destruction and involvement of disc spaces removed and placement of an anterior strut graft are treated surgically by anterior radical debridement and fusion, except in cases with posterior arch affecunder compression will lead to early fusion 5. Late recurrence is uncommon after radical exci- tion, which needs posterior surgery. (3) Cases with sions of the diseased focus and solid fusion have affection of three or more vertebrae, affection of posterior and anterior columns and progressive deformity been achieved 6. Increasing deformity may be prevented while the patient is on medical treatment and bed rest. These three categories are considered as radiological 7. Paraplegia may be prevented 8. In the presence of established paraplegia, anterior signs of instability of the spine. For these cases, both decompression and bone grafting lead to rapid anterior radical debridement and fusion and posterior fixation and fusion are needed (Figs. 31.19,31.20) (Al recovery 9. The anterior approach gives accurate diagnosis Sebai et al. 2001). In our patients this has resulted in and exposure for dealing with penetration of an improvement in the correction of the deformity as well as encouraging neurological recovery and alloworgans, especially of the lung ing early mobilization. Rezai et al. considered the criteria for surgical management, in combination with chemotherapy, of PoU's disease as (Rezai et al. 1995): 1. Neurological deficit including acute neurological deterioration 2. Spinal instability with more than 50% vertebral body collapse or destruction and spinal deformity of more than 5°

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a c

b

Fig.31.19. a Lateral radiography of 3-year-old girl who presented with chronic back pain and incomplete paraplegia, shows destruction of the vertebrae no to L2• There is kyphosis of 86°. b Post-operative lateral radiograph following radical debridement and anterior fusion between no and L3. It shows correction of kyphosis to 55°. c Post-operative lateral radiograph following second-stage of posterior fusion and instrumentation reveals further correction of kyphosis to 26°. (With permission from International Orthopaedics 25,2001)

l> Fig. 31.20. This is a 56-year-old lady who complained of back pain and chest wall pain. Chest radiograph and lateral view of the thoracic spine revealed no gross abnormality. She had increasing pain 4 months later with inability to walk because of incomplete paraplegia. a, b Lateral plain radiographs at this stage showed compression of T7 and lytic lesions affecting L[ and L2 with preservation of disc spaces (arrows). c Bone scan revealed multiple foci of increased uptake interpreted as most likely metastatic disease of the spine. d Post-intravenous contrast computed tomographs show destructive lesion of T7 extending to the pedicle and costovertebral junction with severe cord compression, which is pushed to the right side (arrowheads). Note absence of soft-tissue shadow around the vertebrae (arrow). e Computed tomographs of the lumbar spine show destruction of L} and L2 with fragmentation (arrowhead) and surrounding enhancing soft-tissue shadow (curved arrow). f Post-gadolinium T1 images show destruction of T7 and L1 vertebrae. (arrows) Note enhancing epidural lesion compressing the cord at T7 and to a lesser degree at L}. g, h Lateral radiographs of the thoracic and lumbar spine, 3 weeks following start of anti-tuberculous treatment and bed rest. There is progressive collapse of the vertebrae and obliteration of the disc space between L1 and L2 • (arrows). i, j Lateral and anterior-posterior radiographs following combined operation showing fusion and fixation

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e

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31.8

31.8.2 Drainage of Abscesses

31.8.1 Needle Biopsy (Under Fluoroscopic or CT Guidance)

Aspiration or surgical drainage was carried out for patients with a large cold abscess because it was thought that evacuation of the abscess improves the patient's general condition and rapid progression of the abscess along the spine was prevented. This has been shown to be ineffective and surgical drainage of a cold abscess alone is no longer recommended (Moon et al. 1987, 1996). However, in certain cases with huge psoas abscesses, with or without minimal spinal affection, presenting with abdominal mass causing discomfort to the patient, the patient may get quick relief after drainage (Fig. 31.21).

Approaches and Surgical Techniques

This technique is usually used for the thoracic and lumbar spine disease. The approach depends on the anatomic region and part of the vertebra involved. Spinal needle is used for aspiration to get cytological diagnosis while Tru-cut biopsy could be used for histopathological diagnosis. Definite cytological diagnosis was obtained in up to 88.5% of cases (Kang et al. 1999). Biopsy of the cervical spine poses special problems because of the proximity to many vital organs. With CT, the exact relationship of the skeletal lesion to the adjacent structures can be established, allowing a safe route to be selected (Kattapuram and Rosenthal 1987). Gupta et al. reported the use of ultrasound guidance for needle biopsy of lytic lesions of the cervical spine in four cases without complications (Gupta et al. 1993).

31.8.3 Debridement of Tuberculous Lesion To eradicate the tuberculous lesion, anterior debridement was done first by Ito et al. in 1934. Kondo and Yamada wrote the end results of focal debridement

Fig.31.21. Non-contrast computed tomographs of a 26-year-old male who presented with back pain, abdominal pain and systemic manifestations. There are huge bilateral multiloculated abscesses (A) extending from the upper abdomen down to the pelvis

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in spinal TB and its indications in 1937 (Kondo and Yamada 1937). Hodgson and Stock popularized the anterior spinal surgery and described the anterior radical surgery (Hong Kong operation) (Hodgson and Stock 1956). Focal debridement can effectively remove the diseased tissue and can evacuate the abscess; however, it does not prevent the progression of kyphosis, especially if compared with the radical operation in both adults and children (Upadhyay et al. 1993, 1994). Simple debridement gives no long-term advantage over ambulant chemotherapy alone and, therefore, is no longer accepted as a preferred method of treatment (Medical Research Council Working Party 1982,1985). In the Hong Kong operation, the spine is approached anteriorly so that the affected area may be dealt with more directly. The sequestrated bone and caseous material must be debrided back to bleeding bone above and below and back to the posterior longitudinal ligament. The decompression should go back to the dura in cases of neurological deficit when spinal decompression is necessary. The angular deformity is corrected by insertion of a strut graft. A slightly oversized graft is put under compression by springing open the kyphosis during insertion. The choice of graft material is based on considerations of graft incorporation and structural support. The strut graft should be strong yet osteogenic in nature, tri-cortical or bi-cortical iliac crest grafts are ideal, but frequently the area to be grafted is too large for the iliac grafts to be sufficient. Longer struts can be obtained from the fibula or ribs. These should be supplemented with iliac bone because the fibula is strong but mostly cortical bone (non-osteogenic). Bradford and Daher described the use of vascularized rib grafts for stabilization of kyphosis (Bradford and Daher 1986). Good results were also obtained by the use of allograft in 47 children by Govender and Parbhoo (1999).

and fusion can, however, be associated with fall-off in the post-operative kyphos, frequently because of slipping of the graft, graft fracture, protrusion, absorption or non-union and, in part, because of the continued growth in the posterior elements in the growing child (Bailey et al. 1972). In severe cases, the combined approach of anterior and posterior spinal fusion gives the best results. Comparison of four procedures of fusion revealed that the combined fusion and anterior debridement guaranteed an equal growth of the anterior and posterior heights in children (Schulitz et al. 1997). Long-term follow-up for children who had anterior and posterior fusion without instrumentation for extensive disease and kyphosis, revealed solid fusion and improvement of the kyphotic deformity (Altman et al.I996). However, the use of posterior instrumentation in the face of active disease helps in providing early fusion, prevention and correction of kyphosis as well as earlyambulation (Boachie-Adjei and Squillante 1996; Moon et al.1995, 1996).

31.8.5 Instrumentation

The role of posterior instrumentation and fusion in the treatment of spinal TB has only recently been reported (Korkusuz et al.1997; Moon et al.1995, 1996; Rezai et al.1995). In infectious diseases, instrumentation introduces a foreign body that acts as a focus, the infection is notoriously resistant to antibiotic therapy and usually requires removal of the instrument (Gristina and Costerton 1985; Gristina et al. 1985). However, both clinical and microbiological results suggest that posterior instrumentation is not associated with persistence or recurrence of spinal tuberculous infection and is useful to provide immediate stability and protect against the development of a kyphotic deformity (Oga et al. 1993). In adults with deformity and paraplegia, Moon et al. found the combined two-stage operation to be most successful (Moon et al. 1995, 1996). In their cases, anterior surgery was preceded 31.8.4 by posterior instrumental stabilization surgery. Spinal Fusion Additional posterior spinal fixation after anterior Posterior spinal fusion was used to hasten recovery decompression and fusion was reported by others since 1911 (Albee 1911; Hibbs 1911). This procedure (Abramovitz et al. 1986; Graziano and Sidhu 1993; did not prevent progressive kyphosis or development Jeanneret and Magerl 1994). Despite the general of paraplegia. Debridement followed by anterior acceptance of the Hong Kong operation for the fusion offers the advantage of debridement and a treatment of spinal TB, Guven and co-workers have result in the diminution of the kyphotic deformity used posterior instrumentation and fusion without (Hodgson and Stock 1956, 1960; Medical Research anterior debridement in ten neurologically intact Council Working Party 1974). Anterior debridement patients. They achieved clinical and radiological

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evidence of fusion in all cases (Guven et al. 1994). Chemotherapy was instituted 2 weeks pre-operatively and continued for a mean period of 11 months. Lee et al. also used transpedicular instrumentation as an adjunct in the treatment of thoracolumbar and lumber spine with early stage bone destruction (Lee et al. 1999). Combined posterior decompression and internal fixation was reported by Rath et al., avoiding the risks of anterior approaches for the elderly and debilitated patient (Rath et al. 1996). Jeanneret and Magerl used percutaneous debridement and external spinal fixation as an alternative procedure to conservative or more invasive operative treatment modalities in the following conditions: (a) painful lesion of the spine with minimal bone loss, not amenable to efficient orthotic stabilization, (b) when emergency decompression of the spine is mandatory and anterior decompression is not possible emergently, (c) osteomyelitis of the spine at L51S1, and (d) in the presence of infective wounds, making internal posterior stabilization unsuitable (Jeanneret and Magerl 1994). They had good results, as far as healing of infection, neurological outcome and kyphotic deformitywith shorter period of bed rest. A small number of recent reports deal with anterior spinal cord decompression, block bone grafting and anterior internal fixation in cases of vertebral osteomyelitis (Kostuik 1983; Redfern et al.1988; Yilmaz et al.1999). Yilmaz et al. reported 22 patients who had TB of the spine with moderate to severe localized kyphosis and 16 patients who had more than two involved levels; all had stabilization with anterior instrumentation (Yilmaz et a1.1999). They obtained an average correction of kyphosis of 64% and there was no recurreJ;lce of the disease. However, anterior instrumentation should not be used to correct kyphotic deformity when the posterior column is affected.

31.9 Decompressive Techniques and Treatment of Paraplegia The first case of tuberculous spondylitis treated successfully by laminectomy was in 1882. In the early part of the 20th century it has become a common procedure for patients with Pott's paraplegia. Seddon condemned the procedure because it removes the integrity of the posterior arch and may lead to instability and further neurological damage (Figs. 31.18, 31.22) (Seddon 1934/1935). Laminectomy is considered contraindicated in the usual form of TB (Fel-

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lander 1975; Hodgson et al. 1964; Kemp et al. 1974). The only indication for laminectomy in the treatment of spinal TB is atypical disease involving the neural arch (Fellander 1975; Kemp et al. 1974; Rahman et al. 1987; Rand and Smith 1989). Decompression in the thoracic spine may be performed through a transthoracic approach, through a costotransversectomy or by an extrapleural approach. Transthoracic approach is more successful than costotransversectomy (Kirkaldy-Willis and Thomas 1965). The extrapleural approach has the theoretic benefit of avoiding the tuberculous empyema. However, no studies have demonstrated any actual advantage of an extrapleural approach over a standard thoracotomy. Decompression in the lumbar spine may be done by retroperitoneal approach. A left-sided approach is preferred because the arterial structures are easier to deal with than the venous counterpart. In approaching the lumbosacral junction, the common and external iliac vessels are mobilized. Cervical spine infection has a high incidence of cord compression, more than 40%. Hsu and Leong reported excellent results from using the Hong Kong procedure via anterior approach in conjunction with medical treatment (Hsu and Leong 1984).

31.10 Surgical Treatment of Kyphosis Kyphosis is one of the two major complications of spinal TB. It has been common in patients treated with chemotherapy alone (Moon et al. 1995). Almost 3% of cases of TB of the spine develop a severe kyphotic deformity. The patients at risk are those who develop the disease under the age of 10 years, and who had involvement of three or more vertebral bodies (Tuli 1995). A severe kyphosis is more than a cosmetic disfigurement because nearly all such patients develop cardiopulmonary dysfunction, painful impingement between the ribs and pelvis and compression of the spinal cord with paraplegia at an average of 10 years after the onset of the disease (Smith et al. 1996; Tuli 1995). Severe kyphosis is not only difficult to treat, but also dangerous, with a high complication rate. There are two clinical types of kyphosis, mobile and rigid (Moon et al.1995). Mobile kyphosis could be treated by traction, posterior fusion, anterior radical surgery or two-stage operation (Moon 1997). Skull traction was found effective in correction of non-rigid kyphosis in cervical spine (Fig.31.23) (Moon et al. 1987, 1996). A two-stage

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a

d

Fig.31.22. This is a 50-year-old lady, referred from another hospital because of persistent back pain and inability to walk 6 months following laminectomy and distraction rod fixation for lumbar tuberculous spondylitis. a Lateral radiograph show extensive destruction of L4 , lumbar kyphosis and dislodged rods. b, c Functional flexion and extension radiographs reveal gross instability. d Non-contrast computed tomographs demonstrate destruction of the body of L4 (arrow). They show evidence of previous laminectomy (arrowheads) and dislodgement of the rods (small arrowheads). e, f Plain radiographs, 2 years following staged operation show fusion and correction of deformity

f

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b

Fig.31.23. a Lateral radiograph of a young man that shows destructive lesion of C6-7 with obliteration of the disc in between and kyphotic deformity. Note subluxation of the facet joints C6-7 (long arrow) and large prevertebral soft-tissue shadow (short arrows). b Lateral radiography following skull traction demonstrates reduction of subluxation (arrows) and correction of deformity. c Post-operative plain radiography shows fusion and correction of deformity

c

operation could be done either with the posterior stage done first or as the second stage. Anteri6lr radical debridement followed by posterior resection and instrumentation was recommended by Yau et al. (1974) (Fig. 31.19). Combined two-stage operation, where posterior instrumentation is done first, achieves good correction of kyphosis, provided the deformity is not fixed and severe has been reported by others (Fig. 31.24) (Moon 1991; Moon et al. 1995,

1996). The rigid deformity could be corrected by posterior closing wedge osteotomy, two-stage operation or multi-stage operation (Fig.31.25) (Guven et al. 1994; Wu et al. 1996). Because of technical demands and higher risk of neurological injury, correction of a severe kyphosis without neurological deficit should not be done for cosmetic reasons alone. In a paralytic case, partial correction can be attempted together with decompressive surgery (Fig. 31.26).

Surgical Management of Spinal Tuberculosis

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c

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b

Fig.31.24. This is a 25-year-old lady who has had kyphosis since early childhood following a chronic illness. She presented with recent onset back pain and weakness of lower limbs. a Lateral plain radiography shows kyphosis of 75° between T8 and L4 and destruction of the vertebrae T9 to L3• Note the lordosis of thoracic spine above the kyphos (arrow). b Anterior-posterior view demonstrates the crowding of ribs, loss of disc spaces between no and L4 and increased density of the bone. c Non-contrast computed tomography demonstrates areas of destruction (arrowheads) because of reactivation of tuberculous spondylitis. d Lateral radiography following combined operation shows correction of kyphosis to 30° and fusion with fibular graft between T8 and L4

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a

c

Fig. 31.25. This young lady presented with back pain and deformity. She had kyphosis and cauda equina syndrome since childhood. a Lateral radiography shows kyphosis of 72° between TIO and L2 • There are fused, deformed Til, 12 and L[ vertebrae at the apex (arrow). b Anterior-posterior plain radiograph demonstrates previous laminectomy between TI2 and L2 and old myodil with evidence of arachnoiditis (arrow). c Lateral radiography 2 years following staged operation shows fusion and correction of deformity to 22°

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a

c

d

Fig. 31.26. This is a 35-year-old male who started to have back pain and progressive paraplegia. He had kyphosis since early childhood. a, b Lateral and anterior-posterior plain radiographs show kyphosis 92° between T8 and Lz and fusion of T9 to L1 with no soft-tissue shadow (arrow). c The conventional myelogram demonstrates stretching of the cord over the kyphos without blockage of the dye (arrow). d Postcontrast computed tomographs at the apex of the kyphos revealed indentation of the thecal sac (arrowheads). Note absence of signs of reactivation or surrounding soft-tissue shadow. e, £lateral and anterior-posterior plain radiographs, 3 years following two-stage operation. Note: fusion both anteriorly and posterolaterally as well as partial correction of kyphosis

f

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31.11

Cervical T8 TB of the cervical spine is uncommon. Its incidence, according to the few reports in the literature, varies from 3% to 5% (Dobson 1951; Hsu and Leong 1984; Martin 1970). Because of its low incidence, it has not been included in the MRC trials (Medical Research Council Working Party 1973a, b, 1974, 1976, 1978a, b, 1982,1985,1986,1989). Lifeso recognized three stages of CI-2 tubercular infection and recommended surgical treatment for all of them (Lifeso 1987). We treated four cases with upper cervical spine TB; two of them had fractured odontoid process following car accidents. We assume that the infection precipitated the fracture (Fig. 31.27). The other two cases had subluxation with destruction of the vertebrae. Three of these four cases needed posterior fixation and fusion. The fourth case was treated by traction and chemotherapy, while surgery was directed to the cervico-thoracic lesion in the same patient, which was responsible for the neurological deficit (Fig.31.17). Spinal instability following TB of the spine has been described. Three patients with varying degrees of subluxation following cervical TB were reported from Malaysia (Arumagasamy et al. 1977). Although subluxation of cervical spine TB has been rarely reported, bifacetal dislocation has not been described before 1991. We reported cervical spine

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bifacetal dislocation for the first time in a IS-year-old girl with cervical tuberculous spondylitis (Fig. 31.28). (AI Arabi and Al Sebai 1991). TB of the cervico-thoracic spine junction can be challenging both in visualization on plain radiography as well as in surgical approach. In our own series, we noted diagnostic delay resulting in neurological deficit in 16 of our patients. The surgical approach of C7 TB was better performed from the lower neck in our series (Fig. 31.13). In T1 spinal TB, our approach was periscapular one (Fig. 31.16). However, Horner Syndrome developed post-operatively in one patient who had periscapular approach, which gradually recovered over the subsequent 6 months.

31.12 Summary In recent years, since the discovery of antibiotics, treatment of spinal TB has been revolutionized. Several trials aimed at finding the best methods of treatment have been discussed. We also highlighted the use of antibiotics alone or in conjunction with surgical intervention in the management. Continuous debate among authors on the indications of surgery has been discussed. In our own experiences, we have noted the occurrence of unusual sites of spinal

a

Fig.31.27. a Lateral radiograph of the cervical spine in a 62-year-old man following a car accident shows fracture odontoid process with posterior displacement. Note increased prevertebral shadow (arrow). b Following traction, lateral radiograph demonstrates reduction of displacement and the retropharyngeal soft-tissue shadow (arrow). c Non-contrast computer tomographs demonstrate partial destruction of the occipital condyles and anterior arch of C1(thin arrow). Note fragments of bone that have been extruded into an anterior abscess (thick arrow). d, e T1 magnetic resonance imagine (MRI) indicates diminished signal of odontoid process and Cl while T2 MRI shows increased signal intensity with retropharyngeal abscess (arrowheads). f The post-gadolinium scan outlines the retropharyngeal, tuberculous abscess (arrow). Note degenerative lesion at C5-6. g Lateral radiography following aspiration of prevertebral abscess and posterior fixation of Cl-2

Surgical Management of Spinal Tuberculosis

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d

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a Fig. 31.28. a Lateral radiography of the cervical spine in a 15-year-old girl shows bifacetal dislocation C3-4 (arrow). There is extensive anterior, retropharyngeal tuberculous abscess displacing the airway forward (small arrows). b Post-operative lateral radiograph taken 4 months following two-stage operation demonstrates reduction of dislocation, fusion and fixation

involvement among our patients, such as posterior element, occipito-cervical and cervico-thoracic junctions. We also highlighted the diagnostic and surgical difficulties that we encountered during the management of these unusual cases. Surgical treatment of paraplegia and kyphosis were also discussed.

References Abramovitz IN, Batson RA, Yablon JS (1986) Vertebral osteomyelitis: the surgical management of neurologic complications. Spine 11:418-420 AI Arabi KM, Al Sebai MW (1991) Bifacetal dislocation following tuberculosis of the cervical spine. Tubercle 72: 294-298 AI Arabi KM, AI Sebai MW, AI Chakaki M (1992) Evaluation of radiological investigations in spinal tuberculosis. Int Orthop 16:165-167 Albee FH (1911) Transplantation of a portion of the tibia into the spine for Pott's disease: a preliminary report. JAMA 57: 885-886 AI Sebai MW et al (2001) Operative treatment of progressive deformity in spinal tuberculosis. Int Orthop 25:322-325 Altman GT, Altman DT, Frankovitch KF (1996) Anterior and posterior fusion for children with tuberculosis of the spine. Clin Orthop Relat Res 325:225-231 Arumagasamy N, Pyn CC, Keng KK (1977) Tuberculous abscesses of the cervical spine with quadriparesis. Surg Neurol 8:35-40 Bailey HL et al (1972) Tuberculosis of the spine in children. J Bone Joint Surg 54A:1633-1657 Boachie-Adjei 0, Squillante RG (1996) Tuberculosis of the spine. Orthop Clin North Am 27:95-103

Bradford DS, Daher XH (1986) Vascularized rib grafts for stabilization of Kyphosis. J Bone Joint Surg 68B:357-361 Bront ZM, Burke VD, Jeffrey RB (1983) CT in the evaluation of spine infection. Spine 8:358-364 Dobson J (1951) Tuberculosis of the spine. Analysis of the results of conservative treatment and of the factors influencing the prognosis. J Bone Joint Surg 33B:517-531 Fellander M (1975) Paraplegia in spondylitis: results of operative treatment. Paraplegia 13:75-88 Govender S, Parbhoo AH (1999) Support of the anterior column with allografts in tuberculosis of the spine. J Bone Joint Surg 81:106-109 Graziano GP, Sidhu KS (1993) Salvage reconstruction in acute and late sequelae from pyogenic thoracolumbar infection. J Spinal Discord 6:199-207 Gristina AG, Costerton JW (1985) Bacterial adherence and the glycocalyx and their role in musculoskeletal infection. Orthop Clin North Am 15:517-535 Gristina AG et al (1985) Bacterial adherence and the pathogenesis of osteomyelitis. Science 228:99-103 Gupta RK et al (1993) Ultrasound-guided needle biopsy oflytic lesions of the cervical spine. J Clin Ultrasound 21:194-197 Guven 0 et al (1994a) A single stage posterior approach and rigid fixation for preventing Kyphosis in the treatment of spinal tuberculosis. Spine 19:1039-1043 Guven 0, Yalcin S, Karahan M (1994b) Eggshell procedure in correction of neglected cases of Pott's Kyphosis. Proceedings of the 5th biannual conference of European Spinal Deformities Society. Birmingham, England. Springer, Berlin Heidelberg New York, pp 84-85 Hibbs RA (1911) An operation for progressive spinal deformities. NY State Med J 93:1013-1016 Hodgson AR, Stock FE (1956) Anterior spinal fusion: a preliminary communication on the radical treatment of Pott's disease and Pott's paraplegia. Br J Surg 44:266-275 Hodgson AR, Stock FE (1960) Anterior spinal fusion for the treatment of tuberculosis of the spine. J Bone Joint Surg 42A:295

Surgical Management of Spinal Tuberculosis Hodgson AR et al (1964) A clinical study of 100 consecutive cases of Pott's paraplegia. Clin Orthop 36: 128-150 Hsu LCS, Leong JCY (1984) Tuberculosis of the lower cervical spine (C2 t C7). J Bone Joint Surg 66B:I-5 Ito H, Tsuchiya J, Asami G (1934) A new radical operation for Pott's disease: report of then cases. J Bone Joint Surg 16: 499-515 Jain R, Sawhney S, Berry M (1993) Computed tomography of vertebral tuberculosis: patterns of bone destruction. Clin RadioI47:196-199 Jeanneret B, Magerl F (1994) Treatment of osteomyelitis of the spine using percutaneous suction/irrigation and percutaneous external spinal fixation. J Spinal Disord 7:185-205 Kang Met al (1999) CT guided fine needle aspiration biopsy of spinal lesions. Acta RadioI40:474-478 Kattapuram SV, Rosenthal DI (1987) Percutaneous biopsy of the cervical spine using CT guideance. AJR 149:539-541 Kemp HBS, Jackson JW, Shaw NC (1974) Laminectomy in paraplegia due to infective spondylitis. Br J Surg 61:66-72 Kirkaldy-Willis WH, Thomas TG (1965) Anterior approaches in the diagnosis and treatment of infections of the vertebral bodies. J Bone Joint Surg 47A:87-110 Kondo E, Yamada K (1937) End results of focal debridement in bone and joint tuberculosis and its indications. J Bone Joint Surg 39A:27 Konstam PG, Blesovsky A (1962) The ambulant treatment of spinal tuberculosis. Br J Surg 50:26-38 Konstam PG, Konstam ST (1958) Spinal tuberculosis in southern Nigeria: with special reference to ambulant treatment of thoraco-lumbar disease. J Bone Joint Surg 40B:26-32 Korkusuz F, Islam C, Korkusuz Z (1997) Prevention of postoperative late Kyphosis in Pott's disease by anterior decompression and intervertebral grafting. World J Surg 21:524-528 Kostuik JP (1983) Anterior spinal cord decompression of lesions of the thoracic and lumbar spine, techniques, new methods of internal fixation. Spine 8:512-531 Lee TC et al (1999) Transpedicular instrumentation as an adjunct in the treatment of thoracolumbar and lumbar spine tuberculosis with early stage bone destruction. J Neurosurg 91 [SuppI2]:163-169 Lifeso R (1987) Atlanto-axial tuberculosis in adults. J Bone Joint Surg 69(B):183-187 Lifeso RM, Weaver P, Harder EH (1985) Tuberculosis spondylitis in adults. J Bone Joint Surg 67A:1405-1413 Luk KD (1999) Tuberculosis of the spine in the new millennium. Eur Spine J 8:338-345 Martin NS (1970) Tuberculosis of the spine. A study of the results of treatment during the last twenty-five years. J Bone Joint Surg 52B:613-628 McGraham JP, Dublin AB (1985) Evaluation of spinal infection by plain radiographs, computed tomography, intrathecal metrizamide and CT guided biopsy. Diagn Imag Clin Med 54:11-20 Medical Research Council Working Party on Tuberculosis of the Spine, First Report (1973a) A controlled trial of ambulant out-patient treatment and in-patient rest in bed in the management of tuberculosis of the spine in young Korean patients on standard chemotherapy. A study in Masan, Korea. J Bone Joint Surg 55B:678-697 Medical Research Council Working Party on Tuberculosis of the Spine, Second Report (1 973b) A controlled trial of plaster of Paris jackets in the management of ambulant

533 outpatient treatment of tuberculosis of the spine in children on standard chemotherapy: a study in Pusan, Korea. Tubercle 54:261-282 Medical Research Council Working Party on Tuberculosis of the Spine, Third Report (1974a) A controlled trial of debridement and ambulatory treatment in the management of tuberculosis of the spine in patients on standard chemotherapy: a study in Bulawayo, Rhodesia. J Trop Med Hyg 77:72-92 Medical Research Council Working Party on Tuberculosis of the Spine, Fourth Report (1974b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: a study in Hong Kong. Br J Surg 61:853-866 Medical Research Council Working Party on Tuberculosis of the Spine, Fifth Report (1976) A five-year assessment of controlled trials in in-patient and out-patient treatment and plaster of Paris jackets for tuberculosis of the spine in children on standard chemotherapy. Studies in Masan and Pusan, Korea. J Bone Joint Surg 58B:399-411 Medical Research Council Working Party on Tuberculosis of the Spine, Sixth Report (1978a) Five year assessments of controlled trials of ambulatory treatment, debridement and anterior spinal fusion in the management of tuberculosis of the spine: studies in Vulawayo (Rhodesia) and in Hong Kong. J Bone Surg 60B:163-177 Medical Research Council Working Party on Tuberculosis of the Spine, Seventh Report (1978b) A controlled trial of anterior spinal fusion and debridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: a study in two centers in South Africa. Tubercle 59:79-105 Medical Research Council Working Party on Tuberculosis of the Spine, Eighth Report (1982) A 10 year assessment of a controlled trial comparing debridement and anterior spinal fusion in the management of tuberculosis of the spine in patients on standard chemotherapy in Hong Kong. J Bone Joint Surg 64B:393-398 Medical Research Council Working Party on Tuberculosis of the Spine, Ninth Report (1985) A 10 year assessment of controlled trials of inpatient and outpatient treatment and of plaster of Paris jackets for tuberculosis of the spine in children on standard chemotherapy: studies in Masan and Pusan, Korea. J Bone Joint Surg 6B:I03-110 Medical Research Council Working Party on Tuberculosis of the Spine, Tenth Report (1986) A controlled trial of six month and nine month regimens of chemotherapy in patients undergoing radical surgery for tuberculosis of the spine in Hong Kong. Tubercle 67:243-259 Medical Research Council Working Party on Tuberculosis of the Spine, Eleventh Report (1989) A comparison of 6 or 9 month course regime of chemotherapy in patients receiving ambulatory treatment or undergoing radical surgery for tuberculosis of the spine. Indian J Tuberc [Suppl] 36:1-21 Medical Research Council Working Party on Tuberculosis of the Spine. Thirteenth report (1998) A IS-year assessment of controlled trials of the management of tuberculosis of the spine in Korea and Hong Kong. J Bone Joint Surg 80B: 456-462 Medical Research Council Working Party on Tuberculosis of the Spine. Fourteenth Report (1999) Five-year assessment of controlled trials of short-course chemotherapy regimens of 6, 9 or 18 months duration for spinal tuberculosis

534 in patients ambulatory from the start or undergoing radical surgery. Int Orthop 23:73-81 Menard V (1894) Causes de paraplegie dans Ie mal de Pott. Son traitment Chirurgical Par l'ouverture directe de goyer tuberculeuse des vertebras. Rev Orthop 5:47-54 Moon MS (1991) Combined posterior instrumentation and anterior interbody fusion for active tuberculosis Kyphosis of the thoraxolumbar spine. Curr Orthop 5: 177-179 Moon MS (1997) Tuberculosis of the spine. Controversies and a new challenge. Spine 22:1791-1797 Moon MS et al (1987) Conservative treatment of tuberculosis of the thoracic and lumbar spine in adults and children. Int Orthop 11:315-322 Moon MS et al (1995) Posterior instrumentation and anterior interbody fusion for tuberculosis Kyphosis of dorsal and lumbar spines. Spine 20:1910-1916 Moon MS et al (1996) Pott's paraplegia - 67 cases. Clin Orthop Relat Res 323:122-128 Oga M et al (1993) Evaluation of the risk of instrumentation as a foreign body in spinal tuberculosis. Clinical and biologic study. Spine 18:1890-1894 Pertuiset E (1999) Medical therapy of bone and joint tuberculosis in 1998. Rev Rhumat 66:152-157 Pott P (1936) Remarks on that kind of palsy of the lower limb, which is frequently found to accompany a curvature of the Spine, and is supposed to be caused by it. Williams and Wilkins, Baltimore MD, pp 271-323 (Medical classics, vol I) Rahman N, Al Arabi KM, Khan FA (1987) Atypical forms of spinal tuberculosis. Acta Neuro Chir 88:26-33 Rand C, Smith MA (1989) Anterior spinal tuberculosis: paraplegia following laminectomy. Ann R Coli Surg Engl 71:105-109 Rath SA et al (1996) Neurosurgical management of thoracic and lumbar vertebral osteomyelitis and discitis in adults: a review of 43 consecutive surgically treated patients. Neurosurgery 38:926-933

M. W. Al Sebai et al. Redfern RM et al (1988) Stabilization of the infected spine. J Neurol Neurosurg Psychiatry 51:803-897 Rezai AR et al (1995) Modern management of spinal tuberculosis. Neurosurgery 36:87-97 Schulitz KP et al (1997) Growth changes of solidly fused Kyphotic block after surgery for tuberculosis. Comparison of four procedures. Spine 22:1150-1155 Seddon HJ (1934/1935) Pott's Paraplegia: prognosis and treatment. Br J Surg 22:769-799 Sharif HS et al (1993) Role of CT and MR imaging in the management of tuberculous spondylitis. Radiol Clin North Am 33:787-804 Smith IE et al (1996) Kyphosis secondary to tuberculosis osteomyelitis as a cause of ventilatory failure. Chest 110: 1105-1110 Tuli SM (1975) Results of treatment of spinal tuberculosis by "Middle-path" Regime. J Bone Joint Surg 57B:13-23 Tuli SM (1995) Severe Kyphotic deformity in tuberculosis of the spine. Int Orthop 19:327-331 Upadhyay SS et al (1993) 17-year prospective study of surgical management of spinal tuberculosis in children. Hong Kong operation compared with debridement surgery for short and long term outcome of deformity. Spine 18: 1704-1711 Upadhyay SS et al (1994) Surgical management of spinal tuberculosis in adults. Hong Kong operation compared with debridement surgery for short and long term outcome of deformity. Clin Orthop Relat Res 302:173-182 Wu SS et al (1996) Management of rigid post-traumatic Kyphosis. Spine 21:2260-2267 Yau AMC et al (1974) Tuberculous Kyphosis: correction with spinal osteotomy, halopelvic distraction, and anterior and posterior fusion. J Bone Joint Surg 56A:1419-1434 Yilmaz C et al (1999) Anterior instrumentation for the treatment of spinal tuberculosis. J Bone Joint Surg 81A: 1261-1267

32 Tuberculosis of the Central Nervous System M. ZUHEIR

AL-KAWI

by Hippocrates (460-377 B.C.). Aristotle (384-322 B.C.) observed that persons associated with a person affected 32.1 History 535 by"phthisis" may contract the disease, thereby alluding 32.2 Epidemiology 536 to the possibility of its contagious nature. 32.3 Microbiology 536 Avicenna (Ibn Sina, 980-1037) described the 32.4 Pathogenesis 536 cerebral involvement by hot or cold swelling (inflam32.5 Pathology 537 32.6 Clinical 538 mation). The latter is thought to represent chronic 32.6.1 Tuberculoma 538 meningitis (most likely tuberculous) that frequently 32.6.2 Tuberculous Spondylitis 538 led to death as he noted. 32.6.3 Tuberculous Meningitis 539 With the industrial revolution in Europe, a mas32.7 Complications 539 32.7.1 Hydrocephalus 539 sive population shift toward inner cities resulted 32.7.2 Vascular Complications 540 in crowding and created conditions that favored 32.7.3 Hyponatremia 540 the spread of infection. Consequently, TB became a 32.7.4 Cranial Neuropathies 540 major cause of death between the late 17th and early 32.7.5 Seizures 541 20th centuries. Schoenlein (1793-1864) coined the 32.7.6 Tuberculous Encephalopathy 541 32.7.7 Adhesive Arachnoiditis 541 term tuberculosis to highlight the gross pathological 32.7.8 Myelopathy 541 appearance of small lumps caused by granulomata 32.8 Diagnosis 541 and the word "phthisis" fell into disfavor. Laennec 32.9 Management 543 (1781-1826), who was credited with the invention of 32.10 Prognosis 543 the stethoscope, described in detail the auscultative References 544 findings in pulmonary TB. Following on the research done by Villemin (1827-1892) to show that TB was transmissible, Koch 32.1 (1843-1910) described the necessary postulates for the History proof of a contagious nature of any illness. The conditions he described were widely accepted as classical Tuberculosis (TB) has affected humans since antiq- teachings and were as follows: finding the pathogen uity. References to what is believed to be tuberculous in every lesion in the body, being able to culture the infection were made in some writings from ancient pathogen outside the patient's body and reproducing Egypt and Babylon. Typical spine deformity of Pott's the disease by inoculation into animals. By applying the disease appear in numerous drawings of hunchbacks aforementioned postulates to TB he was able to estabon the walls of ancient Egyptian tombs. By morbid lish the infectious nature of the Bacillus tuberculosis. anatomy, spinal TB can be traced back to about The glory of his discovery, however, was tarnished by 2000 B.C., as was shown by psoas abscess found in the tuberculin blunder. He touted a prepared glycerin extract of the bacillus as a secret cure for TB. In fact, the a mummy. Microscopically, Zimmerman demonstrated the extract injected in large quantities to patients with TB tuberculous bacillus in a mummy of a child (Cave 1939; did cause many deaths. By the turn of the last century, Zimmerman 1979). Symptoms of TB were recognized Osler noted that in 1911, "in a population of one million, seventeen hundred persons died from TB" (Osler 1921). At the Pasteur Institute, Calmette and Guerin M. z. AL-KAWI, MD, FACP Senior Consultant Neurologist & Deputy Chairman, Depart- (1921) produced a live vaccine prepared by successive ment of Neurosciences, King Faisal Specialist Hospital and subculturing of a strain of mycobacterium bovis. This Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia was what came to be known later as BeG vaccine.

CONTENTS

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Until the middle of the last century, treatment remained generally supportive-aimed at boosting the innate defenses of the body to overcome the infection. It was not until 1943that specific treatment against the causative organism was started. Chemotherapy began in earnest with the advent of streptomycin followed by PAS in 1946 and then isoniazid (INH) in 1951; the latter heralded the era of modern effective anti-tuberculous chemotherapy.

32.2 Epidemiology It is estimated that one billion people are infected with M. tuberculosis worldwide. Active TB claims nearly 8 million new victims each year (Barnes and Barrows 1993) Among them, 15% will develop extrapulmonary infection and 6% of that is meningeal (Kochi 1991). Therefore, we can estimate that there are approximately 70,000 new victims of TB meningitis per annum. Most initial infections with M. tuberculosis remain clinically silent. The lifetime risk of developing a clinical case of TB after an initial silent infection has been estimated at 10%. TB of the central nervous system (CNS) is the most serious form of extrapulmonary TB, and about 10% of immuno-competent patients who develop clinical TB manifest CNS involvement (Udani et al. 1971). TB of the CNS has a higher incidence in children with no particular gender preponderance. Prior to the acquired immune deficiency syndrome (AIDS) epidemic, good steps were made in the prevention and treatment of TB and its CNS complications. In a review of a large number of autopsies done in Germany from 1955 to 1969, there was a statistically significant decrease in frequency of TB meningitis to about 1/7 when compared with the data from 1924 to 1938. This difference was attributed to the BCG vaccination and to the effective anti-tuberculous medications (Weigel 1976). In spite of the advances made in the fight against infectious diseases, the overall prevalence of TB is again on the increase worldwide. The AIDS epidemic created circumstances favoring the spread of TB both in the developing and developed countries alike. Extrapulmonary TB is considered an AIDS-defining condition. The likelihood of contracting clinical TB is much higher in the AIDS population (Selwyn et al' 1992). The proportion of AIDS patients who develop TB is estimated at 5-9% (Sanchez-Portocarrero et al. 1999). The importance of this observation

is highlighted by the fact that TB in a human immunodeficiency virus (HIV)-infected patient may present as an overwhelming systemic disease (Gachot et al. 1990). CNS TB may be the initial presentation of AIDS and has a high mortality among such affected individuals. Tuberculous meningitis is the most frequent meningeal infection in the HIV patients living in areas with high prevalence of TB (Berenguer et al. 1992). Infection with HIV may increase the risk of developing TB meningitis five-fold from 2% of patients to 10% (Tagliati et al.I994). Another growing at-risk population is the medically compromised patients with systemic diseases or organ failure who are kept alive with modern management techniques.

32.3 Microbiology The predominant organism in human infections is M. tuberculosis. The organism M. tuberculosis is considered a gram-positive bacterium, though it is difficult to stain by the standard method. Its growth is very slow in culture, which clinically correlates with the slow infection it causes in vivo. Similarly, a long treatment course with anti-tuberculous medications is necessary to eradicate infection and to insure nonresurgence. The genome of M. tuberculosis has been sequenced and it includes approximately 4000 genes in a circular chromosome consisting of over 4 million base pairs (Cole et al. 1998).

32.4 Pathogenesis The microorganism reaches the CNS in the course of dissemination following a primary infection. Entry into the host is most frequently airborne. The fung tissue is infected first along with a regional lymph node. Several factors determine the clinical picture and outcome of CNS TB. These include age, nutritional status, load and virulence of infecting organism, immune deficiency and prior immunization with BCG. The density of bacilli in a unit volume of inspired air is dependent on severity of disease in the infecting person and the effectiveness of air circulation in the environment. The longer the exposure to contaminated air, the more likely the infection is to take place. Acid-fast bacilli do not produce toxins, therefore, they cause no initial tissue reaction or

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inflammation if the host has not been sensitized to tuberculoproteins (non-immune host). Primary hematogenous dissemination usually occurs in childhood and is clinically silent. Proliferation of M. tuberculosis favors foci with high blood flow and oxygenation. Vertebral column and lung apices are common sites. Positive tuberculin test signals establishment of cell-mediated immunity that commonly appears within 2 months. Granulomas may lead to healing-albeit incomplete-of the infected foci or lead to tissue destruction. Persons with impaired cellmediated immunity due to HIV infection or other diseases are more likely to become infected with M. tuberculosis after exposure than persons with normal immunity. Intact cell-mediated immunity decreases the chances of dissemination. Lymphocytopenia of (CD4+) T-lymphocytes was reported in TB patients who were seronegative for HIV (Kony et al. 2000) Cell mediated immunity plays an important role in both the host defense against TB and the tissue destruction that characteristically occurs with the infection. Tuberculoproteins activate T-lymphocytes, which produce cytokines that, in turn, activate macrophages. Macrophages not only perform a bactericidal role, but precipitate tissue destruction as well (Crowle et al. 1983). The production of the free radical nitric oxide is central in this process as it is a vasodilator, inflammatory mediator and cytotoxic (Anggard 1994). Tumor necrosis factor alpha (TNF a) appears to playa significant role in the host defense against TB and in the production of systemic symptoms such as weight loss and fever (Takashima et al. 1990). Recent experience with infliximab, a TNF-a-neutralizing agent developed for the treatment of rheumatoid arthritis and Crohn's disease, caused dissemination of latent tuberculous infection. This highlighted the role ofTNF-a in the host defense against tuberculous infection (Keane et al. 2001). The meninges are infected by organisms carried in the bloodstream. Primary hematogenous dissemination occurs early after primary infection, while rupture of a subpial or subependymal granuloma (Rich focus) may occur any time later in life. Recently the serum and cerebrospinal fluid (CSF) levels of vascular endothelial growth factor were found to be higher in tuberculous meningitis and they decreased in parallel with the clinical improvement (Matsuyama et al. 2001). The complexity of factors and varied methodologies are responsible, in part, for the variability of features of CNS infection reported from different centers. In a series from Riyadh; meningitis consti-

tuted 28% of cases, mass lesions 36% and neurological sequelae of spinal TB 36% (Bahemuka et al.1988), while in a pediatric population from London; meningitis constituted 60%, tuberculomas in 13% and mixed meningitis/tuberculoma in 26%. Vaccination with BCG was shown to protect against tuberculous meningitis (Awasthi and Moin 1999) and to modify the outcome whereby death and severe sequelae are avoided (Farinha et al. 2000).

32.5 Pathology Tuberculomas are granulomatous masses of variable sizes. They develop as the body's immune system attempts to contain a focus of M. tuberculosis. Macrophages induced by T-lymphocytes engulf the bacilli and form giant cells. Caseous material may appear at the center and typically contains a few bacilli. Gliosis and lymphocytic infiltration surround such foci. A variable amount of edema can be demonstrated by imaging studies. Tuberculomas are most frequently seen intraparenchymal but flat granulomas may grow on the meninges and have been called tuberculomas en-plaque (Fig. 32.1a). Tuberculous abscess of the brain is uncommon. It represents failure of the immune mechanism described above and consequently contains a high count of bacilli. It is suspected on imaging studies when an intensely enhancing thin wall surrounds a content that displays imaging characteristics of liquefaction. In tuberculous meningitis, the infection develops at a relatively rapid pace inside the subarachnoid spaces as opposed to the slower rate of progression in other organs. The basilar inflammation produces thick gelatinous exudates, which entrap the cranial nerves as they pass through the cisterns. The third, fourth, sixth and eighth cranial nerves are involved most frequently. Similarly, inflammation may induce tuberculous endarteritis. Penetrating branches of the anterior, middle, and posterior cerebral arteries are most commonly involved. Those include anterior choroidal, medial and lateral lenticulo-striate, thalamogeniculate and thalamoperforating arteries. Major arteries can also be thrombosed, causing massive infarctions. Granulomas surrounding blood vessels at the base of the brain may give a characteristic appearance on contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) that is grape-cluster like.

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Pathological features were noted to be different in the HIV patients with tuberculous meningitis since they show reduced and atypical inflammatory response and extensive vasculopathy. The radiological correlate of this finding was the relatively less meningeal enhancement and the absence of communicating hydrocephalus on CT scan (Katrak et al. 2000).

32.6

Clinical The CNS may be directly compromised by inflammation, mass lesion or infarction or it may be affected by compression from collapsing supportive structures (i.e., spine). In the first instance, the patient may develop meningitis, parenchymal mass lesion (tuberculoma or abscess) or a combination thereof. In the latter instance, spinal cord compression may occur as a consequence of vertebral destructive infection and epidural cold abscess (Pott's disease of the spine). In order of severity, the combination of meningeal-parenchymal type ranks the highest, followed by meningitis. The majority of patients present in a sick state within a few weeks of infection. Cerebral or medullary tuberculomas and spinal TB are rather chronic smoldering infections with significant late complications.

32.6.1 Tuberculoma Tuberculomas are slow-growing inflammatory mass lesions which may be associated with variable perifocal edema. Lesions are mostly intraparenchymal. Any part of the CNS may be involved but it is more common in the cerebral hemispheres, a distribution that is probably proportional to the parenchymal volume. Tuberculoma may rarely be encountered in the spinal cord (intramedullary). Spinal cord tuberculoma may be the only significant manifestation of TB. Spinal or radicular pain and progressive weakness are the usual presenting symptoms. Correct diagnosis is possible in the presence of TB elsewhere. Intramedullary neoplasm is usually suspected before the correct diagnosis is reached (Kocen and Parsons 1970). Imaging studies show a fusiform swelling of the cord along with a central area of iso- or slight hyperintensity on T1WI, surrounded by edema that is typically hyper-intense on T2WI.

Intrasellar tuberculomas are rare and constituted less than 2% of all intrasellar masses in some series. They have female predominance and swelling of the pituitary stalk is a useful sign (Sharma et al. 2000).

32.6.2 Tuberculous Spondylitis Vertebrae are the most commonly involved part of the skeletal system. Approximately half of tuberculous infections of the skeletal system are localized to the spine. During the initial hematogenous dissemination of M. tuberculosis, small foci of infection settle in the skeletal system to be reactivated at a later stage. The infection may as well spread from an adjacent infected lymph node. Any part of the vertebral column may be affected, but over half of the patients develop involvement of the thoracic spine, especially the lower part (Alothman et al. 2001). Back pain usually precedes neurological manifestations. Tuberculous spondylitis frequently presents as progressive paraplegia. Early disease recognition may be hampered by late presentation in the endemic area or by unfamiliarity with the early symptoms in developed parts of the world. This discrepancy is responsible in part for the variability in the reported frequency of neurological complications in tuberculous spondylitis. By the time the patient presents for medical help a few vertebrae have already been damaged. The vertebral body adjacent to the disk space forms the initial lesion. Infection of the intervertebral disk soon follows. Typically, two or more adjacent vertebrae are destroyed with formation of granulomas or cold abscess in the surrounding paraspinal soft tissues. The dura is a strong barrier to the spread of infection into the CNS or development of meningitis. The cord is compressed by the epidural abscess. Pain is an early symptom caused by local inflammation. Root irritation gives a radicular distribution of pain around the trunk. Spinal pain may be dull and localized over the involved vertebrae. It is protracted with fluctuations in severity. Movement induces painful spasms, and to prevent them patients may avoid movements and become stiff. Neurological manifestations range from flaccid paraparesis in cases of cauda equina compression to spastic quadriplegia in cervical lesions. Pyramidal tract signs usually precede sensory and sphincter involvement. Rarely a sinus tract may drain to the skin. The paraspinal abscess may be noted clinically in the cervical or retropharyngeal region or can be demonstrated on spinal radiograph. Systemic symp-

Tuberculosis of the Central Nervous System

toms are similar to tuberculous infection in other parts of the body. These include low-grade fever, anorexia, weight loss, anemia, lassitude and night sweats. The long duration of symptoms, the development of typical gibbus, thoracic spine involvement and elevated erythrocyte sedimentation rate are suggestive of Pott's disease as opposed to spinal epidural infection or neoplastic conditions (Alothman et al. 2001; Buranapanitkit et al. 2001). The diagnosis is suggested by imaging, including plain radiographs of the spine, CT and MRI. The diagnosis is confirmed by obtaining a tissue sample by fine needle aspiration. The treatment is essentially medical. Surgical intervention can be avoided in many cases (Alothman et al. 2001). We noted good results with proper antituberculous treatment even in the face of neurological involvement. In the presence of significant spondylitis and compression, spinal decompression may be required. Removal of pus or granulation tissue through a laminectomy is sufficient when spondylitis is mild (Curling et al.1990). Epidural tuberculous infection is not unique to spinal TB. Disseminated infection may, on rare occasions, affect cranial epidural space and result in cerebral symptoms.

Illustrative case: a 24-year-old lady presented with focal seizures on the left side with secondary generalization. She had a past history of fever and night sweats. Chest films were suggestive of miliary appearance. CT of the head showed an enhancing lesion in the right frontal epidural space (Fig. 32.1a). The material recovered from the lesion after trephine procedure was caseous with a lot of acid-fast bacilli consistent with tuberculous abscess. The patient was treated with triple anti-tuberculous medications. She completed a 6-month course of therapy and remained seizure free after anti-epileptic drugs were discontinued.

32.6.3 Tuberculous Meningitis Fever, headache, lethargy and altered mentation are the most frequent presenting symptoms. Anorexia, night sweats and stiff neck may occur earlier. It is not uncommon for symptoms to be present for an average of 6 weeks before the person seeks medical attention. Approximately 50% of patients have meningeal signs early, while focal signs are seen in up to 20% (Berenguer et al. 1992). Past history of

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pulmonary TB is not an absolute necessity since less than 50% of adults with tuberculous meningitis give such a history. The spread of infection to the subarachnoid spaces results in diffuse meningitis that may rapidly become complicated by vasculitis, cranial nerve palsies, encephalitis or myelitis. Cranial neuropathies may appear at any time during the course of infection but are usually late. Optic, oculomotor and acoustic are most common. Some types of movement disorder may appear during tuberculous meningitis. Tremor is the most common, while chorea is mainly seen in young children. It is believed that deep infarcts are responsible for such manifestations (Alarcon et al. 2000).

32.7 Complications 32.7.1 Hydrocephalus Hydrocephalus is a common complication of tuberculous meningitis. It may occur early or late in the course of illness. Worsening headache and deteriorating level of consciousness are the main symptoms. Adhesive ependymitis may sequester a part of the ventricular system (usually temporal) and cause a localized hydrocephalus with mass effect that can lead to herniation. Imaging studies are necessary for any sudden change in the condition of the patient and hydrocephalus can be easily recognized. Diversion of CSF flow is necessary and usually done by ventriculoperitoneal shunting.

Illustrative case: a 37-year-old man presented with headache, vomiting and low-grade fever for 2 weeks. His examination showed lethargy and nuchal rigidity. Brain CT showed enhancement at the basal cisterns but no mass lesions or hydrocephalus. Lumbar puncture yielded a slightly xanthochromic fluid with protein of 1200 mg/l, sugar 1.8 mmolll and 329 WBC/ mm 3• Few acid-fast bacilli were seen on smear. He improved after treatment with rifampin, isoniazid, pyridoxine and pyrazinamide. He was discharged home after 2 weeks and was compliant with treatment. He returned to the emergency room 4 weeks after discharge, complaining of severe headache and vomiting. He was afebrile but pupils showed right pupil measuring 5 mm and left pupil 3 mm. Fundoscopic exam showed papilledema. On CT examina-

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b

a Fig. 32.1a, b. a Tuberculoma en-plaque in the frontal region. T1 WI with enhancement, sagittal section b CT showing right temporal horn hydrocephalus. Sequestration of the temporal horn occured in the course of TB meningitis

tion there was a large hypodense mass lesion in the right temporal lobe with density compatible with CSF with transependymal edema in the temporal white matter (Fig. 32.1b). A ventriculoperitoneal shunt was placed in the right temporal horn and fluid under high pressure was released. The patient improved following surgery and completed 9 months of anti-tuberculous treatment.

32.7.2 Vascular Complications Arteries that supply the brain emerge in the basal cisterns. The same area that bears the brunt of inflammation in tuberculous meningitis. The walls of vessels immersed in the thick gelatinous exudate are affected by inflammation and arteritis may lead to vascular occlusion or thrombosis. Less commonly, but more seriously, intraparenchymal hemorrhage may occur.

may be lowered by hyponatremia and occurrence of seizures may be enhanced by low serum sodium. Extremely low levels. especially when the concentration decreases rapidly, may lead to encephalopathy. Attention to electrolyte balance is imperative during treatment.

32.7.4 Cranial Neuropathies

Optic: Obstruction of CSF pathways occurring in tuberculous meningitis may result in increased intracranial pressure and papilledema. Ultimately, damage to the optic nerve occurs by ischemia. Direct involvement of the optic nerve or the chiasm may be due to arachnoiditis and chronic granulomatous inflammation (Bruetsch 1948). Oculomotor Palsies: similarly, oculomotor nerve may be involved by microvascular thrombosis or by raised intracranial pressure. Ocular movements and pupillary reaction may be impaired. Ocular signs may develop independently of the level of consciousness.

32.7.3 Hyponatremia

Deafness: Sensorineural hearing loss is a common

Hyponatremia is common in tuberculous meningitis. It is attributed to inappropriate anti-diuretic hormone secretion (Singh et al. 1994). Seizure threshold

complication of meningitis in general and tuberculous meningitis in particular. The use of ototoxic drugs may contribute to this morbidity. It is unlikely to find evidence of labyrinthitis ossificans on CT of

Tuberculosis of the Central Nervous System

temporal bones in people suffering of hearing loss as a sequel of tuberculous meningitis.

32.7.5 Seizures Seizures are common presenting symptoms in cerebral tuberculomas. They occur later in tuberculous meningitis and may be associated with a worse prognosis. Rarely it may be the presenting manifestation of an extraparenchymal lesion such as an epidural TB abscess (Fig. 32.1a). They need to be treated by a suitable anti-epileptic drug, keeping in mind the interaction with anti-tuberculous chemotherapy and the side effects on liver functions.

32.7.6 Tuberculous Encephalopathy This complication was considered an allergic type-IV hypersensitivity occurring in the CNS as a reaction to tuberculous infection. It presents with an encephalopathic picture of drowsiness rapidly progressing to coma and death within weeks. There is mild CSF inflammatory changes and diffuse brain edema. Pathologically there is demyelination and perivascular inflammation (Dastur and Udani 1966). It is of interest that pulmonary TB without direct CNS infection was reported to be associated with neuromyelitis optica syndrome. This was believed to represent another remote immune-mediated complication as well (Silber et al. 1990).

32.7.7 Adhesive Arachnoiditis The thick inflammatory exudate at the base of the brain and around the cord may cause adhesions that compromise blood circulation to adjacent structures, resulting in loculation or block of CSF flow or causing entrapment of nerve roots. Symptoms of cranial nerve dysfunction, myelopathy or radiculopathy may occur.

32.7.8 Myelopathy Ischemia due to arteritis in the cord vasculature is probably the major cause of myelopathy. The result-

541

ing disability is therefore frequently permanent. The development of intramedullary granuloma is less common and may have a better outcome with treatment. Extramedullary mass effect in spinal tuberculous meningitis (Fig 3.1) or a loculated CSF pocket may cause pressure leading to myelopathy.

32.8 Diagnosis As with many other diagnoses, a proper degree of clinical suspicion is necessary. This can be easily achieved in areas of the world with high prevalence of TE. In the developed countries, however, a similar high index of suspicion should be adopted when the patient belongs to a population group susceptible to HIV or already seropositive for HIV. Other indicators for tuberculous infection include history of TB in a family member or contact with a person known to have open pulmonary TE. A positive Mantoux intradermal skin tuberculin test may be helpful but has inadequate sensitivity and specificity. It may be positive in a high proportion of adult population in endemic regions. However, severe infection may be associated with skin anergy and negative test in the presence of disseminated tuberculous infection. The diagnosis is usually based on four sources of evidence: the clinical manifestations, cerebrospinal fluid examination in combination with CT scan of the head, and evidence of TB elsewhere in the patient's systems. Evidence for TB elsewhere is helpful but its absence does not rule out the diagnosis. It should be looked for on chest film. The chance of finding a lesion on a routine chest radiograph has been reported with wide variability in the literature. Hilar lymphadenopathy, primary complex or miliary TB may be strongly suggestive but the latter may be missed if not particularly sought. Chest CT is more sensitive and should be performed in suspected cases. Considering the pathogenesis of CNS TB, the same hematogenous spread of infection should deliver the organism in the vascular choroid layer of the eye. The presence of choroid tubercle, however, is infrequently reported. This may reflect the difficulty in examining the peripheral regions of the fundus in a sick patient. When present, a choroidal tubercle is characteristic and appears as a small slightly raised rounded pale yellowish lesion with indistinct margins. Imaging of tuberculous meningitis usually shows significant enhancement in the basal cisterns. CT or MRI scan usually reveals basilar enhancement

542

assumed to correlate with the intensity of the inflammation and the thickness of the exudates (Fig. 2.1). The parenchyma shows evidence of deep cerebral infarctions commonly in the distribution of the thalamoperforating and lenticulostriate arteries (Fig. 2.3). Stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal segments of its branches, the anterior cerebral and middle arteries, may be identified on cerebral angiogram (Fig. 2.6). It is not unusual to find ischemic areas in addition to parenchymal inflammatory lesions (tuberculomas). Examination of CSF obtained by lumbar puncture is the definitive test for diagnosis of tuberculous meningitis. When the risk of herniation during lumbar puncture is a concern in patients with increased intracranial pressure, puncture may be performed with a small gauge needle to retrieve a small amount of CSF for essential diagnostic tests after the patient is prepared by the administration of intravenous mannitol 20% (0.25-0.5 g/kg) over 30 min. The findings of increased opening pressure, lymphocytic pleocytosis (usually in the range of 10-500 cells/mm\ high protein content and low glucose levels are typical but not universal. Early in the course of infection, there might be polymorphonuclear predominance. CSF glucose is usually low in tuberculous meningitis. Mean glucose values range from 22-38 mg per 100 ml, but 12-15% of patients may have normal glucose. Glucose should always be examined simultaneously in the blood and CSF. Failure to check the blood level may be a source of error when diabetes masks hypoglycorrhachia or iatrogenic hyperglycemia occurs in patients receiving dextrose intravenously. Glucose in the CSF falls below 40% of that in the serum. The low glucose may not be only because of consumption by organisms or white blood cells as had been considered in the past, but the inflammatory reaction may cause a disturbance in the CSF glucose transport system. Protein levels are extremely variable and may be influenced by the intensity of inflammatory reaction, but more importantly by the presence of block due to adhesive arachnoiditis. When protein levels exceed 1 gm/l00 ml, xanthochromia appears and the fluid may form a pellicle on the top or may clot altogether. Identifying acid-fast bacilli in the smear is an irrefutable evidence of tuberculous meningitis. Examining the pellicle stained for acid-fast bacilli may prove to be a richer diagnostic source than the fluid itself. Alternatively, the last tube of lumbar puncture specimen is the best tube to recover acid-fast bacilli on a smear. Positive smears in adults range from 10% to

M. Z. Al-Kawi

40% of cases of tuberculous meningitis. The sensitivity of the smear can be augmented by centrifugation of a larger specimen volume and by intensive examination. It was shown to be directly related to the diligence of the technologist performing the test and to the time spent on the microscope. Culture of M. tuberculosis from a CSF specimen is the gold standard for the diagnosis of tuberculous meningitis. The proportion of positive examinations, however, is not high. Growth of acid-fast bacilli in cultures of CSF requires 4-6 weeks and is positive in approximately 75% of cases of tuberculous meningitis. Its value is therefore confirmatory. Similarly, IgG antibody against M. tuberculosis in spinal fluid has been looked for by enzyme-linked immunosorbent assay (Kalish et al. 1983) but it is currently less often used. The time it takes for intrathecal synthesis of antibody renders the test insensitive in the early stages when the diagnosis is most needed. Recent advances in polymerase chain reaction (PCR) technology methods have shown a faster diagnostic yield. It has a reported sensitivity of 50%, and a 10% falsepositive rate (Lin et al. 1995). However, PCR confirmation of tuberculous meningitis faces difficulties because of inconsistent standards (Macher and Goosby 1995). Currently, the use of PCR to diagnose tuberculous meningitis from CSF specimen cannot be a routine practice because of its unreliability in detecting and confirming correctly the presence of M. tuberculosis. Diagnosis in patients with HIV infection is often delayed. Factors suggestive of tuberculous meningitis include endemicity of TB in the community, the presence of pulmonary TB, and hypoglycorrhachia (Theuer et al. 1990). Tuberculomas manifest as enhancing mass lesions, the usual triad of lesions which show no vascular blush if cerebral angiography is performed and are associated with signs that are less than would normally be expected for the size and location of the lesion. Biopsy is frequently necessary but a surgical procedure on the CNS can be avoided (see management of tuberculoma below). Since CNS TB is usually secondary to tuberculous infection elsewhere, search for an accessible tissue for biopsy and culture (Le., cervical or mediastinal lymph node) should be considered. Stereotactic brain biopsy is often the only certain method for diagnosing mass lesions in HIVinfected patients. Spinal TB recognition on imaging studies is discussed in the chapter on imaging in this book. Fine needle aspiration biopsy is a quick and reliable way for obtaining pathological specimen for microscopic

543

Tuberculosis of the Central Nervous System

examination and bacteriological confirmation of spinal TB. It can be done under radiological guidance (CT or fluoroscopy) with little morbidity and a high diagnostic yield, thereby avoiding more invasive diagnostic procedures. Material obtained is also helpful for culture and sensitivity. This allows immediate initiation of appropriate treatment, and decreases hospitalization time (Francis et al. 1999).

32.9 Management The treatment of CNS TB is more problematic than treatment of pulmonary TB. To be effective, the drugs have to cross the blood-brain or the blood-CSF barriers in adequate concentrations. Treatment of tuberculous meningitis should be initiated with a regimen of at least three drugs. Selection of drugs takes into account their ability to achieve an effective concentration across the blood-brain or the blood-CSF barriers. Compliance needs to be assured and that may necessitate supervised intake in some instances. First line drugs include isoniazid, pyrazinamide and rifampin. Ethambutol or streptomycin may be added in the first 2 months, especially if drug resistance to M. tuberculosis is suggested by knowledge about local incidence or prior treatment (Raviglione and O'Brien 1997). In a study of 150 CSF cultures from Egypt, 10% were resistant to isoniazid, 7% to ethambutol and 3% to rifampin while none showed multi-drug resistance (Girgis et al. 1998). Duration of treatment may extend from 9 months to 2 years depending on the patient's response. Blood tests may show a mild to moderate rise in liver enzymes during the early phase of therapy. This should not by itself constitute an indication for interruption of treatment, unless a serious liver dysfunction is suggested by a significant persistent rise in the enzymes or the development of jaundice. Peripheral neuropathy may develop in patients treated with INH for TB, particularly when pyridoxine is not supplemented. Second-line drugs include: ciprofioxacin, amikacin, kanamycin, cycloserine, rifabutin and clofazimine. The use of corticosteroids is controversial but is believed to improve outcomes in patients with tuberculous meningitis who are HIV negative (Kent et al. 1993). Indications for the use of glucocorticoids have included severe disease, increased intracranial pressure, mass effect from associated tuberculomas,

deterioration following the institution of antituberculous therapy, and spinal block. The rationale for use of corticosteroids is to attempt to reduce the inflammatory response through its potential effects on cytokines, chemokines, and matrix metalloproteinases, and on inhibiting cell recruitment and the synthesis of prostaglandins and leukotriene (Coyle 1999; Dooley et al. 1997). When tuberculoma is suspected and the patient's condition allows a watchful waiting, then a therapeutic trial may spare the patient an invasive diagnostic intervention (i.e., CNS biopsy). Our approach is to start the patient on triple or quadruple anti-tuberculous first line medications and to avoid the use of corticosteroids during the trial period. Corticosteroids may confuse the results of a therapeutic trial by its nonspecific anti-inflammatory effects or by its ability to make lymphoma deposits vanish. After 3 weeks of triple therapy, imaging should be repeated. If the mass lesion increases a biopsy is indicated. If the lesion decreases or remains the same the trial should be continued for an additional 3 weeks. The average time for early visible decrease in the size of a tuberculoma responding to the therapeutic trial is 6-8 weeks. Follow-up imaging in 6 weeks helps in deciding to have a biopsy if no improvement is noted. Treatment is continued if improvement is noted. If the diagnosis is secured early, corticosteroids may be used to ameliorate edema and reduce intracranial pressure. In rare occasions, paradoxical enlargement of lesions occurs during the first weeks of therapy. Corticosteroids may be used to suppress such a "paradoxical response" although their effectiveness is not proven. Initial therapy for most patients with HIV and TB in the CNS should consist of a four-drug regimen because of the possibility of drug-resistant TB. Rifampin-based or rifabutin-based drugs should be administered. Compliance is necessary in the treatment of TB in any host, but more so in patients with HIV infection. Special attention should be paid to interactions between anti-tuberculous medications and anti-retroviral drugs.

32.10 Prognosis Prognosis in tuberculous meningitis correlates with the duration of illness before hospitalization, clinical stage on admission and the presence or absence of hydrocephalus.

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The British Medical Research Council suggested classifying the severity of meningitis into three stages: in stage I are patients who are fully conscious, rational, and do not have focal neurological signs. Stage II patients are confused or have focal neurological signs such as hemiparesis or cranial nerve palsy. Stage III patients are stuporous or comatose. This classification may have some management and prognostic implications. The higher the stage, the worse the prognosis. In a study from India, multivariate analysis identified focal weakness, low score on Glasgow coma scale and abnormalities in somatosensory evoked potential as predictors of poor outcome (Misra et al. 2000). Pediatric patients may have significant sequelae especially if younger than 20 months or show evidence of infarction or hydrocephalus on imaging (Wallace et al. 1991). In patients infected with mv, illness lasting more than 2 weeks before admission and a CD4+ count of less than 200 per cubic millimeter predict poor prognosis (Berenguer et al. 1992). Depressed levels of consciousness and hemiplegia were associated with poor prognosis (Katrak et al. 2000). The presence of tuberculoma does not necessarily preclude a good long-term prognosis in properly treated HIVinfected patients (Malaskyand Reichman 1992). Tuberculous spondylitis has a better prognosis and effective treatment for a compliant patient can lead to resolution of a significant part of neurological manifestations.

References Alarcon F, Duenas G, Cevallos N et al (2000) Movement disorders in 30 patients with tuberculous meningitis. Mov Disord 15:561-569 Alothman A, Memish ZA, Awada A et al (2001) Tuberculous spondylitis: analysis of 69 cases from Saudi Arabia Spine 26:565-570 Anggard E (1994) Nitric oxide, mediator, murderer and medicine. Lancet 343:1199-1206 Awasthi S, Moin S (1999) Effectiveness of BCG vaccination against tuberculous meningitis. Indian Pediatr 36:455-460 Bahemuka M, Babiker MA, Wright SG et al (1988) The pattern of infection of the nervous system in Riyadh: a review of 121 cases. Q J Med 68:517-524 Barnes PF, Barrows SA (1993) Tuberculosis in the 1990 s. Ann Intern Med 119:400-410 Berenguer J, Moreno S, Laguna F et al (1992) Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 326:668 Bruetsch WL (1948) Etiology of optochiasmal arachnoiditis. Arch Neurol Psychiatry 59:215

M. Z. Al-Kawi Buranapanitkit B, Lim A, Kiriratnikom T (2001) Clinical manifestation of tuberculous and pyogenic spine infection. J Med Assoc Thai 11:1522-1526 Cave AJE (1939) The evidence for the incidence of tuberculosis in ancient Egypt. Br J Tuberc 30: 142 Cole ST, Brosch R, Parkhill J et al (1998) Deciphering the biology of Mycobacterium Tuberculosis from the complete genome sequence. Nature 393:537 Coyle PK (1999) Glucocorticoids in central nervous system bacterial infections. Arch Neurol 56:796-801 Crowle AJ, Douvas GS, May MH (1983) The cellular and molecular nature of human tuberculoimmunity. Bull Int Union Tuberc 58:72-80 Curling aD, Gower DJ, McWhorter JM (1990) Changing concepts in spinal epidural abscess: a report of 29 cases. Neurosurgery 27:185 Dastur DK, Udani PM (1966) Pathology and pathogenesis of tuberculous encephalopathy. Acta Neuropathol (Bed) 6: 311-326 Dooley DP, Carpenter JL, Rademachen S (1997) Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 25:872-887 Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM (2000) Tuberculosis of the central nervous system in children: a 20-year survey. J Infect 41 :61-68 Francis 1M, Das DK, Luthra UK et al (1999) Value of radiologically guided fine needle aspiration cytology (FNAC) in the diagnosis of spinal tuberculosis: a study of 29 cases. Cytopathology 10:390-401 Gachot B, Wolff M, Clair B et al (1990) Severe tuberculosis in patients with human immunodeficiency virus infection. Intensive Care Med 16:491-493 Girgis NI, Farid SZ, Mansour MM et al (1998) Tuberculous meningitis, Abbassia Fever Hospital ... 1976-1996. Am J Trop Hyg 58:28-34 Kalish SB, Radin RC, Levitz D et al (1983) The enzyme linked immunosorbent assay method for IgG antibody to purified protein derivative in cerebrospinal fluid of patirnts with tuberculous meningitis. Ann Intern Med 99:630-663 Katrak SM, Shembalkar PK, Bijwe SR et al (2000) The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 181:118-126 Keane T, Gershon S, Wise RP et al (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098-1104 Kent SJ, Crowe SM, Yung A et al (1993) Tuberculous meningitis: a 30-year review. Clin Infect Dis 17:987 Kocen RS, Parsons M (1970) Neurological complications of tuberculosis: some unusual manifestations. Q J Med 39:17 Kony SJ, Hane AA, Larouze B (2000) Tuberculosis-associated severe CD4+ T-lymphocytopenia in HIV-seronegative patients from Dakar. J Infect 41: 167-171 Lin JJ, Harn HJ, Hsu YD, Tsao WL et al (1995) Rapid diagnosis of tuberculous meningitis by polymerase chain reaction assay of cerebrospinal fluid. J NeuroI242:147-152 Macher A, Goosby E (1995) PCR and the misdiagnosis of active tuberculosis. N Engl J Med 332:128-129 Malasky C, Reichman LB (1992) Long-term follow-up of tuberculoma of the brain in an AIDS patient. Chest 101:278-279 Matsuyama W, Hashiguchi T, Umehara F et al (2001) Expression of vascular endothelial growth factor in tuberculous meningitis. J Neurol Sci 186:75-79

Tuberculosis of the Central Nervous System Misra UK, Kalita J, Roy AK et al (2000) Role of clinical, radiological, and neurophysiological changes in predicting the outcome of tuberculous meningitis: a multivariate analysis. J Neurol Neurosurg Psychiatry 68:300-303 Osler W (1921) The evolution of modern medicine. Yale University Press, New Haven, CT Raviglione MC, O'Brien RJ (1997) Tuberculosis. In: Fauci AS et al (eds) Harrison's principles of internal medicine, 14th edn. McGraw-Hill, New York, pp 1004-1014 Sanchez-Portocarrero J, Perez-Cecilia E, Romero-Vivas J (1999). Infection of the central nervous system by Mycobacterium tuberculosis in patients infected with human immunodeficiency virus (the new neurotuberculosis). Infection 27:313 Selwyn PA, Sckell BM,Alcabes P et al (1992) High risk of active tuberculosis in HIV-infected drug users with cuaneous anergy. JAMA 268:504 Sharma MC, Arora R, Mahapatra AK et al (2000) Intrasellar tuberculoma - an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 102:72-77 Silber MH, Willcox PA, Bowen RM (1990) Neuromyelitis optica (Devic's syndrome) and pulmonary tuberculosis. Neurology 40:934-938 Singh BS, Patwari AK, Deb M (1994) Serum sodium and

545 osmolal changes in tuberculous meningitis. Indian Pediatr 31:1345-1350 Tagliati M, Godbold J, Hassett J et al (1994) Neuromuscular disorders in HIV infection: cross-sectional cohort analysis of 250 patients. Neurology 44:A367 Takashima T, Ueta C, Tsuyuguchi I et al (1990) Production of tumor necrosis factor alpha by monocytes from patients with pulmonary tuberculosis. Infect Immun 58:3286-3292 Theuer CP, Hopewell PC, Elias D et al (1990) Human immunodeficiency virus infection in tuberculosis patients. J Infect Dis 162:8 Udani PM, Parekh UC, Dastur DK (1971) Neurological and related syndromes in CNS tuberculosis. Clinical features and pathogenesis. J Neurol Sci 14:341 Wallace RC, Burton EM, Barrett FF et al (1991) Intracranial tuberculosis in children: CT appearance and clinical outcome. Pediatr RadioI21:241-246 Weigel B (1976) Changes of the tuberculosis of the central nervous system since the introduction of prophylactic BCG vaccination and tuberculostatic therapy. Zentralbl Allg PathoI120:21-33 Zimmerman MR (1979) Pulmonary and osseous tuberculosis . in an Egyptian mummy. Bull NY Acad Med 55:604-608

33 Imaging of Brain and Spinal Cord Tuberculosis FRANCIS MCGUINESS

CONTENTS Brain and Spinal Cord Tuberculosis 547 Histopathology of Intracranial Tuberculosis 548 Tuberculous Meningitis (TBM) 548 Imaging Characteristics of TBM 550 Tuberculomas of TBM 554 Parenchymal Cerebral Tuberculosis 555 Parenchymal Tuberculomas 555 Imaging Characteristics of Tuberculomas 557 Paradoxical Response of Tuberculomas to Treatment 560 Late Stage Appearances of Tuberculomas 560 33.7.1 Tuberculous Brain Abscesses 561 33.8 Atypical Tuberculous Masses 561 33.9 Miliary Cerebral Tuberculomas 562 33.10 Tuberculosis of the Calvarium 33.11 with CNS Lesions 563 33.12 Tuberculous Otitis Media and Tuberculosis of the Temporal Bone 564 33.12.1 Imaging 565 33.13 Differential Diagnosis of TBM and Parenchymal Tuberculosis 565 33.14 Tuberculous Radiculomyelopathy and Myelitic Tuberculomas 570 Imaging Methods in Spinal 33.15 Neurotuberculosis 571 33.15.1 Plain Radiography 571 33.15.2 Water-Soluble Contrast Myelography (WSCM) 572 33.15.3 CT Combined with Water-Soluble Myelography 572 33.15.4 Magnetic Resonance Imaging 573 33.16 Differential Diagnosis 575 33.16.1 Spinal Arachnoiditis 575 33.16.2 Infective Leptomeningitis 576 33.16.3 Spinal Meningitis in Neoplastic Conditions 576 33.16.3.1 Meningeal Carcinomatosis 576 33.16.4 Fungal Diseases 579 33.16.5 Spirochetal Disease 580 33.16.6 Other Granulomatous Diseases 581 33.16.7 Parasitic Diseases 582 33.16.7.1 Schistosoma 582 33.16.8 Neurocysticercosis 582 33.16.8 Demyelinating Disease 582 33.16.8.1 Multiple Sclerosis 582 References 583

33.1 33.2 33.3 33.4 33.5 33.6 33.6.1 33.6.2 33.7

F. MCGUINESS Apt. 169, AI Haurin El Grande, 2912 Malaga, Spain

M. Monir Madkour et al. (eds.), Tuberculosis © Springer-Verlag Berlin Heidelberg 2004

33.1 Brain and Spinal Cord Tuberculosis Events during the past decade have dramatically changed the nature and magnitude of the problem of tuberculosis. Much of what many physicians learned in training about this disease is no longer true. In many respects tuberculosis has become a new entity. (Snider and Roper 1992) While taking into account the coinfection of AIDS and tuberculosis, the authors, Drs Snider and Roper, were also stressing the major global increase in tuberculosis infection that occurred in the 1980s. This epidemic led to the World Health Organisation (WHO) declaring a worldwide emergency in April 1993 and describing the spread of tuberculosis as a neglected health crisis. In its most recent report in 2000, WHO estimates that 1.9 billion persons are infected with the tubercle bacillus and have the potential to develop postprimary tuberculosis (TB). That is one third of the world's population (Pio and Chaulet 1998). Central nervous system tuberculosis can affect any of the elements of the neural tissues as well as their investing meninges. Jinkins estimates that between 2% and 5% of patients with active tuberculosis elsewhere in the body and up to 10% of those with the AIDS coinfection develop central nervous system lesions (Jinkins 1991; Kanamalla et al. 2000). The infection shows a predilection for the younger age groups, many patients being under the age of 5 years and the majority below the age of 30 (McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996). However, in the West there is an increase in the incidence of the disease in those over 60 years of age. The structure and reproductive properties of Mycobacterium tuberculosis are such that tuberculous infections develop insidiously. Mycobacterium tuberculosis var. hominis is the common causal agent of infection, although Mycobacterium tuberculosis var. bovis also causes a number of extrapulmonary infections.

F. McGuiness

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Both bacilli have a protective layer of phospholipids, phosphoglycolipids, and waxes, and are not detected by Gram stain. Ziehl-Neelsen stain and fluorescent staining methods reveal the organism, but in only a few cases is the bacillus found in the initial examination of cerebrospinal fluid (CSF). The slow reproductive time of 48 hours makes the organism difficult to culture, and means that clinical presentation and biochemical assessment are paramount to making the initial diagnosis of tuberculous meningitis (TBM), tuberculous meningomyelitis (TBSM), and tuberculoma (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000).

33.2 Histopathology of Intracranial Tuberculosis The manifestations of intracranial tuberculosis are diverse and are reflected in the imaging. In interpreting the images, an understanding of the underlying histopathology of the disease is helpful. Detailed descriptions of these changes are to be found in the literature (McGuinness 2000; Shah 2000; Dastur et al. 1995; Dastur 1972; Kirkpatrick 1991; Reid and Fallon 1992). A brief account of the major pathologic changes in central nervous system tuberculosis follows. Central nervous system tuberculosis is almost invariably the result of hematogenous spread of infection from a focus elsewhere in the body. In the majority of cases, the primary source of the disease is a focus of pulmonary or pulmonary-lymphatic tuberculosis. In infants and children, a primary pulmonary focus leading to local lymph node involvement or the development of progressive postprimary tuberculosis is the common cause of spread of the infection to the nervous system (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000). In older patients (from adolescence onwards), reactivation of pulmonary disease, or miliary tuberculosis is a common cause of hematogenous dissemination to the central nervous system. Dissemination from tuberculous foci in the gastrointestinal or genitourinary systems, or from foci in bones and joints, the paranasal sinuses, or the middle ear are less common occurrences (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000; Dastur et al.1995). Breakthrough of the infection from osteogenic tuberculous foci in the spine or the cranial vault is

less frequent, due to the protective nature of the dura mater. The dura mater, comprising two layers - the outer layer fused to the periosteum and the inner layer bound to it closely - forms a formidable barrier to the spread of infection across its boundary (McGuinness 2000; Shah 2000). Although the initial response of the body to tuberculous infection is a nonspecific inflammatory one, a cell-mediated immune response develops within 2 to 3 weeks. Further foci of tuberculous infection elicit the development of granulomata. Granulomatous tuberculous foci comprise central clumps of epitheliod cells and macrophages containing intracellular tubercle bacilli. The core is surrounded by fibroblasts and mononuclear inflammatory cells and often contains Langerhans giant cells (Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Dastur et al.1995). These foci were described by Rich in 1933 and bear his name (Rich and McCordock 1933; Rich 1944). There are two theories concerning the development of tuberculous lesions in the leptomeninges, the cerebrum, and myelum. The common theory is that Rich foci, resulting from hematologic spread, develop in the leptomeninges and rupture into the subarachnoid space. The cerebrospinal fluid has minimal protection against infection and the space and leptomeninges become widely infected (Kanamalla et al. 2000; McGuinness 2000; Dastur et al. 1995; Dastur 1972). A second theory is that the hematogenous spread to the capillary and venule walls in the leptomeninges and similar vessels penetrating the cerebrum and myelum, causes inflammatory breakdown of the vessel walls and of the blood-brain barrier. This allows spread of the infection both superficially over the leptomeningeal surface and deeper into the brain or spinal cord substance. This seems the likely cause of the development of the meningocerebritis characteristic of tuberculous meningitis, and the associated tuberculomas show a preference for development at the cortico-white matter interface, where the peripheral blood vessels are at their narrowest (Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972).

33.3 Tuberculous Meningitis (T8M) TBM develops when a microscopic granuloma, a Rich focus, situated beneath the pia mater, in the cerebral

Imaging of Brain and Spinal Cord Tuberculosis

cortex, or in the wall of a cerebral venule, ruptures into the subarachnoid space. Untreated, TBM is a fatal disease and unless diagnosed and treated early leads to calamitous neurologic defects. TBM is still a common disease. This is especially so in the 24 high-burden countries named in the WHO report on worldwide tuberculosis (Pio and Chaulet 1998), but it also remains a problem in the economically rich states of the world. Wallace quotes approximately 4,000 cases of TBM per year, reported to the Centers for Disease Control of the United States (Wallace et al. 1991; Ogawa et al. 1987). Both Wallace and Hooijboer (Hooijboer et al. 1996) emphasize that although commonly occurring in immigrant groups in the United States and Europe, meningitis surprises the physician by expressing itself among native-born children as well. TBM is an insidious disease and a high clinical awareness is essential to its diagnosis. Most published series emphasize the fact that the common presentation to the physician is after the initial stages, when the illness is well established (Jinkins 1991; McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Wallace et al. 1991; Hooijboer et al. 1996; Kioumehr et al. 1994; De Castro et al 1995; Jinkins et al.1995; Cremin 1995; Leiguarda et al.1988; Waeker and Connor 1990). The presentation is characterized by malaise, lassitude, low grade fever and an intermittent headache. Unlike the acute pyogenic and viral meningitides, high fever, papilloedema, and focal cerebral symptoms are unusual in the early stages. In this phase of the infection the clinical findings are similar to the other chronic meningitides caused by fungus, parasites, meningeal carcinomatosis, Lyme disease, and neurosarcoidosis (McGuinness 2000; Shah 2000). The severity of the disease is classified according to the Medical Research Council of the United Kingdom staging system of 1948. Stage I disease is characterized by nonspecific symptoms in a conscious patient, including headache, vomiting, irritability, or lethargy with no paresis and a good general condition. Stage II disease shows drowsiness, photophobia, meningeal irritation, and focal neurologic signs with possible seizures. Stage III disease presents with profound changes in the sensorium, major neurologic signs, and coma (McGuinness 2000; Wallace et al. 1991; Waeker and Connor 1990; Medical Research Council 1948; Lincoln et al. 1960). CT scanning is advised before lumbar puncture. Examination of the cerebrospinal fluid after the first few days, demonstrates a lymphocytic pleocytosis, increased protein level, and diminished glucose.

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Bacteriologic or histologic support for the diagnosis is sought by the purified protein derivative skin test (PPD), which is particularly helpful in children producing a high percentage of positives. Examination of sputum, gastric washings, and CSF by direct smear and culture should be carried out in all suspected cases. CSF examination with acid-fast stains is, in most reported series, positive in only a small proportion of cases, usually less than 10% (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Wallace et al. 1991; Hooijboer et al. 1996; Kioumehr et al. 1994; De Castro et al1995; Jinkins et al. 1995; Leiguarda et al. 1988). Waeker (Waeker and Connor 1990) reports only one of 30 children having a positive smear, and 37% with positive CSF cultures. Shah (Shah 2000) suggests a higher proportion of 90% of cases being CSF-positive to acid-fast staining methods. Search for the bacillus should also be made in the urine and in cultures taken from any ear infection (McGuinness 2000; Wallace et al. 1991; Naranbhal et al. 1989). Histologic support or positive bacteriologic cultures may derive from samples taken from other regions, remote from the nervous system. Chest radiography is only positive for visible evidence of tuberculosis in 40-50% of cases, and a negative chest radiograph in no way precludes the diagnosis of TBM (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Hooijboer et al. 1996; De Castro et al 1995; Jinkins et al. 1995; Leiguarda et al.1988; Waeker and Connor 1990; Ozates et al. 2000). Control examinations of family members are of great importance and often reveal active tuberculosis in parents or siblings (McGuinness 2000; Ogawa et al.I987). The most effective radiologic investigation in cases of TBM is a contrast-enhanced CT scan (CECT), and where this investigation is available it should be carried out immediately on presentation of the patient. After the initial compromise of the leptomeninges by Rich foci, cell-mediated immunity leads to the development of a glutinous exudate. In the initial stages the exudate is largely confined to the basal subarachnoid areas, but rapidly involves the basal cisterns, particularly the interpeduncular and suprasellar spaces (McGuinness 2000; Dastur et al. 1995; Dastur 1972; Kirkpatrick 1991; Reid and Fallon 1992). Spread of the exudate along the periarterial spaces of the major arteries and their branches follows, with encasement of the common carotid, anterior, middle, and posterior cerebral arteries. This facilitates spread of the exudate to the ambient system, prepontine cistern, and the supratentorial subarachnoid space, including Sylvius' fissure. The exudate is an inflammatory response to

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the presence of both intra-and extracellular bacilli. The cell-mediated response from activated T cells leads to an outpouring of lymphocytes, plasma cells, and macrophages, which reorganize into countless microscopic tubercles. In the later stages of the disease, these tuberculous granulomas are surrounded by fibroblasts, and caseous necrosis occurs in the central core (Jinkins 1991; McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972; Wallace et al. 1991; De Castro et a11995; Jinkins et al. 1995).

33.4 Imaging Characteristics of T8M The common triad of imaging changes in TBM on contrast-enhanced CT and gadolinium-enhanced MRI are basal meningeal enhancement, hydrocephalus and parenchymal supratentorial infarctions. These changes are the direct result of the underlying histopathologic processes. Enhancement is due to the breakdown of the blood-brain barrier in the leptomeninges and the intense basal inflammatory exudate, hydrocephalus due to the blockage of the normal CSF pathways, and infarctions are the result of spasm or closure of basal cerebral vessels. Basal contrast enhancement in the early stages is confined to the leptomeninges, although in chronic cases the pachymenix may be extensively affected. The enhancement follows the pathway of the basal vessels and the perivascular or Virchow-Robin spaces. As the inflammatory response to the infection develops, exudates are seen in the basal leptomeninges and basal cisterns, especially in the ambient, sylvian, pontine, and suprasellar areas. Widespread enhancement of exudates is the common pattern, although rarely focal enhancement has been reported involving Sylvius' fissure (Shah 2000; Klingensmith and Datu 1978) and the left parietal leptomeninges (Elkeslassy et al. 1997). Linked with the other two elements of the triad this enhancement is highly suggestive of TBM but is by no means pathognomonic. Other conditions - bacillary or viral meningitis, fungal meningitis, other granulomatous diseases, inflammatory response to the rupture of a paracytic or dermoid cyst, and meningeal metastatic disease - may demonstrate basal meningeal enhancement, but usually of a less intense nature and a narrower distribution (Jinkins 1991; McGuinness 2000; Kioumehr et al. 1995).

F. McGuiness

Noncontrast CT studies (NCCT) are of little value in the detection of meningeal disease. The beam hardening artefacts due to the overlying cranium and the bones of the posterior fossa make it difficult to image the meninges. In the few cases where calcification develops at an early stage in TBM, NCCT has an advantage. The presence of basal exudates is suspected when the subarachnoid space is obliterated by isoattenuating tissue. With CECT these can be readily demonstrated. The usual pattern is of long continuous segments of enhanced leptomeninges, often with associated pial enhancement of the perivascular intergyral spaces. In advanced cases, evidence of cerebritis may be seen, signaled by areas of hypoattenuation in the underlying cerebral cortex. The most apparent leptomeningeal pathologic change is evidenced by the predilection of post-contrast enhancement for the basal cisterns, particularly the suprasellar region, the prepontine region, and ambient system (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996; Shah 2000; Dastur et al. 1995; Dastur 1972; Wallace et al. 1991; Kioumehr et al.1994; De Castro et a11995; Jinkins et al.1995; Waeker and Connor 1990; Ozates et al. 2000; Kioumehr et al.1995). (Fig. 33.1a, b) Magnetic resonance imaging (MRI),is the gold standard for the imaging of the brain and leptomeninges. As in the case of CT imaging, precontrast studies are often of little value in acquiring information on meningeal infectious disease (Kanamalla et al. 2000; Shah 2000; Kioumehr et al. 1995; Meltzer et al. 1996). Post intravenous gadolinium enhanced images possess an inherent high contrast resolution and improved tissue differentiation. These qualities linked with multiplanar imaging make it the imaging modality of choice in intracranial infectious disease. It is unfortunate that MRI examination is not universally available in most of the areas of the world with a high burden of tuberculosis. In some of these areas a heightened clinical awareness and often limited laboratory facilities are the only aids available to the physician. Recent MRI applications suggest that fluid attenuation inversion recovery (FLAIR) acquisitions are helpful in cases where meningeal disease is suspected (Kanamalla et al. 2000; Singer et al.1998). Gadolinium-enhanced Tl-weighted MRI images readily reveal the extent of leptomeningeal enhancement in TBM and the distribution of the lesions. They will also bring to light the concomitant changes of subcortical cerebritis, hydrocephalus, brain infarctions, ependymitis, and associated tuberculomas (Kanamalla et al. 2000; McGuinness 2000; Shah 2000; Jinkins et al.1995; Gupta et al.1994). The second com-

551

Imaging of Brain and Spinal Cord Tuberculosis

a

b Fig. 33.1 a Axial Tl-weighted, postgadolinium scan, demonstrating intense enhancement of the basal meninges in a case of tuberculous meningitis. The white arrow points to border-zone disease adjacent to the fourth ventricle. b A similar scan at a lower level. There is enhancement of the surface of the brain stem and of exudates in the surrounding cisterns (arrow). On both scans there is enhancement of the meninges over the convexities, and a number of small parenchymal granulomas. There is hydrocephalus

ponent of the imaging triad, hydrocephalus, is almost sary, although in TBM many stage I and stage II cases universally present at the time of patient presentation. will require ventricular drainage early in the course of It commonly develops in tandem with the glutinous treatment. (Fig. 33.2a, b). Early development of hydrocephalus in TBM basal exudates which cause disruption of CSF circulation and reabsorption. The hydrocephalus is charac- is emphasized by most authors (Jinkins 1991; teristically of high pressure, and the periventricular Kanamalla et al. 2000; McGuinness 2000; Jamieson white matter is suffused to a greater or lesser extent 1995; Schoeman et al. 1988; Cremin and Jamieson with hydrostatic edema. Until recently the reabsorp- 1996; Kioumehr et al. 1994; De Castro et al 1995; tion of CSF was thought to occur solely by the activity Jinkins et al.1995; Ozates et al. 2000; Gupta et al.1994; of the arachnoid granulations overlying the cerebral Bonafe et al. 1985; Dastur et al. 1970; Artopulous et convexities. Hydrocephalus in TBM was thought to be al. 1984; Chang et al. 1990). Wallace (Wallace et al. secondary to obstruction of the flow of CSF around 1991) and Waecker (Waeker and Connor 1990) also the midbrain and in the basal subarachnoid space note its early development and find it a more reliable by leptomeningeal exudates, which also blocked the diagnostic pointer in TBM than the presence of basal arachnoid granulations. Recent work by Greitz et al., exudates. Of Wallace's nine cases, ventriculomegaly however, suggests a new concept of CSF absorption was present in seven, while it was present in all of (Greitz et al. 1997). Using flow-sensitive MRI and Waecker's 30 cases. In Ozates' study of 289 TBM radionuclear cisternography, they propose that the patients (Ozates et al. 2000), 204 developed hydromain site of absorption of CSF is through the walls of cephalus in the course of the disease, and it was prescerebral arterioles, capillaries, and venules. In TBM, ent in 163 patients on presentation. In general, the compromise of these vessels, by spasm and arteritis, severity of hydrocephalus corresponds to the severresulting from encasement by exudate in the sub- ity of the infection, it is more pronounced in children arachnoid space, would be an important factor in the than in adults, and serial CT studies show that it often early development of communicating hydrocephalus. worsens during the first few weeks despite adequate Rarely, in TBM the hydrocephalus is of the obstructing chemotherapy. type, resulting from the obstruction of the aqueduct of Arteritis, vessel encasement by exudate, spasm, and Sylvius or the foramina of Luschka and of Magendie by vessel occlusion lead to compromise of the arterial flow subarachnoid granulomas or glutinous subarachnoid in the vessels of the circle of Willis and their branches. exudates. It is important to recognize this complica- So leading to the third feature of the clinical triad, ceretion, as in these cases early shunt placement is neces- bral infarction. Cerebral cortical, white matter, and tha-

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F. McGuiness

a Fig. 33.2a, b. Sagittal T1 and proton-density scans. There is a grape-like cluster of tuberculous granulomas obstructing the outlet of the fourth ventricle, resulting in hydrocephalus (arrow)

lamic infarction is a major cause of permanent brain damage, occurring despite adequate antituberculous chemotherapy, and may be taken as a good indicator of an eventual poor clinical outcome. Angiographic and postmortem studies have demonstrated occlusions ranging from closure ofthe suprasellar segment of the carotid artery to thrombosis of its major branches, leading to large territorial infarctions (McGuinness 2000; Dastur et al. 1995; Dastur 1972; Leiguarda et al. 1988; Gupta et al. 1994). The typical angiographic changes of irregularities in caliber ofvessels branching from the circle ofWillis, occlusion of the medium-size arteries at the base of the brain, and early venous drainage were described by Lehrer (Lehrer H 1966), and when combined with a hydrocephalic pattern of vessel distribution, were called by him, the angiographic triad of TBM. However, the smaller perforating branches are more commonly affected than the larger arteries, and occlusion of the medial-striate and thalamo-striate perforating arteries, leads to a characteristic picture of infarction in the thalamus and caudate nucleus. As in many of the manifestations of TBM, infarction is more common in patients under 5 years of age (Kanamalla et al. 2000; McGuinness 2000; Jamieson 1995; De Castro et al 1995; Leiguarda et al. 1988). This underscores the notion that the branches of the arteries of the circle of Willis become involved in the' inflammatory process as they pass through the basal exudates. In the case of children, the small caliber of the vessels makes them more vulnerable and susceptible to thrombotic occlusion than the larger caliber vessels of adults. Postmortem studies have shown

that venules as well as arteries are involved in this pathologic process. Large vessel infarction does however occur, even in adults, and may be demonstrated by digital subtraction angiography (DSA) (Fig. 33.3) or magnetic resonance arteriography (MRA). Large vessel infarction in the territories of the anterior or middle cerebral arteries leads to extensive cerebral cortical infarction. These areas subsequently develop encephalomalacia and segmental areas of overlying cortical atrophy. At a later stage, areas of calcification, best seen on CT examination, have been described in these areas (McGuinness 2000; Ogawa et al. 1987; De Castro et al1995; Jinkins et al. 1995). Although there are no reported cases of clinical deterioration after DSA, the examination is today deemed unnecessary in cases of TBM (McGuinness 2000; Rochas-Echeverri et al. 1996). Impending infarction is suggested by a shaggy appearance of the perivascular exudates on CFCT, and the results of infarction are clearly demonstrated on both CT and MRI examinations (Ogawa et al. 1987). Gupta has demonstrated the presence of large and small vessel arteritis by MRA studies, a noninvasive method of examination (Gupta et al.1994). At post mortem, the incidence of infarction is around 40% (Dastur et al. 1995; Dastur 1972; Dastur et al. 1970). Published studies of investigation by CT examination suggest a discovery rate of around 2838%. MRI studies are more sensitive, having a discovery rate of around 50% and demonstrate that many of these lesions are hemorrhagic, which may lead to cavitation (McGuinness 2000; Jamieson 1995; Schoeman et al. 1988; Cremin and Jamieson 1996; Shah 2000; Wal-

Imaging of Brain and Spinal Cord Tuberculosis

553

lace et al.1991; Jinkins et al.1995; Leiguarda et al.1988; Gupta et al.1994; Rochas-Echeverri et al.1996). Schoeman (Rochas-Echeverri et al.1996),described a group of 27 children investigated with MRI, with much higher rates of infarction, 20 of whom presented with stage II or III disease, had midbrain or basal ganglia lesions. Ten presented with brain stem, parahippocampal gyri, or hypothalamic changes. By contrast, Ozates in a review of 289 TBM cases - 214 children and 75 adults - examined by CT, reports a lower overall incidence of infarctions of 13%. Infarctions are seen on CT scans as areas of hypoattenuation. On Tl-weighted gadolinium-enhanced MRI (Tl Gd) the areas of infarc-

a

a

tion stand out as hypodense lesions (Fig. 33.4a, b). On T2 MRI, acquisitions infarctions show a high signal and are difficult to differentiate from areas both of leptomeningitis and border-zone disease. Border-zone changes are a form of cerebritis that develops beneath the inflamed leptomeninges, and these are frequently seen in the superficial cerebral cortex, the cerebral peduncles abutting onto the interpeduncular fossa, and the midbrain and pons adjacent to areas of cisternal enhancement. They are usually present in advanced disease and indicate a poor prognosis (McGuinness 2000; Jamieson 1995; Cremin and Jamieson 1996). (See Fig. 33.5a, b.)

Fig. 33.3a,b. Avertebral artery angiogram with much wall irregularity in the basilar artery and the posterior fossa branches, resulting from tuberculous arteritis (arrows)

b Fig. 33.4a, b. Extensive, bilateral, thalamic infarction and hydrocephalus on coronal MRI (arrows). Images courtesy of Dr J. Lotz, Riyadh Military Hospital, Saudi Arabia

F. McGuiness

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Infarctions are commonly supratentorial, and brain stem infarction only occurs in 2-3% of cases, mostly in infants and children. The clinical syndromes resulting from TBM cerebral and brain stem infarctions encompass a wide variety of patterns, ranging from focal or generalized seizures, mentation and gaze disturbances, monoplegias, hemiplegias, and nuclear cranial nerve lesions. Although rare, the arteritis of TBM can lead to aneurysm formation with fatal consequences, and a small number of such cases have been described (McGuinness 2000; Jinkins et al. 1995; Leiguarda et al. 1988; Gupta et al. 1994; Cross et al. 1995). One such case, reported by Cross et al., responded to endovascular occlusion treatment of the aneurysm, after presenting with life-threatening epistaxis (Cross et al.1995).

a

33.5 Tuberculomas of T8M The wide distribution of microscopic granulomas in the subarachnoid space, leads to the development of tuberculomas. These tend to be small in size and are generally seen related to the supratentorialleptomeninges. Parenchymal tuberculomas complicating TBM tend to be found at the cortico-white matter border, although deeper masses may be found. In adults, most are supratentorial, while in children, tuberculomas of the cerebellum and brain stem are commoner. Initially solid, tuberculomas mature to develop central caseating necrosis. Often developing in clusters they display the radiologic properties of granulomas. When solid they are isodense or hypodense to brain tissue on CT and MRI scans carried out without contrast medium. Postcontrast studies demonstrate homogeneous enhancement in solid lesions and an intense ring enhancement in tuberculomas undergoing central caseating necrosis. An area of edema is often present and in TBM the lesions are usually no greater than 0.5 cm in diameter (Fig. 33.6). Basal inflammatory exudate affects the cranial nerves as well as the vessels that course through it. Cranial nerve deficits are a common complication of stage II and III TBM. The optic nerve or chiasma is open to compression due to suprasellar leptomeningitis. The long, basal, intracranial courses of the third, fourth, and sixth nerves expose them to exudate damage. The fifth and seventh nerves are sometimes affected

b Fig.33.5a, b. Sagittal and axial, T2-weighted images demonstrate extensive basal exudate and border-zone disease. This encroaches on the anterior margin of the right cerebellar hemisphere (arrows)

Fig.33.6. MRI of an enhancing, grape-like cluster of tuberculomas (arrow). Note also the ependymitis in the temporal horn of the right lateral ventricle (arrow head). This was in a terminal case of tuberculous meningitis

Imaging of Brain and Spinal Cord Tuberculosis

as they leave the midbrain. Gupta has demonstrated enhancement of the inflamed nerve sheaths on T1 Gd MRI (McGuinness 2000; Jinkins et al. 1995; Gupta et al. 1994) (Fig. 33.7a, b). Permanent damage results as healing converts the basal exudates into dense, fibrotic material, with the pattern of deficit varying from patient to patient (McGuinness 2000; Jinkins et al. 1995; Gupta et al.1994; Artopulous et al.I984). Long-standing TBM may in some instances lead to infection of the dura mater leading to thickening and pachymeningitis. Common sites include the floor of

555

the middle cranial fossa, the dura overlying the cerebral convexities, and the tentorium. Calcification may be present. Contrast studies reveal intense homogeneous enhancement of the affected areas (Shah 2000; Ng et al.1996; Praharaj et al.I997). Isolated areas of calcification of the dura mater and cases showing punctate gyral calcification are reported (Kanamalla et al. 2000; McGuinness 2000; Shah 2000; Wallace et al. 1991; De Castro et aI1995). Calcification may be an early feature or may occur years later, after successful treatment of the infection.

33.6 Parenchymal Cerebral Tuberculosis Parenchymal cerebral tubercular disease occurs sporadically, and as a complication of TBM. It may be subdivided into 1. Parenchymal tuberculomas 2. Tuberculous abscess 3. Tuberculomas en Plaque 4. Miliary tuberculomas

33.6.1 Parenchymal Tuberculomas a

b Fig. 33.7. a Postgadolinium T1 image demonstrating enhancement of a left-sided tuberculous infection of the middle ear (arrow). There is infection of the temporal lobe (arrow head). b A coronal image confirms the middle ear infection (arrow) and the associated temporal-lobe tuberculoma. Central areas oflow signal caseation are seen (arrow head), as is a surrounding zone of edema (curved arrows)

In cases ofTBM,the incidence ofcerebral tuberculoma varies. Atlas suggests a low incidence of 10% (Atlas 1991), but Jinkins found higher rates in Saudi Arabia: in a study of 80 patients with intracranial tuberculosis, 11 % had compound meningeal/parenchymal lesions and 89% had parenchymal tuberculomas. Of all mass lesions in his practice, Jinkins found that 10-15% were tuberculomas (Jinkins 1991). In developing countries, sporadic parenchymal tuberculomas make up a large proportion of intracranial space-occupying lesions. In patients in India, Gupta suggests that between 10% and 40% of all intracranial mass lesions are tuberculomas (Gupta et al. 1988; Gupta et al. 1990). Salgado points out an increasing incidence of tuberculomas in developed countries (Salgado et al.I989). Cremin and Jamieson (Schoeman et al. 1988; Cremin and Jamieson 1996) recorded parenchymal tuberculoma formation in 10% of their cases in children. Sporadic cerebral tuberculous masses had a different clinical presentation from lesions in TBM, which were multiple in 15-20% ofTBM patients. Tuberculomas may be single or multiple, and when multiple, may demonstrate differing degrees of devel-

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F. McGuiness

opment at the same time. Most tuberculomas occur at the cortico-white matter junction, suggesting an origin by hematologic spread (Fig. 33.8a, b). A small number develop by direct spread from Rich lesions in the pia mater, in which case the overlying meninges enhance on CECT or T1 Gd MRI. The origin, in a few cases, is by spread from a venous sinus (McGuinness 2000). In the less common forms of tuberculomas of the basal ganglia, brain stem, and cerebellum, differentiation from primary or secondary neoplasms is a problem, especially in adults (Fig. 33.9). Beneath the tentorium, both single and multiple lesions are described, but account for only between 1% and 5% of tuberculomas (Jinkins 1991; Kanamalla et al. 2000;

Fig. 33.9. Sagittal postcontrast MRI demonstrates an isolated tuberculoma of the brain stem. It is impossible on this image to differentiate the appearance from that of a primary brain stem tumor

a

b Fig. 33.8a, b. Postcontrast computer scans of a young patient. As well as hydrocephalus, the scans demonstrate multiple enhancing, subcortical tuberculomas in the frontal and parietal regions, and at a higher level beneath the convexity

McGuinness 2000; Schoeman et al. 1988; Cremin and Jamieson 1996; De Castro et al 1995; Jinkins et al. 1995; Gupta et al. 1988; Salgado et al. 1989; Shen et al. 1990; Draouat et al. 1987; Vengsarkar et al. 1986; Van Dyke 1988; ,Jinkins et al.1987; Al Deeb et al.1992; Gupta et al.1991; Rajshekhar and Chandy 1997). All age groups are affected. In developing countries, tuberculomas show a predilection for children, but any age group may be affected (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Atlas 1991; Gupta et al. 1988; Salgado et al. 1989; Vengsarkar et al. 1986; Van Dyke 1988; Jinkins et al. 1987; Abugali et al. 1994). In developed countries, the elderly, as well as patients with a susceptibility, or those suffering from diabetics, alcoholicism, drug-abuse, or AIDS, are likely to be affected, but exceptions occur and even infants may develop tuberculomas (Vallejo et al. 1994). The onset of symptoms is insidious and gradual elevation of intracranial pressure, focal epilepsy, and focal neurologic deficits are the common presenting signs. Fever may be present. Clinically, differentiation from tumor, fungus, or paracytic disease is difficult, and this is also a problem radiologically. Many radiologists have expressed the opinion that the radiologic diagnosis of tuberculoma is always tentative. Recent developments in MRI, have defined groups of appearances in which the probability of the diagnosis of parenchymal tuberculoma is extremely high, especially in areas where tuberculosis is endemic. CT and MRI studies carried out without contrast agents are

Imaging of Brain and Spinal Cord Tuberculosis

Fig. 33.10. Precontrast CT demonstrates an isodense right frontal, subcortical, tuberculous mass (arrow). There is a surrounding zone of edema and a pressure effect on the lateral ventricle (arrow head)

likely to overlook both isodense parenchymal tuberculomas and TBM (Fig. 33.10). In cases of suspected tuberculoma, a careful search for an active focus of infection in other systems should be made. For this, sputum testing, gastric washings, CSF study, and chest radiography (including lateral views in children (Cremin and Jamieson 1996), should be carried out. Abdominal ultrasound or CT will demonstrate peritoneal tuberculosis if present, and in women, pelvic disease can be the source. Urine bacteriology is also necessary. However in some patients, if biopsy of the tumor is thought inadvisable, the response to antituberculous therapy will be the only way to make the diagnosis (Jinkins 1991; McGuinness 2000; Schoeman et al. 1988; Cremin and Jamieson 1996; Gupta et al. 1988; Gupta et al. 1990; Gupta et al. 1991).

33.6.2 Imaging Characteristics ofTuberculomas

In the early phase, tuberculomas are solid granulomas and are slightly hypodense or isodense to normal brain tissue on NECT. After contrast these solid lesions, which are characteristically round, or occasionally oval or lobulated, enhance homogeneously on CECT. When first discovered, tuberculomas are usually about 2 cm in diameter and may be single or multiple. There is accompanying low density white matter edema, which may be intense

557

in these early lesions. The resulting mass effect may displace the ventricular system and give rise to hydrocephalus if foramina are compromised. This is more likely if the lesion lies in the mesencephalon or in the brain stem. Supratentorial sites are commoner. As central caseation and encapsulation develops, the pattern of enhancement on CECT becomes heterogenous centrally and the outer capsule enhances as a ring. A cerebral edema surrounding these caseating lesions is usually less intense than is the case in the solid granulomas. On angiography and dynamic CT, they are centrally avascular. Tuberculomas discovered at this stage are often up to 5 cm in diameter but in endemic regions have been demonstrated up to 8 cm in size, and these may show a laminated pattern, resulting from alternating phases of granuloma formation and caseation (Gupta et al. 1988, Gupta et al. 1990). At the next stage, central necrosis of the tuberculoma develops. The fluid or semifluid center of the mass does not enhance on CECT (Fig. 33.11a-c). Characteristically, a dense ring of enhancing tissue surrounds a hypodense core. This ring comprises glial tissue and the compressed collagen capsule of the tuberculoma. Jinkins suggests that from the very start, new fragile blood vessels develop in this zone, and the passage of contrast through leaky walls allows the blood-brain barrier to be breached and the granuloma to enhance, either totally, or at a later stage peripherally (Jinkins et al.1987). Enhancement is a rough index of activity of the lesion, and in the early stages of the disease may increase in intensity, however with inception of treatment it eventually wanes. Involution of the mass during treatment is a slow process that may take months or years, although some tuberculomas exhibit a reduction in size in as few as 4-6 weeks after commencement of treatment. Other cases may take months or even years to resolve. Any increase in size during treatment raises the question of drug resistance, misdiagnosis, or paradoxical enlargement. Some small lesions may resolve without therapy (Vengsarkar et al. 1986), but in countries where cysticercosis is also endemic, the true diagnosis in these cases is often in doubt (Gupta et al.1990). In children, Cremin and Jaimeson describe grapelike clusters of tuberculomas that may be associated with solid lesions elsewhere (Schoeman et al. 1988; Cremin and Jamieson 1996). In ring enhancing lesions the thickness of the ring may vary around the circumference. Usually it is continuous but when broken is difficult to differ-

558

F. McGuiness

Fig. 33.11. a Precontrast CT reveals an isodense, right occipital mass (arrows). b After contrast injection, there is strong ring enhancement around a caseating or necrotic center (arrow head). c Postcontrast CT demonstrates ring enhancement of solid tuberculomas in the right posterior cerebral white matter (arrows)

entiate from metastatic disease (De Castro et al. 1995, Vengsarkar et al. 1986). Multiple lesions often show different stages of development and difference in size. Large, single lesions are difficult to differentiate from neoplasms and lymphoma, especially when situated deep in the midbrain, the brain stem, or cerebellum. DSA demonstrating avascularity is considered as helpful in these cases (Jinkins et al.1987). The MRI appearances of tuberculomas are described in the literature, but with wide variations in appearance. Many of these descriptions were made before the availability of contrast studies. Later studies are more consistent. That of Jinkins et al. is the standard classification (Jinkins et al. 1995). 1. The noncaseating granuloma is Tl hypointense to brain tissue and T2 hyperintense, enhancing homogeneously with postgadolinium contrast study. (Fig. 33.12a-d) 2. A solid caseating granuloma is hypointense to isointense on Tl images and isointense to hypointense on T2, with a hypointense rim, depending on the degree of capsule development. With contrast examination a strong rim enhancement is seen. Both these types of lesion are surrounded by a zone of edema, which is hypointense on Tl and hyperintense on T2, remaining unchanged in appearance on postgadolinium examination. (Fig. 33.13) 3. When central necrosis or liquefaction occurs, the central signal is Tl hypointense. On T2, the necrotic material gives a fairly homogeneous hyperintense signal, and the surrounding capsule appears hypointense. Tl-weighted postgadolinium MRI study reveals intense ring enhancement of the lesion.

In those cases of long-standing laminated lesions as yet no postcontrast studies have been published, so the enhancing characteristics are not yet known. These lesions show alternating bands of iso- and hypointense tissues on Ti, and of hypo- and hyperintense tissue on T2 (Gupta et al. 1990). The reason for shortening of the T2 signal in some tuberculomas is not clear, but may be the result of the presence of paramagnetic free radicals in enclosed macrophages, distributed inhomogeneously throughout the lesion (Gupta et al. 1991). There is a general agreement that the imaging appearances of intracranial tuberculomas are nonspecific and that the ability of tuberculous lesions to mimic other diseases of pyogenic, fungal, neoplastic, and paracytic origin leads to a wide range both of appearances and of differential diagnoses (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Schoeman et al.1988; Cremin and Jamieson 1996; De Castro et al 1995; Jinkins et al. 1995; Gupta et al. 1988; Jinkins et al. 1987; Al Deeb et al.1992; Bhargava and Tandon 1980). Wechman suggested that one particular CT pattern was specific to tuberculoma and was supported by van Dyke (Wechman 1979; van Dyke 1988). The pattern which they named the "target sign" comprises a round or oval lesion, isodense or slightly hyperdense on NECT, containing a small central nidus of calcification. With examination by CECT, a peripheral enhancing ring was seen as well as the central calcific lesion (Fig. 33.14a, b). But neither author had access to MRI study. Van Dyke noted the appearance in 10 of 30 patients with tuberculomas, all of whom were black South Africans. The appearance has only rarely been described in other parts

Imaging of Brain and Spinal Cord Tuberculosis

559 Fig. 33.12. a Axial, postgadolinium MRI. A group of right-sided thalamic tuberculomas. These are solid and the right lateral ventricle is effaced (arrow). Note also the extensive enhancement of the thickened meninges over the left convexity, in this young patient with tuberculous meningitis. b Coronal, postgadolinium MRI. There is an irregular, ovoid tuberculoma in the right side of the brain stem (arrows). c A sagittal, postgadolinium study of a patient with three tuberculomas. All enhance but show some central relative hypodensity. The lesions are seen in the parasagittal, cerebellar, and brain-stem locations (arrows). d An axial, postgadolinium MRI scan reveals a single enhancing tuberculoma high in the brain stem

Fig. 33.13. An axial nonenhanced, T2-weighted MRI of an occipital tuberculoma of mixed signals (arrow). There is extensive surrounding edema (arrow heads)

Fig. 33.14a, b. A case of tuberculoma. a A lesion with density slightly higher than the surrounding brain tissue. Note the central calcification, as well as the mass effect and the dilatation of the posterior horn of the lateral ventricle. b After injection of contrast medium, showing intense enhancement of the rim of the lesion, and the typical appearance of the "target sign"

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of the world, namely North Africa, India, and Saudi Arabia (Draouat et al. 1987; Vengsarkar et al. 1986; Abduljabbar 1991). Recent studies by Bargallo et al. in Spain, augmented by MRI, have shown the sign present in cases of AIDS, complicated by intracranial toxoplasmosis in one case and lymphoma in another. In a third case it was seen in an elderly woman with a pyogenic brain abscess (Bargallo et al. 1996). In van Dykes' cases, the sign may be due to a specific response of a local population to tuberculosis. Other factors must also be considered. The presence of central calcification suggests a long-term lesion, so delay in presentation at a hospital may be one factor. However, peripheral enhancement indicates an active lesion. The target sign is therefore a suggestive but nonspecific indicator of a tuberculoma.

33.7 Paradoxical Response of Tuberculomas to Treatment Since first described by Lees, McLeod, and Marshall in 1980 (64), a number of cases have been cited where tuberculomas have developed or increased in size during apparently adequate antituberculosis therapy of nonresistant tuberculous organisms. None of these patients were of Caucasian origin, but included Indians, Chinese, Vietnamese, and one North American black (Teoh et al. 1987). The reasons for this paradoxical phenomenon have not yet been discovered. Some patients have associated tuberculous lymph node disease, and the lymph nodes also increase in size. This last feature is well recognized during antituberculous therapy, a possible explanation being a local hypersensitivity and inflammatory response, resulting from the release of tuberculoprotein from dead or dying mycobacteria (Campbell and Dyson 1971). However, while infected lymph nodes contain large numbers of mycobacteria, this is not the case in parenchymal cerebral lesions, where the numbers of mycobacteria are small. The relapse time from the apparently successful treatment of the tuberculoma and the onset of new focal signs,convulsions, or raised intracranial pressure, due to paradoxical expansion, varies between 1 month and 18 months. Patients have come from a wide range of age groups, from infants to the elderly (Teoh et aI. 1987). The phenomenon occurs both in parenchymal tuberculoma and in tuberculoma-complicating TBM and may throw the diagnosis into doubt. In some

F. McGuiness

cases, biopsy of the lesion may be necessary to obtain histologic confirmation of the diagnosis. Brain biopsy or surgery are not without danger in tuberculosis and ideally should be reserved for those cases where intervention is required due to the effects of raised intracranial pressure or where malignancy, fungal, or paracytic disease cannot otherwise be eliminated from the diagnosis (Vengsarkar et al. 1986; Bouchama et al.1991).

33.7.1 Late Stage Appearances ofTuberculomas The behavior of parenchymal tuberculomas during antituberculous therapy is related to the size of the lesion at the time of initial diagnosis. Small, single or multiple lesions of less than 1 em in diameter usually disappear completely during therapy, often within the first few months and almost invariably within 1 year. This is the norm in children (Schoeman et al. 1988; Cremin and Jamieson 1996). This is the case if the lesion is a solid granuloma, without central caseation or calcification. Larger nonsolid or calcifying lesions above 2 em in diameter usually take between 2 and 3 years to resolve, especially if the lesion is both large and lobulated, as in those described by Bhargava (Bhargava and Tandon 1980). Jinkins (Jinkins et al. 1987) in his study of 80 patients with parenchymal tuberculomas, described 57 patients with isolated granulomatous lesions and followed them up with CECT until therapy could be safely stopped. He took failure to enhance on CT study as an indication of healing. Many of these cases required between 18 months and 2 years therapy before resolution. Fourteen of 57 eventually showed a normal CT. Eight showed a residual, nonenhancing, calcified lesion, and 12 displayed calcification with associated overlying cerebral atrophy. Seventeen patients showed focal cerebral atrophy alone. One patient continued to demonstrate an enhancing lesion after 2 years of chemotherapy. Five patients were lost to followup. This is a higher percentage of calcified lesions than in some other studies. Wilkinson (Bouchama et al. 1991) and Reed (Wilkinson et al. 1971) in two separate series stated that 38% of TBM patients showed late stage calcification, but that only 1% and 6% of parenchymal tuberculoma developed this phenomenon in their respective studies. This is in agreement with van Dyke, only one of whose 30 cases developed significant late stage calcification (Fig. 33.15a, b) (van Dyke 1988).

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b

a

Fig. 33.15a, b. Pre- and postcontrast computer scans after craniotomy. a There is extensive cortical and white matter calcification and some cortical atrophy (arrows). b Postcontrast scanning shows a number of areas of enhancement within the lesion (arrows). These areas represent continued activity in this tuberculoma some months after commencement of antituberculous chemotherapy

33.8 Tuberculous Brain Abscesses Although uncommon, true tuberculous abscesses develop from parenchymal tuberculous granulomas or the spread of tuberculous foci in the meninges to the brain substance in patients with TBM. Cremin and Jaimeson have pointed out that two distinct types of necrosis occur in tuberculomas. Microscopically, those possessing a structure of fibrovascular elements, as demonstrated with reticulin stains, undergo gummatous necrosis, where the inflammatory granulatomatous tissue undergoes necrosis. Cremin points out that this type of central necrosis gives an MRI signal on T2 studies that is isodense to brain tissue and surrounded by a dense zone of edema. Tuberculomas of this type do not develop into abscesses (Schoeman et al. 1988,Cremin and Jamieson 1996). Those tuberculomas that do convert into abscesses show a different structure on microscopy as they have no reticulin elements, being composed entirely of cellular elements. The necrosis of these epithelioid cells, macrophages, and polymorphonucleocytes passes through a phase of inspissation or caseation to liquefaction and the development of a true abscess (Cremin and Jamieson 1996). These are usually isolated lesions, occasionally occurring simultaneously with other solid tuberculomas. Radiographically they are indistinguishable

from pyogenic abscesses. They show similar MRI characteristics, being oval or round in shape with a thin, strongly enhancing wall that, on T1 Gd MRI examination, is in marked contrast to the hypodense liquid center (Fig. 33.16a-c). A point of clinical importance is that, while solid or caseating tuberculomas contain few bacteria, the tuberculous abscess contains the mycobacterium in large numbers. If such an abscess ruptures into the ventricular system or the subarachnoid space, a devastating ventriculitis or meningitis ensues. Drainage of these lesions is therefore a dangerous procedure. Seeding of daughter lesions along the needle track has been described by De Castro (De Castro et al 1995) who points out that in the West, abscesses are more likely to develop in the elderly, or in the immunosuppressed.

33.9 Atypical Tuberculous Masses Tuberculoma 'en plaque' lesions occur more commonly as a complication of TBM than as isolated tuberculomas. En plaque lesions may also occur when a tuberculoma abuts onto the meningeal surface of the brain and a proliferation of granulomatous tissue extends into the adjacent meninx. When

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a

b

Fig. 33.16. a A group of right-frontal tuberculous abscesses in the subcortical white matter, causing midline shift. Postgadolinium imaging demonstrates an intense enhancement of the abscess wall (arrow), while the liquid contents remain of low signal (arrow head). b Two deep, midline tuberculous abscesses in the region of the tentorium (arrows). There is a smaller collection posteriorly (arrow head). c Two right, frontal tuberculous abscesses, one of which has been sucessfully drained (arrow). The second shows the characteristic appearance of an enhancing thin wall surrounding hypodense fluid. (arrow head). There is hydrocephalus. This was in a late stage case of tuberculous meningitis

present as isolated lesions, the clinical presentation is similar to any other space-occupying lesion (Gee et al. 1992). A common site of such lesions is the tentorial edge, where the resemblence to meningioma causes difficulty in diagnosis (Fig. 33.17a). The lack of vascularity on DSA is a helpful pointer. Other primary and secondary tumors may be differentiated in the same way, but stereotactic biopsy will be necessary in some cases (Bouchama et al.1991; Rajshekhar and Chandy 1997). When tuberculous meningeal mass lesions are confluent with the cerebral cortex, there is extensive gyral enhancement on both CECT (Fig. 33.17b, c) and TlGd images, the underlying cortex and white matter show edema beneath the lesion. This edema will be hypodense on NECT and Tl MRI, and hyperintense on T2, showing no enhancement on Tl Gd acquisitions. Other atypical tuberculomas are exceedingly rare. Graveli (Graveli et al. 1998) describes a lesion

of the cavernous sinus, with the characteristics of a meningioma. Shah et al. treated a patient with a tuberculoma of the sphenoid sinus showing bone destruction of the superior section of the clivus and a soft tissue mass, and a second patient who presented with a tuberculoma in the brain as a mass in the tectal plate (Shah et al.1993; Shah et al.1994).

33.10 Miliary Cerebral Tuberculomas Miliary tuberculosis is a multiorgan infection which develops when the host defenses prove inadequate in controlling the generalized spread of the disease. It is characterized by Widespread 2-3-mm granulomas, typically seen throughout the lung fields, and histologically present in other organs. However, on presentation only 50% of cases have an abnormal

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b

a

c Fig. 33.17. a An enhancing en plaque tuberculoma at the tentorial edge (arrow). Difficult to differentiate from a meningioma. b, c Pre- and postcontrast CT scans demonstrate a hyperdense lesion in the frontoparietal region. After intravenous contrast injection, there is extensive enhancement of the adjacent meninges. This is associated with ring enhancement of a I-cm tuberculoma with a central, hypodense nidus (arrows). Images courtesy of Dr Ng Chang Gung, Memorial Hospital, Kwei Shan, Tao Yuan, Taiwan

chest radiograph. At autopsy between 47% and 55% of cases are described with cerebral involvement (Slavin et ai. 1980). In children, 68% of those with tuberculous meningitis are reported to show concomitant miliary lesions in the brain (Jinkins 1991; Gee et ai. 1992). Gupta pointed out that cerebral miliary tuberculosis may be more common than previously realized, and found typical lesions in seven patients with pulmonary miliary tuberculosis, who had no symptoms or signs of central nervous system disease (Gupta et ai. 1997). Small solid granulomatous lesions are isodense on NEeT and isointense on T1 images. On T2, these small lesions give a high signal. Larger caseating lesions are revealed as low signal on T2. After contrast injection, small lesions enhance solidly whilst caseating lesions show ring enhancement. Gupta pointed out that the majority of lesions occur at the gray/white matter interface. This suggests embolic hematologic spread, and arrest at the site of narrowing of cortical arterioles. A similar mechanism influences the distribution of cerebral metastases (Atlas 1991).

33.11 Tuberculosis of the Calvarium with CNS Lesions Tuberculosis of the calvarium is a rare condition but in a small proportion of reported cases the inner table is penetrated to give rise to a tuberculous epidural abscess. This in turn has led to focal tuberculosis in the underlying cerebrum. There are three distinct types of lesion. The most common is a single osteolytic lesion in the skull vault. This is usually a well-defined, punched-out defect with smooth but occasionally irregular margins. A thin border of sclerotic bone has been described (McGuinness 2000; Dastur 1972). The inner table is first involved, and the inner defect is often more extensive that the outer (Le Roux et ai.1990). The central fragment of bone is often sequestrated, a button sequestrum, and there is painless overlying soft tissue swelling, while in some cases a cutaneous sinus may develop. The bone defect may cross the suture line. A less frequent appearance is of a more diffuse lesion with ill-defined margins. In both types of lesion there may be a surrounding zone of osteoporosis. Some authors have noted that

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previous trauma had occurred at the site of the lesion (Le Roux et al.1990). The second type of presentation is common in India and Africa. Multiple bone defects are seen, and these may be associated with cystic bone lesions elsewhere in the long bones of the skeleton or with dactylitis (McGuinness 2000; Cremin and Jamieson 1996; De Castro et al1995; Le Roux et al.1990; Wessels et al.1998). In the third presentation, known as "Pott's puffy tumor:' the scalp swelling is the major component and the underlying button sequestrum and calvarial osteomyelitis are only revealed on skull radiography or CT (Fig. 33.l8a,b) (McGuinness 2000; Le Roux et al. 1990).

a

b Fig. 33.18. a Pott's puffy tumor. CT study of a soft tissue lesion in the right frontal region demonstrates an extensive swelling, isodense to brain tissue. There is thinning of the bone of the underlying calvarium. b Postgadolinium MRI. This defines the subcutaneous abscess as a low signal collection, surrounded by a ring of enhancing tissue. The tuberculous osteitis of the frontal bone and an underlying epidural inflammatory lesion are demonstrated

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In cases where underlying infection occurs within the skull or cerebrum, a wide range of clinical patterns have been described (Le Roux et al. 1990). The common complication is seizure, but diabetes insipidus, vision disturbance, 3rd and 6th nerve palsies, mild hemiparesis, and proptosis have been described (McGuinness 2000; Cremin and Jamieson 1996; De Castro et al 1995; Le Roux et al. 1990; Patankar et al. 2000; Gupta et al.1989).

33.12 Tuberculous Otitis Media and Tuberculosis of the Temporal Bone In the pre-chemotherapy era, tuberculous otitis media was common. In 1915, Turner commented that 50% of cases of otitis media in infants were tuberculous, the figure falling to 2% in adolescents. In the post-1950s period, it has become rare in the West, and although sporadic cases occur in Caucasians, most cases are found in immigrant communities (McGuinness 2000; De Castro et al 1995; Buchanan and Rainer 1988; Cavallin and Muren 2000). In South Africa, the condition is common among the socially deprived, and in Natal is an important cause of facial palsy in children. In Singh's 43 patients, 17 developed lower motor neurone 7th nerve palsy (Singh 1991). In young African patients, 50% have pulmonary tuberculosis, and otitis media may be part of a more widespread central nervous system disease, while hematogenous spread may have occurred from foci in the liver, kidney, or spine. Often the infection in the ear is bilateral. In the West, isolated unilateral otitis is more common. Target groups with immune problems may be infected. One of Lee and Drysdale's cases had been treated with steroids for rheumatoid arthritis (Lee and Drysdale 1993). Although rare in the West, if not treated, it remains a chronic, disagreeable condition that leads to deafness in the affected ear. Complications, such as mastoiditis with sinus formation, bony sequestration, and intracranial infection can arise. Profuse otorrhea continues for many years. The condition is usually painless. On clinical examination, the drum is seen to be perforated or partially destroyed. Visually the drum and mucosa are pale, as are granulations when present. The middle ear fills with caseous material, which has the appearance of cottage cheese. Biopsy of the granulations reveals caseating granulomas, and immediate screening sometimes reveals AAFB.

Imaging of Brain and Spinal Cord Tuberculosis

It is essential to send material for culture as almost invariably a misleading secondary pyogenic infection will have occurred (McGuinness 2000; Buchanan and Rainer 1988).

33.12.1 Imaging Plain radiographs show clouding of the mastoid cells or osteoporosis and bone destruction in the middle ear. These nonspecific changes are confirmed by conventional tomography. Axial imaging where available is much superior. Standard middle ear protocols reveal bone destruction and soft tissue masses. And destruction of the ossicles may be documented (Hoshino et al. 1994). On MRI studies postcontrast TlGd images demonstrate the extent of the inflammatory change. Granulation tissue enhances and caseating tissue remains isodense, or hypodense intracranial extension of the disease is shown (Fig. 33.7a, b). The common intracranial complications are tuberculomata, often of the temporal lobe, meningitis, and neural deficits in nearby cranial nerves (VI, VII, VIII, XI, and XII). Grewal et al. describe a tuberculoma of the mastoid bone (Grewal et al. 1995). Differentiation from other chronic conditions depends on culture and biopsy. Of infections, chronic otomastoid cholesteatoma and fungal granulomatous diseases may show similar appearances. Wegener's granulomatosis, Langerhans cell histiocytosis, rhabdomyosarcoma, and recurrent bacterial infections may all produce similar appearances (Mumtaz et al.).

33.13 Differential Diagnosis of TBM and Parenchymal Tuberculosis It is clear from the radiologic literature that there are no specific CT or MRI findings in either TBM or parenchymal cerebral tuberculosis, and that the diagnosis rests on a combination of clinical assessment, imaging appearance, and response to therapy. A wide range of pathologic processes, including malignancy, pyogenic and fungal infections, paracytic infestations, and a range of other disconnected conditions, ranging from trauma to vascular malformation and aneurysm, can mimic either TBM or parenchymal tuberculosis (Jinkins 1991; Kanamalla et al. 2000; McGuinness 2000; Cremin and Jamieson 1996; Shah 2000; Wallace et al. 1991; De Castro et al 1995; Jinkins et al. 1995;

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Rochas-Echeverri et al. 1996; Cross et al. 1995; Atlas 1991; Bargallo et al. 1996; Ng et al. 1996; Rajshekhar and Chandy 1997; Graveli et al.1998; Shah et al.1993; Le Roux et al. 1990). Basal meningitis with infarctions is commonly seen in Haemophilus injluenzae infection. Infarctions are also common in aspergillosis and mucormycosis, where direct spread from the paranasal sinuses is usual. In these cases, infarctions follow extension of the condition though vessel walls, and are seen in the cortex and subcortex, but major vessel infarctions also occur. In disseminated cerebral coccidioidomycosis (DCC), intense basal meningeal enhancement involving the sylvian systems is seen, and is often more intense than that of TBM. However, cases where basal enhancement is absent, even in the presence of hydrocephalus, occur in both conditions (McGuinness 2000; Schoeman et al. 1988; Dublin and Phillips 1980). In DCC, the basal ganglia and white matter lesions are more diffuse than in TBM, and focal granulomas and basal ganglia infarctions are rare. Ventriculitis is also an early finding in DCC, and a late stage development in TBM (McGuinness 2000; Dublin and Phillips 1980). Geographically the distribution areas of DCC, histoplasmosis, blastomycosis, and TB overlap, giving rise to problems of differentiation (Ogawa et al.1987). In cryptococcus neoformans infection, basal meningeal enhancement, arteritis, and basal ganglia infarctions are seen. But in cryptococcal infection the organism can usually be isolated from the CSF and recognized using rapid laboratory techniques. In spirochetal disease, basal meningitis can develop together with parenchymal granulomatous gummas. In syphilitic infection these are often attached to the meninges, and associated cerebral atrophy and basal fibrous nonenhancing pachymeningitis is another diagnostic clue, as well as laboratory findings. Tickborne Lyme disease is another spirochetal infection that may affect the cerebrum. Granulomas in the basal ganglia can be present, but unlike those of tuberculosis are diffuse, and more solid lesions lack ring enhancement. Contrast enhancement of the CSF, on Gd MRI, has been described in both syphilis and Lyme disease, as well as in cryptococcal infection (Good and Jager 2000, Sakamoto et al. 1997). Abscess formation in bacterial, mycobacterial, and fungal disease cannot be differentiated radiologically. Bacteriologic or histologic examination, as well as the response to medical treatment, is the only means of differentiating among them. Single or multiple malignant tumors may mimic tuberculomas. The ring enhancement of tumors is

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often of varying thickness, and the ring is sometimes incomplete. The surrounding zone of edema tends to be less intense than in tuberculoma. With DSA, tuberculomas are avascular (Jinkins 1991; McGuinness 2000; Rochas-Echeverri et al.1996; Gupta et al.1991). Leptomeningitis carcinomatosis shows a patchy enhancement of the basal meninges (McGuinness 2000; Kioumehr et al. 1995). Primary lymphomas tend to be periventricular in position, and may cross the midline, passing through the corpus callosum, unlike supratentorial tuberculomas. Lymphomas have limited mass effect, are structurally diffuse, and show little or no edema and no ring enhancement (McGuinness 2000). Secondary lymphomas commonly affect the meninges, in contrast to the usual subcortical position of multiple tuberculomas. Single en plaque tuberculomas can cause some confusion, but enhance intensely, and have to be differentiated from meningiomas. They are avascular structures on DSA and MRA. Cysticercosis (CC) and TB have similar geographical distributions. CC lesions are distributed throughout the body and the diagnosis is often made from the biopsy of subcutaneous lesions. In cerebral CC, the various radiologic appearances of developing and degenerating cysts are described in the literature (Rajshekar et al.1993; Jena et al. 1988). The mural node of the living cyst can be defined by MRI, but may be difficult to define on CT studies. After death of the parasite, an intense local reaction and ring enhancement on T1 Gd studies are seen, with a central low signal area. Punctate calcification is often present on CT, while on MRI the various stages of development and death of the cyst are seen more clearly. At all stages, however differentiation is difficult and a trial of drugs may be necessary to make the diagnosis (Rajshekar et al. 1993; Jena et al. 1988; Rajshekhar and Chandy 1996). Rajshekhar points out that in a series of 16 patients examined by both CECT and T1 Gd MRI revealing a solitary CC granuloma, no additional information was acquired from the MRI studies. Cost plays an important role in the management of the generally underprivileged patients presenting with CC disease. He sees thin-slice contrast-enhanced CT as the examination of choice (Fig. 33.19a-d) (Rajshekhar and Chandy 1996). Toxoplasmosis produces intracerebral pathology that may be confused with tuberculoma. Toxoplasmosis is the most common infestation in AIDS, where tuberculosis may coexist. Cystic solid or ring enhancing lesions are described, often with a central enhancing nodule (McGuinness 2000; Atlas 1991). The distribution of the lesions in the subcortex

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and deep white matter is similar in both conditions. However, in toxoplasmosis, subependymal lesions are common, the ring enhancement is usually thicker and more irregular than in tuberculoma and hemorrhage into the lesion often occurs. Gupta has described hemorrhage in some tuberculomas analyzed by MRI and proton spectroscopy, but such lesions are uncommon (Gupta et al. 1991). Antitoxoplasmic therapy often reduces the size of the lesions in between 2 to 3 weeks, another way of differentiating them from tuberculomas. Neurosarcoidosis occurs in 5% of sarcoidosis cases and is usually a subacute condition, clinically unlikely to be confused with TBM. However the meningeal enhancement of sarcoidosis produces some similarities to TMB. Subfrontal meningeal enhancement in a patient who is not acutely ill is a common manifestation, and the suprasellar cisterns, parasellar spaces, and hypothalamic parenchyma are commonly involved, which can result in diabetes insipidus. Neurosarcoid changes are usually diffuse and show gyral and subcortical enhancement, and extension along the perivascular spaces. They are therefore likely to be confused with tuberculous border-zone disease. Parenchymal granulomas also occur. They can be of wide distribution above and below the tentorium. They are usually solid enhancing lesions and show little surrounding edema (Fig. 33.20). Hydrocephalus only occurs when periventricular infiltrating lesions cause CSF obstruction. MRI examination is particularly useful in demonstrating the spread of pathologic granulomatous tissue along the vessels in the Virchow-Robin spaces (Urback et al. 1997). When present, destructive lesions of the calvarium are another differential finding. Sarcoid lesions of the skull vault offer a point of biopsy, as do sarcoid lesions in other parts of the body. Other granulomatous disorders are unlikely to be confused with tuberculosis. Intracranial neurobrucellosis is a rare disorder even in areas where brucellosis is endemic. The incidence varies from 4% to 10% in reported series of cases of brucellosis (97). Meningitis tends to be chronic and intermittent rather than acute, although fever, neck stiffness, lethargy, and impaired consciousness are described. As the perineurium, as well as the vessel walls, are affected cranial nerve lesions are common. Madkour notes that sensorineural hearing loss may be the presenting sign, but the 6th, 7th, 2nd, and 5th cranial nerves are also commonly affected. Meningeal enhancement if present is mild and hydrocephalus uncommon. However, deep white matter granulomas have been seen (Fig. 33.21a, b). CT scans may be normal except

Imaging of Brain and Spinal Cord Tuberculosis

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b

a

---:z.;.o,-d Fig. 33.19a-d. Coronal and sagittal contrast-enhanced MRI. a· Coronal and b sagittal, contrast-enhanced MRI in two patients with solitary cysticercus granulomas. Showing a poorly circumscribed area of enhancement, lying beyond the apparent limits of the granuloma itself, in both cases

c

when mild hydrocephalus is present. MRI studies are of help, because evidence of enhancement of cranial nerves is more likely in brucellosis than in TBM (Fig. 33.22a-d) and intracerebral lesions when present are clearly imaged (Madkour 2001, Shakir 1986). Other intracranial mass lesions that may be similar in appearance to tuberculoma include those of tumefactive multiple sclerosis (TMS). In this condition, large, contrast-enhancing, white matter lesions, surrounded by vasogenic edema are found. They are usually low signal on Tl and high signal on T2, with minimal ring enhancement on TlGd acquisitions. The surrounding edema may be very extensive, and

the clinical presentation will usually differentiate TMS from single tuberculoma. The neurologic deficit is generally more widespread, and there can be a history of previous acute spinal myelitis (Fig. 33.23a,b) (Miller et al. 1989). Granulomatous masses in Candida meningitis, a common complication of AIDS, leukemia, and lymphoma, are generally extra-axial and fail to enhance on Tl Gd images. Cryptic angiomatous malformations presenting as mass lesions, develop a layered appearance as a result of local episodes of bleeding into the angioma. The presence of methhemoglobin accounts for the MRI appearance. In the rare cases of layered tuber-

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Fig. 33.20. Coronal Tl-weighted postgadolinium images. Multiple, enhancing, solid granulomatous lesions are seen in the cerebrum and brain stem (arrows). The appearances are indistinguishable from multiple tuberculomas. The patient was a proven case of multisystem sarcoidosis

a

b Fig. 33.21. a Postcontrast CT revealing periventricular enhancement (arrow) and edema (arrow heads). This was a case of cerebral brucellosis. b Diffuse, high signal, thalamic lesions in cerebral brucellosis

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a

b

c

d Fig. 33.22a-d. A case of brucella polyneuritis in a child. a Contrast-enhanced Tl-weighted image. Swelling and contrast enhancement of the prechiasmic portion of the right optic nerve (arrow) b Swelling of the left fifth cranial nerve and marked contrast enhancement of the fifth cranial nerves and gasserian ganglion in Meckel's cave (arrows). c Marked contrast enhancement of both seventh and eighth cranial nerves (arrows). d Coronal Tl-weighted image shows a well-defined, low signal, cystic mass with peripheral contrast enhancement, anteromedial to the left seventh and eighth cranial nerves (arrow)

b

a

Fig. 33.23. a Sagittal, postgadolinium MRI demonstrates two cerebellar tuberculomas (arrows). b A case of multiple sclerosis (MS). There are similar lesions in the cerebrum but in MS they are slightly less well defined (arrows); there is a poorly defined lesion in the cerebellum (arrow head)

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culoma, MRI spectroscopy demonstrates that tuberculomas have low levels of iron and other metallic elements (Gupta et al. 1991). Intracranial aneurysm may be differentiated from tuberculoma by MRI or DSA examinations. Where CT is the only available modality, small aneurysms of the circle of Willis have caused diagnostic problems (Gucuyener et al. 1993). Aneurysm is an uncommon complication of tuberculous arteritis, but does occur and can lead to intracranial hemorrhage, epistaxis, or bleeding from the aural canal (Leiguarda et al. 1988, Cross et al. 1995). MRI will differentiate between tuberculomas and aneurysms.

F. McGuiness

The study of spinal cord tuberculosis has made great strides since the advent of contrast-enhanced computer tomography (CECT) and magnetic resonance (MRI) studies. Before that conventional myelography was limited, both in its scope, and by the nature of the disease process (Chang et al. 1989). Excessive glutinous exudates associated with spinal meningitis impede the normal circulation of CSF, making lumbar puncture and the introduction of contrast agents difficult, and in the later stages almost impossible. Postmortem studies show that the exudates are very extensive, often filling the subarachnoid space completely, and compressing the cord and other spinal contents, with resulting cord edema and ischemia. Cord and nerve root swelling, as well as the development of granulomatous tissue, rapidly produces spinal block (Dastur et al.1995). In the late stages gliotic, collagen, and fibrotic pathologic tissue forms, causing irreversible changes in the theca and myelum. If tuberculous meningitis (TBM) and tuberculous spinal meningitis (TBSM) are present together, the deficits in the peripheral nervous system may be obscured by the low level of consciousness of the patient. Acute onset of back pain, paraesthesia, muscular weakness and, sphincter dysfunction are common features of TBSM. However, an insidious progressive pattern also occurs, mimicking intraspinal tumor, polyradiculopathy, or spinal demyelination. This type

cord cavitation result in permanent neurologic deficits (McGuinness 2000). In all cases, it is essential to investigate both the brain and the spinal lesion, as concomitant intracranial and intraspinal lesions are common (McGuinness 2000; Tandon 1978; Gupta et al.1997; Shen et al.1993). In a small number of cases, CT or MRI at the level of a spinal block will reveal tuberculous osteomyelitis of a vertebral body or, rarely, an isolated tuberculous epidural granuloma (McGuinness 2000). Wadia and Dastur divided tuberculous radiculomyelopathy into two groups: 1. Primary, arising from a focus of tuberculosis outside the central nervous system (CNS). 2. Secondary, arising from intracranial TBM or from spinal tuberculous osteomyelitis. In a series of 70 cases, they found the primary type to be more common (Wadia 1973; Wadia and Dastur 1969). The secondary type of TBSM is either the result of downward spread ofTBM infection, through the cerebrospinal fluid, or of the spreading outward and upward from a focus of spinal osteomyelitis, commonly in the lumbar or low thoracic regions. More recently, Dastur has confirmed that 50% of cases are of the primary type and over 30% follow the pattern of spreading down from intracranial TBM (Dastur et al. 1995). This is supported by the findings of Gupta. Of 20 consecutive cases of intraspinal tuberculosis, 75% were of the primary type and 25% secondary to TBM. None of the cases had vertebral tuberculous osteomyelitis (Gupta et al.1994). Geographical and racial differences may affect the mechanisms of spread, as Chang et aI., in a study of 13 cases, reported 85% associated with TBM, one case resulting from tuberculous spinal osteomyelitis, and only one primary case of an extramedullary tuberculoma arising low in the thoracic spine (Chang et al. 1989).As in TBM, the pressure effect of exudate in the confines of the spinal canal, combined with arteritis, gives rise to small vessel occlusion, with resulting ischemic myelitis. Local hematologic spread results in single or scattered intra-axial tuberculomas. The development of granulomatous tissue in the exudates produces thickening and deformity of the nerve root theca which at a later stage is converted to fibrous tissue. All elements of the theca and axial nervous system can be involved in the infection. Both leptomeningeal TB and tuberculous radiculomyelopathy are descriptive terms in current use,

has also been described as developing many years

but as not all of the intraspinal elements need to be

after apparently resolved intracranial TBM (Chang et al. 1989). In treated TBSM, inactive fibrotic and glial tissue remain in the spinal canal, and combined with

simultaneously affected, the term spinal neurotuberculosis, used by Dastur is also applicable (Dastur et al. 1995) (Figs. 33.24, 33.25).

33.14 Tuberculous Radiculomyelopathy and Myelitic Tuberculomas

Imaging of Brain and Spinal Cord Tuberculosis

Fig.33.24. Sagittal Tl-weighted postgadolinium scan of the thoracic spine. Markedly thickened spinal meninges and thick enhancing exudates compress the thoracic spinal cord and displace it anteriorly (arrows). A case of spinal tuberculous meningitis

Fig. 33.25. A single tuberculous lesion expanding the cord at the Th4 level. Ring enhancement with a central, lower signal due to a tuberculoma

As in TBM, the spread of the infection along the arachnoid-pia mater complex is rapid. Granulomas develop on the leptomeningeal and cord surface, leading to leptomeningeal thickening, and in the areas of cord involvement, to fusiform expansion of

571

the cord. Pitting and excavation of the cord surface often develops, involving the superficial neural tracts in the area. Varying patterns of neurologic deficit are present, because myelitis as well as nerve root pathology underlies the sensory and motor fall-out. The myelitic lesions are usually confined to short lengths of the cord, with intervening normal segments, and some cases show a true transverse myelitis. Cord edema involving considerable lengths of the myelum is another pattern. Fusiform swelling of the cord and eventually cavitation are described (Chang et al.1989; McGuinness 2000; Gupta et al.1994; Kumar et al. 1993). Spinal block occurs commonly, and although it may result from the development of granulomatous tissue at any level in the spinal canal, its usual site is at the level of the conus medullaris. As impediments to CSF flow develop, spinal puncture becomes increasingly difficult and a dry tap may result. The CSF becomes thick, at low pressure, and xanthochromic, due to a high protein content. Injecting of intrathecal contrast agents is increasingly difficult as granulomatous tissue advances and the flow of contrast is impeded. In the absence of MRI facilities, cervical myelography is sometimes necessary, but the same problems of impeded flow can be encountered in this area also. The clinical presentation of TBSM is similar to a large number of conditions, ranging from cord tumors to demyelinating disorders, and polyneuropathies. Tuberculous myeloradiculopathy should always be included in the differential diagnosis of spinal lesions, although rare, isolated TBSM does occur from tuberculous spondylitis or epidural granuloma, as well as that arising from TBM. Tuberculous disease in other body systems outside the nervous system occurs in between 50% and 80% of cases of TBSM (McGuinness 2000; Gupta et al. 1994), so the absence of tuberculosis elsewhere in no way excludes the possibility of tuberculous radiculomyelopathy.

33.15 Imaging Methods in Spinal Neurotuberculosis 33.15.1 Plain Radiography Plain radiography is of little direct help, except in cases where TBSM is associated with tuberculous spondylitis. However, as a method of exclusion of other causes of spinal cord or nerve root pathology,

572

it can be rewarding. If arachnoiditis is due to the remnants of oily contrast medium the cause is demonstrated, as is the case in some patients with vertebral neoplasm, metastasis, myeloma, or lymphoma.

33.15.2 Water-Soluble Contrast Myelography (WSCM) CT and MRI are not available in the majority of hospitals worldwide, and this is particularly the case in many of the 24 countries with a high burden of tuberculosis (WHO. Global tuberculosis control. 2000). By use of a basic radiography unit, myelography of the spinal axial nervous system may be acheived, even without a tilting table (McGuinnes 2000). Using myelography, it is possible in the majority of cases to define the lesion and the extent of the extramedullary disease. The disadvantage is that the pia-arachnoid and nerve root systems are well seen, but only the surface of the myelum can be studied. Variations of volume of the myelum are defined, but the presence of myelitis, intramedullary granulation lesions, and ischemic foci are not demonstrated. Also, it cannot be ascertained whether the lesions of the subarachnoid space and nerve roots are actively inflamed or represent scar tissue. As is the case in TBM, the changes seen in TBSM are nonspecific. Bacterial and fungal inflammatory diseases are mimicked, as are parasitic disease, tumor, arteriovenous malformation, sarcoidosis, polyradiculopathies, and demyelating disease. An attempt should be made to examine the full length of the cord, because in TBSM, multiple lesions are common, with areas of normal cord and theca intervening. In cases of TBSM, a normal myelogram is uncommon (Gupta et al. 1994). The usual patterns of the disease are as follows: 1. Irregular filling of the subarachnoid space, due to the presence of granulomatous exudates, granulomas, and thickening of the dentate ligaments. 2. Thickening of the nerve roots of the cauda equina and the paired nerve roots, particularly in the lower thoracic and lumbar regions. 3. Partial or total extramedullary blockage at the level of the conus medullaris or in the lower tho~ racic region. Blockage at higher levels, Th5, ThlC7, and C5, do occur, but are less common. 4. Long, vertical~ band-like filling defects, perhaps the result of thickening of the anterior midline septum. 5. Variations in the dimensions of the myelum, due to myelitis and cord edema. Most intramedullary tuberculomas in meningitis are too small to cause visible cord expansion.

F. McGuiness

6. Large mass lesions due to arachnoid or pial granulomas, simulating extramedullary tumours. These, in practice, are usually found posterior to the cord and in the lower thoracic area. 7. Epidural spinal abscess, due to extension of tuberculous vertebral osteomyelitis or, rarely, isolated epidural abscess without vertebral involvement. 8. Multiple filling defects in the contrast column, either fine and Widespread or larger and coarser, due to granulomatous lesions. Thecal granulomatous tissue also gives rise to surface irregularities and variations in the dimensions of the thecal sac (Chang et al. 1989; McGuinness 2000; Gupta et al. 1994; Kumar et al. 1993). On lumbar puncture in both TBM and TBSM in the early stages, a polymorph-leucocytic response may be found, suggesting a bacterial cause. Once the immune system has been triggered, then the picture changes to the characteristic findings of CSF pleomorphism, raised protein, and low sugar levels. In contrast to the appearances of spinal extramedullary tumor, the margins of granulomatous tissue are usually irregular and lack the smooth outline of most tumors. Thickening of the elements of the cauda equina is unlikely to be confused with the more serpentine appearance of vascular malformations of the spinal canal. Other granulomatous masses due to syphilitic gummas, or neurosarcoid are confusing, as well as those occurring in paracytic disease, such as schistosomiasis. Similar appearances of coarse filling defects may be the result of leptomeningeal carcinomatosis or due to the lymphomas, but the clinical findings outside the nervous system will usually point to the correct diagnosis in these cases (McGuinness 2000).

33.15.3 CT Combined with Water-Soluble Myelography CT examination in spinal inflammatory disease has the disadvantage that many images may be necessary to pinpoint multilevel pathology. Sagittal reconstructions are not of sufficient quality to define small lesions within the myelum, and there is relatively poor tissue differentiation between CSF, exudates, and the myelum (McGuinnes 2000). Gross volume changes of the myelum are recognized, and Chang et al. describe a pear-shaped cross section of the cord, in the lower thoracic region as being a common finding in cases of TBSM (Chang et al. 1989). Improved images are obtained by combining CT with contrast

Imaging of Brain and Spinal Cord Tuberculosis

myelography, although the disadvantage remains that if multiple level lesions are present, they may lie outside the area programed for examination. Small intramedullary TB lesions are isodense or hypodense on CT, and contrast examination adds little information in such cases. However, extra-axial granulomas may enhance, and if present epidural or paravertebral abscess will be recognized by postcontrast studies.

33.15.4 Magnetic Resonance Imaging In differentiating between the various tissues in the spinal canal, and in its multiplanar image acquisition, MRI is excellent in defining the pathology of spinal neurotuberculosis. This is especially so in the area of the cauda equina and the lumbar nerve roots (McGuinness 2000; Gupta et al. 1994; Kumar et al. 1993; Ross 1987; Gero et al. 1991), although some authors consider that water-soluble contrast CT has advantages (Chang et a11998). However, there is no doubt that in delineation of lesions within the cord, gadolinium-enhanced Tl-weighted MRI studies are superior to WSCM and to CT myelography. Active tuberculous lesions appear isodense or slightly hypodense on Tl images and either solid and hyperintense, or hyperintense with central area of low signal, on T2 imaging. After gadolinium-contrast injection, there is intense enhancement of tuberculomas, granulomatous tissue, and thecal inflammatory lesions. On Tl Gd studies in the areas affected by the disease, there is loss of differentiation between the spinal cord, the CSF, and the spinal meninges. These types oflesions are present either segmentally or throughout the length of the spinal canal. There are also variations in the caliber of the myelum, with thickening due to cord edema, or narrowing following cord compression. Areas of edema show a high signal on T2 images, but do not enhance after contrast injection. Tuberculomas of the cord are commonly of increased signal or isodense on T2. They are differentiated from areas of edema by enhancement after gadolinium on Tl acquisitions. There is no particular pattern of distribution of tuberculomas or extramedullary granulomas, except that those lesions causing spinal block are usually found in the lower thoracic or upper lumbar regions. The MRI findings are not specific to the disease, and are to be seen in other infections, fungal diseases, neoplasm, and paracytic infestations. Isolated epidural granulomatous masses are described by Gupta in the absence of both TBSM and tuberculous spondylitis (Gupta et al. 1994). In MRI

573

studies of the cervical spine, areas of the brain stem and medulla oblongata are invariably included in the disease (Shen et al. 1993). Isodense tuberculomas, if present will only be revealed on postcontrast studies. In all cases of suspected spinal tuberculosis, both the spine and the brain should be studied (McGuinness 2000; Gupta et al. 1997; Shen et al. 1993). Tuberculous radiculopathy of the cauda equina is not well demonstrated by noncontrast MRI. This is in contrast to nonspecific lumbar arachnoiditis, where MRI has been a useful tool (Ross 1987). In suspected lumbar radiculopathy, Tl Gd studies are usually only carried out in the sagittal plane. There is a case for including a coronal, postgadolinium study in the protocol to improve the definition of the cauda equina, the emerging nerve roots, and the associated pathologic changes (McGuinness 2000). WSCM is still a valuable method for imaging the changes of both active tuberculous radiculopathy and chronic adhesive tuberculous radiculopathy. However, a normal WSCM does not exclude spinal tuberculosis. Gupta describes five cases with normal conventional myelography, where subsequent Tl Gd studies revealed lesions in the myelum (Gupta et al. 1994). Despite its limitations in failing to image changes in the myelum, the superior definition of long stretches of nerve roots makes WSCM an important method of investigation, and one that is available to all radiologists (McGuinness 2000). Tl Gd MRI is important in the differentiation of active tuberculous granulomatous tissue from chronic fibrotic posttuberculous scarring, and in separating edema in the myelum from tuberculoma. Both fibrotic tissue and edema fail to enhance on TlGd examination (Chang et al. 1989; McGuinness 2000; Gupta et al. 1994). Although uncommon in the acute stage, syrinx formation and cavitation of cord lesions is described (Chang et al. 1989; McGuinness 2000; Sanchez Pernaute et al. 1996). Cavitation is more likely to develop in thoracic cord lesions than in other areas (Fig. 33.26a-c). Loculation of CSF, resulting from local obliteration of the subarachnoid space, is a common finding in both acute and suba95%) of patients develop exudative free or loculated ascites; however, a small group of patients may have a more advanced dry fibroadhesive (plastic) or purulent form of disease. Plastic peritonitis causes adhesions and matting of bowel loops, mass formation due to matting of bowel loops, adenopathy, mesenteric and omental thickening (omental cake). Purulent peritonitis is usually secondary to tuberculous salpingitis and causes abscess formation due breakdown of caseous lesions in lymph nodes, mesentery, or omentum. These abscesses are present within matted bowel loops and thickened omentum and mesentery. Fistulae, both cutaneous and enteric, are common when such abscesses rupture either through the skin or into the bowel. Clinical Manifestations (Marshall 1993; Singh et al. 1969; Manohar et al. 1990). Tuberculous peritonitis in its ascitic form presents insidiously with progressive abdominal distension. Diffuse abdominal pain (65%), fever (71%), and weight loss (38%) are seen in a variable percentage of patients. Clinical examination reveals shifting dullness, abdominal tenderness, and transverse solid epigastric intra-abdominal mass. The last is caused by rolled-up, thickened omentum infil-

M. S. Khuroo and N. S. Khuroo

trated with tubercles. The encysted form of the disease produces a localized cystic mass usually in the central or lower abdomen, resembling a mesenteric cyst in children and ovarian cyst in females. Plastic peritonitis produces matted small bowel loops with thickening of, and adhesions with omentum and mesentery. Patients often present with recurrent attacks of subacute intestinal obstruction. Acute intestinal obstruction may sometime supervene. Dilated bowel loops produce bacterial overgrowth and cause steatorrhea and wasting. Abdominal examination reveals single or multiple bowel masses which are resonant to percussion (thickened and matted bowel loops). Solid mass may be caused by thickened mesentery. Patients with purulent peritonitis are very sick, wasted, and in moribund clinical status. Abdomen examination reveals tenderness, guarding, multiple bowel masses, and usually a fecal fistula commonly near the umbilicus. Patients with tuberculous peritonitis with cirrhosis of the liver present with similar clinical features to those without liver disease. However, patients with liver disease are younger (42±8 years vs 54±15 years, p----1 25

30

tim. (month)

Fig. 47.1. Kinetics of free circulating IgG antibody levels against diacyl-trehalose (OAT) measured by ELISA in sequential serum from 11 HIV-positive (black squares) and 16 HIVnegative (open squares) patients with tuberculosis during anti tuberculosis treatment (mean ± SEM). The horizontal dotted line represents the cut-off value calculated with control sera and the open arrow the onset of treatment

than those in HIV-negative patients. However, at 15 months in HIV-negative and 30 months in the HIVpositive treated TB patients, the remaining antibody levels against DAT remained still higher than the threshold level . If this ELISA test is used systematically, it will not discriminate new TB patients from non-active TB in already treated patients. Similar results have been obtained using the PGL-Tbl antigen (data not shown) In conclusion, according to these data, two points are worth noting. First, the antibody follow- up do not seem to be very useful at monitoring early treatment efficacy, since both the anti-DAT and anti-PGLTbl antibody levels decline very slowly during the 6 months period of treatment. Second, when a new patient is suspected of TB disease and for the interpretation of the anti-glycolipid antibodies results, it is quite important to know if the patient has been treated in the recent past for a first episode of TB. Prospective Study in TB Patients Under Treatment

body production in the HIV-negative group of TB patients. It is also important to note that, even if the mean antibody titres showed a dramatic decline in this long term follow-up study, the slope of the curve appears to be less pronounced in HIV-positive TB patients

In a group of23 HIV-negative patients with documented TB, 13 were followed sequentially from the onset of the treatment to its completion. During this follow-up, one tube ofserum was harvested every week during the first month and at monthly intervals thereafter.

846

ELISA tests were performed using several individual sera and the dynamics of the free circulating IgG antibodies against a recombinant protein antigen (r38 kDa) and a purified carbohydrate antigen (LAM) were evaluated (Sousa et al. 2000). In all sera, a small but consistent decrease in antibody levels over the first two weeks of chemotherapy was observed. This decrease was followed by a gradual increase in the case of both anti-38 kDa and antiLAM. Thereafter, the mean level of anti-38 kDa IgG decreased from day 60 up to day 180. In all cases, this decreased was observed after M. tuberculosis culture conversion. In contrast, the mean level of anti-LAM IgG remained elevated for the complete duration of follow-up of patients. These results are in agreement with our preceding findings concerning the antibodies against the three glycolipids and also with those against proteins reported in the literature (Kaplan and Chase 1980; Drowart et al. 1991). Circulating Immune Complexes (CIe) Before and During Therapy Detection of Antibodies in the Circulating Immune Complexes In order to understand the false-negative ELISA tests in some TB patients, the presence of circulating immune complexes (CIC) in serum was first evaluated. Then, after CIC dissociation, the patient's anti-glycolipids IgG antibody contents were evaluated. The presence of anti-glycolipids within CIC in lepromatous leprosy sera has been already reported, often masking the real production of antibodies (Tomimori-Yamashita et al. 1999). CIC were isolated in the serum from adults, and children, with TB and in control sera using the 2.5% PEG precipitation technique. This has already been done with leprosy patient sera. Such PEG concentrations did not precipitate aggregated IgG, and all the CIC were precipitated after the first run. The quantity of CIC was measured at 280 nM with a spectrophotometer. CIC levels were significantly higher (p