Asthma and COPD: Basic Mechanisms and Clinical Management

Foreword During the last century, transmissible and acute diseases dominated the interests of the research, clinical, ...

Author: Peter J. Barnes | Jeffrey M. Drazen | Stephen Rennard | Neil C. Thomson

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Foreword

During the last century, transmissible and acute diseases dominated the interests of the research, clinical, and public health communities. Looking back, we can only marvel at the progress that has been made. Indeed, some contagious diseases have been eradicated, totally or virtually, in many parts of the world. Deaths from some acute events, such as myocardial infarction and stroke, have declined remarkably. As a result, quality of life, economic power, and life expectancy have all increased in a number of countries. Over the past 20 years in the United States, for example, life expectancy increased by about six years owing to a reduction in death rates of most major conditions. Chronic diseases of the airways, however, have worked against this favorable trend in life expectancy. Although death rates from asthma are relatively low, chronic obstructive pulmonary disease has a very significant impact on the total number of deaths worldwide. In the United States, it accounted for about 110,000 deaths in 1999, ranking as the fourth most common cause of mortality. Of even greater concern than the death toll from asthma and COPD is their considerable impact on those who live with these chronic diseases. Because of their lingering nature, they constitute an extraordinary burden that reduces the quality of life for the patients and many around them. Furthermore, these diseases have a negative impact on the economic potential of society, especially in developing countries. The burdens on the healthcare system are readily measurable – hospitalizations, emergency room visits, prescription drugs, respiratory therapy, long-term care, among others. But perhaps even more significant are the limitations that these diseases impose on the ability of their victims to fulfill their roles in school, in the workplace, and in the community, to care for their loved ones and, in many cases, even to care for themselves. The strength of a society resides in the independence and productivity of its people, and these qualities, in turn, hinge upon the people’s good health. Asthma and COPD are ominous threats to the strength of societies worldwide. At the end of the twentieth century, several events occurred that may lead to a transformation of this sad situation. First and foremost, the international scientific com-

munity began to arrive at the realization that the path to achievement of its ideal goal – elimination of the main cause of COPD, cigarette smoking – would be a rocky one and that its pursuit must be coupled with an intensive research effort to control and conquer this disease. With regard to asthma, an extraordinary research effort has yielded a greater understanding of the pathogenesis of this disease and a new armamentarium of therapeutic approaches that have proven to be remarkably effective. But there is no room for complacency! Another defining event has been a greater realization of the importance of chronic diseases, especially asthma and COPD, in the newly developed interests of the World Health Organization. This has been largely due to the work of Drs Murray and Lopez.1 They gave the research and public health communities great cause for alarm by demonstrating that the ranking of societal and individual burden from chronic respiratory diseases will rise from twelfth to fifth between the years 1990 and 2020. We, and the public at large, can only applaud the response of these communities. This book is further evidence of that response. First, it presents the best and newest of what is known about these two diseases. The roster of international contributors is stellar. In addition, the volume is comprehensive: all aspects of these two very prevalent diseases are addressed. The reader will soon recognize the complexity of the issues and appreciate the wonderful job that the text does of making them understandable. The most important and innovative feature of this volume, however, is its comparison, where appropriate, of the two diseases. Of course, asthma and COPD are different, but they also share a number of characteristics, and understanding one can greatly help us understand the other. In 1971, the CIBA Foundation sponsored a debate on “Identification of Asthma”.2 One participant led an extensive discussion on the definition of asthma and how it may be differentiated from chronic bronchitis. At its conclusion, another participant wisely observed: “The question that clinicians have to ask themselves before they can apply rational treatment is this: What is the mechanism?”

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Foreword

By comparing and contrasting asthma and COPD, this book helps answer that question. In the end, it is the patients and the societies in which they live who will benefit from this contribution Claude Lenfant, MD Bethesda, Maryland

1. Murray CJL, Lopez AD (eds). The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press, 1996. 2. Porter R, Birch J (eds). Identification of Asthma, pp. 132–50. CIBA Foundation Study Group, no. 38. Edinburgh: Churchill Livingstone, 1971.

Contributors

Ian M. Adcock National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK [email protected] Carlo Agostini Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy Steven M. Albeda Department of Medicine Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 852 BRBII/III 421 Curie Blvd Philadelphia PA 19104-6160 USA Yassine Amrani Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Bvd 805 BRB II/III Philadelphia PA 19104-6160 USA

Morgan Andersson Department of Otorhinolaryngology Lund University Hospital S-221 85 Lund Sweden Nick Anthonisen University of Manitoba 753 McDermot Avenue Winnipeg R3E 0W3 MB Canada [email protected] Jon G. Ayres Department of Respiratory Medicine Birmingham Hartlands Hospital Bordesley Green East Birmingham B9 5SS UK [email protected] Peter J. Barnes Department of Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK [email protected] John Britton Division of Respiratory Medicine City Hospital Hucknall Road Nottingham NG5 1PB UK [email protected]

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Contributors

A. Sonia Buist Oregon Health Sciences University Mail Code UHN 67 Sam Jackson Park Road 3181 SW Portland OR 97201 USA [email protected] Pierre-Regis Burgel Division of Medicine and Physiology University of California 505 Parnassus Avenue M-1325 Box 0130 San Francisco CA 94143-0130 USA [email protected] Edward J. Campbell Department of Medicine University of Utah School of Medicine 410 Chipeta Way Salt Lake City UT 84108 USA Gaetano Caramori National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK S. Cattapan Room A 342, Bldg 1 Hines Hospital 5th and Roosevelt Avenues Hines, IL 60141 USA [email protected]

George H.F Caughey Department of Medicine Cardiovascular Research Institute University of California Box 0911 San Francisco CA 94143-0911 USA [email protected] B.R. Celli Tufts Lung Station St Elizabeth’s Medical Center of Boston 736 Cambridge Street Boston MA 02135-2997 USA [email protected] Richard N. Channick Department of Medicine Division of Pulmonary and Critical Care Medicine University of California San Diego Med Center 9300 Campus Point Drive La Jolla CA 92037-1300 USA [email protected] Moira Chan-Yeung Respiratory Division Vancouver General Hospital 2775, Heather Street Vancouver B.C. V5Z 3J5 Canada [email protected] Kian Fan Chung National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK [email protected]

Contributors

D. W. Cockcroft Division of Respiratory Medicine Royal University Hospital Saskatoon SK S7N 0W8 Canada [email protected] Chris Corrigan Allergy and Respiratory Medicine 14th Floor, Hunts House Guys Hospital St Thomas’ Street London SE1 9RT UK [email protected] Adnan Custovic Department of Respiratory Physiology Wythenshaw Hospital Southmoor Road Manchester M23 9LT UK [email protected] Donna E. Davies Department of Medicine University of British Columbia Vancouver General Hospital Vancouver BC Canada [email protected] W. Bruce Davis Pulmonary Critical Care AF2024 Medical College of Georgia Augusta Georgia 30912-3135 USA [email protected] Dawn L. DeMeo Harvard Medical School Channing Laboratory 181 Longwood Avenue Boston MA 02115 USA

Sujal Desai King’s College Hospital London UK [email protected] Aaron Deykin Pulmonary and Critical Care Division Brigham and Women’s Hospital 75 Francis Street Boston MA 02115 USA [email protected] Jeffery M. Drazen Pulmonary and Critical Care Division Brigham and Women’s Hospital 75 Francis Street Boston MA 02115 USA [email protected] Ellen M. Drost Respiratory Medicine Unit Department of Medical and Radiological Science ELEGI/Colt Resarch Laboratories Medical School Teviot Place Edinburgh EH8 9AG UK Jonas S. Erjefalt Department of Physiological Sciences Lund University Hospital S-221 85 Lund Sweden Leonardo M. Fabbri Section of Respiratory Diseases Department of Medicine Oncology & Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy [email protected]

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Contributors

Marlies Feijen Department of Pediatrics University Hospital of Groningen PO Box 30.001 Groningen, 9700 RB The Netherlands [email protected] Jack Gauldie Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada [email protected] Jorrit Gerritsen Department of Pediatrics University Hospital of Groningen PO Box 30.001 Groningen, 9700 RB The Netherlands [email protected] John Gibson Department of Respiratory Medicine Freeman Hospital Newcastle upon Tyne NE7 7DN UK [email protected] Maurice Godfrey Center for Human Molecular Genetics University of Nebraska Medical Center Omaha NE 68198-5455 USA [email protected] Simon Godfrey Institute of Pulmonology Hadassah University Hospital Jerusalem Israel [email protected]

Lemark Grieff Department of Otorhinolaryngology Lund University Hospital S-221 85 Lund Sweden N.J. Gross Room A 342, Bldg 1 Hines Hospital 5th and Rossevelt Avenues Hines, IL 60141 USA [email protected] Ian Hall Division of Therapeutics University Hospital Nottingham NG7 2UH UK [email protected] David M. Hansell Royal Brompton and Harefield NHS Trust Sydney Street London SW3 6NP UK [email protected] James C. Hogg UBC McDonald Research Laboratories St Paul’s Hospital University of British Columbia 1081 Burrard Street Vancouver, BC V6Z 1Y6 Canada [email protected] Stephen T. Holgate RCMB Division School of Medicine University of Southampton Southampton General Hospital Southampton SO16 6YD UK [email protected]

Contributors

Gabor Horvath Division of Pulmonary and Critical Care Medicine University School of Medicine PO Box 016910 (R-47) Miami, FL 33101 USA [email protected] Sebastian L. Johnston Department of Respiratory Medicine National Heart and Lung Institute at St Mary’s Norfolk Place London W2 1PG UK [email protected] P. Jones Division of Physiological Medicine St George’s Hospital Medical School Cranmer Terrace London SW17 0RE UK [email protected] Susan Kennedy Occupational Hygiene Program University of British Columbia 2206 E Mall 3rd Floor Vancouver V6T 1Z3 Canada [email protected] Sergei A. Kharitonov Department of Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK [email protected] Martin Kolb Centre for Gene Therapeutics Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada

Chakradhar Kotaru University Hospitals of Cleveland 11100 Euclid Avenue Cleveland Ohio 44106-5067 USA Sam Krachman Division of Pulmonary and Critical Care Temple University Philadelphia PA USA [email protected] Vera P. Krymskaya Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Blvd 805 BRB II/III Philadelphia PA 19104-6160 USA Geoffrey J. Laurent Centre for Respiratory Research Royal Free; and University College Medical School Rayne Institute 5 University Street London WC1E 6JJ UK [email protected] Aili L. Lazaar Department of Medicine Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 852 BRBII/III 421 Curie Blvd Philadelphia PA 19104-6160 USA [email protected]

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Contributors

William MacNee Respiratory Medicine Unit Department of Medical and Radiological Science ELEGI/Colt Resarch Laboratories Medical School Teviot Place Edinburgh EH8 9AG UK [email protected] Robin J. McAnulty Centre for Respiratory Research Royal Free; and University College Medical School Rayne Institute 5 University Street London WC1E 6JJ UK E. R. McFadden Jr Division of Pulmonary and Critical Care Medicine MetroHealth Medical Center – BG3 2500 MetroHealth Drive Cleveland, OH 44109-1998 USA [email protected] J. L. Malo Sacré Coeur Hospital 5400 W Gouin Boulevarde Montreal H4J 1C5 Canada [email protected] Fernando D. Martinez College of Medicine University of Arizona 1501 N Campbell Avenue PO Box 245018 Tucson AZ 85724-5018 USA [email protected] Simon Message Department of Respiratory Medicine National Heart and Lung Institute at St Mary’s Norfolk Place London W2 1PG UK [email protected]

Andrew W.P. Molyneux University of Nottingham Division of Respiratory Medicine City Hospital Nottingham NG5 1PB UK Jay A. Nadel Division of Medicine and Physiology University of California 505 Parnassus Avenue M-1325 Box 0130 San Francisco CA 94143-0130 USA [email protected] Paul M. O’Byrne St Joseph’s Hospital Firestone Chest and Allergy Unit 50 Charlton Avenue Hamilton Ontario L8N 4A6 Canada obyrnep@mcmaster Rory A. O’Donnell RCMB Division School of Medicine University of Southampton Southampton General Hospital Southampton S016 6YD UK Reynold A. Panettieri Pulmonary Allergy and Critical Care Division University of Pennsylvania Medical Center 421 Curie Blvd 805 BRB II/III Philadelphia PA 19104-6160 USA [email protected]

Contributors

Martyn Partridge The Faculty of Medicine Imperial College Charing Cross Campus 5th Floor Charing Cross Hospital Fulham Place Road London W6 8RF UK James E. Pease Leukocyte Biology Section Sir Alexander Fleming Building Imperial College School of Medicine London SW7 2AZ UK John Pepper Royal Brompton Hospital Sydney Street London SW3 6NP UK [email protected] Carl Persson Department of Clinical Pharmacology Institute of Laboratory Medicine Lund University Hospital S-221 85 Lund Sweden [email protected] Dirkje S. Postma Department of Pulmonology University Hospital Groningen 9713 GZ The Netherlands [email protected] Neil B. Pride Thoracic Medicine National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK [email protected]

David Proud Johns Hopkins Asthma and Allergy Center 5501 Hopkins Bayview Circle Baltimore MD 21224 USA dproud@jhmi Irfan Rahman Respiratory Medicine ELEGI/Colt Research Laboratories University of Edinburgh Teviot Place Edinburgh EH8 9AG Scotland UK [email protected] Stephen Rennard Department of Internal Medicine University of Nebraska Medical Center 600 S 42nd Street Omaha NE 68198-5300 USA [email protected] L. Richeldi Section of Respiratory Diseases Department of Medicine Oncology & Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy M. Romagnoli Section of Respiratory Diseases Department of Medicine Oncology and Radiology University of Modena and Reggio Modena Largo del Pozzo 71.41100 Italy

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Contributors

Lewis J. Rubin Department of Medicine Division of Pulmonary and Critical Care Medicine University of California San Diego Med Center 9300 Campus Point Drive La Jolla CA 92037-1300 USA [email protected] Marina Saetta Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy Gianpietro Semenzato Department of Clinical and Experimental Medicine Clinical Immunology Branch Padua University School of Medicine Via Giustiniani 2 35128 Padova Italy [email protected] Steven D. Shapiro Department of Pediatrics Campus Box 8208 Washington University School of Medicine 660 South Euclid Avenue St Louis MO 63110 USA [email protected] Sat Sharma Section of Respirology University of Manitoba 753 McDermot Avenue Winnipeg R3E 0W3 MB Canada

Stephanie A. Shore Physiology Program Harvard School of Public Health 665 Huntingdon Avenue Boston MA 02115 USA [email protected] John R. Spurzem Department of Medicine Omaha VA Medical Center Omaha NE 68198-5300 USA [email protected] Scott A. Strassels Department of Pharmacy University of Washington Box 357630 Seattle WA 98195 USA [email protected] Sean Sullivan Department of Pharmacy University of Washington Box 357630 Seattle WA 98195 USA [email protected] Neil C. Thomson Department of Respiratory Medicine Western Infirmary Glagow G11 6NT UK [email protected] Martin J. Tobin Division of Pulmonary and Critical Care Medicine Loyola University Chicago Medical Center 2160 South First Avenue Maywood IL 60153 USA [email protected]

Contributors

Galen B. Toews Division of Pulmonary and Critical Care Medicine University of Michigan 1500 East Medical Center Drive 3916 Taubman Ann Arbor Michigan 48109-0642 USA [email protected] Rubin M. Tuder Division of Pulmonary Sciences and Critical Care University of Colorado Health Sciences Center Box C272 4200 East Ninth Avenue Denver CO 80262 USA Lena Uller Department of Physiological Sciences Lund University Hospital S-221 85 Lund Sweden Norbert F. Voelkel Division of Pulmonary Sciences and Critical Care University of Colorado Health Sciences Center Box C272 4200 East Ninth Avenue Denver CO 80262 USA [email protected] Adam Wanner Division of Pulmonary and Critical Care Medicine University of Miami School of Medicine PO Box 016960 (R-47) Miami Florida 33101 USA [email protected] J. Wedzicha Academic Respiratory Medicine Dominion House St Bartholomew’s Hospital London EC1A 7BE UK [email protected]

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Scott T. Weiss Channing Laboratory Brigham and Women’s Hospital 181 Longwood Avenue Boston MA 02115 USA [email protected] Timothy J. Williams Leukocyte Biology Section Sir Alexander Fleming Building Imperial College School of Medicine London SW7 2AZ UK [email protected] Ashley Woodcock Department of Respiratory Physiology Wythenshaw Hospital Southmoor Road Manchester M23 9LT UK [email protected] A.J. Woolcock formerly Institute of Respiratory Medicine Level 8 Building 82 Royal Prince Alfred Hospital Camperdown NSW 2050 Australia Miel Wouters Faculteit der Geneskude-Pulmonology Universiteit Maastricht PO Box 5800 6202 MZ Maastricht The Netherlands [email protected] Z. Xing Centre for Gene Therapeutics Department of Pathology and Molecular Medicine McMaster University 1200 Main Street West Hamilton Ontario L8N 3Z5 Canada

Preface

Asthma and chronic obstructive pulmonary disease are amongst the two commonest chronic conditions in the world today and both are predicted to increase. Because of their high prevalence and chronicity, these diseases impose an enormous and growing economic and social burden. Enormous strides have been made in our understanding of the basic mechanisms of asthma, with a much better appreciation of the inflammatory mechanisms involved and how this underlies the clinical features of the disease. This is one of the reasons why the management of asthma has improved enormously. Currently available medications are highly effective in most asthmatic patients, although there remain a small group of patients who are still not adequately controlled on existing treatments. But although asthma medications are very effective, many patients with asthma continue to have problems and asthma is still a common cause of hospital admission and time lost from work. There is therefore a need for further research in asthma and for the development of new and even more effective therapies. Although COPD is just as large a problem as asthma, there has been less attention given to this disease, and our understanding of the underlying basic mechanisms are far less advanced than for asthma. COPD has a very high morbidity and mortality and is a growing problem, particularly in developing countries. Treatment is less effective than in asthma, and none of the existing medications is able to reduce the progression of the disease. COPD is still commonly treated as poorly responsive asthma, yet the inflammatory process and effects are very different and there is little reason to think that the same treatments should be effective. There is a pressing need for much more research into underlying mechanisms of COPD, in order to identify novel therapies in the future. Management issues in COPD

are also different in many respects from those involved in asthma. Two of us (PJB and NCT) were involved in editing a book on Asthma: Basic Mechansism and Clinical Management. This was most successful and ran to three editions. In considering the next edition we thought that it would be very useful to include COPD as no other book had taken both these diseases together. In putting together this new volume on Asthma and COPD: Basic Mechanisms and Clinical Management we invited the two North American editors in order to make the book more international. We have retained the structure of the original Asthma book, but have added new chapters that are relevant to COPD. However, we have asked authors to consider both diseases in preparing their chapters. Of course, there is far more information about basic mechanisms pertinent to asthma than to COPD, but we hope that by contrasting this information and identifying areas of uncertainty, this may act as a stimulus to further research in COPD. We hope that this new book will be useful to researchers and to clinicians and will serve as a useful reference source. The format has been changed to make it more attractive and more easily read. Despite the advance of on-line publications on the Internet, we feel that there is still an important place for definitive reference books as a source of information. We would like to thank Margaret MacDonald and Simon Crump of Academic Press for all their help in putting together this book and we hope that you will enjoy the result. Peter J. Barnes London

Jeffery Drazen Boston

Stephen Rennard Omaha

Neil C.Thomson Glasgow

Chapter

Definitions

1

A. Sonia Buist Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, USA

Until recently, the presence or absence of reversibility was considered to be the key distinction between asthma and chronic obstructive pulmonary disease (COPD) – with reversible airflow obstruction the hallmark of asthma, and irreversible airflow obstruction the hallmark of COPD. Better understanding of both diseases has brought new definitions that acknowledge the overlap and highlight the similarities and differences between them. The important change in our understanding is the recognition that chronic inflammation underlies both diseases. The nature of the inflammation differs, however, as does the response to antiinflammatory medications, as described in detail in later chapters.

DEFINITIONS Asthma In the most recent US asthma guideline, the Expert Panel 2 Report,1 asthma is defined as: A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils,T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. COPD In the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines,2 COPD is defined as: A disease state characterized by progressive development of airflow limitation that is not fully reversible.The airflow limitation is usually progressive and usually results from an abnormal response of the lungs to noxious particles or gases.

SIMILARITIES AND DIFFERENCES Over the past 30 years, thinking about asthma and COPD has swung between the concept of asthma and COPD belonging to a spectrum of diseases that all cause airflow obstruction, to the concept of them as very different diseases, and most recently to them both being inflammatory diseases with important similarities and differences. The present thinking is illustrated in Fig. 1.1 from the GOLD guidelines, which shows both diseases causing airflow limitation, but through a gene–environment interaction involving different sensitizing agents, different cell populations in the inflammatory response, and a spectrum of reversibility. The airflow limitation resulting from the inflammatory process ranges from completely reversible (the asthma end of the spectrum) to completely irreversible (the COPD end of the spectrum). Table 1.1 highlights the most important similarities between asthma and COPD. Both are chronic inflammatory diseases that involve the small airways and cause airflow limitation; both result from gene–environment interactions;

ASTHMA Sensitizing agent

Asthmatic airway inflammation CD4 T lymphocytes Eosinophils

Completely reversible

COPD Noxious agent

COPD airway inflammation CD8 T lymphocytes Macrophages Neutrophils

Airflow limitation

Completely irreversible

Fig. 1.1. Schematic of the genesis of airflow obstruction in asthma and COPD.

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Asthma and Chronic Obstructive Pulmonary Disease

Table 1.1. Similarities between asthma and COPD

Both are chronic diseases Inflammation present in both Airflow obstruction Involvement of the small airways Mucus Bronchoconstriction Both are consequences of gene–environment interaction

and both are usually characterized by mucus and bronchoconstriction. Although the similarities are striking, it is the differences between the two diseases that define their natural histories and clinical presentations. The key differences are contrasted in Table 1.2. The first obvious difference is that the diseases involve different anatomic sites in the lungs. COPD affects both the airways and the parenchyma; asthma affects only the airways. The small airways are involved in both diseases, and the structural changes at this level are responsible for much of the lung function impairment associated with these diseases. Also, an important difference anatomically is that emphysema, an irreversible, destructive, parenchymal disease, is variably present in COPD, but is not present in asthma. Perhaps the single most important difference between the two diseases is the nature of the inflammation: it is primarily eosinophilic, CD4-driven in asthma and neutrophilic, CD8driven in COPD.1,2 The nature of the inflammation in turn affects the response to pharmacological agents. There is ample evidence now that inhaled corticosteroids are effective against the eosinophilic inflammation that is characteristic of asthma,1–5 but largely ineffective against the primarily neutrophilic inflammation seen in COPD – although this is not a completely consistent finding. The natural histories of asthma and COPD are very different. COPD is a chronic and progressive disease that is characterized by airflow limitation that is not fully reversible and by an accelerated decline in lung function. Asthma is a

chronic disease, but it is usually not considered a progressive disease, and it is not usually characterized by an accelerated decline in lung function, unless there are other risk factors such as smoking.9,10 The airflow limitation is fully reversible in the early stages of asthma but, at least in a subset of asthmatics, may become progressively less reversible as the disease becomes longstanding.11 The difference in the gene–environment interaction in the two diseases has already been alluded to: in asthma, the inflammation is a response to inhaled allergens. In COPD, the inflammation is a response to noxious particles and gases.

D I F F E R E N T I AT I N G B E T W E E N A S T H M A AND COPD It would be easy to differentiate between asthma and COPD if the latter occurred only in smokers and asthma in nonsmokers. In fact, there is a clear diagnostic bias on the part of physicians, with COPD more likely to be diagnosed in men and asthma in women.11 It is important to emphasize that both conditions may coexist in an individual, so many will have the clinical and pathophysiological features of both diseases. This makes differentiating the diseases sometimes challenging for the clinician, especially in older adults who are or have been smokers. The clinician can be guided by information in the clinical history, such as smoking history, age of onset of symptoms, history of atopic conditions, and description of acute episodes of shortness of breath (see Table 1.3). Asthma usually has its onset in early childhood. However, adult-onset asthma does exist, and many are unable to remember childhood events that would provide a clue to the early stages of asthma. Therefore, unless symptoms are continuous from childhood, the onset of asthma symptoms in adult life may be hard to interpret, especially in the presence of other risk factors such as smoking. COPD typically becomes clinically apparent in the sixth and seventh decades of life. If an individual is physically active, he or she may notice reduced exercise tolerance earlier.

Table 1.2. Differences between asthma and COPD

Characteristic

Asthma

COPD

Anatomic site of disease Nature of inflammation Reversibility of airway obstruction Response to inhaled corticosteroids Progression of disease

Airways involved Eosinophilic, CD4-driven Mostly reversible Inflammation reduced Chronic, but not characterized as progressive Normal or slightly accelerated Allergens are main drivers of inflammation

Airways and parenchyma involved Neutrophilic, CD8-driven Mostly irreversible Inflammation mostly nonresponsive Progressive airflow obstruction

Decline in lung function Gene–environment interaction

Accelerated Particles and gases are main drivers of inflammation

Definitions

5

Table 1.3. Clinical features of asthma and COPD

Clinical feature

Asthma

COPD

Age of onset

Usually early childhood, but may have onset at any age May be non-, ex-, or current smoker History of atopic disorder(s) common Common at all levels of severity except mild intermittent Of atopic disorders or asthma commonly present Normal in mild intermittent and mild persistent; airflow obstruction present at all other steps Characteristic of asthma Characteristic of asthma, usually 20% Usually normal

Mid–late adult life

Smoking history Atopy Exacerbations Family history Lung function

Reversibility of airflow obstruction Peak flow variability Diffusing capacity

COPD in developed countries is mostly a disease of smokers. This is not necessarily true in developing countries where other risk factors, such as heavy outdoor and indoor/occupational air pollution, may be important risk factors that are causally related to COPD.2 The relationship between asthma and smoking is complex. Individuals with asthma may be nonsmokers, smokers, or ex-smokers. Since asthma genes and genes leading to the susceptibility to develop airflow obstruction with smoking are common in the population, the likelihood that an individual may have both is high. One of the unresolved questions about asthma relates to the nature of the complex relationship between asthma and atopy. Most asthmatics are atopic, but not all atopic individuals have asthma. A history of atopic disorders, such as allergic rhinitis or eczema, is therefore common in asthma, but is not a characteristic of COPD. As noted above, because asthmatic/atopic genes are widespread in the population, it is not unusual for atopic disorders to coexist with COPD, but it is not a characteristic of the disease as it is for asthma. Pulmonary function tests can also provide guidance. Both diseases are characterized by airflow obstruction except in the early or mild stages. In asthma, lung function is still normal in patients with mild intermittent or mild persistent disease.1 COPD, in comparison with asthma, is defined by airflow limitation, and this becomes progressively greater as the disease advances. Fig. 1.1 shows the spectrum of reversibility ranging from completely reversible (asthmatic end) to completely irreversible (COPD end). Clinically, reversibility is defined as 12% increase in FEV1 (and at least 200 mL) over baseline.12 If clear-cut reversibility of airflow limitation is found, asthma is likely to be present. If the airflow limitation is irreversible, COPD is likely to be the diagnosis.

Usually smoker or ex-smoker Not a prominent feature Increase in frequency with increasing severity of disease Not usually a feature Airflow obstruction a hallmark of COPD Poorly reversible Often does not vary at all Abnormal when there is emphysema

OVERLAP BETWEEN ASTHMA AND COPD Not acknowledged in the definitions is the fact that longstanding asthma can lead to airway remodeling and partly irreversible airflow obstruction. So, in many (but not all) with longstanding asthma, there is an appreciable component of chronic irreversible airflow obstruction with reduced lung function and incomplete response (or at least, not complete reversibility) to a short-acting bronchodilator or to oral or inhaled corticosteroids.13,14 This complicates the diagnosis of asthma in older adults, and requires that the goals of treatment be modified since maintenance of normal lung function can no longer be a realistic goal. Not clear yet is whether early and aggressive treatment with anti-inflammatory drugs can prevent remodeling, or in what proportion of individuals with longstanding asthma remodeling occurs. Whether longstanding asthma with remodeling can be called COPD is intensely controversial. In so far as there is irreversible or poorly reversible airflow obstruction in the remodeled lungs, the term seems appropriate. Conceptually and practically, the recognition that remodeling is a feature of longstanding asthma in many (but not all) reinforces the notion that these diseases constitute a spectrum of disease, as illustrated in Figure 1.1, ranging from fully reversible to fully irreversible.

E X A C E R B AT I O N S The definition of asthma highlights the importance of exacerbations as a feature of asthma, and emphasizes the fluctuations of the disease.1 The definition of COPD does not include any mention of exacerbations.2 Nevertheless, they may be as important in the natural history of COPD as

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they are in asthma15–17 and account for approximately 70% of the COPD-related costs in the US.2 The commonest causes of exacerbations of COPD are infections of the tracheobronchial tree and air pollution,2,18–21 but the causes of about one-third of severe exacerbations cannot be identified. The commonest symptom of an exacerbation of COPD is increased breathlessness, often accompanied by wheezing, chest tightness, increased cough and sputum, change in color and/or tenacity of sputum, and fever. Enquiring about the nature, frequency, and length of exacerbations is an important part of the clinical history in COPD since exacerbations are an important contributor to the erosion of quality of life in severe disease, and should therefore be an important focus of management.

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L I M I TAT I O N S O F T H E D E F I N I T I O N S Definitions for both asthma and COPD have limitations since they can reflect only our current understanding of the diseases, which is quite limited. Both diseases will continue to be redefined as our understanding of them deepens, and as new effective preventive strategies and treatments become available.

REFERENCES 1. National Asthma Education and Prevention Program Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma, National Institute of Health, National Heart, Lung, and Blood Institute. NIH Publication 97-4051, 1997. 2. Pauwels RA, Buist AS, Calverley MA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am. J. Respir. Crit. Care Med. 2001; 163:1256–76. 3. Haatela T, Järvinen M, Kava T et al. Comparison of a b2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N. Engl. J. Med. 1991; 325:388–92. 4. Haatela T, Järvinen M, Kava T et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N. Engl. J. Med. 1994; 331:700–5. 5. Jeffery PK, Godfrey W, Ädelroth E et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. Am. Rev. Respir. Dis. 1992; 145:890–9. 6. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glutocorticoids on inflammatory indices in

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20.

21.

asthma and COPD. Am. J. Respir. Crit. Care Med. 1997; 155:542–8. Culpitt SV, Maziak W, Loukidis S et al. Effects of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9. Confalonieri M, Mainardi E, Della Porta R et al. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease. Thorax 1998; 53:583–5. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur. J. Respir. Dis. 1987; 70:171–9. Lange P, Groth S, Nyboe J et al. Decline of lung function related to the type of tobacco smoked and inhalation. Thorax 1990; 45:22–6. Dodge R, Cline MG, Burrows B. Comparisons of asthma, emphysema, and chronic bronchitis diagnoses in a general population sample. Am. Rev. Respir. Dis. 1986; 133:981–6. American Thoracic Society, Medical Section of the American Lung Association. Lung Function Testing: Selection of Reference Values and Interpretive Strategies. Official Statement of the American Thoracic Society, adopted by the ATS Board of Directors, March 1991. Busse W, Elias J, Sheppard D, Banks-Schlegel S. Airway remodeling and repair. Am. J. Respir. Crit. Care Med. 1999; 160:1035–42. Fish JE, Peters SP. Airway remodeling and persistent airway obstruction in asthma. J. Allergy Clin. Immunol. 1999; 104:509–16. Burge PS, Calverley PM, Jones PW et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. Gibson PG, Wlodarczyk JH, Wilson AJ, Sprogis A. Severe exacerbation of chronic obstructive airways disease: health resource use in general practice and hospital. J. Qual. Clin. Pract. 1998; 18:125–33. Reguerio CR, Hamel MB, Davis RB et al. A comparison of generalist and pulmonologist care for patients hospitalized with severe chronic obstructive pulmonary disease: resource intensity, hospital costs, and survival. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Am. J. Med. 1998; 105:366–72. Wilson R. The role of infection in COPD. Chest 1998; 113:242S–8S. Soler N, Torres A, Ewig S et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am. J. Respir. Crit. Care Med. 1998; 157:1498–505. Anderson HR, Spix C, Medina S et al. Air pollution and daily admissions for chronic obstructive pulmonary disease in six European cities: results from the APHEA project. Eur. Respir. J. 1997; 10:1064–71. Chodosh S, McCarty J, Farkas S et al. Randomized double-blind study of ciproflaxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group. Clin. Infect. Dis. 1998; 27:722–9.

Chapter

Epidemiology

2

Dawn L. DeMeo and Scott T. Weiss Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

This chapter discusses the epidemiology of both asthma and chronic obstructive pulmonary disease (COPD). After briefly contrasting the disease definitions, the chapter reviews incidence and prevalence data, risk factors, and natural history.

DEFINING THE DISEASES Asthma The study of asthma epidemiology has been plagued by lack of consensus regarding standards for diagnosis. Most definitions have included variable airflow obstruction; but asthma is a clinical syndrome, without a gold standard for its diagnosis. Epidemiology studies have used questionnaires to assess for the presence of disease, but are limited by recall and misclassification bias. Some have suggested that symptoms should be assessed in conjunction with airway hyperresponsiveness.1 Others argue that airway hyperresponsiveness and symptoms should be analyzed separately owing to the poor correlation between clinical asthma and hyperresponsiveness.2 Population-based epidemiology studies have demonstrated a low sensitivity of airway hyperresponsiveness for detecting asthmatic phenotypes, versus a sensitivity of greater than 90% in clinic studies.3 A standard definition of asthma is as a chronic inflammatory disease of the airways with variable reversible airflow obstruction. Beyond definitions, there are differences between languages for the words used to describe asthma symptoms. A novel solution to this problem has been used in the International Study of Asthma and Allergies in Children (ISAAC), which includes an asthma video questionnaire demonstrating clinical signs of asthma as an attempt to improve uniformity in surveying for asthma.4 COPD Before describing epidemiological trends for obstructive lung disease, agreement on definitions should be achieved such that trends in incidence, prevalence, morbidity, and mortality can be properly ascribed.

COPD includes chronic bronchitis and emphysema, and is characterized by airway obstruction that is fixed or only partially reversible. The degree of airflow obstruction assigned to a given patient depends upon the guidelines used, with some defining mild obstruction as a FEV1 greater than 65%, 70%, or 80% of predicted. As in the case of asthma, the lack of international standardization of criteria for diagnosis in COPD makes understanding relative incidence and prevalence more challenging. This is well illustrated by a study by Viegi et al.5 who compared the prevalence rates of COPD in a general population in the Po Delta Valley using European Respiratory (ERS) criteria, American Thoracic Society (ATS) criteria, and standard clinical criteria. In subjects 25–45 years of age: • ERS criteria revealed a 10.8% prevalence of COPD; • ATS criteria revealed a 27% prevalence; • clinical criteria showed a 9.9% prevalence. Similarly, in subjects aged 46 years or more: • ERS criteria revealed a 12.2% prevalence; • ATS criteria had a 57% prevalence; • clinical criteria showed a 28.8% prevalence. This example highlights the difficulty of comparison between international studies and the effort to understand COPD on a global scale. If such discrepant results are obtained within a single population, then the difficulty of comparison between populations is very clear. In summary, both asthma and COPD lack gold standards for diagnosis, which would facilitate epidemiological studies. As a result, comparison of studies of asthma and COPD between populations and between countries must be viewed in the light of differences in criteria used for disease diagnosis.

INCIDENCE Asthma is predominantly a disease of childhood, with more than 17.3 million persons having asthma in the United

8


COPD vary with the age of the population. Asthma is commonly diagnosed in early childhood; COPD is commonly diagnosed after age 60.

States, 12 million are children of less than age 16. In childhood, incidence rates for asthma are highest among the youngest age groups6,7 and among male children until puberty.8–11 In a recent study of an adult Swedish population, Toren and Hermansson12 found the incidence rate for adult-onset asthma to be highest among females of all ages greater than 20, with an incidence of 1.3 per 1000 personyears; among women 16–20 years of age the rate was 3 per 1000 person-years. Analysis of data from a prospective cohort study in Finland demonstrated no increase in incidence for asthma from 1982 to 1990 in adults aged 18–45 years.13 Early investigation into the increasing prevalence of asthma in the United States was noted in a review of medical records from Olmsted County, Minnesota, where the annual incidence of asthma was found to increase from 183 per 100,000 in 1964 to 284 per 100,000 in 1983. The most significant increase was in children aged 1–14 years, suggesting a potential cohort effect early in life. Despite this increased incidence in asthma among children from 1964 to 1983, constant rates were observed among adults.6 Although these data indicate that asthma incidence is increasing, minimal information is available for trends in COPD incidence. Incidence rates for asthma and

P R E VA L E N C E Recent trends in the prevalence of obstructive lung disease are suggested by an analysis of the National Health and Nutrition Examination Survey (NHANES III).14 This included subjects with asthma, chronic bronchitis, and emphysema (Fig. 2.1). In this cohort, outcome measures included a physician diagnosis of chronic bronchitis, asthma or emphysema, respiratory symptoms, and low lung function. Of note, for the purposes of evaluating this cohort the investigators defined low lung function as present when both the FEV1/FVC ratio was < 0.70 and the FEV1 was less than 80% of predicted. Of the investigated population of 20,050 adults, 6.8% had low lung function as thus defined; 7.2% of the population had an FEV1/FVC ratio less than 0.70 with an FEV1 greater than 80% predicted, and were not included as having low lung function. Of the entire population, 8.5% reported obstructive lung disease.

25 Current COPD Past Chronic Bronchitis or Asthma

Current COPD and Asthma Current Asthma

Percentage with condition

20

15

10

5

Black female

Black male

White female

≥85

75–84

65–74

45–64

25–44

17–24

≥85

75–84

65–74

45–64

25–44

17–24

≥85

75–84

65–74

45–64

25–44

17–24

≥85

75–84

65–74

45–64

25–44

17–24

0

White male

Age Fig. 2.1. Age-specific percentage of individuals, stratified by race and sex, with chronic obstructive pulmonary disease and asthma, current COPD, current asthma, and past chronic bronchitis or asthma. Reproduced from National Center for Health Statistics, Plan and Operation of the Third National Health and Nutrition Examination Survey, 1988–94, US Dept of Health and Human Services publication PHS 94-1308, 1994, with permission.

9

Epidemiology

Importantly, 63.3% of those with documented low lung function had no current or prior doctor diagnosis of obstructive lung disease. In addition to prevalence information regarding low lung function, data from NHANES suggests that there is still a significant proportion of disease that goes undiagnosed in the mild stages, thus leading to an underestimation of the true prevalence of obstructive lung disease. Asthma Data from the United States suggest an increase in prevalence of asthma in children as well as in older adults. During the last several decades studies have suggested an increase in prevalence worldwide of 5–6% per year. Data from the National Health Interview Survey reveal an increase of 75% in self-reported asthma rates from 1980 to 1994 (Fig. 2.2). This trend was demonstrated in all age and race strata as well as in both genders. The most significant increase was among:

COPD Susceptibility to cigarette smoke is not uniform. However, COPD is best understood by understanding first the trends for smoking in populations. Although projected smoking rates throughout the world have increased, smoking prevalence in the United States between 1983 and 1995 declined overall: • • • •

• children 0–4 years of age (increase of 160%); • persons 5–14 years of age (increase 74%).15 The prevalence among inner-city children is much higher.15–17 It has been suggested that a doctor’s diagnosis of asthma is made less frequently than asthma symptom reporting, raising concern that despite increasing prevalence there is still a tendency to underdiagnose asthma, and consequently underestimate true prevalence values.18 The increasing prevalence of asthma has been recapitulated in international data. The International Study of Asthma and Allergies in Children (ISAAC) has as its aim to describe, across 155 centers, the prevalence and severity of asthma in children in 56 countries.4 Phase 1 of this trial has demonstrated a large variation in the prevalence of asthma symptoms in children throughout the world, with the

from from from from

30% 32% 34% 41%

to to to to

24% 23% 26% 29%

in white women; in African American women; in white men; in African American men.

Stang et al.22 utilized smoking rates to create a mathematical model for estimating current COPD prevalence. Using their model, they estimated that 15.3 million people in the United States aged 40 years or more have COPD; this was a reasonable estimate compared to the spirometric prevalence of 17.1 million as estimated by the Third National Health and Nutrition Examination Survey. Using this model, they also predicted the prevalence of COPD in Germany (2.7 million), the United Kingdom (3.0 million), Spain (1.5 million), Italy (2.6 million), and France (2.6 million), and suggested smoking rates as a useful surrogate for estimating COPD prevalence.

Prevalence rates of asthma

16 14 Number (millions)

highest prevalence in centers from Australia, New Zealand, the United Kingdom, and Ireland18–21 (Fig. 2.3). While the prevalence of allergic rhinitis has been noted to be scattered in the groups with the highest prevalence of asthma, the lowest prevalence for rhinitis has been found in countries where the asthma prevalence was lowest, such as in Eastern Europe, Indonesia, Greece, and India. In addition to defining prevalence rates, the ISAAC study represents an effort to establish an international standard to facilitate comparability of data from epidemiological studies of asthma.

* 1

B

±

1.0

-^

1

0

1

1 2

1

1

1

3

4

1

1

5 6 Days

Symptoms

1

1

1

7

8

9

••

Smoke Cold air Exercise

10

Fig. 37.2. Allergen-induced increase in nonallergic airway responsiveness to inhaled histamine. A dual asthmatic response, with spontaneous recovery, occurred after a single inhalation of ragweed pollen extract. Airway responsiveness to inhaled histamine, expressed as the provocation concentration causing a 2 0 % FEV, fall (PC20), increased after allergen exposure, and was associated with asthma symptoms on exposure to nonallergic stimuli. Reproduced from Reference 135, with permission.

effect.*'' Regular use of inhaled P2 agonists for a week or more increases the EAR,*^"*' the LAR,*'"*' mast cell mediator release,*' and allergen-induced airway inflammation.*'"*' A larger dose of allergen can be administered after an inhaled P2 agonist and will lead to a larger LAR.'" These features, failure to inhibit the LAR, enhanced airway responses, and ability to tolerate a larger dose of allergen, may be relevant in P2 agonist worsened asthma control." Muscarinic blockers cause variable minor inhibition of the EAR5''''2-74 and no inhibition of the LAR.'^.'^ Allergeninduced airway hyperresponsiveness appears to be uninfluenced by anticholinergics.''' The enhanced airway responsiveness to histamine following allergen inhalation is no more responsive to atropine than it was prior to allergen inhalation.'^ Ingested theophylline offers partial protection against both the EAR and the LAR'*"" and variable protection against induced airway hyperresponsiveness.""" It is not clear whether this is a functional antagonist or an antiinflammatory effect. Inhaled sodium cromoglycate (SCG) given prior to allergen exposure inhibits both the EAR and LAR, 44,45,57,60,77,80 .

well as the allergen-induced responsiveness to both histamine*" and methacholine." Nedocromil sodium appears to have similar effects on allergen-induced asthmatic responses.*' S C G given after the EAR will slightly delay but not inhibit the LAR.**^ A single dose of inhaled corticosteroid, given prior to allergen, has no influence on the EAR but provides effective, often complete inhibition of the lJ^R_11,1s,^^,6o,ao-a6 ^ ^jj^gjg dose given after the EAR will inhibit the LAR.*^ Longer treatment periods with inhaled corticosteroids will partially inhibit the EAR as well.**'*^'** Corticosteroid-induced provides only improvement m airway responsiveness* partial explanation.** Reduction in mucosal mast cells*'"" is likely more important. Hi blockers partially inhibit the early portion of the EAR.''^'^'"'^"''' Newer Hj blockers may also show some inhibition of the LAR;''' further studies are necessary. Ingested anti-allergic drugs such as ketotifen and repirinast have produced variable effects on allergen-induced asthma.'^"'"^ Most studies have failed to show any significant protection.'^•'*'""'"'^ Nonsteroidal anti-inflammatory agents, particularly indomethacin, appear to have no effect or perhaps enhance the EAR;'"^ there is conflicing evidence regarding the late response.'"''"'"* Allergen-induced increase in airway responsiveness appears to be partially inhibited by indomethacin.'"* A thromboxane synthetase inhibitor had no effect on allergen-induced early or late responses or increased airway responsiveness.'"' Interference with the leukotriene pathway with leukotriene receptor antagonists," 5-lipoxygenase inhibitors"" or 5-lipoxygenaseactivating protein inhibitors'" produces modest inhibition of EAR and LAR. A platelet activating factor antagonist proved ineffective against allergen-induced asthma."^ Inhaled furosemide provides inhibition of both EAR and LAR."^ Allergen injection therapy has produced variable results in modulating the EAR"'''"^ but may be particularly effective versus the LAR."* A novel recombinant anti-IgE molecule directed against the Fc component of IgE is very effective at inhibiting both the E A R ' " and LAR."* Mechanisms The mechanisms of allergen-induced asthmatic responses have been studied in humans by indirect means. Animal studies, in-vitro studies on excised human tracheobronchial smooth muscle, drug-inhibition studies and, more recently, bronchoalveolar lavage and induced sputum, have all been used to assess mechanisms. The EAR is due to the allergenIgE-mast cell acute mediator release including histamine,'" prostaglandins,'^" and leukotrienes'^' and is primarily bronchospastic. Individual mediator blockers are only partially effective in inhibiting the EAR,'^''^''"*''"' however, an in-vitro study on human tracheal smooth muscle demonstrated complete inhibition of the EAR by combined Hj blocker, cycloxygenase inhibitor and lipoxygenase inhibitor. '^^ The pathogenesis of the LAR is not so clear. An outdated hypothesis that late responses were type III precipitinmediated responses,'''' controversial at that time,^' has been

Allergens

disproved since both cutaneous123,124 and pulmonary118,125 late responses are IgE-mediated. Animal studies have documented the requirement for inflammatory cells (eosinophils, neutrophils) in the LAR126,127 and induced airway hyperresponsiveness.128–130 This has been confirmed in humans using BAL18,131 and induced sputum.47,109 The precise role of the chemokines and their cellular origin in the recruitment of inflammatory cells is a topic of current research.132–134 Allergens as a cause of asthma The importance of allergens as a cause of asthma (i.e. symptomatic airway hyperresponsiveness and airway inflammation135) which was hypothesized several years ago136 (Fig. 37.3), is now generally accepted.137 The lines of reasoning include the high prevalence of atopy amongst asthmatics,20,21 the correlation of both airway hyperresponsiveness and asthma with atopy in epidemiological population studies32,138–143 (Fig. 37.4), the relationship of both seasonal42,49,50,144,145 and indoor23,24,146 allergen exposure to symptoms and airway hyperresponsiveness, and their reduction with allergen avoidance.147,148 It is speculated that, in sensitized individuals, the duration and magnitude of airways allergic exposure, if not suppressed pharmacologically, may lead not only to transient but also to persistent airway

Allergen IgE

387

hyperresponsiveness and clinical asthma.136 This is supported by parallel observations in animals149 and in human occupational asthma.150,151

INGESTED/INJECTED ALLERGENS Isolated asthma caused by allergens introduced via routes other than inhalation is uncommon but has been reported.152,153 Ingested allergens153 (foods, drugs) or injected allergens154 (hyposensitization injections, intradermal allergen tests, drugs, insect bites and stings) can produce IgE-mediated hypersensitivity reactions. Most often, these produce systemic allergic reactions152,154 (violent gastrointestinal upset, urticaria, angioedema, laryngeal edema, anaphylactic shock, with or without bronchospasm). However, occasionally such exposures produce reactions which appear to be centered primarily in the lung.153,155 It is likely that these represent systemic allergic reactions in subjects with preexisting asthma and high levels of airway hyperresponsiveness who develop disproportionately severe bronchospasm. Some cases of food/bite/sting-induced “asthma” may actually represent laryngeal spasm or edema which has been misdiagnosed. Although relatively uncommon, allergic (asthmatic or otherwise) responses to both ingested and injected allergens occur rapidly and can be exceedingly severe. We have seen subjects with sudden severe asthma due to foods (nuts, shellfish) and two subjects with sudden onset status asthmaticus circumstantially linked to unrecognized black fly bites.

C L I N I C A L F E AT U R E S Allergic reaction Early asthmatic response

Increased nonallergic bronchial reactivity

and

Late asthmatic response

Symptoms on exposure to nonallergic stimuli (irritants, exercise, etc.)

Fig. 37.3. Diagram of hypothesis explaining development and maintenance of perennial allergen-induced asthma. Reproduced from Reference 136, with permission.

Clinical presentation Allergic asthma usually begins at a young age, between about 2 and 20, but can develop at any time. A positive family history of asthma or atopy is common. Other atopic symptoms are often present and include food sensitivity (infancy), childhood eczema, urticaria, conjunctivitis and allergic rhinitis. Asthma or asthma exacerbations should correlate with allergen exposure or seasons. Spring, summer or fall exacerbations suggest fungal spore or pollen sensitivity whereas winter exacerbations are typical of indoor allergen sensitivity but may also occur in nonatopic asthmatics. The polyallergic subject may show little seasonal variability. Because of the gradual onset of airway inflammation and hyperresponsiveness, allergen-induced asthma exacerbations are usually of gradual onset often lagging behind and persisting beyond allergen exposure. An acute exposure– symptom relationship may be lacking. For these reasons, the patient and physician may miss the importance of allergens. When present, nonrespiratory, particularly ocular or cutaneous and, to a lesser extent, nasal symptoms will bear a much closer relationship to exposure and may provide an important historical clue to sensitization. Irritant- and exercise-induced bronchospasm are symptomatic of underlying

388

60 r

Cockcroft

Witt

Witt

Peat

Burney

n = 500

1293

891

2363

511

age = 2 0 - 2 9 years

1 0 |im diameter).' In contrast, air-borne cat and dog allergens are readily measured in houses with pets (and in a quarter of the homes without pets; Fig. 47.1), and ~25% of air-borne Fel d 1 and Can f 1 is associated with small particles ( < 5 |im diameter); Fig. 47.2.8'''

Homes with dogs

10,000

O Homes without dogs

1000

"D J3)

a

o

100

10

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••'ift

o

• •

Or

§8 of

0.1

000006860000 000 Mattress

GOOOOo •o~

Bedroom carpet

Living room carpet

Upholstered furniture

Fig. 4 7 . 1 . Dog allergen levels in homes with and without dogs. Reproduced from Reference 9, with permission.

490


80

Der p 2

Can f 1

70 60

%

50 40 30 20 10 0 >4.7

3.3–4.7

2.1–3.3 µm

1.1–2.1

0.65–1.1

Fig. 47.2. The particle size distribution of air-borne Der p 2 and Can f 1 after artificial disturbance. Reproduced from Reference 7, with permission.

These differences in the aerodynamic characteristics of allergens underlie the difference in the clinical presentation of the disease. Mite- and cockroach-sensitive asthmatics are usually unaware of the relationship between allergen exposure at home and asthma symptoms (exposure is low-grade and chronic), whereas cat or dog allergic patients often develop symptoms within minutes of entering a home with a pet. Furthermore, this implies that air filtration may be useful in removing cat and dog allergen from the air, but has no place in mite or cockroach avoidance. The bed is the most important source of mite allergens and lowering exposure in the bedroom is the primary target of avoidance, while the majority of exposure to pet allergens may occur in the living room area.

CONTROL OF HOUSE DUST MITES AND MITE ALLERGENS Bed and bedding The most effective and probably the most important avoidance measure is to cover the mattress, pillows and duvet with covers that are impermeable to mite allergens. Allergen levels are dramatically reduced after the introduction of covers,10 which should be robust, easily fitted and easily cleaned, as their effectiveness is reduced if they are damaged. Several randomized controlled trials have suggested benefits of such an intervention on symptoms, airway responsiveness and medication use (reviewed in Reference 11). All exposed bedding should be washed at 55°C (the temperature that kills mites).12 Additives for detergents providing a concentration of 0.03% benzyl benzoate, or dilute solutions of essential oils in normal- and low-temperature washing provide alternative methods of mite control.13

Carpets and upholstered furniture Carpets are an important microhabitat for mite colonization and a possible source from which beds can be reinfested. Fitted carpets should ideally be replaced with polished wood or vinyl flooring. Exposure of carpets to direct strong sunlight may be used in loosely fitted carpets in certain climatic areas.14 Alternatively, high-pressure steam cleaning may be utilized as a method of killing mites and reducing allergen levels in carpets.15 A number of different chemicals that kill mites (acaricides) have been identified, and shown to be effective under laboratory conditions.16 However, data on whether these chemicals can be successfully applied in homes to control the mite population in carpets and upholstered furniture are conflicting.17 The main problems of chemical treatment are how to get the chemicals to penetrate deep into carpets and soft furnishings, the persistence of mite allergen until recolonization occurs, and the nuisance of frequent reapplications. Freezing with liquid nitrogen can kill mites.18 However, the technique can only be carried out by a trained operator, which limits its use, especially since treatment needs to be repeated regularly. Both acaricides and liquid nitrogen need to be combined with intensive vacuum cleaning following administration. Due to its protein-denaturing properties, tannic acid has been recommended for the reduction of allergen levels in house dust. However, high levels of proteins in dust (e.g. home with a cat) block its effect.19 Intensive vacuum cleaning may remove large amounts of dust from carpets, reducing the size of the allergen reservoir. However, vacuum cleaners with inadequate exhaust filtration may increase air-borne allergen levels during use.20 Thus, atopic asthmatic patients should use high-effeciency particulate arrest (HEPA)-filter vacuum cleaners with double thickness vacuum cleaner bags. High levels of humidity are essential for mite population growth and reducing humidity may be an effective control

491

Allergen Avoidance

method, but only in areas with appropriate climatic and housing conditions.21–23 Reducing humidity by mechanical ventilation should be used in those regions where the outdoor humidity is low for at least part of the year.24 Owing to the aerodynamic characteristics of mite allergens, it makes little sense to use air filtration units and ionizers as a way of reducing personal exposure. Since mites live in different sites throughout the house, it is unlikely that a single measure can solve the problem of exposure, and an integrated approach including barrier methods, dust removal and removal of mite microhabitats is needed (Table 47.1). One such regimen was recently used and shown to be highly effective in achieving and maintaining a very low-allergen environment in homes of children at high risk of allergic disease.25 Although many of these interventions can reduce mite allergen levels in the environment, the effects on symptoms are not always clear. Indeed, a meta-analysis of house mite avoidance trials suggested that this approach should not be used in the treatment of asthma,26 suggesting that a single intervention may be insufficient. However, this metaanalysis was justifiably subjected to criticism27,28 and much more data are needed before definitive recommendations can be made.

P E T A L L E R G E N AV O I D A N C E Complete avoidance of pet allergens is all but impossible, as sensitized patients can be exposed to pet allergens not only in homes with pets, but also in homes without pets and in public buildings and on public transport (Fig. 47.3).29–32 The best way to reduce high-level exposure to cat or dog allergen is to remove the animal from the home. Even after permanent removal of the animal, it can take many months before reservoir allergen levels decrease.33 Unfortunately, despite continued symptoms, many pet allergic patients refuse to get rid of their pet. Thus there have been attempts to develop strategies for reducing personal exposure, while allowing these patients to keep their pets. Control of air-borne allergen levels with a pet in the home Air-borne pet allergen levels immediately increase by approximately five-fold when the pet is in the room, indicating that the presence of a pet contributes to current airborne allergen levels.9 The pet should be kept out of the bedroom, and preferably outdoors. Several studies on allergen levels have investigated the effects of washing cats.34–37 Washing dogs in a bath, using a hand-held shower unit and

Table 47.1. Measures for reducing house dust mite allergen exposure

Measure

Evidence level for effectiveness in reducing allergen

Evidence level for clinical effectiveness

Encase mattress, pillow and quilt in impermeable covers

Ib

Ib

Wash all bedding in the hot cycle (55–60°C) weekly

IIb

IV

Replace carpets with linoleum or wood flooring

Ib

IV

Treat carpets with acaricides and/or tannic acid

IV

IV

Minimize upholstered furniture/replace with leather furniture

IV

IV

Keep dust-accumulating objects in closed cupboards

IV

IV

Use a vacuum cleaner with integral HEPA filter and double thickness bags

IIb

IV

Replace curtains with blinds or easily washable (hot cycle) curtains

IV

IV

Hot wash/Freeze soft toys

IV

IV

Evidence level was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) recommendations as follows: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

492


100

o o 10

8o

oo ••

o

go o

o o«o oo

Oo

o

0.1 Carpets

Public houses

Seats

Carpets

'

Cinema

Seats

Carpets

Seats

Mattress

Hotel -

'

Carpets

Seats

School

Public transport

Fig. 47.3. Dog allergern \n public buiidirngs arid orn public trarnsport. Based orn data from Reference 30, with permissiorn.

shampoo and rinsing thoroughly, produced substantial but short-lived falls in recovered Can f 1 (Fig. 47.4).^*The main benefit of washing pets regularly (twice weekly) may be the reduction in the build-up of allergen in dust reservoirs, but this too is unproven. Air-borne pet allergens in homes with pets can be reduced by the use of HEPA air cleaner.^' In patients who are allergic to cats or dogs and persist in keeping their pet we propose the set of measures listed in Table 47.2. However, the clinical effectiveness of these measures remains unproven.

50 o

40 o

30 E

o

D) C T—

A V O I D A N C E OF C O C K R O A C H ALLERGENS In areas where housing conditions sustain large cockroach populations, both physical and chemical control measures have been tried (reviewed in Reference 11). Reducing access to food and water is critical, thus waste food should be removed and surface water should be contained by reducing leakage through faulty taps and pipework, and reducing condensation by improved ventilation. Cockroach access can be restricted by caulking and sealing cracks and holes in the plasterwork and flooring. Several chemicals are marketed for controlling cockroach infestation, including diazinon, chlorpyrifos, and boric acid. The most useful for patients with allergic disease are bait stations, where the chemical (hydramethylnon, avermectin) is retained within a plastic housing. A paste formulation of hydramethylonon may be used on cockroach runways and underneath counters, etc. Bait stations are generally effective at reducing cockroach numbers for 2-3 months. Attempts to reduce cockroach allergen exposure rely on improving patient education and concerted attempts by pest control companies and public

•

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o

20

•

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Baseline

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o

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Fig. 47.4. Major dog allergern Carn f 1 recovered from the samples of dog hair irn 1 5 dogs before, arid orn 7 days after washirig the dogs. Washirngthe dog reduces dog al lergern levels (but the dog rneeds to be washed twice a week). Reproduced from Referernce 38, with permissiorn.

health departments to reduce cockroach infestation. To date, they have not produced prolonged falls in allergen exposure or measurable benefits for patients.

493

Allergen Avoidance

Table 47.2. Measures for reducing pet allergen exposure

Measure

Evidence level for effectiveness in reducing allergen

Evidence level for clinical effectiveness

IIb

IV

Keep the pet out of the main living areas and bedrooms

IIb

IV

Install HEPA air cleaners in the main living areas and bedrooms

IIb

IV

Have the pet washed twice a week

IIb

IV

Thoroughly clean upholstered furniture/Replace with leather furniture

IV

IV

Replace carpets with linoleum or wood flooring

IV

IV

Use a vacuum cleaner with integral HEPA filter and double thickness bags

IV

IV

Remove cat/dog from the home If the pet cannot be removed:

Evidence level was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) recommendations as follows: Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-designed controlled study without randomization IIb Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

MOLDS Mold exposure may have an allergen-specific effect on sensitization, but also a nonspecific effect on the immune system facilitating sensitization to other allergens (perhaps via mycotoxins and b-glucans). Removing or cleaning moldladen objects may reduce the number of fungal spores. Maintaining a low humidity (less than 50%) could be important, but may be difficult to achieve in areas with a humid climate. Care should be taken to make sure that if dehumidifiers or air conditioners are used, they do not become contaminated with molds and thus form a new source of allergens or nonspecific irritants. In tropical and subtropical climates, fungi may grow on house walls because of water leakage and humidity. To avoid this, walls can be tiled or should be cleaned as necessary.

AV O I D A N C E O F O U T D O O R A L L E R G E N S The outdoor allergens that most often produce symptoms in susceptible people are pollens and mold spores, but the thresholds required for clinical impact remain to be determined. Although outdoor pollen and molds are impossible to avoid completely, exposure may be reduced by

closing windows and doors, remaining indoors when pollen and mold counts are highest, and using air conditioning with HEPA filters. Knowledge of a patient’s sensitivity to specific allergens may be useful for giving advice about the timing and location of that patient’s travel. In patients who are allergic to pollen we propose the set of measures listed in Table 47.3.

A L L E R G E N AV O I D A N C E I N T H E T R E AT M E N T O F A S T H M A The rationale for the use of allergen avoidance in the treatment of asthma is based on the suggestion that allergen exposure increases asthma severity in sensitized individuals. Allergen exposure and asthma severity Allergen exposure has been related to disease severity.40–43 Following a controlled or seasonal exposure to allergens, sensitized subjects experience an increase in airway reactivity.44 Exposure to Alternaria allergen has been shown to be a risk factor for sudden respiratory arrest in asthmatics.45 Sensitization to mites, cat, and cockroach was found to be a significant risk factor for acute asthma in patients admitted to the hospital Emergency Department in Charlottesville,

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Table 47.3. Measures for reducing grass pollen exposure

Keep car doors and windows tightly shut Avoid open grassy spaces, particularly late afternoons and evenings Consider fitting a car pollen filter Consider taking your holiday during June-July by the sea or abroad (for example Southern Europe)

VA, USA.46 A case-controlled study on patients presenting to an emergency room in Wilmington, DE, USA confirmed a very strong relationship between sensitization to indoor allergens and acute asthma.47 Further data, however, did not establish, or refute, a quantitative relationship between current exposure and the risk of acute asthma among sensitized individuals admitted to hospital.48,49 Showing a direct relationship between allergen exposure and disease severity has always been difficult due to the number of possible confounding factors. Asthmatic patients are often sensitized and exposed to more than one allergen, and relative contribution of each one is sometimes difficult to elucidate. Furthermore, viral infections are known to be important triggers of asthma symptoms.

EVIDENCE FROM EPIDEMIOLOGICAL STUDIES In a comparison of the relationship between mite allergen exposure and asthma, Peat et al.50 investigated two population samples of Australian children living in Lismore (a hot, humid, coastal region) and Moree/Narrabri (a hot, dry, inland region). Mite allergen levels were seven-fold higher by the coast, and airway reactivity (assessed by histamine challenge test) in children sensitized to mites was more severe in coastal children. In a further population-based epidemiological study, Peat et al.51 found that mite-allergic children with asthma had more reactive airways when living in the areas where mite allergen levels are high compared to areas where exposure to mites is low. There is further indirect epidemiological evidence that a high level of exposure to allergens may be associated with asthma symptoms in the UK. Strachan and Carey52 showed that the most powerful risk factors for severe asthma in 11to 16-year-old children were pet ownership and nonfeather bedding. The authors estimated that if the association between nonfeather pillows and severe asthma was causal, it could account for 53% of the severe asthma in the studied population. It has recently been demonstrated that polyester pillows contain five to eight times more mite, cat, and dog allergen than do feather pillows.53–55

ALLERGEN EXPOSURE INCREASES ASTHMA SEVERITY IN SENSITIZED PAT I E N T S A significant correlation has been observed between objective measures of asthma severity and mite allergen levels in the beds of subjects with positive skin tests to mites, but no relationship was seen in those who had negative skin test.56 A study on exposure to mite allergen and pediatric hospital admissions in the UK has shown that the majority of children admitted to hospital with exacerbation of asthma were both sensitized and exposed to mite allergen.57 It also suggested that continued exposure to higher concentrations of mite allergen might be associated with the risk of readmission. There is probably a considerable variability between individuals in the magnitude of response to the same levels of allergen exposure. In a group of individuals with similar levels of IgE antibodies, some will develop symptoms only if they are exposed to high levels of allergens, while others require very low exposure to maintain symptoms – i.e. the level of exposure necessary to induce and maintain airway inflammation, airway reactivity and symptoms varies over a wide range. However, a pattern emerges in which sensitized patients will have more severe disease if their exposure to offending allergen is high, than when it is low. A recent case–control study in Birmingham, UK, has shown that patients with brittle asthma (with frequent physician contacts and high medication requirements), are significantly more often both sensitized and exposed to high levels of allergens (especially to pets) to which they are allergic, compared with patients with mild disease.58 A further study has demonstrated that exhaled NO, a marker of airway inflammation, is much higher in asthmatics who are both sensitized and exposed to the relevant allergen compared with those that are sensitized, but not exposed.59 In the recent National Co-operative Inner-City Asthma Study in the USA, children from eight major inner city areas were assessed for atopy and exposure to allergens in their home.60 Almost 37% of children were allergic to cockroach allergen. Those children who were both allergic to cockroaches and exposed to high levels of cockroach allergens in the dust had 3.5-fold higher hospitalization rates, more unscheduled medical visits for asthma per year, more missed school days, more days of wheezing and nights with disturbed sleep compared with all other children. Neither increased exposure to cockroach allergen alone, nor allergy to cockroaches by itself, was associated with greater morbidity.

ALLERGEN EXPOSURE AND RESPONSE T O T R E AT M E N T A recent study by Nimmagadda et al.61 provides evidence that allergen exposure may confound the pharmacological management of the disease. The effect of allergen exposure

Allergen Avoidance

on glucocorticosteroid receptor (GCR)-binding affinity and GC responsiveness of peripheral blood mononuclear cells (PBMCs) was investigated in atopic asthmatics both in vivo and in vitro. The effect of in-vivo exposure was tested in ragweed-allergic asthmatics, before, during and after the ragweed pollen season. A significant reduction in GCRbinding affinity was observed during the pollen season as compared with pre- and post-season measurements. The effect of in-vitro allergen exposure was also determined by incubating PBMC of atopic asthmatics with either the relevant allergen to which they were sensitized or Candida albicans (as a control). PBMC of ragweed allergic asthmatics obtained outside the pollen season and of cat allergic patients not exposed to cats, had significantly reduced GCR-binding activity after incubation with ragweed and cat allergen, respectively, compared with both baseline and Candida albicans stimulation. The observed effect appears to be allergen specific, and is restricted to atopic asthmatic patients (i.e. no similar effect was found in atopic nonasthmatic individuals or nonatopic subjects). Furthermore, the allergen-induced reduction in GCR-binding activity of PBMCs from atopic asthmatics made the lymphocytes significantly less responsive to the inhibitory effect of hydrocortisone. The finding that allergen exposure can reduce GCR binding activity in atopic asthmatics both in vivo and in vitro, with the resulting functional alteration in cellular response to glucocorticoids, could suggest that high allergen exposure in sensitized individuals may contribute to poor asthma control and maintenance of the inflammatory process in the airways by reducing the effectiveness of treatment with inhaled steroids.

CLINICAL TRIALS Having explored various methods of allergen avoidance and the relationship between allergen exposure and asthma severity, the important question is whether allergen avoidance in homes by these techniques improves asthma control in sensitized patients. This is an area of controversy, mainly because of the inadequacies of the clinical studies on allergen avoidance. Lessons from occupational asthma Occupational asthma is a useful model for the study of asthma. The essential first step in assessing patients with suspected occupational asthma is to identify the causal agent. Early diagnosis and removal from exposure were found to be associated with recovery,62 and this is true both for occupational asthma caused by low molecular weight and high molecular weight agents.63 Determinants of the unfavorable prognosis are long duration of exposure before the onset of symptoms, long duration of symptoms before diagnosis and dual response after specific challenge test.64 Further occupational exposure in sensitized subjects leads to persistence and sometimes progressive deterioration of

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asthma.65 Thus, early detection of the offending agent and immediate cessation of exposure are important factors for favorable prognosis.65 The studies in occupational asthma clearly indicate that: • it is crucially important to identify the sensitizing agent as early as possible • early cessation of exposure to sensitizing agent is associated with good prognosis in terms of objective measures of disease severity, medication requirements and quality of life. This model indicates that early allergy diagnosis and avoidance of domestic allergens in newly diagnosed asthmatics may be important. Lessons from high-altitude studies In Europe, mite allergen levels are very low at high altitude where the ambient humidity is insufficient to support mite populations. There are several sanatoria built in the Alps (e.g. Davos, Switzerland, and Misurina, Italy), in which long-term residence can be beneficial for asthmatic children. Dust mite-sensitive asthmatic children had a progressive reduction in nonspecific airway reactivity after a 1year period spent in Davos.66,67 Several studies from Misurina reported a reduction in asthma symptoms and significant decreases in mite allergen-induced basophil histamine release, mite-specific serum IgE level and methacholine and allergen-induced airway reactivity.4–6 However, further studies also observed reversal of this trend towards improvement after returning to sea level. The results of high-altitude studies suggest that allergen avoidance leads to a decrease of airway inflammation with consequent improvement in specific and nonspecific airway reactivity and symptoms and that re-exposure results in a rapid relapse. These studies were not controlled, and there is a possibility that other domestic factors (e.g. exposure to pets, environmental tobacco smoke etc.) contributed to the improvement observed in asthma control. Nevertheless, allergen avoidance is the most plausible reason for clinical success. High-altitude studies also provide an important proof of principle: a substantial reduction in allergen exposure over a long period of time may result in clinical improvement in allergic asthmatic patients. Mite allergen avoidance in patients’ homes In a recent review,11 31 trials of mite allergen avoidance regimens in asthma in the literature were considered.68–98 Since then, several further studies have been published, but have failed to provide unequivocal evidence as to whether mite allergen avoidance is effective, which patients may benefit, and by how much.99–102 Most of the studies were small, poorly controlled and used measures that failed to reduce mite allergen exposure (Appendix). Of these 35 studies, only 11 showed a significant reduction in mite counts and/or mite allergen levels. In four of these 11, the period of treatment was too short, but none the less three showed some effect. The final seven controlled studies, all of which used bed covers, achieved both

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significant reduction in mite/allergen levels and were of sufficient duration to show an effect on outcomes. Although these seven studies had different endpoints, they all showed some evidence of clinical benefit, but this was usually of questionable clinical significance as a result of the small size of the studies. Certainly, the impact of their widespread use by asthmatics has not been determined in a public health context. Which patients benefit and whether treatment is cost-effective is unknown. Large-scale trials are needed to answer these questions and one such study, which is due to randomize 1800 patients, is underway in the UK. Pet allergen avoidance in patients’ homes A recent study investigated the effectiveness of environmental allergen control using HEPA air cleaners in the management of asthma and rhinitis in cat-allergic patients who were sharing their home with one or more cats.103 Although a small reduction in airborne Fel d 1 was observed in the active (but not in the control) group, there was no difference between the groups in any of the outcome measures during the 3 months of the study. The reduction in cat allergen exposure afforded by the measures used in this trial was modest (~50%). It seems likely that a much more complex series of measures are needed if substantial reduction in exposure to air-borne cat allergen is to be achieved. Very intriguing and interesting data were recently reported, showing that reduction in Fel d 1 concentration by the use of high-efficiency vacuum cleaners can produce a significant improvement in the lung function in patients with cat sensitivity, but who did not possess a cat themselves.104 It is possible that a reduction in passive exposure to pet allergens in pet-sensitized individuals may have a beneficial clinical effect.

lence of wheeze was negatively associated with the use of feather pillows (reduction in the odds of 36% for infrequent wheeze and 61% for frequent wheeze). Furthermore, when changes in potential risk factors over time were investigated, an observed rise in the use of nonfeather pillows from 44% to 67% was estimated to be large enough to explain more than half of the increase in wheeze.105 It is tempting to speculate that the increased use of nonfeather pillows has contributed to increasing allergen exposure, which could be partly responsible for the increase in the prevalence of wheezing. Sensitization and exposure to indoor allergens and asthma Generally, individuals get sensitized to the allergens to which they are exposed. There is overwhelming evidence that sensitization to dust mites is a major independent risk factor for asthma in all areas where the climate is conducive to support the mite population growth.106,107 For allergens other than mites, the relationship depends on the climate, habits and socio-economic features of the local community.108–110 Exposure to allergens may have a profound effect on the development of IgE-mediated sensitization (primary sensitization), progression from sensitization to allergic disease (secondary exposure) and the severity of symptoms in patients with established disease (tertiary exposure) (Fig. 47.5). It has been relatively straightforward to demonstrate a quantitative dose–response relationship between exposure to mite allergens and subsequent sensitization.111,112 Early infancy has been identified as a critical period for primary sensitization. Evidence to support this view comes from studies relating atopy to month of birth,113,114 and the importance of early exposure to mite allergen in primary sensitization has been well-defined in recent studies.115 However, the situation seems to be much more complex with pet allergens.

A L L E R G E N AV O I D A N C E I N T H E P R I M A RY P R E V E N T I O N O F AT O P Y The rising trend in asthma prevalence can be linked to a possible increase in exposure to allergens in indoor environment. While there is no direct evidence to confirm an increase in dust mite allergen exposure, the indirect evidence, that this could be one among several important cofactors, is compelling. For example, over the last few decades, sales of pillows using synthetic fillings have increased enormously based on the concept that they are nonallergenic (as opposed to feather pillows). It has already been outlined that synthetic pillows accumulate mite allergens faster and ultimately contain approximately fivefold more Der p 153,54 and eight to ten times more cat and dog allergen that feather pillows.55 A UK study found a moderate, but significant increase by 20% in the ratio of current childhood wheezers to never wheezers, and an increase of 16% in the 12-month period prevalence of wheezing attacks between 1978 and 1991.105 The preva-

P E T O W N E R S H I P, S E N S I T I Z AT I O N A N D AT O P I C D I S E A S E In recent years, different groups of investigators have published intriguing and often conflicting data on the effect of pet ownership in early life on the subsequent development of sensitization and asthma. Some studies found that exposure to pets in early infancy was associated with specific IgE sensitization and allergic disease later in childhood,116,117 while others reported the opposite finding – an apparent protective effect.118,119 The difficulty in interpretation relates to the retrospective nature of the studies and the possibility of selection bias (e.g. parents at risk have got rid of pets). In the only prospective study with objective measurements of exposure, Wahn et al.112 have demonstrated a strong positive dose–response relationship between cat allergen exposure and specific sensitization during the first 3 years of life.

Allergen Avoidance

Sensitizers (allergens: mite, cat, dog, cockroach, etc.) Genetic predisposition Primary prevention

Enhancers Viruses, endotoxin, air pollution

IgE-mediated hypersensitivity

Sensitizers (allergens: mite, cat, dog, cockroach, etc.)

Genetic predisposition

Secondary prevention Airway inflammation and bronchial hyperreactivity Treatment of established disease

Triggers (inflammatory) Viruses, allergens, air pollution, endotoxin

Asthma symptoms

Triggers (noninflammatory) Exercise, histamine, cold air, methacholine, smoking

Figure 47.5. The potential benefits of allergen avoidance: prevention of allergic sensitization (primary prevention by allergen avoidance); prevention of atopic disease in sensitized individuals (secondary avoidance); and treatment of the established disease.

At present, it is difficult to explain these apparently irreconcilable differences between studies. First, prospective studies indicate that extremely low levels of cat allergen exposure are associated with some risk of sensitization, and that at least in early life, there appears to be a dose–response relationship between exposure and sensitization.112 Cat allergen is ubiquitous, and exposure outside the domestic environment may lead to specific IgE responses. A recent report has indirectly confirmed the potential importance of passive exposure, finding a significant correlation between the community prevalence of cat ownership and community prevalence of sensitization to cats, prevalence of respiratory symptoms, physician-diagnosed asthma and current asthma medication.120 It is possible that later cat allergen exposure is a risk for disease, but early exposure to cats may be protective. Two possible mechanisms for the protective effect of cat own-

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ership (as opposed to passive exposure in homes without pets and/or public areas) are increased microbial exposure (enhancing Th1 immunity),120,121 or the induction of an allergen-specific IgG4, rather that IgE response. Only the long-term prospective follow-up of well-defined cohorts, avoiding recall biases and with objective measure of exposure, will provide a definitive answer to this important question and inform a decision about appropriate public health strategies for prevention (i.e. having or not having a pet). Primary prevention by environmental control Successful environmental control could be anticipated to have a greater impact on prevalence of asthma than interventions directed at other risk factors such as exposure to environmental tobacco smoke, dietary intervention and breast feeding.122 So far, only one prospective, randomized study has investigated the efficacy of avoidance of indoor allergens (house dust mites) in high-risk infants followed from birth (Isle of Wight study).123–125 This study has produced the first indications that even a modest reduction in mite allergen levels in homes of infants at risk of allergy may reduce the prevalence of sensitization to mites and recurrent wheezing during the first years of life. The trial was unfortunately complicated by the very complex nature of intervention strategy, including dietary advice to mothers during pregnancy, as well as an attempt to reduce mite allergen exposure by the use of benzyl benzoate (ineffective mite allergen avoidance measure). Recently, a prospective study in Manchester has documented that mite avoidance measures can achieve and maintain a very low mite allergen environment during pregnancy and in the first year of life in homes of infants at risk of atopy.25 Several other ongoing studies are addressing this important question (Canada, Australia, The Netherlands, and Southampton, UK). The results of these longitudinal studies are still awaited, as reasonable conclusions can only be drawn once the children are at least 5 years of age.

A L L E R G E N AV O I D A N C E I N S E C O N D A RY PREVENTION OF ASTHMA Secondary prevention strategies could be used to prevent development of symptomatic disease in sensitized, but still asymptomatic, individuals. In this context, environmental control might be beneficial. A recent study from Japan suggested that the use of bedding encasement was effective in preventing atopic infants with eczema and food allergy from being sensitized to house dust mites.126

S U M M A RY Minimizing the impact of identified environmental risk factors is an important consideration to reduce the prevalence and severity of asthma. Although environmental control is

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difficult, it is likely to become an integral part of the overall management of allergen-sensitized patients. Nevertheless, which subgroups of patients benefit, and by how much remains unclear. There are few data on the benefits of primary and secondary prevention by environmental control, and several prospective studies are currently underway. Finally, the mechanisms of the interaction between increased allergen exposure and an apparently increased susceptibility of the population to allergic disease need urgent exploration.

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Appendix Clinical studies of measures aimed at the reduction in house dust mite allergen levels applied in homes of patients with asthma. Reproduced from Reference II, with permission.

Author Ref.

Study design and duration

Avoidance measures

Effect on mites/ Allergen

Clinical outcome

Sarsfield et al68. 1974, UK – Leeds

Ch, As, MS; n = 14; UC; 3–12 months

Mattress encased (plastic covers); synthetic pillows; bedding washed weekly; dusting, vacuuming

Reduction in mite counts (from 80 to 2; P < 0.01)

Improvement in symptom scores (9 to 1.89; P < 0.05)

Burr et al.69 1976, UK – Cardiff

Ad, As, MS; n = 32; crossover PC; 6 weeks

Mattress encased (plastic covers); vacuum-cleaning of bed; laundering of bedding

Not monitored

No improvement in daily PEF reading or drug usage


Ch, As, MS; n = 53; PC; 8 weeks

Mattress, carpets and upholstery vacuumed; blankets, sheets laundered; bedding washed; feather pillows, quilts replaced; soft toys removed

No difference in mite counts before and after treatment

Both active and control group improved, no difference between groups


Ch, As, MS; n = 21; crossover, C; 1 month + 1 month

New sleeping bags, pillows and blankets; mattress encased (plastic covers); carpets vacuumed

Colonization occurred on new bedding after second study period

PEF variability lower during treated period, but the difference NS; majority with higher PEF during the treated period (P < 0.01)

Mitchell and Elliott72 1980, Auckland – New Zealand

Ch, As, MS; n = 10; C, cross-over; 8 weeks (4+4)

Electrostatic precipitator in child’s bedroom

Not monitored

Control versus active period: PEF NS; medication use: NS

Continued

502


Appendix (continued)

Author Ref.


Avoidance measures


Clinical outcome

Korsgaard73 1982, Denmark – Aarhus

Ad, As and/or AR, HDS; n = 23; UC; 6 months

Mattress encased (plastic covers) n = 3; synthetic pillows n = 22; bedroom carpet removed n = 7; dusting, vacuuming

Not monitored in the study group over time

Beneficial effect reported by 15 patients, no change by 4

Korsgaard74 1983, Denmark – Aarhus

Ad, Ch, As, MS; n = 46; C; 12 weeks run in +12 weeks intervention

Mattress vacuumed twice; synthetic pillows and quilts; bedding washed; bedroom carpet removed; bedroom aired + no plants

Difference between groups in BC (P < 0.01) but not in LC or M

Improvement active versus control group: PEF NS (both improved) Symptoms: P < 0.05 medication: NS

Murray and Ferguson75 1983, Canada – Vancouver

Ch, As, MS and/or HDS; n = 20; C; 1 month

Mattress, pillows encased (vinyl covers); toys, carpets and upholstery removed (bedroom); washing, dusting, vacuuming

Not monitored

Improvement active versus control group: symptoms (P < 0.01), medication (P < 0.5), PEF (P < 0.05) and BHR (P < 0.001)

Bowler et al.76 1985, Brisbane – Australia

Ad, Ch, As, MS; n = 9; PC, cross-over; 4 weeks (2+2)

Active period: Mattress and pillow covered; washing, dusting, vacuuming; dust retardant and anti-static spray; active electrostatic filter of HEPA filter. Placebo: inactivated air filter

Not monitored

Control versus active period: Symptom scores NS; PEF NS

Walshaw and Evans77 1986, UK – Liverpool

Ad, As; n = 50; C; 1 year

Mattress, pillows encased (plastic covers); synthetic duvets; bedroom carpet, upholstery removed (n = 7); washing, dusting, vacuuming

Significant fall in mite counts in the active (P < 0.001), but not in the control group

Improvement in MS As in active group: FEV1/FVC (P < 0.02), PEFR (P < 0.05), BHR (PC20)(P < 0.01), medication (P < 0.05), total IgE (P < 0.05)

Gillies et al.78 1987, UK – Leeds

Ch, As; n = 26; C; A-12/52 avoidance, B 6/52 observation + 6/52 avoidance

Mattress, pillows encased (plastic covers); synthetic bedding; soft toys and pets excluded from bedroom; vacuuming

Mite counts: A 40 (start), 1.2 (6/52), 0.8 (12/52); B-22 (start), 10 (6/52), 2 (12/52)

Fall in total serum IgE in MS Ch (P < 0.005); BHR, symptoms, medication use and PEF NS

Continued

503

Allergen Avoidance


Author Ref.


Avoidance measures


Clinical outcome

Dorward et al.79 1988, UK – Glasgow

Ad, As, MS; n = 21; C; 8 weeks

Mattress and bedroom carpet treated with liquid nitrogen; washing, dusting, vacuuming; soft toys, plants and upholstery excluded from bedroom

Fall in number of intact mites in active group (P < 0.01); no change in control

Active versus control: Fall in the number of hours wheezing (P < 0.05); reduction in BHR (P < 0.02); total and specific IgE NS

Verrall et al.80 1988, Canada – Hamilton

Ad, Ch, As, MS; n = 13: DB, crossover; 4 periods, 3/52 each

Laminar flow air cleaner device in the bedroom

Not monitored

No difference between the groups in the number of symptom-free days, symptom severity and PEFR

Reiser et al.81 1990, UK – London

Ch, As, MS; n = 46; DB PC; 24 weeks

Mattress sprayed once every 2 weeks for 3 months with either Natamycin or placebo; mattress vacuumed

Small, NS trend to a fall in Der p 1 in both groups

No change in BHR, symptoms and LF

Reisman et al.82 1990, USA – Buffalo

Ad, Ch, As, AR, MS; n = 32; DB PC, cross-over; 8 weeks (4+4)

Active period: HEPA air cleaner; Placebo period: placebo filter

Not monitored

Control versus active period: symptom and medication scores NS; Last 2 weeks of each period: nasal congestion, discharge eye irritation P < 0.05; asthma symptoms NS

Morrow Brown and Merrett83 1991, UK – Derby

Ad and Ch, As and/or AR and/or AD, MS; n = 25; UC; 12 months

Acarosan foam on mattress and bedding and moist powder on carpets and soft furniture

Reduction in Der p 1 level

As (n = 12): 7 better, 5 no change; AR (n = 8): 6 improved, 2 no change; AD (n = 5): 2 improved

Antonicelli et al.84 1991, Italy – Ancona

Ad, Ch, As, MS; n = 9; PC, cross-over; 16 weeks (8+8)

Active period: HEPA air cleaner. Placebo period: placebo filter; Routine house cleaning

No difference in reservoir levels of mite allergens between the periods; fall within both groups P < 0.05

Control versus active period: AR symptoms NS; LF NS; PEF NS; BHR (methacholine) NS

Continued

504



Author Ref.


Avoidance measures


Clinical outcome

Ehnert et al.85 1992, Germany – Berlin

Ch, As, MS; n = 24; DB PC; 12 months

A: Mattress, pillow and quilt covered, carpets sprayed (3% tannic acid) 4 monthly; B: Mattress and carpet treated with benzyl benzoate; C: Placebo on mattress and carpet

Significant decrease in Der 1 in Group A (P < 0.005); no change in Group B and C

Significant increase in BHR (PC20) in the encasing regimen group (A): within group P < 0.01; no change in Groups B and C: between groups P < 0.05

Huss et al.86 1992, USA – Washington

Ad, As, MS; n = 52; 12 weeks

Investigated the effect of supplementary computer instruction on adherence to mite avoidance measures

Significantly lower Group 1 level in bedroom carpet in computer instructed group

No change in FEV1; Computerinstructed group significantly less symptomatic by study weeks 9 and 10 (P = 0.033)

Dietemann et al.87 1993, France – Strasbourg

Ad, Ch, As, MS; n = 26; DB PC; 12 months

Benzyl benzoate foam or placebo on mattress and upholstery; benzyl benzoate powder or placebo on carpets

No significant difference in Der 1 between the groups

Active versus placebo: Clinical score, drug score, LF, PEF NS

Warner et al.88 1993, UK – London

Ch, As, MS; n = 20; DB PC cross-over; 12 weeks (6+6)

Active period: active ionizers. Placebo period: placebo ionizers

Active versus control period: Airborne Der p1– P < 0.0001

Active versus control period: PEF NS; Symptom scores NS (trend towards increased cough during active period); Medication NS

Warburton et al.89 1994, UK – Manchester

Ad, As, MS; n = 12; cross-over (active + passive period 30+24 days)

Active period: HEPA air cleaner. Passive period: no HEPA air cleaner

Airborne Der p 1 below detection limit in twothirds of samples

Active versus passive period: Symptom scores NS; LF NS; BHR (histamine) NS; PEF NS

Marks et al.90 1994, Australia – Sydney

Ad, Ch, As; PC; 3 months run-in + 6 months treatment

Active: tannic acid/ acaricide to mattress, pillow, duvet, blankets, carpets and upholstery; mattress, pillow and quilt covered. Placebo: inactive spray

At 2 weeks Der p 1 fell to 29% of baseline (P = 0.04 compared to placebo); 3 and 6 months NS

Significant improvement in symptoms in both groups, but active versus placebo NS; LF and BHR: active versus placebo NS

Continued

505

Allergen Avoidance


Author Ref.


Avoidance measures


Clinical outcome

Sette et al.91 1994, Italy – Verona

Ch, As, MS; n = 32

All homes: synthetic materials in the bedroom; daily vacuum cleaning and mopping; no feather pillows. Mattress treated with benzyl benzoate or placebo (n = 24)

Assessed by Acarex test: no difference between 3 study groups

No difference in BHR (PC20 ) between 3 study groups; no change in serum IgE concentrations

Huss et al.92 1994, USA – Washington

Ad, As; n = 12; DB PC; 12 months

Benzyl benzoate powder (n = 6) or placebo (n = 6)

No change in mite allergen content in Bc or LC

No difference in LF and PEF between the groups

GellerBernstein et al.93 1995, Israel – Rehovot

Ch, As, AR, MS; n = 32 (As n = 31); C, DB

Acardust or placebo in bedrooms on day 0 and day 90; bedsheet changed every week, damp dusting daily; vacuuming weekly

Active: Fall in Der f 1 from 10.05 to 4.15: Control: Fall in Der f 1 from 6.01 to 3.01

Significant improvement in severity of asthma; No difference in PEFR and wheeze

Carswell et al.94 1996, UK – Bristol

Ch, As, MS; n = 49; DB PC; 6 months

Benzyl benzoate powder or placebo on BC; benzyl benzoate foam or placebo on mattress, pillow and quilt; mattress, pillow and quilt covered (active or placebo); washing, dusting, vacuuming; soft toys excluded

M: 100% reduction in active versus 53% reduction in placebo (P < 0.001); BC: Active versus placebo NS

Active versus placebo: PEF NS; BHR (histamine) NS; LF (FEV1 ) P < 0.05; symptoms P < 0.05; medication use: P < 0.01

Frederick et al.95 1997, UK – Southampton

Ch, As, MS; n = 31; single blind, crossover; run-in 2/52, treatment periods 3/12

Period 1 – Group 1: active covers, Group 2: placebo covers (3/12); wash out 1/12; Period 2 – Group 1: placebo covers, Group 2: active covers (3/12)

Active versus placebo: significant reduction in Der p 1 in mattress, duvet and pillow (P < 0.0001)

Active versus placebo: significantly lower levels of eosinophil peroxidase (P = 0.02); within group: symptoms, FEV1, BHR (PC20 histamine): NS

Continued

506



Author Ref.


Avoidance measures


Clinical outcome

Van der Heide et al.96 1997, The Netherlands – Groningen

Ad, As, MS; n = 45; DB, randomized, 3 parallel group; 6 months

Group 1: active air cleaner; Group 2: placebo air cleaner + mattress and pillow covers; Group 3: active air cleaner + mattress and pillow covers

Significant reduction in Der p 1 with covers (Groups 2 and 3) compared to Group 1

Significant improvement in BHR (histamine) in Group 3; trend to improvement in Group 2

Halken et al.97 1997, Denmark – Odense

Ch, As, MS; n = 60; DB PC 12 months

Active group: semipermeable mattress and pillow covers. Control group: cotton mattress and pillow covers

Active versus placebo: significant reduction in Der p 1 in mattress

Significant reduction in the dose of inhaled steroids, allergen specific BHR, morning PEFR and night asthma symptom score

van der Heide et al.98 1997, The Netherlands – Groningen

Ad, As, MS; n = 59; DBPC randomized, 3 parallel group; 12 months

Group 1: Acarosan on mattresses and floors (n = 21); Group 2: placebo (n = 19); Group 3: mattress and pillow covers (n = 19)

Significant reduction in Der p 1 with covers (Group 3) compared to Groups 1 and 2

Significant improvement in BHR (histamine) in Groups 1 and 3

Kroidl et al.99 1998, Germany – multicenter

Ad, Ch, As MS; n = 118; PC, randomized; 12 months

Active group: Benzyl benzoate Control group: placebo

Not monitored

No difference in self assessment, physician assessment, histamine BHR, IgE and SPT

Cloosterman et al.100 1999, The Netherlands – Nijmegen

Ad, mild As, MS, n = 157; PC, randomized; 20 weeks

Active group: Benzyl benzoate and semipermeable mattress and bedding covers Control group: placebo covers + water

Active versus placebo: significant reduction in Der p 1 in mattress

Active versus placebo: LF (FEV1 ) NS; BHR (histamine) NS; PEFR NS; symptom scores NS

Shapiro et al.101 1999, USA – Seattle

CH, AS, MS; n = 36; DB, R; 12 months

Active: mite impermeable covers to bed; clean blanket + bed linen monthly; tannic acid 2-monthly; vacuum cleaner provided; Control: placebo spray

Active versus placebo: significant reduction in Der p 1

Active versus control: doubling PD20 methacholine 47.0% versus 23.5%; P < 0.05

Continued

507

Allergen Avoidance


Author Ref.


Avoidance measures


Clinical outcome

Warner et al.102 2000, UK – Southampton

CH (n = 27), AD (n = 13), As, MS; R; 12 months; 4 groups

1. Mechanical ventilation + vacuum cleaner; 2. Mechanical ventilation 3. Vacuum cleaner 4. No intervention

Der p 1: trend for Group 1 < Group 2 < Group 3

Trend for Groups 1 and 2 to have higher PC20 than Groups 3 and 4 (P = 0.085)

Ad = adults; Ch=children; As = asthma; MS = mite sensitive; HDS = house dust sensitive; AD = atopic dermatitis; AR = allergic rhinitis; P = placebo; DB = double blind; C = controlled; UC = uncontrolled; BC = bedroom carpet; LC = living room carpet; M = mattress; NS = not significant; Der 1 = Der p 1 + Der f 1.

Chapter

Smoking Cessation

48

Andrew W.P. Molyneux and John Britton University of Nottingham, Division of Respiratory Medicine, City Hospital, Nottingham, UK

Cigarette smoking is the single most important avoidable cause of death and disability in the developed world1 and is a growing cause for concern in many developing countries.2 In the UK it is estimated that most of the deaths and nearly half of the hospital admissions attributable to smoking will be for respiratory diseases, of which COPD makes up the bulk.3 Despite widespread knowledge of its harmful effects, cigarette smoking remains remarkably common, with over 25% of adults in the UK currently smoking.4 In this chapter we outline:

ation is continuous across the population and the concept of two discrete groups of smokers, who are either “susceptible” or “not susceptible” to COPD,6 is probably not valid. In general, however, the greater the number of cigarettes smoked the greater the risk of COPD7 and those with COPD who continue to smoke will experience a more rapid decline in lung function.6,8 In addition, adults exposed to passive smoke are at greater risk of developing symptoms of chronic bronchitis.9

• the effects of smoking on COPD and asthma; • the benefits of stopping smoking (smoking cessation) on COPD and asthma; • the central role of nicotine addiction in smoking; • that smoking is itself in essence a chronic addictive disease; • the evidence for the effectiveness of smoking cessation interventions; • guidance for putting such evidence into clinical practice.

THE EFFECT OF SMOKING ON ASTHMA There is relatively little information available on the effects of smoking on asthma but one longitudinal study has shown that active smoking exacerbates asthma and that asthmatics who smoke experience a more rapid decline in their FEV1.10 In asthmatic adults passive smoking is associated with more severe disease, lower health status and greater health care usage.11 In children, passive smoking increases the risk of developing wheeze or asthma,12 and is associated with more severe disease in asthmatic children.13

THE EFFECT OF SMOKING ON COPD The evidence for the harmful effect of active smoking on COPD is unequivocal: smoking is the single most important etiological factor in the development of COPD. Most adult smokers start to smoke in adolescence,1 before attaining their maximal lung function. Longitudinal studies of lung function (as measured by forced expiratory volume over 1 second, FEV1) have shown that those adolescents who smoke achieve a lesser maximal lung function than their nonsmoking peers, that lung function begins to decline at an earlier age in young adult smokers, and that this decline is faster in smokers (mean loss of 40 mL per year) than in nonsmokers (mean 25 mL per year).5 It should be noted that while the average rate of decline in FEV1 is faster in smokers than in nonsmokers there is a marked variability in this rate of decline in both smokers and nonsmokers.5 This variation accounts for the apparently marked differences in individual susceptibility to COPD in smokers, but the vari-

T H E B E N E F I T S O F S M O K I N G C E S S AT I O N The benefits of stopping smoking in COPD are unequivocal. Fletcher and Peto6 were the first to report that in smokers with COPD, the rate of decline in FEV1, and subsequent mortality from COPD is reduced in those who give up smoking (Fig. 48.1). Several other studies have since demonstrated that smoking cessation results in a reduction in rate of decline in FEV1 to approximately that of typical nonsmokers (see review in Reference 5). This finding is probably most clearly demonstrated in the US Lung Health Study, a prospective 5-year study of smoking cessation in individuals with early COPD8 (Fig. 48.2). Few studies have looked at the benefit of smoking cessation in asthma, but it is reasonable to infer that the benefits of smoking cessation on decline in FEV1 demonstrated in COPD will also apply to asthma.

Forced expiratory volume in 1 second (% of value at age 25)

510


Never smoked or not susceptible to smoke

100 75 50

Smoked regularly and susceptible to its effects

Stopped at 50

Disability

Stopped at 65

25 Death 0 25

50 Age (in years)

75

Fig. 48.1. The natural history of chronic bronchitis and emphysema. Adapted from Reference 6.

2.9

Postbronchodilator FEV1, L

Sustained quitters 2.8

2.7 Continuing smokers 2.6

2.5

2.4 Screen

1

2

3

4

5

Follow-up, years Fig. 48.2. Decline in post bronchodilators forced expiratory volume in one second (FEV1) over five years in smokers and ex-smokers with mild asymptomatic COPD. Reproduced from Reference 8 with permission.

SMOKING AND NICOTINE ADDICTION Smoking has traditionally been seen as a “social habit” that smokers adopt from choice alone. The last 20 years has seen an enormous increase in our understanding of the nature of smoking, and the emergence of clear neurophysiological and clinical evidence that smoking is an addictive behavior due to addiction to nicotine.14,15 Neurophysiological evidence Cigarette smoke is a complex mixture of gases and particulates, a major component of which is nicotine.16 When cigarette smoke is inhaled it reaches the small airways and alveoli of the lung where nicotine is rapidly absorbed into the pulmonary circulation. Within 10–19 seconds of inhalation, nicotine reaches the brain (at arterial concentrations

two to six times venous levels,17,18 and has a number of effects, in particular causing the release of dopamine in the nucleus accumbens in the mesolimbic system.19,20 Animal model work has shown that this pathway plays a central role in addictive behavior.21 Clinical evidence Nicotine meets many of the standard clinical criteria for an addictive drug,22–24 since users have a strong desire to take the drug,25 difficulty in controlling their use (i.e. stopping smoking),26 continued use despite harmful consequences,4 tolerance to the drug24 and withdrawal symptoms when the drug is stopped.25 Comparisons between nicotine and other drugs of addiction indicate that it is as addictive as cocaine, opiates, and amphetamines.27–30 The symptoms of this addiction can start within weeks of the first cigarette, often before the onset of daily smoking.31 The majority of adolescent daily smokers report symptoms of withdrawal,32,33 and over three-quarters of adolescent smokers who try to quit will fail.34 Most adolescent smokers will continue into young adulthood1 and of these about half are likely to still be smoking at the age of 60.26 The majority of smokers report that they would prefer not to smoke, and approximately one in three adult smokers has tried, unsuccessfully, to give up smoking in the past year.4 Most smokers do not thus continue to smoke out of choice, but because of addiction to nicotine. The nicotine withdrawal syndrome One of the reasons that nicotine is so addictive is the severity of the withdrawal syndrome that smokers experience when they stop smoking. This syndrome is characterized by well-recognized changes in mood, physical symptoms, physiological changes, and urges to smoke (Table 48.1). These signs and symptoms are due specifically to withdrawal from nicotine, as opposed to any other aspect of smoking, as evidenced by the fact that they are reduced by nicotine replacement therapy.25 Most symptoms of nicotine withdrawal resolve within the first 4 weeks of stopping smoking; increased appetite can last for considerably longer and is responsible for the weight gain often seen after smokers become abstinent. Of all the symptoms and signs of withdrawal, urges to smoke and depression are the principal features known to predict relapse, of which urges to smoke are probably the most important predictors.35–39

SMOKING AS A CHRONIC DISEASE In addition to being an addictive behavior, smoking shares many of the features of a chronic disease, in particular being characterized by remissions and relapses. Only a minority of smokers stop permanently at their first attempt; most will start smoking again and go through cycles of stopping and starting. Many smokers who do stop for long periods of time will later relapse and start smoking again.40

511

Smoking Cessation

Table 48.1. Major signs and symptoms of nicotine withdrawal (adapted from Reference 25)

Symptom

Duration (Hughes)91

Reduced by NRT

Predicts relapse (Hughes et al.)35

Incidence Self-quitters (%) Clinic patients (%) (Hughes)91 (Hughes and Hatsukami)36

Irritability/aggression Depression Anxiety Restlessness Poor concentration Increased appetite Urges to smoke Night-time awakenings Decreased heart rate

4 weeks 4 weeks 2 weeks 2 weeks 1 week 10 weeks 2 weeks 1 week 10 weeks

Yes Yes Yes Yes Yes Yes Yes Not known Yes

No Yes No No No No Yes No Not known

38 31 49 46 43 53 37 39 61

80 60 87 71 73 67 62 24 79

NRT, nicotine replacement therapy.

Many clinicians fail to appreciate this, and lose their motivation to help smokers stop smoking because of their patients’ or their own perceived failure. Smoking, like a chronic disease, may need continuing care and support with repeated treatments for current smokers, providing motivation to stop and appropriate support for those willing to stop, and for ex-smokers by preventing relapse, with the aim of long-term permanent abstinence.

intensive counselling with pharmacotherapy.43 Individual smoking cessation interventions can be broken down into several components: • • • •

counselling and behavioral therapies; self-help and other supplementary materials; pharmacotherapy; alternative therapies.

EFFECTIVENESS OF SMOKING C E S S AT I O N

There are also other important issues relating to who should deliver these interventions, the setting of the intervention, and the special case of patients with respiratory disease.

There is clear evidence, summarized in systematic reviews,41 and guidelines from both the UK42,43 and USA44,45 that smoking cessation interventions are both effective and costeffective. There is a wide variety of approaches to smoking cessation, ranging from media campaigns, which aim to raise awareness and motivation to stop at a population level, to individual level interventions, which aim to improve a smoker’s chances of stopping successfully with counseling and pharmacotherapy. In this chapter, we will focus on the evidence for the effectiveness of smoking cessation interventions that can be delivered at the individual level by healthcare professionals, and their effect on long-term success in stopping smoking. Long-term success is usually defined as continuous abstinence for 6 or more months, validated by a biochemical test.42,43 The most commonly used test is to measure carbon monoxide in expired air, which should be less than ten parts per million in an abstinent smoker. Cotinine, a metabolite of nicotine, can also be measured in saliva and urine as a marker of nicotine intake. Depending on the overall intensity of the intervention delivered, the incremental increase in sustained cessation achieved by cessation interventions ranges from about 2% for brief opportunistic advice from a clinical to nearly 20% for

Counseling and behavioral therapies Counseling and behavioral therapies aim to motivate a smoker to stop, improve a smoker’s chance of stopping (by helping an individual to develop specific skills and strategies to cope with withdrawal), and to change their behavior following cessation.The success of these therapies is broadly related to amount of contact a smoker has with a counselor,42,43,45,46 that is, the longer or more intensive an intervention, the greater a smoker’s chance of successfully stopping. Paradoxically, however, it is also the case that the more intensive an intervention the greater the financial cost of providing the service and the greater the demand on a smoker’s time, and hence the smaller the proportion of smokers it can reach.46 Thus, brief interventions may offer a relatively low chance of success at an individual level but can be made available to a larger proportion of smokers than more intensive counseling. At a population level, it may therefore be more effective in terms of maximizing smoking cessation to adopt a strategy of applying a less intensive intervention across the entire population than to invest heavily in low coverage, higher success interventions. Brief and intensive interventions are described in more detail below.

512


Brief interventions Brief interventions can be provided by any clinician or health care professional in any setting, but are of especial relevance to those in primary care (general practice) and out-patient clinics. The main effect of such interventions is to motivate the smoker to stop.43 The evidence suggests that even an intervention lasting only 3 minutes can lead to a significant increase in longterm cessation. Although the success rate is small (an intervention lasting 3 minutes has a long-term success rate of 5% compared with 3% in those receiving no help),42,43 because of their high population reach they are highly cost-effective. Such advice should include the following points: • give a clear, strong message to stop smoking; • stress the benefits of giving up smoking (health, financial etc.). If the smoker is willing to stop now, the clinician should: • encourage the smoker to set a quit date; • emphasize the importance of total abstinence, ‘not even one puff’; • provide written support materials; • give advice on pharmacotherapy, with a prescription if appropriate. If the smoker would like additional assistance, the clinician should refer to a trained nurse or specialist smokers’ clinic for further advice and support (see below).

Intensive interventions Intensive interventions are usually provided by smoking cessation specialists, generally in the context of a specialist smokers’ clinic. The main effect of such interventions is to improve a motivated smoker’s chances of stopping.43 Intensive interventions usually involve a formal assessment (including a motivational assessment) followed by a program of four to six sessions, each lasting from 10 minutes to 1 hour, delivered to groups or on an individual basis.47 Because intensive interventions require a substantial time commitment, they work best with smokers who are highly motivated to stop; indeed, the relatively high success achieved by such interventions may in part be due to the selected nature of the smokers who use them.48 In the UK more brief one-to-one support is known as an “intermediate intervention”; usually this consists of two sessions lasting 10 to 30 minutes, with additional weekly follow-up in person or by telephone for at least 4 weeks.43,49 Both intensive and intermediate interventions should deliver strong encouragement to smokers to use pharmacotherapy as appropriate. There are no evidence-based guidelines for what elements intensive interventions should contain. Generally, guidelines recommend providing support based upon teaching problem-solving skills, providing social support45 and coping with the symptoms of withdrawal (Table 48.2). In addition, some evidence suggests that pairing smokers together when they stop smoking (“buddying up”) can improve cessation rates,50 presumably by encouraging mutual support.

Table 48.2. Common components of counseling for smoking cessation (adapted from References 42 and 43)

Theme

Examples

Abstinence

Total abstinence from smoking is essential: “Not even one puff”. Any smoking increases the likelihood of a full relapse

Past attempts to stop

Patients should use their previous experience of trying to stop smoking to identify strategies that have and have not helped in the past

Identify potential challenges

Patients should anticipate difficult situations that are likely to be associated with a strong urge to smoke, e.g. “favorite cigarette”, triggers for smoking (after a meal, with coffee, on the telephone etc.), stress or emotional upset, being with other smokers, alcohol

Prepare coping strategies

Patients should use strategies to tackle difficult situations, e.g. to distract from urges to smoke, to cope with stress (e.g. lifestyle changes) and to avoid potential temptations

Alcohol

Alcohol can cause relapse – patients should limit or avoid drinking alcohol while trying to stop smoking

Other smokers

Stopping smoking is more difficult if family or friends are also smokers – patients should encourage friends and family to quit with them or avoid smoking in their presence

Reasons, benefits and rewards

Identify a patient’s reasons for stopping smoking; stress the benefits to health and finances; patients can save the money they would have spent on cigarettes to reward themselves for success

Smoking Cessation

The “withdrawal orientated model”, developed at the Maudsley Hospital in London and based on a group intensive intervention of six weekly hour-long sessions used in conjunction with nicotine replacement therapy, has a long-term success rate of 20 to 30%.47 The Lung Health Study has shown that a program of prolonged group intensive intervention with nicotine replacement therapy can lead to 1-year cessation rates as high as 35% compared with 9% in controls receiving no intervention,8 although the high cessation rate in the control group reflects the fact that participants in this trial were highly motivated to stop smoking. Recent reviews have found no significant difference between the efficacy of intensive interventions given either to groups or on an individual basis, so on grounds of costeffectiveness preference is generally given to the group approach. Groups may also have the advantage of encouraging mutual support among smokers. However, some of the benefits of group interventions are offset by difficulties in recruiting and retaining sufficient participants. In the UK in particular, groups have been found to be unsustainable when serving the needs of a single general practice,51 and most groups are now run as part of specialist smoking cessation services currently being established throughout the UK to serve health authority areas with typical populations of 500,000. This target population gives rise to between about 300 to 800 smokers willing to participate in group therapy each year,42 which is clearly just a tiny minority of all smokers; this is the major disadvantage of the intensive approach. Self-help and other supplementary materials Written self-help materials do appear to be of some benefit when compared with no intervention, increasing the relative odds of cessation by a factor of 1.23 (95% confidence intervals 1.02 to 1.49),51a and have the advantage that they have the potential to reach a greater number of smokers than advice delivered by a clinician.The additional benefit of selfhelp materials when given together with other interventions is unclear. Some research has shown that materials tailored to the individual smoker are more effective than generic materials, and that telephone support is of additional benefit.52 Such materials are widely available and can be downloaded from the World Wide Web from organizations such as the US Department of Health and Human Services,52 Quit UK,54 and Action on Smoking and Health.55 Pharmacotherapy Pharmacotherapy should almost always be used in smoking cessation as an adjunct to counseling, rather than as an alternative. The two main pharmacological interventions used in smoking cessation are nicotine replacement therapy and bupropion hydrochloride (sustained-release); other pharmacotherapies are also available and will be discussed below. Nicotine replacement therapy Nicotine replacement therapy has been used for smoking cessation for over 20 years. Its main mode of action is

513

thought to be the reduction of symptoms of the nicotine withdrawal syndrome. It is also thought that nicotine replacement therapy may provide a coping mechanism, and make cigarettes less rewarding to smoke.56 No form of nicotine replacement therapy can completely eliminate the symptoms of withdrawal, possibly because no nicotine replacement therapy has yet been developed that can mimic the rapid and high levels of arterial nicotine achieved when cigarette smoke is inhaled14,57 (Fig. 48.3). Of all smoking cessation interventions, nicotine replacement therapy has been subjected to the most rigorous assessment. The most recent Cochrane reviews of the evidence available suggest that nicotine replacement therapy leads to almost a doubling of long-term cessation rates achieved by nonpharmacological intervention (odds ratio 1.71, 95% confidence intervals 1.60 to 1.83), independently from the intensity of the counseling given or setting.58 Therefore, in specialist clinic interventions which can achieve 20% cessation rates, approximately half of the success is attributable to intensive counseling support, and half to nicotine replacement therapy.43 Currently, evidence for the efficacy of nicotine replacement therapy is limited to adults who smoke ten or more cigarettes per day. Six forms of nicotine replacement therapy products are available at present (Table 48.3). There is no evidence to suggest that any product is significantly better than another,59 or that any particular product can be matched to particular smokers.60 Therefore, the choice of which product to use should be guided by a clinician’s judgment and patient preference. However, there is evidence that 4 mg gum is more effective than 2 mg gum in those smoking 20 or more cigarettes per day,58 and that higher dose patches are more effective than low-dose patches in those smoking more than ten cigarettes per day.61 There is also recent evidence that combinations of therapies such as patch and nasal spray,62 or patch and inhaler62 are more effective than single agents alone. Although the use of combined therapies is currently unlicensed, the evidence that does exist suggests that such combinations are safe.64 There is evidence that nicotine replacement therapy, and nicotine gum in particular, can help to control the weight gain commonly experienced after cessation.65 In terms of duration of therapy, 8 weeks therapy appears to be as effective as longer courses; there is no evidence to suggest that tapered withdrawal of nicotine replacement therapy is better than abrupt withdrawal.58 Nicotine is a vasoconstrictor and nicotine replacement therapy is, therefore, contraindicated in acute cardiovascular events such as unstable cardiac disease, acute myocardial infarction or stroke, but has been shown to be safe in stable cardiac disease.66,67 Nicotine replacement therapy should also be used with caution in pregnant and breastfeeding women. Theoretically nicotine from nicotine replacement therapy is safer than that from cigarettes, since it is not accompanied by the other products of tobacco consumption,14 but complete avoidance of all nicotine should be the objective in pregnancy and breastfeeding, and indeed 30%

514


Cigarette (nicotine delivery, 1 – 2 mg)

15

Cigarette (nicotine delivery, 1 – 2 mg)

80 60

10 40 5 20

Plasma nicotine concentration (ng/mL)

0

0

Oral snuff 15

15

10

10

5

5

0

0

Nasal spray (nicotine delivery, 1 mg)

Polacrilex (nicotine delivery, 4 mg)

Transdermal nicotine (nicotine delivery, 15 mg)

15

15

10

10

5

5

0

0 0

30

60

90

120

0

30

60

90

120

600

Minutes Fig. 48.3. Schematic diagram showing rise in venous blood nicotine levels after smoking a cigarette or using oral snuff, and after using different nicotine replacement products, following overnight abstinence from cigarettes. Polacrilex refers to nicotine gum. Reproduced from Reference 57 with permission.

of pregnant women succeed in stopping smoking during pregnancy without nicotine replacement therapy.68 However, for those who cannot stop smoking without pharmacotherapy and wish to try nicotine replacement therapy, it is probably advisable to limit use to short-acting products so that any potential toxicity is minimized. The risk of dependence on nicotine replacement therapy is small, although a minority of patients who quit successfully do use it long-term.69,70 Long-term use of nicotine replacement therapy is not thought to be associated with any significant harmful effects.8 Research is also currently underway to investigate the role of nicotine replacement therapy in assisting smokers to reduce the number of cigarettes they smoke each day, although currently, nicotine

replacement therapy is not recommended in those who are still smoking. Bupropion Bupropion hydrochloride is an atypical antidepressant with dopaminergic and adrenergic activities71 that has been used in North America for some years as an antidepressant. Bupropion has been licensed more recently for use in smoking cessation, firstly in the USA and latterly in the European Union.72 Interest in the effect of bupropion in smoking cessation arose from anecdotal reports that patients taking bupropion for depression found it easier to stop smoking. Two preliminary reports73,74 and two subsequent major clinical trials75,76 have demonstrated efficacy in smokers

Table 48.3. Pharmacotherapies for smoking cessation

Dosage

Duration

Availability

Nicotine gum (polacrilex)

Sore mouth/throat Indigestion

2 or 4 mg/piece Maximum of 15 pieces/day

12 weeks maximum

UK: prescription and OTC (2 mg gum GSL) US: OTC only

Nicotine transdermal patch

Local skin rash Insomnia (24 hour patch)

25 mg/16 hours

8 weeks

Prescription and OTC

21 mg/24 hours 14 mg/24 hours 7 mg/24 hours

4 weeks then 2 weeks then 2 weeks

Nicotine nasal spray

Nasal irritation

500 lg/spray Maximum of 64 sprays daily

3 months

Prescription only

Nicotine inhaler

Sore mouth/throat

10 mg/cartridge Maximum of 12 cartridges/day

3 months

UK: prescription and OTC US: prescription only

Nicotine sublingual tablet

Sore mouth/throat

2 mg/tablet Maximum 40/day

3 months

UK: prescription and OTC

Nicotine lozenge

Sore mouth/throat

1 mg/lozenge Maximum 25/day

3 months

UK: prescription and OTC

Insomnia Dry mouth

150 mg once daily for 3 days then 6 days 150 mg twice daily (started 1–2 weeks before quit date)

8 weeks

Prescription only

Precautions/ Contraindications

Nicotine replacement therapy

Unstable cardiac disease Acute cerebrovascular disease Pregnancy/breastfeeding

Bupropion

History of seizure or eating disorder

Smoking Cessation

Adverse effects

Pharmacotherapy

OTC indicates over the counter. GSL indicates general sales list, i.e. available for sale outside pharmacies. Information derived from manufacturers’ product data sheets and summary of product characteristics.

515

516


antagonist), and sensory replacement (such as ascorbic acid aerosol or citric acid inhalers that recreate the sensation of smoking).46

given bupropion in conjunction with regular counseling support. The first of these studies compared placebo with 100, 150 or 300 mg/day of sustained-release bupropion for 7 weeks in a parallel group study on a total of 615 smokers, and reported cessation rates at 1 year of 12.4, 19.6, 22.9 and 23.1% respectively.75 This effect was independent of any current or previous evidence of depression.77,77a The second study compared sustained-release bupropion 150 mg twice daily (once daily for the first 3 days), either alone or in conjunction with transdermal nicotine, with nicotine alone or placebo.76 Sustained cessation for 1 year was achieved in 5.6% with placebo, 9.8% with transdermal nicotine, 18.4% with bupropion alone, and 22.5% with combined bupropion and nicotine. Bupropion alone was significantly more effective than placebo or transdermal nicotine, and not significantly less effective than bupropion plus nicotine patch. Bupropion significantly reduced weight gain during the drug treatment period, although this effect was subsequently lost. The evidence available is insufficient to show clearly whether bupropion is more effective than nicotine replacement therapy,43,52 so at present there is no obvious first choice between these therapies. The effectiveness of bupropion given with lower levels of counseling support is also not yet established. Until such evidence becomes available, therefore, the decision to use either nicotine replacement therapy or bupropion can probably be based on medical contraindications and patient preference. The main sideeffects of bupropion are insomnia and dry mouth; there is also a low risk of seizure (one in 1000 patients) similar to other antidepressants, so bupropion is contraindicated in those with a history of seizures, and is also contraindicated in those with a history of eating disorders. The combination of bupropion and nicotine replacement therapy carries a theoretical risk of hypertension, and it is recommended that blood pressure is checked weekly during combined therapy.72 The dosage regimen for bupropion is given in Table 48.3.

Who should deliver smoking cessation interventions? A recent update of the Cochrane reviews shows that smoking cessation interventions delivered by doctors are effective (odds ratio for cessation versus no intervention 1.69, 95% confidence intervals 1.45 to 1.98).83 However, in the majority of clinical settings the bulk of smoking cessation interventions are delivered by other health professionals, particularly nurses. The Cochrane reviews confirm that smoking cessation interventions delivered by nurses are effective (odds ratio 1.43, 95% confidence intervals 1.24 to 1.66), but that they are not effective when given as part of a routine screening health check.84 This difference may in part be due to the fact that specific smoking cessation interventions may attract smokers more motivated to stop than those seen during other more general health promotion measures. Combined data from two recent randomized trials in the UK have also shown that pharmacists, trained to provide structured behavioral support with nicotine replacement therapy, can improve cessation rates.85,86 Currently the benefits of other health professionals providing smoking cessation interventions in addition to their usual duties is unclear.43,52

Other drugs Many other drugs have been tested for their effectiveness in helping smokers to stop.46 Of these, clonidine (an a2-nonadrenergic agonist) has been demonstrated to be of proven value in smoking cessation,78 but has gained little use, probably due to significant side-effects, particularly sedation and postural hypotension. Two recent trials have shown that nortriptyline (a tricyclic antidepressant) is also effective in smoking cessation.79,80 Side-effects of nortriptyline include anticholinergic symptoms, nausea, and sedation. Neither drug is licensed in the UK for smoking cessation, although recent US guidelines recommend that clonidine and nortriptyline can be used as second-line agents, in those intolerant or unwilling to use nicotine replacement therapy or bupropion. Other possible therapies for smoking cessation include antidepressants with adrenergic activity (such as doxepin), monoamine oxidase inhibitors, mecamylamine (a nicotine

Setting of the intervention There is clear evidence that brief interventions delivered in primary care are effective, that both general practitioners and primary care nurses should deliver these (the latter in the context of smoking cessation interventions only) and that they should be given with pharmacotherapy as appropriate. Intensive interventions are not viable at a single practice level, but referral to a specialist clinic for more intensive help should be available.43 In hospital, as with primary care, brief interventions are also effective and should be delivered to all smokers attending hospital. More intensive help should also be made available to both in-patients and out-patients, ideally to be delivered by a hospital-based smoking cessation specialist. Pharmacotherapy should be used in out-patients, as appropriate.43 There is clear evidence that intensive interventions delivered by specialist smokers’ clinics are highly effective,

Alternative therapies Alternative therapies such as acupuncture or hypnotherapy appear to be popular in as much as they are widely available and appear commercially successful. Evidence for their efficacy is limited: review of the 20 trials of acupuncture suggests some benefit, but that this is likely to be due to a placebo effect;81 there is no evidence to support any benefit from hypnotherapy.82

OTHER ISSUES

Smoking Cessation

and that such clinics should offer both group and individual treatment, using pharmacotherapy as appropriate.43 It is important that clinicians in all settings systematically identify smokers, to allow smoking cessation interventions to be appropriately targeted.43 Patients with respiratory disease The Lung Health Study demonstrated that an intensive intervention with nicotine replacement therapy was highly effective for smokers with mild asymptomatic COPD.8 However, few studies have looked specifically at smoking cessation in patients with manifest respiratory disease.These studies have tended to focus on in-patients with smokingrelated diseases87,88 or on out-patients attending chest clinics,89 and their results have been mixed. All studies used only brief/intermediate interventions; two used nicotine replacement therapy and both of these were limited in their findings by small sample sizes.87,88 Other studies of hospitalized patients have shown that patients with smoking-related diseases are less successful at stopping smoking than other hospital patients.90 It is possible that because the association between smoking and chronic respiratory disease is so wellrecognized in the general population, many smokers who develop chronic respiratory symptoms give up smoking before presenting to specialist medical services. If so, then those who continue to smoke will represent a hard core of the most dependent smokers who find it especially difficult to stop, and/or those who are least motivated to succeed.

S M O K I N G C E S S AT I O N I N P R A C T I C E Over two-thirds of smokers say that they would like to give up smoking, and one-third will make an attempt to stop smoking every year.4 Unfortunately, most smokers who try to stop do so using willpower alone, a method with at best a 3% long-term success rate among those who try.43 The key to putting the evidence for the effectiveness of smoking cessation into practice is to develop an integrated

517

system of smoking cessation that identifies those smokers motivated to stop as part of routine clinical care, motivates those smokers to try stopping, and aims to improve their chance of succeeding with counseling and pharmacotherapy. The most important elements of practical smoking cessation can be thought of in terms of the five As, a way of integrating smoking cessation into routine practice (Table 48.4) .45 These are designed to be delivered as part of a brief intervention. The five As are outlined in more detail below. Ask about smoking Smoking is of such importance as a risk factor for patients that it is essential that all smokers be identified. Smoking should be treated as a vital sign to be assessed and recorded in all patients’ medical records. Clinicians should develop a system to ensure that every patient’s smoking status is recorded, ideally as part of an expanded set of vital signs. Advise all smokers to stop smoking Clinicians should give a clear, strong and personalized message about stopping smoking, stressing the harmful effects of smoking on present and future health, relating smoking to the patient’s own health or illness, and offering help. Once advice has been given, it should be noted in a patient’s records together with the patient’s response.43 Assess the smoker’s willingness to stop smoking Clinicians should determine whether the patient is currently willing to stop smoking. Those motivated to stop should be provided with assistance to do so most effectively; unmotivated smokers should be encouraged where possible. This distinction between motivated and unmotivated smokers is of important practical value if a clinician is to avoid wasting valuable time providing assistance and pharmacotherapy to a smoker who is unready or unwilling to stop. When assessing smokers it is helpful to have an understanding of some of the psychological aspects of smoking. One psychological model in widespread use in smoking cessation is the transtheoretical model of change, often

Table 48.4. The five As. Brief smoking cessation strategies for routine practice (adapted from Reference 45)

STEP

ACTION

Ask about smoking

Systematically assess smoking status. Smoking should be a vital sign

Advise all smokers to stop

Give a clear, strong and personalized message to stop smoking

Assess willingness to stop

Determine whether the smoker is ready to stop currently or soon. Provide assistance to motivated smokers; motivate those unwilling to stop

Assist motivated smokers to stop

Help smoker with a quit plan, counseling, pharmacotherapy and additional materials

Arrange follow-up

Follow-up soon after the quit date. Assess success and difficulties. Consider referring for a more intensive intervention if there is relapse

518


known as the cycle or stages of change92 which describes a continuum of attitudes that a smoker may hold. Some smokers are contented and have not even considered stopping smoking (those in the precontemplation stage); others are considering stopping smoking (the contemplation stage), before then actively preparing to stop in the next 30 days (the preparation stage). Once a smoker has stopped smoking (the action stage), they may succeed and remain abstinent (the maintenance stage) or may fail (relapse), returning to one of the previous stages (Fig. 48.4). In terms of this psychological model, smokers in the preparation and action stages will require assistance, while those in precontemplation and contemplation stages may require further motivation to make an attempt to stop smoking, but would be unlikely to benefit from receiving additional assistance at the present. Assist motivated smokers in stopping smoking Give assistance to smokers motivated to stop, specifically with a “quit plan”, referral for counseling and providing pharmacotherapy as appropriate.Those smokers who request additional assistance should be referred to a specialist clinic. Quit plans are commonly used in smoking cessation, and provide a framework to help a smoker make adequate preparations before giving up smoking. Features of a quit plan may include:45 • Set a quit date: ideally within the next 1 to 2 weeks; • Tell family,friends and colleagues about stopping smoking; • Anticipate challenges in advance, particularly symptoms of withdrawal; • Remove all tobacco-related products from your environment.

Finally, the smoker’s suitability for pharmacotherapy should be assessed. Unless contraindicated, nicotine replacement therapy (suitable for smokers who smoke ten or more cigarettes per day) or bupropion (suitable for those who smoke 15 or more cigarettes per day) should be offered and prescribed as necessary. Clear advice regarding the side-effects and benefits of pharmacotherapy should be given.43,45 Alternatives, such as clonidine or nortriptyline, should be reserved only for those patients intolerant or unwilling to use nicotine replacement therapy or bupropion.45 Arrange follow-up Arrange follow-up to monitor progress and prevent relapse. The first follow-up visit should take place during the first week after the quit date, which is the time of greatest risk of relapse. Weekly follow-up sessions for at least 4 weeks are recommended.43 Follow-up can be performed in person or by telephone, with the aim of confirming abstinence (ideally verified by measurement of carbon monoxide in expired air), reinforcing previous counseling and monitoring use and problems with pharmacotherapy. Many patients will relapse – it is important to stress the cyclical nature of smoking and that further attempts may be successful. If a patient experiences severe withdrawal symptoms, difficulties with pharmacotherapy, or is particularly interested in more intensive interventions, consider referring for more intensive help from a specialist clinic. More detailed information about the content and operation of such intensive interventions is beyond the remit of this chapter, but information is available elsewhere.47

S U M M A RY Precontemplation Contented smoker

Contemplation

Smoking

Smoking is the most important cause of COPD and worsens the symptoms of asthma, and stopping smoking is clearly beneficial to patients with both COPD and asthma. Smoking is an addictive, chronic behavior due to addiction to nicotine, a substance as addictive as heroin and cocaine.There is substantial evidence for the effectiveness of smoking cessation interventions – the key to putting this evidence into practice is to make smoking cessation a routine part of clinical care.

Willing to stop

REFERENCES Action Relapse

Preparation

Stopping

Maintenance Remaining abstinent Fig. 48.4. Transtheoretical model of change. Italicized boxes indicate different stages. Adapted from Reference 92.

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b2-Adrenoceptor Agonists

Chapter

49

Ian P. Hall Division of Therapeutics, University Hospital, Nottingham, UK

b2-agonists have been the mainstay bronchodilator agents used for the treatment of asthma and COPD since the development of inhaled isoprenaline preparations in the 1960s. While the initial preparations were marketed at relatively high doses and had little b2-selectivity the sideeffect profile of theses agents was markedly improved by the development of short-acting b2-selective agents such as salbutamol and terbutaline. More recently, long-acting b2selective agents have assumed an increasingly important role in the management of asthma and to a lesser extent COPD.

MECHANISM OF ACTION b2-agonists bind to the b2-adrenoceptor which is present in the cell membrane of a number of airway cells including airway smooth muscle, airway epithelial cells, inflammatory cells including mast cells, vascular and endothelium and vascular smooth muscle.1 However, the major site of action of b2-agonists in the airways is the airway smooth muscle cell. Following binding of b2-agonist to the b2-adrenoceptor on airway smooth muscle a signaling cascade is triggered which results in a number of events, all of which contribute to relaxation of airway smooth muscle (Table 49.1).2,3 The majority of these events are dependent on elevation of cell cyclic AMP content, which is brought about following binding of b2-agonist to the b2-adrenoceptor by stimulation of adenylyl cyclase as a result of activation of the G protein coupled to the b2-adrenoceptor, Gs.4 This exists as a heterotrimeric complex but following stimulation of the b2adrenoceptor Gs dissociates releasing free a-subunits which are able to stimulate adenylyl cyclase. Adenylyl cyclase exists in a number of different isoforms although there is at least some evidence suggesting that adenylyl cyclase VI is important in airway smooth muscle; however most of the other adenylyl cyclase isoforms are also present in this tissue.5 Adenylyl cyclase catalyzes the formation of cyclic AMP from ATP. Cyclic AMP is able to convert protein kinase A from an inactive form to the active form in which the catalytic and regulatory subunits dissociate. The catalytic subunit of

protein kinase A then phosphorylates key targets within the cell bringing about the majority of the physiological effects of b2-adrenoceptor stimulation. However, there is at least some evidence to suggest that cyclic AMP independent actions may also occur; for example, direct stimulation by Gsa of the BK channel present in the airway smooth muscle cell membrane has been described.2 This is relevant because the BK channel (a voltage-gated potassium channel) is thought to be important in modulating changes in cell membrane potential following stimulation with b2-agonist, and thus can contribute to the relaxant response of b2adrenoceptor stimulation. The intracellular effects of b2-adrenoceptor stimulation are relatively shortlived. Cyclic AMP is broken down by phosphodiesterase isoenzymes present in the cell, with type 3 and type 4 phosphodiesterase activities believed to be the most important in regulating cyclic AMP content in airway smooth muscle and type 4 phosphodiesterase being physiologically important in many inflammatory cells including eosinophils. Continued stimulation by Gsa is prevented by the free Gsa rapidly reassociating with bc to reconstitute the heterotrimeric Gs complex (Fig. 49.1).

Table 49.1. Mechanisms underlying airway smooth muscle relaxation by b2 adrenoceptor agonists

•

Inhibition of spasmogen-induced inositol 1,4,5 trisphosphate production

•

Inhibition of spasmogen-induced rises in intracellular free calcium

•

Activation of calcium-activated K+ channels

•

Alteration of sensitivity of contractile apparatus

•

Increased extrusion/re-uptake of calcium from cytoplasm

•

Hyperpolarization of cell membrane

522


β2 AGONIST

Phe 290 VI

VII RECEPTOR ACTIVATION

γ

GDP

γ

α

V

I

Ser 207 Ser 204

α β

β

GDP

III

II

IV

Exocite binding

GTP

Pi

Asp 73 γ α

ⴙ β

GTP

DOWNSTREAM EFFECTS Fig. 49.1. G-protein regulatory cycle of activation and deactivation for transmission of the signal from receptor to effector. When GDP is bound the heterotrimeric G-protein is inactive, receptor stimulation causes conformational change in both it and the G-protein which decreases GDP binding affinity. GTP is abundant in the cell and replaces GDP; the active conformation of the Ga subunit dissociates from bc. This activated state remains until GDP is hydrolysed to GDP whereby the subunits reassociate.

STRUCTURE AND FUNCTIONAL R E L AT I O N S H I P S O F b2 - A G O N I S T S A N D T H E b2 - A D R E N O C E P T O R The b2-adrenoceptor is a member of the G protein coupled receptor super family with the typical seven transmembrane spanning domains (Fig. 49.2).6,7 The binding site for b2agonists consists of residues in at least three of the a-helices which pass through the cell membrane. The prolonged duration of action of salmeterol is believed to be due to binding of the lipophilic tail to residues deep in the fourth transmembrane domain.8,9 This process is essentially irreversible. The explanation for the prolonged duration of action of formoterol is less clear although it has been proposed that because of its lipophilicity formoterol partitions in the cell membrane which forms a reservoir allowing prolonged interaction with the receptor.10 The most commonly used b2-agonists in clinical practice are listed in Table 49.2. All the clinically important b2-agonists consist of a benzene ring with a chain of two carbon atoms and either an amine head or a substituted amine head. If a hydroxyl (OH)

Asp 113

Fig. 49.2. Cross sectional view of transmembrane spanning domains of the b2-adrenoreceptor core. The b2 agonist ligand is shown sitting in the binding pocket in the receptor. Key amino acid residues for binding of ligand are shown, Amino acids in transmembrane domain IV are implicated in salmeterol exocite binding.

group is present at positions 3 or 4 on the benzene ring the structure is a catechol nucleus and hence the agent a catecholamine. If these hydroxyl groups are substituted or repositioned the drug is generally less potent than the synthetic catecholamine isoprenaline, which is a full agonist at b2-adrenoceptors. This potential disadvantage may be outweighed by the relative resistance of substituted catecholamines to metabolic degradation by the enzyme catechol – 0-methyltransferase (COMT). Examples of such agents are salbutamol and terbutaline with salbutamol only being a partial agonist. As mentioned above, the prolonged duration of action of salmeterol is due to a long side chain substitution which is believed to bind to an additional site in the fourth transmembrane spanning domain of the receptor. Substitutions on the a carbon atom help block oxidation by monoamine oxidase (MAO).

Table 49.2. Frequently used b2-adrenoceptor agonists

Short-acting b2-adrenoceptor agonists Salbutamol (albuterol)a Terbutaline Tenoterol Long-acting b2-adrenoceptor agonists Salmeterol Formoterol a

USA name


The effects of catecholamines such as adrenaline (noradrenaline) and isoprenaline are terminated by uptake into either sympathetic nerve endings (uptake 1) or other innervated tissues such as smooth muscle (uptake 2). The dominant enzyme present in innervated tissues is COMT whereas the dominant metabolic degradation route in sympathetic nerve endings is through oxidation by MAO. In addition to degradation, exogenously administered b2-agonists can be conjugated to sulfates or glucuronides in the liver, or the lung. Following ingestion the drugs are partially conjugated during first past metabolism which accounts for roughly 50% of the metabolism of the short-acting drug salbutamol.

CLINICAL PHARMACOLOGY OF b 2- A G O N I S T S General pharmacology b2-adrenoceptor agonists are predominantly used in the treatment of airflow obstruction because of their bronchodilator properties.These differ markedly between asthma and COPD (Table 49.3); indeed, reversibility of airflow obstruction with inhaled b2-agonist is often used as a diagnostic marker of asthma and helps distinguish asthma from COPD in patients where the distinction is in doubt (e.g. chronic “asthmatics” who have smoked, or previous smokers who develop symptoms of wheeze in later life). However, as well as reversing airflow obstruction in asthmatic individuals b2-agonists also protect against bronchoconstrictor challenge.11 Because of this latter effect b2-agonists have been considered to have potential antiinflammatory actions (see below). In-vitro b2-agonists prevent mediator release from inflammatory cells including mast cells, an effect which if present in human airways would be expected to reduce airway inflammation.12,13 However, the concentrations of these agents required to demonstrate these effects is in general much higher than those seen in the lungs in vivo.

S H O R T- T E R M E F F E C T S O F b 2 - A G O N I S T S IN ASTHMA AND COPD As mentioned above, the ability of b2-adrenoceptor agonists to reverse airflow obstruction is a hallmark of asthma, with

523

reversibility 15% being considered diagnostic. b2-agonists do produce a measurable bronchodilator effect in normal individuals and in patients with other diseases characterized by airflow obstruction such as COPD and bronchiectasis, although the magnitude of these effects is generally much smaller. In normal individuals bronchodilator responses are generally only observable by measuring specific airway conductance. This contrast between the marked effects of b2-agonists in asthmatic patients and the minimal effects in normal individuals led early investigators to hypothesize that a primary defect in the b2-adrenoceptor signaling pathway was the actual cause of asthma. This hypothesis would not explain many of the inflammatory features present in the disease, but interest in the potential for a primary abnormality of b2-adrenoceptors to contribute in part to the pathophysiology of asthma resurfaced following the description of polymorphic variation within the b2-adrenoceptor (see below). In addition to having a bronchodilator action b2-agonists in asthmatics protect against bronchoconstrictor stimuli.14–17 One feature demonstrated by most (but not all) asthmatics is nonspecific airway hyperreactivity to inhaled irritant challenge including allergen. The most frequently used stimuli are histamine and methacholine although abnormal responses are also seen to exercise, allergen and other challenges. The inhaled dose of histamine and other agents required to provoke a 20% fall in FEV1 (PC 20) is increased markedly (usually by about three doubling doses) by previous treatment with a short-acting b2-agonist. While a degree of such bronchial hyperreactivity can also be demonstrated in other diseases including COPD, bronchiectasis, cystic fibrosis and left ventricular failure this is usually far less marked than in asthmatic subjects.

L O N G - T E R M E F F E C T S O F b 2- A G O N I S T S IN ASTHMA AND COPD While regular treatment of inhaled or nebulized b2-agonist is frequently used in the management of moderate or severe COPD, despite relatively small improvements in symptoms, controversy has reigned over the long-term use of regular b2agonist in the management of asthma.18,19 This controversy originated from discussions following epidemics of asthma

Table 49.3. b2-agonists in asthma and COPD

Asthma

COPD

Bronchodilator response greater than 15% change in FEV1

Bronchodilator response less than 15% change in FEV1

Bronchodilator hyperreactivity present

Bronchial hyperreactivity usually absent

b2-agonist protects against nonspecific airway challenge Marked symptomatic benefit with b2-agonist

Small or moderate symptomatic benefit with b2-agonist

Effective in long-term management

No disease-modifying effects

524


deaths in New Zealand in the late 1960s and late 1970s which were linked to the prescribing of high-dose isoprenaline and fenoterol, respectively. Several studies subsequently concentrated on the possibility that tachyphylaxis may develop as a result of inhaled b2-agonists in asthma. In general, studies attempting to demonstrate tachyphylaxis to the bronchodilator effects of b2-agonists have failed to identify clinically important loss of responsiveness although small effects have been observed when looked for carefully (see for example, Reference 20). However, in contrast, the bronchoprotective effects of b2-agonists against nonspecific airway challenge show tachyphylaxis which generally develops within 24 hours.21,22 Thus, the magnitude of the protective effect against exercise, histamine challenge or methacholine challenge is reduced in magnitude compared with the level of initial protection following administration of b2-agonist for periods of over 24 hours. However, there is still overall protection against bronchoconstrictor challenge even if this is less than the protection seen in the initial hours after treatment. Thus, while it seems clear that tachyphylaxis develops to the bronchoprotective effects of b2-agonists against nonspecific airway challenge, this is only partial, and one would presume that patients would still be better despite this tachyphylaxis than if they were not taking b2-agonist at all. The main concern therefore has revolved around patients taking intermittent treatment or discontinuing treatment. Small rebound increases in airway reactivity have been demonstrated following the cessation of b2-agonist therapy.23 Clinical studies comparing regular (e.g. four times a day) short-acting b2-agonist versus “as required” b2-agonist have not shown clinically important differences despite earlier reports that asthma control deteriorated following regular treatment.24,25 None the less, there is no reason to suppose regular treatment is better than “as required” usage which remains the preferred way of prescribing b2-agonists in asthma. The controversy regarding b2-agonists resurfaced with the introduction into the marketplace of long-acting b2-agonists. Initial concerns that salmeterol might worsen asthma control in the long term have not been proven to be true. This initially seems surprising, given the fact that salmeterol is a partial agonist and essentially binds irreversibly with the b2adrenoceptor. Interestingly, the wheel has now come full circle with the other commonly used long-acting b2-agonist, formoterol, having undergone recent studies for use as an “as required” agent. Although mild COPD is often treated with “as required” b2-agonist regular high-dose inhaled or nebulized b2-agonists have been much more widely used in COPD than in asthma. While small improvements in lung function and symptomatic improvement have been demonstrated in severe COPD, the overall effect on lung function has generally been small, which is hardly surprising given the fixed nature of the airflow obstruction in the majority of patients. There have been no data suggesting deterioration in lung function following chronic administration of high doses of b2-agonist in COPD (these would be difficult to observe in short-term studies in

any case) although there have been concerns about other effects of high doses of b2-agonist in this setting. In particular, high-dose nebulized b2-agonists are known to cause hypokalaemia and both supraventricular and ventricular arrhythmias26 and there have been concerns that these may occur in patients on regular high-dose nebulized bronchodilator therapy for either asthma or COPD at home.

b 2 - A D R E N O C E P T O R P O LY M O R P H I S M I N ASTHMA AND COPD As mentioned above, the identification of polymorphic variation within the gene for the b2-adrenoceptor reawakened interest in the possibility that primary abnormalities of b2adrenoceptor signaling pathways may be involved in the pathogenesis of these airway diseases. The gene for the b2adrenoceptor is situated on chromosome 5q31–33 in a region showing linkage to intermediate phenotypes for asthma and/or atopy.27 The b2-adrenoceptor gene and its immediate controlling regions show a high degree of polymorphic variation with nine single nucleotide type polymorphisms (SNPs) having been identified within the coding region of the gene and a further eight in the immediate 5 prime untranslated region (reviewed in Reference 28). Of the nine coding region polymorphisms five are degenerate (i.e. do not alter the amino acid code of the receptor).29 However, the other four all result in single amino acid substitutions. While the polymorphism at codon 34 (Val34Met) is rare and appears to have no functional effects, the other three nondegenerate polymorphisms appear to produce functional alteration in receptor behavior. Thus, the rare Thr164Ile polymorphism results in reduced affinity for catechol ligands and an altered receptor sequestration profile.30 Interestingly, Thr164 is very close to the salmeterol binding site within the fourth transmembrane spanning domain of the receptor and it seems likely that the isoleucine 164 substitution may alter the binding characteristics of salmeterol to the b2-adrenoceptor. However, the allelic frequency of this polymorphism is only around 2–3% in Caucasian populations, hence homozygous individuals are very rare and to date have not been adequately studied. In contrast, the two N-terminal polymorphisms at codon 16 (Arg16Gly) and 27 (Gln27Glu) are common. While neither alter agonist binding properties of the receptor both result in altered down-regulation profiles following longterm agonist exposure. Thus, the Gly 16 and Gln 27 forms of the receptor show increased receptor down-regulation following agonist exposure while the Glu 27 form of the receptor appears to be partially protected from downregulation.9 These effects have been shown both in transformed cell systems and in primary cultures of human airways smooth muscle. Of the 5 prime untranslated region polymorphisms the strongest evidence for possible functional effects is for the 47 T–C SNP (single nucleotide polymorphism) which alters the terminal amino acid in a short open reading frame which codes for the b-upstream peptide


(also know as the b2-adrenoceptor 5 prime leader cistron); this peptide is believed to be important in maintaining a “brake” on receptor expression and the Cys19Arg polymorphism in this peptide may possibly increase translational inhibition of the b2-adrenoceptor.31,32 The role of b2-adrenoceptor polymorphism has been extensively studied in asthma but less so in COPD. To date, the majority of studies have failed to demonstrate an association between b2-adrenoceptor polymorphism and asthma per se, although weak association with IgE and the degree of bronchial hyperresponsiveness has been seen in some (but not in all) studies.33 These effects may, in part, be due to linkage disequilibrium with other important genes on chromosome 5q such as the nearby Th2 cytokine locus. The possibility that these polymorphisms may contribute to the development of COPD has not been reported upon to date, although studies in this area are currently in progress. The other potential importance of b2-adrenoceptor polymorphism is in pharmacogenetic studies. The possibility that b2-adrenoceptor polymorphism may predict treatment response, particularly following long-term exposure to agonists due to the altered down-regulation profile of individuals carrying particular genotypes (e.g. Gly16, Gln27), has been studied by a number of groups. Initial studies demonstrated an association between Gly16 and subsensitivity to the bronchodilator effects of formoterol following chronic dosing and also a reduced bronchodilator response to salbutamol.20,34 Gly16 has also been shown to be associated with nocturnal asthma. However, more recent studies have failed to identify a relationship between Gly16 and development of severe asthma,35 and in general, it appears that the effects of these polymorphisms upon treatment response are likely to be relatively small and of doubtful clinical significance overall. It is also possible that the combination of groups of polymorphisms around this region (i.e. the haplotype of an individual at this locus) may be the main determinant of functional effects rather than single polymorphisms in isolation.36 It will be interesting to determine whether these polymorphisms are relevant to treatment response in COPD; intuitively, one might imagine this could be the case given the higher doses of agents used in COPD although, to date, no published data are available on this issue.

S U M M A RY b2-adrenoceptor agonists remain the most important bronchodilator therapies available for the management of both asthma and COPD. The response to b2-agonist is markedly greater in asthma than in COPD due to the reversible nature of airflow obstruction in asthma. In addition, in asthma, b2-agonists provide marked protection against nonspecific bronchial challenge. Extensive polymorphic variation exists within the b2-adrenoceptor but at present there are few data to suggest a causal role for b2-

525

adrenoceptor polymorphism in the development of asthma or COPD. Polymorphic variation in the b2-adrenoceptor may, however, be important in determining treatment response although the overall magnitude of these effects appears to be small.

REFERENCES 1. Davis C, Conolly ME, Greenacre JK. Beta-adrenoceptors in human lung, bronchus and lymphocytes Br. J. Clin. Pharm. 1980; 10:425. 2. Kume H, Hall IP, Washabow RJ, Takagi K, Kotlikoff MI. b-Adrenergic agonists regulate KCa channels in airway smooth muscle cAMP dependent mechanisms. J. Clin. Invest. 1994; 93:371. 3. Torphy TJ, Hall IP. Cyclic AMP and the control of airways smooth muscle tone. In: Airways Smooth Muscle: Biochemical Control of Contraction and Relaxation, (eds Raeburn D and Giembycz MA), p. 215. Basel: Birkhauser Verlag, 1994. 4. Johnson M. The b-adrenoceptor. Am. J. Respir. Crit. Care Med. 1999; 158:S146. 5. Billington CK, Hall IP, Stuart J, Mundell JLP et al. Inflammatory and contractile agents sensitize specific adenylyl cyclase isoforms in human airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 1999; 21:597–606. 6. Dohlman HG, Bouvier M, Benovic JL, Caron MG, Lefkowitz RJ. The multiple membrane spanning topography of the b2adrenergic receptor. J. Biol. Chem. 1987; 262:14282. 7. Emorine J, Marullo S, Delavier-Klutchko C, Kaveri SV, DurievTrautmann O, Strosberg AD. Structure of the gene for human b2-adrenergic receptor: Expression and promoter characterisation. Proc. Natl Acad. Sci. USA 1987; 84:6995. 8. Green SA, Spasoff AP, Coleman RA, Johnson M, Liggett SB. Sustained activation of a G protein-coupled receptor via “anchored” agonist binding: Molecular localisation of the salmeterol exocite within the b2-adrenergic receptor. J. Biol. Chem. 1996; 271:24029. 9. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of b2adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 1995; 13:25. 10. Lofdahl CG, Svedmyr N. Formoterol fumarate, a new b2adrenoceptor agonist. Allergy 1989; 44:264. 11. Tattersfield AE. Effect of beta agonists and anticholinergic drugs on bronchial reactivity. Am. Rev. Respir. Dis. 1987; 136:S64. 12. Assem ESK, Schild HO. Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitized human lung. Nature 1969; 224:1028. 13. Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, Holgate ST. Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am. Rev. Respir. Dis. 1985; 132:986. 14. Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting b2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness with mild asthma. N. Engl. J. Med. 1992; 327:1198. 15. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336:1338. 16. Twentyman OP, Finnerty JP, Holgate ST. The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma. Am. Rev. Respir. Dis. 1991; 144:782. 17. Wong BJ, Dolovich J, Ramsdale EH et al. Formoterol compared with beclomethasone and placebo on allergen-induced asthmatic responses. Am. Rev. Respir. Dis. 1992; 146:1156.

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18. Sears MR, Taylor DR, Print CG et al. Regular inhaled b-agonist treatment in bronchial asthma. Lancet 1990; 336:1391. 19. Taylor DR, Sears MR, Herbison GP et al. Regular inhaled bagonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48:134. 20. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between b2-adrenoceptor polymorphism and susceptibility to bronchdilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350:995. 21. Connor BJ, Aikman SL, Barnes BJ. Tolerance to the nonbronchodilator effects of inhaled b2-agonists in asthma. N. Engl. J. Med. 1992; 327:1204. 22. Ramage L, Lipworth BJ, Ingram CG, Cree IA, Dhillon DP. Reduced protection against exercise-induced bronchoconstriction after chronic dosing with salmeterol. Respir. Med. 1994; 88:363. 23. Wahedna I, Wong CS, Wisniewski AFZ, Pavord ID, Tattersfield AE. Asthma control during and after cessation of regular b2-agonist treatment. Am. Rev. Respir. Dis. 1993; 148:707. 24. Drazen JM, Israel E, Boushey HA et al. for the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N. Engl. J. Med. 1996; 335:841. 25. van Schayck CP, Dompeling E, van Herwaarden CLA et al. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. Br. Med. J. 1991; 303:1426. 26. Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 336:1396. 27. Kobilka BK, Dixon RAF, Frielle T et al. cDNA for the human b2adrenergic receptor: A protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc. Natl Acad. Sci. USA 1987; 84:46.

28. Fenech A, Hall IP. Pharmacogenetics of asthma. Br. J. Clin. Pharmacol. 2000 (in press). 29. Reihsaus E, Innis M, MacIntyre N, Ligghett SB. Mutations in the gene encoding for b2-adrenergic receptor in normal and asthmatic subjects. Am. J. Respir. Cell Mol. Biol. 1993; 8:334. 30. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human b2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J. Biol. Chem. 1993; 268:23116. 31. McGraw DW, Forbes SL, Kramer LA, Liggett SB. Polymorphisms of the 5 leader cistron of the human b2-adrenergic receptor regulate receptor expression. J. Clin. Invest. 1998; 102:1927. 32. Scott MG, Swan C, Wheatley AP, Hall IP. Identification of novel polymorphisms within the promoter region of the human b2-adrenergic receptor gene. Br. J. Pharmacol. 1999; 126:841–4. 33. Dewar JC, Wilkinson J, Wheatley A et al. The glutamine 27 b2adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J. Allergy Clin. Immunol. 1997; 100:261. 34. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the b2adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 1997; 100:3184. 35. Weir TD, Malleck N, Sandford AJ et al. Genetic polymorphisms of the b2-adrenergic receptor in fatal and near fatal asthma. Am. J. Respir. Crit. Care Med. 1998; 158:787. 36. Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region b2-adrenergic receptor haplotypes alter receptor expressions and predict in vivo responsiveness. Proc. Natl Acad. Sci. USA 2000; 97:10483–8.

Chapter

Anticholinergic Bronchodilators

50

Steven E. Cattapan and Nicholas J. Gross Loyola University Stritch School of Medicine, Edward Hines Jr. VA Hospital, Hines, IL, USA

Anticholinergic agents, such as atropine, exist in the roots, seeds, and leaves of many plants; as such, they have been used in herbal remedies for many centuries. Seventeenthcentury Aryuvedic literature documents the treatment of asthma with Datura stramonium, a plant commonly known as jimsonweed, which contains atropine. In 1802, this therapy was introduced into Europe by General Gent who, while stationed in Madras, found that smoking Datura stramonium alleviated his asthma.1 In 1859, it was reported that severe bronchospasm was successfully treated by the injection of atropine into the vagus nerve.2,3 Unfortunately, naturally occurring anticholinergics produce many sideeffects that result in poor acceptability by patients. Thus, following the discovery of adrenaline in the 1920s, the use of anticholinergics was largely supplanted by adrenergic agents and later by methylxanthines. Interest in anticholinergics returned with better understanding of the role of the parasympathetic system in controlling airway tone, and with the development of synthetic congeners of atropine that are topically active but much less prone to produce side-effects.4

R AT I O N A L E F O R U S E O F ANTICHOLINERGIC B R O N C H O D I L AT O R S Autonomic control of airway caliber In human airways, most of the efferent autonomic nerves are cholinergic5 (Chapter 34). Branches of the vagus nerve travel along the airways and synapse at peribronchial ganglia, from which short post-ganglionic nerves travel to smooth muscle cells and mucous glands, predominantly in the central airways. The release of acetylcholine from varicosities and terminals of the post-ganglionic nerves activates muscarinic receptors, thereby stimulating smooth muscle contraction, releasing mucus from mucus glands, and possibly accelerating ciliary beat frequency. In resting animals, a low level of cholinergic, vagal (bronchomotor) tone has been demonstrated. This cholinergic activity can be augmented

by a variety of stimuli by means of the neural pathways shown in Fig. 50.1. Afferent activity can arise from irritant receptors and C fibers located anywhere in the upper and lower airways, and probably also from the esophagus and carotid bodies. These impulses are transmitted along vagal afferents, through the vagal nuclei, and then to vagal efferents and the larger airways that receive vagal innervation. Stimuli to which these receptors respond include mechanical irritation, many irritant gases, aerosols, particles, cold dry air, and specific mediators such as histamine and bronchoconstricting eicosanoids.6,7 There is evidence that cholinergic bronchomotor tone is increased in both asthma8 and chronic obstructive pulmonary disease (COPD).9 By competing with acetylcholine at muscarinic receptors, anticholinergic agents inhibit tonic and phasic cholinergic

CNS ? Vagal afferents

Vagal efferents Naso pharynx

Larynx

Fig. 50.1. Diagrammatic representation of vagal reflex pathways from irritant receptors through vagal afferents, central nervous system (CNS), and vagal efferents to effector cells in the airways. Reproduced from Reference 4, with permission.

528


activity and permit airways to dilate; however, airflow limitation is seldom completely reversed, as vagal activity probably accounts for only a part of the airflow obstruction in patients with asthma or COPD. Anticholinergics do not inhibit other mediators of smooth muscle contraction, nor do they affect the numerous other mechanisms of airway obstruction in asthma and COPD. Muscarinic receptor subtypes in airways At least three muscarinic receptor subtypes are expressed in human lung, and they appear to have different physiological functions (Fig. 50.2). Our current understanding is that M1 receptors, located in peribronchial ganglia, facilitate cholinergic transmission and enhance bronchoconstriction; M3 receptors, located on smooth muscle cells and submucosal glands, mediate smooth muscle contraction and mucus secretion.10 M2 receptors, in contrast, are autoreceptors whose stimulation provides feedback inhibition of further acetylcholine release from cholinergic nerves, and thus tend to limit vagal bronchoconstriction. M2 receptors are selectively damaged by certain viruses as well as by some eosinophil products, which may account for the bronchospasm associated with viral infections and asthma.11,12 Another possible implication of this schema is that currently available anticholinergic bronchodilators, none of which is selective for muscarinic receptor subtypes, may be suboptimal. Attempts to develop selective anticholinergic agents have resulted in one, tiotropium bromide, that dissociates more rapidly from M2 receptors, rendering it functionally selective for both M1 and M3 receptors.13-15

PHARMACOLOGY Anticholinergic agents are classified as tertiary or quaternary ammonium compounds, depending on whether the nitrogen atom on the tropane ring is 3-valent or 5-valent, respectively (Fig. 50.3). Naturally occurring anticholinergic agents, such as atropine and scopolamine, are tertiary ammonium compounds. They are freely soluble in water and lipids and well absorbed from mucosal surfaces and the

M2 M3

M1

ACh Airway smooth muscle

Ganglion

Cholinergic nerve M1

M2

M3

Fig. 50.2. Muscarinic receptor subtypes in airways. M1 receptors are localized to parasympathetic ganglia, M2 receptors to post-ganglionic cholinergic nerves (autoreceptors), and M3 receptors to airway smooth muscle. Reproduced from Reference 80, with permission.

skin. They are thus widely distributed in the body and cross the blood–brain barrier, counteracting parasympathetic activity in almost every system and producing widespread dose-related systemic effects. Atropine, for example, in the dose that results in bronchodilatation (1.0–2.5 mg in adults) frequently produces skin flushing, mouth dryness and possibly tachycardia. In slightly higher doses, it produces blurred vision, urinary retention and mental effects such as irritability, confusion and hallucinations. The therapeutic margin of atropine and its natural congeners is thus small, making these agents difficult to use. Quaternary ammonium compounds are all synthetic, e.g. ipratropium bromide. The charge associated with the 5valent nitrogen atom renders these molecules poorly absorbable from mucosal surfaces. Such agents are fully anticholinergic at the site of deposition and will, for example, dilate the pupil if delivered to the eye or dilate the bronchi if inhaled. However, they are not sufficiently absorbed from these sites to produce either detectable blood levels or systemic effects, even when delivered in supramaximal doses.16 Quaternary agents can thus be regarded for practical purposes as topical forms of atropine. The group includes, in addition to ipratropium: • • • •

oxitropium bromide (Oxivent) atropine methonitrate glycopyrrolate bromide (Robinul) tiotropium bromide (Spiriva).

The last agent, tiotropium, is of particular interest in that it is a functionally selective antagonist of the muscarinic receptor subtypes that mediate bronchoconstriction (see above) and is also extremely long-acting.13,14 The long halflife of tiotropium allows for once-daily dosing. Thus, it is likely that tiotropium will prove more convenient and provide more consistent bronchodilation than the currently recommended three- to four-times daily administration of ipratropium bromide. Furthermore, the prolonged protection against cholinergic bronchoconstriction may improve control of nocturnal bronchoconstriction, where cholinergic mechanisms appear to be important. For these reasons, tiotropium may prove preferable to currently available agents. Indeed, in a recent randomized trial of 288 patients with stable COPD, tiotropium was more effective than ipratropium at improving trough, average, and peak lung function over a 13-week period.17 Pharmacokinetics Atropine is quantitatively absorbed from the airways, reaching peak blood levels in 1 hour. The half-life in the circulation is about 3 hours in adults, but longer in children and the elderly.4 Small concentrations can be measured in the feces and in breast milk. Radiolabeling studies of ipratropium in humans show that, following oral or inhaled doses, the serum levels are very low, with a peak at about 1–2 hours and a half-life of about 4 hours. Most of the drug is excreted unchanged in the urine. Following inhalation,

529


Tertiary ammonium compounds CH3

CH3 N

N

Atropine

O

O

CH2 OH

C

CH

O Hysoscine (scopolamine)

O

O

CH2 OH

C

CH

Quaternary ammonium compounds

Br- H2O

CH(CH3)2

Br- H2O

H3C N

O Ipratropium bromide

O

C

CH2 OH CH

H3C

N

CH3

O

O Tiotropium bromide

O

OH

S

C

S

Fig. 50.3. Structures of some anticholinergic agents.

CLINICAL EFFICACY

delivered by turbuhaler was equipotent to 20 lg delivered by MDI.19 The optimal dose of oxitropium MDI is approximately 200 lg. For less commonly used agents, the optimal doses are as follows: atropine, 0.025–0.04 mg/kg; atropine methonitrate, 0.015–0.02 mg/kg; glycopyrrolate, 0.02 mg/kg. In separate studies,14,20 tiotropium was administered in doses ranging from 10 to 80 lg and from 4.5 to 36 lg; in both studies, dose-related improvements in airflow were discernible.

Dose–response The dose–response of anticholinergic agents given by various inhalational methods is provided in a previous review.18 For ipratropium bromide in nebulized solution, the optimal dose is 500 lg in adults and 125–250 lg in children. By metered dose inhaler (MDI), the optimal dose in young adults with asthma is 40–80 lg, but in older patients with COPD the optimal dose is much higher, possibly 160 lg, particularly when airways obstruction is severe. Newer inhalers will employ a dry powder form without propellants, rather than the suspension that is currently used. The optimal dose of the dry powder form may be a little lower than that for the suspension. For instance, 10 lg of ipratropium

Protection against specific stimuli When given in advance of bronchospastic stimuli, anticholinergic agents provide variable degrees of protection.4 They protect more or less completely against cholinergic agonists such as methacholine. In asthmatics, they can prevent bronchospasm induced by b-blocking agents and by psychogenic factors. They provide only partial protection against bronchospasm due to most other stimuli, e.g. histamine,21,22 prostaglandins, nonspecific dusts and irritant aerosols, exercise and hyperventilation with cold dry air. In most of the latter instances, adrenergic agents usually provide greater protection. Ipratropium has no prophylactic effect on leukotriene-induced asthma.23

the bronchodilator effect is somewhat longer than that of atropine, probably because it is not removed from the airways by absorption. Most of an oral dose is recovered in the feces, a small amount as inactive metabolites in the urine. Very little reaches the central nervous system. A similar distribution is likely for tiotropium.

530


commercially available and effective at reducing rhinorrhea;29 thus, in these patients, it may reduce asthma symptoms.

Stable asthma A very large number of studies have compared the bronchodilator potential of the anticholinergic agents with that of adrenergic agents in patients with asthma. While many of these studies are flawed by the fact that they used recommended doses rather than optimal doses, they provide useful information about the comparative actions of these bronchodilators.24 Fig. 50.4, which is typical of most such studies, illustrates many of these points. Anticholinergic agents are slower to reach peak effect, typically 1–2 hours, compared with about 15 minutes for many adrenergic agents. At their peak effect, they almost invariably result in less bronchodilation. The quaternary forms may be slightly longer acting than agents such as salbutamol. Among asthmatic patients, however, there is substantial variation in responsiveness, some patients responding very little to anticholinergic agents, others responding to them almost as well as to adrenergic agents. It has been difficult to identify subgroups of asthmatic patients who are likely to have the greatest response to anticholinergic therapy. The bronchodilating effect of ipratropium may increase with age, in contrast to the decline in response to salbutamol.25 However, children aged 10–18 years have been shown to benefit26 (see below). Individuals with intrinsic asthma and those with a longer duration of asthma may also respond better than individuals with extrinsic asthma,27 although these factors appear to be poor predictors of response. An individual trial remains the best way to identify responsiveness.28 Recently, attention has focused on the role post-nasal drip may play in promoting asthma. Ipratropium nasal spray is

Increase in FEV1 above baseline (mL BTPS)

Pediatric airways disease For acute severe asthma in children, two well-conducted trials in the 1980s showed that the addition of ipratropium

Salbutamol Ipratropium

800 700

Acute severe asthma Most studies suggest that b-agonists are more effective bronchodilators in the setting of acute severe asthma, and that an anticholinergic agent should not be used as the sole initial bronchodilator. The question arises whether an anticholinergic agent can add to the bronchodilatation achieved by the adrenergic agent. In 1987, Rebuck et al.30 found that the combination of 500 lg nebulized ipratropium with 1.25 mg nebulized fenoterol resulted in significantly more bronchodilatation over the first 90 minutes of treatment than either agent alone. Moreover, patients with more severe airway obstruction obtained the greatest benefit from the combination. In the past decade, many studies have addressed this same question. A meta-analysis31 of ten such studies (total of 1377 patients) concluded that the addition of ipratropium reduced hospital admissions (relative risk 0.73) and increased FEV1 by 7.5% (on average 100 cc, 95% CI 50–149 ml) when compared with groups receiving b2 stimulants alone. These benefits were both statistically and clinically significant.32 It seems appropriate to recommend that both classes of bronchodilators be given in acute severe asthma, especially in the early hours of treatment32 and particularly in patients with more severe airflow obstruction.

*

*

*

* *

600 500 400 300 200 100 0 30

60

90

120

180

240

300

360

420

480

Time (minutes)

Fig. 50.4. Increase in forced expiratory volume in 1 second (FEV1) of 25 patients with asthma after inhalation of 200 lg salbutamol by metered dose inhaler (MDI) or 40 lg ipratropium by MDI on separate days. All patients received an additional dose of salbutamol at 480 minutes. Asterisks denote significant differences (P < 0.05). Reproduced from Reference 24, with permission.

531


Asthmatics

0.8

IFT 0.6 Mean increase (liters)

accelerated the rate of improvement in airflow over salbutamol alone.33,34 Subsequent studies35–40 yielded conflicting results regarding the efficacy of combined therapy, although some of these studies lacked statistical power. A systematic review41 of ten studies concluded that combination therapy with multiple doses of ipratropium was safe, improved lung function, and reduced hospitalization rates, especially in children with severe asthma. As in adult status asthmaticus, therefore, the combination of ipratropium with an adrenergic agent is probably more effective than salbutamol monotherapy, particularly in severe exacerbations. In stable childhood asthma, the evidence to support the addition of ipratropium to salbutamol is less clear. Two consensus reports reviewed the published evidence, which is not extensive, and concluded that although ipratropium was safe for the pediatric population, its benefit compared with an adrenergic agent alone was slight at best.42,43 There are scattered reports of ipratropium use in other pediatric conditions such as cystic fibrosis, viral bronchiolitis, exerciseinduced bronchospasm and bronchopulmonary dysplasia, but these do not provide strong and consistent evidence for the benefit of ipratropium over alternative bronchodilators.

FT 0.4

0.2 I

1

2

3

Time (hours)

Bronchitics 0.4 Mean increase (liters)

Stable COPD A large number of studies have compared anticholinergic agents with other bronchodilators in patients with COPD.44,45 Although patients with COPD usually do not exhibit as much improvement in airflow limitation to any agent or combination of agents as do patients with asthma, most studies show that the anticholinergic agent is a more potent bronchodilator than other agents in COPD.28,46–48 After large cumulative doses, the anticholinergic agent alone achieves all the available bronchodilatation.49 In this regard, COPD patients contrast sharply with asthmatic patients. Lefcoe and associates50 performed one of a few studies in which bronchodilator responsiveness was compared between patients with asthma and COPD who had similar baseline airflows. As illustrated in Fig. 50.5, patients with bronchitis had a better response to ipratropium than to the combination of fenoterol and theophylline (change in FEV1 0.29 L versus 0.18 L), whereas in asthmatics ipratropium was a less effective bronchodilator than the combination.50 Why? In asthma, airflow obstruction results from airway inflammation that is, at least partially, modified by adrenergic agents but not by anticholinergics; in COPD, the major reversible component is bronchomotor tone, which is best reversed by anticholinergic agents.49 Accordingly, ipratropium is currently recommended as first-line treatment for stable COPD in the most recent official statements of the European Respiratory Society51 and the American Thoracic Society.52 It should be noted, however, that the clinical utility of ipratropium (and possibly other bronchodilators) is limited to the short-term relief of symptoms and that it has no demonstrated longterm effect on the natural history of COPD. In the Lung Health Study, a large multicenter longitudinal trial of healthy smokers, regular use of ipratropium had no

IFT I 0.2

FT P 1

2 Time (hours)

3

Fig. 50.5. Increase in forced expiratory volume in 1 second (FEV1) of 15 patients with asthma (upper panel) and 15 patients with chronic bronchitis (lower panel). P, placebo metered dose inhaler (MDI); I, ipratropium 40 lg MDI; F T, fenoterol 5 mg plus oxtriphylline 400 mg oral. Reproduced from Reference 50, with permission.

discernible effect on smoking-related accelerated decline in lung function.53 Acute exacerbations of COPD Four studies comparing the efficacy of bronchodilators in acute exacerbations of COPD have failed to discern a difference among adrenergic agents, anticholinergic agents, or their combination.30,54–56 None the less, published guidelines from the American Thoracic Society, European Respiratory Society, and British Thoracic Society all recommend combination therapy with adrenergic and anticholinergic agents.51,52,57

532


Effects on sleep quality Sleep disturbance is common among patients with chronic bronchitis and asthma. In the Tucson Epidemiological Study, 41% of patients with obstructive airways disease reported at least one symptom of disturbed sleep.58 Patients with stable COPD frequently experience nocturnal oxygen desaturation, particularly during REM sleep, even in the absence of concomitant obstructive sleep apnea.59 This contributes to the development of pulmonary hypertension, polycythemia and cardiac arrhythmias.60 Sleep disturbance in children with asthma is associated with psychological problems and impairment of memory.61 A randomized double-blinded study involving 36 patients with moderate to severe COPD showed that ipratropium increased total sleep time, decreased the severity of nocturnal desaturation, and improved the patient’s perceptions of sleep quality.62 Combinations with other bronchodilators Combinations of different classes of bronchodilators often provide more bronchodilatation than single agents, and this effect is seen in many of the studies cited. However, since most clinical studies are performed with recommended rather than optimal doses of the agents, the effects of multiple classes of agents may simply be additive rather than potentiating. None the less, since anticholinergic, adrenergic and methylxanthine agents work by different mechanisms, affect different-sized airways and have different pharmacodynamic and pharmacokinetic properties, their combination is rational and is likely to result in improved bronchodilatation. No unfavorable interactions between these three classes of agents have been reported, so the greater bronchodilation achieved by their combination is achieved without increasing the risk of side-effects. In practice, it is common to use two or even all of these agents simultaneously to manage severe airways obstruction. Single MDIs combining different classes of inhaled bronchodilators have been in use since at least the 1950s. The combination of ipratropium and the b2-agonist fenoterol (Berodual® and DuoVent®) has been widely used since the l970s. Because of the concerns about the safety of fenoterol, a new combination MDI containing ipratropium and salbutamol, both in recommended dosage, has been developed (Combivent®). For patients who need two agents, a single MDI containing both agents is likely to be less expensive than two MDIs, more convenient for the patient to use, and therefore likely to improve patient compliance. Clinical trials with this combination in patients with COPD63–65 suggest it possesses all the advantages mentioned above. A post hoc review of two trials, involving 1067 patients over an 85-day period, concluded that the combination approach appears to be cost-effective.66 Bronchodilation is greater during the first 4–5 hours after administration, but not much prolonged over that achieved by single agents, and no increase in side-effects is incurred. Similarly, in 863 patients with moderately severe COPD, nebulization of a combination of ipratropium bromide and albuterol sulfate (Dey combination, Dey LP, Napa, CA,

USA) resulted in 30% more improvement in bronchodilation than was seen by albuterol alone, and 32% more than with ipratropium alone. However, the 6-minute walking distance was unchanged.67

SIDE-EFFECTS Atropine produces numerous systemic side-effects related to the inhibition of physiological functions of the parasympathetic system, as mentioned above. These effects occur in doses at or only slightly above the bronchodilator dose. Atropine is contraindicated in patients with glaucoma or prostatism. The principal advantage of quaternary anticholinergic agents is that they are so poorly absorbed from mucosa that the risk of such effects is insignificant. Even massive, inadvertent overdosage of one such agent resulted in trivial effects.17 Ipratropium, the most widely studied quaternary anticholinergic, has been exonerated after extensive exploration for atropine-like side-effects.68 It can, for example, be given to patients with glaucoma without affecting intraocular tension69 (provided it is not sprayed directly into the eye). It has been found not to affect urinary flow characteristics in older men. Nor has it been found to alter the viscosity and elasticity of respiratory mucus, or mucociliary clearance, as does atropine.70 It has negligible effects on hemodynamics, minute ventilation,71 and the pulmonary circulation.72 Consequently, quaternary anticholinergics do not carry the risk of worsening hypoxemia, as do adrenergic agents,73–75 an important consideration in exacerbations of asthma and COPD. In normal clinical use, the only side-effects of ipratropium are dryness of the mouth, a brief coughing spell, and paradoxical bronchoconstriction. Paradoxical bronchoconstriction This last effect occurs in perhaps 0.3% of patients and has been variously attributed to hypotonicity of the nebulized solution, idiosyncrasy to the bromine radical, the benzalkonium preservative,76,77 and a selective effect on the M2 receptor. Paradoxical bronchoconstriction, which may also occur with other anticholinergic agents, warrants withdrawal of the drug from the patient. Other than these effects, very extensive investigation and the worldwide use of ipratropium for over two decades demonstrate a remarkably low incidence of untoward reactions. There is no reason at present to believe that the safety profile of the newer quaternary anticholinergic agents will be different from that of ipratropium.

C L I N I C A L R E C O M M E N D AT I O N S The use of anticholinergic bronchodilators is best limited to the poorly absorbed quaternary forms, e.g. ipratropium, oxitropium, atropine methonitrate, glycopyrrolate, and tiotropium, administered by inhalation. They are sometimes


useful in stable asthma as adjuncts to other bronchodilator therapy, and have a demonstrated role in combination with adrenergic agents in the treatment of acute severe asthma. Their principal indication is the long-term management of stable COPD, where they are probably the most efficacious bronchodilators. Because of their slow onset of action they are best used on a regular, maintenance basis, rather than p.r.n.The usual dose of ipratropium, two puffs of 20 lg each, is probably suboptimal78 for many patients with COPD and can safely be doubled or quadrupled.79

20.

21. 22.

23.

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40. Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N. Engl. J. Med. 1998; 339:1030–5. 41. Plotnick L, Ducharme F. Should inhaled anticholinergics be added to b2 agonists for treating acute childhood and adolescent asthma? A systematic review. Br. Med. J. 1998; 317:971–7. 42. Warner JO, Gotz M, Landau LI, Levison H, Milner AD, Pedersen S. Management of asthma: a consensus statement. Arch. Dis. Child. 1989; 64:1065–79. 43. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma: a conference report. J. Allergy Clin. Immunol. 1990; 85:1098–111. 44. Thiessen B, Pedersen OF. Maximal expiratory flows and forced vital capacity in normal, asthmatic and bronchitic subjects after salbutamol and ipratropium bromide. Respiration 1982; 43:304–16. 45. Passamonte PM, Martinez AJ. Effect of inhaled atropine or metaproterenol in patients with chronic airway obstruction and therapeutic serum theophylline levels. Chest 1984; 85:610–15. 46. Bleecker ER, Britt EJ. Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease. Am. J. Med. 1991; 91:24S–7. 47. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease [published erratum appears in Arch. Intern. Med. 1990 Jun; 150:1242]. Arch. Intern. Med. 1989; 149:544–7. 48. Tashkin DP, Ashutosh K, Bleecker ER, Britt EJ, Cugell DW, Cummiskey JM. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am. J. Med. 1986; 81:81–90. 49. Gross NJ, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N. Engl. J. Med. 1984; 311:421–5. 50. Lefcoe NM, Toogood JH, Blennerhassett G, Baskerville J, Paterson NA. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A doubleblind single dose study. Chest 1982; 82:300–5. 51. Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur. Respir. J. 1995; 8:1398–420. 52. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am. J. Respir. Crit. Care Med. 1995; 152:S77–121. 53. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497–505. 54. Karpel JP, Pesin J, Greenberg D, Gentry E. A comparison of the effects of ipratropium bromide and metaproterenol sulfate in acute exacerbations of COPD. Chest 1990; 98:835–9. 55. Patrick DM, Dales RE, Stark RM, Laliberte G, Dickinson G. Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy. Chest 1990; 98:295–7. 56. Koutsogiannis Z, Kelly A. Does high dose ipratropium bromide added to salbutamol improve pulmonary function for patients with chronic obstructive airways disease in the emergency department? Aust. N. Z. J. Med. 2000; 30:38–40. 57. BTS guidelines for the management of chronic obstructive pulmonary disease: The COPD Guideline Group of the Standards of Care Committee of the BTS. Thorax 1997; 52(S5):S1–28. 58. Klink M, Quan SF. Prevalence of reported sleep disturbances in a general adult population and their relationship to obstructive airways diseases. Chest 1987; 91:540–6. 59. Douglas NJ, Calverley PM, Leggett RJ, Brash HM, Flenley DC, Brezinova V. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979; 1:1–4.

60. Douglas NJ. Sleep in patients with chronic obstructive pulmonary disease. Clin. Chest Med. 1998; 19:115–25. 61. Stores G, Ellis AJ, Wiggs L, Crawford C, Thomson A. Sleep and psychological disturbance in nocturnal asthma. Arch. Dis. Child 1998; 78:413–19. 62. Martin RJ, Bucher-Bartleson BL, Smith P et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999; 115:1338–45. 63. Petty TL. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 1994; 105:1411–19. 64. Ikeda A, Nishimura K, Koyama H, Izumi T. Bronchodilating effects of combined therapy with clinical dosages of ipratropium bromide and salbutamol for stable COPD: comparison with ipratropium bromide alone. Chest 1995; 107:401–5. 65. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT Inhalation Solution Study Group. Chest 1997; 112:1514–21. 66. Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999; 115:635–41. 67. Gross N,Tashkin D, Miller R, Oren J, ColemanW, Linberg S. Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration 1998; 65:354–62. 68. Gross NJ. Ipratropium bromide. N. Engl. J. Med. 1988; 319:486–94. 69. Watson WT, Shuckett EP, Becker AB, Simons FE. Effect of nebulized ipratropium bromide on intraocular pressures in children. Chest 1994; 105:1439–41. 70. Pavia D, Bateman JR, Sheahan NF, Clarke SW. Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction. Thorax 1979; 34:501–7. 71. Tobin MJ, Hughes JA, Hutchison DC. Effects of ipratropium bromide and fenoterol aerosols on exercise tolerance. Eur. J. Respir. Dis. 1984; 65:441–6. 72. Chapman KR, Smith DL, Rebuck AS, Leenen FH. Haemodynamic effects of inhaled ipratropium bromide, alone and combined with an inhaled beta 2-agonist. Am. Rev. Respir. Dis. 1985; 132:845–7. 73. Ashutosh K, Dev G, Steele D. Nonbronchodilator effects of pirbuterol and ipratropium in chronic obstructive pulmonary disease. Chest 1995; 107:173–8. 74. Gross NJ, Bankwala Z. Effects of an anticholinergic bronchodilator on arterial blood gases of hypoxaemic patients with chronic obstructive pulmonary disease. Comparison with a betaadrenergic agent. Am. Rev. Respir. Dis. 1987; 136:1091–4. 75. Khoukhaz G, Gross NJ. Effects of salmeterol on arterial blood gases in patients with stable chronic obstructive pulmonary disease. Comparison with albuterol and ipratropium. Am. J. Respir. Crit. Care Med. 1999; 160:1028–30. 76. Beasley R, Fishwick D, Miles JF, Hendeles L. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy 1998; 18:130–9. 77. Boucher M, Roy MT, Henderson J. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann. Pharmacother. 1992; 26:772–4. 78. Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers GW, Donohue JF. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am. Rev. Respir. Dis. 1989; 139:1188–91. 79. Leak A, O’Connor T. High dose ipratropium bromide is it safe? Practitioner 1988; 232:9–10. 80. Barnes PJ, Minette P, Maclagan J. Muscarinic receptor subtypes in airways. Trends Pharmacol. Sci. 1988; 9:412–16.

Chapter

Theophylline

51

Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK

Theophylline remains one of the most widely prescribed drugs for the treatment of airway diseases worldwide since it is inexpensive. In many industrialized countries, however, theophylline has become a third-line treatment that is only used in poorly controlled patients. This has been reinforced by various guidelines to therapy. Some have even questioned whether theophylline is indicated in any patients with asthma,1 although others have emphasized the special beneficial effects of theophylline which still give it an important place in the management of asthma and COPD.2 However, the frequency of side-effects and the relative low efficacy of theophylline have recently led to reduced usage, since inhaled b2-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Despite the fact that theophylline has been used in asthma therapy for over 60 years, there is still considerable uncertainty about its mode of action in asthma and its logical place in therapy. Because of problems with side-effects, there have been attempts to improve on theophylline, and recently there has been increasing interest in selective phosphodiesterase (PDE) inhibitors, which have the possibility of improving the beneficial and reducing the adverse effects of theophylline.

MOLECULAR MECHANISMS OF ACTION Although theophylline has been in clinical use for more than 60 years both its mechanism of action at a molecular level and its site of action remain uncertain. Several molecular mechanisms of action have been proposed, although many of these appear to occur only with higher concentrations of theophylline than effective clinically (Table 51.1). Phosphodiesterase inhibition Theophylline is a weak and nonselective inhibitor of PDEs, which break down cyclic nucleotides in the cell, thereby leading to an increase in intracellular cyclic 35 adenosine monophosphate (cAMP) and cyclic 3,5 guanosine monophosphate (cGMP) concentrations (Fig. 51.1). However, the degree of inhibition is small at concentrations of theophylline that are therapeutically relevant. Thus total PDE activity in human lung extracts is inhibited by only 5–10% by therapeutic concentrations of theophylline.5 There is convincing in-vitro evidence that theophylline relaxes airway smooth muscle by inhibition of PDE activity, but relatively high concentrations are needed for maximal relaxation.6 Similarly, the inhibitory effect of theophylline on mediator release from alveolar macrophages appears to be mediated by inhibition of PDE activity in these cells.7 There is no evidence that airway smooth muscle of inflammatory

C H E M I S T RY Table 51.1. Mechanisms of action of theophylline

Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Several substituted derivatives have been synthesized but none has any advantage over theophylline,3 apart from the 3propyl derivative, enprofylline, which is more potent as a bronchodilator and may have fewer toxic effects.4 Many salts of theophylline have also been marketed, the most common being aminophylline, the ethylene diamine salt used to increase solubility at neutral pH so that intravenous administration is possible. Other salts, such as choline theophyllinate, do not have any advantage and others, such as acepifylline, are virtually inactive.3

• Phosphodiesterase inhibition (nonselective) • Adenosine receptor antagonism (A1, A2A, A2B receptors) • Stimulation of catecholamine release • Mediator inhibition (prostaglandins, TNF-a) • Inhibition of intracellular calcium release • Inhibition of NF-jB (↓ nuclear translocation) • ↑ Histone deacetylase activity (↑ efficacy of corticosteroids)

536


RRRRRRRRRRRRRRf RRRRR

0

Theophylline

0 GTP

PDE3,4,7

PDE5

3',5'cAMP

3',5'cGMP

{@

GMP

Bronchodilatation

j Inflammatory cells

Fig 5 1 . 1 . Effect of phosphodiesterase (PDE) inhibitors in the breakdown of cyclic nucleotides in airway smooth muscle and inflammatory cells.

cells concentrate theophylline to achieve higher intracellular than circulating concentrations. Inhibition of P D E should lead to synergistic interaction with P-agonists, but this has not been convincingly demonstrated in vivo. However, this might be because relaxation of airway smooth muscle by Pagonists may involve direct coupling of P-receptors via a stimulatory G-protein to the opening of potassium channels, without the involvement of cyclic AMR* At least ten isoenzyme families of P D E have now been recognized and some (PDE3, P D E 4 , PDE5) are more important in smooth muscle relaxation.^''" However, there is no convincing evidence that theophylline has any greater inhibitory effect on the P D E isoenzymes involved in smooth muscle relaxation. It is possible that P D E isoenzymes may have an increased expression in asthmatic airways, either as a result of the chronic inflammatory process, or as a result of therapy. Elevation of cyclic A M P by P-agonists may result in increased P D E activity, thus limiting the effect of Pagonists. Indeed, alveolar macrophages from asthmatic patients appear to have increased P D E activity." This would mean that theophylline might have a greater inhibitory effect on P D E in asthmatic airways than in normal airways. Support for this is provided by the lack of bronchodilator effect of theophylline in normal subjects, compared with a bronchodilator effect in asthmatic patients. '^ Adenosine receptor antagonism Theophylline is a potent inhibitor of adenosine receptors at therapeutic concentrations (both Aj and Aj receptors, although it is less effective against A3 receptors), suggesting that this could be the basis for its bronchodilator effects." Although adenosine has little effect on normal human airway smooth muscle in vitro, it constricts airways of asthmatic patients via the release of histamine and leukotrienes, suggesting that adenosine releases mediators from mast cells.'''The receptor involved appears to be an A3 receptor in

rat mast cells,'^ but in humans there is evidence for the involvement of an AJB receptor.'* Adenosine causes bronchoconstriction in asthmatic subjects when given by inhalation." T h e mechanism of bronchoconstriction is indirect and involves release of histamine from airway mast cells.'''"'* The bronchoconstrictor effect of adenosine is prevented by therapeutic concentrations of theophylline." However, this only confirms that theophylline is capable of antagonizing the effects of adenosine at therapeutic concentrations, and this does not necessarily indicate that this is important for its anti-asthma effect. However, adenosine antagonism is likely to account for some of the side-effects of theophylline, such as central nervous system stimulation, cardiac arrhythmias, gastric hypersecretion, gastroesophageal reflux, and diuresis. Endogenous catecholamine release Theophylline increases the secretion of adrenaline from the adrenal medulla,'^ although the increase in plasma concentration is small and insufficient to account for any significant bronchodilator effect.^" Mediator inhibition Theophylline antagonizes the effect of some prostaglandins on vascular smooth muscle in vitro,^^ but there is no evidence that these effects are seen at therapeutic concentrations or are relevant to its airway effects. Theophylline inhibits the secretion of tumor necrosis factor-a (TNF-a) by peripheral blood monocytes,^^ and increases the secretion of the anti-inflammatory cytokine interleukin (IL)-IO.^^ However, these effects are not seen in alveolar macrophages obtained by bronchoalveolar lavage from patients treated with theophylline.^''Theophylline may also interfere with the action of T N F - a , which may be involved in inflammation in severe asthma and in C O P D . A related compound, pentoxifylline, prevents TNF-a-induced lung injury and

537

Theophylline

enhanced hypoxic pulmonary vasoconstriction,25 but its mechanism of action is not yet understood. Calcium ion flux There is some evidence that theophylline may interfere with calcium mobilization in airway smooth muscle.Theophylline has no effect on entry of calcium ions (Ca2+) via voltagedependent channels, but it has been suggested that it may influence calcium entry via receptor-operated channels, release from intracellular stores, or have some effect on phosphatidylinositol turnover (which is linked to release of Ca2+ from intracellular stores). There is no direct evidence in favor of this, other than an effect on intracellular cyclic AMP concentration due to its PDE inhibitory action. An early study suggesting that theophylline may increase Ca2+ uptake into intracellular stores26 has not been followed up. Effect on transcription Theophylline prevents the translocation of the proinflammatory transcription factor NF-jB into the nucleus, thus potentially reducing the expression of inflammatory genes in asthma and COPD.27 Recent studies suggest that theophylline increases the activity of histone deacetylase, which is recruited by corticosteroids to the transcription complex to switch off inflammatory genes.28 This action of theophylline occurs at therapeutically relevant concentrations and is not mediated via PDE inhibition of adenosine antagonism. It predicts a synergistic action between theophylline and corticosteroids. Effects on apoptosis Prolonged survival of granulocytes due to a reduction in apoptosis may be important in perpetuating chronic inflammation in asthma (eosinophils) and COPD

(neutrophils).Theophylline inhibits apoptosis in eosinophils and neutrophils in vitro.29 This is associated with a reduction in the anti-apoptotic protein bcl-2.30 This effect is not mediated via PDE inhibition, but in neutrophils may be mediated by antagonism of adenosine A2A receptors.31

CELLULAR EFFECTS Theophylline has several effects that may contribute to its clinical efficacy in the treatment of asthma and COPD (Fig. 51.2). Airway smooth muscle effects The primary effect of theophylline is assumed to be relaxation of airway smooth muscle and in-vitro studies have shown that it is equally effective in large and small airways.32 In airways obtained at lung surgery, approximately 25% of preparations fail to relax with a b-agonist, but all relax with theophylline.33 The molecular mechanism of bronchodilatation is almost certainly related to PDE inhibition, resulting in an increase in cyclic AMP.6 The bronchodilator effect of theophylline is reduced in human airways by the toxin charybdotoxin, which inhibits large conductance Ca2+activated K+ channels (maxi-K channels), suggesting that theophylline opens maxi-K channels via an increase in cyclic AMP.34 Theophylline acts as a functional antagonist and inhibits the contractile response of multiple spasmogens. In airways obtained at post-mortem from patients who have died from asthma the relaxant response to b-agonists is reduced, whereas the bronchodilator response to theophylline is no different from that seen in normal airways.35 There is evidence that b-adrenoceptors in airway smooth muscle of patients with fatal asthma become uncoupled,36 and

Inflammatory cells

Structural cells Airway smooth muscle

Eosinophil Numbers (apoptosis)

Bronchodilatation

T lymphocytes Cytokines, traffic

Endothelial cell

Mast cell

Theophylline

Leak

Mediators

Macrophage

Respiratory muscles

Cytokines Strength ?

Fig. 51.2. Multiple effects of theophylline.

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theophylline may therefore have a theoretical advantage over b-agonists in severe asthma exacerbations. However, theophylline is a weak bronchodilator at therapeutically relevant concentrations, suggesting that some other target cell may be more relevant for its anti-asthma effect. In human airways the EC50 for theophylline is approximately 1.5 104 M, which is equivalent to 67 mg/L assuming 60% protein binding.33 However, as discussed above, it is important to consider the possibility that PDE activity nay be increased in asthmatic airways so that theophylline may have a greater effect than expected. In-vivo intravenous aminophylline has an acute bronchodilator effect in asthmatic patients, which is most likely to be due to a relaxant effect on airway smooth muscle.37 The bronchodilator effect of theophylline in chronic asthma is small in comparison with b-agonists, however. Several studies have demonstrated a small protective effect of theophylline on histamine, methacholine or exercise challenge.38–41 This protective effect does not correlate well with any bronchodilator effect and it is interesting that in some studies the protective effect of theophylline is observed at plasma concentrations of 10 mg/L. These clinical studies suggest that theophylline may have anti-asthma effects which are unrelated to any bronchodilator action. Anti-inflammatory effects Whether theophylline has significant anti-inflammatory effects in asthma or COPD is still unresolved.42 Theophylline inhibits histamine release from human basophils in vitro43 and mediator release from chopped human lung,44 although high concentrations are necessary and it is likely that this effect involves an increase in cyclic AMP concentration due to PDE inhibition. Theophylline also has an inhibitory effect on superoxide anion release from human neutrophils45 and inhibits the feedback stimulatory effect of adenosine on neutrophils in vivo.46 At therapeutic concentrations in-vitro theophylline may increase superoxide release via an inhibitory effect on adenosine receptors, since endogenous adenosine might normally exert an inhibitory action on these cells.47 Similar results are also seen in guinea-pig and human eosinophils.48 At therapeutic concentrations there is an increased release of superoxide anions from eosinophils, which appears to be mediated via inhibition of adenosine A2 receptors and is mimicked by the adenosine antagonist 8-phenyltheophylline. Inhibition of eosinophil superoxide generation occurs only at high concentrations of theophylline (104 M) which are likely to inhibit PDE. Similar results have also been obtained in human alveolar macrophages.7 Macrophages lavaged from patients taking theophylline have been found to have a reduced oxidative burst response,49 but there is no reduction in the release of the pro-inflammatory cytokines TNF-a or GM-CSF.24 Theophylline inhibits neutrophil chemotaxis via inhibition of adenosine A2A receptors.50 In-vivo theophylline inhibits mediator-induced airway microvascular leakage in rodents when given in high doses,51 although this is not seen at therapeutically relevant

concentrations.52 Theophylline has an inhibitory effect on plasma exudation in nasal secretions induced by allergen in patients with allergic rhinitis, although this could be secondary to inhibition of mediator release.53 In allergen challenge studies in asthmatic patients intravenous theophylline inhibits the late response to allergen, while having relatively little effect on the early response.54 A similar finding with allergen challenge has been reported after chronic oral treatment with theophylline.55 This has been interpreted as an effect on the chronic inflammatory response. This is supported by a reduced infiltration of eosinophils into the airways after allergen challenge following low doses of theophylline.56 In patients with nocturnal asthma low-dose theophylline inhibits the influx of neutrophils and, to a lesser extent, eosinophils seen in the early morning.57 Oral theophylline also inhibits the late response to toluene diisocyanate in TDI-sensitive asthmatics,58 but has no effect on the subsequent increase in methacholine responsiveness. Similarly, theophylline has no effect on the increased airway responsiveness which follows allergen challenge,59 and does not reduce airway responsiveness in asthmatic patients after chronic administration.60 These studies indicate that theophylline on its own may have effects on acute inflammation in the airways, but may be less effective on the chronic inflammatory process. In patients with COPD theophylline reduces the proportion of neutrophils in induced sputum and reduces the concentration of IL-8, suggesting that it may have an antiinflammatory effect unlike corticosteroids.61 Immunomodulatory effects T lymphocytes are now believed to play a central role in coordinating the chronic inflammatory response in asthma. For many years theophylline has been shown to have several actions on T lymphocyte function, suggesting that it might have an immunomodulatory effect in asthma. Theophylline has a stimulatory effect on suppressor (CD8) T lymphocytes, which may be relevant to the control of chronic airway inflammation,62,63 and has an inhibitory effect on graft rejection.64 In-vitro theophylline inhibits IL-2 synthesis in human T lymphocytes, an effect that is secondary to a rise in intracellular cyclic AMP concentration.65,66 At high concentrations theophylline inhibits proliferation in CD4 and CD8 cells, an effect that is mediated via inhibition of PDE4.67 Theophylline also inhibits the chemotactic response of T lymphocytes, an effect that is also mediated through PDE inhibition.68 In allergen-induced airway inflammation in guinea-pigs, theophylline has a significant inhibitory effect on eosinophil infiltration,69 suggesting that it may inhibit the T cell-derived cytokines responsible for this eosinophilic response. Theophylline has been reported to decrease circulating concentrations of IL-4 and IL-5 in asthmatic patients.70 In asthmatic patients low-dose theophylline treatment results in an increase in activated circulating CD4 and CD8 T cells, but a decrease in these cells in the airways, suggesting that it may reduce the trafficking of activated T cells into the airways.71 This is

Theophylline

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supported by studies in allergen challenge, where low-dose theophylline decreases the number of activated CD4 and CD8 T cells in bronchoalveolar lavage fluid after allergen challenge and this is mirrored by an increase in these cells in peripheral blood.72 These effects are seen even in patients treated with high doses of inhaled corticosteroids, indicating that the molecular effects of theophylline are likely to be different from those of corticosteroids. Theophylline induces apoptosis of T lymphocytes, thus reducing their survival.73 This effect may be mediated via PDE4 inhibition, so may not be relevant to clinical doses of theophylline. The therapeutic range of theophylline was based on measurement of immediate bronchodilatation in response to the acute administration of theophylline.37 However, it is possible that the nonbronchodilator effects of theophylline, which may reflect some anti-inflammatory or immunomodulatory effect, may be exerted at lower plasma concentrations and that different molecular mechanisms may be involved.74

bronchoconstriction, higher concentrations may be required to produce bronchodilatation.78 Theophylline is rapidly and completely absorbed, but there are large interindividual variations in clearance, due to differences in hepatic metabolism (Table 51.2). Theophylline is metabolized in the liver by the cytochrome P450/P448 microsomal enzyme system, and a large number of factors may influence hepatic metabolism. Theophylline is predominantly metabolized by the CYP1A2 enzyme, while at higher plasma concentrations CYP2E1 is also involved.79

Extrapulmonary effects For a long time it has been suggested that theophylline may exert its effects in asthma and COPD via some action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved.75 This may indicate that theophylline has effects on cells other than those in the airway. One possible target cell is the platelet, and theophylline has been demonstrated to inhibit platelet activation. An effect of theophylline which remains controversial is its action on respiratory muscles. Aminophylline increases diaphragmatic contractility and reverses diaphragm fatigue.76 This effect has not been observed by all investigators and there are now doubts about the relevance of these observations to the clinical benefit provided by theophylline in COPD.77

Reduced clearance Reduced clearance is found in liver disease, pneumonia and heart failure, and doses need to be reduced to half and plasma levels monitored carefully.80 Increased clearance is also seen with certain drugs including erythromycin, certain quinolone antibiotics (ciprofloxacin, but not ofloxacin), allopurinol, cimetidine (but not ranitidine), serotonin uptake inhibitors (fluvoxamine), and the 5-lipoxygenase inhibitor zileuton, which interfere with CYP 1A2 function. Thus, if a patient on maintenance theophylline requires a course of erythromycin, the dose of theophylline should be halved. Viral infections and vaccination may also reduce clearance, and this may be particularly important in children. Owing to these variations in clearance individualization of theophylline dosage is required and plasma concentrations should be measured 4 hours after the last

PHARMACOKINETICS

Table 51.2. Factors affecting clearance of theophylline

There is a close relationship between the acute improvement in airway function and serum theophylline concentration. Below 10 mg/L therapeutic effects (at least in terms of rapid improvement in airway function) are small and above 25 mg/L additional benefits are outweighed by side-effects, so that the therapeutic range has usually been taken as 10–20 mg/L (55–110 lM).3 It is now apparent that nonbronchodilator effects of theophylline may be seen at plasma concentrations of 10 mg/L and that clinical benefit may be derived from these lower concentrations of theophylline. This suggests that it may be necessary to redefine the therapeutic range of theophylline based on anti-asthma effect, rather than the acute bronchodilator response that requires a higher plasma concentration. The dose of theophylline required to give therapeutic concentrations varies between subjects, largely because of differences in clearance. In addition, there may be differences in bronchodilator response to theophylline and, with acute

Increased clearance Increased clearance is seen in children (1–16 years), and in cigarette and marijuana smokers. Concurrent administration of phenytoin and phenobarbitone increases activity of P450, resulting in increased metabolic breakdown, so that higher doses may be required.

Increased clearance • Enzyme induction (rifampicin, phenobarbitone, ethanol) • Smoking (tobacco, marijuana) • High-protein, low-carbohydrate diet • Barbecued meat • Childhood Decreased clearance • Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton) • Congestive heart failure • Liver disease • Pneumonia • Viral infection and vaccination • High-carbohydrate diet • Old age

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dose with slow-release preparations when steady state has usually been achieved. There is no significant circadian variation in theophylline metabolism,81 although there may be delayed absorption at night, which may relate to the supine posture.82

R O U T E S O F A D M I N I S T R AT I O N Intravenous Intravenous aminophylline has been used for many years in the treatment of acute severe asthma. The recommended dose is now 6 mg/kg given intravenously over 20–30 minutes, followed by a maintenance dose of 0.5 mg/kg/hour. If the patient is already taking theophylline, or there are any factors which decrease clearance, these doses should be halved and the plasma level checked more frequently. Oral Plain theophylline tablets or elixir, which are rapidly absorbed, give wide fluctuations in plasma levels and are not recommended. Several effective sustained-release preparations are now available which are absorbed at a constant rate and provide steady plasma concentrations over a 12–24 hour period.83 Although there are differences between preparations, these are relatively minor and of no clinical significance. Both slow-release aminophylline and theophylline are available and are equally effective (although the ethylene diamine component of aminophylline has very occasionally been implicated in allergic reactions). For continuous treatment twice daily therapy (approximately 8 mg/kg twice daily) is needed, although some preparations are designed for once daily administration. For nocturnal asthma a single dose of slow-release theophylline at night is often effective,84,85 and often more effective than an oral slow-release b-agonist preparation. Once optimal doses have been determined plasma concentrations usually remain stable, providing no factors which alter clearance change. Other routes Aminophylline may be given as a suppository, but rectal absorption is unreliable and proctitis may occur, so is best avoided. Inhalation of theophylline is irritant and ineffective. Intramuscular injections of theophylline are very painful and should never be given. The inhaled route is ineffective.

CLINICAL USE Acute severe asthma Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years, but this use has been questioned in view of the risk of adverse effects compared with nebulized b2-agonists. In patients with acute asthma intravenous aminophylline is less effective than nebulized b2-agonists,86 and should therefore be reserved for those patients who fail to respond to b-agonists. There is

some evidence that the use of aminophylline in the emergency room reduces subsequent admissions to hospital with acute asthma.87 In a meta-analysis of 13 acceptably designed clinical trials to compare nebulized b-agonists with or without intravenous aminophylline there was no overall additional benefit from adding aminophylline.88 This indicates that aminophylline should not be added routinely to nebulized b-agonists. Indeed, addition of aminophylline may only increase side-effects.89 Several deaths have been reported after intravenous aminophylline. In one study of 43 asthma deaths in southern England there was a significantly greater frequency of toxic theophylline concentrations (21%) compared with matched controls (7%).90 These concerns have lead to the view that intravenous aminophylline should be reserved for the few patients with acute severe asthma who fail to show a satisfactory response to nebulized b2-agonists. When intravenous aminophylline is used it should be given as a slow intravenous infusion with careful monitoring and a plasma theophylline concentration should be measured prior to infusion. Chronic asthma In most guidelines for asthma management theophylline is used as an additional bronchodilator if asthma remains difficult to control after high doses of inhaled corticosteroids.91 The introduction of long-acting inhaled b2-agonists has further threatened the position of theophylline since the side-effects of these agents may be less frequent that those associated with theophylline and long-acting inhaled b2agonists are more effective controllers than theophylline.92 Whether theophylline has some additional benefit over its bronchodilator action is now an important consideration. In chronic studies, oral theophylline appears to be as effective as sodium cromoglycate in controlling young allergic asthmatics93 and provides additional control of asthma symptoms even in patients talking regular inhaled steroids.94 In one study in which a group of difficult adolescent asthmatic patients were controlled with oral and inhaled steroids, nebulized b2-agonists, inhaled anticholinergics and cromones, in addition to regular oral theophylline, withdrawal of the oral theophylline resulted in a marked deterioration of asthma control which could not be controlled by further increase in steroids and only responded to reintroduction of theophylline.95 This suggests that there may be a group of severe asthmatics who particularly benefit from theophylline. In a controlled trial of theophylline withdrawal in patients with severe asthma controlled only on high doses of inhaled corticosteroids, there was a significant deterioration in symptoms and lung function when placebo was substituted for the relatively low maintenance dose of theophylline.71 There is also evidence that addition of theophylline improves asthma control to a greater extent than b2agonists in patients with severe asthma treated with high-dose inhaled steroids.96 This suggests that theophylline may have a useful place in the optimal management of moderate to severe asthma and appears to provide additional control above that provided by high-dose inhaled steroids.97

Theophylline

Theophylline may be a useful treatment for nocturnal asthma and a single dose of a slow-release theophylline preparation given at night may provide effective control of nocturnal asthma symptoms.84,98 There is evidence that slow release theophylline preparations are more effective than slow release oral b-agonists and inhaled b-agonists in controlling nocturnal asthma.85,99,100 Theophylline is approximately equal in efficacy to salmeterol in controlling nocturnal asthma, but the quality of sleep is better with salmeterol compared with theophylline.101 The mechanism of action of theophylline in nocturnal asthma may involve more than long-lasting bronchodilatation, and could involve inhibition of some components of the inflammatory response, which may increase at night.57 Several studies have demonstrated that adding low-dose theophylline to inhaled corticosteroids in patients who are not controlled gives better asthma control than doubling the dose of inhaled corticosteroids. This has been demonstrated in patients with moderate to severe and mild asthma.102–104 Interestingly, there is a greater degree of improvement in forced vital capacity than FEV1, possibly indicating an effect on peripheral airways. Since the improvement in lung function was relatively slow, this suggests that the effect of the added theophylline may be anti-inflammatory rather than bronchodilator, particularly as the plasma concentration of theophylline in this study was 10 mg/mL. This study suggests that low-dose theophylline may be preferable to increasing the dose of inhaled steroids when asthma is not controlled on moderate doses of inhaled steroids; such a therapeutic approach would be much less expensive than adding long-acting inhaled b2-agonists.

541

action of b-agonists and theophylline. b-agonists may cause relaxation of airway smooth muscle via several mechanisms. Classically, they increase intracellular cyclic AMP concentrations, which have been believed to be an essential event in the relaxation response. It has recently become clear that bagonists may cause bronchodilatation, at least in part, by opening maxi-K channels in airway smooth muscle cells.8,34 Maxi-K channels are opened by low concentrations of b2agonists, which are likely to be therapeutically relevant. There is now evidence that b-receptors may be coupled directly to maxi-K channels via the a-subunit of Gs,110 and therefore may induce relaxation without any increase in cyclic AMP, thus accounting for a lack of synergy. Another reason for the lack of synergy may be that cells other than airway smooth muscle may be the main target for the antiasthma effect of theophylline. Repeated administration of b2-agonists may result in tolerance. While this may be explained by down-regulation of b2-receptors an additional mechanism may involve upregulation of PDE enzymes (especially PDE4D) which then break down cyclic AMP more readily.111 Theophylline may therefore theoretically prevent the development of tolerance, although this has not yet been studied clinically. Theophylline may provide useful additional bronchodilatation in patients with COPD, even when maximally effective doses of a b-agonist have been given. This means that, if adequate bronchodilatation is not achieved by a b-agonist alone, theophylline may be added to the maintenance therapy with benefit.

SIDE-EFFECTS COPD Theophylline may also benefit patients with COPD, increasing exercise tolerance, although without any improvement in spirometric values unless combined with an inhaled bagonist.105,106 However, theophylline may reduce trapped gas volume, suggesting an effect on peripheral airways, and this may explain why some patients with COPD may obtain considerable symptomatic improvement without any increase in spirometric values.107 Although the effect of theophylline on respiratory muscle weakness has been believed to be important in contributing to symptomatic improvement in patients with COPD,76 this seems unlikely as several investigators have failed to confirm any effect on respiratory muscle function at therapeutic concentrations of theophylline.77 The demonstration that theophylline reduces neutrophils in induced sputum of patients with COPD suggests that theophylline may have some anti-inflammatory effect.61 Interaction with b-agonists If theophylline exerts its effects by PDE inhibition then a synergistic interaction with b-agonists would be expected. Many studies have investigated this possibility, but while there is good evidence that theophylline and b-agonists have additive effects, true synergy is not seen.108,109 This can now be understood in terms of the molecular mechanisms of

There is no doubt that theophylline provides clinical benefit in obstructive airway disease, but the main limitation to its use is the frequency of adverse effects.112 Unwanted effects of theophylline are usually related to plasma concentration and tend to occur when plasma levels exceed 20 mg/L. However, some patients develop side-effects even at low plasma concentrations. To some extent, side-effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved. The commonest side-effects are headache, nausea and vomiting, abdominal discomfort and restlessness. There may also be increased acid secretion, gastroesophageal reflux and diuresis. There has recently been concern that theophylline, even at therapeutic concentrations, may lead to behavioral disturbance and learning difficulties in schoolchildren,113 although it is difficult to design adequate controls for such studies. At high concentrations, convulsions and cardiac arrhythmias may occur and there is concern that intravenous aminophylline administered in the emergency room may be a contributory factor to the deaths of some patients with severe asthma.90 Some of the side-effects of theophylline (central stimulation, gastric secretion, diuresis, and arrhythmias) may be due to adenosine receptor and these may therefore be

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avoided by PDE inhibitors. The commonest side-effects of theophylline are nausea and headaches, which may be due to inhibition of certain PDEs (e.g. PDE4 in the vomiting center).114

FUTURE OF THEOPHYLLINE Although theophylline has recently been used much less in developed countries, there are reasons for thinking that it may come back into fashion for the treatment of chronic asthma, with the recognition that it may have an antiinflammatory and immunomodulatory effect when given in low doses (plasma concentration 5–10 mg/L).74 At these low doses the drug is easier to use, side-effects are uncommon and the problems of drug interaction are less of a problem, thus making the clinical use of theophylline less complicated. Theophylline appears to have an effect that is different from those of corticosteroids and may therefore be a useful drug to combine with low-dose inhaled steroids. The molecular mechanism of anti-inflammatory effects of theophylline is now becoming clearer and it seems likely that there is a synergistic interaction with the anti-inflammatory mechanism of corticosteroids. This interaction may underlie the beneficial effects of theophylline when added to inhaled corticosteroids. As slow-release theophylline preparations are cheaper than long-acting inhaled b2-agonists and antileukotrienes, this may justify the choice of low-dose theophylline as the add-on therapy for asthma control. In addition, compliance with oral therapy is likely to be greater than with inhaled therapies.115 This suggests that low-dose theophylline may find an important place in modern asthma management in patients with moderate asthma as well as in patients with severe asthma. In COPD there is evidence for an anti-inflammatory action of theophylline and it may therefore be preferable to high-dose inhaled corticosteroids which have been shown to have no anti-inflammatory effects in patients with COPD.116

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27. Tomita K, Chikumi H, Tokuyasu H et al. Functional assay of NFkappaB translocation into nuclei by laser scanning cytometry: inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch. Pharmacol. 1999; 359:249–55. 28. Ito K, Lim S, Adcock IM, Caramori G, Keller A, Barnes PJ. Effect of low dose theophylline on histone deacetylase activity in patients with mild asthma. Am. J. Resp. Crit. Care Med. 2000; 161:A614. 29. Yasui K, Hu B, Nakazawa T, Agematsu K, Komiyama A. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J. Clin. Invest. 1997; 100:1677–84. 30. Chung IY, Nam-Kung EK, Lee NM et al. The downregulation of bcl-2 expression is necessary for theophylline-induced apoptosis of eosinophil. Cell Immunol. 2000; 203:95–102. 31. Yasui K, Agematsu K, Shinozaki K et al. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J. Leukoc. Biol. 2000; 67:529–35. 32. Finney MJB, Karlson JA, Persson CGA. Effects of bronchoconstriction and bronchodilation on a novel human small airway preparation. Br. J. Pharmacol. 1985; 85:29–36. 33. Guillot C, Fornaris M, Badger M, Orehek J. Spontaneous and provoked resistance to isoproterenol in isolated human bronchi. J. Allergy Clin. Immunol. 1984; 74:713–18. 34. Miura M, Belvisi MG, Stretton CD, Yacoub MH, Barnes PJ. Role of potassium channels in bronchodilator responses in human airways. Am. Rev. Respir. Dis. 1992; 146:132–6. 35. Goldie RG, Spina D, Henry PJ, Lulich KM, Paterson JW. In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, b-adrenoceptor agonists and theophylline. Br. J. Clin. Pharmacol. 1986; 22:669–76. 36. Bai TR, Mak JCW, Barnes PJ. A comparison of beta-adrenergic receptors and in vitro relaxant responses to isoproterenol in asthmatic airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 1992; 6:647–51. 37. Mitenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N. Engl. J. Med. 1973; 289:600–3. 38. McWilliams BC, Menendez R, Kelly WH, Howick J. Effects of theophylline on inhaled methacholine and histamine in asthmatic children. Am. Rev. Respir. Dis. 1984; 130:193–7. 39. Cartier A, Lemire I, L’Archeveque J. Theophylline partially inhibits bronchoconstriction caused by inhaled histamine in subjects with asthma. J. Allergy Clin. Immunol. 1986; 77:570–5. 40. Magnusson H, Reuss G, Jorres R. Theophylline has a doserelated effect on the airway response to inhaled histamine and methacholine in asthmatics. Am. Rev. Respir. Dis. 1987; 136:1163–7. 41. Magnussen H, Reuss G, Jörres R. Methylxanthines inhibit exerciseinduced bronchoconstriction at low serum theophylline concentrations and in a dose-dependent fashion. J. Allergy Clin. Immunol. 1988; 81:531–7. 42. Persson CGA. Xanthines as airway anti inflammatory drugs. J. Allergy Clin. Immunol. 1988; 81:615–17. 43. Lichtenstein LM, Margolis S. Histamine release in vitro: inhibition by catecholamines and methylxanthines. Science 1968; 161:902–3. 44. Orange RP, Kaliner MA, Laraia PJ, Austen KF. Immunological release of histamine and slow reacting substance of anaphylaxis from human lung. II. Influence of cellular levels of cyclic AMP. Fed. Proc. 1971; 30:1725–9. 45. Nielson CP, Crawley JJ, Morgan ME, Vestal RE. Polymorphonuclear leukocyte inhibition by therapeutic concentrations of theophylline is mediated by cyclic 3,5 adenosine aminophosphate. Am. Rev. Respir. Dis. 1988; 137:25–30. 46. Kraft M, Pak J, Borish L, Martin RJ. Theophylline’s effect on neutrophil function and the late asthmatic response. J. Allergy Clin. Immunol. 1996; 98:251–7. 47. Schrier DJ, Imre KM. The effects of adenosine agonists on human neutrophil function. J. Immunol. 1986; 137:3284–9.

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48. Yukawa T, Kroegel C, Dent G, Chanez P, Ukena D, Barnes PJ. Effect of theophylline and adenosine on eosinophil function. Am. Rev. Respir. Dis. 1989; 140:327–33. 49. O’Neill SJ, Sitar DS, Kilass DJ. The pulmonary disposition of theophylline and its influences on human alveolar macrophage bactericidal function. Am. Rev. Respir. Dis. 1988; 134:1225–8. 50. Yasui K, Agematsu K, Shinozaki K et al. Effects of theophylline on human eosinophil functions: comparative study with neutrophil functions. J. Leukoc. Biol. 2000; 68:194–200. 51. Erjefalt I, Persson CGA. Pharmacologic control of plasma exudation into tracheobronchial airways. Am. Rev. Respir. Dis. 1991; 143:1008–14. 52. Boschetto P, Roberts NM, Rogers DF, Barnes PJ. The effect of antiasthma drugs on microvascular leak in guinea pig airways. Am. Rev. Respir. Dis. 1989; 139:416–21. 53. Naclerio RM, Bartenfelder D, Proud D et al. Theophylline reduces histamine release during pollen-induced rhinitis. J. Allergy Clin. Immunol. 1986; 78:874–6. 54. Pauwels R, van Revterghem D, van der Straeten M, Johanesson N, Persson CGA. The effect of theophylline and enprophylline on allergen-induced bronchoconstriction. J. Allergy Clin. Immunol. 1985; 76:583–90. 55. Ward AJM, McKenniff M, Evans JM, Page CP, Costello JF. Theophylline – an immunomodulatory role in asthma? Am. Rev. Respir. Dis. 1993; 147:518–23. 56. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994; 343:1006–8. 57. Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline: potential antiinflammatory effects in nocturnal asthma. J. Allergy Clin. Immunol. 1996; 97:1242–6. 58. Mapp C, Boschetto P, Dal Vecchio L et al. Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. Am. Rev. Respir. Dis. 1987; 136:1403–7. 59. Cockroft DW, Murdock KY, Gore BP, O’Byrne PM, Manning P. Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine. J. Allergy Clin. Immunol. 1991; 83:913–20. 60. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma, but oral theophylline does not. Am. Rev. Respir. Dis. 1987; 136:1174–8. 61. Culpitt S, Maziak W, Loukides S, Keller A, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices in COPD patients. Am. J. Respir. Crit. Care Med. 1997; 157:A797. 62. Shohat B, Volovitz B, Varsano I. Induction of suppressor T cells in asthmatic children by theophylline treatment. Clin.Allergy 1983; 13:487–93. 63. Fink G, Mittelman M, Shohat B, Spitzer SA.Theophylline-induced alterations in cellular immunity in asthmatic patients. Clin. Allergy 1987; 17:313–316. 64. Guillou PJ, Ramsden C, Kerr M, Davison AM, Giles GR. A prospective controlled clinical trial of aminophylline as an adjunct immunosuppressive agent. Transpl. Proc. 1984; 16:1218–20. 65. Didier M, Aussel C, Ferrua B, Fehlman M. Regulation of interleukin 2 synthesis by cAMP in human T cells. J. Immunol.1987; 139:1179–84. 66. Landells LJ, Szilagy CM, Jones NA, Banner K, Allen JM, Doherty A et al. Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. Br. J. Pharmcol 2001; 133:722–9. 67. Giembycz MA, Corrigan CJ, Seybold J, Newton R, Barnes PJ. Identification of cyclic AMP phosphodiesterases 3, 4 and 7 in human CD4 and CD8 T-lymphocytes. Br. J. Pharmacol. 1996; 118:1945–58. 68. Hidi R, Timmermans S, Liu E et al. Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of Tlymphocyte chemotaxis. Eur. Respir. J. 2000; 15:342–9.

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69. Sanjar S, Aoki S, Kristersson A, Smith D, Morley J. Antigen challenge induces pulmonary eosinophil accumulation and airway hyperreactivity in sensitized guinea pigs: the effect of antiasthma drugs. Br. J. Pharmacol. 1990; 99:679–86. 70. Kosmas EN, Michaelides SA, Polychronaki A et al. Theophylline induces a reduction in circulating interleukin-4 and interleukin5 in atopic asthmatics. Eur. Respir. J. 1999; 13:53–8. 71. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma: demonstration by withdrawal of therapy. Am. J. Resp. Crit. Care Med. 1995; 151:1907–14. 72. Jaffar ZH, Sullivan P, Page C, Costello J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur. Respir. J. 1996; 9:456–62. 73. Ohta K, Yamashita N. Apoptosis of eosinophils and lymphocytes in allergic inflammation. J. Allergy Clin. Immunol. 1999; 104:14–21. 74. Barnes PJ, Pauwels RA. Theophylline in asthma: time for reappraisal? Eur. Respir. J. 1994; 7:579–91. 75. Cushley MJ, Holgate ST. Bronchodilator actions of xanthine derivatives administered by inhalation in asthma. Thorax 1985; 40:176–9. 76. Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos Ch. Aminophylline improves diaphragmatic contractility. N. Engl. J. Med. 1981; 305:249–52. 77. Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin. Chest Med. 1988; 2:325–40. 78. Vozeh S, Kewitz G, Perruchoud A et al. Theophylline serum concentration and therapeutic effect in severe acute bronchial obstruction: the optimal use of intravenously administered aminophylline. Am. Rev. Respir. Dis. 1982; 125:181–4. 79. Zhang ZY, Kaminsky LS. Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem. Pharmacol. 1995; 50:205–11. 80. Jusko WJ, Gardner MJ, Mangiore A, Schentag JJ, Kopp JR, Vance JW. Factors affecting aminophylline clearance: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazepines, barbiturates and ethanol. J. Pharm. Sci. 1979; 68:1358–66. 81. Taylor DR, Ruffin D, Kinney CD, McDevitt DG. Investigation of diurnal changes in the disposition of theophylline. Br. J. Clin. Pharmac. 1983; 16:413–16. 82. Warren JB, Cuss F, Barnes PJ. Posture and theophylline kinetics. Br. J. Clin. Pharmac. 1985; 19:707–9. 83. Weinberger M, Hendeles L. Slow-release theophylline: rationale and basis for product selection. N. Engl. J. Med. 1983; 308:760–3. 84. Barnes PJ, Greening AP, Neville L, Timmers J, Poole GW. Single dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; i:299–301. 85. Heins M, Kurtin L, Oellerich M, Maes R, Sybrecht GW. Nocturnal asthma: slow-release terbutaline versus slow-release theophylline therapy. Eur. Respir. J. 1988; 1:306–10. 86. Bowler SD, Mitchell CA, Armstrong JG. Nebulised fenoterol and i.v. aminophylline in acute severe asthma. Eur. Respir. J. 1987; 70:280–3. 87. Wrenn K, Slovis CM, Murphy F, Greenberg RS. Aminophylline therapy for acute bronchospastic disease in the emergency room. Ann. Intern. Med. 1991; 115:241–7. 88. Littenberg B. Aminophylline treatment in severe acute asthma: a metaanalysis. JAMA 1988; 259:1678–89. 89. Fanta CH, Rossing TH, McFadden ER. Treatment of acute asthma – is combination therapy with sympathomimetics and methylxanthines indicated? Am. J. Med. 1986; 80:5–10. 90. Eason J, Makowe HLJ. Aminophylline toxicity – how many hospital asthma deaths does it cause? Resp. Med. 1989; 83:219–26. 91. Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO Workshop Report. Publication 95–3659, 1995.

92. Wilson AJ, Gibson PG, Coughlan J. Long acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2000; CD001281. 93. Furukawa CT, Shapiro SG, Bierman CW. A double-blind study comparing the effectiveness of cromolyn sodium and sustained release theophylline in childhood asthma. Pediatrics 1984; 74:435–9. 94. Nassif EG, Weinburger M, Thompson R, Huntley W. The value of maintenance theophylline in steroid-dependent asthma. N. Engl. J. Med. 1981; 304:71–5. 95. Brenner MR, Berkowitz R, Marshall N, Strunk RC. Need for theophylline in severe steroid-requiring asthmatics. Clin. Allergy 1988; 18:143–50. 96. Rivington RN, Boulet LP, Cote J et al. Efficacy of slow-release theophylline, inhaled salbutamol and their combination in asthmatic patients on high-dose inhaled steroids. Am. J. Respir. Crit. Care Med. 1995; 151:325–32. 97. Barnes PJ. The role of theophylline in severe asthma. Eur. Respir. Rev. 1996; 6:154S–9S. 98. Martin RJ, Pak J. Overnight theophylline concentrations and effects on sleep and lung function in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1992; 145:540–4. 99. Zwillich CW, Neagey SR, Cicutto L, White DP, Martin RJ. Nocturnal asthma therapy: inhaled bitolterol versus sustainedrelease theophylline. Am. Rev. Respir. Dis. 1989; 139:470–4. 100. Fairfax AJ, Clarke R, Chatterjee SS et al. Controlled release theophylline in the treatment of nocturnal asthma. J. Int. Med. Res. 1990; 18:273–81. 101. Selby C, Engleman HM, Fitzpatrick MF, Sime PM, Mackay TW, Douglas NJ. Inhaled salmeterol or oral theophylline in nocturnal asthma? Am. J. Respir. Crit. Care Med. 1997; 155:104–8. 102. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N. Engl. J. Med. 1997; 337:1412–18. 103. Ukena D, Harnest U, Sakalauskas R et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur. Respir. J. 1997; 10:2754–60. 104. Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 2000; 55:837–41. 105. Taylor DR, Buick B, Kinney C, Lowry RC, McDevitt DG. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible airflow obstruction. Am. Rev. Respir. Dis. 1985; 131:747–51. 106. Murciano D, Avclair M-H, Parievte R, Aubier M. A randomized controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N. Engl. J. Med. 1989; 320:1521–5. 107. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airway disease. Br. Med. J. 1988; 297:1506–10. 108. Handslip PDJ, Dart AM, Davies BTI. Intravenous salbutamol and aminophylline in asthma: a search for synergy. Thorax 1981; 36:741–4. 109. Jenne JW.Theophylline as a bronchodilator in COPD and its combination with inhaled b-adrenergic drugs. Chest 1987; 92:7–14S. 110. Kume H, Graziano MP, Kotlikoff MI. Stimulatory and inhibitory regulation of calcium-activated potassium channels by guanine nucleotide binding proteins. Proc. Natl Acad. Sci. USA 1992; 89:11051–5. 111. Giembycz MA. Phosphodiesterase 4 and tolerance to beta 2adrenoceptor agonists in asthma. Trends Pharmacol. Sci. 1996; 17:331–6. 112. Barnes PJ. Current therapies for asthma: promise and limitations. Chest 1997; 111:17S–22S.

Theophylline

113. Rachelefsky WOJ, Adelson J, Mickey MR et al. Behaviour abnormalities and poor school performance due to oral theophylline use. Pediatrics 1986; 78:1113–38. 114. Nicholson CD, Challiss RAJ, Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol. Sci. 1991; 12:19–27.

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115. Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients’ compliance with prescribed oral and inhaled asthma medications. Arch. Int. Med. 1994; 154:1349–52. 116. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1999; 160:1635–9.

Chapter

Corticosteroids

52

Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK

Corticosteroids are by far the most effective therapy currently available for asthma and improvement with corticosteroids is one of the hallmarks of asthma. Inhaled corticosteroids have revolutionized asthma treatment and have become the mainstay of therapy for patients with chronic disease.1,2 By contrast, corticosteroids are largely ineffective in COPD.3 We now have a much better understanding of the molecular mechanisms whereby corticosteroids suppress inflammation in asthma and why they may be ineffective in COPD and in rare patients with asthma who are resistant to corticosteroids. This chapter discusses current understanding of the mechanism of action of corticosteroids and how corticosteroids are used in the management of airway diseases.

MOLECULAR MECHANISMS Corticosteroids are highly effective anti-inflammatory therapy in asthma and the molecular mechanisms involved in suppression of airway inflammation in asthma are now better understood.4 Corticosteroids are effective in asthma because they block many of the inflammatory pathways that are abnormally activated in asthma and they have a wide spectrum of anti-inflammatory actions. Glucocorticoid receptors Corticosteroids bind to a single class of glucocorticoid receptor (GR) which is localized to the cytoplasm of target cells. Corticosteroids bind at the C-terminal end of the receptor, whereas the N-terminal end of the receptor is involved in gene transcription. Between these domains is the DNA-binding domain which has two finger-like projections formed by a zinc molecule bound to four cysteine residues that bind to the DNA double helix. The inactive GR is bound to a protein complex that includes two molecules of 90 kDa heat shock protein (hsp90) and various other proteins which act as “molecular chaperones” preventing the unoccupied GR from moving into the nuclear compartment. Once corticosteroids bind to GR, conformational changes in the receptor structure result in dissociation of these chaperone molecules, thereby exposing nuclear localization

signals on GR, resulting in rapid nuclear localization of the activated GR-corticosteroid complex and its binding to DNA (Fig. 52.1). Two GR molecules bind to DNA as a dimer, resulting in changed transcription. A splice variant of GR, termed GR-b, has been identified that does not bind corticosteroids, but binds to DNA and may theoretically interfere with the action of corticosteroids.5 Increased gene transcription Corticosteroids produce their effect on responsive cells by activating GR to directly or indirectly regulate the transcription of certain target genes.6 The number of genes per cell directly regulated by corticosteroids is estimated to be between 10 and 100, but many genes are indirectly regulated through an interaction with other transcription factors. GR dimers bind to DNA at consensus sites termed glucocorticoid response elements (GREs) in the 5-upstream promoter region of steroid-responsive genes. This interaction changes the rate of transcription, resulting in either induction or repression of the gene. Interaction of the activated GR homodimer with GRE usually increases transcription, resulting in increased protein synthesis. GR may increase transcription by interacting with a large coactivator molecule, CREB binding protein (CBP), which is bound at the start site of transcription and switches on RNA polymerase, resulting in formation of messenger RNA (mRNA) and then synthesis of protein. Binding of activated GR to CBP results in increased acetylation of core histones around which DNA is wound within the chromosomal structure.7 This results in the binding and activation of RNA polymerase, which then results in mRNA formation. Decreased gene transcription In controlling inflammation, the major effect of corticosteroids is to inhibit the synthesis of inflammatory proteins, such as cytokines. This was originally believed to be through interaction of GR with negative GREs, resulting in repression of transcription. However, negative GREs have rarely been demonstrated. GR may also affect the synthesis of some proteins by reducing the stability of mRNA, through effects on ribonucleases that break down mRNA.

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Glucocorticoid

GR

Lipocortin-1 β2-Adrenoceptors

mRNA

Cytokines iNOS, COX2 Adhesion mols

X

hsp90

GRβ

Nucleus

GRE

GRE

Steroid-responsive target genes

Fig. 52.1. Classical model of corticosteroid action. Corticosteroids enter the cell and bind to cytoplasmic glucocorticoid receptors (GR) that are complexed with two molecules of a 90 kDa heat shock protein (hsp90). GR translocates to the nucleus where, as a dimer, it binds to a glucocorticoid recognition element (GRE) on the 5’-upstream promoter sequence of steroid-responsive genes. GREs increase transcription, whereas nGREs may decrease transcription, resulting in increased or decreased messenger RNA (mRNA) and protein synthesis. An isoform of GR, GR-b, binds to DNA, but is not activated by corticosteroids.

Interaction with transcription factors Activated GRs may bind directly with several other activated transcription factors as a protein–protein interaction. This could be an important determinant of corticosteroid responsiveness and is a key mechanism whereby corticosteroids switch off inflammatory genes. Most of the inflammatory genes that are activated in asthma do not appear to have GREs in their promoter regions yet are repressed by corticosteroids. There is increasing evidence that corticosteroids inhibit the effects of transcription factors that regulate the expression of genes that code for inflammatory proteins, such as cytokines, inflammatory enzymes, adhesion molecules and inflammatory receptors. These “inflammatory” transcription factors include activator protein-1 (AP-1) and nuclear factor-jB (NF-jB), which may regulate many of the inflammatory genes that are switched on in asthmatic airways.8,9 Effects on chromatin structure There is increasing evidence that corticosteroids may have effects on the chromatin structure. DNA in chromosomes is wound around histone molecules in the form of nucleosomes. Several transcription factors interact with large coactivator molecules, such as CBP and the related molecule p300, which bind to the basal transcription factor apparatus. Several transcription factors bind directly to CBP, including AP-1, NF-jB and GR10 (Fig. 52.2). At a microscopic level, chromatin may become dense or opaque due to the winding

or unwinding of DNA around the histone core. CBP and p300 have histone acetylation activity which is activated by the binding of transcription factors, such as AP-1 and NF-jB. Acetylation of histone residues results in unwinding of DNA coiled around the histone core, thus opening up the chromatin structure, which allows transcription factors to bind more readily, thereby increasing transcription. Repression of genes reverses this process by histone deacetylation.11 Deacetylation of histone increases the winding of DNA round histone residues, resulting in dense chromatin structure and reduced access of transcription factors to their binding sites, thereby leading to repressed transcription of inflammatory genes. Activated GR may bind to several transcription co-repressor molecules that associate with proteins that have histone deacetylase activity (HDACs), resulting in deacetylation of histone, increased winding of DNA round histone residues and thus reduced access of transcription factors to their binding sites and therefore repression of inflammatory genes. In addition, activated GR recruits HDACs to the transcription start site, resulting in deacetylation of histones, and a decrease in inflammatory gene transcription.7 Target genes in inflammation control Corticosteroids may control inflammation by inhibiting many aspects of the inflammatory process in asthma through increasing the transcription of anti-inflammatory genes and decreasing the transcription of inflammatory genes (Table 52.1).

Corticosteroids

NF-κB

STATs

CBP inhibitors E1A

AP-1 CBP/p300

CREB

Pol II

HAT

Corticosteroid GR

Histone acetylation Histone Ac Ac Ac Ac Ac Ac deacetylation

Repressive chromatin Decreased transcription Inflammatory gene repression

Active chromatin Increased transcription Inflammatory gene expression

Fig. 52.2. Effect of corticosteroids on chromatin structure. Transcription factors, such as STATs, AP-1 and NF-jB bind to co-activator molecules, such as CREB binding protein (CBP) or p300, which have intrinsic histone acetyltransferase (HAT) activity, resulting in acetylation (Ac) of histone residues. This leads to unwinding of DNA and allows increased binding of transcription factors resulting in increased gene transcription. Glucocorticoid receptors (GR) after activation by corticosteroids bind to a glucocorticoid receptor co-activator which is bound to CBP. This results in deacetylation of histone, with increased coiling of DNA around histone, thus preventing transcription factor binding leading to gene repression.

Table 52.1. Effect of corticosteroids on gene transcription

Increased transcription Lipocortin-1 (phospholipase A2 inhibitor) b2-Adrenoceptor Secretory leukoprotease inhibitor Clara cell protein (CC10, phospholipase A2 inhibitor) IL-1 receptor antagonist IL-1R2 (decoy receptor) IjB-a (inhibitor of NF-jB) Decreased transcription Cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-12, IL-13, IL-16, IL-17, IL-18, TNF-a, GM-CSF, SCF) Chemokines (IL-8, RANTES, MIP-1a, MCP-1, MCP-3, MCP-4, eotaxin) Inducible nitric oxide synthase (iNOS) Inducible cycloxygenase (COX-2) Cytoplasmic phospholipase A2 (cPLA2) Endothelin-1 NK1-receptors, NK2-receptors Adhesion molecules (ICAM-1, E-selectin)

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Anti-inflammatory proteins Corticosteroids may suppress inflammation by increasing the synthesis of anti-inflammatory proteins. For example, corticosteroids increase the synthesis of lipocortin-1, a 37 kDa protein that has an inhibitory effect on phospholipase A2 (PLA2), and therefore may inhibit the production of lipid mediators. Corticosteroids induce the formation of lipocortin-1 in several cells and recombinant lipocortin-1 has acute anti-inflammatory properties. However, lipocortin-1 does not appear to be increased by inhaled corticosteroid treatment in asthma.12 Corticosteroids increase the expression of other potentially anti-inflammatory proteins, such as interleukin (IL)-1 receptor antagonist (which inhibits the binding of IL-1 to its receptor), secretory leukoprotease inhibitor (which inhibits proteases, such as tryptase), neutral endopeptidase (which degrades bronchoactive peptides such as kinins), CC-10 (an immunomodulatory protein), an inhibitor of NF-jB (IjB-a) and IL-10 (an anti-inflammatory cytokine). b2-Adrenoceptors Corticosteroids increase the expression of b2-adrenoceptors by increasing the rate of transcription and the human b2receptor gene has three potential GREs. Corticosteroids double the rate of b2-receptor gene transcription in human lung in vitro, resulting in increased expression of b2 receptors.13 This also occurs in vivo in nasal mucosa with treatment with topical corticosteroids.14 This may be relevant in asthma as corticosteroids may prevent down-regulation of b-receptors in response to prolonged treatment with b2agonists. In rats, corticosteroids prevent down-regulation and reduced transcription of b2-receptors in response to chronic b-agonist exposure.15 Cytokines The inhibitory effect of corticosteroids on cytokine synthesis is likely to be of particular importance in the control of inflammation in asthma. Corticosteroids inhibit the transcription of many cytokines and chemokines that are relevant in asthma (Table 52.1). These inhibitory effects are due, at least in part, to an inhibitory effect on the transcription factors that regulate induction of these cytokine genes, including AP-1 and NF-jB. For example, eotaxin which is important in selective attraction of eosinophils from the circulation into the airways is regulated in part by NF-jB and its expression in airway epithelial cells is inhibited by corticosteroids.16 Many transcription factors are likely to be involved in the regulation of inflammatory genes in asthma in addition to AP-1 and NF-jB. IL-4 and IL-5 expression in T-lymphocytes plays a critical role in allergic inflammation, but NF-jB does not play a role, whereas the transcription factor nuclear factor of activated T cells (NF-AT) is important.17 AP-1 is a component of the NF-AT transcription complex, so that corticosteroids inhibit IL-5, at least in part by inhibiting the AP-1 component of NF-AT. There may be marked differences in the response of different cells and of different cytokines to the inhibitory

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action of corticosteroids and this may be dependent on the relative abundance of transcription factors within different cell types. Thus, in alveolar macrophages and peripheral blood monocytes, GM-CSF secretion is more potently inhibited by corticosteroids than IL-1b or IL-6 secretion. Inflammatory enzymes Nitric oxide (NO) synthase may be induced by proinflammatory cytokines, resulting in NO production. NO may amplify asthmatic inflammation and contribute to epithelial shedding and airway hyperresponsiveness through the formation of peroxynitrite. The induction of the inducible form of NOS (iNOS) is inhibited by corticosteroids. In cultured human pulmonary epithelial cells, pro-inflammatory cytokines result in increased expression of iNOS and increased NO formation, due to increased transcription of the iNOS gene, and this is inhibited by corticosteroids acting through inhibition of NF-jB. Corticosteroids inhibit the synthesis of several other inflammatory mediators implicated in asthma through an inhibitory effect on the induction of enzymes, such as cyclo-oxygenase-2 and cytosolic PLA2.18,19 Inflammatory receptors Corticosteroids also decrease the transcription of genes coding for certain receptors. Thus the gene for the NK1receptor, which mediates the inflammatory effects of tachykinins in the airways, has an increased expression in asthma and is inhibited by corticosteroids, probably via an inhibitory effect on AP-1.20 Corticosteroids also inhibit the transcription of the NK2-receptor, which mediates the bronchoconstrictor effects of tachykinins21 and bradykinin B1 and B2 receptors.22 Adhesion molecules Adhesion molecules play a key role in the trafficking of inflammatory cells to sites of inflammation.The expression of many adhesion molecules on endothelial cells is induced by cytokines and corticosteroids may lead indirectly to a reduced expression via their inhibitory effects on cytokines, such as IL1b and TNF-a. Corticosteroids may also have a direct inhibitory effect on the expression of adhesion molecules, such as ICAM-1 and E-selectin at the level of gene transcription. ICAM-1 andVCAM-1 expression in bronchial epithelial cell lines and monocytes is inhibited by corticosteroids.23 Apoptosis Corticosteroids markedly reduce the survival of certain inflammatory cells, such as eosinophils. Eosinophil survival is dependent on the presence of certain cytokines, such as IL-5 and GM-CSF. Exposure to corticosteroids blocks the effects of these cytokines and leads to programmed cell death or apoptosis, although the corticosteroid-sensitive molecular pathways have not yet been defined.24 By contrast, corticosteroids decrease apoptosis in neutrophils and thus prolong their survival.25 This may contribute to the lack of anti-inflammatory effects of corticosteroids in COPD where neutrophilic inflammation is predominant.

Effects on cell function Corticosteroids may have direct inhibitory actions on several inflammatory cells and structural cells that are implicated in asthma (Fig. 52.3). Macrophages Corticosteroids inhibit the release of inflammatory mediators and cytokines from alveolar macrophages in vitro. Inhaled corticosteroids reduce the secretion of chemokines and proinflammatory cytokines from alveolar macrophages from asthmatic patients, whereas the secretion of IL-10 is increased.26 Eosinophils Corticosteroids have a direct inhibitory effect on mediator release from eosinophils, although they are only weakly effective in inhibiting secretion of reactive oxygen species and eosinophil basic proteins. More importantly, corticosteroids induce apoptosis by inhibiting the prolonged survival due to IL-3, IL-5 and GM-CSF,24 resulting in an increased number of apoptotic eosinophils in induced sputum of asthmatic patients.27 There is a delay in the apoptosis of eosinophils in asthma, which is reversed by treatment with corticosteroids.28 One of the best described actions of corticosteroids in asthma is a reduction in circulating eosinophils, which may reflect an action on eosinophil production in the bone marrow. T-lymphocytes T helper 2 lymphocytes (Th2) play an important orchestrating role in asthma through the release of the cytokines IL-4, IL-5, IL-9 and IL-13 and may be an important target for corticosteroids in asthma therapy. Corticosteroids increase apoptosis in T cells, although the molecular mechanisms are not yet certain. Mast cells While corticosteroids do not appear to have a direct inhibitory effect on mediator release from lung mast cells, chronic corticosteroid treatment is associated with a marked reduction in mucosal mast cell numbers. This may be linked to a reduction in IL-3 and stem cell factor (SCF) production, which are necessary for mast cell expression at mucosal surfaces. Mast cells also secrete various cytokines (TNF-a, IL-4, IL-5, IL-6 and IL-8), and this may also be inhibited by corticosteroids.29 Dendritic cells Dendritic cells in the epithelium of the respiratory tract appear to play a critical role in antigen presentation in the lung as they have the capacity to take up allergen, process it into peptides and present it via MHC molecules on the cell surface for presentation to uncommitted T-lymphocytes. In experimental animals the number of dendritic cells is markedly reduced by systemic and inhaled corticosteroids, thus dampening the immune response in the airways.30

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Corticosteroids

Inflammatory cells

Structural cells

Eosinophil

Epithelial cell

Numbers (apoptosis)

Cytokines Mediators T lymphocyte

Endothelial cell

Cytokines Leak Mast cell

Corticosteroids

Numbers

Airway smooth muscle β2-Receptors Cytokines

Macrophage

Mucus gland

Cytokines Mucus secretion Dendritic cell Numbers

Fig. 52.3. Cellular effect of corticosteroids.

Neutrophils Neutrophils, which are not prominent in the biopsies of asthmatic patients, are not sensitive to the effects of corticosteroids. Indeed, systemic corticosteroids increase peripheral neutrophil counts which may reflect an increased survival time due to an inhibitory action of neutrophil apoptosis.25 High doses of inhaled corticosteroids have no effect on airway neutrophilia induced by ozone.31 Endothelial cells GR gene expression in the airways is most prominent in endothelial cells of the bronchial circulation and airway epithelial cells. Corticosteroids do not appear to directly inhibit the expression of adhesion molecules, although they may inhibit cell adhesion indirectly by suppression of cytokines involved in the regulation of adhesion molecule expression. Corticosteroids may have an inhibitory action on airway microvascular leak induced by inflammatory mediators.This appears to be a direct effect on postcapillary venular epithelial cells. Although there have been no direct measurements of the effects of corticosteroids on airway microvascular leakage in asthmatic airways, regular treatment with inhaled corticosteroids decreases the elevated plasma proteins found in bronchoalveolar lavage fluid of patients with stable asthma. Epithelial cells Epithelial cells may be an important source of many inflammatory mediators in asthmatic airways and may drive and amplify the inflammatory response in the airways through

the secretion of proinflammatory cytokines, chemokines and inflammatory peptides. Airway epithelium may be one of the most important cellular targets for inhaled corticosteroids in asthma32,33 (Fig. 52.4). Inhaled corticosteroids inhibit the increased expression of many inflammatory proteins in airway epithelial cells.32 An example is iNOS, which has an increased expressed in airway epithelial and inflammatory cells in asthma and is reduced by inhaled corticosteroids.34 This is reflected by a reduction in the elevated levels of exhaled NO in asthma after inhaled corticosteroids.35 Mucus secretion Corticosteroids inhibit mucus secretion in airways and this may be a direct action of corticosteroids on submucosal gland cells. Corticosteroids may also inhibit the expression of mucin genes, such as MUC2 and MUC5AC.36 In addition, there are indirect inhibitory effects due to the reduction in inflammatory mediators which stimulate increased mucus secretion.

E F F E C T S O N A S T H M AT I C I N F L A M M AT I O N Corticosteroids are remarkably effective in controlling the inflammation in asthmatic airways and it is likely that they have multiple cellular effects. Biopsy studies in patients with asthma have now confirmed that inhaled corticosteroids reduce the number and activation of inflammatory cells in the airway mucosa and in bronchoalveolar lavage.32 These

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life of patients with asthma and allow many patients to lead normal lives, improve lung function, reduce the frequency of exacerbations and may prevent irreversible airway changes. They were first introduced to reduce the requirement for oral corticosteroids in patients with severe asthma and many studies have confirmed that the majority of patients can be weaned off oral corticosteroids.40

Inhaled corticosteroids Epithelial cells

Cytokines IL-1β IL-6 GM-CSF RANTES Eotaxin MIP-1α

Enzymes iNOS COX2 cPLA2

Peptides ET-1

Adhesion monecules ICAM-1

Inflammation

Fig. 52.4. Inhaled corticosteroids may inhibit the transcription of several “inflammatory” genes in airway epithelial cells and thus reduce inflammation in the airway wall.

effects may be due to inhibition of cytokine synthesis in inflammatory and structural cells and suppression of adhesion molecules.The disrupted epithelium is restored and the ciliated to goblet cell ratio is normalized after 3 months of therapy with inhaled corticosteroids. There is also some evidence for a reduction in the thickness of the basement membrane, although in asthmatic patients taking inhaled corticosteroids for over 10 years, the characteristic thickening of the basement membrane was still present. Effects on airway hyperresponsiveness By reducing airway inflammation inhaled corticosteroids consistently reduce airway hyperresponsiveness (AHR) in asthmatic adults and children.37 Chronic treatment with inhaled corticosteroids reduces responsiveness to histamine, cholinergic agonists, allergen (early and late responses), exercise, fog, cold air, bradykinin, adenosine and irritants (such as sulfur dioxide and metabisulfite). The reduction in AHR takes place over several weeks and may not be maximal until several months of therapy. The magnitude of reduction is variable between patients and is in the order of one to two doubling dilutions for most challenges and often fails to return to the normal range. This may not reflect suppression of the inflammation, but persistence of structural changes which cannot be reversed by corticosteroids. Inhaled corticosteroids not only make the airways less sensitive to spasmogens, but they also limit the maximal airway narrowing in response to spasmogens.

CLINICAL EFFICACY OF INHALED CORTICOSTEROIDS IN ASTHMA Inhaled corticosteroids are very effective in controlling asthma symptoms in asthmatic patients of all ages and severity.38,39 Inhaled corticosteroids improve the quality of

Studies in adults As experience has been gained with inhaled corticosteroids they have been introduced in patients with milder asthma, with the recognition that inflammation is present even in patients with mild asthma. Inhaled anti-inflammatory drugs have now become first-line therapy in any patient who needs to use a b2-agonist inhaler more than once a day and this is reflected in national and international guidelines for the management of chronic asthma. In patients with newly diagnosed asthma inhaled corticosteroids (budesonide 600 lg twice daily) reduced symptoms and b2-agonist inhaler usage and improved lung function.These effects persisted over the 2 years of the study, whereas in a parallel group treated with inhaled b2-agonists alone there was no significant change in symptoms or lung function.41 In another study, patients with mild asthma treated with a low dose of inhaled corticosteroid (budesonide 400 lg daily) showed fewer symptoms and a progressive improvement in lung function over several months and many patients became completely asymptomatic.42 There was also a significant reduction in the number of exacerbations. Although the effects of inhaled corticosteroids on AHR may take several months to reach a plateau, the reduction in asthma symptoms occurs more rapidly.43 High-dose inhaled corticosteroids have now been introduced for the control of more severe asthma. This markedly reduces the need for maintenance oral corticosteroids and has revolutionized the management of more severe and unstable asthma. Inhaled corticosteroids are the treatment of choice in nocturnal asthma, which is a manifestation of inflamed airways, reducing night-time awakening and reducing the diurnal variation in airway function. High doses of inhaled corticosteroids may also substitute for a course of oral steroids in controlling acute exacerbations of asthma. High-dose fluticasone propionate (2000 lg daily) was as effective as a course of oral prednisolone in controlling acute exacerbations of asthma in general practice.44 Although doubling the dose of inhaled corticosteroids is recommended for mild exacerbation of asthma, this does not appear to be useful, but a four-fold increase in dose appears to be effective.45 Inhaled corticosteroids effectively control asthmatic inflammation, but must be taken regularly. When inhaled corticosteroids are discontinued there is usually a gradual increase in symptoms and airway responsiveness back to pretreatment values,43 although in patients with mild asthma who have been treated with inhaled corticosteroids for a long time, symptoms may not recur in some patients.46 Reduction in the dose of inhaled corticosteroids is associated with an

Corticosteroids

increase in symptoms and this is preceded by an increase in exhaled NO and sputum eosinophils.47 Studies in children Inhaled corticosteroids are equally effective in children. In an extensive study of children aged 7–17 years there was a significant improvement in symptoms, peak flow variability and lung function compared with a regular inhaled b2agonist which was maintained over the 22 months of the study,48 but asthma deteriorated when the inhaled corticosteroids were withdrawn.49 There was a high proportion of drop-outs (45%) in the group treated with inhaled b2agonist alone. Inhaled corticosteroids are more effective than a long-acting b2-agonist in controlling asthma in children.50 Inhaled corticosteroids are also effective in younger children. Nebulized budesonide reduces the need for oral corticosteroids and also improved lung function in children under the age of 3.51 Inhaled corticosteroids given via a large volume spacer improve asthma symptoms and reduce the number of exacerbations in preschool children and in infants. Dose–response studies Surprisingly, the dose–response curve for the clinical efficacy of inhaled corticosteroids is relatively flat and, while all studies have demonstrated a clinical benefit of inhaled corticosteroids, it has been difficult to demonstrate differences between doses, with most benefit obtained at the lowest doses used.38,40,52 This is in contrast to the steeper dose– response for systemic effects, implying that while there is little clinical benefit from increasing doses of inhaled corticosteroids the risk of adverse effects is increased. However, the dose–response effect of inhaled corticosteroids may depend on the parameters measured and, while it is difficult to discern a dose–response when traditional lung function parameters are measured, there may be a dose–response effect in prevention of asthma exacerbations. Thus, there is a significantly greater effect of budesonide 800 lg daily compared with 200 lg daily in preventing severe and mild asthma exacerbations.53 Normally, a four-fold or greater difference in dose has been required to detect a statistically significant (but often small) difference in effect on commonly measured outcomes such as symptoms, PEF, use of rescue b2-agonist and lung function, and even such large differences in dose are not always associated with significant differences in response. These findings suggest that pulmonary function tests or symptoms may have a rather low sensitivity in the assessment of the effects of inhaled corticosteroids. This is obviously important for the interpretation of clinical comparisons between different inhaled corticosteroids or inhalers. It is also important to consider the type of patient included in clinical studies. Patients with relatively mild asthma may have relatively little room for improvement with inhaled corticosteroids, so that maximal improvement is obtained with relatively low doses. Patients with more severe asthma or with unstable asthma may have more room for improvement and may therefore show a

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greater response to increasing doses, but it is often difficult to include such patients in controlled clinical trials. More studies are needed to assess whether other outcome measures such as AHR or more direct measurements of inflammation, such as sputum eosinophils or exhaled NO, may be more sensitive than traditional outcome measures such as symptoms or lung function tests.54–56 Higher doses of inhaled corticosteroids are needed to control AHR than to improve symptoms and lung function, and this may have a better long-term outcome in terms of reduction in structural changes of the airways.57 Prevention of irreversible airway changes Some patients with asthma develop an element of irreversible airflow obstruction, but the pathophysiological basis of these changes is not yet understood. It is likely that they are the result of chronic airway inflammation and that they may be prevented by treatment with inhaled corticosteroids. There is some evidence that the annual decline in lung function may be slowed by the introduction of inhaled corticosteroids.58 Increasing evidence also suggests that delay in starting inhaled corticosteroids may result in less overall improvement in lung function in both adults and children.59–61 These studies suggest that introduction of inhaled corticosteroids at the time of diagnosis is likely to have the greatest impact.60,61 Several large studies are now underway to assess the benefit of very early introduction of inhaled corticosteroids in children and adults. So far there is no evidence that early use of inhaled corticosteroids is curative and even when inhaled corticosteroids are introduced at the time of diagnosis, symptoms and lung function revert to pretreatment levels when corticosteroids are withdrawn.59 Reduction in mortality Inhaled corticosteroids may reduce the mortality from asthma, but prospective studies are almost impossible to conduct. In a retrospective review of the risk of mortality and prescribed anti-asthma medication, there was a significant protection provided by regular inhaled corticosteroid therapy.62 Comparison between inhaled corticosteroids Several inhaled corticosteroids are currently prescribable in asthma, although their availability varies between countries. There have been relatively few studies comparing efficacy of the different inhaled corticosteroids, and it is important to take into account the delivery system and the type of patient under investigation when such comparisons are made. Because of the relatively flat dose–response curve for the clinical parameters normally used in comparing doses of inhaled corticosteroids, it may be difficult to see differences in efficacy of inhaled corticosteroids. Most comparisons have concentrated on differences in systemic effects at equally efficacious doses, although it has often proved difficult to establish dose equivalence. There are few studies comparing different doses of inhaled corticosteroids in asthmatic patients. Budesonide has been compared with BDP

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and in adults and children appears to have comparable antiasthma effects at equal doses, whereas FP appears to be approximately twice as potent as BDP and budesonide. Studies have consistently shown that fluticasone propionate (FP) and budesonide have less systemic effects than BDP, triamcinolone and flunisolide.63 A new inhaled corticosteroid mometasone also has less systemic effects.64

CLINICAL USE OF INHALED CORTICOSTEROIDS IN ASTHMA Inhaled corticosteroids are now recommended as first-line therapy for all patients with persistent symptoms. Inhaled corticosteroids should be started in any patient who needs to use a b2-agonist inhaler for symptom control more than three times a week. It is conventional to start with a low dose of inhaled corticosteroid and to increase the dose until asthma control is achieved. However, this may take time and a preferable approach is to start with a dose of corticosteroids in the middle of the dose range (400 lg twice daily) to establish control of asthma more rapidly.65 Once control is achieved (defined as normal or best possible lung function and infrequent need to use an inhaled b2-agonist) the dose of inhaled corticosteroid should be reduced in a step-wise manner to the lowest dose needed for optimal control. It may take as long as 3 months to reach a plateau in response and any changes in dose should be made at intervals of 3 months or more. When daily doses of 800 lg daily are needed, a large volume spacer device should be used with an MDI and mouth washing with a dry powder inhaler in order to reduce local and systemic side-effects. Inhaled corticosteroids are usually give as a twice daily dose in order to increase compliance. When asthma is unstable, four times daily dosage is preferable.66 For patients who require 400 lg daily, once daily dosing appears to be as effective as twice daily dosing, at least for budesonide.67 The dose of inhaled corticosteroid should be increased to 2000 lg daily if necessary, but higher doses may result in systemic effects. It may be preferable to add a low dose of oral corticosteroid, since higher doses of inhaled corticosteroids are expensive and have a high incidence of local sideeffects. Nebulized budesonide has been advocated in order to give an increased dose of inhaled corticosteroid and to reduce the requirement for oral corticosteroids,68 but this treatment is expensive and may achieve its effects largely via systemic absorption. Add-on therapy Conventional advice was to increase the dose of inhaled corticosteroids if asthma was not controlled, on the assumption that there was residual inflammation of the airways. However, it is now apparent that the dose–response effect of inhaled corticosteroids is relatively flat, so that there is little improvement in lung function after doubling the dose of inhaled corticosteroids. An alternative strategy is to add some other class of controller drug.

Long-acting inhaled b2-agonists In patients in general practice who are not controlled on BDP 200 lg twice daily, addition of salmeterol 50 lg twice daily was more effective than increasing the dose of inhaled corticosteroid to 500 lg twice daily, in terms of lung function improvement, use of rescue b2-agonist use and symptom control.69 This has been confirmed in several other studies.70 Similar results have been found with another longacting inhaled b2-agonist formoterol, which in addition reduced the frequency of mild and severe asthma exacerbations.53 This has led to the development of fixed combinations of corticosteroids and long-acting b2-agonists, such as FP and salmeterol (seretide/advair/vianni) and budesonide with formoterol (symbicort), which may be more convenient for patients.71,72 These fixed combination inhalers also ensure that patients do not discontinue their inhaled corticosteroids when a long-acting bronchodilator is used. Theophylline Addition of low doses of theophylline (giving plasma concentrations of 1600 lg daily) give a dose-related decrease in morning serum cortisol levels and 24 hour urinary cortisol, although values still lie well within the normal range. However, when a large volume spacer is used, doses of 2000 lg daily of BDP or budesonide have little effect on 24-hour urinary cortisol excretion. Stimulation tests of HPA axis function similarly show no consistent effects of doses of 1500 lg or less of inhaled corticosteroid. At high doses (>1500 lg daily) budesonide and FP have less effect than BDP on HPA axis function. In children no suppression of urinary cortisol is seen with doses of BDP of 800 lg or less. In studies where plasma cortisol has been measured at frequent intervals there was a significant reduction in cortisol peaks with doses of inhaled BDP as low as 400 lg daily, although this does not appear to be dose-related in the range 400–1000 lg. The clinical significance of these effects is not certain, however.

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Overall, the studies which are not confounded by concomitant treatment with oral corticosteroids, have consistently shown that there are no significant suppressive effects on HPA axis function at doses of 1500 lg in adults and 400 lg in children. Effects on bone metabolism Corticosteroids lead to a reduction in bone mass by direct effects on bone formation and resorption and indirectly by suppression of the pituitary–gonadal and HPA axes, effects on intestinal calcium absorption, renal tubular calcium reabsorption and secondary hyperparathyroidism.89 The effects of oral corticosteroids on osteoporosis and increased risk of vertebral and rib fractures are well known, but there are no reports suggesting that long-term treatment with inhaled corticosteroids is associated with an increased risk of fractures. Bone densitometry has been used to assess the effect of inhaled corticosteroids on bone mass. Although there is evidence that bone density is less in patients taking high-dose inhaled corticosteroids, interpretation is confounded by the fact that these patients are also taking intermittent courses of oral corticosteroids. Changes in bone mass occur very slowly and several biochemical indices have been used to assess the short-term effects of inhaled corticosteroids on bone metabolism. Bone formation has been measured by plasma concentrations of bone-specific alkaline phosphatase, serum osteocalcin or procollagen peptides. Bone resorption may be assessed by urinary hydroxyproline after a 12-hour fast, urinary calcium excretion and pyridinium cross-link excretion. It is important to consider the age, diet, time of day and physical activity of the patient in interpreting any abnormalities. It is also necessary to choose appropriate control groups as asthma itself may have an effect on some of the measurements, such as osteocalcin. Inhaled corticosteroids, even at doses up to 2000 lg daily, have no significant effect on calcium excretion, but acute and reversible dose-related suppression of serum osteocalcin has been reported with BDP and budesonide when given by conventional MDI in several studies. Budesonide consistently has less effect than BDP at equivalent doses and only BDP increases urinary hydroxyproline at high doses. With a large volume spacer even doses of 2000 lg daily of either BDP or budesonide are without effect on plasma osteocalcin concentrations, however. Urinary pyridinium and deoxypyridinoline cross-links, which are a more accurate and stable measurement of bone and collagen degradation, are not increased with inhaled corticosteroids (BDP >1000 lg daily), even with intermittent courses of oral corticosteroids. It is important to monitor changes in markers of bone formation, as well as bone degradation, as the net effect on bone turnover is important. There has been particular concern about the effect of inhaled corticosteroids on bone metabolism in growing children. A very low dose of oral corticosteroids (prednisolone 2.5 mg) causes significant changes in serum osteocalcin and urinary hydroxyproline excretion, whereas daily BDP and budesonide at doses up to 800 lg daily have no

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effect. It is important to recognize that the changes in biochemical indices of bone metabolism are less than those seen with even low doses of oral corticosteroids. This suggests that even high doses of inhaled corticosteroids, particularly when used with a spacer device, are unlikely to have any long-term effect on bone structure. Careful long-term follow-up studies in patients with asthma are needed. There is no evidence that inhaled corticosteroids increase the frequency of fractures. Long-term treatment with highdose inhaled corticosteroids has not been associated with any consistent change in bone density. Indeed, in elderly patients there may be an increase in bone density due to increased mobility. Effects on connective tissue Oral and topical corticosteroids cause thinning of the skin, telangiectasiae and easy bruising, probably as a result of loss of extracellular ground substance within the dermis, due to an inhibitory effect on dermal fibroblasts. There are reports of increased skin bruising and purpura in patients using high doses of inhaled BDP, but the amount of intermittent oral corticosteroids in these patients is not known. Easy bruising, in association with inhaled corticosteroids, is more frequent in elderly patients90 and there are no reports of this problem in children. Long-term prospective studies with objective measurements of skin thickness are needed with different inhaled corticosteroids. Ocular effects Long-term treatment with oral corticosteroids increase the risk of posterior subcapsular cataracts and there are several case reports describing cataracts in individual patients taking inhaled corticosteroids.40 In a recent crosssectional study in patients aged 5–25 years, taking either inhaled BDP or budesonide, no cataracts were found on slit-lamp examination, even in patients taking 2000 lg daily for over 10 years.91 However, epidemiological studies have identified an increased risk of cataracts in patients taking high-dose inhaled steroids over prolonged periods.92 A slight increase in the risk of glaucoma in patients taking very high doses of inhaled corticosteroids has also been identified.93 Growth There has been particular concern that inhaled corticosteroids may cause stunting of growth and several studies have addressed this issue. Asthma itself (as with other chronic diseases) may have an effect on the growth pattern and has been associated with delayed onset of puberty and decceleration of growth velocity that is more pronounced with more severe disease. However, asthmatic children appear to grow for longer, so that their final height is normal. The effect of asthma on growth makes it difficult to assess the effects of inhaled corticosteroids on growth in cross-sectional studies, particularly as courses of oral corticosteroids are a confounding factor. Longitudinal studies have demonstrated that there is no significant effect of

inhaled corticosteroids on statural growth in doses of up to 800 lg daily and for up to 5 years of treatment.40A metaanalysis of 21 studies, including over 800 children, showed no effect of inhaled BDP on statural height, even with higher doses and long duration of therapy94 and in a large study of asthmatics treated with inhaled corticosteroids during childhood, there was no difference in statural height compared with normal children.95 Another long-term follow-up study showed no effect of corticosteroids on final height in children treated over several years.96 Short-term growth measurements (knemometry) have demonstrated that even a low dose of an oral corticosteroid (prednisolone 2.5 mg) is sufficient to give complete suppression of lower leg growth. However inhaled budesonide up to 400 lg is without effect, although some suppression is seen with 800 lg and with 400 lg BDP. The relationship between knemometry measurements and final height are uncertain, since low doses of oral corticosteroid that have no effect on final height cause profound suppression. Metabolic effects Several metabolic effects have been reported after inhaled corticosteroids, but there is no evidence that these are clinically relevant at therapeutic doses. In adults, fasting glucose and insulin are unchanged after doses of BDP up to 2000 lg daily and in children with inhaled budesonide up to 800 lg daily. In normal individuals, high-dose inhaled BDP may slightly increase resistance to insulin. However, in patients with poorly controlled asthma high doses of BDP and budesonide paradoxically decrease insulin resistance and improve glucose tolerance, suggesting that the disease itself may lead to abnormalities in carbohydrate metabolism. Neither BDP 2000 lg daily in adults nor budesonide 800 lg daily in children have any effect on plasma cholesterol or triglycerides. Hematological effects Inhaled corticosteroids may reduce the numbers of circulating eosinophils in asthmatic patients, possibly due to an effect on local cytokine generation in the airways. Inhaled corticosteroids may cause a small increase in circulating neutrophil counts. Central nervous system effects There are various reports of psychiatric disturbance, including emotional lability, euphoria, depression, aggressiveness and insomnia, after inhaled corticosteroids. Only eight such patients have so far been reported, suggesting that this is very infrequent and a causal link with inhaled corticosteroids has usually not been established. Safety in pregnancy Based on extensive clinical experience, inhaled corticosteroids appear to be safe in pregnancy, although no controlled studies have been performed. There is no evidence for any adverse effects of inhaled corticosteroids on the pregnancy, the delivery or on the fetus.97,98 It is important to

Corticosteroids

recognize that poorly controlled asthma may increase the incidence of perinatal mortality and retard intra-uterine growth, so that more effective control of asthma with inhaled corticosteroids may reduce these problems.

SYSTEMIC CORTICOSTEROIDS Oral or intravenous corticosteroids may be indicated in several situations. Prednisolone, rather than prednisone, is the preferred oral corticosteroid, as prednisone has to be converted in the liver to the active prednisolone. In pregnant patients prednisone may be preferable, as it is not converted to prednisolone in the fetal liver, thus diminishing the exposure of the fetus to corticosteroids. Enteric-coated preparations of prednisolone are used to reduce side-effects (particularly gastric side-effects) and give delayed and reduced peak plasma concentrations, although the bioavailability and therapeutic efficacy of these preparations is similar to uncoated tablets. Prednisolone and prednisone are preferable to dexamethasone, betamethasone or triamcinolone, which have longer plasma half-lives and therefore an increased frequency of adverse effects. Short courses of oral corticosteroids (30–40 mg prednisolone daily for 1–2 weeks or until the peak flow values return to best attainable) are indicated for exacerbations of asthma, and the dose may be tailed off over 1 week once the exacerbation is resolved. The tail-off period is not strictly necessary, but some patients find it reassuring. Maintenance oral corticosteroids are only needed in a small proportion of asthmatic patients with the most severe asthma that cannot be controlled with maximal doses of inhaled corticosteroids (2000 lg daily) and additional bronchodilators. The minimal dose of oral corticosteroid needed for control should be used and reductions in the dose should be made slowly in patients who have been on oral corticosteroids for long periods (e.g. by 2.5 mg per month for doses down to 10 mg daily and thereafter by 1 mg per month). Oral corticosteroids are usually given as a single morning dose, as this reduces the risk of adverse effects since it coincides with the peak diurnal concentrations. There is some evidence that administration in the afternoon may be optimal for some patients who have severe nocturnal asthma.99 Alternate day administration may also reduce adverse effects, but control of asthma may not be as good on the day when the oral dose is omitted in some patients. Intramuscular triamcinolone acetonide (80 mg monthly) has been advocated in patients with severe asthma as an alternative to oral corticosteroids.100,101 This may be considered in patients in whom compliance is a particular problem, but the major concern is the high frequency of proximal myopathy associated with this fluorinated corticosteroid. Some patients who do not respond well to prednisolone are reported to respond to oral betamethasone, presumably because of pharmacokinetic handling problems with prednisolone.

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Acute severe asthma Intravenous hydrocortisone is given in acute severe asthma, with a recommended dose of 200 mg IV. While the value of corticosteroids in acute severe asthma has been questioned, others have found that they speed the resolution of attacks.102 There is no apparent advantage in giving very high doses of intravenous corticosteroids (such as methylprednisolone 1 g). Indeed, intravenous corticosteroids have occasionally been associated with an acute severe myopathy.103 No difference in recovery from acute severe asthma was seen whether IV hydrocortisone in doses of 50, 200 or 500 mg 6 hourly were used104 and another placebo-controlled study showed no beneficial effect of IV corticosteroids.105 Intravenous corticosteroids are indicated in acute asthma if lung function is 15% after treatment with oral prednisolone 30–40 mg daily for 2 weeks, providing the oral steroid is taken (verified by plasma prednisolone level or a reduction in early morning cortisol level).These patients are not Addisonian and they do not suffer from the abnormalities in sex hormones described in the very rare familial glucocorticoid resistance. Plasma cortisol and adrenal suppression in response to exogenous cortisol is normal in these patients, so they suffer from side-effects of corticosteroids. Complete corticosteroid resistance in asthma is very rare, with a prevalence of 15% and episodic symptoms. It is also important to identify provoking factors (allergens, drugs, psychological problems) that may increase the severity of asthma and its resistance to therapy. Biopsy studies have demonstrated the typical eosinophilic inflammation of asthma in these patients.110 Mechanisms of corticosteroid resistance There may be several mechanisms for resistance to the effects of corticosteroids. Certain cytokines (particularly IL-2, IL-4 and IL-13) may induce a reduction in affinity of glucocorticoid receptors in inflammatory cells such as T-lymphocytes, resulting in local resistance to the antiinflammatory actions of corticosteroids.110 Another mechanism is an increased activation of the transcription factor AP-1 by inflammatory cytokines, so that AP-1 may consume activated glucocorticoid receptors and thus reduce their availability for suppression of inflammation at inflamed sites.111 There is an increased expression of c-Fos, one of the components of AP-1.112 The reasons for this excessive activation of AP-1 by activating enzymes is currently unknown, but may be genetically determined. Another proposed mechanism is an increase in expression of GR-b, which then interferes with DNA binding of GR,113,114 but any increase in GR-b is insufficient to account for reduced responsiveness to corticosteroids.115

CORTICOSTEROIDS IN COPD Although inhaled corticosteroids are highly effective in asthma, they provide little benefit in COPD, despite the fact that airway and lung inflammation is present.3 Effect on inflammation This may reflect that the inflammation in COPD is not suppressed by corticosteroids, with no reduction in inflammatory cells, cytokines or proteases in induced sputum even with oral corticosteroids.116,117 Corticosteroids do not suppress neutrophilic inflammation in the airways and corticosteroids may prolong the survival of neutrophils.31 There is some evidence that the airway inflammation in COPD is corticosteroid-resistant, as corticosteroids have no inhibitory effect on inflammatory proteins, such as cytokines, that are normally suppressed by corticosteroids. This lack of response to corticosteroids may be explained in part by the inhibitory effect of cigarette smoking on histone deacetylases, thus interfering with an important anti-inflammatory action of corticosteroids.118

Clinical studies Four large studies conducted over 3 years have demonstrated no beneficial effect of inhaled corticosteroids on the decline in lung function in patients from mild to moderate COPD.119–122 There is some evidence for a reduction in more severe exacerbations with high doses of inhaled corticosteroids,121,123 but the effect is small and rather similar to the effect of bronchodilators in this respect. Some patients with COPD (approximately 10%) show some response to inhaled corticosteroids and it is likely that these are patients who have concomitant asthma. Indeed there corticosteroid responders are more likely to have sputum eosinophils and an increase in exhaled NO, which are features of asthmatic inflammation.124 These patients should be treated as if they have asthma.The remaining majority of patients are unlikely to derive much benefit from inhaled corticosteroids and indeed there are good reasons for not prescribing these drugs. They are often given in high doses as this has a risk of systemic side-effects in a vulnerable patient population, who are elderly, relatively immobile, may have a poor diet and have comorbid conditions, all of which increase the risk of side-effects, such as osteoporosis and cataracts. In addition high doses of inhaled corticosteroids are relatively expensive. In the management of acute exacerbations there is evidence that oral corticosteroids increase the rate of recovery, although the effects are relatively small.125,126

FUTURE DIRECTIONS Inhaled corticosteroids are now used as first-line therapy for the treatment of persistent asthma in adults and children in many countries, as they are the most effective treatments for asthma currently available.40 While many patients, particularly with more severe asthma, remain undertreated, there is also a danger of overtreatment and many patients with mild asthma who may require very low doses of inhaled corticosteroids are inappropriately treated with high doses. It is essential that inhaled corticosteroids are slowly reduced to the minimal dose required to control asthma. An important clinical development is the recognition that asthma is better controlled by addition of an alternative class of treatment (long-acting inhaled b2-agonists, low-dose theophylline, anti-leukotrienes) than on increasing the dose of inhaled steroid. The recent introduction of fixed combination inhalers with long-acting b2-agonists is an important advance as it greatly simplifies asthma management and provides very effective control. Improvement in techniques for the noninvasive monitoring of airway inflammation may be valuable in the future for assessing the requirement for inhaled corticosteroids.127 New corticosteroids Budesonide and FP have been important advances in inhaled corticosteroid therapy as they have reduced systemic effects because of greater first-pass hepatic metabolism than

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BDP. New inhaled corticosteroids in development, such as mometasone, show a similar improved profile.128 However, all currently available corticosteroids are absorbed from the lungs into the systemic circulation and therefore inevitably have some systemic component. A class of steroids was developed that was metabolized in the lung, but such so-called “soft” steroids, such as tipredane and butixocort, did not prove to be clinically effective, probably because they were metabolized too rapidly in the airways. A new steroid ciclesonide is a prodrug that releases active corticosteroids in the lungs after enzymatic action. Ciclesonide appears to have good efficacy and is now in clinical development.129 Steroids that are metabolized by enzymes in the circulation may be the safest type of inhaled corticosteroid and novel esterified corticosteroids are now in clinical development. However, it is still not certain whether the anti-inflammatory effects of inhaled corticosteroids in asthma are mediated entirely by local antiinflammatory effects in the airways, and it is possible that there is a systemic component, for example on bone marrow eosinophil precursors or on regional lymph nodes. Furthermore, it is not clear whether inhaled corticosteroids are distributed from their point of deposition in the airways to more peripheral airways via the local circulation. If this is the case then corticosteroids that are degraded by enzymes in the circulation may not reach small airways that are inflamed in asthma. Understanding the molecular mechanisms of action of corticosteroids has led to the development of a new generation of corticosteroids. As discussed above, a major mechanism of the anti-inflammatory effect of corticosteroids appears to be direct inhibition of transcription factors, such as NF-jB and AP-1 that are activated by proinflammatory cytokines (transrepression). By contrast, the endocrine and metabolic effects of steroids that are responsible for the systemic side effects of corticosteroids are likely to be mediated via DNA binding (transactivation). This has led to a search for novel corticosteroids that selectively transrepress, thus reducing the potential risk of systemic side-effects. Since corticosteroids bind to the same GR, this seems at first to be an unlikely possibility, but while DNA binding involved a GR homodimer, interaction with transcription factors AP-1 and NF-jB involves only a single GR. A separation of transactivation and transrepression has been demonstrated using reporter gene constructs in transfected cells using selective mutations of the glucocorticoid receptor. Furthermore, some steroids, such as the antagonist RU486, have a greater transrepression than transactivation effect. Indeed, the topical steroids used in asthma therapy today, such as FP and budesonide, appear to have more potent transrepression than transactivation effects, which may account for their selection as potent anti-inflammatory agents.130 Recently, a novel class of steroids has been described in which there is potent transrepression with relatively little transactivation. These “dissociated” steroids, including RU24858 and RU40066 have anti-inflammatory effects in vitro,131 although there is little separation of anti-inflammatory effects and systemic

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side-effects in vivo.132 This suggests that the development of steroids with a greater margin of safety is possible and may even lead to the development of oral steroids that do not have significant adverse effects.

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118. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001; 10:1110–12. 119. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Longterm effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353:1819–23. 120. Pauwels RA, Lofdahl CG, Laitinen LA et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N. Engl. J. Med. 1999; 340:1948–53. 121. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen T. Randomised, double-blind, placebo-controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease; the ISOLDE trial. Br. Med. J. 2000; 320:1297–303. 122. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343:1902–9. 123. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773–80. 124. Papi A, Romagnoli M, Baraldo S et al. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162:1773–7. 125. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354:456–60. 126. Niewoehner DE, Erbland ML, Deupree RH et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N. Engl. J. Med. 1999; 340:1941–7. 127. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am. J. Respir. Crit. Care Med. 2001; 163:1693–722. 128. Prakash A, Benfield P. Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs 1998; 55:145–63. 129. Taylor DA, Jensen MW, Kanabar V et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5-monophosphate in asthmatic patients. Am. J. Respir. Crit. Care Med. 1999; 160:237–243. 130. Adcock IM, Nasuhara Y, Stevens DA, Barnes PJ. Ligand-induced differentiation of glucocorticoid receptor trans-repression and transactivation: preferential targetting of NF-jB and lack of IjB involvement. Br. J. Pharmacol. 1999; 127:1003–11. 131. Vayssiere BM, Dupont S, Choquart A et al. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. Mol. Endocrinol. 1997; 11:1245–55. 132. Belvisi MG, Wicks SL, Battram CH et al. Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity. J. Immunol. 2001; 166:1975–82.

Chapter

Mediator Antagonists

53

K. Fan Chung and Peter J. Barnes National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK

Many inflammatory mediators are involved in the pathophysiology of asthma and COPD, suggesting that antagonists of mediator receptors or inhibitors of their synthesis would be beneficial in treatment. However, the large number of mediators involved and the redundancy of their effects means that inhibitors of single mediators have little or no clinical benefit. However, some mediators appear to be more important than others and inhibitors have some clinical effect. This is particularly true of anti-leukotrienes, the first new class of therapy for asthma introduced in more than 30 years.

ANTI-LEUKOTRIENES Anti-leukotrienes can be divided into cysteinyl-leukotriene (cys-LT) receptor antagonists which antagonize the effects of cyc-LTs, such as LTD4 and leukotriene synthesis inhibitors, which are inhibitors of 5-lipoxygenase (5-LO) enzyme that generates cys-LTs and LTB4 (Fig. 53.1). Antileukotrienes are mainly indicated for the treatment of asthma, and LTB4 inhibitors, such as LTB4 receptor antagonists, have no effect in asthma and are being considered for the treatment of COPD.

Allergen Exercise

Aspirin

PAF

Eos

MC

SO2

Arachidonic acid 5-lipoxygenase

ⴚ

Plasma exudation

5-LO inhibitors zileuton

Cysteinyl-leukotrienes (LTC4, LTD4, LTE4)

Cys-LT1 receptors

Mucus secretion

Fig. 53.1. Inhibition of leukotrienes.

Bronchoconstriction

ⴚ

LT-antagonists pranlukast zafirlukast montelukast

Eos recruitment

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5-Lipoxygenase inhibitors 5-LO is a critical enzyme involved in the generation of leukotrienes. Inhibitors of 5-LO may be classified as direct inhibitors of the enzyme, and indirect inhibitors which interfere with a nuclear membrane docking protein, 5-LO activating protein (FLAP), that is necessary for enzyme activation.1,2 Many hydroxamates and N-hydroxyureas are 5-LO inhibitors, and act by interfering with the redox state of the active binding site. Zileuton is the most extensively investigated and is the only 5-LO inhibitor available for prescription in asthma. The effect of zileuton is similar to that of leukotriene receptor antagonists, and zileuton inhibits allergen- and exercise-induced asthma, as well as aspirininduced asthma.3 It decreases airway hyper-responsiveness and inflammatory cells in nocturnal exacerbations of asthma.4,5 In addition, zileuton inhibits eosinophil influx induced by allergen challenge.6 Zileuton has a short duration of action, and has to be taken four times daily. Its side-effects are mainly on the liver, with frequent abnormalities of liver function tests. Other redox 5-LO inhibitors have been developed, but have not reached the market. Non-redox 5-LO inhibitors and inhibitors of FLAP (e.g. MK-886, MK-591, Bayx1005) have been developed,7,8 but there is no further clinical development. One theoretical advantage of the 5-LO inhibitors on the receptor antagonists is that they inhibit the formation of LTB4, and other 5-LO products, as well as cysteinyl-leukotrienes. This may make the drugs more applicable to other airway diseases where LTB4 may be involved. Cysteinyl-leukotriene antagonists The role of cys-LTs is discussed in Chapter 24 Cys-LTs cause airway obstruction through the stimulation of specific receptors termed the cys-LT receptor type 1 (Cyst-LT1). This a seven-transmembrane spanning, G-protein-coupled receptor, where the gene is mapped to the X chromosome.9 Signaling through cyst-LT1 occurs through stimulation of phosphoinositide hydrolysis.10 A second cysteinylleukotriene receptor, cyst-LT2, has also been characterized, and is found on pulmonary vessels, but its functional role is unclear.11 Many potent cyst-LT1 receptor antagonists are now available for the treatment of asthma, namely zafirlukast12 and montelukast13 in most countries, while pranlukast14 is currently available only in Japan and Korea. Only one anti-leukotriene is a 5-lipoxygenase inhibitor, zileuton, which is available in the USA.15 Effects of leukotriene receptor antagonists Leukotriene receptor antagonists in clinical use inhibit the bronchoconstrictor effects of inhaled cys-LTs. For example, a single 40 mg dose of zafirlukast produces a 100-fold shift of the LTD4 dose–response curve, and significant protection is present for 24 hours.16 Oral administration of leukotriene receptor antagonist inhibits both the early and late response to allergen, and exercise-induced asthma.17,18

Leukotriene receptor antagonists are able to cause bronchodilation, and their effect is additive to that of short-acting b2agonists.19,20 Effects of anti-leukotrienes in asthma In many studies of anti-leukotrienes such as zileuton, zafirlukast, pranlukast and montelukast, their effectiveness has been compared with that of placebo in short-term studies of 4–6 weeks’ duration.12–15 A greater increase in FEV1, a reduction in asthma medication use and in asthma symptoms, with an increase in morning peak flow has been demonstrated in mild-to-moderately severe asthma with some degree of airflow obstruction and usually in cohorts not on inhaled corticosteroid therapy. These findings have been confirmed and extended in longer studies in patients with mild-to-moderate chronic stable asthma with zileuton,21 zafirlukast,22 montelukast,23 all demonstrating clinical benefit. Their additive effect to the bronchodilation achieved with high doses of inhaled b-agonist19,24 indicate that they may have a place in the treatment of acute severe asthma. Clinical benefit has also been demonstrated with the addition of anti-leukotrienes to the patients with poor asthma control, already taking high doses of inhaled corticosteroids.25 Anti-leukotrienes may also reduce to a small extent the doses of inhaled corticosteroids required for asthma control.26 Anti-leukotrienes may reduce the risk of acute severe asthma exacerbations.27,28 The effects of anti-leukotrienes have been compared with these inhaled corticosteroids.29 In a recent meta-analysis, it was concluded that inhaled corticosteroids (250–400 lg beclomethasone dipropionate equivalent per day) provided better improvements in lung function and quality of life, as well as reduction in symptoms, night awakenings and need for rescue b-agonist. The rate of asthma exacerbations was similar when the anti-leukotrienes were compared with inhaled corticosteroids. The possible added benefit of adding leukotrienereceptor antagonist to inhaled corticosteroids has been evaluated. Addition of pranlukast to half the usual dose of inhaled corticosteroids in patients with moderate-to-severe persistent asthma led to maintained control, while the placebo group demonstrated less improved asthma control.30 Montelukast has been shown to maintain control of asthma in patients in whom removal of inhaled corticosteroids caused worsening of asthma.27 The combination of montelukast and inhaled corticosteroids provided the best control. However, adding montelukast in patients with severe asthma who are symptomatic despite high doses of inhaled corticosteroid provides no clinical benefit.31 Anti-leukotrienes are effective in blocking aspirininduced asthmatic responses,32 and may be particularly indicated in patients with aspirin-sensitive asthma. In addition, anti-leukotrienes are particularly effective in inhibiting exercise-induced asthma,18,33,34 without loss of protection with prolonged usage.35 In addition, leukotriene inhibitors may improve concomitant symptoms of seasonal rhinitis.36,37


Anti-inflammatory effects Cys-LTs can induce airway eosinophilia in patients with asthma.38 Leukotriene-receptor antagonists or synthesis inhibitors can reduce blood and airway eosinophilia associated with poorly controlled asthma,5,27 and reduce airway inflammation associated with allergen-induced airway responses.39 These results indicate that anti-leukotrienes can be considered as an anti-inflammatory therapy for asthma. Safety At the recommended doses, all leukotriene receptor antagonists have not resulted in non-respiratory symptoms nor laboratory abnormalities when compared with placebotreated groups. However, with zileuton, asymptomatic 3fold or greater increases in serum alanine-aminotransferase levels were found in 4.6% of patients receiving zileuton at the standard dose of 600 mg four times per day, compared with 1% of patients receiving standard asthma treatment together with placebo. These elevations usually occurred during the first 3 months of therapy, with sometimes normalization of the values despite continuation of treatment. A rare syndrome of Churg–Strauss, marked by circulating eosinophilia and evidence of tissue or organ infiltration and vasculitis by eosinophils in association with heart failure, cutaneous or gastrointestinal involvement, and peripheral neuropathy has been associated with treatment with zafirlukast and montelukast. Most patients developing Churg–Strauss syndrome have previously received oral glucocorticoid therapy or high-dose inhaled corticosteroid therapy to control their asthma.This may be due to unmasking of vasculitis of Churg–Strauss syndrome, as corticosteroids are tapered with the introduction of leukotriene receptor antagonist therapy.40 Role in COPD There is no evidence that cys-LTs are involved in COPD and no studies of leukotriene antagonists have been reported. LTB4 may play a role in the recruitment of neutrophils in COPD airways and therefore 5-LO inhibitors may have some therapeutic potential. No studies of zileuton or other 5-LO inhibitors in COPD have yet been reported.

A N T I H I S TA M I N E S Histamine mediates most of its effects on airway function via H1-receptors, suggesting that H1-antagonists may have therapeutic effects in airway disease. Non-sedating potent H1-receptor antagonists, such as terfenadine, fexafenadine, loratadine, desloratadine, ebastine and astemizole, may be given in large doses, but while these antihistamines have useful clinical effects in allergic rhinitis, they are far from effective in asthmatic patients, as demonstrated in a metaanalysis of clinical trials.41,42 The effects of antihistamines, even when taken in high doses, are small and clinically insignificant.43 Terfenadine causes about 50% inhibition of the immediate response to allergen, but has no effect on the

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late response.44 Antihistamines cause a small degree of bronchodilatation in asthmatic patients, indicating a certain degree of histamine “tone”, presumably due to the basal release of histamine from activated mast cells, as discussed above.45,46 Chronic administration of terfenadine has a small clinical effect in mild allergic asthmatic patients,47 but is far less effective that other anti-asthma therapies, so that these drugs cannot be recommended in the routine management of asthma. H1-receptor antagonists have not been found to be useful in more severe asthmatic patients.48 Some new antihistamines, such as cetirizine and astemizole have been shown to have beneficial effects in asthma,49,50 but this may be unrelated to their H1-antagonist effects.51 H2-antagonists, such as cimetidine and ranitidine, may be contraindicated in asthma on theoretical grounds, if H2receptors are important in counteracting the bronchoconstrictor effect of histamine. In clinical practice, however, there is no evidence that H2-antagonists have any deleterious effect in asthma. H2-antagonists are of theoretical benefit in patients with gastroesophageal reflux, as they reduce acid reflux, but in practice reflux is rarely associated with worsening of asthma. H3-receptor agonists may have some theoretical benefit in asthma, since they may modulate cholinergic bronchoconstriction and inhibit neurogenic inflammation. Although (R)-a-methylhistamine relaxes rodent peripheral airways in vitro,52 it has no effect when given by inhalation on airway caliber or metabisufite-induced bronchoconstriction in asthmatic patients, indicating that a useful clinical effect is unlikely.53 Anti-histamines have a useful effect in the treatment of rhinitis, and particularly the rhinorrhea. As a large proportion of patients with asthma have concomitant rhinitis, an H1-antagonist may help the overall management of asthma.54 While H1-receptor antagonists alone may be ineffective, some studies suggest that they may have some efficacy in combination with other antagonists. Thus an H1 receptor antagonist when added to an anti-leukotriene was able to inhibit the early and late response to allergen more effectively than the anti-leukotriene alone.55,56 Combination tablets of H1-antagonist and anti-leukotriene (such as montelukast and loratadine) are now in development. There is no evidence that antihistamines have any role in the treatment of COPD.

S E R O T O N I N A N TA G O N I S T S The evidence for involvement of serotonin in asthma is weak. There is no evidence that serotonin is a direct constrictor in human airways and it is not stored in and released from human mast cells, as in rodents. Serotonin receptor antagonists have been studied experimentally in asthmatic patients. Ketanserin, which antagonizes 5HT2 receptors and blocks the bronchoconstrictor effects of serotonin in animals, has no effect on airway function in asthmatic patients, but there is a small inhibitory effect

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on methacholine-induced bronchoconstriction.57 Inhaled ketanserin has no effect on histamine-induced bronchoconstriction, but has a small inhibitory effect on adenosineinduced bronchoconstriction, indicating a possible action on mast cells.58 Tianeptine, which enhances serotonin uptake by platelets, lowers the elevated plasma serotonin levels reported in patients with asthma and is associated with a reduction in asthmatic symptoms.59

THROMBOXANE INHIBITORS Although thromboxane production is increased in asthma and thromboxane analogs are potent bronchoconstrictors in asthmatic patients,60 there is no convincing evidence that thromboxane receptor (TP) antagonists or thromboxane synthase inhibitors are effective in asthma.61 A thromboxane synthase inhibitor (ozagrel) and a receptor antagonist (seratrodast) are used in the treatment of asthma in Japan, but their effects in asthma are minimal.62,63 There is no evidence that thromboxane antagonists are effective in COPD.

PA F A N TA G O N I S T S Although PAF mimics many of the pathophysiological features of asthma. Including induction of airway hyperresponsiveness, PAF antagonists have proved to be very disappointing in asthma therapy. Several potent PAF antagonists have now been tested in bronchial challenge and clinical studies. Apafant (WEB 2086) potently inhibits PAF effects on platelets and the intradermal effects of PAF.64 It also potently inhibits the effects of inhaled PAF on airway function.65 However, there was no effect on the early or late response to allergen or on airway hyper-responsiveness in patients with mild asthma.66 A 3-month study of oral apafant in patients with symptomatic moderate asthma failed to show any effect on lung function, symptoms or on rescue b2-agonist use.67 UK74505 inhibits inhaled PAFinduced bronchoconstriction and its inflammatory effects.68 However, modipafant (UK80067, the racemate of UK74505) had no effect on moderately severe asthmatics taking this drug for 4 weeks.69 A new potent and long-acting PAF receptor antagonist, foropafant (SR27417A), is effective in inhibiting systemic, cellular and pulmonary effects after PAF challenge in patients with mild bronchial asthma.70 However, this antagonist produces a modest, but significant, reduction in the magnitude of the allergen-induced late response, but no effect on the early response, allergeninduced hyper-responsiveness, or on baseline lung function.71 Another PAF antagonist,Y24180, has been shown to reduce airway responsiveness to inhaled methacholine in extrinsic stable asthmatics after oral administration for 2 weeks72 and to decrease the number of activated eosinophils in the bronchoalveolar lavage fluid of asthmatic patients.73 Overall, these clinical data with PAF antagonists suggest

that extracellular PAF plays little or no part in human allergic asthma, despite the convincing data in animal models of asthma. It is possible that intracellular PAF play a more important signaling role, so that inhibitors of PAF synthesis might have more clinical effect. Drugs that inhibit PAF and 5-lipoxygenase have also been developed and it is possible that these dual inhibitors might be more effective.74 There is no evidence that PAF is involved in COPD and no studies with PAF antagonists in this disease have been reported.

B R A D Y K I N I N A N TA G O N I S T S There is convincing evidence for the involvement of bradykinin in asthma, and in particular a role in sensitizing and activating airway sensory nerves. A peptide bradykinin antagonist [D-Arg0,Hyp3,D-Phe7]bradykinin (NPC567) was unable to inhibit the effect of bradykinin on nasal secretions, even when given at the same time as bradykinin,75 presumably because of rapid local metabolism. Icatibant (HOE 140, D-Arg[Hyp3,Thi6,D-Tic7,Oic8]bradykinin is a selective B2-receptor antagonist,76 which is not only potent but has a long duration of action in animals in vivo since it is resistant to enzymatic degradation. This antagonist is potent in inhibiting the bronchoconstrictor and microvascular leakage response to bradykinin77,78 and the effect of bradykinin on airway sensory nerves.79 Clinical studies with icatibant are limited, but there is some evidence that nasal application reduces the nasal blockage induced by allergen in patients with allergic rhinitis.80 In a clinical study of nebulized icatibant in asthma, there was a small improvement in airway function tests after 4 weeks of treatment, but no improvement in asthma symptoms.81 Recently non-peptide antagonists have been identified. WIN 64338 is a non-peptide B2-receptor antagonist that has been shown to block the bronchoconstrictor action of bradykinin in airway smooth muscle in vitro82 and more potent non-peptide antagonists, such as FR167344 have now been developed that have clinical potential.83 Although this compound is not very potent, it may be a lead for the development of more potent non-peptide drugs in the future.84

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(LTD4) antagonist (MK-571) in patients with asthma. Am. Rev. Respir. Dis. 1992; 146:358–63. Virchow CJ, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am. J. Respir. Crit. Care Med. 2000; 162:578–85. Lofdahl C-G, Reiss T, Leff JA et al. Randomized, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. Br. Med. J. 1999; 319:87–90. Laviolette M, Malmstrom K, Lu S et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am. J. Respir. Crit. Care Med. 1999; 160:1862–6. Barnes NC, Miller CJ. Effect of leukotriene receptor antagonist therapy on the risk of asthma exacerbations in patients with mild to moderate asthma: an integrated analysis of zafirlukast trials. Thorax 2000; 55:478–83. Ducharme FM, Hicks GC. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma. Cochrane Database Syst. Rev. 2000; 3(CD 002314). Tamaoki J, Kondo M, Sakai N et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am. J. Respir. Crit. Care Med. 1997; 155:1235–40. Robinson DS, Campbell DA, Barnes PJ. Addition of an antileukotriene to therapy in chronic severe asthma in a clinic setting: a double-blind, randomised, placebo-controlled study. Lancet 2001; 357:2007–11. Israel E, Fischer AR, Rosenburg MA et al. The pivotal role of 5lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am. Rev. Respir. Dis. 1993; 148:1447–51. Leff JA, Busse WW, Pearlman D et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N. Engl. J. Med. 1998; 339:147–52. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O’Byrne PM. Inhibition of exercise-induced bronchoconstriction by MK-751, a potent leukotriene-D4 receptor antagonist. N. Engl. J. Med. 1990; 323:1736–9. Coreno A, Skowronski M, Kotaru C, McFadden ER Jr. Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J. Allergy Clin. Immunol. 2000; 106:500–6. Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am. J. Respir. Crit. Care Med. 1995; 151:1734–9. Meltzer EO, Malmstrom K, Lu S et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J. Allergy Clin. Immunol. 2000; 105:917–22. Laitinen LA, Laitinen A, Haahtela T, Vikka V, Spur BW, Lee TH. Leukotriene E4 and granulocytic infiltration into asthmatics airways. Lancet. 1993; 341:989–90. Calhoun WJ, Lavins BJ, Minkwitz MC, Evans R, Gleich GJ, Cohn J. Effect of zafirlukast (Accolate) on cellular mediators of inflammation: bronchoalveolar lavage fluid findings after segmental antigen challenge. Am. J. Respir. Crit. Care Med. 1998; 157:1381–9. Wechsler ME, Garpestad E, Flier SR et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998; 279:455–7. van Ganse E, Kaufman L, Derde MP, Yernault JC, Delaunois L. Effects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur. Respir. J. 1997; 10:2216–24. Howarth PH. Assessment of antihistamine efficacy and potency. Clin. Exp. Allergy 1999; 29 (Suppl. 3):87–97.

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43. Simmons FER, Simons KJ.The pharmacology and use of H1-receptorantagonist drugs. N. Engl. J. Med. 1994; 330:1663–70. 44. Hamid M, Rafferty P, Holgate ST. The inhibitory effect of terfenadine and flurbiprofen on early and late-phase bronchoconstriction following allergen challenge in atopic asthma. Clin. Exp. Allergy 1990; 20:261–7. 45. Eiser NM, Mills J, Snashall PD, Guz A. The role of histamine receptors in asthma. Clin. Sci. 1981; 60:363–70. 46. Cookson WOCM. Bronchodilator action of the antihistamine terfenadine. Br. J. Clin. Pharmacol. 1987; 24:120–1. 47. Taytard A, Beaumont D, Pujet JC, Sapene M, Lewis PJ. Treatment of bronchial asthma with terfenadine: A randomised controlled trial. Br. J. Clin. Pharmacol. 1987; 24:743–6. 48. Wood-Baker R, Smith R, Holgate ST. A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma. Br. J. Clin. Pharmacol. 1995; 39:671–5. 49. Spector SL, Nicodemus CF, Corren J et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J. Allergy Clin. Immunol. 1995; 96:174–81. 50. Busse WW, Middleton E, Storms W et al. Corticosteroid-sparing effect of azelastine in the management of bronchial asthma. Am. J. Respir. Crit. Care Med. 1996; 153:122–7. 51. Walsh GM. The anti-inflammatory effects of cetirizine. Clin. Exp. Allergy 1994; 24:81–5. 52. Burgaud JL, Javellaud J, Oudart N. Bronchodilator action of an agonist for histamine H3-receptors in guinea pig perfused bronchioles and lung parenchymal strips. Lung 1992; 170:95–108. 53. O’Connor BJ, Lecomte JM, Barnes PJ. Effect of an inhaled H3receptor agonist on airway responses to sodium metabisulphite in asthma. Br. J. Clin. Pharmacol. 1993; 35:55–7. 54. Simons FE. Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma? Clin. Exp.Allergy 1999; 29 (Suppl. 3):98–104. 55. Roquet A, Dahlen B, Kumlin M et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am. J. Respir. Crit. Care Med. 1997; 155:1856–63. 56. Meltzer EO, Malmstrom K, Lu S et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: A randomized, placebo-controlled clinical trial. J. Allergy Clin. Immunol. 2000; 105:917–22. 57. Cazzola M, Assogna G, Lucchetti G, Cicchitto G, D’Amato G. Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma. Allergy 1990; 45:151–3. 58. Cazzola M, Matera MG, Santangelo G et al. Effect of the selective 5-HT2 antagonist ketanserin on adenosine-induced bronchoconstriction in asthmatic subjects. Immunopharmacology 1992; 23:21–8. 59. Lechin F, van der Dijs B, Orozco B et al. The serotonin uptakeenhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study. J. Clin. Pharmacol. 1998; 38:918–25. 60. Saroea HG, Inman MD, O’Byrne PM. U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release. Am. J. Respir. Crit. Care Med. 1995; 151:321–4. 61. O’Byrne PM, Fuller RW. The role of thromboxane A2 in the pathogenesis of airway hyperresponsiveness. Eur. Resp. J. 1989; 2:782–6. 62. Obase Y, Shimoda T, Matsuo N, Matsuse H, Asai S, Kohno S. Effects of cysteinyl-leukotriene receptor antagonist, thromboxane A2 receptor antagonist, and thromboxane A2 synthetase inhibitor on antigen-induced bronchoconstriction in patients with asthma. Chest 1998; 114:1028–32. 63. Manning PJ, Stevens WH, Cockcroft DW, O’Byrne PM.The role of thromboxane in allergen-induced asthmatic responses. Eur. Respir. J. 1991; 4:667–72.

64. Hayes J, Ridge SM, Griffiths S, Barnes PJ, Chung KF. Inhibition of cutaneous and platelet responses to platelet activating factor by oral WEB 2086 in man. J. Allergy Clin. Immunol. 1991; 88:83–8. 65. Adamus WS, Heuer H, Meade CJ, Kempe ER, Brecht HM. Inhibitory effect of oral WEB 2086, a novel selective PAFacether antagonist, on ex vivo platelet aggregation. Eur. J. Clin. Pharmacol. 1988; 35:237–9. 66. Freitag A,Watson RM, Mabos G, Eastwood C, O’Byrne PM. Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses. Thorax 1993; 48:594–8. 67. Spence DPS, Johnston SL, Calverley PMA et al. The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma. Am. J. Resp. Crit. Care Med. 1994; 149:1142–8. 68. O’Connor BJ, Uden S, Carty TJ, Eskra D, Barnes PJ, Chung KF. Effect of a potent and specific platelet activating factor (PAF) receptor antagonist on airway and systemic responses to PAF in man. Am. J. Resp. Crit. Care Med. 1994; 150:35–40. 69. Kuitert LM, Hui KP, Uthayarkumar S et al. Effect of the platelet activating factor antagonist UK 74,505 on the early and late response to allergen. Am. Rev. Respir. Dis. 1993; 147:82–6. 70. Gomez FP, Marrades RM, Iglesia R et al. Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study. Eur. Respir. J. 1999; 14:622–6. 71. Evans DJ, Barnes PJ, Cluzel M, O’Connor BJ. Effects of a potent platelet activating factor antagonist, SR27417A, on allergeninduced asthmatic responses. Am. J. Respir. Crit. Care Med. 1997; 156:11–16. 72. Hozawa S, Haruta Y, Ishioka S, Yamakido M. Effects of a plateletactivating factor antagonist Y 24180 on bronchial hyperresponsiveness in patients with asthma. Am. J. Respir. Crit. Care Med. 1995; 152:1198–202. 73. Mizuki M, Komatsu H, Akiyama Y, Iwane S, Tsuda T. Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor. Life Sci. 1999; 65:2031–9. 74. Cai X, Scannell RT, Yaeger D et al. (/)-Trans-2-[3-methoxy-4(4 - chlorophenylthioethoxy) - 5 - (N-methyl - N - hydroxyureidyl) methylphenyl]-5-(3,4,5trimethoxyphenyl) tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and plateletactivating factor receptor antagonist. J. Med. Chem. 1998; 41:1970–9. 75. Pongracic JA, Naclerio RM, Reynolds CJ, Proud D. A competitive kinin receptor antagonist, [DArg°, Hyp3, DPhe7]-bradykinin, does not affect the response to nasal provocation with bradykin. Br. J. Clin. Pharmacol. 1991; 31:287–94. 76. Wirth K, Hock FJ, Albus U et al. HOE 140, a new potent and long acting bradykinin antagonist: in vivo studies. Br. J. Pharmacol. 1991; 102:774–7. 77. Wirth KJ, Gehring D, Schölkens BA. Effect of HOE 140 on bradykinin-induced bronchoconstriction in anesthetized guinea pigs. Am. Rev. Respir. Dis. 1993; 148:702–6. 78. Sakamoto T, Elwood W, Barnes PJ, Chung KF. Effect of HOE 140, a new bradykinin antagonist, on bradykinin and plateletactivating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig. Eur. J. Pharmacol. 1992; 213:376–83. 79. Miura M, Belvisi MG, Barnes PJ. Effect of bradykinin in airway neural responses in vitro. J. Appl. Physiol. 1992; 73:1537–41. 80. Austin CE, Foreman JC, Scadding GK. Reduction by Hoe 140, the B2 kinin receptor antagonist, of antigen-induced nasal blockage. Br. J. Pharmacol. 1994; 111:969–71. 81. Akbary AM, Wirth KJ, Scholkens BA. Efficacy and tolerability of Icatibant (HOE 140) in patients with moderately severe chronic bronchial asthma. Immunopharmacology 1996; 33:238–42. 82. Scherrer D, Daeffler L, Trifilieff A, Gies J-P. Effects of WIN 64338, a non peptide bradykinin B2-receptor antagonist, on guinea-pig trachea. Br. J. Pharmacol. 1995; 115:1127–8.


83. Inamura N, Asano M, Hatori C et al. Pharmacological characterization of a novel, orally active, nonpeptide bradykinin B2 receptor antagonist, FR167344. Eur. J. Pharmacol. 1997; 333:79–86.

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84. Altamura M, Meini S, Quartara L, Maggi CA. Nonpeptide antagonists for kinin receptors. Regul. Pept. 1999; 80:13–26.

Chapter

Antibiotics

54

Sat Sharma and Nicholas Anthonisen Section of Respirology, University of Manitoba, Winnipeg, Canada

After 60 years of availability of antibiotics, surprisingly little is known about their role in obstructive airway diseases. A review of antibiotic therapy will necessarily involve a discussion of the role of bacterial infection in asthma and chronic obstructive pulmonary disease. This chapter presents an appraisal of the bacterial pathogens causing infective exacerbations, trials of antimicrobial therapy, individual antimicrobial agents and guidelines for their judicious use both in asthma and COPD.

ASTHMA A causal relationship between respiratory tract infection, especially viral infection and exacerbations of bronchial asthma is well established in the medical literature.1 In early prospective studies by McIntosh et al.,2 the relationship between exacerbations of wheezing and infection in hospitalized, previously diagnosed asthmatic children was investigated. A significant fraction (42%) was associated with viral respiratory infections, but not with pathogenic bacteria. Prospective studies on acute exacerbations of asthma in the adult population have suggested that approximately 10–20% of acute exacerbations may be attributable to acute viral infection. Berman and coworkers3 convincingly failed to show an association between bacterial respiratory infection and asthma. Transtracheal aspirates from 27 adult asthmatic patients with acute exacerbations showed no correlation between bacterial isolates and asthma symptoms. This suggested that overt bacterial infection of the lower respiratory tract does not contribute to the exacerbation of asthma. However, studies of older children and young adults have shown that infection with atypical bacteria e.g. Mycoplasma and Chlamydia may be responsible for exacerbations. In these studies, rhinovirus was the most important pathogen, followed by influenza A virus, Mycoplasma and Chlamydia.4–6 Several other studies have suggested a relationship between respiratory infections in infancy and development of asthma, although this hypothesis awaits more definite proof.

Mycoplasma Mycoplasma pneumoniae infection is commonly seen in children and young adults, although it may occur in all age groups.7,8 Seggev et al.9 showed that 21% of adults hospitalized with asthma exacerbation had evidence of a recent infection with mycoplasma. The illness may start with nonrespiratory symptoms such as headache and myalgias, and there is frequently pharyngitis and low-grade fever. A nonproductive cough, which tends to be prolonged and severe, is most characteristic. The diagnosis is made based on clinical history and chest radiograph, which shows patchy segmental pulmonary infiltrates. The definitive diagnosis is made by serological studies, particularly a doubling titer in convalescence. Antibiotic therapy is most effective if given within a few days of onset. Erythromycin or tetracycline are equally effective, and treatment is continued for 2–3 weeks. As well as causing exacerbations of asthma, M. pneumoniae pneumonia in nonasthmatics may well induce bronchial hyperresponsiveness which may be transient or persistent.10 Chlamydia The TWAR strain of Chlamydia (Chlamydia pneumoniae) has been shown to be a common cause of atypical pneumonia and is next in frequency to Mycoplasma.11,12 This is an infection primarily of adolescents and adults. The clinical manifestations are similar to those caused by M. pneumoniae. The severity of illness can be quite variable. The diagnosis is difficult to make, as commercial serological tests are generally not available. Chest radiograph shows findings similar to M. pneumoniae infection. Several studies have suggested that C. pneumoniae infection may precipitate acute bronchospasm and, in addition, may also be a risk factor for the development of chronic bronchospasm. The treatment of C. pneumoniae infection requires further study, but erythromycin or tetracycline may be beneficial if given for 10 days or more.

COPD Although a major cause of COPD is cigarette smoking, infectious organisms play several potential roles:13,14 (Chapter 30)

574


• Childhood respiratory infections can predispose to the development of COPD in later life.15,16 • Infectious organisms can chronically infect the bronchi and small airways contributing to progressive lung destruction (vicious circle hypothesis).17,18 • Acute exacerbations of COPD, caused by infection, result in considerable morbidity and are the leading cause of mortality in this disease. Despite extensive research over the past few decades, our understanding of lower respiratory tract infection in COPD is incomplete. Evidence for the role of bacterial infection in COPD, individual antimicrobial agents and an evidencebased approach to treatment of infection are discussed in the following sections. Normal microbial flora Various aerobic and anaerobic bacteria inhabit the mucosal surfaces of the upper respiratory tract. These include • • • • •

Neisseria sp., Moraxella catarrhalis, a variety of Streptococcus sp., Streptococcus pneumoniae, Hemophilus sp.

A variety of anerobic bacteria are present around the teeth and gums. Enterobacteriaceae and Pseudomonas sp. are isolated in about 15% of pharyngeal swab cultures taken from normal subjects.19,20 The major bronchi and smaller conducting airways in normal humans are relatively sterile. In a study of 25 normal subjects, samples from multiple sites in the lower respiratory tract were obtained with a protected brush specimen. Most cultures contained bacteria (38 out of 52 specimens, or 73%) similar to those found in the nasopharynx, but the colony counts were often so low (none to five colonies per culture plate) that the cultures probably indicated upper respiratory tract contamination rather than true lower respiratory tract colonization.21 The nasopharyngeal bacteria may be transiently aerosolized or aspirated into the lower respiratory tract but are removed by mucociliary clearance or cough. Pathogenic aerobic Gram-negative rods do not inhabit the upper airways mucosa in normal persons, but may do with alterations in health status such as alcoholism, diabetes, residing in a health-care facility.22 Subconscious aspiration of oropharyngeal secretions allows these microbes to enter the lower airways and alveoli and become a nidus for subsequent infection. Airway colonization in chronic bronchitis Pathogenic bacteria can be cultured from bronchial washings of some 82% of chronic bronchitics compared with normal bronchi which are nearly always sterile.23 Routine sputum cultures obtained from patients with chronic bronchitis commonly contain nonencapsulated H. influenzae and Strep. pneumoniae. In most clinical series, one or both of

these species have been recovered from approximately 30 to 50% of sputum specimens in patients with chronic bronchitis, and anaerobic bacteria were recovered in 17% of transtracheal aspirate specimens.24 Airway colonization with H. influenzae and Strep. pneumoniae is of uncertain significance. These bacteria tend to be present in sputum during quiescent intervals although the frequency of their recovery is increased during acute infectious episodes. Development of purulent sputum is not specifically correlated with the presence of one or the other of these bacteria in quantitative cultures.

THE DIAGNOSIS OF ACUTE E X A C E R B AT I O N O F C H R O N I C BRONCHITIS Clinical diagnosis There is no universally accepted definition of an acute exacerbation of COPD (AECB). AECB is basically a clinical diagnosis. A descriptive definition could be: “an acute, episodic deterioration superimposed on stable COPD with increased dyspnea, reduced daily performance, with or without changes in sputum volume and color, coughing, or body temperature; and/or alterations in mental status”.17,18 The three cardinal symptoms (Table 54.1) (Winnipeg Criteria)25 are • increased dyspnea, • increased sputum purulence, • increased sputum volume. These features should be present without an objectively documented cause such as pneumonia, congestive heart failure, myocardial ischemia, upper respiratory tract infection, recurrent aspiration and pulmonary embolism. These conditions may resemble an acute exacerbation and need to be excluded. Laboratory diagnosis of AECB Microbiological data may play a role in diagnosis and management but must be interpreted with caution. One problem Table 54.1. Classification of exacerbations

Type

Characteristics

1

Increased dyspnea, sputum volume and sputum purulence (all 3 symptoms present)

2

2 of the above 3 symptoms present

3

1 of the above symptoms present + at least 1 of the following: upper respiratory tract infection in the last 5 days, fever, increased wheezing and increased cough

Antibiotics

575

is that pathogenic bacteria can be cultured from respiratory secretions in as many as 80% of patients with stable chronic bronchitis, therefore, bacterial colonization complicates the laboratory diagnosis of bacterial infection.

agents recommend early use of these agents based on clinical suspicion and not laboratory confirmation, and COPD patients should probably be treated in the same manner.

Sputum Gram stain The sputum Gram stain has been advocated as a means of objectively demonstrating an increase in bacterial flora and bronchial inflammation. In one study, Baigelman et al.26 compared more than 1000 sputum Gram stains from patients with chronic bronchitis during stable states, acute bacterial infections, acute allergic exacerbations, and recovery from acute bacterial exacerbations. The results showed that fewer than two bacteria per oil-immersion field were found in stable patients, while during exacerbations the sputum revealed 12 organisms per oil-immersion field resembling H. influenzae, eight organisms resembling Strep. pneumonia or 18 organisms resembling M. catarrhalis. Over 99% of patients with chronic bronchitis without clinical evidence of infection fell below these thresholds.These findings suggest that an upper limit may be set for the numbers of micro-organisms seen on a Gram stain of sputum from patients with COPD in the absence of a bacterial infection. Some clinical trials have incorporated the Gram stain as a means of distinguishing bacterial from nonbacterial causes of acute exacerbation. Despite its potential, sputum Gram stain does not alter therapy and is not currently recommended as a routine test.

Chest radiograph Chest X-rays are not routinely recommended in mild to moderate exacerbations, as there is usually no change from baseline. Chest radiography should be performed if the patient has high fever, new abnormalities on auscultation, or is severely ill as characterized by worsening hypoxia, hypercapnia or right heart failure.

Sputum culture The routine sputum culture is less useful than the Gram stain and is often misleading. Studies examining sputum cultures before, during, and after bacterial exacerbations have correlated poorly with clinical parameters and Gram stain results.26,27 Gram-negative bacilli have often been recovered in sputum culture even when they are absent on Gram stain, and clinical recovery has occurred even without specific Gram-negative antibiotic therapy. In one study, more than 50% of sputum cultures remained positive long after clinical recovery.28 The sputum culture may be contributory and should be considered when there is: • failure of initial antibiotic therapy, • patients with chronic bronchial sepsis requiring more than four courses of antibiotic therapy per year, • severe illness or suspected pneumonia. Viral studies Viruses apparently do not play an important role in causing acute exacerbations. Therefore, virological stains, cultures and antibody assays are not routinely recommended in the management of chronic bronchitis because of the expense and relatively low yield. Rapid antigen detection has lowered the turnaround time for identifying respiratory viruses, but the value of these tests in AECB has not been established. Recently chemotherapeutic agents for influenza have become available. The guidelines for use of anti-influenza

ROLE OF BACTERIAL INFECTION COPD is characterized by periodic exacerbations, and acute respiratory infection was the most common cause of death in a prospective study of patients with COPD.29 The role of infection in acute exacerbation of chronic bronchitis is, however, somewhat controversial. Antibiotics are frequently prescribed to these patients but efficacy of this treatment was questioned by Tager and Speizer.30 Several investigators have found increased numbers of bacteria and neutrophils in the sputum during exacerbations.31–33 In some studies34 M. pneumoniae has been isolated in 1 to 10% of patients with acute infections. Bacteria may be the primary cause of the exacerbations; alternatively, they may act as secondary invaders after acute viral or mycoplasma infection. However, evaluating the role of bacterial infection in exacerbations has been a difficult task for a variety of reasons. As the upper airways of many patients with COPD are colonized by H. influenzae, Strep. pneumoniae and M. catarrhalis, the expectorated sputum during exacerbations may be inconclusive. Serologic studies A causal relationship between bacterial infection and acute exacerbation can be inferred by the appearance of an acute antibody response in serum to these bacteria. Documenting a serological response to an organism may demonstrate existence of infection with that organism, but these studies have shown conflicting results. Some have shown no difference between patients with chronic bronchitis and control subjects, other studies have revealed higher titers of antibody to H. influenzae,35 in the serum of patients with chronic bronchitis. However, there was no relationship of titers to exacerbations.36 Such studies generally used the whole organism preparations of unrelated strains as the antigen for serologic studies, and therefore measured a mixture of antibodies to a mixture of antigens. Future studies may utilize antibody response to more specific surface antigens of bacteria to establish the importance of bacterial infection in COPD. Trials of antibiotic therapy in acute exacerbation Another approach to assessing the role of bacterial infection in exacerbations of COPD is to consider the effect of antibiotics on the clinical response (Figs 54.1 and 54.2). A positive

576


response to a specific antibiotic prescribed for an exacerbation by a specific organism would provide evidence of a pathogenic role for the bacteria. In a landmark study, Anthonisen and co-workers25 demonstrated, for the first time, that patients could be stratified according to the symptoms to predict a response to antimicrobial therapy. In patients with at least two of the three cardinal symptoms of acute exacerbation (increased sputum purulence, increased sputum volume and increased dyspnea), broad-spectrum antibiotics (amoxicillin, trimethoprim-sulfamethoxazole, doxycycline)

80 70

Placebo group Antibiotic group

P

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