Bronchial Asthma, Second Edition

Severe Asthma (Fatal Asthma) 1

Bronchial Asthma

Bronchial Asthma Second Edition

D Behera MD (Medicine) FCCP FNCCP FICP FICA MNAMS (Medicine) Dip. NBE (Respiratory Medicine)

Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh (India)

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi

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Bronchial Asthma © 2005, D Behera All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.

First Edition: 2000 Second Edition: 2005 ISBN 81-8061-434-4

Typeset at JPBMP typesetting unit Printed at Gopsons Papers Ltd, A-14, Sector 60, Noida 201 301, India

Dedicated to the loving memory of my distinguished teacher late Dr SK Malik

VALLABHBHAI PATEL CHEST INSTITUTE UNIVERSITY OF DELHI, P.O. BOX NO. 2101 DELHI-110 007, INDIA Tel. (O) (R) Fax E-mail

Dr. V.K. Vijayan MD (Med), Ph D (Med), D Sc, FAMS FCAI, FNCCP (I), FICC, FCCP (USA)

Director

: 91-11-7666180 : 91-11-7667027 : 91-11-7667420 : [email protected]

July 8, 2004 Date: ...........................

Foreword The prevalence of bronchial asthma, a major public health problem is increasing worldwide. Several studies have demonstrated that there is an increase in morbidity and mortality from bronchial asthma. Over and under treatment of asthma may be responsible for high mortality rates. Until recently bronchospasm that results from hyperresponsiveness of the airways to multiplicity of stimuli has been regarded as the main cause of airway dysfunction in asthma. Bronchial asthma is now considered as a chronic inflammatory disease of the airways. This realization that inflammation is the key factor in the pathogenesis of asthma is reflected in the change in asthma therapy with emphasis on inhaled anti-inflammatory drugs. There are many controversies in the management of bronchial asthma especially the role of immunotherapy. Many new drugs are under development and yet there is no cure for asthma. In a country like India with different socio-cultural diversities and beliefs, the treatment of asthma varies and the existence of different systems of medicine in our country complicates the treatment issues. Prof D Behera, a renowned Pulmonologist of our country and Professor of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research, Chandigarh has taken up the challenge of bringing out the updated second edition of his book, “Bronchial asthma”. The tremendous response to the first edition of his book is a testimony to the academic excellence of this book. The second edition has 21 chapters including epidemiology, pathophysiology, clinical presentation, complications, management and various guidelines. This revised edition is a comprehensive review of bronchial asthma and provides practical information for Physicians and Pulmonologists who have to take appropriate diagnostic and therapeutic decisions in patients with bronchial asthma. I congratulate Dr Behera for his tireless efforts to bring out the second edition of this book.

Dr VK Vijayan Director

Preface to the Second Edition Bronchial asthma is a common respiratory disorder affecting approximately 3-5 percent of the population, although there is a wide variation in its prevalence in the world, even in the same country at different parts. Over the years our understanding about the disease has changed. One of the major changes in our thinking about the pathophysiology of the disease is that the disease is inflammatory in nature rather than the earlier simplistic view of it being a simple bronchospastic disorder. A number of cytokines and mediators take part in its causation. Accordingly the approach to management of asthma has also changed. A number of guidelines have come up in recent years and there is a constant renewal in some of the concepts. Although there is no guideline for adult Indian patients, the same is given for children. The chapter on bronchial asthma in children is not complete in all aspects, but it will give a brief account of the same for the pulmonary physician. This edition has brought out some of these changes. Further, the references are updated with Vancouver style. D Behera

Preface to the First Edition Bronchial asthma is a common disease affecting nearly 3 to 5 percent of the population. Although incidence- and prevalence-wise the disease is not more common than tuberculosis in this country, the major difference is its recurring nature with periods of remissions and exacerbation. In some cases life long, and in many cases most of the times, medications with anti-asthma drugs will be required for symptom-free life. This is a major contrast to tuberculosis where treatment for 6 to 9 months will cure the disease. Earlier concepts about bronchial asthma, that it is a bronchospastic disease, have changed in recent years, wherein it is proved that it is an inflammatory disease. A wide array of cells with a number of cytokines take active role in the pathophysiology of the disease. The idea of writing this book came to my mind while I was preparing for the second edition of my textbook entitled Pulmonary Medicine. I thought a chapter on Bronchial Asthma in a textbook may not give sufficient justification to cover the explosion of recent knowledge acquired about the disease, particularly our understanding of its pathophysiology and approach to management. D Behera

Contents 1. Epidemiology ........................................................................................................................ 1 2. Aetiology ............................................................................................................................... 14 3. Pathophysiology of Bronchial Asthma ............................................................................ 40 4. Pathology .............................................................................................................................. 86 5. Clinical Presentation of Bronchial Asthma ..................................................................... 92 6. Diagnosis of Bronchial Asthma ........................................................................................ 98 7. Prognosis of Bronchial Asthma ...................................................................................... 114 8. Complications of Bronchial Asthma .............................................................................. 117 9. Management of Bronchial Asthma ................................................................................ 127 10. Pharmacologic Management of Asthma ....................................................................... 134 11. Inhalation Therapy ........................................................................................................... 176 12. Therapeutic Approach in Patients with Asthma I. Chronic Bronchial Asthma ........................................................................................... 183 13. Therapeutic Approach in Patients with Asthma II. Acute Severe Asthma (SA) ......................................................................................... 208 14. Management of Asthma with Special Problems ......................................................... 235 15. New Treatment Modalities/Newer Drugs for Bronchial Asthma ............................ 247 16. New Guidelines for Asthma Management (Non-pharmacological Management) ............................................................................ 256 17. New Guidelines for Asthma Management (Pharmacological Management) ........ 265 18. New Guidelines for Asthma Management (Acute Asthma) ..................................... 276 19. Alternate Treatments in Asthma .................................................................................... 293 20. Severe Asthma (Fatal Asthma, Refractory Asthma) .................................................... 306 21. Asthma in Children .......................................................................................................... 314 Index ..................................................................................................................................... 337

1 Epidemiology DEFINITION Asthma is a disease whose presence dates back to at least the time of Hippocrates who noted a condition of ‘deep and heavy breathing’. The Greeks had labelled this condition as “asthma”, the meaning of which was panting. Bronchial asthma is difficult to define since it is not one homogenous condition and because there is no one objective measurement or series of measurements that can be used to make the diagnosis of asthma. A widely acceptable definition still remains elusive ever since it was first defined in 1959 by an expert study group during the CIBA Foundation Guest Symposium.1 The Global Initiative for Asthma (1995) defines asthma on the basis of its pathogenesis (vide infra). The clinician, immunologist, physiologist, and pathologist all have their own perspective of asthma, and all these perspectives are difficult to merge into a comprehensive definition sufficiently specific to exclude other diseases. Earlier definitions were non-specific and therefore the condition was both under and over-diagnosed.2,3 However, during the past one-decade there have been major changes in the concepts of pathophysiology of asthma. Whereas the condition was previously considered as a bronchospastic disorder only, it is now recognised that asthma is primarily an inflammatory disease. The current definition incorporates both of these components and a generally agreed-on working definition of asthma is as follows:4 “Bronchial asthma is a disease characterised by (i) airway obstruction (airway narrowing) that is reversible (but not completely so in some patients) either spontaneously or with treatment; (ii) airway inflammation; and (iii) airway hyperresponsiveness to a variety of stimuli”. Subsequently, the Consensus Report5 describes asthma as a “Chronic inflammatory disorder of the airways in susceptible individuals, inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often reversible, either spontaneously or with treatment.” PREVALENCE The prevalence of asthma is not exactly known. This is because the precise way how to define asthma in population studies is defined differently. Questionnaires are the most practical tools to use in screening population for asthma. Such questionnaires have been validated to assess the ability of individual questions and combination of questions to predict which individuals in the population have either clinical diagnoses of asthma or non-specific bronchial hyperreactivity to agents like methacholine or histamine.6 Unfortunately,

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Bronchial Asthma

physician-diagnosis of asthma and bronchial hyperreactivity are not particularly good “gold standards” for identifying asthma. While the former can miss milder forms of asthma, the later is present in many people without asthma.6-8 To avoid these limitations, many studies now use questionnaires.6,9-11 In general, questions about “ever having asthma”, “ever having asthma diagnosed by a physician”, and “having wheezing during the previous 12 months” have been the questions with best sensitivity and specificity for prediction of the flawed gold standards. These questionnaires, of course are being used most often in recent studies. However, earlier surveys will have flaws as mentioned, and the difference prevalence rates in different studies in the past can be explained in part due to these methodological difficulties. Nonetheless, in many countries, the prevalence of asthma has increased in recent decades.12,13 The disease has reached epidemic proportions affecting 155 million individuals in the world. About 15% (one out of seven) of children in United Kingdom wheeze and similar number suffers from the related disorders of atopic dermatitis. The prevalence has risen over the past 30 years all over the world particularly in all Westernised societies perhaps as a result of the loss of childhood infections.14 While asthma is one of the less common causes of death, the magnitude of the problem is evident from the fact that during a 10 years period from 1978 to 1987, there were 1,87,000 deaths in USA, Canada, England, Wales, France, West Germany, and Japan.15,16 Since the definition of asthma was varying, the available statistics is viewed with some skepticism. In general, it seems that asthma remains under diagnosed especially during childhood. There is some evidence that bronchial asthma is increasing in a number of countries particularly New Zealand, UK and USA.15,17 An estimated 10 million persons in the USA had asthma. In the general population, asthma prevalence rates increased 29% from 1980 to 1987. Bronchial asthma is the most common chronic respiratory disorder among all age groups with a reported prevalence of 5 to 10%.18 During the last decade, studies from different countries keeping appropriate statistics have reported a significant rise in asthma morbidity and mortality.18-28 In the United States, approximately 17 million people have asthma (and asthma related symptoms) account for 10 million missed school days, > 1.5 million emergency department visits, approximately 500,000 hospitalisations and > 5000 deaths annually. In 1998, the direct and indirect expenditures for the treatment of asthma in the United States were approximately $11.3 billion.29 The overall 1988 asthma death rate was 1.9/100,000 persons with much lower rates in persons younger than 45 years, rising dramatically with increasing age.18-30 Asthma is the most common chronic disease of children in USA.31,32 About 6 million children in the United States have asthma compared to 3.1 million in 1984, an increase of 80%. Annually, asthma accounts for 12 million primary care visits, 1.6 million emergency department visits, 11 million missed school days, 200,000 hospital admissions, and 150 paediatric deaths.33 Improved personal behaviour and medical care have a limited sustained impact on childhood asthma until basic environmental issues are modified.34 Various other statistics also prove that both asthma and allergic rhinitis have increased in recent years. The effect of these disorders on children and adults is considerable in terms of morbidity and lost productivity resulting from the disease and its treatment .35,36 In addition, hospitalisation due to asthma and deaths attributed to asthma are increasing, despite the availability of effective drugs.37 From 1982 to 1992, the overall annual age-adjusted prevalence rate of self reported asthma increased 42% (from 34.7 per 1,000 people to 49.4

Epidemiology 3 per 1,000 people). Even more alarming is the observation that during this period, the overall annual age-adjusted death rate for asthma increased 40%.38 One disadvantage with these statistics is that these are based on informations obtained by questionnaire and in most cases identical questions were not used at each survey.39 However, from available data, both morbidity and mortality from asthma in New Zealand are amongst the highest in the world.40 A survey of 12-year-old school children carried out in New Zealand and South Wales41 revealed a higher prevalence in the former (17%) than in the later (12%). New Zealand children were also more likely than the Wales children to have a history of “wheeze ever” (27% vs. 22%) and wheeze brought on by running (15% vs. 10.5%). The sex ratio of asthmatic and wheezy children was very similar in the two countries. The overall prevalence of asthma is estimated at 13.7%, bronchial hyperresponsiveness at 13.4%, and atopy at 31.1% in the age range of 13 to 18 years. The prevalence of bronchial hyperresponsiveness in those without asthma symptoms is 3%. Both current asthma symptoms and bronchial hyperresponsiveness are more common among females. In a study to determine the prevalence of asthma in cohorts of Finnish young men in the period 19261989, Haahtela et al42 found that during 1926-1961 the prevalence was steady at between 0.02 and 0.08%. Between 1961 and 1966, however, a continuous, linear rise began, the prevalence increasing from 0.29% in 1966 to 1.79% in 1989, that is, representing a six-fold increase. The rise is 20 folds compared with that in 1961. Much of this increase appears real and not merely due to an improvement in the methods of diagnosis over these years. A review of the available published figures for children in United Kingdom revealed prevalence for “wheeze in the previous year” of between 4.9 and 15% and “wheeze ever” between 9.9 and 24.9%. Figures for “asthma ever” varied between 1.2 and 5%. A simple flow diagram of the natural history of asthma17 based on the prevalence of childhood wheeze in Australia is shown in Figure 1.1.

Fig.1:1. Natural history of bronchial asthma in Australian children. The hatching represents the approximate percentages in each group who are atopic and who have bronchial hyperresponsiveness. The top line indicates the group who are atopic and who wheeze while the bottom line represents those without evidence of (a) allergy; (b) wheeze; (c) and persistent wheeze

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The Figure 1.1 also shows the approximate number of people entering adult life with persistent wheeze. This study showing natural history of asthma is based on the prevalence of atopy as measured by skin tests and the prevalence of childhood wheeze in Australia. A number of studies from around the world show that the prevalence of atopy is between 3050% in children.43-46 In addition, the number of children who have wheezed at sometime is around 25-30%.47-49 Most children with persistent wheeze are atopic.50,51 About 7% of the patients have persistent asthma as reported from Australia by Woolcock et al.18 Adequate prevalence data from most developing countries is not available either for children or adults. Although it is a general perception that bronchial asthma is a very common problem in India, apart from tuberculosis, authentic information is not available regarding its prevalence or incidence. Whatever data is available, it lacks the uniformity of definition, problems of sample size, and analytical methodology used. From different studies, the prevalence of asthma has been reported to be 1.2 to 6.2% in adults in the western world. In a survey of respiratory symptoms in India, the prevalence of asthma has been reported to be 0.6 and 3.2% in rural and urban women respectively. The same in urban males has been 4%.52-55 The prevalence was reported to be 1.76% in an urban population in the mid sixties.56 It was also reported by the same investigators that the prevalence in the morbidity surveys of government employees and their families in Delhi was 1.8%.56 However, in recent years two studies from Mumbai and Northern India are available.57,58 The study from Greater Mumbai revealed a prevalence of 3.5% by physician diagnosis and 17% using a very broad definition including those with asymptomatic bronchial reactivity. Prevalence of asthma in Mumbai was similar in males and females (3.8 and 3.4% respectively). In the North Indian survey, a validated questionnaire was used tested against physician—diagnosed asthma and the prevalence in the population was assessed.58 The true population prevalence was reported as 3.94% in urban and 3.99% in rural males and 1.27% in both urban and rural females. A recent study from Delhi59 estimated the risk of asthma in children to be very high.59 Prevalence of asthma symptoms in children was determined in the International Study of Asthma and Allergies in Childhood (ISAAC) in the age groups of 6-7 and 13-14 years using a standardised sample survey.60,61 Prevalence of “ever asthma” varied from 1.8 to 12.4% with an overall figure of 4.5%. The figure of “ever asthma” in 12 months is not strictly same as prevalence of asthma in adults. The overall prevalence of asthma in children of 10-18 years age at Chandigarh was 2%, using the same methodology as in adults.58,62 Since morbidity depends, at least partly, on prevalence, the trends should be similar. Other indices of morbidity such as days lost from work and restriction in lifestyle, nocturnal disturbances with symptoms and hospital admission rates confirm the trends and extent of problem due to asthma. It is clear that the most dramatic increase in admission to hospitals has been in children. All the data collected on the basis of above informations indicate continuing extensive morbidity from asthma, although more effective treatment may be modifying this. MORTALITY Statistics for deaths from asthma yield widely variable mortality rates between countries.15 Increasing asthma mortality was first highlighted in the early-mid 1960’s63,64 when there was a dramatic increase in asthma deaths in England and Wales, Australia and New Zealand. This was most apparent in children 10-14 years, but was also apparent for all age groups,

Epidemiology 5 particularly in 5-34 age group. The range of such mortality between 1985-1987 in 20 different countries has been depicted in Figure 1.2.15 The intriguing points about asthma mortality are that there are sizeable differences between countries and that death rates from asthma are gradually increasing in most western countries. An analysis of asthma mortality rates in Western countries as well as developed nations such as the United States, Canada, New Zealand, France, Denmark, and Germany has revealed a distinct rise in rates during the 20 years period prior to 1990. Recent trends, however, suggest a stabilisation of mortality rates due to asthma in United States. From 1977 to 1996, there was a rise in deaths due to asthma in the USA from 1,674 (0.8 per 100,000) to 5,667 (2.1 per 100,000).65 The mortality rate increased by 6.2% annually during the 1980’s and faster among subjects aged 5 to 14 years than those aged 15 to 34 years. Among Whites, the mortality has increased more in female subjects than male subjects. The death rates for asthma among African Americans is three times higher than among White Americans. The trend in other countries is less apparent.66-72 In some countries, the rates have doubled over the past 10 years. Two countries, the UK and New Zealand, have experienced “epidemics” of asthma deaths; one epidemic in 1960’s in the UK and two in New Zealand; one in the 1960’s and the other in the 1970’s. At the peak of the New Zealand epidemic in the 1970’s, the mortality rate for asthma was approximately 10 times the rate in the USA. However, the rate has shown a declining trend since 1979. However, this trend is less apparent in other countries.73,74 For example, asthma mortality rate in Israel during the years 1980 to 1997 was low and stable. Most of the patients still died outside the hospital. There was no difference in the asthma death rate and place of death between Jews and Arabs, suggesting that the population genetic predisposition is not likely to be a risk factor for mortality.75

Fig. 1.2: Asthma mortality in 20 different countries of the world. The rate is per 100,000 population (1985-1987)

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Bronchial Asthma

All statistics shown are derived from published population and mortality data available from the national statistics centres in each country. West Germany reported over 9 deaths per 100,000 followed by Norway, New Zealand, and Sweden. Netherlands, USA, and Hong Kong reported asthma mortality rates less than 2/100,000. The reasons for the trends in mortality due to asthma and for the sizeable differences between countries are not clear.76-79 The increase in mortality in most countries cannot be primarily due to an increase in the prevalence of asthma as the rise in mortality is disproportionately greater than that of the prevalence.80 In the last decade, though, the stabilisation of mortality, and even a decrease in mortality, from asthma has been reported.81-84 A number of reasons have been proposed including: (i) Partial contribution from the shift of International code of death (ICD-8 to ICD-9). Due to this, the term asthmatic bronchitis was coded as asthma rather than bronchitis; (ii) Shifts in physician diagnosis patterns, especially from bronchitis to asthma in the 0-5 years age group and from COPD to asthma in smokers past middle life. There is clearly some misclassification of asthma deaths with over-reporting over age 50 and under-reporting in the younger age groups; (iii) An increase in the prevalence and or severity of asthma; (iv) Increased diagnosis of asthma; and (v) Adverse drug effects. In the 60’s overuse of adrenaline in Europe and currently the use of fenoterol have been postulated to be contributory to the mortality due to asthma. However, these postulates have not been confirmed.85-89 Other possible contributors are delay in care, poor compliance, lack of access to health care, theophylline toxicity, besides the overuse of β-agonists.90-92 Most likely cause of the recent decline in asthma deaths is the more judicious use of prophylactic treatment, particularly inhaled steroids, as a possible factor.93,94 Race and socioeconomic status may influence the outcome of an asthma attack.95,96 Hospital admission rates for asthma are high and have increased in the last few decades.97,98 However, some patients die before they can receive medical care.98-100 The exact proportion of deaths occurring outside the hospital and its association with genetic, environmental or social factors is not clear. An estimated 15 million persons in the United States have bronchial asthma, and the number is increasing. Although asthma is generally treated in an outpatient basis, increased hospitalisation rates have been observed. Hospitalisation rates and episodes of asthma have increased in all age groups particularly in boys up to 4 years old.101 Hospitalisation rates are twice as common in African Americans as White Americans.102 Causes for the Increase in Asthma Mortality Besides the above mentioned reasons, many other causes have been advocated for the increase in asthma mortality and morbidity and they include allergen exposure, air pollution, medication use, inadequate access to health care, increased incidence of viral infections, and physician management of asthma (Discussed subsequently). The risk of death due to asthma appears to predominate in large urban areas with high rates of poverty. Risk of hospitalisation for children with asthma is 8.4 times greater in areas with population of lower socioeconomic status and 5.3 times greater in areas with a larger African American population.103 Lower socioeconomic status and African American race are strong risk factors for hospitalisation and mortality from asthma. NATURAL HISTORY OF BRONCHIAL ASTHMA Over the last few decades the natural evolution of asthma from childhood to adulthood has been the subject of many reviews and studies and more than 50 such well-designed

Epidemiology 7 publications highlight the subject.104 It was long believed that the prognosis for asthma originating in infancy or childhood was good, and that in most patients the symptoms would resolve by the age of puberty. However, a review of literature shows that not all patients become asymptomatic in adulthood. In fact, asthma symptoms persist in 30-80% of adult patients. Although epidemiological studies have shown a fair chance of either “remission” or a reduction in asthma symptoms between the ages of 10 and 20 years,105-108 and most population based and clinical studies have also shown a reduction in asthma symptoms with age, the relapse rates after a symptom-free interval is also high.107,109 It has also been shown that, even in the absence of asthma symptoms, subjects may still have obstructive lung functions and increased bronchial hyperresponsiveness.110-116 No definite information is available about the progression of asthma through childhood and adolescence.117 Martinez118 studied the natural history of wheezing in children aged 0-6 years and found that approximately half of the children experienced wheezing illness at sometime during the study period. In some of them wheezing occurred early in life but resolved by the age of three years (transient early wheezing), some experienced wheezing illness between the ages of three and six years (late onset wheezing) and others had wheezing illness throughout the entire study period (persistent wheezing). Different risk factors were associated with these results. Children with transient early wheezing had reduced pulmonary function, as measured by functional residual capacity shortly after birth and before any lower respiratory tract illness had occurred. The risk was also increased in children whose mothers smoked during pregnancy. Congenitally smaller airways may therefore predispose children to wheezing illness early in life. Children with late and persistent wheezing are more likely to be atopic as assessed by elevated serum IgE levels and skin test reactivity, asthmatic mothers, and their lung function decreased after the age of one till they are six years of age. This study suggests the presence of two distinct wheezing illnesses up to the age of six years. As discussed above, there are varying reports about the persistence/disappearance of asthma symptoms in adolescence. However, some reports suggest that up to 80% of asthmatics may become asymptomatic during puberty.119,120 In a cohort study of Australian school children121 tested initially at the age of 8-10 years and then again at 12-14 years of age, the persistence of bronchial hyperresponsiveness at 12-14 years of age was found to be related to the severity of disease at 8-10 years of age, the atopic status of the child, and parental history of bronchial asthma. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness at 8-10 years of age lost their increased response by the age of 12-14 years. Only 15.4% of children with severe or moderate bronchial hyperresponsiveness at the initial assessment had normal levels of bronchial responsiveness at the later assessment. Whether the decline in reported symptoms is real or the result of the children increasingly denying their illness as they reach puberty remains to be clarified. The reduced bronchial responsiveness may favour the hypothesis of a real reduction in the activity of the disease or higher doses of the provocative agents like histamine or methacholine may be needed to provoke hyperresponsiveness in larger airways of rapidly growing children. As against the above figures, the prevalence of bronchial asthma in adolescents in 4 different countries 122 varied from 2.8 to 38% at different ages and is summarised in Table 1.1.123-126 This shows a significant number still will have asthma in adolescence.

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Bronchial Asthma Table 1.1: Prevalence of bronchial asthma in adolescents

Country New Zealand Australia Netherland Finland

Year of study 1991 1992 1989 1991

Age (years)

Prevalence (%)

12-15 12-15 10-23 15-16

32-38 16.5 19 2.8

Several other prospective studies,127-130 which separately examined subjects aged 10 to 19, 20 to 40, and over 60 years, revealed that asthma was frequently preceded by lower respiratory tract symptoms, sometimes for years. Among subjects who were diagnosed with asthma after age 60, one-third reported respiratory symptoms before age 16.130 Similarly 82.7% with asthma diagnosed between the ages of 5 and 11 years had lower respiratory tract symptoms before the age of 5 years.127 REFERENCES 1. CIBA Foundation Guest Symposium: Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. Thorax 1959;14:286-99. 2. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225-44. 3. American College of Chest Physicians, American Thoracic Society: Pulmonary terms and symbols. Chest 1975;67:583. 4. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991. 5. International Consensus Report on the diagnosis and treatment of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, 20892. Publication No. 92-3091, March, 1992. Eur Respir J 1992;5:601-841. 6. Toren K, Brisman J, Jarvholm B. Asthma and asthma like symptoms in adults assessed by questionnaire: A literature review. Chest 1993;104:600-05. 7. Pekkanon J, Pearce N. Defining asthma in epidemiological studies. Eur Respir J 1999;14:951-57. 8. Peat JK, Toelle BG, Marks GB et al. Continuing the debate about measuring asthma in population studies. Thorax 2001;56:406-11. 9. Burney PGJ, Chinn S, Britton JR et al. What symptoms predict bronchial response to histamine? Evaluation in a community survey of the bronchial symptoms questionnaire(1984) of the International Union Against Tuberculosis and Lung Disease. Int J Epidemiol 1989;18:165-73. 10. Jenkins MA, Clarke JR, Carlin JB et al. Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma. Int J Epidemiol 1996;25:609-16. 11. Sistek D, Tschopp JM, Schindler C et al. Clinical diagnosis of current asthma: Predictive value of respiratory symptoms in the SPALDIA study. Eur Respir J 2001;17:214-19. 12. Gorgen PJ, Mullally DI, Evans R III. National survey of prevalence of asthma among children in the United States. 1976 to 1980. Pediatrics 1988;81:01-07. 13. Phelan PD. Asthma in children epidemiology. BMJ 1994;308:1584-85. 14. Strachan DP, Anderson HR, Limb SR et al. A national survey of asthma prevalence, severity and treatment in Great Britain. Arch Dis Child 1994;70:174-78. 15. Buist AS. Worldwide trends in asthma morbidity and mortality. Bull Int Union Tuberc Lung Dis 1991;66:77-78. 16. Sears MR. Worldwide trends in asthma mortality. Bull Int Union Tuberc Lung Dis 1991;66: 79-83.

Epidemiology 9 17. Woolcock AJ. Worldwide trends in asthma morbidity and mortality. Explanation of trends. Bull Int Union Tuberc Lung Dis 1991;66:85-89. 18. Woolcock AJ, Peat JK, Salome CM et al. Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population. Thorax 1987;42:361-368. 19. Sears MR. International trends in asthma mortality. Allergy Proc 1991;12:155. 20. Jackson R, Sears MR, Beaglehole R et al. International trends in asthma mortality:1970 to 1985. Chest 1988;94:914-18. 21. Evans R, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma in the US. Chest 1987;91(Suppl 6):65S-74S. 22. Sly RM. Mortality from asthma. 1979-1984. J Allergy Clin Immunol 1988;82:705-17. 23. Weiss KB, Wagener DK. Changing patterns of asthma mortality: Identifying target populations at high-risk. JAMA 1990;264:1683-87. 24. Gerjen PJ, Weiss KB. Changing patterns of asthma hospitalisation among children; 1979 to 1987. JAMA 1990;264:1688-92. 25. Weiss KB, Gergen PJ, Wagener DK. Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 1993;14:491-513. 26. Whitelaw WA. Asthma deaths. Chest 1991;99:1507-10. 27. Mao Y, Semenciw R, Morrison H et al. Increased rates of illness and death from asthma in Canada. Can Med Assoc J 1987;137:620-24. 28. Williams MH. Increasing severity of asthma from 1960-1987. N Engl J Med 1989;320:1015-16. 29. Center for Disease Control and Prevention. Forecasted state-specific estimates of self reported asthma prevalence – United States, 1998;MMWR Morb Mortal Wkly Rep 1998;47:1002-25. 30. Ehrlich RI, Bourne DE. Asthma deaths among coloured and white South Africans; 1962-88. Respir Med 1994;88:195-202. 31. Gergen PJ, Mullally DI, Evans R. National survey of prevalence of asthma among children in the United States 1976 to 1980. Pediatrics 1988;81:01-07. 32. Taylor WB, Newacheck PW. Impact of childhood asthma on health. Paediatrics 1992;90:657-62. 33. Centers for Disease Control and Prevention. Asthma mortality and hospitalisation among children and young adults 1980-1983. MMWR Morb Mort Wkly rep 1996;45:350-53. 34. Cloutter M, Wakefield D, Hall CB, Bailit H. Childhood asthma in an urban community. Prevalence, care system, and treatment. Chest 2002;122:1571. 35. Anderson HR, Bailey PA, Cooper JS et al. Morbidity and school absence caused by asthma and wheezing illness. Arch Dis Child 1983;58:777-84. 36. Vuurman EFPM, van Vaggel LMa, Uiterwijk MMC et al. Seasonal allergic rhinitis and antihistaminic effects on children’s learning. Ann Allergy 1993;71:121-26. 37. Turkeltaub PC, Gergen PJ. Prevalence of upper and lower respiratory conditions in the US population by social and environmental factors: Data from the Second National Health and Nutrition Examination Survey. 1976 to 1980 (NHANES II). Ann Allergy 1991;67(2 pt 1):147-54. 38. Asthma statistics in the United States from 1982 to 1992. MMWR 1995;43:952-55. 39. Costello J. Asthma-the problem and the paradox. Postgrad Med J 1991;67(Suppl 4):S1. 40. Shaw RA, Crane J, O’Donnell TV. Asthma symptoms, bronchial hyperresponsiveness and atopy in a Maori and European population. NZ Med J 1991;104:175. 41. Barry DM, Burr ML, Limb ES. Prevalence of asthma among 12 years old children in New Zealand and South Wales: A comparative survey. Thorax 1991;46:405. 42. Haahtela T, Lindholm H, Bjorksten F, Koskenvuo K, Laitinen LA. Prevalence of asthma in Finnish young men. Br Med J 1990;301:266. 43. Hurry VM, Peak JK, Woolcock AJ. Prevalence of respiratory symptoms, bronchial hyperresponsiveness and atopy in school going children living in the Villawood area of Sydney. Austr NZ J Med 1988;18:745-52. 44. Goodfrey RC, Griffiths M. The prevalence of immediate skin tests to Dermatophagoides pteronyssinus and grass pollen in school children. Clin Allergy 1976;6:79-82.

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45. Clifford RD, Howell JB, Radford M, Holgate ST. Association between respiratory symptoms, bronchial response to methacholin, and atopy in two age groups of school children. Arch Dis Child 1989;64:1133-39. 46. Burrows B, Lebowitz MD, Barbee RA. Respiratory disorders and allergy skin reactions. Ann Intern Med 1976;84:134-39. 47. Kaplan BA, Masci-Taylor CGN. Asthma and wheezy bronchitis in British National Sample. J Asthma 1987;24:289-96. 48. Schachter EN, Doyle CA, Beck GJ. A prospective study of asthma in a rural community. Chest 1984;85:623-30. 49. Sears MR, Jones DT, Holdaway MD et al. Prevalence of bronchial reactivity to inhaled methacholin in New Zealand children. Thorax 1986;41:283-89. 50. McNichol KH, Williams HE. Spectrum of asthma in children-II. Allergic components. Br Med J 1973;4:12-16. 51. Van Asperen PP, Kemp AS, Mukhi A. Atopy in infancy predicts the severity of bronchial hyperresponsiveness in later childhood. J Allergy Clin Immunol 1990;85:790-95. 52. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels. Chest 1991;100:385. 53. Behera D, Malik SK. Chronic respiratory disease in Chandigarh teachers- a follow up study. Ind J Chest Dis All Sci 1987;29:25. 54. Behera D, Malik SK. Chronic respiratory disease and ventilatory function in adult rural Oriya females. Lung India 1988;6:127. 55. Jindal, S.K., Bhaskar, BV and Behera, D: Respiratory disease pattern in a large referral hospital in India. Lung India 1989; 7: 119-21. 56. Viswanathan R, Prasad M, Thakur AK, Sinha SP, Prakash N, Mody RK et al. Epidemiology of asthma in an urban population; A random survey. J Ind Med Ass 1966;46:480. 57. Chougule R, Shetye VM, Parmer JR et al. Prevalence of respiratory symptoms, bronchial hyperreactivity and asthma in a mega city: Results of the European Community Respiratory Health Survey in Mumbai. Am J Respir Crit Care Med 1998;158:547-54. 58. Jindal SK, Gupta D, Aggarwal AN, Jindal RC, Singh V. Study of prevalence of asthma in adults in North India using a standardised questionnaire. J Asthma 2000;37:345-51. 59. Chhabra SK, Epidemiology of childhood asthma. Indian J Chest Dis Allied SS 1998; 40:179-94. 60. The International Study of Asthma and Allergies in Childhood (ISAAC)Steering Committee: Worldwide variations in the prevalence of symptoms of asthma, allergic rhino conjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225-32. 61. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee: Worldwide variations in the prevalence of symptoms of asthma, and allergies in childhood (ISAAC). Eur Respir J 1998;12:315-35. 62. Jindal SK. Asthma epidemiology in India. Chest2001; 2(Indian Edition):115. 63. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. Br Med J 1968;1:335-39. 64. Fraser PM, Speizer FE, Water SDM, Doll R, Mann NM. The circumstances preceding death from asthma in young people in 1968-1969. Br J Dis Chest 1971;65:71-84. 65. Sly R. decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol 2000;85:121-27. 66. Evans R, Mullally DI, Wilson RW et al. National trends in the morbidity and mortality of asthma in the US prevalence, hospitalisation, and mortality of asthma over two decades; 1965-1984. Chest 1987;91:65S-74S. 67. Buist AS. Asthma mortality: What have we learnt? J Allergy Clin Immunol 1989;84:275-83. 68. Sheffer AI, Buist AS. Proceedings of the asthma mortality task force. J Allergy Clin Immunol 1987;80:361-62.

Epidemiology 11 69. Khanna PM, Linger J. Asthma mortality and hospitalisation among children and young adults; United States, 1980-1993. JAMA 1996;275:1535-37. 70. Buist AS, Vollmer WM. Reflections in the rise in asthma morbidity and mortality. JAMA 19990;264:1719-20. 71. Burney P. Asthma deaths in England and Wales 1931-85: Evidence for a true increase in asthma mortality. J Epidemiol Community Health 1988;42:316-20. 72. Weiss KB, Wagener DK. Changing pattern of asthma mortality. JAMA 1990;264:1683-87. 73. Salas-Ramirez M, Sagura N, Martinez C. Trends in asthma mortality in Mexico. Bol Oficina Sanit Panam 1994, 116:298-306. 74. Molinari J, Chatkin J. Tendencia da mortalidade por asthma bronnquica no Rio Grande do Sul. J Pneumonol 1995;21:103-06. 75. Picard E, Barmeir M, Schwartz S et al. Rate and place of death from asthma among different ethnic groups in Israel. National trends 1980 to 1997. Chest 2002;122:1222-27. 76. Sears MR, Rea HH, De Boer G et al. Accuracy of certification of death due to asthma—A national study. Am J Epidemiol 1986;124:1004-11. 77. Hunt LW, Mair JE, Laplante JM et al. Causes of death in a population with asthma. Am Rev Respir Dis. 1989;139:A486. 78. Riou B, Barriot P. Accuracy of asthma mortality in France. Chest 1990;97:507-08. 79. World Health Organisation. Manual of the international statistical classification of diseases, injuries and causes of death: Based on the recommendation of the ninth revision conference, 1975. WHO, Geneva, 1979, Vol 1. 80. Garrett J, Kolbe J, Richards G et al. Major reduction in asthma morbidity and continued reduction in asthma mortality in New Zealand: What lessons have been learned? Thorax 1995;50:303-11. 81. Sly RM. Changing asthma mortality. Ann Allergy 1994;73:259-68. 82. Vergara C, Caraballo L. Asthma mortality in Colombia. Ann Allergy Asthma Immunol 1998;80:5560. 83. Pearce N, Beasley R, Crane J et al. End of the New Zealand asthma mortality epidemic. Lancet 1995;345:41-44. 84. Sly RM, O’Donnell R. Stabilisation of asthma mortality. Ann Allergy Asthma Immunol 1997;48:347-54. 85. Stolley PD, Schinnar R. Association between asthma mortality and isoprenol aerosols: A review. Preventive Med 1978;7:519-38. 86. Esdaile JM, Feinstein AR, Horwitz RI. Can general mortality data implicate a therapeutic agent? Arch Intern Med 1987;147:543-49. 87. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand. Lancet 1989;1:917-22. 88. Poole C, Lanes SF, Walker AM et al. Fenoterol and fatal asthma. Lancet 1990;335:920. 89. Beasley R, Smith K, Pearce N et al. Trends in asthma mortality in New Zealand, 1908-1986. Med J Aust 1990;152:570-73. 90. Sly RM. Mortality from asthma. J Allergy Clin Immunol 1989;84:421-34. 91. Spitzer WO, Suissa S, Ernst P et al. The use of beta-agonists and the risk of death and near-death from asthma. New Engl J Med 1992;326:501-06. 92. Sly RM. O’Donnell R. Regional distribution of deaths from asthma. Ann Allergy 1989;62:347-54. 93. Goldman M, Rachmiel M,Gendler M et al. Decrease in asthma mortality rate in Israel from 19991-1995: Is it related to increased use of inhaled corticosteroids? J allergy Clin Immunol 2000;105:71-74. 94. Campbell MJ, Gogman GR, Holgate ST et al. Age, specific trends in asthma mortality in England and Wales, 1983-1995; Results of an observational study. BMJ 1997;314:1439-41. 95. Respiratory diseases disproportionately affecting minorities. The NHLBI Working Group. Chest 1995;108:1380-92.

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96. Lang D. Trends in US asthma mortality: Good news and bad news. Ann Allergy Asthma Immunol 1997;78:333-36. 97. Gergen PJ, Weiss KB. Changing patterns of asthma hospitalisation among children. 1979 to 1987. JAMA 1990;264:1688-92. 98. To T, Dick P, Feldman W et al. A cohort study in childhood asthma admissions and readmissions. Paediatrics 1996;98:191-95. 99. Jones AP, Bentham G. Health service accessibility and death from asthma in 401 local authority districts in England and Wales. 1988-92. Thorax 1997;52:218-22. 100. Capewell S. The continuing rise in emergency admissions. BMJ 1996;312:991-992. 101. Vollmer et al. Am Rev Respir Dis 1993;147:347 102. Osborne M. Clinical asthma: Will NAEP guidelines help? Pulm Perspectives 1994;11(1):1-3. 103. Castro M, Halstead J, Schechtman K et al. Risk factors for asthma morbidity and mortality in a large metropolitan city. J Asthma 2001;38:625-36. 104. Roorda RJ. Prognostic factors for the outcome of childhood asthma in adolescence. Thorax 1996;51(Suppl 1):S7-S12. 105. Peckham C, Butler N. A national study of asthma in childhood. J Epidemiol Community Health 1978;32:79-85. 106. Anderson HR, Bland JM, Patel S, Pekham C. The natural history of asthma in childhood. J Epidemiol Community Health 1986;40:121-29. 107. Bronniman S, Burros B. A prospective study of the natural history of asthma. Remissions and relapse rates. Chest 1986;90:480-84. 108. Aberg N, Engstrom I. Natural history of allergic diseases in children. Acta Paediatr Scand 1990;79:206-11. 109. Radford PG, Hopp RJ, Biven RE et al. Longitudinal changes in bronchial hyperresponsiveness in asthmatic and previously normal children. Chest 1992;101:624-29. 110. Friberg S, Bevegard S, Graff-Lonnevig V, Hallback I. Asthma from childhood to adulthood. A follow-up study of 20 subjects with special reference to work capacity and pulmonary gas exchange. J Allergy Clin Immunol 1989;84:183-90. 111. Ferguson AC. Persisting airway obstruction in asymptomatic children with asthma with normal peak expiratory flow rates. J Allergy Clin Immunol 1988;82:19-22. 112. Cooper DM, Cutz E, Levison H. Occult pulmonary abnormalities in asymptomatic asthmatic children. Chest 1977;71:361-65. 113. Blackhall M. Ventilatory function in subjects with childhood asthma who have become symptom free. Arch Dis Child 1970;45:363-65. 114. Cade JF, Pain MCF. Pulmonary function during clinical remission of asthma. How reversible is asthma? Aust NZ J Med 1973;3:545-51. 115. Strachan DP. The prevalence and natural history of wheezing in early childhood. J Royal Coll Gen Pract 1985;35:182-84. 116. Peat JK. Salome CM, Toelle BG, Bauman A, Woolcock AJ. Reliability of a respiratory history questionnaire and effect of mode of administration on classification of asthma in children. Chest 1992;102:153-57. 117. von Mutius E. Progression of allergy and asthma through childhood to adolescence. Thorax 1996;51(Suppl 1):S3-S6. 118. Martinez FD, Wright AL, Taussig LM et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-38. 119. Park Es, Golding J, Carswell F, Stewart-Brown S. Pre-school wheezing and prognosis at 10. Arch Dis Child 1986;61:642-46. 120. Balfour-Lynn. Childhood asthma and puberty. Arch Dis Child 1985;60:231-35. 121. Peat JK, Salome CM, Sedgewick CS, Kerrebijn J, Woolcock AJ. A prospective study of bronchial hyper responsiveness and respiratory symptoms in a population of Australian school children. Clin Exp Allergy 1989;19:299-306.

Epidemiology 13 122. Price JF. Issues in adolescent asthma: What are the needs? Thorax 1996;51(Suppl 1):S13-S17. 123. Robson B, Woodman K, Burgess C et al. Prevalence of asthma symptoms among adolescents in the Wellington region by area and ethnicity. NZ Med J 1993;106:239-41. 124. Forero R, Bauman A, Young L, Larkin P. Asthma prevalence and management in Australian adolescents; results from three community surveys. J adolescent Health 1992;13:707-12. 125. Kolnaar B, Beissel E, van-den-Bosch WJ et al. Asthma in adolescents and young adults: Screening outcome versus diagnosis in general practice. Fam Pract 1994;11:133-40. 126. Rimpela AH, Savonius B, Rimpela MK, Haahtela T. Asthma and allergic rhinitis among Finnish adolescents in 1977-1991. Scand J Soc Med 1995;23:60-65. 127. Dodge R, Martinez FD, Cline MG, Lebowitz MD, Burrows B. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. J Allergy Clin Immunol 1996;95:48-54. 128. Dodge R, Burrows B, Lebowitz MD, Cline MG. Antecedent features of children in whom asthma develops during the second decade of life. J Allergy Clin Immunol 1993;92:744-49. 129. Dodge R, Cline MG, Lebowitz MD, Burrows B. Findings before the diagnosis of asthma in young adults. J Allergy Clin Immunol 1994;94:831-35. 130. Burrows B, Lebowitz MD, Barbee RA, Cline MG. Findings before the diagnosis of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1991;88:870-77.

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2 Aetiology A number of factors are responsible either in the causation or exacerbation of bronchial asthma. A brief account of each of these factors will be discussed. ATOPY AND ALLERGY The association between asthma and allergy has long been recognised. It has been reported that 75-85% of patients with asthma have positive immediate skin reactions to common inhalant allergens. There are at least 6 major evidences to prove that most asthma in young people is due to exposure to allergens or to sensitisers. They are summarised below. i. Most people with asthma are atopic, which can be measured by skin tests or with measurements of specific IgE. In population studies and in clinical practice, it is clear that majority of young people are atopic. Furthermore, in most population studies of asthma, atopy has been found to be the most important single risk factor. House dust mite allergens appear to be the most common one associated with asthma. ii. Challenge with allergens in atopic asthmatics increases the severity of the disease. The stimulus is capable of increasing this for days and sometimes for weeks. This implies that allergens play a role in maintaining the disease. iii. Occupational asthma occurs due to allergens and sensitisers. In some healthy people, who are exposed to these agents, sensitisation occurs and is followed by episodic wheeze. Unless the subject is removed from the source, episodic symptoms continue, and with time become persistent. iv. It has been shown that subjects with apparently intrinsic asthma (normal skin tests), have higher levels of circulating IgE than the non-asthmatic population. v. Improvement in the symptomatology occurs on allergen withdrawal, which proves the causal relationship between the two. vi. Population studies have clearly demonstrated the association between atopy and asthma. It has been shown that in Indonesian children, there is less atopy and less asthma. Similarly studies from France have reported a lower prevalence of asthma where mites are less in number. There is a strong co-relation between allergic sensitisation to common aeroallergens and the subsequent development of asthma. There is also a strong association between allergen exposure in early life and sensitisation to these allergens, although it has not been possible to demonstrate an association between allergen exposure and the development of asthma.1

Aetiology 15 Some studies, however, challenged the assumption that childhood asthma is largely of allergic etiology.2 Pearce et al 3 reviewed the epidemiological evidence implicating aeroallergen exposure in the primary causation of asthma, and concluded that the available data do not indicate that aeroallergen exposure is a major risk factor. In a further study, they reported that atopy attributes only 38% to the causation of asthma.2 Some investigators have observed a weak and inconsistent association between atopy and asthma prevalence. On the contrary, recent studies suggest that among those reporting wheezing in the previous months have a stronger relationship with atopy for those reporting > 12 episodes of wheezing in the past 12 months compared to those reporting 1 to 3 episodes in the last 12 months.4 The proportion of “asthma-ever” attributable to atopy was 33%, while the proportion was 89% for those who were attending hospitals (indicating more severe form). Based on these findings, it is suggested that atopy contributes more to the frequent or severe asthma than to mild or infrequent asthma.4 These findings are consistent with other studies. The important association of atopy with childhood asthma is well recognised.5 A review of studies relating atopy to asthma notes that in cross-sectional studies conducted exclusively or predominantly in children, the proportion of cases attributable to atopy varied from 25 to 63%, with a weighted mean of 38%.6 Relationship of atopy and severity of asthma is a well-known fact.6 Atopy is also related to degree of bronchial hyperreactivity.7,8 Conversely, in patients having wheeze in the previous 12 months, bronchial hyperactivity is related to both atopy and measures of disease severity such as peak expiratory flow variability.9 Taken together these facts are strong evidence for the role of atopy in asthma. Even though not all asthmas are associated with or perpetuated by exposure to common airborne allergens, exposure to these agents plays a major role. Both indoor and outdoor allergen exposures have increased asthma morbidity. People now spend a substantial proportion of the time indoors. Most of the responsible allergens are probably prevalent inside the houses since this is where human beings spend most of their lives. The most important ones throughout the world appear to be the house dust mites, grass pollens, animal proteins, and moulds. Recent changes in housing styles in many western countries may have led to increased allergens levels. Houses tend to have less ventilation, making them more humid, and there has been widespread introduction of carpeted floors and pets living in the houses. Whereas house dust mite is the most important and common indoor allergen linked to asthma,10 Outdoor allergens such as grass pollen, soyabean dust and Alternaria alternate have been specifically linked to severe asthma exacerbations.11,12 There has also been spread of plants, cockroaches and perhaps mites. Moreover, the climate of a particular area may favour the availability of various allergens, which in part may be responsible for the difference in the prevalence of asthma in various countries. Another important factor is the way the allergen is handled. Pollutions add to the allergenicity of aeroallergens. The predominance of these allergens will of course depend upon various factors, particularly local. Studies in asthmatics of allergen skin reactivity, IgE antibody levels, and bronchial provocation have all helped establish the important role of allergens in many asthma exacerbations.13 Further, reducing the patient’s exposure to allergens can help bring asthma symptoms under control. A growing number of uncontrolled and controlled studies suggest that allergen eradication and avoidance measures lead to improvement in bronchial hyperresponsiveness, severity of symptoms, and requirements of asthma medications.14 Recent research suggests that for many allergic disorders associated with aeroallergens, the process of IgE sensitisation begins right early in life while the immune response is still

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developing. It has been shown that the level of dust mite allergen present in the home during the first year of life is a major factor in determining whether an infant born of an allergic mother who is genetically susceptible, did in fact develop allergy or asthma by the time they are 11 years of age. Moreover, the density of allergen (per gram of dust) is an important factor in determining the age of onset of first symptoms. Higher is the concentration of allergen earlier is the onset of disease. Allergenic pollens vary at different places. The predominant offending allergen will vary with locality, lifestyle, season, and climate. For example, in Delhi, Amarantus pollen is the most common offending allergen followed by Cassia siamea, Ricinus, Brassica, Imperata, Prosopis, Cenchrus, Cassia occidentalis, etc.15 Prosopis is the commonest antigenic pollen in Bikaner, Lucknow, and Varanasi.16-18 Brassica is the commonest pollen in Bhopal and Kanpur.19,20 On the other hand Parthenium is the commonest offending agent in Kolhapur .21 In the United kingdom, 50-75% of atopic asthmatics react to house dust mite, similar number to grass pollens, 35-55% to cat dander, 10-20% to dog dander, 10-20% to tree pollens, 10-15% to moulds, and fewer than 10% to food allergens.13 In contrast, keeping cats as pets, unlike in many western countries is not a common practice in India. Therefore, cat or dog dander allergy may not be that important in this country. On the other hand because of tropical climates, and peculiar habit of storage of food articles, cockroaches grow plenty in this country. Therefore, these might be an important allergen for people of India. The importance of allergy is different for different age groups. In infants, allergens play a less important role than other ages and viral respiratory infections are the principal triggers. Although allergic reactions to food can occur in infants, foods are not the common triggers. Studies in children suggest that allergy influences the persistence and severity of asthma. It is reported by several authors that severity of childhood asthma corelates with the number of positive immediate skin tests. Children with multiple positive skin tests are more likely to have daily rather than intermittent symptoms of asthma. The important allergens in children after infancy appear to be inhalants. Aeroallergens are important in patients whose disease has started before the age of 30 years or who are exposed to occupational allergens. Patient can also have allergy for the first time after the age of 30. However, in adults the intensity of allergic skin tests does not appear to be associated with increased severity of asthma. Food allergies are not common triggers for asthma in adults. The patient may have aspirin sensitivity, but it has no immunological basis. Different Allergens (Figs 2.1a to 2.1h) i. Important outdoor allergens include pollens and moulds. Pollen Particles greater than 10 micron in diameter are usually cleared in the nose and mouth and do not penetrate the lower respiratory tract. However, there are some plants, which produce allergen-containing particles that are less than 10 microns. Ragweed and grass pollination are definitely associated with asthma. Pollen allergy is usually season-related and is more closely linked to hay fever and allergic conjunctivitis. Mould Mould spores are generally smaller than pollen grains and are more likely to penetrate the lower respiratory tract. Mould spores exist primarily outdoors and tend to be seasonal. Some fungi sporulate on warm, dry summer days and others prefer the rainy season. The species of the fungus vary with the geographic distribution according to climatic conditions.

Aetiology 17

Fig. 2.1a: Dust during cleaning

Fig. 2.1c: Smoke

Fig. 2.1e: House dust mite in the bedding

Fig. 2.1b: Pollen

Fig. 2.1d: Domestic fuel

Fig. 2.1f: Perfumes

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Fig. 2.1g: Pets (Animal dander)

Fig. 2.1h: Mould in the wall

ii. Although house dust itself is not an allergen, there are allergic components in it. The most important ones are mites, animal danders, and cockroaches. House dust mite plays a major role in the causation of asthma, although it does not leave any immediately perceptible sting or bite. This is the agent most widely implicated in the pathogenesis and provocation of allergic asthma. They are arachnoids distantly related to ticks and spiders. They are ubiquitous, living in the house dust that provides both their shelter and food (scales of skin shed by humans). They occur in environments with sufficient humidity since they are quite dependent for survival on moisture from the atmosphere. Loss of water from the mite body constrains their growth, but mites are capable of extracting water vapour even from air that is only 50% saturated. Live mites are equipped with suckers at the tips of their legs, which make them difficult to remove by vacuuming. The commonest mite is Dermatophagoides pteronyssinus. Other species may also exist in small numbers. Mite antigen is found throughout the home, wherever human dander, the food for the mite, is found. High levels are found in mattresses, pillows, carpets, upholstered furnitures, bed covers, clothes, and soft toys. The principal allergen of the house dust mite is found in its faeces. A gram of dust may contain 1,000 mites and 250,000 faecal pellets. These pellets are quite large and 10-40 microns in size, similar to pollen grains and share some of the aerodynamic properties with them. Like larger pollen grains, they do not easily enter the lower respiratory tract and are rapidly cleared from the airway by

Aetiology 19 gravity. Mite antigen is readily demonstrated in the air during cleaning. Some mite allergens may be smaller that may be in the respirable range for the lower respiratory tract. The major allergens of house dust mites are probably digestive enzymes, collectively designated as group I allergens or Der p I, and there are now tests available to quantitate this. The improvement of asthma in children residing in high altitude where low humidity constrains dust mite growth or in patients admitted to the relatively dust-free environment of a hospital14 indicates the contribution of the house dust mite to asthma exacerbation. A study of children requiring hospitalisation for asthma found that the risk of re-admission was associated with continued exposure to high concentrations of mite allergen.22-28 Animal allergens Dogs, cats, and other pet animals including rodents are commonly kept in homes. Danders from these animals contribute greatly to the allergenic components of house dust. All warm-blooded pets can cause allergic reactions, including the birds and small rodents. Products made from feathers retain the allergens from bird. All breeds of cats produce common allergens, and cat saliva and cat danders are potent allergens. Dogs also produce common allergens, although minor breed differences may exist. For several reasons cat allergen is more likely to cause sensitisation than that of dogs. The major cat allergen is Fel d I, which is a protein secreted by the cat’s salivary, sebaceous, and lacrimal glands. The protein is very stable and loses none of its antigenic potency for at least a month. It is coated on to the fur by the usual grooming, and at the rate cats shed their fur and dander, a reservoir of the antigen rapidly accumulates in household furnishings. In addition, Fel d I, particles are less than 2.5 mm in diameter and flake-shaped, making them easily airborne and easily respirable. While air filtration can remove some of the allergens, little permanent reduction occurs unless carpets, furnishings, and other reservoirs of coated fur (the cat itself) are removed. It takes several months before the concentration of allergens in domestic dust falls after removal of the pet. A number of epidemiological studies suggest that close contact with a cat or dog in very early infancy reduces subsequent prevalence of allergy and asthma. This may be a consequence of high allergen exposure inducing tolerance.29-31 Cockroach allergen The cockroach appears to be important, particularly in warmer climates and inner side of the house in cooler climates. Cockroach allergy has been identified as an important cause of asthma. This form of asthma—“The cockroach asthma”—is a more severe form of the disease, having perennial symptoms, and high levels of IgE. Cockroaches produce several allergens, which produce sensitisation. Usually there is exposure to high levels of this allergen at homes. The important domestic species are Blattella germanica and Periplaneta American. Kinds of Allergens The allergens are Bla g 2 (inactive aspartic protease), Bla g 4 (calycin), Bla g 5 (glutathione – S-transferase), Bla g 6 (troponin), the Group I cross-reactive allergen Bla g 1 and Per a 1, Per a 3 (arylphorin), and Per a 7 (tropomyosin). Although elimination of cockroaches totally is difficult, development of cockroach allergens as recombinant proteins has led to better control of this form of asthma.32 Indoor moulds are prominent in environments with increased humidity. Bathrooms, kitchens, basement areas, and perspiration on pillows are

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the common sites of mould growth. Cockroach sensitivity in children has been associated with greater symptom frequency and more emergency department visits due to asthma.33-36 Similar observations are made for elderly patients with asthma also.37 Risk Allergens: Responsible for Acute Attacks Threshold concentrations of allergens that can be regarded as risk factors for acute attacks include: • 10 μg/g dust of group I mite allergen • 8 μg/g dust of Fel d I, the major cat allergen • 10 μg/g dust of Can f I, the major dog allergen • 8 μg/g dust of cockroach allergen FOOD ALLERGEN AND BREASTFEEDING In the first 1 or 2 years of life, food sensitivity is an important factor in the development of allergies. Breastfeeding has been advocated as a method of preventing allergy and asthma. With breastfeeding there is a decreased risk (about 20%) for development of asthma.38 Impact of exclusive breastfeeding in children at 6 years of age has shown that the introduction of milk other than breast milk before the age of 4 months of age is a significant risk factor for increased likelihood of bronchial asthma.39 However, another study has shown an increased risk of wheezing, particularly in asthmatic mothers and if the child is also atopic.40 There are some reports that regular consumption of oily fish is associated with a reduced risk for asthma in children, although subsequent studies have not shown clinical benefits of supplemental ω3 fatty acids over a 6 months period.41,42 Further, it has been hypothesised that decreased dietary antioxidant vitamin intake is associated with increased asthma.43 Higher concentrations of vitamin intake are associated with a decreased serum levels if IgE and a significant decrease of atopy.44 Recent experimental data showed a reduced risk with intake of lectins (wheat germ agglutinin from whole wheat products).45 INFECTION It has long been recognised that viral respiratory infections provoke and alter asthmatic responses. Over 80% of acute asthma exacerbations in school children and about 60% in adults result from viral infections, mostly common cold viruses. These observations have suggested that viral infections may be intimately involved in the development of asthma and allergy. The susceptibility of the asthmatic airway to viral inflammation is due to persistent allergic mast cell and eosinophil-derived inflammation stimulates the release of cytokines such as tumour necrosis factor-alpha, which cause an increase in the expression of receptors for human respiratory viruses on the airway lining epithelium. In case of most rhinoviruses, the receptor is an adhesion molecule (intracellular adhesion molecule-1). The Viral respiratory illnesses may produce their effect by causing epithelial damage, producing specific immunoglobulin IgE antibodies directed against respiratory viral antigens and enhancing mediator release. Once the virus enters the epithelial cells, it replicates and generates a wide variety of proinflammatory cytokines, which further enhance eosinophil and mast cell inflammation. Apart from aggravating clinical asthma, viral upper respiratory

Aetiology 21 infections increase airway responsiveness, which may persist for many weeks after the infection. Provocateurs of Asthma The principal infection provocateurs of asthma in childhood during the first 2 years of life are respiratory syncytial virus (RSV), parainfluenza virus, and rhinovirus. Influenza virus is much more common in older children and adults. Early hospitalisation for respiratory syncytial virus, croup, or bronchiolitis is associated with greater airway responsiveness and more frequent history of wheezing.46 Other microorganisms that can exacerbate bronchial asthma include Mycoplasma pneumoniae. Although bacterial infection i s no t a cause of such exacerbations, it has been reported recently that H.influenzae and other Gram-negative bacteria can synthesise histamine both in vivo and in vitro.47 The presence of this mediator may contribute to the bronchoconstriction and other effects of histamine that can accompany bronchial infection. Pseudomonas infection in cystic fibrosis is responsible for a hyperreactivity reaction in these patients. A recent study in 101 nonsmoking severe asthmatics shows association between accelerated loss of lung function and seropositivity to Chlamydia pneumoniae.48 Interestingly, in recent years it is also observed that some infections are protective of bronchial asthma. While viral infections can undoubtedly cause deterioration of established asthma, viral or bacterial infections during the first three years of life may serve a protective function against the development of allergic diseases. Possibly they evoke a Th1-like protective response with the generation of IFN-gamma and IL-2. Thus, if multiple infections occur during the first few years of life, high concentrations of these Th1 cytokines could inhibit the release of Th2 cytokines, thereby tuning the mucosal immune response away from allergen sensitisation. This hypothesis is supported from observations from an African study, where children infected with measles during the first year of life had a 63% lesser chance of developing positive skin tests to common aeroallergens. Similarly repeated vaccination with BCG exerted a protective effect against the development of allergy in young Japanese children. Both measles and BCG are potent stimulators of the Th1 cytokine response. Another support of this protective infection comes from observations comes from the fact that the increase in asthma and allergy with movement to urban areas may be related to a decrease in early exposure to parasitic infections. One study from slum are of Caracas, Venezuela showed that antihelminthic treatment causes a decrease in IgE level, but was accompanied by an increase in skin test reactivity to house dust mite. In contrast, in the untreated children, the parasitic colonisation continued, IgE levels increased but the dust mite sensitisation fell. It indirectly means that eradication of parasites or reduced opportunities for infection could, in part, explain the rural to urban differences in the prevalence of allergic diseases. These observations led to the “Hygiene hypothesis” of bronchial asthma. This suggests that early exposure to microbial products will switch off allergic responses preventing allergic disorders like asthma.49 Epidemiological studies comparing large populations who have or have not had such exposures support the hypothesis.50 The hygiene hypothesis explains that allergic diseases were prevented by infections in early childhood, transmitted by unhygienic contact with older siblings or acquired prenatally. Over the past century declining family size, improved household amenities, and higher standards of personal cleanliness may have resulted in more atopic diseases.49 It is further proposed that modern vaccinations, fears of germs and

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obsession with hygiene are depriving the immune system of input on which it is dependent. Recent data suggest that exposure of young children to older children at home or to children at day-care protects against the development of asthma and frequent wheezing later in childhood. A double blind placebo controlled trial using the probiotic. Lactobacillus CG, observed a reduced incidence of atopic eczema but no effect on IgE antibody sensitisation, important for bronchial asthma. However, this study has the limitation of small sample size and early age limit of interpretation.51 DRUGS About 5 to 20 per cent of adults with asthma will experience severe and even fatal exacerbations of bronchoconstriction after ingestion of aspirin or certain non-steroidal antiinflammatory drugs (NSAIDs). These drugs are as follows:52-58 • Aspirin • Ibuprofen • Indomethacin • Piroxicam • Sulindac • Tolmetin • Naproxen • Fenoprofen • Meclofanamate • Mefenamic acid • Diclofenac sodium The list is not complete and aspirin sensitivity implies cross-reactivity with other nonsteroidal medications. The prevalence increases with increasing severity of asthma. In these individuals, ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm, which may be accompanied by rhinitis and/or urticaria. An association between aspirin sensitivity in people with asthma and the presence of sinusitis and nasal polyps is often stressed. Although there is a statistical relation, many patients with nasal polyps are not aspirin sensitive, and many patients with asthma and aspirin sensitivity have not been found to have nasal polyps. It is likely that sinusitis, nasal polyps, and aspirin sensitivity all increase in prevalence with increasing severity of asthma and they are not causally related. Although the exact mechanism is not known, it is nonimmunologic and probably depends on inhibition of cyclo-oxygenase. Accordingly, the arachidonic acid metabolism proceeds via the lipo-oxygenase pathway producing leukotrienes (see pathogenesis). Although the exact pathogenesis of aspirin-induced asthma is unclear, studies have demonstrated that leukotrienes play an important role in airway narrowing and other signs in these patients. These observations are derived from the fact that urinary LTE4 is two-folds to ten-folds higher in these patients than in aspirin tolerant patients.59-61 Several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchial provocation tests, such as aspirin and nonsteroidal anti-inflammatory drugs,62-64 and improve respiratory function by expanding the airway in patients with aspirin induced asthma.65 An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes. The inhibition of cyclo-oxygenase is a property common to all of the drugs producing this adverse reaction. Although analgesics not inhibiting this enzyme are generally considered to be safe, the most frequently employed alternative, acetaminophen, has been reported to cause asthma exacerbations in a few aspirin-sensitive patients. Other drugs that are known to exacerbate asthma include beta-blocker drugs (i.e. propranolol and nadolol). Eye drop preparations of this class of drugs also can induce asthma. Recently, inhaled verapamil, a calcium channel blocker, has been reported to induce severe bronchospasm in mild asthma.

Aetiology 23 EXERCISE-INDUCED ASTHMA66-71 Exercise-induced asthma’ (EIA) is often used to describe the asthma of persons in whom exercise is the predominant or even the only identified trigger to airflow obstruction. No available data support the concept that exercise-induced asthma represents a distinct pathologic or pathophysiologic entity. Exercise-induced bronchoconstriction is one manifestation of the asthmatic diathesis. Most, virtually all, people with asthma have airway hyperirritability that leads to exercise-induced asthma if the provocative stimulus - eucapnic voluntary hyperventilation- is appropriately intensified. Accordingly, this condition should be anticipated in all asthma patients. For some asthmatics, exercise is the only trigger. In addition, most patients in whom exercise is the predominant trigger, will have other additional sensitivities that either can be found in the clinical history or will evolve over time. It is estimated that approximately 40 per cent of children with allergic rhinitis, but without clinical asthma, have EIA. This situation probably holds true for adults. Untreated EIA can limit and disrupt normal life. Although individual episodes of EIA are short lived, the severity and impact is striking. During short (few minutes) periods of exercise, airways actually dilate. Exercise-induced asthma is the airway narrowing that occurs minutes after the onset of vigorous activity. Airway narrowing develops within 2-3 minutes after cessation of exercise. It generally reaches its peak about 5-10 minutes after cessation of activity and usually resolves spontaneously in the next 30-90 minutes or within a few minutes of administration of an inhaled beta-adrenergic bronchodilator. There are some reports now that a late phase of EIA exists.72,73 However, this phase is uncommon (EIA is a nonimmunologic form of asthma) and not severe unlike the late phase of allergen-induced asthma. Ambient air conditions during the post-exercise period also influence the degree of bronchoconstriction that develops. A rapid change to warm, moist air post-exercise tends to worsen the development of airflow obstruction.74 Some patients who engage in continuous, repetitive exercise periods, EIA diminishes or is completely abated during a refractory period that usually lasts 2 hours after an exercise challenge. This is referred to as “refractory period”. Because of this phenomenon, many asthmatic athletes report that a warm-up period of sub-maximal exercise helps to minimise exercise-induced symptoms.75 During sustained exercise they are often able to “work through’ initial respiratory symptoms, i.e. experience resolution of initial symptoms despite continued exercise. In contrast to asthma in general, which is characterised by both smooth muscle contraction and airway inflammation, exercise-induced asthma is due mainly to smooth muscle contraction. Therefore some investigators call this as airflow-induced bronchoconstriction (AIB) or exercise-induced bronchospasm (EIB). Although the exact mechanism of asthma is debated, it is generally established that EIA is due to loss of heat or water or both, from the lung during exercise resulting from hyperventilation of air that is cooler and dryer than that of the bronchial tree. The key aspects of the triggering stimulus are the level of ventilation during exercise and the temperature/water content of the inspired air.70 The higher the minute ventilation during exercise and the colder and drier the inspired air, the greater is the stimulus for bronchoconstriction. How this airway cooling causes bronchoconstriction, is not exactly clear. It has been suggested that heat and water loss leads to changes in airway fluid osmolarity which initiates mediator release that cause constriction in the smooth muscle. Some investigators believe that airway cooling triggers bronchoconstriction in asthmatic subjects, and a rewarming-induced hyperaemia and oedema results in airway

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obstruction. Another hypothesis put forth is that exercise-induced bronchoconstriction results from an imbalance between two opposing mechanisms: an excitatory pathway stimulated by airway drying and an inhibitory pathway initiated by airway cooling. It is speculated that cooling attenuates hypocapnia, hypertonic aerosol- and dry air-induced bronchospasm via a cold induced reduction in neuronal activity or mediator production and release. Effects of Exercise An athlete’s minute ventilation during exercise is determined in part by the workload undertaken as measured by oxygen consumption and in part by the degree of deconditioning as measured by minute ventilation. Thus, for all asthmatics, regular exercise that improves cardiovascular fitness and thereby increased oxygen extraction from the blood by exercising muscle can help reduce exercise-induced bronchoconstriction by lowering the level of ventilation needed during any given exercise task. Rate, depth, and pattern (I:E ratio) of breathing at a given level of ventilation during eucapnic voluntary hyperventilation are not important determinants of bronchoconstriction.71 To reduce/avoid EIA, avoidance of a cold/ dry environment is preferable. Swimming is the preferred exercise for persons with asthma because of this mechanism. Other inhaled irritants in the ambient air including high levels of air pollutants and smoke can also trigger asthma especially during exercise when larger than normal volumes of these irritants are inhaled. OCCUPATION AND ASTHMA Occupational asthma is the commonest industrial lung disease in the developed world with over 400 causes.76-78 It may account for about 10% of adult onset asthma.79 Environmental agents related to work place have been recognised as the causative agents for respiratory diseases for many centuries. Bernardino Ramazzini had recognised the importance of occupation in the causation of asthma as early as 1713 particularly in grain workers, bakers, millers, sulphur workers, and other occupations. With increased industrialisation, simple chemicals and organic compounds have been used more often with a consequent increase in new respiratory hazards, particularly occupational asthma. Occupational asthma may account for about 10% of adult onset asthma.79 It is now the commonest industrial lung disease in the developed world with over 400 causes.80-86 Agents causing occupational asthma are usually encountered in an industrial setting, but it is also possible for persons outside the working area to develop disease after contamination of their environment by a point source industrial chemical irritant or allergen. Industries in which asthma occurs include plastics and paint manufacturing, electronics, welding, metal refining, photography, health-related industries, antibiotics and cosmetic manufacturing, dyeing, forestry, and food processing. Asthma can also result from massive pollution due to transportation accidents or gross contamination of the local environment by manufacturing industries. It can also occur in more unrecognised ways like materials contaminating air conditioning system inlets from near by factories, or by contamination of workers or of their clothing. Thus the strict definition of occupational asthma as reversible obstructive airways disease contracted in the work place may underestimate the real extent of the problem.

Aetiology 25 Prevalence of Asthma in Workers Although the exact prevalence of occupational asthma is not known and will vary according to the setting in which it occurs, on the industrial agent involved, on the intensity of exposure, and on working conditions, industrial hygiene, and engineering factors; it is reported that between 5 to 15% of all cases of asthma in Japan are occupational. Bakers exposed to flour dust develop asthma at a rate of 10-30%, in washing powder industry, up to 60% of the workers become sensitised to Bacillus subtilis, and in the cotton industry the prevalence of byssinosis is 25-29% in workers exposed in the carding process and 10-29% in those exposed in the spinning process. Similarly 5% of the western red cedar workers, 6% of the animal handlers, 5% of the workers in plastics industry (volatile isocyanates), and 30-50% of those working in the metal industry using soluble platinum salts develop the disease. Agents capable of inducing occupational asthma can be vapours, gases, aerosols, or particulate matters and can range from very low molecular weight inorganic chemicals to complex organic macromolecules. Some of these agents are shown in Table 2.1. Table 2.1: Selective agents known to cause occupational asthma

Agents

Occupation

1. Natural organic environmental agents. Animal proteins (urine, danders) Shellfish, egg proteins, pancreatic enzymes papain, amylase B.subtilis enzymes Poultry mites, droppings, feathers Flour grain Storage mites, soyabean, wheat Midges Silk-worm moths and larvae Castor beans, Coffee seeds bean Colophony Wood dusts (red cedar, oak,mahogany, etc) Grain dust (moulds, insects, grain) Cotton dust Storage mites, fungi, ragweed, pollen

Laboratory workers/Veterinarians Food processing Detergent factory Poultry farmers Bakers Farmers Fish food manufacturing Silk workers Farmers Electric soldering Carpenters and Saw mill workers Shipping workers Cotton mill workers Granary workers

2. Organic chemicals. Isocyanates (TDI, MDI, HDI) Antibiotics, piperazine, methyl dopa Disinfectants Paraphenylene diamine Formaldehyde, ethylene diamine Furfuryl alcohol resin Dimethyl ethanolamine toluene di-isocyanate

Plastic and foam Manufacturing Hospital workers Fur dyeing Rubber processing Foundry workers Automobile painting

3. Inorganic chemicals. Platinum salts Nickel salts Cobalt salts Chromium salts Aluminium fluoride Persulphate Vanadium Stainless fumes

Refining Plating Diamond polishing Stainless steel welding Manufacturing Beauty shop Refinery workers Welding

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Occupational asthma can be mediated by any of the several, mechanisms. They include, reflex vagal bronchoconstriction in response to an irritant effect on specific receptors; inflammatory bronchoconstriction secondary to toxic concentration of gases (nonspecific complement activation, neuro-peptide release, disrupted cell membrane releasing arachidonic acid products); direct pharmacological reaction by agents such as organic insecticides (parasympathetic agonists) and beta-adrenergic blocking agents; or by immunologic mechanisms. Some agents also act via alternative path way of complement activation through an antibody-independent mechanism. TARTRAZINE AND SULPHITE SENSITIVITY Tartrazine is a yellow dye commonly employed in food and medications. Beginning in 1958, a number of reports appeared linking this agent with the occurrence of acute bronchoconstriction. The reaction is particularly noted in those with aspirin sensitivity. Although the exact prevalence is not known, there are reports of positive challenge in up to 22% of unselected asthma patients and 25-50% of those with aspirin sensitivity. It is not an inhibitor of cyclo-oxygenase. However, the incidence of tartrazine-induced asthma is very low and perhaps is limited to those rare individuals who appear to have an immunologically mediated sensitivity to the dye.87 Sulphiting agents88-90 have been used to preserve foods and beverages since ancient times. They maintain the crisp and fresh appearance of the foods, prevent browning, and control microbial growth and spoilage. The agents used include sulphur dioxide as well as the sodium and potassium salts of sulphite, bisulphite, and metabisulphite. All these agents release sulphur dioxide gas under suitable conditions of warmth and acidity. Major sources of exposure to sulphites are processed potatoes, shrimp, dried fruits, beer and wine. Another source of sulphite exposure for patients with asthma is medication. Sulphites are used to prevent oxidation of beta-adrenergic agonists. For this purpose, sulphites are contained in some nebuliser solutions, injected epinephrine, and injected local anaesthetics containing epinephrine. Except in vary rare individuals with true allergy to sulphites, the amount of injected solutions is inconsequential. However, the amount in the nebuliser solutions is sufficient to cause paradoxical bronchoconstriction or a blunted bronchodilator response in these subjects. Exposure to sulphites, particularly in restaurant salad bars in western countries, or after drinking wine or beer, has been reported to be responsible for fatal attacks of asthma and its use has been banned in many countries. Sulphur dioxide released in the mouth and stomach from sulphites has been incriminated as the cause of precipitation of asthma in a vast majority of patients. Sulphur dioxide is a known irritant and asthmatics are particularly susceptible. The levels released from food and beverages may be sufficient to account for the bronchoconstriction. However, all patients with asthma do not react adversely to sulphites. This may be due to varying extent of inhalation of liberated sulphur dioxide by different patients or there may be a subset of asthmatics, which have low levels of the enzyme sulphite oxidase. These patients will be able to metabolise sulphites to harmless sulphates. A small number of asthma patients may have true allergy to sulphites, in whom an immediate skin test reactivity can be demonstrated.

Aetiology 27 RHINITIS AND SINUSITIS A possible relation between sinusitis and activation of asthma has been postulated recently. A high incidence of radiographic evidence of sinusitis on the order of 40 to 60 % has been demonstrated in asthmatic patients. However, the question is, does this association represent an epiphenomenon? There is suggestive clinical evidence that sinusitis not only occurs in association with asthma but may also play some role in its pathogenesis. Studies of children and adults after medical or surgical therapy indicate that the asthmatic state may improve with proper management of the underlying sinusitis. It is also likely that nasal and sinus pathology can aggravate asthma, particularly if there is uncontrolled drainage of mucoid or mucopurulent material down the nasopharynx where it can contribute to cough and irritability of larynx. This material may also be aspirated into the lower respiratory tract, especially during sleep. It is also possible, but not proven, that sinus infection may aggravate asthma through reflex mechanisms.91-93 Although historically, it was believed that structurally and functionally there are differences within the respiratory tract which have been used as the basis for separating the airway into upper and lower respiratory tracts, it is now being appreciated that allergic rhinitis and bronchial asthma are considered as ‘one airway, and one disease’.94 The prevalence of asthma and allergic rhinitis is increasing in the general population, and a high proportion of new patients have coexisting upper and lower respiratory tract disease. It is estimated that 60 to 70% of patients who have asthma have also coexisting allergic rhinitis. During the past decade with increased understanding, current thinking is emerging that they should better be described as a continuum of inflammation involving one common airway. Traditional therapies originally indicated for allergic rhinitis and asthma are being reassessed to explore their potential utility in both these conditions. Recently, there has been a renewed interest in the role that histamine plays in lower airway disease, and interest in increasing in the theory that leukotrienes, which are more potent inflammatory mediators than histamine, play a role in upper airway disease as well. Because its important role in the pathogenesis of both airways disease, leukotriene receptor antagonists are recently have emerged as important therapeutic advances that have potential clinical utility in both asthma and allergic rhinitis. GASTRO-OESOPHAGEAL REFLUX (GER) A number of reports are available in the medical literature on the relationship between gastrooesophageal reflux (GER) and pulmonary disease. Since the late seventies, numerous investigators have reported on epidemiology, mechanisms and clinical trials in an effort to piece together the gastro-oesophageal reflux and asthma. Epidemiological evidence for the association suggest that about three-fourth of the asthmatics, independent of the use of bronchodilators, have acid gastro-oesophageal reflux, increased frequency of reflux episodes, or heart burn, and about 40 per cent have reflux oesophagitis. As early as 1967, Urschel and Paulson reported that of 636 patients scheduled for an operative treatment for GER, 60% also had pulmonary symptoms.95 Since then, many studies have shown a high prevalence of GER among patients with asthma.96,97 A recent report says that even asthmatics without having reflux symptoms have a high prevalence (62%) of abnormal results for 24-hours oesophageal tests.98 The simultaneous occurrence of GER and asthma suggests a causal

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relationship. The occurrence of GER after bedtime is strongly associated with asthma, respiratory symptoms, and obstructive sleep apnoea syndrome.99 Two separate mechanisms are involved in the gastro-oesophageal reflux and asthma relationship.99,100 i. Reflex vagal bronchoconstriction occurs secondary to stimulation of sensory nerve fibres in the lower oesophagus. This mechanism is supported by the findings that acid infusion of the oesophagus in asthmatic patients leads to increased airway resistance that rapidly reverses with antacids and infusion of acid into the lower oesophagus of asthmatic children during sleep induces bronchoconstriction. ii. The second proposed mechanism is micro-aspiration, particularly during sleep. This is supported by the findings of (a) a large vagally mediated increase in airway resistance with minute quantities of hydrochloric acid infused into the trachea of cats; (b) a high prevalence rate of hiatus hernia and gastro-oesophageal reflux in patients with bronchial asthma and (c) an incidence of gastro-oesophageal reflux in 63 per cent of children with asthma. The prevalence of gastro-oesophageal reflux is increased at least threefolds in both children and adults with bronchial asthma. The evidence for the relationship also has gained support from the results of clinical trials. iii. The partial narrowing or occlusion of the upper airway during sleep, followed by an increase in intrathoracic pressure, might predispose the patient to nocturnal GER and, consequently, to respiratory symptoms.99 Both medical treatment with antacids and postural therapy and surgical management of gastro-oesophageal reflux have resulted in improvement of asthma symptoms. However, other studies have not demonstrated such a beneficial effect.101-105 Prevalence of gastro-oesophageal reflux in asthmatics can be summarised as follows:106 • 57% of asthmatics have heartburn • 41% of asthmatics note reflux-associated respiratory symptoms • 82% of asthmatics have abnormal oesophageal acid contact times • 43% of asthmatics have oesophagitis • Heartburn is more prevalent in asthmatics over 65 years of age (35%) compared with asthmatics 18-34 years of age (23%) • Heartburn is associated with a higher rate of future asthma hospitalisation • Subjects reporting nocturnal GER have higher asthma prevalence rates and symptoms of obstructive sleep apnoea • Proximal oesophageal acid exposure is present in 48% of asthmatics • In children : abnormal oesophageal pH tests are present in 62% and GER is a risk factor for asthma (OR 1.9). PSYCHOLOGICAL FACTORS There has been a great deal of controversy regarding the cause and effect relationship of asthma and psychological factors. Many patients with asthma acknowledge that exacerbations are provoked by psychological events, such as shock, bereavement, or excitement. However, such factors are rarely the dominant cause of disease. Suggestion and hypnosis may have some beneficial effect in modifying the asthmatic reactions. Depression most often associated with asthma may be secondary to a chronic disease. In rare instances, patients commit suicide. Although the information linking depression and

Aetiology 29 increased death from asthma is derived from clinical reports, the association, however, is striking. In a review of cases in which children died suddenly and unexpectedly of asthma, there is clinical evidence that the children had expressed despair, hopelessness, a wish to die, and other evidence of depression. Other psychological problems that are documented as associated with those at increased risk of mortality include alcohol abuse, documented depression, recent family loss and disruption, recent unemployment, and schizophrenia. The severe asthmatic attack is very frightening and such patients are understandably anxious. Occasionally, psychological illness, family disputes or marital disharmony may be major factors in the aetiology of intractable asthma.107-109 POLLUTION Pollution with particulate matter adds to the allergenicity of aeroallergens. Passive smoking is known to be a risk factor110 and there is evidence that diesel fumes are associated with increased allergic responses. Similarly smokers have increased bronchial hyperreactivity to a variety of stimuli. A small increase in allergen exposure will make the airway more reactive, which will result in a large increase in severity and potential deaths. Ozone and other oxidants contained in photochemical smog which occurs in areas of high traffic density, high sunlight and temperature inversions as in Los Angeles and Athens, act as respiratory irritants and can exacerbate asthma. Similarly other atmospheric pollutants as in highly industrialised area containing sulphur dioxide and other smoke particulates can provoke asthma. Indoor air pollution due to cooking fuels such as gas, biomass, and kerosene contain oxides of nitrogen and are responsible for increased respiratory symptoms as reported in some studies.111 Other environmental pollutants such as diesel particulates, and noxious gases like ozone, sulphur dioxide, and nitrous oxides may be important in the development in young children.112 Air pollution is partly being incriminated as a possible contributing factor in the recent rise in the prevalence, morbidity and mortality of asthma globally.113 Although recent studies have not established a direct causal relation of air pollution and bronchial asthma, there is now substantial evidence that air pollution can contribute significantly to asthma morbidity and mortality. Ambient levels of air pollutants exacerbate mucosal inflammation in asthmatic airways, can affect lung function, and potentiate inhaled response to aeroallergens. Emissions from motor vehicles are a major source of these pollutants. Retrospective analysis of pollution episodes in the world history (Meuse Valley, Belgium -1930; Donnora, Pennsylvania-1948; London 1952) have identified a link between respiratory morbidity and mortality and high levels of sulphur dioxide and black smoke, although these studies were not primarily focussed to study the association between asthma and air pollution.114-116 Reports from the Tokyo-Yokohama area of Japan where USA soldiers were based, revealed many cases of asthmatic bronchitis characterised by cough, wheeze, and breathlessness associated with eosinophilia and positive skin prick tests. This area experienced smog as it was highly industrialised and surrounded by hills. These individuals experienced relief of their symptoms when they moved out to less polluted areas. This entity is known as “TokyoYokohama asthma”. However, since the levels of pollutants were not measured, this could not be attributed to any specific pollutant.117-119 Other studies from Yokkaichi, Japan,120 Birmingham, UK,121 Seattle,122 Utah valley,123 Southern Ontario and Toranto124-126 have shown

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positive correlations between asthma exacerbations and SO2, ozone, fine particulate matter, and sulphates.127-129 Indoor air pollution is a contributory factor in exacerbation of bronchial asthma.130 Environmental tobacco smoke is important in the development of childhood asthma and in the worsening of asthma in children and adults.131 The earlier and the greater the degree of environmental tobacco smoke, the greater the likelihood of asthma developing in children. In infants exposed to prenatal and postnatal cigarette smoking, have altered lung function.130,132,133 These limitations in lung functions may be secondary to smaller lung size, and less maturity of lungs secondary to in utero lung growth retardation because of persistent exposure of lungs to nicotine.134-136 Increased bronchial responsiveness after birth occurs in infants exposed to maternal smoking.137 Infants exposed to smoking are at increased risk of developing asthma later in life.138-146 It is, however, not clear whether increased bronchial reactivity after birth plays a role, if any, in the development of asthma. It is also not clear whether the increased bronchial reactivity in these infants is purely genetic, or whether it is the result of lung injury from exposure to cigarette smoke. Asthmatic smokers have increased hyperresponsiveness to methacholine.147 Asthmatic smokers have higher sputum total cell and neutrophil numbers and IL-8 concentrations compared to asthmatic nonsmokers. In contrast, sputum eosinophils and eosinophil-cationprotein levels are higher in nonsmoking than smoking asthmatics, suggesting a normalising effect of smoking on the Th1/Th2 balance. Thus upon the eosinophils inflammation, smoking induces neutrophilic airway inflammation in asthma.147 Further, smoking asthmatics show no improvement in lung function, airway hyperresponsiveness, and sputum eosinophilia on treatment with steroid inhalation.148 This decreased steroid responsiveness is responsible for the faster decline in FEV1 seen in smoking asthmatics. ENDOCRINAL FACTORS Although the exact role of hormones in asthma has not been defined, a number of patients complain of exacerbation of their symptoms during or preceding menstruation. Retrospective studies suggest that in approximately one-third of women, asthma becomes worse during pregnancy; in one-third, it becomes better; and in one-third, it remains unchanged. In women in whom asthma becomes worse during pregnancy, peak severity occurs at 29-36 weeks of gestation. Asthma becomes less severe during the last 4 weeks of pregnancy. The change in the severity of asthma during pregnancy is sometimes dramatic and tends to be consistent in subsequent pregnancies. Most patients return to a prepregnancy level of severity by 3 months of postpartum.149-152 There may be an improvement in airway responsiveness during pregnancy that is greatest in those with the most hyperresponsive airway initially. It is also reported that improvements in responsiveness are associated with improvements in clinical asthma severity. However, progesterone alone did not appear to be the sole contributor to these improvements. It is also suggested that oestrogen plays a role in the pathophysiology of asthma and long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma.153 Several observations have been made on the influence of thyroid hormones on asthma. Hyperthyroidism is accompanied by many manifestations suggesting over stimulation of the sympathetic system and this condition is a contraindication for use of β-2 agonists. One, therefore would expect that patients of bronchial asthma, who in addition develop hyperthyroidism, should either have a decreased requirements of bronchodilators or amelioration of their symptoms. However, the reverse has been observed. Asthmatics who develop

Aetiology 31 hyperthyroidism, do far worse than euthyroid asthmatics. In some hyperthyroid asthmatics following treatment of hyperthyroidism, not only asthma improves, but in rare instances they become completely asymptomatic. Similar discrepancies have also been observed in hypothyroidism. Various mechanisms such as changes in beta adrenoceptor activity and altered prostaglandin metabolism have been proposed to explain these observations. Bronchodilator response is impaired in the presence of excess thyroid hormones, which improves after euthyroid state is achieved.154 GENETICS AND ASTHMA Genetic factors play a contributing role in the pathogenesis of asthma.155 There are several studies indicating familial aggregation of asthma. It is a frequent clinical observation that asthma runs in families. Moreover, other atopic conditions like allergic rhinitis and atopic dermatitis are common among the family members of the asthma patients. The concordance of asthma in monozygotic (MZ) twins is reported to be significantly greater than that in dizygotic (DZ) twins. Though the dosage of inhaled antigens and other factors influence the likelihood of clinical disease, recent family studies suggest that atopy is dominantly inherited. Molecular genetic linkage studies indicate that the “atopy” gene locus is on chromosome 11.156-159 Cytokines are important components in the pathogenesis of asthma (see below). The genes for these cytokines are encoded in a small region in the long arm of chromosome 5 and a number of them are coordinately regulated. T cells that differentiate along this route and preferentially release cytokines of the IL-4 gene cluster are called Th2-like. These Th2like lymphocytes and their cytokines are over represented in tissue biopsy studies in patients with allergic diseases. The chromosome 5 contains an IL-4 gene cluster which encodes the allergic cytokines IL-3,4,5,9,13 and GM-CSF (granulocyte macrophage colony-stimulating factor). This gene is closely linked to inheritance of an increased IgE response and to increased bronchial hyperresponsiveness. Further, human genome studies have revealed that allergic diathesis is linked with a region on the long arm of chromosome 12 which contains the gene encoding interferon-γ) (INF-γ), which is a powerful suppressor of Th2 responses. It is established that there is a reciprocal relationship between Th2 and Th1 responses with IL-10 derived from Th2 cells inhibiting Th1 responses while INF-γ generated by Th1 cells inhibits Th2 responses. It is possible that, in allergic diseases like asthma, there is an increase in the expression of genes, which regulates Th2 cytokines, a decrease in expression of genes that regulate INF-γ production, or a combination of both.160 The other genetic component that plays an important role is the ability of a susceptible individual to recognise an environmental allergen as foreign and starts an allergic immune response. This component operates through the human lymphocyte antigen (HLA, or MHC class II) molecules HLA-DR, HLA-DP, HLA-DQ, which provide the mechanism for antigen recognition and presentation to and by T and B lymphocytes.160 Many candidate genes and positional cloning have recently been identified.161 The first genome-wide screen for linkages to asthma identifies linkages on chromosomes 4q,6 (near the major histocompatibility complex, (MHC), 7,11q containing FcεR1-β, 13q and 16. Linkages have been confirmed to chromosomes 4,11,13 and 16. Suggestive evidences are also found for linkages and replication for loci on chromosomes 5q, 12q, 19q, and 21q. Different linkages have been reported from different ethnic groups. The loci most consistently and robustly identified are on chromosomes 5, 6, 12 and 13.

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Various candidate genes those have been implicated in atopy and asthma are summarised in Table 2.2.162 Several studies have shown that polymorphisms in the β2 adrenergic receptor gene influences responsiveness to β-agonists. Similarly polymorphisms in the 5-lipoxygenase gene and the leukotriene C4 synthase gene have been associated with response to medications that target leukotriene metabolism. These findings suggest the potential for pharmacogenetic tailoring of therapy in individual asthmatic patients.163 Environmental risk factors for development of asthma are summarised in Table 2.3. Table 2.2: Candidate genes for asthma

Chromosome 1 5

6 11 12 13 14 16

Gene IL-10 IL-4 promoter IL-5 IL-9 IL-12B IL-13 GM-CSF CD 14 β2 adrenergic receptor TNF-α Human leukocyte antigens FcεR1-β, CC16 Interferon γ STAT 5 T-cell receptor α/β complex IL-4 receptor (IL-4α)

Table 2:3: Environmental risk factors for the development of bronchial asthma Allergens Pollutants

Infections

Dietary modifications

Food allergens Inhalant allergens Environmental tobacco smoke Diesel particulates Noxious gases (ozone, SO2, NO2) Viral Respiratory syncytial virus Parainfluenza virus Human rhinovirus Bacterial Mycobacterium Chlamydia Mycoplasma Lactobacillus ω3 fatty acids Vitamins Antioxidants Lectins

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129. Cunningham J, O’Connor GT, Dockery DW, Speizer FE. Environmental tobacco smoke, wheezing, and asthma in children in 24 communities. Am J Respir Crit Care Med 1996;153:218-24. 130. Martinez FD, Wright AL, Tausig LM et al. Asthma and wheezing in the first six years of life. New Engl J Med 1995;332:133-38. 131. Committee of the Environmental and occupational Health Assembly of the American Thoracic Society: Health of outdoor air pollution. Am J Respir Crit Care Med 1996;153:3-50. 132. Stick SM, Burton PR, Gurrin L et al. Effect of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 1996;348:1060-64. 133. Tager IB, Ngo L, Hanrahan JP. Maternal smoking during pregnancy: effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 1995;152:977-83. 134. Chen MF, Kimizuka G, Wang NS. Human fetal lung changes associated with maternal smoking during pregnancy. Pediatr Pneumonol 1987;3:51-58. 135. Lieberman E, Torday J, Barbieri R et al. Association of intrauterine cigarette smoke exposure with indices of fetal lung maturation. Obstet Gynecol 1992;79:564-70. 136. Sheikh S, Goldsmith LJ, Howell L et al. Comparison of lung function in infants exposed to maternal smoking and in infants with a family history of asthma. Chest 2002;116:52-58. 137. Young S, Le Souef PN, Greelhoed GC et al. The influence of family history of asthma and parental smoking on airway responsiveness in early infancy. New Engl J Med 1991;324:1168-73. 138. Infante-Rivard C. Childhood asthma and indoor environmental risk factors. Am J Epidemiol 1003;137:834-44. 139. Arshad SH, hide DW. Effects of environmental factors on the development of allergic disorders in infancy. J Allergy Clin Immunol 1992;90:235-41. 140. Weitzman M, Gortmaker S, walker DK et al. Maternal smoking and childhood asthma. Pediatrics 1990;85:505-11. 141. Stoddard JJ, Miller T. Impact parental smoking on the prevalence of wheezing respiratory illness in children. Am J Epidemiol 1995;141:96-102. 142. Lewis S, Richards D, Bynner J et al. Prospective study of risk factors for early and persistent wheezing in childhood. Eur Respir J 1995;8:349-56. 143. Weiss ST. Environmental tobacco smoke and asthma. Chest 1993;104:991-92. 144. Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers. Pediatrics 1992;89:21-26. 145. Ehrlich RL, Tott DD, Jordan E et al. Risk factor for childhood asthma and wheezing: Importance of maternal and household smoking. Am J Respir Crit Care Med 1996;154:681-85. 146. Wright AL, Holberg C, Martinez FD et al. Relationship of parental smoking to wheezing and non-wheezing lower respiratory tract illness in infancy. J Pediatr 1991;118:207-14. 147. Chalmers DW, MacLeod KJ, Thomson L et al. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917-22. 148. Chalmers DW, MacLeod KJ, Little SA et al. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57:226-30. 149. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy; a prospective study of 198 pregnancies. Thorax 1988;43:12-18. 150. Editorial. Pregnancy and the asthmatic. Respir Med 1991;85:451. 151. Schatz M, Harden KM, Forsythe A et al. The course of asthma during pregnancy, postpartum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988;81:509. 152. Schatz M, Zeiger RS, Harden KM et al. The safety of inhaled β-agonist bronchodilators during pregnancy. J Allergy Clin Immunol 1988;82:686. 153. Troisi RJ, Speizer FE, Willett WC, trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: A prospective cohort study. Am J Respir Crit Care Med 1995;152:1183-88.

Aetiology 39 154. Behera D, Roy R, Dash RJ, Jindal SK: Airway response to inhaled fenoterol in hyperthyroid patients before and after treatment. J Asthma 1992; 29:307, 369-74. 155. Meyers DA, Bleecker ER. Approaches to mapping genes for allergy and asthma. Am J Crit Care Med 1995;152:411-13. 156. Hopkin J. Genetics and lung disease. Advances in our understanding of emphysema, cystic fibrosis, and asthma. Br Med J 1991;302:1222. 157. Cookson WOCM, Hopkin JM. Dominant inheritance of atopic immunoglobulin-E responsiveness. Lancet 1988;i:86. 158. Cookson WOCM, Sharp P, Faux J, Hopkin JM. Linkage between immunoglobulin-E responsiveness underlying asthma and rhinitis and chromosome 11q. Lancet 1989;i:1292. 159. Nieminen MM, Kaprio J, Koskenvuo M. A population-based study of bronchial asthma in adult twin pairs. Chest 1991;100:70. 160. Holgate ST. Asthma and allergy: Interaction of immunology and environment. Pulmonary Perspectives 1997;14:4-6. 161. Cookson WOC. Asthma genetics. Chest 2002;121:7S-13S. 162. Sandford A, Pare P. The genetics of asthma: The important questions. Am J Respir Crit Care Med 2000;161:S202-S206. 163. Joos L, Sandford AJ. Genotype predictors of response to asthma medications. Curr Opin Pulm Med 2002;8:9-15.

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3 Pathophysiology of Bronchial Asthma Bronchial asthma is a disease characterised by wide variation over short periods of time in the resistance to flow in the airways. The hallmark of the disease is the airflow obstruction. Most asthma is of allergic origin. In this form, it is viewed as a sum of three features: the early asthmatic reaction (EAR); the late asthmatic reaction (LAR); and bronchial hyperresponsiveness, with varying contribution from each. The cellular response in LAR in non-allergic asthma is similar, but little is known of the underlying aetiology. Three factors narrow airway caliber to limit the flow: • Airway smooth muscle contraction; • Gland and epithelial secretions and exudation into the airway lumen; and • Inflammatory oedema and vasodilatation (hyperaemia). Early Asthmatic Reaction (EAR) In atopic individuals, bronchial challenge/inhalation of appropriate antigens will elicit an early response, which is maximum at 15 minutes and characterised by smooth muscle contraction, exudation of plasma, and mucus production. This reaches its peak in about thirty minutes and resolves within 90-180 minutes. This early reaction is IgE dependent and is the result of IgE binding to mast cells by its Fc portion and to specific antigens by its F(ab) portion. When IgE-sensitised mast cells are exposed to antigen against which the IgE molecule is directed, pre-formed and newly generated mediators are released.1 These can be detected in the blood as they overflow into the circulation, in bronchoalveolar lavage fluid, and as metabolites in the urine and include histamine, prostaglandin D2, and leukotriene C4 from airway mast cells.2 This early response is due to the release of histamine. This reaction can be prevented by pre-medication with sodium cromoglycate and nedocromil sodium and β-2 agonists,3 but not with steroids. Late Asthmatic Reaction (LAR) and Bronchial Hyperreactivity (BHR) The EAR is followed by a complete or partial recovery period over the next 1 to 2 hours and then by a further progressive fall in respiratory function, which is maximal between 6 to 12 hours. A further recovery occurs by 24 to 36 hours. This response can only be partially reversed by β-2 agonist, but pre-medication with cromolyn and corticosteroids inhibits this response. The LAR is also characterised by the release of inflammatory mediators into the same fluids. However, during this phase there is a striking infiltration of inflammatory

Pathophysiology of Bronchial Asthma 41 cells with activation of these cells which include eosinophils, neutrophils, and lymphocytes. This LAR is thought to be a primary mechanism responsible for airway (bronchial) hyperresponsiveness (BHR). The BHR is an exaggerated bronchoconstriction of smooth muscles and airway narrowing on exposure to small quantity of non-allergic stimulant that usually does not provoke such a reaction in normal subjects.4 The BHR usually precedes the onset of LAR.5 This may last for several days or occasionally weeks.6 The BAL fluid from these subjects contains increased eosinophils, eosinophilic cationic protein, CD4+ T lymphocytes, macrophages, monocytes, basophils, and neutrophils.3,6 The selective recruitment of these leucocytes into the airways during the LAR are probably due to the release of local and circulating messengers, i.e. cytokines from the cells in the airway mucosa in relation to allergen exposure with the subsequent effect of recruiting mature and precursor cells from the bone marrow and other sites of leucocyte sequestration.7 Mucosal oedema and vasodilatation are the important components of airway obstruction during the LAR and contraction of airway smooth muscle contribute substantially to the EAR. It is clear from studies in human and animals that the two phases of bronchoconstriction response to inhaled antigen have distinct characteristics. The immediate response to antigen occurs before airway inflammation is established histologically, is abolished or attenuated by prior bronchodilator drugs like β-2 adrenergic agonist, is sensitive to the effects of antiinflammatory drugs, and is not associated with an increased bronchial hyperreactivity. In contrast, the LAR is associated with histologic evidence of airway inflammation, is relatively resistant to bronchodilator drugs, is lessened by corticosteroids, and is associated with bronchial hyperreactivity. Rabbit experiments showed that if they are depleted of neutrophils and then exposed to inhaled antigen, there will be an immediate bronchoconstrictor response, but there will be no late bronchoconstriction, neither they develop bronchial hyperreactivity. These findings suggest that airway inflammation underlines the bronchial hyperreactivity characteristic of LAR. Non-immunologic causes of airway inflammation are also associated with the development of bronchial reactivity. Inhaled ozone and viral infections damage the bronchial epithelium, leading to an inflammatory response in the bronchial walls and bronchial hyperreactivity develops once airway inflammation become evident. Similarly neutropenic dogs do not develop hyperreactivity after exposure to ozone. All these support the hypothesis that inflammatory processes are important in the pathogenesis of bronchial hyperreactivity.8 The results of skin testing of allergic subjects indicate that isolated immediate hypersensitivity reactions occur in about 20% of positive challenges, isolated late phase reactions in 6-14%, and both reactions in 66 to 85%. Thus, it is apparent that both inflammation and bronchial hyperreactivity are important to bring about these changes. A series of events including cellular elements, mediators, and neuropeptides in a coordinated manner are responsible for the ultimate airway obstruction. A number of cells and chemical by-products take part in the pathogenesis of bronchial asthma to bring about changes outlined above. The stimulus/stimuli in a susceptible host starts the ball rolling so that a number of cells with their products cause various changes that are characteristic of bronchial asthma. The understanding and concept of pathogenesis of bronchial asthma has changed considerably over the past decade. Bronchial asthma is now considered as a heterogeneous disorder with multiple triggers. However, certain features are common to all asthmatics: Airway inflammation and hyperresponsiveness to a broad range of stimuli. It is also known over the last few years that there is a close relationship

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between airway inflammation and hyperresponsiveness. Exposure to oxidants, pollutants, viral infections, chemicals, and allergens are all associated with inflammation and these inflammatory stimuli are associated with airway hyperresponsiveness. Most studies have shown that airway inflammation precedes hyperresponsiveness and may be a prerequisite for the development of hyperresponsiveness and clinical bronchospasm. On the other hand, airway inflammation as in purulent bronchitis may be present without hyperresponsiveness or bronchospasm. Thus, airway inflammation, a hallmark of bronchial asthma is of a specific nature that differs from other types of inflammation. Bronchial asthma is now established as an inflammatory disease of the airways associated with inflammatory cell infiltration, epithelial damage, and subepithelial fibrosis. Bronchoalveolar lavage studies from patients with bronchial asthma have shown increased number of eosinophils, mast cells, epithelial cells, and various humoral and chemical mediators of asthma.9-15 Histopathological studies also have shown epithelial shedding and influx of eosinophils into the airway mucosa.16-18 Fresh biopsies from asthmatics of varying severity have shown epithelial changes, deposition of collagens, and influx of inflammatory cells even in patients with mild asthma.19 Further, presence of increased number of eosinophils in the sputum and peripheral blood of patients with bronchial asthma has been known for many years. It is also reported subsequently that eosinophils and mast cells increase quantitatively during exacerbations of asthma. Substantial data also support the role for both neutrophils and macrophages.20 Specific subtypes of lymphocytes (T-helpers2 [Th2]) may orchestrate a unique inflammatory response in the asthmatic lung and may significantly modulate the function not only of the inflammatory cells, but also non-inflammatory cells which include endothelial cells, platelets, sensory nerves, and airway epithelial cells.21 These non-inflammatory cells may contribute to the inflammatory response and may also directly participate in the regulation of normal airway tone. The function of these cells can be modulated in asthmatics and they may produce mediators with effects on airway function.22-31 INFLAMMATORY CELLS IN ASTHMA Mast Cells Mast cells have been recognised since a long time as the main effectors cells in early asthma reaction.32,33 Normal human respiratory tract contains large numbers of mast cells beneath the bronchial epithelium and alveolar walls. Increased numbers of mast cells and histamine (a product of mast cells) have been found in the bronchoalveolar lavage fluid obtained from patients with bronchial asthma.34,35 These calls are derived from CD34+ cells in the bone marrow.36 Based on the production of proteases, a number of subtypes of mast cells exist in human beings.37 A large number of biologically active molecules, both preformed, i.e. histamine, proteases38 and newly synthesised,39 are released from the mast cell during the allergic reaction when its high affinity, IgE receptors are cross-linked with antigen.40 After immunological activation, some populations of mast cells metabolise arachidonic acid, primarily through the cyclooxygenase pathway to prostaglandin (PGD2), and thromboxane A2, whereas other populations of mast cells metabolize arachidonic acid primarily through the 5'-lipooxygenase pathway to LTB4 and LTC4 (Fig. 3.1). All mast cells have secretory granules that contain large amounts of histamine, proteoglycans, heparin, and proteases. These preformed substances are exocytosed from the cell after immunologic

Pathophysiology of Bronchial Asthma 43

Fig. 3.1: Arachidonic acid metabolism and mediator release (LT- Leukotriene)

activation. It has been shown recently in experimental animals that certain activated mast cells also release transiently a large number of cytokines affect the tissue microenvironment during inflammation. These substances are GM-CSF, INF-γ, IL-1, IL-3-6, PAF, transforming growth factor, JE, and M1P1. These cytokines are capable of recruiting, priming and activating other cells involved in inflammation. Through the release of cytokines similar to those released from TH2 lymphocytes, it is possible that mast cells also play an important role in the development of LAR in addition to its primary role in EAR. It has been suggested that mast cells also possess anti-inflammatory properties through release of heparin and related proteolysis. The tissue damaging properties of cationic protein mediators released from eosinophils (see later) are neutralised by the highly anionic heparin. It has also been shown that heparin inhibits the increased vascular permeability induced by a wide range of agonists, can inhibit lymphocyte activation and trafficking and like glucocorticoids is capable of inhibiting delayed hypersensitivity responses. Thus, it is hypothesised that an imbalance between these inflammatory and anti-inflammatory substances will decide the final outcome. However, this has not yet been proven. Although mast cells are primary cells in EAR through IgE dependent release of spasmogenic mediators, they also have an important role in LAR as they also produce

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GM-CSF, interleukins, etc.41 although some other reports indicate that they are less likely to be involved in the chronic inflammatory response.42,43 Eosinophils44-47 The importance of eosinophils in the causation of bronchial asthma is evident in view of extensive tissue, blood and sputum eosinophilia in this disease. Biopsy studies both postmortem and during life have shown the presence of excess eosinophils in the bronchial mucosa of these patients. They also play a key role in asthma, and their presence in the airways characterises the inflammation of asthma, which has been termed as “chronic eosinophilic bronchitis”. The number of activated eosinophils is closely related to asthma severity and may be associated with epithelial shedding. Their development is dependent on T cell function. The IL-5 specifically stimulates eosinophil differentiation. They have receptors for IgG, IgA, and IgE on their cell surface. These cells are able to produce many mediators that are responsible for the disordered airway function characteristic of asthma. These substances include: • Platelet activating factor • LTB4 • LTC4 • PGE2 • 15-HETE • Oxygen radicals and • Four cytotoxic proteins48-51 i. Major basic protein (MBP) ii. Eosinophil cationic protein (ECP) iii. Eosinophil-derived neurotoxin (EDN) and iv. Eosinophil peroxidase (EPO). All these mediators are released by activated eosinophils. The release of these mediators results in bronchoconstriction, epithelial damage, and recruitment and priming of other inflammatory cells. Eosinophil maturation and priming are under the control of IL-3, IL-4, IL-5, and GM-CSF (Granulocyte macrophage-colony stimulating factor), cytokines released from a number of cell types in the airways including activated T cells of the TH2 type, and mast cells. Another molecule present in the eosinophils is the Charcot-Leydon crystal protein that possesses lysophospholipase activity. Eosinophils have characteristic granules and granule proteins. The granule is composed of a crystalloid core and a matrix. The above four proteins are present in the granules. The genes of these proteins are cloned and the cDNA for MBP specifies the existence of a proMBP molecule that is composed of an acid-rich portion and a basic MBP portion. EDN and ECP are both ribonucleases. In addition, ECP is a potent helminthotoxin. EPO is a member of the peroxidase multigene family that is composed of myeloperoxidase, thyroid peroxidase, and lactoperoxidase. The MBP is toxic to respiratory epithelium and is elevated in the sputum of patients with asthma. It has also been shown that MBP is deposited in the damaged areas in the epithelium. Not only MBP, but also ECP and EPO alone, as well as EPO in the presence of halide and hydrogen peroxidase, damage bronchial epithelium. Experimental studies have shown that eosinophil proteins, particularly MBP applied to respiratory epithelium stimulates smooth muscle contraction and also can increase the sensitivity of the smooth

Pathophysiology of Bronchial Asthma 45 muscle to acetylcholine, which suggests that eosinophil is an effector of the changes of bronchial hyperreactivity in vivo. Lymphocytes52-70 Although production of IgE by B lymphocytes is well known, the role of T lymphocytes in bronchial asthma had received little attention till recently.52,53 Chronic asthma, at least in part, represents a form of delayed-type hypersensitivity involving interactions between “activated” lymphocytes and eosinophils. There are a number of evidences to prove that these cells play important roles in this disease. i. T lymphocytes secrete lymphokines, IL-4, and interferon-γ, that closely regulate IgE production by B lymphocytes. While IL-4 stimulates, interferon-γ inhibits IgE synthesis. ii. IL-3, and IL-5, and GM-CSF regulate eosinophil production, and IL-3, and IL-4 are important regulators of mast cell and basophil production. iii. T cells are attracted to the bronchial mucosal surface to the site of inflammation by specific receptors both on themselves and on the mucosal capillary and endothelial venules. iv. Local accumulation of CD8+ cells in early phase reactions recovered in BAL fluid suggests that the subsequent late phase reaction may be in part, under the control of T cells. Although CD8+ cells are not a part of this reaction, it has been found that substantial infiltration of CD4 IL-2R+ lymphocytes, and activated (EG2+) eosinophils occurs in allergen-induced late phase reaction in atopic subjects. Recently it has been reported that a high percentage of these CD4+ cells are UCLH-1 or memory cells, that respond to recall antigens. v. Patients with acute severe asthma have activated CD4+ lymphocytes in their blood, the number of which returns to baseline value after successful treatment. The elevation is associated with increased serum concentration of IL-2 soluble receptors and INF-γ. These changes corelate well with the severity of disease. vi. Corticosteroid resistant asthmatics have chronically activated circulating T cells (IL-2R and HLA-DR positive). vii. More recently, direct evidence of T cell involvement in bronchial asthma is acquired by the study of mucosal biopsy specimens from volunteers. Electron microscopy has revealed elevated numbers of activated “irregular” lymphocytes in the bronchial mucosa. There is a significant increase in the number of IL-2R+ (CD25) cells both at the central and subsegmental airways. It is now well established that there are two types of T cells.54 They are Th1 and Th2, divided on the basis of lymphokines they secrete. While the Th1 cells secrete IL-2, interferonalpha and tumour necrosis factor-beta, the Th2 cells secrete IL-4,IL-5, IL-6, and IL-10, and IL-3 and GM-CSF are secreted by both. While INF-γ inhibits the development of Th2 cells,55 IL-10 inhibits Th1 proliferation.56 Details of such interaction are being discussed above under genetics and asthma. More recently, another stable phenotype among T-helper clones has been recognised both in mouse and man, which is called Th0. This subtype is characterised by an ability to generate a large variety of cytokines, including IL-4 and INF-γ, which are characteristic of either the Th1 or Th2 subset. Therefore, activated CD4+ cells are a feature of both active and chronic asthma, more so for the later, and their presence is associated with actively secreting eosinophils. T cells may be directly involved in eosinophil recruitment and activation by secreting various

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interleukins which favour the synthesis of IgE and activation of eosinophils and mast cells. There is a preferential expansion of type Th2 T cells secreting IL-3, IL-4, IL-5 and GM-CSF with fewer Th1 cells whose cytokine profile includes IL-2 and interferon-γ. Such a mechanism would explain the peculiarities of allergic inflammation involving isotype switching to IgE synthesis, and the preferential recruitment of eosinophils and mast cells. Lymphokines and various other cytokines that are relevant to airway inflammation in asthma are shown subsequently.57-68 Two important cytokines , that are particularly important in bronchial asthma are IL-4 and NF-KB.69,70 IL-4 is essential for IgE production. INF-γ diminishes cell processing necessary for IL-4 production.69 Thus, interplay of these cytokines will decide whether IL-4 producing cells will be produced, and, thus, whether IgE will be produced in response to various allergic stimuli. The role of transcription-factor NF-KB is emerging recently to play a key role in the pathogenesis of bronchial asthma. It is postulated that inflammatory signals activate transcription factors such as NF-KB and this in turn will switch on the inflammatory genes, which will lead on to the increased expression of inflammatory proteins. Corticosteroids are potent inhibitors of NF-KB and their antiinflammatory action is believed to be mediated through this mechanism.70 Thus, it may be summarised that T cell participation is an important event in allergic diseases and asthma. Th2 cells are more important by the way of production of various cytokines which are necessary for allergic responses. In contrast, Th1 cells are primarily responsible for classic delayed hypersensitivity. Products of Th1 type cells, principally INF-γ, inhibit or antagonize Th2 effector function. IL-4 induces IgE synthesis, and INF-γ is a strong inhibitor of this process. Such control establishes a model of how IgE can be tightly regulated in vitro. The Th2 pathway is also involved in regulation of eosinophilia, mast cell activity and IgE synthesis. The differentiation into Th1 and Th2 cells are again regulated by cytokines. While IL-4 may act directly on the precursor T cell to induce Th2 differentiation, interferon and transforming growth factor-beta TGF-β.71 While T cell sensitisation is an important factor in the development of IgE production to a particular antigen and T cell subsets are important in establishing the process of airway hyperresponsiveness. Experimental data have shown that the transfer of antigen-specific IgE, immediate cutaneous hypersensitivity, and increased airway responsiveness may be mediated, depending on the antigen, by specific Vβ expressing T cell subsets. While the precise mechanisms by which inflammatory cells are recruited into the lungs are not fully understood, increasingly available evidence suggest that the activation of antigen-specific CD4+ T cells of the type 2 T-helper (Th2) subset in the lungs, which results in IL-5 secretion, plays a major role in asthmatic airway inflammation.72 CD4+ T cell activation leading to cytokine production and effector function requires two signals from the antigen-presenting cell (APC). The first signal is triggered by the interaction between antigen-specific T cell receptor and peptide-major histocompatibility complex II complexes on APCs. The second signal or ‘co-stimulatory’ signal is triggered by CD80 (B7-1) and CD86 (B7-2) of the APC binding to the CD28 and cytotoxic T lymphocyte antigen (CTLA-4) of the T lymphocytes.73-76 In the absence of co-stimulatory signals, the T cell-dependent immune response is greatly diminished, or even eliminated.77 Thus, costimulatory signals may fulfill a valuable role in T lymphocyte activation, Type 1 T-helper (Th1) or Th2 cell differentiation, and the production of different cytokines.78 CTLA-4 is a second co-stimulatory molecule and is a homologue of CD28. It is expressed only on activated T cells, binds to accessory molecule B7,79 and mediates T cell-dependent

Pathophysiology of Bronchial Asthma 47 immune response. Signalling through CTLA-4 may down regulate Th1 cell proliferation by inhibiting the production of IL-2 and IL-2 receptor expression.80,81 However, the role of CTLA-4 remains uncertain, with some studies79 the CTLA-4 might also deliver a positive signal to Th2 cell activation. Disruption of this delicate balance of immune regulation could lead to autoimmune diseases or atopic diseases. Therefore, CTLA-4 is considered to be important in the development of many of the immunologic and physiologic features of asthma. Polymorphisms of the CLTA-4 gene, located on chromosome 2q33, could thus have effects on immune response. Three CTLA-4 genes are known at present.82-86 The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. This promoter polymorphism is associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association is found between severe asthma and bronchial hyperresponsiveness.85 Monocytes and Macrophages Several findings favour a role for macrophages in bronchial asthma.86-94 Firstly, after in vivo and in vitro contact with specific allergen or non-specific stimulus, alveolar macrophages from asthmatics have been shown to release lysosomal enzymes, prostaglandin (TxB2), leukotrienes, and platelet-activating factor (PAF). They are also able to generate oxygen free radicals, neutral proteases, and β-glucuronidase after non-specific stimulation. Some of these studies also have shown that macrophages from asthmatics are hyperactive and release more lipid-derived mediators than those from the normal subjects. Secondly, a subpopulation of peripheral blood monocytes and alveolar macrophages are IgE receptor positive.95,96 Whereas in normal healthy humans, only 5 to 10% of the alveolar macrophages and 10-15% of the peripheral monocytes are IgE Fc positive, these numbers increase dramatically in asthmatics. As many as 80% of the monocytes and up to 30% of the macrophages recovered from BAL fluid in mild asthmatics will be IgE receptor positive. The percentage may be still higher in severe forms of asthma. The macrophage IgE receptors (IgE FcR) has a low affinity for IgE compared to that of the mast cell. This lower affinity binding suggests that IgE immune complexes may be more important in activation of these cells compared to mast cells and basophils that are sensitised by monomeric IgE, because of their greater strength of binding to this FcR. Thirdly, it has been demonstrated that active macrophages are present at the air-surface interface of human airways as well as in alveoli. Therefore it is possible that these cells interact with any inhaled allergen. Fourthly, macrophages are capable of releasing several potent neutrophil chemotaxins. These include complement fragments, fibronectins, neutrophil attractant/activating protein1 (IL-8), and LTB4. IL-8 is also chemotactic for lymphocytes. The production of LTB4 from macrophages is greater on a nanogram per cell basis than other cells. LTB4 and PAF are chemo attractants for eosinophils. Macrophages produce histamine-releasing factor(s) that induce the release of histamine from basophils. Fifthly, macrophage function is altered by lymphokines, such as INF-γ. It is reasonable to hypothesize that this lymphokine and/or others, such as IL-4, may regulate the number of IgE FcRs on lung macrophages.

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Basophils Basophils are histamine releasing cells in the late phase reaction of asthma unlike mast cells, which release histamine in the early phase reaction. The spontaneous release of histamine is quite high by these activated basophils (20-40% of total). This release process has slow kinetics and is temperature dependent. Various cytokines (IL-1, IL-3, and histamine releasing factor) and PAF have an up regulatory/stimulatory effect on blood basophils. Any or all of these cytokines could prime the basophils such that they become responsive to very low concentrations of stimuli or some could directly trigger basophil mediator release. Epithelial Cells and Adhesion Molecules The infiltration of inflammatory cells into the airways is dependent on the expression of adhesion molecules on inflammatory cells and endothelial cells of the bronchial circulation.97 One consequence of inflammation is epithelial injury. Morphological studies have shown that asthma is associated with epithelial injury. These changes range from minor disruption of the epithelium with loss of ciliated cells to complete denudation of the epithelium. These structural changes in the epithelial barrier can lead to increased permeability to inhaled allergens, irritants, and inflammatory mediators. In addition, transudation of fluids and reduced clearance of inflammatory substances and respiratory secretions occur with disruption of epithelial mucociliary mechanisms. The epithelium also participates in mediator release and metabolism.98-101 They have the capacity to produce PGE2, PGF2α, 12-and 15-hydroxy eicosatetraenoic acid, GM-CSF, etc. The bronchial hyperresponsiveness in asthma is attributed to the epithelial cell damage. The airway epithelial cells have a protective role against various tachykinins. Currently, adhesion molecules are considered to be important in the causation of airway inflammation, although the specific mechanism is still under investigation.102-109 Adhesion of various inflammatory cells to the bronchial vascular endothelium is a key step in the initiation and propagation of inflammation. This is effected by the interaction of various adhesion molecules expressed on endothelial cells, epithelial cells, platelets, and leucocytes. These molecules are specific glycoproteins that are grouped into different families depending upon their molecular structure. These include integrins, immunoglobulin super gene family (intracellular adhesion molecule-ICAM, vascular cell adhesion molecule-VCAM; platelet endothelial adhesion molecule-PCAM), selectins (E-selectin like ELAM-1, and ECAM-1, P-selectin, L-selectin) and carbohydrates are important for lung inflammation. Expression of various adhesion molecules is regulated by various mediators of inflammation. Neutrophils Although neutrophils are found in large proportions in the bronchial wall and bronchoalveolar lavage fluid in bronchial asthma, it is not clear if they have any definite role to play in bronchial asthma. However, such neutrophils in bronchial asthma show increased expression of membrane complement receptors and enhanced toxicity for complement coated antigens. They also have ability to alter airway function. These finding suggest that neutrophils probably participate in inflammation of bronchial asthma.

Pathophysiology of Bronchial Asthma 49 CYTOKINES IN BRONCHIAL ASTHMA Cytokines are extracellular signalling proteins, usually less than 80 KD in size, and many are glycosylated. They are produced by different cell types. A detailed discussion on the role of different cytokines is given below. Various cytokines and their function are shown in Table 3.1.

Cytokines IL-1 IL-2 IL-3 IL-4 IL-5

IL-6 IL-8 IL-10

Table 3.1: Various cytokines, their source and function in the pathogenesis of bronchial asthma110 Origin Function Various cells Th2-cells Th2 cell, mast cells eosinophils T cell, mast cell T cell, mast cells,

Increased expression of endothelial adhesion molecules Eosinophil activation Eosinophil and neutrophil differentiation, activation, and eosinophils survival, eosinophil chemotaxis IgE synthesis, T cell growth, endothelial adhesion Eosinophil differentiation, maturation, activation, eosinophils, adhesion, priming and chemotaxis, basophil differentiation and priming, cofactor in IgE synthesis T cells T cell growth factor, eosinophil chemo-attractant Monocytes, T cells Neutrophil chemo-attractant and activator, fibroblasts inhibits IgE synthesis T cell Inhibition of Th1 cytokine, stimulates monocytes production T cells NK cell and T cell growth, IgE synthesis inhibition T cells Critical regulator of allergic response T cells, mast cells Granulocyte differentiation, activation, survival, macrophages, eosinophils, epithelial cells T cells Eosinophil and macrophage activation T cell and macrophage activation,

IL-12 IL-13 GM-CSF chemotaxis IFN-γ Tumour necrosis factor Platelet derived Monocytes, growth factor (PDGF) Macrophages

Fibrosis, Th2 cytokine inhibition

INFLAMMATORY MEDIATORS IN ASTHMA From the foregoing paragraphs it is apparent that a number of mediators released by different cells are important for various changes observed in bronchial asthma.111-116 They are generated by recruited cells and resident cells of the airways. These mediators cause contraction of airway smooth muscle, increased mucus secretion, microvascular leak, further recruitment and activation of various inflammatory cells, all essential changes in bronchial asthma. LEUKOTRIENES Of the many mediators that have been implicated in the asthmatic response, the sulphidopeptide leukotrienes are of interest because they have the potential of involvement in both aspects of the asthma syndrome, i.e. hyperresponsiveness, and inflammation. The original discovery of a slow-reacting substance was that of smooth muscle contractile activity distinct from histamine; it was distinguished from histamine on the basis that its effects were slow in onset and prolonged in duration.117 The subsequent isolation and elucidation

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of the structure of slow-reacting substance was identified as cysteinyl leukotrienes (LTC4, LTD4, LTE4) which are synthesised and exported into the microenvironment by a number of the above mentioned inflammatory cells, including mast cells and eosinophils.118-127 Furthermore, since plasma leakage is prominent in more severe asthma, it is likely that the vascular endothelium will be exposed to cells capable of donating LTA4. It is well established that the cysteinyl leukotrienes are formed when LTA4 exporting cells, such as polymorphonuclear leucocytes (neutrophils and eosinophils) provide LTA4 for effector cells such as vascular endothelial cells or platelets. As shown in Figure 3.2 arachidonic acid (AA) released from membrane phospholipids during cell activation may be oxidatively metabolised by the enzymes of the cyclooxygenase or lipooxygenase pathways.109 Arachidonate is presented to the 5-lipooxygenase enzyme by 5-lipooxygenase-activating protein (FLAP).120 This FLAP is a cofactor resident in the nuclear membrane. While cyclooxygenase pathway produces prostaglandins and thromboxane, the 5-lipooxygenase pathway generates 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) or is converted enzymatically to the unstable intermediate LTA4. LTA4 is metabolised by an epoxide hydrolase to LTB4, or by a glutathion-S-transferase (LTC4 synthase) to LTC4.128 LTC4 is cleaved by glutamyl-transpeptidase to LTD4, which is converted by a peptidase to LTE4, these enzymes being ubiquitous in the tissues and circulation (Fig. 3.2). LTB4 is a potent chemo attractant for neutrophils, and the sulphidopeptide leukotrienes (LTC4, LTD4, and LTE4) are potent spasmogens for non-vascular smooth muscle and comprise the activity previously known as slow-reacting substance of anaphylaxis (SRS-A). The leukotrienes have profound biochemical and physiologic effects, even in Pico molar concentrations. The importance of leukotrienes has been suggested in a wide variety of disorders that include hepatorenal syndromes, myocardial ischaemia, and inflammatory conditions of bowel, skin and joints,122 besides their involvement principally in bronchial asthma.123 These include severe airway obstruction, i.e. bronchoconstriction,129 oedema,130 and increased secretion of bronchial mucus from submucosal gland secretion.131 The most

Fig. 3.2: Synthesis of leukotrienes and their function

Pathophysiology of Bronchial Asthma 51 prominent effect is their ability to mediate airway narrowing in normal subjects as well as in subjects with asthma. The airway obstruction is prolonged compared to that induced by histamine. LTC4 and LTD4 are approximately 3000 times more potent in contracting the airway compared to histamine in normal subjects. LT4 is also a potent bronchoconstrictor although 30-100 times less potent than the above two. LTE4 induces a state of enhanced airway responsiveness in asthmatics, but not in normal subjects. Inhalation of LTE4at doses that induce a small but significant contractile response enhances the response to subsequent administration of inhaled histamine. This enhancement is on the order of a four-fold shift in the histamine dose-response curve with the effect lasting approximately 24 hours with small effects persisting for up to a week. Thus a state of airway hyperresponsiveness is maintained. Leukotriene B4 (LTB4) is a potent chemotactic factor and is responsible, in part, for the recruitment of inflammatory cells to the airway and stimulation of secretion of inflammatory products. Their role in the smooth muscle contraction is controversial, although some studies suggest that they may increase airway smooth muscle responsiveness to subsequent stimulation. This can also modulate the immune response by inhibiting the capacity to mount a delayed hypersensitivity response.132 The cells producing leukotrienes are only macrophages, neutrophils, eosinophils, and mast cells that can synthesise them from the substrate arachidonic acid. However, subsequent enzymes like LTA4 hydrolase, and LTC4 synthase are more broadly distributed including non-inflammatory cells, airway epithelial cells and in the lung lining fluids. It is also now recognised that synthesis of leukotrienes in the lung may involve a single inflammatory cell type or an interaction between inflammatory and non-inflammatory cells termed “transcellular metabolism”. Some reports suggest that even transcellular metabolism may be the principal source of LTC4 in the lungs.133,134 These leukotrienes are recovered from nasal lavage fluid after inhalation challenge. Significantly larger quantities are also recovered from the BAL fluid from subjects with symptomatic asthma. Sulphidopeptide leukotrienes have been detected in the plasma during asthma attacks. Larger quantities of these substances have been recovered from the urine of asthma patients during acute spontaneous attacks than found in normal subjects. The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition.135-138 Leukotrienes are important in asthma, and leukotriene modifiers modulate antigeninduced asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma, but also in aspirin induced bronchial asthma, although the mechanisms of such overproduction are different. While in the former the overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma, the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade.140 Pranleukast, a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further, this drug increases FEV1 that falls during such provocation.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients.141-143

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Further, several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144,145 and improve respiratory function by bronchodilatation.146 Mast Cell Proteases As much as 70% of the weight of a mast cell consists of proteases that are enzymatically active at neutral pH. These cells express a complex array of proteases, which consist of serine proteases, tryptases, and chymase. These enzymes regulate neuropeptide regulation in the airways, smooth muscle contraction, and submucosal gland secretion.147-149 Histamine, another mast cell product has a well-established role in the pathogenesis of asthma. It induces bronchospasm, increases vascular and epithelial permeability, and increases the mucous glycoprotein secretion.150 Histamine The role of histamine in the pathogenesis of bronchial asthma is well established for a long time. Histamine induces bronchoconstriction, increases epithelial and vascular permeability, and increases the secretion of mucus glycoproteins.150 In patients of bronchial asthma, the levels of histamine are increased in blood and bronchoalveolar lavage fluid.151,152 Prostaglandins PGD2 and PGF2- A are very potent bronchoconstrictor agents. The former has greater bronchoconstrictor activity compared to that of the later or histamine.153 Both these prostaglandins also potentiates the bronchoconstricting activity of histamine and methacholine.155,156 On the other hand, PGE1 and PGE2 has bronchodilating effect. While Thromboxane A2 (TXA2) is a bronchoconstrictor, vasoconstrictor, and platelet aggregator, PGI2 is a bronchodilator, vasodilator and prevents platelet aggregation.156,157 Platelet-activating Factor (PAF) PAF has attracted attention as an important mediator of bronchial asthma.158-161 Recovery of this substance from bronchoaveolar lavage fluid in antigen exposed individuals supports such a role.162,163 It is an important mediator involved in the bronchial hyperresponsiveness in addition to having action of bronchoconstriction, stimulation of eosinophil and eosinophil accumulation in the airway, induction of airway microvascular leakage and oedema, and increased airway secretions and epithelial permeability. Bradykinin Bradykinin is another important inflammatory mediator in asthma and asthmatics have increased responsiveness to bradykinin,164 and the levels are found to be high in bronchoalveolar lavage fluid from these patients165 The substance causes bronchoconstriction, increases vascular permeability, has vasodilator activity, increases mucus secretion, activates C-fibre nerve endings, enhances neuropeptide release from sensory nerves, and increases cholinergic reflex.164, 166,167 Bradykinin mediates its effects through BK1 and BK2 receptors,166 although the effects on airways are primarily mediated via BK2 receptors. It also releases tachykinins from airway sensory nerves.

Pathophysiology of Bronchial Asthma 53 Cytokines Cytokines are extracellular signalling proteins, usually less than 80 kD in size and many are glycosylated. They are produced by different cell types involved in cell-to-cell interactions, having an effect on closely adjacent cells, and therefore function in a predominantly paracrine fashion. They may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). A classification according to function is proposed in Table 3.2. Table 3.2: Classification of cytokines and cytokine receptors

Cytokines Pro-inflammatory cytokines

IL-1α/β, TNFα/β, IL-6, IL-11, IFN-γ

Cytokines involved in atopy

IL-4, IL-13 (promoters); IFN-γ, IL-12 (inhibitors)

Cytokines of eosinophil chemo-attraction and activation

IL-2, IL-3, IL-4, IL-5, GM-CSF, RANTES, eotaxin, MCP-3, MCP-4

Th2 cytokines

IL-4, IL-5, IL-10, IL-13

Cytokines involved in T cell chemo-attraction

IL-16, RANTES, MIP-1α/β

Cytokines of neutrophil chemo-attraction and activation

IL-8, IL-1α/β, TNFα/β

Anti-inflammatory cytokines

IL-10, IL-4, IL-13, IL-12, IL-1ra

Growth factors

PDGF, TGF-β, FGF, EGF, TNF-α, SCF

Cytokine receptors Cytokine receptor super family

IL-2Rβ-and γ-chains, IL-4R, IL-3R α-and β-chains, IL-5 α-and β-chains, IL-6R, gp130, IL-12R, GM-CSFR; soluble forms by alternative splicing (e.g. IL-4R)

Immunoglobulin super family

IL-1R, IL-6R, PDGFR, M-CSFR

Protein kinase receptor super family

PDGFR, EGFR, FGFR

Interferon receptor super family

IFN-α/β receptor, IFN-γ receptor and IL-10 receptor

Never growth factor super family

NGFR, TNFR-1(p55), TNFR-II(p75)

Seven-transmembrane G-protein coupled receptor super family

Chemokine receptors

The effects of an individual cytokine may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine, and are mediated by binding to cell surface high-affinity receptors usually present in low numbers, which can be up regulated with cell activation. The receptors for many cytokines have been regrouped into super families based on the presence of common homology regions (Table 3.3). Cytokines themselves may induce the expression of receptors which may change the responsiveness of both source and target cells. Some cytokines may stimulate their own production in an autocrine manner, where as others stimulate the synthesis of difference cytokines that have a feedback stimulatory effect on the first cytokine, resulting in an increase in its effects. The effects of cytokines are summarised in Table 3.3.168

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Cytokines Lymphokines IL-2 IL-3 IL-4

IL-5

IL-13

IL-15 IL-16 IL-17

Pro- inflammatory IL-1

TNF-α

IL-6

IL-9

IL-11

GM-CSF

Important cellular and mediator effects • • • • • • • • • • • • • • • • • • • • • •

Eosinophilia in vivo Growth and differentiation of T cells Eosinophilia in vivo Pluripotent haematopoietic factor ↑ Eosinophil growth ↑ Th2; ↓ Th1 ↑ IgE ↑ Mucin expression and goblet cells eosinophil maturation ↓ Apoptosis ↓ Th2 cells BHR Activates eosinophils ↓ apoptosis ↑ IgE ↑ mucin expression and goblet cells As for IL-2 Growth and differentiation of T cells Eosinophil migration Growth factor and chemotaxis of T cells (CD4+) T cell proliferation Activates epithelia, endothelial cells, fibroblasts

• ↑ adhesion to vascular endothelium; cosinophil accumulation in vivo • Growth factor for Th2 cells • B cell growth factor; neutrophil chemo-attractant; T cell and epithelial activation • BHR • Activation epithelium, endothelium, antigen-presenting cells; monocytes/macrophages • BHR • ↑ IL-8 from epithelial cells • ↑ MMPs from macrophages • T cell growth factor • B cell growth factor • ↑ IgE • ↑ Activated T cells and IgE from B cells • ↑ Mast cell growth and differentiation • ↑ Mucin expression and goblet cells • Causes eosinophilic inflammation and BHR • B cell growth factor • Activates fibroblast • BHR • Eosinophil apoptosis and activation; induces release of leukotrienes

Contd...

Pathophysiology of Bronchial Asthma 55 Contd... Cytokines

SCF

Important cellular and mediator effects • Proliferation and maturation of haematopoietic cells; endothelial cell migration • BHR • ↑ VCAM-1 on eosinophils • Growth factor for mast cells

Inhibitory cytokines IL-10 • • • • IL-1ra • • IFN-g • • • • • IL-18 • • • • Growth factors PDGF • • TGF-β • • • • •

↓ Eosinophil survival ↓ Th1 and Th2 ↓ Monocyte/macrophage activation; ↑ B cell; ↑ mast cell growth ↓ BHR ↓ Th2 proliferation ↓ BHR ↓ Eosinophil influx after allergen ↓ Th2 cells Activates endothelial cell, epithelial cells, alveolar macrophages/monocytes ↓ IgE ↓ BHR ↓ Via IFN-γ release Releases IFN-γ from Th1 cells Activates NK cells, monocytes ↓ IgE Fibroblast and airway smooth muscle proliferation Release of collagen ↓ T cell proliferation Blocks IL-2 effects Fibroblast proliferation Chemo-attractant for monocytes, fibroblasts, mast cells ↓ Airway smooth muscle proliferation

Inflammation and Cytokines in Asthma

Asthmatic Inflammation The chronic airway inflammation of asthma is characterised by an infiltration of T lymphocytes, eosinophils, macrophages/monocytes and mast cells, and sometimes neutrophils. An acute or chronic inflammation may be observed with acute exacerbations, with an increase in eosinophils and neutrophils in the airway submucosa and release of mediators, such as histamine and cysteinyl-leukotrienes, from eosinophils and mast cells to induce bronchoconstriction, airway oedema and mucus secretion. Changes in the resident cells are also observed, such as an increase in the thickness of the airway smooth muscle with hypertrophy and hyperplasia, more myofibroblasts with an increase in collagen deposition in the lamina reticularis, more vessels and an increase in goblet cell numbers in the airway epithelium. Cytokines play an integral role in the coordination and persistence of the inflammatory process in the chronic inflammation of the airways (Table 3.3).

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Th2-associated Cytokines CD4+ T lymphocytes of the asthmatic airways express Th2 cytokines including IL-3, IL-4, IL5, IL-10, IL-13 and GM-CSF. The primary signals that activate Th2 cells may be related to the presentation of a restricted panel of antigens in the presence of appropriate cytokines. Dendritic cells are ideally suited to being the primary contact between the immune system and external allergens. Co-stimulatory molecules on the surface of antigen-presenting cells, in particular B7.2/ CD28 interaction, may lead to proliferation of Th2 cells.169 With the expression of IL-4, synthesis of IgE by B lymphocytes on immunoglobulin isotype switching occurs.170 IgE produced in asthmatic airways binds to FcεRI receptors (high-affinity IgE receptors) on mast cells priming them for activation by antigen. The maturation and expansion of mast cells from bone marrow cells involve growth factors and cytokines such as SCF and IL-3 derived from structural cells. Bronchoalveolar mast cells from asthmatics show enhanced release of mediators such as histamine. Mast cells also elaborate IL-4 and IL-5.171 IL-4 also increases the expression of an inducible form of the low-affinity receptor for IgE (FcεRII or CD23) on B lymphocytes and macrophages.172 IL-4 drives the differentiation of CD4+ Th precursors to Th2- like cells. IL-18 is a cytokine with potent interferon (IFN)- γ-inducing activity. It is predominantly produced by activated macrophages and synthesised with IL-12 to induce (IFN)- γ synthesis from T lymphocytes, promoting differentiation of T cells to the Th1 subsets. The IL-18 levels are low in the BAL fluid of patients with bronchial asthma. This inherently low levels of IL18 may be associated with pathogenesis of asthmatic airway inflammation.173

Antigen presentation Cytokines may play an important role in antigen presentation (Fig. 3.3). Airway macrophages are usually poor at antigen presentation and suppress T cell proliferative responses (possible via release of cytokines such as IL-1 receptor antagonist), but in asthma there is reduced suppression after exposure to allergen.174 Both GM-CSF and IFN-γ increase the ability of macrophages to present allergen and express HLA-DR.175 IL-1 is important in activating T lymphocytes and is an important co-stimulator of the expansion of Th2 cells after antigen presentation.176 Airway macrophages may be an important source of first-wave cytokines, such as IL-1, TNF-α and IL-6, which may be released on exposure to inhaled allergens via FcεRI receptors. These cytokines, may then act on epithelial cells to release a second wave of cytokines, including GM-CSF, IL-8 and RANTES which then leads to influx of secondary cells, such as eosinophils, which themselves may release multiple cytokines. Eosinophil-associated cytokines The differentiation, migration and pathobiological effects of eosinophils may occur through the effects of GM-CSF, IL-3, IL-5 and certain chemokines such as eotaxin.177,178 IL-5 and eotaxin also induce the mobilisation of eosinophils and eosinophil precursors into the circulation.179 Mature eosinophils may show increase survival in bronchial tissue.180 Eosinophils themselves may also generate other cytokines such as IL-3, IL-5 and GM-CSF.181 Cytokines such as IL-4 may also exert an important regulatory effect on the expression of adhesion molecules such as VCAM-1, both on endothelial cells of the bronchial circulation and on airway epithelial cells. IL-1 and TNF-α increase the expression of ICAM-1 in both vascular endothelium and airway epithelium.182 Cytokines also play an important role in recruiting inflammatory cells to the airways.

Pathophysiology of Bronchial Asthma 57

Fig. 3.3: Cytokines and cell interaction in bronchial asthma

Airway wall remodelling cytokines Proliferation of myofibroblasts and the hyperplasia of airway smooth muscle may occur through the action of several growth factors such as PDGF and TGF-β. They may be released from inflammatory cells in the airways, such as macrophages and eosinophils, but also by structural cells, such as airway epithelium, endothelial cells and fibroblasts. These growth factors may stimulate fibrogenesis by recruiting and activating fibroblasts or transforming myofibroblasts. Epithelial cells may release growth factors, since collagen deposition occurs underneath the basement membrane of the airway epithelium.183 Growth factors may also stimulate the proliferation and growth of airway smooth muscle cells. PDGF and EGF are potent stimulants of human airway smooth muscle proliferation184 and these effects are mediated via activation of tyrosine kinase and protein kinase C. Cytokines, such as TNF-α and FGF may also play an important role in angiogenesis of chronic asthma. Oxygen Radicals Oxygen radicals have been indirectly implicated in the development of hyperresponsiveness. They are produced by neutrophils, eosinophils, and macrophages in the lungs. The relative importance of these substances in bronchial asthma is poorly defined.

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Nitric Oxide Although it is now well established that normal subjects have measurable concentrations of nitric oxide (NO.) in their expired air, in patients with bronchial asthma the peak or mixed expired NO are about 50% higher.185-187 Furthermore, compared with normal subjects, the airways of patients with asthma have up regulated expression of type II nitric oxide synthase, NOS.188 Taken together, these findings have led to the speculation that expired concentrations of NO reflect the inflammatory microenvironment of the asthmatic airway wall.189 Neurotrophins The neurotrophins are a family of peptides that promote survival, growth, and differentiation of neurons. They may also influence the function of non-neuronal cell types, including immune cells. The development and maintenance of asthma are thought to involve nervous system and the immune system, but the exact role that the neurotrophins play is unclear. The cellular sources of neurotrophins include mast cells, lymphocytes, macrophages, epithelial cells, smooth muscle cells, and eosinophils. The action of neurotrophin receptors like Trk (tyrosine kinase) acts possibly act in concert with known immune regulating factors to modulate the maturation, accumulation, proliferation, and activation of immune cells. Neurotrophins also can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. These neuropeptides may be released from the central terminals of airway afferent neurons, which leads to increased autonomic reflex activity, and increased reactivity in the airways.190 The role of different mediators is summarised in Table 3.4. Table 3.4: Role of mediators causing pathological changes in asthma Pathological changes Mediator implicated Bronchospasm Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandins and TXA2 Bradykinin Platelet activating factor Acetylcholin Mucosal oedema Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandin E Bradykinin Platelet activating factor Cellular infiltration Eosinophil chemotactic factor (airway hyperreactivity) Neutrophil chemotactic factor HETEs LTB4 Mucus secretion Histamine (H1response) LTC4, LTD4, LTE4 Prostaglandins generating Factor of anaphylaxis Prostaglandins HETEs Acetylcholin Macrophage mucus secretagauge Desquamation O–2, H2O2, OH– Proteolytic enzymes Basement membrane thickening O–2, Proteolytic enzymes

Pathophysiology of Bronchial Asthma 59 NEUROPEPTIDES IN ASTHMA There is increasing evidence that abnormal neurogenic mechanisms and neuropeptides contributing in the pathophysiology of bronchial asthma.191-197 Autonomic nerves regulate airways smooth muscle tone, mucous secretion, blood flow, vascular permeability, and migration and release of inflammatory cells.198,199 Neuropeptides are small amino acid components that are localised to neurons. Originally described in the gastrointestinal tract, neuropeptides were first termed “gut hormones”. Upon their discovery subsequently in brains, they were termed as “gut-brain hormones”. However, now it is established that these peptides are present throughout the body and may be produced by, localised to, cells other than cells of the nervous system. In the respiratory tract, they are located in neurons, neuroendocrine cells, and inflammatory cells. Neuroendocrine cells are granulated epithelial cells found throughout the conducting airways. They contain a number of peptides, including calcitonin, katacalcin, CGRP (calcitonin gene-related peptide), and bombesin. Neuropeptides such as VIP (vasoactive intestinal peptide) has been identified in various inflammatory cells including eosinophils, mast cells, and mononuclear and polymorphonuclear leucocytes. Once released these peptides act as either neurotransmitters, hormones, or mediators. They modulate airway caliber, vascular tone, mucus secretion, and vascular permeability. They are also capable of affecting inflammatory cell function by modulating mediator release and chemotactic responses. Their wide spread distribution and different physiological effects make neuropeptides excellent candidates to play important roles in asthma. The neural control of the airways is mediated by three pathways: cholinergic (parasympathetic); adrenergic (sympathetic); and the nonadrenergic noncholinergic (NANC) pathways.191 The cholinergic nervous system is considered excitatory in nature because it plays an important role in maintaining bronchial smooth muscle tone and in mediating acute bronchospastic responses. The system consists of vagal afferent fibres in and around the airway lumen that travels to the central nervous system and then terminate in efferent fibres. The later innervate airway smooth muscle. There are three types of pharmacologically defined muscarinic receptors, which are important in regulating the smooth muscle tone. The M1 receptor is located in the parasympathetic ganglia and facilitates vagal transmission. The M3 receptors are present in large airways and in some peripheral airways and are largely responsible for smooth muscle contraction. The M2 receptor functions as an autoreceptor in airway tissue, acting as a feedback-inhibitory receptor to reduce neurotransmission. Acetylcholin is the cholinergic messenger. Acetylcholin normally binds to the cholinergic receptor and causes release of cyclic 3',5'-guanosine monophosphate (cyclicGMP). This causes bronchoconstriction. Cholinergic nerves are the dominant neural bronchoconstrictor pathways for human lungs. Triggers like sulphur dioxide, prostaglandins, histamine, and cold air stimulate afferent receptors causing reflex bronchoconstriction. Inflammatory mediators like histamine, prostaglandins, and bradykinin stimulate irritant receptors and C-fibre endings in the airway leading to a reflex bronchoconstriction.200 Neurotransmitters like TxA2, PGD2, and tachykinins enhance Acetylcholine release from the postganglionic nerves in the airways. It is suggested that M2 autoreceptors are dysfunctional in bronchial asthma.201 The sympathetic nervous system in the bronchial tree is inhibitory because of its prominent airway relaxant effect. This is mediated by β-receptor stimulation and by cAMP. Adrenergic

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fibres represent only a minor component of the total nerve fibres in human airways. Although there is little or no direct sympathetic innervations of human airways, there are many αand β-adrenergic receptors that are important in regulating bronchomotor tone. Earlier it was believed the imbalance between cGMP and cAMP production was the underlying mechanism of bronchial asthma, (Yin-Yang hypothesis). The neurotransmitters for the NANC nervous system were initially thought to be purine nucleotides, such as adenosine and adenosine triphosphate and accordingly the NANC nerves were termed “purinergic”. However, now it is believed that the neurotransmitters are not purines, but peptides, and thus the nerves are “peptidergic”. Although a number of neurotransmitters have been identified, only VIP, peptide histidine methionine (PHM), and nitric oxide may be the neurotransmitters of the nonadrenergic inhibitory nervous system and thus are important endogenous bronchodilators.202,203 They also decrease mucus secretion and manifest anti-inflammatory actions. Deficiency of this system has been postulated to contribute to the development of bronchial hyperreactivity. Functional deficiencies of the system can result from blockade of nonadrenergic pathways at the level of ganglia or nerve endings; from deficiency of airway VIP or PHM receptors, or from enhanced breakdown of neuropeptides by peptidases released from inflammatory cells in the asthmatic airway. It has been demonstrated recently that there is a loss of VIP from pulmonary nerve fibres in asthmatics. Immunoreactive VIP is observed within nerves in more than 90% of lung sections from normal subjects but is not identified in any lung sections from patients with asthma. However, it is not clear whether it is a primary or secondary event. Other peptides such as substance P, neurokinin A (substance K, neuromodulin L) and calcitonin gene-related peptide (CGRP) are believed to be neurotransmitters of the noncholinergic excitatory system and thus act as endogenous bronchoconstrictors.204-209 These peptides also play a role in regulating mucus production, pulmonary vasomotor tone, mucosal permeability, and inflammatory cell function. A number of substances are known to release neuropeptides from these nerves include capsaicin (most potent), irritant gases, antigen, and various inflammatory mediators, including histamine, bradykinin, and prostaglandins. These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough, mucus secretion, smooth muscle contraction, plasma extravasations, and neutrophil adhesion. This series of effects is termed as “neurogenic inflammation”.210-215 An enzyme neutral endopeptidase (NEP) exists on the surfaces of all lung cells. The enzyme inactivates the neuropeptides limiting their concentration. Angiotensin converting enzyme (ACE) also helps in the degradation of these neuropeptides. Thus neurogenic inflammatory responses are normally mild and probably protective in nature. It is proposed that in asthma, a decrease in the normal degradation process of substance P occurs by NEP or ACE. Cigarette smoke, respiratory viral infections, and inhalation of industrial pollutant toluene diisocyanate inhibit NEP and exaggerate neurogenic inflammation. In addition, there are reports that there are more substance P immunoreactive nerves in the lungs of patients with asthma compared to that in normal subjects. Therefore, in addition to the proposed changes in the cholinergic and adrenergic nervous systems, subjects with asthma have now been revealed to potentially have changes in their nonadrenergic inhibitory and noncholinergic excitatory nervous system. These changes will lead to an imbalance in the autonomic nervous system and predispose subjects with asthma towards bronchospasm (Fig. 3.4).

Pathophysiology of Bronchial Asthma 61

Fig. 3.4: Autonomic imbalance postulated for bronchial asthma

It is suggested that abnormal control of the airway is the underlying mechanism of bronchial hyperreactivity, with a preponderance of excitatory (cholinergic and α-adrenergic) or a deficiency of inhibitory (α-adrenergic) control. Bronchial Hyperreactivity Airway hyperresponsiveness to a large number of stimuli is a characteristic feature of asthma in humans. Various components of the tracheobronchial tree might contribute to this phenomenon, such as smooth muscle, the bronchial epithelium, various neurohumoral mechanisms and the mechanical linkage between the lung parenchyma and the airways including the baseline airflow obstruction. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would be ordinarily tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness. The level of airway responsiveness usually correlates with the clinical severity of asthma and medication requirement. The airways of asthmatic subjects are 14-fold, 15-fold, 5-fold, 9-fold, and 194-fold more responsive than were the airways of normal subjects to histamine, methacholine, LTC4, LTD4, and LTE4 respectively in a direct comparison of the potencies of these substances in six asthmatics and six controls.112 Further, cumulative data suggest that hyperresponsiveness to the leukotrienes may be more marked in the central rather than the peripheral airways of asthmatic subjects. Bisgard reported that the airways of 8 asthmatic subjects were more responsive to LTD4 than were those of 9 nonasthmatic controls; the relative differences in potencies between asthmatic and controls were 100- to 1000-fold when measured in terms of FEV1 but they were only 15fold differences in V30.216 Similarly Smith et al reported a 30% fall in V30 in response to LTD4

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was accompanied by a 60% fall in sGaw in asthmatic subjects but only a 30% fall in sGaw in normal controls.217 In another study Davidson et al reported a 30% fall in V30 induced by inhaled histamine was accompanied by a 10 and 13% fall in FEV1 in asthmatic and normal subjects, respectively. But when the same individuals inhaled LTE4, a 30% fall in V was accompanied by a 17% fall in FEV1 in asthmatic subjects and a 3% fall in FEV1 in normal controls.218 While FEV1 represents the central airway function, V30 represents small or peripheral airways function. The interaction of various factors and the pathophysiology of bronchial asthma is summarised in Figure 3.5. β AR) and Asthma Beta-adrenergic Receptors (β β ARs belong to the family of adrenergic receptors that use the endogenous catecholamines epinephrine and norepinephrine (and, to a lesser extent dopamine) as agonists. Nine different adrenergic receptor subtypes have been cloned.219 There are three β AR subtypes (β1, β2, β3) and they couple to the stimulatory G-protein, Gs, which results in activation of adenyl cyclase and increases in intracellular cAMP. The β2 AR is expressed to some extent in virtually every tissue in the body. In the lung, this is present in epithelium, smooth muscle of bronchi and bronchioles, submucosal glands, the endothelium and smooth muscle of pulmonary arteries, alveolar walls, immune cells including mast cells, macrophages, eosinophils, neutrophils, and lymphocytes. There are reports that β3AR also regulates bronchial smooth muscle tone in pharmacological in vivo studies. β2 AR has been studied extensively and thought to have important therapeutic implications. Recent genetic polymorphisms of the β2 AR have been identified in the population, which may be the basis of a more severe form of the disease or the basis of the heterogeneity of receptor expression and response to betaagonists observed clinically.220 Some of the important molecular domains that have been found to be important for receptor function have also been identified. Although a number of studies have addressed whether β2 AR are dysfunctional in asthma, there appears to be no consensus in this matter.221 It seems that beta-receptor dysfunction may not be the primary lesion in asthma. Perhaps this occurs as a secondary phenomenon in asthma either because of the drugs used and thus acquired or there may be a receptor mutation or polymorphism. Szentivanyi proposed in 1968 that asthma may be due to an inherited or acquired deficit in β-adrenoceptor function.222 Several lines of evidence suggest that the β2-adrenoceptor may be abnormal in asthma, making the β2-adrenoceptor gene an attractive candidate gene in this disease. Administration of β2-adrenoceptor agonists increases airway tone and responsiveness in patients with asthma.223 Bronchial or tracheal smooth muscle obtained at either autopsy or surgery from asthmatic patients show a deficit in β-adrenoceptor function.224-227 A large number of polymorphisms or point mutations have been described in the human β2-adrenoceptor gene. A restriction fragment length polymorphism (RFLP) of this gene has been reported using the restriction enzyme Ban I.228 Another biallelic polymorphism is reported using the restriction enzyme Fnu4HI,229 while subsequent investigations reported nine different point mutations within the coding region, four of which result in changes in amino acid residues 16, 27, 34 and 164.230 Moreover, cells transferred with β2-adrenoceptor complimentary DNA containing the mutations at amino acid positions 27 or 164 showed altered β-adrenoceptor function. Studies on the distribution of Ban I polymorphisms in South African asthmatics showed the presence of both these alleles in this group, but the genotypes were found with similar frequencies in

Pathophysiology of Bronchial Asthma 63

Fig. 3.5: Interaction of various factors in the causation of asthma

allergic and nonallergic subjects. Further studies on sequencing of the β2-adrenoceptor gene identified nine separate point mutations or polymorphisms, but there was no significant difference in the frequency of alleles between the asthmatic and nonasthmatic patients.230 Japanese investigation on family members of asthmatics found a higher prevalence of asthma in family members who lacked the 3.1 kb Ban I RFLP, but the findings were not sufficient to exclude genetic linkage to either methacholine responsiveness or allergy.231 Subsequent

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studies also showed that distribution of these alleles was not different between asthmatics and nonasthmatics,232 although it was not possible to exclude an association. In a more recent study to exclude genetic linkage between the β2-adrenoceptor gene and asthma, allergy, and methacholine airway hyperresponsiveness, indicated that these are not linked to a dominant β2-adrenoceptor gene with strong effect in families with an inherited pattern of asthma.233 Nitric Oxide (NO) and Bronchial Asthma185-188 Nitric oxide is synthesised from L-arginine by the enzyme NO synthase (NOS). Two forms of NO is known; iNOS (independent of Ca++) and cNOS (Ca++/calmodiulin-dependent, constitutive form). While the former is induced by TNF-alpha and beta, interferon gamma, endotoxins, interleukin-1 and other cytokines, stimulation of the later occurs through mediators like bradykinin, histamine, PAF, acetylcholine, and leukotrienes. Thus, it is obvious that NO has the potential to affect a number of cells critical for normal lung function and NO possibly plays a key role in the pathogenesis of asthma and its inhibitors may be useful therapeutically to treat asthma.221 Nitric oxide is present in the expired air of healthy individuals.234 It is a known bronchial smooth muscle relaxant. Thus its level should be reduced in bronchial asthma. But on the contrary, NO is higher in the expired air of asthmatics,185,235 and epithelial NOS is higher in the epithelial cells in them.236 This implies that NO may increase in asthma as a compensatory response to other factors, such as those that cause bronchoconstriction or inflammation. Further, elevated NO might exacerbate bronchial obstruction because NO relaxes vascular smooth muscle and thus, vascular engorgement which is an important pathogenetic mechanism. In addition, elevated NO may result in elevated NO reaction products, such as superoxides, particularly peroxynitrite, which may cause airway damage if excess. However, it is not clear whether elevated NO is part of the primary pathologic process in asthma or is a compensatory response. SUMMARY OF EVENTS LEADING TO AIRWAYS INFLAMMATION The pathogenesis of bronchial asthma is more clearly understood in extrinsic or allergic asthma and is summarised in Figure 3.6.237 Although the terms “intrinsic” and “extrinsic” no longer adequately reflect our knowledge of the clinical syndrome of asthma, recent advances in the understanding of its pathophysiology indicate that it is a heterogenous disorder with multiple triggers. There are, however, features, which are virtually common to all asthmatics. These include airways inflammation and hyperreactivity to a broad range of stimuli. The chronic allergic response is a continuous process of IgE generation, mast cell activation, and eosinophil recruitment. These processes are orchestrated by T lymphocytes. In atopic individuals, T lymphocytes receive an allergen-specific signal from highly specialised antigen presenting cells, called dendritic cells, at mucosal surfaces. Presentation of allergen peptides to the T cell usually occurs in local lymphoid tissue along with the essential engagement of co-stimulatory molecules (B7 and CD28) and results in the differentiation of the naive T cell to one that generates a range of cytokines which upregulate cells and antibodies involved in the allergic response. CD4+ lymphocytes of the Th2-type are activated and clonally expand after capture and processing of inhaled allergens like cigarette smoke, house dust mites, pollen, viral infection, fungi, etc. by the dendritic cells

Pathophysiology of Bronchial Asthma 65

Fig. 3.6: Pathogenesis of bronchial asthma

which migrate to the regional lymph nodes and present allergens, together with major histocompatibility antigen II, to lymphocytes.237,238 A number of cytokines are then released. The genes for these cytokines are encoded in a small region on the long arm of chromosome 5 and a number of them (IL-4, IL-5, and GMCSF) are coordinately regulated. While Th2 lymphocytes produce these cytokines, Th1 lymphocytes are involved in cell-mediated immunity. A number of Th2-derived cytokines are involved in mast cell, basophil, and eosinophil recruitment and maturation, IL-4 and IL-3 play a particularly important role in this arm of the immune process by interacting with B lymphocytes, they change the immunoglobulin isotope being secreted from the shortterm protective antibody IgM to the allergic antibody IgE. As with dendritic T cell interactions, effective signalling to β cells requires an interaction with the Th2 cell and

66

Bronchial Asthma

involves antigen presentation and engagement of a second set of co-stimulatory molecules (CD40 and its ligand, CD40L). If T and B cell interact in the presence of antigen, IL-4 or IL-13, and co-stimulatory molecules, allergen-specific IgE is generated. If IL-4 or IL-3 is present, but cell-cell contact does not occur, only non-specific IgE is generated. Thus IgE has the important role of linking allergen recognition to cell signalling in a variety of cells, which release a range of active mediators. IL-4 produced by Th2 lymphocytes ‘fuels’ the inflammatory reactions in the airways and leads to production of further Th2 lymphocytes and to differentiation and maturation of IgE producing B lymphocytes. A strong genetic component plays important role in the form of an ability of a susceptible individual to recognise an environmental allergen as foreign and mounts an allergic immune response through the human lymphocyte antigen (HLA or MHC class II) molecules. The second component of the gene involves the genes responsible for cytokine response. Allergen specific IgE binds to IgE receptors on several inflammatory cell types such as eosinophils, mast cells, and macrophages. High affinity IgE receptors are an important link between the presence of specific antigen in the microenvironment and activation of mast cells and other cells. Antigen-specific IgE binds to effector cells via specific IgE receptors; when antigen binds an adequate number of these receptors to initiate receptor clustering, signal transduction occurs. The molecular nature of the IgE receptor has now been clearly defined;221 it is composed of four chains: an alpha chain, a beta chain, and two gamma chains. While the alpha chain binds IgE, it is thought that the gamma chains are the units that initiates intracellular signal transduction; however, the specific mechanisms of transduction are not established. The inflammatory cells then release various inflammatory mediators outlined above, which accentuates airways’ inflammation including the release of 5-lipooxygenase products and proteases. Leukotrienes along with other products cause bronchoconstriction and other changes characteristic of bronchial asthma. Mast cell proteases are also important players in the inflammatory process. Neutral endopeptidase (NEP) is a major enzyme of importance in limiting the biologic activity of small peptide mediators such as substance P or neurokinin A. The beta-adrenergic receptor and nitric oxide represent two effector mechanisms that are important in modifying the biology of an asthmatic response. Although smooth muscle constriction can lead to airways obstruction, it is now understood that nonmuscular airway obstruction is not less important. The importance of airway wall remodelling with thickening of the airway wall due to infiltration with inflammatory cells and alteration in the amount and type of collagen deposited in the airway is reflected in the enhanced degree of obstruction that is observed for a given level of smooth muscle activation in the remodelled wall. The wall is also thickened and obstructed due to the engorgement of the bronchial blood vessels. Such engorgement could account for a significant component of asthmatic airway narrowing under certain circumstances. The presence of intraluminal fluids including mucosubstances further obstruct airways and could make it more difficult for individuals to clear secretions from their airways. The relationship between airway inflammation and the development of airway hyperresponsiveness and clinical asthma has been well established during the last decade. Exposure to oxidant pollutants, some chemicals, antigens, and viral respiratory tract infections are all associated with inflammatory cell infiltration into the airway and these inflammatory stimuli are also associated with the development of airway hyperresponsiveness. Most studies have shown that airway inflammation precedes the development of hyperresponsiveness

Pathophysiology of Bronchial Asthma 67 and may be the prerequisite feature necessary for the development of both hyperresponsiveness and clinical bronchospasm. The relationship between airway inflammation, bronchial hyperreactivity and airway obstruction in asthma is shown in Figure 3.7. Although, approximately one-half of the children with wheezing in infancy and young childhood will no longer be wheezing at 6 years of age,239 a different type of observation has been noted in children with wheezing in their bronchoalveolar lavage fluid. Increased numbers of cells and increased neutrophils in BAL samples have been reported in children having wheezing.240-244 In contrast, BAL eosinophilia is a common finding in adults with asthma. Eosinophilia and elevated IgE levels have also been found in infants who subsequently develop asthma. It is possible that neutrophil-induced inflammation is important in the early stages of wheezing in infants. It is also possible that this neutrophil response may be a response to an unrecognised infection. While the pathogenesis of occupational asthma, intrinsic asthma and other forms of asthma is less clearly understood, these conditions are thought to involve a cytokine “cascade” similar to that involved in extrinsic or allergic asthma.237 The mechanisms of allergy in causing episodic and chronic asthma are shown in Figure 3.8. Aspirin Induced Asthma Patients with bronchial asthma and sensitivity to aspirin (ASA) and other nonsteroidal antiinflammatory drugs are often corticosteroid-dependent and have the accompanying symptoms of rhinosinusitis, rhinorrhoea, nasal congestion, anosmia, loss of taste, and recurrent severe nasal polyposis.245 Upon challenge with aspirin or other cyclooxygenase inhibitors these patients have increased cysteinyl leukotriene release as detected in urine,246,247 in nasal lavage,248,249 and in bronchial lavage fluids,250 in contrast to aspirin-tolerant subjects. These

Fig. 3.7: Interaction of various factors

68

Bronchial Asthma

Fig. 3.8: Mechanisms of episodic and chronic asthma. (TH-:T-lymphocyte; MC-; Mast cell ; Ag-; Antigen)

observations conclude that cysteinyl leukotrienes are involved in aspirin-induced asthma (AIA). The mechanism of AIA is due to the inhibition of cyclooxygenase and bronchospasm is because of an increased generation of spasmogenic leukotrienes via lipooxygenase pathway. In patients with AIA, ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm, which may be accompanied by rhinitis and/or urticaria. Majority of these subjects can be desensitised by the administration of aspirin orally, which may lead to an improvement in the severity of asthma and of rhinitis. Further, inflammatory cell population in bronchial biopsies from aspirin-sensitive asthmatic patients demonstrates significantly greater numbers of mast cells and eosinophils per square millimetre of tissue than do similar biopsies from asthmatic subjects without aspirin sensitivity.251 Furthermore, the percentage of cells that immunostained for lipooxygenase and that are identified as eosinophils and mast cells are significantly increased in aspirin-sensitive patients. An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes.112 The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma including that of aspirin-induced asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition.135-138 Leukotrienes are important in asthma, and leukotriene modifiers modulate antigen-induced asthma. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma, but also in aspirin induced bronchial asthma, although the mechanisms of such overproduction are different. While in the former, the overproduction occurs with an antigen-antibody reaction, in aspirin-induced asthma, the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade.140 Pranleukast a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further, this drug increases FEV1 that falls during such provocation.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway

Pathophysiology of Bronchial Asthma 69 narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients.142-144 Further, several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144,145 and improve respiratory function by bronchodilatation.146 Virus-induced Asthma Viral infections have been considered to play a significant role in the development and consolidation of obstructive airway disease. This may occur by amplification of the response to cigarette smoke, induction of steroid resistance,252 enhanced sensitisation to inhaled allergens due to increased permeability and recruitment of dendritic cells,253 or reactivation of latent but persistent virus due to insufficient T-helper-1-type immune response and/or administration of corticosteroids.254 Viral respiratory infections increase symptoms of bronchial asthma in many patients.255 Rhinovirus increases airway responsiveness and also promotes the likelihood of a late allergic reaction to allergen.256,257 Enhanced airway responsiveness and the late allergic reaction persist for weeks beyond the viral infection. Lymphocytes are activated during incubation with rhinovirus and secrete cytokines, like γ -interferon. Although γ-interferon does not have any proinflammatory activity like those of Il-4 and 5, it does affect eosinophil function, including promotion of survival. Furthermore, γ-interferon can augment basophil mediator release. Thus, lymphocyte activation by virus may provide a very different cytokine profile and in this manner selectively enhances inflammation.71,258 Exercise-induced Asthma (EIA) Exercise-induced asthma is a temporary increase in the airway resistance following vigorous physical activity. Obstruction to airflow begins soon after cessation of exercise and peaks in 5-10 minutes.259 Most patients will recover completely in the next 30-60 minutes, but in few this EAR will be followed by a LAR several hours after the initial response subsides.260,261 Two major hypotheses have been put forward to explain the mechanism whereby water and heat loss by hyperventilation with exercise causes airway narrowing. i. The EIA is a consequence of thermodynamic events that occur within the tracheobronchial tree during or after hyperventilation that is associated with exercise.262 Because of this hyperventilation during exercise, there is a fall in the airway temperature and respiratory water loss, i.e. evaporation causes cooling.263 Mouth breathing to meet increased demand of oxygen further aggravates this factor because air bypasses the nasal air-conditioning mechanism. Thus, during re-warming of the airways by reactive hyperaemia of the bronchial circulation with subsequent airway oedema of the bronchial wall during the post-exercise period.264 Further, the event precipitates bronchoconstriction. The magnitude of bronchospasm is directly proportional to the heat loss from the respiratory tract required to bring the inspired air to alveolar conditions.265 Oedema due to hyperaemia of microcirculation may be the cause of bronchial obstruction developing after exercise. It is also possible that patients with EIA may have hyperplastic capillary bed that develop exaggerated hyperaemia and airway oedema leading on to bronchial obstruction.262 ii. The other mechanism of EIA may be as a result of water loss from mucosal surface and resulting increase in osmolarity of the fluid interface of the mucosal surface in the airways,

70

Bronchial Asthma which may lead to mast cell and basophil degranulation and precipitating EIA.266,267 Exercise-induced bronchoconstriction, a feature of 70-80% of asthmatics,268 is triggered by drying of the bronchial epithelium due to airway water loss from the tracheobronchial tree.269-273 During exercise, the ventilation rate increases, and thus the respiratory tract needs to condition much larger volumes of air over a much shorter time during exercise compared with rest, and airway dehydration occurs with subsequent exercise-induced bronchoconstriction. The findings that269 inhaling fully humidified air at body conditions could prevent exercise-induced bronchoconstriction demonstrated the importance of water loss from the airway. It is also been recommended swimming as the exercise least troublesome to asthmatic patients because of the humidity of the inspired air, a phenomenon that is supported by comparative studies of diverse sporting activities.274,275

Since mast cell-derived mediators, such as histamine and leukotrienes, may cause not only airway smooth-muscle contraction, but also airway oedema, it is possible that both of these hypotheses are related to the airway narrowing following exercise in asthmatics. Exerciseinduced bronchospasm is, at least in part, due to bronchial microvascular phenomena such as vascular engorgement and plasma leakage that could thicken the mucosa and thereby narrow airway diameters, which could in turn amplify the effects of airway smooth muscle contraction. Various reports give conflicting results concerning the role of inflammation in EIA.276,277 However, some believe that EIA, to a larger extent, is mediated through the release of bronchoconstrictor substances from inflammatory cells in the airway wall. Leukotrienes seem to play a particularly important role in this response. This conclusion is arrived from observations made in antileukotriene drug studies in EIA.278,279 Similarly antileukotrienes are helpful in cold air-induced bronchial asthma280 highlighting the role of cold air in causing EIA. Further, eucapnic voluntary hyperventilation manoeuvres designed to simulate exerciseinduced bronchoconstriction in the laboratory, demonstrate that airway fluid-loss has a similar bronchoconstrictor effect to histamine.281-284 It is also demonstrated that the release of histamine, a potent bronchoconstrictor, and other pro-inflammatory bronchoconstrictor mediators, including cysteinyl-leukotrienes,285 from mast cells and other airway cells under hyperosmolar conditions.286-288 These findings underline the bronchoconstrictor potential of airway dehydration. Presence of thermally sensitive neural receptors in the airways of patients susceptible to EIA may be responsible for bronchoconstriction in response to cold air.267 Recently another hypothesis suggests that increased excessive production of nitric oxide during exercise289,290 increases airway vascular permeability, that co-relates with the severity of exercise-induced bronchoconstriction in asthmatics. Assessment of albumin flux in airway lining fluid stimulated by hypertonic saline solution is a sensitive predictor of the severity of this phenomenon.291 Occupational Asthma Bronchial hyperreactivity is a characteristic feature of occupational asthma.292 Specific inhalation challenge tests may induce any of the five types of reactions: (i) isolated early; (ii) isolated late; (iii) biphasic; (iv) continuous; or (v) atypical asthmatic reactions.293 An early reaction occurs within a few minutes after an inhalation challenge, reaches maximal intensity within 30 minutes, and ends within 60-90 minutes. An isolated late asthma reaction occurs 4-6 hours after the challenge, reaches maximal intensity within 8-10 hours, and ends after

Pathophysiology of Bronchial Asthma 71 24-48 hours. A biphasic reaction is an early reaction with spontaneous recovery followed by a late asthma reaction. In a continuous type of asthma reaction there will be no remission between the early and late reactions. Atypical reactions usually start 2 hours after a challenge and last for a few hours.294 Generally, IgE-dependent agents induce isolated early reactions or biphasic reactions, and IgE-independent agents will induce isolated late, biphasic or atypical asthma reactions. Occupational asthma induced by IgE-dependent agents is similar to allergic asthma.295 Most high-molecular-weight compounds (5000 or more daltons) induce asthma by producing specific IgE antibodies. These molecules such as proteins, glycoproteins and polysaccharides are usually complete antigens. Some low-molecular-weight molecules ( 20% diurnal variation on > 3 days in a week for two weeks (to be maintained in a diary) • or FEV1 > 15% (and 200 ml) increase after short acting β2-agonist (salbutamol 400 μg by metered dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser) • or FEV1 > 15% (and 200 ml) increase after trial of steroid tablets (prednisolone 30 mg/ day for 14 days) • or FEV1 > 15% decrease after six minutes of exercise (running) • Histamine or methacholine challenge in difficult cases Methods for Measuring Reversibility • An increase after inhalation of a short acting β2-agonist (e.g. salbutamol 400 mg by metered dose inhaler (pMDI) +spacer or 2.5 mg by nebuliser) • An increase after a trial of steroid tablets (prednisolone 30 mg/day for 14 days) • A decrease after six minutes of exercise, e.g. running. A resting measurement is to be taken first and then the patient is to be asked to exercise for six minutes, a further reading is to be taken and then every 10 minutes for 30 minutes. As this procedure may rarely induce significant asthma, facilities for immediate treatment should be available. Objective tests should be used to try to confirm a diagnosis of asthma before long-term therapy is started. Each of the above methods can be used, measuring either PEF (a 20% change from baseline and at least 60 l/min) or FEV1 (15% change and at least 200 ml).24 Bronchodilators reduce hyperinflation. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.25 Other investigations that may be helpful include rhinoscopy, sinus X-ray and bronchoprovocation tests,26,27 provocative challenge with occupational allergens and evaluation of pH for gastro-oesophageal reflux. Bronchoprovocation Test Bronchoprovocation test is indicated to assess the airway hyperresponsiveness in the form of increased bronchoconstrictor response to a variety of physical, chemical, or pharmacological stimuli.28-30 This can better be assessed in a specialised pulmonary testing facility using bronchial challenge or provocation techniques. The most commonly employed methods used to evaluate airway hyperresponsiveness include inhalation provocation with methacholine or histamine and exercise challenge. During such a test changes in pulmonary function are measured with serial spirometry after inhaling incremental doses of an agonist such as methacholine or histamine or after exercise.31 The results are then expressed either as the cumulative dose or the concentration of agonist that produces a 20% fall in FEV1 (PD20). Methacholine bronchoprovocation testing is frequently used to diagnose airway

104 Bronchial Asthma hyperresponsiveness and asthma. A > 20% reduction in FEV1 following methacholine administration is a common parameter used to determine airway hyperresponsiveness. Some observed that the slope of the decline of FEV1 with increasing dose of methacholine is a better way of measuring responsiveness because a value can be assigned to all subjects. Alternatively, a > 40% reduction in specific airway conductance (sGaw) can be used to determine airway hyperresponsiveness.32,33 Regardless of which test is selected, according to the American Thoracic Society guidelines, the changes in the test parameter following methacholine challenge must exceed 2 SDs or coefficients of variation for repeated measures in the same individual before a statistically significant change can be established.33 Although either of the two measurements is good enough, a substantial number of patients have a reduction in SGaw alone in response to methacholine, and this response is seen in patients with a higher FEF25-75 / FVC ratio.34 Large, central airway obstruction is best detected by SGaw measurements, while both large and small airway narrowing will affect measurements of FEV1. Methacholine responsiveness is often used to confirm asthma status in patients, and as a predictor of later development of respiratory disease.35,36 It is widely used in epidemiological studies, where a standardised tool for measurements of bronchial responsiveness to methacholine has been developed to estimate variation in prevalence of increased bronchial responsiveness and predictors of asthma in different groups.37 Various such predictors are the FEV1 and symptom status, female sex, smoking, atopy, occupational exposure, and geographical regions are associated with increased responsiveness. Smaller airways are more responsive than larger ones, and the reduction in responsiveness diminishes with each increase of lung size.38 Methacholine challenge testing may cause an acute episode of vocal cord adduction and thus, positive results may not reflect underlying reactive airways disease. However, a flattening or truncation of the inspiratory flow-volume loop after the patient undergoes methacholine testing is not diagnostic for the presence of inspiratory vocal cord adduction.39 Results of exercise provocation are expressed as the peak fall in FEV1 after exercise. Asthmatics respond to bronchoprovocation with greater degree of airflow obstruction than normal subjects.40 Other conditions that are associated with an increased bronchial hyperreactivity include allergic rhinitis, cystic fibrosis, COPD, normal persons after a viral upper respiratory tract infection or oxidant exposure, and smokers.40,41 Diurnal variation in the measurement of PEFR is an indirect but clinically useful way of the degree of bronchial hyperreactivity even if there may be some variation.42 Bronchial provocation test is helpful in the differential diagnosis of asthma when the respiratory history, physical findings, and PEFR variations are not adequate to confirm the clinical diagnosis. These situations include cough variant asthma and exercise-induced dyspnoea.28,43 There is no one test or set of tests that should be ordered for every patient. Selection of tests should be individualised. However, with careful attention to the history, physical examination, and laboratory results, a correct diagnosis of asthma will be made in virtually all instances. Asthma may be under diagnosed particularly in young children, if they only wheeze when they have respiratory infections which may be dismissed as wheezy bronchitis, asthmatic bronchitis, bronchitis, or pneumonia. Although recurrent episodes of cough and wheezing are almost always due to asthma in both children and adults, there are other

Diagnosis of Bronchial Asthma 105 causes of airway obstruction which produce similar symptoms that need to be excluded. In adults, such conditions include mechanical obstruction of the airways, laryngeal dysfunction, chronic bronchitis, pulmonary emphysema, congestive cardiac failure, pulmonary embolism, pulmonary infiltration with eosinophilia, and cough secondary to drugs. Of particular interest is the confusion with chronic bronchitis more so in elderly smokers. Presence of crepitations; absence of eosinophils in the nasal secretion, sputum, and blood eosinophilia; lack of good reversibility after bronchodilators; and an abnormal diffusion capacity favours chronic bronchitis with emphysema. Occasionally, it is not possible to differentiate the two conditions. Of all the battery of tests utilised to diagnose asthma (methacholine challenge testing, peak expiratory flow variability over a 2-week period, the FEV1/FVC ratio, the reversibility testing, and the differential count of eosinophils in blood and sputum), methacholine airway responsiveness and the sputum differential eosinophil count seems to be the most useful objective tests in patients with mild asthma. The sensitivity of these two tests are 91 and 72% respectively, and the specificity is 90 and 80% respectively.44 Increase bronchial responsiveness demonstrated by methacholine or histamine challenge is associated with symptomatic asthma, but is also common in the general population and in patients with COPD. However, failure to demonstrate hyperresponsiveness in an untreated person with suspected asthma should prompt reconsideration of the diagnosis. Other Tests Lung function tests may show changes suggestive of an alternative lung disease. For example, COPD may be suspected in the presence of obstructive spirometry, reduced diffusing capacity (CO uptake) and pressure dependent airway collapse on flow volume curves, but these changes are not diagnostic and do not exclude asthma, which may anyway coexist with other conditions. Failure to respond to asthma treatment should prompt a search for an alternative, or additional, diagnosis. Chest X-rays in all patients with atypical symptoms should be done. The differential diagnosis of bronchial asthma includes: COPD, cardiac diseases, laryngeal tumours, tracheal tumours, bronchogenic carcinoma, bronchiectasis, foreign body, interstitial lung disease, pulmonary embolism, aspirations, vocal cord dysfunction, pulmonary infiltrations with eosinophilia, cough due to drugs (beta blockers, ACE inhibitors) and hyperventilation. A detailed clinical history as well as investigations as outlined will be helpful in differentiating these conditions. In spite of a cautious and careful approach, there may be situations when one has to refer the case to a specialist for opinion and further investigations. These situations include: • Diagnosis unclear or in doubt • Unexpected clinical findings (like crepitations, collapse, effusion, cardiac murmur, clubbing, heart failure, cyanosis, etc.) • Spirometry or PEFR does not fit the diagnosis (like restrictive defect) • Suspected occupational asthma • Persistent shortness of breath (non-episodic, or without wheeze) • Unilateral or fixed wheeze • Stridor • Persistent chest pain or atypical features

106 Bronchial Asthma • Weight loss • Persistent cough or sputum production • Non-resolving pneumonia A suggested algorithm for the diagnostic work up in younger subjects with suspected asthma is shown in Figure 6.1. Cough, Wheezing, Dyspnoea

Spirometry with bronchodilators (Reversibility testing)

Positive

Negative

Skin testing

Positive

Exercise/Methacholine

Positive

Negative

Consider other diagnosis

Negative

Bronchial asthma Fig. 6.1: Diagnostic work-up for bronchial asthma

COPD and Bronchial Asthma Most often there is a confusion whether the patient is having bronchial asthma or COPD as both the conditions has similar symptoms like cough, wheezing and breathlessness. There are some similarities also between the two conditions. Tissue eosinophilia, sputum eosinophilia, increased bronchial hyperreactivity, inflammatory cells, cytokines, etc. can be similar in COPD, but the types of cells and degree of involvement differ. Because the overall prognosis and course of the disease are entirely different in both the conditions. Hence, the differentiation should always be made. It must, however, be possible that both conditions may coexist. The important differentiating points between the two are shown in Table 6.1.45 Diagnosis of Occupational Asthma Careful history and temporal relationship of symptoms with work place will clinch the diagnosis. However, it is important to establish objectively a relationship between work and asthma symptoms. Specific challenge tests of occupational exposure tests are often considered a reference standard for the diagnosis of occupational asthma. The various tests used are:

Diagnosis of Bronchial Asthma 107 Table 6:1: Important differentiating points between bronchial asthma and COPD

Parameter

Bronchial asthma

Clinical

• Young age of onset • Associated history of allergy (rhinitis, urticaria, eczema etc) • Episodic wheezing • Signs of hyperinflation unusual • Crepitations—unusual findings • Evidence of cor pulmonale—absent • Cyanosis—unusual except in acute severe asthma • Signs of hypercarbia unusual • Chest skiagram—frequently normal

Airflow obstruction

•

Postmortem

•

Sputum

• •

Surface epithelium Bronchiolar mucus cells Reticular basement membrane Congestion/oedema Bronchial smooth muscle Bronchial glands Cellular infiltrates

Cytokines

• • • •

COPD

• More older people • History of smoking, exposure to pollution • No history of allergy • Signs of hyperinflation (hyperresonant notes on percussion, obliteration of cardiac dullness, low, diaphragm) • Air entry diminished • Rhonchi and crepitation present • Cor pulmonale is a frequent complication • Cyanosis may be a finding • Signs of hypercarbia, frequent • Chest skiagram will show changes of COPD like increased lung volumes, tubular heart, low, flat diaphragms, attenuation of peripheral vessels, emphysematous bullae etc. Variable (irreversible component • Progressive deterioration of may be there in late stages) lung function Hyperinflation, mucus plugs • Excessive mucus (mucoid/ purulent) (exudates + mucus), • Small airway disease, Emphysema No or little emphysema Eosinophilia, metachromatic • Neutrophils (infective exacerbations) cells, creola bodies Fragility undetermined • Fragility loss Mucus metaplasia debated • Metaplasia/hyperplasia definite Homogenously thickened and • Variable or normal hyaline present Present • Variable/fibrotic Enlarged mass (large airways) • Enlarged (Small airways)

• Enlarged mass, but no change in mucin histochemistry • Predominantly CD3, CD4, CD25 (IL-2R)+, • Marked eosinophilia (activation) • Mast cells increase (Decrease in severe/fatal cases) • IL-4, IL-5, eotaxin, and RANTES gene expression

• Enlarged mass, increased acidic glycoprotein • Predominantly CD3, CD8, CD68, CD25, HLA-1 and HLA-DR+, • Mild eosinophilia except during exacerbations, • Mast cells increase in smokers • IL-4 and IL-5 gene expression RANTES only in exacerbations

108 Bronchial Asthma i. Measurement of lung function before and after a work shift. This is not very helpful in establishing a causal relationship between symptoms and work exposure. ii. Measurements of lung function (FVC and FEV1) when the patient has been away from the work environment for a period of time and again when he returns to work. An improvement in symptoms and lung functions away from work and recurrence of symptoms and deterioration in lung function after returning to work, confirms that the symptoms are related to the work environment. iii. Prolonged recording of PEFR by the patient at work and at home is a good method of establishing the causal relationship. The patient is asked to measure and record the PEFR every 2 hours from waking to sleep for at least 2 to 3 weeks at work, followed by at least 10 days off work. Different patterns of PEFR are described. The method has the disadvantage of falsification of data and inaccurate readings. iv. Serial measurements of nonspecific airway responsiveness in conjunction with prolonged recording of PEFR has been proposed as an additional test to provide objective evidence of sensitisation. Significant increases in airway responsiveness when away from work, associated with appropriate changes in PEFR, suggest an occupational relationship. Specific challenge tests are required to identify the substances in the work place causing the symptoms. However, this is time consuming and not devoid of danger. They should be performed by experienced personnel in hospital settings where resuscitation facilities are available and frequent observations can be made. Allergy skin tests with high molecular weight compounds may be useful in identifying the responsible agent. Animal products, flour, coffee, and castor bean produce immediate positive reactions on skin testing in sensitised subjects. Specific IgE antibodies to various occupational allergens may be demonstrated by RAST or by ELISA. Such specific antibodies against low molecular weight compounds conjugated to a protein like trimellite anhydride and isocyanate have been demonstrated in some exposed subjects. However, positive skin tests and the presence of IgE antibodies indicate sensitisation and may occur in exposed workers without asthma. The clinical investigation of occupational asthma is shown in Figure 6.2.46 Classification of Asthma Bronchial asthma can be defined as mild, moderate, and severe on severity of disease.47 This enables the clinician to categorize the overall assessment of a patient’s asthma and select appropriate therapy. The characteristics are shown in Table 6.2 and are recommended by the Expert Panel of the National Asthma Education Program by the National Heart, Lung, and Blood Institute, USA.47 The characteristics are general, and because asthma is highly variable, these characteristics may overlap. Furthermore, an individual may switch into different categories over time. Thus, severity of bronchial asthma, as defined by the National Asthma Education Programme (NAEP) Expert Panel of 1991, can be summarised as:

Mild: It is characterised by intermittent daytime symptoms up to two times in a week, brief wheezing, cough, or breathlessness with activity, and infrequent nocturnal cough or wheezing less than two times in a month. The FEV1 or PEFR is expected to be greater than 80% when asymptomatic and to vary 20% with symptoms.

Diagnosis of Bronchial Asthma 109

Fig. 6.2: Diagnostic work-up of occupational asthma

110 Bronchial Asthma Table 6.2: Classification of bronchial asthma

Characteristics Pretreatment Frequency of exacerbations

Mild Exacerbation of cough and wheezing no more often than 1-2 times/week

Moderate

Severe

Virtually daily. Exacerbations frequent. Often severe. Tends to have sudden severe urgent visits to emergency department or doctor’s office > 3/year Hospitalization > 2/yr Frequency of Few clinical Cough and low grade wheezing Continuous symptoms symptoms signs/symptoms between acute exacerbations of cough and wheezing between exacerbations almost often present always present Degree of Good. May not tolerate Diminished Very poor. Marked exercise vigorous exercise activity limitation tolerance like prolonged running Frequency of Not more than 1-2 2-3 times/week Considerable. Almost nocturnal times per month nightly sleep interrupasthma tion. Early morning chest tightness School or work Good May be affected Poor attendance Attendance > 80% predicted. 60-80% predicted. < 60% predicted. Pulmonary function PEFR Normal or minimal Airway obstruction Substantial degree of Spirometry airway obstruction. evident. Flow airway obstruction. Normal expiratory volume curve shows Flow volume flow volume curve. reduced expiratory flow curve shows Lung volumes at low lung volumes. marked concavity. not increased. Lung volumes often Spirometry may not be Usually a > 15% increased. Usually a normalised even with response to acute > 15% response to steroids. May have aerosol bronchoaerosol bronchosubstantial increase in dilator even with near dilator lung volumes and normal baseline marked unevenness values. of ventilation. Incomplete reversibility to acute aerosol bronchodilator Methacholine > 20 mg/ml Between 2-20 mg/ml < 2 mg/ml sensitivity (PC20)

After optimal treatment is established Response to Exacerbations respond and duration of to bronchodilators therapy. without the use of systemic steroids Regular therapy not required except for exacerbations

Exacerbations of cough and wheezing more frequent. Severe exacerbations infrequent. Urgent care treatment < 3/year

Periodic use of bronchodilators required during exacerbations for a week or more Steroids needed for short periods

Requires continuous multiple round-theclock drug therapy including daily steroids either aerosol or systemic in high doses

Diagnosis of Bronchial Asthma 111 Moderate: Moderate asthma is characterised by symptoms more than 1-2 times weekly affecting sleep and activity levels, exacerbations lasting several days, and occasional emergency care. The FEV1 or PEFR is expected to be 60-80% at baseline and vary between 20-30% with symptoms. Severe: This is characterised by continuous symptoms including nocturnal symptoms, limited activity levels, frequent exacerbations, and occasional hospitalisation, and emergency treatment. The FEV1 or PEFR is less than 60% at baseline and highly variable. The British Guidelines are parallel to the NAEP guidelines. However, the Global Strategy for Asthma Management and Prevention Workshop, a joint effort of the National Heart, Lung, and Blood Institute and the WHO, 1995 (NIH Publication No. 96-3659A) classifies severity of asthma into different (discussed subsequently). REFERENCES 1. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel A. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131. 2. Behera D. Normal values of Pulmonary Function Tests. In: Pulmonary functions tests in Health and Disease (Ed). PS Shankar. Indian College of Physicians, 1998; 150-59. 3. Wagner EM, Liu MC, Weinnman GG, Permutt S, Bleecker ER. Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584. 4. Cibella F, Cuttitta G, Bella V et al. Lung function decline in bronchial asthma. Chest 2002;122: 1944-48. 5. Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Hest 2002;121:715-21. 6. Wassermann K. Is asthma another interstitial lung disease? Chest 2002;121:673-74. 7. Gupta ML, Behera D: Pattern of airflow obstruction in Bronchial Asthma—An observation on Home-Monitoring of Peak Expiratory Flow Rate. J Ass Phy India, 1997;45:94-96. 8. Clark TJH, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest 1977;71:87-92. 9. Jamison JP, McKinley RK. Validity of peak expiratory flow rate variability for the diagnosis of asthma. Clin Sci 1993;85:367-71. 10. Hunter CJ, Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;121:1051-57. 11. Allergy skin testing. Board of Directors,; American Academy of Allergy and Immunology J Allergy Clin Immunol 1993;92:636-37. 12. Corne J, Smith S, Schreiber J et al. Prevalence of atopy in asthma. Lancet 1994;344:344-45. 13. Holt PG, Macaubas C, Stumbles PA et al. The role of allergy in the development of asthma. Nature 1999;402:B12-B17, 14. Holgate ST. The epidemic of allergy and asthma. Nature 1999;402:B2-B4. 15. Busse WW, Lemanske RF. Advances in immunology: Asthma. N Engl J Med 2001;344:350-62. 16. Graif Y, Yigla M, Tov N, Kramer MR. Value of a negative aeroallergen skin-prick test result in the diagnosis of asthma in young adults. Co-relative study with methacholine challenge testing. Chest 2002;122:821-25. 17. Higgins BG, Britton JR, Chinn S et al. The distribution of peak flow variability in a population sample. Am Rev Respir Dis 1989;140:1368-72. 18. Kesten S, Rebuck AS. Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD! Chest 1994;105:1042-1045. 19. Thiadens HA, De Bock GH, Dekker FW et al. Value of measuring diurnal peak flow variability in the recognition of asthma: a study in general practice. Eur Respir J 1998;12:842-47.

112 Bronchial Asthma 20. Kunzli N, Stutz EZ, Perruchaoud AP et al. Peak flow variability in the SAPALDIA study and its validity in screening for asthma-related conditions. The SAPALDIA Team. Am J Respir Crit Care Med 1999;160:427-34. 21. Siersted HC, Mostgaard G, Hyldebrandt N et al. Interrelationships between diagnosed asthma, asthma like symptoms, and abnormal airway behaviour in adolescence. The Odense Schoolchild Study. Thorax 1996;51:503-09. 22. Quackenboss JL, Libowitz MD, Krzyzanoski M. The normal range of diurnal changes in peak expiratory flow rates. Relationship to symptoms, and respiratory disease. Am Rev Respir Dis 1991;143:323-30. 23. Reddel HK, Salome CM, Peat JK et al. Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995;151:1320-25. 24. Tweeddale PM,Alexander F, McHardy GJ. Short-term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax 1987;42:487-90. 25. Newton MF, O’Donnell E, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 2002;121:1042-50. 26. Anderson SD. Nonisotonic aerosol challenge in the evaluation of bronchial hyper-responsiveness. Allergy Proc 1991;12:143. 27. Boulet LP, Legris C, Thibault L, Turcotte H. Comparative bronchial response to hyperosmolar saline and methacholine in asthma. thorax 1987;42:953-58. 28. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyper-reactivity. Am Rev Respir Dis 1980;121:389-414. 29. Hopp RJ, Townley RG, Biven RE, Bewtra AK, Nair NM. The presence of airway reactivity before the development of asthma. Am Rev Respir Dis 1990;141;2-8. 30. Jones A. Asymptomatic bronchial hyper-reactivity and the development of asthma and other respiratory tract illnesses. Thorax 1994;49;757-61. 31. Chatham M, Bleecker ER, Smith PL, Rosenthal RR, Mason P, Norman PS. A comparison of histamine, methacholine, and exercise airway reactivity in normal and asthmatic subjects. Am Rev Respir Dis 1982;126:235-40. 32. American Thoracic Society Guidelines for methacholine and exercise challenge testing, 1999. Am J Respir Crit Care Med 2000;161:309-329. 33. American Thoracic Society Guidelines for bronchial inhalation challenges with pharmacologic and antigenic agents. ATS News 1980 (Spring). 34. Parker AL, McCool FD. Pulmonary function characteristics in patients with different patterns of methacholine airway hyper-responsiveness. Chest 2002;121:1818-23. 35. Laprise C, Boulet LP. Asymptomatic airway hyper-responsiveness: A three year follow-up. Am J Respir Crit Care Med 1997;156:403-409. 36. Pattemore PK, Asher MH, Harrison AC et al. The interrelationship among bronchial hyperresponsiveness, the diagnosis of asthma, and asthma symptoms. Am Rev Respir Dis 1990;142: 549-554. 37. Burney PGJ, Luczynska G, Chinn S et al. The European Community Respiratory Health Survey. Eur Respir J 1994;7:954-60. 38. Schwartz J, Schindler C, Zemp E et al. Predictors of methacholine responsiveness in a general population. Chest 2002;122:812-20. 39. Perkins PJ, Morris MJ. Vocal cord dysfunction induced by methacholine challenge testing. Chest 2002;122:1988-93. 40. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine in asthma: Measurement and clinical significance. J Allergy Clin Immunol 1981;68:347-55. 41. Chatham M, Bleecker ER, Norman P, Smith PL, Mason P. A Screening test for airways reactivity. Chest 1982;82:15-18.

Diagnosis of Bronchial Asthma 113 42. Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, airway caliber. Thorax 1982;37:423-29. 43. Galvez RA, McLaughlin FJ, Levison H. The role of the methacholine challenge in children with chronic cough. J Allergy Clin Immunol 1987;79:331-35. 44. Hunter CJ, Brightling CE, Voltman G et al. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002;122:1051-57. 45. Jeffery P. Immunopathology: Comparison of COPD and asthma. In: Hansel TT, Barnes PJ (Eds): New Drugs for Asthma, Allergy, and COPD. Prog Respir Res. Basel, Karger, 2001; 31:24-29. 46. Chan-Yeung M, Malo JL. Occupational asthma. New Engl J Med 1995;333:107-12. 47. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991.

114 Bronchial Asthma

7 Prognosis of Bronchial Asthma FACTORS FOR ASTHMA MORTALITY Although the possibility of asthma-related death exists for all patients with asthma, several studies have revealed factors associated with an increased risk of such deaths.1-6 Several studies from many countries of the world including Britain, New Zealand, United States, France, Germany, and Canada have shown increases over the last two decades in the incidence of deaths from asthma. The cause of such increase in deaths remains a puzzle. There are many hypotheses to explain this, but little emphasis has been placed on the possibility that confidence in better drug treatment may modify patient’s behaviour so as to place him at greater risk of illness. Excessive confidence in bronchodilator inhalers and nebulisers can make patients stay away from hospitals too long during acute attacks. It is also very likely that prevention of symptoms by use of antiasthma drugs could allow patients to spend more time in environments containing antigens or other agents that provoke asthma, resulting in more serious and long-lasting bronchial inflammation and reactivity. Some of these recognised factors that increases the susceptibility to death from asthma are as follows. Age and Ethnicity Asthma-related death rates are higher among older patients than in any other age group. Although the death rate is relatively low in younger patients, an increased trend in asthma deaths among these individuals between the age group of 5 to 34 years have been noted during the last 10 years. People in their late teens and early twenties, particularly members of minority groups, are over represented in asthma mortality statistics groups. AfricanAmericans have asthma related mortality rates that are higher than those of Caucasians, especially in relatively young age groups, and the mortality rate in this group has increased significantly during the past decade. In 1979, African-Americans of both sexes were about twice as likely to die of asthma as Caucasians. Previous Life-threatening Acute Asthma Exacerbations Individuals who have had acute exacerbations of asthma that resulted in respiratory failure and required intubation are at increased risk for subsequent fatal exacerbations. Those who have experienced respiratory acidosis without requiring intubation are also high-risk patients.

Prognosis of Bronchial Asthma 115 Hospital Admission for Asthma within the Last Year Those patients hospitalised for asthma within the last year have a greatly increased risk of dying from asthma when compared to severity-matched asthma patients in the community that have not been hospitalised. Those with more than two hospitalisations for status asthmaticus in spite of long-term oral steroid therapy are at the highest risk of dying from asthma. In some patients, deterioration during an acute exacerbation occurs very rapidly. Underestimation of the severity of such exacerbations may lead to a life-threatening delay in starting medical treatment or seeking medical care. Some patients may fail to appreciate a poor response to treatment during an acute exacerbation and may rely on frequent repetitive use of inhaled β2-agonist far in excess of recommended doses for therapy at home. This treatment may temporarily blunt symptoms but mask increasing inflammation and airway hyperresponsiveness, which may in turn, lead to abrupt and severe deterioration of lung function. Without the documented objective measures of pulmonary function or realisation by the patient and/or the physician of the severity of the disease, risk of death is increased. Psychological and Psychosocial Problems Depression leads to increased death particularly in children. Other psychological problems that have been documented as associated with those at increased risk include alcohol abuse, documented depression, recent family loss and disruption, recent unemployment, and schizophrenia. Patients who have experienced a life-threatening asthma exacerbation have been reported, on the whole, to deny that they are at risk of death. Following a near fatal exacerbation, they tend to either develop decompensating psychiatric disease and symptoms of extreme anxiety or develop even higher levels of denial. Some tend to minimise their symptoms and avoid access to health care. Other associations include life crises, family conflict, and social isolation. Regardless of the possible physiologic and psychological interactions that link anxiety, depression, and asthma fatality, it is evident that patients who have these psychological disruptions are at increased risk for death.7-15 Lack of Access to Medical Care Lack of access to medical care is another risk factor associated with asthma-related death. Patients of lower socioeconomic class are unable to obtain routine preventive asthma care. As a result, these patients seek help only when their asthma symptoms are severe and report to the emergency room for initial care.16 In rural areas, lack of access to adequate emergency care can result in life-threatening delay in medical treatment during exacerbations. Even in some urban centers, adequate facilities like ventilatory support are not available. Medication Use Medications, particularly steroids, are underused at the time of death. The controversy of the asthma mortality because of β-agonist use is still on.17-19

116 Bronchial Asthma REFERENCES 1. Wissow LS, Gittelsohn AM, Szklo M, Starfield B, Mussman M. Poverty, race, and hospitalisation for childhood asthma. Am J Public Health 1988;78:777. 2. Miller BD. Depression and asthma: A potentially lethal mixture. J Allergy Clin Immunol 1987;80:481. 3. Strunk RC. Identification of the fatally-prone subject with asthma. J Allergy Clin Immunol 1989;83:477. 4. Rea HH, Scragg R, Jackson R et al. A case-controlled study of deaths from asthma. Thorax 1986;41:833. 5. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423. 6. Barriot P, Riou B. Prevention of fatal asthma. Chest 1987;92:460. 7. Campbell DA, McLennan G, Coates JR et al. A comparison of asthma deaths and near fatal asthma attacks in South Australia. Eur Respir J 1994;7:490-97. 8. Strunk RC, Mrazek DA, Fuhrmann GSW, LeBreque JF. Death from asthma in childhood. Can they be predicted? JAMA 1985;254:1193-98. 9. Wareham NJ, Harrison BDW, Jenkins PF, Nicholls J, Stableforth DE. A district confidential enquiry into death due to asthma. Thorax 1993;48;1117-20. 10. Campbell DA, Yellowlees PM, McLennan G, et al. Psychiatric and medical features of near fatal asthma. Thorax 1995;50;254-59. 11. Creer TL. Psychological factors and deaths from asthma; Creation and critique of a myth. J Asthma 1986;23;261-69. 12. Boseley CM, Fosbury JA, Cochrane GM. The psychological factors associated with poor compliance with treatment in asthma. Eur Respir J 1995;8;899-904. 13. Fitzgerald JM. Psychological barriers to asthma education. Chest 1994;1069(Suppl4):2S-3S. 14. Gibson GJ. Perception, personality, and respiratory control in life-threatening asthma. N Engl J Med 1994;330:1329-34. 15. Weiss KB, Wagener DK. Geographical variations in US asthma mortality: Small area analysis of exercise mortality, 1981-85. Am J Epidemiol 1990;132:s107. 16. Barger LW, Vollmer WM, Felt RW, Buist AS. Further investigations into the recent increase in asthma death rates; a review of 41 asthma deaths in Oregon in 1982. Ann Allergy 1988;60:31-39. 17. Crane J, Flatt A, Jackson R et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: Case control study. Lancet 1989;1:917-27. 18. Crane J, Pearce N, Burgess C, Beasley R. Asthma and the beta agonist debate. Thorax 1995;50(Suppl 1):S5-S10. 19. Suissa S, Ernst P, Boivin JF et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta agonists. Am J Respir Crit Care Med 1994;149:604-10.

Complications of Bronchial Asthma 117

8 Complications of Bronchial Asthma Infections, pneumothorax, pneumomediastinum, and atelectasis due to mucus plugging are the complications of acute bronchial asthma. Allergic broncho-pulmonary mycosis (ABPM) is an important complication of asthma.1 The most common fungus involved is Aspergillus fumigatus. Sensitisation to aspergillus antigens may occur in asthmatics without full-blown picture of ABPA. The prevalence of such sensitisation reportedly occurs in 20-50% of cases of bronchial asthma and the incidence of full-blown pictures of ABPA occurs in about 65 of cases, although higher figures have been reported.2-11 Other organisms that can cause such bronchopulmonary reactions include other species of Aspergillus, Candida albicans, Pseudoallescheria boydii, Stemphylium sp, Helminthosporium sp, Pseudomonas aeruginosa, Curvularia lunata, Drechslera hawaiiensis, Torulopsis glabrata, Rhizopus, Penicillium, Bipolaris, and Fusarium vasinifectum.12 Cor pulmonale secondary to bronchial asthma is extremely uncommon and in fact, the presence of this complication should be an indication that the underlying problem is not asthma. Respiratory failure is common during acute severe asthma. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) Allergic bronchopulmonary aspergillosis is a complex hypersensitivity reaction to Aspergillus antigens because of the presence of the fungus in the bronchial tree and the disorder characterised by bronchospasm, pulmonary infiltrates, eosinophilia, and immunologic evidence of allergy to the antigens of Aspergillus species. Aspergillus fumigatus is the one responsible for the condition although other species may also be responsible. The first three cases were diagnosed in 1952 in England by Hinson et al.13 Subsequently the entity has been reported more frequently from that country as well as from other regions of the world like Australia,14 North America15 and parts of Asia.16 It was first reported from India in 197117 and a few case series have subsequently been documented.18-27 The disease is typically seen in patients with long-standing asthma or cystic fibrosis. The incidence of the condition in asthmatics is reported to vary from 3 to 20% of corticosteroid dependent asthma patients28 and 6% of patients with cystic fibrosis meet the diagnostic criteria of ABPA.29 Pathophysiology Patients with ABPA are usually atopic and have a history of bronchial asthma. The basic underlying pathophysiologic process in ABPA is a hypersensitivity reaction to the presence

118 Bronchial Asthma Flow Chart: Clinical spectrum of inhalation of Aspergillus spores Inhalation of Aspergillus

Colonisation

Normal host

No sequel

Cavitary lung disease

Aspergilloma

Chronic lung disease or mild immunocompromised

Chronic Nercotising Aspergillosis

Immunocompromised host

Invasive Pulmonary Aspergillosis

Asthma

ABPA

Colonisation

Tracheobronchitis

Ulcerative Tracheobronchitis Pseudomembranous tracheobronchitis

of fungus in the bronchial tree. Tissue invasion by the fungus usually does not occur. The factors favouring the initial colonisation of the bronchial tree are unclear. Other host factors, including cellular immunity, may contribute to the pathologic changes seen in ABPA.30,31 The changes brought about by the ensuing local immunologic reactions and the tenacious sputum of bronchial asthma favour the trapping of fungal spores and further colonisation. Antigenic material from the fungus stimulates production of IgE, IgG, and IgA antibodies. A number of immunologic reactions, notably type I (immediate) and type III (antigenantibody, immune complex) hypersensitivity reactions occur in this condition. The type I immediate hypersensitivity reaction is IgE mediated and account for the bronchospastic symptoms of the condition. Type III reactions mediated by IgG result in polymorph aggregation, inflammation of bronchial and peribronchial tissue and is responsible for the radiological features of ABPA. Both these reactions play a central role in the pathogenesis of ABPA.32,33 Recently a possible role of type IV hypersensitivity reaction has been inferred from the demonstration of in vitro lymphocyte transformation in response to Aspergillus antigens in patients with ABPA and the presence of parenchymal granuloma and mononuclear cell infiltration seen on histopathology. Alternate pathway complement

Complications of Bronchial Asthma 119 activation may also take part in the inflammatory response of ABPA. Long-standing involvement of the bronchial tree leads on to bronchiectasis, fibrosis, lung contraction, and lobar shrinkage. Lung biopsy in ABPA (done rarely as diagnosis is mainly clinical and laboratory findings) demonstrates different stages of chronic inflammatory process involving bronchial walls and peribronchial tissues. There is no tissue invasion by the fungus and granulomas may be seen. The most significant findings involve bronchi and bronchioles34 with bronchocentric granulomas and mucoid impaction. Other findings include granulomatous inflammation. The cellular infiltration consists of eosinophils, monocytes, plasma cells and multinucleated giant cells. The bronchi are dilated and are filled with tenacious exudates containing eosinophilic material and mycelia. In long-standing cases variable degrees of interstitial and alveolar fibrosis are seen. Presence of immune complexes has been demonstrated in some cases with immunofluorescent studies. Vasculitis is very rare. Bronchi contain tenacious mucus, fibrin, Curschmann’s spirals, Charcot-Leyden crystals, eosinophils, and mononuclear cells. Fungal hyphae may be seen in the bronchial lumen without tissue invasion.34 Clinical Features of ABPA The patient is usually an atopic individual with established bronchial asthma of many years. There is no clear relationship between exposure to antigens and the onset of symptoms. The onset is insidious with nonspecific complaints like anorexia, progressive fatigue, headache, generalised aches and pains, low grade fever, and loss of weight. The underlying asthma usually increases in frequency and severity with less degree of control with the usual anti-asthmatic medications. The increased frequency of wheezing is associated with intermittent or continuous sputum production. Rubbery golden-brown plugs of sputum production are characteristic of this condition and have been reported in 5 to 54% of cases. Expectoration of such plugs is associated with a dramatic improvement in symptoms particularly wheezing.35 These plugs consist of fungal hyphae with eosinophils and mucus. Cough is universal and dyspnoea may be present in a substantial number of cases. Haemoptysis has been reported in 34 to 85% of cases. Pleuritic chest pain may be present in about half of the patients and is usually localised to the side involved on chest X-ray. Chronic cases may present with symptoms compatible with bronchiectasis. Patients may exhibit minimal symptoms, yet demonstrate extensive pulmonary consolidation on chest radiography. Wheezing and diffuse crepitations are the common findings on chest examination. Five stages have been identified in patients with ABPA,36,37 which help to guide the management of the disease. It is not necessary for a patient to progress through all these stages. The stages are: • Stage I (Acute stage); • Stage II (Remission stage); • Stage III (Exacerbation stage); • Stage IV (Corticosteroid-dependent asthma stage); and • Stage V (Fibrotic stage).

Stage I The classic signs, symptoms, and laboratory findings present at diagnosis characterize the acute stage. Bronchial asthma, a markedly elevated IgE levels, peripheral eosinophilia, pulmonary infiltrates, and the presence of IgE and IgG antibodies to A.fumigatus characterize this stage. In practice, patients are rarely identified at this stage.

120 Bronchial Asthma

Stage II The remission stage is characterised by radiological clearing, a decline in total serum IgE levels, but not to the normal levels, eosinophilia is absent, control of respiratory symptoms, and a discontinuation of corticosteroid therapy over a six month period without recurrence of ABPA. Serum IgG antibodies to Aspergillus may be slightly elevated. Prolonged and permanent remissions may occur after treatment of the acute stage with steroids, and maintenance therapy is not required in these patients. In some, asthma may become refractory to aminophylline, β-agonists and Cromolyn and inhaled steroids may be necessary. Stage III The exacerbation stage is the one when the patent is a known case of ABPA and demonstrates all characteristics of the acute stage or when there is a two-fold rise in the total serum IgE levels in association with radiological finding in the absence of other causes of infiltrates like bacterial or viral pneumonias. Remission after an exacerbation is induced in these patients with corticosteroids and prolonged therapy is not necessary. Stage IV The corticosteroid-asthma stage is present when patients require oral steroid therapy to control asthma (steroid-dependent asthma) or to prevent recurrent exacerbations. The dose of steroids needed to control asthma usually is not sufficient for preventing the exacerbations of ABPA or the occurrence of both. Attempt to taper steroid therapy will result in worsening of symptoms and the development of pulmonary infiltrates. Stage V The fibrotic lung disease stage is present when there are extensive fibrotic changes on chest X-ray (end-stage lung disease) with irreversible obstructive lung disease on pulmonary testing. Steroid therapy is not able to reverse these changes completely. Dyspnoea, cyanosis, crepitations, clubbing, cor pulmonale, respiratory failure and death may occur in some patients. The serum IgE level and eosinophil count may be low or high. A minority of patients progress to this stage. ABPA may precede the clinical recognition of the disease for many years. Usually there are two sets of ABPA patients based on the onset of asthma before the age of 30 who have greater skin reactivity to other common allergens, and who show additional features of allergic disease such as eczema and allergic rhinitis. In the other subset of patients who have the onset of their asthma after the age of 30, generally have less cutaneous skin reactivity to common allergens and no other clinical symptom suggests allergic disease. Radiology The roentgenography changes in ABPA may be normal in early stages of the disease or they may be transient or permanent.38 (Figs 8.1 to 8.5 plate 1 and 2) During acute exacerbations, the typical changes are fleeting pulmonary infiltrates that tend to be in the upper lobe and central in location. Transient changes, which may clear with or without steroid therapy is due to parenchymal infiltrates, mucoid impactions or secretions in damaged bronchi. These transient findings include: i. Perihilar infiltrates simulating adenopathy; ii. Air-fluid levels from dilated central bronchi filled with fluid and debris; iii. Massive homogenous consolidation which may be unilateral or bilateral; iv. Radiographic infiltrates; v. “Tooth-paste shadows” due to impaction of mucus in the damaged bronchi; vi. “Gloved-finger” shadows due to distally occluded bronchi filled with secretions; and,

Complications of Bronchial Asthma 121 vii. Tram-line shadows, which are two parallel hairline shadows extending out from the hilum. Permanent changes include: i. Proximal bronchiectasis; ii. Parallel line shadows which are tram-line shadows resulting from bronchiectasis; and iii. Ring shadows which are dilated bronchi. Other rare findings may be cavitation, local emphysema, contracted upper lobes, honeycomb fibrosis, total lung collapse due to mucus impaction, and spontaneous pneumothorax. Normal chest X-ray does not exclude the diagnosis of ABPA. The chest CT may be more sensitive in demonstrating the above changes and has replaced the necessity of bronchography. Laboratory Findings Peripheral eosinophilia is common, and sputum contains eosinophils in most of the patients. Leucocytosis and raised ESR are found during acute episodes. The serological abnormalities include a marked increase in total serum IgE and specific IgE and IgG antibodies against A.fumigatus. The levels of both total and specific serum IgE levels are high during the development of pulmonary infiltrations; the levels decline after remission. Serial determination of total serum IgE may thus be helpful in detecting patients with ABPA or following the course of ABPA and determining the onset of an acute exacerbation.39 Occasionally, the serum IgE may be low. Skin testing with potent A.fumigatus extracts demonstrates an immediate wheal and flare reaction in most cases. This reaction is frequently followed by a late onset of erythema and edema occurring at the injection site over the next 4 to 6 hours. The reaction reaches its peak by 8 hours and subsides by 24 hours. These late reactions are due to deposits of IgG, IgM, IgA, and complement components. Serologic tests using double gel diffusion method reveal precipitating antibodies in most patients of ABPA. Radio immunoassay or ELISA techniques detects antibodies specific for Aspergillus belonging to several immunoglobulin classes. It has been demonstrated that up to 25% of patients of asthma have immediate skin reactivity to A.fumigatus and 10% demonstrate positive precipitating antibodies against this. Thus, neither of these parameters is specific for ABPA. Aspergillus can be cultured from sputum of nearly two-thirds of patients during acute episodes of ABPA. Repeated cultures are necessary to demonstrate the fungi. Bronchial challenges with A.fumigatus characteristically show a dual response in patients with ABPA. β-2 agonists can prevent the immediate reaction and the late reaction may be prevented by corticosteroids. Cromolyn sodium may prevent both types of reactions. However, bronchial challenge test is not required to confirm ABPA and may be risky. Abnormalities of pulmonary function tests in ABPA depend upon the stage at which they are performed. During the earlier stages of pure bronchospasm there will be an obstructive physiologic profile, whereas during the irreversible stages of the disease with bronchiectasis and fibrosis, the tests will reflect a restrictive physiologic profile. The degree of reversibility is much less compared to that in classic extrinsic-asthma. The diffusion capacity is reduced in most patients with a good correlation with the duration of the disease.

122 Bronchial Asthma Diagnosis There are no universally accepted criteria for the definite diagnosis of ABPA. Rosenberg et al35 have suggested the following which is accepted by most investigators. Greenberger and Patterson recently modified the diagnostic criteria for ABPA.39 They are listed in Tables 8.1 and 8.2. Table 8.1: Rosenberg criteria for diagnosis of ABPA

Primary 1. 2. 3. 4. 5. 6. 7. Secondary 1. 2. 3.

Episodic bronchial obstruction Peripheral blood eosinophilia Immediate skin reactivity to Aspergillus antigens Precipitating antibodies against Aspergillus antigens Elevated serum IgE History of infiltrates in the chest X-ray Central bronchiectasis

Aspergillus in sputum History of mucus plug expectoration Late skin (Arthus) reactivity to Aspergillus antigen

The diagnosis of ABPA is considered likely if the first six primary criteria are present; certain if all seven are present. Table 8.2: Modified diagnostic criteria of ABPA 1. 2. 3. 4. 5. 6. 7. 8.

Bronchial asthma Immediate skin reactivity to Aspergillus Serum precipitin to A.fumigatus Increased serum IgE and IgG to A.fumigatus Total serum IgE > 1000 ng/ml Current or previous pulmonary infiltrates Central bronchiectasis Peripheral eosinophilia (1,000 cells/μL)

Not all of these criteria need to be present to diagnose ABPA. Withholding therapy until the development of all clinical symptoms and evidence of bronchiectasis may lead to a missed diagnosis in a significant number of patients and to delayed treatment resulting in irreversible pulmonary damage. Therefore, ABPA may be subdivided into the following groups of patients with or without central bronchiectasis.40 A. Essential criteria for the diagnosis of ABPA with central bronchiectasis : Asthma, Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml Central bronchiectasis B. Minimal criteria for the diagnosis of ABPA without central bronchiectasis: (labelled ABPA-seropositive) Asthma, Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml History of pulmonary infiltrates Elevated levels of serum IgE and IgG antibodies to A.fumigatus

Complications of Bronchial Asthma 123 From a North Indian hospital (PGIMER, Chandigarh) a total of 651 patients with clinical suspicion of ABPA27 were reported during a period of 8 years (January 1991 to December 1998). Overall, 338 cases (52%) were positive either by sputum microscopy/culture (66 of 203 patients), by skin reactivity (150 of 309 cases), or by precipitating antibodies (122 of 338 cases) against Aspergillus species. However, in 89 patients, diagnosis was confirmed on the basis of Rosenberg’s criteria. Clinical profile and laboratory findings showed that the disease was more common among males. Poor control of asthma, constitutional symptoms, mucopurulent expectoration, increased dyspnoea or wheezing and rhonchi were the main presenting symptoms. Skin reactivity against aspergillin was seen in 73 (82%), precipitating antibodies against aspergillus species were positive in 64 (72%) and sputum microscopy/ culture was positive in 56 (63%) of these 89 patients. Central bronchiectasis and fleeting shadows were the most common radiological findings. Differential Diagnosis A number of disorders may be confused with ABPA. Tuberculosis, because of its similar upper lobe involvement on chest X-ray, may be the initial diagnosis. It is not uncommon to find patients receiving antitubercular therapy. A high degree of suspicion is necessary to avoid this confusion.19 History of asthma with such chest X-ray should arouse the suspicion. Repeated sputum examination will be negative for acid-fast bacilli. In that situation a diagnostic work-up for ABPA is warranted. Cystic fibrosis patients also may be confused with ABPA. In fact, these patients have a number of features in common with ABPA including isolation of the fungus from the sputum, bronchospasm, skin test reactivity and elevated serum IgE levels. However, the age of onset of cystic fibrosis, sweat chloride test, and other associated nonpulmonary features will help to distinguish the two conditions. Carcinoma of the lung, particularly, bronchoalveolar cell carcinoma, may some times be confused with ABPA particularly in elderly individuals. The other etiologies of eosinophilic pneumonias can usually be differentiated on clinical and immunological grounds. Although classically ABPA is caused by Aspergillus fumigatus, some cases can also be due to other species of Aspergillus. In recent years, allergic bronchopulmonary reactions have also been observed due to moulds or bacteria. Stemphylum species, Helminthosporium species, Pseudomonas aeruginosa, Curvularia lunata, Candida albicans, Dreschslera hawaiiensis, and Torulopsis globata are examples which have been shown to cause such reactions similar to ABPA in the lungs. Treatment Therapeutic approach to treat ABPA may be directed to achieve two goals: (i) to remove the source of antigenic stimulation by eliminating the fungus from the bronchial tree; and (ii) suppressing the bronchial hypersensitivity reactions and their associated local parenchymal changes. The first one was thought to be achieved by employing inhalation of anti-fungal agents such as amphotericin B, nystatin, natamycin, and cotrimazole. However this approach has now largely been abandoned because of frequent recurrences and because of the need for repetitive treatments more often. Oral corticosteroid therapy is the treatment of choice in ABPA. They act by suppressing the allergic inflammatory reaction by suppressing the immunologic response to aspergillus antigen and decrease sputum production. Because of the later effect the bronchus becomes

124 Bronchial Asthma less favourable for further fungal colonisation. Resolution of radiographic infiltrates and improvements in symptoms have been observed in most patients. Prednisone therapy maintains clinical improvement in over 80% of patients by relief of bronchospasm, clearing of pulmonary infiltrates, and decreasing serum IgE level and peripheral eosinophilia.41,42 The current treatment of exacerbation of ABPA consists of daily administration of prednisone in a dose of 0.5 mg/kg, given as a single morning dose for a period of two weeks and then gradually decreasing the dose.43 This dose is usually sufficient to improve pulmonary lesions in two weeks, at which time the same dosage is changed to a single alternate-day regimen. This dosage is maintained for a minimum of three months. Most patients, however, require more prolonged therapy to control their symptoms and minimize relapse.43,44 If the chest X-ray shows improvement and there is a substantial reduction in total serum IgE levels, slow reduction of prednisone, at a rate of 5 mg/day may be attempted. Treatment must be individualised depending upon the stage of ABPA, frequency of exacerbations, and severity of asthma. Monthly serum IgE levels are to be obtained, and when a twofold increase is present, a chest X-ray should be obtained to rule out exacerbation. Usually there is an exacerbation of symptoms during particularly seasons due to an increase in the fungal spores in the atmosphere. This varies with geographic locations and accordingly the steroid therapy should be reduced with caution during these months. The frequency of chest X-ray to be taken in following a patient of ABPA is not known. It is perhaps best to obtain the X-ray every three to six months during the first year of follow-up and on a yearly basis thereafter to avoid missing intercurrent pulmonary damage. Serum IgE levels should also be monitored regularly. Pulmonary function tests should be obtained yearly. Inhaled therapy may be beneficial, but its use is limited by the degree of obstruction and mucus plugging. Inhaled steroids are not helpful in preventing the progression of lung damage associated with ABPA.45,46 Since there are side effects associated with long-term use of corticosteroid therapy, including an increased risk of invasive aspergillosis,47 attempts were made to use alternative drugs. The role of itraconazole, an anti-fungal agent has been evaluated.48 When the drug is used in a dose of 200 mg twice daily for 4 months, 46% of the patients showed a significant response (a 50% reduction in corticosteroid dose, a decrease of at least 25% in the serum IgE level, and a 25% improvement in exercise tolerance or pulmonary function test results, or the resolution or absence of pulmonary infiltrates). The study concluded that patients with ABPA generally benefit from concurrent itraconazole therapy without much side effect and suggested that a lower dose of 200 mg daily is equally beneficial and may be used as a maintenance therapy to sustain remission. The disease has been seen throughout the world and has been a subject of extensive review from across the globe.49-53 REFERENCES 1. Bredin CP, Donnely S. Period prevalence of allergic bronchopulmonary mycosis in an outpatient population is over 1 percent. Eur Respir J 1991;4(Suppl 14):1715. 2. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating antibodies against A.fumigatus in bronchial asthma. Lung India 1989;7:67-69. 3. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergy Bronchopulmonary Aspergillosis: A Retrospective study of 35 cases. Indian J Chest Dis All Sci 1994;36:173-79. 4. Malik SK, Talwar P. Allergic bronchopulmonary aspergillosis. Bull PGI 1980;14:95-98.

Complications of Bronchial Asthma 125 5. Subramanium S, Viswanathan R. Allergic bronchopulmonary aspergillosis. Ind J Chest Dis 1972;14:72-77. 6. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys India 1971;19: 835-841. 7. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis. in India. Scand J Respir Dis 1972;503:289-301. 8. Pamra SP, Khan ZU, Sandhu RS, Ilyas M. Allergic bronchopulmonary aspergillosis. Ind J Tubercl 1972;19:61-67. 9. Khan ZU, Sandhu RS, Randhwa HS et al. Allergic bronchopulmonary aspergillosis. A study of 46 cases with special reference to laboratory aspects. Scand J Respir Dis 1976;57:73-87. 10. Shivpuri DN, Aggarwal MK. Studies on the allergic fungal spores of Delhi., India, metropolitan area. J allergy 1969;44:204-13. 11. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. Ann Allergy 1985;54:46-49. 12. Backman KS, Roberts M, Patterson R. Allergic bronchopulmonary mycosis caused by Fusarium vasinfectum. Am J Respir Crit Care Med 1995;152:1379-81. 13. Hinson KFW, Moon AJ, Plummer NS. Bronchopulmonary aspergillosis. A review and a report of eight cases. Thorax 1952;7:317-33. 14. Elder JL, Smith JT. Allergic bronchopulmonary aspergillosis. Med J Australia 1967;1:231-33. 15. Patterson R, Golbert F. Hypersensitivity disease of the Lung. University Michigan Med Centre J 1968;34:8-11. 16. Subramianiam S, Viswanathan R. Allergic aspergillosis. Ind J Chest Dis 1972;14:72-77. 17. Shah JR. Allergic bronchopulmonary aspergillosis. J Ass Phys Ind 1971;19:835-41. 18. Khan ZU, Sandhu RS, Randhawa HS, Menon MPS, Dusaj IS. Allergic bronchopulmonary aspergillosis: A study of 46 cases with special reference to laboratory aspects. Scand J Respir Dis 1976;57:73-87. 19. Behera D, Guleria R, Jindal SK, Chakrabarti A, Panigrahi D. Allergic bronchopulmonary aspergillosis: a retrospective study of 35 cases. Ind J Chest Dis All Sci 1994;36:173-79. 20. Bedi RS. Allergic bronchopulmonary aspergillosis: Review of 20 cases. Ind J Chest Dis All Sci 1994;36:181-86. 21. Shah A, Khan ZU, Chaturvedi S, Bazaz Malik G, Randhawa HS. Concomittant allergic Aspergillus sinusitis and allergic bronchopulmonary aspergillosis with familial occurrence of allergic bronchopulmonary aspergillosis. Ann allergy 1990;64:507-12. 22. Shah A, Khan ZU, Sircar M, Chaturvedi S, Bazaz Malik G, Randhawa HS. Allergic aspergillus sinusitis; an Indian report. Respir Med 1990;84:249-51. 23. Aggarwal AK, Behera D, Malik SK, Kumar L, Talwar P. Skin hypersensitivity and precipitating antibodies against A.Fumigatus in bronchial asthma. Lung India 1989;7:67-69. 24. Chetty A, Bhargava S, Jain RK. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. Ann Allergy 1985;54:46-49. 25. Sandhu RS, Mishra SK, Randhawa HS, Prakash D. Allergic bronchopulmonary aspergillosis in India. Scand J Respir Dis 1972;53:289-301. 26. Chakrabarti A, Sharma SC, Chander J. Epidemiology and pathogenesis of Para nasal sinus mycoses. Otolaryngol Head Neck Surg 1992;107:745-50. 27. Chakrabarti A, Sethi S, Raman DSV, Behera D. Eight-year study of allergic bronchopulmonary aspergillosis in an Indian teaching hospital. Mycoses 2002;45:295-99. 28. Basich JE, Graves TS, Baz MN et al. Allergic bronchopulmonary aspergillosis in corticosteroid dependent asthmatics. J Allergy Clin Immunol 1981;68:98-102. 29. Mrouch S, Spok A. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Chest 1994;105:32-36. 30. Knutsen AP, Slavin RG. Invitro T-cell response in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. J Lab Clin Med 1989;113:428-35.

126 Bronchial Asthma 31. Chauhan B, Santiago I, Kirschmann DA et al. The association of HLA-DR alleles and T-cell activation with allergic bronchopulmonary aspergillosis. J Immunol 1997;159:4072-76. 32. Wang JL, Patterson R, Rosenberg M et al. Serum IgE and IgG antibody activity against Aspergillus fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1978;117:917-27. 33. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Med 1999;50:303-16. 34. Bosken CH, Myers JL, Greenberger PA et al. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol 1988;12:216-22. 35. Rosenberg M, Patterson R, Mintzer R et al. Clinical and immunological criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14. 36. Patterson R, Greenberger PA, Radin RC et al. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med 1982;96:286-91. 37. Patterson R, Greenberger PA, Hawig JM et al. Allergic bronchopulmonary aspergillosis; natural history and classification of early disease by serologic and roentgenographic studies. Arch Intern Med 1986;146:916-18. 38. Mintzer RA, Rogers LF, Kruglik GD et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology 1978;127:301-07. 39. Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann allergy 1986;56:444-48. 40. Greenberger PA. Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997;278: 1924-30. 41. Rosenberg M, Patterson R, Robert M et al. The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med 1978;64:599-606. 42. Wang JL, Patterson R, Roberts M et al. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1979;120:87-92. 43. Capewell S, Chapman BJ, Alexander F et al. Corticosteroid treatment and prognosis in pulmonary eosinophilia. Thorax 1989;44:925-29. 44. Safirstein BH, D’Souza MF, Simon g et al. Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1973;108:450-59. 45. British Thoracic Association. Inhaled beclamethasone dipropionate in allergic bronchopulmonary aspergillosis: Report to the Research Committee of the British thoracic Association. Br J Dis Chest 1979;79:349-56. 46. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121:1988-99. 47. Ganassinni A, Cazzadori A. Invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis. Respir Med 1995;89:143-45. 48. Stevens DA, Schwartz HJ, Lee JY et al. A randomised trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-62. 49. Davis SF, Sarosi GA. Role of serodiagnostic tests and skin tests in the diagnosis of fungal disease. Clin Chest Med 1987;8:135. 50. Pennington JE. Aspergillus lung disease. Med Clin North Am 1980;64:475. 51. Glimp RA, Bayer AS. Fungal pneumonias. Part 3. Allergic bronchopulmonary aspergillosis. Chest 1981;80:85 52. Ricketti AJ, Greenberger PA, Mintzer RA, Patterson R. Allergic bronchopulmonary aspergillosis. Chest 1984;86:773. 53. Fink JN. Allergic bronchopulmonary aspergillosis. Chest 1987;87(Suppl):81S.

Management of Bronchial Asthma 127

9 Management of Bronchial Asthma A number of guidelines on the management of bronchial asthma, both in children and adults are developed in recent years.1-11 They include those of the British Thoracic Society, NHLB, USA, and the Global Initiative for Asthma, etc. The recommendations are based on the same principle and basically the same. The goals of management of bronchial asthma as recommended by these agencies are as follows: i. To recognise asthma ii. To maintain a normal activity level including exercise. iii. To maintain a normal or near normal (best) pulmonary function rates. iv. To prevent chronic and troublesome symptoms like coughing or breathlessness in the night, early in the morning, or after exertion. v. To prevent recurrent exacerbations. vi. To minimise absence from work or school vii. To enable normal growth to occur in children, and viii. To use the least minimum drugs to avoid adverse reactions from medications used for asthma. Since bronchial asthma is a chronic condition with acute exacerbations, treatment requires a continuous care approach to control symptoms, to prevent exacerbations, to treat adequately such exacerbations, and to reduce chronic airway inflammation. Prevention of exacerbation is an important principle of therapy. This includes avoidance of triggers and allergens. Round-the-clock medication may be beneficial to many patients. Children and adults, who have poor exercise tolerance, recurrent symptoms, and frequent nocturnal attacks and patients with moderate asthma will often benefit from the regular administration and more aggressive use of antiasthma medication, particularly anti-inflammatory drugs. In contrast, patients with mild intermittent asthma with uninterrupted sleep at night, and good exercise tolerance may need only occasional treatment for the relief of symptoms. Periodic assessment of these patients is essential to assure that their therapy is appropriate. The treatment of asthma should also be based on the understanding of the underlying pathophysiologic mechanisms and the objective assessment of severity of the disease. It is now appreciated that asthma is an inflammatory disease and therapy should include antiinflammatory agents to reduce inflammation and to relieve or prevent symptomatic airway narrowing. Anticipatory or early interventions in treating acute exacerbations of asthma reduce the likelihood of developing severe airway narrowing.

128 Bronchial Asthma Thus, the integral components of asthma therapy include patient education, environmental control, and medication with the use of objective measures to monitor the severity of disease and the efficacy of therapy. The interrelationship of all these approaches is shown in Figure 9.1. Basically the treatment of asthma consists of both; i. Nonpharmacologic therapy and ii. Pharmacologic therapy. The optimal nonpharmacological treatment consists of i. Patient and family education; ii. Avoidance of agents that induce or trigger asthma like allergens, irritants like smoke, and reasonable attempts at reducing exposure to respiratory viruses; and iii. Immunotherapy. The pharmacologic therapy is used to treat reversible airflow obstruction and airway hyper-responsiveness. Medications include bronchodilators and antiinflammatory agents with some acting as both. NONPHARMACOLOGIC MANAGEMENT Patient and Family Education Patient education by the treating physician is a powerful tool for helping patients to gain self-confidence to control their asthma.12,13 Since much of the day-to-day responsibility for

Fig. 9.1: General principles of management of asthma

Management of Bronchial Asthma 129 managing asthma falls on the patient and the patient’s family, encouraging active participation in a partnership with the clinician can improve patient adherence to the treatment plan and stimulate family effort to improve control of asthma.14,15 In fact a patient is his best physician since he alone can recognise well about his illness, its progression, regression, response to treatment, and imminent acute attack. It should start at the time of diagnosis and should be continued throughout as an integral component during continued care. Family participation is an essential component of this programme. Establishment of a partnership with the patient, encouraging adherence to the treatment plan, teaching about the triggers (exercise, viral respiratory tract infections, allergens and irritants) and how to avoid, eliminate, or control them, explaining the patient regarding medications both preventive and rescue therapy, their adverse effects and educating about the adverse drug reactions are important components of this plan. Moreover teaching the patient how to recognise the severity of asthma and the appropriate time to seek medical advice during acute exacerbations are important. Giving information alone does not alter behaviour. Written and audiovisual reinforcement of spoken language further helps patient confidence. Giving these informations along with written self management plans will help the patient who may adjust treatment to keep themselves symptom free that reduces morbidity and health costs.16,17 Although now there is definite evidence of benefit from patient education and issuing of self management plans, certain areas like who need them, and what form they should take (number of action levels, thresholds for intervention) are poorly defined. Proper use of inhalers is very essential.18,19 Patient should demonstrate use of the metereddose inhaler to the physician, and the technique should be reviewed at every visit. Since home-monitoring of PEFR is an essential component of asthma management, the patient needs to be taught how to use a peak flow meter correctly and how to interpret it.20,21 Psychosocial issues as outlined above which increases asthma morbidity and mortality need to be taken care of. Management of Allergy Since allergy has a very significant role in the pathophysiology of asthma, interventions to control this are important. There can be two ways to approach this problem: (i) environmental controls; and (ii) immunotherapy.

Environmental Control Outdoor allergens like pollens and mould are best avoided by staying indoors particularly during the midday and afternoons. An air conditioned environment is the best way. Various nasal filters are available, which may be helpful to prevent penetration of allergens. However, this has not been proved to be very effective. Indoor allergen elimination is possible by paying special attention to the following. To avoid exposure to animal danders, the animal should be removed from the house. Removal of pets may not afford immediate relief even when followed by vigorous cleaning, since allergens continue to stay in the home for many months. Application of 3% tannic acid will denature and render such substances nonallergic. If the pet cannot be kept out of the house, there should be least contact with the patient and the animal should not be allowed at all to the bed room. Washing and bathing the pet frequently may reduce the amount of dander and dried saliva to be deposited on carpets and furnitures.22

130 Bronchial Asthma Reducing exposure to dust mites can be achieved by the following four plans of attack:23-25 a. By placing barriers between the patient and reservoirs of dust mite Elimination of mite exposure is possible by encasing the mattress in an airtight cover and encasing the pillow, particularly plastic mattress covers. These are not only inexpensive, but they effectively reduce dust mite exposure and clinical symptoms of asthma. Microporous covers are also available which allow passage of water vapour for patient comfort while excluding mites and their allergens. b. To kill and remove mites Regular washing of bedding and pillows by washing it at least once weekly. The bedding should be washed in hot water (>58°C) frequently. This kills mites and removes mites from an important exposure source. Ascaricides, tannic acid, dry heating, and liquid nitrogen have been used to kill mites, but they need further study particularly in terms of side effects to the patient and they need professional application.26 It is also important to remove the dead mites once they are killed, by vacuuming otherwise they continue to be the source antigen. HEPA filtration removes air-borne mites but leaves undisturbed the major reservoir antigen in carpets, beddings, and upholstery. c. Making the environment less hospitable for mites The patient should avoid sleeping or lying on upholstered furnitures. The carpets and other dust collectors that are laid on concrete are to be removed. Reduction of indoor humidity to less than 50% by air conditioning or mechanical ventilation are less favourable to the growth of mites. Although not so effective in removing live mites, regular vacuuming removes their food and shelter. d. To remove the patient to dust-free environment Although practically inconvenient and expensive, this is a very effective measure, and can be adopted whenever feasible while dust busting is completed at home. To prevent growth of moulds, special attention should be paid to areas with increased humidity. Such areas like bathrooms, kitchens, and basements require adequate ventilation and frequent cleaning using chlorine bleach. Sweat on foam pillows encourage mould growth. They should be encased or changed frequently. While cleaning, the patient should wear a dust mask. Climate control by air conditioning is beneficial, because it allows windows and doors to be closed and by reducing indoor humidity, discourages mould and mite growth. Humidifiers are potentially hazardous. If not cleaned regularly and properly, they facilitate the growth and aerosolise mould spores. A number of other devices are available for cleaning allergens from the indoor air. Two such major devices are mechanical filters and electrical filters. Other indoor irritants like tobacco smoke,27 wood smoke, strong odours or sprays (perfumes, talcum powders), household cleaning substances, and fresh paints irritate the airway and trigger asthma symptoms. Therefore, these should be avoided. Exposure to ozone and sulphur dioxide worsen asthma by interacting with allergens or other triggers and should be avoided as far as possible. Since occupational exposure is an important cause of bronchial asthma in adults, avoidance to such exposure is important. However, patients with suspected occupational asthma should not be advised to cease work until the diagnosis is proven and until all methods for reducing exposure at the work place have been explored. Specialist respiratory physician, occupational physicians, and employers will all need to be involved in this process.

Management of Bronchial Asthma 131 Immunotherapy Allergenic extract immunotherapy is in use since the early 1900’s in an attempt to protect against grass pollen. Allergy immunotherapy has been shown to reduce the symptoms of asthma in a number of double-blind studies with a wide variety of allergens, including house-dust , grass pollen , cat dander and cladosporium and alternaria.28-31 Such therapy reduces the late reaction to allergens in the lung, reduces asthma symptoms following injections. Long-term use also reduces bronchial hyperresponsiveness. These suggest that allergen immunotherapy can be employed to prevent the development of allergic inflammation and perhaps the resulting bronchial hyperresponsiveness.32-37 However, the British Thoracic Society guidelines recommends that hyposensitisation (immunotherapy) is not indicated in the management of bronchial asthma.9 This therapy is employed only after performing a careful diagnostic study of history and skin tests to identify possible offending inhalant allergens. The history of symptoms must correlate accurately with allergen exposure with confirmed IgE-mediated reactivity to one or more suspected allergens, usually by wheal and flare skin reactivity or by serology such as RAST. The decision regarding immunotherapy depends upon three important considerations. (i) It must be established that there is a clinically important allergic component to asthma. (ii) In patients with a significant allergic components who are not obtaining full clinical improvement with standard environmental control and medication, and (iii) Failure of maximal environmental control measures. Currently the methods and frequency of administration of allergenic extract immunotherapy vary considerably. The dosage and frequency vary considerably. The allergens used are often poorly standardised and characterised, and the methodology is illdefined. With most forms of allergenic extracts, the initial frequency of injections is usually once weekly, with doubling of the dosage at regular intervals and progression to a series of monthly maintenance injections, depending upon the antigen preparation employed and the individual patient requirements. The therapy is dose-dependent and specific for the allergen employed, the higher the dose, the greater the clinical improvement. Allergic signs and symptoms may develop subsequent to injections, manifested either as local or systemic anaphylactic reactions (rare). There are no well-defined guidelines regarding the duration of therapy. Most physicians attempt to discontinue therapy after three or four years of a successful regimen, The National Blood, Heart, and Lung Institute, USA1 recommends that once patient achieves maintenance levels of immunotherapy, the interval between injections should be extended, with a goal of monthly injections. If the patient’s symptoms improve, treatment is usually continued for 3-5 years, although under some circumstances more prolonged therapy at monthly intervals may be warranted. If there is no evidence of response following two allergy seasons after reaching the maintenance or highest level tolerated by the patient, immunotherapy should be discontinued. Allergy immunotherapy should be administered only under the direct supervision of a physician who is adequately trained. The mechanisms for clinical improvement are unknown, but one or more immunological changes may be responsible for such improvement. Among these changes are: a. A rise in serum IgG blocking antibodies; b. Suppression of the usual seasonal rise in IgE antibodies, which follows environmental exposure,

132 Bronchial Asthma c. An increase in blocking IgG and IgA antibodies in respiratory secretions, d. A reduced basophil reactivity to allergens, e. Reduced lymphocyte responsiveness to allergen, and f. An increase in specific T-suppressor cell generation. However, the problem of immunotherapy is the recognisation of the allergen. Most of the times, identification is not feasible and as mentioned, immunotherapy is only allergenspecific. The duration of treatment is often prolonged and costly. Moreover relapse occurs in most patients after discontinuation of therapy. Therefore, immunotherapy is not widely used as an important component in the management of bronchial asthma. REFERENCES 1. National Asthma Education Programme. Expert Panel Report. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland, USA, Publication No. 91-3042A, June 1991. 2. Guidelines for the management of asthma in adults. 1-Chronic persistent asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:651-53. 3. Guidelines for the management of asthma in adults. 2-Acute severe asthma. Statement by the British Thoracic Society, Research Unit of the Royal College of Physicians of London, King’s Fund Center, National Asthma Campaign. BMJ 1990;301:797-800. 4. Warner JO, Gotz M, Landau LI et al. Management of asthma: A consensus statement. Arch Dis Child 1989;64;1065-79. 5. International Paediatric asthma Consensus Group. Asthma, a follow-up statement. Arch Dis Child 1992;67:240-48. 6. International Consensus report on the diagnosis and management of asthma. Clin Exp Allergy 1992;22(Suppl):1-72. 7. British thoracic Society and others. Guidelines for the management of asthma: A summary. BMJ 1993;9:287-92. 8. The British Guidelines on Asthma Management. 1995 Review and Position Statement. Thorax 1997;52(Suppl 1): S2-S8. 9. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Guidelines on the management of asthma. Thorax 1993;48:S1-S24. 10. British thoracic Society, British Paediatric Association, Royal College of Physicians of London, The King’s Fund Center, national asthma Campaign et al. Summary charts. BMJ1993;306:77682. 11. Global Initiative for Asthma. A practical guide for public health officials and health care professionals. US Department of Health and human services. NIH Publication No. 96-3659A, December 1995. 12. Brewis RAL. Patient education, self-management plans and peak flow measurements. Respir Med 1991;85:457. 13. Feldman CH, Clark NM, Evans D. The role of health education in medical management in asthma. Clin Rev Allergy 1987;5:195-205. 14. Mellians RB. Patient education is key to successful management of asthma. J Rev Respir Dis 1989;Suppl:S47-S52. 15. Clark NC. Asthma self-management education: Research and implications for clinical practice. Chest 1989;95:1110-13. 16. D’Souza W, Crane J, Burgess C, et al. Community-based asthma care; trial of a “credit card” asthma self-management plan. Eur Respir J 1994;7:1260-65.

Management of Bronchial Asthma 133 17. Iganacio-Gracia JM, Gonzalez-Santos P. Asthma self management education programme by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995;151:353-59. 18. Shim C, Williams MH. The adequacy of inhalation of aerosol from canister nebullisers. Am J Med 1980;69:891-94. 19. Newman SP, Pavia D, Clarke SW. Simple instructions for using pressurised aerosol bronchodilators. J R Soc Med 1980;73:776-79. 20. Vathenen AS, Cooke NJ. Home peak flow meters. Br Med J 1991;302:738. 21. Mendoza GR. Peak flow monitoring. J Asthma 1991;28:161. 22. Glinert R, Wilson P, Wedner HJ. Fel; D1 is markedly reduced following sequential washing of cats. J Allergy Clin Immunol 1990;85:225. 23. Wallshaw MJ, Evans CC. allergen avoidance in house dust mite sensitive adult asthma. Q J Med 1986;58:199-215. 24. Ehnert B, Lau-Schadendorf S, Weber A, Buettner P, Sehou C, Wahn U. Reducing domestic exposure to dust mite allergen reduces bronchial hyper-reactivity in sensitive children with asthma. J Allergy Clin Immunol 1993;90:135-38. 25. Murray AB, Fergusson AC. Dust free bedroom in the treatment of asthmatic children with house dust mite allergy: A controlled trial. Paediatrics 1983;91:418-22. 26. Colloft MJ, Ayres J, Carswell F, et al. The control of dust mites and domestic pets: A position paper. Clin Exp Allergy 1992;22(Suppl 2):1-28. 27. Andrae S, Axelson O, Bjorksten B, Fredriksson M, Kiellman NM. Symptoms of bronchial hyper reactivity and asthma in relation to environmental factors. Arch Dis Child 1988;63:474-78. 28. Reid MJ, Moss RB, Hsu YP. Seasonal asthma in Northern California; allergy causes and efficacy of immunotherapy. J Allergy Clin Immunol 1986;78:590-600. 29. Aas K. Controlled trial of hyposensitisation to house dust. Acta Paediatrc Scand 1971;60:264-68. 30. Ohman JL Jr, Findlay SR, Leiterman KM. Immunotherapy in cat-induced asthma: Double-blind trial with evaluation of in vivo and invitro responses. J Allergy Clin Immunol 1984;74:230-39. 31. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double-blind, placebo-controlled rush immunotherapy with a standardised alternaria extract. J Allergy Clin Immunol 1990;85:460-72. 32. Lilja G, Sundin B, Graff-Lonnevig v, et al. Immunotherapy wit cat and dog dander extracts IV. Effect of 2 years treatment. J Allergy Clin Immunol 1989;83:37-44. 33. Bousquet J, Maasch HJ, Hejjaoui A et al. Double-blind, Placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecularweight preparations in rhinoconjunctivitis and asthma. J Allergy Clin Immunol 1989;84:546-56. 34. Boulet LP, Cartier A, Thomson NC et al. Asthma and increases in nonallergic bronchial responsiveness from seasonal exposure. J Allergy Clin Immunol 1983;71:399-406. 35. Van Bever HP, Stevens WJ. Suppression of late asthmatic reaction by hyposensitisation in asthmatic children allergic to house dust mites (Dermatophagoides pteronyssiunus). Clin Expt Allergy 1989;19:399. 36. Chapman MD. Use of nonstimulatory peptides: A new strategy for immunotherapy? J Allergy Clin Immunol 1991;88:300. 37. Hoshino K, Hawasaki A, Mizushima Y, Yano S. Effect of antiallergic agents and bronchial hypersensitivity in short-term bronchial asthma. Chest 1991;100:57.

134 Bronchial Asthma

10 Pharmacologic Management of Asthma The drugs used for the treatment of bronchial asthma are classified as: 1. Bronchodilators • β-adrenergic agonists • Anticholinergics • Methylxanthines (now can be classified as anti-inflammatory) 2. Anti-inflammatory agents • Corticosteroids • Cromolyn sodium or cromolyn-like compounds • Methylxanthines • Leukotriene antagonists • Miscellaneous compounds including antihistamines. METHYLXANTHINES Theophylline, the principal methylxanthine used in asthma therapy over the past six decades and the most widely prescribed anti-asthma treatment worldwide, is a dimethylxanthine similar in structure to the common dietary xanthines, caffeine and theobromine.1-3 Other substituted xanthines have also bronchodilator property and include: Dyphylline (dihydroxypropyl theophylline), Etophylline (β-hydroxyethyl theophylline), Proxyphylline (β-hydroxypropyl theophylline), and Enprophylline (3-propylxanthine). Many “salts” of theophylline preparations are commonly marketed and have been in use over many years. Aminophylline, the ethylenediamine salt is perhaps the commonest compound used in many countries. Other commonly salts include formulations with calcium salicylate, sodium glycinate, and choline (oxtryphylline). Mechanism of action of theophylline remains unclear despite the long history and widespread use of the drug.4 Various mechanisms proposed for the molecular mechanism of action has been proposed and are shown in Table 10.1. Phosphodiesterase Inhibition Earlier it was believed that theophylline acts as an anti-asthma drug as it relaxes bronchial smooth muscle. Although the exact mechanism of such relaxation was not known, in vitro, theophylline inhibits phosphodiesterase (PDE) which breaks down cyclic nucleotides in the cell, that results in delayed degradation of cAMP and cGMP. Several families of PDE

Pharmacologic Management of Asthma 135 Table 10.1: Mechanism of action of theophylline Phosphodiesterase inhibition Adenosine receptor antagonist Increase in circulating adrenaline Mediator antagonism (anti-inflammatory effect) Inhibition of calcium ion flux Effect on respiratory muscles

are now recognised,5 of which PDE III is predominant in airway smooth muscle relaxation and PDE IV is important in inflammatory cells.5-8 Theophylline is a nonselective PDE inhibitor. Such inhibition occurs at concentrations ten-fold higher than those usually attained clinically. Total PDE activity in human lung extracts is inhibited by only 5-20% at therapeutic concentrations of theophylline.9,10 However, this modest inhibition may be sufficient to cause a substantial increase in intracellular cyclic nucleotide levels in the presence of endogenous activators of adenylyl cyclase.11 Inhibition of PDE could also lead to synergistic interaction with β-agonists. Since there is some evidence that PDE levels may be higher in asthmatics than normal individuals, theophylline may have a greater than expected inhibitory effects on PDE in asthmatic airways than in normal airways. 12 Bronchodilating effects of theophylline appear to closely parallel the serum concentrations. Although a steady-state serum concentration between 10-20 μg/ml gives optimal effect, a more conservative approach would be to aim for levels between 5-15 mg/ml. Since there is a linear relationship between log serum concentration and bronchodilator effect within this range, the dose should be increased if symptoms persist and the patient is at the lower end of the serum concentration range. Adenosine Receptor Antagonism Adenosine causes bronchoconstriction in bronchial asthma both in vitro and clinically when given by inhalation.13,14 This involves the release of histamine and leukotrienes from airway mast cells. This bronchoconstricting effect of adenosine is prevented by theophylline.15 This shows that theophylline is capable of antagonising the effects of adenosine at therapeutic concentrations. Theophylline is a potent inhibitor of adenosine receptors (both A1 and A2 receptors) at therapeutic concentrations and this may be the basis of its bronchodilator effect.16 Since the potent bronchodilators enprophylline doxofylline, do not have action against adenosine receptors, adenosine antagonism may not be the exact cause of bronchodilatation. However, inhibition of different adenosine receptor types and subtypes may be important for this differential action. Increased Catecholamine Release Intravenous theophylline increases the secretion of adrenaline from the adrenal medulla.17,18 Although the increase is small, it may be important. Anti-inflammatory Effect Recent evidence shows that theophylline may also possess some anti-inflammatory activity.19 Theophylline reduces both bronchial hyper-reactivity20,21 and the inflammatory response. The anti-inflammatory effect has been shown both in vitro and in vivo studies. The effects

136 Bronchial Asthma include decreased mediator release from mast cells, decreased release of reactive oxygen species from macrophages, decreased cytokine release from monocytes, decreased basic protein release by eosinophils, decreased proliferation of T-lymphocytes, decreased release of ROS (reactive oxygen species), and inhibition of late response to allergens, increased + CD8 cells in peripheral blood and decreased T-lymphocytes in airways in asthmatic patients. Theophylline inhibits plasma exudation in guinea pigs.20 It also demonstrates immunomodulatory effects in vivo because of the inhibitory effects on T-lymphocytes. The antiinflammatory effect is seen in much lower concentrations than its bronchodilatory concentrations. Effect on Respiratory Muscles In addition to bronchodilatation, it improves respiratory function by increasing the strength and reducing the fatigue of respiratory muscles particularly diaphragm.21,22 A number of studies suggest that during various contractile maneuvers theophylline increases Pdi/Edi, where Pdi denotes intrathoracic pressure swings across the diaphragm which reflects muscle force and Edi is the electromyographic recordings taken at the skin surface opposite the diaphragm insertion to measure the nervous input to the muscle. The ratio represents force/ unit of input. Inhibition of Calcium Ion Flux and Other Extrapulmonary Effects Some evidence suggest that theophylline may interfere with calcium mobilisation in airway smooth muscle. Although it has no effect on entry of calcium ions through voltage-dependent channels, it may influence calcium entry via receptor-operated channels. Other possible effects may be release of calcium from intracellular stores or may have some effect ion phosphatidylinositol turnover which is linked to release of calcium ion from intracellular stores. Theophylline may increase calcium uptake into the intracellular stores also.23,24 The drugs also increase mucociliary clearance. Other pharmacological effects of theophylline include a transient diuretic effect, stimulation of the central nervous system, cerebral vascular constriction, gastric acid secretion, and inhibition of uterine contractions. These effects are of little clinical importance when appropriate doses are used for the treatment of asthma (or apnea of prematurity). Theophylline also exert activity on cardiac ventricular contractility. Theophylline is rapidly and completely absorbed from the gastrointestinal tract when it is administered in the form of solutions and tablets. Once absorbed, it is distributed rapidly through extracellular body fluid, and to some extent into intracellular space. Theophylline is then eliminated through multiple parallel pathways that include demethylation and oxidation. Approximately 90% of orally administered theophylline is metabolised in liver. The drug’s elimination is reduced by such factors as liver disease, congestive heart failure, sustained high fever, and with drugs like cimetidine, troleandomycin, and erythromycin. Therefore, the dose of the drug should be reduced in these circumstances. Cigarette and marijuana smoking, phenobarbital, phenytoin, and intravenous isoproterenol increases the elimination of the drug. Major changes in diet also have a potential effect with 25% increases in clearance associated with a low carbohydrate, high protein diet and about a 25% mean decrease in clearance associated with a high carbohydrate low protein diet. The drug is also eliminated rapidly from the body by some individuals, especially children. In obese individuals,

Pharmacologic Management of Asthma 137 with greater than 120% ideal body weight, initial theophylline should be calculated on the basis of ideal rather than actual body weight to avoid overdosing. Theophylline has long been marketed in a wide variety of formulations. The traditional preparation for oral and parenteral use has been theophylline with ethylenediamine known as aminophylline. Suppository and rectal solutions are also available. Fixed dose combinations of theophylline with ephedrine that were the most frequently used formulations previously were associated with synergistic toxicity while providing a small additive effect. They are now not been used. During the past decade, newer formulations have been developed with slower controlled release preparations because of unacceptable fluctuations during the use of plain tablets. Both twice-dosing and once-a day dosing are now available. Although once-a-day dosing may be satisfactory in adults who eliminate the drug slowly, substantial peak-to-trough differences in serum concentrations are found in individuals who eliminate the drug rapidly. Furthermore, intestinal transit time in some patients may be so rapid that sustained-release preparations designed to release drugs especially slowly with long absorption half-lives, will pass out of the gut before absorption is complete. These longer acting preparations may also be affected by the presence of food in the gut or by the fat content. In some cases, the rate of drug release is greatly accelerated, and in other cases drug absorption is impaired. Other products are relatively unaffected by food administration. One should be familiar with these properties of the product selected. Theophylline is used for the treatment of both acute and chronic asthma. In chronic asthma, the usual starting dose is 10 mg/kg/day up to 800 mg maximum dose. In children the starting dose is 10 mg/kg/day; with usual maximum is as; 1 year or more < 1 year

16 mg/kg/day 0.2(age in weeks) + 5 = mg/kg/day

For the management of acute asthma, the drug may have an additive effect on other medications. Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years. However, its has been questioned recently in view of the risk of adverse effects compared with nebulised β-agonists. Intravenous aminophylline is less effective than nebulised β-agonists.25 Thus some authors recommend that the drug should be reserved for those patients who fail to respond to β-agonists. On the other hand, there are evidences to suggest that use of aminophylline in the emergency room reduces subsequent admissions to hospitals.26 There is no added advantage if aminophylline is used in addition to β-agonists. Use of intravenous aminophylline may increase the death rates.27 However, this is a drug which is cheap and still used as an important drug in many hospitals in the management of acute severe asthma. Whenever a decision is taken to use aminophylline intravenously, it should be given as a slow intravenous infusion with careful monitoring and a plasma theophylline concentration should be monitored, if possible, prior to infusion. The loading dose is aimed for a target serum concentration no higher than the mid point of the 10 to 20 μg/ml that is determined by multiplying the desired change in serum concentration by an average volume distribution of about 0.5 L/kg. In other words, each μg/ml increase in serum concentration requires 0.5 mg/kg of a loading dose. A repeat serum concentration 30 minutes after the loading infusion determines the need for an additional loading dose and provides a baseline for monitoring change during a subsequent maintenance infusion. A conservative maintenance infusion based on mean clearance and targeting a steady state serum concentration of 10 μg/ml is maintained with as follows:

138 Bronchial Asthma Infants under age 1 0.008 × age in weeks + 0.22 mg/kg/hr Children (1-9 years) 0.8 mg/kg/hr Children (9-16 years) 0.6 mg/kg/hr Adults 0.4 mg/kg/hr The adult dose should be decreased by one half for those with heart failure or liver disease. Subsequent infusion is adjusted according to the serum concentration. The other important use of theophylline is its use as maintenance therapy for chronic asthma. To attend an optimal dosage one should proceed with patience. Rapid attainment of therapeutic concentrations is associated with a high degree of minor complaints which may discourage the patient from continuing therapy. Therefore, the aim should be to attend such optimum concentration over a period of 1-2 weeks. Because of the variability in the rates of elimination, the final doses requirements are highly variable. While average doses are higher on a weight-adjusted basis for children than adults, considerable variability is observed at all ages. According to these principles the initiation of therapy should be at doses of 400 mg/day or 16 mg/kg/day, whichever is less. Since this dosage is low, adequate control of symptoms is not expected and for that period, another drug should be used for control of symptoms. The dose is then to be increased every three days to 600 mg/day for those more than 45 mg/kg or if the patient weighs less than 45 mg/kg, either 600 mg/kg or 16-20 mg/kg, whichever is less. After the next three days, the dose is to be increased to 800 mg/kg for those more than 45 kg in weight and if less than 45 kg in weight, the dose should be 800 mg/day or 18-24 mg/kg/day, whichever is less. The dose is then adjusted according to the serum concentration which should be measured about 4 hours after a dose when none have been missed or added for three days. Theophylline has little or no effect on bronchomotor tone in normal airways, but it reverses bronchoconstriction in asthmatics. The routine of theophylline in chronic stable asthma has recently been questioned.28-30 In various guidelines of management of bronchial asthma (discussed subsequently), theophylline is used as an additional bronchodilator if asthma remains difficult to control after moderate to high dose inhaled steroids. The recent use of salmeterol and formoterol may still threaten the position of theophylline. Nonetheless, the drug is cheap and is in use for several decades in many developing countries as a main stay of treatment. Monitoring serum concentrations is an important part of acute or chronic care of asthma. The frequency of measurements depend upon the specific clinical situation. Monitoring is required in those who fail to exhibit the expected clinical effect while receiving an appropriate therapeutic regimen and in patients who develop an adverse effect to an usual dose. It is useful to monitor serum theophylline concentrations when a patient begins his therapy and then at 6-12 months, as long as no adverse effects are observed. The therapeutic range of theophylline was based on measurements of acute bronchodilatation in response to the acute administration of theophylline.31 However, it is possible that the nonbronchodilator effects of theophylline may be exerted at lower plasma concentrations. Since side effects are also related to plasma concentration, these may be markedly reduced by aiming for plasma concentrations of 5-15 mg/l (28-55μM), rather than the previously recommended doses of 10-20 mg/l (55-110μM). This level should be in the steady state (at least 48 hours in the same dose). Improvements in slow-release preparations, including that of once-a-day products, have further improved the problem of fluctuations in plasma concentrations.

Pharmacologic Management of Asthma 139 Side Effects The signs and symptoms of theophylline intoxication involve many organ systems. The commonest toxicity are caffeine-like side effects including minor degrees of central nervous stimulation, headache, restlessness and nausea and vomiting or a queasiness of the stomach occur frequently after a loading dose and have no direct relationship to the serum concentration. Most patients rapidly acquire tolerance of these side effects when therapy is maintained and avoid them when the dose is gradually built up. As serum concentrations exceed 20 μg/ml, there is an associated progressively increasing risk of more serious side effects including seizures and death, most commonly when the level exceeds 40 μg/ml. The seizures may not be preceded by other central nervous system symptoms. Cardiopulmonary effects include tachycardia, and arrhythmias even at serum concentrations considered to be therapeutic. Multifocal atrial tachycardia may herald sudden cardiac death.32 Other adverse effects include stimulation of respiratory center causing tachypnoea, diuresis, relaxation of the detrusor muscle causing difficulty in urination in older men with prostatism, and important metabolic effects such as hyperglycaemia and hypokalaemia. The effect of theophylline on behaviour and learning of children have received attention recently. Because the drug stimulates the central nervous system, it may produce behaviour disturbances in children. Of more serious consequence are the reports that its use is associated with impairment of learning,33-35 although a carefully designed study could not confirm this.36 Some of the side effects of theophylline like central stimulation, gastric secretion, diuresis, and arrhythmias may be due to adenosin receptor antagonism and may, therefore, be avoided by drugs such as enprofylline, which has no significant adenosine antagonism at bronchodilator doses.37 However, the commonest side effects of theophylline like nausea, vomiting and headache are also seen with enprofylline.38 Prevention of toxicity is important by monitoring the serum concentrations and by aiming for lower plasma concentrations as indicated earlier to some extent, side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved .39-41 Acute accidental or suicidal overdoses of theophylline are better tolerated than sustained high levels encountered due to uncontrolled therapy. Since theophylline-induced seizures are more dangerous including brain damage and death, an aggressive approach to the treatment of an overdose is necessary. Initial therapy with ipecac or other measures to induce vomiting removes remaining aminophylline in the stomach. Activated charcoal stops further absorption, and simultaneous administration of a cathartic such as sodium sulphate increases the transit time of charcoal and any remaining undisclosed drug. Repeated doses of activated charcoal increases the rate of elimination of theophylline already absorbed by two folds, possibly due to the result of a gastrointestinal dialysis. Extracorporeal charcoal haemoperfusion allows more rapid clearance. There are many factors which affect serum theophylline concentrations. These factors and actions to be taken are shown in Table 10.2. β-ADRENERGIC AGONISTS Normal β-adrenergic Receptor Physiology The autonomic nervous system is responsible for regulating the airway tone through the release of neurotransmitters that activate specific autonomic receptors. The autonomic

140 Bronchial Asthma Table 10.2: Factors affecting serum theophylline levels

Factor

Decreases

Increases

Action to be taken

Food

↓ or delays absorption

↑absorption (fatty foods)

Select appropriate preparation

Diet

↑metabolism (high protein)

↓metabolism (high carbohydrate)

Major changes in diet not advised

Systemic, febrile viral illness

↓metabolism

↓dose by 50%, if serum level not available

Hypoxia, cor pulmonale CCF, cirrhosis Age

↓metabolism

Decrease dose

↓metabolism ( 12 > 12

Pharmacologic Management of Asthma 143 cyclase activity. The final effect is an increase in cellular cyclic adenosine monophosphate. This effect derives from and is mediated through a plasma membrane-associated β-adrenergic receptor: the guanine nucleotide regulatory protein, which in turn activates adenylate cyclase and leads to generation of cAMP. β2-adrenoceptor agonists vary in their selectivity for β2adrenoreceptors, but none is β2-specific. They all stimulate β- receptors to a lesser but dosedependent extent. The duration of action is dose dependent, but to a limited extent. Since the human airway smooth muscle cells express β2-receptors from the trachea to the terminal bronchioles,63,64 these drugs as functional antagonists can prevent and reverse the effects of all substances,65 including leukotrienes, acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because of the widespread presence of β-receptors, the β2- agonists may affect many cells like stabilisation of mast cells,66 which may be the cause of effectiveness of these agents in blocking the bronchoconstricting effects of allergens, exercise, and fog. Further, β2-agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction. The other mechanisms of action of β-agonists, although not proved conclusively, include, inhibition of mediator release, modulation of neural pathways, reduction of microvascular leak, and increased mucociliary clearance.67 Long acting β2-agonists, salmeterol xinafoate and formoterol fumarate, are currently available in many countries.68-70 They are available in inhaled forms. While salmeterol acts longer but is a partial agonist, formoterol is a nearly full agonist.71 Both provide effective bronchodilatation over a 12-hours period and thus, they are more useful for patients who have nocturnal asthma.72,73 Because these drugs have no anti-inflammatory effect, they should always be used with an inhaled glucocorticoid. Both drugs also protect against airways challenge with methacholine for a period of 12 hours.72,74 International guidelines have recommended both drugs to be added in the treatment of bronchial asthma. Several studies have demonstrated the superiority of salmeterol and formoterol to regular treatment with either salbutamol or placebo.75-77 Both these drugs differ pharmacologically, but there is no difference in the efficacy between the two drugs in any severity of bronchial asthma,78-80 although formoterol is more potent than salmeterol in vitro, with a faster onset but a shorter duration of action,81 but with similar bronchodilator action at 12h. Relative potency estimates show that 50 mg salmeterol corresponds to 9 mg formoterol.82 Optimal Pharmacological Profile of β-adrenoceptor Agonists They exhibit a range of physico-chemical properties, which arise from differences in molecular structure, and determine their pharmacological profiles with respect to affinity, efficacy, and duration of action at subtypes of β-adrenoceptors in a number of target cells. All β-agonists are racemic mixtures of optical isomers, there being two isomers, R and S in salmeterol and four isomers (RR, RS, SR, and SS) in fenoterol and formoterol. β-agonist activity resides predominantly in the R-form, which ranges from 40-fold to 1000-fold more potent than the S-isomer. At β2-adrenoceptors, salmeterol, formoterol, and fenoterol have a higher affinity than isoprenaline and salbutamol, the associated rank order of potency being: formoterol > salmeterol > fenoterol = isoprenaline > salbutamol. Fenoterol and formoterol are full agonists, and salmeterol and salbutamol are partial agonists, compared with isoprenaline. Salbutamol, and particularly salmeterol are weak and have low efficacy at β1 and β2-adrenoceptors, whereas formoterol and fenoterol are potent, full agonists. The functional β2-adrenoceptor

144 Bronchial Asthma selectivity is lowest for fenoterol and highest for salmeterol. β2-agonists such as salbutamol and fenoterol are hydrophilic and interact with the β-receptor directly, whereas formoterol is moderately lipophilic, and salmeterol is highly lipophilic, gaining access to the active site of the β2-adrenoceptor through the cell membrane. The rates of onset of action of salbutamol, fenoterol, and formoterol are more rapid than those of salmeterol. The duration of action is concentration-dependent for all β-agonists, with the exception of salmeterol, which appears to be intrinsically long-acting (salmeterol >> formoterol>fenoterol>salbutamol) due to additional exo-site binding in the β2-receptor protein. Aerosol or oral inhaled therapy is comparable or better than oral therapy in producing bronchodilatation and cause fewer systemic side effects such as cardiovascular stimulation, anxiety, and tremor. Inhaled therapy has a more rapid onset of action when compared with oral formulations and a similar duration of action, even when administered in substantially lower dosages. Furthermore, inhaled therapy appears superior to oral therapy because the latter causes more adverse effects and require higher doses to achieve similar effects. β2agonists are the medications of first choice for treatment of acute exacerbations and for the prevention of exercise-induced asthma. They can be used either intermittently to control episodic airway narrowing or chronically to aid in the control of persistent airway narrowing. Salbutamol inhalation reduces hyperinflation of the lungs. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.83 Recently there is a trend to use more of inhaled form of these drugs rather than oral preparations because of adverse effects and slow onset of action. The advantage of slowrelease oral agents has been taken over by the introduction of long-acting inhaled β2- agonists, which are more effective in preventing induced bronchoconstriction than equivalent doses of oral β2-agonists.84 Further, inhaled drugs may reach superficial cells in the airways, such as mast cells and epithelial cells, that are less easily reached by oral drugs. Thus, nebulised β2-agonists are the first choice for acute severe asthma and may be life saving.85 Since the onset of action is rapid, and the therapeutic ratio of bronchodilatation to side effects is greatly improved, inhaled administration is preferred. Since there is a rapid action, this can be attributable to the direct effect of the drug on the smooth muscle β-adrenoceptor. When given by inhalation, all currently available β-agonists achieve a measurable effect within 5 minutes and by 10 minutes, 80-90% of the maximal response has actually been achieved.42 Another advantage of giving bronchodilators by inhalation is that they are not distributed to the rest of the body in large concentrations and therefore may be given in much smaller doses. The doses of some of these drugs are given in Table 10.4. Side Effects The predictable side effects of β-agonists include tachycardia, palpitation, dysrhythmia, hypokalemia, tremor, restlessness and rarely hypoxemia. Tremor, due to stimulation of β2adrenoceptors in skeletal muscles is a common side effect of these class of drugs. Tremor is inseparable from bronchodilator action, but, incidence usually declines with continued administration.86 Since the frequency of adverse effects are directly proportional to the plasma concentration, administration via inhalation results in less drug absorption and therefore fewer adverse effects than either oral or inject able routes. Although, the adrenergic aerosols are currently among the safest drugs available for asthma therapy, there are some

Pharmacologic Management of Asthma 145 Table 10.4: Dosage of sympathomimetic agents per treatment

Drug Adrenaline (1:1000) Isoproterenol Isoetharine Metaproterenol Salbutamol Terbutaline Bitolterol Formoterol Salmeterol

Subcutaneous (ml) 0.1-0.5 — — — 0.5 0.25-0.5 — — —

Metered dose inhaler or MDI (mg) 0.32-0.9 0.16-0.39 0.68-1.02 1.3-1.95 0.18-0.27 0.4-0.6 0.37-1.11 6-12 μg 50 μg

Nebulizer (mg)

Oral (mg)

2.5-22 0.63-3.8 1.25-5 10-15 — — — — —

— — — 5-20 2-4 2.5-5 — — —

areas of concern. Adverse drug reactions involving the cardiovascular system may also occur. Cardiovascular complications may result from decreased serum potassium levels or direct stimulation of the myocardium. Adverse reactions of the cardiovascular system may occur with the combination of systemic adrenergic agonists and theophylline. However, cardiac arrhythmias and myocardial ischaemia resulting from β-agonist therapy usually occurs in patients with preexisting cardiovascular disease, especially among the elderly. Very rarely, patients with asthma may experience paradoxical bronchoconstriction as a result of inhaled β-agonists administered by metered-dose inhalers (MDI). The paradoxical response is an abrupt worsening of asthma symptoms and/or a decrease in expiratory flow rates shortly after inhaling a therapeutic aerosol. It is not clear whether the reaction is due to the drug itself or due to another component or contaminant of the particular canister or batch of canisters or due to a hypersensitivity reaction to the hydrocarbon propellant. Very rarely lactic acidosis may occur. Several recent studies have suggested that regular use of β-agonists increases the responsiveness of airways to challenges with agents such as methacholine and histamine in children and adults. Similarly some recent reports associate the regular use of a potent inhaled β2-agonist with diminished control of asthma. Although the mechanisms of diminished control or increased hyperreactivity are not known, possibilities include the development of rebound airway hyperresponsiveness, increased bronchial secretions, or both. There are also some concern regarding damage to the mucosal epithelium due to repeated inhalation. There are controversies regarding the link between the use of fenoterol and increased asthma deaths in New Zealand. Another potential reason for increased asthma symptoms during prolonged therapy with these drugs may be the development of tolerance or subsensitivity resulting from downregulation of β-adrenoreceptors. This phenomenon is a tendency of biological responses to wane over time in the presence of a stimulus of constant intensity, and may develop to the antiasthmatic effects of inhaled β2-agonists.65,86 Although some evidences suggest that tolerance to the bronchoprotective effects of both short- and long-acting β2-agonists does develop,87-91 numerous other studies using a recommended dose of β-agonists by metered dose inhalers have failed to show the development of complete tolerance.92 Most studies suggest that clinically significant tolerance does not usually develop in patients with asthma. When tolerance develops, it is characterised by a small reduction in the bronchodilator response and by a slight shortening in the duration of action after inhaling a β-agonist. Thus, tolerance is not

146 Bronchial Asthma usually of major clinical significance and does not diminish the overall usefulness of inhaled β2-agonists in asthma therapy. It is possible, however, that receptor down-regulation could account for some of the diminished control of asthma and increased airway hyper-reactivity reported during chronic regular use of these drugs. Subsensitisation occurs because of the receptors in the tissue are exposed to persistent stimulation by agonists. The problem can occur at one or several different points in the formation of cAMP. It could occur at the level of the receptor, stimulatory or inhibitory, and/or involve down regulation mechanisms. These will involve an uncoupling of the hormone-receptor complex from the guanine nucleotide binding protein. Further, repeated exposure to catecholamines may reduce the number of β-receptors in the airways that are free to interact with catecholamine bronchodilators.43 Thus repeated administration of β-agonists makes the airways even less responsive. Tolerance is seen most commonly with triggers that operates through mast cell activation, such as adenosine, allergens, and exercise. Whether steroids protect against development tolerance is not known. The problem may be avoided by taking long acting β 2-agonists only at night. Recent studies of the polymorphism of human β2-receptors suggest that some forms of the receptors may be more likely to be down regulated.93 Patients having Arg-16 → Gly form of the receptor, which is more likely to be down regulated have more frequent asthma in the night.94 In contrast, the Gln→Glu form, resist down regulation and is having less airway hyperreactivity.95 There is some concern recently regarding the use of β2-agonists and excess asthma mortality. The two epidemics of asthma death recorded in the literature, one in several countries in the 1960’s and the other in New Zealand in the late 1970s, were associated with a rapid increase in the use of a β-agonist formulation delivering a high dose by metered-dose inhalers, isoprenaline in the 1960s and fenoterol in the late 1970s. Although, reports are conflicting, it seems likely that those epidemics were due to high-dose β2-agonist use. There is no epidemiological evidence to suggest that β-agonists have an appreciable effect on mortality outside these epidemics.96-101 Some Controversial Facts About β2-Agonists Despite the worldwide use and the significant contributions of inhaled synthetic sympathomimetic agents in the therapeutic management of bronchial asthma, the risk/benefit ratio of these agents have evoked controversy throughout the last half of the 20th century. Concerns about possible deleterious effects of the first reported from the United Kingdom, Australia and New Zealand in the mid-1960s, when a sudden increase in asthma mortality was attributed to overuse of a short-acting, dose-fortified formulation of isoproterenol.102 A similar phenomenon occurring a decade later in New Zealand appeared to be associated specifically with regular use of inhaled fenoterol, a more selective, relatively short-acting β2-agonist (SABA),.97 A Canadian retrospective case-control analysis of pressurised SABA in patients with asthma suggested that increased asthma mortality was not necessarily due to fenoterol alone but also occurred after overuse of any pressurised SABA of the same class.96 A subsequent meta-analysis of six similar surveys not only failed to confirm this conclusion but found that mortality was increased to a slight extent only in patients who used SABA on a regular basis.103 Even if this controversy keeps on appearing off and on, most clinicians believe that the mortality attributable to SABA is most likely based on over dosage and/or abuse by poorly controlled patients.104

Pharmacologic Management of Asthma 147 The above controversies led to more intensive exploration of the nonbronchodilator properties of SABAs and also long-acting β2-agonists (LABAs). The interactive effects of these agents as well as individual agents have been studied extensively. 105,106 Such investigations have revealed a complex and contradictory array of biological activities that encompass both proinflammatory and anti-inflammatory effects. As examples of antiinflammatory effects, β2-agonists are known to attenuate release of mediators from mast cells, suppress airway smooth muscle growth, and inhibit the function of immunocompetent lymphocytes. By contrast, the proinflammatory effects include suppression of interleukin12 production in antigen-presenting cells, intensification of the T-helper type 2 immune response, augmentation of eosinophil survival and enhancement of the late allergic response. SABAs may also favor the synthesis of receptors associated with neurogenic inflammation that could play a role in the phenomenon of increased airway hyperresponsiveness that has been noted after long-term use of these agents. Similar concerns were expressed about the LABAs. The lipophilic nature of these agents would enable them to partition into the outer phospholipid layer of cell membranes, where they have better access to receptors and downstream signalling cascades. Fortunately, downregulation of β2-agonist receptors on smooth muscle is not clinically relevant, presumably because of their overabundant distribution and relative refractoriness to tachyphylaxis in this tissue site. A number of studies in the mid 1980s and early 1990s demonstrated that regular use of SABAs increased airway hyperresponsiveness and actually worsen asthma control, and many asthma management guidelines recommended against their regular use over prolonged periods. Similar concerns were also expressed when LABAs were available, and in fact early clinical trials reported that both short-term and long-term use of LABAs dampened the β2-agonist protective effect against methacholine-induced bronchospasm without evidence of smooth muscle tachyphylaxis.90,107 However, more recent studies demonstrated that the LABA-induced protective effect against airway hyperresponsiveness was unimpaired after relatively long-term, continuous use of LABAs without evidence of a rebound effect after cessation of therapy.108,109 These contradictory results have been ascribed to patient-specific differences in sensitivity to the deleterious effects of bronchodilators, variability of allergic status among patient groups, or a masking activity of β2-agonists .110 The later effect might occur because these agents inhibit only the early allergic response and might exacerbate the ongoing inflammation associated with the late allergic response. A recent controlled study111 performed over a 6-week period using placebo or salmeterol that utilised a well-defined allergic phenotype of mild asthma, (pollen sensitive asthmatics), and a well-defined exposure period (a grass pollen season), measured both direct and indirect airway hyperresponsiveness using methacholine and adenosine monophosphate and exhaled NO was measured as an index of airway inflammation. Airway caliber (FEV1), airway hyperresponsiveness indices and exhaled NO were measured before the administration of salmeterol or placebo and at mid season. Patients receiving salmeterol experienced significant protection against a fall in FEV1 during the height of the allergy season. The increase in airway hyperresponsiveness showed only a small insignificant increase in the treated group compared to the placebo group. The result emphasised the difference between natural exposure and a single experimental allergen challenge studies reported earlier. There was a failure to detect a significant difference in adenosine monophosphate-induced airway responsiveness between salmeterol-treated and placebo-treated patients when they were challenged with the agent during the height of the pollen season. Since the adenosine monophosphate indirect

148 Bronchial Asthma challenge reflects bronchoconstriction caused by mast cell mediators, long-term salmeterol did not attenuate the chronic effects of mediators during the season and therefore did not function as an anti-inflammatory agent. The exhaled NO levels were increased both treatment arms during the height of the pollen season, but there was neither an augmentative nor inhibitory effect in the salmeterol group. These results strengthened the safety profile of salmeterol and indicated that long-term use of a LABA alone will not provide a clinically effective anti-inflammatory effect. Ultimately perhaps, the balance between the salutary and adverse effect of both SABAs and LABAs are tilted towards a more clinical benefit to the patient in the management of bronchial asthma. Anticholinergics Anticholinergics are the oldest forms of bronchodilator therapy for asthma and are recommended as early as the 17th century.112 The recreational and medicinal properties of atropine have been well-known to many cultures for many centuries. Atropine, in the form of the leaves and roots of Datura stramonium, was very well known to Indians for use in respiratory disorders, and it was introduced to Western medicine by the British military officers in the early 1800s, who in turn learnt its usefulness from Indians. At that time, stramonium, belladonna, and their alkaloid extract, atropine, had their place in most pharmacopoeias. Atropine was used for many years for the management of bronchial asthma. With the availability of potent β-adrenergic agonists in the 1920s, its use declined. In recent years there has been an increased interest in inhaled atropine sulphate, especially in patients with chronic bronchitis. Atropine is usually given as a powder nebuliser with a β-adrenergic agent. Its side effects include tachycardia, dryness of the oral mucosa, blurred vision, urinary retention, and constipation. The drug has a delayed onset of action. Atropine should not be used in patients with narrow angle glaucoma and prostatic hypertrophy. With the advent of newer more selective drugs without these unpleasant side effects of atropine, the later is almost no more used.112,113 The newer anticholinergic agents are watersoluble, quaternary ammonium compounds that are poorly absorbed, and when they are given by inhalation, they cause fewer systemic side effects.114-118 A better understanding of the cholinergic mechanisms that control airway caliber in health and disease and the development of newer synthetic analogs of atropine that are poorly absorbed, but retain the anticholinergic properties of the atropine, have revitalised the interest in anticholinergic therapy. Several anticholinergic agents that are in use worldwide include: • Atropine • Ipratropium bromide • Thiazinamum • Oxytropium bromide • Glycopyrrolate • Tiotropium bromide

Rationale for the Use of Anticholinergics To understand the rationale of use of these agents it is important to understand the mechanisms of bronchoconstriction and bronchodilatation that are mediated by the autonomic nervous system. The majority of the autonomic nerves in human airways are

Pharmacologic Management of Asthma 149 branches of the vagus nerve, the efferent paraganglionic fibres of which enter the lungs at the hilum and travel along the airways into the lungs.119 The efferent innervations is derived from the postganglionic fibres that end in the epithelium, submucosal glands, and smooth muscle of the airways as well as in the vascular structures. Thus, the release of acetylcholine at these sites results in smooth muscle contraction and the release of secretions from submucosal glands stimulated by their muscuranic receptors. Cholinergic pathways are important to regulate the acute bronchomotor responses, and many stimuli can provoke bronchoconstriction via vagal pathways. Anticholinergic medications antagonise transmission at the muscarinic receptors. They will only block reflex cholinergic bronchoconstriction and will have no effect on bronchoconstriction resulting from the action of, for example, histamine on the airways. Cholinergic-induced bronchoconstriction appears to involve primarily the larger airways, whereas β-agonist medications relax both large and small airway contraction equally. In humans, there are at least three pharmacologically distinct subtypes of muscarinic receptors within the airways, which are known as M1, M2, and M3 receptors.120 Recently, the types described are up to 5, M1 to M5. The M1 receptors are present within the parasympathetic ganglion and mediate increased cholinergic transmission. They may facilitate nicotineic transmission or be responsible for maintaining cholinergic tone. Inhibition would reduce cholinergic tone and thus would reduce bronchoconstriction. M1 receptors are also found on alveolar walls, although their function is unknown. Prejunctional M2 receptors on the postganglionic nerves act as negative feedback loop in neuronal transmission. They are activated by the release of acetylcholine and promote its reuptake, thereby limiting the degree of bronchoconstriction produced. These receptors are thought to be dysfunctional in asthma, resulting in exaggerated cholinergic reflexes. The loss of M2 receptor function has been demonstrated after viral infections. Similar changes can be seen after ozone exposure or antigen challenge.121 When the M2 receptors are dysfunctional, the resulting excessive concentrations of acetylcholine at the motor endplate can promote significant bronchoconstriction. Finally, M3 receptors are located on the airway smooth muscle. The receptor activation leads to a release of calcium ions from intracellular stores and a decrease in intracellular adenosine 3’,5’-cyclic monophosphate levels, resulting in the contraction of airway smooth muscle. M3 receptors also are located on submucosal glands, where they are likely to be involved in mucus secretion. Ipratropium bromide and oxytropium bromide are quaternary ammonium derivatives of atropine and are bronchoselective when delivered by inhalation.122,123 Ipratropium bromide is a muscarinic cholinergic antagonist that inhibits smooth muscle contraction by competing with the neurotransmitter acetylcholine at the muscarinic receptor.124 These drugs are thus less effective than inhaled β2-agonists because they counteract only cholinergic neural bronchoconstriction, which may be a relatively minor part of the broncho-constrictor mechanism in asthma. As discussed earlier, recently it is recognised that there are at least five subtypes of muscarinic receptors expressed in the airways.120, 125 The M3 receptors play the major role in causing bronchoconstriction, whereas the M2receptors mediate the feedback inhibition of acetylcholine release from airway sensory nerves.126 Atropine, ipratropium bromide and oxytropium bromide are nonselective antagonists and produce their beneficial effect by blocking M3 receptors. However by blocking prejunctional M2 receptors, they increase the release of acetylcholine and thus may have relatively deleterious effects.126 This may weaken the effect of the postjunctional M3 muscarinic receptor blockade on airway smooth

150 Bronchial Asthma muscle and submucosal glands. This suggests that antagonists that bind selectively to M1 and M3 receptors may be more effective in inhibiting cholinergic effects on the airways. The drugs also inhibit hypersecretion of mucus in the airways.127 The anticholinergic drugs act by reducing intrinsic vagal tone to the airways. They also block reflex bronchoconstriction caused by inhaled irritants. The agents also block postganglionic efferent vagal pathways. They are relatively free of systemic side effects because they are minimally absorbed into the systemic circulation and do not cross blood-brain barrier. The natural antichiolinergic, atropine, is rarely used in patients at the present time, however, this drug was used extensively as a nebulised solution by intensivists and emergency department specialists for years.128 It is readily absorbed across the oral and respiratory mucosa and when higher doses are used to maximize bronchodilator effect, the incidence of dry mouth, blurred vision, urinary retention, nausea and tachycardia may limit the usefulness of atropine. The principal anticholinergic agent is ipratropium bromide, a nonselective muscarinic antagonist.129,130 The drug is topically active, and the compound is poorly lipophilic and not significantly absorbed from the respiratory or GI tract. It has no or very little systemic effect. The drug has been found to be an effective bronchodilators in patients with COPD and selective patients with asthma both alone and when used in combination β2-agonists and theophylline. When used via MDI aerosol, the recommended dose of ipratropium bromide is 2 puffs (40 μg) 4 times daily. The drug has been shown to be effective during status asthmaticus when used in nebulised form in combination with β-adrenergics.131-133 It does not appear to affect mucus secretion and ciliary movement. Another significant advantage of ipratropium bromide in the critically ill asthma patients is the lack of tachycardia, which does occur with β2-agonist use.134 The only remarkable side effect is the inhibition of salivary secretions at high doses. It has no effect on urinary flow, or intraocular tension, and possible effects on the eye (glaucoma) can be prevented by using a mouth piece during nebulisation. The onset of action is 3 to 30 minutes with up to 50% of the response occurring in 3 minutes and 80% in 30 minutes, with a peak bronchodilator effect observed within 1 to 2 hours, and the duration of action is up to approximately 6 hours. These properties are ideal for acute asthma treatment. Oxytropium bromide is a quaternary ammonium anticholinergic compound that is based on scopolamine instead of atropine. It is also a nonselective muscarinic antagonist. The drug is used in a dose of 200-400 μg per day and is perhaps less effective in chronic asthma.134 It has a longer duration of action, up to 8 hours than ipratropium bromide, but has a slower onset of effect.135 The peak onset of action is 1-2 hours. In children ipratropium has bronchodilator action in acute exacerbations of asthma. However, the benefits of its use in day-to-day management of asthma in children and adults have not been established, although its use appears to be most effective in patients with COPD with partially reversible airflow obstruction. Tiotropium bromide is a recently developed, long acting, selective, anti-muscarinic medication. This agent is selective for both M1 and M3 receptors. In human bronchi, the drug has a similar inhibitory effect with a slow onset of action with the peak bronchodilator effect observed after 1.5 to 2 hours and a very prolonged effect compared to ipratropium bromide. The effect lasts for 10-15 hours.136,137 The drug has a prolonged inhibitory effect acetylcholine released from postganglionic nerve endings in the airways, probably via an inhibitory effect on M1 receptors. The drug is available as a lactose based powder formulation containing 18 mg of active substance and is used once daily.

Pharmacologic Management of Asthma 151 In certain clinical situations these drugs may be useful bronchodilators for the treatment of bronchial asthma.138 They are recommended for patients who cannot tolerate β-adrenergic agonists because of severe tremor or underlying cardiac disease and for patients with bronchospasm precipitated by β-adrenergic antagonists139 or acetylcholinesterase inhibitors. They can be used in combination with β-agonists. Corticosteroids Glucocorticosteroids are the most potent anti-inflammatory drugs useful in the treatment of bronchial asthma. With the realisation of the role of inflammation as an essential and important component of asthma, their frequent use is justified. Inhaled glucocorticosteroids have revolutionised the treatment of asthma and are highly effective in controlling asthma in all patients.140 Glucocorticosteroids are active against bronchial asthma, mainly through their antiinflammatory effects.141,142 The anti-inflammatory action of corticosteroids is as follows. The hormone penetrates freely into the cell and binds to the receptor forming an inactive complex, which is further activated or transformed to an active complex having an enhanced affinity for DNA forming the nuclear-bound complex. Then it is translocated to the nucleus where it binds to specific sequences (glucocorticoid-responsive element) on the upstream regulatory part of steroid-responsive gene.143 This complex then by binding to regulatory elements associated with certain genes, can activate or inhibit transcription of these genes. The hormone thereby increases or decreases the levels of mRNA and usually of the proteins that the genes encode. These proteins may be enzymes, secretory products, and regulators of various functions including transcription of other genes, which are the primary effectors of hormone actions. The particular genes and proteins regulated by corticosteroids depend on the type of cells. This may increases the production of a substance called lipocortin-1, which inhibits the enzyme phospholipase A2, an enzyme essential for activation of arachidonic acid metabolism. The complex may cause reduced transcription with inhibition of protein synthesis like cytokines. An important effect of steroids in asthma may be the inhibition of synthesis of key cytokines like IL-3, Il-5, and GM-CSF, which play significant role in perpetuating the inflammatory response.144 It is also likely that steroids act on many different cells of the airways. Although they do not reduce the release of mediators from mast cells themselves,145 they lead to a significant reduction in mast cell numbers, possibly due to inhibition of IL-3, which is necessary for mast cell survival in the airways.146 Steroids inhibit release of mediators by macrophages,147 but eosinophils are less responsive.148 But, eosinophil survival is markedly reduced due to blockage of the effect of cytokines like IL-3, Il-5, and GM-CSF.149 Inhaled steroids also reduce markedly the proportion of circulating low-density eosinophils in asthmatic patients through inhibition of IL-5 secretion.150 The other most important effect of steroids is on T lymphocytes where the synthesis of cytokines is reduced. Additional effects directly related to antiinflammatory action include reduced plasma exudation from postcapillary venules in the airways,151 and inhibition of mucus glycoprotein secretion.152 Further, inhaled steroid therapy causes a reduction in bronchial hyperresponsiveness to histamine and the underlying T-cell-dominated inflammation in the bronchial wall.153 Although the molecular mechanisms of the anti-inflammatory action of steroids are better understood,154 the key cellular targets in asthma have not yet been conclusively established. It appears that airway epithelial cells are important target cells and besides the above

152 Bronchial Asthma mentioned mechanisms including the inhibition of expression of cytokines like IL-1, IL-8, regulated on activation normal T-expressed and secreted (RANTES) and GM-CSF, they also inhibit lipid mediators,155 nitric oxide,156 and adhesion molecules.157 They also may inhibit the expression of inducible genes in airway epithelial cells by blocking key transcription factors such as nuclear factor-kappa B and activator protein-1.154 Thus, the important mechanisms of anti-inflammatory action of corticosteroids can be summarised as follows: i. Interference with arachidonic acid metabolism through alteration of lipocortin synthesis and that of the synthesis of leukotrienes, cytokines and prostaglandins. They inhibit the production of IL-1, collagenase, elastase, and plasminogen activator. ii. Prevention of the direct migration and activation of inflammatory cells. Dampening of the recruitment and activation of eosinophils results from their direct effect on these cells as well as upon T-lymphocytes, endothelial cells, and macrophages. Local activation of a variety of cell types including neutrophils, basophils, macrophages and possibly eosinophils by γ-interferon may be blocked by inhibition of this substance from T-lymphocytes by glucocorticoids. iii. Inhibition of cytokine gene transcription and translation leading to inhibition of cytokine secretion and increased intranuclear breakdown of these mediators. iv. Inhibition of cellular response to cytokines, such as increased release of mast cell mediators, expression of adhesion molecules, and prolonged survival of inflammatory cells. v. An acute anti-inflammatory action mediated via inhibition of microvascular leakage. Direct evidence for the anti-inflammatory effect of inhaled steroids is provided by biopsy studies in asthmatic patients. After regularly inhaling steroids over one to three months, bronchial biopsy shows many fewer eosinophils, mast cells, and lymphocytes,146, 153, 158 and in patients with mild inflammation of the airways, there is complete resolution. In biopsies of patients after ten years of inhaled steroids, inflammatory cells disappear completely, although basement membrane thickening may persist.159 Steroids facilitate the action of adrenergic bronchodilators, apparently by altering the ratio of α to β- adrenergic receptors on cell surface.160,161 Oral prednisolone therapy prevents the development of down regulation and subsensitivity of lymphocyte β2-adrenoceptors in subjects given long-term treatment with oral β2-agonists.162 Effects of corticosteroids in asthma patients are considerable.163-168 Treatment with inhaled corticosteroids improves FEV1, peak expiratory flow, and symptoms within weeks. Improvements in airways hyperresponsiveness are slower in onset, and gradual amelioration usually continues up to at least 1 year.164 Exacerbation rates are markedly reduced by treatment with inhaled corticosteroids in asthma.164,167,168 Some studies have even indicated that delayed introduction of inhaled corticosteroids results in an impaired response.169,170 Recent studies on the longterm effect in patients who are treated with terebutaline and beclomethasone dipropionate indicate that the initial improvement in lung function are well preserved over 5 years.171 Inhaled steroids prevent the accelerated decline of FEV1.172 The wide-ranging clinical benefits associated with corticosteroids are shown in Table 10.5. Corticosteroids can be administered parenterally, orally, or as aerosols. Because of the availability of inhaled steroids, there has been less fear now to treat patients with steroids

Pharmacologic Management of Asthma 153 Table 10.5: Clinical benefits of glucocorticosteroids * Improved pulmonary function Diurnal variability in pulmonary function Protection against antigen-induced bronchoconstriction Asthma exacerbation rate Hospital admission rate Asthma mortality rate * Prevention of long-term lung damage and therefore irreversible airflow obstruction The anti-inflammatory effects of glucocorticosteroids are shown in Figure 10.1: Glucocorticosteroids

Eosinophils Mast cells T-Lymphocytes Mucus secretion Plasma exudation Mediator formation

CYTOKINES

β-Adrenoceptors

INFLAMMATION Fig.10.1: Anti-inflammatory effects of glucocorticosteroids

either with a short course therapy or for longer times. It is now clear that the duration and severity of an acute asthma attack can be substantially reduced by therapy with corticosteroids. Early treatment of severe acute exacerbations of asthma with oral corticosteroids prevents progression of the exacerbation, decreases the need for emergency visits and hospitalisation, and reduces the morbidity of the illness. When oral steroids are used to treat acute severe asthma, the onset of action is gradual, occurring approximately 3 hours after administration with peak effectiveness occurring about 6-12 hours after administration. Acute short-term therapy is begun usually with a relatively high dose of 40-80 mg of prednisone daily and can be maintained up to 5-10 days or tapered over the same interval. Therapy with oral steroids should be maintained until peak expiratory flow rates are stable near the best predictable value. The major adverse effects associated with high-dose shortterm systemic therapy are: reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, rounding of face, mood alteration, hypertension, peptic ulcer, and aseptic necrosis of the femur. In all patients requiring chronic maintenance therapy with steroids, a trial of inhaled steroids, which have minimal systemic side effects, should be attempted to see if oral corticosteroids could be reduced or eliminated. Oral therapy can be continued only if that shows to reduce chronic symptoms substantially or reduce the frequency of severe episodes.

154 Bronchial Asthma Oral steroids should not be used alone without maximising other forms of therapy. Long-term oral steroid therapy is associated with significant side effects such as osteoporosis, hypertension, Cushing’s syndrome, cataracts, myopathy, hypothalamo-pituitary-adrenal axis suppression, and in rare instances, impaired immune mechanisms. Therefore, prolonged use of oral steroids should be reserved for patients with severe asthma despite use of high-dose inhaled corticosteroids. The lowest possible drug dose should be employed including attempts of alternate-day therapy. The drug should be given as a single-morning dose and pulmonary function tests should be used to objectively assess efficacy. Inhaled steroids are safe and effective for the treatment of asthma. They are very effective in controlling the symptoms of asthma and usually achieve rapid control. As a companion drug to β2-agonists, inhaled steroids reduce symptoms, reduce the need for rescue bronchodilators, and improved lung function compared to regular treatment with β2-agonist alone.173 Inhaled steroids inhibit the late response reflecting inflammation to allergen and prevent the increase in airway hyperresponsiveness that follows allergen exposure.174 They also reduce AHR when given regularly, although the reduction takes place slowly over two months or more as the chronically inflamed airway heals slowly.175 When discontinued, symptoms and AHR revert to pretreatment levels.176 In patients with mild asthma treated with inhaled steroids for a long time, there may be long symptom free periods before recurrence.177 In patients with atopic asthma, changes in the bronchial eosinophils and lung function during steroid therapy occur , but independently.178 Some basic principles regarding inhaled corticosteroids include:179,180 • Both efficacy and side effects of aerosol glucocorticoids are dose dependent, and patients vary in their dose requirement. Patients with chronic asthma severe enough to need large oral maintenance doses are unlikely to respond adequately to inhaled treatment alone. • Aerosol treatment is not effective in acute severe asthma. • A part of the inhaled drug is absorbed resembling parenteral injection bypassing liver with reduced hepatic degradation of the active compound and able to produce systemic effects. • Aerosol treatment is more effective if divided into several doses throughout the day. The introduction of beclomethasone dipropionate to asthma therapy in the early 1970’s represented a major advance in asthma management. Various guidelines described subsequently advocate use of inhaled corticosteroids for longer periods of time than previously recommended in patients with mild asthma and at higher doses than previously considered feasible in patients with severe asthma. Inhaled corticosteroids are now gaining widespread acceptance as safe and effective agents for the management of childhood asthma. They are unique among anti-asthma medicines that no other anti-asthma drug currently available share such a wide ranging profile of clinical benefits. An important unresolved question is whether inhaled steroids exert a therapeutic effect on the airways through a systemic action. Since they reduce the number of circulating lowdensity eosinophils, it is suggested that inhaled steroids have an effect in the circulation or in the bone marrow.150 However, this phenomenon can be as a result of local airway effect through inhibition of synthesis of the eosinophil-stimulating cytokine IL-5 and RANTES. Studies in dogs have suggested that inhaled steroids affect the production of leucocyte progenitors in the bone marrow, but it is not clear whether this results from affecting the synthesis of some stimulatory factor in the airways or from the action of the systemically

Pharmacologic Management of Asthma 155 absorbed fraction of the inhaled steroid on the bone marrow.181 It is also uncertain whether steroids deposited in the proximal airways can be distributed via the airway circulation to the more distal airways. The inflammation of asthma affects the whole of the bronchial tree, from the large central airways down to the small peripheral airways.182,183 Steroid receptors, the site of action of inhaled corticosteroid therapy, are likewise located through out the bronchial tree.184 Various inhaled steroids available for clinical use include Beclomethasone dipropionate, betamethasone valerate, Budesonide, Flunisolide, Triamcinolone acetonide, Fluticasone propionate, Mometasone furoate, and Ciclesonide.185-189 Beclomethasone is the first inhaler steroid available nearly for the past 30 years and is used widely. The dose varies from < 400 μg per day to as high as 1600 μg depending upon the severity of bronchial asthma. Budesonide is a glucocorticoid aerosol with high ratio between topical and systemic corticosteroid effects.190,191 The drug is usually administered in a dose of 200-400 μg twice daily. Fluticasone propionate introduced in the 1990s, is one of the most potent inhaled steroids currently available, and is developed from the androstane 17 β-carboxylic acid and is a highly potent, selective anti-inflammatory steroid which binds with a high affinity to the glucocorticoid receptor of the human lung (18 times that of dexamethasone and 3 times that of budesonide). It has greater airway selectivity, rapid fast-pass metabolism (so less systemic side effects, and increased uptake and retention in the lungs as a result of its high lipophilicity. It is approximately 2-fold more potent than beclomethasone dipropionate and 4-fold more potent than budesonide.192 500 μg b.d. Fluticasone propionate is at least as effective as beclomethasone dipropionate 1000 μg b.d.193 Estimated clinical comparability of doses for inhaled corticosteroids are shown in Table 10.6. It is estimated that beclomethasone and budesonide achieve comparable effects at similar microgram doses by MDI. Beclomethasone has similar effects to twice the dose of triamcenoline acetonide on a microgram basis. However, fluticasone has effects similar to twice the dose of budesonide and beclomethasone when given via MDI in a microgram basis. Budesonide given by a Turbuhaler has effects similar to twice the dose delivered by MDI, implying greater bronchial delivery by the delivery device. These observations are made on the basis of clinical trials comparing effects in reducing symptoms and improving PEFR. The potency of a glucocorticosteroid is described by its receptor affinity and intrinsic activity. For all therapeutically used corticosteroids in asthma, the intrinsic activity directly corresponds to the receptor affinity, which is a compound-specific property. If the receptor activity of a corticosteroid is determined under standardised conditions (usually with dexamethasone as reference), the relative receptor affinity can be calculated and compared with other corticosteroids. The same is shown in Table 10.7.194 Table 10.6: Comparison of potency of inhaled corticosteroids

Drug Beclomethasone Budesonide Flunisolide Fluticasone Triamcinolone

Topical potency (skin blanching) 600 980 330 1,200 330

Corticosteroid receptor binding half-life (hrs) 7.5 5.1 3.5 10.5 3.9

Receptor binding affinity 13.5 9.4 1.8 18.0 3.6

156 Bronchial Asthma Table 10.7: Pharmacokinetic basis for evaluation of efficacy and safety of inhaled glucocorticosteroids

Glucocorticoid

Activation in the lung

Beclomethasone dipropionate Flunisolide Triamcinolone acetonide Budesonide Fluticasone propionate Mometasone furoate Ciclesonide

Relative receptor activity

Lung tissue affinity Oral bioavailability (%)

Expected theoretical therapeutic ratio

+

1345

High

41

Intermediate

– –

180 361

Low Low

20 23

Less favourable Less favourable

– –

935 1800

Medium/low High

11 2 SDs compared to those receiving placebo, although no differences between the good responders and the poor responders could be identified.118 A follow-up case series119 reported clinical improvement in 9 of 11 patients with severe asthma exacerbations that were refractory to conventional medical therapy with the addition of inhaled furosemide. Furosemide can cause allergic reactions due to its incorporated sulfa moiety and has been reported to cause ototoxicity with high-dose rapid IV infusion. None of the clinical trials using inhaled furosemide have reported significant side effects, and no diuretic effect has been reported. CONCLUSION Standard anti-asthma therapy is highly successful in most patients. Therefore, the use of alternate agents for treating asthma should be reserved for the steroid-resistant asthma patient or for the steroid-dependent asthma patient in whom a thorough evaluation to exclude other diagnoses and exacerbating factors has been performed. Of all the agents that have been examined in prospective randomized trials, methotrexate and gold appear to be the most important in terms of steroid-sparing and side effect. Methotrexate has been shown to reduce oral corticosteroid requirements modestly in steroiddependent asthma patients in some short-term, randomized, clinical trials, although its mechanism of action remains unclear and the data examining this issue remain limited and conflicting. Two case series have suggested that long-term therapy with methotrexate may be required to demonstrate objective benefit. Gold also has significant steroid-sparing effects in patients with high daily corticosteroid requirements, but this conclusion must be made with caution due to the confounding effects of the high dropout rate in the Auranofin Multicenter Drug Trial. Side effects with gold therapy are common but generally are minor and self-limited with dose reduction or the cessation of therapy. Until further data from controlled clinical trials are available, however, it is unclear whether methotrexate or gold

300 Bronchial Asthma offers a significant risk/benefit ratio compared to close follow-up, intensive standard therapy, and patient education alone. Cyclosporine offers an attractive mechanism of action and reasonable efficacy data in two of three small prospective randomized trials, but it also carries with it a significant side effect profile. Because of the risk of permanent renal damage and the need for intensive monitoring, further studies with larger prospective randomized trials should be performed before cyclosporine is considered as an appropriate alternate agent for asthma therapy. Although troleandomycin (TAO) appears to be an effective methylprednisolone dosereducing agent, the drug has not been shown to significantly improve asthma control or to reduce steroid-related side effects, and it was associated with an increased rate of osteoporosis and hypercholesterolemia in one clinical trial. Data demonstrating the beneficial effects of IVIG also are limited, while cost, convenience, and a possible risk of aseptic meningitis are all potential detractors to this therapy. At this time, the use of TAO appears to offer no advantage over conventional asthma therapy and patient education, and therapy with IVIG should be limited to clinical trials. Although its postulated mechanism of action and effects on exercise-induced bronchospasm are intriguing, the majority of clinical data currently available on inhaled heparin therapy is limited to single-blind trials involving < 20 patients. The enoxaparin data suggest that the accepted dosing regimens may be too low to demonstrate a full therapeutic effect, and larger prospective placebo-controlled trials are needed to determine the efficacy, dose, and patient population that may benefit from this therapy. Furosemide and other loop diuretics appear to attenuate a variety of indirect bronchoconstrictor mechanisms, although their exact mechanism of action remains unknown. The fact that loop diuretics seem to have little direct effect on bronchial smooth muscle is a likely explanation for their lack of effect as a single agent or in combination with β-agonists alone in patients with asthma exacerbations. The current data and the lack of significant side effects make them potential steroid-sparing agents in the long-term treatment of mild persistentto-severe asthma. The current clinical data are limited, however, and larger randomized trials are necessary to confirm the efficacy of loop diuretics and their role in the treatment of asthma. REFERENCES 1. Niven AS, Argyros G. Alternate treatment in asthma. Chest 2003;123:1254-65. 2. Boushey HA. Experiences with monoclonal antibody therapy for allergic asthma. J Allergy Clin Immunol 2001;108:S77-S83. 3. Oettgen HC, Geha RS. IgE regulation and roles in asthma pathogenesis. J Allergy Clin Immunol 2001;107:429-40. 4. Mohapatra SS, San Juan HS. Novel immunotherapeutic approaches for the treatment of allergic diseases. Immunol Allergy Clin North Am 2000;20:625-42. 5. Suarez CR, Pickett WC, Bell DH, et al. Effect of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5a. J Rheumatol 1987;14:9-11. 6. Cronstein, BN Molecular mechanism of methotrexate action in inflammation. Inflammation 1992;16:411-423. 7. Lynch JP, McCune, WJ Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997;155:395-420. 8. Tsai JJ, Wang TJ, Wang SR. The inhibitory effect of methotrexate on PAF-induced neutrophil and eosinophil locomotion in asthmatic patients. Asian Pac J Allergy Immunol 1994;12:65-71

Alternate Treatments in Asthma 301 9. Glynn-Barmhart, AM Erzurum, SC Leff, JA, et al. Pharmacokinetics of low-dose methotrexate in adult asthmatics. Pharmacotherapy 1992;12:383-390. 10. Vrugt B, Wilson S, Bron A, et al. Low-dose methotrexate treatment in severe glucocorticoiddependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. Eur Respir J 2000;15:478-85. 11. Mullarkey MF, Blumenstein BA, Andrade WP, et al. Methotrexate in the treatment of corticosteroid dependent asthma. N Engl J Med 1988;318,603-07. 12. Shiner RJ, Nunn AJ, Chung KF, et al. Randomized, double-blind, placebo controlled trial of methotrexate in steroid dependent asthma. Lancet 1990;336:137-40. 13. Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe, steroiddependent asthma. Ann Intern Med 1991;114:353-60. 14. Dyer PD, Vaughan TR, Weber RW. Methotrexate in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1991;88:208-12. 15. Trigg, CJ, Davies, RJ Comparison of methotrexate 30 mg per week with placebo in chronic steroiddependent asthma: A 12-week double-blind, cross-over study. Respir Med 1993;87,211-16. 16. Taylor DR, Flannery EM, Herbison GP, et al. Methotrexate in the management of severe steroiddependent asthma. N Z Med J 1993;106:409-11. 17. Stewart GE, Diaz JD, Lockey RF, et al Comparison of oral pulse methotrexate with placebo in the treatment of severe glucocorticoid-dependent asthma. J Allergy Clin Immunol 1994;94: 482-89. 18. Coffey MJ, Sanders G, Eschenbacher WL, et al. The role of methotrexate in the management of steroid-dependent asthma. Chest 1994;105:117-21. 19. Kanzow G, Nowak D, Magnussen, H Short-term effects of methotrexate in severe steroiddependent asthma. Lung 1995;173:223-31. 20. Ogirala, RG, Sturm, TM, Aldrich, TK, et al. Single, high-dose intramuscular triamcinolone acetonide vs weekly oral methotrexate in life-threatening asthma: A double-blind study. Am J Respir Crit Care Med 1995;152,1461-66. 21. Hedman J, Seideman P, Albertioni F, et al. Controlled trial of methotrexate in patients with severe chronic asthma. Eur J Clin Pharmacol 1996;49:347-49. 22. Marin MG. Low-dose methotrexate spares steroid usage in steroid-dependent asthmatic patients: A meta-analysis. Chest 1997;112:29-33. 23. Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: A meta-analysis of randomized clinical trials. Respir Med 1998;92:1059-65. 24. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults (Cochrane Review). The Cochrane Library, Issue 4 2000 Update Software. Oxford: UK. 25. Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med 1990;112:577-81. 26. Shiner RJ, Katz I, Shulimzon T, et al. Methotrexate in steroid-dependent asthma: Long-term results. Allergy 1994;49:565-68 27. Jones G, Mierins E, Karsh J. Methotrexate-induced asthma. Am Rev Respir Dis 1991;143:179-81. 28. Spector SL, Katz FH, Farr RS. Troleandomycin: Effectiveness in steroid-dependent asthma and bronchitis. J Allergy Clin Immunol 1974;54:367-79. 29. Ong KS, Grieco MH, Rosner W. Enhancement by oleandomycin of the inhibitory effect of methylprednisolone on phytohemagglutinin-stimulated lymphocytes. J Allergy Clin Immunol 1978;62:115-18. 30. Szefler SJ, Rose JQ, Ellis EF, et al. The effect of troleandomycin on methylprednisolone elimination. J Allergy Clin Immunol 1980;66:447-51. 31. Townley RG, Selenke WM. Metabolic effects of macrolide antibiotics on bronchial asthma, experimental anaphylaxis and corticosteroid metabolism: Ninth International Congress of Allergy (vol 144) 1967;90 Excerpta Medica. Hillsborough, NJ.

302 Bronchial Asthma 32. Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the treatment of asthma. J Allergy 1970;45:146-62. 33. Siracusa A, Brugnami G, Fiordi T, et al. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol 1993;92:677-82. 34. Zeiger RS, Schatz M, Sperling W, et al. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol 1980;66:438-46. 35. Wald JA, Friedman BF, Farr RS. An improved protocol for the use of troleandomycin (TAO) in the treatment of steroid-requiring asthma. J Allergy Clin Immunol 1986;78:36-43. 36. Nelson HS, Hamilos DL, Corsello PR, et al. A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids. Am Rev Respir Dis 1993;147:398-404. 37. Dasgupta A, Marcoux JP Hepatic abnormalities associated with long-term use of troleandomycin in asthma: A case report. Ann Allergy 1978;41:297-98. 38. Larrey D, Amouyal G, Danan G, et al. Prolonged cholestasis after troleandomycin-induced acute hepatitis. J Hepatol 1987;4:327-29. 39. Uzzan B, Vassy R, Nicholas P, et al. Troleandomycin hepatotoxicity: A case report of overt jaundice and a placebo-controlled trial. Therapie 1993;48:61-62. 40. Ledford DK. Treatment of steroid-resistant asthma. Immunol Allergy Clin North Am 1996;16: 777-796. 41. Walz DT, DeMartino MJ, Griswold DE, et al. Biologic actions and pharmacodynamic studies of auranofin. Am J Med 1983;75,90-108. 42. Marone G, Columbo M, Galeone D, et al. Modulation of the release of histamine and aracidonic acid metabolites from human basophils and mast cells by auranofin. Agents Actions 1986;18: 100-02. 43. Parente J, Wong K, David P, et al. Effects of gold compounds on leukotriene B4, leukotriene C4 and prostaglandin E2 production by polymorphonuclear leukocytes. J Rheumatol 1986;3:47-51. 44. Bernstein DI, Berstein IL, Bodenheimer SS, et al. An open study of auranofin in the treatment of steroid-dependent asthma. J Allergy Clin Immunol 1988;81:6-16 45. Suzuki S, Okubo M, Kaise S, et al. Gold sodium thiomalate selectively inhibits interleukin-5mediated eosinophil survival. J Allergy Clin Immunol 1995;96:251-56. 46. Alvarez J, Szefler SJ. Alternative therapy in severe asthma. J Asthma 1992;29:3-11. 47. Honoma M, Tamura G, Shirato K, et al. Effect of an oral gold compound, auranofin, on nonspecific bronchial hyperresponsiveness in mild asthma. Thorax 1994;49:649-651. 48. Klaustermeyer WB, Noritake DT, Kwong FK, et al. Chrysotherapy in the treatment of steroiddependent asthma. J Allergy Clin Immunol 1987;79:720-25. 49. Bernstein IL, Bernstein DI, Dubb JW, et al. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma: Auranofin Multicenter Drug Trial. J Allergy Clin Immunol 1996;98:317-24. 50. Muranaka MM, Miyamoto T, Shida T, et al. Gold salt in the treatment of bronchial asthma: A double blind study. Ann Allergy 1978;40:132-37. 51. Nierop G, Gijzel WP, Bel EH, et al. Auranofin in the treatment of steroid dependent asthma: A double blind study. Thorax 1992;47:349-54. 52. Sihra BS, Kon OM, Durham SR, et al. Effect of cyclosporin A on the allergen-induced late asthmatic reaction. Thorax 1997;52:447-52. 53. Frew AJ, Plummeridge MJ. Alternative agents in asthma. J Allergy Clin Immunol 2001;108:3-10. 54. Alexander AG, Barnes NC, Kay AB, et al. Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations. Eur Respir J 1995;8:574-78. 55. Sano T, Nakamura Y, Matsunaga Y, et al. FK506, and cyclosporin A inhibit granulocyte/ macrophage colony-stimulating factor production by mononuclear cells in asthma. Eur Respir J 1995;8:1473-79.

Alternate Treatments in Asthma 303 56. Mori A, Suko M, Nishizaki Y, et al. IL-5 production by CD4+ T cells of asthmatic patients is suppressed by glucocorticoids and the immunosuppressants FK506 and cyclosporine A. Int Immunol 1995;7:449-57. 57. Khan LN, Kon OM, MacFarlane A. Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor and eotaxin. Am J Respir Crit Care Med 2000;162: 1377-82. 58. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992;339:324-28. 59. Lock SH, Kay AB, Barnes NC. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 1996;153:509-14. 60. Nizankowska E, Soja J, Pinis G, et al. Treatment of steroid-dependent bronchial asthma with cyclosporin. Eur Respir J 1995;8:1091-99. 61. Mazer BD, Gelfand EW. An open-label study of high dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991;87:976-83. 62. Amran D, Renz H, Lack G, et al. Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol 1994;73:180-86. 63. Leung DY, Burns J, Newburger J, et al. Reversal of immunoregulatory abnormalities in Kawasaki syndrome by intravenous gammaglobulin. J Clin Invest 1987;79:468-72. 64. Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reductions in asthmatic patients treated with intravenous immunoglobulin. J Allergy Clin Immunol 1999;103:421-26. 65. Jakobsson T, Croner S, Kjellman N, et al. Slight steroid-sparing effects of intravenous immunoglobulin in children and adolescents with moderately severe bronchial asthma. Allergy 1994;49:413-20. 66. Landwehr LP, Jeppson JD, Katlan MG. Benefits of high-dose IV immunoglobulin in patients with severe steroid-dependent asthma. Chest 1998;114:1349-56. 67. Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: A double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999;103:810-15. 68. Kishiyama JL, Valacer D, Cunningham-Rundles C, et al. A multi-center, randomized, doubleblind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroiddependent asthma. Clin Immunol 1999;91:126-33. 69. Ragazzi E, Chinellato A. Heparin: pharmacological potentials from atherosclerosis to asthma. Gen Pharmacol 1995;26:697-701. 70. Lasser EC, Lang JH, Curd JG, et al. The plasma contact system in atopic asthma. J Allergy Clin Immunol 1983;72:83-88. 71. Lasser EC, Simon RA, Lyon SG, et al. Heparin-like anticoagulants in asthma. Allergy 1987;42: 619-25. 72. Motojima S, Frigas E, Wegering DA, et al. Toxicity of eosinophil cationic protein from guineapig tracheal epithelium in vitro. Am Rev Respir Dis 1989;139:801-05. 73. Fath MA, Wu X, Hileman RE, et al. Interaction of secretory leukocyte protease inhibitor with heparin inhibits proteases involved in asthma. J Biol Chem 1998;273:13563-569. 74. Lider O, Mekori YA, Miller T, et al. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity. Eur J Immunol 1990;20:493-99. 75. Matzner Y, Marx G, Drexler R, et al. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb Haemost 1984;52:134-37. 76. Karnovsky MJ, Edelman ER. Heparin/heparin sulphate regulation of vascular smooth muscle behavior. Black, J Page, CP (Eds). Airways and vascular remodeling in asthma and cardiovascular disease: Implications for therapeutic intervention. 1994,45-70 Academic Press. London, UK.

304 Bronchial Asthma 77. Ekre HPT, Fjellner B, Hagermark O. Inhibition of complement dependent experimental inflammation in human skin by different heparin fractions. Int J Immunopharmacol 1986;8: 277-86. 78. Ahmed T, Syriste T, Mendelssohn R, et al. Heparin prevents antigen-induced airway hyperresponsiveness: Interference with IP3-mediated mast cell degranulation. J Appl Physiol 1994;76:893-901. 79. Dolowitz DA, Dougherty TF. The use of heparin as an anti-inflammatory agent. Laryngoscope 1960;70:873-84. 80. Boyle JP, Smart RH, Shirey JK. Heparin in the treatment of chronic obstructive bronchopulmonary disease. Am J Cardiol 1964;14:25-28. 81. Fine NL, Shim C, Williams MH. Objective evaluation of heparin in the treatment of asthma. Am Rev Respir Dis 1968;98:886-87. 82. Ahmed T, Abraham WM, D’Brot, J. Effects of inhaled heparin on immunologic and nonimmunologic bronchoconstrictor responses in sheep. Am Rev Respir Dis 1992;145:566-70. 83. Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993;329:90-95. 84. Garrigo J, Danta I, Ahmed T. Time course of the protective effect of inhaled heparin on exerciseinduced asthma. Am J Respir Crit Care Med 1996;153:1702-07. 85. Ahmed T, Gonzalez BJ, Danta I. Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 1999;160:576-81. 86. Bianco S, Vaghi A, Robuschi M, et al. Prevention of exercise-induced bronchoconstriction by inhaled frusemide. Lancet 1988;2:252-55. 87. Welsh MJ. Inhibition of chloride secretion by furosemide in canine tracheal epithelium. J Membr Biol 1993;71:218-26. 88. Alton EW, Kingsleigh-Smith DJ, Munkonge FM, et al. Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. Am J Respir Cell Mol Biol 1996;14:380-87. 89. Perkins R, Dent G, Chung KF, et al. Effect of anion transport inhibitors and extracellular Clconcentrations on eosinophil respiratory burst activity. Biochem Pharmacol 1992;107;481-88. 90. Elwood W, Lotvall JO, Barnes PJ, et al. Loop diuretics inhibit cholinergic and non-cholinergic erves in guinea pig airways. Am Rev Respir Dis 1991;143:1340-44. 91. Anderson SD, Wei HE, Temple DM. Inhibition by furosemide of inflammatory mediators from lung fragments [letter]. N Engl J Med 1991;324:131. 92. Miyanoshita A, Terada M, Endou H. Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle’s loop. J Pharmacol Exp Ther 1989;251:1155-59. 93. Barnes PJ. Diuretics and asthma. Thorax 1993;48:195-96. 94. Levasseur-Acker GM, Molimard M, Regnard J, et al. Effect of furosemide on prostaglandin synthesis by human nasal and bronchial epithelial cells in culture. Am J Respir Cell Mol Biol 1994;10:378-83. 95. Pavord ID, Wisniewski A, Tattersfield AE. Inhaled furosemide and exercise induced asthma: Evidence of a role for inhibitory prostanoids. Thorax 1992;47:797-800. 96. O’Connor BJ, Barnes PJ, Chung KF. Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: Role of cyclooxygenase products. Thorax 1994;49:307-11. 97. Gilbert IA, Lenner KA, Nelson JA, et al. Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients. J Appl Physiol 1994;76:409-15. 98. Freed AN, Taskar V, Schofield B, et al. Effect of furosemide on hyperpnea-induced airway obstruction, injury and microvascular leakage. J Appl Physiol 1996;81:2461-67. 99. Daviskas E, Anderson SD, Gonda I, et al. Mucociliatory clearance during and after isocapnic hyperventilation with dry air in the presence of frusemide. Eur Respir J 1996;9:716-24. 100. Hasani A, Pavia D, Spiteri MA, et al. Inhaled frusemide does not affect lung mucociliary clearance in health and asthmatic subjects. Eur Respir J 1994;7:1497-1500.

Alternate Treatments in Asthma 305 101. Bianco S, Pieroni MG, Refini RM, et al. Protective effect of inhaled furosemide on allergeninduced early and late asthmatic reactions. N Engl J Med 1989;321,1069-73. 102. Moscato G, Dellabianca A, Falagiani P, et al. Inhaled furosemide prevents both the bronchoconstriction and the increase in neutrophil chemotactic activity induced by ultrasonic “fog” of distilled water in asthmatics. Am Rev Respir Dis 1991;143:561-66. 103. O’Conner BJ, Chung KF, Chen-Worsdell, YM, et al. Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate- and sodium metabisulfate-induced bronchoconstriction in asthmatic subjects. Am Rev Respir Dis 1991;143:1329-33. 104. Nichol GM, Alton EW, Nix A, et al. Effect of inhaled furosemide on metabisulfite- and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects. Am Rev Respir Dis 1990;142:576-80. 105. Vargas FS, Croce M, Teizeira LR, et al. Effect of inhaled furosemide on the bronchial response to lysine-aspirin inhalation in asthmatic subjects. Chest 1992;102:408-11. 106. Myers JD, Higham MA, Shakur BH, et al. Attenuation of propranolol-induced bronchoconstriction by furosemide. Thorax 1997;52:861-65. 107. Vaghi A, Robuschi M, Chilaris M, et al. Inhaled furosemide does not alter the bronchial response to methacholine in asthmatics. Eur Respir J 1988;1:85. 108. Stone RA, Yeo TC, Barnes PJ, et al. Frusemide inhibits cough but not bronchoconstriction to prostaglandin F2α in patients with asthma. Am Rev Respir Dis 1991;143:A548. 109. Stone RA, Barnes PJ, Chung KF. Effect of frusemide on cough responses to chloride-deficient solution in normal and mild asthmatic subjects. Eur Respir J 1993;6:862-67. 110. Siffredi M, Mastropasqua B, Pelucchi A, et al. Effect of inhaled furosemide and cromolyn on bronchoconstriction induced by ultrasonically nebulized distilled water in asthmatic subjects. Ann Allergy Asthma Immunol 1997;78:238-43. 111. Ventresca PG, Nichol GM, Barnes PJ, et al. Inhaled frusemide inhibits cough induced by lowchloride solutions but not by capsaicin. Am Rev Respir Dis 1990;142,143-46. 112. Stone RA, Barnes PJ, Chung KF. Effect of frusemide on cough response to low-chloride solution in subjects with mild asthma. Thorax 1991;46:752P. 113. Chung KF Furosemide and other diuretics in asthma. J Asthma 1994;31:85-92. 114. Bianco S, Robuschi M, Vaghi A, et al. Steroid sparing effect of inhaled lysine-aspirin and furosemide in steroid-dependent asthma. Melillo, G O’Byrne, PH Marone, G (Eds). Respiratory Allergy 1993,261-69 Elsevier. Amsterdam, the Netherlands. 115. Bianco S, Vaghi A, Robuschi M, et al. Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone-dependent asthma. J Allergy Clin Immunol 1995;95,937-43. 116. Karpel JP, Dworkin F, Hager D, et al. Inhaled furosemide is not effective in acute asthma. Chest 1994;106:1396-1400. 117. Pendino JC, Nannini LJ, Chapman KR. Effect of inhaled furosemide in acute asthma. J Asthma 1998;35,89-93. 118. Ono Y, Kondo T, Tanigaki T, et al. Furosemide given by inhalation ameliorates acute exacerbations of asthma. J Asthma 1997;34:283-89. 119. Tanigaki T, Kondo T, Hayashi Y, et al. Rapid response to inhaled frusemide in severe acute asthma with hypercapnia. Respiration 1997;64:108-10.

306 Bronchial Asthma

20 Severe Asthma (Fatal Asthma, Refractory Asthma) INTRODUCTION Severe or fatal asthma or refractory asthma constitutes about 50% of the previous year

Minor Criteria • • • •

Aspects of lung function, Exacerbations, Disease stability, Amount of additional medications For a diagnosis of fatal asthma at least one major and additional two of the seven minor criteria are to be fulfilled. Patients also must have had compliance and exacerbating factors

Severe Asthma (Fatal Asthma, Refractory Asthma) 307 should be fully addressed. These definitions are a guide, but the list of criteria still may not be definitive and may have many pitfalls. Some suggest that expanding the minor criteria requirements to three would likely improve the capture of those who fulfill the “spirit” of the definition, rather than the “letter” of the definition. Epidemiology Very little is known about the development of severe asthma. It is not clear whether most patients with severe asthma have a life-altering event in childhood that irreversibly alters their lungs, from which they will never recover, or whether they slowly but steadily decline over the years. It is also not certain whether those patients with a history of adult-onset disease actually have some level of asthma as children those were ignored, or if at all they have a more rapid decline in function once the asthma begins. No satisfactory answer to these questions has been found although some information has come from the large cohort of asthma patients studied in Melbourne, Australia followed for 35 years.2 Those data suggest that reduced lung function in childhood leads to reduced lung function in adulthood, although there is little “progressive decline” of the mean data. Two studies3,4 from Europe have suggested that late-onset asthma is associated with a more rapid decline in lung function. In the database of > 100 patients with severe asthma who were seen at National Jewish Medical and Research Center (Denver, CO), approximately two-thirds of patients had onset in childhood, and the remaining one third experienced onset after the age of 20 years.5 Existence of any distinct phenotypic differences in adult-onset and childhood onset asthma or severe asthma is not known. Aetiology Various risk factors for development of severe asthma are shown in Table 20.1. Table 20.1: Various risk factors for development of severe asthma

Genetic Mutations in both the interleukin-4 gene or the interleukin-4 receptor Non-T helper (Th) type 2 factors Transforming growth factor (TGF)-β1 Monocyte chemotactic protein-1 Environmental factors Allergens (house dust mite; cockroach; alternaria exposure) Smoking Pet allergy Infections Respiratory syncytial virus infections in childhood Mycoplasma and Chlamydia infections in adults Lung-externa factors Obesity (Increased body mass index) Gastroesophageal reflux disease Chronic sinusitis Compliance/adherence to medications Inadequate response to therapy

308 Bronchial Asthma As is the case for many diseases, risk factors can be divided into genetic and environmental. Unfortunately, asthma itself is a disease involving multiple genes. Severe asthma is not likely to be different and is less well-studied. There are reports6,7 of relevant mutations in both the interleukin-4 gene or the interleukin-4 receptor, some of which have been linked to loss of lung function, and others to near-fatal events. Interestingly, two non-T helper (Th) type 2 factors also have been associated with severity of asthma, transforming growth factor (TGF)β1 and monocyte chemotactic protein-1, both of which can promote fibrotic reactions.8,9 Whether mutations of the receptors for the primary treatments for asthma (β2 and glucocorticoid receptors [GRs]) decrease responsiveness to medications and influence outcomes is not yet clear. Environmental factors include both allergen and tobacco exposure, with the strongest data for house dust mite, cockroach, and Alternaria exposures.10-12 Additionally, many patients will continue to smoke or own a cat despite being aware of the negative effects.13 Infection also may contribute to severe disease, with respiratory syncytial virus infections implicated in childhood, while pathogens like Mycoplasma and Chlamydia may play a role in adults.4 Although not precisely “environmental,” additional “lung-external” factors may include obesity, gastroesophageal reflux disease, and chronic sinusitis. Epidemiologic study of patients with severe/difficult-to-treat asthma suggested that body mass index increases with increasing severity of disease and that 76% of the cohort of patients with severe disease were either overweight or obese.14 However, similar to gastroesophageal reflux disease and chronic sinusitis, the relationship of effective treatment of obesity to severity of disease is not clear. Another external factor related to severity of disease is compliance/adherence to medications. Studies15 have suggested that in children and adolescents, instability of disease is related to adherence to therapy with corticosteroids. Adherence to medication may be influenced by lack of responsiveness to medication. If the patient is receiving therapy with oral corticosteroids, the early-morning measurement of cortisol level can be helpful in determining compliance. If this is not helpful, then treatment trials with injectable longacting steroids, such as depomethylprednisolone or triamcinolone, can be informative.16 Physiology Progressive increase in airflow limitation, which is often irreversible leads to a more rapid decline in the FEV1, although there is poor correlation between FEV1 and disease symptoms .17 This may be true in some patients. Others may have severe airflow limitation at presentation, while others, particularly adults, may develop a more rapid decline in lung function over a 10-year-period of time.4 These changes are not completely irreversible. There may be irreversibility to current aggressive medical management. However, it does not necessarily mean the lungs are in a fixed fibrotic state. Airway hyperreactivity also plays a role in the severity of asthma. The provocative concentration causing a 20% fall in FEV1 with disease severity is often present but is poor indicators.18 This instability may be an important aspect to the symptomatology of a subgroup of patients with severe asthma, in whom continuous airflow limitation may play a role.19 FEV1 and airway reactivity changes do not adequately explain disease severity. It is possible that other physiologic factors, such as changes in elastic recoil and/or small airway physiology, are important. The elastic recoil properties of the lung in asthma patients are not normal.20,21 Compliance is increased in patients with moderate persistent asthma, although the precise pathologic mechanism behind the change is not clear. It is suggested that the airways and the parenchyma are more collapsible than are the airways in healthy

Severe Asthma (Fatal Asthma, Refractory Asthma) 309 individuals.22 The FVC1 slow vital capacity ratio is decreased in a group of patients with severe asthma who had persistent eosinophilia.23 These patients are at a higher risk of nearfatal events than those with a more normal (1:1) ratio. There is air-trapping in patients with severe asthma, without associated hyperinflation. Residual volumes are routinely > 200% of predicted in severe asthma, with only modestly increased thoracic gas volumes.23 Whether this increase in residual volume may be reflective of small airway disease. There is no correlation of physiologic measures with inflammatory or structural changes. Pathology Up to two-thirds of patients with severe asthma have persistent tissue eosinophils, despite continued therapy with high-dose systemic steroids. There are associated increases in T lymphocytes and markers for activation of a Th-2 pathway.23 This pattern of inflammation represents steroid resistance, whereas a Th-2 pattern of inflammation persists despite the presence of high-dose steroid therapy. This lack of effect is due to a number of factors those include high levels of proinflammatory mediators sequestering the glucocorticoid receptors (GR), diminished binding of the GR to the genome, or increased levels of an alternatively spliced GR (i.e. GR-β), which has lessened inhibitory capabilities.24-26 Other, non-Th-2, proeosinophilic factors also play a role in the process. These changes lead to poor/modified drug response in patients with more unstable asthma. The apparent progressive loss of lung function in more severe forms of asthma is due to structural or remodeling changes in the airways and perhaps the parenchyma as well although tthe precise changes are unclear. Numerous structures have been implicated, including the sub-basement membrane (SBM), epithelium, smooth muscle, nerves, and blood vessels. Although the SBM is thickened in asthma patients, the relationship to disease severity is unclear. Patients with severe asthma with persistent eosinophil levels had the thickest SBM when compared to those of healthy control subjects, patients with milder cases of asthma. This thickened SBM was seen in association with high numbers of TGF-β-positive cells in the submucosa.23,27 However, the absolute increase in thickness is small and cannot explain the increase in airflow limitation. It may be used as a marker for abnormalities in composition, distribution, or quantity of extracellular matrix elements in other regions of the airway or parenchyma. The epithelium is abnormal in asthma patients. There is an increase in the ratio of goblet cells to ciliated epithelial cells. Mucus plugging of the small and medium airways contributes further to airflow limitation and air trapping in patients with severe asthma. Other studies28,29 suggested alterations in epithelial growth factor receptor and TGF-β1 and/or TGF-β2 in asthma patients, which may contribute to inappropriate and inadequate repair process, augmenting goblet cell metaplasia and mucus production. The amount (and perhaps phenotypes) of smooth muscle in the airways of patients with severe asthma is also increased. Patients dying of status asthmaticus have increased smooth muscle mass in the airways from the largest airways to nearly the smallest.30 Relationship of increased airway smooth muscle to severity of disease is possible although relationship of any of these structural changes to functional changes is not very clear. In addition to airflow limitation, airtrapping, hyperresponsiveness, and loss of elastic recoil/collapsibility are important. Alterations in the alveolar attachments to the airways and the airways themselves play a role in collapsibility, but the cause of changes in elastic recoil is not clear.

310 Bronchial Asthma Elastin levels have been shown to be abnormal (i.e. decreased or disordered) in patients who have died of asthma. The numbers of proteolytic enzymes that alter elastin composition are increased in several instances in asthma.31,32 It is possible that changes in elastin composition, secondary to chronic inflammatory elements, contribute to the unique structural/functional relationships of patients with severe asthma. Physiologic and pathologic data suggest that inflammatory changes exist in the lung periphery. Autopsy studies33,34 have suggested that both increased inflammation and wall thickness may exist in patients who have died of asthma, as opposed to those with milder asthma and healthy control subjects. Studies35,36 of living asthma patients also have suggested that distal lung inflammation may be more important than proximal lung inflammation. These observations have implications for current drug therapy, as most inhaled medications are unlikely to reach the lung periphery in high amounts.37 These structural and inflammatory changes in the small airway and parenchyma may interact to a greater degree in the small airways than the large airways due to the smaller general mass of the airway structure. Classically bronchial asthma has continued eosinophilic inflammation but, patients with severe asthma have neutrophil predominance or very little inflammation23,38, 39 The patients without eosinophils also do not appear to have the same degree of collapsibility and have less severe asthma attacks, also supporting a different presentation for this disease subtype. Recently CT scan findings confuse the issue whether other, less well-defined obstructive diseases like bronchiolitis obliterans also could masquerade as severe asthma.40 Management The treatment of severe asthma remains difficult. Corticosteroids remain the drug of choice because of their broad and nonspecific effects, and there are few alternatives in existence. Leukotriene modifiers may be helpful in some cases, especially as a large percentage of patients with severe asthma may be aspirin-sensitive.41 Anti-IgE also appears to be efficacious in patients with more severe forms of asthma and may be of benefit in some of these patients.42 Other forms of therapy, such as cyclosporine and methotrexate have limited value.43 However, use of alternate agents in treating asthma patients, whose disease remains poorly controlled while receiving standard therapy, may be considered. It is important to recognize that the reasons for lack of response to treatment are numerous, and the clinical approach to the patient with poorly controlled asthma must be systematic and individualised. The objective confirmation of asthma and the exclusion of other pulmonary conditions with screening blood tests, chest radiograph, spirometry, bronchoprovocation challenge, and cardiopulmonary exercise testing is vital in any patient who does not respond to asthma therapy. It is of importance of maximising standard asthma therapy with close outpatient follow-up, patient education, and compliance monitoring. The treatment of concomitant gastroesophageal reflux44 and chronic sinusitis45,46 and the removal of environmental triggers of asthma have been shown to improve asthma control. Glucocorticoid absorption and metabolism can be affected by thyroid disease and a variety of drugs, including antacids, rifampin, cholestyramine, and numerous antiepileptic agents.47 The increased detection of Mycoplasma pneumoniae and Chlamydia pneumoniae by polymerase chain reaction in the airways of patients with chronic asthma has led to questions regarding their role in pathogenesis48 and several small case series49,50 have demonstrated statistically significant improvements in lung function and reductions in bronchial reactivity to histamine after treatment with macrolides. Due to the significant side effects of many alternate asthma

Severe Asthma (Fatal Asthma, Refractory Asthma) 311 therapies, it is essential to thoroughly address these issues before going for a novel treatment strategy. It is also important to distinguish the “difficult-to-manage” asthma patient from the patient who is steroid-resistant. This asthma subgroup, which was first described in 196851 is characterised by patients with larger than usual daily oral corticosteroid requirements and poor symptom control, a blunted eosinopenic response to cortisol-21-succinate, and increased clearance of cortisol. Other clinical characteristics that are associated with steroid resistance include African-American race, symptoms requiring oral glucocorticoid agents at an early age, and < 15% improvement in FEV1 following 7 to 14 days of treatment with high-dose (i.e. > 40 mg daily) oral glucocorticoids.52 The recognition and early identification of these patients may isolate a subgroup of patients who could benefit from early intervention with alternate asthma therapies with better long-term asthma control and reduction in corticosteroid side effects. REFERENCES 1. Wenzel SE, Fahy JV, Irvin CG, et al. Proceedings of the ATS Workshop on Refractory Asthma: Current understanding, recommendations and unanswered questions. Am J Respir Crit Care Med 2000;162:2341-51. 2. Oswald H, Phelan PD, Lanigan A, et al. Childhood asthma and lung function in mid-adult life. Pediatr Pulmonol 1997;23:14-20. 3. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med 1994;150:629-34. 4. Ten Brinke A, van Dissel JT, Sterk PJ, et al. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 2001;107:449-54. 5. Gibbs R, Miranda C, Wenzel S. Initial demographic information from an extensive data base of severe, steroid dependent asthmatics studied at National Jewish. Am J Respir Crit Care Med 2002;165,A119. 6. Sandford AJ, Chagani T, Zhu S, et al. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000;106:135-40. 7. Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Am J Respir Crit Care Med 1999;160:919-22. 8. Pulleyn LJ, Newton R, Adcock IM, et al. TGF-β-1 allele association with asthma severity. Hum Genet 2001;109:623-27. 9. Szalai C, Kozma GT, Nagy A, et al. Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity. J Allergy Clin Immunol 2001;108:375-81. 10. Squillace SP, Sporik RB, Rakes G, et al. Sensitisation to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: Multiple regression analysis of a populationbased study. Am J Respir Crit Care Med 1997;156:1760-64. 11. Halonen M, Stern DA, Wright AL, et al. Alternaria as a major allergen for asthma in children raised in a desert environment. Am J Respir Crit Care Med 1997;155:1356-61. 12. Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356-63. 13. Siroux V, Pin I, Oryszczyn MP, et al. Relationships of active smoking to asthma and asthma severity in the EGEA study: Epidemiological study on the genetics and environment of asthma. Eur Respir J 2000;15:470-77. 14. Weiss ST, Tager IB, Speizer FE, et al. Persistent wheeze: Its relation to respiratory illness, cigarette

312 Bronchial Asthma

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

smoking and level of pulmonary function in a population sample of children. Am Rev Respir Dis 1980;122:697-707. Milgrom H, Bender B, Ackerson L, et al. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol 1996;98:1051-57. Ogirala RG, Sturm TM, Aldrich TK, et al. Single, high-dose intramuscular triamcinolone acetonide versus weekly oral methotrexate in life-threatening asthma: A double-blind study. Am J Respir Crit Care Med 1995;152:1461-66. Teeter JG, Bleecker ER Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Chest 1998;113:272-77. Weiss ST, Van Natta ML, Zeiger RS. Relationship between increased airway responsiveness and asthma severity in the childhood asthma management program. Am J Respir Crit Care Med 2000;162:50-56. Chan MT, Leung DY, Szefler SJ, et al. Difficult-to-control asthma: Clinical characteristics of steroid-insensitive asthma. J Allergy Clin Immunol 1998;101:594-601. Woolcock AJ, Rebuck AS, Cade JF, et al. Lung volume changes in asthma measured concurrently by two methods. Am Rev Respir Dis 1971;104:703-09. Woolcock AJ, Read J. The static elastic properties in the lungs in asthma. Am Rev Respir Dis 1968;98:788-94. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162:1778-82. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001-08. Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. J Immunol 1993;151:3460-66. Lane SJ, Adcock IM, Richards D, et al. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 1998;102: 2156-64. Leung DY, Hamid Q, Vottero A, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 1997;186:1567-74. Minshall EM, Hogg JC, Hamid QA. Cytokine mRNA expression in asthma is not restricted to the large airways. J Allergy Clin Immunol 1998;101:386-90. Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med 2001;163:511-16. Howat WJ, Holgate ST, Lackie PM. TGF-β isoform release and activation during in vitro bronchial epithelial wound repair. Am J Physiol 2002;282:L115-L23. James AL, Pare PD, Hogg JC. The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989;139:242-46. Vignola AM, Riccobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med 1998;158:1945-50. Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am J Respir Crit Care Med 1999;159:12981307. Carroll NG, Elliot J, Morton AR, et al. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405-10. Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002;19:879-85. Kraft M, Djukanovic R, Wilson S, et al. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154:1505-10.

Severe Asthma (Fatal Asthma, Refractory Asthma) 313 36. Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002;20:254-59. 37. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFAbeclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998;12:1346-53. 38. Wenzel SE, Szefler SJ, Leung DYM, et al. Bronchoscopic evaluation of severe asthma: Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156: 737-43. 39. Louis R, Lau LCK, Bron AO, et al. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000;161:9-16. 40. Jensen SP, Lynch DA, Brown KK, et al. High-resolution CT features of severe asthma and bronchiolitis obliterans. Radiology 2000;217(suppl):595. 41. Virchow JC, Jr. Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000;162:578-85. 42. Holgate S, Bousquet J, Wenzel S, et al. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. Curr Med Res Opin 2001;17:233-40. 43. Wenzel S. Severe/Fatal Asthma. Chest 2003;123:405S-10S. 44. Irwin RS, Curley FJ, French CL. Difficult-to-control asthma: Contributing factors and outcome of a systematic management protocol. Chest 1993;103:1662-69. 45. Rachelefsky GS, Goldberg M, Katz RM, et al. Sinus disease in children with respiratory disease. J Allergy Clin Immunol 1978;61:310-14. 46. Rachelefsky GS, Katz RM, Siegel SC Chronic sinus disease with associated reactive airway disease in children. Pediatrics 1984;73:526-29. 47. Spahn JD, Covar R. Steroid-resistant asthma. Immunol Allergy Clin North Am 2001;21:569-87. 48. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med 1998;158:998-1001. 49. Ekici A, Ekici M, Erdemoglu AK. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma 2002;39:181-85. 50. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: Effect of clarithromycin. Chest 2002;121:1782-88. 51. Schwartz HJ, Lowell FC, Melby JC. Steroid resistance in bronchial asthma. Ann Intern Med 1968;69:493-99. 52. Chan MTS, Leung DYM, Szefler SJ, et al. Difficult-to-control asthma: Clinical characteristics of steroid insensitive asthma. J Clin Immunol 1998;101:594-601.

314 Bronchial Asthma

21 Asthma in Children The previous chapters have dealt with bronchial asthma in general, which is applicable, both in cases of adult as well as childhood asthma. However, this chapter will highlight certain important points about childhood asthma. PREVALENCE International Scene A worldwide rise in the prevalence of asthma is being reported with increase in wheeze at an alarming rate of 5% per year. From 1983 onwards an increase in asthma mortality and morbidity has been noticed worldwide.1 Data on prevalence of bronchial asthma on children are few from most countries but many from countries like Australia and UK.2 Table 21.1 shows the prevalence of current asthma, diagnosed asthma, wheeze ever, airway hyperresponsiveness, and atopy in children. There are large differences in the prevalence among the rich, partly rich, and poor populations, with the highest prevalence found in Australia. It is possible that the differences may be as a consequence of responses to different allergens, to different allergen loads, or to other factors in the environment in the affluent and not-so-affluent populations. There are some suggestions that patients with high levels of parasitic infections are less atopic, although there is no convincing experimental confirmation. This protection of parasitic infections against asthma may be a cause of less prevalence of the later in many developing countries. Diet may also be a factor. Exposure to allergens may be important although the most common allergen, the house dust mite has been found everywhere it has been looked for. However, these mites are mainly found in bedding and it is possible that steeping on a bed rather than on a floor, which many poor children do, increases exposure to them. There was considerable concern that the prevalence of asthma and allergic diseases is increasing in Western and developing countries. However, the etiology of these conditions remains poorly understood, despite a large volume of clinical and epidemiological research within populations that has been directed at explaining why some individuals and not others develop asthma and allergies. Little is known about such worldwide variations in the prevalence of asthma and allergic diseases. More authentic data was available from the International Study of Asthma and Allergies in Childhood (ISAAC) designed in late 90’s.3 The study allowed comparisons between populations in different countries. ISAAC Phase One used standardized simple surveys conducted among representative samples of school children from centres in most regions of the world. Two age groups (13-14 years and

Asthma in Children 315 Table 21.1: Prevalence of asthma in children in different countries

Country

Number

Age

Current asthma

Diagnosed Wheeze asthma ever

Airway Hyperresponsiveness

Atopy (SPT)

Australia

1,487 1,217 1,575

8 to 10 8 to 11 8 to 11

5.4 6.7 9.9

11.10 17.3 30.8

21.7 26.5 40.7

10.1(H) 10.0 (1.1) 16.0 (H)

29.3 31.9 37.9

New Zealand

813 1,084 873

9 6 to 11 12

11.1 9.1 8.1

27.0 14.2 16.8

22.0 (M) 20.0 (H) 12.0 (E)

45.8

27.2 26.6

England Wales Germany Denmark Spain Indonesia China Papua New Guinea

1,613

8.0

965

5.3

1.2 7.9

5,768

9 to 11

4.2

14.8* 22.3

?(H) 8.0 (E) ?

527

7 to 16

5.3

2,216

9 to 14

?

406

7 to 15

1.2

2.3

14.5

2.2 (H)

11 to 17

1.9

2.4

6.3

4.1 (H)

?30

1.7

1.0 (H)

17

3,067

16.0 (H) ?

257

6 to 20

0

0

Kenya Australia Indigenous

402

9 to 12

3.3

11.4

Aborigines

215

7 to 12

0.1

0

31

6.9(E)

10.7 (E)

1.4

1.8(H)

20.5

• Current asthma: Airway hyperresponsiveness (AHR) + wheeze in the last 12 months; Diagnosed asthma: asthma ever diagnosed; H:histamine; M:methacholine; E: exercise; • All figures are a percentage of the population tested.

6-7 years) with approximately 3,000 children in each group were studied in each centre. The 13-14 years-old (n = 463,801) were studied in 155 centres (56 countries) and the 6-7 year-old (n=257,800) were studied in 91 centres (38 countries). There were marked variations in the prevalence of asthma symptoms with up to 15-fold differences between countries. The prevalence of wheeze in the last 12 months ranged from 2.1-32.2% in the older age group and 4.1-32.1% in the younger age group and was particularly high in English-speaking countries and Latin America. A video questionnaire completed in the older age group in 99 centres (42 countries) showed a similar pattern. The major differences between populations found in the International Study of Asthma and Allergies in Childhood Phase One are likely to be due to environmental factors. The results provide a framework for studies between populations in contrasting environments that are likely to yield new clues about the aetiology of asthma.3 Self completed wheezing questionnaire data in 13-14 years and 6-7 years old age group from different regions of the world are shown in Tables 21.2 and 21.3. The ISAAC study has demonstrated, by means of simple standardized questionnaires, that there are large variations in the prevalence of asthma symptoms throughout the world. The self-reported 12 months prevalence of wheezing among 13-14 years-old between countries

316 Bronchial Asthma Table 21.2: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Africa

11.7

3.4

5.4

23.3

23.3

10.2

20,475

Asia Pacific Eastern Mediterranean

8 10.7

2.2 2.9

1.8 3.8

16 16.9

17.8 20.2

9.4 10.7

83,826 28,468

Latin America North America

16.9 24.2

3.4 7.6

4.5 9.2

19.1 30.9

28.6 33.7

13.4 16.5

52,549 12,460

Northern and Eastern Europe Oceania

9.2

1.9

1.8

12.3

12.2

4.4

60,819

29.9

9.9

8.1

39.0

29.3

25.9

31,301

South East Asia Western Europe

6.0 16.7

1.6 4.6

3.0 4.2

9.5 20.0

14.1 27.1

4.5 13.0

37,171 1,35,559

Grand Total (All World)

13.8

3.7

3.8

18.8

22.3

11.3

4,63,801

Table 21.3: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Asia Pacific

9.6

2.2

1.5

5.0

17.6

10.7

39,476

Eastern Mediterranean Latin America North America

6.8

1.7

1.7

4.0

13.6

6.5

12,853

19.6 17.6

4.0 5.5

4.5 3.0

9.1 9.6

30.6 25.1

12.4 14.7

36,264 5,755

Northern and Eastern Europe Oceania

8.8

2.0

1.5

3.6

11.4

3.2

23,827

24.6

8.9

4.6

15.9

29.4

26.8

29,468

South East Asia Western Europe

5.6 8.1

1.5 1.9

1.9 1.5

3.6 3.7

12.3 16.1

3.7 7.2

31,697 68,460

11.8

3.1

2.4

6.2

19.1

10.2

2,57,800

Grand Total (All World)

ranged from 2.1% in Indonesia to 32.2% in the UK. Parental reported 12 months prevalence of wheezing in 6-7 years-old ranged from 4.1% in Indonesia to 32.1% in Costa Rica. The highest values for 12-moth prevalence of wheeze were found in developed English-speaking countries (e.g. Peru and Costa Rica). There were considerable variations within regions, e.g. the 12 months prevalence in the 13-14 years-old age group varied within Europe from 30% in the UK; and within Latin America from 25% in centre in Brazil and Peru.

Asthma in Children 317 The analysis shows that there is consistently more variation between countries than within countries. Three countries with a very large number of centres were represented across the range of prevalence, India with 14 centres representing the low prevalence group, Italy with 14 centres representing the middle prevalence group and the UK with 15 centres representing the high prevalence group. However, it must be remembered that the countries, and centres within countries were self-selected, and it is possible that countries with larger within-country variation did not participate. The only other comparable international survey of asthma is the European Community Respiratory Health Survey (ECRHS),4,5 which studied males and females aged 20-44 years., mainly from European centres. Among the 13 centres 10 countries that were reported in both studies, the ranking of prevalence of wheeze in the last 12 months was similar, with the English-speaking countries (Australia, New Zealand, Republic of Ireland, and the UK) having the highest and Italy and Greece the lowest rates. Subsequent other studies from different parts of the world also show similar trends.6-14 Indian Scene The ISAAC data from 12 different parts of the country shows wide variability in the history of wheeze over a 12 months period in children between 13-14 years-old age group ( Table 21.4). In Akola the prevalence was 1.6% whereas the highest figures was reported from Kottayam (17.8%) in the South. The children from this town also had history of “Ever had asthma” of 12.4%. The prevalence was also the highest 24.6% from Kottayam in the 6-7 years-old age group (Table 21.5). There is a difference in the prevalence of asthma in children from Northern and Southern part of the country. From the Northern part of the country the figure varied between 5.4 to 6.9% in the 6-7 years-old age group. The figures from the Western part were less compared to those from the Northern and Southern regions.5 Another hospital based study from South India, Bangalore on 20,000 children under the age of 18 years from 1979, 1984, 1989, 1994 and 1999 in the city of Bangalore showed a prevalence of 9%, 10.5%, 18.5%, 24.5% and 29.5% respectively. The increased prevalence correlated well with demographic changes of the city. Further to the hospital study, a school survey in 12 schools on 6,550 children in the age group of 6 to 15 years was undertaken for prevalence of asthma and children were categorized into three group-depending upon the geographical situation of the school in relation to vehicular traffic and the socioeconomic group of children. Group I—children from schools of heavy traffic area showed prevalence of 19.34%, group II—children from heavy traffic region and low socioeconomic population had 31.14%, and group III—children from low traffic area school had 11.15% respectively. A continuation of study in rural areas showed 5.7% in children of 6-15 areas. The persistent asthma also showed an increase from 20% to 27.5% and persistent severe asthma 4% to 6.5% between 1994-99.15 Another study from Delhi in 1999 revealed the prevalence of current asthma was 11.9% while past asthma was reported by 3.4% of children. Exclusive exercise-induced asthma was reported by 2.1% while that associated with colds by 2.4% of children. Boys had significantly higher prevalence of current asthma as compared with girls (12.8% and 10.7%, respectively). Multiple logistic regression analysis showed that male sex, a positive family history of atopic disorders, and the presence of smokers in the family were significant factors influencing the development of asthma while economic class, air pollution (total suspended particulates), and type of domestic kitchen fuel were not. The prevalence of current asthma in children in Delhi is 11.9%. Significant risk factors for its development are male sex, a positive family history of atopic disorders, and the

318 Bronchial Asthma Table 21.4: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group in different parts of India

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Akola Bombay (Area 1)

1.6 1.9

0.5 1.2

1.0 1.0

2.7 2.6

3.8 6.5

2.6 3.6

2,138 4,225

Bombay (Area 2) Bombay (Area 3)

10.6 3.6

1.8 1.0

3.2 1.4

11.1 7.4

22.4 14.9

6.5 5.2

2,226 3,178

3.4 4.2

0.6 1.5

1.6 2.7

5.3 8.0

10.2 8.0

5.9 3.3

3,878 3,139

10.7 17.8

3.5 1.7

4.8 13.5

15.9 17.9

18.4 32.2

6.4 12.4

1,094 2,047

8.4 6.0

1.9 3.3

2.9 3.6

7.7 7.4

14.6 11.5

2.8 1.8

1,903 3,086

13.0 6.0

3.0 1.9

4.8 2.5

18.4 23.2

25.8 16.9

5.3 2.4

3,026 3,281

3.8 1.8

0.8 0.8

2.1 1.3

6.8 4.0

13.5 9.4

2.8 4.9

1,248 2,702

Borivali Chandigarh Jodhpur Kottayam Madras (Area 1) Madras (Area 2) New Delhi Neyveli Orissa Pune

Table 21.5: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group in different parts of India

Region

Wheeze

≥4Attacks

Severe wheeze

Exercise wheeze

Night cough

Ever had asthma

Number studied

Akola Bombay (Area 1)

5.6 0.8

1.5 0.6

1.9 0,6

3.6 1.0

12.3 3.3

3.7 1.3

31,697 2,030

Bombay (Area 2) Bombay (Area 3)

3.8 1.8

1.3 0.7

1.6 0.7

3.0 1.8

12.6 8.3

3.8 2.3

3,967 3,568

Borivali Chandigarh

5.2 5.4

2.0 1.9

1.7 2.8

3.1 3.8

12.3 10.7

3.4 2.8

1,672 2,891

3.5 24.6

1.3 4.7

1.4 7.5

2.9 13.3

13.6 27.0

4.1 14.4

1,104 2,156

Madras (Area 1) Madras (Area 2)

7.2 8.5

2.1 2.4

1.4 2.5

2.5 3.8

16.4 15.4

1.4 2.2

1,406 2,491

New Delhi Neyveli

6.9 1.5

1.4 0.1

1.6 0.3

4.1 1.4

14.6 8.1

3.7 1.0

2,938 1,498

Orissa Pune

4.1 2.3

1.4 1.0

2.2 1.3

3.8 2.5

8.7 9.5

3.8 4.2

1,520 3,248

Jodhpur Kottayam

presence of smokers in the family.16 A more recent study from Chandigarh, North India examined the prevalence of asthma and its association with environmental tobacco smoke exposure among adolescent school children. Using a previously standardized questionnaire, data from 9,090 students in the 9 to 20 years age range were analyzed. There were 4,367 (48%) boys, in whom the observed prevalence of asthma was 2.6%. Among 4,723 (52%) girls, asthma

Asthma in Children 319 was present in 90 (1.9%) students. 31% students reported presence of one or more respiratory symptoms. More students with asthma had either parents or other family members smoking at home as compared to nonasthmatics (41% vs. 28%, p 1 time/week

PEF>60 to 2 time/month

PEF ≥80 % predicted

≤ 2 time/month

PEF ≥80 %

Moderate persistent step 3 Mild persistent step 2 Mild intermittent step 1

Limited physical activity Frequent exacerbations Daily symptoms Daily use of beta-agonist Exacerbation affecting activity, ≥ 2/weeks, lasting days Symptoms > 2/week But 600 or FP* step 4 200-400 μg + Long acting beta sympathomimetic or SR Theophylline or oral steroids. For infants ≤ 2 years inhaled medication with spacer and/or mask Moderate Daily therapy. Medium-dose inhaled pesistent steroid (BDP 600-1200 μg or BUD step 3 400-600 or FP 100-200 μg) or Low-medium dose inhaled steroid + SR Theophylline or long acting beta sympathomimetic. For infants inhaled medication with spacer and mask Mild Daily medication NSAIDs like Cromolyn persistent (1-5 mg/dose Oh) or low-dose inhaled step 2 steroid (BDP 200-600 or BUD 100-400 or

Quick relief

Education

Short-acting broncho- Step 1 + selfdilator. Infants as monitoring in step 1 Group education

Short-acting broncho- Step 1 + selfdilator Infants as monitoring in step I education/ counselling

Short-acting broncho- Step 1 + selfdilator. Infants as in monitoring step 1 Group education

Contd...

Asthma in Children 329 Contd... Grade

Mild asduna, intermittent step 1

Long-term

Quick relief

Education

FP50-100 μg) and Theophylline 5-15 mg/kg spacer and mask for infants ≤ 2 years No daily medications needed Short acting bronchodilator, inhaled β2 agonists sos use of β2-agonist > 2 times/ week indicates need for preventative drugs. For infants (< 2 years) bronchodilator as needed for symptoms. Use facemask with holding chamber or nebuliser or oral β2agonist

Basic facts about inhaler technique, discuss role of medication, selfmanagement and action plans, environmental control

Abbreviation: BDP-beclomethasone dipropionate, BUD-budesonide, FP-fluticasone propionate, SR-sustained release, FP is recommended for children older than 4 years Table 21.8: Classifying severity of asthma exacerbations

Mild

Moderate

Severe

While at rest (infant—stops feeding)

Can lie down

While talking (infant—softer, shorter cry; difficult feeding) Prefers sitting

Phrases

Words

Symptoms Breathlessness While walking

Talks in sentences Alertness

May be agitated Usually agitated

Signs Respiratory rate Increased

Increased

ReiTiratory Arrest Imminent

Sits upright

Usually agitated

Drowsy/confused

Often >30/ m

(Guide to breathing rates in awake children): Age Normal rate < 2months < 60/niin < 2-12 months < 50/n-dn 1-5 years < 40/n-dn 6-8 years < 30/min Use of accessory muscles: Suprasternal retractions

Usually not

Commonly

Usually

Paradoxical thoracoabdominal movement

Contd...

330 Bronchial Asthma Contd... Mild

Moderate

Severe

ReiTiratory Arrest Imminent

Wheeze

Moderate often only end expiratory

Loud; throughout exhalation

Usually loud; throughout inhalation and

Absence of wheeze

Pulse/min

< 100

100-120

> 120

Bradycardia

(Guide to heart rate in normal children): Age Normal rate 2-12 months < 160 min 1-2 years < 120 min 2-8 years < 110 min

Ask and record

Examine for

1. 2. 3. 4.

1. Sensorium 2. Respiratory rate, heart rate, colour, use of accessory muscles, breath sounds intensity, wheeze 3. Saturation-SaO2 if pulse oxymeter is available 4. Peak expiratory flow rate

Duration of present episode Medications already being used Time of last aminophylline dose (if taking) Precipitating factors—infections, exercise, drugs, stress, seasonal, etc. 5. Severity of previous episodes of treatment required

Treatment Phase I—Ist one hour 1. Oxygen by mask to achieve saturation >90% (minimum 5 L/min through simple facemask) 2. Start β2 sympathomimetic nebulisation 0.15 mg/kg/dose (minimum dose 2.5 mg) every 20 min for 3 doses. For delivery dilute aerosols to minimum of 4 ml of saline at (flow of 6-8 1/minutes) or β2 sympathomimetic through MDI and spacer with/without facemask 4 to 8 puffs every 20 minutes (10-20 puffs in one hour). In case of nonavailability of nebuliser or MDI and spacer or where the patient cannot move the needle of the peak flowmeter—parenteral beta-agonists (adrenaline/terbutaline) should be given in the dose of 0.01mg/kg up to 0.3 to 0.5 mg every 20 minutes for 3 doses in the first hour subcutaneously. 3. All children presenting with acute exacerbation should receive systemic steroids. Prednisolone 2 mg/kg/dose or methylprednisolone 1-2 mg/kg/dose or hydrocortisone 10 mg/kg/dose. At the end of hour repeat assessment with more emphasis on symptoms and signs, PEFR done if possible. In interpreting PEFR value is compared with predicted value of Indian children or personal best of the child if available. From the assessment 2 groups are identified: A. Good response Physical examination normal (decrease in heart rate from the previous value, respiratory rate, pulses paradoxus 90 per cent, PEFR>70%. B. Incomplete response/poor response Mild to moderately severe symptoms and signs (see Table No. 21.8) for mild, moderate and severe classification of symptoms signs, PEFR< 50 to < 70%.

Contd...

Asthma in Children 331 Contd... Phase II—Management A. Good response group - Discharge home,continue treatment with β2-agonist and course of oral systemic corticosteroid 1-2 mg/kg/day maximum 60 mg/day in a single or 2 divided doses for 3-10 days. - Patient education, review medicine use, initiate action plan, recommend close medical follow-up. B. Incomplete/Poor responders - Continue O2, β2-sympathomimetic inhalation every 20 mts Continuous nebulization can also be used under strict monitoring for heart rate and blood potassium levels. - Continue systemic steroids. - Add ipratropium bromide nebulization 250 micrograms every 20 mts for three doses, May mix in same nebulizer with β2-sympathomimetic. - If no response, aminophylline infusion, (0.25 mg/kg/hr) can be tried. - IV Magnesium sulphate 50% 50 mg/kg/dose IV infusion in 30 ml normal saline/30 mt can be given before transfer to ICU. Continue to assess every one—hour, continue same treatment for 4 hours. Improvement at end of 6 hours since initiation of treatment decrease the frequency of β2sympathomimetic inhalations every 1 to 4 hr as needed, Stop parenteral aminophylline, Continue systemic steroids 1-2 mg/kg/day in 2 divided doses for 3-10 days. If no deterioration continue same treatment. If deterioration, follow intensive care of the child with asthma in pediatric ICU for possible intubation and mechanical ventilation in presence of: i. Exhaustion, shallow respiration, confusion or drowsiness ii. Coma/respiratory arrest iii. Worsening or persisting hypoxia. Fig. 21.1: Management protocol for acute exacerbation of childhood asthma emergency room

Assess Severity Measure PEF: Value 80% predicted or personal best

Moderate episode PEF 50-80% predicted or personal best

Severe episode PEF