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MAJOR ISSUES IN UNDERSTANDING AS th ma I he purpose of this chapter is to provide background infor- mation helpful to the understanding of the material covered in the report. It contains a summary of the 1993 Institute of Medi- cine report Indoor Allergens, which covered some of the same top- ics examined here. It also addresses some of the major issues in understanding the medical condition called asthma: the contro- versy over the definition of the illness; the characteristics of its clinical presentation in children, adolescents, and adults; and the concepts of the "development of asthma" and "exacerbations of asthma." Finally, the chapter presents brief discussions of four topics addressed in greater detail later in the report: risk factors, trends in prevalence, pathophysiology, and tools for evaluating the effectiveness of interventions to reduce asthma. ORIGIN OF THE STUDY In 1993, as a result of joint funding between the U.S. Environ- mental Protection Agency (EPA) Indoor Air Division (IAD) and several agencies within the Department of Health and Human Services, the Institute of Medicine (IOM) issued a major report: Indoor Allergens: Assessing and Controlling Adverse Health Effects (hereafter called Indoor Allergens). Indoor Allergens received wide public and press attention and helped to focus public health 19

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20 CLEARING THE AIR policy on the dramatic increases in asthma, especially in children. The report also pointed out the role of indoor allergens such as dust mites, cockroaches, fungi, and pet dander in the etiology of asthma. At about the same time, IAD and the EPA Office of Re- search and Development issued a major assessment of the health impacts of environmental tobacco smoke (ETS), which found a correlation between exposure to ETS and asthma in children. EPA's asthma and indoor air initiatives are now the responsi- bility of the Indoor Environments Division (IED), a part of the Office of Radiation and Indoor Air. IED has been actively involved in public outreach efforts on asthma and its relationship to indoor environmental pollutants. These include educational campaigns in high-risk communities, the Indoor Air Quality (IA Q) Tools for Schools Action Kit, and cooperative efforts with other government agencies. EPA is currently developing an outreach strategy focused on reducing asthma-related morbidity and mortality associated with exposure to indoor environments. To help ensure that such ef- forts are based on sound science, EPA requested that the National Academies undertake an assessment of asthma and its relation- ship to indoor air quality. This report presents the conclusions of that research effort. SUMMARY OF THE INDOOR ALLERGENS REPORT The early 1990s saw an increase in the level of concern about the potential adverse health effects of indoor air quality. Moti- vated by this concern, several agencies of the federal government asked the IOM to undertake an assessment of the public health significance of indoor allergens. The IOM responded by assem- bling a committee of experts in such fields as allergy and immu- nology, epidemiology, mycology, engineering, industrial health, pulmonology, education, and public policy. The study undertaken by the committee had three primary objectives: 1. to identify airborne biological and chemical agents found indoors that can be directly linked to allergic diseases; 2. to assess the health impacts of these allergens; and

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 21 3. to determine the adequacy of the knowledge base that is currently available on this topic. That report described what was then known about the ad- verse human health effects caused by indoor allergens, the mag- nitude of the problem nationally, the specific causative agents and their sources, the testing methods used for identifying allergens and diagnosing related diseases, and associated educational and research needs. The committee responsible for the study identi- fied and developed a list of research agenda items and priority recommendations. The recommendations focused primarily on the need to improve awareness and education, while the research agenda focused on the longer-term, more expensive, and more technical aspects of fundamental research and data collection. Indoor Allergens details the 1993 study committee's conclu- sions. Although some of these conclusions address medical con- ditions and topics outside the scope of the present report, several address issues related to asthma and the impact of indoor air ex posures. The Indoor Allergens committee recommended that steps be taken to improve estimates of allergenic disease incidence and prevalence, and to establish effective mechanisms for medical professionals to acquire assessments of potential exposure to in- door allergens in residential environments. It called for improve- ments in heating, ventilating, and air-conditioning (HVAC) equip- ment in order to minimize allergen reservoirs and amplifiers, and for the development of consensus standards for controlling mois- ture in buildings to help control microbial and arthropod aeroallergens and allergen reservoirs. The committee also recom- mended several educational initiatives including the develop- ment of focused intervention programs for allergic populations with different socioeconomic and educational characteristics. It called for efforts to inform architects, engineers, contractors, building maintenance personnel, and others responsible for the design and maintenance of indoor environments about the mag- nitude and severity of diseases caused by indoor allergens and the health implications of the design, construction, and operation of buildings. Among the report's research agenda items were calls to

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22 CLEARING THE AIR better characterize rates of initial asthma sensitization, in- cidence, prevalence, and morbidity, and clarify the relation be- tween these and socioeconomic status, race, and other factors; identify, characterize, and determine the health impact of indoor allergens, specifically suggesting research on allergenic chemicals, arthropods, dust mites, fungi, and indoor animals and plants; conduct dose-response studies in humans to determine both the relationship between allergen concentration and immu- nologic response and the threshold environmental exposure con- centration for sensitization; and evaluate the effectiveness and cost-effectiveness of a broad variety of environmental control measures on patient symptoms, and determine whether long-term allergen avoidance has a posi- tive effect on quality of life. DEFINITIONS OF ASTHMA Although patients of all ages are routinely diagnosed with asthma, finding a widely accepted definition for this disease has proven to be problematic (Samet, 1987; Toelle et al., 1992, 1997~. One commonly used definition of asthma (Murphy, 1997) states: Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithe- lial cells. In susceptible individuals, this inflammation causes re- current episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These epi- sodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyper-responsiveness to a variety of stimuli. (Murphy, 1997) There are two important concerns with this definition: (1) the definition implies that asthma is a single disease entity, although much of the contemporary evidence suggests that asthma is a syn- drome caused by several different mechanisms (Borish, 1999~; and (2) many interpret this definition to mean that asthma results from an aberration or variation of the immune system leading to

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 23 chronic inflammation. There is general agreement that asthma is always associated with inflammation within the lungs, and the intensity of the inflammation is related to the severity of respira- tory symptoms and the degree of bronchial hyperresponsiveness (slough and Dow, 1987; Ingram, 1991; Pattemore and Holgate, 1993~. (Hyperresponsiveness refers to the abnormally large re- sponse of the lungs to the inhalation of minor irritants such as cold air.) There is also consensus that inflammation is the cause of hyperresponsiveness (Ingram, 1991; Jeffrey et al., 1989; Richmond et al., 1996; Woolley et al., 1996~. Discovering the origin or origins of the inflammatory response, however, remains a critical unan- swered question for researchers. The absence of a universally accepted definition of asthma makes it especially difficult to arrive at a consistent operational definition for epidemiologic studies. One of the most commonly used definitions of asthma in epidemiology is a "physician's di- agnosis" (Barbee et al., 1985; Dodge et al., 1986; Samet, 1987; Yunginger et al., 1992~. This term is imprecise since there is little information about the reasoning and consistency used by physi- cians when making this diagnosis. A variety of definitions, based on questions about symptoms, have been proposed. The validity of these symptom-based definitions has rarely been rigorously evaluated (Toelle et al., 1997~. For the purposes of this report, asthma is understood to be a chronic disease of the airways characterized by an inflammatory response involving many cell types. Both genetic and environ- mental factors appear to play important roles in the initiation and continuation of the inflammation. Although the inflammatory re- sponse may vary from one patient to another, the symptoms are often episodic and usually include wheezing, breathlessness, chest tightness, and coughing. Symptoms may occur at any time of the day but are more commonly seen at night. These symp- toms are associated with widespread airflow obstruction that is at least partially reversible with pharmacologic agents or time. Many persons with asthma also have varying degrees of bron- chial hyperresponsiveness (Britton, 1992; Ingram, 1991~. Research has shown that after long periods of time this inflammation may cause a gradual alteration or remodeling of the architecture of the

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24 CLEARING THE AIR lungs that cannot be reversed with therapy Jeffrey et al., 1989; Kamm and Drazen, 1992; Murphy, 1997; Richmond et al., 1996~. CLINICAL PRESENTATION OF ASTHMA . Asthma may present at any age, but most studies suggest that in the majority of patients, asthma will present before puberty (Barbee et al., 1985; Martinez et al., 1995~. Discussing the presen- tation of asthma is complicated by a lack of consensus on criteria for defining the onset of asthma. Many children who are sick with respiratory infections will experience asthma-like symptoms. In some children the symptoms will diminish, whereas in others the symptoms will persist (Brooke et al., 1995; Dodge et al., 1996; Martinez et al., 1995; Ross et al., 1995; Williams and McNicol, 1969~. A diagnosis of asthma is dependent upon the recurring na- ture of these symptoms over a period of time. It appears that the more frequently these episodes occur, the more likely the child is to have asthma (Dodge et al., 1996; Martin et al., 1982; Martinez et al., 1995; Williams and McNicol, 1969~. Unfortunately, no clear criteria mark the transition from recurrent wheezing with infec- tions to asthma, and there are no tests capable of confirming a diagnosis (Brooke et al., 1995; Dodge et al., 1996~. Tests of pulmo- nary function are very helpful in the diagnosis of asthma in ado- lescents and adults, but testing the lung function of children ages 1-6 is very difficult and possible only in a small number of re- search settings. This means that defining the onset of asthma de- pends on the variable skills and criteria applied by different phy . . slclans. In most children, asthma begins as episodes of prolonged coughing, with or without wheezing, within the first few years of life. In young children, these symptomatic episodes are almost always associated with infections of the respiratory tract. The agents most often associated with these respiratory infections are common viral respiratory pathogens (Busse, 1989,1995; Folkerts and Nijkamp, 1995; Martinez, 1995; Pattemore et al., 1992) . The potential roles of other infectious agents including mycoplasma and chlamydia have been questioned but not defined (Hahn et al., 1991, 1998; von Hertzen et al., 1999~. In the majority of chil- dren these symptomatic episodes resolve with time. For others,

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 25 the episodes will continue and will gradually begin to occur with- out the concomitant presence of infection (Brooke et al., 1995; Martinez et al., 1995~. The frequency and severity of these epi- sodes appear to increase with exposure to tobacco smoke and other forms of airborne pollutants (Arlian et al., 1993; Gidding and SchydIower, 1994; Menon et al., 1991~. A family history of asthma and allergy and a personal atopic predisposition increase the likelihood that asthma will develop (Brooke et al., 1995; Martinez et al., 1995; Williams and McNicol, 1969~. With asthma symptoms ranging from clearly episodic to nearly continuous, from mild to severe, and from an isolated cough to a loud wheeze, diagnosing patients accurately can prove to be very difficult. In some children, asthma presents as distinct episodes of wheezing and difficulty breathing, whereas in others, cough may be the only complaint. When episodes are distinct events and wheezing is a prominent symptom, a diagnosis of asthma is relatively easy to make. However, when symptoms are less episodic and when wheezing is minimal or absent, asthma can be misdiagnosed or missed altogether. In many children the episodes of symptoms are diagnosed as recurrent bronchitis, bronchiolitis, or pneumonia (Brooke et al., 1995; Dodge et al., 1996; Sherman et al., 1990~. When treated with antibiotics, these ill- nesses seemingly "resolve." If these episodes occur only a few times each year, the true asthma diagnosis may be missed for years (Davis, 1976; Martin et al., 1982; Schwartz et al., 1990~. Phy- sician recognition of asthma symptoms is further complicated by the parents' and child's perceptions, expectations, and abilities to describe the symptoms. When a diagnosis of asthma has been made, many parents of asthmatic children often state that the symptoms they now recognize as coming from asthma were present months or years before a diagnosis was made. These variations in the presentation of asthma lead to confu- sion between the concepts of the "development of asthma" and the "exacerbations of asthma." The concept of developing asthma is that the lungs of a normal individual go through a process in which they develop characteristic, chronic, eosinophilic inflam- mation. The eosinophilic inflammation is associated with symp- toms, such as cough and wheezing, that are recognized as asthma. Because there is no distinct finding or test that allows precise iden

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26 CLEARING THE AIR tification of these changes, it is usually impossible to pinpoint when asthma actually begins or develops. The term asthma exac- erbation is used when referring to the sudden onset of symptoms in someone who already has developed asthma. In older children and some adults, the onset of asthma can be defined by the first exacerbation that brought the patient to medical attention. How- ever, even in these individuals there was presumably a gradual process that took days, weeks, or months before the exacerbation appeared. There is essentially no information concerning whether changes in lung function or immune process in the lung can be detected prior to or during the development of asthma. Another important but difficult concept is referred to as "growing out of asthma," which originated from the experiences of many parents and physicians. As already mentioned, many in- fants and young children wheeze in association with viral respi- ratory infections (Brooke et al., 1995; Martinez et al., 1995; Ross et al., 1995~. As these infants grow older they cease to wheeze with this type of infection. If the child had been diagnosed as having asthma, he or she has now "outgrown" that asthma. There are also children who have recurrent episodes of wheezing during childhood and are diagnosed as having asthma, but cease to wheeze during adolescence, often during the years of puberty. The probability that the symptoms of asthma will remit appears to be higher if the child has little evidence of allergic disease (Martinez et al., 1995; Ross et al., 1995; Williams and McNicol, 1969~. Some of the children whose asthma has remitted will rede- velop asthma symptoms in adulthood. Because of the length of time required, there have been few prospective studies of the risk of asthma recurring once remission has occurred; hence there is no information about risk factors for redeveloping asthma. As children move into adolescence and adulthood, respira- tory infections remain a common cause of symptomatic episodes (Busse, 1995; Martinez, 1995~. Additionally, symptoms may occur "spontaneously" or with exercise. Spontaneous symptoms are of- ten discovered to be the result of exposure to either an allergen or a potent airborne irritant. When symptoms of coughing and wheezing are associated only with exercise, it is often difficult to distinguish whether these are new symptoms or unrecognized symptoms that have been present for years. Symptoms associ

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 27 ated with exercise are more easily recognized in older children because they typically have a higher level of physical activity and have developed the verbal means to describe their symptoms. In some adolescents and adults, symptoms are perceived more as chest tightness or chest pain than as difficulty breathing. People who experience these symptoms may not recognize them as com- ing from the chest and complain instead of chronic fatigue or of becoming fatigued rapidly during the day (Brooke et al., 1995; Dodge et al., 1993~. An interesting change that takes place between childhood and adulthood is in the ratio of males to females with asthma. In child- hood, boys with asthma outnumber girls by 1.5-2 to 1. By 20-30 years of age, women with asthma outnumber men by 1.5-2 to 1, a complete reversal of the childhood ratio (Barbee et al., 1985; Clough, 1993~. Although it is tempting to speculate that this change, which occurs over the years of sexual maturation, results from hormonal changes, little is known about the actual cause. Although asthma can develop anytime, there are times in a person's life when it can be especially troublesome. For some women, asthma first appears or markedly increases during preg- nancy. Because poorly managed asthma is associated with an in- creased risk of maternal and fetal complications, the prompt rec- ognition and appropriate treatment of asthma during pregnancy are important. During pregnancy, the onset of asthma and changes in the severity of preexisting asthma are presumed to be related to the major hormonal changes that occur, but the exact cause is unknown. Occupational asthma is another complex problem (Cartier, 1994; Park et al., 1986~. In some individuals, asthma symptoms first develop as a result of an occupation-related exposure. In most cases the agent responsible for the onset is an allergen to which the worker has become sensitized. In other cases the agent is a strong respiratory irritant. Occupational problems are beyond the scope of this report, however, and are therefore not discussed in detail. A final important concern about the progression of asthma throughout life is the relationship between asthma and chronic obstructive pulmonary disease. As mentioned earlier, the chronic inflammatory process of asthma appears to ultimately result in

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28 CLEARING THE AIR irreversible obstructive changes in the lungs. The progression from a largely reversible airway obstruction, asthma, to an essen- tially irreversible state, chronic obstructive lung disease, appears to be highly variable and dependent upon a variety of factors such as smoking. The contribution of indoor sources of allergens and irritants to respiratory disease is important because chronic ob- structive pulmonary disease is an important cause of increased morbidity and mortality among adults. RISK FACTORS FOR ASTHMA As early as the 1920s, studies demonstrated that a familial predisposition to asthma existed, suggesting that genetics may play a role in asthma development. This genetic influence has remained constant in subsequent studies; however it explains only 30-80% of the asthma risk. The remaining risk appears to be related to environmental exposure. The recently noted increase in the prevalence of asthma suggests a change in some environmen- tal influence since it is hard to imagine a significant change in human genetics in such a short time (Borish, 1999~. Major studies have been conducted to better define the genes related to the development of asthma. These studies reveal com- plex relationships between genes and asthma (Borish, 1999~. It appears that asthma results from the effects of multiple genes, not a single gene. Further complicating the association between ge- netics and asthma has been the discovery that genes closely linked to asthma in one population may not be significantly linked in another population. Some of these discrepancies appear to be ra- cial, and some appear to be related to the peculiarities of rela- tively isolated and therefore somewhat inbred populations. These findings raise the question of whether asthma is best thought of as a single disease entity, a syndrome, or a final common manifes- tation of several different disease processes (Borish, 1999~. Many different environmental variables have been evaluated in relationship to asthma. Some of these are nonspecific such as an increase in global pollution, a decrease in exercise or outdoor play because of television and computer games, fewer childhood infections because of immunizations, more childhood respiratory infections because of day care, alterations in microbial flora be

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 29 cause of the frequent use of antibiotics, or changes in indoor envi- ronments. Alternatively, there are relatively specific factors, such as increased exposure to dust mite allergens, that are discussed in more detail in Chapters 5-8. TRENDS IN THE PREVALENCE OF ASTHMAS Many studies have shown that the prevalence of asthma has been increasing in the United States for the past 30 years. Al- though this subject is explored further in Chapter 3, it is impor- tant to summarize some of the most important aspects of asthma trends to provide a better understanding of the problem of asthma in the United States today. In 1998, the Centers for Disease Control and Prevention (CDC) published a study concerning the change in the prevalence of asthma across the United States from 1960 to 1995 (Manning et al., 1998~. That report combined information from several sources to produce a broad picture of the changes in asthma prevalence. Population estimates were based on the 1960,1970,1980, and 1990 censuses and the 1996 intercensal estimate. Each data set was stratified by region, sex, race, and age group. Self-reported asthma data came from the National Health Interview Survey, which is conducted annually. Data on visits to physicians' offices for asthma have been collected since 1975 by the National Center for Health Statistics (NCHS). The data have been gathered on five different occasions within the study interval, and each time ap- proximately 2,000 physician offices or about 30,000-60,000 patient encounters, were evaluated. Also since 1992, NCHS has gathered annual data on hospital emergency and outpatient department visits. Hospitalizations attributable to asthma were estimated from 1979 to 1994 from the National Hospital Discharge Survey. Only cases with a primary discharge diagnosis of asthma were included. Finally, mortality was estimated from the Underlying Cause of Death data set from NCHS for 1960 through 1995 to identify all deaths in which asthma was selected as the underly- ~ng cause. The results of this study show an increase in the prevalence of asthma and death rates from asthma over 15 years both nation- ally and regionally. Regional differences were found for some end

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30 CLEARING THE AIR points such as hospitalization but not for others such as preva- lence. The self-reported prevalence of asthma increased by 75% from 1980 to 1994. In 1993-1994, an estimated 13.7 million resi- dents of the United States reported asthma during the preceding 12 months. A significant increase in asthma was found for all races, both sexes, and for all age groups. The increase was most prominent among children 0-4 years (160%) and 5-14 years (74%~. During 1993-1994, the self-reported prevalence of asthma was slightly higher among children <14 years of age than among per- sons 215 years of age. In this same year, prevalence rates were similar in all four regions of the country. When office visits for asthma are considered, the estimated annual number of visits increased from 4.6 million to 10.4 million between 1975 and 1993-1994. Again, the increasing rates were found for all race strata, both sexes, and all age groups. During 1993-1994, the rate of office visits for asthma was lowest for the 15-34 year age group. Data on emergency room (ER) visits for asthma were avail- able only from 1992-1995, and during this interval there was no significant change. In 1995, there were in excess of 1.8 million ER visits for asthma. African Americans had consistently higher rates of ER visits than whites. The rate of ER visits decreased with in- creas~ng age. From 1979-1980 to 1993-1994, the estimated number of asthma-related hospitalizations increased, but the rate of hospi- talization did not change over this interval. Hospitalization rates were consistently higher among African Americans than among whites. In 1993-1994, the age-adjusted asthma hospitalization rates were higher in the Northeast than in the West. In each time interval examined, the hospitalization rates were highest among children 0-4 years, lowest among persons aged 15-34 years, and intermediate for those 235. Mortality rates from asthma are confused by the changes in the International Classification of Diseases (ICD) coding criteria. Asthma death rates declined from 1960-1962 to 1975-1978, and then began to rise again by 1993-1994. The 1960-1962 death rate was 28.2 per 100,000 in contrast to a rate of 17.9 per 100,000 in 1993-1994. The lowest death rate was in 1975-1978 at 8.2 per 100,000 or less than half the rate of 1993-1994.

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 31 These national statistics are consistent with many local and regional reports showing an increase in the prevalence of asthma predominantly in children (Gergen et al., 1988; Gerstman et al., 1993; Vollmer et al., 1998; Yunginger et al., 1992~. This problem has been found in all regions of the United States and affects all races. Even though all races are affected, most studies have con- sistently shown a greater impact of asthma in African Americans in comparison to whites (Cunningham et al., 1996; Gergen, 1996; Gergen et al., 1988; Gerstman et al., 1993~. Similar trends have been observed in most developed countries. This increase in the prevalence of asthma over the relatively short interval of approxi- mately 30 years strongly suggests that some as yet unidentified environmental or behavioral change is responsible. MECHANISMS OF ASTHMA Details of the pathophysiology of asthma are presented in Chapter 4; thus, only the major concepts are discussed here. Fig- ure 1-1 attempts to illustrate these major concepts in a schematic form. Asthma appears to present in two different forms, allergic and nonallergic asthma, illustrated on the left and right sides of the figure, respectively. The critical difference is that in persons with allergic asthma, inhalation of allergens initiates an inflam- matory response that leads to hyperreactivity of the airways and symptoms of asthma. In persons with nonallergic asthma, the in- flammatory process and airway hyperreactivity appear the same as in individuals with allergic asthma, but allergic responses, de- fined by the presence of immunoglobulin E (IgE) antibodies spe- cific for allergens, cannot be demonstrated. As shown in the fig- ure, allergic asthma is the result of allergen exposure leading to allergic sensitization of a genetically predisposed individual. The development of allergic sensitization during allergen exposure may be influenced by other environmental effects such as the fre- quency and type of respiratory infections, passive exposure to to- bacco smoke, or intensity of allergen exposure. Airway hyperre- activity may be a direct result of allergic airway inflammation or may result from one or more genes. Once asthma is present, a variety of exposures may result in acute or chronic asthma symp- toms. In addition to allergen exposure, the exposures capable of

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32 Genetic Predisposition Allergen ~ I Exposure Respiratory,' Allergic *~~~~---- lnfections .' Sensitization . . _ ,, , , ~ ~ ,- lnflammation Airway in the Lungs + Hyperreactivity Allergic Asthma \ CLEARING THE AIR Genetic Predisposition ~ \ ,' \ Respiratory ~ , ~ ~ Factors ~~~~~~~~,~~----~\,, ' Infections i ~ -~- Environmental Exercise-_ \: Pollutants- _ am/ Allergen Exposure ~ \* --Temperature Changes ./ \~ Infections ~ / \ Emotions - - - - ~ ~ ~ ~ +/ Asthma Symptoms Inflammation Airway in the Lungs + Hyperreactivity ""' 1 '1 Nonallergic Asthma FIGURE 1-1 Development of asthma symptoms. This figure attempts to il- lustrate schematically the interrelationships of a number of factors thought to be important in the development of both allergic and nonallergic asthma. The weight of the lines attempts to provide some information about the strength of the evidence for the relationships: bold lines where there is ample evidence for a relationship and regular lines where the relationships have been demonstrated or at least strongly suggested. Dashed lines illustrate relationships that are likely to exist but for which there is little direct evi- dence at present. The phrase "genetic predisposition" is used to convey all of the genes in the human genome that are likely to be directly related to the outcome. causing symptoms include airborne irritants, infections, and ex- ercise. The development of nonallergic asthma is somewhat harder to explain, although there are suggestions that chronic infections may be related to asthma in some nonallergic individuals (von Hertzen et al., 1999~. As in the case of allergic asthma, inflamma- tion occurs in the lungs and is typically accompanied by airway Hyperreactivity A variety of exposures may lead to wheezing in the nonallergic asthmatic; however, the origin of the inflamma- tion cannot be directly identified. It is probable that various ge- netic influences on the immune system lead to inflammation in the lungs following some as yet undefined environmental expo

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MAJOR ISSUES IN UNDERSTANDING ASTHMA 33 sure. It is possible that nonallergic asthma is the result of an uni- dentified allergen, but for many reasons this appears unlikely. Estimates suggest that approximately 80% of asthma in chil- dren is allergic asthma. In adults, the percentage of those with allergic asthma is lower, in the 30-50% range depending on the population studied (Burr, 1993; Eriksson, 1990; von Mutius, 1996; Wever and Wever-Hess, 1993~. The lower prevalence of allergic asthma in adults may arise in many different ways. The preva- lence of allergic sensitivity is lower in adults than in children. It is possible that the inflammatory response that started as an allergic response in a child may become self-perpetuating by adulthood even as the allergic sensitization is lost. It is also possible that these are two different disease processes that merely have similar clinical appearances. EVALUATING THE EFFECTIVENESS OF INTERVENTIONS TO REDUCE ASTHMA Before an asthma intervention can be evaluated, the goals of the intervention must be defined. The goal of asthma therapy is ultimately to prevent a patient's asthma from altering or unduly influencing their life. Specific goals proposed in the Guidelinesfor the Diagnosis and Management of Asthma include (1) prevention of chronic and troublesome symptoms; (2) maintenance of "normal" pulmonary function; (3) prevention of recurrent exacerbations of asthma and minimization of the need for emergency department visits or hospitalizations; (4) provision of optimal pharmaco- therapy with minimal or no adverse effects; and (5) meeting pa- tients' and families' expectations and satisfaction with asthma care (Murphy, 1997~. Once goals are agreed upon, tools must be selected to evalu- ate how close the intervention comes to achieving all of the goals. In a typical clinical practice, the physician simply asks patients how they are doing. This is imprecise, and responses can vary depending upon how well the person can perceive his or her symptoms. Since many patients perceive their symptoms poorly, other tools are necessary to assess the adequacy of asthma control. Pulmonary function tests, primarily spirometry, are essential

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34 CLEARING THE AIR tools for evaluating a patient with asthma. Good control of asthma is reflected in normal or near-normal spirometry. Sequential i] spirometry allows the physician to follow the course of disease and judge the adequacy of therapy. In children old enough to per- form spirometry, lung growth can be monitored and assessed more easily. There has been increasing recognition that control of asthma evolves more than the absence of symptoms and the normality of lung function tests. Important aspects of asthma management involve the total impact of the disease on a person's life. How much does it affect what a person tries to accomplish? How does it affect daily activities? Do people avoid certain situations for fear of an attack? These diverse aspects have been grouped under the term "quality of life," and questionnaires have been devel- oped that attempt to capture and estimate these aspects of dis- ease control Quniper et al., 1993; Rowe and Oxman, 1993~. Other methods for evaluating asthma are constantly being developed and evaluated. One of the most important areas in need of an adequate means of testing is the intensity of Jung in- flammation. In research settings it is possible to directly sample the linings of the airways and the numbers of inflammatory cells within the lungs, but these techniques are very expensive and involve some risk to the patient. Techniques are needed that could estimate Jung inflammation accurately and yet be simple and in- expensive enough for use on a routine clinical basis. The present state of the art in assessing any form of interven- tion for the control of asthma typically involves four components: (1) patient symptom scores or checklists, (2) physician assess- ments, (3) spirometry (often supplemented with home peak flow monitoring), and (4) completion of quality-of-life questionnaires. Given the lack of precision of these instruments, it is usually nec- essary to apply them with a relatively large number of persons for weeks or months before the effect of the intervention can be estimated adequately. In some cases, other measurements can be used to supplement the components listed above. These measures could include some attempt at estimating Jung inflammation, de- termining allergen-specific IgE levels in serum, or assessing exer cise tolerance.

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