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Clearing the Air: Asthma and Indoor Air Exposures (2000)

Chapter: 5 Indoor Biologic Exposures

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Suggested Citation:"5 Indoor Biologic Exposures." Institute of Medicine. 2000. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: The National Academies Press. doi: 10.17226/9610.
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5 INDOOR BIOLOGIc Expos u res I he allergic constituents of indoor air are predominantly bio- logic in origin (Becher, 1996~. As early as the sixteenth century, associations between a number of these exposures and asthma were suspected; however, the scientific data available were un- able to confirm such an association. Concern in recent years re- garding the potential health effects of indoor air, as well as the marked increase in the prevalence of asthma in industrialized countries, has prompted an influx of scientific data on exposure to airborne biologic agents and asthma. The committee was charged with the task of evaluating the strength of the scientific evidence concerning the possible asso- ciation between these agents and asthma prevalence and severity. The committee was also tasked with examining possible means of mitigating or preventing exposure to these agents. In this chap- ter the committee evaluates indoor exposure to biologic agents, addressing the following to the extent permitted by available re- search: 1. which factors influence exposures to the agent; 2. whether a relationship exists between the agent and asthma prevalence or severity, taking into account the strength of the sci- entific evidence and the appropriateness of the methods used to detect the relationship; 105

106 CLEARING THE AIR 3. what type of relationship exists between the agent and asthma; 4. whether there are special considerations regarding the agent (e.g., subpopulations at risk and interactions with other ex- posures); 5. which strategies effectively mitigate or prevent exposure to the agent; 6. whether these strategies only reduce exposures or decrease the occurrence or exacerbation of asthma; and 7. whether these strategies are reasonable for use by the tar- get populations. Each section begins by providing a definition of the agent and a summary of the factors that influence exposure. The evidence concerning the possible association between the agent and asthma is discussed, followed by the committee's conclusions regarding the health impacts. Where information is available, evidence re- garding possible means of mitigating or preventing exposure to the agent is addressed. Each section concludes with any commit- tee recommendations for areas for which additional research is needed with respect to the agent. Because there are great differ- ences in the amount and type of information available on specific agents, the sections vary in their depth and focus. ANIMALS Cats Definition of the Agent and Means of Exposure Cats are kept as pets in 27% of U.S. households. The major cat allergen, Fe! ~ I, is a glycoprotein structured as a heterodimer with two chains of amino acids, which have been defined by poly- merase chain reaction (PCR) and subsequent DNA sequencing (Griffith et al., 1992; Morgenstern et al., 1991; Schou, 1993~. It is found on cat hair and is produced in cat sebaceous, salivary, and anal glands (De Andrade et al., 1996~. In male cats, Fe! ~ I glandu- lar production is under hormonal control and decreases after cas- tration (Zielonka et al., 1994~. As discussed in the Third Interna

INDOOR BIOLOGIC EXPOSURES 107 tional Workshop report (Platts-MilIs et al., 1997), the clinical sig- nificance of this decrease in allergen production is not certain, since many symptomatic cat-allergic asthmatics in the United States have neutered cats. Further investigation of hormonal and genetic control of Fe! ~ I production could be relevant to the con- tro] of allergen levels in homes with cats. Although 90°/O of pa- tients allergic to cats make immunogIobulin E (IgE) to Fe! ~ I (de Groot et al., 1988; Schou, 1993), making Fe! ~ I a marker for the immune response to cat allergens, at least eight other cat aller- gens have been identified (Duffort et al., 1987), suggesting that protection from Fe! ~ I exposure may not be the equivalent of pro- tection from cat allergen exposure. This conclusion is supported by the findings that 66% of the histamine-releasing activity of cat hair and dander extract, and about 60% of the cat dander radioallergosorbent test (RAST) activity, was carried by Fe! ~ I (Schou, 1993~. Touching the cat is only one mode of contact that may result in airborne suspension of allergen and potential direct hand-to- nose deposition of allergen-associated particles. In contrast with cockroach allergen, which is airborne only transiently during the disturbance of household dust, cat allergen can remain airborne for long periods of time, in part because Fe! `1 I is associated to a significant extent with smaller particles of less than 5 ,um (Custovic et al., 1998b). Particles on which cat allergen is carried, coming primarily from cat dander, are also very adherent. Conse- quently cat allergen is spread easily throughout a house, even when cats are kept out of certain rooms. Moreover, cat allergen is easily carried from home to home, office, school, or day care cen- ter by those who touch cats or visit households with cats (Custovic et al., 1998a; Dybendal and Elsayed, 1994; Warner, 1992~. At trace or small amounts that may be significant for sensi- tization or exacerbation of disease in sensitized individuals, Fe! `1 I in settled dust is found in most homes without cats (Bollinger et al., 1996; Chew et al., 1998), although allergen levels are generally higher in homes with cats. A Baltimore, Maryland, study found measurable levels of airborne Fe! ~ I in 37 homes with cats (range, 1.8-578 ng/m3; median, 45.9 ng/m3) and in 10 of 40 homes with- out cats (range for detectable samples, 2.8-88.5 ng/m3; median, 17 ng/m3) (Bollinger et al., 1996~. In 38 of 40 homes without cats,

108 CLEARING THE AIR Eel d I was present in the settled dust (range, 39-3,750 ng/g; me- dian,258 ng/g); dust levels were weakly correlated with airborne levels. Carpeting, bedding, and upholstered furniture can be res- ervoirs for deposited cat allergen (Wood et al., 1989~; shaking the bedding in rooms with cats resuspends cat allergen in the air. As well as being detected in homes without cats, cat allergen has also been detected in public places such as hospitals and schools. In one British study that measured both settled and air- borne cat allergen in hospitals, the amount of cat allergen in settled dust in upholstered chairs was as high as in homes with cats (geometric mean, 23,ug/g dust), but airborne levels were low (0.22 ng/m3) (Custovic et al., 1998a). Evidence Regarding Asthma Exacerbation In cat-sensitized asthmatics, cat allergen can induce allergic symptoms, asthmatic symptoms, and decrements in lung func- tion. Exposure to inhaled cat allergen in an experimental cat room led to significant decreases in forced expiratory volume in one second (FIVE range, 6-57%; mean, 25%) in a study of 13 adults with cat allergy. The percentage decrease in FEVER did not corre- late significantly with either the intradermal titration end point with cat allergen or the magnitude of the RAST response with cat allergen. Those cat-allergic subjects classified as asthmatic by methacholine challenge testing experienced almost identical re- sponses to environmental allergen challenge in an experimental cat room and inhalation challenge with cat allergen (Sicherer et al., 1997~. Norman and colleagues documented progressive in- creases in both nasal and lung symptom scores during a 60- minute period in a cat room (Norman et al., 1996~. While initial cat room studies involved very high airborne cat allergen levels, a later experimental cat room exposure study by Bollinger and colleagues (1996) evaluated symptom and lung function responses of cat-sensitive subjects to low-level airborne cat allergens. They demonstrated that cat-sensitive individuals can have increases in upper- (congestion, rhinorrhea, pruritus) and lower- (chest tightness, wheezing) respiratory symptoms and decrements in Jung function at levels of cat allergen occurring in

INDOOR BIOLOGIC EXPOSURES 109 homes without cats. The median FEVER change was 15% in the seven challenges with a Fe! ~ I level less than 100 ng/m3. In a Delaware case-control study, Gelber and colleagues (1993) studied allergen predictors of emergency room visits for asthma. This study compared 93 patients, 15 to 55 years of age, who pre- sented with breathlessness and airway obstruction, to 93 patients presenting without breathlessness. For cat and cockroach, the combination of sensitization and the presence of allergen in the house was associated with asthma presenting to hospitals (14/93 asthmatics versus 1/93 controls). Whether other exposures po- tentiate the response of cat-allergic asthmatics to cat exposure is unknown. In a cross-sectional study of children in New Mexico with asthma or bronchial hyperresponsiveness, cat sensitization and exposure to cat allergen were common (Sporik et al., 1995~. Among children with asthma (defined as symptomatic bronchial reactivity), 13/19 were sensitized to cat. Numbers were too small to compare symptoms in cat-sensitized asthmatics with and with- out significant home exposure to cat allergen (Ingram et al., 1995~. Evidence Regarding Asthma Development Insufficient data are available to assess whether exposure to cats influences the development of asthma. Cross-sectional stud- ies of children suggest an association between sensitization to cats and home exposure in the first six months of life (Suoniemi et al., 1981; Warner et al., 1991~. These studies may be subject to recall bias. A longitudinal birth cohort study from the Isle of Wight found that the presence of a cat in the home predicted a greater risk of skin test reactivity to cat and a greater risk of any skin test reactivity by 2 years of age (Hide et al., 1994~. Sensitization to cat predicts asthma development, but this may simply be a confir- mation of the well-documented fact that atopic individuals are more likely to develop asthma than nonatopic individuals. In a New Zealand birth cohort study, the development of asthma by 13 years of age was associated with sensitization to cats and dogs at age 13 (Sears et al., 1989~. Sensitization to cats predicted the development of bronchial hyperresponsiveness in a longitudinal study of adults in Boston, Massachusetts (Litonjua et al., 1997~. However, neither of these studies provides evidence of whether

110 CLEARING THE AIR exposure to cats predicts either asthma or bronchial hyperrespon- siveness. Since cat allergen exposure can potentially take place either at home or in schools and public places, the relative impor- tance of home versus community-wide exposure to cat allergen in the risk of specific sensitization to cats is unknown. Although the field of the genetics of asthma is in its infancy, preliminary studies suggest that certain genetic phenotypes are associated with allergy to specific insects or animals (Fukuda et al., 1995; Hizawa et al., 1998; Young et al., 1992, 1993~. Under- standing the genetics of allergy and asthma, including under- standing the phenotypes associated with allergy specificity, may eventually prove useful in understanding gene-by-environment interaction in the development of asthma. Conclusions: Asthma Exacerbation and Development In cat-sensitive asthmatics, cat allergen exposure leads to worsening of respiratory symptoms and to a decline in Jung func- tion. Although sensitization to cats is a prerequisite to reactivity to cat exposure, the level of airborne cat allergen that exacerbates asthma varies by individual and is not necessarily predictable by the size of the skin test reaction to cat or the titer of IgE antibody. However, specific sensitive subgroups have not been defined. The relationship between cat allergen in the home and asthma devel- opment is uncertain. Because cat allergen is frequently found out- side the home and in households without cats, the assessment of individual exposures to cats is difficult, making evaluation of the association between cat allergen exposure and asthma develop- ment difficult as well. In summary: · There is sufficient evidence of a causal relationship between cat allergen exposure and exacerbation of asthma in individuals specifically sensitized to cats. · There is inadequate or insufficient evidence to determine whether or not an association exists between cat allergen expo- sure and the development of asthma.

INDOOR BIOLOGIC EXPOSURES Evidence Regarding Exposure Mitigation and Prevention: Homes 111 Removal of the cat from the home will decrease exposure to cat allergen and is widely recommended for symptomatic cat-sen- sitive asthmatics. However even when the owner removes the cat, cat allergen levels may remain elevated for 20 weeks or more (Wood et al., 1989~. Removal of carpets and upholstery, with en- casement of mattresses and pillows, may be required for dimin- ishing cat allergen to levels commonly measured in homes with- out cats (Wood et al., 1989~. No studies are available that evaluate symptoms or Jung func- tion in cat-sensitive asthmatics before and after removal of the cat from the home. Nor are there studies of change in symptoms or lung function after moving from a home with a cat to a home without a cat. However, exposure studies suggest that in cat-sen- sitive subjects the decline in lung function associated with low- leve] airborne exposure to cat allergen, which can be present in a home with no cats, tends to be less extreme than the decline in Jung function associated with higher-level airborne exposure (Bollinger et al., 1996~. The experiments demonstrating entry into a room with a cat as a source of exacerbation of asthma in cat- sensitive individuals also suggest that removal of the cat from the household may decrease symptoms in cat-allergic asthmatic. Because of the reluctance of cat-allergic symptomatic asthmat- ics to get rid of their cats, a number of studies have focused on the potential for lowering cat allergen levels by washing the cat. In eight households with cats, de Blay and colleagues (1991a) found that the combination of washing the cat weekly, reducing furnish- ings, vacuum cleaning, and air filtration reduced airborne cat al- lergen levels. In a second study, however, Avner and colleagues (1997) from the Platts-MilIs group found that while washing cats by immersion will transiently remove significant allergen from the cat and reduce the quantity of airborne Fe! ~ I, this reduction in allergen is not maintained by one week. Klucka and colleagues (1995) found no significant reduction of Fe! ~ I by washing, use of Allerpet-C (a widely advertised topical spray), or acepromazine, a tranquilizer advocated as efficacious in subsedating doses. While removal of the cat from the living room and bedroom areas

112 CLEARING THE AIR of the home and use of a High-Efficiency Particulate Air (HEPA) filter reduced airborne levels of cat allergen in homes with cats, the reduction was not evenly spread across the particle size range (Custovic et al., 1998b). It is unclear that the level of reduction of allergen obtained in this study is sufficient to influence symp- toms in cat-sensitized asthmatics. No studies are available to as- sess the efficacy of recommendations to wash cats in reducing symptoms in cat allergic-asthmatics. Although the combination of HEPA filter use, mattress and pillow covers, and exclusion of cats from the bedroom reduced airborne cat allergen levels, a Maryland study detected no improvement in daily symptom scores, peak flow rates, medication use, monthly spirometry, pre- and post-study cat-specific IgE levels, and methacholine chal- lenge studies in cat-allergic subjects (Wood et al., 1998~. On the other hand, in a double-blind, placebo-controlled, cross-over study of twenty asthmatic children sensitized to cat or dog aller- gens, and living in homes with these animals, airway hyperresponsiveness was improved and peak flow variation was decreased during the use of air cleaners in the living room and bedroom of the child (van der Heide et al., 1999~. The authors report that substantial amounts of cat and dog allergen were cap- tured by the air cleaners; floor cat and dog allergen levels were unchanged by air cleaner use. Evidence Regarding Exposure Mitigation and Prevention: Schools and Hospitals Even if the cat is removed from the home, continued low- grade exposures may occur in public places or via clothes from cat owners. Since cat allergen is everywhere, there is little poten- tial for absolute avoidance (Dybendal and Elsayed, 1994; Warner, 1992~. Norwegian investigators have demonstrated the presence of Fe! ~ 1 in schools on both smooth and carpeted floors, with approximately 11 times more allergen on the carpeted floors (Dybendal et al., 1991, 1989a, 1989b). The frequency of cleaning floors and furniture was believed to influence the level of cat and dog allergen, which were higher on chairs than in floor dust (Warner, 1992~. Upholstered chairs and mattresses in hospitals are

INDOOR BIOLOGIC EXPOSURES 113 also demonstrated reservoirs for cat and dog allergen (Custovic et al., 1998a). To lessen the risk of exacerbation of asthma in cat- or dog- sensitized asthmatics in public buildings, Warner and others (1992) have recommended the use of smooth floors and frequently cleaned wooden or plastic chairs. In their study demonstrating the presence of significant cat and dog allergen levels in a hospi- tal in Manchester, England, Custovic and colleagues (1998a) ques- tioned the introduction of soft furnishings and carpets into hospi- tals where highly cat- or dog-allergic asthmatics may come for care. Where upholstered chairs were present, they demonstrated that vacuuming three times a week significantly reduced allergen levels. Conclusions: Exposure Mitigation and Prevention Cat allergen levels can be reduced to levels found in homes without cats by removal of the cat from the home, but the reduc- tion in allergen levels may require a prolonged period of time. The combination of HEPA filter use, mattress and pillow covers, and exclusion of cats from the bedroom may not reduce airborne cat allergen levels sufficiently to improve symptoms in cat-sensi- tive asthmatics. The absence of carpet, the use of plastic or wooden rather than upholstered chairs, and of frequent vacuum- ing in schools and hospitals may decrease the levels of cat aller- gen in public places. No studies are available to evaluate whether these measures improve symptoms or lung function in cat-sensi- tized asthmatics or whether they decrease the potential for sensi- tization in nonsensitized individuals. In summary: · There is sufficient evidence of an association between re- moval of a cat from the home and a decrease in levels of cat aller- gen in the home; this decrease in levels of allergen may be slow if reservoirs of cat allergen are not simultaneously removed from the home. · There is limited or suggestive evidence of an association between removal of a cat from the home and improvement of symptoms or lung function in cat-allergic asthmatics. · There is limited or suggestive evidence of an association

114 CLEARING THE AIR between measures short of removal of a cat from the home (e.g., washing the cat, HEPA filter use) and some transient reduction in cat allergen levels in the home. · There is inadequate or insufficient evidence to determine whether or not an association exists between measures short of removal of a cat from the home (e.g., washing the cat, HEPA filter use) and improvement in symptoms in cat-allergic asthmatics. Dogs Definition of the Agent and Means of Exposure Dogs are present in 31% of U.S. households and are also sources of allergens (Schou, 1993~. Allergy to cats is reported to be about twice as common as allergy to dogs, despite the fact that dogs are as common in U.S. households as cats (Bollinger et al., 1996~. CanfI and CanfII are purified dog allergens that have been identified (Schou, 1993~. CanfIis a polypeptide whose molecular weight and structure have been partially but not fully defined (Schou, 1993~. It is present in dander, pelt, hair, and saliva, but not in the urine or feces of dogs (Schou, 1993~. Though there are likely to be other dog allergens, no others have been found to have clini- cal importance. CanfIis considered a major allergen, because it accounts for at least half of the allergenic activity in dog hair and dander. In addition, 92% of dog-allergic patients had a positive skin prick test to CanfI (Schou, 1993; Yman et al., 1973~. It is still a controversial matter whether true breed-specific dog allergens exist or whether the differences observed between breeds are quantitative rather than qualitative (Schou, 1993~. Hair is not the only source of dog allergen, and it is not known whether short- haired dogs are less allergenic. Cross-reactivity can be found be- tween dog and cat allergen (Vanto and Koivikko, 1983~. Dog allergen, like cat allergen and unlike cockroach, is easily aerosolized and widely disseminated throughout the community (Custovic et al., 1997~. In a Baltimore study of 42 homes, dog anti- gen was demonstrated in more than half of households (Lied et al., 1987; Schou, 1993~. In Sweden, dog allergen has been mea- sured in homes that have never had dogs (Munir et al., 1992~. Like cat allergen, dog allergen has been found in significant

INDOOR BIOLOGIC EXPOSURES 115 amounts in public buildings such as schools (Berge et al., 1998; Dybendal et al., 1989a; Schou, 1993; Warner, 1992) and hospitals (Custovic et al., 1998a). In dust from upholstered English hospital chairs, CanfI levels (geometric mean = 22,ug/g, range, 4-63) were as high as levels in settled dust from households with dogs (Custovic et al., 1998a; Munir et al., 1994~. Hospital airborne Canf I levels were detectable in 7 of 10 testing days but were lower (range 0.09-0.22 ng/m3) than those often found in homes with dogs (range 0-100 ng/m3 Canf I) (Custovic et al., 1998a; Hodson et al., 1999~. Evidence Regarding Asthma Exacerbation The asthmatic response to bronchial provocation test (PT) with dog allergen was evaluated in a cross-sectional Finnish study of 203 asthmatic children selected from the Children's Asthma Registry (Vanto and Koivikko, 1983~. Of those with a positive PT, 64% had kept dogs, whereas only 36% with a negative PT had kept dogs. A positive PT was correlated with a positive skin prick test to dog (correlation coefficient = 0.8), but not with the fre- quency of reported asthma symptoms. In immunotherapy trials, positive response to bronchial provocation with dog allergen has also been associated with elevated levels of IgE to dog allergen in asthmatic subjects (Hedlin et al., 1995; Valovirta et al., 1984; Vanto et al., 1980~. Some investigators consider symptomatic and bron- chial response to animal allergen in an experimental animal room to be more definitive proof that animal allergen triggers asthma than allergen bronchial PT. They question whether the airway re- sponse to bronchial provocation with an allergen is always an allergic rather than an irritant response. The committee could find no published studies of the response of dog-sensitized asthmatics to exposure to dogs in an experimental dog room analogous to the cat room set up by the Hopkins group (Sicherer et al., 1997~. Evidence Regarding Asthma Development There is insufficient evidence regarding the role of dog aller- gen in the development of asthma. In keeping with the ecology of Los Alamos, New Mexico, which is high and dry, with less dust

116 CLEARING THE AIR mite, the allergens to which asthmatics are sensitized tend to be the predominant allergens in the indoor and outdoor environ- ment. These allergens include dog and Alternaria, as well as cat (Ingram et al., 1995; Sporik et al., 1995~. A cross-sectional retro- spective Finnish study suggested that dog allergy was more prevalent in children from homes where dogs were present in the first few months of life, compared to homes where the dog was introduced after the child had reached the age of 1 (Vanto and Koivikko, 1983~. As mentioned above, in a New Zealand birth cohort study the development of asthma by 13 years of age was associated with sensitization to dogs at age 13 (Sears et al., 1989~. In contrast, the presence of a dog in the home in childhood was negatively associated with asthma (OR = 0.85,95% CI = 0.78-0.92) among adults reporting no parental allergy, in the cross-sectional European Community Respiratory Health Survey of 13,932 20- to 44-year-old subjects from 36 areas in Europe, New Zealand, Aus- tralia, and the United States (Svanes et al., 1999~. Among 1,649 Swedish school children aged 7-13 years, a report of keeping a cat or a dog in the first year of life was also negatively associated with asthma and allergic rhinitis (Hesselmar et al., 1999~. Conclusions: Asthma Exacerbation and Development · There is sufficient evidence of an association between dog allergen exposure and exacerbation of asthma in individuals spe- cifically sensitized to dogs. · There is inadequate or insufficient evidence to determine whether or not an association exists between dog allergen expo- sure and development of asthma. Evidence Regarding Exposure Mitigation and Prevention Because the aerodynamic properties, carrier material, and chemical composition of dog and cat allergens are similar, issues related to mitigation of dog allergen are likely to be similar. How- ever fewer studies are available related to the mitigation of dog allergen exposure and its health consequences. In a cross-sectional study of 203 asthmatic children listed in the Finnish Asthma Reg- ister, 68 of 203 had kept a dog, but 59 of 68 (87%) had removed the

INDOOR BIOLOGIC EXPOSURES 117 dogs from their homes. Parents tended to report that removal of the dog had improved asthma symptoms and had not been detri- mental because of emotional deprivation (Vanto and Koivikko, 1983~. The Finnish study also demonstrated that homes with dogs had higher dog antigen levels in dust than homes without dogs, some of which had a past history of a dog in the home. Homes in which occupants had indirect contact with dogs had more dog allergen than homes in which no one reported contact with dogs. Despite reported avoidance of dogs, a rising or steadily high level of dog-specific IgE was observed in follow-up of 24 dog-allergic subjects. The authors hypothesized that dog allergen encountered outside the home might be sufficient to boost IgE synthesis in most sensitive subjects (Vanto and Koivikko, 1983~. In a study of 25 homes with dogs, Custovic found that dogs had to be washed at least twice a week to maintain a reduction in recoverable Canf I from the hair (Hodson et al., 1999~. Airborne dog allergen levels were not significantly affected by washing the dog. No studies are available regarding the effect of this mitiga- tion measure on symptoms or Jung function in dog-sensitive asth- matics. Conclusions: Exposure Mitigation and Prevention · There is limited or suggestive evidence of an association between removal of the dog from the home and reduction of dog allergen levels. This evidence comes from an association between the absence of a dog in the home and the measurement of low dog allergen levels in a study including homes that had a history of keeping dogs (Vanto and Koivikko, 1983~. · There is inadequate or insufficient evidence to determine whether or not an association exists between removal of a dog from the home and improvement in symptoms or Jung function in dog-sensitized asthmatics. The one epidemiologic study report- ing an association between dog removal and symptom improve- ment in asthmatic children relies on retrospective parental report- ing without measures of sensitization at the time of dog removal or measures of symptoms or Jung function before and after dog removal (Vanto and Koivikko, 1983~.

118 CLEARING THE AIR Rodents Definition of the Agent and Means of Exposure Exposure to rodents can come either from keeping pets or from their presence as pests in the home. Rodents (mouse, rat, and guinea pig) can also be found in school settings. They have been studied as sources of allergens, particularly because of their extensive use as laboratory animals (Schou, 1993~. Hair and epi- thelial fragments carry allergenic molecules, the allergens mea- sured are believed to be from urine, saliva, or skin. The relative importance of these allergen sources has been debated (Kern, 1994; Longbottom and Austwick, 1987; Walls and Longbottom, 1985~. As described by Schou (1993), rodents have permanent pro- teinuria; allergenic protein from sprayed urine dries up and be- comes airborne on dust particles. Airborne rodent allergen has been measured in laboratory facilities (Sakaguchi et al., 1990a; Swanson et al., 1985; Twiggs et al., 1982) and, in one study, in inner city apartments (Swanson et al., 1985~. Clinically important allergens that have been identified include Mus m I and Mus m II for mouse, Rat n I for rat, and Cav p I and II for guinea pig (Schou, 1993~. Assessment of rodent exposure in the home has been lim- ited, to some extent, by limitations in the ability to measure aller- gens from all species of wild mice potentially present in the home. Evidence Regarding Asthma Exacerbation A number of cross-sectional studies document the association between handling animals in a laboratory setting and allergy (Beeson et al., 1983; Cockcroft et al., 1981; Cullinan et al., 1994; Davies and McArdle, 1981; Gross, 1980; Newman-Taylor, 1982; Schumacher et al., 1981; Venables et al., 1988~. Hollander and col- leagues (1996) conducted a prospective pane! study of self-re- ported symptoms and peak flow in Dutch laboratory animal workers. Workers who reported asthmatic symptoms (chest tight- ness) due to working with rats had significant decreases in peak expiratory flow on days they worked with the animals; 86% of them were sensitized to rat allergens (Hollander et al., 1996~. A cross-sectional study of British laboratory workers demonstrated

INDOOR BIOLOGIC EXPOSURES 119 an association between positive skin tests to animal extracts and asthmatic symptoms (Cockcroft et al., 1981~. Whereas IgE anti- body to rat allergen was present in only 2 of 135 laboratory work- ers without asthmatic symptoms, it was present in 12 of 18 labo- ratory workers with symptoms (Platts-Milis et al., 1987~. In the U.S. National Cooperative Inner City Asthma Study, 19% of asthmatic children were allergic to rats and 15% were al- lergic to mice, suggesting exposure to rat or mouse allergens in the home (Kattan et al., 1997~. No data are available on rat or mouse allergen levels in the home and the exacerbation of asthma among rodent-sensitized asthmatics. Evidence Regarding Asthma Development Although there are retrospective reports of the incidence of asthma symptoms after beginning laboratory work with rodents (Platts-Milis et al., 1987), the committee could find no relevant studies on rodent allergen exposure and the development of asthma. Conclusions: Asthma Exacerbation and Development · There is sufficient evidence of an association between ex- posure to rodents in a laboratory setting and exacerbation of symptoms or Jung function in rodent-sensitized asthmatics. · There is inadequate or insufficient evidence to determine whether or not an association exists between exposure to rodents (wild or as pets) in the home and exacerbation of symptoms or lung function in rodent-sensitized asthmatics. · There is inadequate or insufficient evidence to determine whether or not an association exists between exposure to rodents and the development of asthma. Evidence and Conclusions: Exposure Mitigation and Prevention No studies are available to document the influence of rodent eradication on the level of rodent allergen or on the severity of asthma in sensitized asthmatics.

120 CLEARING THE AIR · There is inadequate or insufficient evidence to determine whether or not an association exists between removal of rodents from the home and the reduction of rodent allergen levels. · There is inadequate or insufficient evidence to determine whether or not an association exists between removal of rodents from the home and improvement in symptoms or Jung function in rodent-sensitized asthmatics. Cow and Horse Definition of the Agent and Means of Exposure Relatively few people in the United States live on farms where exposure to cows, horses, or pigs can be significant; only 1.5% of U.S. households keep horses as pets. Cow hair and dander con- tain at least 17 antigens, 4 of which have been identified as aller- gens and 3 of which have been purified (Bos ~ I, II, and III). Horse hair and dander have been demonstrated to contain three impor- tant allergens (Equ c I, II, and III) (Schou, 1993~. Evidence and Conclusions: Asthma Exacerbation and Development Allergies to cows and horses are considered occupational dis- eases of farm workers and veterinarians (Prah] and Roed- petersen, 1979; Schou, 1993~. Data on the effect of non-occupa- tional exposures is lacking. In summary: · There is inadequate or insufficient evidence to determine whether or not an association exists between cow or horse aller- gen in the home and the exacerbation of asthma in sensitive chil- dren or the development of asthma. Living on a Farm and Development of Asthma The epidemiologic literature on allergy in farmers and chil- dren from farming families was reviewed in a 1999 article dem- onstrating a lower prevalence of hay fever and allergic sensitiza- tion in farmer's children compared to peers from nonfarming

INDOOR BIOLOGIC EXPOSURES 121 families living in the same rural Swiss community (Braun- FahrIander et al., 1999~. While farm animals can be allergenic, lower rates of sensitization to pollen and animal dander have been reported in adult farmers compared to other occupational groups (Iversen and Pedersen, 1990; Kohier et al., 1983; Rautalahi et al., 1987; Sigsgaard et al., 1996~. Swedish conscripts and Finnish uni- versity students raised on farms have reported fewer allergic symptoms than students from nonagricultural backgrounds (Aberg, 1989; Kilpelainen et al., 1997~. This may be the result of self-selection out of the farming community by individuals and families with a genetic predisposition toward allergy (von Mutius et al., 1994~. These findings have led investigators to question whether the farm environment itself might play a protective role in the devel- opment of allergy and allergic asthma. One hypothesis is that con- tact with farm animals and their bacterial products (including endotoxin, which is discussed later in this chapter) may be pro- tective against allergy or asthma through early-life stimulation of TH1 immunity, particularly for individuals with specific genetic characteristics (Baldini et al., 1999~. However, no additional evi- dence is available to confirm or reject the hypothesis that for some children, exposure to farm animals early in life might be protec- tive against either allergy or asthma. The farm is a complex envi- ronment that varies by country and culture, and many other as- pects of farm living may contribute to the observed epidemiologic differences between asthma or atopy in children from farming versus nonfarming families. Birds Definition of the Agent and Means of Exposure Birds are kept in 5°/O of U.S. households. While it is clear that hypersensitivity pneumonitis can be associated with antigens from bird excrete, serum protein, and proteinaceous material in dispersed dust from birds (Christensen et al., 1975; Hendrick et al., 1978), specific bird antigens associated with allergy and asthma have not been defined with certainty. Tauer-Reich and col- leagues (1994) studied five bird fanciers who complained of asth

122 CLEARING THE AIR matic symptoms during contact with their birds and also had documented bronchial hyperreactivity to acety~choline. These in- dividuals had positive IgE antibody reactions to bird sera as well as to extracts of feathers. Skin prick tests to mites, molds, pollen, and domestic animals other than birds were negative in all five patients. Evidence Regarding Asthma Exacerbation and Development A few additional case reports describe bird handlers with the combination of asthmatic symptoms in the presence of birds, symptoms of egg hypersensitivity, and specific IgE antibodies against blood serum proteins of chicken, parrot, budgerigar, or pigeon serum (de Blay et al., l991b). A portion of what is called bird allergy may be an expression of allergy to dust mites. Bird feathers can harbor mites (Kemp et al., 1996~. The material used in skin prick testing for bird allergy may also be contaminated with mite allergen. Although clinicians have traditionally advised asthmatic patients not to use feather pillows, an epidemiologic study found an increased risk of wheeze in children using foam pillows compared to children us- ing feather pillows (Strachan and Carey, 1995~. This association could occur if parents of symptomatic children tend to provide their children with synthetic rather than feather pillows because of advice from health professionals. On the other hand, this asso- ciation may relate to increase mite exposure from synthetic pil- lows. New Zealand researchers found that after four months of use, dust mite (Der p I) levels were significantly higher in syn- thetic than in feather pillows (Crane et al., 1997; Rains et al., 1999~. To prevent the feathers from coming out, feather pillows may have more impermeable covers than synthetic pillows; which could result in less dust mite infestation. Conclusions: Asthma Exacerbation and Development · There is limited or suggestive evidence of an association between bird exposure and exacerbation of symptoms in bird- sensitized asthmatics. This association may be confounded by the allergic asthmatic response to mites harbored by birds.

INDOOR BIOLOGIC EXPOSURES 123 · There is inadequate or insufficient evidence to determine whether or not an association exists between bird allergen expo- sure and the development of asthma. · There is inadequate or insufficient evidence to determine whether or not an association exists between down pillows and exacerbation of symptoms or Jung function in asthmatics. Pillows are believed to be a risk factor for asthma because of their docu- mented mite content, rather than because of the presence of bird allergen. Evidence and Conclusions: Exposure Mitigation and Prevention There is inadequate or insufficient evidence to determine whether or not an association exists between removal of a bird from the home and reduction in bird allergen levels or improve- ment in symptoms or lung function in bird-sensitized asthmatics. Research Needs The associations between dust mite allergen, asthma exacer- bation, and asthma development are much more well defined than the associations between larger animals and asthma. This is only partly a function of the number of years and intensity of efforts to investigate the health effects of dust mites. Compared with dust mite allergen, once the allergen source is present, cat and dog allergens are more easily dispersed throughout the household. Cat and dog allergens remain airborne for much longer than dust mite. The potential for exposure to allergens out- side the home is markedly greater for cats and dogs than for dust mites. The potential for home exposure to cat or dog allergen in homes without cats or dogs has also been underestimated. The absence of adequate information regarding allergen exposure may, in part, account for contradictory data regarding the effects of cats or dogs in the home on the development of asthma. Research is needed to assess whether removal of the cat or dog from the home results in sufficient reduction in overall allergen ex- posure to reduce symptoms and improve bronchial reactivity in spe- cifically sensitized asthmatics. Further research is needed to assess the level of animal allergen exposure (cat and dog) in day care cen

124 CLEARING THE AIR ters and schools. When significant levels are noted, the potential for lowering exposure should be investigated. Since so many cat- or dog-allergic asthmatics are emotionally attached to their pets, in- vestigators should explore the success of efforts that recommend the removal of the pet for sensitized symptomatic child and adult asthmatics. Further research is also needed to evaluate the effect of mitigation measures short of animal removal on asthma symptoms, Jung function, or bronchial responsiveness in specifically sensitized asthmatics. Although frequent animal washing and PUPA filter use are widely recommended, their efficacy in reducing asthma sever- ity has not been proven. Two retrospective cross-sectional studies suggest that expo- sure to cat or dog in early life may actually be protective against asthma development in some subsets of children (Hesselmar et al., 1999; Svanes et al., 1999~. The relationship between cat or dog allergen exposure in early childhood, the development of sensiti- zation, and the development of asthma merits further investiga- tion. This investigation will require better assessment of expo- sure. It is likely that the genetic phenotype will modify the response to cat or dog allergen at different levels of exposure, but gene-by-environment interactions cannot be effectively explored until the genetics of asthma is better understood. Further research is needed to evaluate rodent allergen expo- sure in the home as a potential factor in the exacerbation of asthma in rodent-sensitized asthmatics. Particularly in socially disadvan- taged populations, research should focus on effective reduction of rodent allergen and its effect on symptoms or lung function in specifically sensitized asthmatics. Researchers should also consider the possibility that animal (or animal allergen) exposure may be either protective or aller- genic. The effects may depend on the mode of exposure, the ge- netic characteristics of the populations, the timing in the life cycle when exposure occurs, and many other cofactors (e.g., early-life viral, bacterial, and parasitic infection experience). . . COCKROACH Many insects have been identified as sources of inhalant al- lergens in case reports or small outbreaks; these include moths,

INDOOR BIOLOGIC EXPOSURES 125 crickets, locusts, beetles, "green nimitti" midges, lake flies, and houseflies (IOM, 1993~. Cockroaches, however, are the only insect that has been repeatedly recognized as a common source of in- door allergens. Definition of the Agent and Means of Exposure Agent Definition and Biology Cockroach is an important source of indoor allergen worId- wide. Although more than 60 species have been identified, the most common indoor species in North America are the German (Blattelia germanica), American (Periplaneta americana), and Orien- tal (Blatta orientalist. There are multiple allergens from cockroach that have been identified (Bla g I or Per a I, Bla g II, IV, and V) and cloned (Bla g II, IV, and V). Schou and colleagues (1990) purified an allergen from B. germanica and P. Americana extract, which re- sulted in positive reaction to skin tests in 50°/O of patients who were allergic to cockroaches and was designated Bla g I (or Per a I). Monoclonal antibodies have been produced against extracts of both cockroach species and used for cockroach allergen identifi- cation and purification. Enzyme-linked immunosorbent assays have been developed that can be used to estimate exposure to some of these cockroach allergens (Bla g I, Per a I, and Bla g II) in the environment. Bla g I is a 25-kD (kilodaltons, a unit of molecu- lar weight; also abbreviated kDa) cross-reacting antigen from both the German and the American cockroach. Bla g II is a 36-kD spe- cies-specific antigen derived from the German cockroach. Spe- cific allergens have not been purified from Oriental cockroaches. Neither the antigenic relationships between cockroach spe- cies nor the precise source of cockroach allergens are well under- stood. The source of the allergens derived from cockroaches is not known, but there are speculations to suggest that they may come from feces, parts of the body, or other sources in the body. Se- quence homology searches are useful tools for investigation of the biologic function of cockroach allergens, and as more se- quences become available it will be possible to make compari- sons of biologic function and allergenicity, to compare allergen

126 CLEARING THE AIR expression in different species, and to localize the source of the allergens in cockroach tissues. At present, cockroach extracts are not standardized; however! the Food and Drug Administration's (FDA's) Center for Biologics Evaluation and Research has embarked on a program to standard- ize B. germanica extracts on the basis of skin testing, protein con- tent, RAST inhibition, and specific allergen assays. Most patients in the United States appear to be sensitized to B. germanica, al- though there is a cross-reactivity between B. germanica and P. Americana on skin tests and serum IgE antibody assay. The prevalences of IgE antibodies to Bla g I and Bla g II in patients allergic to cockroaches are 40°/O and 60-80%, respectively (Pollart et al., 1991a). Approximately 20% of patients lack detectable IgE antibody to either allergen, which suggests that cockroaches pro- duce other important allergens (Chapman, 1993~. However, the levels of the two allergens have been found to be highly corre- lated (r = 0.92; p < .01) in dust samples (Pollart et al., 1991a). Factors Influencing Exposure Studies have suggested that cockroach sensitization is an af- fliction of the inner city poor, but the complex interrelationship of race, poverty, and residence has been difficult to unravel (Bernton and Brown, 1964; Call et al., 1992; Garcia et al., 1994; Gelber et al., 1993; KoehIer et al., 1987~. Sarpong and colleagues (1996a) exam- ined race and socioeconomic status (SES) as risk factors for cock- roach allergen exposure and sensitization. In their cohort of 48 white and 39 African-American children, they found that both factors were independent predictors of cockroach sensitization. Among low-SES subjects, sensitization was common with 50°/O (4 of 8) of white participants and 75°/O (15 of 20) of African-American participants exhibiting a positive skin test. Cockroach antigens are widely distributed in homes and schools, and the kitchen is the most common source of cockroach allergen (Rosenstreich et al., 1997; Sarpong et al., 1996b, 1997~. The cockroach allergen in school dust was similar to that reported in homes. The level of antigen reported in school dust is of concern because it may con- stitute a very important occupational risk to students, teachers, and other school workers. The source of the allergen is not known,

INDOOR BIOLOGIC EXPOSURES 127 but it is likely that the schools may have been infested with cock- roaches since there was evidence of dead cockroaches in the schools examined (Sarpong et al., 1997~. In kitchens, food and water sources may be important factors for the proliferation of cockroaches. The humidity in the home may be an important factor for increased cockroach allergen in infested homes. However, in a study evaluating allergen levels in schools, the presence of air conditioners, which may lower the humidity, did not affect the distribution of allergen levels (Sarpong et al., 1997~. Despite the evidence that cockroach aller- gen levels are higher in the kitchens of both asthmatic and nonasthmatic individuals, the concentration of cockroach aller- gen in the bedroom has been used as the surrogate marker of exposure (Eggleston et al., 1998; Rosenstreich et al., 1997; Sarpong and Han, 1999; Sarpong et al., 1996a, 1996b). Exposure to cockroach allergens are dependent on their aero- dynamic properties and the characteristics of the surface on which they are deposited. In an Ohio study, there was no difference be- tween dust mite allergen concentrations in low-pile carpet and smooth floors, but allergen levels were significantly higher in high-pile carpets (Arlian et al., 1982~. In a school study in the Bal- timore metropolitan area, there was no difference in cockroach allergen, Bla g I between low-pile carpet and uncarpeted floors (Sarpong et al., 1997~. However, kitchen areas are generally noncarpeted, and this may have distorted the level of allergen in uncarpeted compared to carpeted areas. Cockroach allergens may behave like the dust mite antigen; that is, they are carried on large particles that become airborne for short periods of time during active disturbance. High concentra- tions of cockroach allergen are found in the kitchen, compared to the living room or bedroom. However, some studies have re- ported similar levels of cockroach allergen in all these sites. Taken together, the cockroach allergen may be more relevant in the bed- room than the kitchen or the living room because of close contact with the pillow while in bed. Interestingly, about 20% of homes with no evidence of cockroach infestation have significant levels of cockroach allergen in settled dust (Pollart et al., l991b). Al- though the possibility of reporting bias cannot be excluded, it is

128 CLEARING THE AIR likely that cockroach allergen may be present in a home long after the infestation has been controlled. Cockroach hypersensitivity is a unique risk factor for asthma among the urban poor. Many case-control studies have docu- mented that cockroach allergen exposure and sensitization are significantly more common in patients with asthma living in ur- ban homes compared to those living in suburban homes (Bernton et al., 1972; Kang et al., 1993; Sarpong et al., 1996a). However, despite higher rates of exposure and sensitization among urban subjects, place of residence was not independently associated with cockroach exposure after correction for socioeconomic sta- tus; families of lower SES were likely to be exposed wherever they lived (Sarpong et al., 1996a). This agrees with the observations of Gelber and colleagues (1993), who used lack of health insurance as a marker of poverty and showed that this was a more impor- tant correlate of sensitization than urban residence per se as well as with others who have categorized patients on the basis of ac- cess to private medical care (Garcia et al., 1994~. A 1999 report from Morgantown, West Virginia, documented the role of sensiti- zation in infantile asthma (Wilson et al., l999~. These children who were at least 3 years of age with documented wheezing episodes demonstrated cockroach hypersensitivity at a rate of 25%. The rate of sensitivity in this predominantly white population was not related to low socioeconomic status. Evidence Regarding Asthma Exacerbation and Development Biologic Plausibility Bernton and colleagues (1972) reported that inhalation of cockroach extract could induce an immediate asthmatic reaction in cockroach-sensitive asthmatic subjects. Subsequently, con- trolled inhalation challenge confirmed the production of antigen- specific, acute and late bronchospasm in cockroach-sensitive asth- matics (Kang, 1976~. These antigen-induced asthmatic reactions were blocked by premedication with disodium cromoglycate. Challenge of these subjects with inhaled cockroach extract pro- duced a significant antigen-specific peripheral eosinophilia,

INDOOR BIOLOGIC EXPOSURES 129 which progressed to its peak 24-36 hours after exposure and of- ten more than doubled the baseline value. In animal studies there is evidence to suggest that cockroach antigen can induce lung eosinophilia (Campbell et al., 1998~. Previous data in guinea pigs have shown that aerosolized cockroach antigen can be utilized to induce airway inflammation and alter airway physiology (Kang et al., 1996~. The development of these models will allow the evaluation of mediators involved in both stages of cockroach al- lergen challenge, as well as the testing of specific therapeutic mo- dalities. Consistency There is now good evidence from epidemiologic studies in several parts of the world which demonstrates that the develop- ment of immediate sensitivity to cockroach allergens is associ- ated with asthma morbidity and that sensitization is related to the degree of allergen exposure (Eggleston et al., 1998; Rosenstreich et al., 1997; Sarpong and Han, 1999; Sarpong et al., 1996a; Sastre et al., 1996~. In the original description of cockroach sensitivity in 1967, Bernton and Brown (1967) found higher rates of sensitization among Puerto Ricans and African Americans than among Jews and Italians in New York City and believed that the difference was related to the improved economic conditions of the latter groups. Shulaner (1970) also found a relationship to pov- erty and overcrowding, and a report by Gelber and colleagues (1993) relates exposure and sensitization to urban housing, race, and poverty as indicated by lack of medical insurance. Strength of Association Sensitization, with production of specific IgE antibodies to cockroach, is a strong risk factor for acute severe asthma, espe- cially when sensitized persons are exposed to high concentration of allergen in their homes. R.P. Nelson and colleagues (1996) com- pared 29 children with acute asthma, ages 3-16 years, first seen in a Florida emergency department, to 25 control subjects. They found that sensitization to cockroach allergens was associated with acute asthma that required emergency treatment. Gelber and

130 CLEARING THE AIR colleagues (1993) and Call and colleagues (1992) showed that cockroach sensitization was a risk factor for acute asthma in pa- tients visiting emergency departments in Wilmington, Delaware, and Atlanta, Georgia, respectively. The multicenter National Co- operative Inner City Asthma Study (NCICAS) of the home envi- ronment of asthmatic children aged 4-9 years living in seven ma- jor urban areas and eight centers reported that cockroach allergen was the predominant indoor allergen in these homes. In the NCICAS, it was suggested that sensitization to cockroach aller- gen and exposure to high levels of cockroach allergen may ex- plain the asthma-related health problems of inner city children (Rosenstreich et al., 1997~. Dose-Response A dose-response relationship between cockroach allergen ex- posure and sensitization has been established in asthmatic chil- dren. Sarpong and colleagues (1996a) report that children who were exposed to Bla g I or Bla g II of 1 unit per gram (U/g) or higher demonstrated skin sensitivity to cockroach allergen. For Bla g I, all the children who were exposed to more than 10 U/g were sensitized to cockroach allergen. Similarly, 100% of the chil- dren who were exposed to more than 5 U/g of Bla g II were sensi- tized to cockroach allergen. Following this report, the NCICAS has suggested that cockroach allergen (Bla g I) exposure is related to sensitization in a dose-response manner (Eggleston et al., 1998~. Preliminary data from a population of pregnant women have sug- gested that total cockroach allergen (Bla g I and Bla g II) exposure and sensitization were related in a dose-response fashion (Sarpong and Han, 1999~. This relationship was demonstrated in both asthmatic and nonasthmatic controls. However, the dose of cockroach allergen concentration required to induce sensitization rates in the asthmatic population was at least a factor of ten lower than in the nonasthmatic population. A dose-response relation- ship was also demonstrated in the inner city asthma study be- tween cockroach allergen (Bla g I) exposure and morbidity due to asthma. Children who were exposed to more than 8 U/g of Bla g I were more likely to be hospitalized for asthma symptoms than those who were exposed to less. In a prospective study by Gold

INDOOR BIOLOGIC EXPOSURES 131 and colleagues (1999), infants who were born in homes with Bla g I levels greater than 2 U/g reported increased risk of wheezing by the age of 1 year. A study by Litonjua and colleagues available as a conference abstract (1998) evaluated the relationship between home allergen levels and the prevalence and incidence of asthma 16 months later among 215 children younger than 5 years old. The researchers found that, among the children with new onset of asthma, 7 (87.5%) lived in homes with high Bla g I or II levels while 1 (12.5%) lived in a home with low levels (p = .028~. Although it seems clear that exposure to cockroach allergen precedes disease, it has not been shown that sensitization consis- tently precedes disease. However, it is the combination of strong association, biological plausibility, dose-response, and provoca- tion experiments that creates the strength of the argument. Conclusions: Asthma Exacerbation and Development Cockroach antigen exposure can elicit a strong IgE immune response to induce sensitization. Sensitization to cockroach anti- gen has been linked to the season of birth (Sarpong and Karrison, 1998a), although this study does not necessarily support cock- roach antigen as a disease promoter, it at least gives some insight that exposure during the perinatal period may be critical. Because of the likely aerodynamic nature of the cockroach allergen, it is difficult to predict whether cockroach allergen per se is an initia- tor of asthmatic symptoms. However, data suggest that infants who are exposed to cockroach allergen are more likely to wheeze during infancy. Moreover, researchers have shown that cockroach sensitization is a risk factor for acute asthma in patients visiting emergency departments (Call et al., 1992; Gelber et al., 1993; R.P. Nelson et al., 1996~. In a retrospective study of asthmatic children in Chicago, it was suggested that children with combined sensiti- zation to cat, dog, dust mite, and cockroach allergens were at in- creased risk of having more severe asthma (Sarpong and Karrison, 1998b). Researchers have also found that there is an increased risk of sensitization to cockroach allergen in asthmatic children born in the winter months (Sarpong and Karrison, 1998a). Because the risk of respiratory syncytial virus (RSV) infection is high in win- ter months and RSV is also known to give rise to asthma-like

132 CLEARING THE AIR symptoms, others have even suggested that it may promote IgE sensitization. The level of cockroach allergen in settled dust may not demonstrate seasonality. It is therefore attractive to postulate an interaction between RSV bronchiolitis and cockroach allergen- induced sensitization. Thus, there may be virus-antigen interac- tion in initiating sensitization and possibly inducing asthma. Every individual is at risk for cockroach allergen exposure and sensitization. However sensitization risk is higher among the asthmatic population. Understanding the genetics of allergy and asthma, including understanding the phenotypes associated with cockroach allergy, may eventually prove useful in the understand- ing of gene-environment interaction in the development of asthma. There are no prospective data demonstrating the association of exposure to cockroach allergen with subsequent development of sensitization to cockroach allergen and asthma. However, a number of case-control studies demonstrate a link between cock- roach allergen exposure in sensitized individuals and asthma morbidity, as well as a dose-response relationship between cock- roach exposure and sensitization (Gerber et al., 1993; Rosenstreich et al., 1997; Sarpong et al., 1996a). In summary: · There is sufficient evidence of a causal relationship between cockroach allergen exposure and exacerbation of asthma in indi- viduals specifically sensitized to cockroaches. · There is limited or suggestive evidence of an association between cockroach allergen exposure and the development of asthma in preschool-aged children. · Inadequate or insufficient evidence exists to determine whether or not an association exists between cockroach allergen exposure and the development of asthma in older children and adults. Evidence Regarding Exposure Mitigation and Prevention In principle, control of exposure to cockroach allergens com- bines three approaches directed through an indoor environment:

INDOOR BIOLOGIC EXPOSURES 133 1. control of reservoirs of allergen in beds, carpets, furnish- ings, and clothing, which are the main sources of exposure; 2. control of the sources of new allergen (e.g., cockroach reinfestation); and 3. direct control of cockroach airborne allergens. There are several potential strategies for achieving these forms of control. These are noted below, along with some of their practical limitations. The bed is probably the most important site of cockroach al- lergen exposure because of the high level of exposure during sleep, the proximity of the subject to the source, the proportion of time spent indoors at this one site, and the large amounts of dust present in the bed. The relative success and simplicity of inter- ventions directed at this site make it a key target for allergen con- trol. Strategies known to reduce allergen exposure include encas- ing mattresses and pillows and laundering bedding in hot (>130°F, or 55°C) water. (This strategy is also effective for dust mite allergen.) However, there may be problems of subject com- pliance with regular washing of some items, such as blankets, even in the setting of a clinical trial. Carpets serve as a major reservoir of cockroach and many other indoor allergens and may serve as an additional primary source of allergen. Replacement of fitted carpets with smooth flooring has been shown to reduce dust mite allergen levels (Hayden et al., 1997) and is often recommended as a cockroach allergen management strategy. However, this intervention is sometimes unpopular and may be impractical in rental units, pub- lic housing, and other environments where occupants do not have control over floor coverings. Dry vacuum cleaners are useful for picking up excess dust and reducing reservoirs and allergen con- centration. Whether this achieves significant reductions in expo- sure remains to be demonstrated. Further, while wet vacuuming and steam cleaning may reduce allergen levels, they also may en- hance the environment for dust mites and other potential aller- gens if the surface does not dry properly or promptly. Extermination is a primary approach to control new sources.

134 CLEARING THE AIR The use of avermectin or hydramethyInon has, for example, been shown to reduce cockroach populations (Cochran, 1995, 1996~. Finally, housekeeping measures aimed at limiting open food- stuffs (using sealed containers, cleaning under refrigerators and stoves, washing dishes promptly after meals, and the like) and water sources (fixing leaking faucets and pipes; eliminating pet water dishes) are often suggested as part of an overall cockroach management strategy. As noted in Chapter 10, ventilation rates are not likely to have an appreciable direct impact on indoor concentrations of the larger particles associated with cockroach allergens. Attempts to eliminate cockroach allergen from the environ- ment have had limited success. A short-term effect of extermina- tion and cleaning on cockroach antigen levels was noted in a study conducted in an urban college dormitory (Sarpong et al., 1996b). Other studies have found that the number of cockroaches seen in a dwelling can be drastically reduced with roach insecti- cides such as hydramethyInon. However, the elimination of cock- roach sightings did not decrease the levels of Bla g I or Bla g II in vacuum dust over the next six months in single-family dwellings in North Carolina. No extra cleaning was performed in these homes (Williams et al., 1999~. Eggleston and colleagues (1999) evaluated the effect of professional pest control and home clean- ing on infestation and allergen concentrations in 13 inner-city homes with active infestations. Occupants were instructed on how to conduct follow-up cleaning and pest control measures, and study personnel monitored compliance over the eight months of the study. The researchers reported decreases in infestation and in allergen concentrations in settled dust. While mean allergen concentrations were reduced between 74°/O and 93°/O in various rooms of the homes, they still exceeded 20 U/g, a level associated with increased morbidity in the NCICAS study. In the NCICAS, integrated intervention to reduce cockroach allergen in homes was conducted. Despite a significant but short-lived reduction, cockroach allergen levels remained well above those previously found to be clinically significant (Gergen et al., 1999~. Insufficient evidence is available to determine whether or not reduction of cockroach allergen levels in the home reduces asthma severity in cockroach-sensitized asthmatics. Additional studies are needed

INDOOR BIOLOGIC EXPOSURES 135 to evaluate, within both multi-unit and single family housing, the effectiveness of various proposed methods of reducing cockroach allergen to levels below those associated with symptoms in asth- matic subjects. Until more effective methods of reduction of cock- roach allergen levels are developed, it may prove difficult to as- sess the effectiveness of cockroach allergen reduction programs in reducing asthma morbidity. Ongoing intervention studies may provide further data as to whether, for some subsets of sensitized asthmatics, moderate reductions in allergen levels or in allergen load influence asthma morbidity. Given the evidence that decreas- ing exposure to dust mites can help control the symptoms of dust mite-allergic asthmatics, it is prudent to identify patients who are allergic to cockroaches and educate them to reduce allergen expo- sure indoors. Conclusions: Exposure Mitigation and Prevention There is preliminary evidence to suggest that reduction in cockroach allergen in settled dust can be achieved with extermi- nation on a short-term basis; there are ongoing studies to evalu- ate whether long-term reduction of cockroach allergen in settled dust can be achieved with extermination. It appears that the use of abatement strategies combining extermination and cleaning can reduce cockroach allergen exposure. However, research has not to date demonstrated that these strategies result in an im- provement in symptoms or Jung function in cockroach-sensitized asthmatics. It is important to remember that the absence of evi- dence does not mean an absence of effect. The science regarding indoor environmental interventions, exposure limitation, and ef- fects on asthma outcomes is not nearly as well developed as that regarding the health effects of exposures. Given the evidence that decreasing exposure to dust mites can help control the symptoms of dust mite-allergic asthmatics, it is prudent to identify patients who are allergic to cockroaches and educate them to reduce aller- gen exposure indoors. In summary: · There is sufficient evidence of an association between the implementation of intensive cockroach allergen exposure mitiga

136 CLEARING THE AIR lion strategies and short-term reduction of cockroach allergen lev- els. Such strategies must include both removal of the allergen from reservoirs and control of sources (i.e., abatement and pre- vention of reinfestation) to be effective. · There is inadequate or insufficient information to deter- mine whether or not an association exists between cockroach re- duction interventions and improvement in symptoms or lung function in cockroach-sensitized asthmatics. Research Needs The preceding discussion suggests that there is still a need for fundamental research on cockroach allergens and asthma out- comes. Future research should focus on the efficacy of cockroach allergen reduction in the homes of asthmatic patients, the aerody- namic properties of cockroach allergen, the efficacy of cockroach immunotherapy, and B and T cell reactive epitopes. Further stud- ies are also needed to better elucidate any relationship between cockroach allergen exposure and asthma development; explore the interaction of cockroach allergen with infectious agents, irri- tants, and other allergens in causing asthma; and examine the in- fluences of genetics, socioeconomic status, and location on expo- sure and sensitization. HOUSE DUST MITES In 1967, Voorhorst and colleagues identified dust mites of the genus Dermatophagoides as the most important source of allergens in house dust (Voorhorst et al., 1969~. Using dust mite extracts, they demonstrated that sensitization was common among chil- dren with asthma and later developed techniques for growing mites. By 1974, extracts were widely available for skin testing, and mite sensitization became recognized in many countries. In- deed, mite sensitization was found to be strongly associated with asthma in all countries that had reported increases in asthma up to 1980 (i.e., the United Kingdom, Australia, New Zealand, la- pan) (Clarke and Aldons, 1979; Miyamoto et al., 1968; Smith et al., 1969~. Since the original research by Voorhurst and colleagues (1969),

INDOOR BIOLOGIC EXPOSURES 137 most of the studies on allergen avoidance have focused on mite- allergic patients. Studies have included moving children from Holland to Davos (Kerrebijn, 1970), keeping mite-allergic adults in special hospital rooms (Platts-Milis et al., 1982), and controlled trials of dust mite reduction in patients' rooms (Murray and Ferguson, 1983~. In each of these models, change in environment with reduction in exposure to mite allergen was associated with decreased symptoms of asthma and decreased bronchial hyper- reactivity (BHR) (Platts-Milis and de Weck, 1988~. Definition of the Agent and Means of Exposure Agent Definition and Biology Purification of indoor allergens is dependent on the quality of source materials. Before the discovery of dust mites, several un- successful attempts were made to purify allergens from dust ob- tained from carpets and bedding. Even when dust mite cultures became available, the early attempts at purification used only a small amount of material, ~40 g. The first purification of the ma- jor allergen Der p I was by classical immunochemistry from 400 g of "spent" culture (Chapman and Platts-Milis, 1980~. The spent culture was very rich in fecal material. Purification made it pos- sible to measure the quantity of allergen in extracts, in dust samples, and airborne (Tovey et al., 1981a). In addition, the puri- fied allergens have been used to study the immune response to allergens, as well as the properties of these proteins. Each of these approaches has relevance to the causes of lung symptoms. Epidemiologic evidence about the relationship between sen- sitization to indoor allergens and asthma is based on skin tests or on serum assays of IgE antibodies. However, the immune re- sponse to inhalant allergens also includes IgG antibodies, IgA an- tibodies, and T cells. These T cells in allergic individuals are pre- dominantly CD4+ cells of the TH2 type (Romagnani, 1992; Wierenga et al., 1990~. There are two important questions about this response: (1) Can differences in the immune response predict which skin test-positive individuals will develop asthma? Most of the evidence suggests that skin test-positive asymptomatic in- dividuals have very similar IgE antibodies and T cells (i.e., TH2)

138 CLEARING THE AIR compared to symptomatic patients. (2) What, if anything, is the immune response to mite allergens in skin test-negative individu- als? Here, the evidence is conflicting. Several groups are propos- ing that nonallergic individuals have made a TH1 response. This is supported by evidence that T cells in the cord blood of indi- viduals who are going to become allergic produce less interferon (IFN-~) in response to nonspecific stimuli, and also by evidence that it is possible to clone mite-specific TH1 T cells from the pe- ripheral blood of nonallergic individuals (Miles et al., 1996; Prescott et al., 1998; Warner et al., 1997; Wierenga et al., 1990~. On the other hand, most investigators have not found evidence of an immune response to mite proteins in nonallergic individuals. For example, most skin test-negative individuals have no detectable IgG antibodies to purified antigens, have poor or no in vitro T cell responses, and have no immediate or delayed skin responses. These results suggest (1) that the primary issue is who makes an IgE antibody response and (2) that most individuals who are nonallergic have not made any immune response to dust mites. Almost all of the well-defined allergens are proteins or glyco- proteins, and it is not surprising that many of them have amino acid sequence homology with known enzymes (Arruda et al., 1997; Stewart and Thompson, 1996~. In some cases these proteins have enzymatic activity that could play a role in their immunoge- nicity. For example, Der p I is a potent protease that has been shown to cleave CD23 and CD25 on the surface of lymphocytes in vitro (Hewitt et al., 1995; Schulz et al., 1998~. Furthermore, in animal experiments, it appears that the enzymatic activity of Der p I can influence immunogenicity (Comoy et al., 1998~. However, enzymatic activity is not a prerequisite for a protein to be a sig- nificant allergen, and there are considerable doubts about whether these enzymes are active in viva. Some of the allergens that have homology with enzymes have not been shown to have enzymatic activity. More significantly, it has not been established that any of these proteins have enzymatic activity under the conditions that occur in the human respiratory tract. In addition, many impor- tant allergens do not have homology with enzymes, including Der p II. It is certainly possible that enzymatic activity is relevant to the effects of some allergens; however, it is unlikely that this

INDOOR BIOLOGIC EXPOSURES 139 property plays an important role either in inducing IgE antibody . . responses or In causing symptoms. Factors Influencing Exposure The quantities of dust mite allergen that have been found in the air of houses range from <0.2 to 2100 ng/m3. Thus, accurate determination of the quantity and particle size of airborne aller- gen is dependent on immunoassays capable of accurately mea- suring quantities as small as 1 ng (Chapman et al., 1987; Luczynska et al., 1989; Sakaguchi et al., l990b). After it became clear that Der p I was concentrated in mite fecal particles, experi- ments were designed to answer whether the allergen became air- borne in this form. Using various approaches to air sampling, sev- eral conclusions became clear: (1) there is very little or no airborne mite allergen in an undisturbed room; (2) the allergen that be- comes airborne during disturbance is predominantly on particles 210 ,um; and (3) allergen falls rapidly after disturbance, in keep- ing with an aerodynamic size of ~10 ,um (Tovey et al., 1981b). In addition, allergen-containing particles identified using a micro- immunodiffusion technique have been shown to be mite fecal particles (Tovey et al., 1981a). These properties are strikingly dif- ferent from those of other indoor allergens (e.g., of cat or dog). However, the size of the particle is very similar to pollen grains. A small proportion (i.e., 5-15%) of the fecal particles that are breathed through the mouth would be expected to enter the lungs, and we assume that these particles are assumed to produce the inflammatory response (Bates et al., 1966; Svartengren et al., 1987~. At present the question of how allergen particles enter the lungs is not resolved, and this issue is of considerable importance since it may well define the distribution of "inflammation" and airway obstruction. Evidence Regarding Asthma Exacerbation and Development Association with Sensitization Many studies have shown an association between dust mite

140 CLEARING THE AIR sensitization and asthma (Platts-MilIs et al., 1997~. These studies include case-control studies in clinics, emergency rooms, and hos- pitals (Gerber et al., 1993~; population-based studies in schools (Peat et al., 1996; Squillace et al., 1997~; and prospective studies (Sears et al., 1989; Sporik et al., 1990~. The results consistently show odds ratios for asthma of 6 to >12 in individuals with dust mite sensitization. However, in all studies there are a significant number of individuals who are skin test positive but not symp- tomatic. Using multiple regression analysis, a prospective study in New Zealand demonstrated that mite sensitization was an in- dependent risk factor for asthma (Sears et al., 1989~. In the same analysis, pollen sensitization was not significantly associated with bronchial reactivity. This pattern has now been seen in many stud- ies and in several different countries (Table 5-1~. Furthermore, similar results have been found in areas where other indoor aller- gens are most important (Sporik et al., 1995~. That is, the relation- ship between sensitization and asthma is not for allergens in gen- eral but specifically for those allergens to which patients are exposed perennially in the environment. Although most of the perennial allergens are found indoors, the airborne fungus Alter- naria is also an important factor in areas of the world where expo- sure persists for many months of the year (Halonen et al., 1997~. In many of these studies the odds ratios for asthma for indi- viduals who are allergic to dust mites are very high (i.e., 26) (Table 5-1~. However there are several features of the prospective and case control studies that need to be emphasized. In all reported studies, there were a significant number of individuals who were skin test positive to dust mites (or other indoor allergens) but did not have symptoms. In many countries or areas, dust mites are the most important source of allergens. In the south, the south- east, and the west coast of the United States, as well as in New Zealand, Australia, Japan, and the UK, mites of the genus Dermatophagoides are dominant. By contrast in areas where dust mites do not thrive, other allergens are important (e.g., animal dander in the mountain states of the United States and in Scandinavia; or cockroach in the apartments of Chicago, Boston, New York, and Philadelphia). In addition the studies shown in Table 5-1 illustrate the fact that in most areas sensitization to out- door pollens is not significantly associated with asthma.

141 . _ . _ Cat Cal Q - C~ . _ Cal ~0 Q Cal . _ Cal to Q cn - E cn o o C~ C~ cn . _ tr C~ cn C~ o . _ C~ . _ .~ cn CD - m o o O C~ ~r U' ~7 ~7 o C~ . _ o C] Q > ~7 CD o C~ oO O ~ ~C~ ~C;3_ C~ -~ ~C~ lS C.) Cl ~ - U' ~ ~-~ ~ ~ - ° Cl, ~ Cl, ~ = -° ° Q ~ o ~ c~ c~ Q C/' C/' ~ ~C/' C~ I C/' · C~ U~ U . . . _ .. . . . U~U~ U ~U~ U iC O `. ~O (D C ~C~ tD C~ Al tD oo ~tD - - Q C~ U C~ C~ o _ - =7 c~ - c' c~ c' - c~ .~: ~ o o ~ ~ co ~ i ~ ~ c~ - - - ~ Q Q- o o c, Q o O Q ~° ~a' ~ ~ o ~ CD CD U' =7 CD C~ ( =7 ~ =7 C~ . ~ Z CD U' ClS C~ CD .~ ~ o =7 ~ C~ ~ .~ ~ ~ ~ o o C' CD o C' . _ X z ~7 . _ ~7 o . U' ~7 C~ . ~ o o >` C' 11 ~r llJ . ~ C' C~ o C' o C' 11 C~ CO Q CO 11 Q U' C~ . . o z o o . V Q

142 CLEARING THE AIR Sensitization to storage mites (Lepidoglyphus destructor, Tyrophagus putrescentiae, Acarus sire, and others) is an important risk factor in occupational asthma in agricultural settings (ATS, 1998~. These mites may also play a role in nonoccupational asthma from exposures in indoor environments in rural and perhaps other areas, although research characterizing exposure levels and responses is lacking. Association with Exposure Sampling. The measurement of allergen entering the lungs or even the measurement of dust mite allergen inhaled has proved very difficult. The essential problem is that the allergen is carried on particles that behave aerodynamically as if they are 10-25 ,um in diameter. This means that in still air, they remain airborne only for a few minutes. Thus, all measurements of airborne dust mite have required artificial disturbance, and it has not proved pos- sible to standardize disturbance (Sakaguchi et al., l990b; Tovey et al., 1981b). Because of this, other measurements of mite allergen have been used as an index of exposure. The accepted measure- ment is the concentration of Group 1 mite allergen, which is Der p I + Derf I in house dust expressed as micrograms per gram of dust. The immunoassays available use monoclonal antibodies in a two-site enzyme-linked immunosorbant assay (ELISA). The sig- nificance of this measurement has been endorsed by three inter- national workshops (Platts-MilIs et al., 1997~. While there are many different ways of obtaining samples, the most widely used technique is to sample reservoir dust from bedding, bedroom floors, and the living room with a hand-held vacuum cleaner. In areas of the world that are humid persistently or for at least eight months of the year, mites flourish inside houses, and it is not unusual to find 100 or even 500 mites per gram of dust. This translates to 2 or 10 ,ug of Group 1 allergen per gram of dust, respectively. In areas where most houses (i.e., at least 80%) have greater than 2 ,ug of mite allergen per gram of dust, sensitization to these allergens has consistently been found in a large propor- tion (45-85%) of children with asthma. In some studies the con- centration in individual houses has been shown to be an impor- tant predictor of sensitization (Peat et al., 1996; Sporik et al., l990~.

INDOOR BIOLOGIC EXPOSURES 143 In Germany, Kuehr and his colleagues demonstrated that the con- centration necessary to convert "non-atopic" children to positive skin tests to dust mite was ~60 ,ug/g. In the same study, children who already had a positive skin test to another allergen were at risk of becoming sensitized with exposures greater than 2 ,ug/g (Kuehr et al., 1994~. Taken together, the results strongly support a dose-response relationship between exposure and development of sensitization, with an approximate threshold of 2 ,ug/g. This threshold is a statistical concept representing the concentration at which exposure to mite allergen becomes a risk for sensitization. However, there is no sense in which the threshold for mite expo- sure is comparable to thresholds for airborne toxic gases: (1) high concentrations of mite allergen are not toxic to nonallergic indi- viduals; (2) concentrations below this level may cause symptoms for highly allergic or highly reactive asthmatics; and (3) the mea- surement is an index of exposure, which may not reveal high lev- els of exposure elsewhere in the house and has only an indirect relationship to exposure of the lungs. Experimental Evidence The earliest experiments on bronchial provocation confirmed that allergens inhaled into the lungs could produce an asthmatic response (Blackley, 1873~. With the development of the nebulizer it became much easier to challenge the lungs. The exposure repre- sents ~108 droplets with 0.1-10 ,ug Der p I per milliliter in a 2- minute challenge giving approximately 0.5 mL inhaled. In aller- gic individuals this challenge consistently gives rise to an immediate fall in FEVER and often produces a late response as well (Cockcroft et al., 1979~. Following a bronchial challenge, eosino- phils are recruited into the lungs in keeping with the events that are thought to occur in asthma. These changes can also be pro- duced by a segmental challenge, and in these experiments the eosinophils may persist in the lung for up to two weeks after chal- lenge (Shaver et al., 1997~. The lungs of patients with asthma are characterized by in- flammation and nonspecific BHR. In several different types of studies it has been shown that these changes can be reversed un- der conditions that include reduction of exposure to mite aller

144 CLEARING THE AIR gens. Mite allergic children moved from the Netherlands; Marseille, France; or Verona, Italy to sanatoriums in the Alps have consistently shown clinical improvement and decreased nonspe- cific BHR. These sanatoriums have many features that are differ- ent from the children's homes, including very low mite allergen levels (Platte-Mills and de Weck, 1988~. Piacentini and his col- leagues (1996) in Italy have also shown that the children who spend three months in the Dolomite Mountains have a decrease in eosinophils and eosinophil products in induced sputum in par- allel with decreased BHR. With adults, similar data have been obtained by moving patients from their homes in London to mite- free hospital rooms. Again, there were many other changes asso- ciated with the move to mite-free rooms (e.g., no animals, very low spore counts, increased physical activity as patients felt bet- ter). However, it is clear that BHR is reversible in many mite-al- lergic patients. Conclusions: Asthma Exacerbation and Development In mite-sensitive asthmatics, continual exposure to mite aller- gens is a contributing cause of exacerbations and chronic bron- chial hyperreactivity. The risk of disease, however, is not a func- tion of either the magnitude of the positive response to skin tests or the level of IgE antibody measured in serum. Therefore, in sum- mary: · There is sufficient evidence of a causal relationship between dust mite allergen exposure and exacerbations of asthma indi- viduals specifically sensitized to dust mites. Continual exposure to dust mite allergens is also a contributing cause of chronic bron- chial hyperreactivity. · There is sufficient evidence of a causal relationship between dust mite allergen exposure and the development of asthma in susceptible children. It is very difficult to prove a causal relationship between an agent that is present in the environment every day and a chronic disease. Certainly, none of the studies reported here taken on its own can be considered to prove that dust mite antigens cause

INDOOR BIOLOGIC EXPOSURES 145 asthma. However, when all of these studies are taken together the case becomes compelling. In 1965, Bradford Hill presented the argument that many different types of study should be consid- ered together to make a case for causality. He was addressing the specific case of a dust causing chronic lung disease (Hill, 1965~. When these criteria are applied to the role of dust mites in asthma, the case becomes very strong (Box 5-1~. It is the combination of association, biological plausibility, provocation experiments, and the results of avoidance that create the strength of the argument. Evidence Regarding Exposure Mitigation and Prevention Distribution of Mites in Houses Most houses contain at least three of the four requirements for mite growth: (1) there are multiple sites that can provide a nest for mites (i.e., carpets, sofas, mattresses, pillows, bedding); (2) the presence of humans guarantees an abundant food source in the form of skin scales; (3) in the latter half of the twentieth century, most houses are kept close to the optimal temperature for mite growth. For these reasons, the fourth requirement hu- midity is the major and often the only factor that determines whether a house has high concentrations of mites and mite aller- gen. In areas where humidity is high for most of the year, mites will grow well and may be found in almost any fabric including drapes and clothing, as well as traditional nests. By contrast, in truly dry areas (e.g., the mountain states [25,000 feet elevation]), and in Chicago in winter, mites cannot grow and houses are gen- erally devoid of mites (Rosenstreich et al., 1997; Sporik et al., 1995~. It is in areas where humidity is marginal or raised for a prolonged season that the structural features of a house may make a large difference in the concentration of mites (see Box 5-2~. The three biggest factors are the position of the living area within a building; the presence of carpeting on unventilated floors, which will both trap water leaks and lead to local condensation; and buildings whose ventilation rates are so low that humidity pro- duced by the occupants will accumulate even though the outdoor humidity is not high. The scale of these effects is well illustrated by the fact that a sample of houses and duplexes in Boston was

146 CLEARING THE AIR

INDOOR BIOLOGIC EXPOSURES 147 between two and three times more likely to have "high" (in ex- cess of 10 ,ug/g) dust mite allergen concentrations than apart- ments in the same city (Chew et al., 1998~. Strategies to Control Mite Growth According to Climate Humid Climates (i.e., eight months of the year or more with out- door air water content of 25 g/g). In these climates, controlling mite growth can be achieved only by air conditioning or reducing the nests for mite growth. Air conditioning to maintain indoor relative humidity below 50°/O requires tight housing and is expen- sive in terms of energy costs. Controlling or minimizing nests can be achieved by removing carpets; reducing furniture or using sur- faces such as leather; and avoiding unnecessary fabrics such as drapes, soft toys, and excess unenclosed clothing. In these areas of the country, the normal practices for bedding are effective (e.g., covering mattresses and pillows; regular hot [>130°F or 55°C] washing of all bedding).

148 CLEARING THE AIR Areas of Moderate or Seasonal Humidity. Many strategies can be helpful in controlling mite growth in these areas (see Box 5-3~. During dry seasons, simply opening windows for one hour per day will ensure removal of humidity from the house (Harving et al., 1994~. In addition, moving to an upper-level apartment can dramatically decrease mite exposure. The simple physical strate- gies normally advised are effective. In particular, the recommen- dations for bedding, carpets, and reducing furnishings can all help. Chemical treatment of a carpet using benzy! benzoate can be effective in controlling mite growth for a period of months (Hayden et al., 1992~. Critical issues include the nature of the fabrics used to cover mattresses and pillows and whether fabrics that breathe but block passage of mites can prevent colonization of mattresses, pillows, or furniture (Vaughan et al., 1999~. Dry Areas. Here, control of mites can be achieved simply by en- suring ventilation on a daily basis. In these areas, only very tight housing will allow accumulation of humidity within the build- ing. Thus, this is more likely to be a problem in cold areas where the temptation to control heat loss may prevent loss of water pro- duced by the inhabitants of a house. In the Mountain States and the Southwest, mite growth in houses is unusual. Conclusions: Exposure Mitigation and Prevention · There is sufficient evidence of an association between the use of a combination of the physical measures described above and a reduction in dust mite allergen levels. As noted, the most appropriate measures vary according to the type and characteris- tics of the indoor environment and the prevailing climate. · There is sufficient evidence of an association between the use of a combination of the physical measures described above and an improvement in symptoms or lung function in mite-sensi- tized asthmatics. These have been shown to be effective at reduc- ing symptoms in controlled trials and should be part of normal management of asthma in mite-allergic individuals. · There is inadequate or insufficient evidence to determine whether dust mite allergen mitigation strategies have an effect on

INDOOR BIOLOGIC EXPOSURES 149 asthma development. Because dust mites cannot survive in dry environments, living in such conditions does limit the opportu- nity for sensitization to mite allergens. Summary There are many reasons why dust mites of the genus Dermatophagoides have played such an important role in the evi- dence about the role of indoor allergens in asthma. These eight- legged arthropods are invisible to the eye and do not produce any odor that we can detect. Nonetheless, they grow extremely well in houses, requiring only humidity and a nest such as bedding, mattresses, or a carpet. As a result, a large proportion of the popu- lation is unknowingly exposed to high concentrations of these highly immunogenic proteins. In keeping with experimental re- sponses to repeated low-dose antigen, the immune response is characterized by IgE antibodies. The factors that influence the development of asthma in allergic individuals are not fully un- derstood. However, most of the allergens associated with asthma are perennial and are predominantly indoors. Indoor or peren- nial exposure characteristically produces symptoms that persist for much of the day and cannot be related to exposure. Indeed there is no characteristic history of symptoms that can be used to identify patients who are allergic to dust mites. It has been sug- gested that year-round exposure to dust mite allergens, which are inhaled as a "few" particles per day (i.e., ~100), may be the ideal way to establish chronic inflammation of the lungs and the asso- ciated bronchial hyperreactivity, without individuals' being aware that they are exposed. Given the evidence that decreasing exposure can help control the symptoms of an allergic patient, patients who are allergic should be identified and educated. How- ever, it is equally important to try to identify the factors that have led to an increase in the number of individuals who have asthma associated with immediate hypersensitivity to dust mites. Al- though this may in part reflect an increased number of allergic individuals, it appears that much of the rise is due to an increase in asthma among allergic individuals.

150 CLEARING THE AIR Research Needs Although more is known about dust mite allergen and its im- pact on asthma than most indoor exposures, research remains to be done. Particularly important is additional work on the effec- tiveness of specific environmental interventions in limiting asthma exacerbations and development (rather than simple mea- surement of allergen levels). Several studies now under way are evaluating whether aggressive allergen avoidance regimes have an effect on the subsequent development of asthma (Tovey and Marks, 1999~. The results of such studies will inform the question of whether primary prevention of dust mite-induced asthma is possible, although the burdensome nature of such interventions suggests they may be difficult to implement in many circum- stances. The development of methods to identify individuals, es- pecially infants, at high risk would provide the information needed to focus primary prevention activities. A major issue in this regard is whether sensitization can occur before birth. ENDOTOXINS Endotoxins are components of some bacterial cell walls. They are released when the bacteria die or when the cell wall is dam- aged. Endotoxins originally came to the attention of physicians because of their potential to cause fevers; more recently it has been established that they can cause airway inflammation and airflow obstruction at higher exposure levels. Research on endotoxin exposure and asthma is not as mature as that for many of the other exposures addressed in this chapter. Accordingly, this section focuses primarily on the background biologic information that underlies current research into endotoxin's role in the pathogenesis of asthma. Definition of Agent and Means of Exposure Agent Definition and Biology i' Endotoxin is the substance responsible for certain character- stic toxic effects of gram-negative bacteria. The toxic compound,

INDOOR BIOLOGIC EXPOSURES 151 lipopolysaccharide (LPS), is a structural component of the outer membrane of these bacteria, the polysaccharide portion of which represents the antigenic surface (Sonesson et al., 1994~. The lipid portion of the molecule (lipid A) is essential for its characteristic toxicity. The outer portion of the polysaccharide (O-specific anti- gen) varies among serotypes of a single bacterial species. The core polysaccharide and lipid A are conserved within species but vary in structure and composition between species and to a greater extent between genera. Variations in lipid A structure are associ- ated with variations in toxic potency over a wide range, and there is some evidence for qualitative variations in toxicity. Gram-nega- tive bacterial endotoxin should not be confused with Bacillus thuringensis delta endotoxin (Du et al., 1999; Potekhin et al., 1999), a protein from a gram-positive bacterium that has recently been genetically engineered into certain crops. Factors Influencing Exposure Because gram-negative bacteria are the natural surface flora for plants and are abundant in soil (Edmonds, 1979), endotoxin is ubiquitous in the outdoor environment, particularly during the growing season. High-leve! exposures to endotoxin occur when organic dust is generated in agriculture and related industries such as animal feed production and in cotton mills (Rylander and Morey, 1982~. Recirculating water systems can also be sources of endotoxin, and high level exposures have been recorded in in- dustries where machining fluids and recirculated wash water are used (Milton and Johnson, 1995; Walters et al., 1994~. Humidifica- tion systems are also potentially abundant reservoirs for gram- negative bacteria and thus for endotoxin (Flaherty et al., 1984; Rylander et al., 1978~. Therefore, even home humidifiers can gen- erate high levels of endotoxin exposure (Tyndall et al., 1995~. Measurement of endotoxin exposure in homes is usually per- formed with a Limulus amebocyte lysate assay because this bioas- say correlates well with endotoxin measured in the rabbit pyro- gen assay. However, Limulus-based assays are prone to interference (Milton et al., 1997) and likely underestimate expo- sures in organic dusts, including house dust, compared to chemi- cal assay (Saraf et al., 1999~. Furthermore, endotoxin in organic

152 CLEARING THE AIR dust contains a wide variety of lipid A structures, not all of which are equally reactive in the Limulus-based assay (Saraf et al., 1997~. These compounds may not stimulate significant production of the inflammatory cytokine interieukin-1 (IL-1), but may be able to stimulate other effects such as reversing tolerance to certain anti- gens (Baker et al., 1990, 1992) that may be important in directing immune responses. Endotoxin exposures in homes have not been extensively studied. A doctoral thesis described the association of airborne endotoxin levels with home characteristics recorded on question- naires (Park, 1999~. The strongest predictors of increased endo- toxin in living room air were the presence of a dog, signs of mice, a concrete floor in the living room, and mold or mildew in the bedroom during the past year. Dehumidifiers were associated with reduced airborne endotoxin. However, airborne endotoxin levels in homes were similar to those in outdoor air. The particle size distribution of endotoxin in ambient and indoor air is not known. Inhaling typical home air, containing one endotoxin unit (KU) per cubic meter, for 24 hours (a total daily dose of approxi- mately 1 EU in a small child and 10 EU in an adult) may be the source of the low levels of endotoxin present in bronchoalveolar ravage fluid (0.1 ng/mI) (Dubin et al., 1996~. In addition to endotoxin exposure from environmental sources, endogenous endotoxin exposure may arise from infec- tion. It has been suggested that a strong association between peri- odontal disease and premature birth may be caused by endotoxin exposure from gram-negative bacteria present in subclinical in- fections (Damare et al., 1997~. While periodontal disease is not likely a source of endotoxin exposure in children, other infectious agents common in children, such as Hemophilus sp., may be im- portant sources of exposure, as may commensal conforms. Evidence Regarding Asthma Exacerbation and Development Biologic Evidence It has long been recognized that endotoxin is a potent stimu- lus for macrophage production of (TNFoc), IL-1, and a variety of

INDOOR BIOLOGIC EXPOSURES 153 other cytokines; arachidonic and linoleic acid metabolites, and reactive oxygen species (Rietsche] and Brade, 1992~. The recep- tors responsible for binding endotoxin and triggering responses are still in the process of being described. The pathway for endo- toxin binding and cell activation includes an opsonin, LPS bind- ing protein (LBP), which presents LPS to CD14 (Wright et al., 1990~. After binding LPS-LBP complexes, membrane-bound CD14, attached to myeloid cells via a glycosy~phosphatidyI-inosi- to! (GPI) anchor, activates myeloid cells and soluble CD14 acti- vates nonmyeloid (endothelial or epithelial) cells (Pugin et al., 1993~. The signal is apparently transduced via the human toll-like receptors TLR4 and TLR2 in myeloid and nonmyeloid cells, re- spectively (Chow et al., 1999; Kirschning et al., 1998; Ulevitch, 1999; Wright, 1999; Yang et al., 1998~. There may also be a role in signaling for heterotrimeric G proteins associated with the GPI anchors for CD14 (Solomon et al., 1998~. CD14 and the toll-like receptors are pattern receptors and are also involved in the recognition of peptidoglycan and lipoteichoic acid, and other microbial products (Cleveland et al., 1996; Dziarski et al., 1998; Schwandner et al., 1999~. However, opson- ization by LBP appears to confer approximately a hundredfold greater sensitivity to LPS compared with peptidoglycan or lipoteichoic acid (Kirschning et al., 1998; Schwandner et al., 1999; Sugawara et al., 1999~. The monocyte lineage, including macrophages and dendritic celIs, has abundant membrane-bound CD14 and exhibits sensi- tive and prolific responses to endotoxin. Cytokines produced in- clude IL-1, 6, 8, 10, 12; TNFoc, INF-,B, TGF-,8; MIP-loc; CSF-1; and GM-CSF. Expression of MHC-II and B7.1 are also upregulated (Me~zhitov et al., 1997; Santiago-Schwarz et al., 1989; Weatherstone and Rich, 1989~. LPS also is a B cell mitogen and promotes isotype switching from IgM to IgE in the presence of IL- 4 (Snapper et al., 1991~. Thus, endotoxin not only serves as a po- tent stimulus to innate immune responses but also serves as a stimulus and bridge to cognitive immunity. The gene for CD14 maps to chromosome 5q31.1, a candidate region for loci regulating IgE expression. Baldini and colleagues (1999) observed that a C to T transposition in the promoter region of CD14 (bp-159) was associated, in TT homozygotes, with sig

154 CLEARING THE AIR nificantly higher sCD14 levels. Among white children with posi- tive skin tests to local antigens, TT homozygotes had lower total IgE levels. Among those with any positive skin test, the TT ho- mozygotes had significantly fewer positive tests. Much experimentation suggests that the net effect of endo- toxin exposure is to promote THl-type immune responses such as those typically seen in bacterial infections (Baldini et al., 1999; Fearon and Locksley, 1996) (see also Chapter 4~. However, endo- toxin is noted for the peculiar patterns of response to repeated exposures known as the Schwartzman phenomenon and endo- toxin tolerance, for which cellular mechanisms have been de- scribed (Berg et al., 1995; Bohuslav et al., 1998~. It is clear from mechanistic studies of repeated exposure that endotoxin stimula- tion of production of IL-10, which suppressed the TH1 response, is at least as important a phenomenon as stimulation of IL-12, which enhances this response. Furthermore, much of the data in- dicating that endotoxin promotes TH1 responses, except Baldini et al. (1999), come from single-exposure in vitro studies. Human data on TH1 /TH2 responses to endotoxin and studies of repeated experimental exposure in viva are sparse. Two studies suggest that under at least certain circumstances, endotoxin promotes TH2 immune responses. A study of human volunteers injected with 4 ng/kg of endotoxin (Zimmer et al., 1996) demonstrated that IL-12 levels were unchanged following injection but IL-10 levels increased, suggesting that systemic endotoxin exposure promoted a TH2 immune response. A mouse mode] for periodon- tal disease, produced by repeatedly injecting LPS at 48-hour in- tervals, found that after the first several injections, gingival T cells were primarily of the TH1 subgroup, based on in situ hybridiza- tion. However, after 10 injections, T cell subgroups changed from a TH1 to a TH2 predominance (Iwasaki et al., 1998~. Thus, chronic exposure may produce qualitatively different responses from a single acute exposure. The route of exposure as well as dose rate may be important factors, so that the net effect on development of immune responses following chronic low-level, airborne endo- toxin exposure may be difficult to predict.

INDOOR BIOLOGIC EXPOSURES Epidemiologic Evidence 155 Several laboratory and cross-sectional epidemiologic studies suggest that asthmatics may be sensitive to the proinflammatory effects of endotoxin at lower levels of exposure than non- asthmatics. After endotoxin exposure, increased bronchial respon- siveness to histamine challenge was observed among asthmatics, but not among nonasthmatic adults (Miche] et al., 1989~. In a cross-sectional study of asthmatic adults, the endotoxin content of house dust was associated with increased asthma severity (Miche! et al., 1996~. High levels of endotoxin in agriculture and industry are asso- ciated with both acute and chronic effects on respiratory symp- toms and Jung function, regardless of preexisting Jung disease. The increasing body of epidemiologic evidence for respiratory ef- fects of occupational exposure to endotoxin at 10 or more times the ambient outdoor levels has been reviewed by Douwes and Heederik (1997) and Milton (1999~. One occupational study sug- gested that the chronic airways disease associated with daily ex- posure to high levels of endotoxin is characterized by an increased peak flow amplitude and thus may represent a form of asthma (Milton et al., 1996~. However, except for the use of contaminated humidifiers, most homes have airborne endotoxin levels similar to those found in ambient urban and suburban air. Thus, it is not clear what effect if any exposure at these levels can have on per- sons who do not already possess inflamed airways with increased LOP and sCD14. If endotoxin influences the development of the asthmatic in- flammatory response, it is unclear whether the influence will be as a risk factor or a protective factor; basic laboratory research (see above) suggests that either is possible. Both German and Swiss studies suggest associations between living on a farm and decreased risk of asthma (Braun-Fahriander, 1999; von Mutius, 1994~. The authors suggest that exposure to endotoxin early in life may be protective against asthma development and that there may be a gene-by-environment interaction in creating tolerance. At this time there are no data on home endotoxin exposure and the risk of asthma development in children.

156 CLEARING THE AIR Conclusions: Asthma Exacerbation and Development Endotoxin is associated with occupational lung disease among workers exposed to high levels. Although endotoxin is suspected at lower levels to be a trigger for asthma, and may be either a disease promoter or a beneficial exposure depending on time course, dose, and route of exposure, there are too few data on low-level exposures to draw any firm conclusions at this time. Therefore, the committee concludes: · There is inadequate or insufficient information to deter- mine whether or not an association exists between low-level in- door endotoxin exposure and asthma exacerbation or develop- ment. Evidence Regarding Exposure Mitigation and Prevention There are few data on sources in the home environment and none on the effects of interventions aimed at altering domestic endotoxin exposure. However, experimental data do exist to dem- onstrate that coo! mist (spinning disk and ultrasonic) humidifiers can emit very high levels of endotoxin aerosol, that filtration of the mist is not effective, and that warm mist or steam humidifiers do not emit aerosols of endotoxin or other pathogenic organisms (Tyndall et al., 1995~. Attempts to prevent microbial contamina- tion of coo] mist humidifiers with antifouling agents have not been successful to date (Burge et al., 1980~. Thus, prevention of high-level endotoxin exposure from humidifiers would appear to be best accomplished by elimination of coo! mist units. However, the impact of these units on the severity and occurrence of asthma is not known. In summary: · There is inadequate or insufficient evidence to determine whether or not an association exists between endotoxin interven- tions and reduction of endotoxin levels. Conclusions: Exposure Mitigation and Prevention No general conclusions about the means of altering exposure to low levels of endotoxin can be drawn at the present time. How

INDOOR BIOLOGIC EXPOSURES 157 ever, avoiding the use of coo] mist humidifiers would appear to be a simple and effective means of eliminating the risk of high- leve! exposure to endotoxin at home as well as to organisms asso- ciated with hypersensitivity pneumonitis (Burke et al., 1977; Ganier et al., 1980; Seabury et al., 1976; Suda et al., 1995~. Research Needs Given the significant body of data on the exquisite sensitivity of the innate immune system to small quantities of endotoxin, the hypotheses that domestic endotoxin exposure may influence the development of the immature immune system or affect the sever- ity of asthma warrant further investigation. This review suggests several avenues of research directed at understanding the role of endotoxin exposure and endotoxin sus- ceptibility in the pathogenesis of asthma. These include studies of gene-environment interactions and the risk of developing atopy or asthma, preferably with prospective assessment of endotoxin exposure from birth, improved endotoxin exposure assessment across populations likely to have significant differences in expo- sure, and studies of endotoxin exposure and asthma severity. Gene-environment interactions between the CD14 polymor- phism and endotoxin exposure should take into account that CD14 is a pattern receptor and thus not specific for LPS-LBP com- plexes. Thus, future studies should include an assessment of ex- posure to other bacterial products that stimulate innate immunity via CD14 such as peptidoglycan. Prospective studies will be re- quired to determine whether endotoxin exposure early in life plays a role in determining the direction of immune system de- velopment. Studies that can compare populations with possibly larger variations in exposure to endotoxin and other components of organic dusts than can be found within an urban or suburban area would likely have increased power to detect the effects of endotoxin exposure. Because the CD14 polymorphism is associ- ated with atopy, a focus on specific and nonspecific IgE and TH phenotypes will likely be the most important variables for these studies. Given that the Limulus bioassay has limitations and that "un- usual" lipid A structures dominate the composition of house and

158 CLEARING THE AIR other organic dusts, additional exposure assessment methods that can detect the range of environmental LPS should be employed along with Limulus assays in future studies. The possibility that endogenous sources of endotoxin exposure may be important in modulating the level of tolerance to environmental exposure (or vice versa) should also be examined. FUNGI Definition of Agent and Means of Exposure Introduction There are more than 1,000,000 species of fungi, 200 different types to which people are routinely exposed. Exposure occurs universally, both outdoors and indoors, and is impossible to avoid completely. Fungal exposure (even to one type of fungus) is com- plex with respect to disease agents and usually includes allergens, irritants, toxins, and sometimes potentially infectious units. These factors have led to confusion, poorly constructed stud- ies on the role of fungi especially in the area of allergic disease, inconclusive results, and avoidance of the field by the best inves- tigators. However, clearly and unequivocally, fungal exposure does cause allergic, toxic, and infectious disease, and it remains only to document the extent of the problem, factors leading to disease, and approaches for control. Fungi may play a role in asthma in several ways. The most obvious of these is via fungal allergen exposure that leads to sen- sitization, perhaps leads to the development of asthma, and exac- erbates symptoms in sensitized people. Fungi also contain and release irritants that may enhance the potential for sensitization, potentiate allergen-induced symptoms, and (possibly) exacerbate asthma in nonsensitized people. Finally, fungal toxins could play a role in modulating the immune response and may cause direct lung damage leading to pulmonary diseases other than asthma. Definition of Agents Nature of Fungi Fungi are eukaryotic organisms characterized

INDOOR BIOLOGIC EXPOSURES 159 primarily by their filamentous morphology and saprobic life- style. Fungal cells are bounded by rigid cell walls that are usually composed of chitin fibrils embedded in a matrix of (1~3) ,8-D- glucans and/or mannans. Cell walls may be coated externally with waxes or hydrophilic extracellular polysaccharides that carry various levels of antigenic specificity. To digest food, fungi excrete enzymes into the environment initially as probes to evalu- ate food availability, then to digest complex carbon compounds. These enzymes are some of the major fungal allergens. While pro- cessing organic material, the fungi produce many ancillary me- tabolites, some of which are highly toxic (antibiotics, mycotox- ins). These compounds may accumulate in the fungal body, in spores, and in the environment. The primary mode of fungal re- production is by airborne spores, which form a major fraction of both the outdoor and the indoor large-particle aerosol. Fungi also colonize manmade environments, releasing both spores and metabolic materials. Fungal Allergens Fungi produce an enormous array of com- pounds that are potentially allergenic. Each fungus produces many different allergens of a range of potency. Table 5-2 lists the major defined allergens isolated from fungi. Others have been identified, but they are generally "minor" (i.e., few patients react to them). Many others remain to be identified. Sources and Variability Fungal allergen production varies by isolate (strain), species, and genera (Burge et al., 1989~. Different allergen amounts and profiles are contained within spores, myce- lium, and culture medium (Cruz et al., 1997; Fade! et al., 1992~. In addition, substrate (growth) medium strongly influences the amount and patterns of allergen production. For example, the al- lergen content of Alternaria spores produced on ceiling tiles prob- ably differs from that of spores produced on dead grass. Fungi release proteases during germination and growth, and fungal ex- tracts contain sufficient protease to denature other allergens in mixtures. This has been demonstrated clearly for Alternaria ex- tracts (Nelson HS et al., 1996~. Cross-Reactivity Patterns Patterns of cross-reactivity among

160 TABLE 5-2 Major Definecl Allergens Isolated from Fung CLEARING THE AIR Major Nature of Fungus Allergen Allergents) Reference Aspergillus fumigates Asp f 1 18 kD; mitogillin Arruda et al., 1990 Asp t l l l Peroxisomal Crameri, 1998 membrane protein Aspergillus oryzae Alkaline serine Shen et al., 1998 protease Alternariaaltemata A/tal Yungingeretal., 1980 Aft a 11 Sanchez and Bush, 1994 Cladosporium herbarum Cla h 1 13-kD glycoprotein Aukrust and Borch, 1979 Penicillium citrinum 33-kD protein Shen et al., 1997 Penicillium chrysogenum 68-kD protein Shen et al., 1995 Trichophyton tonsurans Tri t 1 30-kD protein Deuell et al., 1991 Malassezia femur Mat f 1 36-kD protein Schmidt et al., 1997 Psilocybecubensis Psicll 23-kD protein; Horneretal., 1995 cyclophilin fungal allergens have been examined using in vitro methods in which inhibition of heterologous assays is assumed to indicate cross-reactivity (although nonspecific assay inhibition must be ruled out). RAST is the most often used assay (O'Nei! et al., 1990), although allergens derived from many genera of fungi have also been shown to cross-react using IgE immunoblot techniques (Verma et al., 1995~. In addition, cross-reactivity has also been in- ferred from patterns of skin reactivity to fungal extracts. Although this latter case could result from cross-reactivity, it could also hap- pen with multiple exposures leading to (separate) multiple sensi- tizations (O'Nei! et al., 1990~. Unfortunately, data on fungal aller- gen cross-reactivity are inconsistent and appear to depend on the specific strains used and on methods of allergen extraction. Other Fungal Agents Exposure to some kinds of fungal spores induces inflammatory changes in the lung independent of allergy or sensitization (Rag, 1999; Shahan et al., 1998~. MIP-2, lactase de- hydrogenase, and myeloperoxidase are released in response to fungal exposure, and blood cell patterns change. These effects are

INDOOR BIOLOGIC EXPOSURES 161 dependent on the type of fungus and on the concentration of spores administered. The role these processes might play in the development or exacerbation of asthma remains unknown. Glucans Fungal cell walls are composed of acety~glucosamine polymer (chitin) fibrils embedded in a matrix of glucose poly- mers (~1~3) ,8-D-glucans). The glucans maybe chemically bound to the chitin or may form a soluble matrix (Sietsma and Wessels, 1981~. Potent T cell adjuvants, the (1~3) ,8-D-glucans have been investigated as antitumor agents (Kiho et al., 1991; Kitamura et al., 1994; Kraus and Franz, l991~. They increase resistance to gram- negative bacterial infection by stimulating macrophages and af- fecting the release of TNFoc mediated by endotoxin (Adachi et al., 1994a, 1994b; Brattg~erd et al., 1994; Saito et al., 1992; Sakurai et al., 1994; Zhang and Petty, 1994~. Soluble glucans have an effect in the lung similar to that of endotoxin (Fogelmark et al., 1994~. Glucans may be involved in the development of fungal-induced hypersensitivity pneumonitis by affecting the inflammation-regu- lating capacity of airway macrophages. They also probably play a role in organic dust toxic syndrome in workers exposed to dust that includes high concentrations of fungal spores. The possible role of glucans in the development and/or exacerbation of asthma has not been studied. Mycotoxins Most mycotoxins are cytotoxic and interfere with protein synthesis, causing cell lysis and death. Some mycotoxins are potent carcinogens, and a few affect cell division (cytochala- sins) or are estrogenic (zearalenone) or vasoactive (ergot alka- loids). Some cross the blood-brain barrier and affect the central nervous system. Some mycotoxins selectively kill macrophages (Gerberick et al., 1984; lakab et al., 1994; Nikulin et al., 1996, 1997; Richard and Thurston, 1975; Sorenson and Simpson, 1986; Sorenson et al., 1985, 1986~. A toxin produced by Aspergillus fumigatus inhibits macrophage functioning and may play a role in allergic bronchopulmonary aspergillosis (ABPA) by facilitating colonization of the airways of asthmatics (Amitani et al., 1995; Murayama et al., 1996~. Gliotoxin, another A. fumigatus toxin, causes fragmentation of DNA, especially in thymocytes, and may facilitate tissue invasion leading to aspergillosis in immunosup

162 CLEARING THE AIR pressed patients (Sutton et al., 1996; Waring and Beaver, 1996; Waring et al., 1997~. Some fungal components directly cause the release of mediators of inflammation, including cytokines, reac- tive oxygen metabolites, and chemotactic factors (Shahan et al., 1998~. The role of mycotoxins in the development and exacerba- tion of asthma has not been studied. Means of Exposure Measurement of Fungal Exposure Visual observation is the most frequently used approach to estimate potential for fungal exposure, with observational data often obtained from occupant questionnaires (e.g., Brunekreef et al., 1989~. Observational data are limited by the fact that fungi are microscopic and are not vis- ible until growth is extensive. Culture of air or dust samples is also often used indoors (e.g., ACGIH, 1999; Burge and Solomon, 1987; Su et al., 1992; Verhoeff et al., 1992~. Since the presence of allergens does not always depend on culturability, this type of measure is likely to underestimate actual allergen exposure, as well as (possibly) confounding results with high levels of nonallergenic types. Microscopic identification and counting of spores from air samples (e.g., Delfino et al., 1997) represent the usual approach for outdoor samples and constitute the only cur- rently available method that assesses nonculturable spores. The method is limited by the relatively few species that can be identi- fied and the time commitment required for analysis. Although a few assays are available, no epidemiological studies have emerged that use fungal allergen measures of exposure. Other methods have been proposed that evaluate total fungal biomass (ergosterol, glucan assays) or that identify the presence of specific fungi (PCR techniques). None of these has been used in studies of asthma. Factors Influencing Exposure Nature of the Particles Spore walls may be hydrophobic with a waxy outer coat, or hydrophilic with an outer surface of water- soluble polysaccharides. Most fungi release single spores that

INDOOR BIOLOGIC EXPOSURES 163 range in size from 2 to 10,um. Some spores can exceed 100,um in length, although aerodynamic diameters are usually much smaller. Some spores are released as chains or clumps. CIadospo- rium spores are frequently encountered as large branching chains, as well as individual spores, so that particle sizes of CIadosporium units can range from near 1 ,um to many hundreds of microme- ters in diameter. However, air sampling with particle size-sepa- rating cascade impactors indicates that most fungal spores are <5 ,um in aerodynamic diameter. Fungal hyphae also become air- borne with disturbances such as high winds. Studies are not avail- able that document the natural presence (or absence) of fungal allergens on particles other than intact fungal spores. Studies of Fungal Aerosol Release Fungal aerosols may be pro- duced through intrinsic spore discharge mechanisms or mechani- cal agitation (Ingold, 1971~. Most indoor release relies on active disturbance. Few studies document actual types and intensities of mechanical disturbance necessary to release spores from sur- face growth. At least for some types, strong agitation or even di- rect abrasion is necessary (e.g., Stachybotrys chartarum), whereas for others, air movement such as that produced by a fan may be sufficient (Madelin and Johnson, 1992~. Outdoor Exposure to Fungi Many studies document the almost continuous presence of fungal spores in outdoor air, and the factors affecting prevalence for different types (e.g., AAAAI, 1998; Cross, 1997; Li and Kendrick, 1995; Munuera et al., 1998; Takahashi,1997~. Fungal spores are always present in outdoor air, although levels can be very low during periods of snow cover (Cross, 1997~. Patterns of prevalence depend on seasonal and cli- matic factors, geography, and to some extent, human activity, es- pecially that associated with agriculture. Because fungi are con- tinuously present outdoors, often in concentrations far higher than those indoors, it is difficult to rule out outdoor exposure as the primary determinant of sensitization and symptoms. It is also difficult to document the presence of indoor growth using air sampling.

164 How Does the Indoor Environment Affect or Influence Exposure7 CLEARING THE AIR Penetration of Outdoor Aerosols Fungal particles probably penetrate indoor environments following the same physical prin- ciples as other types of particles. Published studies that compare indoor-outdoor relationships for fungi have not clearly addressed the relative contribution of the outdoor aerosol. Although out- door fungal spores readily enter through open windows, few pen- etrate into closed environments (e.g., buildings and automobiles) (Muilenberg et al., 1991; Solomon et al., 1980~. Indoor Sources Fungi are always present in dust and on sur- faces. Fungal growth occurs only in the presence of moisture. Food materials and temperature affect the amount of water re- quired, as does the strain of fungus. Several reports present data on laboratory conditions that lead to fungal growth on building materials (Chang et al., 1996; Grant et al., 1989~. With relatively concentrated inocula, some xerophilic fungi increase at relatively low substrate water activities. However, extensive growth was reported only at humidities near 100%, and most fungi require very wet conditions (near saturation), lasting for many days, to extensively colonize an environment. Human habits may affect the numbers and types of active fungal sources in buildings. Poorly maintained water-based appliances (e.g., humidifiers, va- porizers) harbor and release fungi. Wood stored indoors contains many fungi, although exposure from this source has not been studied. Moldy food is an obvious source, and indoor recoveries from air may be dominated by these small sources if recently dis- turbed. Evidence Regarding Asthma Exacerbation and Development Sensitization to Fungal Allergens Exposure to fungi clearly plays a role in asthma. Good-qual- ity studies have been reported that document the sensitizing po- tential of fungal allergens and relate fungal sensitization to the

INDOOR BIOLOGIC EXPOSURES 165 existence of asthma. Challenge studies have documented asth- matic responses in sensitized patients, and several studies have begun to make the connection between natural exposure and symptom development. Prevalence of Sensitization It has been estimated that about 6-10% of the population and 15-50% of atopics are sensitized to fungal allergens (Table 5-3~. In studies where Alternaria extracts were used alone (i.e., not in a mixture), overall rates for allergy patients range from 3 to 36% and for asthmatics, 7 to 39%. Skin test surveys most often focus on broad panels of aller- gens, with fungi included either as a single representative extract (usually Alternaria), two or three extracts, or mixtures of several different fungi. However, Galant et al. (1998), in a survey of Cali- fornia allergy patients, revealed that nine different fungal extracts were necessary to detect 90°/O of mold allergy patients. Interest- ingly, most studies that focus specifically on fungal sensitivity also use only a few extracts, with Alternaria again being the domi- nant type. One study (Szantho et al., 1992) suggests that the prevalence of sensitivity to fungi is increasing and attributes the increase to an increase in concentrations of outdoor fungi due to growth on pollution-weakened plants. However, no monitoring data support this hypothesis. Fungal skin sensitivity rates in- crease with age (Ere] et al., 1998~. Production of IgG antibodies as a result of allergen exposure may block the skin test response even in patients clearly experiencing symptoms with exposure (Witteman et al., 1996~. Fungal allergens can produce a strong IgG response, possibly making reported incidences of skin reac- tivity underestimates. Fungal Sensitization and Asthma In a population of adults in Sweden, sensitivity to CIadospo- rium or Alternaria (but not dust mites) was associated with a cur- rent asthma odds ratio (OR) of 3.4 (1.4-8.5) (Norback et al., 1999~. In an Arizona population, responses to A. alternate were the most frequent among asthmatic children, and a positive Alternaria skin

166 TABLE 5-3 immediate Skin Reactivity to Fung CLEARING THE AIR Geography PopulationNFungi Israel Randomadults395Mold (A' Alters IsleofWight Allchildrenborn1989-1990981Alternar Saudi Arabia Atopic Americans1,159Alternar California Allergy patients141Molds Spain 7-to68-year-oldallergypatients171A.altem Switzerland <12-year-oldallergyoutpatients1,207Boletus, Midwest Allergicrhinitis referrals100Mold (A Helmi Asper Curve Turkey Allergy patients614A.fumis Denmark Allergy patients292Ac hredrb~ Italy Allergic children253Alternar New Orleans Adult allergy patients150Basidior clamor Alters "Fungi Italy Italians with respiratory symptoms2,942Alternar UnitedStates Asthmaticinnercitychildren500Alternar Taiwan Asthmatic children(5-15years)195Alternar Hungary Extrinsicasthmaticchildren700Mold (A Asper Japan Asthmatic children(3-18years)94Aspergil A. fun, A. alto Thailand Asthmatic children100Alternar clamor Penici~ Asper

INDOOR BIOLOGIC EXPOSURES 167 Fungi Prevalence (%) Author Mold (Aspergillus, Penicillium, Alternaria, CladosporiumJ Alternaria, Cladosporium Alternaria Molds A. alternate Boletus, Coprinus, Pleurotus Mold (Alternaria, Helm in th osporium, Aspergillus, Candida, Curvularia) A. fumigatus A. iridis C. herbarum Alternaria Basidiomycetes Cladosporium, Alternaria, "Fungi" Alternaria Alternaria, Penicillium Alternaria Mold (Alternaria, Phoma betae, Aspergillus, Cladosporium) 10.9 6 36 11-22 14.5 44 26 3.1 0.7 9.48 only: 3.55 Angrisano et al., 1987 32 Lehrer et al., 1986 6 13 58 1 0.4-29.3 39 (combined: 41) 24.4 Wang and Chen, 1992 1977: 10 Szantho et al., 1992 1985: 30.4 1987-1988: 38.5 Katz et al., 1999 Tariq et al., 1996 Suliaman et al., 1997 Galant et al., 1998 Sastre et al., 1996 Helbling et al., 1998 Corey et al., 1997 Guneser et al., 1994 Frost, 1 988 Corsico et al., 1998 Eggleston et al., 1998 Aspergillus (restrictusJ 8.5 Sakamoto et al., 1990 A. fumigatus 8.5 A. alternate 16.0 Alternaria 7 Kongpanichkul et al., 1997 Cladosporium 7 Penicillium 3 Aspergillus 2

168 CLEARING THE AIR test was the only independent association with asthma (Halonen et al., 1997~. In a University of Virginia study, Alternaria sensitiv- ity was also a significant independent risk factor for asthma in school children in Charlottesville, Virginia, and Los Alamos, New Mexico, but not in Albemarie County, Virginia (Perzanowski et al., 1998~. Of the 1,218 children born on the Isle of Wight, 6% of the 918 4-year-old children tested had positive skin tests to Alter- naria and/or Cia~osporium. In these 61 children, a positive test to Alternaria was associated with a diagnosis of asthma (Tariq et al., 1996~. In Costa Rica, where the prevalence of childhood asthma is 20-30%, dust mite, cat, Alternaria, and CIa~losporium-specific IgEs predict asthma (Soto-Quiros et al., 1998~. A case-control study in Denver (acute asthmatics 3-16 years old) versus matched con- trols used RAST to document specific IgE levels: 45°/O of asthmat- ics versus 4°/O of controls had high IgE to Alternaria (Nelson RP et al., 1996~. In a large (6,394 children) questionnaire-based study, Peat et al. (1995) reveal that among asthmatic children, Alternaria sensitivity rates are higher inland in New South Wales, but in the damp coastal climate, sensitivity to dust mites is most prevalent. In 4,295 6- to 25-year-olds in the second National Health and Nu- trition Examination Survey (NHANES II) cohort, asthma was as- sociated with sensitivity to dust mite (OR = 2.9 [1.7-5~; and Alter- naria (OR = 5.1 [2.9-8.9~) (Gergen and Turkeltaub, 1992~. Retrospective investigation of asthma deaths in teenagers re- vealed that a large majority had positive skin tests to Alternaria, and the authors concluded that sensitivity to Alternaria is a risk for severe asthma and death from an attack (O'Hollaren et al., 1991~. (The authors concluded that exposure to Alternaria is a risk factor, although they did not measure exposure.) Many studies focusing on asthma ignore fungi completely (e.g., Gottlieb et al., 1996~. Immunotherapy Data Further evidence for the role of fungal sensitization in symp- tomatic asthma is provided in immunotherapy data. Bousquet and Miche] (1994) have reviewed the overall literature on immu- notherapy. The literature on mold immunotherapy has been re- viewed by Dhillon (1991) and Bonifazi (1994~. Immunotherapy

INDOOR BIOLOGIC EXPOSURES 169 with partially characterized and standardized A. alternate aller- gens in a small case-control study has been shown to decrease asthma symptoms overall and during challenge with relevant al- lergens (Cantani et al., 1988; Horst et al., 1990~. In both of these studies, children who were sensitive only to Alternaria ply skin prick test) were treated. Dreborg et al. (1986) selected 30 children who were skin test, RAST, and provocation positive to CIadospo- rium. Most had other sensitivities as well. He treated 16 of these children; the remaining 14 served as controls. Although symptom scores remained similar for the two groups (probably because of multiple sensitivities), nasal and bronchial challenge responses and medication usage were significantly lower in the treated ver- sus the control group. Of the 16 children treated in the Dreborg (1986) study, 13 ex- perienced general reactions during treatment. Kaad and Ostergaard (1982) report that 19% of 38 children treated with fun- gal extracts had to be withdrawn from immunotherapy because of apparent type III reactions. All had slightly elevated IgG (pre- cipitating antibodies) to the relevant extracts before hyposensiti- zation was begun and developed increased titers during therapy. Overall, carefully controlled studies of mold immunotherapy show good effect. Negative studies are small, with too few pa- tients and nonstandardized allergens. These data support the no- tion that there is a relationship between fungal allergen sensitiza- tion and symptoms of asthma. However, there are too few studies to confirm that mold immunotherapy is an effective public health intervention. Fungal Exposure and Asthma Challenge Experiments Challenge tests with Stemphylium in children with positive skin and RAST tests to Stemphylium extracts resulted in bronchial responses in 13 of 59 children (12 others had nasal responses) (Lelong et al., 1986~. Mailing (1986) used posi- tive bronchial challenge in adult asthmatics with CIadosporium as a patient selection criterion for his studies on relationships be- tween natural exposure and symptoms. Licorish et al. (1985) re- produced symptoms of asthma with Penicillium spore challenges.

170 Measured Natural Exposure CLEARING THE AIR Outdoors Neas and colleagues (1996) associated pulmonary function changes in Pennsylvania school children with measured outdoor concentrations of several kinds of fungal spores. Peak flows, symptoms and time spent outdoors were recorded daily, and 24-hour average outdoor spore concentrations were mea- sured using a Burkard spore trap. Changes in morning peak flow of -1 liter/min (CI -1.9 to 0.2) were associated with increments of 10,000 CIadosporium spores in unselected school children. Like- wise, increases of 50 Epicoccum spores was associated with decre- ments in morning peak flows of 1.5 liter/min (CI -2.8 to -0.2~. Epicoccum exposure was also associated with incidence of morn- ing cough (OR = 1.8, CI = 1.0-3.2~. Delfino et al. (1997) report associations between asthma severity (symptom scores and peak expiratory flow rates) and exposure to outdoor fungal spores measured with a spore trap. Symptoms were associated with to- tal fungal spore increases of 4,000 spores per cubic meter, with a decrease in evening peak flow of 12 L per minute. Analysis of specific fungal genera increased the associations. The most im- portant fungal correlates were Alternaria, basidiospores, and hy- phal fragments. Mailing (1986) related daily symptom scores to CIadosporium counts during the autumn mold season. He studied 24 adult asthmatics with positive provocation tests to CIadospo- rium extracts. Significant associations with spore counts were found for symptom scores and medication use. Although some patients were also sensitive to Alternaria, Alternaria counts did not relate to health outcomes in this population. Indoors Su et al. (1992) describe relationships between indoor measured levels of culturable Aspergillus and asthma in Topeka, Kansas schoolchildren. They used culture plate impactors to col- lect short "grab" samples in homes of children recruited through the public schools. The relationship between Aspergillus and asthma symptoms was non-linear, possibly reflecting the differ- ent species of Aspergillus that are common in indoor environ- ments. Garrett et al. (1998) report associations between measured concentrations of fungal spores (counted) and culturable fungi, observed indicators of dampness and molds, fungal sensitivity,

INDOOR BIOLOGIC EXPOSURES 171 and respiratory symptoms. Eighty households with 148 children (36% asthmatic) were sampled 6 times for airborne fungi. Penicil- lium exposure was associated with asthma, and Aspergillus expo- sure with atopy. CIadosporium and Penicillium exposure were as- sociated with the presence of fungal allergy. No associations were seen for total fungal counts. Exposure measures to specific fungi showed a stronger association with symptoms than did damp- ness indicators. Other studies of indoor fungi and asthma report comparisons between fungal levels in homes of asthmatics compared to homes of control subjects. Li and Hsu (1997) compared culturable fungi in homes of 46 asthmatic children, 20 atopic (presumably non- asthmatic) children, and 26 nonatopic controls. Although fungal concentrations were highest in the asthmatic and control homes, CIadosporium concentrations were higher in asthma homes than in control homes. In a study by Horak et al. (1996), Bacillus, As- pergillus, and total fungal concentrations were higher in homes of asthmatics than in control homes. These kinds of studies are com- promised by the fact that families of asthmatic children often take measures to reduce exposure to allergens. Visible Mold, Odors, and Dampness The majority of studies that attempt to associate fungal expo- sure and asthma rely on reports of visible mold or other damp- ness indicators. Dampness is clearly associated with a variety of respiratory symptoms. In addition, Williamson et al. (1997) report a correlation be- tween mold growth indicators and asthma (196 age- and sex- matched subjects); r = 0.23, p < .035~. These researchers also iden- tified a relationship between severity of asthma and total dampness (r = 0.3, p = .006), and mold growth (r = 0.23, p = .35~. A reduction in FEVER of 10.6% (CI 1.0-20.3) was associated with liv- ing in a damp home. Dampness and even visible mold growth could be indicators for dust mite allergen exposure as well as fungal exposure. How- ever, Garrett et al. (1998) report that homes with musty odor, wa- ter intrusion, high humidity, limited ventilation, and visible mold growth had higher fungal spore concentrations than dry homes.

172 - C~ a - ~r to cn o Q CD o Cal . _ Q cn to ~5 Cal cn o Cal C~ . _ ~5 - ~5 ~5 C~ cn cn Q C~ C] - m O ~ O ~ U' _ ~ Q ~C' _ _ _ _ ~_ _ _ O. ~ ~ `1 - . ~ I I I ~I ~ ~I I I ~ ~ ~ ~ CO CO C~ LO 1 L ~00 ~ ^ (D CO C~ CO C ~I ~ ~ C~ cO ~ C\l L() . - C~ O ~ ~t -~ _ ~Cx! Lt~ (D C\l ~ ~O C\l L~ O ' ~ ~ O . . . . . . . 113 . (D . . . C~ C~ C~ C~ ~C~ ~ ~ CO ~ C~ CO C,,) O O ~ ~ 2` Q _>' o~ 5 O U~ ~ ~ ~ ~Q ~ (~ O ~ ~ '~ =7 ClS Q ~ O - >~ ~ _ ~ ~ ~U~ >~_ cn ~ 5 ~ ~ cn ~ cn5 ~ ~ o =7 U' o ~ ,C ~O ~ ~=7 Q U' =7 ~ _ _ ~O Cl, O U' O C\3 _ U ~=7 ~ =7 ~ =7 ~ E ° E c:~ E Q ~C~ Q ~C3L C~ 2 o >` ~O ~ Q - ~.,l .,l U' ,U' C ~ ~ Q D CD ~ ~ C] CD CD O E u' ._ U' o U' ~ ClS ~' ~O ,o c C'' o c ~ ~ ~ c' C ~C ~ >~ C ~'t- 't- C~ U _ 00 LO ~ LO C.) C.) ~ C~ O LO O O (D ~ LO ~ O 00 C' ~r ~00 00 CO a' co ~ ~ ~ClS~ ~m,, ~ O o ~ce ~ t~_ E ~C/'I ~C/' Z~ 5 o C~ . _ Q X C~ Q 11 L~ llJ ~7 . ~ O C~ U' ~7 ~7 o 11 ~r o . ~ o ~i o C~ . _ Q X ~7 o 11 L~ llJ L~ . ~ C~ . _ C' ~7 o C' - C~ . . I1J

INDOOR BIOLOGIC EXPOSURES 173 Visible mold was associated with high concentrations of CIadospo- rium spores, but not total spores. Pasanen et al. (1992) report that airborne CIadosporium and yeast counts were significantly higher in damp than in dry residences. CIadosporium, in particular, ap- peared to be derived from indoor sources. Nicolai et al. (1998) report that the relationship between dampness and bronchial hy- perreactivity in adolescents in Munich remains when controlled for dust mite allergen exposure, providing indirect evidence for a possible role of fungi. Conclusions: Asthma Exacerbation and Development The extent of fungal-related asthma remains unknown, and the exposure parameters leading to fungal-related asthma devel- opment or exacerbation are not clear. This is due (in part) to inad- equate diagnostic and environmental testing procedures and lack of adequate study. Sensitization (i.e., positive skin test) to fungal allergens is associated with the presence of asthma in both chil- dren and adults. Although the evidence regarding asthma devel- opment is provocative, it is inclusive. In summary: · There is sufficient evidence of an association between fun- gal exposure and symptom exacerbation in sensitized asthmatics. Exposure may also be related to nonspecific chest symptoms. · There is inadequate or insufficient evidence to determine whether or not there is an association between fungal exposure and the development of asthma. Evidence and Conclusions: Exposure Mitigation and Prevention As with any relatively large-particle aerosol, fungal spores can be prevented from entering enclosed spaces. However, the health effects of such prevention have not been studied. Fungi are diffi- cult to kill, and dead fungal material probably contains allergens, although this has not been thoroughly tested. TerIecky~ and AxIer (1987) discuss the effects of various disinfectants on fungi. ChIo- rine dioxide, glutaraldehyde, and ethyl alcohol affected most fungi after 15 minutes of contact time. However, Aspergillus

174 . CLEARING THE AIR fumigates was highly resistant to most disinfectants, and a quater- nary ammonium com Pound and an iodophor were the least ef- fective for all fungi. It is possible to physically remove active fungal growth from indoor environments. While such removal is undoubtedly advis- able, its health impact has not been studied. Rautiala et al. (1998) studied spore levels during removal of fungal-contaminated ma- terial. They found that negatively pressurized containment is nec- essary to prevent the spread of spores to unaffected parts of the building and that, within the containment field, spore levels may remain high and workers should wear protection. Overall, miti- gation and prevention of fungal growth in the indoor environ- ment has not been studied, either from the viewpoint of effective- ness or with respect to health impact. In summary: · There is limited or suggestive evidence of an association between the fungal removal measures described above and a re- duction in the levels of fungi in the indoor environment. The pau- city of studies with adequate exposure characterization and the possibility that cleaning may not eliminate the problematic com- ponent of fungal exposures prevent a more confident conclusion from being drawn. · There is inadequate or insufficient evidence to determine whether or not an association exists between fungal control mea- sures and improvement in symptoms or Jung function in sensi- tized asthmatics. Research Needs Few fungal allergens have been identified, and patterns of cross-reactivity among fungal allergens have not been docu- mented. Standardized methods for assessing exposure to fungal allergens are essential, preferably based on measurement of aller- gens rather than culturable or countable fungi. Acquisition of these data is a necessary step before adequate estimates of the role of fungal allergen in asthma can be documented. Studies seeking to find environmental factors that either lead to the development of asthma or precipitate symptoms in exist- ing asthmatics must include good measures of fungal exposure.

INDOOR BIOLOGIC EXPOSURES 175 No studies have attempted to control exposure to fungal aller- gens either indoors or out. Intervention studies that seek to con- tro! indoor exposure to fungi are especially needed. INFECTIOUS AGENTS Infectious agents are unlike other indoor exposures addressed in this report because their source is the occupants themselves. They are nonetheless an appropriate exposure to address because they contribute to the overall risk of asthma disease outcomes from indoor exposures and may have some role in the observed increase in asthma incidence and mortality. There are a number of infectious agents that have been associ- ated with asthma (Johnston et al., 1995; Pattemore et al., 1992; Shaheen, 1995~. This section focuses on four that have received particular attention from researchers: two viral agents rhinovi- rus and respiratory syncytial virus and two bacterial agents- chIamydia and mycoplasma. Rhinovirus Definition of the Agent and Means of Exposure Rhinovirus is the medical term used to designate a large group of viruses responsible for a variety of respiratory infections including the common cold. There are more than 120 serotypes of the rhinovirus, of which few have been associated with lower- respiratory abnormality. Rhinovirus is transmitted through the respiratory route, with virus particles shed in nasal secretions and spread by coughing and sneezing. It can also be transmitted through direct contact with tissues or hands. Evidence Regarding Asthma Exacerbation and Development Widespread clinical experience and epidemiologic research indicate that rhinovirus is associated with wheezing and exacer- bations of asthma in established asthmatics Johnston, 1997; Johnston et al., 1995; Lemanske et al., 1989; Micillo et al., 1998; Rakes et al., 1999~. The evidence of this is especially strong for

176 CLEARING THE AIR children. The mechanism by which the virus traffics from the up- per airway to the lower airway to cause asthma symptoms is not known. It is speculated that individuals with asthma may make more of a specific cytokine than those without asthma, leading to increased airway inflammation and the development of symp- toms. Alternatively, individuals with asthma and those without asthma may make the same amount of cytokines in response to viral infections, but these cytokines may react differently in indi- viduals with asthma and produce different effects in the airway. Individuals with asthma have a different cytokine profile from those without asthma, which may result in a different clinical phe- notype. Studies have not identified an association between rhinovi- rus infection and asthma development. Martinez (1995) observes that most infants who wheeze during viral infections become symptom free later in life and suggests that viral infections in in- fants are likely to play a minor role in the subsequent develop- ment of asthma. There is burgeoning research interest in this is- sue, however, with investigators suggesting both the possibility of a mechanistic association and the prospect that certain viruses may have a protective effect (Grunberg and Sterk, 1999; Martinez, 1994). Respiratory Syncytial Virus Definition of the Agent and Means of Exposure Respiratory Syncytial Virus (RSV) belongs to the Paramyxo- viridae family and to the genus Pneumovirus. Human paramyx- oviruses are a common cause of respiratory disease in children with RSV particularly important in infants. RSV has been found in every geographical area examined for evidence of infection (Glezen et al., 1981; Hall et al., 1979), and RSV infection appears to have similar characteristics in areas with widely differing cli- mates. Outbreaks of infection occur yearly, typically in the spring and winter. Indeed, RSV is the only viral respiratory agent that can be relied on to produce a sizable crop of infection each year. Socioeconomic status and race or ethnicity appear to influence the risk of RSV bronchiolitis (Glezen et al., 1981~.

INDOOR BIOLOGIC EXPOSURES Evidence Regarding Asthma Exacerbation and Development 177 The study of RSV and asthma exacerbations is complicated by the problematic diagnosis of asthma in infants and young chil- dren. However, viruses in general have been identified as respon- sible for most wheezing illnesses and asthma exacerbations oc- curring in childhood, with RSV among the predominant organisms recognized (Hegele, 1999; Pattemore et al., 1992~. An association has also been noted for adults (Nicholson et al., 1993~. Significant attention has been paid to the possibility of an as- sociation between RSV bronchiolitis in infancy and later develop- ment of asthma. RSV bronchiolitis is associated with the develop- ment of high titers of virus-specific IgE in respiratory secretions during both the acute and the convalescent stages of illness in some patients (Robinson et al., 1993; Welliver and Duffy, 1993~. An exaggerated RSV IgE response at the time of RSV bronchioli- tis in infancy is associated with recurrent wheezing in later child- hood (Scott et al., 1984~. Various mechanisms may be proposed to explain this association. These include direct induction of release of inflammatory mediators from pulmonary mast cells, participa- tion in a cascade of mediators of airway obstruction, reflection of general IgE hyperresponsiveness to multiple allergens, and in- duction of persistent T helper type 2 responses (Roman et al., 1997~. Although an exaggerated RSV IgE response to RSV infec- tion during infancy may correlate with recurrent wheezing dur- ing a child's early years, this may not represent asthma per se but rather repeated similar responses to multiple infections with RSV and other respiratory pathogens (Welliver et al., 1986~. A study by Sigurs and associates (1995) tends to support the hypothesis that RSV infection may cause or promote asthma by inducing atopy in infected individuals. Since the rate of sensitization among con- trols with and without IgG antibodies to RSV is similar, an en- counter with the virus without development of bronchiolitis does not seem sufficient to increase the risk of sensitization. Other in- vestigators have reached different conclusions about the relation- ship between RSV infection in infancy and the development of atopy and asthma later in childhood. In a study by Pullan and Hey (1982), the frequency of positive skin tests for common aller- gens was similar for individuals with previous bronchiolitis and

178 CLEARING THE AIR for controls. Murray and colleagues (1992) found no difference in skin test reactivity to dust mites between bronchiolitis patients and controls. A precise mechanism by which RSV bronchiolitis might in- duce allergies and asthma has not been elucidated (Dezateux et al., 1997~. However, one possible pathogenic mechanism could be through increasing the synthesis of IgE since it has been demon- strated that RSV bronchiolitis can induce an IgE antivirus re- sponse and that RSV-specific IgE responses in infancy are associ- ated with later recurrence of wheezing. Welliver and colleagues (1981) found that IgE titers to RSV in nasal secretions were high- est in patients with evidence of airway obstruction. Chang and colleagues (1990) prospectively followed 38 of these infants for 48 months after an initial episode of RSV bronchiolitis. Only 20% of infants with undetectable titers of RSV IgE had subsequent epi- sodes of documented wheezing. In contrast, 70% of children with high RSV IgE antibody titers experienced wheezing. In a four- year prospective study of 13 infants of history-positive bilaterally allergic parents, Frick and colleagues (1979) noted that viral infec- tions including RSV occurred one to two months before the onset of allergic sensitization in 10 of the 11 children who subsequently became atopic. Despite the strong correlation between virus-specific IgE, me- diator release, and the clinical pattern of acute and recurrent dis- ease, it is premature to conclude that virus-specific IgE is causal in this process. Moreover, whether those infants who had persis- tent wheezing and/or airway obstruction were concurrently both sensitized and exposed to indoor allergens is not known. Chlamydia Definition of the Agent and Means of Exposure There are two forms of the bacterium Chiamydia that have been examined in relation to asthma. Chiamydia trachomatis is a sexually transmitted infectious disease that may be spread from mother to child during birth and perhaps through close contact with secretions of an infected individual. Chiamydia pneumonias is an important cause of adult respiratory disease including pneu

INDOOR BIOLOGIC EXPOSURES 179 mania, bronchitis, sinusitis, and pharyngitis and may be associ- ated with atherosclerosis (Kalman et al., 1999~. A 1991 editorial in the journal of the American Medical Association suggested that C. pneumoniae infection might provide an explanation for the in- creased incidence of asthma (Bone, 1991~. Evidence Regarding Asthma Exacerbation and Development An anecdotal report suggests that C. trachomatis produces asthma-like symptoms in infants that may be treated successfully with antichiamydial antibiotic therapy (Bavastrelli et al., 1992~. Bjornsson and colleagues (1996) report that serological signs of a previous C. trachomatis infection were found significantly more often in subjects who reported having had asthma at some time, asthma during the past year, wheezing during the past year, and bronchial hyperresponsiveness. It is unclear, however, whether such reports uniquely implicate C. trachomatis or are unrecognized C. pneumoniae infections since the two species are cross-reactive. Chiamydia pneumoniae infection has been associated with asthma exacerbations in both adults and children. Bjornsson and colleagues (1996) found a statistically significant relationship be- tween current or recent C. pneumoniae infection and wheezing. Johnston (1997) found that immune responses to C. pneumoniae were positively associated with an increased frequency of asthma exacerbations in a group of 9- to 11-year-olds. Cunningham and colleagues (1998) report increased numbers of asthma exacerba- tions in children with higher local antibody responses to C. pneumoniae. Miyashita and colleagues (1998) found a significantly higher frequency and geometric mean titer of C. pneumoniae anti- bodies in adult patients with exacerbations of asthma. However, Cook and colleagues (1998) did not find an association between asthma exacerbations (termed "acute asthma" in the study) and seropositivity in a two-year study of 123 adult asthmatics and 1,518 controls. Several groups of researchers have reported a serological as- sociation between C. pneumoniae and chronic adult asthma in studies that controlled for one or more known confounders. Hahn and colleagues (1991) found that patients with serologically con- firmed C. pneumoniae infection were more likely than seronega

180 CLEARING THE AIR five patients to develop bronchial asthma subsequent to their in- fection. A later study of 163 adolescents and adults by Hahn and McDonald (1998) had the same findings, leading the authors to conclude that acute C. pneumoniae respiratory tract infections in previously unexposed nonasthmatic individuals can result in chronic asthma. Cook and colleagues (1998) found a statistically significant association between severe chronic asthma and sero- positivity in their two-year study of 123 adult asthmatics and 1,518 controls. Johnston (1999) reports a high prevalence of C. pneumoniae infection in a group of 9- to 11-year-old asthmatics. Von Hertzen and colleagues (1999) found asthma to be signifi- cantly associated with IgG antibody levels to C. pneumoniae, with the strongest association for nonatopic, long-standing asthma. However, not all studies find this association. Kraft and col- leagues (1998) did not find C. pneumoniae in the lungs or airways of 18 asthmatic subjects. Larsen and colleagues (1998) found that a group of 22 asthmatics did not differ from 55 controls with rela- tion to two markers of C. pneumoniae infection. The authors note two weaknesses in many of the studies reporting a relationship: (1) a diagnosis of asthma was seldom well-established in these cases, and (2) no pathobiologic mechanism was proposed to ac- count for initiation in adults (production of specific IgE was noted as a possible initiating mechanism in children). At present (late 1999) there is a debate in the literature over the meaning of these studies. Although their results are consis- tent with an association between C. pneumoniae (and perhaps C. trachomatis) and asthma development, present data are insuffi- cient to distinguish this premise from other reasonable hypoth- eses, notably whether asthma predisposes individuals to other chronic respiratory infections. Mycoplasma Definition of the Agent and Means of Exposure Mycoplasma pneumoniae is a bacterial infection that is respon- sible for a number of respiratory diseases including tracheobron- chitis, rhinitis, pharyngitis, otitis, and a form of pneumonia. Over the past several years there have been multiple anecdotal reports

INDOOR BIOLOGIC EXPOSURES 181 and epidemiologic studies suggesting an association between M. pneumoniae infection and exacerbations of asthma (e.g., Seggev et al., 1986~. Among the more recent studies, Freymuth and col- leagues (1999) found that C. pneumoniae and M. pneumoniae infec- tions alone or in combination were present in nearly 82% of asthmatic exacerbations. However, Cunningham and colleagues (1998) and Johnston (1997,1999) found no evidence of a role for M. pneumoniae in acute asthma exacerbations. Evidence Regarding Asthma Exacerbation and Development The literature regarding M. pneumoniae and asthma develop- ment is sparse. Yano and colleagues (1994) suggested in a case report that an adult male may have developed asthma as a result of M. pneumoniae infection. Kraft and colleagues (1998) found M. pneumoniae present in the lower airways of chronic stable asth- matics with significantly greater frequency (10 of 18) than in con- trols (1 of 11~. Conclusions: Asthma Exacerbation and Development · There is sufficient evidence of an association between in- fection with rhinovirus and exacerbation of asthma. · There is limited or suggestive evidence of an association between infection with RSV and exacerbation of asthma. · There is limited or suggestive evidence of an association between infection with Chiamydia pneumoniae and the exacerba- tion of asthma. · There is inadequate or insufficient evidence to determine whether or not there is an association between infection with Chiamydia trachomatis and exacerbation of asthma. · There is limited or suggestive evidence of an association between Mycoplasma pneumoniae infection and exacerbation of asthma. · There inadequate or insufficient information to determine whether or not there is an association between infection with rhi- novirus and the development of asthma in infants. There is lim- ited or suggestive evidence of no association between infection with rhinovirus and the development of asthma in older children and adults.

182 CLEARING THE AIR · There is limited or suggestive evidence of an association between infection with RSV and the development of asthma. · There is inadequate or insufficient information to deter- mine whether or not there is an association between Chiamydia trachomatis or Chiamydia pneumonias infections and the develop- ment of asthma. · There is inadequate or insufficient information to deter- mine whether or not there is an association between Mycoplasma pneumonias infection and the development of asthma. Evidence Regarding Exposure Mitigation and Prevention A primary infection prevention strategy is the avoidance of transmission and exposure through proper personal hygiene practices. Vaccination has also been mentioned as a means of pre- vention. Although the data are conflicting, breast feeding offers a possible mechanism of passive immunization of infants that may play some role in protection against infection. Further studies are needed to evaluate this notion. A detailed discussion of these strategies and their effectiveness is outside the scope of this report. Some data are available on the characteristics of RSV that may inform infection mitigation and prevention strategies for this agent. RSV withstands changes in temperature and pH relatively poorly. Only 10% of RSV remained after the virus was exposed to 55°C for 5 minutes. At 37°C, the virus was stable for 1 hour, and only 10% of the infectivity remained after 24 hours. RSV also with- stands an acid medium poorly, and the optimal pH is 7.5. Ether, chloroform, and a variety of detergents such as sodium dodecy! sulfate quickly inactivate the virus. At room temperature, RSV in the secretions of patients may survive on nonporous surfaces, such as countertops for 3-30 hours, depending on the humidity. On porous surfaces such as cloth and paper, survival is shorter, usually lasting less than an hour. The infectivity of RSV on the hands is variable from person to person but usually lasts less than one hour. The survival of RSV in the environment appears to de- pend in part on the drying time as well as on the humidity. These data suggest that proper cleaning of objects and surfaces exposed to RSV may serve to limit exposure to the virus.

INDOOR BIOLOGIC EXPOSURES 183 Aspects of the indoor environment may also increase the risk of respiratory infection. Building characteristics would have an indirect effect on asthma symptoms if these characteristics influ- enced the prevalence of the relevant respiratory illnesses among building occupants. Crowded living conditions found more of- ten among urban residents and lower-income individuals in the United States may facilitate the spread of infectious disease. Certain indoor spaces such as day care facilities and schools may also present more favorable conditions for their spread. One study suggested higher rates of transmission of infectious pulmonary disease in more tightly constructed military barracks (Brundage et al., 1988~. As reviewed by Fisk (1999), the results of ten studies suggest that the prevalence of respiratory illness can be influenced significantly by building characteristics such as ventilation rate, space sharing, or occupant density, with relative risks typically between 1.2 and 1.5. None of these studies have confirmed that the responsible agents were rhinoviruses, and only one older study involved children; therefore, this indirect linkage of build- ing characteristics to asthma exacerbation remains theoretical. Nevertheless, the evidence of an indirect link is sufficient to war- rant further investigation. Conclusions: Exposure Mitigation and Prevention · The committee declined to draw conclusions about the ef fectiveness of specific personal hygiene or medical practices in mitigating or preventing exposure to infectious agents because it believes this to be outside the scope of this report. · There is inadequate or insufficient information to deter- mine whether or not there is an association between building characteristics that reduce close contact between individuals and decreased spread of infectious diseases. There is also inadequate or insufficient evidence of an association with ventilation rates. Research Needs Numerous studies suggest an association between the infec- tions discussed in this section and asthma exacerbations, although uncertain ascertainment of asthma and questions about the iden

184 CLEARING THE AIR tity of the specific infections responsible limit the confidence with which some conclusions can be drawn. Advances in analysis tech- niques that allow more sensitive and confident identification of viruses, such as PCR and ELISA, will facilitate research on this topic. These advances will also aid studies of other viruses that may be associated with asthma such as adenovirus, coronavirus, cytomegalovirus, and parainfluenza. Research on the possible association between infectious agents and asthma development is continuing and is encouraged. There are gaps in the knowledge concerning the mechanisms by which agents may promote asthma and whether particular inter- ventions aimed at limiting infections result in decreased rates of asthma. Among the interesting questions are whether the lower respiratory tract acts as a potential reservoir for common respira- tory viruses and whether maternal immunization has the poten- tial to protect both the mother and the infant. Research on the impact of building characteristics on the transmission of infec- tious agents, which is in its infancy, may yield important public health benefits. HOUSEPIANTS Definition of the Agent and Means of Exposure Houseplants have the potential to release pollen, sap, and other plant parts; arthropod pest allergens; and fungi. Houseplant Pollen The data on houseplant pollen allergy is restricted to the oc- cupational literature and to case reports. Allergy to some flower pollens has been clearly documented in occupational situations and could occur in residential environments with cut flowers (de long et al., 1998~. Co-sensitization with some houseplant pollen allergens and some outdoor allergens is extremely common (e.g., mugwort, daffodil) and may indicate that these plants share aller- gens. In cases of this sort, asthma related to outdoor pollen expo- sure could be exacerbated by houseplant pollen, although very

INDOOR BIOLOGIC EXPOSURES 185 little pollen is produced by most houseplants and close contact would be required. Other Plant Parts and Fluids Exposure to plant materials during the production of plant extracts as medicines has led to occupational asthma (Giavina- Bianchi et al., 1997~. The expanding use of herbal medicines may lead to an increase in these types of exposures. Several papers report cases of houseplant (in particular, Ficus) latex causing con- tact sensitization and even inhalation allergy. The available data are restricted entirely to the case study literature, and only two reports were retrieved (Diez-Gomez et al., 1998; Schenkelberger et al., 1998~. Arthropods Arthropods that inhabit plants (particularly spider mites) may release allergens. However, again, all data are in the occupational case study literature, and no information is available on the ex- tent of the problem (Orta et al., 1998~. The potential for cross-reac- tivity with dust mite allergens has not been evaluated. Fungi Several reports implicate houseplants as sources of fungi in indoor environments, with a focus on human infectious agents rather than allergens. These studies, in general, rely on source (soil) sampling and do not relate exposure to any allergic disease (Staib, 1992, 1996; Staib et al., 1978a, b, 1980; Summerbell et al., 1989~. Burge and colleagues (1982) found no relationship between the presence of houseplants and either concentration or type of fungal spores or pollen in the air. Conclusions: Asthma Exacerbation and Development There is no evidence that exposures from houseplants lead to the development of asthma. Although patients occasionally com- plain of worsening symptoms related to houseplants or exposure

186 CLEARING THE AIR to cut flowers, no studies have been conducted to document this connection. While some epidemiologic studies suggest that occu- pational exposure to plant extracts may lead to allergic diseases including asthma, the relevance of this literature to casual, non- occupational exposure is not clear. Mites or fungi that may be associated with houseplants could be involved in asthma devel- opment or exacerbation, but there is no evidence bearing on this hypothesis. In summary: · There is inadequate or insufficient evidence to determine whether or not an association exists between exposures from houseplants and the exacerbation or development of asthma. Evidence and Conclusions: Exposure Mitigation and Prevention The committee did not identify any literature regarding the effectiveness or impact on asthma outcomes of measures intended to limit houseplant exposure. Research Needs Further research is needed to determine whether or not houseplants release fungal spores into the air. This research will benefit both the allergy community and the infectious disease literature. Additionally, research should be conducted to deter- mine what risks, if any, are associated with occupational expo- sure to plant materials. POLLEN Definition of the Agent and Means of Exposure Introduction Pollen exposure has long been recognized as a stimulant for symptoms of allergic disease. Allergic rhinitis (hay fever) has been considered the primary outcome, and outdoor environments are

INDOOR BIOLOGIC EXPOSURES 187 the major source of exposure. The role of pollen in the develop- ment and exacerbation of asthma has received relatively little di- rect attention, and very few studies are available that document indoor exposure to pollen allergens. Nature of the Agent Structure and Function Pollen is the male reproductive struc- ture of flowering plants and gymnosperms. Pollen grains are usu- ally unicellular, with a rigid and highly resistant cell wall formed of a complex polysaccharide-based substance called sporopolle- nin. Each pollen grain contains the systems required for recogni- tion of genetically relevant female flowers and the production of a pollen tube that grows into contact with the egg cell to effect fertilization. Pollen Allergens The list of pollens from which extracts have been derived that produce positive skin tests in some fraction of the population is long. In one California study, 57 skin test allergens were neces- sary to detect 90°/O of the atopic patients. This set included 2 grasses, 16 weeds, and 27 trees (Galant et al., 1998~. The list of purified allergens from pollens is also growing. These include Amb a I (short ragweed, Ambrosia artemisiifolia), Bet v I (birch pollen, Betula verrucosa ) , and Lo ! p I (rye grass, Lo lium perenne). One study has estimated that a single pollen grain of B. verrucosa contains 0.006 ng Bet v I (Schappi et al., 1997~. Other Pollen-Associated Agents Serine proteases that could directly affect respiratory func- tion apart from allergic reactions have been detected in ragweed and mesquite pollen (Bagarozzi and Travis, 1998; Travis et al., 1996~. Characteristics of Pollen Exposure Particle Size Considerations Intact pollen grains range from

188 CLEARING THE AIR about 10 to 100 ,um, with the most common types in the range of 15-30 ,um. However, pollen allergens have been documented in air on much smaller particles. During light rein, 1.2 ng Bet v I/per cubic meter (200 birch pollen equivalents) were present on the particle fraction less than 7.5 ,um in outdoor air (Schappi et al., 1997~. Grass pollen grains have been shown to rupture during rainfall, and allergen (Lo! p V) has been recovered in particle frac- tions less than 5 ,um both as free molecules and attached to other particles such as starch grains and combustion (diesel exhaust) particles (Suphioglu,1998~. Pollen allergens have been visualized on the surface of diesel particles under laboratory conditions (Knox et al., 1997~. Ragweed allergens have also been recovered from small particles (Habenicht et al., 1984; Solomon et al., 1983~. Patterns of Pollen Prevalence 11 Outdoors An enormous body of literature documents preva- lence patterns for pollens throughout the world. In the United States, the American Academy of Allergy, Asthma, and Immunol- ogy has been collecting pollen prevalence data for more than 30 years and currently publishes an annual report containing data from about 100 stations across the nation (e.g., AAAAI, 1998~. In the United States, the pollen types most often considered impor- tant are mountain cedar, birch, and oak (trees); grasses (which cross-react broadly across genera); and ragweed (a late-summer weed). Pollen is produced seasonally. In general, tree pollens are re- leased early in the year, grasses during late spring and early sum- mer, and weed pollens in the late summer and fall. Major excep- tions occur. For example, some grass pollen is produced throughout the year in some areas. Meteorological variables directly affect pollen concentrations n air (in addition to their effects on pollen production). Most pol- len types are released during the morning hours, but dispersal may occur later in the day with increase in wind and other distur- bances. Wind is a well-known dispersal agent for pollens, which may travel long distances (hundreds of miles) in traveling air masses (Levetin and Buck, 1986~. Rain generally washes pollen from the air.

INDOOR BIOLOGIC EXPOSURES 189 Indoors Outdoor infiltrate is the primary source of pollen in in- door environments. Birch pollen allergen (Bet v I) has been found associated with suspended particles indoors (Holmquist and Vesterberg, 1999; Ormstad et al., 1998~. Evidence Regarding Asthma Exacerbation and Development Pollen Exposure and Asthma Sensitization to Pollen Allergens In 3,371 Canadian allergy pa- tients, skin tests indicated that 52% were sensitive to grass aller- gens and 45% to ragweed allergens (Boulet et al., 1997~. In the Swiss population (random, more than 8,000 individuals studied) 32% were atopic, with sensitivity to grass allergen the most preva- lent (12%), followed by dust mite (8.9%) and birch pollen (7.9%) (Wuthrich et al., 1995~. In 1,159 random participants in Hamburg and Ehrfurt, respectively, grass and birch allergen sensitivities were 24 versus 19% and 19 versus 8% (Nowak et al., 1996~. Of inner city asthmatics in Chicago, 45% were sensitized to ragweed pollen (76% were sensitive to indoor allergens) (Kang et al., 1993~. In 7,079 retrospectively observed patients with asthma and/or rhinitis, 44% had one or more positive skin tests, with grass, cat, and birch allergens eliciting the greatest number of positive tests. Of the 35% of sensitized patients who were monosensitized, 7.4% reacted only to mite allergens and 7.0% to grass allergen (Eriksson and Holmen, 1996~. On the other hand, Subiza and colleagues (1994) report that 92% of Madrid allergy patients are sensitive to grass allergens, 63% to olive allergens, and 56% to sycamore (Platanus) allergens. Relationships to Asthma Pollen Sensitization Related to Asthma In general, pollen sen- sitization has been associated primarily with hay fever rather than asthma, and this opinion is supported in several studies. In a study reported by Eriksson and Holmen (1996), patients with grass allergen sensitivity were more likely to have rhinitis than asthma. In a Tucson population, sensitivity to ryegrass and mul

190 CLEARING THE AIR berry pollen independently predicted rhinitis but not asthma (Halonen et al., 1997~. In a case-control study of 343 random chil- dren, 35% were atopic, and 90°/O of those with five or more epi- sodes of wheezing had one or more positive skin tests (Henderson et al., 1995~. Pollen sensitivity was not associated with wheezing in this population. On the other hand, in an Australian population of 745 young adults, sensitivity to ryegrass pollen was among the four top al- lergen sensitivities that posed a risk for the existence of current asthma (Abramson et al., 1996~. Winter respiratory symptoms (in- cluding asthma) have been related to positive prick, RAST, or endonasal challenge tests with alder and haze] pollen allergens (Laurent et al., 1994~. Grass allergen elicited the most positive skin tests among black asthmatics in Johannesburg (Luyt et al., 1995~. Pollen Exposure and Asthma Ordaz and colleagues (1998) fol- lowed symptoms in 104 asthmatic patients and related exacerba- tion events to airborne pollen counts. When infectious disease- related events were excluded, there was a good correlation between event days and pollen counts (r = 0.7, p < .01~. In a pro- spective study of mild to moderate asthmatics (N = 139), Epton and colleagues (1997) were unable to distinguish a relationship between measured pollen concentrations and measured peak flow. Baraldi and colleagues (1999) documented a twofold increase in exhaled NO in grass-sensitive asthmatic children during the grass pollen season. Natural allergen exposure was shown to in- duce T cell, mast cell, and eosinophi! inflammatory response in grass-sensitive patients undergoing seasonal exacerbation (N = 17) (D,ukanovic et al., 1996~. Rosas and colleagues (1998) report an association between grass pollen counts and asthma admis- sions in Mexico City in both dry and wet seasons. Celenza and colleagues (1996) related changes in grass pollen concentrations and decreases in temperature to epidemic asthma. Their patients, who were involved in a thunderstorm-associated epidemic in England, had high serum IgE levels specific for grass pollen aller- gens (Venables et al., 1997~. Newson and colleagues (1997) counted asthma admissions in two age groups (0-14 and >14 years) and related these events to lightning episodes and grass

INDOOR BIOLOGIC EXPOSURES 191 pollen concentrations. Although there were excess densities of lightning and grass pollen counts in epidemics, many (in fact, most) epidemics were not preceded by thunderstorms. In a fol- low-up study, they report that thunderstorms following periods of high pollen counts are more likely to lead to asthma epidemics (Newson et al., 1998~. In an analysis of 59,624 asthma hospitalizations in Finland, a peak was observed in May that was attributed to the exposure of sensitized people to birch pollen allergens (Harju et al., 1997~. As part of the increase in doctor-diagnosed asthma and episodes of breathlessness in children in Norway, symptoms with exposure to birch pollen increased from 3.7 to 6.1% of children between 1981 and 1993 (Skjonsberg et al., 1995~. Woodcock and Custovic (1998) suggest that exposure to rag- weed allergen reduces corticosteroid binding capacity in sensi- tized asthmatics, contributing to poor asthma control. In 20 subjects, airway responsiveness to histamine challenge was highest during the privet season, and symptom scores and bronchodilator use increased. However, challenge with privet pollen allergens induced no immediate asthmatic responses, and late responses occurred in only 6 of 17 tested patients (Richards et al., 1995~. Pollen-Air Pollutant Interactions Laboratory Studies Strand and colleagues (1997) report that in a group of 18 pollen-sensitive asthmatics, short exposure in the laboratory to concentrations of NO2 representative of those that occur in outdoor air enhances pollen allergen-induced late asth- matic responses. Repeated short exposures to NO2 enhanced ef- fects of otherwise nonsymptomatic doses of pollen allergen (Strand et al., 1998~. However, in similar studies, Hanania and colleagues (1998) found no change in allergen response following ozone challenge. Field Studies Anderson and colleagues (1998) report a synergis- tic effect for pollen and SO2 with respect to hospital admissions of children (but not adults) for asthma. No other pollen-pollutant interactions were observed. In a comparison between randomly

192 CLEARING THE AIR selected participants in Hamburg and Ehrfurt, Germany, the prevalence of atopy and pollen sensitization was highest in Ham- burg, while air pollutant exposures were highest in Ehrfurt (Nowak et al., 1996~. Conclusions: Asthma Exacerbation and Development Evidence from studies of outdoor exposure indicates that pol- len exacerbates existing asthma in sensitized individuals. Infor- mation does not permit a conclusion concerning whether or not there is an overall role for pollen allergens in the development of asthma. Although pollen allergens have been documented in both dust and indoor air, data is lacking to draw a informed conclu- sion. Thus: There is inadequate or insufficient evidence to determine whether or not an association exists between pollen exposure in the indoor environment and the exacerbation or development of asthma. The committee concludes: · There is inadequate or insufficient evidence to determine whether or not an association exists between interventions to lower pollen concentrations in indoor environments and im- provement of symptoms or Jung function in pollen-allergic asth- matics. Indoors is typically a protective environment for such in- dividuals. Evidence and Conclusions: Exposure Mitigation and Prevention There is relatively little information on the impact of ventila- tion and air-cleaning measures on indoor pollen levels, although it is axiomatic that shutting windows and other measures that generally limit outdoor infiltrate can be effective. Chapter 10 dis- cusses the studies identified by the committee and draws conclu- sions about the effectiveness of ventilation and air-cleaning mea- sures in reducing indoor concentrations in general.

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Since about 1980, asthma prevalence and asthma-related hospitalizations and deaths have increased substantially, especially among children. Of particular concern is the high mortality rate among African Americans with asthma.

Recent studies have suggested that indoor exposures--to dust mites, cockroaches, mold, pet dander, tobacco smoke, and other biological and chemical pollutants--may influence the disease course of asthma. To ensure an appropriate response, public health and education officials have sought a science-based assessment of asthma and its relationship to indoor air exposures.

Clearing the Air meets this need. This book examines how indoor pollutants contribute to asthma-- its causation, prevalence, triggering, and severity. The committee discusses asthma among the general population and in sensitive subpopulations including children, low-income individuals, and urban residents. Based on the most current findings, the book also evaluates the scientific basis for mitigating the effects of indoor air pollutants implicated in asthma. The committee identifies priorities for public health policy, public education outreach, preventive intervention, and further research.

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