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5 Indoor Biologic Exposures
Pages 105-222

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From page 105...
... Concern in recent years regarding 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 association between these agents and asthma prevalence and severity.
From page 106...
... households. The major cat allergen, Fe!
From page 107...
... , suggesting that protection from Fe! ~ I exposure may not be the equivalent of protection from cat allergen exposure.
From page 108...
... . Evidence Regarding Asthma Exacerbation In cat-sensitized asthmatics, cat allergen can induce allergic symptoms, asthmatic symptoms, and decrements in lung function.
From page 109...
... , 13/19 were sensitized to cat. Numbers were too small to compare symptoms in cat-sensitized asthmatics with and without significant home exposure to cat allergen (Ingram et al., 1995~.
From page 110...
... Conclusions: Asthma Exacerbation and Development In cat-sensitive asthmatics, cat allergen exposure leads to worsening of respiratory symptoms and to a decline in Jung function. 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.
From page 111...
... found that the combination of washing the cat weekly, reducing furnishings, vacuum cleaning, and air filtration reduced airborne cat allergen levels. In a second study, however, Avner and colleagues (1997)
From page 112...
... No studies are available to assess 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, preand post-study cat-specific IgE levels, and methacholine challenge studies in cat-allergic subjects (Wood et al., 1998~.
From page 113...
... 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 reduction 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-sensitive asthmatics.
From page 114...
... Like cat allergen, dog allergen has been found in significant
From page 115...
... 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 allergen in the development of asthma.
From page 116...
... · There is inadequate or insufficient evidence to determine whether or not an association exists between dog allergen exposure 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.
From page 117...
... 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.
From page 118...
... 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 colleagues (1996)
From page 119...
... , 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 exposure to rodents in a laboratory setting and exacerbation of symptoms or Jung function in rodent-sensitized asthmatics.
From page 120...
... In summary: · There is inadequate or insufficient evidence to determine whether or not an association exists between cow or horse allergen in the home and the exacerbation of asthma in sensitive children or the development of asthma. Living on a Farm and Development of Asthma The epidemiologic literature on allergy in farmers and children from farming families was reviewed in a 1999 article demonstrating a lower prevalence of hay fever and allergic sensitization in farmer's children compared to peers from nonfarming
From page 121...
... These findings have led investigators to question whether the farm environment itself might play a protective role in the development of allergy and allergic asthma. One hypothesis is that contact with farm animals and their bacterial products (including endotoxin, which is discussed later in this chapter)
From page 122...
... . A portion of what is called bird allergy may be an expression of allergy to dust mites.
From page 123...
... Research Needs The associations between dust mite allergen, asthma exacerbation, 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.
From page 124...
... 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 exposure in the home as a potential factor in the exacerbation of asthma in rodent-sensitized asthmatics.
From page 125...
... Sequence homology searches are useful tools for investigation of the biologic function of cockroach allergens, and as more sequences become available it will be possible to make comparisons of biologic function and allergenicity, to compare allergen
From page 126...
... as risk factors for cockroach 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.
From page 127...
... In an Ohio study, there was no difference between 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 Baltimore metropolitan area, there was no difference in cockroach allergen, Bla g I between low-pile carpet and uncarpeted floors (Sarpong et al., 1997~.
From page 128...
... Many case-control studies have documented that cockroach allergen exposure and sensitization are significantly more common in patients with asthma living in urban homes compared to those living in suburban homes (Bernton et al., 1972; Kang et al., 1993; Sarpong et al., 1996a)
From page 129...
... Consistency There is now good evidence from epidemiologic studies in several parts of the world which demonstrates that the development of immediate sensitivity to cockroach allergens is associated 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)
From page 130...
... Dose-Response A dose-response relationship between cockroach allergen exposure and sensitization has been established in asthmatic children. Sarpong and colleagues (1996a)
From page 131...
... In a retrospective study of asthmatic children in Chicago, it was suggested that children with combined sensitization to cat, dog, dust mite, and cockroach allergens were at increased risk of having more severe asthma (Sarpong and Karrison, 1998b)
From page 132...
... · 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.
From page 133...
... 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)
From page 134...
... 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.
From page 135...
... 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 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 allergen exposure indoors.
From page 136...
... Further studies are also needed to better elucidate any relationship between cockroach allergen exposure and asthma development; explore the interaction of cockroach allergen with infectious agents, irritants, and other allergens in causing asthma; and examine the influences of genetics, socioeconomic status, and location on exposure 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~.
From page 137...
... 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 unsuccessful attempts were made to purify allergens from dust obtained from carpets and bedding.
From page 138...
... 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 glycoproteins, 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~.
From page 139...
... 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 allergen is dependent on immunoassays capable of accurately measuring quantities as small as 1 ng (Chapman et al., 1987; Luczynska et al., 1989; Sakaguchi et al., l990b)
From page 140...
... 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)
From page 142...
... 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.
From page 143...
... However, there is no sense in which the threshold for mite exposure is comparable to thresholds for airborne toxic gases: (1) high concentrations of mite allergen are not toxic to nonallergic individuals; (2)
From page 144...
... Therefore, in summary: · There is sufficient evidence of a causal relationship between dust mite allergen exposure and exacerbations of asthma individuals specifically sensitized to dust mites. Continual exposure to dust mite allergens is also a contributing cause of chronic bronchial hyperreactivity.
From page 145...
... 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.
From page 147...
... . In these climates, controlling mite growth can be achieved only by air conditioning or reducing the nests for mite growth.
From page 148...
... 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 characteristics of the indoor environment and the prevailing climate.
From page 149...
... Indeed there is no characteristic history of symptoms that can be used to identify patients who are allergic to dust mites. It has been suggested that year-round exposure to dust mite allergens, which are inhaled as a "few" particles per day (i.e., ~100)
From page 150...
... 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 circumstances. The development of methods to identify individuals, especially infants, at high risk would provide the information needed to focus primary prevention activities.
From page 151...
... However, Limulus-based assays are prone to interference (Milton et al., 1997) and likely underestimate exposures in organic dusts, including house dust, compared to chemical assay (Saraf et al., 1999~.
From page 152...
... 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 important 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 stimulus for macrophage production of (TNFoc)
From page 153...
... LPS also is a B cell mitogen and promotes isotype switching from IgM to IgE in the presence of IL4 (Snapper et al., 1991~. Thus, endotoxin not only serves as a potent stimulus to innate immune responses but also serves as a stimulus and bridge to cognitive immunity.
From page 154...
... Among those with any positive skin test, the TT homozygotes had significantly fewer positive tests. Much experimentation suggests that the net effect of endotoxin exposure is to promote THl-type immune responses such as those typically seen in bacterial infections (Baldini et al., 1999; Fearon and Locksley, 1996)
From page 155...
... 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.
From page 156...
... Therefore, the committee concludes: · There is inadequate or insufficient information to determine whether or not an association exists between low-level indoor endotoxin exposure and asthma exacerbation or development. 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.
From page 157...
... This review suggests several avenues of research directed at understanding the role of endotoxin exposure and endotoxin susceptibility 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 exposure, and studies of endotoxin exposure and asthma severity.
From page 158...
... The most obvious of these is via fungal allergen exposure that leads to sensitization, perhaps leads to the development of asthma, and exacerbates symptoms in sensitized people. Fungi also contain and release irritants that may enhance the potential for sensitization, potentiate allergen-induced symptoms, and (possibly)
From page 159...
... Fungal Allergens Fungi produce an enormous array of compounds that are potentially allergenic. Each fungus produces many different allergens of a range of potency.
From page 160...
... 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 dehydrogenase, and myeloperoxidase are released in response to fungal exposure, and blood cell patterns change.
From page 161...
... Glucans may be involved in the development of fungal-induced hypersensitivity pneumonitis by affecting the inflammation-regulating 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.
From page 162...
... 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.
From page 163...
... Studies are not available that document the natural presence (or absence) of fungal allergens on particles other than intact fungal spores.
From page 164...
... Evidence Regarding Asthma Exacerbation and Development Sensitization to Fungal Allergens Exposure to fungi clearly plays a role in asthma. Good-quality studies have been reported that document the sensitizing potential of fungal allergens and relate fungal sensitization to the
From page 165...
... Fungal allergens can produce a strong IgG response, possibly making reported incidences of skin reactivity underestimates. Fungal Sensitization and Asthma In a population of adults in Sweden, sensitivity to CIadosporium or Alternaria (but not dust mites)
From page 166...
... fun, A alto Thailand Asthmatic children100Alternar clamor Penici~ Asper
From page 167...
... INDOOR BIOLOGIC EXPOSURES 167 Fungi Prevalence (%) Author Mold (Aspergillus, Penicillium, Alternaria, CladosporiumJ Alternaria, Cladosporium Alternaria Molds A
From page 168...
... (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.
From page 169...
... 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~.
From page 170...
... They used culture plate impactors to collect 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 different species of Aspergillus that are common in indoor environments.
From page 171...
... was associated with living in a damp home. Dampness and even visible mold growth could be indicators for dust mite allergen exposure as well as fungal exposure.
From page 172...
... 172 C~ a ~r to cn o Q CD o Cal .
From page 173...
... (1998) report that the relationship between dampness and bronchial hyperreactivity in adolescents in Munich remains when controlled for dust mite allergen exposure, providing indirect evidence for a possible role of fungi.
From page 174...
... · There is inadequate or insufficient evidence to determine whether or not an association exists between fungal control measures and improvement in symptoms or Jung function in sensitized asthmatics. Research Needs Few fungal allergens have been identified, and patterns of cross-reactivity among fungal allergens have not been documented.
From page 175...
... This section focuses on four that have received particular attention from researchers: two viral agents rhinovirus and respiratory syncytial virus and two bacterial agentschIamydia 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.
From page 176...
... . Respiratory Syncytial Virus Definition of the Agent and Means of Exposure Respiratory Syncytial Virus (RSV)
From page 177...
... , the frequency of positive skin tests for common allergens was similar for individuals with previous bronchiolitis and
From page 178...
... found no difference in skin test reactivity to dust mites between bronchiolitis patients and controls. A precise mechanism by which RSV bronchiolitis might induce allergies and asthma has not been elucidated (Dezateux et al., 1997~.
From page 179...
... 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.
From page 180...
... and asthma development, present data are insufficient to distinguish this premise from other reasonable hypotheses, 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 responsible for a number of respiratory diseases including tracheobronchitis, rhinitis, pharyngitis, otitis, and a form of pneumonia.
From page 181...
... · 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.
From page 182...
... · There is inadequate or insufficient information to determine 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.
From page 183...
... · There is inadequate or insufficient information to determine 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.
From page 184...
... 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.
From page 185...
... However, again, all data are in the occupational case study literature, and no information is available on the extent of the problem (Orta et al., 1998~. The potential for cross-reactivity with dust mite allergens has not been evaluated.
From page 186...
... Mites or fungi that may be associated with houseplants could be involved in asthma development 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.
From page 187...
... Each pollen grain contains the systems required for recognition 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.
From page 188...
... particles (Suphioglu,1998~. Pollen allergens have been visualized on the surface of diesel particles under laboratory conditions (Knox et al., 1997~.
From page 189...
... 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 patients, skin tests indicated that 52% were sensitive to grass allergens and 45% to ragweed allergens (Boulet et al., 1997~.
From page 190...
... pollen allergens (Laurent et al., 1994~. Grass allergen elicited the most positive skin tests among black asthmatics in Johannesburg (Luyt et al., 1995~.
From page 191...
... 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~.
From page 192...
... 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 improvement of symptoms or Jung function in pollen-allergic asthmatics.
From page 193...
... 1982. The prevalence of house dust mites Dermatophagoides spp, and associated environmental conditions in homes in Ohio.
From page 194...
... . American Journal of Respiratory and Critical Care Medicine 158~5~:S1-S76.
From page 195...
... Clinical and Experimental Allergy 29~1~:28-34. Brundage JF, Scott RM, Lednar WM, Smith DW, Miller RN.
From page 196...
... 1987. Monoclonal immunoassays for the major dust mite (Dermatophagoides)
From page 197...
... 1998. The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma.
From page 198...
... III: house dust mite, cat, dog and cockroach allergens in British hospitals. Clinical and Experimental Allergy 28~1~:53-59.
From page 199...
... American Journal of Respiratory and Critical Care 155~4~:1349-1355. [Published erratum appears in Am J Respir Crit Care Med 1997.
From page 200...
... 1998. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma.
From page 201...
... environmental intervention to reduce cockroach allergen exposure in inner-city homes. Journal of Allergy and Clinical Immunology 103~3 Pt 1~:501-506.
From page 202...
... The relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. American Journal of Respiratory and Critical Care Medicine 160~1~:227-236.
From page 203...
... 1995. A major house dust mite allergen disrupts the immunoglobulin E network by selectively cleaving CD23: innate protection by antiproteases.
From page 204...
... 1999. Washing the dog reduces dog allergen levels, but the dog needs to be washed twice a week.
From page 205...
... 1996. House dust mite allergen in pillows [see comments]
From page 206...
... American Journal of Respiratory and Critical Care Medicine 158~3~:998-1001. [Published erratum appears in Am J Respir Crit Care Med 1998.
From page 207...
... The Normative Aging Study. American Journal of Respiratory and Critical Care Medicine 156~1~:23-27.
From page 208...
... American Journal of Respiratory and Critical Care Medicine 154:1641-1646. Micillo E, Marcatili P
From page 209...
... 1983. Dust-free bedrooms in the treatment of asthmatic children with house dust or house dust mite allergy: a controlled trial.
From page 210...
... American Journal of Respiratory and Critical Care Medicine 154~6 Pt 1~:1623-1628. Nowak D, Heinrich J
From page 211...
... 1996. House dust mite allergens.
From page 212...
... 1999. House dust mite allergen (Der p I)
From page 213...
... 1990b. Measurement of allergens associated with dust mite allergy.
From page 214...
... 1996a. Socioeconomic status and race as risk factors for cockroach allergen exposure and sensitization in children with asthma.
From page 215...
... 1989. The relative risks of sensitivity to grass pollen, house dust mite, and cat dander in the development of childhood asthma.
From page 216...
... 1996. Skin prick test to house dust mite, asthma and hyperreactivity in a cohort of young rurals.
From page 217...
... 1990. Exposure to house-dust mite allergen (Der p I)
From page 218...
... Clinical and Experimental Allergy 24~12~:1123-1129.
From page 219...
... 1999. Evaluation of materials used for bedding encasement: effect of pore size in blocking cat and dust mite allergens.
From page 220...
... 1991. The influence of exposure to house dust mite on sensitization in asthma.
From page 221...
... American Journal of Respiratory and Critical Care Medicine 158~1~:115-120. Woodcock A, Custovic A
From page 222...
... American Journal of Respiratory and Critical Care Medicine 149~5~:1348-1353. Yman L, Brandt R


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