Key Points
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Studies in both inner city and suburban locations indicate that more than 80% of school age children with asthma are sensitized to at least one indoor allergen.
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The level of early life environmental exposure to a specific indoor allergen influences the development of sensitization to that allergen and subsequent atopic conditions.
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Humidity levels greater than 50% promote house dust mite growth and house dust mite allergy has been associated with asthma development, severity and morbidity.
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Given the lack of scientific evidence, it is standard for current guidelines to state that hypoallergenic cats and dogs should not be recommended for individuals who are sensitized.
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In urban environments, several important studies have demonstrated the relationship between cockroach exposure and poor asthma outcomes in children.
Introduction
Allergens found in house dust have been associated with asthma since the 1920s, when Kern and Cooke independently reported a high prevalence of immediate skin tests to house dust extracts among patients with asthma. Van Leeuwen showed that asthmatics who were admitted to a modified hospital room free of ‘climate allergens’ (thought to be bacteria and molds) showed clinical improvement. Allergists sought to explain how a heterogenous material such as house dust could contain a potent allergen that appeared to be ubiquitous. The puzzle was finally resolved in 1967, when Voorhorst and Spieksma showed that the origin of house dust allergen was biologic. Extracts of mite cultures gave positive skin tests, and asthma symptoms correlated with seasonal variation in mite numbers. Exposure to 100 mites per gram of dust was associated with sensitization, and 500 mites per gram was associated with symptom exacerbation.
Over the past few decades, the investigation of the important role of indoor allergens in the pathogenesis of allergic disease has included the identification of the most important allergens, the evaluation of the effect of allergen exposure on allergic disease, and the development of techniques to accurately monitor allergen exposure. The primary indoor allergens include allergens from house dust mite, pets such as dogs and cats, molds, and pests such as cockroach and rodents. This chapter reviews the structure and biologic function of indoor allergens, the clinical significance of the primary indoor allergens and the methods for assessing environmental exposure.
Allergen Structure and Function
Allergens are proteins or glycoproteins of 10 to 50 kDa that are readily soluble and able to penetrate the nasal and respiratory mucosae. A systematic allergen nomenclature has been developed by the International Union of Immunological Societies’ (IUIS) Allergen Nomenclature Subcommittee: the first three letters of the source genus followed by a single letter for the species and a number denoting the chronologic order of allergen identification. For example, the abbreviated nomenclature for the house dust mite allergen, Dermatophagoides pteronyssinus allergen 1, is Der p 1 (see http://www.allergen.org ). To be included in the IUIS nomenclature, the allergen must have been purified to homogeneity and/or cloned, and the prevalence of IgE antibody must have been established in an appropriate allergic population by skin testing or in vitro IgE antibody assays. Molecular cloning has determined the primary amino acid sequences of more than 500 allergens and most common allergens can be manufactured as recombinant proteins. There are over 50 three-dimensional structures of allergens in the Protein Database (PDB) and allergens are found in protein families in the Pfam protein family database ( http://www.sanger.ac.uk/software/Pfam ).
The x-ray crystal structures of Der p 1 and Der f 1 ( Dermatophagoides farinae 1) are shown in Figure 21-1 . It is noted that only a small percentage of the more than 10,000 protein families in Pfam are allergens. This implies that only a limited group of proteins (with certain structural features) have the potential to become allergens; however, detailed structural analyses have not revealed any common features or motifs that are associated with the induction of IgE responses.
Allergens belong to protein families with diverse biologic functions including enzymes, enzyme inhibitors, lipid-binding proteins, ligand-binding proteins, structural proteins or regulatory proteins ( Box 21-1 ). Some dust mite allergens are digestive enzymes excreted with the feces, such as Der p 1 (cysteine protease), Der p 3 (serine protease) and Der p 6 (chymotrypsin). Enzymatic activity of mite allergens promotes IgE synthesis and local inflammatory responses via cleavage of CD23 and CD25 receptors on B cells and by causing the release of proinflammatory cytokines (interleukin [IL]-8, IL-6, monocyte chemotactic protein-1 [MCP-1] and granulocyte-monocyte colony-stimulating factor [GM-CSF]) from bronchial epithelial cells. Mite protease allergens cause detachment of bronchial epithelial cells in vitro and disrupt intercellular tight junctions. Activation of mite proteases could damage lung epithelia and allow access of other nonenzymatic allergens, such as Der p 2, to antigen-presenting cells. Der p 2 has structural homology to MD-2, the lipopolysaccharide (LPS) binding component of the Toll-like receptor 4 (TLR4) complex. Recent studies have shown that Der p 2 can drive signaling of the TLR4 complex and may enhance the expression of TLR4 on the airway epithelium and have intrinsic adjuvant activity. Mite feces contain other elements, including endotoxin, bacterial DNA, mite DNA and chitin that could also influence IgE responses and inflammation.
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Allergens are soluble proteins or glycoproteins of molecular weights of 10 to 50 kDa.
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More than 500 allergen sequences are deposited in protein databases (GenBank, PDB), and more than 50 tertiary structures have been resolved by x-ray crystallography.
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Allergens have diverse biologic functions and may be enzymes, enzyme inhibitors, lipid-binding proteins, lipocalins or regulatory or structural proteins.
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Allergens promote T cells to differentiate along the Th2 pathway to produce IL-4 and IL-13 and to initiate isotype switching to IgE.
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Biologic functions of allergens, such as proteolytic enzyme activity or other adjuvant-like effects, can enhance IgE responses, damage lung epithelium and cause allergic inflammation.
With the exception of cat allergen Fel d 1 ( Felis domesticus 1), most animal allergens are ligand-binding proteins (lipocalins) or albumins. Lipocalins are 20–25kDa proteins with a conserved, eight-stranded, antiparallel β-barrel structure that bind and transport small hydrophobic chemicals. In contrast, Fel d 1 is a calcium-binding, steroid-inducible, uteroglobin-like molecule – a tetrameric 35 kDa glycoprotein, comprising two subunits which are heterodimers of two chains comprising eight α-helices. Fel d 1 has two amphipathic water-filled cavities which may bind biologically important ligands. Rat and mouse urinary allergens are pheromone- or odorant-binding proteins. The cockroach allergen Bla g 4 ( Blattella germanica 4) is a lipocalin that is produced in utricles and conglobate glands of male cockroaches and may have a reproductive function. Other important cockroach allergens include: Bla g 1, a gut-associated allergen; Bla g 2, an inactive aspartic proteinase; Bla g 5 (glutathione transferase family); and the Group 7 tropomyosin allergens.
Clinical Significance of Indoor Allergens
Exposure data collected in epidemiologic studies, population surveys and birth cohort studies have strengthened the association between indoor allergen exposure and the pathogenesis of allergic respiratory diseases including asthma and allergic rhinitis. The measurement of indoor allergen levels in dust and air samples has allowed for the determination of risk levels for allergen exposure leading to both sensitization and symptom exacerbation. International workshop reports recommend that allergen exposure be expressed as µg allergen/gram dust (µg/g) for dust samples or ng/m 3 for air samples. Childhood asthma is more closely linked to allergic sensitization and allergen exposure than adult asthma. Sensitization to indoor allergens likely occurs earliest in life as young children have been shown to have higher rates of sensitization to indoor allergens as compared to outdoor allergens. Studies in both inner city and suburban children with asthma indicated that more than 80% of school age children with asthma are sensitized to at least one indoor allergen and that allergic sensitization is a strong predictor of disease persistence in later life. In one large inner city study, 94% of the study population of severe asthmatics was sensitized to at least one allergen and the number of sensitivities correlated with asthma severity. Furthermore, European cohorts have demonstrated that high-level allergen exposure in early life is associated with chronic asthma in children. Epidemiologic studies have demonstrated risk of allergic sensitization to be attributable to certain levels of allergen exposure among different populations of atopic individuals ( Table 21-1 ).
| ALLERGEN LEVEL IN DUST SAMPLE | |||||
|---|---|---|---|---|---|
| Risk for Sensitization * | Mite Group 1 (µg/g) | Fel d 1 (µg/g) | Can f 1 (µg/g) | Bla g 1 (U/g) | Bla g 2 (µg/g) |
| Low | <0.3 † | <0.5 or >20 | <0.5 or >20? | <0.6 | <0.08 |
| Medium | 2–10 | 8–20 | 8–20 | 1–8 | 0.08–0.4 |
| High | >10 | 1–8 | 1–8 | >8 | >1 |
† Levels found in ‘allergen-free’ hospital rooms or in houses/apartments maintained for at least 6 months at less than 45% relative humidity.
Dust Mites
The two principal mite species, D. pteronyssinus (Der p) and D. farinae (Der f), account for more than 90% of the mite fauna in US house dust samples. Other allergenic mites include Euroglyphus maynei and Blomia tropicalis (found in subtropical regions such as Florida, southern California, Texas and Puerto Rico). Storage mites, such as Lepidoglyphus destructor, Tyrophagus putrescentiae and Acarus siro, cause occupational asthma among farmers, farm workers and grain handlers.
House dust mites (Der p and Der f) are found in dust and products with woven material or stuffing such as mattresses, pillows, stuffed animals and bedding. Warmth and humidity greater than 50% are the major factors that promote dust mite growth. Rabito et al found that, in New Orleans, asthmatic children living indoors with average humidity greater than 50% were three times more likely to be exposed to elevated levels of house dust mites. In contrast, house dust mite levels are generally low or undetectable in areas of high altitude or low humidity. In fact, maintaining an indoor humidity below 50% is one of the recommended components of interventions to reduce dust mite exposure.
More than 50% of children and adolescents with asthma are sensitized to house dust mites. There is strong evidence for a dose-response relationship of exposure to house dust mites and sensitization in both cross-sectional and prospective studies. Mite allergen levels at high altitude or in ‘allergen-free’ rooms are generally <0.3 µg/g and <10% of atopic individuals are likely to become sensitized at this low level of mite exposure. Persistent exposure of atopic individuals to ≈2 µg of mite allergen is likely to result in sensitization in a majority of atopic individuals, increasing as mite allergen levels exceed 2 µg/g ( Table 21-1 ). A prospective study of German schoolchildren demonstrated a 7-fold increase in sensitization to dust mites between children exposed to dust mite allergen levels in the first quartile (<0.3 µg/g) as compared to those exposed in the highest quartile (1–240 µg/g). Exposure to dust mite allergen levels greater than 10 µg/g is considered high risk for sensitization, and findings from the National Survey of Lead and Allergens in Housing (NSLAH) indicate that these levels are found in ≈23% of US homes (22 million housing units).
Asthma development, severity and morbidity have been strongly associated with house dust mite allergy. Dust mite exposure influences the development of asthma by exposure leading to sensitization and subsequent asthma symptoms. Sporik et al demonstrated dust mite exposure to be an important factor in the development of childhood asthma, particularly if there was exposure to high levels in the first year of life. The relative risk of asthma was almost five times greater in the subjects who were exposed to high levels of dust mite allergen (>10 µg/g). Tovey et al showed a nonlinear relationship between levels of dust mites in homes and the development of asthma at 5 years of age in a high risk cohort of children. The trends showed increasing prevalence of sensitization and asthma correlating with dust mite exposure up to a critical point and then sharply dropping at the highest level of exposure (>23.40 µg/g for Der p 1). The explanation of attenuated disease development with very high levels of dust mite exposure is unclear but may indicate that high concentrations of nonallergenic immune modifiers such as endotoxin are accompanying the house dust mites. Celedon et al found a dose response relationship between levels of dust mite exposure in high risk infants at age 2–3 months and asthma at school age. In this study, the high allergen threshold was ≥10 µg/g, much lower than the critical threshold found in Tovey’s evaluation. A survey of middle school children in Virginia showed that dust mite sensitization was independently associated with asthma (OR 6.6, P < .0001) and that dust from 81% of homes contained more than 2 µg/g mite group 1 allergen. In addition to the implications for developing asthma, sensitization to dust mites predicts worse lung function as compared to those not sensitized.
Pets (Cat and Dog)
The major cat allergen, Felis domesticus 1 (Fel d 1), is primarily found in cat skin and hair follicles and is produced in sebaceous, anal and salivary glands. The major dog allergen, Canis familiaris 1 (Can f 1), is found in hair, dander and saliva. What distinguishes pet allergen exposure from other indoor allergens is the wide range of exposure levels (from <0.5 to >3000 µg/g) and the ubiquitous allergen distribution. The small particles of cat and dog allergen can scatter easily in the air and adhere to clothing for further dispersal. As such, these allergens are found in non-pet homes, schools and public places.
Data on cat and dog allergen exposure in relation to sensitization are more difficult to interpret as there is a nonlinear relationship. This nonlinear relationship of pet allergen exposure and risk of sensitization is seen in Table 21-1 . Exposure to Fel d 1 of <0.5 µg/g is considered to be low and is a low risk for sensitization. Paradoxically, the prevalence of sensitization is also reduced among atopic individuals who are continuously exposed to high levels of Fel d 1 (>20 µg/g). This high level of exposure appears to reduce the prevalence of sensitization by ≈50%. High exposure to Fel d 1 (>20 µg/g) gives rise to a modified Th2 response – a form of tolerance that results in a lower prevalence of IgE antibody responses. Studies have demonstrated that infants exposed to the highest levels of cat allergen had decreased cat-specific IgE levels and high allergen-specific IgG levels corresponding to a low risk phenotype for atopy. This helps to explain why early exposure to cat has been found protective for asthma and other atopic conditions. The nonlinear dose response may also explain why, in population surveys, sensitization to cats is often lower than that to dust mites. In countries such as New Zealand, where 78% of the population owns cats and high levels of allergen occur in houses, the prevalence of sensitization to cat is only 10% and cat is not as important a cause of asthma as dust mites. Most houses that contain cats or dogs have Fel d 1 or Can f 1 levels of greater than 10 µg/g, whereas homes that do not contain these pets usually have allergen levels of 1 to 10 µg/g, placing those inhabitants at the highest risk for sensitization.
In addition to risk of sensitization, studies have demonstrated that cat allergen exposure early in life is associated with the development of asthma. In geographic areas where dust mite levels are low, dog and cat have been found to be the primary allergens associated with asthma. Increased exposure in sensitized individuals may lead to higher rates of asthma; however, a Norwegian study reported that cat exposure led to an increased risk of asthma independent of cat sensitization. This result indicates a possible nonallergic mechanism. Regardless, an already sensitized child who lives in a home without a cat can become symptomatic by visiting homes or attending schools where cat allergen is present, even if those locations do not physically have any cats. Schools are the best example of this phenomenon. A Swedish study showed a 9-fold increased risk of asthma exacerbations at school among elementary schoolchildren who attended classes with other students from cat homes as compared to children who attended classes with fewer than 18% cat owners. Thus, passive exposure of schoolchildren to animal allergens can exacerbate asthma, even among asthmatic children who are purposely avoiding pets.
Similar to cat allergen, dog allergen has a nonlinear dose-response relationship between exposure and development of sensitization. A medium-dose exposure of Fel d 1 (1–8 µg/g) is most strongly associated with the development of sensitization as seen in Table 21-1 . Dog exposure and asthma is less studied. A recent meta-analysis noted a slightly increased, statistically significant, relative risk of asthma in pet owners, not taking into account allergic sensitization. Other birth cohort studies have not been suggestive of an association.
Recently, issues regarding so-called ‘hypoallergenic’ pets have arisen. Many pet companies have aggressively marketed the benefits of these pets. It is important to stress that there is no scientific evidence to support the existence of ‘hypoallergenic’ pets. In fact, Vredegoor et al actually found higher levels of Can f 1 in hair and fur samples of ‘hypoallergenic’ dog breeds as compared to non-hypoallergenic breeds. In the homes of these pets, the same study found that there were not any differences in Can f 1 levels in settled floor dust or air samples between the two groups. Currently, it is standard for guidelines to state that hypoallergenic cats and dogs should not be recommended for individuals who are sensitized.
Cockroach
The German ( Blattella germanica ) and American ( Periplaneta americana ) cockroaches are the most common species to cause allergies. The major allergens, Bla g 1, Bla g 2 and Per a 1, are found in saliva, fecal material, secretions, cast skins and debris. Urban environments, low socioeconomic status, multifamily homes and old buildings are risk factors for cockroach infestation and higher levels of cockroach allergen. The National Cooperative Inner-City Asthma Study (NCICAS) found that 85% of collected dust samples had detectable levels of cockroach allergen. In public housing residences of New York City, 77% were found to have evidence of cockroaches. Cockroach allergen exposure is typically assessed by measuring Bla g 1 and Bla g 2, which cause sensitization in 30% and 60% of cockroach-allergic patients, respectively. Most dust samples from cockroach-infested homes contain both allergens, and there is a modest, but significant, correlation between levels of the two allergens.
Increased cockroach exposure leads to increased risk of sensitization. Although the highest levels of cockroach allergen are typically found in kitchens, Eggleston et al demonstrated that the bedroom concentration of cockroach allergen was most associated with cockroach sensitization. More recent work by Chew et al showed this relationship to be dose responsive between inner city home cockroach level and cockroach sensitization in children. Cockroach allergens appear to be particularly potent. Atopic individuals develop IgE-specific responses after exposure to 10-fold to 100-fold lower levels of cockroach allergen as compared to dust mite or cat.
Several important studies have demonstrated the relationship between cockroach exposure and poor asthma outcomes in children. Most notably, Rosenstreich et al demonstrated that asthmatic children living in inner cities who were sensitized to cockroach and exposed to high levels of cockroach allergen (>8 U/g) had significantly more frequent hospitalizations, more days with wheezing, more unscheduled medical visits for asthma, more missed school days and more nights with lost sleep. This study demonstrates the important principle of allergic disease – that sensitization plus exposure leads to symptoms. In that inner city study, similar patterns were not found for the combination of sensitization to dust mites or cat and exposure to higher levels. A follow-up study confirmed these findings with cockroach allergen having a greater effect on asthma morbidity in the inner city as compared to dust mite or pet allergens. These findings underscore the importance of cockroach allergen as a major factor in asthma control for children living in urban environments. Additionally, cockroach allergen exposure has been shown to increase the risk of development of childhood wheeze in longitudinal studies.
Mouse
The major mouse allergens are Mus musculus 1 and 2 (Mus m 1 and Mus m 2). These allergens are found in mouse urine, dander and hair. The allergen can be found in homes with and without mice infestation as the allergens easily migrate on dust particles. Factors that increase mouse infestation are high population density (high rise apartments and multifamily dwellings), clutter and integrity of the residence. It is one of the few allergens to span environments from inner city to suburban areas, affecting both homes and schools. Phipatanakul et al found that 95% of inner city homes in multiple US cities had detectable mouse allergen levels and the highest levels in those homes were found in the kitchens. Similar rates of detectable mouse allergen have been discovered in urban schools and the levels of mouse allergen found in those schools can be higher than the surrounding homes.
Data from inner city studies have shown that subjects living in homes with higher mouse allergen concentrations had significantly higher rates of mouse sensitization. In sensitized individuals, exposure to mouse allergen affects clinical asthma outcomes, leading to increased asthma morbidity. Furthermore, exposure to mouse allergen may lead directly to asthma development. Early life mouse exposure was shown to be associated with increased risk of wheezing in early life. Likewise, current mouse exposure was associated with current wheeze through 7 years of age; however, early mouse exposure in infancy did not predict later wheeze or asthma at 7 years of age. Mouse allergen may lead to current wheeze by acting as a direct irritant, as seen in laboratory workers. Additionally, mouse allergen exposure may lead to sensitization, which has been significantly associated with wheezing in the early years of life.
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