Indoor environmental exposures and their relationship to allergic diseases

Abstract

Cockroach, dust mite, cat, dog, mouse, and molds are major indoor allergens that have been associated with the development of allergic diseases and disease morbidity in allergen-sensitized individuals. Physical characteristics, such as allergen particle size, hydrophobicity, and charge, can determine an allergen’s propensity to become airborne, location of respiratory tract penetration, and ability to elicit IgE responses in genetically predisposed individuals. Standardization and recent advancements in indoor allergen assessment serve to identify sources and distribution of allergens in a patient’s home and public environment, inform public policy, and monitor the efficacy of allergen avoidance and therapeutics. Allergen exposure interventions have yielded mixed results with current US and international asthma guidelines differing on recommendations. A pragmatic, patient-centered approach to allergen avoidance includes: i) tailoring intervention to the patient’s sensitization and exposure status; ii) using a rigorous multi-faceted intervention strategy to reduce allergen exposure as much as possible; iii) beginning the intervention as soon as the patient is diagnosed. Further research into the risks/benefits of early allergen exposure, rapid and affordable in-home allergen assessment, and best practices for environmental control measures for asthma are needed.

Introduction

Environmental allergen exposure is a known risk factor for allergic sensitization and is associated with the development of allergic diseases, such as allergic rhinitis and asthma.^1–7 Allergen exposure has been extensively associated with allergic rhinitis and asthma morbidity in allergen-sensitized patients.^8–17 Clinical trials have reported an association between reduction in allergen exposure and improvement in asthma symptoms and outcomes^18–23 with national asthma guidelines recommending multicomponent allergen-specific mitigation intervention in patients with symptoms around indoor allergens.²⁴ Therefore, there is great interest in the proper assessment of environmental allergen exposures and how these exposures relate to clinical disease and can be applied to patient management. Knowledge of the structural biology of allergens has increased exponentially over the past 20 years.²⁵ Reliable and consistent immunoassays have been developed to monitor environmental allergen exposures and used in epidemiologic studies to investigate relationship(s) between exposure, sensitization, and allergic disease.²⁶ These assays have also played a pivotal role in developing household cleaning products, devices, and procedures that are designed for consumer use to reduce allergen exposures and improve indoor air quality (IAQ). This review will focus on major indoor allergens (cockroach, dust mite, cat, dog, mouse, and molds), their clinical importance, and how environmental exposure assessment can improve health outcomes.

Major indoor allergens, distribution, particle sizes

While outdoor allergens can be found indoors, here we focus on the major indoor allergens that have been associated with allergic rhinitis and asthma, principally cockroach, dust mite, cat, dog, mouse, and fungi (“molds”). Allergen particle size is a key determinant in enabling allergens to become airborne and predicts where in the respiratory tract allergens can penetrate to cause allergic inflammation and symptoms. Particles ≥10μm in size are largely deposited in the upper airways while the majority of particles <10μm can penetrate the lower airways.^27–29

Cockroach:

German cockroach (Bla g 1 and Bla g 2) and American cockroach (Per a 1) are well-studied cockroach allergens^30,31 found in cockroach saliva, debris, secretions, and fecal matter.³² The majority of cockroach allergens are associated with large particles ≥10μm and are more likely to be found in settled dust.³³ However, cockroach allergen has been found on small particles <5 μm and can be found in airborne samples and penetrate the lower airways to a lesser degree.³⁴ Cockroaches are highly prevalent in the United States (US), with highest allergen levels being found in low-income urban areas.^11,35,36 Cockroach allergens can be found in suburban homes, but at lower concentrations than urban homes.³⁷ Cockroaches infest kitchens, cafeterias, bathrooms, and basements and these sites are important to consider when collecting settled dust for exposure assessment.^30,33

Dust mite:

Dermatophagoides pteronyssinus (Der p 1) and D. farinae (Der f 1) are the most clinically relevant dust mites in the United States and worldwide.^2,30,38 Dust mites live on dead skin cells and proliferate in high humidity.⁹ Mattresses, pillows, upholstered furniture, carpeting, and stuffed toys serve as the main dust mite reservoirs in homes. Dust mite allergen is found in mite fecal particles (10–40μm) that occur in high concentrations in settled dust.^38,39 Dust mite allergen becomes airborne during cleaning and vacuuming. Older homes, single-family homes, low-income homes, homes with carpeting, homes in humid locations, and homes without air conditioning commonly have higher concentrations of dust mite allergen.⁹

Cat:

Cats are the second most common American pet, with a recent survey estimating 35% of US households own at least one cat.⁴⁰ Fel d 1, the major cat allergen, is found in saliva, skin, hair follicles, and anal and sebaceous glands.^30,31 Cat allergen is associated with small particles (2–15 μm) that remain airborne for several hours.^28,34 Cat allergen is readily transferred from cat owners’ clothing or belongings to homes without cats and public places such as schools, daycares, workplaces, public buildings, and transportation.^41–48 Given the particle size of cat allergen, airborne sampling is a realistic approach to exposure assessment, although to date, most studies have relied on sampling settled dust.

Dog:

Dogs are the most common American pet, with 54% of US households having at least one dog.⁴⁰ The major dog allergen, Can f 1, is found in dog hair, dander, saliva, and glands. Similar to cat allergen, dog allergen associated with small particles (2–15 μm), remains airborne for extended periods and is transferred to homes and public places.^{28,34,46,47,49} While there is great interest in “hypoallergenic” dog breeds, similar Can f 1 concentrations were reported for hypoallergenic and regular dog breeds.⁵⁰

Mouse:

Mus m 1, the primary mouse allergen, is found in highest concentrations in mouse urine,³⁴ and is also found in dander and hair follicles. Similar to cockroach allergen, mouse allergen exposure is ubiquitous in low-income urban areas with high concentrations reported in urban homes and schools and detection in up to 95–100% of inner-city homes and schools.^{31,42,51–54} Poor housing repair, including cracks in walls and doors, mouse sightings, and the presence of cockroaches have been associated with mouse allergen concentrations.^36,55,56 Mouse allergen is found at lower concentrations in suburban homes.^57,58 Like cat and dog allergen, mouse allergen is associated with small particles^28,34,59 that readily become airborne and can penetrate the lower airways.⁶⁰ Occupational exposure to mouse allergen in university and government research laboratories and the pharmaceutical industry is a cause of laboratory animal allergy. The pharmaceutical industry has adopted arbitrary guidelines to reduce airborne exposure to <5ng/m³ Mus m 1 to mitigate exposure and reduce health risks.⁶¹

Molds:

The two most common clinically relevant indoor molds are Penicillium and Aspergillus.³⁰ Outdoor molds, such as Alternaria, Fusarium, Helminthosporium, and Cladosporium, come indoors by way of open doors and windows or by being carried in by humans and pets.^30,31 Dampness, water leaks, poor plumbing, inadequate ventilation, and home disrepair are risk factors for indoor mold exposure.⁶² Assessment of mold exposure is complicated and even more confusing given the multitude of companies promising mold assessment and abatement. Sampling using settled dust, air filtration, and gravity (i.e. open petri dishes collected after 3–7 days) are all utilized in different settings.

Taking these aerodynamic properties into account, environmental exposure conditions that consistently give rise to allergic sensitization can be defined. Exposure to soluble, low molecular weight proteins on particles of 2–50μm in diameter preferentially elicits IgE responses in genetically predisposed individuals (Table 1). Typical exposures in dust that give rise to sensitization are from <1–50μg/g dust, depending on the allergen, and from 10–200 ng/m3 airborne allergen. The biologic activity of allergens, intrinsic properties of allergen particles (hydrophobicity and charge), and evolutionary distance from humans (the immune system’s ability discriminate between foreign and self proteins is likely different for mammalian allergens versus arthropod allergens)⁶³ may also contribute to their ability to cause sensitization and allergic inflammation. For example, dust mite feces contain endotoxin, bacterial DNA, and chitin which may contribute to Th2 inflammatory responses.⁶⁴ The molecular structures and, in many cases, the biological function(s) of clinically important indoor allergens have been determined and can be accessed through the Protein Data Base (Figure 1).²⁵ Most recently, actual allergenic epitopes on Der p 2 have been identified by X-ray crystallography using a natural human IgE monoclonal antibody to Der p 2.⁶⁵ These epitopes are likely to be biologically significant, but may not account for the full allergenic repertoire of this allergen. In some cases, there is good evidence that allergen function directly contributes to IgE sensitization and inflammation (e.g. the proteolytic activity of Der p 1). The proteolytic activity of Der p 1 has been associated with higher Der p 1-specific IgE and total IgE production.⁶⁶ This increase in IgE may result from proteases in Der p 1 increasing airway permeability and, thus, increasing allergen exposure, activating innate immunity.^67,68

Table 1.

Environmental exposure conditions that ‘predictably’ result in allergic (IgE) responses

Route:	Inhalation (genetically predisposed host)
Antigen:	Soluble 10–50 kDa protein
Particle Size:	2–50 microns diameter
Dose (In dust):	Mite	1–50μg/g
	Cat	0.5–25μg/g
	Roach	0.1–16μg/g
	Mouse	2–30μg/g
Dose (Airborne):	10–200 ng/m3
Annual Exposure:	1–1000μg

Figure 1.

Molecular structures of common indoor allergens (© InBio, 2023).

Value of indoor allergen exposure assessment

The development of sensitive and specific immunoassays for environmental exposure assessment was one of the first uses of specific allergen molecules and preceded their use in component resolved diagnostics. Simple monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) for major allergens were an integral part of clinical and epidemiologic studies to establish primary sources of allergen exposure, geographic distribution and dose responses that were associated with allergic disease. Standardized dust sampling methods and consistent expression of the data (in μg allergen per gram dust) enabled direct comparison of clinically relevant exposure levels. The need for high throughput assays that measured multiple allergens prompted the development of a Multiplex ARray for Indoor Allergens (MARIA) which typically measures 6–12 allergens simultaneously. The use of dust and air sampling devices together with MARIA technology has recently been reviewed.²⁶ The multiplex technology is more sensitive than ELISA and is especially useful for monitoring airborne allergen exposure. The technology has been validated in large population studies of allergen exposure, including the National Health and Nutrition Examination Survey (NHANES) and the Schools Inner City Asthma Studies (SICAS).^69,70 These studies involve thousands of samples being tested for multiple allergens, which would not be practicable using ELISA.²⁶ Allergen exposure assessment using MARIA has become almost ‘routine,’ with the exception that this technology is laboratory-based. Rapid and quantitative point-of-care tests and devices for multiple allergens are needed to enable allergic patients to assess allergen exposures in their homes.

The value of allergen exposure assessment to clinical outcomes and public health may be summarized as follows:

1. Identification of the sources and distribution of allergens in homes, schools and workplaces. Definition of environmental factors or conditions in the built environment that predispose to allergen exposure or adversely affect IAQ.

2. Epidemiologic studies of exposure assessment that can drive health care policy decisions. The NHANES outcomes demonstrated multiple allergen exposures in homes across the U.S. and that exposure to cat and dog allergens was associated with ~700,000 emergency department visits per year.¹³ A key SICAS outcome was that mouse allergen was the dominant exposure in public schools in the Northeastern U.S.⁷⁰ These findings inform the policy debate about the significance of these exposures and how they can be used to improve allergy and asthma outcomes in these populations.

3. Monitoring the efficacy of allergen avoidance or mitigation efforts using physical and/or chemical reduction strategies, engineering controls (e.g. high-efficiency particulate air filters, directional air flow, differential air pressures), reductions in humidity or other allergen control systems.

4. Monitoring the efficacy of allergy therapeutics and new anti-asthma drugs and biologics. For many years, European allergen manufacturers have used indoor allergen measurements as part of their potency assessments for immunotherapy products in accordance with European regulatory guidelines. The US FDA uses measurements of Fel d 1 and Amb a 1 for potency of cat and ragweed standardized extracts.⁷¹ Airborne allergen measurements are critical for monitoring exposure levels in Environmental Exposure Chambers (EEC) that are being used in clinical trials of anti-asthma drugs and biologics.^72,73

Indoor allergen exposure and allergic sensitization, the development of allergic diseases, and asthma morbidity

Indoor allergen exposure has been extensively associated with allergic sensitization.^2,3,5,57,74 Multiple studies have shown exposure to higher cockroach, dust mite, and mouse allergen concentrations are associated with risk of allergen-specific sensitization, with evidence of dose-response relationships for cockroach, dust mite, and mouse allergen exposure and risk of sensitization.^2,5,57,75. In one inner-city asthma study, allergen-specific IgE to cockroach, dust mite, and mouse correlated with allergen-specific settled dust concentrations exposure among sensitized participants.⁷⁶ Sensitization to cat and dog are common in the US, but there is less compelling evidence that sensitization to cat and dog increases with exposure and studies have described conflicting results.^5,76,77

Interestingly, the association between indoor allergen exposure and the development of allergic diseases is less clear cut. Indoor allergen sensitization, which is associated with allergen exposure per above, has been repeatedly associated with the development of allergic disease, yet emerging data suggest early life exposure to indoor allergens may actually be protective against the development of allergic disease in high risk populations. Several studies have shown an association between sensitization to cockroach, dust mite, cat, dog, and mouse and subsequent risk of wheeze, asthma, rhinitis, and atopic dermatitis.^6,7,78–80 Similarly, exposure to mold and dampness have also been associated with wheezing and the development of asthma.^81–85 However, early life (age < 3 years) exposure to cockroach, cat, and mouse in children has been associated with decreased risk of wheezing at age 3 and decreased risk of development of asthma at age 7 in children at high risk for atopic disease.^86,87 This complex relationship between exposure and the development of allergic disease is likely influenced by other factors associated pest and cat allergen exposure (e.g. the microbiome of the pest or cat) and is beyond the scope of this review.

While our understanding of the relationship between indoor allergen exposure and allergic disease development continues to evolve, it is abundantly clear that indoor allergen exposure in allergen-sensitized patients with asthma is a major cause of asthma morbidity. There is extensive evidence that cockroach and mouse exposure in sensitized urban patients with asthma is associated with asthma symptoms, days of missed school and work, medication use, controller medication treatment step, lower lung function, air trapping, exacerbations, healthcare utilization, and asthma severity.^{11,14–16,60,88} Dust mite, cat, dog, and mold exposure have also been associated with asthma symptoms, exacerbations, lower lung function, and healthcare utilization.^{10,13,17,85,89,90}

Indoor allergen avoidance and mitigation

Although allergen avoidance to reduce asthma symptoms has been practiced for over 100 years, currently there are differing opinions about the role of avoidance in asthma management.

Pro

• In areas of the world with very low humidity, allergic sensitization and asthma is not related to dust mites, suggesting that removal of the dust mite allergen could mitigate asthma. These include Los Alamos, NM, the Italian Dolomites and Northern Sweden.⁹¹ In some of these areas, asthma is associated with sensitization and exposure to cat and dog allergens, but not to dust mite as is commonly seen in other areas with cat and dog exposure.

• Admission of asthma patients to hospital rooms or sanatoria at high altitude with negligible dust mite allergen levels (<0.3μg/g Der p 1) is associated with reduced airway hyper-reactivity and improvement in asthma symptoms. A recent EAACI position paper recommended Alpine Altitude Climate Treatment (AACT) for severe and uncontrolled asthma because of environmental allergen avoidance and a concomitant reduction in inflammatory effects.^91,92

• A landmark study by Morgan et al showed that tailored reduction of dust mite and cockroach allergens was associated with improved asthma symptoms and a decrease in unscheduled ED or clinic visits for asthma.¹⁸ Impressively, in the year following the study, reductions in both allergen concentrations and asthma symptoms were sustained without continued intervention and the magnitude of the effect was equivalent to or greater than using inhaled corticosteroids.¹⁸ A 2005 study also demonstrated a reduction in cockroach allergen concentration and an associated reduction in asthma symptoms.⁹³

• The recent PAXAMA study (Preventing asthma exacerbations by avoiding mite allergen), a double blind placebo controlled study of mite-impermeable bed covers, showed significant reduction in asthma exacerbations in children aged 3–17 years over a 12 month period, with 45% lower risk compared with the placebo group.^22,94

• Current US asthma management guidelines from the National Asthma Education and Prevention Program (NAEPP) Expert Panel recommend multi-component allergen-specific mitigation interventions, including integrated pest management for cockroaches and rodents and mattress covers to be part of a multi-component approach for dust mite.²⁴

Con

• Several recent studies have failed to achieve a difference in allergen reduction or clinical outcomes between treatment groups. These studies targeted multiple allergens (dust mite, cockroach, mouse, cat, and dog, plus mold in one study) and found no difference in asthma treatment step, control, and/or symptom days between groups.^95–97 Both groups experienced allergen reduction in one study.⁹⁵ Allergen concentrations were not different between groups in the other two studies,^96,97 possibly explaining the lack of clinical effect. Meta-analyses have also concluded that dust mite allergen mitigation has not proven to be consistently effective.^98,99

• Recent single allergen intervention trials have also shown mixed results. Matsui et al²⁰ targeted mouse allergen in sensitized and exposed urban children with asthma. Both groups achieved large reductions in mouse allergen concentrations, which was not different between groups. Only when groups were combined for analyses, mouse allergen exposure reduction was associated with an improvement in asthma symptom days, which was not different by trial group.²⁰ Rabito et al²¹ targeted cockroach allergen in children with asthma and in-home cockroach infestation. Cockroach counts were markedly reduced in both groups, but to a greater extent in the intervention group. The intervention group experienced a significant reduction in maximum symptom days, urgent visits, and proportion of participants with an FEV₁ <80% predicted.²¹

• The Global Initiative for Asthma (GINA) strategy for asthma management and prevention does not recommend allergen avoidance for treatment of asthma because of lack of perceived clinical benefit of single avoidance measures (though acknowledging limited benefit of multi-faceted approaches).¹⁰⁰

Both the NAEPP Expert panel and the GINA recommend further investigation of environmental control measures for asthma.¹⁰⁰ Based on a thorough examination of the evidence pro and con, Custovic, Simpson and colleagues have recently proposed a pragmatic approach to allergen avoidance for use in clinical practice: i) tailor the intervention to the patient’s sensitization and exposure status; ii) use a rigorous multi-faceted intervention strategy to reduce allergen exposure as much as possible; iii) begin the intervention as soon as the patient is diagnosed.⁹⁴

Clinical use of allergen exposure measurements and allergen mitigation

The interventions recommended by Custovic, Platts-Mills, and others^91–94 raise questions about the role of allergen exposure assessments in clinical practice. Allergen exposure measurements are commonplace in allergy research. Literally hundreds of thousands of dust and air samples have been analyzed since the 1980s, yet exposure assessments are not routinely performed in clinical practice, where they have most potential to improve healthcare outcomes. The NAEPP and GINA guidelines use IgE sensitization as a surrogate for exposure, though a positive skin test is not necessarily indicative of current exposure. Other surrogates for exposure include questions about the patient’s home environment, such as the presence of pets in the home, sightings of cockroach and mice, and known dampness, mold, or water leaks. Patients can be exposed to these allergens without allergen sightings in the home and the use of questionnaires has not been adequately validated against specific allergen measurements. US health insurance does not currently cover the cost of allergen exposure assessment in patients’ homes nor does it cover the cost of allergen mitigation. Likewise, health insurance does not cover the costs or mitigation of other health related environmental exposures in the home, including radon, volatile organic compounds, nitrogen oxides, and other air pollutants. Typically, these kinds of exposures in the built environment are handled by IAQ consultants. Current trends in healthcare are for patient-centered approaches to disease management, including asthma.¹⁰¹ This provides an opportunity for healthcare providers including allergists, IAQ providers, and community clinics (medical homes) to evaluate exposure assessment as part of a patient-centered asthma management plan.

Conclusions

Environmental allergen exposure is a well-established risk for allergic sensitization and, allergic disease morbidity, in allergen-sensitized individuals. Allergen particle size determines how readily allergen is airborne and transferred and where in the respiratory tract the allergen can penetrate, and thus cause disease morbidity. Standardized dust and air sampling methods in combination with newer MARIA technology enable multiple allergens to be sampled simultaneously in research. Clinical assessment of environmental allergen exposure remains infrequent and faces obstacles, including lack of insurance coverage.

Advantages and arguments for broader environmental allergen exposure include identification of allergen sources and distribution in homes and public places, epidemiological data to help inform public policy, and monitoring of response to allergen intervention and allergic therapies. However, mixed results from environmental intervention studies, including failure to consistently reduce allergen concentrations and lack of clinical effect, have likely prevented NAEPP and GINA guidelines from more broadly recommending allergen avoidance and control measures. Further research into whether early allergen exposure is protective against allergic disease in the all populations is needed before general recommendations can be given. Future research into best practices as to how to affordably and accurately assess an individual patient’s home, school, and work allergen exposure are needed to allow for a patient-centered approach involving individually tailored, multi-faceted intervention based on the patient’s sensitization beginning at the time of diagnosis.

Abbreviations:

ELISA

Enzyme-linked immunosorbent assay

FDA

Food and Drug Administration

GINA

Global Initiative for Asthma

IgE

Immunoglobulin E

IAQ

Indoor air quality

MARIA

Multiplex ARray for Indoor Allergens

NAEPP

National Asthma Education and Prevention Program

NHANES

National Health and Nutrition Examination Survey

SICAS

Schools Inner City Asthma Studies

US

United States