The role of house dust mites and other aeroallergens in atopic dermatitis

The Role of House Dust Mites and Other Aeroallergens in Atopic Dermatitis VINCENT S. BELTRANI, MD

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anaging patients with atopic dermatitis (AD) can be a frustrating experience for many clinicians because of the multiplicity of triggers known to exacerbate the condition. The recognized triggers that must be considered include xerosis, sweating, stress, and contactants such as wool and pets.1,2 Because of these various nonallergic triggers, many dermatologists tend to refute the important role played by allergens. This misapprehension may also result from their inclination to limit the concept of allergy to essentially an Immunoglobulin (Ig)E-type phenomenon, which implies the immediate hypersensitivity mastcell-effector mechanism—and this we know does not produce an eczematous eruption. However, in the last few years, IgE allergen-reactive type-2 T helper (Th2) cells have been detected in atopic individuals, and these cells are now considered to play a pivotal role in the induction and continuation of the chronic allergic inflammatory cascade.3,4

Role of IgE in Antigen Presentation The IgE/mast cell pathway, when first acknowledged, elucidated the mechanisms of anaphylaxis and the socalled atopic diathesis— especially for respiratory symptoms.5 However, dermatologic manifestations, namely eczematous skin lesions, could not be adequately explained by the IgE/mast cell flow of events. Yet, few would deny the existence of a small subset of patients, who associated exacerbations of their eczema with recognized IgE triggers such as foods, animal dander, mold, and even pollens.6 Was elevated IgE in eczema patients merely an epiphenomenon, an indicator of other concurrent atopic disease or did it in fact play a role in inducing AD lesions? It is only recently that IgE receptors have been found not only on mast cells, but also on Langerhans cells and other dendritic antigen-presenting cells of atopic individuals, and it is this finding that has led to studies ultimately showing a direct role for IgE in AD pathogenesis.7,8 From the Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York. Address correspondence to Dr. Vincent S. Beltrani, 29 Fox Street, Poughkeepsie, NY 12601. E-mail address: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

Dendritic antigen-presenting cells have been shown to be necessary for initiating and controlling the immunologic response to pathogens present at the interface with the environment.9 They have a significant capacity to take up and process antigens in this location, but their ability to prime T cells is limited until they undergo phenotypic changes and become effective immunostimulatory cells. Maturation of dendritic cells occurs as they migrate to regional lymph nodes. They begin to express coreceptors and elaborate chemokines that enhance their ability to present antigen to T cells. The high-affinity IgE receptor (Fc⑀RI) that on mast cells facilitates the release of inflammatory mediators plays a different role on Langerhans cells. In AD lesional skin, Langerhans cells expressing Fc⑀RI are present in higher numbers than in the skin of nonatopics; these cells have been shown to be essential in the sensitization phase of AD.5 Moreover, the presence of Fc⑀RI⫹ Langerhans cells bearing IgE molecules is a prerequisite for provoking eczematous lesions in aeroallergen patch tests in atopic patients.10 We now understand that activated Th2 cells are the effector cells for the early stages of AD, and similarly activated Th1 cells account for the later phases.11 Thus, we now have a rational mechanism for the chronicity of AD (in a subset of patients) triggered, and then maintained by IgE antigens which include aeroallergens such as dust, animal danders, etc. The second deterrent to appreciating the putative role of contactants as triggers of AD is that an additional diagnosis, such as allergic contact dermatitis, is not sought once atopy is recognized. Moreover, atopic patients are considered by many clinicians to be less prone to sensitization by contact allergens. On the contrary, atopic patients are indeed sensitized just as frequently to contactants as their nonatopic counterparts under many circumstances.12 In fact, numerous reports document that they react equally to most common allergens, eg, fragrances, rubber accelerators, lanolin, formaldehyde, and others.13,14 Nickel is the most common contact allergen with equal frequency in atopic and nonatopic subjects.15 Most recently, allergy to topical corticosteroids has been increasingly reported in individuals with AD because of the frequent use of such agents on the impaired 0738-081X/03/$–see front matter doi:10.1016/S0738-081X(02)00366-8

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epidermal layer of these patients. Nonfluorinated corticosteroids are especially likely to cause this type of reaction.16 The possibility of corticosteroid allergy should be suspected clinically when there is worsening of eczema at corticosteroid-treated sites.

The Role of Dust Mites in Allergic Diseases Dust mites are the most frequently encountered aeroallergens in temperate climates. Their role in sensitizing asthmatic patients was first reported in 1921, and the association of house dust mite allergy, asthma, and perennial rhinitis has been repeatedly corroborated.17 Accordingly, the treatment of asthma and perennial rhinitis frequently includes immunotherapy with dust mite extract.18 In a 1967 study, dust mites of the Dermatophagoides genus were identified as the single most important allergen in house dust.19 Mites are Arachnids (members of the spider family) with Dermatophagoides farinae the species encountered in North America and Dermatophagoides pternoyssinus common in Europe. Presently, both species are found worldwide. The house dust mite life cycle includes three larval stages, and the total life span is about 3 months. Their principal habitat is fomites— carpet, fabric, upholstery, pillows and mattresses, and there are approximately 100 living mites in each gram of house dust. Their diet consists of human epidermal scale, animal dander, and trace nutrients. The more bare skin present in a home, the more dust mites are likely to be present in that environment. Becaue mites cannot take in fluids by mouth, however, their primary source of water is ambient water vapor. The upper humidity limit is constrained by the occurrence of mold growth, which can inhibit mite development, particularly at relative humidities above 88%. The survival of active adult mites is limited to 4 to 11 days at a relative humidity below 50% at 25°C. The most allergenic material is, in fact, mite fecal matter. The amount of fecal matter produced increases with increasing relative humidity, and the highest levels of allergens found in the environment usually correspond to optimal humidity conditions.20 A 1992 study reported that home air conditioning, by reducing relative humidity, reduces the dust mite population as compared to homes without air conditioning or dehumidification. Der pI and Der pII are the major dust mite respiratory antigens, and importantly, they can persist in the environment long after the death of the mites.21 Dust mite antigens also include other allergenic components such as acaridials, dialdehydes, cysteine proteases, trypsin, eicosapentanoic acid, and citral.22,23 House dust proteases exert profound effects on epithelial cells and promote allergic sensitization. These effects include disruption of intercellular adhesion, increased paracellular permeability, and initiation of cell death.24

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Allergen avoidance is recognized as an integral part of the management of patients with asthma along with antiasthma drugs and immunotherapy.25 The National Institute of Environmental Health Sciences recently reported that over 45% of American homes have bedding with dust mite allergen concentrations that exceed the level necessary for allergic sensitization. They found that certain simple steps—allergen-proof mattresses and pillow covers, weekly laundering of other bedding, careful vacuuming and dry steam cleaning of bedroom carpets and upholstery— can significantly reduce the levels of dust mite allergens in bedrooms.26 In addition, most studies have noted that when indoor humidity is kept below 50%, mite populations do not grow to significant levels.

Dust Mites and Atopic Dermatitis The ubiquity and allergenicity of the dust mite should make it suspect as another possible trigger for exacerbations of the eczematous itchy skin of some atopics. In addition, dust mites have the capability of acting as irritants contact haptens, and IgE antigens on the atopic-impaired, epidermal barrier layer. A 1932 paper reported that patients with atopic eczema improved when they were placed in a dust-free environment, a finding confirmed subsequently by many investigators.27–31 A 1982 study reported positive patch test results when patients with AD were patch tested to purified allergen.32 A PubMed (Medline) search listed almost 60 articles addressing the role of patch testing patients with AD. All but one of these papers support a positive correlation (16 –92% positivity) between dust mites and their putative role as a trigger for exacerbations of AD.33 Despite this overwhelmingly supportive literature, there still remains significant skepticism, primarily among dermatologists, regarding the relevance of these findings to the overall management of patients with AD—perhaps as an antithetic reaction to the zealous support voiced by so many allergists toward the role of aeroallergens in AD. More recently, other investigators have tested patients with AD for dust mite contact sensitivity, and all have similarly reported positive results in a subset of patients.34 –38 (Table 1) The variability in the number of positive patch test results in patients with AD in different studies probably results from different testing techniques used by each investigator. The major flaws in these studies have been the lack of standardized dust mite patch-test material, patient selection bias, and a lack of uniformity in testing. While the lyophilized Der p1 and Der p2 aqueous material used for skin prick testing was used by all the early investigators, many of the later investigators (this author included) have been using a protocol utilizing mite whole body material.38

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Table 1.

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Summary of dust mite patch testing for atopic dermatitis

Investigator Mitchell, et al (1982)31 Young et al (1985)49 Gondo et al (1986)50 Reitamo et al (1986)51 Norris et al (1988)52 Bruynzeel-Koomen et al (1988)53 Langeland et al (1989)54 Clark et al. (1989)55 Tanaka et al (1990)56 Voorst Vader et al (1991)57 Imayama et al (1992)36 Castelain et al (1993)33 Vicenzi et al (1994)37 Gaddoni et al (1994)58 Castelain et al (1995)41 Darsow et al (1995)35 Darsow (1996)38 Ring et al (1996)39 Beltrani (1997)34 Beltrani (1997)34 Pigatto et al (1997)59 Ingordo et al (2000)60 Nedorost et al (2001)61 Yamada et al (1996)62 Manzini et al (1995)63 Wananukul et al (1993)64 Wakugawa et al (1995)65 Totals

Dust Mite Patch

Patients with AD 17 18 6 17 30 15 35 12 20 21 130 272 86 46 450 36 57 26 54 22(head/neck only) 186 17 20 11 313 30 9 1956

Recently, a group of investigators using aeroallergen patch testing has identified a more definite role for aeroallergens in patients who have an air-exposed pattern of their dermatitis.39,40

Patch Testing With Whole-Body Dust Mite Preparations A standardized dust mite allergen is now available from Chemotechnique (Malmo, Sweden). It is available as a 20% and a 30% Dermatophagoides mix in petrolatum. Concentrations above 30% are considered too irritating to the skin to be of value in patch testing. The patch test material is a 1:1 mix of D. farinae and D. pteronyssinus. Using a combination of the whole body preparations of these two most common house dust mites instead of purified allergen decreases the likelihood of missing other possibly relevant dust mite antigens that might contact the skin.41 A standardized protocol for patch testing patients with AD for dust mite contact allergy has been proposed by the Dermatologic Disease Interest Group of the American Academy of Allergy, Immunology, and Asthma. (Table 2) Since this author and others have shown that there is no correlation between dust mite-specific serum IgE levels and dust mite antigen patch testing results, routine skin (prick and/or intradermal) testing is not necessary except possibly for academic confirmation.37,42

17(100%) 15(83%) 5(83%) 11(35%) 10(33%) 12(80%) 6(17%) 4(31%) 14(70%) 7(29%) 51(39%) 60(22%) 37(43%) 22(47%) 83(18.4) 33(92%) 30(53%) 18(69%) 18(33%) 17(77%) 30(16%) 10(58) 10(50%) 9(82%) 122(39%) 21(70%) 6(67%) 678(35%)

IgE⫹

32

34 12

11 121 same as controls 9

When this author included whole-body dust mite antigen to the standard patch test tray, only patients with an atopic history reacted positively at the dust mite application sites. Not a single nonatopic patient tested for contact allergy reacted to dust mites.

Coincidental Benefits of Dust Mite Contact Management An interesting, coincidental benefit of dust mite elimination was noted in a particular patient. When he created a dust mite-free environment to control his perennial dust mite allergic rhinitis, his chronic eyelid dermatitis disappeared! When patch-tested to dust mites, he reacted positively. Subsequently, 12 additional patients with chronic eyelid dermatitis were similarly patch tested. Six reacted positively to dust mite Table 2. Protocol for Dust Mite Patch Testing in Patients with Atopic Dermatitis 1. 2. 3. 4.

A standardized 20% whole body dust mite (1:1) mixture in petrolatum is used. The mixture is applied using the larger (3/4ıˆ) Finn Chamber on non-abraded back skin. The patch test is left in place for 48 hours. The patch-test site should be read at 48 hours, 96 hours and at 7 days. A petrolatum control is also placed, removed and read concomitantly.

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allergen but negatively to routine standard antigens. Not one of the positive reactors had a history or current evidence of eczema anywhere else on the body—and all the reactors were atopic. Several allergists have reported similar observations to me, ie, resolution of eyelid dermatitis in patients who had created a dust mitefree environment because of coexistent respiratory dust mite allergy. Perhaps of greater significance are the findings of the ETAC (Early Treatment of the Atopic Child) Study Group.42 They reported that of 817 infants with AD, the progression of the allergic march (from AD to allergic asthma) was such that after 18 months, the incidence of asthma was highest in those who were sensitized to dust mite, cat dander or grass pollen (Relative Risk (RR) ⫽ 1.4 –1.7). There is a strong association between AD and the subsequent development of asthma, and approximately 40% of infants with AD in early infancy will develop asthma by age 4 years.42 Moreover, the more severe the AD, the greater the possibility of progressing to asthma. It also has been shown that exposure to high levels of allergen in early life is a major trigger for sensitization.43 Since sensitization can only occur in genetically predisposed individuals— only after exposure to an allergen—it is imperative to avoid exposure to allergens as early as possible in this population.44,45 I have found that 93 of 100 infants and young children (3 months old to 5 years old), who were skin prick test or RAST test positive to aeroallergens (in my office), reacted to D. farinae and/or D. pteronisinnus.

Conclusions Until the immunologic aberrations of atopy can be interdicted, treatment of the clinical symptoms resulting from the activation of relevant effector cells remains essentially symptomatic. Namely, the sneezing of allergic rhinitis is quelled by antihistamines, which antagonize the effect of the histamine released by activated, atopic mast cells and basophils. The wheezing of allergic asthma is abated by the spasmolytic effect of ␤-agonists to counteract bronchoconstrictive mediators released from activated effector cells. The eczema of AD is suppressed by nonspecific topical and/or systemic immunomodulators. Unfortunately, many afflicted atopics are only half-heartedly instructed to avoid the recognized triggers that initiate the inflammatory cascade that sets off their symptoms. We usually stress the importance of prevention for patients prone to anaphylaxis. Its immediate catastrophic consequences compel physicians to recommend the avoidance of peanuts, hymenoptera, etc in their sensitized patients. Meanwhile individuals afflicted with AD endure chronic insidious limitations on their quality of life yet continue to be prescribed Band-

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Aids. Avoidance of the recognized triggers of itch for patients with AD can be quite difficult in some cases— and relatively easy in others. In the subset of patients specifically sensitized to house dust mites, the avoidance of dust, which can be fairly easily achieved, is often most rewarding. Since house dust mite sensitivity is a potential problem for all atopics, especially in regard to the allergic march, and particularly those with AD, elimination of mites from the home environment becomes urgent. An objective evaluation of the data presented regarding the role of dust mites in AD should leave little doubt of their direct effect in a subset of patients and indirect effect on many others. Intradermal testing with dust mite antigens is not nearly as valuable as patch testing with contact antigens (aeroallergens) in these patients. A standardized patch test antigen is now available (from Chemotechnique, Malmo, Sweden), which could help identify those eczematous patients whose exacerbations are triggered by contact with dust mite particles. Whereas creating a dust mite-free environment is beneficial for many atopics ie, those with asthma or allergic rhinitis, it is particularly helpful to those with eczema. Fairly simple procedures are sufficient to significantly reduce the quantity of dust mite particles in a home. The Atopy Patch Test Study Group in Germany has been patch testing AD patients with cat dander (n ⫽ 243), grass pollen (n ⫽ 243), birch pollen (n ⫽ 88), and mugwort pollen (n ⫽ 88). They have concluded that aeroallergens besides house dust mites are able to elicit eczematous skin reactions after epidermal application.46 There are other reports of domestic animal dander acting as a trigger for AD exacerbations.47,48 The problems of standardization of antigens used, method, etc all have to be resolved before any validity can be placed on results. The contact role of animal dander and other aeroallergens remains to be appropriately documented.

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