ATOPIC DERMATITIS [Eczema/Atopic Eczema]*

ATOPIC DERMATITIS [Eczema/Atopic Eczema]*

NON-ATOPIC DERMATITIS ECZEMA

ALLERGIC # CONTACT DERMATITIS

NON-ALLERGIC CONTACT DERMATITIS CONTACT DERMATITIS

DERMATITIS

‡

40 The Role of Inhalant Allergens in Atopic Dermatitis

E.A. Erwin, J.A. Woodfolk, T.A.E. Platts-Mills

40.1

Introduction

Uncertainty surrounding the allergic nature of atopic dermatitis (AD) is evident in the writings of the foun- ders of the modern study of allergic disease. In 1931, Coca described atopic eczema and contact dermatitis in only four pages of his text [1]. He labeled atopic eczema an inherited disease that occurs in individuals with a family history of atopy, or in people who at the same time or later in life had asthma or hay fever. In addition, he emphasized that the application of inciting sub- stance to uninvolved skin in atopic eczema would have no effect; however, intracutaneous injection of the same would result in wheal formation. In 1947, Cooke wrote more extensively but began by stating, “In no important group of commonly accepted diseases of allergy is our knowledge more scanty and more superficial, and the dermatologic and allergic literature more contradictory and confusing, than in that group designated as allergic dermatitis” [2]. In general, his comments contradicted those of Coca concerning family history, coexistence with other allergic disease and skin test responses. In

Fig. 40.1. A diagram of the terminology recommended by the World Allergy Orga- nization to create common international vocabulary and to differentiate atopic der- matitis from other types of dermatitis

* Usage varies by country

# The term “allergic” here refers to a T cell mecha- nism in the skin

contrast, Sulzberger generally agreed with Coca but went further to acknowledge the existence of two sepa- rate groups of patients, atopic and nonatopic [3].

In the years since, the classification of AD has been structured like that of asthma, with patients character- ized as “intrinsic” and “extrinsic.” Those having posi- tive skin tests and elevated total IgE levels are labeled as

“extrinsic.” With recent immunological advances, there has been some blurring of the lines between groups. Furthermore, in the field of dermatology, the word allergic is widely used to indicate specific contact sensitivity, so the word atopic must be used to indicate that the form of sensitivity we are concerned with includes IgE antibodies. Recently, the World Allergy Organization has considered the terminology and rec- ommended keeping the terms “atopic dermatitis”

(AD), “atopic eczema,” or “eczema” to recognize the use of different terms in different countries [4]

(Fig. 40.1). However, it is inherent that to establish the diagnosis of atopic eczema or atopic dermatitis requires evidence of specific IgE to foods or common inhalants. In this manuscript, we have used the term AD, the most widely used term in the United States.

Chapter 40

Based on the classification scheme outlined above, it can be inferred that there are variations in the patho- genesis of AD. The goal of this chapter is to emphasize the evidence for a role for aeroallergens in the individ- uals with high total IgE. The chapter begins with gener- al evidence for a relationship between AD and allergy.

Data that direct exposure to dust mite allergens can produce lesions of AD will then be presented with an overview of the underlying immunological results. Fol- lowing a discussion of the evidence for removal of dust mite allergen as a treatment of AD, the chapter will end with an evaluation of the influence of other aeroaller- gens in AD.

40.2

Parallels to Allergic Disease

AD shares many common features with other allergic diseases and often exists concurrently with or prior to asthma and rhinitis. Though this does not provide proof of causation, it does suggest a relationship between aeroallergen sensitivity and AD. Without spe- cific cutaneous signs, distinctive histological findings or pathognomonic laboratory features, the diagnosis of AD itself is made by the occurrence of many associa- tions. Even taking a most basic approach and compar- ing aspects of a historical nature, one can observe char- acteristics of allergy. AD is characterized by intense pruritus, as are other allergic diseases like allergic rhi- nitis. Also, features of an individual’s medical history, as well as family history are often suggestive of atopy.

Two recent studies confirmed a correlation between AD and other allergic diseases. In one study from Japan, infants with a diagnosis of AD were followed prospectively and 35 % developed asthma after 4 years;

an additional 11 % had wheezing that was not labeled as asthma [5]. Mite sensitization was already common at enrollment, as 11 % were sensitized; it remained the most significant risk factor for asthma during follow- up. In a Dutch study, it was determined that 85 % of patients with AD had a history of nasal symptoms that was confirmed upon challenge [6]. The physical exami- nation can also be supportive in those patients whose lesions occur in areas of the skin that are exposed to relevant allergens.

The most common laboratory analyses of AD pro- vide more parallels with asthma and allergic rhinitis.

Though not all patients with any of these diseases have

an elevated total or specific IgE, eosinophilia can be found in all groups. In AD, eosinophilia is common in patients with more severe disease. Though intact eosinophils are not found in high numbers locally in skin lesions (except in patch tests), extracellular major basic protein, most predominantly found in eosino- phils, can be identified in the upper dermis [7]. The mechanisms resulting in tissue eosinophilia have not been established and results of studies show variations between allergics and nonallergics. For instance, when both groups were compared, grass allergen and plate- let-activating factor stimulated eosinophilia in allergic subjects only [8]. In contrast, in both groups, eosino- phils exhibited delayed programmed cell death in cul- ture and had elevated levels of GM-CSF and/or IL-5, cytokines that promote eosinophil survival [9].

Finally, in some studies, the prevalence of AD has been increasing at the same rate as asthma prevalence.

Though investigators acknowledge the underlying dif- ficulties with determining an accurate prevalence of AD, such as trouble defining the disorder in question- naire-based studies, their results are consistent. In Brit- ish and Danish cohorts, reported rates of a pruritic skin rash before 1960 were less than 5 %, during the 1960’s were between 5 % and 10 %, and after 1970 were greater than 10 % [10, 11]. Ninan and Russell compared the prevalence of each allergic disease by serial surveys in the same area of the United Kingdom and found an increase in all forms of atopy [12]. Both asthma and AD increased by a factor of 2.5. Recent prevalence studies have correlated questionnaires and overall allergic sen- sitivity by skin prick test or CAP. In East Germany, investigators found that the prevalence of AD was increased in children born after the reunification of Germany and correlated with the increase in allergic sensitization [13]. The International Study of Asthma and Allergies in Childhood (ISAAC) group reported a very wide range in the prevalence of AD (0.3 % – 20.5 %); however, the values generally correlated with the prevalence of asthma and allergic rhinitis [14].

40.3

Atopy Patch Tests

In contrast to Coca’s early comments, application of

allergen directly to the skin in AD has become a useful

method for evaluating patients and studying the dis-

ease. Application of allergen to uninvolved skin (some-

Der p 1

Fig. 40.2. Atopy patch test results using Der p 1. Erythema and papules can be observed

times mildly abraded or “stripped”) in subjects with AD and evaluation of the resulting reaction after 48 h has been termed the atopy patch test (APT) (Fig. 40.2).

Since its first use with known concentrations of puri- fied allergens, it has become the primary method of challenge in AD [15]. The development of a gold stan- dard test is still needed. In spite of variations in meth- ods, materials, and interpretation, consistent patterns have emerged through a wide range of studies.

It is generally agreed that the methodology consists of applying a concentration of allergen greater than that used for standard epicutaneous puncture skin testing to uninvolved skin on the back with a Finn Chamber that is subsequently occluded for 48 h [16].

The treatment of skin for the test, appropriate vehicles for the allergen, and the desirable dose of allergen have been objectives of study. Darsow et al. showed that pet- rolatum was the best vehicle and observed a dose–

response relationship between allergen concentration and reaction [17]. A later double-blind, randomized, multicenter study resulted in their recommendation that optimal allergen concentrations for APT ranged between 5,000 and 7,000 PNU/g for Dermatophagoides pteronyssinus, cat, and grass [18]. In 1997, the Europe- an Task Force for AD (ETFAD) established a consensus for an APT reading key designated as 1+ to 4+ with the lowest positive score for erythema and infiltration, the

highest positive score dependent on the presence of vesicles, and scores in between based on the number of papules [19]. New bioengineering methods are being investigated for their usefulness in grading responses.

Specifically, chromametry has been used for quantifi- cation of erythema and laser Doppler has been used for assessment of skin blood perfusion [20]. The goal for these objective techniques is to improve evaluation of reactions.

Certain generalizations can also be made from an allergen-specific standpoint. The most frequent posi- tive reactions by APT are to dust mite [18]. Grass and cat allergens are the other common positive results. In general, APT results have been shown to correlate with specific IgE. However, positive responses have been reported in patients without specific IgE [17]. The APT may be a useful diagnostic tool in certain subgroups of individuals with AD. In particular, those individuals who provide a history of disease fluctuation dependent on aeroallergen exposure and possibly those who have an air exposed pattern of distribution, though the sig- nificance of this factor varies from study to study [21].

Regardless, the APT has a lower sensitivity but higher specificity compared to skin prick tests or the presence of specific serum IgE. Thus it may be more useful in determining the clinical significance of a specific sensi- tivity.

40.4

Immunology

The APT has primarily served as a method of studying the immunological basis of AD. A biopsy taken at the site of APT allows observation of lesions in a controlled fashion based on time and inciting factor. This was exemplified in early investigations by Mitchell et al.

[15]. They observed that eosinophils were the predom- inant inflammatory cells but that there was also a sig- nificant increase in basophils. This provided evidence of a possible connection between immediate hypersen- sitivity and a delayed cellular response in AD patients.

Eosinophils could be recruited by eosinophil chemo- tactic factor released upon mast cell degranulation.

The presence of basophils was thought to imply T cell involvement through the release of basophil chemotac- tic factor; however, recent evidence suggests that PGD2 derived from mast cells could also play a role in baso- phil recruitment. In subsequent studies, Mitchell et al.

392 40 The Role of Inhalant Allergens in Atopic Dermatitis

demonstrated that the ability to recruit eosinophils locally could be passively transferred with specific IgE antibodies (Table 40.1) [22]. Furthermore, they showed that prolonged application of mite allergen to the skin (i.e., 10 days) caused eosinophil recruitment followed by a dramatic fall in the number of eosinophils visible in the skin biopsies [23] (Table 40.2). Other investiga- tors confirmed the eczematous response to APT and detailed the timing and location of eosinophil recruit- ment. Eosinophils were present as early as 2 – 6 h after APT [24]. The eosinophils observed in the dermis were activated (EG2

); by contrast, the eosinophils found in the epidermis were generally not activated. In addition, some eosinophils were observed near IgE-bearing Lan- gerhans cells.

Recent immunological advances have resulted in many new studies, but the focus of this discussion will be the evidence for an allergic etiology in AD. Since the mechanism is not fully understood, each study pro- vides part of the picture. In general, many studies have

Table 40.1. Cell infiltrate observed in biopsies of atopy patch test using 10 µg Der p 1 following passive transfer of serum or antibodies

Transfer N Basophils Eosinophils

Mean (range) Mean (range) Systemic

Preplasma 5 0 (0 – 1) 1 (0 – 5)

Postplasma 5 1 (0 – 4) 145 (3 – 535) Local

Saline 8 0 (0 – 4) 1 (0 – 2)

Serum 7 69 (12 – 161) 320 (20 – 560) Heated serum

3 6 (0 – 6) 0 (0 – 10)

Antibody 5 0 (0 – 7) 99 (45 – 188)

a

Following plasma infusion, patches applied at 2 h and biop- sied at 48 h

b

Following local passive transfer, patches were applied at 24 h

c

Intradermal injection of sera diluted 1 : 2 from subjects with atopic dermatitis

d

Serum heated at 56 °C for 3 h

Table 40.2. Cellular infiltrate after prolonged exposure to Der p 1

in atopy patch test

Patch Days at biopsy

Basophils Mast cells Eosino- phils

Mono- cytes

Neutro- phils

Total

Saline 2 2 46 0 303 16 367

Der p 1

2 26 56 337 795 37 1,251

Der p 1

6 22 77 1249 833 13 2,194

Der p 1

10 21 113 96 932 9 1,171

a

Der p 1 was applied to three separate sites to allow multiple biopsies. The allergen was reapplied to each site every 2 days until biopsy.

Biopsies were fixed in Karnovsky’s solution, embedded in methacrylate, and stained with Giemsa

shown subcellular differences in acute and chronic lesions as well as between intrinsic and extrinsic dis- ease consistent with the differences seen in phenotypes based on examination and serum results.

An important breakthrough occurred with the dis- covery that T cells had a specific marker for homing to the skin, cutaneous lymphocyte antigen (CLA). Santa- maria Babi et al. went further to show that when der- matitis is the primary manifestation of atopy, effector T cells are primarily CLA

[25]. Furthermore they showed that in vitro T cell proliferation in response to house dust mite extract or purified Der p 1 was greater in CLA

T cells in patients with AD. In contrast, in patients with asthma, the strongest response was seen in the CLA

fraction. Characterization of these T lym- phocytes in terms of cytokine production and chemo- kine receptors has been consistent with the Th2 or atopic subset. T lymphocytes, predominantly CD4

, in the peripheral blood or cultured from biopsies, secrete decreased or no measurable IFN- * [26]. In addition, the cultured T cells were found to secrete small but sig- nificant amounts of TNF- [ and significant amounts of IL-4 and GM-CSF. Circulating T cells bearing CCR4 typically respond to Th2 chemokines such as TARC and MDC while CCR5

and CXCR3

T cells respond to Th1 chemokines. Several groups have reported that among T cells in AD, the number of CCR4

cells is sig- nificantly higher, while the number of CCR5

and CXCR3

cells is lower [27]. Furthermore, IL-4, IL-13, serum IgE, and eosinophils were positively correlated with CCR4

T cells and the frequency of CCR4

cells was linked to disease activity.

Akdis et al. recently proposed a mechanism for pre-

dominance of Th2 cells in AD [28]. They observed

decreased apoptosis in the skin among T cell clones

with a Th2 cytokine profile consisting of decreased

IFN- * and increased IL-4 and IL-13. Thus, they con-

cluded that apoptosis of circulating memory T cells was

focused on Th1 cells.

Langerhans cells (CD1a

) are the antigen-present- ing cells in the epidermis; however, in inflammatory skin lesions, two CD1a

cell populations are found [29].

The first type is considered “classic” Langerhans cells that contain Birbeck granules and the second type has been termed inflammatory dendritic epidermal cells (IDEC) that lack Birbeck granules. In AD patients, flow cytometry for quantitative receptor expression shows increased expression of Fc 5 R1 on Langerhans cells (mainly among the IDEC subgroup). The Fc 5 R1 pre- formed chain is present in normal Langerhans cells, but its constitutive expression is low. On APCs, Fc 5 R1 is present as a trimeric variant with an alpha chain and a gamma chain dimer but no beta chain. With the tri- meric form, signals are weaker and expression is upre- gulated by IgE. Kerschenlohr et al. have extended their studies to include intrinsic AD patients with positive APT and observed that although IDECs were increased, Fc 5 R1 expression was low [30]. The results suggest that sensitization to aeroallergens can occur in a subset of intrinsic AD patients without specific IgE.

They also emphasized that among patients with extrin- sic AD, upregulation of Fc 5 R1 is a late event, thus the Fc 5 R1/Fc * R11 ratio (>1.5) can be a diagnostic marker for chronic disease but is not useful in acute lesions.

Toda et al. examined another link to allergic disease when they looked at skin biopsies for cytokines that have been associated with remodeling in asthma [31].

They were increased in both acute and chronic AD but to a greater extent in chronic lesions. The expression of profibrotic cytokines IL-17 (chronic AD) and IL-11 (acute AD) was also observed. Together these results were taken as evidence that chronic changes compara- ble to those associated with remodeling in the lungs occur in the skin lesions of AD.

40.5 Avoidance

Previously, it has been argued that AD could not be an allergic disease because it does not respond to immu- notherapy. In fact, there have been few controlled stud- ies using immunotherapy to treat AD. Publications of anecdotal experience showing improvement with house dust mite immunotherapy have been more com- mon [32, 33]. Without a complete understanding of either the immunological basis of AD or immunothera- py, this argument is not convincing. In fact, new evi-

dence suggests that there may be a defect in cytotoxic T cells related to quantity and/or function. Nevertheless, the Th2 effector cells may be intact. Turning to other forms of allergen-specific treatment poses further dif- ficulties.

Studies of allergen avoidance to treat AD share the problems of similar studies using allergen avoidance to treat asthma; in particular, a large placebo effect can result in similar improvement in both groups. An anal- ysis of the available results still provides valuable infor- mation.

Studies have been performed in different areas of the world using variations in avoidance techniques.

Uniformly, studies have included use of a dust mite impermeable mattress cover (e.g., Goretex, semiper- meable plastic, or fine woven fabrics). Other additional measures include using hot water to wash sheets and bedding; the use of special vacuum cleaners, increased frequency of vacuuming or carpet removal; and use of acaricides. Generally, active avoidance techniques suc- cessfully reduced dust mite levels dramatically during the 1st month [34]. However, usually both active and placebo groups experienced improvement in symp- toms [35]. The double-blind placebo-controlled study by Tan and colleagues in the United Kingdom showed both a decrease in dust mite levels and a significantly greater decrease in AD severity and area of involve- ment in the active treatment group vs the placebo group [36]. Nishioka et al. also distinguished between placebo and active treatment groups by looking at out- come measures other than skin response [37]. They found a decreased incidence of dust mite sensitization among infants with AD, who were not previously sensi- tized, when they used mattress encasings. The study by Holm et al. in Sweden is an example that raises some important issues [38]. In their study, dermatitis severi- ty was decreased by 45 % in the active group and 39 % in the placebo group. However, due to the climate, exposure to house dust mite was not common there;

instead, exposure to cat allergen was more frequent.

For some reason, patients not sensitized or exposed to

dust mite benefited just as much from bed covers even

though cat allergen levels were unchanged with mat-

tress covers. The first question that arises from these

data is the importance of distinguishing the predomi-

nant exposures in a specific area when planning avoid-

ance. But equally, the results suggest that certain sub-

groups of patients are more likely to benefit from

avoidance; however, the characteristics of these groups

394 40 The Role of Inhalant Allergens in Atopic Dermatitis

Measured by Pharmacia CAP assay (1) and antigen binding radioimmunoprecipitation assay (2)

Ig E (I U /m l) a n d I g G (U /m l) A b

0.1 1 10 100 1000 10000

x 7 >

x 10

|---|

T otal IgE

x 10 x 10

|---|

C at IgE (1)

|---|

F eld1 IgE (2) 50000

are not clear. Some investigators have suggested that children are more responsive to avoidance because in contrast to adults, they are less likely to be polysensi- tized. Some successful avoidance studies such as those of Tan et al. and Ricci et al. actually also indirectly included pet avoidance since they limited their studies to patients who did not have pets at home [36, 39].

Current evidence supports the use of avoidance techniques in patients who have severe AD, especially if they have other allergic diseases. However, since dust mite levels are known to fall quickly, investigation into the contribution of other aeroallergens may be required if improvement is not seen after the first month.

40.6

The Relevance of Other Allergens

Though there have been many studies regarding the relationship between dust mite sensitivity and AD, there has not been much investigation into the impor- tance of other aeroallergens. In Clark’s investigation of APT and avoidance on a case-by-case basis, he con- cluded that among his patients, danders, grasses, weeds, and molds could each play a role [40]. The con- tribution of a variety of aeroallergens was also assessed in a cross-sectional study of 2,200 children in East Ger-

Fig. 40.3. Levels of IgE anti- body to cat and the major allergen Fel d 1 are tenfold higher in allergic patients with AD compared with other allergic patients and patients with nonallergic dermatitis

many that used skin examinations and IgE measure- ments to compare children with AD to those without AD [41]. The prevalence of sensitization to each aller- gen, grass (O.R. 2.9), birch (O.R. 5.1), Cladosporium (O.R. 6.7), D. pteronyssinus (O.R. 4.3), and cat (O.R.

8.8), was greater among children with AD. In addition, the association between AD and RAST class was linear for all allergens. Furthermore, there was a linear asso- ciation between prevalence of sensitization and severi- ty of AD that was most pronounced for the indoor allergens dust mite and cat. Barnetson and his col- leagues studied adults in the United Kingdom [42].

Based on skin testing, the prevalence of sensitization to dust mite was the highest, followed by cat and grass.

Out of 45 patients, 32 had a RAST score that was Class 3 or 4 to each inhalant allergen and the remaining 13 had a similar score to at least one allergen. The highest levels of IgE were to house dust mite. Finally, of the 12 individuals who owned cats, eight had specific IgE anti- bodies to cat over 100 RAST units, where the RAST unit was approximately equal to International Units, and the other four also had IgE but at lower levels.

We observed similar antibody results when we com-

pared IgE levels to cat in a group of AD patients

(Fig. 40.3). In vitro studies of peripheral blood mono-

nuclear responses to Fel d 1 and Fel d 1 peptides

showed only weak proliferative responses to the immu-

nodominant T cell epitopes of chain 2 that have been

associated with induction of IL-10 in nonallergic con- trols with and without AD [43, 44]. Furthermore, blocking IL-10 effects within the assay failed to restore proliferation. Overall, the results suggested that T cell- specific hyporesponsiveness that is not mediated by IL-10 contributes to allergic responses in AD patients.

Scalabrin et al. looked at the relationship between IgE antibodies to fungi and AD and compared the results to those of a group of asthmatics and controls [45]. Many of the patients with AD had specific IgE to inhaled fungi (Alternaria and Aspergillus), but the concentrations of IgE were much lower than that to D. pteronyssinus. Also, there was a correlation between specific IgE to mite and fungi and total IgE. Overall, IgE to mite seemed to make up about 15 % of the total IgE level.

40.7 Conclusion

Although there is no doubt that a large proportion of patients with severe or moderately severe AD have IgE antibodies to common allergens, formal proof that these allergens contribute to the disease has been diffi- cult to obtain. Following the initial enthusiasm of Coca, Sulzberger, Tuft, and others, several questions were raised. Today, there is much more extensive evidence on the immunological mechanism involved in the skin;

however, the case for allergen-specific treatment still remains controversial.

The atopy patch test has established beyond doubt that the application of allergen to the skin can produce an eczematous response. Furthermore, using specific cell surface markers uniquely found on T cells in the skin, it has been possible to establish that patients with AD have made a specific immune response to allergens such as dust mite that includes a Th2 profile in terms of the cytokines and chemokine receptors present. Fur- thermore, for cat allergens, it is clear that patients with AD do not develop tolerance with high exposure, which is common among children with asthma or con- trols living in a house with an animal.

The studies of avoidance that have been “unsuccess- ful” have decreased enthusiasm for this form of treat- ment but have also reduced acceptance of the role of allergens in AD. Strikingly, although the improvement with avoidance can be very marked, in controlled trials improvement may occur in both active and placebo treatment groups. Similar problems have complicated

studies of allergen avoidance in asthma, suggesting that it is difficult to create a true placebo group in patients’ homes. However, avoidance studies focused on dust mite are also complicated by the multiple other factors that can contribute to the disease. These include food allergens, skin infection with bacteria or fungi as well as other inhalant allergens. It is important to remember that allergen avoidance is just one treatment measure for a multifactorial disease.

From published reports, it appears that dust mite is the most important source of allergens related to AD, which may reflect direct contact with the skin in bed or on furniture. However, there is good evidence for the relevance of other allergens. In light of the recent evi- dence about a unique immune response to cat aller- gens, it is clear that dose–response relationships can be different. Our view is that not only allergen avoidance but also newer forms of immunotherapy could (indeed should) play a major role in the treatment of AD. Fur- ther, detailed studies on exposure and the immune response to different allergens will be needed to better define these approaches.

Acknowledgements. Supported by grants from the NIH: AI-20565; General Clinical Research Center MO1RR00847.

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398 40 The Role of Inhalant Allergens in Atopic Dermatitis