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Allergy 2008: 63: 205–210 Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard DOI: 10.1111/j.1398-9995.2007.01556.x Original article Epicutaneous aeroallergen sensitization in atopic infants – determining the role of epidermal barrier impairment

Background: Sensitization to atopens is an early phenomenon that overlaps with F. Boralevi1,*, T. Hubiche1,*, C. Laut- the onset of (AD) in infancy. Early epidermal barrier impair- Labrze1, E. Saubusse2, M. Fayon3, ment may facilitate the epicutaneous penetration of atopens. S. Roul1, S. Maurice-Tison2, A. Taeb1 Objective: To correlate transepidermal water loss (TEWL) and aeroallergen 1Pediatric Dermatology Unit, Bordeaux ChildrenÕs sensitization in infants with AD. Hospital; 2Inserm U593, Bordeaux2 University; Methods: In this cross-sectional study we enrolled 59 AD children and 30 con- 3Pediatric Pulmonology Unit & CEDRE, Bordeaux trols aged 3–12 months. Transepidermal water loss in uninvolved skin, specific ChildrenÕs Hospital, CHU de Bordeaux, France , patch test (APT) and skin prick tests were performed with respect to seven aeroallergens, i.e., Dermatophagoides pteronyssinus, Key words: aeroallergen sensitization; ; atopic D. farinae, cat, dog, , ambrosia, and cockroach. Environmental dermatitis; atopy; atopy patch test; skin prick test; conditions were assessed by a questionnaire, and the house dust mite (HDM) transepidermal water loss. concentration was determined in dust samples. Results: Eighty-nine percent of AD infants had a positive APT vs one out of F. Boralevi eleven controls. AD infants had a significantly higher mean TEWL than controls Unit de dermatologie pdiatrique (27.4 vs 11.1 g/m2/h, P < 0001). Children with two or more positive APT had Hpital Pellegrin-Enfant 2 Place Amlie Raba-Lon higher TEWL than the others (31.1 vs 19.0 g/m /h, P < 0.025). No correlation F-33076 Bordeaux Cedex was found between indoor APT results and exposure to HDM, cats, and dogs at France home. Conclusions: This study confirms the high prevalence of delayed sensitization to *These authors contributed equally to this work. indoor and outdoor aeroallergens in AD infants, and shows that the higher the TEWL, the higher the prevalence of sensitization to aeroallergens. These data Presented at the 4th Rajka International Symposium are in favor of a major role of a constitutive epidermal barrier impairment in on Atopic Dermatitis (ISAD 2005), September 15–17, 2005, Arcachon, France. determining early atopen sensitization in infants with AD. Accepted for publication 22 August 2007

Atopic dermatitis (AD) is one of the most common house dust mite (HDM), pet dander, and from pediatric diseases which considerably affects the quality trees and plants are the most prevalent (5). of life of children and their families, and its incidence has Transepidermal water loss (TEWL) represents the increased over recent decades (1). AD presents clinically outward diffusion of water through skin and its as a chronic relapsing dermatitis, which is initiated in a measurements are used to gauge skin barrier function large part of the pediatric population by intrinsic defects (6). Readings increase when the integrity of the stratum in the uppermost layer of the epidermis, the stratum corneum barrier is compromised, and they correlate corneum (2). Epicutaneous sensitization is a possible with percutaneous absorption (7). Few studies have major route of penetration for allergens and antigens that characterized either aeroallergen sensitization (8) or may pertain to later mucosal allergic disorders, as already TEWL (9) in young AD children, and to the best of suggested in animal models (3). At the clinical level, skin our knowledge, no study has simultaneously evaluated symptoms are the earliest manifestations of the atopic epidermal barrier impairment measured using a tewam- status. Moreover, given that initial skin lesions are more eter and the risk of aeroallergen sensitization in infants prominent on air-exposed areas and that sensitization to with AD. aeroallergens occurs very early in life, infantile AD may Because sensitization to atopens is an early phenom- reflect the penetration phase (4). Amongst the enon that overlaps with the onset of AD in infancy, we aeroallergens involved in the sensitization of AD patients, hypothesized that early epidermal barrier impairment may facilitate the epicutaneous penetration of atopens Abbreviations: AD, atopic dermatitis; APT, atopy patch test; HDM, (4). More specifically, the aim of our study was to house dust mite; RAST, radioallergosorbent test; SPT, skin prick establish whether TEWL correlates with aeroallergen test; TEWL, transepidermal water loss. sensitization in AD infants.

205 Boralevi et al.

Atopy patch tests. Atopy patch tests were performed with extracts Methods containing 200 index of reactivity/g of allergen in a petrolatum Subjects vehicle (Stallerge` nes, Anthony, France). Atopy patch tests were performed on the back on clinically uninvolved back skin for 48 h This cross-sectional study, conducted from May 2002 to June 2004, in 10 mm Finn ChambersÒ (Epitest Ltd Oy, Tuusala, Finland). enrolled children with AD according to the UK working party cri- A patch test with the vehicle served as negative control. Readings teria (10). Patients were aged 3 to 12 months and had a Scoring were taken at 72 h and graded according to the international criteria Atopic Dermatitis (SCORAD) index (11) greater than 10. Exclusion revised by the European Task Force on Atopic Dermatitis (13). To criteria included the administration of systemic immunosuppressive avoid nonspecific reactions, APT were considered positive from or steroid therapy during the previous 2 months, or ++ (i.e., erythema, papules, and/or vesicles) onwards. Atopy patch treatment within 7 days prior to inclusion. During the same period, a tests were applied and read by the same trained investigator control group of 30 children aged 3–12 months was recruited with throughout the procedure. the following exclusion criteria: personal history of atopic diseases, any skin disease, fever, and steroid or immunosuppressive therapy Skin prick tests. Skin prick tests were performed on uninvolved skin within the last 2 months. All control subjects answered the stan- at the flexor part of the right forearm with standardized allergen dardized questionnaire and accepted the TEWL measure, but only a extracts (Stallerge` nes) for the seven aeroallergens mentioned above, minority of the parents (11 children) consented to testing and and for a panel of four common food allergens (cowÕs milk, egg, were patch/prick/immunoglobulin E (IgE) tested. Two years after , and wheat). Histamine phosphate and physiological saline enrollment, AD children underwent a follow-up visit with clinical solution were used as positive and negative controls, respectively. examination, TEWL and allergy testing. The study was approved by The cutaneous response was scored 15 min after challenge as the the Regional Ethics Committee. wheal diameter, and SPT were regarded as positive if the wheal diameter was at least 3 mm and superior or equal to the positive control. Procedures

After obtaining written consent, a complete history was recorded Specific IgE. Serum samples were obtained at enrollment. Total IgE using a standardized questionnaire, and a thorough clinical and specific IgE antibodies to HDM, cat, dog, birch pollen, examination was carried out by the same investigators. The envi- ambrosia and cockroach were determined using the CAP-RAST ronment of the children was assessed using the following items: FEIA (Pharmacia Diagnostics, Uppsala, Sweden). Sensitization was rural or urban housing, pets at home, presence of a fitted carpet, defined as a concentration of IgE of 0.35 kU/l or greater. or cuddly toys in the childrenÕs room. The severity of AD was assessed using the SCORAD index, a score that records the per- Assessment of HDM concentration at home centage of involved skin, the intensity of the lesions, i.e., erythema, papules, crusts, lichenification and xerosis, and subjective but Parents were asked to collect dust by vacuuming the mattress and essential parameters such as pruritus and sleep disturbance (11). the fitted carpet of their childÕs bedroom, according to a published 2 The following tests were performed: TEWL (g/m /h) in nonin- standardized protocol (14). The HDM concentration in dust sam- volved skin, serum specific IgE (sIgE), atopy patch test (APT) and ples was determined by the same investigator using the Acarex testÒ, skin prick tests (SPT) using a panel including seven aeroallergens. (Karapharm, Marseille, France) a semi-quantitative guanine test. Using a semi-quantitative technique, the HDM concentration was Results were graded into four classes as follows: absence or very low measured in a dust sample collected from the childrenÕs room by (<2 lg/g), low (2–10 lg/g), moderate (10–100 lg/g), or high con- their parents according to a standardized procedure. Topical ste- centration of HDM (>100 lg/g). roid therapy was discontinued at least 3 days prior to allergy testing. TEWL and skin testing were not performed during sum- mer (June–September). Data analysis

The StudentÕs t-test was used to compare the mean values of Transepidermal water loss measurement the TEWL measurements and the SCORAD index. We used the chi-squared test to assess the associations between qualitative 2 Transepidermal water loss measurements (g/m /h) were performed variables. Data without a normal distribution were assessed using Ò using an evaporimeter (Tewameter T210, Monaderm ; Monaco) the nonparametric statistical Wilcoxon test. Differences were con- according to published guidelines (12). In particular, measure- sidered significant for P<0.05. SAS software was used for all ments were performed in a windowless room maintained at statistical analyses. constant temperature, far from the heating system. For an ade- quate reading, children had to remain still during the whole procedure, and the parents were requested to refrain from applying a skin moisturizer during the previous 24 h. The tew- Results ameter probe was applied to the medial aspect of the uninvolved volar forearm and held in place for 2 min until a steady TEWL Fifty-nine children with AD aged (mean ± SD) value was obtained. 7.3 ± 2.4 months (sex ratio = 0.37) were included in the study. According to the SCORAD index, AD was moderate in 64%, mild in 17%, and severe in 19%. The Assessment of aeroallergen sensitization control group comprised 30 children (17 males) aged We performed allergy skin tests and sIgE to seven common aero- 7.0 ± 2.4 months. All of them answered the standardized allergens, i.e., Dermatophagoides pteronyssinus, D. farinae, cat, dog, questionnaire and accepted the TEWL measurement, but birch pollen, ambrosia, and cockroach (Blatella germanica).

206 Sensitization to atopens only a minority of the parents (11 children) consented to one of the seven aeroallergens tested. The percentage of allergy testing and were patch/prick/IgE tested. The (++) APT-positive reactions ranged from 76% (D. pter- general characteristics of the population studied are onyssinus) to 37% (B. germanica) (Table 2). In controls, shown in Table 1. 10 out of 11 had negative APT and total IgE <15 kIU/l; Eighty-nine percent of infants with AD had at least one the control infant with positive APT (to HDM) had total positive APT to the seven aeroallergens tested, 16% had IgE = 202 kIU/l without specific IgE to the seven at least one positive SPT, and 30% had at least one allergens tested. positive radioallergosorbent test (RAST) directed against With a mean TEWL of 27.4 g/m2/h compared with 11.1 g/m2/h in control infants, infants with AD had a significantly greater TEWL (P < 0001) (Fig. 1). Children Table 1. Demographic and AD characteristics of patients included in the study with two or more positive APT had a greater TEWL (31.13 g/m2/h) compared to those with no or only one Mean € SD or n (%) positive APT (19.03 g/m2/h, P < 0.05) (Table 3). More- Characteristic AD (n = 59) Controls (n = 30) over, SCORAD mean values were 33.8 and 38.8 in children with a TEWL below and above 30, respectively. Age, months 7.3 € 2.4 7.0 € 2.8 House dust mite concentration in carpets and mat- Male 43 (72.9)17(56.6) tresses was <2, 2–10, 10–100, and >100 lg/g in 16%, Female 16 (27.1)13(43.4) Parental history of atopy 47 (79)12(40) 39%, 31%, and 14% of cases, respectively. No associa- Parental history of 7 (12)4(13) tion was found between HDM APT results and exposure Palmar hyperlinearity 10 (17)0(0) to HDM, or between cat or dog APT and exposure to cat Personal history of recurrent wheezing 15 (25)5(16) or dog at home (data not shown). Housing Rural 28 (47.5)13(43.4) Urban 31 (52.5)17(56.6) 50 Fitted carpet in the childÕs bedroom 48 (81)25(83) Pets (cat and/or dog) at home 33 (56)18(60) Severity of AD 40 Mild (SCORAD <20) 10 (17)NA AD Moderate (SCORAD 20–50) 38 (64)NA 30 Severe (SCORAD >50) 11 (19)NA Controls Hypereosinophilia 40/51 (78) 0/11 (0) ( >700/mm3) % of patients 20 Total sIgE >15 kU/l 29/53 (55) 1/11 (9) 10 Food sensitization SPT (%) sIgE (%) 0/11 (0)

Hen's egg 28/50 (56) 29/49 (47) 0 Peanut 6/49 (12) 8/49 (16) 0 10 20 30 40 50 60 70 80 90 2 CowÕs milk 6/49 (12) 12/48 (12) TEWL (g/m /h) Wheat 6/49 (12) 6/47 (12) Figure 1. Distribution of transepidermal water loss (TEWL) SD, standard deviation; AD, atopic dermatitis; SCORAD, Scoring Atopic Dermatitis; readings in atopic dermatitis (AD) and control groups. The 2 SPT, skin prick test; sIgE, specific immunoglobulin E; NA, not applicable. Important majority of AD patients (79%) had a TEWL above 15 g/m /h, values are expressed in bold. while TEWL was less than 15 g/m2/h in 83% of controls.

Table 2. APT, SPT and specific IgE results in the AD group (n = 59), and in the subset of patients from 3 to 6 months (n = 23) and from 7 to 12 months (n = 36)

Allergen D. pteronyssinus D. farinae Dog Cat Birch pollen Cockroach Ambrosia

Positive APT Total 45 (76)34(58)27(46)25(42)26(44)22(37)33(56) 3–6 months 17 (74) 12 (52) 11 (48) 12 (52) 12 (52) 13 (56) 11 (48) 7–12 months 28 (78) 22 (61) 16 (44) 13 (36) 14 (39) 9 (25) 22 (61) Positive SPT Total 2 3 1 3 1 3 1 3–6 months 0 0 0 1 0 0 0 7–12 months 2 3 1 2 1 3 1 Specific IgE Total 6 (12)4(7)8(16)5(10)0 1 0 3–6 months 0 0 3 2 0 0 0 7–12 months 6 4 5 3 0 1 0

Values are expressed as n (%). APT, atopy patch test; SPT, skin prick test; IgE, immunoglobulin E. Important values are expressed in bold.

207 Boralevi et al.

Table 3. Correlation between TEWL and aeroallergen sensitization Table 4. APT, SPT and specific IgE results in the AD group at the 2-year follow-up visit (V2) compared to those at baseline (V1) (n = 30) 0 or 1 positive APT 2 or more positive APT D. pteronyssinus D. farinae Dog Cat Birch pollen Cockroach Ambrosia Mean TEWL (g/m2/h) 19.031 31.134 P = 0.0256 SD 10.7 19.0 APT 95% CI 12.8–25.2 25.2–37.9 V2 20 (66.5)12(40)3(10)0(0)5(17)2(6.5)0(0) V1 21 (70) 18 (60) 9 (30) 9 (30) 15 (50) 7 (23) 9 (30) TEWL, transepidermal water loss; APT, atopy patch test; SD, standard deviation; CI, SPT confidence interval. V2 14 (46.5)17(56.5)2(6.5)6(20)3(10)0(0)0(0) V1 1 (3) 0 (0) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0) sIgE Total IgE was greater than 2 kIU/l in 53 cases, with a V2 22 (73)19(63)9(30)9(30)9(30)6(20)7(23) mean of 240 kIU/l (range 4–4768). Regarding sensitization V1 5 (16) 3 (10) 7 (23) 4 (13) 0 (0) 0 (0) 0 (0) to food products in the AD group, we found positive SPT and sIgE to henÕs eggs in 56% and 47% of patients, Values are expressed as n (%). APT, atopy patch test; SPT, skin prick test; sIgE, serum immunoglobulin E. Important values are expressed in bold. respectively, and to , cowÕs milk, and wheat in 12%. Two years after enrollment, 30 children from the AD group, aged (mean ± SD) 33 ± 2.8 months (sex ratio AD (5, 15), while SPT and RAST were mostly negative 0.42) underwent a follow-up visit. According to the (Fig. 2). This is also in accordance with studies that SCORAD index, AD was mild in 80%, moderate in showed more frequently positive APT in the younger age 13.5%, and severe in 6.5%. Mean TEWL was group, i.e., before the age of 2 or 3 years, compared with 17.3 ± 9.6 g/m2/h compared with 30.4 ± 20.6 g/m2/h older children (16). Patch testing is a useful tool to assess in this subset of patients at enrollment. Thirteen cases sensitization to allergens, i.e. aeroallergens, contact and (43%) of physician-diagnosed asthma were identified. food allergens, and it has been shown that positive SPT or Mean initial TEWL values in the asthma group (31 g/m2/h, sIgE are not a prerequisite for a positive APT response n = 13) and in the nonasthma group (28.7 g/m2/h, (17). Based on the history of aeroallergen-triggered AD n = 17) were not significantly different. Atopy patch tests, flares, APT proved to have higher specificity than SPT SPT and sIgE were positive in 60%, 63% and 76.5% of and sIgE (1). In this study, owing to the young age of our children, respectively (Table 4). Significant differences patients and the absence of gold standards, we were not were found when comparing the results with those able to determine the sensitivity and specificity of the obtained at baseline, especially in SPT and sIgE results different tests with regard to the patientsÕ history, as is (Fig. 2). recommended in older patients (1). However, to reduce reading bias, especially irritation phenomena, we consid- ered APT as positive only results from ++ onwards. Transepidermal water loss is the outward diffusion of Discussion water through skin (18). One could consider TEWL Very few studies examining skin parameters have been mainly as a marker for the inside–outside barrier, but the conducted in AD infants prior to the age of 1 year. In the majority of studies investigating TEWL and percutane- present study, such parameters were assessed at a very ous absorption found a quantitative correlation (7), early stage of AD. Despite the limited sample size, our leading to consider TEWL also as a marker for the study confirms the high prevalence of positive APT to outside–inside barrier. Our study shows that uninvolved indoor and outdoor aeroallergens in young children with skin of infants with AD differs from that of control

80

70 Dpter 60 Dfar Dog 50 Cat 40 Birch pollen 30 Cockroach Ambrosia 20

10 % of patients with positive tests 0 APTSPTslgE APT SPT slgE

V1 V2

Figure 2. Atopy patch test, skin prick test and immunoglobulin E results at baseline (V1) compared with the results at the 2-year follow-up visit.

208 Sensitization to atopens subjects by showing significantly greater TEWL readings. observations showing that older children and adults with Moreover, our results in infants tend to confirm the atopic eczema are more likely to demonstrate positive positive correlation between AD severity and epidermal SPT and sIgE than positive APT to the same aeroaller- barrier impairment (TEWL) previously observed in older gens (27), and SPT have been shown to be more children by Seidenari et al. (9). As gender differed slightly frequently positive in children than in infants (28, 29). in the AD and control groups, a possible bias could be Our data confirm a time-dependent switch from delayed considered in our TEWL results (19). Indeed, in adults reactions to immediate/early reactions in childhood, and only a slight tendency toward higher TEWL values has a minor role for specific IgE-dependent mechanisms at been shown in males compared to females (20) and the onset of AD (4). This hypothesis suggesting that confirmed in our study (11.3 in males vs 10.9 in females), IgE sensitization is not a necessary prerequisite for the which it is not sufficient to explain the significant results development of AD skin features is now advocated we found when comparing AD and control patients for (30, 31). Thus, a distinction between extrinsic and intrinsic TEWL readings. forms of AD is irrelevant in very young children. More interesting was the finding that the greater the In contrast to several studies conducted in children TEWL, the higher the prevalence of sensitization to with AD and/or asthma (32, 33), our study failed to show aeroallergens, which points to a possible causative role of a strong correlation between atopen exposure and sensi- epidermal barrier impairment in the sensitization to tization to HDM or cat/dog dander. Indeed, even in very atopens in AD infants. It may also explain the lesional young children, a cat or a dog at home does not increase pattern, as suggested a century ago by Hall, as an the risk of sensitization to cat or dog dander. Likewise, indication that infantile AD may be, at least in some living in a place with a high concentration of HDM does patients, the clinical manifestation of an atopen penetra- not correlate with a higher prevalence of HDM sensiti- tion syndrome (4). To explain this defective barrier zation. Because HDM and pet dander are very ubiquitous function, genetically determined skin defects should be in our environment, sensitization may occur as easily at considered (21): there is now strong evidence that variants home as in nondomiciliary settings. The influence of of the epidermal barrier protein filaggrin may lead to home atopen exposure on subsequent sensitization to the constitutional epidermal barrier impairment and predis- same allergens or on clinical AD flaring in patients is still pose to AD and later to asthma (2, 22). Other epidermal controversial (34). However, it has recently been shown barrier proteins, i.e., protease KLK7 and protease inhib- that such correlations may be specific to some allergens, itor SPINK 5, may also be involved, but in a recent study e.g., Der f1 or Fel d1 but not Der p1 (35). from our group investigating simultaneously filaggrin, Together with genetic findings (reviewed in 31), our SPINK 5 and KLK7 mutations or polymorphisms in a clinical study suggests that defective barrier functions are French AD cohort, a significant association was found likely to play a very significant role in the pathogenesis of only for the most common European population filaggrin AD. A constitutively abnormal stratum corneum barrier mutations (23). For others, who tend to follow the inside– may facilitate contact between atopens and the actors of outside hypothesis, such a defective barrier may be not the innate and adaptative , leading to primary but secondary to CLA+ T-cell activation and sensitization. secretion leading to subclinical inflammation (24). It may also be speculated that environmental factors such as exposure to airborne volatile organic compounds Acknowledgments (25) or to proteolytic allergen (Der p1), exaggerated use of detergents for skin hygiene, and infectious agents or This work was supported by the French Society of Dermatology toxins (26), can aggravate some constitutional predispo- (Socie´te´ Franc¸ aise de Dermatologie). We thank Stallerge` nes for sition to damage the epidermal barrier. providing the APT material, La Roche Posay for a generous grant In the subset of 30 AD children who were reassessed allowing us to purchase a Tewameter, and Karapharm for provid- ing the guanine tests. We thank particularly the children and their 2 years later, the number of positive APT markedly families and the nurses Cathy Masseron, Nathalie Chung, and decreased while the number of positive APT and sIgE Marie-Berthe Chabat, without whom this study could not have been increased (Fig. 2). This is in agreement with previous possible.

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