Early Childhood Atopic Phenotypes and the Development of Allergic Respiratory DiseaseTo the Editor,Pediatric atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disorder that affects up to 20% of children worldwide1. Often the earliest sign of atopy, AD has been recognized as the start of the “atopic march”, described as the progression of AD to allergic respiratory diseases (ARD) including asthma and allergic rhinitis2. Although these atopic conditions often share a common T2 enriched pathway influenced by both genetic and environmental factors, not all children with AD have subsequent risk of ARD. Additionally, recent investigations dispute the theory that the temporal progression of the atopic march occurs in a sequential pattern3. Early AD can facilitate allergen sensitization due to a dysfunctional skin barrier4. Both aeroallergen and food sensitization has been associated with risk of ARD5, but it is less clear whether AD may partially mediate that risk. Additionally, food allergy has been recognized to be part of the atopic march, however its role in the march to ARD is less well identified. It is also unclear how these risks may appear in ethnically diverse populations. Distinct atopic phenotypes may better predict risk of ARD. Our objective was to identify whether associations between early food sensitization, aeroallergen sensitization, or food allergy (FA) and the subsequent risk of ARD by age 10 was modified by the development of early AD by age 2 years.We analyzed data from our racially and socioeconomically diverse birth cohort, Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) that enrolled pregnant women 21–45 years of age and their offspring. Recruitment period was from September 2003–December 2007. Eligibility and recruitment are described in previous publications 6 and all study protocols were approved by the Henry Ford Health System Institutional Review Board.Offspring sensitization to aeroallergens (Alternaria, cat, cockroach, dog, Dermatophagoides farina, ragweed, timothy grass), milk, egg, or peanut was determined at 2 years of age by sIgE≥0.35 IU/mL and skin prick testing (SPT; wheal size ≥3 mm larger than the saline control defined a positive test). As sensitization does not always translate to clinical allergy, we also formed an algorithm to determine those most likely to have true IgE-mediated food allergy7. Two allergists reviewed subjects with at least one of the following criteria: (1) at least one food (milk, egg or peanut) with sIgE ≥0.35 IU/mL; (2) a positive SPT; or (3) parental report of infant symptoms potentially related to food allergy plus at least one sIgE >0.10 IU/mL. To standardize classifying infants to the presence of IgE-mediated food allergy (IgE-FA), physicians were asked to combine professional experience with investigator-developed protocols based on the Guidelines for the Diagnosis and Management of Food Allergy in the United States8. A third allergist independently reviewed and ruled on discordant decisions. Data on asthma and AR by age 10 diagnosed by the study physician was collected using clinical history, physical exam, spirometry, and methacholine test.Adjusted relative risk (aRR) was calculated using Poisson regression with robust error variance and following adjustment for sex, child’s race, parental history of asthma, parental history of AR, BMI z-score at age 2, delivery mode, 1-month breastfeeding status, prenatal indoor dog exposure, prenatal indoor cat exposure, and 1-month daycare status.Of the 1258 mother-child pairs enrolled in WHEALS, 347 had sufficient data for analyses (Supplemental Figure 1). Demographics are shown in Table 1. The overall rate of early AD by age 2 years was 25.4% (88 out of 347 subjects). Supplemental Table 1 shows the overall rates of asthma and allergic rhinitis by age 10 by 2-year AD status. AD by age 2 years significantly modified the association between FA at 3-5 years and the risk of ever having asthma by age 10 (p=0.027) (Figure 1). In the absence of AD, FA to milk, egg, or peanut was associated with an increased risk of ever having asthma (aRR 3.36(1.71, 6.58), p<0.001), while no difference was observed in the presence of AD (aRR 1.24(0.57, 2.68), p=0.99). Food sensitization in the absence of AD was associated with increased risk of ever asthma (aRR 2.04(1.03, 4.05), p=0.038), but was not associated with ever AR (aRR 1.10(0.81, 1.48), p=0.97). Food sensitization in the presence of AD was not associated with ever asthma (aRR 0.89(0.45,1.78), p=0.99) or ever allergic rhinitis (aRR 1.45(0.97-2.16), p=0.078).In terms of aeroallergen sensitization, AD by age 2 did not significantly modify the association between aeroallergen sensitization at age 2 and the risk of ARD by age 10. This was true for aeroallergen sensitization overall and when sub-analyzed by seasonal versus perennial (Table 2, Figure 1). However, among those without AD by age 2, perennial aeroallergen sensitization was associated with an increased risk of ever having asthma by age 10 (aRR 2.15 (1.06, 4.36), p=0.031). This association was not significant for those with AD by age 2 (aRR 1.68 (0.78, 3.63), p=0.26).Our findings among a racially and socioeconomically diverse birth cohort suggest that early AD modifies the relationship between FA and the risk of ever having asthma by age 10. However, the association between FA and increased risk of ever having asthma was only seen among those without AD by age 2, which does not support the previously reported atopic progression of disease as described by the atopic march. This held true after correcting for several environmental and parental factors that may increase risk of ARD in our cohort. Our findings may represent a distinct atopic phenotype more characteristic among non-White subgroups, as our cohort is 67% self-identified Black. Previous reports have highlighted the differences in AD phenotypes among ethnically diverse subgroups9. Additionally, recent reports highlight atopic trajectories differ among White and Black children, with Black children more likely to have asthma without FA, AR, or allergen sensitization10. Due to sample size, we were unable to assess the differing trajectories in whites versus blacks. However, because our cohort is composed of 64.8% black children, we believe that black race may be contributing to the outcomes of our study as previous studies have reported atopic trajectories that are different in Black children10. Future studies investigating these endotypes that differ by ethnicity would be beneficial to identify potential immunological markers that would guide therapies for ethnically diverse populations and allow appropriate anticipatory guidance.Keywords : Atopic march, atopic dermatitis, food allergy, food sensitization, aeroallergen sensitization, asthma, allergic rhinitisKey message: Identifying early atopic phenotypes may help identify later ARD risk. This study reiterates that the “march” is not always a chronological process, but rather a complex relationship between heterogenous allergic phenotypes.

Race is a Modifier between Parental Allergy and Food Allergy in OffspringAmy A. Eapen, MD, MS*1, Erica Ridley MD*1, Alexandra R. Sitarik MS2, Christine Joseph PhD2, Christian Nageotte, MD1, Rana Misiak, MD1, Dennis Ownby MD3, Christine Johnson PhD2, Edward Zoratti MD1, Haejin Kim MD1.1Division of Allergy and Clinical Immunology, Henry Ford Health System, Detroit, Michigan2Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan3Department of Pediatrics, Augusta University, Augusta, Georgia.*Dr. Eapen and Dr. Ridley are listed as co-first authorsCorresponding author: Amy A. Eapen, MD, One Ford Place, 4B Detroit, MI 48202; Telephone (313) 971-6182; Fax (313) 876-2094; E-mail: [email protected]: Grants from the National Institute of Allergy and Infectious Diseases (R01 A1051598 and P01 A1089473) and the Fund for Henry Ford Hospital.Financial disclosure : There are no financial disclosures of conflicts of interest.Word count: 1191Keywords : Food allergy, race, parental allergy, total IgETo the Editor,Studies indicate associations between maternal allergy and development of food allergy in their offspring1, with higher food allergy risk among those with more than one first degree relative with allergic disease2. However, unnecessary food avoidance among children of allergic parents has important implications since diverse diets in children may decrease risk for food allergy, and early food introduction with foods such as peanut, can be protective for food allergy3. We sought to assess the association between parental allergic markers and offspring food sensitization and clinical allergy to milk, egg, or peanut.We analyzed data from the racially and socioeconomically diverse population birth cohort, Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) that enrolled pregnant women between 21 to 45 years of age and their offspring following recruitment between September 2003 to December 2007. Details regarding the cohort have been previously published4,5. Institutional Review Board (IRB) approval was obtained for all aspects of the study.Parental factors assessed included questionnaire responses regarding history of allergy or asthma; maternal total IgE and maternal serum allergen specific IgE (sIgE) levels during pregnancy or one month postpartum were also evaluated. Atopy was defined as at least one sIgE ≥ 0.35 IU/mL to eight allergens (dust mite, dog, cat, grass, ragweed,Alternaria , egg, cockroach). Maternal asthma, atopic dermatitis, and food allergy were determined by questionnaire. Due to a paucity of paternal data, only paternal asthma was assessed.Offspring sensitization to milk, egg, or peanut was determined at 2 years of age by sIgE≥ 0.35 IU/mL and also skin prick testing (SPT; wheal size ≥3 mm larger than the saline control defined a positive test). As sensitization to foods does not translate to clinical allergy in all cases, we formed an algorithm to determine those most likely to have true IgE-mediated food allergy6. A consensus panel of allergists determined food allergy status in offspring based on review of the aforementioned data and abstracted chart informations as previously described7. Briefly, infant data were forwarded to the panel only if more than one of the following criteria were met for milk, egg, or peanut allergens: (1) 1 sIgE ≥0.35 IU/mL; (2) a positive SPT; or (3) parental report of infant symptoms potentially related to food allergy plus at least one specific IgE greater than 0.10 IU/mL. To enhance standardization in classifying infants to the presence of IgE- mediated food allergy (IgE-FA), physicians were asked to combine professional experience with investigator-developed protocols based on the Guidelines for the Diagnosis and Management of Food Allergy in the United States8. A third allergist independently reviewed and ruled on discordant decisions.Logistic regression models of parental variables with each outcome were fit. Interaction terms were added to logistic regression models to assess differences in associations based on race, (p<0.10 was considered a significant interaction). Predicted probabilities were used to construct receiver operating characteristic (ROC) curves and calculate area-under-the-curve (AUC) values.Of 1258 maternal-child pairs, 761 had sufficient data for analysis (Supplemental Figure el). Participant characteristics indicated that families not lost to follow up had higher household incomes, as well as higher maternal education, and a higher proportion of mothers who were married, kept pets, and breastfed the child. rates (Table e1).Associations between parental variables and physician panel determination of food allergy are shown in Table 1. After adjusting for child race, seven out of eight parental characterics of the were significant or of borderline signficance. However, the maximum AUC for ROC curves for any individual variable was 0.54 (maternal total IgE), indicating poor prognostic value (Supplemental Table e2). Maternal atopy, multi-sensitization, and total IgE significantly interacted with race (p=0.012, 0.092, 0.068, respectively) indicating strong associations among African American (AA) children only (Table 1). For example, maternal atopy in non-AA children was not associated with food allergy, but was highly associated among AA children (OR [95% CI]=3.56 [1.55, 9.66], p=0.006).Maternal current asthma was also associated with childhood food allergy (OR [95% CI]=2.27 [1.02, 4.71], p=0.034), and patterns varied by race with history of maternal asthma associated with food allergy only in non-AA children (OR [95% CI]= 4.92 [1.22, 17.14], p=0.015), and current asthma among AA children (OR [95% CI]=2.64 [1.10, 5.92], p=0.022; Table 1).Combined, parental variables only modestly impacted food allergy ROC analyses resulting in an AUC of 0.66. However, the ROC curves differed by race (non-AA AUC 0.36 vs AA AUC 0.71, p=0.002) as shown in Figure 1.Apart from food allergy, parental variables were analysed for associations with offspring sensitization (positive sIgE or SPT) to peanut, milk, or egg at age 2 years. Maternal atopy, multi-sensitization, and total IgE were associated with offspring positive food sIgE sensitization to at least one food. Analysis stratified by race indicated these associations were significant only among AA children. (Supplemental Table e3). Furthermore, maternal current asthma was associated with food sIgE sensitization only among non-AA children (OR [95% CI]=4.90 [1.69, 16.20], p=0.005). ROC curves were significantly different between AA and non-AA children (p=0.036) but predictive ability remained poor in both (AUC 0.55 and 0.44 respectively as in supplemental Figure e2).Maternal multisensitization, total IgE and current asthma, and paternal asthma were statistically significantly associated with any positive food SPTs only among AA children. (Supplemental Table e4). Additionally, race modified the relationship between maternal atopy and SPTs (p=0.039); AA children of atopic mothers had elevated odds of food SPT positivity (OR [95% CI]=1.96 [1.15, 3.45], p=0.016). Despite ROC differences by race (p=0.015; Figure e3), parental variables again had minimal predictive ability.The importance of genetic factors in food allergy is supported by twin studies showing higher concordance of peanut allergy among monozygotic compared with dizygotic twins (64.3% and 6.8%, respectively)9. In addition, heritability among parents and offspring for overall food sensitization have been reported1. However, our report indicates parental variables related to allergy have poor predictive ability for offspring food sensitization. The results from the physician panel demonstrate a moderate degree of risk and capability of predicting food allergy in offspring from parents having clinical characteristics of allergy.We previously reported similar food allergy prevalence for milk, egg, and peanut in AA and non-AA children7. We report here that the inherited risk as measures by parental allergic variables and predictive ability of parental allergic variables on food allergy development in offspring varies by race and is more strongly associated with clinical food allergy versus sensitization, among AA children. The potential mechanisms behind this racial discrepancy are require further studies.Potential study limitations include the physician panel to determine clinical food allergy status as opposed to performing oral food challenges. These challenges are time consuming and impractical to implement in large epidemiological studies10. Another limitation is that non-AA children included multiple ethnicites, which was done to preserve sample size. These groups may have different incidences of disease, and risk may vary. Finally, included and excluded WHEALS participants differed by demographic variables, so findings may not be generalizable to the target population.Parental allergy and atopy, although associated with offspring food allergy, is only a weak predictor and depends upon race. Further studies of familial factors contributing to food allergy and these disparities are needed to precisely identify children at risk for food allergy.Amy A. Eapen, MD, MS*1, Erica Ridley MD*1, Alexandra R. Sitarik MS2, Christine Joseph PhD2, Christian Nageotte, MD1, Rana Misiak, MD1, Dennis Ownby MD3, Christine Johnson PhD2, Edward Zoratti MD1, Haejin Kim MD1.1Division of Allergy and Clinical Immunology2Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan3Department of Pediatrics, Augusta University, Augusta, Georgia.*Dr. Eapen and Dr. Ridley are listed as co-first authors