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Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort

Published:August 13, 2014DOI:https://doi.org/10.1016/j.jaci.2014.06.033

      Objective

      Previous data suggest that food allergy (FA) might be more common in inner-city children; however, these studies have not collected data on both sensitization and clinical reactivity or early-life exposures.

      Methods

      Children in the Urban Environment and Childhood Asthma birth cohort were followed through age 5 years. Household exposures, diet, clinical history, and physical examinations were assessed yearly; levels of specific IgE to milk, egg, and peanut were measured at 1, 2, 3, and 5 years of age. On the basis of sensitization (IgE ≥0.35 kU/L) and clinical history over the 5-year period, children were classified as having FA or being possibly allergic, sensitized but tolerant, or not allergic/not sensitized.

      Results

      Five hundred sixteen children were included. Overall, 55.4% were sensitized (milk, 46.7%; egg, 31.0%; and peanut, 20.9%), whereas 9.9% were categorized as having FA (peanut, 6.0%; egg, 4.3%; and milk, 2.7%; 2.5% to >1 food). The remaining children were categorized as possibly allergic (17.0%), sensitized but tolerant (28.5%), and not sensitized (44.6%). Eighteen (3.5%) reported reactions to foods for which IgE levels were not measured. Food-specific IgE levels were similar in children with FA versus sensitized but tolerant children, except for egg, levels of which were higher in patients with FA at ages 1 and 2 years. FA was associated with recurrent wheeze, eczema, aeroallergen sensitization, male sex, breast-feeding, and lower endotoxin exposure in year 1 but not with race/ethnicity, income, tobacco exposure, maternal stress, or early introduction of solid foods.

      Conclusions

      Even given that this was designed to be a high-risk cohort, the cumulative incidence of FA is extremely high, especially considering the strict definition of FA that was applied and that only 3 common allergens were included.

      Key words

      Abbreviations used:

      FA (Food allergy), IQR (Interquartile range), OR (Odds ratio), URECA (Urban Environment and Childhood Asthma)
      Food allergy (FA) is a common condition affecting approximately 3% to 6% of the US population,
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      Epidemiology of food allergy.
      and this diagnosis is associated with a significant impairment in quality of life.
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      • et al.
      Health-related quality of life of food allergic patients: comparison with the general population and other diseases.
      The prevalence of this condition appears to be increasing in industrialized countries, with an estimated 18% increase in childhood FA between 1997 and 2007.
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      • Sampson H.A.
      US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up.
      Recent studies have also suggested that the prevalence of FA might vary by race/ethnicity and geographic location, which is possibly similar to the trends that have been consistently reported for asthma
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      • Fenton M.J.
      • Gergen P.J.
      • Rotrosen D.
      • Fauci A.S.
      Asthma in the inner city: the perspective of the National Institute of Allergy and Infectious Diseases.
      and other atopic conditions.
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      • MacNeill S.
      • Hole A.M.
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      • et al.
      Crete: does farming explain urban and rural differences in atopy?.
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      • Von Mutius E.
      • Illi S.
      • Baumann L.
      • Bohm O.
      • von Kries R.
      Reduced risk of hay fever and asthma among children of farmers.
      Several studies have now shown that self-reported FA appears to be more prevalent in highly populated areas, after controlling for race/ethnicity and income,
      • Gupta R.S.
      • Springston E.E.
      • Smith B.
      • Warrier M.R.
      • Pongracic J.
      • Holl J.L.
      Geographic variability of childhood food allergy in the United States.
      and among children of black race/ethnicity.
      • Sicherer S.H.
      • Munoz-Furlong A.
      • Sampson H.A.
      Prevalence of seafood allergy in the United States determined by a random telephone survey.
      • Bloom B.
      • Cohen R.A.
      • Freeman G.
      Summary health statistics for U.S. children: National Health Interview Survey, 2009.
      These trends also persist when examining the estimated prevalence of FA based only on the measurement of food-specific IgE levels.
      • Liu A.H.
      • Jaramillo R.
      • Sicherer S.H.
      • Wood R.A.
      • Bock S.A.
      • Burks A.W.
      • et al.
      National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.
      • Kumar R.
      • Tsai H.J.
      • Hong X.
      • Liu X.
      • Wang G.
      • Pearson C.
      • et al.
      Race, ancestry, and development of food-allergen sensitization in early childhood.
      However, all of these studies are limited in that both self-report and sensitization substantially overestimate the prevalence of true FA.
      • Woods R.K.
      • Stoney R.M.
      • Raven J.
      • Walters E.H.
      • Abramson M.
      • Thien F.C.
      Reported adverse food reactions overestimate true food allergy in the community.
      • Keet C.A.
      • Wood R.A.
      • Matsui E.C.
      Limitations of reliance on specific IgE for epidemiologic surveillance of food allergy.
      Furthermore, no studies have yet looked at exposures that are more common in urban environments, such as stress, changes in dietary habits, and allergens, such as mouse and cockroach, which might promote the development of this condition. The aim of this study was to use clinical and serologic data from the Urban Environment and Childhood Asthma (URECA) study to better estimate the true prevalence of FA in inner-city children and to evaluate the effect of urban environmental exposures on the development of food sensitization and FA.

      Methods

       Study design

      URECA is a prospective, observational, inner-city birth cohort designed to study the effects of specific urban exposures on the development of recurrent wheeze and asthma. Detailed information regarding the design, methods, and study population has been previously reported.
      • Gern J.E.
      • Visness C.M.
      • Gergen P.J.
      • Wood R.A.
      • Bloomberg G.R.
      • O'Connor G.T.
      • et al.
      The Urban Environment and Childhood Asthma (URECA) birth cohort study: design, methods, and study population.
      Briefly, pregnant women in Baltimore, Boston, New York City, and St Louis were recruited between February 2005 and March 2007. Selection criteria included a mother or father with a history of allergic rhinitis, eczema, or asthma; gestational age of 34 weeks or greater; and collection of a suitable cord blood sample. Exclusion criteria included congenital anomalies, pulmonary or immunologic disorders, or maternal HIV infection. Overall, 1850 families were screened, 889 children were found to be eligible, and 560 were enrolled. An additional 49 children without a family history of atopy were also added to the study. Children who had food-specific IgE levels measured at 1 or more time points were included in this study.
      Maternal questionnaires regarding smoking, stress, and depression were collected prenatally, and cord blood and clinical information were collected at birth. Telephone surveys were performed every 3 months to assess the child's respiratory and allergy symptoms, medications, tobacco exposure, and diet. Starting at 1 year, the children were seen annually, when physical examinations and eczema assessments were performed and blood samples were obtained. For this study, the children were followed through age 5 years.
      Household dust samples were collected at 3 months and yearly thereafter and were analyzed for the common indoor allergens German cockroach (Bla g 1), dog (Can f 1), cat (Fel d 1), Dermatophagoides farinae (Der f 1), Dermatophagoides pteronyssinus (Der p 1), and mouse (Mus m 1) by using 2-site mAb ELISA (Indoor Biotechnologies, Charlottesville, Va). First-year samples were also analyzed for endotoxin by using the recombinant factor C assay
      • Alwis K.U.
      • Milton D.K.
      Recombinant factor C assay for measuring endotoxin in house dust: comparison with LAL, and (1 → 3)-beta-D-glucans.
      and for ergosterol, a component of fungal cell membranes, by using gas chromatography–mass spectroscopy.
      Mononuclear cells from cord blood and samples obtained at ages 1 and 3 years were incubated for 24 hours (PHA, LPS, polyinosinic-polycytidylic acid, CpG, peptidoglycan, respiratory syncytial virus, or medium alone) or 5 days (cockroach extract, D pteronyssinus extract, tetanus toxoid, or medium alone). The supernatants were then collected and analyzed with a multiplex assay (Beadlyte; Upstate Biotechnology, Lake Placid, NY) for the production of cytokines associated with both innate and adaptive immunity (see Table E1 in this article's Online Repository at www.jacionline.org).

       FA data collection and definitions

      At each annual visit, parents were asked specifically about the child's ingestion of milk, egg, and peanut and whether there was any concern for possible FA in a physician-administered FA questionnaire. If the study physician determined that the symptoms were consistent with FA, an allergy consult was recommended outside of the study protocol. In addition, allergen-specific IgE levels (ImmunoCap; Phadia, Uppsala, Sweden) were measured to milk, egg, and peanut at ages 1, 2, 3, and 5 years. An allergy consult was further recommended if food-specific IgE levels exceeded the 95% positive predictive threshold and there was either ambiguity in the clinical or dietary history or a history of either atopic dermatitis or failure to thrive. Because 95% predictive food-specific IgE cutoffs vary by age, we used previously validated values for preschool-aged children for milk (5 kU/L)
      • Garcia-Ara C.
      • Boyano-Martinez T.
      • Diaz-Pena J.M.
      • Martin-Munoz F.
      • Reche-Frutos M.
      • Martin-Esteban M.
      Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant.
      and egg (2 kU/L)
      • Boyano-Martinez T.
      • Garcia-Ara C.
      • Diaz-Pena J.M.
      • Martin-Esteban M.
      Prediction of tolerance on the basis of quantification of egg white-specific IgE antibodies in children with egg allergy.
      and the derived value for peanut from the Consortium of Food Allergy Research (5 kU/L).
      • Sicherer S.H.
      • Wood R.A.
      • Stablein D.
      • Burks A.W.
      • Liu A.H.
      • Jones S.M.
      • et al.
      Immunologic features of infants with milk or egg allergy enrolled in an observational study (Consortium of Food Allergy Research) of food allergy.
      Data on FA diagnosis and food avoidance recommendations were collected from all allergy consultations.
      Because oral food challenges were only performed as clinically indicated outside of this study, children were divided into 4 groups at each time point based on their food-specific IgE levels and clinical histories.
      Group 1 (FA) was defined as having a positive IgE level (≥0.35 kU/L) to milk, egg, and/or peanut; documented dietary avoidance of foods to which they were sensitized; and clinical confirmation by any of the following: (1) classified as FA to milk, egg, or peanut on allergy consultation or (2) parental documentation of a previous reaction to milk, egg, or peanut confirmed as consistent with true FA by the site investigator. In addition, all children who met the criteria for FA were individually reviewed by the authors to further ensure accurate categorization.
      Group 2 (possibly food allergic) was defined as having food sensitization with either documented dietary avoidance of the foods to which they were sensitized or unknown dietary consumption but without a confirmed clinical history of food reaction.
      Group 3 (sensitized but tolerant) was defined as having food sensitization but with reported consumption of the culprit food without adverse reactions.
      Finally, group 4 (not sensitized) was defined as all IgE levels being less than 0.35 kU/L.

       Statistical analysis

      For the purpose of analyses, each child was placed in the highest FA category (with FA being highest) that he or she attained for milk, egg, or peanut at any time over the 5 years. The cumulative incidence of FA by age 5 years was then calculated as a percentage of the total number of children included in the analysis (n = 516). Both t tests (continuous variables) and χ2 tests (categorical variables) were performed to compare baseline demographic and clinical characteristics among FA classifications. Differences in IgE and IgG4 levels between groups, as defined by yearly FA classifications, were tested by using Wilcoxon rank sum 2-sample tests. Comparisons across time points within each cumulative group were tested by using a linear trend test. IgE and IgG4 data were positively skewed, and therefore values were log-transformed for all statistical analyses.
      Several data reduction techniques were used to reduce the 61-item cytokine panel to 12 composite factor scores or linear combinations of the original, correlated, stimulant-specific cytokine responses (see Table E1). The factors were identified separately for the innate and adaptive panels of stimulant-cytokine combinations and without including unstimulated responses. Clustering of responses first showed that there was little to no association across years. Hierarchic clustering with a distance matrix was done within each year to determine which cytokine-stimulant responses were most similar to one another. These showed consistent results across the 3 years; when factors were calculated, all years were considered. Once the patterns of response were determined from the hierarchic clusters, a separate independent factor analysis was performed. The factors obtained by using factor analysis were similar to those obtained by using hierarchic clustering and confirmed that 6 factors accounted for the majority of the variance for each panel (66% for the innate panel and 84% for the adaptive panel). Odds ratios (ORs) to determine associations between FA groups and cytokine factors were calculated by using logistic regression while controlling for site, sex, season of birth, and family history of atopy.
      Associations between clinical outcomes, first-year bedroom dust exposure, and FA classifications were examined by using univariate and multivariable logistic regression, with adjustments for site, child's sex, and family history of atopic disease. Statistical analyses were performed with R 3.0.2 (http://www.r-project.org) and SAS 9.2 (SAS Institute, Cary, NC) software.

      Results

       Study population

      Of the 609 children initially enrolled, 516 (85%) were included in this study. Subjects missing all food-specific IgE measurements were excluded (n = 93), and comparison of this population with the remaining cohort revealed a difference only in gestational age (see Table E2 in this article's Online Repository at www.jacionline.org). Forty-four children from the nonatopic cohort were included in this study, and sensitivity analyses with removal of these children did not reveal any significant differences in our findings.
      Overall, 284 (55.4%) children were sensitized (IgE ≥0.35 kU/L) to milk, egg, or peanut (46.7%, 31.0%, and 20.9%, respectively) at any age. Fifty-one (9.9%) children fulfilled our criteria for FA (milk, 2.7%; egg, 4.3%; and peanut, 6.0%) and were thus included in group 1. Although all 51 children had both documented sensitization and dietary avoidance, 14 children were classified as having FA based on allergy consultation, and 37 were classified based on parental report and investigator confirmation. The remaining children were classified into groups 2 (possible FA, 17.0%), 3 (sensitized but tolerant, 28.5%), or 4 (not sensitized, 44.6%; Table I). Thirteen (2.5%) children were allergic to more than 1 of these foods. An additional 9 (1.7%) children reported reactions to other common food allergens (tree nuts, fish, shellfish, soy, and wheat) but were not included in group 1 because IgE levels to these foods were not measured. Similarly, 9 (1.7%) children reported reactions to other less allergenic foods (eg, chocolate and peaches) and were also not included in group 1. Among those in group 4 (not sensitized), 2 children (0.9%) reported clinical reactions and food avoidance that the authors felt could be consistent with food allergy.
      Table ICumulative incidence of FA by age 5 years in the URECA cohort (n = 516)
      Allergic (group 1)Possibly allergic (group 2)Sensitized and tolerant (group 3)Not allergic (group 4)
      Milk14 (2.7)41 (7.9)186 (36.1)275 (53.3)
      Egg22 (4.3)70 (13.5)68 (13.2)356 (69.0)
      Peanut31 (6.0)45 (8.7)32 (6.2)408 (79.1)
      Total51 (9.9)88 (17.0)147 (28.5)230 (44.6)
      Values are reported as numbers (percentages).
      Over the 5 years of follow-up, when examining FA classifications cross-sectionally, milk, egg, and peanut allergy were all most prevalent at age 2 years (milk, 1.7%; egg, 3.4%; peanut, 2.9%; overall, 6.3%; Fig 1). However, IgE levels in children with FA were highest for milk at age 1 year (median, 5.1 kU/L; interquartile range [IQR], 4.9-6.5 kU/L), peanut at age 3 years (4.0 kU/L; IQR, 1.3-17.8 kU/L), and egg at age 5 years (4.3 kU/L; IQR, 0.8-5.2 kU/L; Fig 2). Food-specific IgE levels were similar in group 1 versus group 3 children at each age over the 5 years, except for egg, which was higher in those in group 1 at ages 1 (median, 3.5 vs 1.6 kU/L; P = .02) and 2 (median, 2.5 vs 0.9 kU/L; P = .04) years. When examining the trend in IgE levels over time, food-specific IgE levels significantly decreased over time for milk (test for trend P < .001) and egg (P = .01) in those classified as having FA but increased for sensitized but tolerant children for milk (P < .001) and peanut (P < .001).
      Figure thumbnail gr1
      Fig 1Percentage of children classified as having FA (group 1) during each year of follow-up in the URECA cohort. Children were characterized as having FA if they had serologic and clinical evidence of allergy to the food and documentation of food avoidance during that year.
      Figure thumbnail gr2
      Fig 2Differences in food-specific IgE levels between those classified as being in group 3 (sensitized but not allergic, red) and group 1 (FA, blue) at ages 1, 2, 3, and 5 years. Significant differences (P < .05) were noted for egg at age 1 and 2 years and are depicted with an asterisk.
      Children in group 1, when compared with those in groups 3 and 4, were more likely to be male (P = .01) and to receive diagnoses of other allergic conditions (Table II and Table E3 in this article's Online Repository at www.jacionline.org), including eczema before age 3 years; aeroallergen sensitization at ages 2, 3, and 5 years; and wheezing during years 3, 4, and 5.
      Table IIDemographic characteristics of children with FA and food-sensitized children in the URECA cohort
      Allergic (n = 51)Not allergic
      Children who were classified as either group 3 or group 4; group 2 is not included in this analysis.
      (n = 377)
      P valueSensitized (n = 286)Not sensitized (n = 230)P value
      Male sex36 (70.6)192 (50.9).01148 (51.7)120 (52.2).99
      Race/ethnicity.56.16
       Black41 (80.4)271 (71.9)207 (72.4)161 (70.0)
       Hispanic6 (11.8)75 (19.9)57 (19.9)47 (20.4)
       Other4 (7.8)31 (8.2)22 (7.7)22 (9.6)
      Annual household income <$15,00039 (76.5)255 (67.8).28196 (68.5)160 (69.9).82
      Mother completed high school35 (68.8)211 (56.1).12182 (63.9)123 (53.5).02
      Mother married6 (11.8)52 (13.8).8545 (15.8)26 (11.3).18
      Mother's age at delivery (y)
      Mean ± SD.
      24.2 ± 6.024.5 ± 6.0.7324.5 ± 6.024.3 ± 5.9.84
      Type of delivery.31.96
       Vaginal39 (76.5)258 (68.4)196 (68.5)159 (69.1)
       Cesarean section12 (23.5)119 (31.6)90 (31.5)71 (30.9)
      Gestational age (wk)
      Mean ± SD.
      38.5 ± 1.738.8 ± 1.5.2438.9 ± 1.538.7 ± 1.5.14
      Maternal asthma25 (49.0)165 (44.0).60133 (46.8)101 (43.9).57
      Maternal stress
      Stress was measured by using the Perceived Stress Scale, and depression was measured by using the Edinburgh Postnatal Depression Scale.
      at age 1 y
      4.9 ± 2.94.6 ± 2.8.564.5 ± 2.84.7 ± 2.6.40
      Maternal depression
      Stress was measured by using the Perceived Stress Scale, and depression was measured by using the Edinburgh Postnatal Depression Scale.
      at age 1 y
      6.9 ± 6.66.5 ± 6.7.235.9 ± 6.46.7 ± 6.5.19
      Smokers in the home (no.).63.72
       029 (56.9)186 (49.6)150 (52.8)116 (50.4)
       1-219 (37.3)168 (44.8)117 (41.2)102 (44.4)
       ≥33 (5.8)21 (5.6)17 (6.0)12 (5.2)
      Breast-feeding
      Data collected at age 3 months (n = 501).
       Ever35 (68.8)193 (52.9).05161 (58.3)121 (53.8).35
       At 3 mo16 (32.7)76 (22.8).1864 (25.1)48 (23.4).76
      Solid food introduced (wk)
      Children who were classified as either group 3 or group 4; group 2 is not included in this analysis.
      Mean ± SD.
      13.9 ± 7.415.1 ± 8.9.2714.8 ± 8.515.2 ± 8.6.63
      Vitamin D3 (ng/mL)
      Mean ± SD.
       Cord blood19.9 ± 9.420.1 ± 8.8.8520.3 ± 9.620.3 ± 8.7.99
       At age 3 y
      N = 413 from age 3-year blood collections.
      19.1 ± 8.420.1 ± 6.8.4819.8 ± 6.920.1 ± 6.8.66
      Values are expressed as numbers (percentages), unless otherwise noted. P values were determined by using the Pearson χ2 or t test.
      Children who were classified as either group 3 or group 4; group 2 is not included in this analysis.
      Mean ± SD.
      Stress was measured by using the Perceived Stress Scale, and depression was measured by using the Edinburgh Postnatal Depression Scale.
      § Data collected at age 3 months (n = 501).
      N = 413 from age 3-year blood collections.

       Dietary and environmental exposures

      Breast-feeding for any duration was found to be significantly associated with FA (P = .05, Table II), whereas higher maternal education was associated with food sensitization (P = .03) but not FA. Race/ethnicity, household income, type of delivery, maternal smoking during pregnancy, maternal stress and/or depression, timing of introduction of complementary foods, and vitamin D levels were not found to be different between those with and without food sensitization or FA.
      With regard to other exposures, neither food sensitization nor FA was associated with exposure to ergosterol or environmental tobacco smoke. FA and sensitization were likewise not associated with cat, dog, mouse, cockroach, or dust allergen exposure in the bedroom during the first year of life (see Table E4 in this article's Online Repository at www.jacionline.org). In contrast, higher levels of endotoxin in the bedroom during the first year of life were significantly protective for the development of overall FA (OR, 0.4; 95% CI, 0.2-0.8) and egg allergy (OR, 0.2; 95% CI, 0.1-0.6).

       Immunologic profiling

      Food-specific IgG4 levels were measured at ages 1 and 3 years and PBMC cytokine profiles were analyzed at birth and ages 1 and 3 years to examine immunologic changes associated with the development of FA. Looking year by year, children in group 1 were found to have higher IgG4 levels to peanut and egg at age 1 year and to peanut at age 3 years than those in group 4 (Fig 3). Similarly, those in group 3 who were sensitized but tolerant to casein, egg, and peanut had significantly higher IgG4 levels to these foods at both ages 1 and 3 years when compared with group 4. Mean IgG4 values increased for all children between ages 1 and 3 years, and this trend was significant for all foods in group 4 (P < .01), casein and egg in group 3 (P < .001), and solely egg for group 1 (P < .001).
      Figure thumbnail gr3
      Fig 3Food-specific IgG4 levels among those in groups 4 (green), 3 (red), and 1 (blue) at ages 1 and 3 years. Significant differences between groups (P < .05) are noted with a line and asterisk.
      Children in group 1 were further found to have altered innate and adaptive cytokine profiles as early as 1 year of age (Fig 4). These children were found to have increased IL-8 and decreased IFN-α production on viral stimulation at age 3 years compared with group 4. Those with FA and food sensitization had increased PBMC expression of pro-TH2 cytokines (IL-4, IL-5, IL-13, and IFN-γ) on dust mite and cockroach stimulation at 1 year of age when compared with those without FA or sensitization, and this altered adaptive immune response persisted on cockroach stimulation at age 3 years.
      Figure thumbnail gr4
      Fig 4OR for development of FA (left panel) or food sensitization (right panel) for summary variables of PBMC cytokine response. Allergic, Group 1 (FA) versus groups 3 (sensitized but tolerant) and 4 (not sensitized). Sensitized, Groups 1, 2 (possibly food allergic), and 3 versus group 4. Solid circles represent statistical significance in models adjusted for site, sex, and season of birth. A, Innate panel. B, Adaptive panel. See for abbreviation definitions and a list of stimulants and cytokines measured.

      Discussion

      In this observational, high-risk, inner-city birth cohort, we found that 9.9% of children had convincing clinical and serologic evidence of FA by age 5 years. Although previous studies have suggested that FA might be more common among children living in urban environments,
      • Gupta R.S.
      • Springston E.E.
      • Smith B.
      • Warrier M.R.
      • Pongracic J.
      • Holl J.L.
      Geographic variability of childhood food allergy in the United States.
      this study supports this finding by using a stringent definition of FA based on both clinical and serologic data. Furthermore, this is the first study to longitudinally examine the influence of urban environmental exposures on the development of both FA and food sensitization.
      Although it is possible that the true incidence is lower, it is far more likely that the cumulative incidence estimate of 9.9% is an underestimation of true FA in this population. Not only did we use a strict definition requiring both sensitization and clinical correlation, our cumulative incidence estimate was only based on milk, egg, and peanut, which have been shown to account for only about 80% of FA in young children.
      • Osterballe M.
      • Hansen T.K.
      • Mortz C.G.
      • Host A.
      • Bindslev-Jensen C.
      The prevalence of food hypersensitivity in an unselected population of children and adults.
      • Venter C.
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      • Voigt K.
      • Grundy J.
      • Clayton C.B.
      • Higgins B.
      • et al.
      Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life.
      Although we did not include them in our incidence estimate, it is likely that at least some of the additional 1.7% of children who reported reactions to fish, shellfish, tree nuts, wheat, or soy truly did have FA not to mention those who reported reactions to less common food allergens. Finally, some of the children who were classified as “possibly allergic” because of lack of confirmatory clinical data could also be truly allergic and were not included in our estimate. In fact, if only serologic evidence of FA was required, as in other studies,
      • Liu A.H.
      • Jaramillo R.
      • Sicherer S.H.
      • Wood R.A.
      • Bock S.A.
      • Burks A.W.
      • et al.
      National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.
      an additional 37 (7.2%) children would have been classified as having FA by using 95% positive predictive cutoff values.
      This cumulative incidence estimate of 9.9% is higher than the recent prevalence estimate of 6.5% for self-reported FA in the general pediatric population from the National Health and Nutrition Examination Survey 2007-2010.
      • McGowan E.C.
      • Keet C.A.
      Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.
      However, differences in definitions used, time periods examined, and populations included make meaningful comparisons across FA studies very difficult. In a recent systematic review the prevalence of FA was found to be greater than 1% to 2% but less than 10% of the population.
      • Chafen J.J.
      • Newberry S.J.
      • Riedl M.A.
      • Bravata D.M.
      • Maglione M.
      • Suttorp M.J.
      • et al.
      Diagnosing and managing common food allergies: a systematic review.
      Although it has been shown that studies that rely on self-report overestimate the true prevalence of FA when compared with oral food challenges,
      • Woods R.K.
      • Stoney R.M.
      • Raven J.
      • Walters E.H.
      • Abramson M.
      • Thien F.C.
      Reported adverse food reactions overestimate true food allergy in the community.
      performing oral food challenges in large-scale epidemiologic studies is often unfeasible. Thus studies such as the URECA cohort that rely on robust clinical and serologic data to provide accurate estimates are extremely valuable.
      In a recent study examining the effect of urbanization on FA, Gupta et al
      • Gupta R.S.
      • Springston E.E.
      • Smith B.
      • Warrier M.R.
      • Pongracic J.
      • Holl J.L.
      Geographic variability of childhood food allergy in the United States.
      found that self-reported FA was more prevalent in urban (9.8%) versus rural (6.2%) locations. Although the URECA estimate is similar to Gupta et al's urban prevalence estimate, it is difficult to directly compare these studies because our estimate is based on cumulative incidence over 5 years, was ascertained in a high-risk cohort, involves a population younger than 5 years, and only includes FA to milk, egg, and peanut, whereas Gupta et al reported a cross-sectional prevalence estimate based on a population younger than 18 years who had reactions to any food. In contrast, our estimate was significantly higher than the recently published prevalence estimate of 3.8% by Taylor-Black and Wang
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      The prevalence and characteristics of food allergy in urban minority children.
      in a general pediatrics clinic in East Harlem, New York, although they did express concern that their population might be underdiagnosed or undertreated.
      Consistent with previous studies, FA in our cohort was more common among male subjects.
      • Sicherer S.H.
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      • et al.
      Immunologic features of infants with milk or egg allergy enrolled in an observational study (Consortium of Food Allergy Research) of food allergy.
      FA was further found to be more common among children who were breast-fed, for which conflicting results have been shown in other studies on asthma and atopic dermatitis.
      • Sears M.R.
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      Breastfeeding duration is a risk factor for atopic eczema.
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      Breast-feeding in relation to asthma, lung function, and sensitization in young schoolchildren.
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      • et al.
      Breastfeeding protects against current asthma up to 6 years of age.
      Interestingly, other risk factors that are more commonly associated with inner-city environments, such as stress, black race/ethnicity, poverty, vitamin D deficiency, and early introduction of complementary foods, were not found to be associated with FA. It is possible that this might be explained by the fact that the URECA population was relatively homogenous in terms of race/ethnicity and poverty level, and thus there was not substantial variation in these measures.
      In contrast, there was a significant protective effect of endotoxin exposure for the development of egg and overall FA. This finding is similar to those of previous longitudinal studies for eczema
      • Perzanowski M.S.
      • Miller R.L.
      • Thorne P.S.
      • Barr R.G.
      • Divjan A.
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      • et al.
      Endotoxin in inner-city homes: associations with wheeze and eczema in early childhood.
      and asthma,
      • Douwes J.
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      • Doekes G.
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      • Kerkhof M.
      • Gerritsen J.
      • et al.
      Does early indoor microbial exposure reduce the risk of asthma? The Prevention and Incidence of Asthma and Mite Allergy birth cohort study.
      but to our knowledge, this is the first study to prospectively examine this relationship for the development of FA. Previous studies have demonstrated that endotoxin levels are lower in urban environments than in rural farming areas,
      • Barnig C.
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      • et al.
      Indoor dust and air concentrations of endotoxin in urban and rural environments.
      • Lee A.
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      • Goh D.L.
      • et al.
      Endotoxin levels in rural Thai and urban Singaporean homes.
      and a recent study examining the indoor microbiome in the same URECA cohort found that exposure to specific allergens and bacteria was associated with reduced sensitization to inhalant allergens, as well as recurrent wheeze.
      • Lynch S.V.
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      • et al.
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      Therefore although it has been previously suggested that the high rates of allergy and asthma in the inner city contradict the hygiene hypothesis,
      • Platts-Mills T.A.
      • Erwin E.
      • Heymann P.
      • Woodfolk J.
      Is the hygiene hypothesis still a viable explanation for the increased prevalence of asthma?.
      both of these studies suggest that this is not actually the case.
      Among children who were considered allergic to each food in a given year, milk-specific IgE levels peaked at age 1 year and then trended down, whereas peanut- and egg-specific IgE levels peaked at ages 3 and 5 years, respectively. Interestingly, with the exception of IgE to egg at ages 1 and 2 years, food-specific IgE levels were similar among those with FA and those who were asymptomatically sensitized, in whom levels actually increased over time for milk and peanut. This finding highlights the fact that the presence of food-specific IgE alone cannot be used to diagnose FA either in the clinic or in epidemiologic studies.
      • Keet C.A.
      • Wood R.A.
      • Matsui E.C.
      Limitations of reliance on specific IgE for epidemiologic surveillance of food allergy.
      • Chafen J.J.
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      • et al.
      Diagnosing and managing common food allergies: a systematic review.
      Our data further suggest that peanut allergy decreased at 5 years of age, a finding that would be inconsistent with the usual persistence of peanut allergy. We suspect that this finding is most likely an artifact related to missing data at age 5 years because when the 31 children who were ever classified as having peanut allergy were individually examined at age 5 years, 19 did not have sufficient information regarding ingestion to be accurately classified, although 5 (16.1%) did have serologic or clinical evidence suggesting they might have outgrown the allergy. We similarly suspect that children were not given a diagnosis of milk allergy at age 5 years because of these missing dietary data.
      Children with FA and those who were asymptomatically sensitized were found to have higher food-specific IgG4 levels compared with those seen in children who were not sensitized. These findings are similar to those of previous studies demonstrating an association between peanut sensitization and increased peanut IgG4 levels,
      • Sverremark-Ekstrom E.
      • Hultgren E.H.
      • Borres M.P.
      • Nilsson C.
      Peanut sensitization during the first 5 yr of life is associated with elevated levels of peanut-specific IgG.
      • Tay S.S.
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      • Deighton J.
      • King Y.
      • Ewan P.W.
      Patterns of immunoglobulin G responses to egg and peanut allergens are distinct: ovalbumin-specific immunoglobulin responses are ubiquitous, but peanut-specific immunoglobulin responses are up-regulated in peanut allergy.
      • Dreskin S.C.
      • Tripputi M.T.
      • Aubrey M.T.
      • Mustafa S.S.
      • Atkins D.
      • Leo H.L.
      • et al.
      Peanut-allergic subjects and their peanut-tolerant siblings have large differences in peanut-specific IgG that are independent of HLA class II.
      although our findings are inconsistent with the notion that IgG4 is a marker of tolerance, as it might be in food immunotherapy.
      • Vickery B.P.
      • Lin J.
      • Kulis M.
      • Fu Z.
      • Steele P.H.
      • Jones S.M.
      • et al.
      Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens.
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • Fleischer D.M.
      • Sicherer S.H.
      • Lindblad R.W.
      • et al.
      Oral immunotherapy for treatment of egg allergy in children.
      As previous authors have hypothesized,
      • Dreskin S.C.
      • Tripputi M.T.
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      • Atkins D.
      • Leo H.L.
      • et al.
      Peanut-allergic subjects and their peanut-tolerant siblings have large differences in peanut-specific IgG that are independent of HLA class II.
      it is possible that this increased IgG4 level in sensitized children in this cohort indicates that the aberrant immune response in children with FA might occur before IgE class-switching.
      Children with FA were also found to have evidence of abnormal innate and adaptive immune responses as early as 1 year of age, with increased production of IL-4, IL-5, and IL-13, which is consistent with a TH2 phenotype. At age 3 years, they were further found to have increased IL-8 and decreased IFN-α production in response to viral infections. This finding is consistent with recent studies demonstrating that children with higher FcεRI expression on plasmacytoid dendritic cells have decreased IFN-α production in response to human rhinovirus exposure.
      • Durrani S.R.
      • Montville D.J.
      • Pratt A.S.
      • Sahu S.
      • DeVries M.K.
      • Rajamanickam V.
      • et al.
      Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.
      Our study is limited by the fact that the children did not undergo double-blind, placebo-controlled food challenges, the gold standard for FA diagnosis. However, the robust clinical, dietary, and serologic information available enabled us to make informed assessments regarding those likely to have true FA.
      We are further limited because a large proportion of children (n = 88) were still classified as “possibly allergic.” Although our power to detect potential risk factors for the development of FA might have been diminished by not including these children in our analyses, we believed that it was most important to focus on the subset with a firm diagnosis.
      Finally, because this is a prospective cohort study, sufficient data were only available for 85% of the original participants, which might have introduced selection bias into our study and possibly underestimated the true prevalence of FA at year 5 because of missing dietary data.
      In conclusion, this is the first study to examine the cumulative incidence of FA in inner-city children through the use of both prospective clinical and serologic data. Although the results might not be fully generalizable given that this was designed to be a high-risk cohort in a small number of US cities, we found that despite a strict definition of FA and the inclusion of only 3 food allergens, the cumulative incidence of FA among inner-city children is substantially higher than recent estimates among the general US pediatric population. It is possible that previously lower estimates of FA in inner-city populations were a result of underdiagnosis and undertreatment, and future studies should be conducted to address this significant health disparity. Although this study further identified potential environmental factors associated with the development of FA, additional study is clearly needed to further explore those factors that might be modifiable.
      Clinical implications
      When using a stringent definition, the cumulative incidence of FA in a high-risk inner-city cohort was substantially higher than recent estimates among the general US pediatric population.
      The URECA study is a collaboration of the following institutions and investigators (principal investigators are indicated by asterisks, and protocol chairs are indicated by double asterisks): Johns Hopkins University, Baltimore, Md: R. Wood,* E. Matsui, H. Lederman, F. Witter, J. Logan, S. Leimenstoll, D. Scott, L. Daniels, L. Miles, D. Sellers, A. Swift, and K. Smith; Boston University School of Medicine, Boston, Mass: G. O'Connor,* W. Cruikshank, M. Sandel, A. Lee-Parritz, C. Stamoulos, E. Gjerasi, P. Price-Johnson, B. Caldwell, and M. Tuzova; Columbia University, New York, NY: M. Kattan,* C. Lamm, N. Whitney, P. Yaniv, C. Sanabia, A. Valones, R. Rios, and C. Maher; Mount Sinai School of Medicine, New York, NY: H. Sampson and M. Mishoe; Washington University School of Medicine, St Louis, Mo: G. Bloomberg,* L. Bacharier, Y. Sadovsky, E. Tesson, C. Koerkenmeier, R. Sharp, K. Ray, I. Bauer, A. Freie, and V. Morgan; Statistical and Clinical Coordinating Center–Rho, Inc, Chapel Hill, NC: H. Mitchell,* P. Zook, C. Visness, M. Walter, R. Bailey, S. Hicks, M. Bader, W. Taylor, and R. Budrevich; Scientific Coordination and Administrative Center–University of Wisconsin, Madison, Wis: W. Busse,* J. Gern,** P. Heinritz, C. Sorkness, W. M. Lee, K. Grindle, A. Dresen, and T. Pappas; National Institute of Allergy and Infectious Diseases, Bethesda, Md: P. Gergen, A. Togias, E. Smartt, and K. Thompson.

      Appendix

      Table E1Stimulants used, cytokines measured, and resultant cytokine response factors from mononuclear cell assays
      Innate immune responsesAdaptive immune responses
      StimulantsCytokinesStimulantsCytokines
      LPSIFN-αPHAIFN-γ
      PICIFN-γCRIL-10
      PGIL-10DM
      Dermatophagoides pteronyssinus.
      IL-13
      CpGIL-12p40TTIL-4
      RSVTNF-αMAB
      Stimulation not conducted on cells from umbilical cord samples.
      IL-5
      Not measured in umbilical cord samples.
      RV
      Stimulation not conducted on cells from umbilical cord samples.
      IL-8Medium alone
      Medium aloneIFN-α
      Innate immune response factorsAdaptive immune response factors
      IL-10 and TNF-α responses to viral stimuli (PIC, CpG, RSV, RV)IL-10 responses to adaptive stimuli (DM, CR)
      IFN-γ responses to viral stimuliResponses to DM (no IL-10)
      IL-12 p40 responses to viral stimuliResponses to CR (no IL-10)
      IL-8 responses to viral stimuliAll cytokine responses to PHA
      IFN-α responses to viral stimuliAll cytokine responses to MAB
      IL-10 and TNF-α responses to viral stimuli (PIC, CpG, RSV, RV)All cytokine responses to TT
      CR, Cockroach extract; DM, dust mite extract; MAB, CD3 + CD28 mAb; PG, peptidoglycan; PIC, polyinosinic-polycytidylic acid; RSV, respiratory syncytial virus; RV, rhinovirus; TT, tetanus toxoid.
      Dermatophagoides pteronyssinus.
      Stimulation not conducted on cells from umbilical cord samples.
      Not measured in umbilical cord samples.
      Table E2Demographic characteristics of the URECA study population and those with missing IgE data
      Study population (n = 516)Missing IgE data (n = 93)P value
      Male sex268 (51.9)44 (47.3).48
      Race/ethnicity.25
       Black368 (71.3)58 (65.2)
       Hispanic104 (20.2)21 (23.6)
       Other44 (8.5)10 (11.2)
      Site.11
       Baltimore149 (28.8)16 (17.2)
       Boston120 (23.3)26 (28.0)
       New York97 (18.8)23 (24.7)
       St Louis150 (29.1)28 (30.1)
      Low household income
      Defined as less than $15,000 per year.
      356 (69.1)46 (64.8).55
      Mother completed high school305 (59.2)51 (58.6).99
      Mother married71 (13.8)9 (10.3).48
      Mother's age at delivery (y)
      Mean ± SD.
      24.4 ± 5.924.2 ± 5.9.70
      Type of delivery.93
       Vaginal355 (68.8)65 (69.9)
       Cesarean section161 (31.2)28 (30.1)
      Child's birth weight (g)
      Mean ± SD.
      3249.0 ± 500.03154.0 ± 577.0.14
      Gestational age (wk)
      Mean ± SD.
      38.8 ± 1.538.4 ± 1.8.03
      Maternal asthma234 (45.5)36 (41.4).55
      Smokers in the home (no.).83
       0266 (51.8)47 (54.0)
       1-2219 (42.6)37 (42.5)
       ≥329 (5.6)3 (3.5)
      Breast-feeding
       Ever282 (56.3)36 (70.6).07
       At 3 mo112 (24.3)11 (24.4).99
      Values are expressed as numbers (percentages), unless otherwise noted. P values were determined by using the Pearson χ2 test or t test.
      Defined as less than $15,000 per year.
      Mean ± SD.
      Table E3Association between FA and other atopic conditions
      Comparison between group 1 (allergic) versus groups 3 (sensitized but not allergic) and group 4 (not allergic).
      Crude ORP valueAdjusted OR
      Adjusted for site, sex, and family history of atopy/allergy.
      P value
      Wheeze
       Year 11.7 (0.9-3.1).091.5 (0.8-2.8).19
       Year 21.5 (0.8-2.6).211.3 (0.7-2.4).35
       Year 33.1 (1.7-5.7)<.0012.9 (1.6-5.5)<.001
       Year 43.5 (1.9-6.3)<.0013.1 (1.7-5.9)<.001
       Year 52.9 (1.6-5.3)<.0012.7 (1.4-5.0).003
      ≥2 Episodes of wheeze
       Year 11.4 (0.8-2.7).271.4 (0.7-2.7).34
       Year 21.4 (0.7-2.6).361.3 (0.6-2.5).50
       Year 31.7 (0.9-3.3).121.6 (0.8-3.2).18
       Year 43.1 (1.6-5.9)<.0012.7 (1.3-5.2).005
       Year 53.0 (1.5-5.9).0012.7 (1.4-5.4).005
      Eczema
       Year 13.2 (1.8-5.9)<.0013.6 (1.8-7.1)<.001
       Year 22.7 (1.3-5.5).012.7 (1.3-5.7).01
       Year 32.6 (1.1-6.2).032.6 (1.1-6.3).04
       Year 41.3 (0.4-4.0).631.5 (0.5-4.6).50
       Year 51.7 (0.5-5.1).381.8 (0.6-5.7).33
      Aeroallergen sensitization
       Year 214.9 (7.2-31.1)<.00113.3 (6.2-28.8)<.001
       Year 36.2 (3.1-12.7)<.0016.3 (3.1-13.0)<.001
       Year 55.7 (2.6-12.3)<.0015.3 (2.4-11.7)<.001
      Values are reported as ORs (95% CIs).
      Comparison between group 1 (allergic) versus groups 3 (sensitized but not allergic) and group 4 (not allergic).
      Adjusted for site, sex, and family history of atopy/allergy.
      Table E4Associations between first-year bedroom dust exposures and food sensitization/FA
      Food sensitization
      Comparison between groups 1 (allergic), 2 (possibly food allergic), and 3 (sensitized but tolerant) versus group 4 (not sensitized).
      FA
      Comparison between group 1 (allergic) versus groups 3 (sensitized but tolerant) and 4 (not sensitized).
      OverallP valueMilkP valueEggP valuePeanutP valueOverallP value
      Cat0.9 (0.7-1.1).311.3 (0.6-2.6).441.0 (0.5-1.7).991.0 (0.6-1.7).881.0 (0.6-1.5).95
      Dog0.9 (0.8-1.2).601.1 (0.6-1.9).631.4 (0.9-2.1).070.8 (0.4-1.2).311.0 (0.7-1.4).95
      Dust mite
      Dermatophagoides farinae.
      0.8 (0.4-1.6).502.5 (0.3-11.0).260.8 (0.1-3.2).732.0 (0.4-6.5).311.1 (0.4-3.6).81
      Mouse1.0 (0.8-1.2).840.8 (0.5-1.4).500.7 (0.4-1.1).140.9 (0.6-1.4).770.8 (0.6-1.1).18
      Cockroach0.9 (0.7-1.2).481.2 (0.5-2.3).660.6 (0.3-1.1).090.9 (0.5-1.5).640.8 (0.5-1.2).29
      Endotoxin0.7 (0.5-1.1).120.4 (0.1-1.2).070.2 (0.1-0.6).0050.7 (0.3-1.4).300.4 (0.2-0.8).01
      Ergosterol0.8 (0.5-1.4).470.4 (0.1-2.3).240.3 (0.1-1.2).070.9 (0.3-2.8).900.9 (0.4-2.4).88
      Values are expressed as ORs (95% CIs) for each log10 increase in endotoxin/dust adjusted for site, sex, and family history of atopy/allergy.
      Comparison between groups 1 (allergic), 2 (possibly food allergic), and 3 (sensitized but tolerant) versus group 4 (not sensitized).
      Comparison between group 1 (allergic) versus groups 3 (sensitized but tolerant) and 4 (not sensitized).
      Dermatophagoides farinae.

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