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Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study

Published:November 15, 2017DOI:https://doi.org/10.1016/j.jaci.2017.08.024

      Background

      The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years.

      Methods

      Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available.

      Results

      Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36).

      Conclusions

      Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

      Key words

      Abbreviations used:

      aRR (Adjusted relative risk), CHILD (Canadian Healthy Infant Longitudinal Development), FLG (Filaggrin), RERI (Relative excess risk due to interaction), RR (Relative risk)
      Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.
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      In the German Multicenter Allergy Study birth cohort FLG variants were highly predictive of asthma in children with eczema and sensitization to food allergens.
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      In the Isle of Wight birth cohort, allergic sensitization and eczema status were found to be independent effect modifiers of the relationship between FLG variants and asthma but not rhinitis.
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      How atopic is atopic dermatitis?.
      This is especially important considering the global epidemic of asthma, allergy, and allergic rhinitis.
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      The Canadian Healthy Infant Longitudinal Development (CHILD) study
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      • Anand S.S.
      • Becker A.B.
      • Befus A.D.
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      • Brook J.R.
      • et al.
      The Canadian Healthy Infant Longitudinal Development (CHILD) Study: examining developmental origins of allergy and asthma.
      is a multicenter prospective birth cohort established to determine the root causes of allergic diseases in children. Here we investigated whether allergic sensitization enhances associations between atopic dermatitis in infancy with subsequent allergic diseases, including asthma, allergic rhinitis, food allergy, and persistent atopic dermatitis.

      Methods

       Study design and cohort

      The CHILD study is a multicenter longitudinal cohort of 3495 Canadian infants recruited during pregnancy and followed from birth to age 5 years. Child health questionnaires and clinical assessments of allergic diseases were conducted at regular intervals, including 1 and 3 years of age. The current analysis involves 2311 children who had complete data for clinical assessment at age 1 and 3 years, and all required adjustment variables.

       Assessment of allergic sensitization

      At age 1 year, children were administered epicutaneous skin tests to a battery of 6 inhalant (Alternaria alternata, cat hair, dog epithelium, house dust mites [Dermatophagoides pteronyssinus and Dermatophagoides farinae], and German cockroach) and 4 food (cow's milk, egg white, peanut, and soybean) allergens. As in our previous epidemiologic studies,
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      • et al.
      A longitudinal population-based cohort study of childhood asthma followed to adulthood.
      • Sears M.R.
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      • Taylor D.R.
      • Flannery E.M.
      • Cowan J.O.
      • et al.
      Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study.
      • Hancox R.J.
      • Welch D.
      • Poulton R.
      • Taylor D.R.
      • McLachlan C.R.
      • Greene J.M.
      • et al.
      Cigarette smoking and allergic sensitization: a 32-year population-based cohort study.
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      • Konya T.
      • Guttman D.S.
      • Field C.J.
      • Sears M.R.
      • HayGlass K.T.
      • et al.
      Infant gut microbiota and food sensitization: associations in the first year of life.
      • Sbihi H.
      • Allen R.W.
      • Becker A.
      • Brook J.R.
      • Mandhane P.
      • Scott J.A.
      • et al.
      Perinatal exposure to traffic-related air pollution and atopy at 1 year of age in a multi-center Canadian birth cohort study.
      • Arrieta M.-C.
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      • Russell S.
      • Yurist-Doutsch S.
      • et al.
      Early life microbial and metabolic alterations affect risk of childhood asthma.
      children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control (glycerin) to at least 1 of the allergens. In cases in which skin tests were refused, some parents provided the results of external tests performed by other physicians, which were used to determine atopic status.

       Assessment of allergic diseases

      At the clinical assessment at age 1 year, the CHILD study physicians (A.B.B., P.J.M., P.S., and S.E.T.; all experienced pediatricians specializing in allergy and asthma) or other highly trained health care professional under their direction answered the question “Does this child meet the criteria for diagnosis of atopic dermatitis?” with the options “yes” or “no.” These criteria were derived from the UK Working Party document,
      • Williams H.C.
      • Jburney P.G.
      • Pembroke A.C.
      • Hay R.J.
      The UK Working Party's diagnostic criteria for atopic dermatitis. III. Independent hospital validation.
      namely an itchy skin condition with 1 or more of the following: a history of involvement of the skin creases of elbows, behind the knees, in front of the ankles, or around the neck; a history of general dry skin in the last year; or visible flexural eczema or eczema involving the cheeks/foreheads and outer limbs.
      At the clinical assessment at age 3 years, the CHILD study physician or health care professional undertook a careful assessment of the clinical history during the past year and then responded to the following question: “In your opinion, does the child have any of the following: asthma, allergic rhinitis, food allergy, atopic dermatitis (Yes/Possible/No)?” Children were considered to have the outcome only if the response was definitively “yes.” All diagnoses were reviewed by the study physician.

       Covariate measures

      Covariates considered in the study were child sex, study center, first-born status, ethnicity, household income, parental atopy based on skin prick testing, and parental self-reported history of allergic diseases (asthma, allergic rhinitis, food allergy, or atopic dermatitis). Parental atopy and disease history were considered positive if at least 1 of the parents had a positive test response (≥2-mm wheal to any allergen) or reported an allergic history. When data were missing for 1 parent and the other parent had a negative result, the child was considered not to have a parental history for atopy or allergic disease. Parental ethnicity was used to define child ethnicity, with a child considered white if at least 1 parent was white.

       Statistical analysis

      The relationship between atopic dermatitis and allergic sensitization at age 1 year with the outcomes of allergic disease at age 3 years was assessed by using multivariable modified Poisson regression.
      • Zou G.
      A modified Poisson regression approach to prospective studies with binary data.
      Relative risks (RRs) and adjusted relative risks (aRRs) were calculated for both unadjusted and adjusted (for child's sex, study center, ethnicity, parental history of allergic diseases, and pet ownership) effects of atopic dermatitis and allergic sensitization at age 1 year. Interaction between atopic dermatitis and allergic sensitization was assessed in both the multiplicative and additive scales.
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      • Knol M.J.
      A tutorial on interaction.
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      Recommendations for presenting analyses of effect modification and interaction.
      Multiplicative interaction was assessed by adding an interaction term to the adjusted and unadjusted model.
      Relative excess risk due to interaction (RERI) was used to assess for additive interaction, in which an RERIRR value of greater than 0 indicates a positive additive interaction and an RERIRR value of less than 0 indicates a negative additive interaction. Calculation of 95% CIs was done by using the methods of variance estimates recovery.
      • Zou G.Y.
      On the estimation of additive interaction by use of the four-by-two table and beyond.
      The comparison group consisted of nonsensitized children without atopic dermatitis at age 1 year.
      Two sensitivity analyses were undertaken. In the first analysis the definition of sensitization was changed from a wheal size of 2 mm or greater to a wheal size of 3 mm or greater, which is traditionally regarded as indicating clinically relevant sensitization. In the second analysis we excluded children with reported food allergy at age 3 months, 6 months, and/or 1 year to determine whether food allergy at age 3 years was simply a continuation of food allergy from early childhood.
      All analyses were conducted with SAS 9.4 software (SAS Institute, Cary, NC).

      Results

       Study population

      At 1 year, among 2311 children eligible for this analysis, 317 (13.7%) were sensitized, with 252 (10.9%) sensitized to 1 or more food allergens and 95 (4.1%) sensitized to 1 or more inhalant allergens (Table I; for data on full cohort, see Table E1 in this article's Online Repository at www.jacionline.org). The most frequent food sensitization was to egg white (7.4%), followed by peanut (5.1%) and cow's milk (1.9%). At the 1-year clinic visit, 265 children were determined to have atopic dermatitis (11.5%). Considering allergic sensitization and atopic dermatitis, 221 (9.6%) children were sensitized but did not have atopic dermatitis, 169 (7.4%) had atopic dermatitis but were not sensitized, 96 (4.2%) had both, and 1825 (78.9%) had neither.
      Table ICharacteristics of the study sample (n = 2311)
      DemographicsNo. (%)
      Sex
       Male1238 (53.6)
       Female1073 (46.4)
      Study center
       Edmonton480 (20.8)
       Toronto461 (20.0)
       Vancouver558 (24.2)
       Winnipeg812 (35.1)
      Parental atopic status
       ≥1 Positive skin test result1855 (80.3)
       Negative results on all skin tests456 (19.7)
      Child atopic status at age 1 y
       Any sensitization317 (13.7)
      Any food allergen252 (10.9)
      Peanut118 (5.1)
      Milk43 (1.9)
      Egg white171 (7.4)
      Any inhalant allergen95 (4.1)
       Nonsensitized1994 (86.3)
      Atopic dermatitis at age 1 y
       Yes265 (11.5)
       No2046 (88.5)
      Allergic sensitization and atopic dermatitis at age 1 y
       Sensitized only221 (9.6)
       Atopic dermatitis only169 (7.4)
       Both96 (4.2)
       Neither1825 (78.9)
      Ethnicity
       Both white parents1534 (66.5)
       White and other428 (18.5)
       Both parents nonwhite346 (15.0)
      Mother's ethnicity
       First Nation77 (3.3)
       Southeast Asian298 (12.9)
       South Asian50 (2.2)
       Black41 (1.8)
       White1742 (75.6)
       Other96 (4.2)
       Unknown2 (0.09)
      Father's ethnicity
       First Nation80 (3.5)
       Southeast Asian243 (10.5)
       South Asian73 (3.2)
       Black62 (2.7)
       White1755 (76.0)
       Other86 (3.7)
       Unknown11 (0.5)
      Atopic status at age 3 y
       Any sensitization328 (14.6)
      Any food allergen133 (5.9)
      Peanut92 (4.1)
      Milk28 (1.3)
      Egg white55 (2.5)
      Any inhalant allergen215 (9.6)
       Nonsensitized1924 (85.4)
      Atopic dermatitis at age 3 y
       Yes250 (10.8)
       No2061 (89.2)
      Diagnosed asthma at age 3 y
       Yes81 (3.5)
       No2230 (96.5)
      Allergic rhinitis at age 3 y
       Yes54 (2.3)
       No2257 (97.7)
      Food allergy at age 3 y
       Yes103 (4.5)
       No2208 (95.6)
      Household income
       $0-$49,999310 (14.8)
       $50,000-$99,999830 (40.0)
       $100,000-$149,999554 (26.6)
       >$150,000392 (18.8)
      Parental history of allergic diseasesMotherFather
      Any allergic disease1811 (79.0)1418 (70.7)
       Atopic dermatitis (eczema)1433 (62.6)933 (46.5)
       Allergic rhinitis1142 (49.8)973 (48.5)
       Food allergy509 (23.4)348 (17.6)
       Asthma514 (22.5)396 (19.8)
      No parental history482 (21.0)589 (29.4)
      At the 3-year clinic visit, 81 (3.5%) of these 2311 children were considered to have definite asthma (53 received oral or inhaled corticosteroids in the last year), 54 (2.3%) were considered to have allergic rhinitis, 103 (4.5%) were considered to have food allergy, and 250 (10.8%) were considered to have atopic dermatitis.

       Associations with asthma at age 3 years

      The strongest interaction between atopic dermatitis and sensitization was observed for diagnosed asthma. Assessed independently, both atopic dermatitis (ignoring sensitization) and sensitization (ignoring atopic dermatitis) at age 1 year independently increased the risk of asthma at age 3 years (aRR, 2.23 [95% CI, 1.36-3.67] and 4.37 [95% CI 2.85-6.69], respectively) after adjustment for child's sex, ethnicity, study center, pet ownership, parental atopy, and parental history of any allergic diseases (Table II). However, children with atopic dermatitis without allergic sensitization were not at an increased risk (aRR, 0.46; 95% CI, 0.11-1.93) compared with the reference group of nonsensitized children without atopic dermatitis, whereas children with both atopic dermatitis and allergic sensitization had a 7-fold increased risk of asthma (aRR, 7.04; 95% CI, 4.13-11.99) after adjustment as above (Table III). Atopic dermatitis and sensitization had a significant positive interaction on both the multiplicative (RR ratio, 5.80; 95% CI, 1.20-27.83) and additive (RERI, 5.06; 95% CI, 1.33-11.04) scales (Table III) after adjustment for covariates. When sensitization was further categorized as food or inhalant sensitization, food sensitization and atopic dermatitis had a significant positive interaction on the risk of asthma at age 3 years but only on the additive scale, whereas inhalant sensitization did not (see Table E2, Table E3 in this article's Online Repository at www.jacionline.org).
      Table IIEffects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2311)
      Outcome at age 3 yAtopic dermatitis at age 1 y (n = 265)Allergic sensitization at age 1 y (n = 317)
      No. of events at age 3 y (%)
      Percentage of events calculated among children who had atopic dermatitis/sensitization at 1 year of age.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment. For unadjusted data see Table E4 in this article's Online Repository at www.jacionline.org.
      No. of events at age 3 y (%)
      Percentage of events calculated among children who had atopic dermatitis/sensitization at 1 year of age.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment. For unadjusted data see Table E4 in this article's Online Repository at www.jacionline.org.
      Asthma19 (7.17)2.37 (1.44-3.89)
      Statistically significant at the .05 level.
      2.23 (1.36-3.67)
      Statistically significant at the .05 level.
      31 (9.78)3.90 (2.53-6.01)
      Statistically significant at the .05 level.
      4.37 (2.85-6.69)
      Statistically significant at the .05 level.
      Allergic rhinitis23 (8.68)5.73 (3.39-9.67)
      Statistically significant at the .05 level.
      4.44 (2.59-7.63)
      Statistically significant at the .05 level.
      25 (7.89)5.42 (3.22-9.14)
      Statistically significant at the .05 level.
      4.85 (2.84-8.27)
      Statistically significant at the .05 level.
      Food allergy46 (17.36)6.23 (4.32-9.00)
      Statistically significant at the .05 level.
      4.61 (3.02-7.05)
      Statistically significant at the .05 level.
      77 (24.29)18.63 (12.14-28.59)
      Statistically significant at the .05 level.
      16.47 (10.64-25.49)
      Statistically significant at the .05 level.
      Atopic dermatitis93 (35.1)4.57 (3.66-5.71)
      Statistically significant at the .05 level.
      3.79 (2.98-4.83)
      Statistically significant at the .05 level.
      78 (24.61)2.85 (2.24-3.63)
      Statistically significant at the .05 level.
      2.43 (1.89-3.12)
      Statistically significant at the .05 level.
      Percentage of events calculated among children who had atopic dermatitis/sensitization at 1 year of age.
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment. For unadjusted data see Table E4 in this article's Online Repository at www.jacionline.org.
      Statistically significant at the .05 level.
      Table IIIInteractive effects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2311)
      Asthma at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No atopic dermatitis48/1825Reference (1.0)14/2212.87 (1.60 to 5.14)
      Statistically significant at the .05 level.
      2.87 (1.60 to 5.14)
      Statistically significant at the .05 level.
      Atopic dermatitis2/1690.46 (0.11 to 1.93)17/967.04 (4.13 to 11.99)
      Statistically significant at the .05 level.
      12.46 (3.06 to 50.77)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization0.48 (0.11 to 2.00)2.53 (1.31 to 4.91)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: aRR, 5.80; 95% CI, 1.20 to 27.83
      Statistically significant at the .05 level.
      Interaction on additive scale: RERI, 5.06; 95% CI, 1.33 to 11.04
      Statistically significant at the .05 level.
      Allergic rhinitis at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No atopic dermatitis19/1825Reference (1.0)12/2215.35 (2.70 to 10.60)
      Statistically significant at the .05 level.
      5.35 (2.52 to 11.36)
      Statistically significant at the .05 level.
      Atopic dermatitis10/1694.53 (2.13 to 9.63)
      Statistically significant at the .05 level.
      13/9611.75 (5.73 to 24.12)
      Statistically significant at the .05 level.
      1.87 (0.78 to 4.49)
      RR for atopic dermatitis within strata of sensitization4.63 (2.08 to 10.31)
      Statistically significant at the .05 level.
      2.35 (1.01 to 5.43)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: aRR, 0.49; 95% CI, 0.17 to 1.36
      Interaction on additive scale: RERI, 2.62; 95% CI, −5.48 to 14.05
      Food allergy at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No atopic dermatitis21/1825Reference (1.0)36/22113.76 (7.95 to 23.81)
      Statistically significant at the .05 level.
      13.35 (7.68 to 23.21)
      Statistically significant at the .05 level.
      Atopic dermatitis5/1692.50 (0.97 to 6.44)41/9633.79 (18.89 to 60.47)
      Statistically significant at the .05 level.
      14.03 (5.71 to 34.45)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization2.14 (0.77 to 5.90)2.18 (1.42 to 3.32)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: aRR, 0.77; 95% CI, 0.29 to 2.03
      Interaction on additive scale: RERI, 15.11; 95% CI, 4.19 to 35.36
      Statistically significant at the .05 level.
      Atopic dermatitis at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No. with outcome/totalRR (95% CI)
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      No atopic dermatitis127/1825Reference (1.0)30/2211.84 (1.27 to 2.68)
      Statistically significant at the .05 level.
      1.84 (1.27 to 2.67)
      Statistically significant at the .05 level.
      Atopic dermatitis45/1693.33 (2.44 to 4.55)
      Statistically significant at the .05 level.
      48/966.00 (4.36 to 8.23)
      Statistically significant at the .05 level.
      1.73 (1.24 to 2.39)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization3.28 (2.40 to 4.50)
      Statistically significant at the .05 level.
      3.16 (2.08 to 4.79)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: aRR, 0.89; 95% CI, 0.54 to 1.45
      Interaction on additive scale: RERI, 1.44; 95% CI, −0.61 to 3.81
      Adjusted for ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Unadjusted values are available in Table E4 in this article's Online Repository at www.jacionline.org.
      Statistically significant at the .05 level.

       Associations with allergic rhinitis at age 3 years

      Among all children, atopic dermatitis (ignoring sensitization) at age 1 year significantly increased the risk of allergic rhinitis at age 3 years (aRR, 4.44; 95% CI, 2.59-7.63), as did sensitization (ignoring atopic dermatitis) at age 1 year (aRR, 4.85; 95% CI, 2.84-8.27), after adjustment for covariates (Table II). Compared with nonsensitized children without atopic dermatitis, atopic dermatitis alone increased the risk of allergic rhinitis more than 4-fold (RR, 4.53; 95% CI, 2.13-9.63), sensitization alone increased the risk of allergic rhinitis more than 5-fold (RR, 5.35; 95% CI, 2.70-10.60), and atopic dermatitis with sensitization increased the risk of allergic rhinitis at age 3 years more than 11-fold (aRR, 11.75; 95% CI, 5.73-24.12) in adjusted analyses (Table III). There was no evidence of an interactive effect (RR ratio, 0.49 [95% CI, 0.17-1.36] and RERI, 2.62 [95% CI, −5.48 to 14.05]; Table III).

       Associations with food allergy at age 3 years

      Atopic dermatitis at age 1 year was associated with an increased risk of food allergy at age 3 years (aRR, 4.61; 95% CI, 3.02-7.05), whereas sensitization at age 1 year was an even stronger risk factor (aRR, 16.47; 95% CI, 10.64-25.49) after adjustment for covariates (Table II). The presence of both atopic dermatitis and sensitization at age 1 year was associated with a greatly increased risk of food allergy at age 3 years (aRR, 33.79; 95% CI, 18.89-60.47) relative to the reference group of nonsensitized children without atopic dermatitis (Table III). The presence of sensitization and atopic dermatitis had a highly significant positive interaction on the additive scale (RERI, 15.11; 95% CI, 4.19-35.36) but not on the multiplicative scale (RR ratio, 0.77; 95% CI, 0.29-2.03) after adjustment for covariates (Table III). Specifically, sensitization to food allergens and atopic dermatitis had significant additive interactive effects on the risk of food allergy at age 3 years; sensitization to inhalant allergens and atopic dermatitis did not interact significantly (see Table E3). A sensitivity analysis revealed that excluding children with reported food allergy at age 3 months, 6 months, and/or 1 year did not change the effect of atopic dermatitis and sensitization at age 1 year on food allergy at age 3 years (data not shown but available on request).

       Associations with atopic dermatitis at age 3 years

      Within the study sample, atopic dermatitis at age 1 year greatly increased the risk of atopic dermatitis at age 3 years (aRR, 3.79; 95% CI, 2.98-4.83; Table II). Any sensitization at age 1 year also increased the risk of atopic dermatitis at age 3 years, although to a somewhat lesser extent (aRR, 2.43; 95% CI, 1.89-3.12), after adjustment for covariates. Compared with the reference group of nonsensitized children without atopic dermatitis, sensitized children with atopic dermatitis at age 1 year exhibited a 6-fold increased risk of atopic dermatitis at age 3 years (aRR, 6.00; 95% CI, 4.36-8.23; Table III). However, there was no evidence of an interactive effect between sensitization and atopic dermatitis on the risk of atopic dermatitis either on the multiplicative (RR ratio, 0.89; 95% CI, 0.54-1.45) or additive (RERI, 1.44; 95% CI, −0.61 to 3.81) scale (Table III).
      Unadjusted values can be found in Table E4 in this article's Online Repository at www.jacionline.org. The sensitivity analysis performed with a 3-mm or greater wheal cutoff instead of a 2-mm or greater cutoff to define sensitization yielded similar results that remained consistent across all outcomes (see Table E5 in this article's Online Repository at www.jacionline.org).
      Fig 1 shows the additive interactions for all allergic outcomes at age 3 years.
      Figure thumbnail gr1
      Fig 1Interactive effects of atopic dermatitis (AD) and sensitization at age 1 year (1Y) on subsequent allergic outcomes at age 3 years (additive scale). *Significant at the .05 level. RERI and RR values are adjusted for child's sex, ethnicity, study center, pet ownership, parental atopy, and parental history of any allergic diseases. Unadjusted values are available in in this article's Online Repository at www.jacionline.org.

      Discussion

      Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma at age 3 years, whereas atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold. The presence of both atopic dermatitis and sensitization had positive additive and multiplicative interactions in their effects on asthma. There was a strong positive additive interaction between atopic dermatitis and sensitization in the risk for food allergy, although interaction in the multiplicative scale was not significant. In other words, for asthma, the combined effect of atopic dermatitis and sensitization was greater than the sum of or the product of their individual effects. For food allergy, the combined effect of atopic dermatitis and sensitization at age 1 year was greater than the sum of their individual effects.
      Based on the Isle of Wight birth cohort, Ziyab et al
      • Ziyab A.H.
      • Karmaus W.
      • Zhang H.
      • Holloway J.W.
      • Steck S.E.
      • Ewart S.
      • et al.
      Association of filaggrin variants with asthma and rhinitis: Is eczema or allergic sensitization an effect modifier?.
      reported previously that the effects of eczema and allergic sensitization interacted with the effect of FLG loss-of-function mutations on asthma but not rhinitis. “Preceding allergic sensitization and filaggrin variants” and “preceding eczema and filaggrin variants” increased the risk of subsequent asthma by 4.93- and 3.33-fold, respectively, in the first 18 years of life. Interaction was assessed on the multiplicative but not the additive scale. In our study we found that the presence of atopic dermatitis with allergic sensitization at age 1 year increased the risk of asthma more than 7-fold at age 3 years, with interacting effects on both the additive and multiplicative scales. Similar to the findings of Ziyab et al, we found no evidence to suggest an interactive effect on the risk of rhinitis. We were able to assess additional allergic outcomes, including atopic dermatitis and food allergy. Notably, atopic dermatitis and allergic sensitization at age 1 year had a highly significant positive interaction in the additive scale on the risk of food allergy.
      The finding that sensitized children with atopic dermatitis at age 1 year had a significantly higher risk of food allergy at age 3 years is consistent with previous findings.
      • Zheng T.
      • Yu J.
      • Oh M.H.
      • Zhu Z.
      The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma.
      • Shaker M.
      New insights into the allergic march.
      A potential explanation is that children shown to be sensitized to food allergens at age 1 year who also had atopic dermatitis might have consequently avoided the foods to which they were sensitized. We have previously shown in the CHILD study that children who avoided cow's milk products, egg, and peanut during the first year of life were at increased risk of allergic sensitization to the same foods.
      • Tran M.
      • Lefebvre D.L.
      • Dai D.
      • Dharma C.
      • Subbarao P.
      • Lou W.
      • et al.
      Timing of food introduction and development of food sensitization in a prospective birth cohort.
      A general pattern of delayed feeding was also associated with an increased risk of food sensitization. Because food sensitization is known to be on the pathway to food allergy, food avoidance might explain the substantial proportion of sensitized children with atopic dermatitis who have subsequent food allergy.
      The potentially interactive effects of atopic dermatitis and allergic sensitization at age 1 year on allergic outcomes at age 3 years have not been well characterized. Previous studies have typically assessed atopic dermatitis and allergic sensitization as effect modifiers of the relationship between FLG variants and asthma or rhinitis
      • Ziyab A.H.
      • Karmaus W.
      • Zhang H.
      • Holloway J.W.
      • Steck S.E.
      • Ewart S.
      • et al.
      Association of filaggrin variants with asthma and rhinitis: Is eczema or allergic sensitization an effect modifier?.
      or assessed children with atopic dermatitis and allergic sensitization as a subgroup.
      • Marenholz I.
      • Kerscher T.
      • Bauerfeind A.
      • Esparza-Gordillo J.
      • Nickel R.
      • Keil T.
      • et al.
      An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma.
      A primary strength of our study was the longitudinal, population-based design. This allowed us to determine whether the finding of allergic sensitization in a 1-year-old child provides prognostic value alongside the presence of atopic dermatitis. We addressed this important research question by using objective skin prick test data at age 1 year and longitudinal clinic visit data up to age 3 years, with clear definitions of sensitization and atopic dermatitis. We found that atopic dermatitis and allergic sensitization could be combined to improve the prediction of all 4 of the allergic outcomes in our study. Moreover, we were able to report interaction on both the additive and multiplicative scales, which is a recommended practice in assessing the biological mechanism and public health effect of a disease.
      • VanderWeele T.J.
      • Knol M.J.
      A tutorial on interaction.
      • Knol M.J.
      • VanderWeele T.J.
      Recommendations for presenting analyses of effect modification and interaction.
      Care must be taken in interpreting these results because of the wide CIs for some outcomes resulting from a low number of events at age 3 years.
      We have not conducted genotyping for FLG, an epidermal protein that plays an important role in skin barrier function; subjects with FLG-deficient skin are predisposed to atopic dermatitis and have an increased risk of allergic rhinitis, food allergy, and asthma.
      • Palmer C.N.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      • Henderson J.
      • Northstone K.
      • Lee S.P.
      • Liao H.
      • Zhao Y.
      • Pembrey M.
      • et al.
      The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study.
      • Irvine A.D.
      • McLean I.
      • Leung D.Y.M.
      Filaggrin mutations associated with skin and allergic diseases.
      Although the majority of children with atopic dermatitis do not have an FLG loss-of-function mutation,
      • Morar N.
      • Cookson W.
      • Harper J.I.
      • Moffatt M.F.
      Filaggrin mutations in children with severe atopic dermatitis.
      meta-analysis shows that FLG's effect on atopic dermatitis risk is higher than that of any other confirmed candidate gene for atopic diseases.
      • Rodriguez E.
      • Baurecht H.
      • Herberich E.
      • Wagenpfeil S.
      • Brown S.J.
      • Cordell H.J.
      • et al.
      Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease.
      Incorporating FLG mutations into our analyses alongside atopic dermatitis and allergic sensitization might have further strengthened the prediction of allergic outcomes in our study. However, FLG genotyping is a costly and invasive process that is not usually feasible in the clinical setting.
      A potential limitation of our study was that cases of atopic dermatitis classified as definite by physicians or health care professionals during clinical assessments were likely more severe. Infants with milder atopic dermatitis might have been misclassified.
      • Lowe A.J.
      • Abramson M.J.
      • Hosking C.S.
      • Carlin J.B.
      • Bennett C.M.
      • Dharmage S.C.
      • et al.
      The temporal sequence of allergic sensitization and onset of infantile eczema.
      Future studies should investigate the relationship between low-to-moderate severity atopic dermatitis and allergic sensitization on the risk for allergic diseases. Additionally, food allergy was not confirmed by using oral challenges in our study, and we do not have a gold standard for the diagnosis of asthma at age 3 years. By using only definitive “yes” reports by experienced pediatric allergists and asthma specialists at the clinical visit at age 3 years rather than including reports of “possible,” we have a conservative estimate of the prevalence of these diseases; the mix of steroid-treated (65%) and steroid-naive (35%) children given a diagnosis of definite asthma reflects the range of severity of illness in this group.
      In conclusion, the atopic march refers to the natural progression of atopic dermatitis to asthma and allergic rhinitis. In a population-based, longitudinal birth cohort we compared allergic disease prognoses between sensitized and nonsensitized children with atopic dermatitis. We found that atopic dermatitis without allergic sensitization was not associated with increased asthma risk. Conversely, the combination of atopic dermatitis and allergic sensitization at age 1 year was associated with an increased risk of asthma and food allergy at age 3 years. The combined effect of atopic dermatitis and allergic sensitization was greater than the sum of their individual effects on the risk of food allergy and greater than the sum or the product of their individual effects on the risk of asthma. Children with atopic dermatitis and evidence of sensitization to common food or inhalant allergens as early as age 1 year represent a high-risk subgroup that warrants further examination in primary intervention studies.
      Clinical implications
      The combination of atopic dermatitis with allergic sensitization at age 1 year predicts children who are more likely to have asthma and food allergy.
      CHILD study Investigators
      P. Subbarao (Director), The Hospital for Sick Children and University of Toronto; S. E. Turvey, University of British Columbia (Co-Director), S. S. Anand, McMaster University; M. Azad, University of Manitoba; A. B. Becker, University of Manitoba; A. D. Befus, University of Alberta; M. Brauer, University of British Columbia; J. R. Brook, University of Toronto; E. Chen, Northwestern University, Chicago; M. Cyr, McMaster University; D. Daley, University of British Columbia; S. D. Dell, The Hospital for Sick Children and University of Toronto; J. A. Denburg, McMaster University; Q. Duan, Queen's University; T. Eiwegger, The Hospital for Sick Children and University of Toronto; H. Grasemann, The Hospital for Sick Children and University of Toronto; K. HayGlass, University of Manitoba; R. G. Hegele, The Hospital for Sick Children and University of Toronto; D. L. Holness, University of Toronto; P. Hystad, Oregon State University; M. Kobor, University of British Columbia; T. R. Kollmann, University of British Columbia; A. L. Kozyrskyj, University of Alberta; C. Laprise, Université du Québec à Chicoutimi; W. Y. W. Lou, University of Toronto; J. Macri, McMaster University; P. J. Mandhane, University of Alberta; G. Miller, Northwestern University, Chicago; T. J. Moraes, The Hospital for Sick Children and University of Toronto; P. Paré, University of British Columbia; C. Ramsey, University of Manitoba; F. Ratjen, The Hospital for Sick Children and University of Toronto; A. Sandford, University of British Columbia; J. A. Scott, University of Toronto; J. Scott, University of Toronto; M. R. Sears (Founding Director), McMaster University; F. Silverman, University of Toronto; E. Simons, University of Manitoba; T. Takaro, Simon Fraser University; S. Tebbutt, University of British Columbia; and T. To, The Hospital for Sick Children and University of Toronto.
      We thank all the families who took part in this study and the whole CHILD team, which includes interviewers, nurses, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, and receptionists.

      Appendix

      Figure thumbnail fx1
      Fig E1Interactive effects of atopic dermatitis (AD) and sensitization at age 1 year (1Y) on subsequent allergic outcomes at age 3 years (additive scale): unadjusted effects. *Significant at the .05 level.
      Table E1Comparisons of study sample with missing participants and full CHILD study cohort
      DemographicsStudy sample (n = 2311), no. (%)Missing participants (n = 1166),
      Numbers might not add up to 1166 or 3495 because of missing data.
      no. (%)
      P value (sample vs missing)Full cohort (n = 3495),
      Numbers might not add up to 1166 or 3495 because of missing data.
      no. (%)
      P value (sample vs full cohort)
      Sex
       Male1238 (53.6)580 (50.6)1818 (52.6)
       Female1073 (46.4)567 (49.4).101640 (47.4).46
      Study center
       Edmonton480 (20.8)344 (29.5)824 (23.7)
       Toronto461 (20.0)358 (30.7)819 (23.5)
       Vancouver558 (24.2)230 (19.7)788 (22.7)
       Winnipeg812 (35.1)234 (20.1)<.0011046 (30.1)<.001
      Skin test: mother
       ≥1 Positive skin test response1338 (58.3)472 (55.1)1343 (42.6)
       Negative responses on all skin tests959 (41.8)384 (44.9).121810 (57.4).53
      Skin test: father
       ≥1 Positive skin test response1275 (68.0)490 (69.3)1765 (68.3)
       Negative responses on all skin tests601 (32.0)217 (30.7).51818 (31.7).79
      Parental atopy
       ≥1 Positive skin test response1855 (80.3)731 (74.5)2586 (78.6)
       Negative responses on all skin tests456 (19.7)250 (25.5).002706 (21.5).12
      Child's atopic status at age 1 y
       Any sensitization317 (13.7)97 (13.5).89414 (13.7).96
       Any food allergen252 (10.9)78 (10.9).98330 (10.9).99
      Peanut118 (5.1)26 (3.6).10144 (4.8).56
      Milk43 (1.9)11 (1.5).5654 (1.8).83
      Egg white171 (7.4)51 (7.1).79222 (7.3).92
       Any inhalant allergen95 (4.1)29 (4.0).93124 (4.1).98
       Nonsensitized1994 (86.3)621 (86.5).892615 (86.3).96
      Atopic dermatitis at age 1 y
       Yes265 (11.5)96 (13.7)361 (12.0)
       No2046 (88.5)607 (86.3).122653 (88.0).57
      Mother's ethnicity
       First Nation77 (3.3)68 (6.1)145 (4.2)
       Southeast Asian298 (12.9)121 (10.9)420 (12.3)
       South Asian50 (2.2)66 (5.9)116 (3.4)
       Black41 (1.8)32 (2.9)73 (2.1)
       White1742 (75.6)757 (30.3)2499 (73.1)
       Other96 (4.2)63 (39.6)159 (4.7)
       Unknown2 (0.09)4 (0.06)<.0016 (0.2).03
      Father's ethnicity
       First Nation80 (3.5)51 (4.6)51 (4.6)
       Southeast Asian243 (10.5)87 (7.8)87 (7.8)
       South Asian73 (3.2)61 (5.5)61 (5.5)
       Black62 (2.7)45 (4.0)45 (4.0)
       White1755 (76.0)777 (69.6)777 (69.6)
       Other86 (3.7)85 (7.6)85 (7.6)
       Unknown11 (0.5)11 (1.0)<.00111 (1.0).08
      Atopic status at age 3 y
       Any sensitization328 (14.6)79 (13.7).61407 (14.4).86
       Any food allergen133 (5.9)27 (4.7).27160 (5.7).71
      Peanut92 (4.1)15 (2.7).10107 (2.1).59
      Milk28 (1.3)3 (0.5).1431 (1.1).63
      Egg white55 (2.5)8 (1.4).1363 (2.2).62
       Any inhalant allergen215 (9.6)47 (8.2).31262 (9.3).73
       Nonsensitized1924 (85.4)497 (86.3).612422 (85.6).86
      Atopic dermatitis at age 3 y
       Yes250 (10.8)88 (15.4)350 (12.2)
       No2061 (89.2)482 (84.6).0072351 (87.9).14
      Diagnosed asthma at age 3 y
       Yes81 (3.5)24 (4.2)105 (3.6)
       No2230 (96.5)550 (95.8).442780 (96.4).80
      Allergic rhinitis at age 3 y
       Yes54 (2.3)15 (21.7)69 (2.4)
       No2257 (97.7)559 (97.4).702816 (97.6).89
      Food allergy at age 3 y
       Yes103 (4.5)21 (3.7)124 (4.3)
       No2208 (95.6)553 (96.3).402761 (95.7).78
      Household income
       $0-$49,999310 (14.8)81 (18.9)391 (55.8)
       $50,000-$99,999830 (40.0)142 (33.1)972 (38.7)
       $100,000-$149,999554 (26.6)116 (27.0)670 (54.7)
       >$150,000392 (18.8)90 (21.0).03482 (19.2).85
      Parental history of allergic diseases
       Any allergic disease2099 (90.8)937 (85.5)<.0013040 (89.2).05
      Atopic dermatitis1746 (75.6)750 (68.6)<.0012505 (73.6).09
      Allergic rhinitis1593 (68.9)706 (64.5).0062306 (67.7).34
      Food allergy768 (33.4)302 (28.2).0021075 (31.9).24
      Asthma818 (35.4)335 (30.5).0051154 (33.9).23
       No parental history212 (9.2)159 (14.5)<.001367 (10.8).05
      Numbers might not add up to 1166 or 3495 because of missing data.
      Table E2Effects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2311) by food versus inhalant sensitization
      Outcome at age 3 yFood sensitization at age 1 y (n = 252)Inhalant sensitization at age 1 y (n = 95)
      No. of events (%)
      Percentage of events calculated among children who had food/inhalant sensitization at age 1 year.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      No. of events (%)
      Percentage of events calculated among children who had food/inhalant sensitization at age 1 year.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      Asthma28 (11.1)4.32 (2.78-6.69)
      Statistically significant at the .05 level.
      4.58 (2.95-7.10)
      Statistically significant at the .05 level.
      7 (7.4)2.21 (1.05-4.66)
      Statistically significant at the .05 level.
      2.64 (1.26-5.55)
      Statistically significant at the .05 level.
      Allergic rhinitis19 (7.5)4.44 (2.57-7.63)
      Statistically significant at the .05 level.
      3.54 (2.09-6.04)
      Statistically significant at the .05 level.
      8 (8.4)4.06 (1.97-8.35)
      Statistically significant at the .05 level.
      4.74 (2.42-9.29)
      Statistically significant at the .05 level.
      Food allergy76 (30.2)23.00 (15.12-34.97)
      Statistically significant at the .05 level.
      20.38 (13.13-31.64)
      Statistically significant at the .05 level.
      9 (9.5)2.23 (1.16-4.29)
      Statistically significant at the .05 level.
      1.77 (0.91-3.42)
      Atopic dermatitis69 (27.4)3.11 (2.44-3.98)
      Statistically significant at the .05 level.
      2.63 (2.04-3.41)
      Statistically significant at the .05 level.
      18 (19.0)1.81 (1.17-2.79)
      Statistically significant at the .05 level.
      1.53 (0.99-2.37)
      Percentage of events calculated among children who had food/inhalant sensitization at age 1 year.
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      Statistically significant at the .05 level.
      Table E3Interactive effects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2311): Adjusted effects separated by food versus inhalant sensitization
      Asthma at age 3 yNo food sensitization at 1 yFood sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis49/1878Reference (1.0)13/1683.40 (1.88 to 6.14)
      Statistically significant at the .05 level.
      3.41 (1.88 to 6.16)
      Statistically significant at the .05 level.
      Atopic dermatitis4/1810.86 (0.31 to 2.40)15/847.04 (4.08 to 12.17)
      Statistically significant at the .05 level.
      6.21 (2.25 to 17.17)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization0.89 (0.32 to 2.48)2.07 (1.04 to 4.11)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 2.60; 95% CI, 0.76 to 8.90
      Interaction on additive scale: RERI, 4.10; 95% CI, 0.11 to 9.87
      Statistically significant at the .05 level.
      Allergic rhinitis at age 3 yNo food sensitization at 1 yFood sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis23/1878Reference (1.0)8/1683.60 (1.69 to 7.65)
      Statistically significant at the .05 level.
      3.61 (1.70 to 7.66)
      Statistically significant at the .05 level.
      Atopic dermatitis12/1814.46 (2.25 to 8.80)
      Statistically significant at the .05 level.
      11/849.81 (5.04 to 19.10)
      Statistically significant at the .05 level.
      1.68 (0.61 to 4.64)
      RR for atopic dermatitis within strata of sensitization4.56 (2.32 to 8.95)
      Statistically significant at the .05 level.
      2.52 (0.85 to 7.52)
      Interaction on multiplicative scale: RR, 0.60; 95% CI, 0.20 to 1.77
      Interaction on additive scale: RERI, 1.98; 95% CI, −4.73 to 11.41
      Food allergy at age 3 yNo food sensitization at 1 yFood sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis21/1878Reference (1.0)36/16818.42 (10.78 to 31.50)
      Statistically significant at the .05 level.
      17.88 (10.42 to 30.69)
      Statistically significant at the .05 level.
      Atopic dermatitis6/1812.74 (1.11 to 6.74)
      Statistically significant at the .05 level.
      40/8440.23 (22.37 to 72.34)
      Statistically significant at the .05 level.
      14.27 (6.10 to 33.37)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization2.47 (0.94 to 6.51)1.96 (1.30 to 2.95)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.60; 95% CI, 0.24 to 1.50
      Interaction on additive scale: RERI, 15.31; 95% CI, 1.98 to 38.84
      Statistically significant at the .05 level.
      Atopic dermatitis at age 3 yNo food sensitization at 1 yFood sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis132/1878Reference (1.0)25/1681.99 (1.34 to 2.98)
      Statistically significant at the .05 level.
      1.99 (1.34 to 2.98)
      Statistically significant at the .05 level.
      Atopic dermatitis49/1813.31 (2.45 to 4.46)
      Statistically significant at the .05 level.
      44/846.31 (4.54 to 8.77)
      Statistically significant at the .05 level.
      1.80 (1.30 to 2.51)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization3.26 (2.41 to 4.41)
      Statistically significant at the .05 level.
      3.09 (1.98 to 4.81)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.86; 95% CI, 0.51 to 1.43
      Interaction on additive scale: RERI, 1.56; 95% CI, −0.63 to 4.15
      Asthma at age 3 yNo inhalant sensitization at 1 yInhalant sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis59/1975Reference (1.0)3/711.72 (0.54 to 5.43)1.72 (0.54 to 5.42)
      Atopic dermatitis15/2411.96 (1.12 to 3.41)
      Statistically significant at the .05 level.
      4/246.30 (2.54 to 15.61)
      Statistically significant at the .05 level.
      2.95 (1.06 to 8.24)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization2.00 (1.15 to 3.48)
      Statistically significant at the .05 level.
      6.40 (0.79 to 51.56)
      Interaction on multiplicative scale: RR, 1.77; 95% CI, 0.41 to 7.70
      Interaction on additive scale: RERI, 3.49; 95% CI, −2.18 to 15.13
      Allergic rhinitis at age 3 yNo inhalant sensitization at 1 yInhalant sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis27/1975Reference (1.0)4/715.40 (2.10 to 13.89)
      Statistically significant at the .05 level.
      5.39 (2.09 to 13.87)
      Statistically significant at the .05 level.
      Atopic dermatitis19/2414.30 (2.37 to 7.82)
      Statistically significant at the .05 level.
      4/249.86 (3.59 to 27.07)
      Statistically significant at the .05 level.
      3.84 (0.90 to 16.29)
      RR for atopic dermatitis within strata of sensitization4.36 (2.40 to 7.90)
      Statistically significant at the .05 level.
      8.56 (0.55 to 134.02)
      Interaction on multiplicative scale: RR, 0.45; 95% CI, 0.12 to 1.61
      Interaction on additive scale: RERI, 2.02; 95% CI, −10.64 to 23.97
      Food allergy at age 3 yNo inhalant sensitization at 1 yInhalant sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis53/1975Reference (1.0)4/711.76 (0.64 to 4.85)1.81 (0.65 to 4.98)
      Atopic dermatitis41/2414.78 (3.12 to 7.33)
      Statistically significant at the .05 level.
      5/244.29 (1.72 to 10.69)
      Statistically significant at the .05 level.
      1.19 (0.53 to 2.67)
      RR for atopic dermatitis within strata of sensitization4.68 (3.03 to 7.25)
      Statistically significant at the .05 level.
      4.07 (0.80 to 20.71)
      Interaction on multiplicative scale: RR, 0.54; 95% CI, 0.15 to 1.94
      Interaction on additive scale: RERI, −0.77; 95% CI, −5.76 to 6.86
      Atopic dermatitis at age 3 yNo inhalant sensitization at 1 yInhalant sensitization at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No. with outcome/totalRR (95% CI)
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      No atopic dermatitis149/1975Reference (1.0)8/711.38 (0.70 to 2.72)1.38 (0.70 to 2.72)
      Atopic dermatitis83/2413.86 (3.00 to 4.95)
      Statistically significant at the .05 level.
      10/243.92 (2.27 to 6.78)
      Statistically significant at the .05 level.
      1.11 (0.67 to 1.83)
      RR for atopic dermatitis within strata of sensitization3.83 (2.98 to 4.92)
      Statistically significant at the .05 level.
      7.42 (1.80 to 30.54)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.75; 95% CI, 0.32 to 1.74
      Interaction on additive scale: RERI, −0.20; 95% CI, −2.80 to 3.53
      Adjusted for parental ethnicity, study center, pet ownership, parental atopy, child's sex, and parental history of any allergic diseases. Numbers are different from unadjusted models because of missing values.
      Statistically significant at the .05 level.
      Table E4Interactive effects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2683): Unadjusted effects
      Asthma at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)No. with outcome/totalRR (95% CI)
      No atopic dermatitis54/2116Reference (1.0)15/2462.39 (1.37 to 4.17)
      Statistically significant at the .05 level.
      2.39 (1.37 to 4.17)
      Statistically significant at the .05 level.
      Atopic dermatitis4/2030.77 (0.28 to 2.11)20/1186.64 (4.12 to 10.72)
      Statistically significant at the .05 level.
      8.72 (3.05 to 24.89)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization0.77 (0.28 to 2.10)2.80 (1.49 to 5.28)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 3.65; 95% CI, 1.11 to 11.97
      Statistically significant at the .05 level.
      Interaction on additive scale: RERI, 4.48; 95% CI, 1.55 to 8.39
      Statistically significant at the .05 level.
      Allergic rhinitis at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)No. with outcome/totalRR (95% CI)
      No atopic dermatitis26/2116Reference (1.0)13/2464.30 (2.24 to 8.26)
      Statistically significant at the .05 level.
      4.30 (2.24 to 8.26)
      Statistically significant at the .05 level.
      Atopic dermatitis12/2004.88 (2.50 to 9.53)
      Statistically significant at the .05 level.
      15/11810.35 (5.63 to 18.99)
      Statistically significant at the .05 level.
      2.15 (1.04 to 4.43)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization4.86 (2.49 to 9.48)
      Statistically significant at the .05 level.
      2.43 (1.19 to 4.93)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.50; 95% CI, 0.19 to 1.32
      Interaction on additive scale: RERI, 2.16; 95% CI, −4.34 to 9.92
      Food allergy at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)No. with outcome/totalRR (95% CI)
      No atopic dermatitis25/2113Reference (1.0)39/24613.40 (8.25 to 21.75)
      Statistically significant at the .05 level.
      14.32 (8.78 to 23.33)
      Statistically significant at the .05 level.
      Atopic dermatitis8/2033.33 (1.52 to 7.29)
      Statistically significant at the .05 level.
      47/11833.66 (21.50 to 52.71)
      Statistically significant at the .05 level.
      10.24 (5.01 to 20.93)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization3.45 (1.57 to 7.59)
      Statistically significant at the .05 level.
      2.47 (1.72 to 3.54)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.75; 95% CI, 0.30 to 1.70
      Interaction on additive scale: RERI, 17.94; 95% CI, 9.21 to 33.20
      Statistically significant at the .05 level.
      Atopic dermatitis at age 3 yNonsensitized at 1 ySensitized at 1 yRR for sensitization within strata of atopic dermatitis
      No. with outcome/totalRR (95% CI)No. with outcome/totalRR (95% CI)
      No atopic dermatitis149/2114Reference (1.0)34/2451.97 (1.39 to 2.79)
      Statistically significant at the .05 level.
      2.04 (1.45 to 2.88)
      Statistically significant at the .05 level.
      Atopic dermatitis58/2004.11 (3.15 to 5.37)
      Statistically significant at the .05 level.
      55/1176.67 (5.21 to 8.54)
      Statistically significant at the .05 level.
      1.64 (1.23 to 2.20)
      Statistically significant at the .05 level.
      RR for atopic dermatitis within strata of sensitization4.12 (3.16 to 5.38)
      Statistically significant at the .05 level.
      3.32 (2.31 to 4.77)
      Statistically significant at the .05 level.
      Interaction on multiplicative scale: RR, 0.81; 95% CI, 0.51 to 1.26
      Interaction on additive scale: RERI, 1.59; 95% CI, −0.12 to 3.35
      Statistically significant at the .05 level.
      Table E5Effects of atopic dermatitis and sensitization at age 1 year on subsequent allergic outcomes at age 3 years (n = 2311) comparing a 2-mm or greater wheal cutoff with a 3-mm or greater wheal cutoff to define sensitization
      Outcome at age 3 ySensitization at age 1 y (≥2 mm wheals), n = 317Sensitization at age 1 y (≥3 mm wheals), n = 214
      No. of events (%)
      Percentage of events calculated among children who had atopic dermatitis and allergic sensitization at age 1 year.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      No. of events (%)
      Percentage of events calculated among children who had atopic dermatitis and allergic sensitization at age 1 year.
      Unadjusted RR (95% CI)aRR (95% CI)
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      Asthma31 (9.78)3.90 (2.53-6.01)
      Statistically significant at the .05 level.
      4.37 (2.85-6.69)
      Statistically significant at the .05 level.
      28 (13.08)5.18 (3.35-8.00)
      Statistically significant at the .05 level.
      5.46 (3.53-8.44)
      Statistically significant at the .05 level.
      Allergic rhinitis25 (7.89)5.42 (3.22-9.14)
      Statistically significant at the .05 level.
      4.85 (2.84-8.27)
      Statistically significant at the .05 level.
      18 (8.41)4.90 (2.83-8.48)
      Statistically significant at the .05 level.
      3.78 (2.12-6.74)
      Statistically significant at the .05 level.
      Food allergy77 (24.29)18.63 (12.14-28.59)
      Statistically significant at the .05 level.
      16.47 (10.64-25.49)
      Statistically significant at the .05 level.
      64 (29.91)16.08 (11.08-23.34)
      Statistically significant at the .05 level.
      13.55 (8.97-20.47)
      Statistically significant at the .05 level.
      Atopic dermatitis78 (24.61)2.85 (2.24-3.63)
      Statistically significant at the .05 level.
      2.43 (1.89-3.12)
      Statistically significant at the .05 level.
      56 (26.17)2.83 (2.18-3.68)
      Statistically significant at the .05 level.
      2.38 (1.81-3.13)
      Statistically significant at the .05 level.
      Percentage of events calculated among children who had atopic dermatitis and allergic sensitization at age 1 year.
      Adjusted for ethnicity, study center, child's sex, pet ownership, parental atopy, and parental history of any allergic diseases. Numbers for adjusted models are lower because of missing data required for adjustment.
      Statistically significant at the .05 level.

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