Persistent cow’s milk allergy is associated with decreased childhood growth: A longitudinal study

Food allergy is a prevalent problem, with well-described risks involving safety, comorbidities, and quality of life. An expanding body of research suggests that food allergy and elimination diets can also affect childhood growth and nutrition and that allergy to cow's milk (CM)1Hobbs C.B. Skinner A.C. Burks A.W. Vickery B.P. Food allergies affect growth in children.J Allergy Clin Immunol Pract. 2015; 3: 133-134Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 2Jhamnani R.D. Levin S. Rasooly M. Stone K.D. Milner J.D. Nelson C. et al.Impact of food allergy on the growth of children with moderate-severe atopic dermatitis.J Allergy Clin Immunol. 2018; 141: 1526-1529Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 3Robbins K.A. Wood R.A. Keet C.A. Milk allergy is associated with decreased growth in US children.J Allergy Clin Immunol. 2014; 134: 1466-1468Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 4Sinai T. Goldberg M.R. Nachshon L. Amitzur-Levy R. Yichie R.D. Katz Y. et al.Reduced final height and inadequate nutritional intake in cow’s milk-allergic young adults.J Allergy Clin Immunol Pract. 2019; 7: 509-515Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar or multiple foods5Flammarion S. Santos C. Guimber D. Jouannic L. Thumerelle C. Gottrand F. et al.Diet and nutritional status of children with food allergies.Pediatr Allergy Immunol. 2011; 22: 161-165Crossref PubMed Scopus (118) Google Scholar impart particular risk. Nearly all studies to date have been cross-sectional, and the few longitudinal investigations of growth in children with food allergy have been limited to the first years of life.6Beck C. Koplin J. Dharmage S. Wake M. Gurrin L. McWilliam V. et al.Persistent food allergy and food allergy coexistent with eczema is associated with reduced growth in the first 4 years of life.J Allergy Clin Immunol Pract. 2016; 4: 248-256Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar,7Tuokkola J. Luukkainen P. Nevalainen J. Ahonen J. Toppari J. Ilonen J. et al.Eliminating cow’s milk, but not wheat, barley, or rye, increases the risk of growth deceleration and nutritional inadequacies.Acta Paediatrica. 2017; 106: 1142-1149Crossref PubMed Scopus (23) Google Scholar Data are lacking on growth patterns for children with ongoing food allergy that persists after the early childhood years, raising questions about the long-term effect on body morphology and adult height. Here we present the first description of growth in a longitudinal cohort of children with persistent food allergy that extends from early childhood to adolescence. A retrospective chart review of patients from the Johns Hopkins Pediatric Allergy Clinic was completed for children with a diagnosis of either persistent CM or peanut and/or tree nut (PN/TN) allergy (and no known history of CM allergy). Persistent food allergy was defined as physician-diagnosed IgE-mediated allergy at age 9 years or older based on a convincing history of clinical symptoms, food-specific IgE levels, skin prick test responses, and/or positive food challenge results. For inclusion, all children were required to have at least 1 clinic visit with complete clinical data (including height and weight measurement) during the following age ranges: 2 to 4, 5 to 8, and 9 to 12 years. Children were also required to adhere to a strict elimination diet (for CM, no extensively heated milk or ingredients were allowed). Children were excluded if they had any other major medical disorder with expected effect on growth. Clinical data (including comorbid diagnoses, other allergy, and medication use) and anthropometric measurements were recorded for all documented visits between the ages of 2 and 12 years, and additional data were collected, if available, for visits after age 13 years. Differences in mean weight, height, and body mass index (BMI) z scores were determined by using a generalized estimation equation regression model (to adjust for clustering on individual given variation in number of clinic visits), adjusting for age category, sex, and ethnicity. Additional description of the methods used in this study is included in the Methods section in this article’s Online Repository at www.jacionline.org. The study was approved by the Johns Hopkins Hospital Institutional Review Board. One hundred ninety-one children with persistent IgE-mediated allergy (CM, n = 111; PN/TN, n = 80) seen between November 1994 and March 2015 were included in this study. Patients’ characteristics are listed in Table I and in Table E1 in this article’s Online Repository at www.jacionline.org. One hundred seventy-eight children had a clinical history of reactivity (either a positive oral food challenge result [n = 22] or a history of convincing reaction to food). Fifty-three children (32 with CM and 21 with PN/TN allergy) had clinical data after age 13 years that were also included for analysis. A total of 1186 clinic visits were included (1098 between the ages of 2 and 12 years). Consistent with previous data, children with CM allergy tended to restrict other major allergens, such as egg, peanut, and tree nuts, and had high prevalence of asthma.8Skripak J.M. Matsui E.C. Mudd K. Wood R.A. The natural history of IgE-mediated cow’s milk allergy.J Allergy Clin Immunol. 2007; 120: 1172-1177Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar,9Wood R.A. Sicherer S.H. Vickery B.P. Jones S.M. Liu A.H. Fleischer D.M. et al.The natural history of milk allergy in an observational cohort.J Allergy Clin Immunol. 2013; 131: 805-812Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar Children with CM allergy had lower weight (mean z score difference, 0.39; 95% CI, 0.13-0.66; P = .004) and height (mean z score difference, 0.39; 95% CI, 0.11- 0.67; P = .006) but not BMI-for-age (P = .11) z scores compared with children with PN/TN allergy (Fig 1), adjusting for age, sex, and ethnicity. Findings were unaffected by other atopic conditions (asthma, rhinitis, early-onset or any eczema, and eosinophilic esophagitis) or inhaled corticosteroid (ICS) use.Table IStudy populationChildren with CM allergy (n = 111)Children with PN/TN allergy (n = 80)P valueMale sex, no. (%)68 (61.3)41 (51.3).17Female sex, no. (%)43 (38.7)39 (48.8)Race/ethnicity, no. (%).12 White78 (70.3)67 (83.8) Black9 (8.0)7 (8.75) Hispanic2 (1.8)0 (0) Asian10 (8.9)3 (3.8) Other12 (10.7)3 (3.8)Allergens avoided, no. (%) Peanut only—4 (5.0) Tree nuts only—7 (8.8) Peanut and tree nut—69 (86.3) CM111 (100)—Clinic visits per patient, mean (SD [range]) 2-4 y2.24 (1.05 [1-6])1.65 (0.75 [1-4])<.01 5-8 y2.46 (1.00 [1-5])2.20 (1.00 [1-5]).10 9-12 y1.68 (0.96 [1-5])1.44 (0.67 [1-3)].14 ≥13 y∗Visits at an age of 13 or more years were not required for study inclusion, but data were collected if available: 21 (26%) of 80 children with PN/TN allergy and 32 (29%) of 112 with CM allergy had at least 1 visit after age 13 years.0.53 (1.04 [0-5])0.43 (0.98 [0-5]).32Comorbid conditions Atopic dermatitis, no. (%)Any visit86 (77.5)53 (66.3).072- to 4-year-old visit (any)69 (62.3)40 (50.0).105- to 8-year-old visit (any)69 (62.3)40 (50.0).109- to 12-year-old visit (any)51 (45.9)30 (47.5).24 Asthma or use of asthma medicationAny visit98 (88.2)54 (67.5)<.012- to 4-year-old visit (any)75 (67.6)29 (36.3)<.015 to 8-year-old visit (any)95 (85.6)46 (57.5)<.019- to 12-year-old visit (any)90 (81.1)44 (55.0)<.01 RhinitisAny visit96 (86.5)73 (91.3).492- to 4-year-old visit (any)52 (46.8)45 (56.3).245- to 8-year-old visit (any)83 (74.5)61 (76.3)>.999- to 12-year-old visit (any)84 (75.7)61 (76.3)>.99 Eosinophilic esophagitis/gastrointestinal diseaseAny visit15 (13.5)—2- to 4-year-old visit (any)7 (6.3)—5- to 8-year-old visit (any)6 (5.4)—9- to 12-year-old visit (any)9 (8.1)—Medication use ICS (daily/intermittent)Any visit79 (71.2)34 (42.5)<.012-4 y45 (40.5)19 (23.8).025-8 y65 (58.6)28 (35.0)<.019-12 y64 (57.7)26 (32.5)<.01 Topical corticosteroid (daily/intermittent)Any visit61 (55.0)38 (47.5).382-4 y47 (4.3)24 (30.0).105-8 y35 (31.5)22 (27.5).639-12 y31 (27.9)16 (20.0).24 ICS (daily/intermittent)Any visit52 (46.8)28 (35.0).112-4 y9 (8.1)10 (12.5).345-8 y38 (34.2)19 (23.8).159-12 y34 (30.6)19 (23.8).33Serum IgE level > predictive threshold†Predictive IgE levels were defined as follows: CM, >15 kUA/L; peanut, >14 kUA/L; and tree nut, >0.1 kUA/L.100 (90.1)78 (97.5).08History of reaction to food109 (98.2)69 (86.3)<.01Positive oral food challenge result to food14 (12.6)8 (10.0).65Any visit was defined as visits at age 2 to 12 years not including additional data collected after age 13 years. P values were determined by using the Fisher exact test.∗ Visits at an age of 13 or more years were not required for study inclusion, but data were collected if available: 21 (26%) of 80 children with PN/TN allergy and 32 (29%) of 112 with CM allergy had at least 1 visit after age 13 years.† Predictive IgE levels were defined as follows: CM, >15 kUA/L; peanut, >14 kUA/L; and tree nut, >0.1 kUA/L. Open table in a new tab Any visit was defined as visits at age 2 to 12 years not including additional data collected after age 13 years. P values were determined by using the Fisher exact test. Persistent CM allergy was also associated with a greater decrease in weight and also BMI z scores from the baseline visit (2-4 years of age) at older ages (weight: mean z score difference, 0.25; 95% CI, 0.06-0.43; P = .008; BMI: mean z score difference, 0.34; 95% CI, 0.09-0.59; P = .007; see Table E2 in this article’s Online Repository at www.jacionline.org). These differences were larger in the 5- to 8-year-old (mean z score difference, 0.43; 95% CI, 0.13-0.73; P = .004) and 9- to 12-year-old (mean z score difference, 0.52; 95% CI, 0.21-0.84; P = .001) age ranges than in the less than 5-year-old age range for weight but not height (P < .05 for interaction with age; see Table E3 in this article’s Online Repository at www.jacionline.org). However, there was a trend toward greater height differences at the older ages also (mean z score differences, 0.38 [95% CI, 0.07-0.69; P = .02] at age 5-8 years and 0.42 [95% CI, 0.11-0.74; P = .01] at age 9-12 years; P value for interaction with age > .25). There were no increased odds for very low height or weight measures (z score < −2) detected in children with milk allergy that would correspond to stunting or wasting (data not shown). For the children with clinical data at age 13 years or older (n = 53), adjusted differences in weight and height were more pronounced for children with milk allergy (weight: mean z score difference, −0.63; 95% CI, 0.09-1.17; P = .02; height: mean z score difference, −0.82; 95% CI, 0.36-1.28; P ≤ .01; Fig 1), and there remained no significant differences in BMI. ICS exposure alone was not a predictor of growth differences. It is unclear whether these findings predict final adult height and body measures, but our data raise important questions regarding the potential effect of persistent food allergy on growth and development. Both early childhood and puberty are periods punctuated by increased growth requirements in the normal state. If these patterns are significantly influenced by allergic status and diet, there could be long-term effects that are not well described to date. Our findings are consistent with a recent report from Sinai et al4Sinai T. Goldberg M.R. Nachshon L. Amitzur-Levy R. Yichie R.D. Katz Y. et al.Reduced final height and inadequate nutritional intake in cow’s milk-allergic young adults.J Allergy Clin Immunol Pract. 2019; 7: 509-515Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar that demonstrates growth deficiencies in a cross-sectional study of postpubertal patients with CM allergy, suggesting that young adults with CM allergy might not reach their growth potential. It is also important to note that the phenotype of CM allergy appears to often be one of multiple food allergies. There are some notable limitations to our study, including recruitment from a single referral center and requirement for long-term follow-up, introducing a potential selection bias for patients with greater morbidity. We lacked a true control population; however, this was addressed by comparison of children with CM allergy with those who avoided only PN/TN (which might be expected to have a lesser overall effect on the diet). However, selection of this control group might result in underestimation of the relationship between CM allergy and childhood growth. Management of CM allergy has evolved in recent years, and it is possible that some subjects who avoided milk strictly in this study would now be offered baked milk challenges (which were used more routinely starting in the late 2000s). Also, during the time period included here, we saw improved access and referral for dietetic advice, improved availability of allergen-free foods and nutritional alternatives, and passage of the FALCPA law (2004) to allow for more clear identification of food allergen ingredients. As such, the effect of food allergy on growth might now be different. We noted growth differences, yet patients’ measurements did not deviate to a large extent from the normal range. Diagnoses were not all challenge confirmed; however, nearly all patients reported a history of clinical reactivity, and all avoided CM. Because of the retrospective nature of the study, we could not assess nutritional supplementation or guidance, adequacy of diet, eczema or asthma severity, or cumulative corticosteroid use. Still, our findings are reflective of the phenotype of persistent CM allergy, which is likely influenced by a number of factors that might contribute to a picture of disease that is not entirely explained by simple nutritional inadequacy. In conclusion, we found that in a longitudinal cohort of children with persistent IgE-mediated food allergy, those with CM allergy were smaller and lighter than peers with limited PN/TN allergy, and these differences persisted to early adolescence and beyond. Weight differences increased with advancing age, and there was a trend toward greater differences in height also at older ages. For those children who had ongoing allergy and clinical data available into the teenage years, weight and height differences persisted and appeared more pronounced. To our knowledge, this is the first study to characterize growth trajectory in children with persistent food allergy and only longitudinal analysis to date to follow growth through childhood. A retrospective chart review of clinic records for patients seen in the Pediatric Allergy Clinic at Johns Hopkins between 1994 and 2015 was completed, selecting for children who had diagnosis of either persistent IgE-mediated CM allergy or PN/TN allergy (with no known history of milk allergy) at age 9 years or older. All children were required to have at least 1 clinic visit for food allergy with complete clinical documentation, including height and weight measurement, during the following age ranges: 2 to 4 years, 5 to 8 years, and 9 to 12 years. Additional visits during these age ranges were also included, if available. Data were included if the child adhered to a strict allergen avoidance diet but not subsequent to passed challenge or challenges and/or introductions of any form of CM (including extensively heated milk) or PN/TN for the 2 respective groups. In the group with PN/TN allergy, we only allowed for concurrent food allergy or avoidance of nonsoy legumes and sesame allergy because allergies to these are frequently associated with allergy to nuts but are unlikely to have significant independent nutritional consequence. In the group of children with allergy to CM, we allowed for the presence of food allergy to any other foods, including peanut and tree nuts, given the frequent co-occurrence of multiple food hypersensitivities with the milk allergy phenotype and relative rarity of isolated milk allergy. Other food avoidances were noted at every visit and summarized by age range in Table E1. Data were collected for each visit if there were multiple clinic visits during the aforementioned age ranges and also if patients had additional visits at or after age 13 years. Clinic visits with missing height and/or weight measurements were not included in the analysis. Race/ethnicity was defined by entry in the electronic medical record at patient registration. Data on medication use were collected, including use of topical corticosteroids, intranasal corticosteroids, ICSs, and other asthma medications. However, given the extended intervals between visits and the tendency of patients to use these medications with variable consistency, we were unable to quantify exposure to these medications with precision. Therefore corticosteroid exposure was defined as any use of these medications (daily or intermittent) noted at a clinic visit. Age-adjusted z scores for height, weight, and BMI for age and sex were calculated by using the Centers for Disease Control and Prevention’s Epi Info software package (Epi Info v.3.5.4; July 23, 2008), with comparison with Centers for Disease Control and Prevention reference growth curves (2000). Analysis was completed with STATA SE/12.1 software (StataCorp, College Station, Tex). Extreme outliers, defined as ±5 or more z scores, were excluded, and sensitivity analysis also was then completed for outliers of 2 or more z scores to ensure plausibility of measurements. Between-group comparisons for baseline characteristics and clinical features used the Fisher exact test for categorical measures presented with means, SDs, and ranges. P values of less than .05 were considered statistically significant. Differences in mean weight, height, and BMI z scores were determined by using a generalized estimating equation regression model (to adjust for clustering on individual given variation in number of clinic visits per individual in each age range), adjusting for age category, sex, and ethnicity. Changes from baseline z scores were calculated as differences in mean weight, height, and BMI-for-age z scores compared with the initial visit (2-4 years of age). An interaction term was added to evaluate whether differences in anthropometric measures observed between groups were modified by age, ICS use, or both. For the latter variable, ICS exposure was defined as exposure at (1) early age (2-4 years), (2) any visit, or (3) all visit categories. Logistic regression with generalized estimating equation models were used to explore odds for very low growth measures (<−2 z).Table E1Study populationCM allergy (n = 111)PN/TN allergy∗Other food avoidance was limited to sesame and non-soy legumes. (n = 80)2-4 y5-8 y9-12 y2-4 y5-8 y9-12 yOther foods avoided, no. (%)†Food avoidance noted at any visit during the age range is shown. Children might have not incorporated other foods (eg, egg or wheat) for nonallergic reasons, but these data were not able to be collected. Egg96 (86.5)97 (87.4)83 (74.8)——— Wheat50 (45.0)39 (35.1)28 (25.2)——— Soy45 (40.5)23 (20.7)22 (19.8)——— Fish65 (58.6)42 (37.8)29 (26.1)——— Shellfish72 (64.9)66 (59.5)46 (41.4)——— Sesame35 (31.5)48 (43.2)45 (40.5)8 (10.0)9 (11.3)10 (12.5) Non-soy legume(s)20 (18.0)25 (22.5)26 (23.4)1 (1.3)3 (3.8)1 (1.3) Peanut105 (94.6)97 (87.4)86 (77.5)NANANA Tree nuts98 (88.3)96 (86.5)93 (83.8)NANANAVisits at 13 or more years of age were not required for study inclusion, but data were collected if available: 21 (26%) of 80 children with PN/TN allergy and 32 (29%) of 112 children with CM allergy had at least 1 visit at age 13 years or older.NA, Not available.∗ Other food avoidance was limited to sesame and non-soy legumes.† Food avoidance noted at any visit during the age range is shown. Children might have not incorporated other foods (eg, egg or wheat) for nonallergic reasons, but these data were not able to be collected. Open table in a new tab Table E2Mean change from baseline (2 to 4 years old) z scores for weight, height, and BMI in children with CM versus PN/TN allergyΔ z Score from baseline visitCM allergy (n = 112)PN/TN allergy (n = 80)Adjusted difference (β)P value2-4 y5-8 y9-12 y2-4 y5-8 y9-12 yWeight for age—−0.30 (−0.43 to −0.16)−0.44 (−0.60 to −0.28)—−0.06 (−0.21 to 0.09)−0.16 (−0.35 to 0.04)−0.25 (−0.43 to −0.06)<.01Height for age—−0.19 (−0.34 to −0.04)−0.28 (−0.43 to −0.13)—−0.18 (−0.29 to −0.06)−0.24 (−0.39 to −0.08)−0.04 (−0.20 to 0.13).7BMI for age—−0.24 (−0.39 to −0.09)−0.41 (−0.60 to −0.22)—0.05 (−0.17 to 0.27)0.03 (−0.23 to 0.29)−0.34 (−0.59 to −0.09)<.01Mean differences were determined by using multivariate linear regression (general estimating equation for clustering within subjects), adjusting for age category, sex, and ethnicity. Values are presented with 95% CIs. Values in boldface indicate statistical significance. Open table in a new tab Table E3Interaction of age on weight-for-age, height-for-age, and BMI-for-age z score differences in children with CM versus PN/TN allergy2-4 years old5-8 years old9-12 years old≥13 years old∗Data were collected if available but not required for inclusion (n = 53; 32 with CM allergy and 21 with PN/TN allergy).βP valueβP valueβP valueWeight-for-ageBaseline−0.24 (−0.42 to −0.05).01−0.28 (−0.53 to −0.02).03−0.07 (−0.52 to 0.37).75Height-for-ageBaseline−0.05 (−0.20 to 0.10).50−0.10 (−0.29 to 0.10).32−0.20 (−0.53 to 0.14).25BMI-for-ageBaseline−0.32 (−0.59 to −0.06).02−0.42 (−0.76 to −0.08).02−0.17 (−0.68 to 0.33).50Mean differences were determined by using multivariate linear regression (general estimating equation for clustering within subjects), adjusting for age category, sex, and ethnicity, are shown. Values are presented with 95% CIs. Values in boldface indicate statistical significance.∗ Data were collected if available but not required for inclusion (n = 53; 32 with CM allergy and 21 with PN/TN allergy). Open table in a new tab Visits at 13 or more years of age were not required for study inclusion, but data were collected if available: 21 (26%) of 80 children with PN/TN allergy and 32 (29%) of 112 children with CM allergy had at least 1 visit at age 13 years or older. NA, Not available. Mean differences were determined by using multivariate linear regression (general estimating equation for clustering within subjects), adjusting for age category, sex, and ethnicity. Values are presented with 95% CIs. Values in boldface indicate statistical significance. Mean differences were determined by using multivariate linear regression (general estimating equation for clustering within subjects), adjusting for age category, sex, and ethnicity, are shown. Values are presented with 95% CIs. Values in boldface indicate statistical significance.