490 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2014
the Departments of fMathematics and Statistics and kPediatrics, University of Turku, Turku, Finland; hthe Department of Laboratory Medicine and Medical Research Unit, Sein€ajoki Central Hospital and University of Tampere, Tampere, Finland; ithe Center for Laboratory Medicine, Pirkanmaa Hospital District, Tampere, Finland; jthe Immunogenetics Laboratory, University of Turku, Turku, Finland, and the Department of Clinical Microbiology, University of Eastern Finland, Joensuu, Finland; lthe Department of Pediatrics, Tampere University Hospital, Tampere, Finland; othe Department of Pediatrics, University of Oulu, Oulu, Finland; and pthe Research Center for Child Health and Science Centre of Pirkanmaa Hospital District, Tampere University Hospital and University of Tampere, Tampere, Finland. E-mail: [email protected]. Supported by the National Graduate School of Clinical Investigation, the Academy of Finland (grants 63672, 79685, 79686, 80846, 201988, 210632), the Finnish Paediatric Research Foundation, the Foundation of the Finnish Anti–Tuberculosis Association, the V€ain€ o and Laina Kivi Foundation, the Juho Vainio Foundation, the Yrj€o Jahnsson Foundation, Medical Research Funds of Turku and Oulu University Hospitals, Competitive Research Funding of the Tampere University Hospital, JDRF (grants 197032, 4-1998-274, 4-1999-731, 4-2001-435), Novo Nordisk Foundation, and EU Biomed 2 Program (BMH4-CT98-3314). Disclosure of potential conflict of interest: M. Lumia has received grants from the Allergy Foundation and the V€ain€o and Laina Kivi Foundation. M. Kaila’s institution has received funding from a Tampere University Hospital EVO grant. R. Veijola’s institution has received funding from the Juvenile Diabetes Research Foundation International; she has received compensation for board membership from Novo Nordisk, Medtronic, Lilly Diabetes, and Sanofi; she and her institution have received grants or have grants pending from the National Institutes of Health, Juvenile Diabetes Research Foundation, Alberta Livestock and Meat Agency and K. A. Snellman Foundation, Foundation for Pediatric Research, and the Foundation for Clinical Chemistry; and she has received payment from ApotheCom for the development of educational presentations, as well as from Novo Nordisk, Medtronic, Pfizer, Lilly, Merck, and Serono, for travel-related expenses. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Calder PC. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie 2009;91:791-5. 2. Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10:6-12. 3. Sala-Vila A, Miles EA, Calder PC. Fatty acid composition abnormalities in atopic disease: evidence explored and role in the disease process examined. Clin Exp Allergy 2008;38:1432-50. 4. Kupila A, Muona P, Simell T, Arvilommi P, Savolainen H, Hamalainen AM, et al. Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia 2001;44:290-7. 5. Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippila C, Hakulinen T, et al. Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia 2006;49:1512-21. 6. Nwaru BI, Lumia M, Kaila M, Luukkainen P, Tapanainen H, Erkkola M, et al. Validation of the Finnish ISAAC questionnaire on asthma against anti-asthmatic medication reimbursement database in 5-year-old children. Clin Respir J 2011;5:2011-8. 7. Uusitalo L, Nevalainen J, Salminen I, Ovaskainen ML, Kronberg-Kippila C, Ahonen S, et al. Fatty acids in serum and diet—a canonical correlation analysis among toddlers. Matern Child Nutr 2013;9:381-95. 8. Craiu RV, Duchesne T, Fortin D. Inference methods for the conditional logistic regression model with longitudinal data. Biom J 2008;50:97-109. 9. Virtanen SM, Nevalainen J, Kronberg-Kippil€a C, Ahonen S, Tapanainen H, Uusitalo L, et al. Food consumption and advanced b cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested casecontrol design. Am J Clin Nutr 2012;95:471-8. 10. Magnusson J, Kull I, Rosenlund H, Hakansson N, Wolk A, Melen E, et al. Fish consumption in infancy and development of allergic disease up to age 12 y. Am J Clin Nutr 2013;97:1324-30. Available online May 27, 2014. http://dx.doi.org/10.1016/j.jaci.2014.04.012
Winter birth in inner-city asthmatic children is associated with increased food allergen sensitization risk To the Editor: Food allergies affect as many as 1 in 13 children in the United States,1 and estimates suggest that the prevalence is increasing.2
Understanding factors that affect the development of food allergy is a particular area of interest, with theories including timing of food introduction, season of birth, environmental exposures, and both excess and deficiency of vitamin D.3 Season of birth may affect the development of food allergy by several mechanisms, including infectious exposures, indoor allergen exposure, and vitamin D status during the first year of life. Vitamin D has been postulated to have a role in the allergic response primarily by means of inhibition of the inflammatory response of innate immune cells.4 Using previously collected serum samples and historical information from an Inner-City Asthma study,5 we sought to uncover the potential role of season of birth, and because of the capability of measuring vitamin D status in the population, the potential effect of serum vitamin D on the development of food allergen sensitization in an inner-city asthmatic cohort. Four hundred twenty-four samples from the National Institutes of Health-National Cooperative Inner-City Asthma Study5 were available for analysis of serum 25-hydroxyvitamin D levels. Vitamin D was characterized as both a continuous variable and as a dichotomous variable using 20 ng/mL as a cutoff on the basis of the distribution of vitamin D within the population. The Pearson x2 test was used for comparison of categorical data, and the Kruskal-Wallis test was used for testing between quantitative and categorical data: for example, food and environmental allergen sensitization. The relationship between food allergen sensitization and season of birth (winter—December, January, and February; spring—March, April, and May; summer—June, July, and August; fall—September, October, and November) was also examined. Season of birth was analyzed as a proxy for vitamin D levels in the first year of life.6 Because of known differences in vitamin D status and race,7 analyses were performed on the black portion of the population because the overwhelming majority of our population was black (n 5 340; Table I). Statistical analyses were performed using R (http:// www.r-project.org/). This inner-city asthmatic population, the overwhelming majority of which was from northern latitudes (96%), was 64% male, with a median age of 6 years (Table I); 82% of the TABLE I. Population characteristics Characteristic
N 5 427
Sex: male Race Black Hispanic Other Age (y) Site Boston Bronx Chicago Others Body mass index (kg/m2) Season Fall Winter Spring Summer 25-Hydroxyvitamin D (ng/mL)
270 (64) 340 (82) 54 (13) 21 (5) 6 (5-8) 43 43 9 4 16.7 (15.5-18.6) 25 25 25 25 18.0 (12.9-23.2)
Values are n (%), percentages, or medians with (interquartile ranges).
LETTERS TO THE EDITOR 491
J ALLERGY CLIN IMMUNOL VOLUME 134, NUMBER 2
Egg IgE
Milk IgE p = 0.03
Wheat IgE p = 0.65
p = 0.06
10
10
1
1
Peanut IgE
Geometric Mean (kU/L)
Cod IgE p = 0.44
Soy IgE p = 0.01
Shrimp IgE p = 0.04
D. Farinae IgE p = 0.12
p = 0.62
10
10
1
1
Cockroach IgE
Alternaria IgE p = 0.26
p = 0.26
10
10
1
1
Winter
Spring Summer
Fall
Winter
Spring Summer
Fall
FIG 1. Association between specific IgE values and season of birth for black participants. Each bar represents the geometric mean and vertical lines the standard error of the mean.
individuals were black and 13% Hispanic. Participants were sensitized to foods and select environmental allergens, as shown in Table E1 of this article’s Online Repository at www.jacionline.org. No significant relationship was detected between vitamin D status and food allergen sensitization, environmental allergen sensitization (Table E1), environmental allergen exposure, or likelihood of clinically relevant food allergy on the basis of established predictive values for allergic reactivity to milk, egg, or peanut (data not included). A trend toward significance was noted for egg sensitization and vitamin D status (P 5 .07) (Table E1), although we do not have an explanation for this trend. In models adjusting for the current vitamin D level, a significant relationship was detected between winter birth and increased likelihood of sensitization to egg white, peanut, or soy and a trend toward significance for wheat sensitization (P 5 .06) (Fig 1). Data were also analyzed adjusting for time of year when the blood sample was drawn, and no changes in results were observed (data not included). Investigators have reported various associations between food allergen sensitization and either fall or winter birth. Keet et al6 recently reported a strong relationship between fall birth and an increased likelihood of developing food allergy in a white cohort of children from the National Health and Nutrition Examination Survey III database, and Mullins et al8 have shown significantly higher rates of food allergy in Australian children born in fall/winter than in spring/summer. We are the first to report a positive correlation between winter birth and sensitization to egg, peanut, and soy in a predominantly black, inner-city population. A common hypothesis linking the season of birth with the development of allergen sensitization implies that vitamin D
deficiency in a neonate may be responsible.9 Season of birth may affect vitamin D status during infancy, a period of time when the developing immune system may be particularly susceptible to the acquisition of allergen sensitivities. One limitation of our analysis is that samples in our cohort were taken in later childhood, after sensitization had likely occurred in most of the individuals, and thus current vitamin D status may not have a bearing on preexisting sensitivities. Thus, we used season of birth as a proxy for vitamin D status in the first year of life, which has previously been shown to be reflective of seasonal associations with food allergy,6 though this is clearly not a precise measurement. In addition to the effect of season of birth on vitamin D status, one must consider its effects on infectious exposures (eg, winter viruses) and indoor allergen exposures, factors we were not able to measure in the first year of life in our cohort. Another limitation to the interpretability of vitamin D status and food allergen sensitization in our cohort may be that most of the individuals were either vitamin D deficient or insufficient at the time of serum acquisition (see Fig E1 in this article’s Online Repository at www.jacionline.org), which limits interpretability based on the lack of normal controls within the population. However, we also saw no relationship of food sensitivity to vitamin D levels when analyzed as a continuous variable (data not shown). Our data suggest an important role between season of birth and the development of food allergen sensitization. In addition to vitamin D status, other factors may affect the development of allergen sensitivity for an infant born during winter, including exposure to winter viruses, global geographic location, and indoor allergen exposure. Additional considerations during the first year of life include the effects of breast-feeding and cesarian birth,
492 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2014
factors we were not able to analyze in our sample. Given the lack of food allergy history in our population and variability in vitamin D levels with other ethnicities, we caution against drawing firm conclusions with regard to the presence of clinical reactivity and vitamin D status in other ethnicities; however, these data are suggestive of a relationship that warrants further investigation. Future epidemiologic studies should prospectively measure numerous factors, including vitamin D status and the development of allergy, in a diverse population. J. Andrew Bird, MDa Julie Wang, MDb Cynthia M. Visness, PhD, MPHc Agustin Calatroni, MSc Hugh A. Sampson, MDb Rebecca Gruchalla, MD, PhDa From athe University of Texas Southwestern Medical Center, Dallas, Tex; bIcahn School of Medicine at Mount Sinai, New York, NY; and cRho Federal Systems Division, Inc, Chapel Hill, NC. E-mail: [email protected]. The National Cooperative Inner-City Asthma Study was supported by grants UOI A1-30752, A1-30752, A1-30756, A1-30772, A1-30773-01, A1-30777, A1-30779, A1-30780, and N01-A1-15105. Funding for this analysis was provided by the Dedman Family Scholar in Clinical Care funds. Disclosure of potential conflict of interest: J. A. Bird has received research support from DBV Technologies, Allergen Research Corporation, and Food Allergy Research and Education and has received payment for lectures from Nutricia North America. J. Wang has consultant arrangements with Merck, is employed by Icahn School of Medicine at Mount Sinai, has received research support from the National Institutes of Health, receives royalties from UpToDate, and has stock/stock options with JDP Therapeutics. C. M. Visness and A. Calatroni have received research support from the National Institutes of Health-National Institute of Allergy and Infectious Diseases. H. A. Sampson has received research support from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and Food Allergy Research
and Education; has received travel expenses as Chair of PhARF Award review committee; has consultant arrangements with Allertein Therapeutics, Regeneron, and Danone Research Institute; and has received payment for lectures from ThermoFisher Scientific, UCB, and Pfizer. R. Gruchalla has received research support from the National Institutes of Health-National Institute of Allergy and Infectious Diseases and the National Institutes of Health-Inner City Asthma Consortium and is employed by the Food and Drug Administration.
REFERENCES 1. Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011;128:e9-17. 2. Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief 2008;1-8. 3. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121: 1331-6. 4. Dimeloe S, Nanzer A, Ryanna K, Hawrylowicz C. Regulatory T cells, inflammation and the allergic response—the role of glucocorticoids and vitamin D. J Steroid Biochem Mol Biol 2010;120:86-95. 5. Wang J, Visness CM, Sampson HA. Food allergen sensitization in inner-city children with asthma. J Allergy Clin Immunol 2005;115:1076-80. 6. Keet CA, Matsui EC, Savage JH, Neuman-Sunshine DL, Skripak J, Peng RD, et al. Potential mechanisms for the association between fall birth and food allergy. Allergy 2012;67:775-82. 7. Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 2009;124:1404-10. 8. Mullins RJ, Clark S, Katelaris C, Smith V, Solley G, Camargo CA Jr. Season of birth and childhood food allergy in Australia. Pediatr Allergy Immunol 2011;22: 583-9. 9. Vassallo MF, Banerji A, Rudders SA, Clark S, Camargo CA Jr. Season of birth and food-induced anaphylaxis in Boston. Allergy 2010;65:1492-3. Available online June 19, 2014. http://dx.doi.org/10.1016/j.jaci.2014.05.002
LETTERS TO THE EDITOR 492.e1
J ALLERGY CLIN IMMUNOL VOLUME 134, NUMBER 2
10
0
10
20
30
40
50
60
20
30
40
50
60
Boxplot
0
10
6 4
Histogram
8
2 0
25−hydroxyvitamin D (ng/mL)
FIG E1. Distribution of 25-hydroxyvitamin D (ng/mL) among black participants (n 5 340). In the box plot, boxes represent the IQR, which contains data between the 25th and 75th percentiles. Whiskers extend to the 1.5 IQR beyond each box. Circles represent extreme observations. The median is represented by a vertical line within the box. In the histogram, the superimposed solid line over the histogram corresponds to the Gaussian theoretical curve for the distribution. IQR, Interquartile range.
492.e2 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2014
TABLE E1. Association between specific IgE and total 25-hydroxyvitamin D for black participants 25-Hydroxyvitamin D (ng/mL) Allergen
Category of specific IgE (kU/L)
Egg (kU/L)
Negative 0.34 Positive 0.35-32.3 Negative 0.34 Positive 0.35-99.3 Negative 0.34 Positive 0.35-94.8 Negative 0.34 Positive 0.35-81.3 Negative 0.34 Positive 0.35-75.3 Negative 0.34 Positive 0.35-48.6 Negative 0.34 Positive 0.35-646 Negative 0.34 Positive 0.35-100 Negative 0.34 Positive 0.35-100 Negative 0.34 Positive 0.35-100
Milk (kU/L) Cod (kU/L) Wheat (kU/L) Peanut (kU/L) Soy (kU/L) Shrimp (kU/L) Dermatophagoides farinae (kU/L) Cockroach (kU/L) Alternaria (kU/L) Total IgE (kU/L)
Values are n (%) or medians with (interquartile ranges).
All (n 5 340)
290 50 269 71 314 26 260 80 282 57 281 59 242 98 235 105 205 135 207 133 196
(85.3) (14.7) (79.1) (20.9) (92.4) (7.65) (76.5) (23.5) (83.2) (16.8) (82.6) (17.4) (71.2) (28.8) (69.1) (30.9) (60.3) (39.7) (60.9) (39.1) (71.3-522)
5-20 (n 5 209)
20-54 (n 5 131)
172 37 162 47 192 17 161 48 178 30 176 33 145 64 147 62 126 83 129 80 197
118 13 107 24 122 9 99 32 104 27 105 26 97 34 88 43 79 52 78 53 195
(82.3) (17.7) (77.5) (22.5) (91.9) (8.13) (77.0) (23.0) (85.6) (14.4) (84.2) (15.8) (69.4) (30.6) (70.3) (29.7) (60.3) (39.7) (61.7) (38.3) (73.2-521)
(90.1) (9.92) (81.7) (18.3) (93.1) (6.87) (75.6) (24.4) (79.4) (20.6) (80.2) (19.8) (74.0) (26.0) (67.2) (32.8) (60.3) (39.7) (59.5) (40.5) (69.7-514)
P value
.07 .43 .83 .86 .18 .42 .42 .62 .99 .77 .84
J ALLERGY CLIN IMMUNOL AUGUST 2014
the Departments of fMathematics and Statistics and kPediatrics, University of Turku, Turku, Finland; hthe Department of Laboratory Medicine and Medical Research Unit, Sein€ajoki Central Hospital and University of Tampere, Tampere, Finland; ithe Center for Laboratory Medicine, Pirkanmaa Hospital District, Tampere, Finland; jthe Immunogenetics Laboratory, University of Turku, Turku, Finland, and the Department of Clinical Microbiology, University of Eastern Finland, Joensuu, Finland; lthe Department of Pediatrics, Tampere University Hospital, Tampere, Finland; othe Department of Pediatrics, University of Oulu, Oulu, Finland; and pthe Research Center for Child Health and Science Centre of Pirkanmaa Hospital District, Tampere University Hospital and University of Tampere, Tampere, Finland. E-mail: [email protected]. Supported by the National Graduate School of Clinical Investigation, the Academy of Finland (grants 63672, 79685, 79686, 80846, 201988, 210632), the Finnish Paediatric Research Foundation, the Foundation of the Finnish Anti–Tuberculosis Association, the V€ain€ o and Laina Kivi Foundation, the Juho Vainio Foundation, the Yrj€o Jahnsson Foundation, Medical Research Funds of Turku and Oulu University Hospitals, Competitive Research Funding of the Tampere University Hospital, JDRF (grants 197032, 4-1998-274, 4-1999-731, 4-2001-435), Novo Nordisk Foundation, and EU Biomed 2 Program (BMH4-CT98-3314). Disclosure of potential conflict of interest: M. Lumia has received grants from the Allergy Foundation and the V€ain€o and Laina Kivi Foundation. M. Kaila’s institution has received funding from a Tampere University Hospital EVO grant. R. Veijola’s institution has received funding from the Juvenile Diabetes Research Foundation International; she has received compensation for board membership from Novo Nordisk, Medtronic, Lilly Diabetes, and Sanofi; she and her institution have received grants or have grants pending from the National Institutes of Health, Juvenile Diabetes Research Foundation, Alberta Livestock and Meat Agency and K. A. Snellman Foundation, Foundation for Pediatric Research, and the Foundation for Clinical Chemistry; and she has received payment from ApotheCom for the development of educational presentations, as well as from Novo Nordisk, Medtronic, Pfizer, Lilly, Merck, and Serono, for travel-related expenses. The rest of the authors declare that they have no relevant conflicts of interest. REFERENCES 1. Calder PC. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie 2009;91:791-5. 2. Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10:6-12. 3. Sala-Vila A, Miles EA, Calder PC. Fatty acid composition abnormalities in atopic disease: evidence explored and role in the disease process examined. Clin Exp Allergy 2008;38:1432-50. 4. Kupila A, Muona P, Simell T, Arvilommi P, Savolainen H, Hamalainen AM, et al. Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia 2001;44:290-7. 5. Virtanen SM, Kenward MG, Erkkola M, Kautiainen S, Kronberg-Kippila C, Hakulinen T, et al. Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes. Diabetologia 2006;49:1512-21. 6. Nwaru BI, Lumia M, Kaila M, Luukkainen P, Tapanainen H, Erkkola M, et al. Validation of the Finnish ISAAC questionnaire on asthma against anti-asthmatic medication reimbursement database in 5-year-old children. Clin Respir J 2011;5:2011-8. 7. Uusitalo L, Nevalainen J, Salminen I, Ovaskainen ML, Kronberg-Kippila C, Ahonen S, et al. Fatty acids in serum and diet—a canonical correlation analysis among toddlers. Matern Child Nutr 2013;9:381-95. 8. Craiu RV, Duchesne T, Fortin D. Inference methods for the conditional logistic regression model with longitudinal data. Biom J 2008;50:97-109. 9. Virtanen SM, Nevalainen J, Kronberg-Kippil€a C, Ahonen S, Tapanainen H, Uusitalo L, et al. Food consumption and advanced b cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested casecontrol design. Am J Clin Nutr 2012;95:471-8. 10. Magnusson J, Kull I, Rosenlund H, Hakansson N, Wolk A, Melen E, et al. Fish consumption in infancy and development of allergic disease up to age 12 y. Am J Clin Nutr 2013;97:1324-30. Available online May 27, 2014. http://dx.doi.org/10.1016/j.jaci.2014.04.012
Winter birth in inner-city asthmatic children is associated with increased food allergen sensitization risk To the Editor: Food allergies affect as many as 1 in 13 children in the United States,1 and estimates suggest that the prevalence is increasing.2
Understanding factors that affect the development of food allergy is a particular area of interest, with theories including timing of food introduction, season of birth, environmental exposures, and both excess and deficiency of vitamin D.3 Season of birth may affect the development of food allergy by several mechanisms, including infectious exposures, indoor allergen exposure, and vitamin D status during the first year of life. Vitamin D has been postulated to have a role in the allergic response primarily by means of inhibition of the inflammatory response of innate immune cells.4 Using previously collected serum samples and historical information from an Inner-City Asthma study,5 we sought to uncover the potential role of season of birth, and because of the capability of measuring vitamin D status in the population, the potential effect of serum vitamin D on the development of food allergen sensitization in an inner-city asthmatic cohort. Four hundred twenty-four samples from the National Institutes of Health-National Cooperative Inner-City Asthma Study5 were available for analysis of serum 25-hydroxyvitamin D levels. Vitamin D was characterized as both a continuous variable and as a dichotomous variable using 20 ng/mL as a cutoff on the basis of the distribution of vitamin D within the population. The Pearson x2 test was used for comparison of categorical data, and the Kruskal-Wallis test was used for testing between quantitative and categorical data: for example, food and environmental allergen sensitization. The relationship between food allergen sensitization and season of birth (winter—December, January, and February; spring—March, April, and May; summer—June, July, and August; fall—September, October, and November) was also examined. Season of birth was analyzed as a proxy for vitamin D levels in the first year of life.6 Because of known differences in vitamin D status and race,7 analyses were performed on the black portion of the population because the overwhelming majority of our population was black (n 5 340; Table I). Statistical analyses were performed using R (http:// www.r-project.org/). This inner-city asthmatic population, the overwhelming majority of which was from northern latitudes (96%), was 64% male, with a median age of 6 years (Table I); 82% of the TABLE I. Population characteristics Characteristic
N 5 427
Sex: male Race Black Hispanic Other Age (y) Site Boston Bronx Chicago Others Body mass index (kg/m2) Season Fall Winter Spring Summer 25-Hydroxyvitamin D (ng/mL)
270 (64) 340 (82) 54 (13) 21 (5) 6 (5-8) 43 43 9 4 16.7 (15.5-18.6) 25 25 25 25 18.0 (12.9-23.2)
Values are n (%), percentages, or medians with (interquartile ranges).
LETTERS TO THE EDITOR 491
J ALLERGY CLIN IMMUNOL VOLUME 134, NUMBER 2
Egg IgE
Milk IgE p = 0.03
Wheat IgE p = 0.65
p = 0.06
10
10
1
1
Peanut IgE
Geometric Mean (kU/L)
Cod IgE p = 0.44
Soy IgE p = 0.01
Shrimp IgE p = 0.04
D. Farinae IgE p = 0.12
p = 0.62
10
10
1
1
Cockroach IgE
Alternaria IgE p = 0.26
p = 0.26
10
10
1
1
Winter
Spring Summer
Fall
Winter
Spring Summer
Fall
FIG 1. Association between specific IgE values and season of birth for black participants. Each bar represents the geometric mean and vertical lines the standard error of the mean.
individuals were black and 13% Hispanic. Participants were sensitized to foods and select environmental allergens, as shown in Table E1 of this article’s Online Repository at www.jacionline.org. No significant relationship was detected between vitamin D status and food allergen sensitization, environmental allergen sensitization (Table E1), environmental allergen exposure, or likelihood of clinically relevant food allergy on the basis of established predictive values for allergic reactivity to milk, egg, or peanut (data not included). A trend toward significance was noted for egg sensitization and vitamin D status (P 5 .07) (Table E1), although we do not have an explanation for this trend. In models adjusting for the current vitamin D level, a significant relationship was detected between winter birth and increased likelihood of sensitization to egg white, peanut, or soy and a trend toward significance for wheat sensitization (P 5 .06) (Fig 1). Data were also analyzed adjusting for time of year when the blood sample was drawn, and no changes in results were observed (data not included). Investigators have reported various associations between food allergen sensitization and either fall or winter birth. Keet et al6 recently reported a strong relationship between fall birth and an increased likelihood of developing food allergy in a white cohort of children from the National Health and Nutrition Examination Survey III database, and Mullins et al8 have shown significantly higher rates of food allergy in Australian children born in fall/winter than in spring/summer. We are the first to report a positive correlation between winter birth and sensitization to egg, peanut, and soy in a predominantly black, inner-city population. A common hypothesis linking the season of birth with the development of allergen sensitization implies that vitamin D
deficiency in a neonate may be responsible.9 Season of birth may affect vitamin D status during infancy, a period of time when the developing immune system may be particularly susceptible to the acquisition of allergen sensitivities. One limitation of our analysis is that samples in our cohort were taken in later childhood, after sensitization had likely occurred in most of the individuals, and thus current vitamin D status may not have a bearing on preexisting sensitivities. Thus, we used season of birth as a proxy for vitamin D status in the first year of life, which has previously been shown to be reflective of seasonal associations with food allergy,6 though this is clearly not a precise measurement. In addition to the effect of season of birth on vitamin D status, one must consider its effects on infectious exposures (eg, winter viruses) and indoor allergen exposures, factors we were not able to measure in the first year of life in our cohort. Another limitation to the interpretability of vitamin D status and food allergen sensitization in our cohort may be that most of the individuals were either vitamin D deficient or insufficient at the time of serum acquisition (see Fig E1 in this article’s Online Repository at www.jacionline.org), which limits interpretability based on the lack of normal controls within the population. However, we also saw no relationship of food sensitivity to vitamin D levels when analyzed as a continuous variable (data not shown). Our data suggest an important role between season of birth and the development of food allergen sensitization. In addition to vitamin D status, other factors may affect the development of allergen sensitivity for an infant born during winter, including exposure to winter viruses, global geographic location, and indoor allergen exposure. Additional considerations during the first year of life include the effects of breast-feeding and cesarian birth,
492 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2014
factors we were not able to analyze in our sample. Given the lack of food allergy history in our population and variability in vitamin D levels with other ethnicities, we caution against drawing firm conclusions with regard to the presence of clinical reactivity and vitamin D status in other ethnicities; however, these data are suggestive of a relationship that warrants further investigation. Future epidemiologic studies should prospectively measure numerous factors, including vitamin D status and the development of allergy, in a diverse population. J. Andrew Bird, MDa Julie Wang, MDb Cynthia M. Visness, PhD, MPHc Agustin Calatroni, MSc Hugh A. Sampson, MDb Rebecca Gruchalla, MD, PhDa From athe University of Texas Southwestern Medical Center, Dallas, Tex; bIcahn School of Medicine at Mount Sinai, New York, NY; and cRho Federal Systems Division, Inc, Chapel Hill, NC. E-mail: [email protected]. The National Cooperative Inner-City Asthma Study was supported by grants UOI A1-30752, A1-30752, A1-30756, A1-30772, A1-30773-01, A1-30777, A1-30779, A1-30780, and N01-A1-15105. Funding for this analysis was provided by the Dedman Family Scholar in Clinical Care funds. Disclosure of potential conflict of interest: J. A. Bird has received research support from DBV Technologies, Allergen Research Corporation, and Food Allergy Research and Education and has received payment for lectures from Nutricia North America. J. Wang has consultant arrangements with Merck, is employed by Icahn School of Medicine at Mount Sinai, has received research support from the National Institutes of Health, receives royalties from UpToDate, and has stock/stock options with JDP Therapeutics. C. M. Visness and A. Calatroni have received research support from the National Institutes of Health-National Institute of Allergy and Infectious Diseases. H. A. Sampson has received research support from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and Food Allergy Research
and Education; has received travel expenses as Chair of PhARF Award review committee; has consultant arrangements with Allertein Therapeutics, Regeneron, and Danone Research Institute; and has received payment for lectures from ThermoFisher Scientific, UCB, and Pfizer. R. Gruchalla has received research support from the National Institutes of Health-National Institute of Allergy and Infectious Diseases and the National Institutes of Health-Inner City Asthma Consortium and is employed by the Food and Drug Administration.
REFERENCES 1. Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011;128:e9-17. 2. Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief 2008;1-8. 3. Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol 2008;121: 1331-6. 4. Dimeloe S, Nanzer A, Ryanna K, Hawrylowicz C. Regulatory T cells, inflammation and the allergic response—the role of glucocorticoids and vitamin D. J Steroid Biochem Mol Biol 2010;120:86-95. 5. Wang J, Visness CM, Sampson HA. Food allergen sensitization in inner-city children with asthma. J Allergy Clin Immunol 2005;115:1076-80. 6. Keet CA, Matsui EC, Savage JH, Neuman-Sunshine DL, Skripak J, Peng RD, et al. Potential mechanisms for the association between fall birth and food allergy. Allergy 2012;67:775-82. 7. Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 2009;124:1404-10. 8. Mullins RJ, Clark S, Katelaris C, Smith V, Solley G, Camargo CA Jr. Season of birth and childhood food allergy in Australia. Pediatr Allergy Immunol 2011;22: 583-9. 9. Vassallo MF, Banerji A, Rudders SA, Clark S, Camargo CA Jr. Season of birth and food-induced anaphylaxis in Boston. Allergy 2010;65:1492-3. Available online June 19, 2014. http://dx.doi.org/10.1016/j.jaci.2014.05.002
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FIG E1. Distribution of 25-hydroxyvitamin D (ng/mL) among black participants (n 5 340). In the box plot, boxes represent the IQR, which contains data between the 25th and 75th percentiles. Whiskers extend to the 1.5 IQR beyond each box. Circles represent extreme observations. The median is represented by a vertical line within the box. In the histogram, the superimposed solid line over the histogram corresponds to the Gaussian theoretical curve for the distribution. IQR, Interquartile range.
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TABLE E1. Association between specific IgE and total 25-hydroxyvitamin D for black participants 25-Hydroxyvitamin D (ng/mL) Allergen
Category of specific IgE (kU/L)
Egg (kU/L)
Negative 0.34 Positive 0.35-32.3 Negative 0.34 Positive 0.35-99.3 Negative 0.34 Positive 0.35-94.8 Negative 0.34 Positive 0.35-81.3 Negative 0.34 Positive 0.35-75.3 Negative 0.34 Positive 0.35-48.6 Negative 0.34 Positive 0.35-646 Negative 0.34 Positive 0.35-100 Negative 0.34 Positive 0.35-100 Negative 0.34 Positive 0.35-100
Milk (kU/L) Cod (kU/L) Wheat (kU/L) Peanut (kU/L) Soy (kU/L) Shrimp (kU/L) Dermatophagoides farinae (kU/L) Cockroach (kU/L) Alternaria (kU/L) Total IgE (kU/L)
Values are n (%) or medians with (interquartile ranges).
All (n 5 340)
290 50 269 71 314 26 260 80 282 57 281 59 242 98 235 105 205 135 207 133 196
(85.3) (14.7) (79.1) (20.9) (92.4) (7.65) (76.5) (23.5) (83.2) (16.8) (82.6) (17.4) (71.2) (28.8) (69.1) (30.9) (60.3) (39.7) (60.9) (39.1) (71.3-522)
5-20 (n 5 209)
20-54 (n 5 131)
172 37 162 47 192 17 161 48 178 30 176 33 145 64 147 62 126 83 129 80 197
118 13 107 24 122 9 99 32 104 27 105 26 97 34 88 43 79 52 78 53 195
(82.3) (17.7) (77.5) (22.5) (91.9) (8.13) (77.0) (23.0) (85.6) (14.4) (84.2) (15.8) (69.4) (30.6) (70.3) (29.7) (60.3) (39.7) (61.7) (38.3) (73.2-521)
(90.1) (9.92) (81.7) (18.3) (93.1) (6.87) (75.6) (24.4) (79.4) (20.6) (80.2) (19.8) (74.0) (26.0) (67.2) (32.8) (60.3) (39.7) (59.5) (40.5) (69.7-514)
P value
.07 .43 .83 .86 .18 .42 .42 .62 .99 .77 .84
