To the Editor,
Vitamin D has important roles beyond calcium and bone homeostasis. One important role of vitamin D is in immune modulation. Vitamin D deficiency is associated with autoimmune disease, susceptibility to infection, and allergic diseases, including asthma, allergic rhinitis, and food allergies (1). Additionally, asthma and atopic disorders are classically associated with immunoglobulin E (IgE) mediated sensitization (2). Thus, an investigation of the relationship between vitamin D status and IgE levels is warranted. Observational studies in the general population reveal an inconsistent association between serum 25-hydroxyvitamin D (25(OH)D) and total IgE, with some studies showing positive, negative, or non-linear relationships (3,4). Studies have shown mixed results among the pediatric population (5,6). However, no studies have examined the association between early childhood vitamin D status and age 6 years IgE among children with a history of severe bronchiolitis. Bronchiolitis is the most common cause of infant hospitalization in the United States and is associated with recurrent wheezing and allergic sensitization (7). Given the inconsistency of prior studies in the scientific literature and the specific lack of studies on infants with severe bronchiolitis, our objective was to investigate the association between serum 25(OH)D level at age 3 years and subsequent plasma IgE levels at age 6 years among children with a history of severe bronchiolitis in infancy.
We analyzed data from a prospective cohort of 921 infants hospitalized with bronchiolitis across 17 sites in the United States (8). Children were followed longitudinally, and 25(OH)D and IgE testing were conducted at ages 3 and 6 years, respectively. To adjust for seasonal variations in serum 25(OH)D levels, we used a sinusoidal model to calculate de-seasonalized serum 25(OH)D levels (8). We analyzed serum 25(OH)D level as a binary (≥20ng/ml vs. <20ng/ml) and an ordinal (quintiles) variable. Serum-specific IgE (sIgE) was measured using two different assays at the Phadia Immunology Reference Laboratory in infancy, 3- and 6-year-old. Positive sIgE was defined as sIgE ≥0.35 kU/L or ISAC ≥0.3 ISAC Standardized Units (9). Since we investigated IgE sensitization at age 6 years, we excluded participants with any positive IgE at infancy or age 3 years for total and allergen-specific IgE. We used the Wilcoxon–Mann–Whitney test or the Chi-squared test, as appropriate, to examine the inter-group participant characteristics. We used multivariable logistic regression modeling to assess the association between age 3-year serum 25(OH)D level and age 6-year serum elevated total and sIgE. The models were further adjusted for race/ethnicity, annual household income, secondhand smoke exposure, and family history of atopy. A two-sided p<0.05 was considered statistically significant. All analyses were performed using Stata 15.1 (Stata Corp, College Station, TX, USA). More information about the methods and results is available at https://doi.org/10.5281/zenodo.11194065.
Restricting the cohort to children who have age 3-year serum 25(OH)D and age 6-year IgE testing results yielded an analytical cohort of 280 participants. There were no significant differences in patient characteristics between the analytical cohort (280 participants) and the non-analytical cohort (641 participants). The median serum 25(OH)D level in the analytical cohort was 26.6 ng/mL, with a range of 7.8 to 52.7 ng/mL. There were no significant differences among quintiles in the proportion of females, secondhand smoke exposure, and family history of atopy. Participants in the lowest quintile of serum 25(OH)D were more likely to be non-Hispanic Black, participants in the second quintile were more likely to be Hispanic, and participants in the top three quintiles were more likely to be White. Participants in the higher two 25(OH)D quintiles were more likely to live in households making more than $80,000 per year.
The percentage of elevated/positive serum IgE at 6 years was 6% for total IgE, 22% for food sIgE, 32% for aeroallergen sIgE, 26% for indoor aeroallergen sIgE and 19% outdoor aeroallergen sIgE. The adjusted analysis showed a statistically significant association between quintiles of serum 25(OH)D and aeroallergen and indoor aeroallergen sIgE (Table 1). Compared to participants in the third quintile (Q3), those in the lowest quintile (Q1) had higher odds of developing aeroallergen (aOR: 3.9, 95%CI: 1.5-10.1, p=0.01) and indoor aeroallergen sIgE (aOR: 3.1, 95%CI: 1.2-8.4, p=0.02). There was no association between quintile of serum 25(OH)D and total and the other allergen-specific serum IgE.
Table 1.
Association between quintiles of early childhood serum 25(OH)D and age 6-year IgE outcomes.
| Quintiles of serum 25(OH)D, median (IQR) |
Unadjusted OR (95% CI) |
P-value | Adjusted OR (95% CI) |
P-value |
|---|---|---|---|---|
| Elevated Total IgE, n=253 * | ||||
|
Q1 serum 25(OH)D, n= 51 18.9 (16.5-20.2) ng/mL |
0.5 (0.08-2.7) | 0.40 | 0.5 (0.08-3.4) | 0.48 |
|
Q2 serum 25(OH)D, n = 51 23.7 (22.6-24.5) ng/mL |
0.2 (0.02-2.1) | 0.20 | 0.2 (0.02-1.9) | 0.16 |
|
Q3 serum 25(OH)D, n = 50 27.3 (26.8-27.9) ng/mL |
Reference | |||
|
Q4 serum 25(OH)D, n = 51 30.2 (29.3-31.4) ng/mL |
0.7 (0.2-3.4) | 0.68 | 0.7 (0.1-3.5) | 0.66 |
|
Q5 serum 25(OH)D, n = 50 36.1 (34.3-39.8) ng/mL |
1.3 (0.3-5.1) | 0.73 | 0.7 (0.1-3.2) | 0.63 |
| Food sIgE, n=206 * | ||||
|
Q1 serum 25(OH)D n = 42 19.1 (16.4-19.8) ng/mL |
1.6 (0.6-4.3) | 0.36 | 1.5 (0.5-4.2) | 0.48 |
|
Q2 serum 25(OH)D n =41 23.6 (22.5-24.4) ng/mL |
0.7 (0.2-2.2) | 0.58 | 0.7 (0.2-2.2) | 0.53 |
|
Q3 serum 25(OH)D n =41 27.2 (26.5-28.0) ng/mL |
Reference | |||
|
Q4 serum 25(OH)D n =41 30.2 (29.0-31.1) ng/mL |
0.6 (0.2-1.9) | 0.39 | 0.6 (0.2-2.1) | 0.45 |
|
Q5 serum 25(OH)D n =41 35.8 (33.9-39.7) ng/mL |
1.3 (0.5-3.6) | 0.61 | 2.0 (0.7-5.8) | 0.23 |
| Aeroallergen sIgE, n = 241 * | ||||
|
Q1 serum 25(OH)D n=49 18.1 (16.5-19.1) |
2.9 (1.2-6.8) | 0.02 | 3.9 (1.5-10.1) | 0.01 |
|
Q2 serum 25(OH)D n=48 22.9 (21.7-24.0) |
1.2 (0.5-3.0) | 0.65 | 1.3 (0.5-3.5) | 0.57 |
|
Q3 serum 25(OH)D n=48 26.8 (25.8-27.5) |
Reference | |||
|
Q4 serum 25(OH)D n=48 29.9 (29.1-31.0) |
1.0 (0.4-2.5) | 0.99 | 1.0 (0.4-2.7) | 0.97 |
|
Q5 serum 25(OH)D n=48 35.1 (33.5-38.7) |
1.4 (0.6-3.3) | 0.50 | 1.9 (0.7-5.1) | 0.19 |
| Indoor aeroallergen, sIgE n=247 * | ||||
|
Q1 serum 25(OH)D n=50 18.2 (16.7-19.1) |
2.5 (1.0-6.0) | 0.05 | 3.1 (1.2-8.4) | 0.02 |
|
Q2 serum 25(OH)D n=49 23.0 (21.7-24.0) |
1.3 (0.5-3.4) | 0.59 | 1.4 (0.5-3.9) | 0.50 |
|
Q3 serum 25(OH)D n=50 27.0 (25.8-27.7) |
Reference | |||
|
Q4 serum 25(OH)D n=49 30.0 (29.2-31.3) |
0.6 (0.2-1.9) | 0.45 | 0.7 (0.2-2.1) | 0.52 |
|
Q5 serum 25(OH)D n=49 35.2 (33.9-39.0) |
1.7 (0.7-4.4) | 0.22 | 2.2 (0.8-6.2) | 0.11 |
| Outdoor aeroallergen, sIgE n=280 * | ||||
|
Q1 serum 25(OH)D n=56 18.5 (16.1-19.3) |
1.9 (0.8-4.8) | 0.17 | 1.7 (0.6-4.6) | 0.33 |
|
Q2 serum 25(OH)D n=56 22.8 (21.6-23.9) |
0.9 (0.3-2.4) | 0.79 | 0.5 (0.1-1.5) | 0.21 |
|
Q3 serum 25(OH)D n=56 26.6 (25.8-27.2) |
Reference | |||
|
Q4 serum 25(OH)D n=56 29.6 (28.8-30.6) |
1.4 (0.5-3.7) | 0.47 | 1.3 (0.5-3.5) | 0.62 |
|
Q5 serum 25(OH)D n=56 35.2 (33.5-39.7) |
1.0 (0.4-2.7) | 0.99 | 1.0 (0.3-3.0) | 0.99 |
Abbreviations: OR, Odds Ratio; 25(OH)D, 25-hydroxyvitamin D; Q1, first (lowest) quintile of serum 25(OH)D; Q2, second quintile of serum 25(OH)D; Q3, third quintile of serum 25(OH)D; Q4, fourth quintile of serum 25(OH)D; Q5, fifth (highest) quintile of serum 25(OH)D. Bold denotes p < 0.05.
Each group has a different number of participants after excluding participants already sensitized at infancy or 3 years.
The adjusted analysis using categorical 25(OH)D showed a significant association between serum 25(OH)D and aeroallergen sIgE. Participants with low serum 25(OH)D levels (<20ng/ml) were more likely to develop aeroallergen sIgE (aOR:2.4, 95%CI: 1.1-5.0, p=0.03). There were no statistically significant associations between serum 25(OH)D levels and total and the other sIgE. The results for serum 25(OH)D <20ng/ml persisted when the analysis was repeated using three categories of serum 25(OH)D.
The study has some limitations. First, only a portion of the original cohort was analyzed, causing the study to be underpowered to detect significant associations for some outcomes, such as elevated total IgE. Second, vitamin D levels were measured only once, potentially missing long-term trends. Third, we did not control for geographic factors and individual allergen exposure. Finally, the lack of participants with very low or high vitamin D levels limits the applicability of the findings to the broader population.
Our study showed that among children with severe bronchiolitis in infancy, low serum 25(OH)D levels at age 3 years were associated with increased aeroallergen-specific IgE at age 6 years. Our observations should facilitate further research into the role of vitamin D during early infancy in allergic sensitization and the development of asthma and other atopic diseases.
Key messages.
Low serum 25(OH)D levels in early childhood were associated with aeroallergen-specific IgE.
Serum 25(OH)D levels were not associated with total, food-specific, or outdoor-aeroallergen-specific IgE.
Acknowledgments
We thank the families for their participation in the study and the MARC-35 study staff across all sites.
Funding Source
The study was supported by NIH grants U01 AI087881, R01 AI114552, R01 AI127507, and UH3 OD023253. Dr. Mehta was supported by NIH grant T32 AI007306. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations/Acronyms:
- IgE
immunoglobulin E
- 25(OH)D
25hydroxyvitmain D
- sIgE
specific IgE
- IQR
interquartile range
- Q1
first (lowest) quintile of serum 25(OH)D
- Q2
second quintile of serum 25(OH)D
- Q3
third quintile of serum 25(OH)D
- Q4
fourth quintile of serum 25(OH)D
- Q5
fifth (highest) quintile of serum 25(OH)D
- OR
Odds Ratio
- aOR
adjusted odds ratio
Footnotes
Conflicts of Interest
The authors have no conflicts of interest to disclose.
IRB Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of the Mass General Brigham (protocol code 2009P002310 approved 9 February 2010; protocol code 2014P001771 approved 29 September 2014; and protocol code 2016P001880 approved 27 September 2016). All participating sites obtained local IRB approval. Written informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The datasets analyzed during the current study are not publicly available due to privacy or ethical restrictions but are available from the corresponding author upon reasonable request.
References
- 1.Mirzakhani H, Al-Garawi A, Weiss ST, Litonjua AA. Vitamin D and the development of allergic disease: how important is it? Clin Exp Allergy. 2015. Jan;45(1):114–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Oettgen HC, Geha RS. IgE in asthma and atopy: cellular and molecular connections. J Clin Invest. 1999. Oct 1;104(7):829–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hyppönen E, Berry DJ, Wjst M, Power C. Serum 25-hydroxyvitamin D and IgE - a significant but nonlinear relationship. Allergy. 2009. Apr;64(4):613–20. [DOI] [PubMed] [Google Scholar]
- 4.Jacobs ZD, Dai H, Feldt M, Dinakar C. Relationship between Serum 25-Hydroxyvitamin D and IgE: National Health and Nutrition Examination Survey 2-Year Results. Journal of Allergy and Clinical Immunology. 2011. Feb 1;127(2):AB151. [Google Scholar]
- 5.Rosser FJ, Han YY, Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, et al. Effect of vitamin D supplementation on total and allergen-specific IgE in children with asthma and low vitamin D levels. Journal of Allergy and Clinical Immunology. 2022. Jan 1;149(1):440–444.e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rothers J, Wright AL, Stern DA, Halonen M, Camargo CA. Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona. J Allergy Clin Immunol. 2011. Nov;128(5):1093–1099.e1-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Schauer U, Hoffjan S, Bittscheidt J, Köchling A, Hemmis S, Bongartz S, et al. RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life. European Respiratory Journal. 2002. Nov 1;20(5):1277–83. [DOI] [PubMed] [Google Scholar]
- 8.Doumat G, Mehta GD, Mansbach JM, Hasegawa K, Camargo CA. Association between Early Childhood Vitamin D Status and Age 6-Year Lung Function among Children with a History of Severe Bronchiolitis in Infancy. Nutrients. 2023. May 19;15(10):2379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Westwood M, Ramaekers B, Lang S, Armstrong N, Noake C, de Kock S, et al. Background and definition of the decision problem(s). In: ImmunoCAP® ISAC and Microtest for multiplex allergen testing in people with difficult to manage allergic disease: a systematic review and cost analysis [Internet]. NIHR Journals Library; 2016. [cited 2023 Aug 7]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK384702/ [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets analyzed during the current study are not publicly available due to privacy or ethical restrictions but are available from the corresponding author upon reasonable request.