The interplay between serum Interleukin-33 and vitamin D3 in childhood asthma: Diagnostic utility and severity predictors in an Iraqi community
Article Sidebar
Main Article Content
Abstract
Background: The epithelial alarmin Interleukin-33 (IL-33) and the immunomodulator vitamin D3 are implicated in asthma pathogenesis, yet their combined clinical utility and interplay in pediatric populations remain underexplored.
Objectives: This study aimed to investigate the diagnostic performance and predictive value of serum IL-33 and vitamin D3 in childhood asthma, and their association with disease severity.
Materials and methods: A case-control study was conducted involving 120 children (60 asthmatics and 60 age- and gender-matched healthy controls) in Karbala, Iraq. Serum levels of IL-33 and 25-hydroxyvitamin D3 were quantified using enzyme-linked immunosorbent assay (ELISA). Diagnostic utility was evaluated via Receiver Operating Characteristic (ROC) curve analysis, and independent predictors were identified using multivariate binary logistic regression.
Results: Asthmatic children exhibited significantly elevated IL-33 (395.56±218.75 vs 159.95±55.32 ng/L, p<0.001) and lower vitamin D3 (17.01±7.38 vs 28.20±10.60 ng/mL, p<0.001) than controls. A strong inverse correlation was observed between IL-33 and Vitamin D3 (r = -0.614, p<0.001), both of which showed a dose-dependent relationship with asthma severity. ROC analysis revealed exceptional diagnostic accuracy for IL-33 (AUC=0.933). Multivariate regression identified body mass index (aOR = 1.528, p=0.014) and IL-33 (aOR=1.015 per 1 ng/L increase, p=0.020) as significant independent predictors of asthma, yielding an overall model accuracy of 95.8%. Notably, male asthmatics exhibited significantly lower vitamin D3 levels than females (p<0.001).
Conclusion: The inverse relationship between elevated IL-33 and vitamin D3 deficiency underscores their synergistic role in asthma exacerbation. IL-33 serves as a highly accurate diagnostic biomarker, highlighting the potential for targeted anti-alarmin therapies and gender-stratified nutritional interventions in pediatric asthma management.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Personal views expressed by the contributors in their articles are not necessarily those of the Journal of Associated Medical Sciences, Faculty of Associated Medical Sciences, Chiang Mai University.
References
Lu W, Rylance S, Schotte K, Aarsand R, Lebedeva E, Bill W, et al. Tobacco and asthma: presenting the World Health Organization (WHO) tobacco knowledge summary. Subst Abuse Treat Prev Policy. 2025; 20(1): 34. doi.org/10.1186/s13011-025-00632-6.
Taherian MR, Fatemian F, Halimi A, Soleimani Y, Jorjani G, Nozari P, et al. Prevalence of asthma among children and adolescents in WHO’s Eastern Mediterranean Region: a meta-analysis of over 0.5 million participants. BMC Public Health. 2024; 24(1): 2148. doi.org/10.1186/s12889-024-19614-5.
Mirzaei M, Karimi M, Beheshti S, Mohammadi M. Prevalence of asthma among Middle Eastern children: a systematic review. Med J Islam Repub Iran. 2017; 31: 9. doi.org/10.18869/mjiri.31.9.
Duchesne M, Okoye I, Lacy P. Epithelial cell alarmin cytokines: frontline mediators of the asthma inflammatory response. Front Immunol. 2022; 13:975914. doi.org/10.3389/fimmu.2022.975914.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005; 23(5): 479-90. doi.org/10.1016/j.immuni.2005.09.015.
Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014; 31: 31-7. doi.org/10.1016/j.coi.2014.09.004.
Wang Y, Wang L, Hua S. Interleukin-33 in children with asthma: a systematic review and meta-analysis. Allergol Immunopathol (Madr). 2017; 45(4): 387-92. doi.org/10.1016/j.aller.2016.12.003.
Litonjua AA. Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol. 2009; 9(3): 202-7. doi.org/10.1097/ACI.0b013e32832b36cd.
Al-Ghamdi MA, Lanham-New SA, Kahn JA. Differences in vitamin D status and calcium metabolism in Saudi Arabian boys and girls aged 6 to 18 years: effects of age, gender, extent of veiling and physical activity with concomitant implications for bone health. Public Health Nutr. 2012; 15(10):1845-53. doi.org/10.1017/S136898001100344X.
Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA, Kerley CP, et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respiratory Medicine. 2017; 5(11): 881-90. doi.org/10.1016/S2213-2600(17)30306-5.
Pfeffer PE, Chen YH, Woszczek G, Matthews NC, Chevretton E, Gupta A, et al. Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33. J Allergy Clin Immunol. 2015; 135(3): 824-7.e3. doi.org/10.1016/j.jaci.2014.09.044.
El Abd A, Dasari H, Dodin P, Trottier H, Ducharme FM. Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies. Respiratory Research. 2024; 25(1): 344. doi.org/10.1186/s12931-024-02947-6.
Al-Tuama NMJ, Almusawi ZM, Abood HAAN, Abutiheen A, Al-tuama KMJ. The association between vitamin D deficiency and childhood asthma. J Prev Diagn Treat Strateg Med. 2022; 1(2): 115-20. doi.org/10.4103/jpdtsm.jpdtsm_31_22.
AL-Hasnawi ATN, AL-Hasnawi SMJ. Role of interleukin 25 and interleukin 33 as immunological markers in pediatric asthma. Eurasia J Biosci. 2020; 14: 4625-30. www.ejobios.org/article/role-of-interleukin-25-and-interleukin-33-as-immunological-markers-in-pediatric-asthma-7975.
Al-Sharifi ZAR, Al-Ammar HAJ, Mahmood HG, Turki KM, Al-Karkhi II. Lack of vitamin D in Iraqi children with asthma. Biomed Pharmacol J. 2017; 10(1): 89-93. doi.org/10.13005/bpj/1085.
Hoque F, Nayak R. Focused overview of the 2024 Global Initiative for Asthma guidelines. APIK J Int Med. 2025; 13(1): 4-12. doi.org/10.4103/ajim.ajim_45_24.
Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008; 122(2): 398-417. doi.org/10.1542/peds.2007-1894.
Deng X, Ma J, Yuan Y, Zhang Z, Niu W. Association between overweight or obesity and the risk for childhood asthma and wheeze: an updated meta-analysis on 18 articles and 73 252 children. Pediatr Obes. 2019; 14(9): e12532. doi.org/10.1111/ijpo.12532.
Azizpour Y, Delpisheh A, Montazeri Z, Sayehmiri K, Darabi B. Effect of childhood BMI on asthma: a systematic review and meta-analysis of case-control studies. BMC Pediatr. 2018; 18(1): 143. doi.org/10.1186/s12887-018-1117-0.
Reyes-Angel J, Kaviany P, Rastogi D, Forno E. Obesityrelated asthma in children and adolescents. Lancet Child Adolesc Health. 2022; 6(10): 713-24. doi.org/10.1016/S2352-4642(22)00185-7.
He Z, Wu H, Zhang S, Lin Y, Li R, Xie L, et al. The association between secondhand smoke and childhood asthma: a systematic review and meta-analysis. Pediatr Pulmonol. 2020; 55(10): 2518-31. doi.org/10.1002/ppul.24961.
Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011; 242(1): 10-30. doi.org/10.1111/j.1600-065X.2011.01008.x.
Bjerg A, Hedman L, Perzanowski MS, Platts-Mills T, Lundbäck B, Rönmark E. Family history of asthma and atopy: in-depth analyses of the impact on asthma and wheeze in 7-to 8-year-old children. Pediatrics. 2007; 120(4): 741-8. doi.org/10.1542/peds.2006-3112.
Grant TL, Wood RA. The influence of urban exposures and residence on childhood asthma. Pediatr Allergy Immunol. 2022; 33(5): e13784. doi.org/10.1111/pai.13784.
Aligne CA, Auinger P, Byrd RS, Weitzman M. Risk factors for pediatric asthma: contributions of poverty, race, and urban residence. Am J Respir Crit Care Med. 2000; 162(3 Pt 1): 873-7. doi.org/10.1164/ajrccm.162.3.9908085.
Shaban SA, Brakhas SA, Ad’hiah AH. Interleukin-33 is up-regulated in serum of asthma patients. AIP Conf Proc. 2022; 2437(1): 020015. doi.org/10.1063/5.0092770.
Bahrami Mahneh S, Movahedi M, Aryan Z, Bahar MA, Rezaei A, Sadr M, et al. Serum IL-33 is elevated in children with asthma and is associated with disease severity. Int Arch Allergy Immunol. 2016; 168(3): 193-6. doi.org/10.1159/000442385.
Yang Q, Zheng Y, Dong J, Xu Q, Li S, Li A, et al. Serum interleukin-33 combined with FEF75% z-score and FeNO improves the diagnostic accuracy of asthma in children. J Pediatr (Rio J). 2024; 100(1): 81-7. doi.org/10.1016/j.jped.2023.05.008.
Bener A, Ehlayel MS, Tulic MK, Hamid Q. Vitamin D deficiency as a strong predictor of asthma in children. Int Arch Allergy Immunol. 2012; 157(2): 168-75. doi.org/10.1159/000327389.
Esfandiar N, Alaei F, Fallah S, Babaie D, Sedghi N. Vitamin D deficiency and its impact on asthma severity in asthmatic children. Ital J Pediatr. 2016; 42(1): 108. doi.org/10.1186/s13052-016-0318-z.
Rai V, Agrawal DK. Immunomodulation of IL-33 and IL-37 with vitamin D in the neointima of coronary artery: a comparative study between balloon angioplasty and stent in hyperlipidemic microswine. Int J Mol Sci. 2021; 22(16): 8824. doi.org/10.3390/ijms22168824.
Bonanno A, Gangemi S, La Grutta S, Malizia V, Riccobono L, Colombo P, et al. 25-hydroxyvitamin D, IL-31, and IL-33 in children with allergic disease of the airways. Mediators Inflamm. 2014; 2014: 520241. doi.org/10.1155/2014/520241.
Fang C, Jiang Z, Su X, Fan W. The association between body mass index and asthma in children: a cross-sectional study from NHANES 1999 to 2020. Sci Rep. 2025; 15(1): 9448. doi.org/10.1038/s41598-025-89476-y.
Li RJ, Wen YX. Association of body mass index with asthma occurrence and persistence in adolescents: a retrospective study of NHANES (2011–2018). Heliyon. 2023; 9(9): e19623. doi.org/10.1016/j.heliyon.2023.e19623.
Li CJ, Chang LS, Guo MMH, Wang LJ, Kuo HC. Sex differences in vitamin D and behavioral profiles among children with allergic diseases. Food Science & Nutrition. 2023; 11(9): 5492-500. doi.org/10.1002/fsn3.3504.
Hollams E, Hart P, Holt B, Serralha M, Parsons F, De Klerk N, et al. Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study. Eur Respir J. 2011; 38(6): 1320-7. doi.org/10.1183/09031936.00032911.
Pfeffer PE, Hawrylowicz CM. Vitamin D in asthma: mechanisms of action and considerations for clinical trials. Chest. 2018; 153(5): 1229-39. doi. org/10.1016/j.chest.2017.09.005.
Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD, Ross K, et al. Effect of vitamin D3 supplementation on severe asthma exacerbations in children with asthma and low vitamin D levels: the VDKA randomized clinical trial. JAMA. 2020; 324(8): 752-60. doi.org/10.1001/jama.2020.12384.
