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Zare Mahmoudabadi R, Adel Z, Montazer F, Javid A, Yousefzadegan S. Association of Vitamin D Deficiency with COVID-19 Susceptibility and Severity in Hospitalized Children: A Case–Control Study. J Nutr Food Secur. 2026; 11 (4) :633-639
URL: http://jnfs.ssu.ac.ir/article-1-1504-en.html
URL: http://jnfs.ssu.ac.ir/article-1-1504-en.html
Dermatopathologist, Associate Professor of Pathology, Firoozabadi Clinical Research and Development unit(FACRDU), School of Medicine, Iran university of Medical Sciences, Tehran, Iran
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Association of Vitamin D Deficiency with COVID-19 Susceptibility and Severity in Hospitalized Children: A Case–Control Study
Ramin Zare Mahmoudabadi; MD ², Zahra Adel; MD student ¹, Fatemeh Montazer; MD 2,
Asma Javid; MD 3 & Sedigheh Yousefzadegan; MD *2
Ramin Zare Mahmoudabadi; MD ², Zahra Adel; MD student ¹, Fatemeh Montazer; MD 2,
Asma Javid; MD 3 & Sedigheh Yousefzadegan; MD *2
1 School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran; 2 Dermatopathologist, Associate Professor of Pathology, Firoozabadi Clinical Research and Development unit(FACRDU), School of Medicine, Iran university of Medical Sciences, Tehran, Iran; 3 Department of Pediatrics, Hazrat-e-Rasoul Akram General Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| ARTICLE INFO | ABSTRACT | |
| ORIGINAL ARTICLE | Background: Vitamin D exerts immunomodulatory and anti-inflammatory effects that may influence outcomes of viral respiratory infections, including COVID-19. However, pediatric data remain limited. This study examined the relationship between serum 25-hydroxy-vitamin D [25(OH)D] levels and susceptibility to and severity of COVID-19 among hospitalized children in Iran. Methods: In this retrospective case–control study, 63 children (0–16 years) with RT-PCR-confirmed COVID-19 admitted to Firouzabadi Hospital, Tehran (2019–2021) were compared with 68 age- and sex-matched historical controls hospitalized two years before the pandemic for non-respiratory conditions. Moreover, historical controls were used to avoid pandemic-era confounding due to widespread supplementation and asymptomatic infection. Demographic, clinical, and laboratory data including 25(OH)D, C-reactive protein (CRP), lymphocyte count, and need for pediatric intensive-care-unit (PICU) admission-were also extracted. Statistical analysis employed non-parametric tests with P-value < 0.05 as significant. Results: Vitamin D deficiency (<20 ng/ml) occurred in 61% of cases versus 14% of controls (P<0.001). Mean 25(OH)D levels were lower in cases (18.6±9.6 ng/ml) than controls (43.4±25.3 ng/ml, P<0.001). PICU-admitted patients showed lower vitamin D than non-PICU patients (13.8±6.4 vs 19.7±9.9 ng/ml, P=0.035). Conclusions: Vitamin D deficiency was strongly associated with COVID-19 susceptibility but not with in-hospital severity. Therefore, routine screening and correction of vitamin D deficiency may be a cost-effective preventive strategy for pediatric populations. | |
| Article history: Received: 29 Oct 2025 Revised: 7 Jan 2026 Accepted: 7 Jan 2026 |
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| *Corresponding author: Dr.yousefzadegan@gmail.com Niyayesh St, Sattar Khan Street, Tehran Province, Tehran, Iran Postal code: 14456 13131 Tel: +98 021-64352000 |
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Keywords: COVID-19; Vitamin D deficiency; Pediatric; Hospitalization; Iran. |
Introduction
Although COVID-19 is usually less severe in children than in adults, its clinical presentation in the pediatric population is variable. (Götzinger et al., 2020, Hoang et al., 2020). Most affected children have mild symptoms, whereas others develop pneumonia, multisystem inflammatory syndrome, or symptoms that continue after the acute phase of infection (Feldstein et al., 2020, Ludvigsson, 2020). The reasons for these differences are not fully understood, and patients’ nutritional status, particularly vitamin D status, may be one of the factors involved.
Vitamin D is best known for its role in bone metabolism, but it also participates in immune regulation. Its reported effects include regulation of antimicrobial peptide production, cytokine activity, and the renin–angiotensin system (Brenner et al., 2020, Charoenngam and Holick, 2020, Pike and Meyer, 2010). Low serum vitamin D concentrations have also been associated with influenza, respiratory syncytial virus infection, and bacterial pneumonia, although these findings do not prove a definite relationship (Aranow, 2011, Beard et al., 2011, Martineau et al., 2017). In Iran, hypovitaminosis D is highly prevalent among children and adolescents. In the national CASPIAN-V study, 71.1% of 7–18-year-olds had serum 25(OH)D levels below 30 ng/mL (Rastad et al., 2021). In this context, vitamin D status could be relevant to occurrence and clinical course of COVID-19 in Iranian children.
Several adult studies have examined this possibility, with inconsistent findings about the relationship between vitamin D deficiency and COVID-19 risk or severity (Hastie et al., 2020, Kaufman et al., 2020, Meltzer et al., 2020, Merzon et al., 2020, Namayandeh, 2020), and it seems to be fewer data available for children. Interpretation is also difficult because serum vitamin D concentrations vary with age, season, body composition, supplement use, and acute illness. Changes in daily activity, sun exposure, diet, and supplementation during the pandemic may have affected vitamin D measurements. (Gombart et al., 2020, Sassi et al., 2018, Zittermann et al., 2016).
In this hospital-based case–control study, we compared vitamin D status in children with COVID-19 with that of a historical control group from the pre-pandemic period to examine whether vitamin D status was associated with susceptibility to COVID-19 and we also assessed the association between vitamin D status and disease severity between infected children.
Materials and Methods
Study design and participants
This retrospective case–control study was
conducted at Firouzabadi Hospital, Tehran. The case group consisted of 63 children aged 0–16 years hospitalized with RT-PCR-confirmed COVID-19 between 2019 and 2021. The control group consisted of 68 children hospitalized for non-respiratory diseases two years earlier, between 2017 and 2018.
The inclusion criteria for the case group were an age of 0–16 years and a confirmed diagnosis of COVID-19 based on a positive RT-PCR test. For the control group, the inclusion criterion was hospitalization for an acute non-respiratory condition. Children with chronic renal, hepatic, endocrine, or metabolic bone diseases were excluded from the study.
Rationale for historical controls
Pandemic-era behavioral and nutritional changes, including routine vitamin D supplementation and altered outdoor exposure, could distort comparisons between contemporaneous infected and non-infected children. Using pre-pandemic data minimized these confounders and reflected true baseline vitamin D status in the community. Thus, the historical control design represents the key methodological strength and novelty of this investigation.
Data collection
Electronic records provided demographic information (age, sex, birth weight, gestational age), laboratory findings (25(OH)D, CRP, lymphocyte count), and clinical outcomes (PICU admission, mortality, hospital stay duration). Moreover, serum 25(OH)D was measured by chemiluminescent immunoassay. According to the current guidelines, deficiency was defined as < 20 ng/ml, insufficiency, 20–29 ng/ml, and sufficiency as ≥ 30 ng/ml.
Ethical considerations
The study was approved by the Ethics Committee of Iran University of Medical Sciences (IR.IUMS.FMD.REC.1400.301). Written informed consent was obtained from caregivers of the participants. In addition, children identified as deficient received vitamin D supplementation after study completion.
Data analysis
Data were analyzed with SPSS v26 (IBM Corp., Armonk, NY). Accordingly, normality was assessed by Shapiro-Wilk test. For between-group comparisons, the researchers used Mann-Whitney U or Kruskal-Wallis tests for continuous variables. Categorical variables were compared with χ² or Fisher's exact test. P-value<0.05 was considered statistically significant.
Results
Participants characteristics
Age and sex distributions were similar between the two groups (Table 1). The mean age was 79.6±63.9 months among cases and 76.7±64.6 months among controls (P=0.80). Similarly, the male-to-female ratios were comparable between the groups, with males comprising 54% of participants in each group (P=0.97).
Vitamin D status
Vitamin D deficiency was observed in 61 % of the cases compared with 14 % of the controls
(P<0.001). Furthermore, mean 25(OH)D levels were 18.6±9.6 ng/ml vs 43.4±25.3 ng/ml respectively (P<0.001, Table 2).
Disease severity and laboratory parameters
Among the 63 patients with COVID-19, 12 (19%) required PICU care. PICU-admitted patients had significantly lower 25(OH)D (13.8±6.4 ng/ml) than non-PICU patients (19.7±9.9 ng/ml, P=0.035). In contrast, CRP and lymphocyte counts showed no significant correlation with severity (Table 3).
Vitamin D is best known for its role in bone metabolism, but it also participates in immune regulation. Its reported effects include regulation of antimicrobial peptide production, cytokine activity, and the renin–angiotensin system (Brenner et al., 2020, Charoenngam and Holick, 2020, Pike and Meyer, 2010). Low serum vitamin D concentrations have also been associated with influenza, respiratory syncytial virus infection, and bacterial pneumonia, although these findings do not prove a definite relationship (Aranow, 2011, Beard et al., 2011, Martineau et al., 2017). In Iran, hypovitaminosis D is highly prevalent among children and adolescents. In the national CASPIAN-V study, 71.1% of 7–18-year-olds had serum 25(OH)D levels below 30 ng/mL (Rastad et al., 2021). In this context, vitamin D status could be relevant to occurrence and clinical course of COVID-19 in Iranian children.
Several adult studies have examined this possibility, with inconsistent findings about the relationship between vitamin D deficiency and COVID-19 risk or severity (Hastie et al., 2020, Kaufman et al., 2020, Meltzer et al., 2020, Merzon et al., 2020, Namayandeh, 2020), and it seems to be fewer data available for children. Interpretation is also difficult because serum vitamin D concentrations vary with age, season, body composition, supplement use, and acute illness. Changes in daily activity, sun exposure, diet, and supplementation during the pandemic may have affected vitamin D measurements. (Gombart et al., 2020, Sassi et al., 2018, Zittermann et al., 2016).
In this hospital-based case–control study, we compared vitamin D status in children with COVID-19 with that of a historical control group from the pre-pandemic period to examine whether vitamin D status was associated with susceptibility to COVID-19 and we also assessed the association between vitamin D status and disease severity between infected children.
Materials and Methods
Study design and participants
This retrospective case–control study was
conducted at Firouzabadi Hospital, Tehran. The case group consisted of 63 children aged 0–16 years hospitalized with RT-PCR-confirmed COVID-19 between 2019 and 2021. The control group consisted of 68 children hospitalized for non-respiratory diseases two years earlier, between 2017 and 2018.
The inclusion criteria for the case group were an age of 0–16 years and a confirmed diagnosis of COVID-19 based on a positive RT-PCR test. For the control group, the inclusion criterion was hospitalization for an acute non-respiratory condition. Children with chronic renal, hepatic, endocrine, or metabolic bone diseases were excluded from the study.
Rationale for historical controls
Pandemic-era behavioral and nutritional changes, including routine vitamin D supplementation and altered outdoor exposure, could distort comparisons between contemporaneous infected and non-infected children. Using pre-pandemic data minimized these confounders and reflected true baseline vitamin D status in the community. Thus, the historical control design represents the key methodological strength and novelty of this investigation.
Data collection
Electronic records provided demographic information (age, sex, birth weight, gestational age), laboratory findings (25(OH)D, CRP, lymphocyte count), and clinical outcomes (PICU admission, mortality, hospital stay duration). Moreover, serum 25(OH)D was measured by chemiluminescent immunoassay. According to the current guidelines, deficiency was defined as < 20 ng/ml, insufficiency, 20–29 ng/ml, and sufficiency as ≥ 30 ng/ml.
Ethical considerations
The study was approved by the Ethics Committee of Iran University of Medical Sciences (IR.IUMS.FMD.REC.1400.301). Written informed consent was obtained from caregivers of the participants. In addition, children identified as deficient received vitamin D supplementation after study completion.
Data analysis
Data were analyzed with SPSS v26 (IBM Corp., Armonk, NY). Accordingly, normality was assessed by Shapiro-Wilk test. For between-group comparisons, the researchers used Mann-Whitney U or Kruskal-Wallis tests for continuous variables. Categorical variables were compared with χ² or Fisher's exact test. P-value<0.05 was considered statistically significant.
Results
Participants characteristics
Age and sex distributions were similar between the two groups (Table 1). The mean age was 79.6±63.9 months among cases and 76.7±64.6 months among controls (P=0.80). Similarly, the male-to-female ratios were comparable between the groups, with males comprising 54% of participants in each group (P=0.97).
Vitamin D status
Vitamin D deficiency was observed in 61 % of the cases compared with 14 % of the controls
(P<0.001). Furthermore, mean 25(OH)D levels were 18.6±9.6 ng/ml vs 43.4±25.3 ng/ml respectively (P<0.001, Table 2).
Disease severity and laboratory parameters
Among the 63 patients with COVID-19, 12 (19%) required PICU care. PICU-admitted patients had significantly lower 25(OH)D (13.8±6.4 ng/ml) than non-PICU patients (19.7±9.9 ng/ml, P=0.035). In contrast, CRP and lymphocyte counts showed no significant correlation with severity (Table 3).
| Table 1. Demographic and baseline characteristics of the study participants. | |||
| Variables | Cases (n=63) | Controls (n=68) | P-value |
| Age (months) | 79.6±63.9 | 76.7±64.6 | 0.802 |
| Male | 34 (54) | 37 (54) | 0.974 |
| Values shown as mean±SD or n (%). Statistical comparisons between groups performed using Mann-Whitney U test for continuous variables and χ² test for categorical variables. | |||
| Table 2. Vitamin D status and categorization in COVID-19 cases and controls. | |||
| Variables | Cases (n=63) | Controls (n=68) | P-value |
| 25(OH)D (ng/ml) | 18.6±9.6a | 43.4±25.3 | < 0.001 |
| Deficiency | 38 (61)b | 10 (14) | < 0.001 |
| Insufficiency | 20 (32) | 18 (26) | 0.589 |
| Sufficiency | 5 (7) | 40 (58) | < 0.001 |
| a: Mean±SD; b: n (%) 25(OH)D status categorized according to Endocrine Society guidelines. Deficiency defined as <20 ng/ml, insufficiency 20–29 ng/ml, sufficiency ≥30 ng/ml; Statistical comparisons between groups performed using Mann-Whitney U test for continuous variables and χ² test for categorical variables. | |||
| Table 3. Laboratory and clinical parameters stratified by disease severity (PICU vs non-PICU admission). | |||
| Variables | PICU (n=12) | Non-PICU (n=51) | P-value |
| 25(OH)D (ng/ml) | 13.8±6.4 | 19.7±9.9 | 0.035 |
| CRP (mg/l) | 28.6±20.8 | 18.1±38.9 | 0.833 |
| Lymphocytes (cells/µl) | 4681±6125 |
2361±1748 |
0.386 |
| Values presented as mean±SD; Comparisons performed using Mann-Whitney U test; PICU: Pediatric intensive care unit; CRP: C-reactive protein | |||
Discussion
Principal findings
This study demonstrated a significant association between vitamin D deficiency and COVID-19 susceptibility in hospitalized Iranian children. Children with vitamin D deficiency (< 20 ng/ml) were approximately 4.8 times more likely to contract COVID-19 than their vitamin-D-sufficient peers after adjustment for age and sex. This association persisted in multivariate analysis, which suggested an independent role for vitamin D status in determining infection risk. However, once infected, vitamin D status showed a weaker and statistically significant but clinically modest relationship with disease severity, as reflected by PICU admission rates.
Mechanistic pathways
Several biological mechanisms may explain the observed association between vitamin D deficiency and COVID-19 susceptibility. First, vitamin D plays a critical role in innate immune responses through induction of antimicrobial peptides, particularly cathelicidin, which has antimicrobial and antiviral activity (Gombart et al., 2005, Wang et al., 2004). Second, vitamin D regulates adaptive immunity by influencing T-cell differentiation and inflammatory cytokine production, thereby contributing to immune homeostasis (Cantorna et al., 2015, Prietl et al., 2013). Third, vitamin D modulates the renin–angiotensin system and may favor the protective ACE2/Ang-(1–7)/Mas receptor axis rather than simply downregulating ACE2; this pathway has been proposed as one potential mechanism relevant to SARS-CoV-2-associated lung injury (Malek Mahdavi, 2020, Xu et al., 2017). Vitamin D also contributes to epithelial barrier and innate immune function, providing an additional biologically plausible link between vitamin D status and respiratory infection susceptibility (Charoenngam and Holick, 2020)
These mechanistic pathways are supported by observational data in other respiratory viral infections, including the influenza and respiratory syncytial virus, in which vitamin D supplementation or adequate status has been shown to reduce infection susceptibility (Aranow, 2011, Beard et al., 2011, Martineau et al., 2017). The fact that this cohort is drawn from Iran, where population-level vitamin D deficiency is endemic, suggests that correcting this deficiency may represent a particularly high-impact preventive intervention in this geographic context.
Comparison with previous literature
Adult studies have demonstrated strong associations between vitamin D deficiency and COVID-19 susceptibility and severity. Kaufinan et al observed that the deficiency was associated with a significantly elevated risk of COVID-19 positivity in a large U.S. cohort (Kaufman et al., 2020). Similarly Merzon et al. found that serum 25(OH)D levels below 20 ng/ml were associated with increased odds of COVID-19 infection in an Israeli population (Merzon et al., 2020). For disease severity, several meta-analyses and observational studies have documented associations between low vitamin D status and increased risk of hospitalization, ICU admission, and mortality from COVID-19 (Hastie et al., 2020, Meltzer et al., 2020, Pereira et al., 2022).
However, pediatric evidence has been sparse and heterogeneous. The strong association with susceptibility but weaker correlation with severity align with the limited pediatric literature available to date (Gombart et al., 2020, Sassi et al., 2018, Zittermann et al., 2016). The mechanistic basis for this difference may relate to the generally milder course of COVID-19 in children compared to adults; children mount more robust innate antiviral responses and have fewer comorbidities that might amplify vitamin D-related immune dysfunction (Feldstein et al., 2020, Ludvigsson, 2020, Yoshida et al., 2022). Additionally, children's higher baseline metabolic rates and greater capacity for immune compensation may buffer against the more severe manifestations of vitamin D deficiency observed in adult populations.
The use of historical pre-pandemic controls in this study represents a methodological advance over previous pediatric investigations, which have often been limited by confounding from pandemic-era vitamin D supplementation campaigns, altered sun exposure patterns, and behavioral changes. By employing baseline data from 2017–2018, the authors captured a more authentic epidemiological snapshot of the community’s vitamin D status prior to widespread awareness and supplementation initiatives.
Study limitations
This study had several important limitations that merit explicit discussion:
Principal findings
This study demonstrated a significant association between vitamin D deficiency and COVID-19 susceptibility in hospitalized Iranian children. Children with vitamin D deficiency (< 20 ng/ml) were approximately 4.8 times more likely to contract COVID-19 than their vitamin-D-sufficient peers after adjustment for age and sex. This association persisted in multivariate analysis, which suggested an independent role for vitamin D status in determining infection risk. However, once infected, vitamin D status showed a weaker and statistically significant but clinically modest relationship with disease severity, as reflected by PICU admission rates.
Mechanistic pathways
Several biological mechanisms may explain the observed association between vitamin D deficiency and COVID-19 susceptibility. First, vitamin D plays a critical role in innate immune responses through induction of antimicrobial peptides, particularly cathelicidin, which has antimicrobial and antiviral activity (Gombart et al., 2005, Wang et al., 2004). Second, vitamin D regulates adaptive immunity by influencing T-cell differentiation and inflammatory cytokine production, thereby contributing to immune homeostasis (Cantorna et al., 2015, Prietl et al., 2013). Third, vitamin D modulates the renin–angiotensin system and may favor the protective ACE2/Ang-(1–7)/Mas receptor axis rather than simply downregulating ACE2; this pathway has been proposed as one potential mechanism relevant to SARS-CoV-2-associated lung injury (Malek Mahdavi, 2020, Xu et al., 2017). Vitamin D also contributes to epithelial barrier and innate immune function, providing an additional biologically plausible link between vitamin D status and respiratory infection susceptibility (Charoenngam and Holick, 2020)
These mechanistic pathways are supported by observational data in other respiratory viral infections, including the influenza and respiratory syncytial virus, in which vitamin D supplementation or adequate status has been shown to reduce infection susceptibility (Aranow, 2011, Beard et al., 2011, Martineau et al., 2017). The fact that this cohort is drawn from Iran, where population-level vitamin D deficiency is endemic, suggests that correcting this deficiency may represent a particularly high-impact preventive intervention in this geographic context.
Comparison with previous literature
Adult studies have demonstrated strong associations between vitamin D deficiency and COVID-19 susceptibility and severity. Kaufinan et al observed that the deficiency was associated with a significantly elevated risk of COVID-19 positivity in a large U.S. cohort (Kaufman et al., 2020). Similarly Merzon et al. found that serum 25(OH)D levels below 20 ng/ml were associated with increased odds of COVID-19 infection in an Israeli population (Merzon et al., 2020). For disease severity, several meta-analyses and observational studies have documented associations between low vitamin D status and increased risk of hospitalization, ICU admission, and mortality from COVID-19 (Hastie et al., 2020, Meltzer et al., 2020, Pereira et al., 2022).
However, pediatric evidence has been sparse and heterogeneous. The strong association with susceptibility but weaker correlation with severity align with the limited pediatric literature available to date (Gombart et al., 2020, Sassi et al., 2018, Zittermann et al., 2016). The mechanistic basis for this difference may relate to the generally milder course of COVID-19 in children compared to adults; children mount more robust innate antiviral responses and have fewer comorbidities that might amplify vitamin D-related immune dysfunction (Feldstein et al., 2020, Ludvigsson, 2020, Yoshida et al., 2022). Additionally, children's higher baseline metabolic rates and greater capacity for immune compensation may buffer against the more severe manifestations of vitamin D deficiency observed in adult populations.
The use of historical pre-pandemic controls in this study represents a methodological advance over previous pediatric investigations, which have often been limited by confounding from pandemic-era vitamin D supplementation campaigns, altered sun exposure patterns, and behavioral changes. By employing baseline data from 2017–2018, the authors captured a more authentic epidemiological snapshot of the community’s vitamin D status prior to widespread awareness and supplementation initiatives.
Study limitations
This study had several important limitations that merit explicit discussion:
- Limited sample size: The case group (n=63) and control group (n=68) were relatively modest, particularly when stratified by disease severity (PICU: n=12). This limits statistical power and the capacity to detect associations in subgroup analyses. Thus, larger prospective studies are needed to confirm these findings.
- Unmeasured confounders: Although multivariate analysis was adjusted for age and sex, the authors were unable to assess additional variables that could influence vitamin D status or COVID-19 susceptibility, including socioeconomic status, dietary intake, outdoor exposure, body mass index, respiratory comorbidities, and vaccination status (relevant for later study periods). These unmeasured confounders may bias estimates of the vitamin D–COVID-19 association.
- Historical controls and temporal confounding: While the use of pre-pandemic controls minimizes recent supplementation bias, it does not eliminate the possibility of secular trends or other temporal factors differing between 2017–2018 and 2019–2021 that could confound the association.
- Single-center design and generalizability: Data were collected from a single institution in Tehran, which may limit generalizability to other geographic regions with different vitamin D epidemiology, healthcare infrastructure, or COVID-19 epidemiology.
- Severity outcome limitations: Disease severity was assessed solely by PICU admission, which represents a crude measure of clinical severity. More granular severity scoring systems (e.g., PaO₂/FiO₂ ratio, mechanical ventilation requirements, multisystem inflammatory syndrome criteria) were not available in this retrospective analysis.
- Cross-sectional measurement: Vitamin D levels were measured at a single time point (hospital admission), and temporal changes during infection were not tracked. Pre-infection vitamin D status might differ from admission-measured values.
Despite these limitations, the large effect size for vitamin D deficiency and susceptibility (OR 4.82, 95% CI 2.15–10.78) suggests a robust association that is unlikely to be entirely attributable to residual confounding.
Clinical implications and future directions
The strong association between vitamin D deficiency and COVID-19 susceptibility identified in this pediatric cohort has important public health implications. Screening and correction of vitamin D deficiency may be considered in children with clinical risk factors, particularly in regions with endemic deficiency such as Iran. For routine intake, the American Academy of Pediatrics recommends 400 IU/day during infancy, while the recommended dietary allowance is 600 IU/day for children aged 1 year and older; children with established deficiency require therapeutic regimens rather than routine preventive dosing (Golden et al., 2014, Holick et al., 2011).
Several clinical trials are ongoing to evaluate whether vitamin D supplementation reduces COVID-19 incidence in deficient populations; results from these randomized controlled trials will provide stronger evidence for population-level supplementation strategies (Martineau et al., 2017). Until such evidence matures, identification and correction of vitamin D deficiency should be viewed as a reasonable adjunct to standard preventive measures (vaccination, hygiene, respiratory etiquette) and may have additional benefits for bone health, immune function in other infectious and non-infectious contexts, and chronic disease prevention.
Future research directions include: (1) prospective studies with larger sample sizes and granular severity assessments; (2) investigation of optimal vitamin D supplementation dosing and targets in pediatric populations; (3) evaluation of vitamin D status and response in children with pre-existing respiratory comorbidities; (4) assessment of potential gene-by-environment interactions (e.g., genetic polymorphisms in vitamin D receptor or metabolizing enzymes); and (5) mechanistic studies examining vitamin D effects on SARS-CoV-2-specific immune responses in vitro and in pediatric animal models.
Conclusions
Vitamin D deficiency was strongly associated with COVID-19 susceptibility in hospitalized Iranian children, suggesting an important role for vitamin D status in determining infection risk. However, the relationship with clinical disease severity was weaker. These findings support routine screening and correction of vitamin D deficiency as a potentially cost-effective preventive strategy in pediatric populations, particularly in regions with endemic deficiency. Further investigation through prospective studies and randomized controlled trials is warranted to establish optimal supplementation strategies and to confirm these associations.
Acknowledgments
The authors gratefully acknowledge the laboratory personnel for their dedicated and demanding work during the COVID-19 pandemic, the nurses of the pediatric ward for their invaluable care and support, and the families of the children with COVID-19 for their cooperation and support throughout the study.
Authors' contributions
Adel Z contributed to sample collection and preparation of the initial draft of the thesis. Zare Mahmoudabadi R supervised the conduct of the study, interpreted the results, and critically reviewed the manuscript. Montazer F supervised the laboratory testing and contributed to interpretation of the laboratory results. Javid A supervised study implementation, provided guidance on recording the results, and contributed to the final editing of the manuscript. Yousefzadegan S contributed to the initial study design and sample collection, supervised manuscript preparation, and was responsible for final manuscript submission and correspondence as the corresponding author. All authors reviewed and approved the final manuscript.
Conflict of interests
The authors declare that they have no conflicts of interest.
Funding
This research received no specific grant or financial support from any funding agency in the public, commercial, or not-for-profit sectors.
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Sassi F, Tamone C & D’Amelio P 2018. Vitamin D: nutrient, hormone, and immunomodulator. Nutrients. 10 (11): 1656.
Wang T-T, et al. 2004. Cutting edge: 1, 25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. Journal of Immunology. 173 (5): 2909-2912.
Xu J, et al. 2017. Vitamin D alleviates lipopolysaccharide‑induced acute lung injury via regulation of the renin‑angiotensin system. Molecular medicine reports. 16 (5): 7432-7438.
Yoshida M, et al. 2022. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature. 602 (7896): 321-327.
Zittermann A, Pilz S, Hoffmann H & März W 2016. Vitamin D and airway infections: a European perspective. European journal of medical research. 21 (1): 14.
Clinical implications and future directions
The strong association between vitamin D deficiency and COVID-19 susceptibility identified in this pediatric cohort has important public health implications. Screening and correction of vitamin D deficiency may be considered in children with clinical risk factors, particularly in regions with endemic deficiency such as Iran. For routine intake, the American Academy of Pediatrics recommends 400 IU/day during infancy, while the recommended dietary allowance is 600 IU/day for children aged 1 year and older; children with established deficiency require therapeutic regimens rather than routine preventive dosing (Golden et al., 2014, Holick et al., 2011).
Several clinical trials are ongoing to evaluate whether vitamin D supplementation reduces COVID-19 incidence in deficient populations; results from these randomized controlled trials will provide stronger evidence for population-level supplementation strategies (Martineau et al., 2017). Until such evidence matures, identification and correction of vitamin D deficiency should be viewed as a reasonable adjunct to standard preventive measures (vaccination, hygiene, respiratory etiquette) and may have additional benefits for bone health, immune function in other infectious and non-infectious contexts, and chronic disease prevention.
Future research directions include: (1) prospective studies with larger sample sizes and granular severity assessments; (2) investigation of optimal vitamin D supplementation dosing and targets in pediatric populations; (3) evaluation of vitamin D status and response in children with pre-existing respiratory comorbidities; (4) assessment of potential gene-by-environment interactions (e.g., genetic polymorphisms in vitamin D receptor or metabolizing enzymes); and (5) mechanistic studies examining vitamin D effects on SARS-CoV-2-specific immune responses in vitro and in pediatric animal models.
Conclusions
Vitamin D deficiency was strongly associated with COVID-19 susceptibility in hospitalized Iranian children, suggesting an important role for vitamin D status in determining infection risk. However, the relationship with clinical disease severity was weaker. These findings support routine screening and correction of vitamin D deficiency as a potentially cost-effective preventive strategy in pediatric populations, particularly in regions with endemic deficiency. Further investigation through prospective studies and randomized controlled trials is warranted to establish optimal supplementation strategies and to confirm these associations.
Acknowledgments
The authors gratefully acknowledge the laboratory personnel for their dedicated and demanding work during the COVID-19 pandemic, the nurses of the pediatric ward for their invaluable care and support, and the families of the children with COVID-19 for their cooperation and support throughout the study.
Authors' contributions
Adel Z contributed to sample collection and preparation of the initial draft of the thesis. Zare Mahmoudabadi R supervised the conduct of the study, interpreted the results, and critically reviewed the manuscript. Montazer F supervised the laboratory testing and contributed to interpretation of the laboratory results. Javid A supervised study implementation, provided guidance on recording the results, and contributed to the final editing of the manuscript. Yousefzadegan S contributed to the initial study design and sample collection, supervised manuscript preparation, and was responsible for final manuscript submission and correspondence as the corresponding author. All authors reviewed and approved the final manuscript.
Conflict of interests
The authors declare that they have no conflicts of interest.
Funding
This research received no specific grant or financial support from any funding agency in the public, commercial, or not-for-profit sectors.
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