Importance of Vitamin D in Critically Ill Children with Subgroup Analyses of Sepsis and Respiratory Tract Infections: A Systematic Review and Meta-Analysis

Abstract

Background: Critical care and sepsis remain high priority concerns in children. Observational studies report high prevalence of vitamin D deficiency and present mixed results regarding the correlation between vitamin D status and adverse outcomes. Associations between deficiency and mortality, particularly in children with sepsis, remain unclear. We performed a systematic review and meta-analysis to address this uncertainty. Methods: PubMed, OVID and Google Scholar were searched for observational studies in critically ill children. We obtained pooled prevalence estimates for vitamin D deficiency and odds ratios for the association of mortality in critically ill children treated in intensive care units, with subgroup analysis for those with sepsis and those with respiratory tract infections. Meta-regression and sensitivity analyses were used to investigate heterogeneity. Findings: Forty-eight studies were included. Total sample size was 7,199 with 1,679 (23%) children acting as controls in case-control studies. Of 5,520 critically ill children, 2,664 (48%) were vitamin D deficient (< 50 nmol/L). Results of the random effects model demonstrated a pooled prevalence of vitamin D deficiency of 54·9% (95% CI 48·0-61·6, I²=95·0%, 95% CI 94·0-95·8, p < 0·0001). In subgroup analysis of children with sepsis (16 studies, 788 total individuals) we observed higher prevalence of deficiency (63·8%, 95% CI 49·9-75·7, I²=90·5%, 95% CI 86·2-93·5%, p < 0·0001). In patients admitted for respiratory tract infections (24 studies, 1,683 total individuals), prevalence was 49·9% (95% CI 37·6- 62·2; I² = 93·9%, 95% CI 92·1-95·3, p < 0·0001). Only one identified study assessed vitamin D levels in sepsis and mortality. A metaregression model with all available variables (year of publication, total study sample size, quality score, study design, country group and clinical setting) explained 37·52% of I² (F = 5·1119, p = 0·0005) with clinical setting and country groups being significant predictors for prevalence. Meta-analysis of mortality (18 studies, 2,463 total individuals) showed an increased risk of death in vitamin D deficient critically ill children both with random (OR 1·81, 95% CI 1·24-2·64, p-value = 0·002) and fixed effects (OR 1·72, 95% CI 1·27-2·33, p= 0·0005) models with low heterogeneity (I² = 25·7%, 95% CI 0·0-58·0, p = 0·153) and low evidence of publication bias (p = 0·084, Egger's test). There were insufficient studies to perform meta-analyses for sepsis and respiratory tract infection related mortality. Interpretation: Circulating vitamin D deficiency is common amongst critically ill children, particularly in those with sepsis. Our results suggest that vitamin D deficiency in critically ill children is associated with increased mortality. Clinical trials, studies with larger sample sizes and standardized approaches are needed to further assess associations between circulating levels of vitamin D and mortality and other outcomes in the paediatric population. Funding Statement: The study received funding from the UK Medical Research Council. AJBT was supported by the Medical Research Council (UK MED-BIO Programme Fellowship, MR/L01632X/1). The funders had no role in data collection, analysis, interpretation or writing of the report. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study protocol is registered in PROSPERO (CRD42016050638). The authors declare ethics approval not applicable.