Importance of vitamin D in critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis
Authors: Cariolou Margarita , Cupp Meghan A. , Evangelou Evangelos , Tzoulaki Ioanna , Berlanga-Taylor Antonio J. 
Published: August 2018

SummaryBackgroundCritical 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.MethodsPubMed, 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.FindingsForty-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 meta-regression 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.InterpretationCirculating 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.FundingMedical Research Council UKRegistrationPROSPERO (CRD42016050638)CopyrightOpen access article under terms of CC BYResearch in contextEvidence before this studyVitamin D deficiency is common worldwide and has been associated to numerous diseases in observational studies. The extent of deficiency and relevance to mortality in children receiving acute and intensive care is unclear and only recently has gained more attention. We searched PubMed, OVID, Google Scholar and the Cochrane Library from inception up until 5thNovember 2017 without language restrictions. Search terms used across these databases included: “critical care”, “acute care”, “vitamin D”, “pediatric”, “child”, “neonate”, “toddler”, “intensivecareunit”, “sepsis” and “septic shock” (full search terms are listed in the appendix). Most (81·3%) included studies were published between 2014 and 2017. We did not identify randomised clinical trials assessing the value of vitamin D supplementation in this population. We did not find sufficient studies to perform meta-analyses for mortality from sepsis or respiratory tract infection.Added value of this studyOur systematic review and meta-analysis provides an in-depth assessment of the magnitude and relevance of vitamin D circulating levels in paediatric acute and critically ill patients with pre-specified sub-group analyses. We found that studies were highly heterogeneous across a number of important study variables including clinical setting, patient age groups, sample size, geographic location, case definitions, study quality, study design, biomarker thresholds and assay measurements. Pooled estimates of prevalence of vitamin D deficiency were overall extremely high, showing that around half of patients in general and acute paediatric care are deficient. Estimates were similar for respiratory tract infections but higher in sepsis, with overlapping confidence intervals across all outcomes. Individual study estimates were highly variable however. We analysed this heterogeneity using meta-regression and identified clinical setting and country of study as important contributors, likely indicating that patient age and environmental exposure to vitamin D, amongst other likely important factors, are key determinants and should be adequately assessed and reported. Pooled estimates for mortality outcomes showed a clear increased risk with lower vitamin D levels, despite the variation in study characteristics. We were unable to assess the importance of vitamin D levels in sepsis and respiratory tract infections due to the small number of studies investigating these outcomes.Implications of the available evidenceVitamin D deficiency in acute and critical care settings is common and associated with increased mortality in paediatric patients. Our review highlights the heterogeneous nature of the study population however and emphasizes the need for adequate power and control of confounding factors in future work. Few studies have investigated specific diseases such as sepsis and respiratory tract infections in relation to vitamin D despite their high prevalence, social and economic costs. Understanding the causal nature and therapeutic value of vitamin D in paediatric critical care remain key areas for investigation.