Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI.
To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI.
A prospective birth cohort study was performed in healthy term neonates. Concentrations of 25-hydroxyvitamin D (25-OHD) in cord blood plasma were related to RSV LRTI in the first year of life, defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen.
The study population included 156 neonates. Eighteen (12%) developed RSV LRTI. The mean plasma 25-OHD concentration was 82 nmol/L. Overall, 27% of neonates had 25-OHD concentrations <50 nmol/L, 27% had 50-74 nmol/L and only 46% had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy. Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not (65 nmol/L versus 84 nmol/L, P = .009). Neonates born with 25-OHD concentrations <50 nmol/L had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥75 nmol/L.
Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life. Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy.
Comments
Susceptibility to respiratory syncytial virus bronchiolitis linked to vitamin D deficiency? Cautious interpretation of study findings required
We read with interest the recent report by Belderbos and colleagues entitled 'Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis'[1]. We are concerned that the title may be misleading to readers, that the authors may have overstated their conclusions and therefore urge caution in interpretation of the study findings.
In the study Belderbos and colleagues provide preliminary data on a potential association between low cord vitamin D levels and subsequent risk of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in the first year of life. As a result, they suggest that 'vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI'.
Before accepting the conclusion by Belderbos et al several points need to be taken into consideration. Figure 1 illustrates the somewhat unusual study design by the authors in relation to recruitment and consent. Of 1007 eligible infants, fewer than half had an initial cord blood sample taken. Of the remaining 481 infants, 465 (97%) had a second interview at one month, not when the 'infant was aged 1 to 3 weeks' as reported. Only at this point was informed consent obtained, with 65% refusing to be included in the study. The potential influence of this extraordinarily high number of excluded infants on overall study results is not discussed. Of the 156 infants that were included in analysis, only 18 (12%) subsequently developed an RSV LTRI.
Although the 18 infants that developed 'parent-reported RSV LTRI' had '1.3-fold lower' mean cord 25-OHD concentrations compared to infants that did not develop a RSV LRTI (65 nmol/L vs. 84 nmol/L, p=0.009), both groups had a 'normal' mean vitamin D levels. The authors do not actually define vitamin D deficiency in their manuscript, but we presume a level of < 50 nmol/L was deemed deficient given further analyses. Furthermore, the authors do not provide data on vitamin D levels in the 'cases' or 'controls' at any time during follow up. This is important as almost 60% of all infants in the study by Belderbos and colleagues were commenced on vitamin D supplementation following delivery. The authors state that infants with a cord vitamin D level of <50 nmol were six times more likely to develop RSV LRTI in the first year of life compared to infants with a cord vitamin D level > 75 nmol. The imprecision of this estimate is highlighted in the accompanying wide confidence interval (1.6-24.9), reflecting the small number of cases that developed an RSV related LRTI. This questions the validity of performing logistic regression analysis in the situation[2].
We also have some concerns regarding the study methodology. In defining primary and secondary outcomes in the methods section, the authors refer readers to a previous study with purported similar methodology[3]. However there are important differences between these studies. In the referenced study Houben at el report on the first ever episode of RSV LRTI[3]. Furthermore, when infants had symptoms suggestive of LRTI, a study researcher did a home visit and performed nasopharyngeal aspiration (NPA). Disease severity was assessed by the researcher using a standardised questionnaire and clinical examination. In contrast, Belderbos et al used a parental daily log of LRTI symptoms to define severity. Whether 'moderate or severe cough or wheeze of any severity lasting at least 2 days' is 'strict' criteria is questionable. Furthermore, parents, rather than researchers performed the NPA raising many potential problems related to successful sampling, specimen handling and transport.
The report by Belderbos and colleagues has generated considerable media interest[4]. Given the significant study limitations, we believe the authors have not shown a firm association between cord 25-OHD and RSV LRTI in the first year of life. However, we agree with Belderbos and colleagues that determining the 'true' association between vitamin D status during pregnancy and subsequent risk of RSV LRTI would require an alternative study design but is important. If an association between vitamin D levels in pregnancy and subsequent risk of RSV LRTI truly exists, the public health implications from a relatively simple and inexpensive intervention could be significant.
Nadja James MRCP UK, Department of General Medicine, Royal Children's Hospital Melbourne, Victoria, Australia
Lawrence Gray MBBS, Department of General Medicine, Royal Children's Hospital Melbourne, Victoria, Australia
Phillipa Bolton MBBS, Department of General Medicine, Royal Children's Hospital Melbourne, Victoria, Australia
Susan Donath Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne
Tom G Connell FRACP Department of General Medicine, Department of Paediatrics, University of Melbourne, Royal Children's Hospital Melbourne, Victoria, Australia
References 1. Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin d deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics 2011;127:e1513-20 2. Nemes S, Jonasson JM, Genell A and Steineck G. Bias in odds ratios by logistic regression modelling and sample size. BMC Med Res Methodol 2009;9:56 3. Houben ML, Coenjaerts FE, Rossen JW, et al. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community. J Med Virol 2010;82:1266-71 4. Infant RSV linked to vitamin D deficiency: CBS News Canada May 9 2011.
Conflict of Interest:
None declared