‘Curiouser and curiouser’: the role of vitamin D in the prevention of acute respiratory infection

Acute respiratory infections (ARI) are among the leading causes of childhood mortality worldwide. In 2013, pneumonia was responsible for an estimated 935 000 deaths among children aged between one and 59 months, a mortality rate that was second only to complications of preterm birth (1). Observational studies report consistent and independent associations between susceptibility to ARI and low vitamin D status, as indicated by serum concentrations of the major circulating vitamin D metabolite 25-hydroxyvitamin D or 25(OH)D (2). Laboratory studies reporting that 25(OH)D supports both antiviral and antibacterial responses (Fig. 1) have strengthened the case that such associations may be causal and several clinical trials of vitamin D supplementation for the prevention of ARI have now been performed. Aggregate data meta-analysis of 11 of these studies has revealed a protective effect of supplementation, with an odds ratio (OR) of 0.64 and a 95% confidence interval (CI) of 0.49–0.84 (3), but noted significant heterogeneity of effect. This is reflected in results of the seven trials conducted in children to date: four have shown at least some protective efficacy (4–7), while three have reported null results (8–10). This heterogeneity has been attributed to interstudy variation in baseline vitamin D status and the dosing regimens employed. In this issue of the Journal, Grant et al. report results of an eighth intervention study in children. This is an exploratory analysis of data from a clinical trial of vitamin D supplementation in pregnant mothers and their offspring, conducted to determine the effects of the intervention on incidence of ARI in children aged from birth to 18 months (11). The authors randomised 260 healthy pregnant women in Auckland, New Zealand, to receive daily oral placebo, lower dose vitamin D (1000 IU) or higher dose vitamin D (2000 IU) from 27 weeks’ gestation to birth. Their infants then received corresponding daily oral placebo, lower dose (400 IU) or higher dose (800 IU) vitamin D from birth to 6 months of age. Children were followed up to the age of 18 months, and the proportion of those making at least one primary care visit for ARI was compared between the study arms. In comparison with placebo, higher dose – but not lower dose – vitamin D supplementation was found to be associated with a modestly reduced risk of making at least one primary care visit for ARI, quantified as 87% risk for the higher dose vitamin D versus 99% risk for the placebo (p = 0.004). Intriguingly, this effect was driven by a decrease in ARI visits made by children in the higher dose arm of the study from the age of 6–18 months, that is when the children were no longer taking study medication. No effects of either the higher dose or lower dose vitamin D were seen on time to the first primary care visit for ARI or on the risk of hospitalisation for ARI. This study is the first trial in children to compare the efficacy of two different dosing regimens for the prevention of ARI. The higher of the two doses is significantly more generous than that currently recommended in pregnancy and infancy by guidelines in Europe, Australasia and the United States. This is an important advance, because observational epidemiological studies tend to report that optimal protection against ARI is associated with 25(OH)D concentrations >75 nmol/L, which are not consistently achievable with the regimens that are currently recommended, particularly in pregnancy. The study is also novel in that both pregnant women and their offspring were randomised. This design feature acknowledges that the major determinant of neonatal vitamin D status is maternal 25(OH)D concentration; it also accommodates the potential for intrauterine vitamin D status to influence outcomes in offspring, as has been shown for other health outcomes such as bone mass. The study also has several noteworthy methodological strengths. Events for the primary analysis were derived from medical record audit, rather than selfreport, and outcome data were available for 91% of randomised children. Reported compliance was at least 93% among pregnant mothers and at least 74% among infants at 6 months. A daily dosing regimen was employed: this is significant, because a question mark has recently been raised over the efficacy of intermittent bolus dosing regimens of vitamin D for the prevention of ARI (12). The study also has some limitations. First, different measures of ARI incidence – parent report, hospitalisation data and primary care consultation data – were utilised for analysis at different follow-up time points. Second, although the majority of pregnant women (66%) had serum 25(OH)D concentrations below the optimum level of 75 nmol/L at baseline, a minority (42%) were vitamin D deficient at the 50 nmol/L threshold. There is some evidence to suggest that individuals with the lowest baseline