Our trial in a population known to be vitamin D deficient shows that 100 000 IU (2·5 mg) of vitamin D3 supplementation once every 3 months did not affect the incidence or severity of childhood pneumonia, in this population. Similarly, vitamin D3 supplementation did not affect hospital admissions and all-cause mortality.
Our trial had a large sample size with a low loss to follow-up that remained within our sample size estimates. The ascertainment of study outcomes was robust, and done clinically through masked experienced and retrained paediatricians with Integrated Management of Childhood Illnesses clinical definitions of pneumonia applied in other trials18
and radiologically through the interpretation of chest radiographs by masked, experienced, and external readers by use of WHO standards. Frequent home visits confirmed outcomes of interest. Supplementation raised the serum concentration of calcifediol in the intervention group at several points in our study. Thus the lack of a protective effect of vitamin D against pneumonia is probably not due to misclassification of outcomes or inadequate supplementation. Any misclassification of other causes of raised respiratory rate as pneumonia, under-reporting, or over-reporting would be distributed equally between the two groups since the families, doctors, radiographers, radiologists, and data entry staff were masked to the randomisation groupings and the randomisation was successful since the characteristics were balanced between the two groups. However, a limitation due to the high-risk nature of our population is that the generalisability of our findings to populations with low-to-moderate risk of vitamin deficiency is unknown. There were fewer deaths than we predicted in both groups, possibly due to the intense health surveillance possible during our study. Genotyping, which was not practical in our study setting, might have aided the interpretation of our findings, as shown in a vitamin D supplementation trial for tuberculosis.20
We accounted for nutritional factors through a diet questionnaire, weight at recruitment, and growth comparison at the end of our study—any nutritional deficiencies would have been equally balanced between the two groups. As with other studies, dietary calcium deficiency might have led to so-called wastage of body stores of vitamin D in both groups, affecting the maintenance of even higher vitamin D levels in the intervention group. Nevertheless, there was a higher (adequate level) mean serum concentration of calcifediol at the end of first supplementation period in the intervention group compared with the lower (not adequate) mean concentrations in the placebo group (data not shown). Furthermore, adult fracture-outcome supplementation studies21
show no benefit from adding calcium.
A further limitation of our study is that it was not feasible to undertake biochemical assessment of the supplements or assess serum concentrations in all participants after each and between supplementation. Our sample testing suggest that the vitamin D group maintained above mean adequate vitamin D concetrations verses consistently low concentrations in the placebo group. It can be argued that a steady-state adequate vitamin D concentration was not reached in some children because of fluctuations in serum concentrations due to our study regimen. Although this is probably true, a sufficient serum concentrations for the immunological effects of vitamin D is unknown and could be higher or lower than that of the skeletal system accepted concentrations.6
The need for a steady state is currently highly speculative and relates to vitamin D2
supplementation for negative cancer22
and bone outcomes.23
Our findings are at odds with smaller case-control hospital studies that show an enhanced rate of vitamin D deficiency or rickets in children with pneumonia and the increasing evidence suggesting that calcitriol, the biologically active metabolite of vitamin D, has an important role in the human immune system.4
A systematic review of the role of vitamin D supplementation in infectious diseases had mixed findings, concluding that more rigorously designed clinical trials are needed (panel
No studies report the effect of vitamin D on radiologically confirmed pneumonias. Other trials assessing infections of the upper respiratory tract also had mixed findings: one trial in post-menopausal women26
identified reduced self-reported episodes of infection of the upper respiratory tract, specifically in winter, whereas two others in elderly24
and general adults27
did not identify a difference between the groups with regards to self-reported episodes. One trial in schoolchildren28
(measuring influenza A antigen from swabs) found a statistically significant reduced incidence in the intervention group (RR 0·58, 95% CI 0·34–0·99).
Panel. Research in context
We searched PubMed/Medline with the terms “vitamin D supplement*”, “pneumonia”, “respiratory infections”, “immune*”, “cancer”, “heart disease”, and “diabetes”, supplemented with secondary citation (ie, assessing the references in the identified reports for more references). We did not limit our searches by language or date. No studies reported on radiologically confirmed pneumonias. One masked placebo trial assessed the effect of bolus supplementation of vitamin D3
in a high-risk population clinically diagnosed with pneumonia (100 000 IU [2·5 mg] vitamin D3
[cholecalciferol] supplementation along with antibiotic treatment to children younger than 3 years) in Kabul. Treatment had no effect on the time to recovery but reduced the risk of clinically defined pneumonia 13% up to 3 months after treatment.3
Trials assessing infections of the upper respiratory tract had mixed findings: one trial in post-menopausal women24
identified a reduction in self-reported episodes of infections during winter, whereas two other studies in adults did not identify effects on self-reported episodes. One trial in schoolchildren noted a 42% reduction in the risk of influenza A by use of antigen titre as a proxy measure. The reported in-vitro and case-control studies suggest a link between respiratory infections and vitamin D as an immunoregulator, but the evidence on the effect of vitamin D supplementation on acute respiratory infections is conflicting. Given that pneumonia is a leading cause of mortality in young children, the effects of vitamin D supplementation to infants on the incidence of pneumonia merits investigation.
Our findings show that bolus quarterly supplementation of 100 000 IU vitamin D3 did not reduce the rate or severity of radiologically confirmed or clinically defined pneumonia. This finding is surprising in view of evidence suggesting an association between vitamin D deficiency and respiratory infections. However, our findings are similar to some previous studies on the effect of supplementation on infections of the upper respiratory tract or other outcomes such as bone fractures, cancers, and heart disease, and they contribute to the debate on factors that determine the immunological effectiveness of vitamin D supplementation.
The benefits of supplementation for tuberculosis are similarly unclear. One paediatric trial showed 16% higher rates of tuberculosis symptom resolution,29
an adult trial showed 23% greater sputum conversion rate at 6 months,30
another trial showed 20% greater restriction of BCG-lux growth in blood,31
another trial found accelerated sputum conversion only in a certain genotype of the sample,20
whereas yet another found no significant difference in sputum conversion32
in the intervention compared with the placebo group. Vitamin D is linked with other non-bone health outcomes, but the few completed and adequately powered trials assessing the effect of supplementation have mixed findings in improving outcomes—ie, cancers, vascular disease, and diabetes. As in our studies, these inconsistent findings point to the existence of complicated pathways for the function of vitamin D in disease processes, or simply that the correct effective dose of vitamin D supplementation needs to be better defined. The optimum concentrations of vitamin D for adults and children6
are based on non-immunological and, mostly, bone outcomes. An associated issue is that, after the start of our trial, speculations arose that high fluctuations of natural or supplemented vitamin D intake might be linked to negative outcomes. These speculations relate two studies in which supplementation of a single large dose (300 00033
or 500 00023
IU) of vitamin D for reducing fractures in elderly women led to an increase in fractures, plus similar discrepancies in prostate cancer research with vitamin D.22
Our findings and particularly the slightly higher repeat episodes of pneumonia in the vitamin D group could be due to such fluctuations if the hypothesis is true. If so, then in terms of policy and guidelines, it is hard to know what regimen to recommend for future trials, given that clinical practice and evidence suggests that daily or weekly supplementations though ideal are not complied with13,14
and are impractical for families, especially in developing countries, and food fortification at the population level will not be an option during exclusive breastfeeding periods (aged <6 months), nor is it likely to be adequate in highly deficient populations.
Alternately, it might be that immunological effectiveness of supplementation is highly dependent upon other factors as yet unidentified, or other prevalent factors in this high-risk population (for example, other malnutrition factors and that 5·5% of the children in our study had a Z
score of weight for age below −3). Further questions arise with respect to the previous treatment trial in the same region of Kabul, which showed that a single high-dose supplementation with 100 000 IU vitamin D3
given orally to young children, along with antibiotic treatment at the time of diagnosis, reduced repeat episodes of pneumonia in the subsequent 3 months.3
The inconsistent results could be related to the evidence that stimulation of Toll-like receptors on macrophages and monocytes by bacterial antigens is important in up-regulation of CYP27B1 and the vitamin D receptor,5
which are crucial in production of cathelicidins in vitamin-D-depleted individuals. In other words, this system might not be effective unless there is existing infection with pathogens when vitamin D supplementation is given. Finally, any possible reduction in the incidence of pneumonia in our trial might be restricted to only certain genotypes as recorded in a single tt
genotype after the start of our trial in a study of tuberculosis.20
Both the pneumonia treatment and the population supplementation trials need to be repeated in other settings for confirmation, and frequent determination of serum calcifediol concentrations might guide the interpretation of the findings.
As with the trials in the older children, giving higher doses of vitamin D,25,34
we too did not record any adverse effects associated with vitamin D supplementation. However, the number of children and the length of follow-up involved in these studies could only detect common and early adverse effects. Although vitamin D overload is a theoretical possibility, 100 000 IU of vitamin D3
has been shown to provide the best protection against vitamin D deficiency without overload or side-effects in high-risk infants aged 0–9 months with normal baseline ranges of vitamin D.16
Furthermore, single intramuscular injection of three times this dose (300 000 IU) was safe in treating nutritional rickets in 6–30-month-old children residing in lower socioeconomic regions of sunny Istanbul.35
Higher than recommended doses of daily supplementation of vitamin D (500–1000 IU per day, adding up to 120 000 IU over 3 months) plus additional milk fortified with vitamin D, has been shown not to induce an overload,13
including in infants starting with normal ranges of vitamin D, even when supplementation continued during the summer (in France) and when mothers had antenatal vitamin D supplementation.36
It is important to note that in our study, where community supplementation was in a population with known high rates of vitamin D deficiency, 1% of children tested had a calcifediol concentration greater than 375 nmol/L—thought undesirably high.6
Although these did not produce any clinical signs and symptoms, these measurements raise a need for caution with doses for population supplementation. The speculative negative role of fluctuations is vitamin D needs to be considered with caution until further evidence is available.
We have shown that a quarterly 100 000 IU supplementation of vitamin D3 did not reduce the incidence of pneumonias in children living in regions with high vitamin D deficiency. In populations with similar characteristics, quarterly population level supplementation of vitamin D to infants and young children is not a policy option for reducing the burden of pneumonia in children.