Articles
The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial

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Summary

Background

Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections.

Methods

We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763.

Findings

Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant.

Interpretation

Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection.

Funding

National Health and Medical Research Council.

Introduction

Acute respiratory tract infection is common, with most people experiencing at least one each year. Severe infections often require admission to hospital, accounting for up to 50 per 10 000 hospital admissions in developed countries,1, 2, 3, 4 and costing billions of dollars annually in both direct and indirect costs.3, 4, 5 The economic and disease burden increases with age.3, 4 Many organisms can cause acute respiratory tract infections, but for most of these, particularly the common cold, no vaccine is available. In Australia, the influenza vaccine is strongly recommended for people aged 65 years and older, and for others considered to be at high risk; however, population coverage is variable, and the vaccine does not offer complete protection. Alternative approaches to the prevention and treatment of acute respiratory tract infections are required.

Research in context

Evidence before this study

Observational studies have shown a consistent link between serum 25-hydroxy vitamin D (25[OH]D) concentration and the risk or severity of acute respiratory tract infection. There have been several meta-analyses of randomised controlled trials that have assessed the effect of vitamin D supplementation on the risk and severity of these infections. However, the results were inconsistent in terms of the overall effect on the risk, and whether the effect is influenced by baseline 25(OH)D concentration or dosing regimen. We recently published a meta-analysis of observational studies and identified a consistent link between low 25(OH)D concentration and increased risk (n=78,127). Martineau and colleagues published two meta-analyses of randomised controlled trials, one in 2017 and one in July, 2020. The pooled effect estimate reported in the most recent meta-analysis was 0·89 (95% CI 0·81 to 0·98) for the overall risk of acute respiratory tract infection. However, there was high heterogeneity (I2 40·0%, p=0·009); there have been few truly population-based studies and questions remain about interactions with dosing regimen and baseline 25(OH)D concentration. There has been limited exploration of the effect of vitamin D on duration and severity of symptoms.

Added value of this study

Our results suggest that supplementing the general population with vitamin D is unlikely to reduce the risk of developing an acute respiratory tract infection. The observed reduction in duration of symptoms, and in the number of days with severe symptoms, is of unclear clinical significance, but suggests a potential impact of vitamin D on the immune response to infection. This is the second-largest trial to have reported on the effect of vitamin D supplementation on acute respiratory tract infections to date and thus makes an important contribution to the literature.

Implications of all the available evidence

The evidence, in its totality, suggests that vitamin D supplementation of adult populations that are largely vitamin D replete is unlikely to have a clinically significant effect on the risk or duration of acute respiratory tract infections.

Vitamin D is best recognised for its role in regulating calcium homoeostasis. Pre-clinical studies have suggested it also has an important role in supporting immune function,6, 7, 8, 9 with reasonably consistent evidence from observational studies of an inverse association between serum 25-hydroxy vitamin D (25(OH)D) concentration and risk or severity of acute respiratory tract infections. A previous systematic review and meta-analysis concluded that the association with acute respiratory tract infections risk was non-linear, with the sharpest increase in risk of infection occurring in people with serum 25(OH)D concentration less than 37·5 nmol/L.10

Findings from observational studies might have been influenced by bias, and meta-analyses of randomised controlled trials of vitamin D supplementation have produced inconsistent results; although more than half concluded that vitamin D supplementation reduced the risk of acute respiratory tract infections,11, 12, 13, 14 some found no benefit of vitamin D supplementation.15, 16, 17 A meta-analysis using individual participant data from trials suggested a greater protective effect of supplementation in people with vitamin D deficiency than in those who were not deficient,13 but this was not the case in an updated meta-analysis of stratified aggregate data.14 Evidence suggests that bolus dosing (ie, less frequently than daily or weekly) might be less effective than more frequent dosing,13 although the meta-regression analysis in the most recent meta-analysis did not find a significant interaction with dosing regimen.14 There have been few studies among large groups of people randomly selected from the general population.

The D-Health Trial is one of the largest randomised controlled trials of vitamin D supplementation to date; the primary endpoint is all-cause mortality, and the secondary endpoints are total cancer incidence and colorectal cancer incidence. Acute respiratory tract infection is one of many pre-specified tertiary outcomes.18 We analysed data from the D-Health Trial to determine whether supplementing older Australian adults recruited from the general population with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections.

Section snippets

Study design and participants

The D-Health Trial is a randomised, placebo-controlled, double-blind trial with two parallel arms. Participants were randomly assigned to receive capsules containing either 60 000 international units (IU) of cholecalciferol (vitamin D3) or placebo (1:1), taken orally once per month. Potential participants aged between 60 and 79 years were randomly selected from the Australian Commonwealth Electoral Roll (excluding people from the Northern Territory) and invited to participate. Volunteers aged

Results

Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised to receive edither vitamin D or placebo (figure 1). Data have been deleted for five people at their request and were therefore not included in the analyses.

From the remaining 213 10 participants, 16 000 participants were randomly selected for analysis of survey data (subsample 1), with 8000 selected from the vitamin D group

Discussion

This analysis of D-Health Trial data found no significant benefit of monthly supplementation with 60 000 IU of vitamin D on the incidence of acute respiratory tract infection. However, some evidence of a reduction in the overall duration of symptoms and of severe symptoms was observed.

In the D-Health Trial, the percentage of participants reporting an acute respiratory tract infection in the previous 4 weeks varied from 19% in annual survey 1 to 30% in annual survey 3. This is somewhat higher

Data sharing

Data are not available as open access because participants did not consent to their data being made available in this way.

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