What’s this all about?
Acute respiratory tract infections are a major cause of global morbidity and mortality. They are one of the leading causes of sepsis in the UK. Of late, ‘Flu’ like illnesses and confirmed influenza amongst ventilated patients on ITU is ever increasing.
Amongst a massive dataset of patients, a possible causative factor and susceptibility association was low levels D (25-hydroxyvitamin D and 34 25-hydroxyvitamin D). These vitamins support induction of antimicrobial peptides in response to both viral and bacterial stimuli. There is also potential for replacement to induce protection against respiratory pathogens. Other metabolites may induce other innate antimicrobial effector mechanisms, including induction of autophagy and synthesis of reactive nitrogen intermediates and reactive oxygen intermediates.
Trials so far??
Randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory tract infection have yielded conflicting results thus far.
5 meta-analyses incorporating data from up to 15 primary trials have been conducted to date, of which two report statistically significant protective effects:
3 report no statistically significant effects:
People with chronic obstructive pulmonary disease who have lower baseline vitamin D status have been reported to derive greater clinical benefit from supplementation than those with higher baseline status. See here. There were so many confounding variables amongst many of these trials, it seemed prudent to undertake a meta-analysis based on all 25 randomised controlled trials of vitamin D supplementation for prevention of acute respiratory tract infection that were completed up to the end of December 2015.
- Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion i
- Included if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.
- They excluded studies reporting results of long term follow-up of primary randomised controlled trials.
What were they looking for?
- Primary outcome:
- incidence of acute respiratory tract infection, incorporating events classified as upper respiratory tract infection, lower respiratory tract infection, and acute respiratory tract infection of unclassified location (ie, infection of the upper respiratory tract or lower respiratory tract, or both).
- Secondary outcomes
- incidence of upper and lower respiratory tract infections, analysed separately
- incidence of emergency department attendance or hospital admission, or both for acute respiratory tract infection
- use of antimicrobials for treatment of acute respiratory tract infection; absence from work or school due to acute respiratory tract infection; incidence and nature of serious adverse events
- incidence of potential adverse reactions to vitamin D (hypercalcaemia or renal stones)
- mortality (acute respiratory tract infection related and all cause)
What were the results?
- Baseline serum 25-hydroxyvitamin D concentrations were determined in 19/25 trials: mean baseline concentration ranged from 18.9 to 88.9 nmol/L.
- All studies administered oral vitamin D3 to participants in the intervention arm:
- this was given as bolus doses every month to every three months in seven studies
- weekly doses in three studies
- a daily dose in 12 studies
- a combination of bolus and daily doses in three studies
- Study duration ranged from seven weeks to 1.5 years.
- Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96, P=0.003)
- Statistically significant protective effects of vitamin D were also seen for one step analyses of acute respiratory tract infection rate
- Two step analyses also showed consistent effects for the proportion of participants
- experiencing at least one acute respiratory tract infection (adjusted odds ratio 0.80, 0.69 to 0.93, P=0.004)
- acute respiratory tract infection rate (adjusted incidence rate ratio 0.91, 0.84 to 0.98, P=0.018; P for heterogeneity <0.001)
- time to first acute respiratory tract infection (adjusted hazard ratio 0.92, 0.85 to 1.00, P=0.051)
Subgroup analysis revealed a strong protective effect of vitamin D supplementation among those with baseline circulating 25-hydroxyvitamin D levels less than 25 nmol/L (adjusted odds ratio 0.58, 0.40 to 0.82, NNT=8)
- There was no statistically significant effect among those with baseline levels of 25 or more nmol/L (adjusted odds ratio 0.89, 0.77 to 1.04)
- An exploratory analysis testing the effects of vitamin D supplementation in those with baseline 25-hydroxyvitamin D concentrations in the ranges 25-49.9 nmol/L, 50-74.9 nmol/L, and 75 or more nmol/L did not reveal evidence of a statistically significant interaction
- Meta-analysis of data from trials in which vitamin D was administered using a daily or weekly regimen without additional bolus doses revealed a protective effect against acute respiratory tract infection (adjusted odds ratio 0.81, 0.72 to 0.91, NNT=20)
- No such protective effect was seen among participants in trials where at least one bolus dose of vitamin D was administered (adjusted odds ratio 0.97, 0.86 to 1.10)
- Baseline vitamin D status and dosing frequency, but not age, independently modified the effect of vitamin D supplementation on risk of acute respiratory tract infection.
- Daily or weekly vitamin D treatment was associated with an even greater degree of protection against acute respiratory tract infection among participants with baseline circulating 25-hydroxyvitamin D concentrations less than 25 nmol/L
- Moreover, use of daily or weekly vitamin D also protected against acute respiratory tract infection among participants with higher baseline 25-hydroxyvitamin D concentrations (adjusted odds ratio 0.75, 0.60 to 0.95; NNT=15, 9 to 86)
- Protective effects of daily or weekly vitamin D supplementation were statistically significantly greater in the subgroup of participants with profound vitamin D deficiency.
- Bolus dose vitamin D supplementation did not offer any protection against acute respiratory tract infection even when administered to those with circulating 25-hydroxyvitamin D concentrations less than 25 nmol/L (adjusted odds ratio 0.82, 0.51 to 1.33)
Surely there were detrimental effects?
Use of vitamin D did not influence risk of serious adverse events of any cause or death due to any cause. Instances of potential adverse reactions to vitamin D were rare. Hypercalcaemia was detected in 21/3850 (0.5%) and renal stones were diagnosed in 6/3841 (0.2%)
So where do we go from here?
Vitamin D supplementation reduced the risk of experiencing at least one acute respiratory tract infection. Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not. Among those receiving daily or weekly vitamin D, protective effects were strongest in those with profound vitamin D deficiency at baseline, although those with higher baseline 25-hydroxyvitamin D concentrations also experienced benefit.
So why then might use of bolus dose vitamin D be ineffective for prevention of acute respiratory tract infection? One explanation relates to the potentially adverse effects of wide fluctuations in circulating 25-hydroxyvitamin D concentrations, which are seen after use of bolus doses but not with daily or weekly supplementation. It is proposed that the bolus attenuates the ability of 25-hydroxyvitamin D to support protective immune responses to respiratory pathogens. It is clear why those with lower circulating levels responded better than those with normal levels…you are topping up the tanks where deficiency would have led to morbidity with infection on board.
Strengths and limitations of this study
This meta-analysis targeted and attempted to eliminate confounders well. The concepts that vitamin D supplementation may be more effective when given to those with lower baseline 25-hydroxyvitamin D levels and less effective when bolus doses are administered, can be supported by the fact that vitamin D supplementation reduces the risk of severe asthma exacerbations, which are commonly precipitated by viral upper respiratory tract infections. What the trial could not do was to exclude dosing regime effect modifiers.
A second limitation was that their power to detect effects of vitamin D supplementation was limited for some subgroups (eg, individuals with baseline 25-hydroxyvitamin D concentrations <25 nmol/L receiving bolus dosing regimens) and for some secondary outcomes (eg, incidence of lower respiratory tract infection). There may have been an element of type 2 error here.
We also have to consider the often rather ‘loose’ definition of acute respiratory tract infection. Also, virological, microbiological, or radiological confirmation was obtained only for the minority of events.
Final conclusion then…
The study reports a major new indication for vitamin D supplementation: the prevention of acute respiratory tract infection. It also shows that people who are very deficient in vitamin D and those receiving daily or weekly supplementation without additional bolus doses experienced particular benefit. The results add to the body of evidence supporting the introduction of public health measures such as food fortification to improve vitamin D status, particularly in settings where profound vitamin D deficiency is common.
Will this change my practice?
It’s all over the national press, but we are always cautious about that!! I don’t think this is going to change what I do on ICU. Are we going to screen every patient we suspect to have a chest source of sepsis, or all of those who come up with pre-admission coryzal symptoms? This will be costly, and I suspect will lead to many negative results. It is ONLY those with low levels who will benefit, and not from boluses either.
The cost of supplementation itself may be low, but there is likely to be no purported benefit to prescribing it to ALL respiratory infections on ITU and rendering them with secondary complications of hypervitaminosis D! Nonetheless, a very interesting and well done study.
Food for thought….well at least those containing Vitamin D anyway. Vitamin C for cold and respiratory infections….old wives’ tale!!
A bit on Vitamin D metabolism…we know you wanted this!
Here’s a bit on the functions of Vit D and it’s role in immunomodulation