Does vitamin D supplementation fight off the common cold?

Current estimates suggest that acute respiratory tract infections are responsible for about 2.7 million deaths^[1] worldwide and are the most common reason^[2] for doctor visits and antibiotic prescription in the United States. Respiratory infections include, but are not limited to the common cold, sinus infections, and ear infections^[3].

These diseases are highly opportunistic and often manifest themselves in people with reduced immune function. Low levels of vitamin D have been associated with worse immune function^[4] and increased rates^[5] of acute respiratory infection, possibly due to its role in regulating the immune system (as outlined in Figure 1). For example, it has been well documented that low levels of vitamin D in countries with suboptimal sunlight (about 32-42^o N or S of the equator^[6]) as well as a genetic predisposition for low vitamin D status are both associated with increased^[7] rates of acute respiratory tract infections. This observation has also appeared in the United States^[8]. These data suggest that adequate vitamin D status might be a protective factor against acute respiratory tract infections.

There is also genetic data demonstrating a link between vitamin D status and acute respiratory infections. Genetic polymorphisms that result in a reduction in the total number of vitamin D receptors in the human body are associated with an increased risk^[9] of acute respiratory tract infections) in children, , further supporting a role for vitamin D in immune regulation.

The most recent meta-analysis^[10] of controlled trials investigating the effect of vitamin D supplementation on the risk of developing respiratory tract infections found that vitamin D supplementation did not have a significant effect. However, heterogeneity was high and there was a marginally significant benefit in people who were deficient and in people who took vitamin D daily rather than in weekly boluses.

By examining individual patient data (IPD), it may be possible to overcome inconsistencies at the trial level. IPD can be used to determine whether specific treatments are effective for what kinds of people and under which circumstances. In addition to allowing for conduct subgroup analysis on consistently defined criteria, utilizing IPD data overcomes several key issues with trial-level meta-analyses that use aggregate data. Trial-level meta-analyses ignore the effect of missing data and omit important correlational structures, which are overcomed by IPD analyses^[11]. Recently, IPD-based meta-analysis methods were utilized to compile data across vitamin D intervention trials and examine patient level data to determine which patients would benefit from vitamin D supplementation and which dosing strategies were effective for lowering risk of acute respiratory tract infection.

Vitamin D has well-established immunomodulatory properties and there is some evidence to suggest that vitamin D levels are linked to infections. It has been well documented that lower levels of vitamin D, either genetically or due to environment, are associated with higher levels of acute respiratory tract infections. The current study was a meta-analysis of individual participant data that sought to determine whether vitamin D supplementation can lower ones’ risk of acute respiratory tract infections, as well as identify people that might benefit from supplementation and those that might not.

This study compiled data from randomized, double-blind, placebo controlled trials of supplementation with vitamin D₃ or vitamin D₂ that recorded the incidence of acute respiratory tract infections. Eligible studies had to have prespecified acute respiratory tract infections as an outcome to ensure the data was sensitive enough to minimize misclassification bias that often occurs post facto.

Twenty-five studies were found to meet the inclusion criteria, having a total of 11,321 participants. The samples in these studies were diverse, ranging in age from newborn babies (less than six months of age) to elderly individuals (over 90 years old) and spanning across a number of racial and ethnic backgrounds (e.g., Finnish, Polish, Japanese, Afghani, American, Indian, Canadian, Israeli, and Australian).

The authors confirmed the validity of the individual data for each study by reanalyzing the raw data, confirming the findings with the original authors, and resolving any discrepancies. The authors then conducted one-step and two-step IPD meta-analyses. In the one-step analysis, they examined IPD from all the studies at the same time, but controlled for each trial as its own cluster. In the two-step analysis, they examined the IPD in each study to determine what the effect was for that specific study, and then combined those effects. Lastly, they determined the number of people that vitamin D would have to be administered to (known as number needed to treat) to prevent a single acute respiratory tract infection.

The primary outcome of this study was defined as the incidence of acute respiratory tract infections. This included any events classified as the following: upper respiratory tract infection, lower respiratory tract infection, and acute respiratory tract infection of unclassified location (i.e., infection of the upper respiratory tract or lower respiratory tract, or both).

This was a meta-analysis of the raw, individual-level data from 25 randomized controlled trials investigating the effect of vitamin D supplementation on risk of acute respiratory tract infection. The studies included participants of a wide age range (infant to geriatric populations) and diverse racial and ethnic groups.

The main findings are summarized in Figure 2. The study showed that people who supplemented with vitamin D were less likely to experience an acute respiratory tract infection. The one-step analysis (where everyone was pooled and the study was controlled for statistically) indicates that there was about a 12% reduction in the odds of experiencing an acute respiratory tract infection with vitamin D supplementation compared to the placebo. The number needed to treat was 33 people. The two-step analysis showed very comparable results to the one-step analysis, with a roughly 20% reduction in the odds of experiencing an acute respiratory tract infection with vitamin D supplementation.

Subgroup analysis suggested that vitamin D supplementation had a highly protective effect among those people with baseline levels of vitamin D less than 10 nanograms per milliliter (ng/mL), whereby supplementing with vitamin D lowered the odds of experiencing an acute respiratory tract infection by about 42% compared to placebo. The number needed to treat in these individuals was a mere eight people to prevent one acute respiratory tract infection. However, no significant benefit of vitamin D supplementation was observed in people with levels greater than 10 ng/mL, which is well below the cutoff for vitamin D deficiency of 20 ng/mL. The other important finding was that daily or weekly doses of vitamin D exerted the protective effect but larger, less frequent bolus doses every one to three months did not, not even among participants with vitamin D levels less than 10 ng/mL.

Vitamin D supplement did not increase the risk of serious adverse events or death in the study, and incidence of hypercalcemia and kidney stores were not increased due to vitamin supplementation, regardless of dose or administration type. However, the authors report that small trials showing adverse effects of vitamin D supplementation may not have been included in the meta-analysis.

Overall, vitamin D lowered the odds of acute respiratory tract infection by 12%. Subgroup analysis showed that this benefit was restricted to people with vitamin D levels below 10 ng/mL, where vitamin D supplementation lowered the risk of acute respiratory tract infection by 42%. Interestingly, only daily and weekly dosing was shown to confer a protective effect, while acute, large bolus doses of vitamin D did not lower the odds of acute respiratory tract infections, regardless of vitamin D status.

By utilizing a meta-analysis with very strict inclusion criteria and using individual patient-level data as opposed to averages, this study was able to determine which types of people’s odds of acute respiratory infections drop when given vitamin D. They were also able to determine how many people one would have to treat to prevent an infection from occurring. In the general population, vitamin D supplementation decreases the odds of acquiring an acute respiratory tract infection by about 12%. Thirty-three people would have to be treated with vitamin D before preventing a single infection. However, if only people with vitamin D levels below 10ng/mL are supplemented, the odds of infection is reduced by 46%, and only eight people need to be treated to prevent one infection.

The study has some notable limitations that impact the interpretation of the findings. One of the major limitations is that the subgroup of people with baseline vitamin D of less than 10 ng/mL who received bolus doses of vitamin D was underpowered, as such the null finding may be a type II error (false negative), and bolus doses in this subgroup may indeed be effective. A larger sample size is required to confirm this null finding. Another key limitation is the lack of adherence data on some of the participants. Inclusion of people who were non-adherent can bias results towards the null, thus the authors conclude that effects of vitamin D on acute respiratory tract infections in those who are fully adherent to supplementation should be no less than those reported for the study sample overall.

Using patient level data compiled across twenty-five studies, the authors were able to demonstrate that correcting vitamin D deficiency with daily or weekly vitamin supplementation substantially reduces the risk of acute respiratory tract infections. Daily or weekly supplementation appears to be the effective form of supplementation. However, due to statistical power issues it is not certain that bolus doses do not also convey some benefit.

The common culprits of acute respiratory tract infections such as rhinoviruses and influenza viruses are highly virulent and are spread through social interactions. Therefore, reducing the risk of acquiring a viral infection by 46% amongst people with suboptimal vitamin D levels not only impacts the individuals infected but may also reduce the pool of infectious people and lower the overall disease burden seen by a society during a cold or flu season. As roughly 23% of people are at risk of vitamin D inadequacy (serum levels between 12-20 ng/mL and 6-10% are at risk of vitamin D deficiency (less than 12 ng/mL)), reducing the reservoir of virulent hosts might also reduce overall burden.

Methodologically, this type of analysis has far reaching implications, and can be used to examine the patient level data of other large clinical trials to determine which patients are most likely to benefit from intervention and which ones will not. For example, there are very good theoretical, mechanistic, and observational data to suggest that there are responders and non-responders to drugs like statins, and the latter might be better served by treating them non-statin based therapy. For example, the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) increases circulating LDL-C and is known to increase in response to statin therapy. A recent study^[12] demonstrated that baseline serum levels of PCSK9 and increases in serum levels of PCSK9 in response to statin therapy were higher in people who were non-responders to statin therapy. This can serve to identify patients who do not respond to statin therapy but might benefit from PCSK-9 inhibition^[13].

The findings of this study suggest that vitamin D supplementation may lower the risk of acute respiratory tract infections, which then could reduce the overall infectious burden in communities. Additionally, this study highlights a unique methodology to identify subpopulations of individuals who benefit from specific interventions and those that do not.

Q. What are the different forms of vitamin D that can be tested for in the blood?

There are several forms of vitamin D (shown in Figure 3) that can be tested for in the blood: pre-vitamin D, 25-hydroxy vitamin D25(OH)D and 1,25-hydroxy vitamin D 1,25(OH)D. The standard blood test for vitamin D measures the 25(OH)D form of vitamin D. While it is true that the 1,25(OH)D form is the most biologically active form of vitamin D, levels of the 25-OH forms of vitamin D more accurately reflect the body's vitamin D stores.

Q.What level of vitamin D is considered normal?

The standard blood test typically reports vitamin D in concentrations of nanograms per milliliter, (abbreviated as ng/mL) or nanomol per liter (nmol/L). “Normal” vitamin D levels are a topic of great discussion amongst clinicians and researchers. However, according to the National Academies of Science, the current clinical guidelines for normal vitamin D levels are between 20 and 50 ng/mL. Vitamin D levels between 20 and 12 ng/mL are considered moderately deficient, between 12 and 5 ng/mL are considered deficient, and less than 5 ng/mL are considered extremely deficient.

Q. What should I know?

Acute respiratory tract infections are responsible for about 2.7 million deaths worldwide and are the most common reason for antibiotic use and doctors visits in the United States. Low levels of vitamin D have been associated with increased rates of respiratory infections, opening the possibility that supplementation could prevent them.

The current study was a meta-analysis of the individual patient data (as opposed to study averages) from 25 studies that examined the effect of vitamin D supplementation on prevention of acute respiratory tract infections. By looking at patient level data, the study showed that vitamin D supplementation in people with vitamin D levels of less than 10 ng/mL lowers the odds of acute respiratory tract infection. Furthermore, it appears that standard supplementation regimens (daily or weekly) are superior to large bolus doses.