To our knowledge, this is the first population-based study to evaluate and demonstrate an association between serum 25(OH)D level and URTI. The association seems to be robust, with a clinically and statistically significant association present in all seasons and when controlling for potential confounders. The dose-response association between lower levels of vitamin D and recent URTI provides further credibility to the findings.
Although early clinical studies14–22
supported an association between rickets found with serum 25(OH)D levels less than 10 ng/mL and RTI, more recent studies25–27
have found an effect of low (including nonrachitic) serum 25(OH)D levels. For example, Laaksi et al25
found that young male Finnish soldiers with serum 25(OH)D levels of less than 16 ng/mL at baseline had a 63% increased risk of absence from duty due to RTI than did soldiers with serum 25(OH)D levels 16 ng/mL or more during the following 6 months. In addition, case-control studies from India26
reported an association between serum 25(OH)D levels of less than 20 ng/mL and acute lower RTI in children and neonates, respectively.
In this study, we also found that individuals with respiratory tract diseases (ie, asthma and COPD) are of particular interest. Effect modification by asthma, and possibly COPD, on the association between serum 25(OH)D level and recent URTI indicates that the role of vitamin D may be of greater importance for individuals with these common conditions. Potential explanations may be that those with respiratory tract diseases are more susceptible to RTI31,32
and have increased frequency of lower respiratory tract symptoms of higher severity and longer duration.33,34
These findings are particularly important given the high morbidity from asthma and COPD exacerbation and merit further investigation.
Preliminary studies on vitamin D supplementation and RTI also have been promising. Two interventional cohort studies with 600 to 700 IU daily of vitamin D from cod liver oil and multivitamin supplementation35
and 60 000 IU weekly from a vitamin D or calcium supplement36
found a decrease in RTIs in children receiving supplementation. One randomized controlled trial37
of bone loss in postmenopausal black women found that 7.7% of women randomized to receive 800 to 2000 IU of vitamin D daily reported respiratory tract symptoms during 3-year follow-up compared with 25.0% in the control group. Another substudy38
of a randomized controlled trial for fracture prevention found a nonsignificant 10% reduced odds of wintertime infection in participants randomized to receive 800 IU of vitamin D daily (P
=.23). However, these studies were post hoc analyses of adverse events reported in studies of skeletal health, and dedicated trials are warranted.
The emerging role of vitamin D in innate immunity provides a plausible mechanism for the inverse association between serum 25(OH)D level and URTI.14
The only known human cathelicidin, hCAP-18 (LL-37), enhances microbial killing in phagocytic vacuoles, acts as a chemoattractant for neutrophils and monocytes, and has a defined vitamin D-dependent mechanism.39,40
Pathogenic antigens interact with toll-like receptors on macrophages to upregulate the expression of genes that code for the vitamin D receptor and for the 1α-hydroxylase enzyme that converts 25(OH)D to the biologically active 1,25-dihydroxyvitamin D.41,42
In turn, 1,25-dihydroxyvitamin D interacts with the promoter of the gene for cathelicidin,43
which enhances the production of hCAP-18.44,45
The presence of sufficient levels of 25(OH)D, the major circulating form of vitamin D, is necessary to activate hCAP-18 expression and to enhance macrophage function and innate immunity.45
In studies of Mycobacterium tuberculosis
, Liu et al42
found a direct association of serum 25(OH)D levels with cathelicidin expression and killing of intracellular M tuberculosis
. Furthermore, black individuals, known to have increased susceptibility to tuberculosis infection, had low serum 25(OH)D levels and inefficient cathelicidin messenger RNA induction, but supplementation of 25(OH)D to the reference range restored induction of cathelicidin messenger RNA.42
The results from our article provide additional evidence from a large, diverse population of the inverse association between serum 25(OH)D level and RTI. Although serum 25(OH)D levels of less than 10 ng/mL were associated with the highest rate of recent URTI, serum 25(OH)D levels of 10 to less than 30 ng/mL also were associated with higher adjusted odds of URTI compared with levels of 30 ng/mL or more. Although individuals with serum 25(OH)D levels of less than 10 ng/mL have the least efficient cathelicidin expression, serum 25 (OH)D levels of 30 ng/mL or more may be necessary for the optimal induction of cathelicidin messenger RNA.42
Although comparison of groups with 25(OH)D levels of 30 to less than 40 ng/mL and 40 ng/mL or more suggested a possible plateau of effect after approximately 30 ng/mL, this analysis was underpowered to evaluate whether higher 25(OH)D levels (ie, 40 ng/mL) provide additional benefit.
Current recommendations for vitamin D supplementation (200–600 IU/d) are unlikely to achieve optimal serum 25(OH)D levels (ie, approximately 30–40 ng/mL) in most of the US population.46
Randomized controlled trials of higher-dose vitamin D supplementation (≥1000 IU/d), particularly in the winter season, at higher latitudes, and for individuals with respiratory tract diseases, will help clarify the role of vitamin D supplementation in the reduction of RTI.
This study has some potential limitations. We could not control for all potential confounders, but we selected covariates most likely to be associated with serum 25(OH)D level and recent URTI. Unmeasured confounders may have an effect on the association between 25(OH)D level and URTI. Thus, causal inference is not possible, and we cannot exclude that the results are merely an epiphenomenon; randomized controlled trials are valuable for determining the causal nature of an observed association. Reverse causation (ie, lower serum 25[OH]D levels due to recent URTI and, thus, decreased outdoor activity) seems unlikely because the half-life of serum 25(OH)D is 2 to 3 weeks11
and URTIs last only 3 to 4 days,3
but it may affect the enhanced vitamin D-URTI association in participants with asthma and COPD owing to longer symptom duration in those individuals.
The primary outcome (recent URTI) is a relatively crude and self-reported measure that may include other non-RTIs; however, limitations on the accuracy of this outcome would be expected to reduce the magnitude of associations. Serum samples were collected at only 1 point in time and were preferentially collected in northern states in the summer and in southern states in the winter. As a result, serum 25(OH)D levels are likely higher than would be expected by random sampling across all seasons. Although the overall serum 25(OH)D level and the recent URTI rate may be affected, it is unlikely that their association would be materially different. Nevertheless, we encourage efforts to replicate these findings in independent samples.
In conclusion, serum 25(OH)D levels have an independent, inverse association with recent URTI. Although 25(OH)D levels less than 30 ng/mL and URTI were higher in the winter season, the inverse association was present throughout the year. Individuals with respiratory tract diseases, such as asthma, who have low serum 25(OH)D levels may be even more susceptible to RTI. Vitamin D supplementation may reduce the incidence of URTI and exacerbations of respiratory tract diseases. Randomized controlled trials are warranted to explore the direct effect of vitamin D supplementation and to establish optimal levels of serum 25(OH)D in the prevention of RTI.