Vitamin D Deficiency Associated With Increased Incidence of Gastrointestinal and Ear Infections in School-age Children

Kathryn A. Thornton, DMD, MPH; Constanza Marín, RD; Mercedes Mora-Plazas, MSc, RD; Eduardo Villamor, MD, DrPH

Disclosures

Pediatr Infect Dis J. 2013;32(5):585-593. 

In This Article

Discussion

In this prospective study of school-age children, VDD was associated with increased rates of vomiting, diarrhea with vomiting and earache or ear discharge with fever. These associations persisted after adjustment for potential confounders, including age, sex and socioeconomic status.

The association of VDD with diarrhea and vomiting could represent an effect on incidence or severity of gastrointestinal infections. Diarrhea and vomiting are symptoms often present in children with acute viral and bacterial gastrointestinal infections.[36–40] Norovirus infection is a common cause of diarrhea with vomiting or vomiting alone in school-age children.[41–43] These symptoms are likely the result of the virus's pathogenic effects on the intestinal epithelial barrier.[44] A protective effect of vitamin D in the course of norovirus infection could be related to VDR-mediated upregulation of tight junction proteins expressed in the intestinal epithelium.[45,46] Bacterial agents, such as Salmonella and Shigella, also cause diarrhea and vomiting in school-age children.[47,48] Animal and in vitro studies have demonstrated that VDR expression is associated with reduced Salmonella colonization and mucosal invasion.[49]Shigella can downregulate expression of antimicrobial peptides, a component of the innate immune system that serves as part of the first line of mucosal defense against invading pathogens.[50] On the contrary, vitamin D influences innate immunity through expression of the cathelicidin antimicrobial peptide gene as well as promotion of macrophage activity.[51,52] Thus, vitamin D-deficient children may be more susceptible to develop more severe symptoms or may be more likely to become infected with these microorganisms through different mechanisms that are likely pathogen-specific.

Few previous studies have reported on the potential effect of vitamin D on gastrointestinal infections in children (Table 3). Tanzanian children born to mothers with serum 25(OH)D <80 nmol/L during pregnancy had no increased risk of diarrhea over a median follow-up time of 58 months.[56] Vitamin D supplementation in a randomized controlled trial in school-age children did not reduce the incidence of gastroenteritis, a secondary outcome of the trial.[16] Consistent with our findings, a cross-sectional study of 458 Qatari children reported a significantly higher prevalence of gastroenteritis among those who were vitamin D-deficient.[65] However, in this cross-sectional study, vitamin D status was measured concurrently with disease diagnosis; thus, the potential for reverse causation in which infection may have affected 25(OH)D concentrations cannot be excluded. Immune cells are able to alter vitamin D metabolism in several diseases.[68]

We also found that VDD was associated with increased report of days with earache or ear discharge and fever, especially among boys. These symptoms are typical of otitis media, usually caused by bacteria including Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae.[69,70] Increased production of antimicrobial peptides that form part of the initial mucosal defense in the respiratory tract is one possible mechanism through which vitamin D might enhance resistance to infection by these pathogens.[71] Although an association of VDD with ear infection has not been documented before, previous investigations suggest a protective role of vitamin D against other respiratory tract infections. In infants and children, maternal or child 25(OH)D serum or plasma levels have been inversely associated with risk or severity of acute lower respiratory infection,[11–14,57,59] RSV[15] or tuberculosis.[67] In addition, a polymorphism of the VDR gene was associated with higher risk of severe RSV disease in case-control studies of hospitalized children with RSV infection in The Netherlands and South Africa.[72,73] By contrast, 1 case-control study of Yemeni children found an inverse relation between VDD and chronic suppurative otitis media.[62] This study may have been limited by reverse causation bias given that 25(OH)D levels were measured in children who had had ear discharge for at least 2 weeks before enrollment. Although VDD increased the risk of earache/discharge with fever in our cohort, vitamin D insufficiency was associated with a reduced incidence of these symptoms. Whether this might be due to heterogeneity in the etiology of ear disease deserves further investigation. Chronic suppurative otitis media involves a broader spectrum of bacterial pathogens than acute otitis media,[74] and the nonlinearity of the association of vitamin D status with ear symptoms in our study may represent a weaker or detrimental effect of vitamin D on chronic infection than on the acute forms of disease.

Although several previous studies have found increased risk of respiratory illness with VDD, we did not find an elevated rate of cough with fever among vitamin D-deficient school-age children. Most of the literature describing the effects of vitamin D on infection in children has been limited to age groups less than 5 years. It is possible that the effect of vitamin D on respiratory illness varies among children of different ages because the pathogens involved in the etiology of respiratory infection differ. For example, in a study of children hospitalized with lower respiratory tract infections, the proportion of infections due to viral agents was highest in infants, whereas the proportion of identifiable infections attributable to bacterial pathogens was greatest in children more than 5 years of age.[75] Cough and fever are nonspecific symptoms of respiratory infections, such that they cannot be used to differentiate among the potential etiologic agents of disease, including viruses, bacteria and atypical organisms.[76] We relied on self-reported symptoms of common childhood infections but it was not possible to establish clinical diagnoses or confirm an infectious etiology of the reported morbidities.

It is unclear why the association between vitamin D serostatus and rates of earache/discharge with fever and cough with fever varied by sex. Randomized trials show sex-differential effects of vitamin A supplementation administered with bacille Calmette-Guérin vaccine with respect to vaccine response, mortality and measles incidence.[77–80] While boys demonstrated a more prominent Th1 profile than girls, girls had a more robust Th2 profile. Data from in vitro and animal studies generally show that vitamin A enhances the Th2-type response to infection.[81] Vitamin D similarly dampens the Th1-type response in favor of a Th2-type response,[82] and this might help explain the differential effects of inadequate vitamin D status on morbidity in boys and girls.

One strength of our study is its longitudinal design, which largely precludes the possibility of reverse causation bias. In addition, prospective collection of information on the morbidity events prevents the occurrence of outcome misclassification bias due to differential recall. A possible limitation is the use of 1 measurement of 25(OH)D levels to ascertain exposure status at baseline. However, repeated measures of 25(OH)D concentrations over time indicate that within-subject correlation is high, suggesting that a single measurement could represent long-term exposure.[83]

In summary, VDD was associated with increased rates of ear and gastrointestinal morbidity in a cohort of school-age children. These results add to the growing body of evidence supporting a role for vitamin D in the susceptibility to infection-related illness in children. Randomized intervention trials are needed to ascertain whether vitamin D supplementation reduces the risk of otitis media and gastrointestinal morbidities experienced in children more than 5 years of age.

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