We found that daily multivitamin supplementation in children with TB in a resource-limited setting resulted in an improvement in hemoglobin levels after two months of follow-up in all age groups and irrespective of HIV status. However, there was no effect of the supplement on albumin levels and growth indices, including weight, length/height, mid-upper arm circumference, head circumference, and triceps skin-fold thickness in the overall cohort. In subgroup analyses, significant weight gain among the youngest children (six weeks to six months) was observed. The results were similar in children also co-infected with HIV; however, these children had a significantly higher increase in height if between the ages of 6 months and three years.
There have been no earlier studies of multivitamin supplementation among children with TB. However, similar beneficial effects of supplements on hemoglobin levels have been obtained with micronutrient supplementation in children in other parts of the world. A recent review by Allen et al
reported that multiple micronutrient supplementation leads to a significant increase in hemoglobin in children (effect size 0.39; 95% CI 0.25, 0.53) [26
]. A pooled analysis used data from intervention trials in Indonesia, Peru, South Africa, and Vietnam among 1134 infants who had been randomized to either a placebo, weekly multiple micronutrient supplement (including vitamins A, D, E, K, C, B-1, B-2, B-6, and B-12, niacin, folate, iron, zinc, copper, and iodine), daily multiple micronutrient supplement, or daily iron supplements. The daily micronutrient supplement was found to be the most effective in controlling anemia and iron deficiency [27
The results are biologically plausible since the vitamins included in the supplement may lead to better hematologic status through several mechanisms [28
]. For example, vitamin C improves intestinal absorption of iron and may also enhance mobilization of iron stores and riboflavin is necessary for the synthesis of the globin component of hemoglobin.
The effects on growth indices have comparatively been less consistent; the review by Allen et al
reported small yet statistically significant improvements in length/height and weight in children supplemented with multiple micronutrients [26
]. On the other hand, the pooled analysis cited above found that infants receiving a daily micronutrient supplement had significantly greater weight gain, whereas there were no differences in height gain [27
]. In another meta-analyses of effects of micronutrient interventions on growth of children under five years of age, Ramakrishnan et al
. found that multiple micronutrient interventions improve linear growth only and had no effect on weight gain [18
]. Additionally, a few studies of multiple micronutrient supplementation in adults with tuberculosis have also been equivocal in their results on weight gain. For example, a study in Mwanza, Tanzania, found that multiple micronutrient supplementation (vitamins A, B-complex, C, D, and E, selenium, copper, and zinc) for the first two months of TB treatment led to reduced weight gain among the HIV-infected TB patients; the HIV-uninfected TB patients demonstrated a non-significant increase in weight at the end of follow-up [29
Several studies have found that serum albumin is lower among patients with TB [13
]; however, there are no studies assessing the effect of multivitamin supplementation on albumin levels among children with TB that we can directly compare our results to. The increase in albumin in all children observed in this trial is probably a response to adequate treatment for TB.
The main limitations of our trial were the small sample size and a short period of supplementation and follow-up; this could have led us to miss a beneficial effect of multivitamins on growth indices in the overall cohort, the primary outcome. The trial also was not designed to measure effects of multivitamins in subgroups such as those defined by age or HIV status; therefore, the findings of weight gain among the youngest children or height differences among HIV infected children between the ages of 6 months and 3 years cannot be treated as conclusive. Further, it is possible that we may have included children with other diseases, as TB diagnosis was not optimal. It is also possible that the nutrients such as zinc and vitamin D that were not included in our supplement are more essential for growth. The results of this trial should be generalizable to children with TB, with or without HIV co-infection, in most resource-limited settings.
The multivitamin supplement that we used has the potential to have several beneficial effects including on immune function in growing children, particularly those with TB as they may have several underlying micronutrient deficiencies, including those of vitamins B-complex, C, and E [36
]. These nutrients are extensively involved in the immune system and its ability to fight infectious diseases such as TB. For example, the B-vitamins are involved in increasing lymphocyte production, cell-mediated cytotoxicity, delayed-type hypersensitivity responses, and antibody production [37
]. Vitamin C helps improve T- and B-lymphocyte proliferative responses and reduces the concentration of proinflammatory cytokines [39
]. Vitamin E is responsible for improving delayed type hypersensitivity skin response, increasing IL-2 production, neutrophil phagocytosis, lymphocyte proliferation, and antibody response to T-cell dependent vaccines, and reducing production of inflammatory cytokines such as TNF- α and IL-6 [42
]. However, we did not observe an association between immune markers such as CD4, CD8, and CD3 T-cell count with multivitamin supplementation, except for children older than 3 years of age. We are not aware of any known age-specific effects of vitamins on CD8 cells in this age group that may explain this finding.
In conclusion, multivitamin supplementation had no effect on weight gain, the primary outcome of the trial. However, supplementation, even for a short period of eight weeks, improved the hematological profile of all children with TB and led to significant weight gain amongst the youngest patients (n = 22; age six weeks to six months). It is possible that older children need even greater doses of such nutrients to demonstrate an effect and for longer periods of time. The impact of multivitamin supplementation on other parameters such as treatment outcomes needs to be assessed in larger trials with a longer period of supplementation. If proven to be efficacious, multivitamin supplementation could represent an inexpensive adjunct to anti-tuberculous therapy, particularly in resource-limited settings.