age group. Height and weight were measured accurately for nearly 80% of those screened, and over 1.7 million individuals were followed up for a mean of 12.1 years. The incidence of pulmonary, but not extrapulmonary, TB declined logarithmically with increasing BMI.
The age-adjusted incidence of new pulmonary TB was five times higher in the lowest BMI category than in the highest. The author argued that this association was a function of body build and did not discuss nutrition. Comstock94 suggested that body build may affect pulmonary mechanics and, thereby influence susceptibility to pulmonary TB, but no data are available to support this hypothesis. It seems unlikely that body build by itself predisposes to or protects against TB with no link to general nutritional status.
More recently, a number of trials of nutritional intervention during conventional chemotherapy of TB patients have been published. In one RCT96, 80 Indonesian patients with TB were found to have significant indices of malnutrition, including low BMI, and low plasma retinol and zinc. They were assigned to receive both retinol and zinc supplements (treated group) and placebo in addition to their standard anti-TB drugs. Significant improvements in sputum conversion and resolution of radiographic abnormalities were observed in the treated group, in association with a significant increase in plasma retinol after 6 months of therapy. Beginning at 2 weeks post-therapy, the percentage of patients with negative sputum smears was significantly higher (p<0.01) in the micronutrient-treated group (23%) compared with the placebo group (13%). Mean reduction in lesion area as determined radiographically was significantly greater in the micronutrient-treated group after two months of therapy (p<0.01). Furthermore, plasma retinol concentrations were correlated inversely with a reduction in mean lesion area at 6 months (r=−0.367; p=0.02).
Another RCT in a large (n=499) population of TB patients in Tanzania97, 98 examined the effect of supplementation with either zinc alone, multiple micronutrients (MMN, vitamins A, B, C, D, E and minerals Se, Cu), MMN + zinc, or a placebo. Approximately 43% of each group was HIV-infected, and all received standard anti-mycobacterial chemotherapy.
After 8 weeks of therapy, neither supplement had a significant effect on sputum culture positivity: however, the patients receiving the MMN experienced a significant improvement in body weight. HIV status had no influence on the outcome97. In a later publication on the same study, the authors reported that after 8 months of therapy, the group receiving the combined nutritional supplements (zinc + MMN) had a significantly reduced mortality (RR=0.29; CI: 0.10−0.80), but only in TB patients who were co-infected with HIV98.
Hanekom et al.99 conducted a RCT of vitamin A supplementation in 85 South African children with TB who were not co-infected with HIV. Children were given either 200 000 IU of retinyl palmitate or placebo on day 0 and day 1 after initial clinical evaluation and then followed up during 3 months of conventional anti-TB therapy. Nearly two-thirds of the patients were vitamin A-deficient at the beginning of the study, and the deficiency was more pronounced in children with extra-pulmonary disease. Vitamin A status improved in both groups during chemotherapy, but supplementation had no significant effect on the outcome of therapy as measured by weight gain, radiological improvement, serum biochemical parameters, etc. In a subsequent publication from the same RCT100, these authors reported that vitamin A supplementation did decrease significantly the circulating levels of CD30, a protein biomarker of a type 2 cytokine response.
Plasma CD30 concentrations were decreased by a factor of 0.99+/-0.02 in vitamin A-supplemented children, compared with 1.05+/-0.02 in the placebo group (p=0.02).
These results indicate that vitamin A supplementation may promote the establishment of a beneficial type 1 cytokine profile in children with TB.
Three other RCTs examined the impact of supplementing zinc, iron or vitamin D on the outcome of chemotherapy in TB patients. In the first study101, 66 HIV-infected TB patients in Singapore who were receiving antiretroviral and anti-TB therapies were assigned to 28 days of oral zinc sulfate supplements or placebo. The authors examined several parameters of TB-specific immunity, including PPD-stimulated IFNγ production, and found no significant effect of zinc supplementation. Perhaps this is not surprising since nearly all (94%) of the subjects exhibited normal plasma zinc levels at baseline. In another study102, 117 adult, male TB patients in India with anaemia were enrolled in an RCT of iron supplementation during the first 2 months of conventional anti-TB therapy.
Follow-up assessment was conducted at 1, 2 and 6 months after initiation of the trial. The authors reported improvement in haematological status as the TB disease improved, but supplemental iron appeared to have no additional beneficial effect on treatment outcome as determined principally by degree of radiographic abnormality that was still present after 6 months of standard chemotherapy. Finally, 24 newly diagnosed paediatric TB patients in Egypt were enrolled in an RCT to examine the effect of vitamin D supplementation (1000 IU/day for 8 weeks) on the outcome of anti-TB therapy103. Although the authors reported that most of the children were vitamin D-deficient at baseline and serum levels of 1,25 (OH)2D3 improved in both groups during chemotherapy, supplementation did not affect this parameter. However, the supplemented group showed significant radiological and clinical improvement at follow-up compared with the placebo group. Body weights of vitamin D-supplemented children increased significantly at 8 weeks after treatment (3.3 kg) compared with the placebo group (2.2 kg) (p<0.05).
Inducible nitric oxide (NO) is a critical proximal mediator of anti-mycobacterial resistance in rodent models of TB104. The central role of NO in human TB remains controversial; however, some supportive evidence has been published recently105. Since the amino acid arginine is a precursor in the biosynthetic pathway of NO production, a case can be made for the value of arginine supplementation to improve infectious disease outcomes106. An RCT of oral arginine supplementation was conducted in 120 HIV-infected and HIV–uninfected Ethiopian TB patients107. The patients received either 1 g/day of arginine or placebo daily for 4 weeks along with standard anti-TB therapy and clinical outcomes were assessed at 8 weeks. Arginine supplementation resulted in significant improvement in serum arginine levels, weight gain, sputum conversion rate, and reduction of symptoms compared with the placebo group, but only in HIV- uninfected patients. The percentage of patients with cough was reduced significantly (p<0.05) in the arginine-supplemented group (25%) compared with the placebo group (65%). The percentage of patients with negative sputum smears was significantly higher in the supplemented patients (100%) compared with the placebo group (85%) (p<0.05).
No treatment effect was observed in HIV co-infected patients.
Two additional recent RCTs of macronutrient supplementation during TB therapy may be worth noting, although both were quite small. Paton et al.108 gave a high-energy oral nutritional supplement (600−900 kcal/day) for 6 weeks to 19 HIV-uninfected TB patients in Singapore in conjunction with standard anti-TB therapy. Compared to 17 control TB patients who received nutritional advice but no supplements, the treated group exhibited significant increases in weight gain, total lean body mass, and grip strength. Unfortunately, no disease-specific results were reported in this publication, so the effect of supplementation on the outcome of TB treatment cannot be assessed. In a second small RCT109, investigators in Mexico City compared the clinical responses of 10 HIV-uninfected TB patients who received a cholesterol-rich diet (800 mg/day) with those of a group of 11 TB patients who consumed a control diet containing 250 mg/day of cholesterol during the first 8 weeks of standard anti-TB chemotherapy. Respiratory symptoms improved in both groups: however, the rate of sterilisation of sputum cultures increased significantly and sputum production decreased significantly in the patients consuming a high-cholesterol diet. At two weeks, the proportion of patients with negative sputum samples on the high-cholesterol diet (91%) was much higher than in the placebo group (20%) (p<0.002). The bacillary load in the sputum (measured in log10 colony- forming units per ml) was much lower in the cholesterol-supplemented patients (0.05) than in the placebo patients (3.4) (p<0.0002). The cholesterol content of the membranes of macrophage vesicles (i.e. phagosomes, lysosomes) has been shown to affect the ability of the phagocytes to suppress the intracellular growth of mycobacteria110, although the authors did not measure that parameter in cells from their patients.