In cross-sectional and case-control studies, patients with and without active TB are compared in terms of their concurrent nutritional status51–61. However, as stated above, TB itself causes physiological and metabolic changes resembling malnutrition. Such studies do not prove that pre-existing malnutrition contributes to the development of TB because there have been no accurate measurements of antecedent nutritional status in comparable cases and controls, but they do demonstrate the nutritional aberrations that accompany TB.
Several studies examined micronutrient status in TB patients and compared them with healthy individuals in a cross-sectional design, or before and after chemotherapy in a prospective design. In some studies, the effect of HIV status on micronutrient levels within the TB patients was examined. Karyadi et al.62 reported that TB patients were more anemic and had lower plasma concentrations of retinol and zinc than controls, and these abnormalities were exacerbated in patients with other indices of general malnutrition (e.g. low body mass index [BMI]). In a study in Ecuador, Koyanagi et al.63 observed that TB patients had significantly lower serum concentrations of zinc, retinol and selenium associated with an acute phase reponse. Similar observations were made in Malawi64, where more than 800 TB patients demonstrated deficiencies in circulating selenium, carotenoids and vitamin A, and these deficiencies were exacerbated in the most severely wasted group (BMI<16). Interestingly, there were no significant differences in plasma micronutrient concentrations between the HIV-infected and HIV-uninfected
TB patients. A second paper from the same research group65 confirmed that low plasma selenium levels were associated with anemia in TB patients, as were high HIV loads and elevated IL-6 concentrations.
A similar cross-sectional study was carried in out in Ethiopia66 in 155 TB patients, 74 of whom were co-infected with HIV. HIV co-infection was associated with lower serum zinc and selenium concentrations and an elevated copper/zinc ratio compared with TB patients without HIV. After the intensive phase of antibiotic therapy, serum levels of both selenium and zinc had improved in both patient groups. A beneficial effect of anti- mycobacterial therapy was also reported in a study of paediatric TB patients in India67. Prior to therapy, these children had markedly reduced levels of plasma zinc, irrespective of their general nutritional status, and there was significant improvement after 6 months of anti-TB therapy. Turkish investigators68 also observed a significant improvement in serum zinc (which increased) and copper/zinc ratios (which decreased) after 2 months of anti-TB therapy in 22 adult patients.
Anti-oxidant vitamins have been associated with clinical TB in several recent cross- sectional studies. A study of Ethiopian TB patients, with and without HIV, reported that serum concentrations of vitamins C, E and A were significantly lower in patients than in healthy controls. High malonaldehyde concentrations, an indicator of overall oxidant stress, were associated with increased clinical severity of TB, and these parameters were exacerbated in co-infected individuals69. Similar results were obtained in 159 Russian TB patients, who were found to have reduced dihydroascorbic acid levels compared with control patients with pneumonia70. Wiid et al.71 observed significantly lower total antioxidant status (TAS) in TB patients compared with community controls, and TAS values increased during anti-mycobacterial chemotherapy. Similar results were seen with vitamin A and zinc levels, but not with vitamin E. The vitamin A status of 100 HIV-infected and HIV–uninfected TB patients was studied in Tanzania before and after the intensive phase of anti-TB therapy72. The authors reported that vitamin A levels were low in TB patients and improved with therapy in HIV-negative, but not in HIV- infected patients. HIV infection was also associated with low vitamin A status in healthy controls. In India, Ramachandran et al.73 observed low serum vitamin A levels in 47 newly-diagnosed TB patients compared with household contacts and healthy controls.
Their vitamin A status improved significantly following anti-TB therapy without the need for vitamin A supplementation. Reduced serum concentrations of vitamin A were observed in HIV-infected, TB patients in Rwanda, and were lowest in patients who had experienced recent wasting. Unfortunately, no HIV-uninfected TB patients or healthy control groups were included in that study74.
Another vitamin that has been linked to TB is vitamin D because of its importance as a macrophage-activating hormone. Two cross-sectional studies examined the dynamics
vitamin D in lymphocytes and macrophages from patients with TB compared with controls. T lymphocytes, predominantly CD4+ cells obtained by bronchoalveolar lavage from TB patients, expressed specific receptors for the directly bioactive hormonal form (i.e. 1,25(OH)2 vitamin D3), but not its precursor 25(OH)D375. Purified T lymphocytes from all patients with TB produced 1,25(OH)2D3 which correlated closely with that produced by lavage cells. Since 1,25(OH)2D3 can improve the capacity of macrophages to kill mycobacteria, the authors concluded that macrophage activation by vitamin D may contribute to anti-tuberculosis resistance76. In addition, a few studies have detected vitamin D receptor genetic polymorphisms that are associated with vitamin D deficiency and increased incidence of TB. Two studies demonstrated that TB patients of Asian and African origin in the United Kingdom were significantly vitamin D deficient77, and that vitamin D receptor polymorphisms were found among vegetarians from Gujarati, India78. Two additional studies, one in India79 and the other in Africa80 also found vitamin D deficiency associated with receptor polymorphisms in TB patients. Recently, in vitro studies of human macrophages have begun to reveal the mechanisms that may underly the link between vitamin D deficiency and TB. Cellular immune functions that depend on vitamin D include the induction of important innate macrophage functions via Toll-like receptor ligation of mycobacterial cell surface molecules81, the mycobacteria- specific activation of T lymphocytes by infected macrophages82, and the critical fusion of phagosomes containing mycobacteria with lysosomes within infected macrophages83 (see also Chapter 4: Human Nutrition) .
Cohort studies
The unique strength of cohort studies is that nutritional status is measured prior to the onset of TB. Only two cohort studies, both assessing vitamin C, examined the relationship between micronutrients and TB incidence. Getz et al.84 examined 1100 men for the onset of TB by clinical, radiographic and laboratory criteria for up to 5 years.
Plasma levels of both vitamins A and C were low in most men who developed active TB compared with those who did not. Investigators in Finland85 randomised 26.975 healthy males to supplementation with tocopherol, beta-carotene, both or neither, to determine the impact of these anti-oxidants on cancer, and followed up the subjects for a mean 6.7 years. The data were analysed for a relationship between the intake of vitamin C and vitamin C-rich foods and a diagnosis of TB. Increased intake of vitamin C and fruits and vegetables was associated with an adjusted relative risk of TB of 0.4 (95% confidence interval 0.2–0.7).
Indicators of general nutritional status were analysed as part of the long-term follow-up of participants in the large-scale BCG vaccine trials in Georgia and Alabama.
Comstock and Palmer reported that the incidence of TB was 2.2 times higher in children with 0–4 mm subcutaneous fat than in those with >10 mm subcutaneous fat86. Cegielski et al. examined the relationship between under-nutrition and the incidence of TB based on data from a nationally representative population of adults in the US from 1971 to 1987. Baseline data on nutritional status were derived from the first National Health and Nutrition Examination (NHANES-1), a cross-sectional survey of the US population from 1971 to 1975, after excluding persons with previous TB. The NHANES-1 Epidemiological Follow-up Study (NHEFS) followed up more than 95% of the adult subjects of NHANES-1 for a median of 9 years to relate health outcomes to baseline characteristics. Individuals with a BMI, average skin-fold thickness, or upper arm muscle area in the lowest decile of the population suffered an increased risk of TB from six- to ten-fold, controlling for other known risk factors87. Of all the cohort studies, this is the only one that was (1) based on a representative sample of any national population, (2) excluded patients who had TB before enrollment (or that developed shortly after enrollment), and (3) used multivariable analysis to isolate the effects of nutritional status independent of other known risk factors for TB. In later analyses of these data, the BMI cut-off point for under-nutrition in the US at the time these data were collected (<20.0 vs. >20.0) was compared with the cut-off point that is currently used in the US (<18.5 vs. >18.5) and the same results were obtained. Defining under-nutrition in absolute terms rather than in relative terms may make these results more broadly applicable to populations outside of the US.
Palmer et al.88 studied the relationship of TB incidence to PPD hypersensitivity in 68,754 US Navy recruits from 1949 to 1951. During 4 years of follow-up, 109 developed TB. These investigators related the risk of TB to a weight-height index calculated from the entrance medical examination on a stratified random sample of 1138 subjects. TB incidence was 75/100 000 for those 15% or more below the median weight for their height and decreased to 19/100 000 for those at least 5% overweight for their height (p< 0.01). The trends were the same regardless of the degree of tuberculin sensitivity.
Edwards et al.89–90 extended Palmer’s study to over 823 000 Navy recruits, and found that TB developed three times more often in young men 10% or more below their ideal body weight than those 10% or more above it. Despite some methodological flaws91, these studies are important because of the large sample size and consistency of the findings. Curiously, these authors did not interpret low weight-for-height as an indication of malnutrition. Rather, they concluded that there was an association between “body build” and risk of TB disease88–90.
Although ignoring the obvious implications of low weight-for-height as an indicator of malnutrition seems counter-intuitive, the concept of body build as an independent risk factor for tuberculosis has been reported by others92. A mass radiography screening programme for TB in Norway93 covered 42% to 85% of the population depending upon the
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.