Infection with Mycobacterium tuberculosis Beijing genotype strains is associated with polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis.

Differences in host immune genes may predispose to tuberculosis caused by particular Mycobacterium tuberculosis genotypes. We examined this hypothesis in Indonesia by spoligotyping M. tuberculosis isolates recovered from 336 patients with pulmonary tuberculosis and typing the patients' SLC11A1 gene (formerly known as "NRAMP1"), which is involved in susceptibility to tuberculosis. The M. tuberculosis Beijing genotype, which comprised 29.8% of all isolates, was strongly associated with 2 polymorphisms in SLC11A1: the D543N G allele (odds ratio [OR], 2.15; P=.005) and the 3' untranslated region (3'UTR) insertion/insertion genotype (OR, 2.5; P=.001). This finding supports the hypothesis of coevolution of M. tuberculosis and the human immune system.

The effect of type 2 diabetes mellitus on the presentation and treatment response of pulmonary tuberculosis.

BACKGROUND: Diabetes mellitus (DM) is a known risk factor for tuberculosis (TB), and with the increasing prevalence of type 2 DM in less developed regions, many patients with TB will have concomitant DM. Presently, little is known about the effect of DM on the clinical presentation and treatment outcome of TB. METHODS: In an urban setting in Indonesia, 737 patients with pulmonary TB were screened for DM and were followed up prospectively during TB treatment. Clinical characteristics and outcome were compared between patients with TB who had DM and patients with TB who did not have DM. RESULTS: DM was diagnosed in 14.8% of patients with TB and was associated with older age and a greater body weight. On presentation, diabetic patients with TB had more symptoms but had no evidence of more-severe TB. After 2 months, results of sputum microscopic examination was more often positive in diabetic patients (18.1% vs. 10.0%). After 6 months, 22.2% of cultured sputum specimens from diabetic patients were positive for Mycobacterium tuberculosis (adjusted odds ratio, 7.65; P=.004). CONCLUSION: DM seems to have a negative effect on the outcome of TB treatment. The underlying mechanisms for the different response to treatment in diabetic patients with TB must be explored. Screening for DM and subsequent glycemic control may improve the outcome of TB treatment.

Cytokines related to nutritional status in patients with untreated pulmonary tuberculosis in Indonesia.

Although several studies have dealt with the patterns of cytokine production in tuberculosis, little is known about the association between nutrient deficiencies and cytokines in tuberculosis. The objective of this study was to assess the concentration of cytokines related to nutritional status during tuberculosis. In 41 untreated tuberculosis patients and matched healthy controls in an urban hospital in Indonesia, we measured: height and weight, parameters of iron, vitamin A and zinc; and cytokines concentrations in the circulation and production in whole blood cultures. Plasma interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were significantly higher in patients than in controls. Patients with cavities (n=26) had higher concentrations of IL-6 than patients without cavities (n=15). Body mass index <18.5 kg/m2 was associated with high concentrations of tumor necrosis factor-alpha (TNF-alpha) and IL-6. Anaemia was associated with high concentrations of IL-6 and IL-1ra. Zinc deficiency was associated with high LPS-stimulated production of TNF-alpha and IL-1ra. Marginal plasma retinol concentrations were associated with high concentrations of IL-6 after LPS stimulation. In conclusion, low concentrations of micronutrients in tuberculosis were associated with increased cytokine production. An intervention study would allow causality to be examined.

Dynamic changes in pro- and anti-inflammatory cytokine profiles and gamma interferon receptor signaling integrity correlate with tuberculosis disease activity and response to curative treatment.

Pro- and anti-inflammatory cytokines and their signaling pathways play key roles in protection from and pathogenesis of mycobacterial infection, and their balance and dynamic changes may control or predict clinical outcome. Peripheral blood cells' capacity to produce proinflammatory (tumor necrosis factor alpha [TNF-alpha], interleukin-12/23p40 [IL-12/23p40], and gamma interferon [IFN-gamma]) and anti-inflammatory (IL-10) cytokines in response to Mycobacterium tuberculosis or unrelated stimuli (lipopolysaccharide, phytohemagglutinin) was studied in 93 pulmonary tuberculosis (TB) patients and 127 healthy controls from Indonesia. Their cells' ability to respond to IFN-gamma was examined to investigate whether M. tuberculosis infection can also inhibit IFN-gamma receptor (IFN-gammaR) signaling. Although there was interindividual variability in the observed responses, the overall results revealed that M. tuberculosis-induced TNF-alpha and IFN-gamma levels showed opposite trends. Whereas TNF-alpha production was higher in active-TB patients than in controls, IFN-gamma production was strongly depressed during active TB, correlated inversely with TB disease severity, and increased during therapy. By contrast, mitogen-induced IFN-gamma production, although lower in patients than in controls, did not change during treatment, suggesting an M. tuberculosis-specific and reversible component in the depression of IFN-gamma. Depressed IFN-gamma production was not due to decreased IL-12/IL-23 production. Importantly, IFN-gamma-inducible responses were also significantly depressed during active TB and normalized during treatment, revealing disease activity-related and reversible impairment in IFN-gammaR signaling in TB. Finally, IFN-gamma/IL-10 ratios significantly correlated with TB cure. Taken together, these results show that M. tuberculosis-specific stimulation of IFN-gamma (but not TNF-alpha) production and IFN-gammaR signaling are significantly depressed in active TB, correlate with TB disease severity and activity, and normalize during microbiological TB cure. The depression of both IFN-gamma production and IFN-gammaR signaling may synergize in contributing to defective host control in active TB.

Imported malaria in Jakarta, Indonesia: passive surveillance of returned travelers and military members postdeployment.

BACKGROUND: Autochthonous malaria does not currently occur in Jakarta, the most populous city in Indonesia. Military, forestry, mining, and tourist activities draw Jakarta residents to distant parts of the archipelago with high rates of malaria. Although malaria is a reportable disease in Jakarta, little has been published. METHODS: We collected demographic and travel information from patients in Jakarta with microscopically confirmed malaria from January 2004 to February 2005, using a standardized data collection form. These results were compared to regional rainfall statistics and transit patterns of Jakarta residents to and from rural areas. RESULTS: Data from 240 patients were collected. Aceh Province was the travel destination most commonly recorded for military members, while Papua and Bangka Island were the most frequently cited by civilians. Plasmodium falciparum accounted for 53% of cases, of which 15% had detectable gametocytemia. The most common admission diagnoses were malaria (39%), febrile illness not otherwise specified (23%), viral hepatitis (19%), and dengue (11%). The median time from admission to microscopic diagnosis was 2 days for civilian patients and 2.5 days for military patients. The highest number of cases occurred in May, July, and December with the nadir in October. CONCLUSIONS: The diagnosis of malaria may be overlooked and therefore delayed, in nonendemic areas such as Jakarta. Travel destinations associated with contracting malaria vary significantly for civilian and military populations. The factors affecting the peak months of importation likely include rainfall, holiday transit, military flight availability, and referral center locations.

A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status.

BACKGROUND: The results of cross-sectional studies indicate that micronutrient deficiencies are common in patients with tuberculosis. No published data exist on the effect of vitamin A and zinc supplementation on antituberculosis treatment. OBJECTIVE: Our goal was to investigate whether vitamin A and zinc supplementation increases the efficacy of antituberculosis treatment with respect to clinical response and nutritional status. DESIGN: In this double-blind, placebo-controlled trial, patients with newly diagnosed tuberculosis were divided into 2 groups. One group (n = 40) received 1500 retinol equivalents (5000 IU) vitamin A (as retinyl acetate) and 15 mg Zn (as zinc sulfate) daily for 6 mo (micronutrient group). The second group (n = 40) received a placebo. Both groups received the same antituberculosis treatment recommended by the World Health Organization. Clinical examinations, assessments of micronutrient status, and anthropometric measurements were carried out before and after 2 and 6 mo of antituberculosis treatment. RESULTS: At baseline, 64% of patients had a body mass index (in kg/m(2)) < 18.5, 32% had plasma retinol concentrations < 0.70 micromol/L, and 30% had plasma zinc concentrations < 10.7 micromol/L. After antituberculosis treatment, plasma zinc concentrations were not significantly different between groups. Plasma retinol concentrations were significantly higher in the micronutrient group than in the placebo group after 6 mo (P < 0.05). Sputum conversion (P < 0.05) and resolution of X-ray lesion area (P < 0.01) occurred earlier in the micronutrient group. CONCLUSION: Vitamin A and zinc supplementation improves the effect of tuberculosis medication after 2 mo of antituberculosis treatment and results in earlier sputum smear conversion.

Decreased plasma leptin concentrations in tuberculosis patients are associated with wasting and inflammation.

Tuberculosis patients often suffer from severe weight loss, which is considered to be immunosuppressive and a major determinant of severity and outcome of disease. Because leptin is involved in weight regulation and cellular immunity, its possible role in tuberculosis-associated wasting was investigated. In an urban clinic in Indonesia, plasma leptin concentrations, indicators of adipocyte mass, appetite, C-reactive protein (CRP), tuberculin reactivity, and cytokine response were measured in tuberculosis patients and healthy controls. Plasma leptin concentrations were lower in patients than in controls (615 vs. 2,550 ng/liter; P < 0.001). Multivariate regression analysis showed that body fat mass and inflammation were two independent factors determining plasma leptin concentrations; there was a positive correlation between fat and leptin, whereas, unexpectedly, leptin was inversely associated with CRP and tumor necrosis factor-alpha production. Concentrations of both CRP and leptin were independently associated with loss of appetite. Our results do not support the concept that weight loss in tuberculosis is caused by enhanced production of leptin. Rather, loss of body fat leads to low plasma leptin concentrations, and prolonged inflammation may further suppress leptin production. Because leptin is important for cell-mediated immunity, low leptin production during active tuberculosis may contribute to increased disease severity, especially in cachectic patients.