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Competing Interests: SM declares an unpaid board membership in VitaScan, which is a company that develops assays for quantifying micronutrient biomarkers at the point-of-care, partially based on technology developed in his research laboratory at Cornell University and has work underway related to iron status diagnostics but not tuberculosis or food or nutrition supplements. PS declares no competing interests.

Objectives: Our study goal was to evaluate a set of nutritional indicators among adults with confirmed or suspected active tuberculosis disease in southern India, given the limited literature on this topic. Study objectives were to assess the: I) double burden of malnutrition at individual and population levels; II) relative performance of anthropometric indicators (body mass index, waist circumference) in diabetes screening; and III) associations between vitamin D and metabolic abnormalities., Design: Cross-sectional study., Setting: Hospital in rural southern India., Participants: Among adult patients (n = 834), we measured anthropometry, body composition, and biomarkers (vitamin D, glycated hemoglobin, hemoglobin) of nutritional status. Subsets of participants provided blood and sputum samples., Results: Among participants, 91.7% had ≥ 1 malnutrition indicator; 34.6% had both undernutrition and overnutrition indicators. Despite the fact that >80% of participants would be considered low-risk in diabetes screening based on low body mass index and waist circumference, approximately one-third had elevated glycated hemoglobin (≥ 5.7%). The lowest quintile of serum 25-hydroxyvitamin D was associated with an increased risk of glycated hemoglobin ≥ 5.7% (adjusted risk ratio 1.61 [95% CI 1.02, 2.56]) compared to the other quintiles, adjusting for age and trunk fat., Conclusions: Malnutrition and diabetes were prevalent in this patient population; since both can predict poor prognosis of active tuberculosis disease, including treatment outcomes and drug resistance, this emphasizes the importance of dual screening and management of under- and overnutrition-related indicators among patients with suspected or active tuberculosis disease. Further studies are needed to determine clinical implications of vitamin D as a potential modifiable risk factor in metabolic abnormalities, and whether population-specific body mass index and waist circumference cut-offs improve diabetes screening., Competing Interests: E.A.Y., J.L.F., P.M.B., W.B., and D.G.R. have no conflicts of interest. S.M. is an unpaid board member of and holds equity stake in a diagnostic start-up focused on developing assays for low-cost and point-of-care measurement of certain nutrients from a drop of blood using results from his research as a faculty member at Cornell University. M.J.G. receives funding to his institution from Gilead Sciences for an investigatorinitiated study unrelated to the current work. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The identification of immune correlates that are predictive of disease outcome for tuberculosis remains an ongoing challenge. To address this issue, we evaluated gene expression profiles from peripheral blood mononuclear cells following ex vivo challenge with Mycobacterium tuberculosis, among participants with active TB disease (ATBD, n = 10), latent TB infection (LTBI, n = 10), and previous active TB disease (after successful treatment; PTBD, n = 10), relative to controls (n = 10). Differential gene expression profiles were assessed by suppression-subtractive hybridization, dot blot, real-time polymerase chain reaction, and the comparative cycle threshold methods. Comparing ATBD to control samples, greater fold-increases of gene expression were observed for a number of chemotactic factors (CXCL1, CXCL3, IL8, MCP1, MIP1α). ATBD was also associated with higher IL1B gene expression, relative to controls. Among LTBI samples, gene expression of several chemotactic factors (CXCL2, CXCL3, IL8) was similarly elevated, compared to individuals with PTBD. Our results demonstrated that samples from participants with ATBD and LTBI have distinct gene expression profiles in response to ex vivo M. tuberculosis infection. These findings indicate the value in further characterizing the peripheral responses to M. tuberculosis challenge as a route to defining immune correlates of disease status or outcome.

AbstractThe human microbiome is an intriguing potentially modifiable risk factor in our arsenal against Mycobacterium tuberculosis , the leading infectious disease killer globally. Previous studies have shown associations between the human microbiome and pulmonary disease states; however, etiological links between the microbiome and tuberculosis (TB) infection or disease remain unclear. Immunomodulatory roles of the microbiome may prove to be a critical asset in the host response against TB, including in preventing TB infection, reducing progression from latency, mitigating disease severity, and lowering the incidence of drug resistance and coinfections. This review examined the associations between TB and the gut and lung microbiome. Eight studies were identified through a PubMed database search, including one animal study ( N = 1), case report ( N = 1), and case-control studies ( N = 6). TB infection and disease were associated with reduced gastrointestinal microbial diversity in a murine model and human case report. Sputum microbial diversity differed by TB status in case-control studies, although some reported heterogeneous findings. Current evidence suggests that the gut and lung microbiome are associated with TB infection and disease. However, as studies are limited, etiological and longitudinal research is needed to determine clinical relevance.

Background: Children with tuberculosis often have underlying nutritional deficiencies. Multivitamin supplementation has been proposed as a means to enhance the health of these children; however, the efficacy of such an intervention has not been examined adequately., Methods: 255 children, aged six weeks to five years, with tuberculosis were randomized to receive either a daily multivitamin supplement or a placebo in the first eight weeks of anti-tuberculous therapy in Tanzania. This was only 64% of the proposed sample size as the trial had to be terminated prematurely due to funding constraints. They were followed up for the duration of supplementation through clinic and home visits to assess anthropometric indices and laboratory parameters, including hemoglobin and albumin., Results: There was no significant effect of multivitamin supplementation on the primary endpoint of the trial: weight gain after eight weeks. However, significant differences in weight gain were observed among children aged six weeks to six months in subgroup analyses (n=22; 1.08 kg, compared to 0.46 kg in the placebo group; 95% CI=0.12, 1.10; p=0.01). Supplementation resulted in significant improvement in hemoglobin levels at the end of follow-up in children of all age groups; the median increase in children receiving multivitamins was 1.0 g/dL, compared to 0.4 g/dL in children receiving placebo (p<0.01). HIV-infected children between six months and three years of age had a significantly higher gain in height if they received multivitamins (n=48; 2 cm, compared to 1 cm in the placebo group; 95% CI=0.20, 1.70; p=0.01; p for interaction by age group=0.01)., Conclusions: Multivitamin supplementation for a short duration of eight weeks improved the hematological profile of children with tuberculosis, though it didn't have any effect on weight gain, the primary outcome of the trial. Larger studies with a longer period of supplementation are needed to confirm these findings and assess the effect of multivitamins on clinical outcomes including treatment success and growth failure. CLINICALTRIALS.GOV IDENTIFIER: NCT00145184.

A triage test for tuberculosis: Tuberculosis remains a global health burden. Ahmad et al. used machine learning to develop an algorithm that distinguished active tuberculosis from other diseases with similar symptoms by measuring expression of four proteins in blood samples. The authors validated their triage test's discriminatory power using blood samples from subjects with persistent cough across several continents, showing that performance was improved when detection of antibodies against a mycobacterial antigen was added to the panel. These promising results support further development and field testing using a point-of-care format. Improved tuberculosis (TB) prevention and control depend critically on the development of a simple, readily accessible rapid triage test to stratify TB risk. We hypothesized that a blood protein-based host response signature for active TB (ATB) could distinguish it from other TB-like disease (OTD) in adult patients with persistent cough, thereby providing a foundation for a point-of-care (POC) triage test for ATB. Three adult cohorts consisting of ATB suspects were recruited. A bead-based immunoassay and machine learning algorithms identified a panel of four host blood proteins, interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF), that distinguished ATB from OTD. An ultrasensitive POC-amenable single-molecule array (Simoa) panel was configured, and the ATB diagnostic algorithm underwent blind validation in an independent, multinational cohort in which ATB was distinguished from OTD with receiver operator characteristic–area under the curve (ROC-AUC) of 0.80 [95% confidence interval (CI), 0.75 to 0.85], 80% sensitivity (95% CI, 73 to 85%), and 65% specificity (95% CI, 57 to 71%). When host antibodies against TB antigen Ag85B were added to the panel, performance improved to 86% sensitivity and 69% specificity. A blood-based host response panel consisting of four proteins and antibodies to one TB antigen can help to differentiate ATB from other causes of persistent cough in patients with and without HIV infection from Africa, Asia, and South America. Performance characteristics approach World Health Organization (WHO) target product profile accuracy requirements and may provide the foundation for an urgently needed blood-based POC TB triage test. [ABSTRACT FROM AUTHOR]

Background: Despite increasing reports of the linkage between diabetes and tuberculosis (TB), there is limited information regarding diabetes and TB drug resistance.Methods: In this cross-sectional study, sputum and blood samples were collected from 304 adult patients in rural Andhra Pradesh. Rifampin resistance was assessed by Xpert MTB/RIF (Xpert), and diabetes status was based on self-report. Additionally, samples were assayed by acid-fast bacilli sputum smear microscopy (AFB) and QuantiFERON-TB Gold In-Tube (QFT-G), in order to compare relative diagnostic performances.Results: Among patients with confirmed TB (n = 194), diabetes was associated with 3.0-fold higher risk of rifampin resistance (95 % CI 1.3-6.7). Considering Xpert MTB/RIF the gold standard, AFB had lower sensitivity (72.2 vs. 82.5 %) and higher specificity (96.4 vs. 37.0 %) compared to QFT-G for diagnosing TB.Conclusions: The increased risk of rifampin resistance in patients with diabetes highlights the need for integrated diabetes surveillance in TB programs, particularly in settings undergoing the epidemiological transition. [ABSTRACT FROM AUTHOR]

Background: HIV has fuelled the TB epidemic in sub-Saharan Africa. Mortality in patients co-infected with TB and HIV is high. Managing factors influencing mortality in TB patients might help reducing it. This study investigates factors associated with mortality including patients' HIV serostatus, CD4 cell count, laboratory, nutritional and demographic characteristics in AFB smear positive pulmonary TB patients. Methods: We studied 887 sputum smear positive PTB patients, between 18 and 65 years of age receiving standard 8 months anti-TB treatment. Demographic, anthropometric and laboratory data including HIV, CD4 and other tests were collected at baseline and at regular intervals. Patients were followed for a median period of 2.5 years. Results: Of the 887 participants, 155 (17.5%) died, of whom 90.3% (140/155) were HIV-infected, a fatality of 29.7% (140/471) compared to 3.6% (15/416) among HIV-uninfected. HIV infection, age, low Karnofsky score, CD4 cell counts and hemoglobin, high viral load, and oral thrush were significantly associated with high mortality in all patients. Conclusion: Mortality among HIV-infected TB patients is high despite the use of effective anti-TB therapy. Most deaths occur after successful completion of therapy, an indication that patients die from causes other than TB. HIV infection is the strongest independent predictor of mortality in this cohort. [ABSTRACT FROM AUTHOR]