Malnutrition leads to increased inflammation and expression of tuberculosis risk signatures in recently exposed household contacts of pulmonary tuberculosis.

Background: Most individuals exposed to Mycobacterium tuberculosis (Mtb) develop latent tuberculosis infection (LTBI) and remain at risk for progressing to active tuberculosis disease (TB). Malnutrition is an important risk factor driving progression from LTBI to TB. However, the performance of blood-based TB risk signatures in malnourished individuals with LTBI remains unexplored. The aim of this study was to determine if malnourished and control individuals had differences in gene expression, immune pathways and TB risk signatures. Methods: We utilized data from 50 tuberculin skin test positive household contacts of persons with TB - 18 malnourished participants (body mass index [BMI] < 18.5 kg/m2) and 32 controls (individuals with BMI ≥ 18.5 kg/m2). Whole blood RNA-sequencing was conducted to identify differentially expressed genes (DEGs). Ingenuity Pathway Analysis was applied to the DEGs to identify top canonical pathways and gene regulators. Gene enrichment methods were then employed to score the performance of published gene signatures associated with progression from LTBI to TB. Results: Malnourished individuals had increased activation of inflammatory pathways, including pathways involved in neutrophil activation, T-cell activation and proinflammatory IL-1 and IL-6 cytokine signaling. Consistent with known association of inflammatory pathway activation with progression to TB disease, we found significantly increased expression of the RISK4 (area under the curve [AUC] = 0.734) and PREDICT29 (AUC = 0.736) progression signatures in malnourished individuals. Conclusion: Malnourished individuals display a peripheral immune response profile reflective of increased inflammation and a concomitant increased expression of risk signatures predicting progression to TB. With validation in prospective clinical cohorts, TB risk biomarkers have the potential to identify malnourished LTBI for targeted therapy.

Recommendations for Screening and Diagnosis of Chagas Disease in the United States.

BACKGROUND: Chagas disease affects an estimated 326 000-347 000 people in the United States and is severely underdiagnosed. Lack of awareness and clarity regarding screening and diagnosis is a key barrier. This article provides straightforward recommendations, with the goal of simplifying identification and testing of people at risk for US healthcare providers. METHODS: A multidisciplinary working group of clinicians and researchers with expertise in Chagas disease agreed on 6 main questions, and developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, after reviewing the relevant literature on Chagas disease in the United States. RESULTS: Individuals who were born or resided for prolonged time periods in endemic countries of Mexico and Central and South America should be tested for Trypanosoma cruzi infection, and family members of people who test positive should be screened. Women of childbearing age with risk factors and infants born to seropositive mothers deserve special consideration due to the risk of vertical transmission. Diagnostic testing for chronic T. cruzi infection should be conducted using 2 distinct assays. CONCLUSIONS: Increasing provider-directed screening for T. cruzi infection is key to addressing this neglected public health challenge in the United States.

Risk factors for death during treatment in pulmonary tuberculosis patients in South India: A cohort study.

OBJECTIVE: Identifying the risk factors for deaths during tuberculosis (TB) treatment is important for achieving the vision of India's National Strategic Plan of 'Zero Deaths' by 2025. We aimed to determine the proportion of deaths during TB treatment and its risk factors among smear positive pulmonary TB patients aged more than 15 years. STUDY DESIGN: We performed a cohort study using data collected for RePORT India Consortium (Regional Prospective Observational Research in Tuberculosis). SETTING: Revised TB Control Program (RNTCP) in three districts of South India. PARTICIPANTS: The cohort consisted of newly diagnosed drug sensitive patients enrolled under the Revised National TB Control Program during 2014-2018 in three districts of southern India. Information on death was collected at homes by trained project staff. PRIMARY OUTCOME MEASURES: We calculated 'all-cause mortality' during TB treatment and expressed this as a proportion with 95% confidence interval (CI). Risk factors for death were assessed by calculating unadjusted and adjusted relative risks with 95% CI. RESULTS: The mean (SD) age was of the 1167 participants was 45 (14.5) years and 79% of them were males. Five participants (0.4%) were HIV infected. Among the males, 560 (61%) were tobacco users and 688 (75%) reported consuming alcohol. There were 47 deaths (4%; 95% CI 3.0-5.3) of which 28 deaths (60%) occurred during first two months of treatment. In a bi-variable analysis, age of more than 60 years (RR 2.27; 95%CI: 1.24-4.15), male gender (RR 3.98; 95% CI: 1.25-12.70), alcohol use in last 12 months (RR 2.03; 95%CI: 1.07-3.87), tobacco use (RR 1.87; 95%CI: 1.05-3.36) and severe anaemia (RR 3.53: 95%CI: 1.34-9.30) were associated with a higher risk of death. In adjusted analysis, participants with severe anaemia (<7gm/dl) had 2.4 times higher risk of death compared to their counterparts. CONCLUSION: Though deaths during TB treatment was not very high, early recognition of risk groups and targeted interventions are required to achieve zero TB deaths.

Effect of malnutrition on radiographic findings and mycobacterial burden in pulmonary tuberculosis.

BACKGROUND: The relationship between malnutrition and tuberculosis (TB) severity is understudied. We investigated the effect of malnutrition on radiographic findings and mycobacterial burden. METHODS: Subjects included newly diagnosed, smear-positive, culture-confirmed, pulmonary TB cases enrolled in the Regional Prospective Observational Research for TB (RePORT) cohort. Multivariate regression models were used to evaluate the relationship at start of treatment between body mass index (BMI) and chest radiograph (CXR) findings of cavitation and percentage of lung affected and mycobacterial growth indicator tube (MGIT) time to positive (TTP). Severe malnutrition was defined as BMI<16 kg/m2, moderate malnutrition as 16-18.4kg/m2, and "normal"/overweight as ≥18.5 kg/m2. RESULTS: Of 173 TB cases with chest x-ray data, 131 (76%) were male. The median age was 45 years (range 16-82); 42 (24%) had severe malnutrition and 58 (34%) moderate malnutrition. Median percentage of lung affected was 32% (range 0-95), and 132 (76%) had cavitation. Individuals with severe malnutrition had, on average, 11.1% [95% CI: 4.0-13.3] more lung affected, compared to those with normal BMI, controlling for diabetes and cavitation. In multivariable analyses, cases with severe malnutrition had a 4.6-fold [95% CI, 1.5-14.1] increased odds of cavitation compared to those with normal BMI, controlling for smoking. Median MGIT TTP was 194.5 hours. Neither severe (aRR 0.99; 95% CI, 0.9-1.2) nor moderate (aRR 0.97; 95% CI, 0.8-1.1) malnutrition was associated with MGIT TTP. CONCLUSION: We found that malnutrition was associated with increased extent of disease and cavitation on CXR. These findings may reflect the immunomodulatory effect of malnutrition on pulmonary pathology.