Plasma Immune Biomarkers Predictive of Progression to Active Tuberculosis in Household Contacts of TB Patients.

BACKGROUND: The progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index pulmonary TB (PTB) patients who either progressed to TB or remained as non-progressors. METHODS: A cohort of household contacts of adults with PTB was enrolled, consisting of 15 contacts who progressed to TB disease and 15 non-progressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive TB progression markers. RESULTS: Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of IFNγ, IL-2, TNFα, IL1α, IL1ß, IL-17A, and IL-1Ra at baseline, months 4 and 12. In contrast, the progressor group displayed significantly elevated levels of IFNα, IFNß, IL-6, IL-12, GM-CSF, IL-10, IL-33, CCL2, CCL11, CXCL8, CXCL10, CX3CL1, VEGF, Granzyme-B and PDL-1 compared to the non-progressor group at baseline, months 4 and 12. ROC analysis identified IFNγ, GM-CSF, IL-1Ra, CCL2 and CXCL10 as the most promising predictive markers, with an AUC of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10 and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active TB disease. CONCLUSIONS: Our study suggests that a specific set of plasma biomarkers GM-CSF, CXCL10 and IL-1Ra, can effectively identify household contacts at significant risk of developing TB disease. These findings have important implications for early intervention and preventive strategies in TB-endemic regions.

QuantiFERON Supernatant-Based Host Biomarkers Predicting Progression to Active Tuberculosis Disease Among Household Contacts of Tuberculosis Patients.

BACKGROUND: The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB). METHODS: We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors. The supernatants were tested for an expanded panel of 45 cytokines, chemokines, and growth factors using the Luminex Multiplex Array kit. RESULTS: We found significant differences in the levels of TB-antigen induced production of several analytes between progressors and non-progressors. Dominance analysis identified 15 key predictive biomarkers based on relative percentage importance. Principal component analysis revealed that these biomarkers could robustly distinguish between the 2 groups. Receiver operating characteristic analysis identified interferon-γ inducible protein (IP)-10, chemokine ligand (CCL)19, interferon (IFN)-γ, interleukin (IL)-1ra, CCL3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most promising predictive markers, with area under the curve (AUC) ≥90. IP-10/CCL19 ratio exhibited maximum sensitivity and specificity (100%) for predicting progression. Through Classification and Regression Tree analysis, a cutoff of 0.24 for IP-10/CCL19 ratio was found to be ideal for predicting short-term risk of progression to TB disease with a positive predictive value of 100 (95% confidence interval [CI] 85.8-100). CONCLUSIONS: The biomarkers identified in this study will pave way for the development of a more accurate test that can identify individuals at high risk for immediate progression to TB disease for targeted intervention.

Comorbidities in pulmonary tuberculosis cases in Puducherry and Tamil Nadu, India: Opportunities for intervention.

BACKGROUND: We aimed to define characteristics of TB patients in Puducherry and two districts of Tamil Nadu, India and calculate the population attributable fractions (PAF) of TB from malnutrition and alcohol. METHODS: New smear-positive TB cases were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT India) cohort. Census and National Family Health Survey data were used for comparisons. RESULTS: Data were analyzed for 409 participants enrolled between May 2014-June 2016; 307 (75.1%) were male, 60.2% were malnourished (body mass index [BMI] <18.5 kg/m2), and 29.1% severely malnourished (BMI <16). "Hazardous" alcohol use (based on AUDIT-C score) was reported by 155/305 (50.8%) of males. Tuberculosis cases were more likely than the Puducherry population to be malnourished (62.6% v 10.2% males and 71.7% v 11.3% of females; both p<0.001), and male cases were more likely to use alcohol than male non-cases (84.4% v 41%; p < .001). The PAF of malnutrition was 57.4% in males and 61.5% in females; the PAF for alcohol use was 73.8% in males and 1.7% in females. CONCLUSIONS: Alcohol use in men and malnutrition are helping drive the TB epidemic in Southern India. Reducing the TB burden in this population will require efforts to mitigate these risk factors.

Molecular characterisation of parvoviruses from domestic cats reveals emergence of newer variants in India.

Objectives The present study was undertaken to characterise the viral polypeptide 2 (VP2) gene of parvovirus from domestic cats in India. Methods The faecal samples from diarrhoeic/healthy domestic cats were collected from different geographical regions of India for screening by PCR assay followed by sequence analysis of the VP2 gene. Results Canine parvovirus (CPV)/feline panleukopenia virus (FPV) infections were found in 12 (11.3%) of 106 faecal samples tested. Two new CPV-2a (297Ala and Asn426) and three FPV strains were identified by VP2 gene analysis. Several unique and existing amino acid mutations were found, suggesting continuous evolution and emergence of newer variants. The phylogenetic analysis of the CPV sequences revealed that the two new CPV-2a strains from Mumbai (MC8) and Puducherry (P15) were clustered together in a single clade but had evolved independently and were ancestrally related to Chinese CPV-2a isolates. The FPV sequences (T-C-6 and T-C-1) from Thrissur, Kerala, formed a different clade (FPV clade) and were closely related to each other and had an ancestral relationship with an FPV isolate from the USA. Another FPV isolate from Goa (GC1) was positioned in the same clade but had evolved independently. Conclusions and relevance Detection of CPV in both diarrhoeic/healthy cats and the occurrence of FPV infection in a vaccinated cat provide new insights into parvovirus infections in cats in India.

Full-length VP2 gene analysis of canine parvovirus reveals emergence of newer variants in India.

The canine parvovirus (CPV) infection is a highly contagious and serious enteric disease of dogs with high fatality rate. The present study was taken up to characterize the full-length viral polypeptide 2 (VP2) gene of CPV of Indian origin along with the commercially available vaccines. The faecal samples from parvovirus suspected dogs were collected from various states of India for screening by PCR assay and 66.29% of samples were found positive. Six CPV-2a, three CPV-2b, and one CPV-2c types were identified by sequence analysis. Several unique and existing mutations have been noticed in CPV types analyzed indicating emergence of newer variants of CPV in India. The phylogenetic analysis revealed that all the field CPV types were grouped in different subclades within two main clades, but away from the commercial vaccine strains. CPV-2b and CPV-2c types with unique mutations were found to be establishing in India apart from the prevailing CPV-2a type. Mutations and the positive selection of the mutants were found to be the major mechanism of emergence and evolution of parvovirus. Therefore, the incorporation of local strain in the vaccine formulation may be considered for effective control of CPV infections in India.