Factors associated with hospitalization and mortality in adult and pediatric extrapulmonary tuberculosis at a tertiary care hospital in Central India.

BACKGROUND: Comorbidities complicate the management of tuberculosis (TB) and have become an essential part of the end TB strategy to eradicate TB. However, pulmonary TB has received the most attention, and little is known about the impact of comorbidities and other factors on outcomes in patients with extrapulmonary tuberculosis (EPTB). OBJECTIVES: Our aim was to analyze the factors associated with hospitalization and mortality in EPTB at a hospital in Central India, using non-TB patients with similar clinical presentations as a comparison. METHODS: Patients with presumptive EPTB were prospectively enrolled and followed up until the end of treatment or for at least 6 months. Detailed demographic and clinical information was collected for all participants, and patients were categorized as TB or non-TB using a composite reference standard. Multivariate logistic regression was used to analyze the impact of various clinical findings and risk factors on hospitalization and mortality. RESULTS: A total of 276 patients were categorized as TB cases and 175 as non-TB cases. Factors associated with hospitalization in children were younger age and non-adenitis site of disease. In adults, factors associated with mortality were older age, non-adenitis site of disease and HIV infection regardless of TB diagnosis, while diabetes mellitus increased the odds of mortality in EPTB patients. CONCLUSION: Our results show that comorbidities increase the odds of death in both TB and non-TB patients in low-resource settings. This argues for a shift away from the traditional vertical management of diseases in these areas and supports a continued focus on building robust healthcare systems.

Diagnosing adult and pediatric extrapulmonary tuberculosis by MPT64 antigen detection with immunohistochemistry and immunocytochemistry using reproduced polyclonal antibodies.

Diagnosing extrapulmonary tuberculosis (EPTB) is challenging. Immunohistochemistry or immunocytochemistry has been used to diagnose tuberculosis (TB) by detection of MPT64 antigen from various extrapulmonary specimens and has shown good diagnostic performance in our previous studies. The test can distinguish between disease caused by Mycobacterium tuberculosis (Mtb) complex and nontuberculous mycobacteria and can be applied on formalin-fixed paraffin-embedded tissue. As the antibodies previously used were in limited supply, a new batch of polyclonal antibodies was developed for scale-up and evaluated for the first time in this study. Our aim was to assess the diagnostic accuracy of the MPT64 test with reproduced antibodies in the high burden settings of Pakistan and India. Patients were enrolled prospectively. Samples from suspected sites of infection were collected and subjected to histopathologic and/or cytologic evaluation, routine TB diagnostics, GeneXpert MTB/RIF (Xpert), and the MPT64 antigen detection test. Patients were followed until the end of treatment. Based on a composite reference standard (CRS), 556 patients were categorized as TB cases and 175 as non-TB cases. The MPT64 test performed well on biopsies with a sensitivity and specificity of 94% and 75%, respectively, against a CRS. For cytology samples, the sensitivity was low (36%), whereas the specificity was 81%. Overall, the MPT64 test showed higher sensitivity (73%) than Xpert (38%) and Mtb culture (33%). The test performed equally well in adults and children. We found an additive diagnostic value of the MPT64 test in conjunction with histology and molecular tests, increasing the yield for EPTB. In conclusion, immunochemical staining with MPT64 antibodies improves the diagnosis of EPTB in high burden settings and could be a valuable addition to routine diagnostics.

Significance of non-granulomatous cytomorphology on fine needle aspirate in lymphadenitis cases classified as tuberculous by using a composite reference standard.

BACKGROUND: Fine needle aspiration cytology (FNAC) is established as a first line investigation for tuberculous lymphadenitis (TBLA). We aimed to describe the various cytomorphologic features of tuberculosis (TB) on FNAC and their contribution in the diagnostic decision-making in suspected TBLA cases. METHODS: Patients with presumptive TBLA were prospectively enrolled (n = 266) and subjected to routine diagnostic work-up for TB, including FNAC samples, and followed until the end of treatment. Patients were categorized as TB or non-TB cases based on a composite reference standard of which the various cytomorphologic patterns were compared. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy was calculated using cross-tabulation. RESULTS: Fifty-six patients were categorized as bacteriologically confirmed TB, 102 as clinically confirmed TB and 108 as non-TB. The most common cytomorphologic pattern among TB cases (59%) was granulomatous inflammation with necrosis, however, about one-third of tuberculous lymphadenitis patients presented with non-granulomatous inflammation, with 21% showing only necrosis and 13% presenting with a reactive pattern. The overall sensitivity and specificity of FNAC was 85% and 66%, respectively. CONCLUSIONS: We found that about one-third of TBLA patients presented without granulomas on FNA, highlighting the importance of considering TB in a wide spectrum of cytomorphology in a high TB burden setting. Our study supports the use of FNAC as a first-line investigation tool for diagnosing TBLA in a low-resource setting due to its relative simplicity and good sensitivity. However, the low specificity of FNAC, emphasizes the need for a second-tier confirmatory test with improved specificity.

Low frequency of parental mosaicism in de novo COL4A5 mutations in X-linked Alport syndrome.

BACKGROUND: Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies. METHODS: In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents. RESULTS: A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic. CONCLUSION: These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.