Tuberculosis Challenges: Mycobacterial Culture Confirmation And Disease Recurrence

Background: Tuberculosis (TB) is global pandemic. The ongoing challenges of TB control include inadequate diagnostics and treatment. Culture is the reference standard for laboratory confirmation of disease. However, extrapulmonary TB (EPTB) culture confirmation is low. Successful treatment of TB is compromised by TB recurrence. The epidemiology is poorly characterised in the UK. Methods: Two studies were conducted. The first, a nested case-control study examined the epidemiology of TB recurrence in Leicester. Cases were identified from the Leicester TB service database (TBIT) and matched to controls on a ratio of one-to-two on date of notification. Multivariate conditional logistic regression examined risk factors for recurrence. The second, a pilot diagnostic study, compared the number of mycobacteria isolated from EPTB samples in the presence or absence of resuscitation promoting factorcontaining culture supernatant (CS). Diagnostic performance was assessed by a composite reference standard. Results: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%); 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p=0∙04), grade 3-4 adverse drug reactions (OR 5.6; p=0∙02), ethnicity ‘Indian subcontinent’ (OR 8∙5; p<0∙01), ethnicity ‘other’ (OR 31.2; p=0.01) and receipt of immunosuppressants (OR 6.8; p<0∙01) were independent predictors of TB recurrence. In 8 of 19 samples, CS-dependent differentially culturable tubercle bacilli (DCTB) were present. The peripheral lymphocyte count (PLC) positively correlated (p=0.04) with CS most probable number assay counts. CS increased culture sensitivity from 36 to 43%; specificity remained at 100%. Conclusion: Within Leicester, TB recurrence was infrequent, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health. CS may improve culture diagnostic performance although larger studies are required. The PLC represents a candidate biomarker of host CS-DCTB populations.