Performance of Xpert® MTB/RIF and Xpert® Ultra for the diagnosis of tuberculous meningitis in children.

OBJECTIVE: To assess Xpert® MTB/RIF (Xpert) and Xpert® MTB/RIF Ultra (Ultra) performance in diagnosing pediatric tuberculous meningitis (TBM).METHODS: We conducted a study among children with suspected meningoencephalitis in Pune, India. Clinical, radiological, laboratory, and treatment data were analyzed to classify disease as definite, probable, possible or no TBM, using microbiologic or composite reference standards. We tested cerebrospinal fluid (CSF) either using Xpert or Ultra and estimated test performance characteristics.RESULTS: Of 341 participants, 149 (43.7%) were tested using Ultra and 192 (56.3%) with Xpert. Ultra had higher sensitivity (50% vs. 18%), lower specificity (91% vs. 99%), poor positive predictive value (PPV) (13% vs. 75%), and higher negative predictive value (NPV) (99% vs. 93%) than Xpert using the composite reference standard, with similar results by the microbiologic reference standard. Of 10 participants with trace positivity on Ultra, none met clinical TBM definitions.CONCLUSION: This is the first study to report on diagnostic performance of Ultra in pediatric TBM, which showed higher sensitivity and NPV than Xpert. For children presenting with nonspecific clinical features, Ultra is a promising diagnostic test. Further studies are required to define its optimal clinical use, including interpretation of trace positive results.

Concomitant pulmonary disease is common among patients with extrapulmonary TB.

BACKGROUND: Microbiologic screening of extrapulmonary TB (EPTB) patients could inform recommendations for aerosol precautions and close contact prophylaxis. However, this is currently not routinely recommended in India. Therefore, we estimated the proportion of Indian patients with EPTB with microbiologic evidence of pulmonary TB (PTB).METHODS: We characterized baseline clinical, radiological and sputum microbiologic data of 885 adult and pediatric TB patients in Chennai and Pune, India, between March 2014 and November 2018.RESULTS: Of 277 patients with EPTB, enhanced screening led to the identification of 124 (45%) with concomitant PTB, including 53 (19%) who reported a cough >2 weeks; 158 (63%) had an abnormal CXR and 51 (19%) had a positive sputum for TB. Of 70 participants with a normal CXR and without any cough, 14 (20%) had a positive sputum for TB. Overall, the incremental yield of enhanced screening of patients with EPTB to identify concomitant PTB disease was 14% (95% CI 12-16).CONCLUSIONS: A high proportion of patients classified as EPTB in India have concomitant PTB. Our results support the need for improved symptom and CXR screening, and recommends routine sputum TB microbiology screening of all Indian patients with EPTB.

Unhealthy alcohol use independently associated with unfavorable TB treatment outcomes among Indian men.

BACKGROUND: Approximately 10% of incident TB cases worldwide are attributable to alcohol. However, evidence associating alcohol with unfavorable TB treatment outcomes is weak.METHODS: We prospectively evaluated men (≥18 years) with pulmonary TB in India for up to 24 months to investigate the association between alcohol use and treatment outcomes. Unhealthy alcohol use was defined as a score of ≥4 on the Alcohol Use Disorders Identification Test-Concise (AUDIT-C) scale at entry. Unfavorable TB treatment outcomes included failure, recurrence, and all-cause mortality, analyzed as composite and independent endpoints.RESULTS: Among 751 men, we identified unhealthy alcohol use in 302 (40%). Median age was 39 years (IQR 28-50); 415 (55%) were underweight (defined as a body mass index [BMI] <18.5 kg/m²); and 198 (26%) experienced an unfavorable outcome. Unhealthy alcohol use was an independent risk factor for the composite unfavorable outcome (adjusted incidence rate ratio [aIRR] 1.47, 95% CI 1.05-2.06; P = 0.03) and death (aIRR 1.90, 95% CI 1.08-3.34; P = 0.03), specifically. We found significant interaction between AUDIT-C and BMI; underweight men with unhealthy alcohol use had increased risk of unfavorable outcomes (aIRR 2.22, 95% CI 1.44-3.44; P < 0.001) compared to men with BMI ≥18.5 kg/m² and AUDIT-C <4.CONCLUSION: Unhealthy alcohol use was independently associated with unfavorable TB treatment outcomes, highlighting the need for integrating effective alcohol interventions into TB care.

Measuring TB drug levels in the hair in adults and children to monitor drug exposure and outcomes.

INTRODUCTION: Testing for anti-TB drugs in small hair samples may serve as a non-invasive tool to measure cumulative drug exposure and/or adherence, as these determine treatment success. We aimed to assess how well hair assays of TB drugs predict TB treatment outcomes.METHODS: A small thatch of hair, ~30 strands, was cut from the occipital region in adults and children from a prospective TB cohort in India. Isoniazid (INH), acetyl-INH and pyrazinamide (PZA) were extracted from the hair samples and quantified using liquid-chromatography-tandem mass spectrometry. The relationship between drug concentrations in hair and time to unfavourable outcomes was assessed using Cox-proportional hazards regression models.RESULTS: A two-fold increase in hair acetyl-INH concentrations in the 264 participants in our cohort with hair assays for TB drugs indicated a lower hazard of unfavourable TB treatment outcomes (aHR 0.67, 95%CI 0.44-1.02) and TB treatment failure (aHR 0.65, 95%CI 0.42-1.01). Higher summed concentrations (a summed measure of INH and acetyl-INH) indicated a lower hazard of treatment failure (aHR 0.69, 95%CI 0.45-1.05)CONCLUSION: Hair levels of INH and its metabolite may predict TB treatment outcomes, indicating the potential utility of this measure to assess and optimise TB treatment outcomes.

Challenges in conducting trials for pediatric tuberculous meningitis: lessons from the field.

SETTING: TBM-KIDS is a phase I/II trial enrolling children with tuberculous meningitis (TBM) in three tertiary referral centers in India and Malawi.OBJECTIVE: To describe the challenges encountered in conducting the first randomized clinical trial of antimicrobial agents in pediatric TBM.DESIGN: The sources of the data were primarily monthly trial reports, non-enrollment case report forms, study diaries and registers maintained for recruitment, experiences shared by key team members during regular study calls and comments from site review visits. We reviewed, broadly categorized, and describe in detail the challenges encountered by study teams in trial implementation.RESULTS: Over 17 months, 3371 children with clinical presentations consistent with meningoencephalitis or undergoing lumbar puncture were assessed for eligibility; 21 (<1%) met enrollment criteria. We encountered challenges related to diagnosis, management of sick children, large catchment areas, adverse event attribution, concomitant medications, infrastructure requirements, expensive pediatric formulations with short expiry, and detection of treatment response in a highly variable disease across the age continuum. Training and adaptation of tools for neurocognitive and neurologic function assessment were necessary. Special care was undertaken to explain study participation to distraught caregivers and manage children longitudinally.CONCLUSION: Interventional trials in pediatric TBM are challenging but are critically important for improving the treatment of a disease that disables children physically, cognitively and emotionally. Sharing these challenges may help to address them more effectively as a TB research community and to advance treatments for this at-risk population.

Respiratory health status is associated with treatment outcomes in pulmonary tuberculosis.

The association between respiratory impairment and tuberculosis (TB) treatment outcomes is not clear. We prospectively evaluated respiratory health status, measured using the Saint George's Respiratory Questionnaire (SGRQ), in a cohort of new adult pulmonary TB cases during and up to 18 months following treatment in India. Associations between total SGRQ scores and poor treatment outcomes of failure, recurrence and all-cause death were measured using multivariable Poisson regression. We enrolled 455 participants contributing 619 person-years at risk; 39 failed treatment, 23 had recurrence and 16 died. The median age was 38 years (interquartile range 26-49); 147 (32%) ever smoked. SGRQ scores at treatment initiation were predictive of death during treatment (14% higher risk per 4-point increase in baseline SGRQ scores, 95%CI 2-28, P = 0.01). Improvement in SGRQ scores during treatment was associated with a lower risk of failure (1% lower risk for every per cent improvement during treatment, 95%CI 1-2, P = 0.05). Clinically relevant worsening in SGRQ scores following successful treatment was associated with a higher risk of recurrence (15% higher risk per 4-point increase scores, 95%CI 4-27, P = 0.004). Impaired respiratory health status was associated with poor TB treatment outcomes. The SGRQ may be used to monitor treatment response and predict the risk of death in pulmonary TB. .

Diabetes and pre-diabetes among household contacts of tuberculosis patients in India: is it time to screen them all?

SETTING: Pre-diabetes mellitus (pre-DM) and DM increase the risk of developing tuberculosis (TB). Screening contacts of TB patients for pre-DM/DM and linking them to care may mitigate the risk of developing TB and improve DM management. OBJECTIVE: To measure the prevalence of pre-DM/DM and associated factors among the adult household contacts (HHCs) of pulmonary TB patients. METHODS: Between August 2014 and May 2017, adult HHCs of newly diagnosed adult PTB patients in Pune and Chennai, India, had single blood samples tested for glycosylated haemoglobin (HbA1c) at enrolment. DM was defined as previously diagnosed, self-reported DM or HbA1c 6.5%, and pre-DM as HbA1c between 5.7% and 6.4%. Latent tuberculous infection (LTBI) was defined as a positive tuberculin skin test (5 mm induration) or QuantiFERON® Gold In-Tube (0.35 international units/ml). RESULTS: Of 652 adult HHCs, 175 (27%) had pre-DM and 64 (10%) had DM. Forty (64%) HHCs were newly diagnosed with DM and 48 (75%) had poor glycaemic control (HbA1c 7.0%). Sixty-eight (22%) pre-DM cases were aged 18-34 years. Age 35 years, body mass index 25 kg/m2, chronic disease and current tobacco smoking were significantly associated with DM among HHCs. CONCLUSIONS: Adult HHCs of TB patients in India have a high prevalence of undiagnosed DM, pre-DM and LTBI, putting them at high risk for developing TB. Routine DM screening should be considered among all adult HHCs of TB.