Study protocol: a pragmatic, cluster-randomized controlled trial to evaluate the effect of implementation of the Truenat platform/MTB assays at primary health care clinics in Mozambique and Tanzania (TB-CAPT CORE).

BACKGROUND: In 2020, the WHO-approved Molbio Truenat platform and MTB assays to detect Mycobacterium tuberculosis complex (MTB) and resistance to rifampicin directly on sputum specimens. This primary health care center-based trial in Mozambique and Tanzania investigates the effect of Truenat platform/MTB assays (intervention arm) combined with rapid communication of results compared to standard of care on TB diagnosis and treatment initiation for microbiologically confirmed TB at 7 days from enrolment. METHODS: The Tuberculosis Close the Gap, Increase Access, and Provide Adequate Therapy (TB-CAPT) CORE trial employs a pragmatic cluster randomized controlled design to evaluate the impact of a streamlined strategy for delivery of Truenat platform/MTB assays testing at primary health centers. Twenty-nine centers equipped with TB microscopy units were selected to participate in the trial. Among them, fifteen health centers were randomized to the intervention arm (which involves onsite molecular testing using Truenat platform/MTB assays, process process optimization to enable same-day TB diagnosis and treatment initiation, and feedback on Molbio platform performance) or the control arm (which follows routine care, including on-site sputum smear microscopy and the referral of sputum samples to off-site Xpert testing sites). The primary outcome of the study is the absolute number and proportion of participants with TB microbiological confirmation starting TB treatment within 7 days of their first visit. Secondary outcomes include time to bacteriological confirmation, health outcomes up to 60 days from first visit, as well as user preferences, direct cost, and productivity analyses. ETHICS AND DISSEMINATION: TB-CAPT CORE trial has been approved by regulatory and ethical committees in Mozambique and Tanzania, as well as by each partner organization. Consent is informed and voluntary, and confidentiality of participants is maintained throughout. Study findings will be presented at scientific conferences and published in peer-reviewed international journals. TRIAL REGISTRATION: US National Institutes of Health's ClinicalTrials.gov, NCT04568954. Registered 23 September 2020.

Performance of spirometry assessment at TB diagnosis.

BACKGROUND: Spirometry is considered relevant for the diagnosis and monitoring of post-TB lung disease. However, spirometry is rarely done in newly diagnosed TB patients.METHODS: Newly diagnosed, microbiologically confirmed TB patients were recruited for the study. Spirometry was performed within 21 days of TB treatment initiation according to American Thoracic Society/European Respiratory Society guidelines. Spirometry analysis was done using Global Lung Initiative equations for standardisation.RESULTS: Of 1,430 eligible study participants, 24.7% (353/1,430) had no spirometry performed mainly due to contraindications and 23.0% (329/1,430) had invalid results; 52.3% (748/1,430) of participants had a valid result, 82.8% (619/748) of whom had abnormal spirometry. Of participants with abnormal spirometry, 70% (436/619) had low forced vital capacity (FVC), 6.1% (38/619) had a low ratio of forced expiratory volume in 1 sec (FEV1) to FVC, and 19.1% (118/619) had low FVC, as well as low FEV1/FVC ratio. Among those with abnormal spirometry, 26.3% (163/619) had severe lung impairment.CONCLUSIONS: In this population, a high proportion of not performed and invalid spirometry assessments was observed; this was addressed by removing tachycardia as a (relative) contraindication from the study guidance and retraining. The high proportion of patients with severe pulmonary impairment at the time of TB diagnosis suggests a huge morbidity burden and calls for further longitudinal studies on the relevance of spirometry in predicting chronic lung impairment after TB.

Diagnosis of paediatric TB using Xpert® MTB/RIF Ultra on fresh respiratory samples.

OBJECTIVE: To evaluate the diagnostic accuracy of Xpert® MTB/RIF Ultra (Ultra) on fresh respiratory samples for the diagnosis of pulmonary TB (PTB) in children.METHODS: Between July 2017 and December 2019, children with presumed TB were prospectively enrolled at clinical sites in three African countries. Children were assessed using history, physical examination and chest X-ray. Sputum or gastric aspirate samples were analysed using Ultra and culture. The diagnostic accuracy of Ultra was calculated against culture as the reference standard.RESULTS: In total, 547children were included. The median age was 4.7 years, 77 (14.1%) were HIV infected and 77 (14.1%) had bacteriologically confirmed TB. Ultra detected an additional 20 cases in the group of children with negative culture results. The sensitivity of Ultra was 66.3% (95% CI 47-82), and the specificity was 95.4% (95% CI 89-99) when assessed against culture as the reference standard.CONCLUSION: Despite the improved performance of Ultra as compared to Xpert as was previously reported, its sensitivity remains sub-optimal for the detection of TB in children. Ultra detected additional 20 cases which otherwise could not have been detected by culture alone, suggesting that the latter is an imperfect reference standard.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Pulmonary TB bacteriologically confirmed by induced sputum among children at Bugando Medical Centre, Tanzania.

BACKGROUND: The diagnosis of paediatric tuberculosis (TB) remains difficult in resource-: poor settings. OBJECTIVE: To evaluate induced sputum collection and examination using microscopy, culture and Xpert(®) MTB/RIF assay for the diagnosis of pulmonary TB (PTB) in a Tanzanian hospital vs. PTB diagnosis using clinical scoring tools alone. METHODS: We conducted a cross-sectional study from October 2013 to April 2014 at our hospital in northwestern Tanzania. Children presumed to have TB were assessed using four TB score charts and sputum examination. Sputum samples were analyzed using fluorescence microscopy, solid culture and Xpert. The number of cases microbiologically confirmed was compared to the number of TB cases suspected based on TB score charts. RESULTS: A total of 192 patients were enrolled. Sputum specimens were successfully obtained in 187 (97.4%) patients without any major complications. Ten (5.2%) children were confirmed to have PTB by sputum examination. More than half (50-90%) of the confirmed cases were not detected by score charts alone. CONCLUSION: Sputum induction is both safe and feasible in a severely resource-limited hospital, and can lead to microbiological PTB diagnosis that would not be detected by clinical criteria alone.