Comparison of two methods for acquisition of sputum samples for diagnosis of suspected tuberculosis in smear-negative or sputum-scarce people: a randomised controlled trial

Abstract

Sputum obtained either under instruction from a health-care worker or through induction can improve case detection of active tuberculosis. However, the best initial sputum sampling strategy for adults with suspected smear-negative or sputum-scarce tuberculosis in primary care is unclear. We compared these two methods of sample acquisition in such patients. In this randomised controlled trial, we enrolled adults (age ≥18 years) with sputum-scarce or smear-negative suspected tuberculosis from three primary care clinics in Cape Town, South Africa. Patients were randomly assigned (1:1) to receive either health-care worker instruction or induction to obtain sputum samples. Neither patients nor investigators were masked to allocation. The primary outcome was the proportion of patients who had started treatment after 8 weeks in a modified intention-to-treat population. Secondary outcomes were proportions starting treatment within different time periods, proportion of patients producing sputum for diagnosis, adverse effects, sputum samples' quality, and case detection by diagnostic method. This study is registered with ClinicalTrials.gov, number NCT01545661. We enrolled 481 patients, of whom 213 were assigned to health-care worker instruction versus 268 assigned to induction. The proportion of patients who started treatment in the 8 weeks after enrolment did not differ significantly between groups (53/213 [25%] vs 73/268 [27%]; OR 0·88, 95% CI 0·57-1·36; p=0·56). A higher proportion of instructed versus induced patients initiated empiric treatment based on clinical and radiography findings (32/53 [60%] vs 28/73 [38%]; p=0·015). An adequate sputum sample ≥1 mL was acquired in a lower proportion of instructed versus induced patients (164/213 [77%] vs 238/268 [89%]; p<0·0001), and culture-based diagnostic yield was lower in instructed versus induced patients (24/213 [11%] vs 51/268 [19%]; p=0·020). However, same-day tuberculosis case detection was similar in both groups using either smear microscopy (13/213 [6%] vs 22/268 [8%]; p=0·38) or Xpert-MTB/RIF assay (13/89 [15%] vs 20/138 [14%]; p=0·98). No serious adverse events occurred in either group; side-effects related to sample acquisition were reported in 32 of 268 (12%) patients who had sputum induction and none who had instruction. Cost per procedure was lower for instructed than for induced patients (US$2·14 vs US$7·88). Although induction provides an adequate sample and a bacteriological diagnosis more frequently than instruction by a health-care worker, it is more costly, does not result in a higher proportion of same-day diagnoses, and-because of widespread empiric treatment-may not result in more patients starting treatment. Thus, health-care worker instruction might be the preferred strategy for initial collection of sputum samples in adults with suspected sputum-scarce or smear-negative tuberculosis in a high burden primary care setting. South African National Research Foundation, European Commission, National Institutes of Health, European and Developing Countries Clinical Trials Partnership, Discovery Foundation.