Early Microbiologic Markers of Pulmonary Tuberculosis Treatment Outcomes

Abstract

Rationale: Earlier biomarkers of pulmonary tuberculosis (PTB) treatment outcomes are critical to monitor shortened anti-TB treatment (ATT). Objectives: To identify early microbiologic markers of unfavorable TB treatment outcomes. Methods: We performed a subanalysis of 2 prospective TB cohort studies conducted from 2013 to 2019 in India. We included participants aged ⩾18 years who initiated 6-month ATT for clinically or microbiologically diagnosed drug-sensitive PTB and completed at least one follow-up visit. Sputum specimens were subjected to a baseline Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay, acid-fast bacilli (AFB) microscopy and liquid and solid cultures, and serial AFB microscopy and liquid and solid cultures at weeks 2, 4, and 8. Poisson regression was used to assess the impact of available microbiologic markers (test positivity, smear grade, time to detection, and time to conversion) on a composite outcome of failure, recurrence, or death by 18 months after the end of treatment. Models were adjusted for age, sex, nutritional status, diabetes, smoking, alcohol consumption, and regimen type. Results: Among 1,098 eligible cases, there were 251 (22%) adverse TB treatment outcomes: 127 (51%) treatment failures, 73 (29%) recurrences, and 51 (20%) deaths. The primary outcome was independently associated with the Xpert MTB/RIF assay (medium-positive adjusted incidence rate ratio [aIRR], 1.91; 95% confidence interval [CI], 1.07-3.40; high-positive aIRR, 2.51; 95% CI, 1.41-4.46), positive AFB smear (aIRR, 1.48; 95% CI, 1.06-2.06), and positive liquid culture (aIRR, 1.98; 95% CI, 1.21-3.23) at baseline; Week 2 positive liquid culture (aIRR, 1.47; 95% CI, 1.04-2.09); and Week 8 positive AFB smear (aIRR, 1.63; 95% CI, 1.06-2.50) and positive liquid culture (aIRR, 1.54; 95% CI, 1.07-2.22). There was no evidence of Mycobacterium tuberculosis growth in the Mycobacterium Growth Indicator Tube at Week 4 conferring a higher risk of adverse outcomes (aIRR, 1.25; 95% CI, 0.89-1.75). Conclusions: Our analysis identifies Week 2 respiratory mycobacterial culture as the earliest microbiologic marker of unfavorable PTB treatment outcomes.

Keywords: PTB; microbiologic markers; treatment outcomes.

Figure 1.

Study flow of adults with pulmonary tuberculosis enrolled in the parent cohort studies conducted in India from 2013 to 2019. The subanalysis included 1,098 participants with drug-sensitive microbiologically confirmed or clinically diagnosed pulmonary tuberculosis who completed at least one follow-up visit. Microbiologic confirmation was defined by an Xpert MTB/RIF assay, acid-fast bacilli microscopy, liquid Mycobacterium Growth Indicator Tube culture, or solid Löwenstein-Jensen culture positivity. AFB = acid-fast bacilli; DSTB = drug-sensitive tuberculosis; LJ = Löwenstein-Jensen; MDR = multidrug-resistant; MGIT = Mycobacterium Growth Indicator Tube; MTB = Mycobacterium tuberculosis; RIF = rifampicin; TB = tuberculosis.

Figure 2.

(A) Forest plot summarizing associations between baseline respiratory microbiologic markers and the composite unfavorable tuberculosis (TB) treatment outcome. Independent predictors were baseline Xpert MTB/RIF assay, acid-fast bacilli smear, and liquid MGIT culture positivity. Results are presented as adjusted incidence rate ratios from Poisson regression models adjusted for baseline age, sex, body mass index, diabetes, smoking, alcohol consumption, and regimen type (daily or thrice-weekly anti-TB treatment). (B) Forest plot summarizing associations between longitudinal respiratory microbiologic markers and the composite unfavorable TB treatment outcome. Independent predictors were Week 2 liquid culture positivity, Week 8 acid-fast bacilli smear and liquid and solid Löwenstein-Jensen culture positivity, and change in baseline time to detection on liquid culture at Week 8. Results are presented as adjusted incidence rate ratios from Poisson regression models adjusted for baseline age, sex, body mass index, diabetes, smoking, alcohol consumption, and regimen type (daily or thrice-weekly anti-TB treatment). aIRR = adjusted incidence rate ratio; CI = confidence interval; LJ = Löwenstein-Jensen; MGIT = Mycobacterium Growth Indicator Tube; MTB = Mycobacterium tuberculosis; RIF = rifampicin.

Figure 3.

Longitudinal time to detection of growth of Mycobacterium tuberculosis on (A) liquid MGIT and (B) solid LJ culture media. Box plots summarize time to detection of growth at each time point from baseline to the end of the intensive phase of treatment according to tuberculosis treatment outcome. LJ = Löwenstein-Jensen; MGIT = Mycobacterium Growth Indicator Tube.

Figure 4.

ROC curves illustrate similar performance among Week 2 (A and B) and Week 4 (C and D) acid-fast bacilli smear microscopy and liquid MGIT cultures as markers of the composite unfavorable tuberculosis treatment outcome. MGIT = Mycobacterium Growth Indicator Tube; ROC = receiver operating characteristic.