Empiric treatment of pulmonary TB in the Xpert era: Correspondence of sputum culture, Xpert MTB/RIF, and clinical diagnoses

Abstract

Background: Clinical tuberculosis diagnosis and empiric treatment have traditionally been common among patients with negative bacteriologic test results. Increasing availability of rapid molecular diagnostic tests, including Xpert MTB/RIF and the new Xpert Ultra cartridge, may alter the role of empiric treatment.

Methods: We prospectively enrolled outpatients age > = 15 who were evaluated for pulmonary tuberculosis at three health facilities in Kampala, Uganda. Using sputum mycobacterial culture, interviews, and clinical record abstraction, we estimated the accuracy of clinical diagnosis relative to Xpert and sputum culture and assessed the contribution of clinical diagnosis to case detection.

Results: Over a period of 9 months, 99 patients were diagnosed with pulmonary tuberculosis and subsequently completed sputum culture; they were matched to 196 patients receiving negative tuberculosis evaluations in the same facilities. Xpert was included in the evaluation of 291 (99%) patients. Compared to culture, Xpert had a sensitivity of 92% (95% confidence interval 83-97%) and specificity of 95% (92-98%). Twenty patients with negative Xpert were clinically diagnosed with tuberculosis and subsequently had their culture status determined; two (10%) were culture-positive. Considering all treated patients regardless of Xpert and culture data completeness, and considering treatment initiations before a positive Xpert (N = 4) to be empiric, 26/101 (26%) tuberculosis treatment courses were started empirically. Compared to sputum smear- or Xpert-positive patients with positive cultures, empirically-treated, Xpert-negative patients with negative cultures had higher prevalence of HIV (67% versus 37%), shorter duration of cough (median 4 versus 8 weeks), and lower inflammatory markers (median CRP 7 versus 101 mg/L).

Conclusion: Judged against sputum culture in a routine care setting of high HIV prevalence, the accuracy of Xpert was high. Clinical judgment identified a small number of additional culture-positive cases, but with poor specificity. Although clinicians should continue to prescribe tuberculosis treatment for Xpert-negative patients whose clinical presentations strongly suggest pulmonary tuberculosis, they should also carefully consider alternative diagnoses.

Fig 1. Xpert results at time of diagnosis, and eventual Xpert and sputum culture results, among empirically treated patients.

No other bacteriologic testing such as sputum smear examination was used in diagnosing these individuals.

Fig 2. Xpert results and treatment decisions, by sputum culture result.

Red dashed outlines highlight the patients for whom culture results were discordant with their previous diagnosis, including 4 with positive culture who had not been treated (false-negative Xpert) and 27 with negative cultures who had been treated either based on Xpert or empirically. For some patients with positive Xpert, the decision to treat was made before the Xpert result became available; these patients are classified as “Positive Xpert” here, but they are also included in Fig 1 which describes all empirically treated cases. Controls were included in this figure only if their matched case also had Xpert and culture results.

Fig 3. Key characteristics of patients with culture-concordant and culture-discordant clinical TB diagnoses.

Error bars represent 80% binomial confidence intervals. Patients with negative evaluations (controls) but subsequent positive cultures are excluded, as are individuals with no culture result and the matched controls of cases with no culture result. Numerical values are also listed in S6 Table.