Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid

Abstract

Rationale: The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear.

Methods: South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (∼10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management.

Results: 27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18-41) to 0 (0-0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1-49) versus 7 (0-21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy.

Conclusions: MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.

Keywords: Tuberculosis.

Figure 1

Study flow diagram showing the patients included in the analysis and test results. *All patients provided bronchoalveolar lavage fluid. Bronchial brushings and biopsies were provided at the discretion of the attending clinician to the reference laboratory. Smear and culture were performed on these latter two specimens when possible by the reference laboratory. †MTB/RIF was performed on fresh BALF from 82 patients. Fluid thawed from a frozen specimen was used for MTB/RIF for 78 patients recruited prior to the World Health Organization’s endorsement of MTB/RIF. ‡Histology was considered compatible with active TB if necrotising or caseating granulomatous inflammation were observed by the reference laboratory. Five individuals had a record of histology being requested, but the result was missing. §One MTB/RIF ERROR result was recorded. **One MTB/RIF ERROR result and one INVALID result were recorded. BALF, bronchoalveolar lavage fluid; PBS, phosphate buffer saline.

Figure 2

Relationship between MTB/RIF-generated cycle threshold (C_T) values and bacterial load in BALF.

Figure 3

Time-specific proportion of definite TB cases detected by different diagnostic methods when MTB/RIF results were used for patient management in phase two. *Positive results are included here from different specimens for smear microscopy: of all 12 smear-positives, two did not have smear-positive bronchoalveolar lavage fluid but did have smear-positive bronchial biopsies. Histology was only performed on bronchial biopsies in 12 of the 18 definite TB cases. For liquid culture, all 17 detected individuals had culture-positive bronchoalveolar lavage fluid and there were no additional cases detected on bronchial brushings and biopsies. MTB/RIF was performed only on bronchoalveolar lavage fluid.

Figure 4

Venn diagrams (A) and bar graph (B) showing the proportion of patients either initiated onto treatment on the basis of different positive test results, or who treated empirically in the absence of a positive result before (phase one) and after (phase two) Xpert MTB/RIF was used for patient management. *22% of 64 patients in phase one and 35% of patients in phase two were placed on treatment and have known dates of treatment initiation. Three patients in phase one and one patient in phase two who were placed on anti-TB treatment were missing the date of anti-TB treatment initiation and are omitted. Histology detected no patients in phase one and seven patients in phase two (all of which were initiated onto treatment before the histology result was available as they were also smear- or MTB/RIF-positive). †Empiric anti-TB treatment is defined as the initiation of treatment on clinical grounds in the absence of positive smear microscopy, histology or culture result (in phase one), plus the absence of a positive MTB/RIF result (phase two only), at the time of treatment initiation.

Figure 5

Time-specific proportion of patients initiating anti-TB treatment before (phase one) and after (phase two) MTB/RIF was used for patient management.