Faculty Bibliography

BACKGROUND:Sputum smear microscopy for tuberculosis (TB) diagnosis lacks sensitivity in HIV-infected symptomatic patients and increases the likelihood that mycobacterial infections particularly disseminated TB will be missed; delays in diagnosis can be fatal. Given the duration for MTB growth in blood culture, clinical predictors of MTB bacteremia may improve early diagnosis of mycobacteremia. We describe the predictors and mortality outcome of mycobacteremia among HIV-infected sputum smear-negative presumptive TB patients in a high prevalence HIV/TB setting. METHODS:Between January and November 2011, all consenting HIV-infected adults suspected to have TB (presumptive TB) were consecutively enrolled. Diagnostic assessment included sputum smear microscopy, urine Determine TB lipoarabinomannan (LAM) antigen test, mycobacterial sputum and blood cultures, chest X-ray, and CD4 cell counts in addition to clinical and socio-demographic data. Patients were followed for 12 months post-enrolment. RESULTS:Of 394 sputum smear-negative participants [female, 63.7%; median age (IQR) 32 (28-39) years], 41/394 (10.4%) had positive mycobacterial blood cultures (mycobacteremia); all isolates were M. tuberculosis (MTB). The median CD4 cell count was significantly lower among patients with mycobacteremia when compared with those without (CD4 31 versus 122 cells/μL, p < 0.001). In a multivariate analysis, male gender [OR 3.4, 95%CI (1.4-7.6), p = 0.005], CD4 count <100 cells/μL [OR 3.1, 95% CI (1.1-8.6), p = 0.030] and a positive lateral flow urine TB LAM antigen test [OR 15.3, 95%CI (5.7-41.1), p < 0.001] were significantly associated with mycobacteremia. At 12 months of follow-up, a trend towards increased mortality was observed in patients that were MTB blood culture positive (35.3%) compared with those that were MTB blood culture negative (23.3%) (p = 0.065). CONCLUSIONS:Mycobacteremia occurred in 10% of smear-negative patients and was associated with higher mortality compared with smear-negative patients without mycobacteremia. Advanced HIV disease (CD4 < 100 cells/mm(3)), male gender and positive lateral flow urine TB LAM test predicted mycobacteremia in HIV-infected smear-negative presumptive TB patients in this high prevalence TB/HIV setting.

OBJECTIVE:In settings of high HIV prevalence, tuberculosis control and patient management are hindered by lack of accurate, rapid tuberculosis diagnostic tests that can be performed at point-of-care. The Determine TB LAM Ag (TB LAM) test is a lateral flow immunochromatographic test for detection of mycobacterial lipoarabinomannan (LAM) in urine. Our objective was to determine sensitivity and specificity of the TB LAM test for tuberculosis diagnosis. DESIGN/METHODS:Prospective diagnostic accuracy study. SETTING/METHODS:Hospital and outpatient settings in Uganda and South Africa. PARTICIPANTS/METHODS:HIV-infected adults with tuberculosis symptoms and/or signs. METHODS:Participants provided a fresh urine specimen for TB LAM testing, blood for mycobacterial culture, and 2 respiratory specimens for smear microscopy and mycobacterial culture. MAIN OUTCOME MEASURES/METHODS:For the TB LAM test, sensitivity in participants with culture-positive tuberculosis and specificity in participants without tuberculosis. RESULTS:A total of 1013 participants were enrolled. Among culture-positive tuberculosis patients, the TB LAM test identified 136/367 (37.1%) overall and 116/196 (59.2%) in the group with CD4 ≤100 cells per cubic millimeter. The test was specific in 559/573 (97.6%) patients without tuberculosis. Sensitivity of the urine TB LAM test plus sputum smear microscopy was 197/367 (53.7%) overall and 133/196 (67.9%) among those with CD4 ≤100. CD4 ≤50 [adjusted odds ratio (AOR), 6.2; P < 0.001] or 51-100 (AOR, 7.1; P < 0.001), mycobacteremia (AOR, 6.1; P < 0.01) and hospitalization (AOR, 2.6; P = 0.03) were independently associated with a positive TB LAM test. CONCLUSIONS:In HIV-positive adults with CD4 ≤100, the TB LAM urine test detected over half of culture-positive tuberculosis patients, in <30 minutes and without the need for equipment or reagents.

BACKGROUND:Xpert MTB/RIF ('Xpert') and urinary lipoarabinomannan (LAM) assays offer rapid tuberculosis (TB) diagnosis, but have suboptimal sensitivity when used individually in HIV-positive patients. The yield of these tests used in combination for the diagnosis of active TB among HIV-infected TB suspects is unknown. DESIGN/METHODS:Study of comparative diagnostic accuracy nested into a prospective study of HIV-infected individuals with signs and/or symptoms of TB in Uganda. METHODS:Xpert testing of archived sputum was conducted for culture-confirmed TB cases and TB suspects in whom a diagnosis of TB was excluded. Additional testing included sputum smear microscopy, sputum culture (solid and liquid media), mycobacterial blood culture, and urinary testing for LAM using a lateral flow test ('LF-LAM') and an enzyme-linked immunosorbance assay ('ELISA-LAM'). RESULTS:Among 103 participants with culture-confirmed TB, sensitivity of Xpert was 76% (95% confidence interval, CI 0.66-0.84), and was superior to that of LF-LAM (49%, 95% CI 0.39-0.59, P < 0.001). Specificity was greater than 97% for both tests among 105 individuals without TB. The combination of smear microscopy and LF-LAM identified 67% (95% CI 0.57-0.76) of culture-confirmed TB cases and approached sensitivity of Xpert testing alone (P = 0.15). The sensitivity of the combination of Xpert and LF-LAM was 85% (88/103 95% CI 0.77-0.92), which was superior to either test alone (P < 0.05) and approached sensitivity of sputum liquid culture testing (94%, 95% CI 0.88-0.98, P = 0.17). CONCLUSION/CONCLUSIONS:Sputum Xpert and urinary LAM assays were complementary for the diagnosis of active TB in HIV-infected patients, and sensitivity of the combination of these tests was superior to that of either test alone.

SETTING/METHODS:Improved strategies are needed for detecting Mycobacterium tuberculosis infection in children in TB-endemic settings. OBJECTIVE:To determine the prevalence of M. tuberculosis infection by tuberculin skin testing (TST) and by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test in children with an adult household contact with pulmonary TB in South Africa. DESIGN/METHODS:Cross-sectional study. RESULTS:A total of 167 adult pulmonary TB cases (153/167, 92% human immunodeficiency virus [HIV] infected) and 270 pediatric contacts (median age 6 years, 14/270, 5% HIV-infected) were enrolled. All children completed QFT-GIT testing and 254 (94.1%) completed TST testing. Prevalence of M. tuberculosis infection was 28% (71/254, 95%CI 23-34) using TST (5 mm cut-off) and 29% (79/270, 95%CI 24-35) using QFT-GIT (P = 0.49). Agreement between TST and QFT-GIT was 81% (kappa 0.58). Nineteen (7%) QFT-GIT results were indeterminate. Children aged <2 years were more likely than older children to have indeterminate QFT-GIT results (aOR 5.7, 95%CI 1.5-22, P = 0.01) and discordant QFT-GIT and TST results (aOR 3.5, 95%CI 1.7-7.6, P = 0.001). CONCLUSION/CONCLUSIONS:Prevalence of M. tuberculosis infection in pediatric contacts was high regardless of the diagnostic method used. TST should not be excluded for the detection of pediatric M. tuberculosis infection in this setting, but QFT-GIT may be a feasible alternative in children aged ≥ 2 years.