Risk score for predicting mortality including urine lipoarabinomannan detection in hospital inpatients with HIV-associated tuberculosis in sub-Saharan Africa: Derivation and external validation cohort study

Abstract

Background The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. Methods and findings A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30–43), 45.4% were female, median CD4 cell count at admission was 76 cells/μl (IQR 23–206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%–55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%–25.4%) in the low-risk group ( p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4–15.2) in high-risk patients compared to low-risk patients ( p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63–0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61–0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21–145). OR for mortality was 5.3 (95% CI 2.2–9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortali...

Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

“…3 Unidad de Atención Integral del VIH e Infecciones Crónicas del Hospital Roosevelt "Dr. Carlos Rodolfo Mejía Villatoro", Guatemala City, Guatemala. 4 Sección de Microbiología, Departamento de Laboratorios Clínicos, Hospital Roosevelt, Guatemala City, Guatemala. 5 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.…”

“…Conversely, severely immune suppressed PLWH with presumptive extrapulmonary or disseminated TB fail in getting a positive Xpert result, mainly because they are too ill to produce a quality sputum sample, or their sputum contains very few AFB. For these individuals, currently the Xpert is unlikely to be useful and thus, the need of alternative TB diagnostic tests with increased sensitivity to provide early treatment and care and reduce mortality in PLWH having extrapulmonary or disseminated TB [4].…”

Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study

“…The prognostic importance of male gender in predicting mortality was correlated with older age and smoking history in our model, and we chose to include the single gender variable rather than two additional variables (age ≥ 55 and smoking) in the CD4-dependent clinical score to make the most parsimonious clinical score and because male gender is a more generalizable predictor of poor outcomes in SSA [ 29 , 57 , 58 ]. In addition, similar to many ART programs in SSA [ 20 , 59 ], pregnant women in XPRES, who were (1) more likely to be diagnosed at an earlier disease stage through routine testing at antenatal care and (2) able to initiate ART immediately once diagnosed unlike non-pregnant women diagnosed with HIV at the time [ 15 ], had lower mortality than non-pregnant women starting ART in bivariate analysis [ 20 , 59 ].…”

“…In addition, similar to many ART programs in SSA [ 20 , 59 ], pregnant women in XPRES, who were (1) more likely to be diagnosed at an earlier disease stage through routine testing at antenatal care and (2) able to initiate ART immediately once diagnosed unlike non-pregnant women diagnosed with HIV at the time [ 15 ], had lower mortality than non-pregnant women starting ART in bivariate analysis [ 20 , 59 ]. However, if ART programs in SSA are able in the future to achieve earlier testing and ART initiation for male and non-pregnant female PLHIV, it is likely gender and pregnancy status could become less important predictors, while predictors like smoking and older age will become more important [ 57 ]. Although smoking is not part of the clinical score, this article provides additional evidence for the need for tobacco smoking reduction programs for PLHIV, separate or included in early ART care intensification algorithms, to minimize not only the risk of ischemic cardiovascular diseases but also the risk of malignancies and bacterial infections, including TB [ 60 ].…”

Determine TB-LAM point-of-care tuberculosis assay predicts poor outcomes in outpatients during their first year of antiretroviral therapy in South Africa

“…They had advanced immunosuppression (median CD4 59 cells/μL) and tended to be anemic (Table 1). More than 90% of all patients started ART, with a median time to ART initiation of 15 days (IQR, [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Baseline characteristics did not differ between the two study sites and thus data from two sites were combined for all subsequent analyses (data not shown).…”