Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays

Abstract

HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.

Figure 1

Venn diagram showing the proportions of Mycobacterium tuberculosis blood culture positive patients (n = 41) who had a TB diagnosis made by rapid microbiological tests. (A) Sputum-based diagnostics and (B). Urine-based diagnostics. Percentages represent the proportion of patients with positive mycobacterial blood culture diagnosed by a respective test and ‘n’ is the actual number of patients with positive mycobacterial blood culture diagnosed by a respective test. Any proportion (n) within the red portion was not diagnosed by any test, i.e. was exclusively detecting using mycobacterial blood culture. AFB = acid fast bacilli, LAM = Lipoarabinomannan. *Both sputum Xpert and sputum microscopy had identical diagnostic yield. Sputum microscopy and sputum Xpert had identical diagnostic yield for Mycobacterium tuberculosis bacteraemia and both tests diagnosed n = 3/9 Mycobacterium tuberculosis blood culture positive patients who died within 90 days.

Figure 2

Principle components analysis (PCA) showing main dimensions of variation in laboratory and clinical variables for patients diagnosed with TB. The PCA was constructed with 10 major laboratory and clinical variables [haemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), serum sodium, C-reactive protein (CRP), albumin, HIV viral load, total lymphocyte count, CD4 + cell count, and a symptom score based on number of ‘TB symptoms’ present (cough, haemoptysis, night sweats, fever, weight loss)]. Correlation of each of these variables with the first two principle components (shown as coordinates on panel A) demonstrated that the first principle component (PC1, red arrow) of clinical variation was dominated by markers of systemic inflammation (e.g. CRP, albumin, haemoglobin) while the second principle component (PC2, blue arrow) captured variation in HIV disease and immune status. These PCs were rotated using the varimax method and are therefore orthogonal (independent), and explained 26% and 18% of variation in the 10 clinical variable respectively. Although not used to construct these PCs, site of TB disease groupings clustered distinctively on these dimensions (panel B, each point is PC1 and PC2 coordinates of an individual patient, n = 129). PC1 and PC2 varied significantly overall by TB site (Kruskal-Wallis p = 0.003 and p < 0.001 respectively). Total number of positive tests out of the three assays {urine LAM, urine Xpert, M. tuberculosis blood culture} was associated with greater inflammation and immunosuppression (panel C). Compartmentalised extra-pulmonary TB in absence of dissemination (i.e. pleural TB or TB meningitis with negative urine LAM, urine Xpert and MTB blood culture) had significantly lower PC1 and PC2 values compared to disseminated TB. TB 90-day mortality was also strongly associated with “inflammation” and “immunosuppression” (panel D); a logistic regression model containing both PC1 and PC2 as independent variables showed adjusted odds ratios for mortality of 2.6 (95%CI 1.3–6.4, p = 0.017) and 2.4 (95%CI 1.3–4.5, p = 0.005) per one unit (one standard deviation) increase in PC1 and PC2 respectively. uXp = urine Xpert; uLAM = urine LAM; BC = MTB blood culture. Suffix “−” = test negative; suffix “ +” = test positive.

Figure 3

Plot of 90-day mortality outcome by number of TB tests positive (urine LAM, urine Xpert, and M. tuberculosis blood culture). *Note: area corresponds to absolute count of patients in category; proportion who died corresponds to height of red area.