Summary Background Most tuberculosis-related deaths in people with HIV could be prevented with earlier diagnosis and treatment. The only commercially available tuberculosis point-of-care test (Alere Determine TB LAM Ag [AlereLAM]) has suboptimal sensitivity, which restricts its use in clinical practice. The novel Fujifilm SILVAMP TB LAM (FujiLAM) assay has been developed to improve the sensitivity of AlereLAM. We assessed the diagnostic accuracy of the FujiLAM assay for the detection of tuberculosis in hospital inpatients with HIV compared with the AlereLAM assay. Methods For this diagnostic accuracy study, we assessed biobanked urine samples obtained from the FIND Specimen Bank and the University of Cape Town Biobank, which had been collected from hospital inpatients (aged ≥18 years) with HIV during three independent prospective cohort studies done at two South African hospitals. Urine samples were tested using FujiLAM and AlereLAM assays. The conduct and reporting of each test was done blind to other test results. The primary objective was to assess the diagnostic accuracy of FujiLAM compared with AlereLAM, against microbiological and composite reference standards (including clinical diagnoses). Findings Between April 18, 2018, and May 3, 2018, urine samples from 968 hospital inpatients with HIV were evaluated. The prevalence of microbiologically-confirmed tuberculosis was 62% and the median CD4 count was 86 cells per μL. Using the microbiological reference standard, the estimated sensitivity of FujiLAM was 70·4% (95% CI 53·0 to 83·1) compared with 42·3% (31·7 to 51·8) for AlereLAM (difference 28·1%) and the estimated specificity of FujiLAM was 90·8% (86·0 to 94·4) and 95·0% (87·7–98·8) for AlereLAM (difference −4·2%). Against the composite reference standard, the specificity of both assays was higher (95·7% [92·0 to 98·0] for FujiLAM vs 98·2% [95·7 to 99·6] for AlereLAM; difference −2·5%), but the sensitivity of both assays was lower (64·9% [50·1 to 76·7] for FujiLAM vs 38·2% [28·1 to 47·3] for AlereLAM; difference 26·7%). Interpretation In comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and could transform rapid point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The applicability of FujiLAM for settings of intended use requires prospective assessment. Funding Global Health Innovative Technology Fund, UK Department for International Development, Dutch Ministry of Foreign Affairs, Bill & Melinda Gates Foundation, German Federal Ministry of Education and Research, Australian Department of Foreign Affairs and Trade, Wellcome Trust, Department of Science and Technology and National Research Foundation of South Africa, and South African Medical Research Council.

While it is known that a substantial proportion of individuals with tuberculosis disease (TB) present subclinically, usually defined as bacteriologically-confirmed but negative on symptom screening, considerable knowledge gaps remain. Our aim was to review data from TB prevalence population surveys and generate a consistent definition and framework for subclinical TB, thus enabling an estimate of the proportion of TB that is subclinical, explore associations with overall burden and programme indicators, and performance of screening strategies. We extracted data from all publicly available prevalence surveys conducted since 1990. Between 36.1–79.7% (median 50.4%) of prevalent bacteriologically-confirmed TB was subclinical. No association was found between prevalence of subclinical and all bacteriologically confirmed TB, patient diagnostic rate or country-level HIV prevalence (p-values, 0.32, 0.4, 0.34, respectively). Chest X-ray detected 89% (range 73–98%) of bacteriologically-confirmed TB disease, highlighting the potential of optimizing current TB case-finding policies.

Background In high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis. Methods and findings Adult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31–43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21–120) and a median HIV viral load of 5.1 log 10 copies/mL (IQR = 3.3–5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1β]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9–2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sam...

Background Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data. Methods and findings Adult PLHIV (�18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who

Inflammation, or the prolonged resolution of inflammation, contributes to death from tuberculosis. Interest in inflammatory mechanisms and the prospect of beneficial immune modulation as an adjunct to antibacterial therapy has revived and the concept of host directed therapies has been advanced. Such renewed attention has however, overlooked the experience of such therapy with corticosteroids. Areas covered: The authors conducted literature searches and evaluated randomized clinical trials, systematic reviews and current guidelines and summarize these findings. They found evidence of benefit in meningeal and pericardial tuberculosis in HIV-1 uninfected persons, but less so in those HIV-1 coinfected and evidence of harm in the form of opportunist malignancy in those not prescribed antiretroviral therapy. Adjunctive corticosteroids are however of benefit in the treatment and prevention of paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome. Expert commentary: Further high-quality clinical trials and experimental medicine studies are warranted and analysis of materials arising from such studies could illuminate ways to improve corticosteroid efficacy or identify novel pathways for more specific intervention.

Diagnosing tuberculosis (TB) in people living with HIV (PLHIV) remains challenging in part, because of its diversity of clinical manifestations, including high rates of extra-pulmonary and disseminated disease [1]. In particular, disseminated TB, involving multiple organ systems, is associated with high mortality but often presents non-specifically, which may hinder prompt diagnosis [2, 3]. Xpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, USA), is currently recommended by the World Health Organization (WHO) as the first line assay for evaluating a subset of extra-pulmonary TB disease (EPTB) manifestations [4]. To detect specific forms of EPTB, such as pleural TB, TB meningitis or TB lymphadenitis, Xpert may require an invasive sample to be collected, which often limits its use for EPTB detection to hospitals where appropriate equipment is available and invasive sampling can be safely performed. Furthermore, even when concomitant pulmonary disease is present, it can be very difficult to obtain sputum in the sickest HIV patients to submit for Xpert testing [5, 6]. Therefore, an urgent priority for improving TB detection among PLHIV remains the development of rapid, point-of-care (POC) assays that use an easily obtainable clinical specimen, such as urine, and that have good diagnostic accuracy for both pulmonary and EPTB, including disseminated disease [7]. The commercially available Alere Determine TB LAM (AlereLAM; Abbott, Chicago, IL, USA) assay is a rapid, inexpensive, urinary POC TB test [8]. While its use is associated with a mortality benefit in severely ill and immunocompromised PLHIV [9, 10], it has only moderate sensitivity that is limited to patients with low CD4 counts, which has led to limited programmatic uptake [11]. We have previously reported on the Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan) POC assay that, similar to AlereLAM, detects the presence of lipoarabinomannan (LAM) in urine [12]. It offers on average 30% improved sensitivity for detecting TB (independent of whether it is PTB or EPTB) compared to AlereLAM across subgroups stratified by CD4 strata, while maintaining high specificity. Here we report the sensitivity of FujiLAM in comparison to AlereLAM specifically for detecting EPTB in the same patient cohorts. This post hoc analysis utilised data from two previously published, prospective cohort studies of adults (>18 years) living with HIV who were admitted to South African district hospitals on the outskirts of Cape Town [13, 14]. Cohort A enrolled patients without a current TB diagnosis regardless of presenting signs or symptoms, and independent of CD4 count [13]. Cohort B enrolled patients with a CD4 count <350 cells•μL −1 in whom TB was considered the most likely diagnosis on admission [14]. A third previously published cohort was not included in the present analysis as it excluded patients with exclusively extra-pulmonary TB disease [12]. Informed consent was obtained from patients who had capacity or regained capacity and all study-related activities were approved by the H...

Background: Prevalence surveys have found a substantial burden of subclinical (asymptomatic but infectious) TB, from which individuals can progress, regress or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of TB disease. Methods: We created deterministic framework of TB disease with progression and regression between three states of pulmonary TB disease: minimal (non-infectious), subclinical, and clinical (symptomatic and infectious) disease. We estimated ranges for each parameter by considering all data from a systematic review in a Bayesian framework, enabling quantitative estimation of TB disease pathways. Findings: Twenty-four studies contributed data from 6030 individuals. Results suggested that, after five years, 24.7%(95% uncertainty interval, UI, 21.3%-28.6%) of individuals with prevalent subclinical disease at baseline had either progressed to clinical disease or died from TB, whereas 16.1%(95%UI, 13.8%-18.5%) had recovered after regressing to minimal disease. Over the course of five years 30% (95%UI, 27.2%-32.6%) of the subclinial cohort never developed symptoms. For those with clinical disease at baseline, 39%(95%UI, 35.8%-41.9%) and 10.3%(95%UI, 8.5%-12.4%) had died or recovered from TB, with the remainder in, or undulating between, the three disease states. The ten-year mortality of people with untreated prevalent infectious disease was 38%. Interpretation: Our results show that for people with subclinical disease, classic clinical disease is neither inevitable nor an irreversible outcome. As such, reliance on symptom- based screening means a large proportion of people with infectious disease may never be detected. Funding: TB Modelling and Analysis Consortium and European Research Council

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