Tuberculosis diagnostics to reduce HIV-associated mortality: Barnett Christie Lecture 2020

Tuberculosis (TB) was declared a global emergency in 1993 by the World health Organization (WHO), with global and African regional TB incidence rates driven by the HIV epidemic. Much of this burden lay in health facilities in sub-Saharan Africa, with post-mortem studies showing almost half of fatal TB goes undiagnosed, reflecting a failure in the approach to TB diagnostics. HIV-associated TB is often under the clinical radar, and this paper describes strategies to improve TB diagnostics to expedite treatment, reduce the amount of undiagnosed disease and ultimately reduce mortality. Through studies assessing the diagnostic accuracy and yield of new, rapid TB diagnostics, including the Xpert MTB/RIF nucleic acid amplification and urinary lipoarabinomannan (LAM) lateral flow assays, and clinical trials to measure impact on mortality and clinically relevant outcomes, this paper describes how TB diagnostics can reduce HIV-associated morbidity and mortality. With improved TB diagnostics in the pipeline, the future of urine-LAM assays for TB are also discussed

Xpert MTB/RIF - why the lack of morbidity and mortality impact in intervention trials?

: Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings.<br/

Investigating mortality risk in hospitalised patients in Africa with HIV-associated tuberculosis and positive urine diagnostics: a clinical, epidemiological and immunological study.

HIV-associated tuberculosis (HIV/TB) was responsible for an estimated 374,000 deaths globally in 2016. Much of this burden resides in hospitals in sub-Saharan Africa, where HIV/TB is usually disseminated and is the major cause of admission and death. Recently, urine-based detection of mycobacterial lipoarabinomannan (LAM) or nucleic acids (using the Xpert MTB/RIF assay) has improved diagnosis of HIV/TB in this population, with the potential to improve outcomes. However, disseminated ‘urine-positive’ TB may also be associated with a higher mortality risk and impaired immune responses compared to patients with HIV/TB disease who are urine TB test negative. This thesis addresses the hypothesis that positive urine-diagnostics in inpatients with HIV/TB disease are associated with mortality, can identify patients with impairment of immune responses, and can be used as useful prognostic markers for identifying patients with poor outcomes. First, a systematic review and meta-analysis was undertaken to synthesise existing evidence of the association between urine-LAM detection and mortality risk in HIV/TB (Gupta-Wright et al, BMC Med 2016). Ten eligible studies were identified, and random-effects meta-analysis demonstrated urine-LAM positive patients had a 2.3-fold greater mortality risk, and 2.5-fold greater adjusted odds of death than urine-LAM negative HIV-TB patients. Secondly, a prospective observational cohort study nested within a large randomised trial of urine-based TB screening was undertaken (STAMP trial in Malawi and South Africa, Gupta- Wright at al BMC Inf Dis 2016 and Lancet 2018). It included 322 patients with laboratoryconfirmed HIV/TB disease and demonstrated a remarkably high (31%) 2-month mortality risk despite rapid initiation of TB treatment. It also demonstrated that advanced immunosuppression was common in HIV/TB disease despite high antiretroviral therapy (ART) coverage. Cohort data were used to identify clinical phenotypes associated with poor outcomes: urine-test positivity (LAM, Xpert or both) was independently associated with a 50% increase in 2 month case-fatality. Thirdly, a study of immune responses was nested in the Malawi STAMP trial site. A functional whole blood assay of phagocytic activity was developed (Gupta-Wright et al, Frontiers Immunology 2017) and utilised in 65 HIV/TB patients and 16 matched HIV-positive TB-negative controls. Cellular and soluble markers of immune activation, ex-vivo monocyte and T-cell cytokine responses and multiplex plasma cytokine and chemokine levels were also measured. Poor outcomes and urine-positive HIV/TB disease were associated with broadly impaired immune responses, including phagocytic oxidative burst function, monocyte activation and dominant innate immune responses. Finally, urine-LAM was included in a simple, pragmatic clinical score to identify patients at high risk of a poor outcome in resource-poor settings, which was externally validated on an individual-patient record dataset combining data from 2 different studies over 5 African countries (Gupta-Wright et al, PLOS Medicine 2019). This PhD has demonstrated the high prevalence and case-fatality associated with disseminated HIV/TB disease in HIV-positive hospital admissions despite widespread access to ART, and the utility of urine-diagnostics in identifying patients at high risk of mortality, in addition to their diagnostic use. These linked studies could potentially inform on the choice and nature of interventions to reduce the high mortality of HIV/TB, including better identification and management of ART failure, therapies to address TB-related immune dysfunction, and improved supportive care and prevention and treatment of co-morbidities

Managing malaria in the intensive care unit.

The number of people travelling to malaria-endemic countries continues to increase, and malaria remains the commonest cause of serious imported infection in non-endemic areas. Severe malaria, mostly caused by Plasmodium falciparum, often requires intensive care unit (ICU) admission and can be complicated by cerebral malaria, respiratory distress, acute kidney injury, bleeding complications, and co-infection. The mortality from imported malaria remains significant. This article reviews the manifestations, complications and principles of management of severe malaria as relevant to critical care clinicians, incorporating recent studies of anti-malarial and adjunctive treatment. Effective management of severe malaria includes prompt diagnosis and early institution of effective anti-malarial therapy, recognition of complications, and appropriate supportive management in an ICU. All cases should be discussed with a specialist unit and transfer of the patient considered

Detection of lipoarabinomannan (LAM) in urine is an independent predictor of mortality risk in patients receiving treatment for HIV-associated tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis

BackgroundSimple immune capture assays that detect mycobacterial lipoarabinomannan (LAM) antigen in urine are promising new tools for the diagnosis of HIV-associated tuberculosis (HIV-TB). In addition, however, recent prospective cohort studies of patients with HIV-TB have demonstrated associations between LAM in the urine and increased mortality risk during TB treatment, indicating an additional utility of urinary LAM as a prognostic marker. We conducted a systematic review and meta-analysis to summarise the evidence concerning the strength of this relationship in adults with HIV-TB in sub-Saharan Africa, thereby quantifying the assay’s prognostic value.MethodsWe searched MEDLINE and Embase databases using comprehensive search terms for ‘HIV’, ‘TB’, ‘LAM’ and ‘sub-Saharan Africa’. Identified studies were reviewed and selected according to predefined criteria.ResultsWe identified 10 studies eligible for inclusion in this systematic review, reporting on a total of 1172 HIV-TB cases. Of these, 512 patients (44%) tested positive for urinary LAM. After a variable duration of follow-up of between 2 and 6months, overall case fatality rates among HIV-TB cases varied between 7% and 53%. Pooled summary estimates generated by random-effects meta-analysis showed a two-fold increased risk of mortality for urinary LAM-positive HIV-TB cases compared to urinary LAM-negative HIV-TB cases (relative risk 2.3, 95% confidence interval 1.6–3.1). Some heterogeneity was explained by study setting and patient population in sub-group analyses. Five studies also reported multivariable analyses of risk factors for mortality, and pooled summary estimates demonstrated over two-fold increased mortality risk (odds ratio 2.5, 95% confidence interval 1.4–4.5) among urinary LAM-positive HIV-TB cases, even after adjustment for other risk factors for mortality, including CD4 cell count.ConclusionsWe have demonstrated that detectable LAM in urine is associated with increased risk of mortality during TB treatment, and that this relationship remains after adjusting for other risk factors for mortality. This may simply be due to a positive test for urinary LAM serving as a marker of higher mycobacterial load and greater disease dissemination and severity. Alternatively, LAM antigen may directly compromise host immune responses through its known immunomodulatory effects. Detectable LAM in the urine is an independent risk factor for mortality among patients receiving treatment for HIV-TB. Further research is warranted to elucidate the underlying mechanisms and to determine whether this vulnerable patient population may benefit from adjunctive interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0603-9) contains supplementary material, which is available to authorized users

World TB Day 2018: The Challenge of Drug Resistant Tuberculosis.

On 24th March, the world commemorates the day in 1882 when Dr Robert Koch announced his discovery of Mycobacterium tuberculosis (MTB). Over 130 years later, tuberculosis (TB) continues to affect individuals, communities, and entire health systems and economies. Koch unsuccessfully tried to 'cure' TB, and despite major advances in other areas of medicine, control of TB remains elusive- in 2016 TB was the leading infectious cause of death. The STOP TB partnership and World Health Organization (WHO) have announced their theme for World TB Day 2018 "Wanted: Leaders for a TB-Free World. You can make history. End TB." This theme recognizes that TB is much larger than any one person, institute or discipline of research, and provides an opportunity for us to reflect on the major challenges and consider how we, as a scientific community, can work together and take the lead to address the global crisis of drug-resistant TB (DR-TB)

The Geometry of PSR B0031-07

PSR B0031-07 is well known to exhibit three different modes of drifting sub-pulses (mode A, B and C). It has recently been shown that in a multifrequency observation, consisting of 2700 pulses, all driftmodes were visible at low frequencies, while at 4.85 GHz only mode-A drift or non-drifting emission was detected. This suggests that modes A and B are emitted in sub-beams, rotating at a fixed distance from the magnetic axis, with the mode-B sub-beams being closer to the magnetic axis than the mode-A sub-beams. Diffuse emission between the sub-beams can account for the non-drifting emission. Using the results of an analysis of simultaneous multifrequency observations of PSR B0031-07, we set out to construct a geometrical model that includes emission from both sub-beams and diffuse emission and describes the regions of the radio emission of PSR B0031-07 at each emission frequency for driftmodes A and B. Based on the vertical spacing between driftbands, we have determined the driftmode of each sequence of drift. To restrict the model, we calculated average polarisation and intensity characteristics for each driftmode and at each frequency. The model reproduces the observed polarisation and intensity characteristics, suggesting that diffuse emission plays an important role in the emission properties of PSR B0031-07. The model further suggests that the emission heights of this pulsar range from a few kilometers to a little over 10 kilometers above the pulsar surface. We also find that the relationships between height and frequency of emission that follow from curvature radiation and from plasma-frequency emission could not be used to reproduce the observed frequency dependence of the width of the average intensity profiles.Comment: 15 pages, 9 figures, 8 tables, accepted for publication in A&