Publications
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Du Bruyn E, Fukutani KF, Rockwood N, et al., 2021, Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis., Lancet Microbe, Vol: 2, Pages: e375-e385
BACKGROUND: HIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1. METHODS: In this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1-5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per μL and a high clinical suspicion of new tuberculosis were recruited. FINDINGS: Between March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1-43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and ha
Altmann MC, Rinchai D, Baldwin N, et al., 2021, Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data, Nature Communications, Vol: 12, Pages: 1-19, ISSN: 2041-1723
As the capacity for generating large-scale molecular profiling data continues to grow, the ability to extract meaningful biological knowledge from it remains a limitation. Here, we describe the development of a new fixed repertoire of transcriptional modules, BloodGen3, that is designed to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome data. The construction of this repertoire is based on co-clustering patterns observed across sixteen immunological and physiological states encompassing 985 blood transcriptome profiles. Interpretation is supported by customized resources, including module-level analysis workflows, fingerprint grid plot visualizations, interactive web applications and an extensive annotation framework comprising functional profiling reports and reference transcriptional profiles. Taken together, this well-characterized and well-supported transcriptional module repertoire can be employed for the interpretation and benchmarking of blood transcriptome profiles within and across patient cohorts. Blood transcriptome fingerprints for the 16 reference cohorts can be accessed interactively via: https://drinchai.shinyapps.io/BloodGen3Module/.
Wasserman S, Davis AG, Stek C, et al., 2021, Plasma pharmacokinetics of high dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial, Antimicrobial Agents and Chemotherapy, Vol: 65, Pages: 1-12, ISSN: 0066-4804
BackgroundHigher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.Materials and methodsWe performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).ResultsForty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg·h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing.ConclusionsPlasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.
Zurcher K, Reichmuth ML, Ballif M, et al., 2021, Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing: a multicentre cohort study, The Lancet Microbe, Vol: 2, Pages: E320-E330, ISSN: 2666-5247
BackgroundDrug resistance threatens global tuberculosis control. We aimed to examine mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and whole-genome sequencing (WGS).MethodsIn this multicentre cohort study, we collected pulmonary Mycobacterium tuberculosis isolates and clinical data from individuals with tuberculosis from antiretroviral therapy programmes and tuberculosis clinics in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, and Thailand, stratified by HIV status and drug resistance. Sites tested drug susceptibility using routinely available methods. WGS was done on Illumina HiSeq 2500 in the USA and Switzerland, and TBprofiler was used to analyse the genomes. We included individuals aged 16 years or older with pulmonary tuberculosis (bacteriologically confirmed or clinically diagnosed). We analysed mortality in multivariable logistic regression models adjusted for sex, age, HIV status, history of tuberculosis, and sputum positivity.FindingsBetween Sept 1, 2014, and July 4, 2016, of 634 patients included in our previous analysis, we included 582 patients with tuberculosis (median age 33 years [IQR 27–43], 225 [39%] women, and 247 [42%] HIV-positive). Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-extensively drug-resistant (pre-XDR) or XDR. The analysis of mortality was based on 530 patients; 63 (12%) died and 77 (15%) patients received inappropriate treatment. Mortality ranged from 6% (18 of 310) in patients with pan-susceptible tuberculosis to 39% (nine of 23) in patients with pre-XDR or XDR tuberculosis. The adjusted odds ratio for mortality was 4·92 (95% CI 2·47–9·78) among undertreated patients, compared with appropriately treated patients.InterpretationIn seven countries with a high burde
Davis A, Donovan J, Bremer M, et al., 2021, Host directed therapies for tuberculous meningitis [version 2; peer review: 1 approved, 1 approved with reservations], Wellcome Open Research, Vol: 5, ISSN: 2398-502X
A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.
Burke RM, Rickman HM, Singh V, et al., 2021, What is the optimum time to start antiretroviral therapy in people with HIV and tuberculosis coinfection? A systematic review and meta-analysis, Journal of the International AIDS Society, Vol: 24, Pages: 1-16, ISSN: 1758-2652
Background: HIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of tuberculosis treatment start, at any CD4 count. We aimed to assess whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis.Methods: We did a systematic review by searching nine database for for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studied published from database inception to 12 March 2021. We compared ART within four weeks vs. ART more than four weeks after TB treatment, and ART within two weeks vs. ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS-defining events. We used random effects meta-analysis to pool effect estimates.Results: 2468 abstracts were screened, from which we identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤ 4 week) vs. later ART (> 4 week) (risk difference [RD] 0%; 95% confidence interval [CI] -2% to +1%). Among people with CD4 count ≤50 cells/mm3, earlier ART (≤4 weeks) reduced risk of death (RD -6%; -10% to -1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS defining events (RD -2%, 95% CI -4% to 0%). Results were similar when trials were restricted to the five trials which permitted comparison of ART within two weeks to ART between two and eight weeks.Discussion: Earlier ART did not alter risk of death overall among people living with HIV who had TB disease. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase in
Bunjun R, Soares AP, Thawer N, et al., 2021, Dysregulation of the immune environment in the airways during HIV infection, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224
HIV-1 increases susceptibility to pulmonary infection and disease, suggesting pathogenesis in the lung. However, the lung immune environment during HIV infection remains poorly characterized. This study examined T cell activation and the cytokine milieu in paired bronchoalveolar lavage (BAL) and blood from 36 HIV-uninfected and 32 HIV-infected participants. Concentrations of 27 cytokines were measured by Luminex, and T cells were phenotyped by flow cytometry. Blood and BAL had distinct cytokine profiles (p=0.001). In plasma, concentrations of inflammatory cytokines like IFN-γ (p=0.004) and TNF-α (p=0.004) were elevated during HIV infection, as expected. Conversely, BAL cytokine concentrations were similar in HIV-infected and uninfected individuals, despite high BAL viral loads (VL; median 48,000 copies/ml epithelial lining fluid). HIV-infected individuals had greater numbers of T cells in BAL compared to uninfected individuals (p=0.007); and BAL VL positively associated with CD4+ and CD8+ T cell numbers (p=0.006 and p=0.0002, respectively) and CXCL10 concentrations (p=0.02). BAL T cells were highly activated in HIV-infected individuals, with nearly 2-3 fold greater frequencies of CD4+CD38+ (1.8-fold; p=0.007), CD4+CD38+HLA-DR+ (1.9-fold; p=0.0006), CD8+CD38+ (2.8-fold; p=0.0006), CD8+HLA-DR+ (2-fold; p=0.022) and CD8+CD38+HLA-DR+ (3.6-fold; p<0.0001) cells compared to HIV-uninfected individuals. Overall, this study demonstrates a clear disruption of the pulmonary immune environment during HIV infection, with readily detectable virus and activated T lymphocytes, which may be driven to accumulate by local chemokines.
Bremer M, Kadernani Y, Wasserman S, et al., 2021, Strategies for the diagnosis and management of meningitis in HIV-infected adults in resource limited settings, Expert Opinion on Pharmacotherapy, Vol: 22, Pages: 2053-2070, ISSN: 1465-6566
Introduction:The incidence of human immunodeficiency virus-1 (HIV-1) associated meningitis has been declining in the post-combination antiretroviral treatment (ART) era, although survival rates remain low for the common causes like tuberculosis and cryptococcal disease. Diagnosis and treatment of meningitis in HIV-1 is complicated by atypical clinical presentations, limited accuracy of diagnostic tests, access to diagnostic tests, and therapeutic agents in low- and middle-income countries (LMIC) and immune reconstitution inflammatory syndrome (IRIS).Areas covered:We provide an overview of the common etiologies of meningitis in HIV-1-infected adults, suggest a diagnostic approach based on readily available tests, and review specific chemotherapeutic agents, host-directed therapies, supportive care, timing of ART initiation, and considerations in the management of IRIS with a focus on resource-limited settings. They identify key knowledge gaps and suggest areas for future research.Expert opinion:Evidence-based management of HIV-1-associated meningitis is sparse for common etiologies. More readily available and sensitive diagnostic tests as well as standardized investigation strategies are required in LMIC. There is a lack of availability of recommended drugs in areas of high HIV-1 prevalence and a limited pipeline of novel chemotherapeutic agents. Host-directed therapies have been inadequately studied.
Davis AG, Wasserman S, Maxebengula M, et al., 2021, Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM], Wellcome Open Research, Vol: 6, ISSN: 2398-502X
Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).
Davis AG, Wasserman S, Maxebengula M, et al., 2021, Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM], Publisher: F1000 Research Ltd
Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM.Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM.Clinicaltrials.gov registration: NCT03927313 (25/04/2019)
du Bruyn E, Stek C, Daroowala R, et al., 2021, Communicable and non-communicable co-morbidities and the presentation of COVID-19 in an African setting of high HIV-1 and tuberculosis prevalence, Publisher: Cold Spring Harbor Laboratory
Objectives To describe the presentation and outcome of SARS-CoV2 infection in an African setting of high non-communicable co-morbidity and also HIV-1 and tuberculosis prevalence.Design Case control analysis with cases stratified by HIV-1 and tuberculosis status.Setting A single-centre observational case-control study of adults admitted to a South African hospital with proven SARS-CoV-2 infection or alternative diagnosis.Participants 104 adults with RT-PCR-proven SARS-CoV2 infection of which 55 (52.9%) were male and 31 (29.8%) HIV-1 co-infected. 40 adults (35.7% male, 30.9% HIV-1 co-infected) admitted during the same period with no RT-PCR or serological evidence of SARS-CoV2 infection and assigned alternative diagnoses. Additional in vitro data from prior studies of 72 healthy controls and 118 HIV-1 uninfected and infected persons participants enrolled to a prior study with either immune evidence of tuberculosis sensitization but no symptoms or microbiologically confirmed pulmonary tuberculosis.Results Two or more co-morbidities were present in 57.7% of 104 RT-PCR proven COVID-19 presentations, the commonest being hypertension (48%), type 2 diabetes mellitus (39%), obesity (31%) but also HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features could be dominated by either SARS-CoV-2 or tuberculosis: lymphopenia was exacerbated, and some markers of inflammation (D-dimer and ferritin) elevated in singly SARS-CoV-2 infected patients were even further elevated (p < 0.05). HIV-1 and SARS-CoV2 co-infection resulted in lower absolute number and proportion of CD4 lymphocytes, with those in the lowest peripheral CD4 percentage strata exhibiting absent or lower antibody responses against SARS-CoV2. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis.Conclusions In this South African setting, HIV-1 and tuberculosis are common co-m
Riou C, Du Bruyn E, Stek C, et al., 2021, Relationship of SARS-CoV-2-specific CD4 response to COVID-19 severity and impact of HIV-1 and Tuberculosis co-infection, Journal of Clinical Investigation
Davis AG, Wilkinson RJ, 2021, Aspirin in tuberculous meningitis, EClinicalMedicine, Vol: 35, ISSN: 2589-5370
Barr DA, Omollo CO, Mason M, et al., 2021, Flow cytometry method for absolute counting and single-cell phenotyping of mycobacteria, Publisher: Cold Spring Harbor Laboratory
Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and precision owing to inherent characteristics of mycobacterial cell biology - including the tendency to clump, and "differential" culturability - and technical challenges consequent on handling an infectious pathogen under biosafe conditions. We developed an absolute counting method for mycobacteria in liquid cultures using a bench-top flow cytometer, and the low-cost fluorescent dyes Calcein-AM (CA) and SYBR-gold (SG). During exponential growth CA+ cell counts are highly correlated with CFU counts and can be used as a real-time alternative to simplify the accurate standardisation of inocula for experiments. In contrast to CFU counting, this method can detect and enumerate cell aggregates in samples, which we show are a potential source of variance and bias when using established methods. We show that CFUs comprise a sub-population of intact, metabolically active mycobacterial cells in liquid cultures, with CFU-proportion varying by growth conditions. A pharmacodynamic application of the flow cytometry method, exploring kinetics of fluorescent probe defined subpopulations compared to CFU is demonstrated. Flow cytometry derived Mycobacterium bovis BCG time-kill curves differ for rifampicin and kanamycin versus isoniazid and ethambutol, as do the relative dynamics of discrete morphologically-distinct subpopulations of bacilli revealed by this high-throughput single-cell technique.
Stek C, Buyze J, Menten J, et al., 2021, Diagnostic accuracy of the INSHI consensus case definition for the diagnosis of paradoxical tuberculosis-IRIS, JAIDS: Journal of Acquired Immune Deficiency Syndromes, Vol: 86, Pages: 587-592, ISSN: 1525-4135
BackgroundThe diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatorysyndrome (TB-IRIS) relies on characteristic clinical features synthesized as the InternationalNetwork for the Study of HIV-associated IRIS (INSHI) case definition. There is noconfirmatory laboratory test.SettingSite B HIV-TB clinic in Khayelitsha, Cape Town, South Africa.MethodsUsing data of participants with HIV-associated tuberculosis starting antiretroviral treatmentfrom a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latentclass analysis to model a gold standard for TB-IRIS.The model-predicted probability of TB-IRIS for each participant was used to assess theperformance of the INSHI case definition and compare its diagnostic accuracy with severaladapted case definitions.ResultsData for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latentclass model included the following parameters: respiratory symptoms, night sweats, INSHImajor criteria 1, 2, and 4, maximum CRP >90 mg/l, maximum heart rate >120/min,maximum temperature >37.7 0C, and pre-ART CD4 count <50 cells/μl. The model estimateda TB-IRIS incidence of 43% and had optimal goodness of fit (Χ2=337, p=1.0). The INSHI casedefinition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minorINSHI criteria with objectives measures (CRP elevation, fever, and/or tachycardia) resultedin a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of0.88.ConclusionThe INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the casedefinition by replacing INSHI minor criteria with objective variables improved sensitivitywithout loss of specificity.
Allie T, Jackson A, Ambler J, et al., 2021, TBDBT: A TB DataBase Template for collection of harmonized TB clinical research data in REDCap, facilitating data standardisation for inter-study comparison and meta-analyses, PLoS One, Vol: 16, ISSN: 1932-6203
Clinical tuberculosis research, both within research groups and across research ecosystems, is often undertaken in isolation using bespoke data collection platforms and applying differing data conventions. This failure to harmonise clinical phenotype data or apply standardised data collection and storage standards in turn limits the opportunity to undertake meta-analyses using data generated across multiple research projects for the same research domain. We have developed the Tuberculosis DataBase Template (TBDBT), a template for the well-supported, free and commonly deployed clinical databasing platform, REDCap. This template can be used to set up a new tuberculosis research database with a built-in set of standardised data conventions, to ensure standardised data capture across research projects and programs. A modular design enables researchers to implement only the modules of the database template that are appropriate for their particular study. The template includes core modules for informed consent data, participant demographics, clinical symptoms and presentation, diagnostic imaging and laboratory tests. Optional modules have been designed for visit scheduling and calendar functionality, clinical trial randomisation, study logistics and operations, and pharmacokinetic data. Additional fields can be added as needed. This REDCap template can facilitate collection of high-quality data for tuberculosis research, providing a tool to ensure better data harmonisation, analysis and meta-analysis.
Wilkinson KA, Schneider-Luftman D, Lai R, et al., 2021, Antiretroviral treatment-induced decrease in immune activation contributes to reduced susceptibility to tuberculosis in HIV-1/Mtb co-infected persons, Frontiers in Immunology, Vol: 12, Pages: 1-10, ISSN: 1664-3224
Antiretroviral treatment (ART) reduces the risk of developing active tuberculosis (TB) in HIV-1 co-infected persons. In order to understand host immune responses during ART in the context of Mycobacterium tuberculosis (Mtb) sensitization, we performed RNAseq analysis of whole blood-derived RNA from individuals with latent TB infection coinfected with HIV-1, during the first 6 months of ART. A significant fall in RNA sequence abundance of the Hallmark IFN-alpha, IFN-gamma, IL-6/JAK/STAT3 signaling, and inflammatory response pathway genes indicated reduced immune activation and inflammation at 6 months of ART compared to day 0. Further exploratory evaluation of 65 soluble analytes in plasma confirmed the significant decrease of inflammatory markers after 6 months of ART. Next, we evaluated 30 soluble analytes in QuantiFERON Gold in-tube (QFT) samples from the Ag stimulated and Nil tubes, during the first 6 months of ART in 30 patients. There was a significant decrease in IL-1alpha and IL-1beta (Ag-Nil) concentrations as well as MCP-1 (Nil), supporting decreased immune activation and inflammation. At the same time, IP-10 (Ag-nil) concentrations significantly increased, together with chemokine receptor-expressing CD4 T cell numbers. Our data indicate that ART-induced decrease in immune activation combined with improved antigen responsiveness may contribute to reduced susceptibility to tuberculosis in HIV-1/Mtb co-infected persons.
Gliddon H, Kaforou M, Alikian M, et al., 2021, Identification of reduced host transcriptomic signatures for tuberculosis disease and digital PCR-based validation and quantification, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224
Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate diagnostic test development. To identify minimal transcript signatures, we applied a transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were further investigated using reverse transcriptase (RT)—digital PCR (dPCR). A four-transcript signature (GBP6, TMCC1, PRDM1, and ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2–100%). A three-transcript signature (FCGR1A, ZNF296, and C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3–100%), regardless of HIV. These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.
Du Bruyn E, Ruzive S, Lindestam Arlehamn CS, et al., 2021, Mycobacterium tuberculosis-specific CD4 T cells expressing CD153 inversely associate with bacterial load and disease severity in human tuberculosis, Mucosal Immunology, Vol: 14, Pages: 491-499, ISSN: 1933-0219
Recent data from mice and non-human primate models of tuberculosis suggested that CD153, a TNF super family member, plays an important role in Mycobacterium tuberculosis (Mtb) control. However, this molecule has not been comprehensively evaluated in humans. Here, we show that the proportion of Mtb-specific CD4 T cells expressing CD153 was significantly reduced in active TB patients compared to latently infected persons. Importantly, the CD153+ Mtb-specific CD4 response inversely correlated with lung bacterial load, inferred by Xpert cycle threshold, irrespective of HIV status. Antitubercular treatment partially restored CD153 expression on Mtb-specific CD4 T cells. This is the first report of a subset of Mtb-specific CD4 T cells showing strong negative correlation with bacterial burden. Building on substantial evidence from animal models implicating CD153 as a mediator of host protection, our findings suggest it may play a similar role in humans and its measurement may be useful to evaluate TB vaccine efficacy.
Ordonez AA, Tucker EW, Anderson CJ, et al., 2021, Visualizing the dynamics of tuberculosis pathology using molecular imaging, Journal of Clinical Investigation, Vol: 131, Pages: 1-12, ISSN: 0021-9738
Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.
Morris TC, Hoggart CJ, Chegou NN, et al., 2021, Evaluation of host serum protein biomarkers of tuberculosis in sub-Saharan Africa, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224
Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity for Mycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.
Pouget M, Coussens AK, Ruggiero A, et al., 2021, Generation of liposomes to study the effect of Mycobacterium Tuberculosis lipids on HIV-1 cis- and trans-infections, International Journal of Molecular Sciences, Vol: 22, Pages: 1-21, ISSN: 1422-0067
Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis (Mtb) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection (cis- and trans-infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic (Mycobacterium bovis BCG and Mycobacterium smegmatis) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis- and trans-infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans-infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M. bovis, Mtb H37Rv and Mtb EU127 strains when using Raji-DC-SIGN cells or immature and mature dendritic cells (DCs) to capture virus. SL1, PDIM and TDM lipids were identified to be involved in DC-SIGN recognition and impairment of HIV-1 trans-infection. These findings indicate that variant strains of Mtb have differential effect on HIV-1 trans-infection with the potential to influence HIV-1 disease course in co-infected individuals.
Schiff AE, Linder AH, Luhembo SN, et al., 2021, T cell-tropic HIV efficiently infects alveolar macrophages through contact with infected CD4+ T cells, Scientific Reports, Vol: 11, ISSN: 2045-2322
Alveolar macrophages (AMs) are critical for defense against airborne pathogens and AM dysfunction is thought to contribute to the increased burden of pulmonary infections observed in individuals living with HIV-1 (HIV). While HIV nucleic acids have been detected in AMs early in infection, circulating HIV during acute and chronic infection is usually CCR5 T cell-tropic (T-tropic) and enters macrophages inefficiently in vitro. The mechanism by which T-tropic viruses infect AMs remains unknown. We collected AMs by bronchoscopy performed in HIV-infected, antiretroviral therapy (ART)-naive and uninfected subjects. We found that viral constructs made with primary HIV envelope sequences isolated from both AMs and plasma were T-tropic and inefficiently infected macrophages. However, these isolates productively infected macrophages when co-cultured with HIV-infected CD4+ T cells. In addition, we provide evidence that T-tropic HIV is transmitted from infected CD4+ T cells to the AM cytosol. We conclude that AM-derived HIV isolates are T-tropic and can enter macrophages through contact with an infected CD4+ T cell, which results in productive infection of AMs. CD4+ T cell-dependent entry of HIV into AMs helps explain the presence of HIV in AMs despite inefficient cell-free infection, and may contribute to AM dysfunction in people living with HIV.
Du Bruyn E, Fukutani KF, Rockwood NS, et al., 2021, Inflammatory profile of HIV uninfected and co-infected patients with tuberculosis: a prospective cohort study and immunological network analysis, The Lancet Microbe, ISSN: 2666-5247
BackgroundHuman immunodeficiency virus type 1 (HIV-1) mediated dysregulation of the immuneresponse to tuberculosis (TB) and its effect on the response to antitubercular treatment(ATT) is incompletely understood. Our aim was to perform an in-depth analysis of theinflammatory profile of HIV-1-uninfected and co-infected TB patients undergoing ATT,with sub-analysis of the effect of antiretroviral therapy and HIV-1 viraemia in the lattergroup.MethodsAn extensive panel of inflammatory markers were measured in plasma of aprospective patient cohort undergoing ATT at Khayelitsha Site B Clinic, SouthAfrica between March 2013 and July 2014. Plasma samples were collected at baseline(1-5 days after commencing ATT), week 8 and week 20 of ATT. We applied networkand multivariate analysis to investigate the dynamic inflammatory profile of thesepatients in relation to ATT and by HIV status. FindingsHIV-1 status markedly influenced the inflammatory profile regardless of ATT duration.HIV-1 viral load emerged as a major factor driving differential inflammatory markerexpression and impacting on correlation profiles observed in the HIV-1 co-infectedgroup. Unexpectedly, IL-17A emerged as a key correlate of HIV-1 inducedinflammation during HIV-TB co-infection. We validated these findings in a secondcohort of hospitalized HIV-TB co-infected patients where the number of statisticallysignificant correlations with IL-17A in network analysis predicted mortality.InterpretationOur findings demonstrate the effect of HIV-1 co-infection on the complexity of plasmainflammatory profiles in TB patients. Through network analysis we identified IL-17A asan important node in HIV-TB co-infection, thus implicating this cytokine’s capacity tocorrelate with, and regulate, other inflammatory markers. Further mechanistic studiesare thus required to identify specific IL-17A related inflammatory pathways mediatingimmunopathology in HIV-TB co-infection, which may illuminate targets for future hostdirected the
Cresswell F, Davis A, Sharma K, et al., 2021, Recent developments in tuberculous meningitis pathogenesis and diagnostics, Wellcome Open Research, Vol: 4, Pages: 1-26, ISSN: 2398-502X
The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.
Glanzmann B, Jooste T, Ghoor S, et al., 2021, Human whole genome sequencing in South Africa, Scientific Reports, Vol: 11, Pages: 1-8, ISSN: 2045-2322
The advent and evolution of next generation sequencing has considerably impacted genomicresearch. Until recently, South African researchers were unable to access affordable platformscapable of human whole genome sequencing locally and DNA samples had to be exported. Herewe report the whole genome sequences of the first six human DNA samples sequenced andanalysed at the South African Medical Research Council’s Genomics Centre. We demonstratethat the data obtained is of high quality, with an average sequencing depth of 36.41, and that theoutput is comparable to data generated internationally on a similar platform. The GenomicsCentre creates an environment where African researchers are able to access world class facilities,increasing local capacity to sequence whole genomes as well as store and analyse the data.
Boyles T, Stadelman A, Ellis J, et al., 2021, The diagnosis of tuberculous meningitis in adults and adolescents: protocol for a systematic review and individual patient data meta-analysis to inform a multivariable prediction model, Wellcome Open Research, Vol: 19, Pages: 1-21, ISSN: 2398-502X
Background: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. Delayed diagnosis and treatment, which is a risk factor for poor outcome, is caused in part by lack of availability of diagnostic tests that are both rapid and accurate. Several attempts have been made to develop clinical scoring systems to fill this gap, but none have performed sufficiently well to be broadly implemented. We aim to identify and validate a set of clinical predictors that accurately classify TBM using individual patient data (IPD) from published studies. Methods: We will perform a systematic review and obtain IPD from studies published from the year 1990 which undertook diagnostic testing for TBM in adolescents or adults using at least one of, microscopy for acid-fast bacilli, commercial nucleic acid amplification test for Mycobacterium tuberculosis or mycobacterial culture of cerebrospinal fluid. Clinical data that have previously been shown to be associated with TBM, and can inform the final diagnosis, will be requested. The data-set will be divided into training and test/validation data-sets for model building. A predictive logistic model will be built using a training set with patients with definite TBM and no TBM. Should it be warranted, factor analysis may be employed, depending on evidence for multicollinearity or the case for including latent variables in the model. Discussion: We will systematically identify and extract key clinical parameters associated with TBM from published studies and use a ‘big data’ approach to develop and validate a clinical prediction model with enhanced generalisability. The final model will be made available through a smartphone application. Further work will be external validation of the model and test of efficacy in a randomised controlled trial.
Ross JM, Badje A, Rangaka MX, et al., 2021, Isoniazid Preventive Therapy Added to ART to Prevent TB: An Individual Participant Data Meta-Analysis, The Lancet HIV, Vol: 8, ISSN: 2405-4704
Background: Isoniazid preventive therapy (IPT) prevents active TB in people living with HIV (PLHIV), but prior studies found no evidence of benefit in PLHIV with a negative tuberculin skin test (TST) and non-significant impact on mortality. We conducted an individual participant data meta-analysis of randomized controlled 56 trials to estimate the effect of IPT given with ART to prevent TB and death among PLHIV across population subgroups. Methods: We searched PubMed, Embase, the Cochrane database, and conference abstracts. Eligible studies included trials of HIV-positive adults taking ART randomized to daily IPT versus no IPT. We performed a single-stage individual participant data meta-analysis of the outcomes of incident TB disease and all- cause mortality using stratified Cox-proportional hazards models. Registration: PROSPERO (CRD42019121400). Findings: We found 838 citations and included 2611 participants from three trials in Cote D’Ivoire, Malawi, and South Africa. IPT with ART was associated with lower risk for TB than ART alone (hazard ratio=0·68, 95% CI 0·49–0·95, p=0·02) and non-significantly lower all -cause mortality (hazard ratio=0·69, 95% CI 0·43–1·10, p=0.12). TB risk differed by baseline CD4 <200 cells/mm3, but there was no evidence of varying benefit of IPT with ART by sex, baseline CD4, or results of TST or interferon gamma release assays. Elevated alanine aminotransferase occurred in 65/2611 (2.5%) of participants, but data were insufficient to calculate a hazard ratio. Interpretation IPT with ART prevents TB across demographic and HIV- and TB-specific subgroups, which supports efforts to further increase use of IPT with ART broadly among PLHIV.
Wilkinson R, 2021, Tuberculosis and type 2 Diabetes Mellitus: an inflammatory danger signal in the time of COVID-19, Clinical Infectious Diseases, Vol: 72, Pages: 79-81, ISSN: 1058-4838
Ross JM, Badje A, Rangaka MX, et al., 2021, Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data, The Lancet HIV, Vol: 8, Pages: e8-e15, ISSN: 2405-4704
BackgroundIsoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups.MethodsWe searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400.FindingsOf 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49&
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