Publications
521 results found
Riou C, Schäfer G, du Bruyn E, et al., 2020, Rapid, simplified whole blood-based multiparameter assay to quantify and phenotype SARS-CoV-2 specific T cells., Publisher: Cold Spring Harbor Laboratory
Rapid tests to evaluate SARS-CoV-2-specific T cell responses are urgently needed to decipher protective immunity and aid monitoring vaccine-induced immunity. Using a rapid whole blood assay requiring minimal amount of blood, we measured qualitatively and quantitatively SARS-CoV-2-specific CD4 T cell responses in 31 healthcare workers, using flow cytometry. 100% of COVID-19 convalescent participants displayed a detectable SARS-CoV-2-specific CD4 T cell response. SARS-CoV-2-responding cells were also detected in 40.9% of participants with no COVID-19-associated symptoms or who tested PCR negative. Phenotypic assessment indicated that, in COVID-19 convalescent participants, SARS-CoV-2 CD4 responses displayed an early differentiated memory phenotype with limited capacity to produce IFNγ. Conversely, in participants with no reported symptoms, SARS-CoV-2 CD4 responses were enriched in late differentiated cells, co-expressing IFNγ and TNFα and also Granzyme B. This proof of concept study presents a scalable alternative to PBMC-based assays to enumerate and phenotype SARS-CoV-2-responding T cells, thus representing a practical tool to monitor adaptive immunity in vaccine trials. Summary: In this proof of concept study, we show that SARS-CoV-2 T cell responses are easily detectable using a rapid whole blood assay requiring minimal blood volume. Such assay could represent a suitable tool to monitor adaptive immunity in vaccine trials.
Kroon E, Kinnear C, Orlova M, et al., 2020, An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa, EBioMedicine, Vol: 61, ISSN: 2352-3964
BackgroundMycobacterium tuberculosis (Mtb) infection is inferred from positive results of T-cell immune conversion assays measuring Mtb-specific interferon gamma production or tuberculin skin test (TST) reactivity. Certain exposed individuals do not display T-cell immune conversion in these assays and do not develop TB. Here we report a hitherto unknown form of this phenotype: HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN).MethodsA community-based case-control design was used to systematically screen and identify adults living with HIV (HIV+), aged 35–60 years, who met stringent study criteria, and then longitudinally followed up for repeat IGRA and TST testing. Participants had no history of TB despite living in TB hyper-endemic environments in Cape Town, South Africa with a provincial incidence of 681/100,000. Mtb-specific antibodies were measured using ELISA and Luminex.FindingsWe identified 48/286 (17%) individuals who tested persistently negative for Mtb-specific T-cell immunoreactivity (three negative Quantiferon results and one TST = 0mm) over 206±154 days on average. Of these, 97·2% had documented CD4 counts<200 prior to antiretroviral therapy (ART). They had received ART for 7·0±3·0 years with a latest CD4 count of 505·8±191·4 cells/mm3. All HITTIN sent for further antibody testing (n=38) displayed Mtb-specific antibody titres.InterpretationImmune reconstituted HIV+ persons can be persistently non-immunoreactive to TST and interferon-γ T-cell responses to Mtb, yet develop species-specific antibody responses. Exposure is evidenced by Mtb-specific antibody titres. Our identification of HIV+ individuals displaying a persisting lack of response to TST and IGRA T-cell immune conversion paves the way for future studies to investigate this phenotype in the context of HIV-infection that so far have received only scant attention.
Donovan J, Cresswell F, Nguyen TTT, et al., 2020, Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis: a small step forward, Clinical Infectious Diseases, Vol: 71, Pages: 2002-2005, ISSN: 1058-4838
The delayed diagnosis of tuberculous meningitis (TBM) leads to poor outcomes, yet the current diagnostic methods for identifying Mycobacterium tuberculosis in cerebrospinal fluid (CSF) are inadequate. The first comparative study of the new GeneXpert MTB/RIF Ultra (Xpert Ultra) for TBM diagnosis suggested increased sensitivity of Xpert Ultra. Two subsequent studies have shown Xpert Ultra has improved sensitivity, but has insufficient negative predictive value to exclude TBM. Collecting and processing large volumes of CSF for mycobacterial testing are important for optimal diagnostic test performance. But clinical, radiological, and laboratory parameters remain essential for TBM diagnosis and empiric therapy is often needed. We therefore caution against the use of Xpert Ultra as a single diagnostic test for TBM; it cannot be used to “rule out” TBM.
Sossen B, Broger T, Kerkhoff AD, et al., 2020, ‘SILVAMP TB LAM’ rapid urine tuberculosis test predicts mortality in hospitalized HIV patients in South Africa, Clinical Infectious Diseases, Vol: 71, Pages: 1973-1976, ISSN: 1058-4838
Reducing diagnostic delay is key towards decreasing tuberculosis-associated deaths in people living with HIV. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.
Peterson TE, Baker JV, Wong L-Y, et al., 2020, Elevated N‐terminal prohormone of brain natriuretic peptide among persons living with HIV in a South African peri‐urban township, ESC Heart Failure, Vol: 7, Pages: 3246-3251, ISSN: 2055-5822
AimsEfforts to improve access to antiretroviral therapy (ART) have shifted morbidity and mortality among persons living with HIV (PLWH) from AIDS to non‐communicable diseases, such as cardiovascular disease (CVD). However, contemporary data on CVD among PLWH in sub‐Saharan Africa in the current ART era are lacking. The aim of this study was to assess the burden of cardiac stress among PLWH in South Africa via measurement of N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP).Methods and resultsNT‐proBNP was measured at baseline in 224 PLWH enrolled in a sub‐study of a tuberculosis vaccine trial in Khayelitsha township near Cape Town, South Africa. Thresholds were applied at the assay's limit of detection (≥137 pg/mL) and a level indicative of symptomatic heart failure in the acute setting (>300 pg/mL).Mean (SD ) age of participants was 39 (6) years, 86% were female, and 19% were hypertensive. Mean (SD ) duration of HIV diagnosis was 8.3 (3.9) years and CD4 + count was 673 (267) with 79% prescribed ART for a duration of 5.6 (2.7) years. Thirty‐one percent of participants had NT‐proBNP > 300 pg/mL. Elevated vs. undetectable NT‐proBNP level was associated with older age (P = 0.04), no ART (P = 0.03), and higher plasma tumour necrosis factor‐α (P = 0.01).ConclusionsAmong South African PLWH largely free of known CVD and on ART with high CD4 + counts and few comorbidities, we observed a high proportion with elevated NT‐proBNP levels, suggesting the burden of cardiac stress in this population may be high. This observation underscores the need for more in‐depth research, including the current effect of HIV on heart failure risk among a growing ART‐treated population in sub‐Saharan Africa.
Riou C, Du Bruyn E, Ruzive S, et al., 2020, Disease extent and anti‐tubercular treatment response correlates with Mycobacterium tuberculosis ‐specific CD4 T‐cell phenotype regardless of HIV‐1 status, Clinical & Translational Immunology, Vol: 9, Pages: 1-17, ISSN: 2050-0068
ObjectivesThe development of non‐sputum‐based assays for tuberculosis (TB) diagnosis and treatment monitoring is a key priority. Recent data indicate that whole blood‐based assays to assess the phenotype of Mycobacterium tuberculosis (Mtb)‐specific CD4 T cells hold promise for this purpose and require further investigation in well‐characterised TB cohorts. In this study, we investigated the relationship between the phenotypic signature of Mtb‐specific CD4 responses, TB disease extent and treatment response.MethodsUsing flow cytometry, we measured the expression of phenotypic and functional markers (HLA‐DR, CD27, CD153, KLRG1, IL‐2, MIP‐1β, TNF‐α and IFN‐γ) on Mtb‐specific CD4 T‐cells in whole blood from 161 participants of varying TB and HIV status. TB disease extent was graded as a continuum using the Xpertct value, C‐reactive protein, Timika radiographic score and monocyte/lymphocyte ratio.ResultsThe phenotypic profile of Mtb‐specific CD4 T cells pre‐anti‐tubercular treatment (ATT) strongly correlated with disease extent, irrespective of HIV status. ATT associated with major changes in the phenotype of Mtb‐specific CD4 T cells, with decreased expression of HLA‐DR and increased CD27 and CD153 expression. Principal component analysis showed an almost complete separation between latent TB infection (LTBI) and active TB (aTB) pre‐ATT groups, whereas the profile of the aTB post‐ATT group overlapped with the LTBI group. However, in patients experiencing treatment failure or relapse, no significant changes were observed in Mtb‐specific CD4 T‐cell phenotype pre‐ and post‐ATT.ConclusionWhole blood‐based assays of Mtb‐specific CD4 T‐cell activation and maturation markers can be used as non‐sputum‐based biomarkers of disease extent and treatment monitoring in TB, regardless of HIV‐1 status.
Loiseau C, Brites D, Reinhard M, et al., 2020, HIV coinfection is associated with low fitness rpoB variants in rifampicin-resistant Mycobacterium tuberculosis., Antimicrobial Agents and Chemotherapy, Vol: 64, Pages: 1-7, ISSN: 0066-4804
We analysed 312 drug-resistant genomes of Mycobacterium tuberculosis (Mtb) collected from HIV coinfected and HIV negative TB patients from nine countries with a high tuberculosis burden. We found that rifampicin-resistant Mtb strains isolated from HIV coinfected patients carried disproportionally more resistance-conferring mutations in rpoB that are associated with a low fitness in the absence of the drug, suggesting these low fitness rpoB variants can thrive in the context of reduced host immunity.
Garay-Baquero DJ, White C, Walker N, et al., 2020, Comprehensive plasma proteomic profiling reveals novel biomarkers for active tuberculosis, JCI Insight, Vol: 5, Pages: 1-20, ISSN: 2379-3708
BackgroundTuberculosis (TB) kills more people than any other infection and new diagnostic tests to identify active cases are urgently required. We aimed to discover and verify novel markers for TB in non depleted plasma.MethodsWe applied an optimised quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation hyphenated with high-resolution mass spectrometry (q3D LC-MS) to study non-depleted plasma of 11 patients with active TB compared to 10 healthy control donors. Prioritised candidates were verified in an independent UK-based (n=118) and a South African cohorts (n=203). Results We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We further analysed the predominantly low molecular weight sub-proteome; identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide false discovery rate, FDR ≤1%, q77 value ≤0.05). Biological network analysis showed regulation of new pathways involving lipid and organophosphate ester transport. Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in two independent cohorts. These proteins were elevated in both TB and other respiratory diseases (ORD). Receiver-operating-characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP and SAA1) exhibited discriminatory power in distinguishing between TB and ORD (AUC =0.81). Conclusions We report the most comprehensive TB plasma proteome to date, identifying numerous novel markers with verification in two independent cohorts, which led to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostictriage test.
Reichmuth ML, Hömke R, Zürcher K, et al., 2020, Natural polymorphisms in mycobacterium tuberculosis conferring resistance to delamanid in drug-naïve patients., Antimicrobial Agents and Chemotherapy, Vol: 64, Pages: 1-5, ISSN: 0066-4804
Mutations in the genes of the F420 signaling pathway, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, of Mycobacterium tuberculosis (Mtb) complex can lead to delamanid resistance. We searched for such mutations among 129 Mtb strains from Asia, South-America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For ten strains with mutations, we determined the minimum inhibitory concentration (MIC) of delamanid. We found one strain from a delamanid-naïve patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical MIC to delamanid.
Kubjane M, Berkowitz N, Goliath RT, et al., 2020, Tuberculosis, HIV and the association with transient hyperglycaemia in peri-urban South Africa, Clinical Infectious Diseases, Vol: 71, Pages: 1080-1088, ISSN: 1058-4838
BackgroundDiabetes mellitus (DM) increases tuberculosis (TB) risk. We assessed the prevalence of hyperglycaemia (DM and impaired glucose regulation (IGR)) in TB patients and the association between hyperglycaemia and TB at enrolment and 3 months after TB treatment in the context of HIV-infection.MethodsAdults presenting at a Cape Town TB clinic were enrolled. TB cases were defined by South African guidelines, while non-TB participants were those who presented with respiratory symptoms, negative TB tests and resolution of symptoms 3 months later without TB treatment. HIV status was ascertained through medical records or HIV-testing. All participants were screened for DM using HbA1c and fasting plasma glucose at TB treatment and after 3 months. The association between TB and DM was assessed.ResultsOverall DM prevalence was 11.9% (95% CI: 9.1–15.4) at enrolment and 9.3% (95% CI: 6.4–13) at follow-up; IGR prevalence was 46.9% (95% CI 42.2–51.8) and 21.5% (95% CI 16.9–26.3) at enrolment and follow-up. TB/DM association was significant at enrolment (OR 2.41 (95% CI 1.3–4.3)) and follow-up (OR 3.3 (95% CI 1.5–7.3)), whilst TB/IGR association was only positive at enrolment OR 2.3 (95% CI 1.6–3.3). The TB/DM association was significant at enrolment in both new and pre-existing DM, but only persisted at follow-up in HIV-1-infected pre-existing DM.ConclusionOur study demonstrated high prevalence of transient hyperglycaemia and a significant TB/DM and TB/IGR association at enrolment in newly diagnosed DM, but persistent hyperglycaemia and TB/DM association in HIV-1-infected pre-existing DM, despite TB therapy.
Sabeel S, Motaung B, Ozturk M, et al., 2020, Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases, BMJ Open, Vol: 10, ISSN: 2044-6055
Introduction: Statins, also known as 3-Hydroxy-3-Methylglutaryl Co-A (HMG-CoA) reductase inhibitors, are lipid-lowering agents that are central in preventing or reducing the complications of atherosclerotic cardiovascular disease. Because statins have anti-inflammatory properties, there is considerable interest in their therapeutic potential in other chronic inflammatory conditions. We aim to identify the statin with the greatest ability to reduce systemic inflammation, independent of the underlying disease entity.Methods and analysis: We aim to conduct a comprehensive search of published and peer-reviewed randomized controlled clinical trials (RCT), with at least one intervention arm of an FDA or EMA-licensed statin and a minimum treatment duration of 12 weeks. Our objective is to investigate the effect of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) on lipid profile, particularly, cholesterol low-density lipoprotein (LDL-C) and inflammation markers such as hsCRP, CRP, TNF-α, IL-1β, IL-6, IL-8, sCD14, or sCD16 in adults, published in the last 20 years (between January 1999 and December 2019). We aim to identify the most potent statin to reduce systemic inflammation and optimal dosing. The following databases will be searched: Medline, Scopus, Web of Science, and Cochrane Library of Systematic Reviews. The risk of bias of included studies will be assessed by Cochrane Risk of Bias tool and Quality Assessment Tool for Quantitative Studies. The quality of studies will be assessed, to show uncertainty, by the Jadad score. If sufficient evidence is identified, a meta-analysis will be conducted with risk ratios or odds ratios with 95% confidence intervals (CI) in addition to mean differences.Ethics and dissemination: Ethics approval is not required as no primary data will be collected. Results will be presented at conferences and published in a peer-review journal. PROSPERO registration number: PendingStrengths and l
Wilson DJ, Crook DW, Peto TEA, et al., 2020, GenomegaMap: within-species genome-wide dN/dS estimation from over 10,000 genomes, Molecular Biology and Evolution, Vol: 37, Pages: 2450-2460, ISSN: 0737-4038
The dN/dS ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters, such as dN/dS, but analyzing very large data sets poses a major statistical challenge. Here, I introduce genomegaMap for estimating within-species genome-wide variation in dN/dS, and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: 1) It is fast no matter how large the sample size and 2) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well estimated even when genomegaMap’s simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in Mycobacterium tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species.
Cresswell F, Davis A, Sharma K, et al., 2020, Recent developments in Tuberculous meningitis pathogenesis and diagnostics [version 2; peer review: 1 approved], Wellcome Open Research, Vol: 4, 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.
Rohlwink U, Chow F, Wasserman S, et al., 2020, Standardized approaches for clinical sampling and endpoint ascertainment in tuberculous meningitis studies [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 4, ISSN: 2398-502X
Tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, has poorly understood immunopathology and high mortality and morbidity despite antituberculous therapy. This calls for accelerated clinical and basic science research in this field. As TBM disproportionally affects poorer communities, studies are often performed in resource-limited environments, creating challenges for data collection and harmonisation. Comparison of TBM studies has been hampered by variation in sampling strategies, study design and choice of study endpoints. Based on literature review and expert consensus, this paper provides firstly, practical recommendations to enable thorough diagnostic, pathophysiological and pharmacokinetic studies using clinical samples, and facilitates better data aggregation and comparisons across populations and settings. Secondly, we discuss clinically relevant study endpoints, including neuroimaging, functional outcome, and cause of death, with suggestions of how these could be applied in different designs for future TBM studies.
Lerner TR, Queval CJ, Lai RP-J, et al., 2020, Mycobacterium tuberculosis cords within lymphatic endothelial cells to evade host immunity, JCI insight, Vol: 5, ISSN: 2379-3708
The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. Here, we show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLECs) in vitro and in the lymph nodes of patients with tuberculosis. We identified via RNA-Seq a transcriptional program that activated, in infected-hLECs, cell survival and cytosolic surveillance of pathogens pathways. Consistent with this, cytosolic access was required for intracellular M. tuberculosis cording. Mycobacteria lacking ESX-1 type VII secretion system or phthiocerol dimycocerosates expression, which failed to access the cytosol, were indeed unable to form cords within hLECs. Finally, we show that M. tuberculosis cording is a size-dependent mechanism used by the pathogen to avoid its recognition by cytosolic sensors and evade either resting or IFN-γ–induced hLEC immunity. These results explain the long-standing association between M. tuberculosis cording and virulence and how virulent mycobacteria use intracellular cording as strategy to successfully adapt and persist in the lymphatic tracts.
Walker NF, Opondo C, Meintjes GA, et al., 2020, Invariant Natural Killer T cell dynamics in HIV-associated tuberculosis, Clinical Infectious Diseases, Vol: 70, Pages: 1865-1874, ISSN: 1058-4838
RationaleTuberculosis (TB) is the leading cause of mortality and morbidity in people living with HIV infection. HIV-infected patients with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence anti-retroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking.ObjectivesWe investigated the hypothesis that invariant Natural Killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS.MethodsIn a cross-sectional study of 101 HIV-infected and -uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterised by flow cytometry. In a second study of 49 HIV-1-infected TB patients commencing anti-retroviral therapy, iNKT cells in TB-IRIS patients with non-IRIS controls were compared longitudinally.Measurements and main resultsCirculating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in HIV-infected patients with active TB was associated with development of TB-IRIS following anti-retroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8- subset deplete and degranulated around the time of TB-IRIS onset.ConclusionsReduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality towards cytotoxicity. Increased CD4- cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.
Schutz C, Chirehwa M, Barr D, et al., 2020, Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus associated tuberculosis, British Journal of Clinical Pharmacology, Vol: 86, Pages: 966-978, ISSN: 0306-5251
Aims: Patients hospitalized at the time of human immunodeficiency virus-associatedtuberculosis (HIV-TB) diagnosis have high early mortality. We hypothesized thatcompared to outpatients, there would be lower antituberculosis drug exposure inhospitalized HIV-TB patients, and amongst hospitalized patients exposure would belower in patients who die or have high lactate (a sepsis marker).Methods: We performed pharmacokinetic sampling in hospitalized HIV-TB patientsand outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations weremeasured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the thirdday of standard antituberculosis therapy. Twelve-week mortality was ascertained forinpatients. Noncompartmental pharmacokinetic analysis was performed.Results: Pharmacokinetic data was collected in 59 hospitalized HIV-TB patients and48 outpatients. Inpatient twelve-week mortality was 11/59 (19%). Rifampicin,isoniazid and pyrazinamide exposure was similar between hospitalized andoutpatients (Cmax:7.4 vs. 8.3 μg·mL-1, p=0.223; 3.6 vs. 3.5 μg·mL-1, p=0.569; 50.1 vs.46.8 μg·mL-1, p=0.081; AUC0-8:41.0 vs. 43.8 mg·h·L-1, p= 0.290; 13.5 vs. 12.4mg·h·L-1, p=0.630; 316.5 vs. 292.2 mg·h·L-1, p=0.164, respectively) and not lower ininpatients who died. Rifampicin and isoniazid Cmax were below recommended rangesin 61% and 39% inpatients and 44% and 35% outpatients. Rifampicin exposure washigher in patients with lactate >2.2mmol·L-1.Conclusion: Mortality in hospitalized HIV-TB patients was high. Early antituberculosisdrug exposure was similar to outpatients and not lower in inpatients who died.Rifampicin and isoniazid Cmax were sub-optimal in 61% and 39% of inpatients andrifampicin exposure was higher in patients with high lactate. Treatment strategiesneed to be optimized to improve survival.
Waters R, Ndengane M, Abrahams M-R, et al., 2020, The Mtb-HIV syndemic interaction: why treating M. tuberculosis infection may be crucial for HIV-1 eradication, Future Virology, Vol: 15, Pages: 101-126, ISSN: 1746-0794
Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized. We present a rationale for the critical consideration of ‘latent’ Mtb infection in HIV-1 prevention and cure strategies. In support of this position, we review evidence of the effect of Mtb infection on HIV-1 acquisition, replication and persistence. We propose that ‘latent’ Mtb infection may have considerable impact on HIV-1 pathogenesis and the continuing HIV-1 epidemic in sub-Saharan Africa.
Stek C, Allwood B, Du Bruyn E, et al., 2020, The effect of HIV-associated tuberculosis, tuberculosis-IRIS, and prednisone on lung function, European Respiratory Journal, Vol: 55, Pages: 1-10, ISSN: 0903-1936
Residual pulmonary impairment is common after treatment for tuberculosis. Lung function data in patients with HIV-associated tuberculosis are scarce, especially in the context of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and prophylactic prednisone. We aimed to determine the prevalence of lung function abnormalities in patients with HIV-associated tuberculosis and CD4 counts ≤ 100 cells/μl and assess the effect of prophylactic prednisone and the development of paradoxical TB-IRIS on pulmonary impairment.We performed spirometry, six-minute walk test, and chest radiography at baseline (week 0), week 4, 12, and 28 in participants of the PredART trial, which evaluated a 28-day course of prednisone to prevent TB-IRIS in patients with HIV-associated tuberculosis commencing antiretroviral therapy. 153 participants underwent spirometry and/or six-minute walk test at one or more time points. Abnormal spirometry measurements were present in 66% of participants at week 0 and 50% at week 28; low forced vital capacity was the commonest abnormality. Chest radiographs showed little or no abnormalities in the majority of participants.Prednisone use resulted in a 42 meters greater six-minute walk distance and a 4.9 % higher percentage of predicted forced expiratory volume in 1 second at week 4; these differences were no longer significantly different from week 12 onwards. TB-IRIS did not significantly impair lung function outcome. Residual pulmonary impairment is common in HIV-associated tuberculosis. In patients with low CD4 counts, neither prophylactic prednisone as used in our study nor the development of TB-IRIS significantly affected week 28 pulmonary outcome.
Li Y, Wilkinson KA, Wilkinson R, et al., 2020, Elevated matrix metalloproteinases offer novel insight into their role in pediatric tuberculous meningitis, Journal of the Pediatric Infectious Diseases Society, Vol: 9, Pages: 82-86, ISSN: 2048-7193
We collected lumbar and ventricular cerebrospinal fluid and serum from 40 children treated for tuberculous meningitis and measured the concentrations of gelatinases and their inhibitors. The concentrations of matrix metalloproteinase 9 (MMP-9), MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 were significantly elevated in the lumbar CSF samples, and we found interesting dynamics for MMP-9 that offer novel insight into its role in pediatric patients with tuberculous meningitis.
Davis AG, Wilkinson RJ, 2020, The diagnosis of tuberculous meningitis, Lancet Infectious Diseases, Vol: 20, Pages: 262-263, ISSN: 1473-3099
Marais S, Van Toorn R, Chow FC, et al., 2020, Management of intracranial tuberculous mass lesions: how long should we treat for? [version 3; peer review: 3 approved], Wellcome Open Research, Vol: 4, Pages: 1-18, ISSN: 2398-502X
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis (M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-base
Marais S, Van Toorn R, Chow FC, et al., 2020, Management of intracranial tuberculous mass lesions: how long should we treat for? [version 1; peer review: awaiting peer review], Publisher: Wellcome Open Research
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis (M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-base
Tezera LB, Bielecka MK, Ogongo P, et al., 2020, Anti-PD-1 immunotherapy leads to tuberculosis reactivation via dysregulation of TNF-alpha, eLife, Vol: 9, ISSN: 2050-084X
Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.
Howlett PJ, Du Bruyn E, Morrison H, et al., 2020, The immunopathogenesis of tuberculous pericarditis, Microbes and Infection: a journal on infectious agents and host defenses, Vol: 22, Pages: 172-181, ISSN: 1286-4579
Tuberculous pericarditis is a severe form of extrapulmonary tuberculosis and is the commonest cause of pericardial effusion in high incidence settings. Mortality ranges between 8 and 34%, and it is the leading cause of pericardial constriction in Africa and Asia. Current understanding of the disease is based on models derived from studies performed in the 1940–50s. This review summarises recent advances in the histology, microbiology and immunology of tuberculous pericarditis, with special focus on the effect of Human Immunodeficiency Virus (HIV) and the determinants of constriction.
Donovan J, Rohlwink UK, Tucker EW, et al., 2020, Checklists to guide the supportive and critical care of tuberculous meningitis, Wellcome Open Research, Vol: 4, Pages: 1-19, ISSN: 2398-502X
The assessment and management of tuberculous meningitis (TBM) is often complex, yet no standardised approach exists, and evidence for the clinical care of patients, including those with critical illness, is limited. The roles of proformas and checklists are increasing in medicine; proformas provide a framework for a thorough approach to patient care, whereas checklists offer a priority-based approach that may be applied to deteriorating patients in time-critical situations.We aimed to develop a comprehensive assessment proforma and an accompanying ‘priorities’ checklist for patients with TBM, with the overriding goal being to improve patient outcomes. The proforma outlines what should be asked, checked, or tested at initial evaluation and daily inpatient review to assist supportive clinical care for patients, with an adapted list for patients in critical care. It is accompanied by a supporting document describing why these points are relevant to TBM. Our priorities checklist offers a useful and easy reminder of important issues to review during a time-critical period of acute patient deterioration. The benefit of these documents to patient outcomes would require investigation; however, we hope they will promote standardisation of patient assessment and care, particularly of critically unwell individuals, in whom morbidity and mortality remains unacceptably high.
Riou CR, Jhilmeet N, Rangaka MX, et al., 2020, Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment, Journal of Infectious Diseases, Vol: 221, Pages: 162-167, ISSN: 0022-1899
The reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.
Davis AG, Donovan J, Bremer M, et al., 2020, Host Directed Therapies for Tuberculous Meningitis., Wellcome Open Res, 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.
Cerrone M, Bracchi M, Wasserman S, et al., 2020, Safety implications of combined antiretroviral and antituberculosis drugs, Expert Opinion on Drug Safety, Vol: 19, Pages: 23-41, ISSN: 1474-0338
Introduction:Antiretroviral and anti-tuberculosis (TB) drugs are often co-administered in people living with HIV (PLWH). Early initiation of antiretroviral therapy (ART) during TB treatment improves survival in patients with advanced HIV disease. However, safety concerns related to clinically significant changes in drug exposure resulting from drug-drug interactions; development of overlapping toxicities and specific challenges related to co-administration during pregnancy represent barriers to successful combined treatment for HIV and TB.Areas covered: Pharmacokinetic interactions of different classes of ART when combined with anti-TB drugs used for sensitive-, drug-resistant (DR) and latent TB are discussed. Overlapping drug toxicities, implications of immune reconstitution inflammatory syndrome (IRIS), safety in pregnancy and research gaps are also explored.Expert opinion:New antiretroviral and anti-tuberculosis drugs have been recently introduced and international guidelines updated. A number of effective molecules and clinical data are now available to build treatment regimens for PLWH with latent or active TB. Adopting a systematic approach that also takes into account the need for individualized variations based on the available evidence is the key to successfully integrate ART and TB treatment and improve treatment outcomes.
Tait DR, Hatherill M, van der Meeren O, et al., 2019, Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis, New England Journal of Medicine, Vol: 381, Pages: 2429-2439, ISSN: 0028-4793
BackgroundResults of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity.MethodsFrom August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo.ResultsA total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI]
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