ORCID Profile
0000-0002-2753-1800
Current Organisations
Imperial College London
,
The Francis Crick Institute
,
Royal College of Physicians
,
University of Cape Town
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Publications
TheMtb-HIV syndemic interaction: why treatingM. tuberculosisinfection may be crucial for HIV-1 eradication
Publisher: Future Medicine Ltd
Date: 02-2020
Abstract: Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis ( Mtb)-coinfected in iduals 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.
Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-09-2010
Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings
Publisher: Elsevier BV
Date: 08-2008
Host-Directed Therapies for Tackling Multi-Drug Resistant Tuberculosis: Learning From the Pasteur-Bechamp Debates: Table 1.
Publisher: Oxford University Press (OUP)
Date: 28-07-2015
DOI: 10.1093/CID/CIV631
Abstract: Tuberculosis remains a global emergency causing an estimated 1.5 million deaths annually. For several decades the major focus of tuberculosis treatment has been on antibiotic development targeting Mycobacterium tuberculosis. The lengthy tuberculosis treatment duration and poor treatment outcomes associated with multi-drug resistant tuberculosis (MDR-TB) are of major concern. The sparse new tuberculosis drug pipeline and widespread emergence of MDR-TB signal an urgent need for more innovative interventions to improve treatment outcomes. Building on the historical Pasteur-Bech debates on the role of the "microbe" vs the "host internal milieu" in disease causation, we make the case for parallel investments into host-directed therapies (HDTs). A range of potential HDTs are now available which require evaluation in randomized controlled clinical trials as adjunct therapies for shortening the duration of tuberculosis therapy and improving treatment outcomes for drug-susceptible tuberculosis and MDR-TB. Funder initiatives that may enable further research into HDTs are described.
Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases
Publisher: American Thoracic Society
Date: 05-2012
Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S43018-021-00274-W
Abstract: Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with in iduals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Correction for Newton et al., A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion
Publisher: Proceedings of the National Academy of Sciences
Date: 09-01-2007
Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification
Publisher: Frontiers Media SA
Date: 02-03-2021
DOI: 10.3389/FIMMU.2021.637164
Abstract: 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), ided 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% (CI 95% 82.2–100%). A three-transcript signature ( FCGR1A, ZNF296, and C1QB ) differentiated TB from LTBI (AUC 97.3%, CI 95% : 93.3–100%), regardless of HIV. These signatures have been validated across platforms and across s les offering strong, quantitative support for their use as diagnostic biomarkers for TB.
Detectable Changes in The Blood Transcriptome Are Present after Two Weeks of Antituberculosis Therapy
Publisher: Public Library of Science (PLoS)
Date: 02-10-2012
Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment
Publisher: Proceedings of the National Academy of Sciences
Date: 04-09-2012
Abstract: Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.
High levels of multidrug resistant tuberculosis in new and treatment-failure patients from the revised national tuberculosis control programme in an urban metropolis (Mumbai) in Western India
Publisher: Springer Science and Business Media LLC
Date: 29-06-2009
Abstract: India, China and Russia account for more than 62% of multidrug resistant tuberculosis (MDRTB) globally. Within India, locations like urban metropolitan Mumbai with its burgeoning population and high incidence of TB are suspected to be a focus for MDRTB. However apart from sporadic surveys at watched sites in the country, there has been no systematic attempt by the Revised National Tuberculosis Control Programme (RNTCP) of India to determine the extent of MDRTB in Mumbai that could feed into national estimates. Drug susceptibility testing (DST) is not routinely performed as a part of programme policy and public health laboratory infrastructure, is limited and poorly equipped to cope with large scale testing. From April 2004 to January 2007 we determined the extent of drug resistance in 724 {493 newly diagnosed, previously untreated and 231 first line treatment failures (sputum-smear positive at the fifth month after commencement of therapy)} cases of pulmonary tuberculosis drawn from the RNTCP in four suboptimally performing municipal wards of Mumbai. The observations were obtained using a modified radiorespirometric Buddemeyer assay and validated by the Swedish Institute for Infectious Disease Control, Stockholm, a supranational reference laboratory. Data was analyzed utilizing SPSS 10.0 and Epi Info 2002. This study undertaken for the first time in RNTCP outpatients in Mumbai reveals a high proportion of MDRTB strains in both previously untreated (24%) and treatment-failure cases (41%). Amongst new cases, resistance to 3 or 4 drug combinations ( lified drug resistance) including isoniazid (H) and rif icin (R), was greater (20%) than resistance to H and R alone (4%) at any point in time during the study. The trend for monoresistance was similar in both groups remaining highest to H and lowest to R. External quality control revealed good agreement for H and R resistance (k = 0.77 and 0.76 respectively). Levels of MDRTB are much higher in both previously untreated and first line treatment-failure cases in the selected wards in Mumbai than those projected by national estimates. The finding of lified drug resistance suggests the presence of a well entrenched MDRTB scenario. This study suggests that a wider set of surveillance sites are needed to obtain a more realistic view of the true MDRTB rates throughout the country. This would assist in the planning of an adequate response to the diagnosis and care of MDRTB.
Reversion and conversion of Mycobacterium tuberculosis IFN-γ ELISpot results during anti-tuberculous treatment in HIV-infected children
Publisher: Springer Science and Business Media LLC
Date: 27-05-2010
1α,25‐dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection
Publisher: Wiley
Date: 06-07-2009
Cardio-Thoracic Ratio Is Stable, Reproducible and Has Potential as a Screening Tool for HIV-1 Related Cardiac Disorders in Resource Poor Settings
Publisher: Public Library of Science (PLoS)
Date: 04-10-2016
High resolution imaging and five-year tuberculosis contact outcomes
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2023
DOI: 10.1101/2023.07.03.23292111
Abstract: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. 250 HIV-uninfected, adult household contacts of rif icin-resistant TB with a negative symptom screen underwent baseline 18 F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum s ling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p .001]). These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.
Distribution of strain families of Mycobacterium tuberculosis causing pulmonary and extrapulmonary disease in hospitalized children in Cape Town, South Africa
Publisher: American Society for Microbiology
Date: 11-2005
DOI: 10.1128/JCM.43.11.5779-5781.2005
Abstract: We studied the association between strain family and extrapulmonary tuberculosis among 285 children presenting to a pediatric hospital. Extrapulmonary disease occurred in 56% of children without known human immunodeficiency virus infection, with meningitis accounting for 22% of the cases. Two strain families, LAM3/F11 and W-Beijing, predominated but there was no overall association with extrapulmonary disease.
Hypoxia Induces an Immunodominant Target of Tuberculosis Specific T Cells Absent from Common BCG Vaccines
Publisher: Public Library of Science (PLoS)
Date: 23-12-2010
QuantiFERON conversion following tuberculin administration is common in HIV infection and relates to baseline response
Publisher: Springer Science and Business Media LLC
Date: 07-10-2016
Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa
Publisher: Springer Science and Business Media LLC
Date: 12-01-2023
DOI: 10.1038/S41467-022-35689-1
Abstract: Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated ( p 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. 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. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.
Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer
Publisher: Elsevier BV
Date: 04-2022
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Nanostars Carrying Multifunctional Neurotrophic Dendrimers Protect Neurons in Preclinical In Vitro Models of Neurodegenerative Disorders
Publisher: American Chemical Society (ACS)
Date: 11-10-2022
Modern lineages of Mycobacterium tuberculosis exhibit lineage-specific patterns of growth and cytokine induction in human monocyte-derived macrophages
Publisher: Public Library of Science (PLoS)
Date: 16-08-2012
Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania
Publisher: Public Library of Science (PLoS)
Date: 04-04-2023
DOI: 10.1371/JOURNAL.PPAT.1010893
Abstract: In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.
Matrix Degradation in Human Immunodeficiency Virus Type 1–Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study
Publisher: Oxford University Press (OUP)
Date: 05-05-2017
DOI: 10.1093/CID/CIX231
Relationship Between HIV Coinfection, Interleukin 10 Production, andMycobacterium tuberculosisin Human Lymph Node Granulomas
Publisher: Oxford University Press (OUP)
Date: 26-07-2016
Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis
Publisher: Public Library of Science (PLoS)
Date: 12-2022
DOI: 10.1371/JOURNAL.PONE.0278295
Abstract: Mycobacterium tuberculosis ( M . tb ) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose s les were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for in iduals spanning from early stages of M . tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13–18 months, 742 at 7–12 months and 5,131 detected 1–6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1–6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.
Immune interaction between SARS-CoV-2 and Mycobacterium tuberculosis
Publisher: Frontiers Media SA
Date: 27-09-2023
Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome
Publisher: Oxford University Press (OUP)
Date: 08-08-2014
DOI: 10.1093/CID/CIU641
Recent and rapid emergence of W-Beijing strains of Mycobacterium tuberculosis in Cape Town, South Africa
Publisher: Oxford University Press (OUP)
Date: 15-11-2008
DOI: 10.1086/592575
Abstract: There is increasing evidence of a strain-related variation in the virulence in Mycobacterium tuberculosis that may afford a selective advantage to certain strains. The W-Beijing strain family is globally distributed, highly virulent in animal models, associated with human immunodeficiency virus infection and drug resistance, and may be an emerging strain family. Our goal was to determine whether W-Beijing strains are expanding in a region of South Africa where rates of tuberculosis are among the highest in the world. We used spoligotyping and single nucleotide polymorphism analysis to genotype all strains of tuberculosis from children presenting to the major pediatric referral hospital in Cape Town, South Africa over a period of 4 years and strains present in 352 archived histological s les from over a 76-year period. The proportion of W-Beijing strains from children increased from 13% to 33% from 2000 to 2003 (P= .026). With regard to the histological s les, W-Beijing strains were absent in the s les from the period 1930-1965 and rare in the s les from the period 1966-1995 (2.8% of s les), but they were increasingly common in s les from the period 1996-2005 (20% of s les P= .001). The rapid expansion of W-Beijing strains in a region with a very high background incidence of tuberculosis suggests that these strains have a significant selective advantage. The biological reasons for this observation remain unclear but warrant further study. The rapid spread of this virulent strain lineage is likely to present additional challenges for tuberculosis control.
Effect of HIV on the Frequency and Number of Mycobacterium tuberculosis–Specific CD4+ T Cells in Blood and Airways During Latent M. tuberculosis Infection
Publisher: Oxford University Press (OUP)
Date: 05-10-2017
Corticosteroid Therapy, Vitamin D Status, and Inflammatory Cytokine Profile in the HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome
Publisher: Oxford University Press (OUP)
Date: 19-06-2012
DOI: 10.1093/CID/CIS577
The effect of antiretroviral treatment on selected genes in whole blood from HIV-infected adults sensitised by Mycobacterium tuberculosis
Publisher: Public Library of Science (PLoS)
Date: 27-12-2018
Tuberculosis, Human Immunodeficiency Virus, and the Association With Transient Hyperglycemia in Periurban South Africa
Publisher: Oxford University Press (OUP)
Date: 26-09-2019
DOI: 10.1093/CID/CIZ928
Abstract: Diabetes mellitus (DM) increases tuberculosis (TB) risk. We assessed the prevalence of hyperglycemia (DM and impaired glucose regulation [IGR]) in persons with TB and the association between hyperglycemia and TB at enrollment and 3 months after TB treatment in the context of human immunodeficiency virus (HIV) infection. Adults 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 glycated hemoglobin and fasting plasma glucose at TB treatment and after 3 months. The association between TB and DM was assessed. Overall DM prevalence was 11.9% (95% confidence interval [CI], 9.1%–15.4%) at enrollment 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 enrollment and follow-up. TB/DM association was significant at enrollment (odds ratio [OR], 2.41 [95% CI, 1.3–4.3]) and follow-up (OR, 3.3 [95% CI, 1.5–7.3]), whereas TB/IGR association was only positive at enrollment (OR, 2.3 [95% CI, 1.6–3.3]). The TB/DM association was significant at enrollment in both new and preexisting DM, but only persisted at follow-up in preexisting DM in patients with HIV-1 infection. Our study demonstrated high prevalence of transient hyperglycemia and a significant TB/DM and TB/IGR association at enrollment in newly diagnosed DM, but persistent hyperglycemia and TB/DM association in patients with HIV-1 infection and preexisting DM, despite TB therapy.
Patterns of HIV, TB, and non-communicable disease multi-morbidity in peri-urban South Africa- a cross sectional study
Publisher: Springer Science and Business Media LLC
Date: 17-01-2015
Evidence guiding the treatment of children with mycobacterial diseases
Publisher: Oxford University Press (OUP)
Date: 15-04-2007
DOI: 10.1086/512654
Vitamin D supplementation to prevent tuberculosis infection in South African schoolchildren: multicenter phase 3 double-blind randomized placebo-controlled trial (ViDiKids)
Publisher: Elsevier BV
Date: 09-2023
Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer
Publisher: Elsevier BV
Date: 10-2022
Transcriptomic Characterization of Tuberculous Sputum Reveals a Host Warburg Effect and Microbial Cholesterol Catabolism
Publisher: American Society for Microbiology
Date: 21-12-2021
Abstract: Although a few studies have described the microbiome composition of TB sputa based on 16S ribosomal DNA, these studies did not compare to non-TB s les and the nature of the method does not allow any functional inference. This is the first study to apply such technology using clinical specimens and obtained functional transcriptional data on all three aspects simultaneously.
Plasmacytoid Dendritic Cells Infiltrate the Skin in Positive Tuberculin Skin Test Indurations
Publisher: Elsevier BV
Date: 2012
DOI: 10.1038/JID.2011.246
Rifampicin resistance and mortality in patients hospitalised with HIV-associated tuberculosis
Publisher: AOSIS
Date: 27-09-2022
DOI: 10.4102/SAJHIVMED.V23I1.1396
Abstract: Background: Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death.Objectives: We investigated the association between rif icin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis.Method: Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks.Results: Participants with microbiologically confirmed TB (n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rif icin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88 95% confidence interval: 1.07–3.29 P = 0.03).Conclusion: Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.
Prevalence and Determinants of Vitamin D Deficiency in 1825 Cape Town Primary Schoolchildren: A Cross-Sectional Study
Publisher: MDPI AG
Date: 16-03-2022
DOI: 10.3390/NU14061263
Abstract: Vitamin D deficiency (25-hydroxyvitamin D[25(OH)D] nmol/L) is common among adults in Cape Town, South Africa, but studies investigating vitamin D status of children in this setting are lacking. We conducted a cross-sectional study to determine the prevalence and determinants of vitamin D deficiency in 1825 Cape Town schoolchildren aged 6–11 years. Prevalence of vitamin D deficiency was 7.6% (95% Confidence Interval [CI] 6.5% to 8.9%). Determinants of vitamin D deficiency included month of s ling (adjusted odds ratio [aOR] for July–September vs. January–March 10.69, 95% CI 5.02 to 22.77 aOR for October–December vs. January–March 6.73, 95% CI 2.82 to 16.08), older age (aOR 1.25 per increasing year, 95% CI: 1.01–1.53) and higher body mass index (BMI aOR 1.24 per unit increase in BMI-for-age Z-score, 95% CI: 1.03–1.49). In a subset of 370 participants in whom parathyroid hormone (PTH) concentrations were measured these were inversely related to serum 25(OH)D concentrations (p 0.001). However, no association between participants with hyperparathyroidism (PTH .9 pmol/L) and vitamin D deficiency was seen (p = 0.42). In conclusion, we report that season is the major determinant of vitamin D status among Cape Town primary schoolchildren, with prevalence of vitamin D deficiency ranging from 1.4% in January–March to 22.8% in July–September.
Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study
Publisher: Public Library of Science (PLoS)
Date: 05-07-2019
The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
Publisher: Elsevier BV
Date: 04-2022
HIV Coinfection Is Associated with Low-Fitness rpoB Variants in Rifampicin-Resistant Mycobacterium tuberculosis
Publisher: American Society for Microbiology
Date: 21-09-2020
DOI: 10.1128/AAC.00782-20
Abstract: We analyzed 312 drug-resistant genomes of Mycobacterium tuberculosis isolates collected from HIV-coinfected and HIV-negative TB patients from nine countries with a high tuberculosis burden. We found that rif icin-resistant M. tuberculosis 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.
Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
DOI: 10.1038/S41564-021-01049-W
Abstract: Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis ( Mtb ) infection and healthy controls. We detected ,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort ( n = 46), which were validated in a subsequent multi-ethnic Singapore cohort ( n = 29), as well as a longitudinal cohort from South Africa ( n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15 , which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.
Host-directed therapies for infectious diseases: current status, recent progress, and future prospects
Publisher: Elsevier BV
Date: 04-2016
Impairment of IFN-Gamma Response to Synthetic Peptides of Mycobacterium tuberculosis in a 7-Day Whole Blood Assay
Publisher: Public Library of Science (PLoS)
Date: 08-08-2013
A deletion defining a common Asian lineage ofMycobacterium tuberculosisassociates with immune subversion
Publisher: Proceedings of the National Academy of Sciences
Date: 17-10-2006
Abstract: Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H 2 O 2 -tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519 , but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.
A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images
Publisher: Springer Science and Business Media LLC
Date: 25-06-2018
Mortality from drug-resistant tuberculosis in high-burden countries comparing routine drug susceptibility testing with whole-genome sequencing: a multicentre cohort study
Publisher: Elsevier BV
Date: 07-2021
Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2
Publisher: Springer Science and Business Media LLC
Date: 26-05-2021
DOI: 10.1038/S41591-021-01387-6
Abstract: Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population.
Transmission of Mycobacterium tuberculosis undetected by tuberculin skin testing
Publisher: American Thoracic Society
Date: 05-2006
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
Date: 11-05-2021
DOI: 10.1101/2021.05.11.21256479
Abstract: 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. Case control analysis with cases stratified by HIV-1 and tuberculosis status. A single-centre observational case-control study of adults admitted to a South African hospital with proven SARS-CoV-2 infection or alternative diagnosis. 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. 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. In this South African setting, HIV-1 and tuberculosis are common co-morbidities in patients presenting with COVID-19. In environments in which tuberculosis is common, SARS-CoV-2 and tuberculosis may co-exist with clinical presentation being typical of either disease. Clinical suspicion of exacerbation of co-existent tuberculosis accompanying SARS-CoV-2 should be high. It has been quite widely thought that Africa has been spared the worst effects of the COVID-19 pandemic. There are very few reported case series and no case-control studies comparing COVID-19 patients admitted to hospital to those admitted for other reasons. However several studies have indicated both HIV-1 and tuberculosis co-infection that are endemic in Africa constitute risk factors for poor outcome. In addition Africa is subject to demographic transition and the prevalence of non-communicable co-morbidities such as type 2 diabetes, hypertension and cardiovascular disease is rising rapidly. No study from Africa has described the clinical impact on the presentation of COVID-19 infection. Two or more co-morbidities were present in over half COVID-19 presentations, including HIV-1 (30%) and active tuberculosis (14%). Patients dually infected by tuberculosis and SARS-CoV-2, presented as either SARS-CoV-2 or tuberculosis. HIV-1 and SARS-CoV2 co-infection resulted in lower absolute number and proportion of CD4 lymphocytes, and those with low CD4 counts had absent or lower antibody responses against SARS-CoV2. Death occurred 29% of all COVID-19 patients and in 40% of patients with coincident SARS-CoV-2 and tuberculosis. Thus in environments in which tuberculosis is common, SARS-CoV-2 and tuberculosis may co-exist with clinical presentation being typical of either disease and clinical suspicion of exacerbation of co-existent tuberculosis accompanying SARS-CoV-2 should be high.
Tuberculosis, HIV, and type 2 diabetes mellitus: a neglected priority
Publisher: Elsevier BV
Date: 07-2013
Vitamin D Status and Its Consequences for Health in South Africa
Publisher: MDPI AG
Date: 18-10-2016
Smoking, BCG and Employment and the Risk of Tuberculosis Infection in HIV-Infected Persons in South Africa
Publisher: Public Library of Science (PLoS)
Date: 09-10-2012
The clinical consequences of strain diversity in Mycobacterium tuberculosis
Publisher: Oxford University Press (OUP)
Date: 10-2008
DOI: 10.1016/J.TRSTMH.2008.03.025
Abstract: The influence of strain variation on the outcome of infection with Mycobacterium tuberculosis is an emerging area of research. Significant genetic ersity is generated within the species through deletion, duplication and recombination events however, unlike many bacterial pathogens gene exchange is rare in M. tuberculosis, resulting in the evolution of distinct clonal lineages. One such lineage, W-Beijing, is particularly virulent in animal models, may be emerging worldwide, has distinct phenotypic and genotypic characteristics and is associated with extrapulmonary disease and drug resistance. Strains of M. tuberculosis responsible for outbreaks have been shown to vary in virulence in animal models, which in turn has been related to their ability to inhibit innate immune responses. However, there is no clear evidence that this variability manifests as differences in human disease. An improved understanding of the phylogenetic relationship between strains of M. tuberculosis, based on increased availability of sequence data from the major strain lineages, will allow a structured approach to understand further the consequences of strain ersity in M. tuberculosis.
Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-γ
Publisher: American Society for Clinical Investigation
Date: 09-2005
DOI: 10.1172/JCI19316
Neutrophils: Innate Effectors of TB Resistance?
Publisher: Frontiers Media SA
Date: 14-11-2018
The prevalence and determinants of active tuberculosis among diabetes patients in Cape Town, South Africa, a high HIV/TB burden setting
Publisher: Elsevier BV
Date: 04-2018
Utility of second-generation line probe assay (Hain MTBDRplus) directly on 2-month sputum specimens for monitoring tuberculosis treatment response
Publisher: American Society for Microbiology
Date: 05-2017
DOI: 10.1128/JCM.00025-17
Abstract: The utility of a line probe assay (Genotype MTBDR plus ) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown. We assessed if direct testing of 2-month sputa with MTBDR plus can predict 2-month culture conversion and long-term treatment outcome. Xpert MTB/RIF-confirmed rif in-susceptible tuberculosis cases were recruited at tuberculosis diagnosis and followed up at 2 and 5 to 6 months. MTBDR plus was performed directly on 2-month sputa and on all positive cultured isolates at 2 and 5 to 6 months. We also investigated the association of a positive direct MTBDR plus at 2 months with subsequent unsuccessful tuberculosis treatment outcome (failure/death during treatment or subsequent disease recurrence). A total of 279 patients (62% of whom were HIV-1 coinfected) were recruited. Direct MTBDR plus at 2 months had a sensitivity of 78% (95% confidence interval [CI], 65 to 87) and specificity of 80% (95% CI, 74 to 84) to predict culture positivity at 2 months with a high negative predictive value of 93% (95% CI, 89 to 96). Inconclusive genotypic susceptibility results for both rif in and isoniazid were seen in 26% of MTBDR plus tests performed directly on sputum. Compared to a reference of MTBDR plus performed on positive cultures, the false-positive resistance rate for direct testing of MTBDR plus on sputa was 4% for rif in and 2% for isoniazid. While a positive 2-month smear was not significantly associated with an unsuccessful treatment outcome (adjusted odds ratio [aOR], 2.69 95% CI, 0.88 to 8.21), a positive direct MTBDR plus at 2 months was associated with an unsuccessful outcome (aOR 2.87 95% CI, 1.11 to 7.42). There is moderate utility of direct 2-month MTBDR plus to predict culture conversion at 2 months and also to predict an unfavorable outcome.
Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus–1
Publisher: Oxford University Press (OUP)
Date: 26-09-2018
DOI: 10.1093/CID/CIY823
Abstract: The risk of in iduals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1–infected in iduals are likely to progress to active disease is unknown. Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma s les in 421 HIV-1–infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. In iduals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. Unstimulated s les showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC & 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected in iduals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.
The Influence of HIV on the Evolution of Mycobacterium tuberculosis
Publisher: Oxford University Press (OUP)
Date: 21-03-2017
Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification
Publisher: Cold Spring Harbor Laboratory
Date: 21-03-2019
DOI: 10.1101/583674
Abstract: 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 the development of diagnostic tests. To identify minimal transcript signatures, we applied a novel transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), ided into training and test sets. Signatures were validated using reverse transcriptase (RT) - digital PCR (dPCR). A four-transcript signature ( GBP6 , TMCC1 , PRDM1 , ARG1 ) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI 95% 82.2 – 100%). A three-transcript signature ( FCGR1A, ZNF296, C1QB ) differentiated TB from LTBI (AUC 97.3%, CI 95% : 93.3 – 100%), regardless of HIV. These signatures have been validated across platforms and across s les offering strong, quantitative support for their use as diagnostic biomarkers for TB.
Identification and control for the effects of bioinformatic globin depletion on human RNA-seq differential expression analysis
Publisher: Springer Science and Business Media LLC
Date: 02-2023
DOI: 10.1038/S41598-023-28218-7
Abstract: When profiling blood s les by RNA-sequencing (RNA-seq), RNA from haemoglobin (Hgb) can account for up to 70% of the transcriptome. Due to considerations of sequencing depth and power to detect biological variation, Hgb RNA is typically depleted prior to sequencing by hybridisation-based methods an alternative approach is to deplete reads arising from Hgb RNA bioinformatically. In the present study, we compared the impact of these two approaches on the outcome of differential gene expression analysis performed using RNA-seq data from 58 human tuberculosis (TB) patient or contact whole blood s les–29 globin kit-depleted and 29 matched non-depleted—a subset of which were taken at TB diagnosis and at six months post-TB treatment from the same patient. Bioinformatic depletion of Hgb genes from the non-depleted s les (bioinformatic-depleted) substantially reduced library sizes (median = 57.24%) and fewer long non-coding, micro, small nuclear and small nucleolar RNAs were captured in these libraries. Profiling published TB gene signatures across all s les revealed inferior correlation between kit-depleted and bioinformatic-depleted pairs when the proportion of reads mapping to Hgb genes was higher in the non-depleted s le, particularly at the TB diagnosis time point. A set of putative “globin-fingerprint” genes were identified by directly comparing kit-depleted and bioinformatic-depleted s les at each timepoint. Two TB treatment response signatures were also shown to have decreased differential performance when comparing s les at TB diagnosis to six months post-TB treatment when profiled on the bioinformatic-depleted s les compared with their kit-depleted counterparts. These results demonstrate that failure to deplete Hgb RNA prior to sequencing has a negative impact on the sensitivity to detect disease-relevant gene expression changes even when bioinformatic removal is performed.
Phenylbutyrate Is Bacteriostatic against Mycobacterium tuberculosis and Regulates the Macrophage Response to Infection, Synergistically with 25-Hydroxy-Vitamin D₃
Publisher: Public Library of Science (PLoS)
Date: 02-07-2015
Ethnic Variation in Inflammatory Profile in Tuberculosis
Publisher: Public Library of Science (PLoS)
Date: 04-07-2013
Generation of Liposomes to Study the Effect of Mycobacterium Tuberculosis Lipids on HIV-1 cis- and trans-Infections
Publisher: MDPI AG
Date: 16-02-2021
DOI: 10.3390/IJMS22041945
Abstract: Tuberculosis (TB) is the leading cause of death among HIV-1-infected in iduals 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 in iduals.
Comparison of T-SPOT. TB assay and tuberculin skin test for the evaluation of young children at high risk for tuberculosis in a community setting
Publisher: American Academy of Pediatrics (AAP)
Date: 2009
Abstract: OBJECTIVE. We wished to compare the sensitivity of an enzyme-linked immunospot assay (T-SPOT.TB Oxford Immunotec, Oxford, United Kingdom) and the tuberculin skin test for the detection of tuberculosis infection in very young children being evaluated for active tuberculosis in a rural community setting. METHODS. Children with a history of exposure to tuberculosis and children presenting to a local clinic or hospital with symptoms suggesting tuberculosis were admitted to a dedicated case verification ward. T-SPOT.TB testing was performed, and children were evaluated with a clinical examination, a tuberculin skin test, chest radiographs, and cultures of induced sputum and gastric lavage specimens. The diagnosis was determined by using a clinical algorithm. RESULTS. A total of 243 children (median age: 18 months) were recruited, of whom 214 (88%) had interpretable T-SPOT.TB results. Children ≥12 months of age were more likely than younger children to have positive T-SPOT.TB results, whereas tuberculin skin test results were unaffected by age. The sensitivity of the T-SPOT.TB was no better than that of the tuberculin skin test for culture-confirmed tuberculosis (50% and 80%, respectively) and was poorer for the combined group of culture-confirmed and clinically probable tuberculosis (40% and 52%, respectively). For the 50 children clinically categorized as not having tuberculosis, the specificity of both the T-SPOT.TB and the tuberculin skin test was 84%. CONCLUSIONS. For young children presenting in a community setting after exposure to tuberculosis or with symptoms suggesting tuberculosis, T-SPOT.TB cannot be used to exclude active disease. The sensitivity of this assay may be impaired for very young children.
Towards host-directed therapies for tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 17-07-2015
DOI: 10.1038/NRD4696
Abstract: The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing adjunct host-directed therapies.
TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development
Publisher: Frontiers Media SA
Date: 2017
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 08-2010
DOI: 10.1038/NATURE09247
Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis
Publisher: Elsevier BV
Date: 04-2022
Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S43018-021-00275-9
Abstract: Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4 + responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Trilateral overlap of tuberculosis, diabetes and HIV-1 in a high-burden African setting: implications for TB control
Publisher: European Respiratory Society (ERS)
Date: 07-2017
DOI: 10.1183/13993003.00004-2017
Abstract: The diabetes mellitus burden is growing in countries where tuberculosis (TB) and HIV-1 remain major challenges, threatening TB control efforts. This study determined the association between TB and diabetes/impaired glucose regulation in the context of HIV-1. A cross-sectional study was conducted at a TB clinic in Cape Town (South Africa). Participants were screened for diabetes and impaired glucose regulation using fasting plasma glucose, oral glucose tolerance test and glycated haemoglobin (HbA1c). 414 TB and 438 non-TB participants were enrolled. In multivariable analysis, diabetes was associated with TB (OR 2.4, 95% CI 1.3–4.3 p=0.005), with 14% population-attributable risk fraction however, this association varied by diagnostic test (driven by HbA1c). The association remained significant in HIV-1-infected in iduals (OR 2.4, 95% CI 1.1–5.2 p=0.030). A high prevalence of impaired glucose regulation (65.2% among TB cases) and a significant association with TB (OR 2.3, 95% CI 1.6–3.3 p .001) was also found. Diabetes and impaired glucose regulation prevalence was high and associated with TB, particularly in HIV-1-infected in iduals, highlighting the importance of diabetes screening. The variation in findings by diagnostic test highlights the need for better glycaemia markers to inform screening in the context of TB and HIV-1.
Type 1 Helper T Cells and FoxP3-positive T Cells in HIV–Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome
Publisher: American Thoracic Society
Date: 15-11-2008
Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer
Publisher: Elsevier BV
Date: 02-2022
Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa
Publisher: Proceedings of the National Academy of Sciences
Date: 24-10-2011
Abstract: Vitamin D deficiency is associated with susceptibility to tuberculosis (TB) in HIV-uninfected people in Europe, but it is not known whether such an association exists among HIV-infected people in subtropical Africa. We conducted a cross-sectional study to determine whether vitamin D deficiency was associated with susceptibility to active TB in HIV-uninfected ( n = 196) and HIV-infected ( n = 174) black Africans in Cape Town, South Africa. We also investigated whether there was evidence of seasonal variation in vitamin D status and TB notifications in this setting over an 8-y period. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] nmol/L) was present in 232 (62.7%) of 370 participants and was associated with active TB in both HIV-uninfected (odds ratio = 5.2, 95% confidence interval: 2.8–9.7 P 0.001) and HIV-infected (odds ratio = 5.6, 95% confidence interval: 2.7–11.6 P 0.001) people. Vitamin D status varied according to season: The mean serum 25(OH)D concentration was highest in January through March and lowest in July through September (56.8 vs. 30.7 nmol/L, respectively P 0.001). Reciprocal seasonal variation in TB notifications was observed: The mean number of TB notifications per quarter for Cape Town in 2003 to 2010 was lowest in April through June and highest in October through December (4,222 vs. 5,080 P 0.001). Vitamin D deficiency is highly prevalent among black Africans in Cape Town and is associated with susceptibility to active TB both in the presence and absence of HIV infection. Reciprocal seasonal variation in serum 25(OH)D concentration and TB notifications suggests that seasonal variations in vitamin D status and TB incidence in this setting are causally related.
Neutrophil extracellular trap formation and gene programs distinguish TST/IGRA sensitization outcomes among Mycobacterium tuberculosis exposed persons living with HIV
Publisher: Public Library of Science (PLoS)
Date: 24-08-2023
DOI: 10.1371/JOURNAL.PGEN.1010888
Abstract: Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to Mycobacterium tuberculosis ( Mtb ) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to in iduals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil s les from 17 HITTIN (PMN HITTIN ) and 11 HIT (PMN HIT ) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMN HITTIN and PMN HIT , we focused on the 6h timepoint. When compared to uninfected PMN, PMN HITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log 2 FC of 0.2, FDR 0.05) whereas PMN HIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log 2 FC 6h infection response to Mtb from PMN HITTIN against PMN HIT , 2285 genes showed significant differential response between the two groups. Overall PMN HITTIN had a lower fold change response to Mtb infection compared to PMN HIT . According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMN HITTIN compared to PMN HIT , showing that PMN HITTIN have a distinct response to Mtb .
Antibodies against endogenous retroviruses promote lung cancer immunotherapy
Publisher: Springer Science and Business Media LLC
Date: 12-04-2023
DOI: 10.1038/S41586-023-05771-9
Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS) 1,2 . Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive 1,2 . Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma 3 . We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are lified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa
Publisher: Massachusetts Medical Society
Date: 05-2014
Programmed death ligand 1 is over‐expressed by neutrophils in the blood of patients with active tuberculosis
Publisher: Wiley
Date: 27-05-2011
Enzyme-linked immunospot assay responses to early secretory antigenic target 6, culture filtrate protein 10, and purified protein derivative among children with tuberculosis
Publisher: Oxford University Press (OUP)
Date: 05-2005
DOI: 10.1086/429245
Abstract: The ability to detect tuberculosis-specific lymphocytes by enzyme-linked immunospot (ELISPOT) assay may have important implications for the diagnosis and monitoring of tuberculosis in children, for which routine methods lack sensitivity. We conducted a study to determine the presence and time course of ELISPOT responses in children with tuberculosis. Blood s les were obtained from children with a clinical diagnosis of tuberculosis, and interferon-gamma ELISPOT assays were performed using purified protein derivative (PPD), early secretory antigenic target 6 (ESAT-6), and culture filtrate protein 10 (CFP10) as stimulants. A subset of children were retested after 1, 3, and 6 months of therapy. Detectable responses to ESAT-6 or CFP10 were found in 49 of 70 children with clinical tuberculosis but were more frequently found in those with culture-proven disease (P = .05). The number of subjects with responses to PPD increased after 1 month of therapy (P = .0004) and decreased at 3 and 6 months. Tuberculosis-specific ELISPOT testing is a promising tool that should be evaluated as a potential diagnostic test for childhood tuberculosis. We caution against the use of an early decrease in response as a marker of successful antituberculous chemotherapy.
Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-04-2013
Comprehensive plasma proteomic profiling reveals biomarkers for active tuberculosis
Publisher: American Society for Clinical Investigation
Date: 17-09-2020
High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial
Publisher: Elsevier BV
Date: 2011
Activation Profile of Mycobacterium tuberculosis–Specific CD4+ T Cells Reflects Disease Activity Irrespective of HIV Status
Publisher: American Thoracic Society
Date: 06-2016
HIV–TB Drug Interactions
Publisher: Wiley
Date: 14-10-2009
A Recent HIV Diagnosis Is Associated with Non-Completion of Isoniazid Preventive Therapy in an HIV-Infected Cohort in Cape Town
Publisher: Public Library of Science (PLoS)
Date: 20-12-2012
Recent progress in understanding immune activation in the pathogenesis in HIV–tuberculosis co-infection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2018
Selective reduction of IFN-γ single positive mycobacteria-specific CD4+ T cells in HIV-1 infected individuals with latent tuberculosis infection
Publisher: Elsevier BV
Date: 12-2016
High prevalence of subclinical tuberculosis in HIV-1-infected persons without advanced immunodeficiency: implications for TB screening
Publisher: BMJ
Date: 31-05-2011
Cytotoxic Mediators in Paradoxical HIV–Tuberculosis Immune Reconstitution Inflammatory Syndrome
Publisher: The American Association of Immunologists
Date: 15-02-2015
Abstract: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) frequently complicates combined antiretroviral therapy and antituberculosis therapy in HIV-1–coinfected tuberculosis patients. The immunopathological mechanisms underlying TB-IRIS are incompletely defined, and improved understanding is required to derive new treatments and to reduce associated morbidity and mortality. We performed longitudinal and cross-sectional analyses of human PBMCs from paradoxical TB-IRIS patients and non-IRIS controls (HIV-TB–coinfected patients commencing antiretroviral therapy who did not develop TB-IRIS). Freshly isolated PBMC stimulated with heat-killed Mycobacterium tuberculosis H37Rv (hkH37Rv) were used for IFN-γ ELISPOT and RNA extraction. Stored RNA was used for microarray and RT-PCR, whereas corresponding stored culture supernatants were used for ELISA. Stored PBMC were used for perforin and granzyme B ELISPOT and flow cytometry. There were significantly increased IFN-γ responses to hkH37Rv in TB-IRIS, compared with non-IRIS PBMC (p = 0.035). Microarray analysis of hkH37Rv-stimulated PBMC indicated that perforin 1 was the most significantly upregulated gene, with granzyme B among the top five (log2 fold difference 3.587 and 2.828, respectively), in TB-IRIS. Downstream experiments using RT-PCR, ELISA, and ELISPOT confirmed the increased expression and secretion of perforin and granzyme B. Moreover, granzyme B secretion reduced in PBMC from TB-IRIS patients during corticosteroid treatment. Invariant NKT cell (CD3+Vα24+) proportions were higher in TB-IRIS patients (p = 0.004) and were a source of perforin. Our data implicate the granule exocytosis pathway in TB-IRIS pathophysiology. Further understanding of the immunopathogenesis of this condition will facilitate development of specific diagnostic and improved therapeutic options.
Risk Factors Associated with Indeterminate Gamma Interferon Responses in the Assessment of Latent Tuberculosis Infection in a High-Incidence Environment
Publisher: American Society for Microbiology
Date: 08-2012
DOI: 10.1128/CVI.00166-12
Abstract: The performance of gamma interferon (IFN-γ) release assays (IGRA) in the detection of latent tuberculosis (TB) infection is limited by the higher rates of indeterminate results in HIV-infected persons, who bear the brunt of TB disease in some high-burden settings. The objective of the study was to evaluate predictors of indeterminate IGRA results in the overall study population and in HIV-infected persons. The study setting is Khayelitsha, an informal township in the Western Cape of South Africa, with a high burden of TB and HIV infection. A total of 561 asymptomatic persons were recruited from the day hospital and youth centers. A questionnaire was used to collect demographic information, and blood tests, including CD4 counting and a 7-day in-house IGRA, were performed. The overall prevalence of indeterminate IGRA results was 8.6% (48/561), and this was higher in HIV-infected than in HIV-uninfected persons (11.5% [38/330] versus 4.3% [10/231], respectively P = 0.003). In the overall study population, predictors of indeterminate IGRA results were the presence of HIV infection (odds ratio [OR], 2.36 95% confidence interval [CI], 1.10 to 5.08) and the presence of a Mycobacterium bovis BCG scar (OR, 2.48 95% CI, 1.23 to 5.01). Long-term township residents were significantly less likely to have indeterminate results than recent migrants (OR, 0.30 95% CI, 0.11 to 0.80). Among HIV-infected persons, participants with CD4 counts of cells/mm 3 and long-term residents were significantly less likely to have indeterminate IGRA results (OR of 0.21 with a 95% CI of 0.09 to 0.48 and OR of 0.22 with a 95% CI of 0.07 to 0.68, respectively). We evaluated risk factors for indeterminate IGRA results and report a higher rate of indeterminate results among HIV-infected persons, particularly those with lower CD4 counts. Of note, a recent move to the township was associated with a higher risk of indeterminate IGRA results.
Author Correction: Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection
Publisher: Springer Science and Business Media LLC
Date: 02-09-2022
Strains of Mycobacterium tuberculosis from Western Maharashtra, India, exhibit a high degree of diversity and strain-specific associations with drug resistance, cavitary disease, and treatment failure
Publisher: American Society for Microbiology
Date: 10-2010
DOI: 10.1128/JCM.00430-10
Abstract: We performed spoligotyping of Mycobacterium tuberculosis isolates from 833 systematically s led pulmonary tuberculosis (TB) patients in urban Mumbai, India (723 patients), and adjacent rural areas in western India (110 patients). The urban cohort consisted of two groups of patients, new cases (646 patients) and first-time treatment failures (77 patients), while only new cases were recruited in the rural areas. The isolates from urban new cases showed 71% clustering, with 168 Manu1, 62 CAS, 22 Beijing, and 30 EAI-5 isolates. The isolates from first-time treatment failures were 69% clustered, with 14 Manu1, 8 CAS, 8 Beijing, and 6 EAI-5 isolates. The proportion of Beijing strains was higher in this group than in urban new cases (odds ratio [OR], 3.29 95% confidence limit [95% CL], 1.29 to 8.14 P = 0.003). The isolates from rural new cases showed 69% clustering, with 38 Manu1, 7 CAS, and 1 EAI-5 isolate. Beijing was absent in the rural cohort. Manu1 was found to be more common in the rural cohort (OR, 0.67 95% CL, 0.42 to 1.05 P = 0.06). In total, 71% of isolates were clustered into 58 spoligotypes with 4 predominant strains, Manu1 (26%), CAS (9%), EAI-5 (4%), and Beijing (4%), along with 246 unique spoligotypes. In the isolates from urban new cases, we found Beijing to be associated with multidrug resistance (MDR) (OR, 3.40 95% CL, 1.20 to 9.62 P = 0.02). CAS was found to be associated with pansensitivity (OR, 1.83 95% CL, 1.03 to 3.24 P = 0.03) and cavities as seen on chest radiographs (OR, 2.72 95% CL, 1.34 to 5.53 P = 0.006). We recorded 239 new spoligotypes yet unreported in the global databases, suggesting that the local TB strains exhibit a high degree of ersity.
Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis
Publisher: Proceedings of the National Academy of Sciences
Date: 16-01-2018
Abstract: The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [ 18 F]-fluoro-2-deoxy- d -glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1–infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where s les were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fcγ receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.
Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study
Publisher: Public Library of Science (PLoS)
Date: 22-10-2013
Anti-Inflammatory and Antimicrobial Actions of Vitamin D in Combating TB/HIV
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/903680
Abstract: Tuberculosis (TB) disease activation is now believed to arise due to a lack of inflammatory homeostatic control at either end of the spectrum of inflammation: either due to immunosuppression (decreased antimicrobial activity) or due to immune activation (excess/aberrant inflammation). Vitamin D metabolites can increase antimicrobial activity in innate immune cells, which, in the context of HIV-1 coinfection, have insufficient T cell-mediated help to combat Mycobacterium tuberculosis (MTB) infection. Moreover, maintaining vitamin D sufficiency prior to MTB infection enhances the innate antimicrobial response to T cell-mediated interferon- γ . Conversely, vitamin D can act to inhibit expression and secretion of a broad range of inflammatory mediators and matrix degrading enzymes driving immunopathology during active TB and antiretroviral- (ARV-) mediated immune reconstitution inflammatory syndrome (IRIS). Adjunct vitamin D therapy during treatment of active TB may therefore reduce lung pathology and TB morbidity, accelerate resolution of cavitation and thereby decrease the chance of transmission, improve lung function following therapy, prevent relapse, and prevent IRIS in those initiating ARVs. Future clinical trials of vitamin D for TB prevention and treatment must be designed to detect the most appropriate primary endpoint, which in some cases should be anti-inflammatory and not antimicrobial.
Bioinformatic and Empirical Analysis of Novel Hypoxia-Inducible Targets of the Human Antituberculosis T Cell Response
Publisher: The American Association of Immunologists
Date: 15-12-2012
Abstract: We analyzed whole genome–based transcriptional profiles of Mycobacterium tuberculosis subjected to prolonged hypoxia to guide the discovery of novel potential Ags, by a combined bioinformatic and empirical approach. We analyzed the fold induction of the 100 most highly induced genes at 7 d of hypoxia, as well as transcript abundance, peptide-binding prediction (ProPred) adjusted for population-specific MHC class II allele frequency, and by literature search. Twenty-six candidate genes were selected by this bioinformatic approach and evaluated empirically using IFN-γ and IL-2 ELISPOT using immunodominant Ags (Acr-1, CFP-10, ESAT-6) as references. Twenty-three of twenty-six proteins induced an IFN-γ response in PBMCs of persons with active or latent tuberculosis. Five novel immunodominant proteins—Rv1957, Rv1954c, Rv1955, Rv2022c, and Rv1471—were identified that induced responses similar to CFP-10 and ESAT-6 in both magnitude and frequency. IL-2 responses were of lower magnitude than were those of IFN-γ. Only moderate evidence of infection stage–specific recognition of Ags was observed. Reconciliation of bioinformatic and empirical hierarchies of immunodominance revealed that Ags could be predicted, providing transcriptomic data were combined with peptide-binding prediction adjusted by population-specific MHC class II allele frequency.
“SILVAMP TB LAM” Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa
Publisher: Oxford University Press (OUP)
Date: 09-01-2020
DOI: 10.1093/CID/CIAA024
Abstract: Reducing diagnostic delay is key toward decreasing tuberculosis-associated deaths in people living with human immunodeficiency virus. 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%.
Neurologic Manifestations of Paradoxical Tuberculosis‐Associated Immune Reconstitution Inflammatory Syndrome: A Case Series
Publisher: Oxford University Press (OUP)
Date: 06-2009
DOI: 10.1086/598988
Abstract: Paradoxical neurologic tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a potentially life-threatening condition that occurs within 3 months after starting combination antiretroviral therapy (ART). The reports in the published literature are anecdotal, and the prevalence and outcomes of neurologic TB-IRIS are unknown. We prospectively assessed patients with suspected TB-IRIS from June 2005 through October 2007 at our hospital in Cape Town, South Africa. We defined paradoxical TB-IRIS and paradoxical neurologic TB-IRIS with use of consensus clinical case definitions. We collected data on tuberculosis diagnosis, ART, details of TB-IRIS diagnosis, other opportunistic infections, corticosteroid use, and outcome. We reviewed 279 patients with suspected TB-IRIS, 54 (19%) of whom had suspected neurologic TB-IRIS, and 225 (81%) of whom had suspected non-neurologic TB-IRIS. Paradoxical TB-IRIS was diagnosed in 190 patients 23 (12%) of these 190 patients had neurologic TB-IRIS (95% confidence interval, 7%-17%). Eight had meningitis, 7 had tuberculoma, 5 had both tuberculoma and meningitis, and 3 had radiculomyelopathy. Twenty (87%) of the 23 patients with neurologic TB-IRIS required hospital admission (median duration, 12 days interquartile range, 6-24 days), and 21 (91%) received corticosteroids (median duration, 58 days interquartile range, 29-86 days). Outcomes 6 months after the initial assessment for neurologic deterioration were as follows: 16 (70%) of the patients were alive (10 of these patients had documented full physical and mental recovery), 3 (13%) were dead, and 4 (17%) were lost to follow-up. Paradoxical neurologic TB-IRIS accounts for 12% of paradoxical TB-IRIS cases. Neurologic TB-IRIS causes considerable short-term morbidity but has reasonable long-term outcomes. Further research is needed to devise optimal diagnostic and management strategies for patients with tuberculosis who experience neurologic deterioration after starting ART.
Enhanced diagnosis of HIV-1-associated tuberculosis by relating T-SPOT.TB and CD4 counts
Publisher: European Respiratory Society (ERS)
Date: 14-01-2010
Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors
Publisher: Springer Science and Business Media LLC
Date: 30-03-2010
Tuberculous meningitis
Publisher: Springer Science and Business Media LLC
Date: 08-09-2017
DOI: 10.1038/NRNEUROL.2017.120
Abstract: Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is h ered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies - including corticosteroids, aspirin and thalidomide - has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation vascular and hypoxia-mediated tissue injury the role of intensified antibiotic treatment and the importance of rapid and accurate diagnostics and supportive care in TBM.
Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[18F]fluoro-D-glucose positron emission and computed tomography
Publisher: Springer Science and Business Media LLC
Date: 05-09-2016
DOI: 10.1038/NM.4161
Xpert Ultra testing of blood in severe HIV-associated tuberculosis to detect and measure Mycobacterium tuberculosis blood stream infection
Publisher: Elsevier BV
Date: 07-2022
Related Organisations
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
The Francis Crick Institute
Location: United Kingdom of Great Britain and Northern Ireland
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
Royal College Of Physicians
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Robert Wilkinson.