Publications
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Esmail H, Thienemann F, Oni T, et al., 2016, QuantiFERON conversion following tuberculin administration is common in HIV infection and relates to baseline response, BMC Infectious Diseases, Vol: 16, ISSN: 1471-2334
BACKGROUND: HIV-1 infection impairs tuberculosis (TB) specific immune responses affecting the diagnosis of latent TB. We aimed to (1) determine the proportion of HIV-1-infected adults with a negative QuantiFERON®-TB Gold in-tube (QFT-GIT) and Tuberculin skin testing (TST) that convert to QFT-GIT positive following TST, and (2) evaluate the relationship between conversion and baseline QFT-GIT results. METHODS: HIV-1 infected adults being screened for a TB vaccine study in South Africa underwent QFT-GIT followed by TST. As per protocol, QFT-GIT was repeated if randomization was delayed allowing for evaluation of TST boosting in a proportion of participants. RESULTS: Of the 22 HIV-1 infected, TST and QFT-GIT negative adults (median CD4 477/mm(3) IQR 439-621) who had QFT-GIT repeated after median 62 days (IQR 49-70), 40.9 % (95 % CI 18.6-63.2 %) converted. Converters had a significantly greater increase in the background subtracted TB antigen response (TBAg-Nil - all units IU/mL) following TST, 0.82 (IQR 0.39-1.28) vs 0.03 (IQR -0.05-0.06), p = 0.0001. Those who converted also had a significantly higher baseline TBAg-Nil 0.21(IQR 0.17-0.26) vs 0.02(IQR 0.01-0.07), p = 0.002. Converters did not differ with regard to CD4 count or ART status. ROC analysis showed a baseline cut off of 0.15 correctly classified 86.4 % of converters with 88.9 % sensitivity. CONCLUSIONS: Our findings support the possibility that there are 2 distinct groups in an HIV-1 infected population with negative QFT-GIT and TST; a true negative group and a group showing evidence of a weak Mtb specific immune response that boosts significantly following TST resulting in conversion of the test result that may represent false negatives. Further evaluation of whether a lower cut off may improve sensitivity of QFT-GIT in this population is warranted.
Esmail H, Oni T, Thienemann F, et al., 2016, Cardio-thoracic ratio is stable, reproducible and has potential as a screening tool for HIV-1 related cardiac disorders in resource poor settings, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundCardiovascular disorders are common in HIV-1 infected persons in Africa and presentation is often insidious. Development of screening algorithms for cardiovascular disorders appropriate to a resource-constrained setting could facilitate timely referral. Cardiothoracic ratio (CTR) on chest radiograph (CXR) has been suggested as a potential screening tool but little is known about its reproducibility and stability. Our primary aim was to evaluate the stability and the inter-observer variability of CTR in HIV-1 infected outpatients. We further evaluated the prevalence of cardiomegaly (CTR≥0.5) and its relationship with other risk factors in this population.MethodologyHIV-1 infected participants were identified during screening for a tuberculosis vaccine trial in Khayelitsha, South Africa between August 2011 and April 2012. Participants had a digital posterior-anterior CXR performed as well as history, examination and baseline observations. CXRs were viewed using OsiriX software and CTR calculated using digital callipers.Results450 HIV-1-infected adults were evaluated, median age 34 years (IQR 30–40) with a CD4 count 566/mm3 (IQR 443–724), 70% on antiretroviral therapy (ART). The prevalence of cardiomegaly was 12.7% (95% C.I. 9.6%-15.8%). CTR was calculated by a 2nd reader for 113 participants, measurements were highly correlated r = 0.95 (95% C.I. 0.93–0.97) and agreement of cardiomegaly substantial κ = 0.78 (95% C.I 0.61–0.95). CXR were repeated in 51 participants at 4–12 weeks, CTR measurements between the 2 time points were highly correlated r = 0.77 (95% C.I 0.68–0.88) and agreement of cardiomegaly excellent κ = 0.92 (95% C.I. 0.77–1). Participants with cardiomegaly had a higher median BMI (31.3; IQR 27.4–37.4) versus 26.9; IQR 23.2–32.4); p<0.0001) and median systolic blood pressure (130; IQR 121–141 versus 125; IQR 117–135; p = 0.01).ConclusionCTR is a robust measurement
Bana TM, Lesosky M, Pepper DJ, et al., 2016, Prolonged tuberculosis-associated immune reconstitution inflammatory syndrome: characteristics and risk factors, BMC Infectious Diseases, Vol: 16, ISSN: 1471-2334
BACKGROUND: In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS. METHODS: We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher's exact test, multivariate logistic regression and Cox proportional hazards models. RESULTS: Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0-113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13-4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of border
Brilha S, Sathyamoorthy T, Stuttaford LH, et al., 2016, ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis., American Journal of Respiratory Cell and Molecular Biology, Vol: 56, Pages: 223-232, ISSN: 1535-4989
Tuberculosis (TB) causes disease worldwide and multi-drug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb) infected macrophages and in conditioned medium from Mtb infected monocytes (CoMtb)-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, while CoMtb increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of TB patients from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared to controls and patients with other respiratory diseases (both p<0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain BCG (p<0.001), whereas both mycobacteria upregulated TNFα secretion equally. Using overlapping short linear peptides covering the sequence of ESAT-6, a virulence factor secreted by Mtb but not BCG, we found that stimulation of human macrophages with a single specific 15 amino acid peptide sequence drove 3-fold greater MMP-10 secretion than any other peptide (p<0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and ERK MAPK blockade (p<0.001 and p<0.01 respectively), but was not affected by inhibition of NF-ĸB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10 and this is partly driven by the virulence factor ESAT-6, implicating it in TB-associated tissue destruction.
Wilkinson RJ, Esmail H, Lesosky M, et al., 2016, [18F]-FDG PET/CT characterisation of progressive HIV-associated tuberculosis, Nature Medicine, ISSN: 1546-170X
Tuberculosis is classically divided into states of latent infection and active disease. Usingcombined positron emission and computed tomography in 35 asymptomatic, antiretroviraltherapy naïve, HIV-1 infected adults with latent tuberculosis, we identified ten individualswith pulmonary abnormalities suggestive of subclinical, active disease who weresignificantly more likely to progress to clinical disease. Our findings challenge theconventional two-state paradigm and may aid future identification of biomarkers predictiveof progression.
Esmail H, Lai RP, Lesosky M, et al., 2016, Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography, Nature Medicine, Vol: 22, Pages: 1090-1093, ISSN: 1546-170X
Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.
Stek C, Schutz C, Blumenthal L, et al., 2016, Preventing Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in High-Risk Patients: Protocol of a Randomized Placebo-Controlled Trial of Prednisone (PredART Trial)., JMIR Research Protocols, Vol: 5, ISSN: 1929-0748
BACKGROUND: Early antiretroviral therapy (ART) initiation in patients diagnosed with HIV-associated tuberculosis (TB) reduces mortality among those with the lowest CD4 counts. At the same time, both early ART and a low CD4 count heighten the risk of paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). TB is common in patients starting ART in sub-Saharan Africa. Safe interventions that reduce the incidence or severity of TB-IRIS are needed. Prednisone has been shown to reduce symptoms and markers of inflammation when used to treat TB-IRIS. OBJECTIVE: To determine whether prophylactic prednisone in patients at high risk for paradoxical TB-IRIS initiating ART reduces the incidence of TB-IRIS. METHODS: We are conducting a randomized, double-blind, placebo-controlled trial of prophylactic prednisone (40 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks) initiated at the same time as ART in patients at high risk for TB-IRIS (starting ART within 30 days of TB treatment and CD4 count ≤100/μL). The primary endpoint is development of TB-IRIS, defined using an international consensus case definition. Secondary endpoints include time to TB-IRIS event, severity of TB-IRIS, quality of life, mortality, hospitalization, other infections and malignancies, and adverse events including corticosteroid adverse effects. RESULTS: Enrollment for the trial began in August 2013. All 240 participants have been enrolled, and safety follow-up will be completed in March 2017. CONCLUSION: No preventive strategies for TB-IRIS currently exist. If results of this trial demonstrate the efficacy and safety of prednisone, this will provide clinicians with an evidence-based preventive strategy in patients at high risk for paradoxical TB-IRIS when initiating ART.
Jacobs A, Mongkolsapaya J, Screaton GR, et al., 2016, Antibodies and tuberculosis, Tuberculosis, Vol: 101, Pages: 102-113, ISSN: 1873-281X
Tuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 milliondeaths worldwide in 2014. The Bacillus Calmette-Guérin vaccine is the only licensed vaccine against TB, but itsprotective effect does not extend to controlling the development of infectious pulmonary disease in adults. Thedevelopment of a more effective vaccine against TB is therefore a pressing need for global health. Although it isestablished that cell-mediated immunity is necessary for the control of latent infection, the presupposition that suchimmunity is sufficient for vaccine-induced protection has recently been challenged. A greater understanding ofprotective immunity against TB is required to guide future vaccine strategies against TB. In contrast to cell-mediatedimmunity, the human antibody response against M.tb is conventionally thought to exert little immune control over thecourse of infection. Humoral responses are prominent during active TB disease, and have even been postulated tocontribute to immunopathology. However, there is evidence to suggest that specific antibodies may limit thedissemination of M.tb, and potentially also play a role in prevention of infection via mucosal immunity. Further,antibodies are now understood to confer protection against a range of intracellular pathogens by modulating immunityvia Fc-receptor mediated phagocytosis. In this review, we will explore the evidence that antibody-mediated immunitycould be reconsidered in the search for new vaccine strategies against TB.
Riou C, Bunjun R, Müller TL, et al., 2016, Selective reduction of IFN-γ single positive mycobacteria-specific CD4+ T cells in HIV-1 infected individuals with latent tuberculosis infection, Tuberculosis, Vol: 101, Pages: 25-30, ISSN: 1873-281X
HIV-1 is recognized to increase the risk for tuberculosis even before CD4+ T cell deficiency is profound. To better understand how HIV-1 alters immunity to latent tuberculosis, we compared the magnitude and functional profile of mycobacteria-specific CD4+ T cells between HIV-uninfected and HIV-infected individuals, using flow cytometry. In HIV-1 infection, IFN-γ single positive mycobacteria-specific CD4+ T cells were decreased, while the frequency of polyfunctional cells (IFN-γ+IL-2+TNF-α+) remained unchanged. Moreover, the proportion of IFN-γ single positive cells correlated inversely with viral replication. Our results suggest that HIV-1 affects mycobacteria-specific cells differentially, depending on their functional capacity.
Rockwood N, Meintjes G, Chirewha M, et al., 2016, HIV-1 co-infection does not reduce exposure to rifampicin, isoniazid, and pyrazinamide in South African tuberculosis outpatients, Antimicrobial Agents and Chemotherapy, Vol: 60, Pages: 6050-6059, ISSN: 1098-6596
There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0–24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0–24. The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients.
Diedrich CR, O'Hern J, Gutierrez M, et al., 2016, Relationship between HIV-1 co-infection, IL-10, and M. tuberculosis in human lymph node granulomas, Journal of Infectious Diseases, Vol: 214, Pages: 1309-1318, ISSN: 1537-6613
Background. HIV-1 infected persons are more susceptible to tuberculosis (TB) than HIV-1-uninfected persons. Low peripheral (p)CD4 T cell count is not the sole cause of higher susceptibility because HIV-1 infected persons with high pCD4 and those prescribed successful anti-retroviral therapy (ART) remain more prone to active TB than HIV-1-uninfected persons. We hypothesized that the increase in susceptibility is caused by HIV-1's ability to manipulate the M. tuberculosis (Mtb) granuloma.Methods. We examined 71 excised cervical lymph nodes (LN) from HIV-1-TB-co-infected and singly-HIV-1 or TB-infected persons with a spectrum of pCD4 counts and ART status. We quantified differences in Mtb, HIVp24, cellular and cytokine presence.Results. HIV-1 increased Mtb bacillary numbers and reduced CD4 T cell counts within granulomas. pCD4 depletion correlated with granulomas that contained fewer CD4 and CD8 T cells, less IFN-gamma, more neutrophils, more IL-10 and increased Mtb bacilli. Mtb numbers correlated positively with IL-10 and IFN-alpha, and fewer CD4 and CD8 T cells. ART reduced IL-10 production.Conclusion. pCD4 depletion correlated with increased Mtb bacilli presence, IL-10 production, and other phenotypic changes within granulomas, demonstrating HIV-1 infection progressively changes these granulomas.
Riou C, Oni T, Gideon HP, et al., 2016, Activation profile of Mycobacterium tuberculosis-specific CD4+T cells reflects disease activity, irrespective of HIV status, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 1307-1310, ISSN: 1535-4970
Wilkinson RJ, Wilkinson KA, Oni T, et al., 2016, Activation profile of Mycobacterium tuberculosis-specific CD4+ T cells reflects disease activity, irrespective of HIV status, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 1307-1310, ISSN: 1535-4970
Scriven JE, Graham LM, Schutz C, et al., 2016, A Glucuronoxylomannan-Associated Immune Signature, Characterized by Monocyte Deactivation and an Increased Interleukin 10 Level, Is a Predictor of Death in Cryptococcal Meningitis., The Journal of infectious diseases, Vol: 213, Pages: 1725-1734, ISSN: 0022-1899
<h4>Background</h4>Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation.<h4>Methods</h4>A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis.<h4>Results</h4>Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan.<h4>Conclusions</h4>Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.
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Bangani N, Nakiwala J, Martineau AR, et al., 2016, HIV-1 infection impairs CD16 and CD35 mediated opsonophagocytosis of M.tuberculosis by human neutrophils., Journal of Acquired Immune Deficiency Syndromes, Vol: 73, Pages: 263-267, ISSN: 0894-9255
Using a flow cytometric assay we investigated neutrophil-M.tuberculosis opsonophagocytosis and the impact of HIV-1-infected serum on this process. The mean (±SD) percentage of neutrophils internalising bacilli after 30 minutes incubation was significantly reduced by pre-treatment with anti-CD16 (18.2±8.1%, p<0.001) or anti-CD35 antibody (23.2±10.6%, p<0.05) versus anti-CD4 controls (29.9±8.1%). Blocking CD88 or CD11a did not affect internalisation. Using heat-inactivated serum, maximal internalisation was lower using HIV-1-infected serum versus HIV-1-uninfected. Using non-heat-inactivated serum, internalisation decreased more rapidly with sequential dilutions of HIV-1-infected versus HIV-1-uninfected serum. CONCLUSIONS: CD16 and CD35 are important for neutrophil internalisation of M.tuberculosis while HIV-1 infection adversely affects opsonophagocytosis.
Sumner T, Houben RMGJ, Rangaka MX, et al., 2016, Post-treatment effect of isoniazid preventive therapy on tuberculosis incidence in HIV-infected individuals on antiretroviral therapy., AIDS (London, England), Vol: 30, Pages: 1279-1286, ISSN: 0269-9370
<h4>Background</h4>In HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV-infected/antiretroviral therapy (ART)-naive individuals, high TB rates have been observed following completion of IPT, consistent with a lack of 'cure' of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa, have suggested that the effect of IPT persisted following completion of IPT.<h4>Methods</h4>Using mathematical modelling, we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection and proportion of individuals whose latent infection was 'cured' by IPT, defined such that they must be reinfected to be at risk of disease.<h4>Results</h4>The estimated annual risk of infection was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent Mycobacterium tuberculosis infection was cured following IPT was 35.4% (2.4-76.4), higher than that previously estimated for HIV-infected/ART-naive individuals. Our results suggest that IPT can cure latent M. tuberculosis infection in approximately one-third of HIV-infected individuals on ART and therefore provide protection beyond the period of treatment.<h4>Conclusion</h4>Among HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long-term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited because of continued risk of reinfection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB.
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Zumla A, Rao M, Wallis RS, et al., 2016, Host-directed therapies for infectious diseases: current status, recent progress, and future prospects., Lancet Infectious Diseases, Vol: 16, Pages: e47-e63, ISSN: 1473-3099
Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen-host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.
Riou C, Strickland N, Soares AP, et al., 2016, HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells., Journal of immunology (Baltimore, Md. : 1950), Vol: 196, Pages: 3006-3018, ISSN: 0022-1767
HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets.
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Rockwood N, du Bruyn E, Morris T, et al., 2016, Assessment of treatment response in tuberculosis, Expert Review of Respiratory Medicine, Vol: 10, Pages: 643-654, ISSN: 1747-6348
Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.
Diedrich CR, O'Hern J, Wilkinson RJ, 2016, HIV-1 and the Mycobacterium tuberculosis granuloma: A systematic review and meta-analysis, Tuberculosis, Vol: 98, Pages: 62-76, ISSN: 1873-281X
Infection with HIV-1 greatly increases the risk of active tuberculosis (TB). Although hypotheses suggest HIV-1 disrupts Mycobacterium tuberculosis (Mtb) granuloma function, few studies have examined this directly. The objective of this study was to determine what evidence exists about the effect HIV-1 co-infection has upon Mtb granulomas. A systematic search of PubMed, Web of Science, and Medline up to 20 March 2015 was conducted, to identify studies comparing Mtb-infected tissue from HIV-1 infected and uninfected persons, or HIV-1 infected persons with stratified peripheral CD4 T cell (pCD4) counts. We summarized findings that focused on how HIV-1 changes granuloma formation, bacterial presence, cellular composition, and cytokine production. Nineteen studies with a combined sample size of 899 persons were included. Although studies frequently were limited by variable or inadequately described definitions of outcomes and analytical methods, HIV-1 was found to be associated with increased bacillary load within Mtb-infected tissue. Reductions in pCD4 counts within co-infected persons associated with both poorer granuloma formation and higher bacterial load. The high degree of heterogeneity among studies combined with experimental limitations made it difficult to conclusively support previously published and prevalent hypotheses about HIV-1/Mtb co-infection granulomas. To elucidate the validity of these hypotheses we have described areas that can be improved in future studies in order to clarify the influence HIV-1 co-infection has upon the Mtb granuloma.
Bahr NC, Marais S, Caws M, et al., 2016, GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last, Clinical Infectious Diseases, Vol: 62, Pages: 1133-1135, ISSN: 1537-6591
Lerner TR, Carvalho-Wodarz CDS, Repnik U, et al., 2016, Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis, Journal of Clinical Investigation, Vol: 126, Pages: 1093-1108, ISSN: 1558-8238
In extrapulmonary tuberculosis, the most common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for Mycobacterium tuberculosis in the lymph nodes of patients with tuberculosis. In cultured primary human LECs (hLECs), we determined that M. tuberculosis replicates both in the cytosol and within autophagosomes, but the bacteria failed to replicate when the virulence locus RD1 was deleted. Activation by IFN-γ induced a cell-autonomous response in hLECs via autophagy and NO production that restricted M. tuberculosis growth. Thus, depending on the activation status of LECs, autophagy can both promote and restrict replication. Together, these findings reveal a previously unrecognized role for hLECs and autophagy in tuberculosis pathogenesis and suggest that hLECs are a potential niche for M. tuberculosis that allows establishment of persistent infection in lymph nodes.
Marais S, Meintjes G, Lesosky M, et al., 2016, Interleukin-17 mediated differences in the pathogenesis of HIV-1-associated tuberculous and cryptococcal meningitis, AIDS, Vol: 30, Pages: 395-404, ISSN: 0269-9370
Objective: Mycobacterium tuberculosis and Cryptococcus neoformans are major causes of meningitis in HIV-1-infected patients. Identifying differences in the inflammatory profiles of HIV-1-associated tuberculous meningitis (TBM) and cryptococcal meningitis may inform differences in immunopathogenic mechanisms in these diseases. In this study we compared the clinical and inflammatory features of HIV-1-associated TBM, and cryptococcal meningitis.Methods: A prospective study of HIV-1-infected adults who presented with either TBM [antiretroviral therapy (ART)-naive] or cryptococcal meningitis (regardless of ART prescription). Clinical and laboratory findings and concentrations of 40 inflammatory mediators measured in cerebrospinal fluid (CSF, 33 paired with blood) were compared between TBM and cryptococcal meningitis patients regardless of ART prescription and between TBM and cryptococcal meningitis patients not receiving ART.Results: Clinical and laboratory findings were similar in TBM (n=34) and cryptococcal meningitis (n = 19; ART prescribed: n = 10, no ART prescribed: n = 9). Exceptions included a higher median CD4+ cell count [interquartile: 113 (69–199) vs. 25 (8–49) cells/µl, P = 0.0001] and higher HIV-1 median viral load [plasma: 5.46 (4.82–5.89) vs. 4.87 (4.36–5.17) log10copies/ml, P = 0.037; CSF: 6.05 (5.43–6.56) vs. 5.56 (4.52–5.80) log10copies/ml, P = 0.03] in TBM vs. cryptococcal meningitis patients not receiving ART. CSF interleukin (IL)-17A was lower in TBM compared with cryptococcal meningitis [1.00 (0.25–2.35) vs. 9.31 (1.24–23.36) pg/ml, P-adjusted = 0.03].Conclusion: Despite presenting with higher peripheral CD4+ cell counts, TBM patients also presented with higher HIV-1 viral loads compared with cryptococcal meningitis patients, suggesting a greater propensity of M. tuberculosis compared with C. neoformans to increase HIV-1 replication in vivo. CSF IL-17A was lower in TBM; its role in the immunopath
Scriven JE, Graham LM, Schutz C, et al., 2015, Flow cytometry to assess cerebrospinal fluid fungal burden in cryptococcal meningitis, Journal of Clinical Microbiology, Vol: 54, Pages: 802-804, ISSN: 1098-660X
Fungal burden in the cerebrospinal fluid is an important determinant of mortality in cryptococcal meningitis, but its use in aiding clinical decision making is hampered by the time involved to perform quantitative cultures. Here, we demonstrate the potential of flow cytometry as a novel and rapid technique to address this issue.
Subbarao S, Wilkinson KA, van Halsema CL, et al., 2015, Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa., Journal of Acquired Immune Deficiency Syndromes, Vol: 70, Pages: 406-413, ISSN: 0894-9255
INTRODUCTION: Case fatality among in-patients with HIV-associated tuberculosis (HIV-TB) in Africa is high. We investigated the factors associated with mortality in a rural South African hospital. METHODS: This was a prospective observational study of HIV-TB in-patients, with death by 8 weeks the endpoint. RESULTS: Of 99 patients (median CD4 count 72 cells/mm), 32 (32%) died after median 8-day TB treatment. TB was diagnosed microbiologically in 75/99 and clinico-radiologically in 24, with no mortality difference between these groups [31% versus 38% (P = 0.53)]. Median venous lactate was 5.5 mmol/L (interquartile range 3.9-6.2) in those who died and 3.1 mmol/L (interquartile range 2.2-4.1) in survivors (P < 0.001). In multivariable analysis, lactate ≥4 mmol/L [adjusted odds ratio (aOR) 9.8, 95% confidence interval (CI): 3.0 to 32.2], Glasgow Coma Score <15 (aOR 6.6, 95% CI: 1.5 to 29.6), CD4 count <50 cells per cubic millimeter (aOR 5.5, 95% CI: 1.6 to 18.5), and age ≥50 (aOR 7.7, 95% CI: 1.2 to 46.9) independently predicted death. In a nested case-control study, comparing those who died versus CD4-matched survivors, median plasma lipopolysaccharide concentrations were 93 and 57 pg/mL (P = 0.026) and intestinal fatty acid-binding protein, 132 and 0 pg/mL (P = 0.002). CONCLUSIONS: Mortality was high and predicted by elevated lactate, likely reflecting a sepsis-syndrome secondary to TB or bacterial coinfection with intestinal barrier dysfunction appearing to contribute.
Subbarao S, Wilkinson KA, van Halsema CL, et al., 2015, Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV-Associated TB in Rural South Africa, Journal of Acquired Immune Deficiency Syndromes, Vol: 70, Pages: 406-413, ISSN: 1944-7884
INTRODUCTION:Case fatality among in-patients with HIV-associated tuberculosis (HIV-TB) in Africa is high. We investigated the factors associated with mortality in a rural South African hospital.METHODS:This was a prospective observational study of HIV-TB in-patients, with death by 8 weeks the endpoint.RESULTS:Of 99 patients (median CD4 count 72 cells/mm³), 32 (32%) died after median 8-day TB treatment. TB was diagnosed microbiologically in 75/99 and clinico-radiologically in 24, with no mortality difference between these groups [31% versus 38% (P = 0.53)]. Median venous lactate was 5.5 mmol/L (interquartile range 3.9-6.2) in those who died and 3.1 mmol/L (interquartile range 2.2-4.1) in survivors (P < 0.001). In multivariable analysis, lactate ≥4 mmol/L [adjusted odds ratio (aOR) 9.8, 95% confidence interval (CI): 3.0 to 32.2], Glasgow Coma Score <15 (aOR 6.6, 95% CI: 1.5 to 29.6), CD4 count <50 cells per cubic millimeter (aOR 5.5, 95% CI: 1.6 to 18.5), and age ≥50 (aOR 7.7, 95% CI: 1.2 to 46.9) independently predicted death. In a nested case-control study, comparing those who died versus CD4-matched survivors, median plasma lipopolysaccharide concentrations were 93 and 57 pg/mL (P = 0.026) and intestinal fatty acid-binding protein, 132 and 0 pg/mL (P = 0.002).CONCLUSIONS:Mortality was high and predicted by elevated lactate, likely reflecting a sepsis-syndrome secondary to TB or bacterial coinfection with intestinal barrier dysfunction appearing to contribute.
Rockwood N, Wilkinson RJ, 2015, Understanding and intervening in HIV-associated tuberculosis., Clinical medicine (London, England), Vol: 15 Suppl 6, Pages: s43-s49, ISSN: 1470-2118
HIV-associated tuberculosis can present as extremes, ranging from acute life-threatening disseminated disease to occult asymptomatic infection. Both ends of this spectrum have distinct pathological correlates and require specific diagnostic and treatment approaches. Novel therapeutics, targeting both pathogen and host, are needed to augment pathogen clearance. In latent tuberculosis infection, enhancement of immune activation could be desirable. Antiretroviral therapy augments the beneficial effects of antitubercular therapy. However, in the context of high bacillary burden, antiretroviral therapy can also result in pathology (tuberculosis immune reconstitution inflammatory syndrome). In the immune reconstituting patient, modulation of immune activation controls tissue destruction. Interventions should also be appropriate and sustainable within the programmatic setting.
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Matthews K, Deffur A, Ntsekhe M, et al., 2015, A Compartmentalized Profibrotic Immune Response Characterizes Pericardial Tuberculosis, Irrespective of HIV-1 Infection., American journal of respiratory and critical care medicine, Vol: 192, Pages: 1518-1521, ISSN: 1073-449X
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Horvati K, Bosze S, Gideon HP, et al., 2015, Population tailored modification of tuberculosis specific interferon-gamma release assay, Journal of Infection, Vol: 72, Pages: 179-188, ISSN: 1532-2742
Zumla A, Maeurer M, Chakaya J, et al., 2015, Host-Directed Therapies for Tackling Multi-Drug Resistant Tuberculosis: Learning From the Pasteur-Bechamp Debates, CLINICAL INFECTIOUS DISEASES, Vol: 61, Pages: 1432-1438, ISSN: 1058-4838
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