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Find video protocols related to scientific articles indexed in Pubmed.
Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome.
PLoS Pathog.
PUBLISHED: 10-01-2014
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Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14(++)CD16(-) monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment.
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Rapid diagnosis of cryptococcal meningitis by use of lateral flow assay on cerebrospinal fluid samples: influence of the high-dose "hook" effect.
J. Clin. Microbiol.
PUBLISHED: 09-17-2014
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Cryptococcal meningitis is the most frequent cause of meningitis and a major cause of mortality in HIV-infected adults in Africa. This study evaluated the performance of the lateral flow assay (LFA) on cerebrospinal fluid (CSF) samples for the diagnosis of cryptococcal meningitis against that of existing diagnostic tests. LFA performed on 465 undiluted CSF samples had a sensitivity of 91%. When the LFA was paired with Gram staining, a sensitivity of 100% was achieved after implementation of a dilution step for samples with negative LFA results and the presence of yeasts on microscopy. Microscopy is essential for preventing the reporting of false-negative results due to the high-dose "hook" effect.
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Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome.
Clin. Infect. Dis.
PUBLISHED: 08-08-2014
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The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS.
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The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis.
Clin. Infect. Dis.
PUBLISHED: 07-23-2014
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Cryptococcal meningitis is the most common cause of adult meningitis in sub-Saharan Africa. Raised intracranial pressure (ICP) is common in cryptococcosis. Prior studies suggest elevated ICP is associated with mortality, and guidelines recommend frequent lumbar punctures (LPs) to control ICP. However, the magnitude of the impact of LPs on cryptococcal-related mortality is unknown.
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Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.
N. Engl. J. Med.
PUBLISHED: 06-26-2014
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Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome-related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.
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Very low levels of 25-hydroxyvitamin D are not associated with immunologic changes or clinical outcome in South African patients with HIV-associated cryptococcal meningitis.
Clin. Infect. Dis.
PUBLISHED: 05-13-2014
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Vitamin D deficiency is associated with impaired immune responses and increased susceptibility to a number of intracellular pathogens in individuals infected with human immunodeficiency virus (HIV). It is not known whether such an association exists with Cryptococcus neoformans.
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AIDS-related mycoses: the way forward.
Trends Microbiol.
PUBLISHED: 03-04-2014
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The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.
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A neglected epidemic: fungal infections in HIV/AIDS.
Trends Microbiol.
PUBLISHED: 01-02-2014
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Invasive fungal infections (IFIs) are a major cause of HIV-related mortality globally. Despite widespread rollout of combined antiretroviral therapy, there are still up to 1 million deaths annually from IFIs, accounting for 50% of all AIDS-related death. A historic failure to focus efforts on the IFIs that kill so many HIV patients has led to fundamental flaws in the management of advanced HIV infection. This review, based on the EMBO AIDS-Related Mycoses Workshop in Cape Town in July 2013, summarizes the current state of the-art in AIDS-related mycoses, and the key action points required to improve outcomes from these devastating infections.
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Management of drug-resistant TB in patients with HIV co-infection.
J Int AIDS Soc
PUBLISHED: 01-01-2014
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The World Health Organization estimates that 450,000 cases of drug-resistant (DR) tuberculosis (TB) occurred worldwide in 2012. In South Africa, over 15,000 cases were diagnosed. Over half of patients in South Africa with TB are HIV co-infected. The management of drug-resistant TB is complex, prolonged, costly, associated with multiple toxicities and thus difficult for patients to complete. Disengagement from follow-up is common. Co-infection with HIV presents a number of additional challenges in DR TB management including shared drug toxicities between TB and HIV drugs, potential for increased drug toxicity due to underlying HIV-related organ disease such as nephropathy, pharmacokinetic drug-drug interactions and immune reconstitution inflammatory syndrome including manifestations at extrapulmonary sites. Mortality with multi-drug-resistant (MDR) TB is higher in HIV-positive patients. Mortality is similar for HIV-positive and uninfected patients with extremely drug-resistant (XDR) TB, given the current lack of effective therapy, with over 70% case fatality by five years. ART improves survival in patients with DR TB, and timing of ART initiation in relation to TB treatment should be similar to patients with drug-susceptible TB. New (e.g. bedaquiline and delaminid) and repurposed (e.g. linezolid and clofazamine) drugs promise to improve the prognosis of patients with DR TB. Several clinical trials of new regimens are ongoing and planned, and early data from the Bedaquiline Clinical Access Programme in South Africa suggests much improved short-term outcomes when bedaquiline +/- linezolid and/or clofazamine are included in the regimen of patients with XDR and pre-XDR TB including patients with HIV co-infection. There are important considerations with respect to QT prolongation and ART drug interactions related to bedaquiline that need to be factored in treatment decisions and monitoring plans.
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Antiretroviral treatment outcomes amongst older adults in a large multicentre cohort in South Africa.
PLoS ONE
PUBLISHED: 01-01-2014
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Increasing numbers of patients are starting antiretroviral treatment (ART) at advanced age or reaching advanced age while on ART. We compared baseline characteristics and ART outcomes of older adults (aged ?55 years) vs. younger adults (aged 25-54 years) in routine care settings in South Africa.
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Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast.
Emerging Infect. Dis.
PUBLISHED: 01-01-2014
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Cryptococcal meningitis is common in sub-Saharan Africa. Given the need for data for a rapid, point-of-care cryptococcal antigen (CRAG) lateral flow immunochromatographic assay (LFA), we assessed diagnostic performance of cerebrospinal fluid (CSF) culture, CRAG latex agglutination, India ink microscopy, and CRAG LFA for 832 HIV-infected persons with suspected meningitis during 2006-2009 (n = 299) in Uganda and during 2010-2012 (n = 533) in Uganda and South Africa. CRAG LFA had the best performance (sensitivity 99.3%, specificity 99.1%). Culture sensitivity was dependent on CSF volume (82.4% for 10 ?L, 94.2% for 100 ?L). CRAG latex agglutination test sensitivity (97.0%-97.8%) and specificity (85.9%-100%) varied between manufacturers. India ink microscopy was 86% sensitive. Laser thermal contrast had 92% accuracy (R = 0.91, p<0.001) in quantifying CRAG titers from 1 LFA strip to within <1.5 dilutions of actual CRAG titers. CRAG LFA is a major advance for meningitis diagnostics in resource-limited settings.
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Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes.
Clin. Infect. Dis.
PUBLISHED: 12-06-2013
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Background.?Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes. Methods.?Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality. Results.?Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART). Conclusions.?CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
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Central nervous system immune reconstitution inflammatory syndrome.
Curr Infect Dis Rep
PUBLISHED: 11-01-2013
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Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS) develops in 9 %-47 % of persons with HIV infection and a CNS opportunistic infection who start antiretroviral therapy and is associated with a mortality rate of 13 %-75 %. These rates vary according to the causative pathogen. Common CNS-IRIS events occur in relation to Cryptococcus, tuberculosis (TB), and JC virus, but several other mycobacteria, fungi, and viruses have been associated with IRIS. IRIS symptoms often mimic the original infection, and diagnosis necessitates consideration of treatment failure, microbial resistance, and an additional neurological infection. These diagnostic challenges often delay IRIS diagnosis and treatment. Corticosteroids have been used to treat CNS-IRIS, with variable responses; the best supportive evidence exists for the treatment of TB-IRIS. Pathogenic mechanisms vary: Cryptococcal IRIS is characterized by a paucity of cerebrospinal inflammation prior to antiretroviral therapy, whereas higher levels of inflammatory markers at baseline predispose to TB meningitis IRIS. This review focuses on advances in the understanding of CNS-IRIS over the past 2 years.
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A dimorphic fungus causing disseminated infection in South Africa.
N. Engl. J. Med.
PUBLISHED: 10-11-2013
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The genus emmonsia contains three species that are associated with human disease. Emmonsia crescens and Emmonsia parva are the agents that cause adiaspiromycosis, and one human case of Emmonsia pasteuriana infection has been described. We report a fungal pathogen within the genus emmonsia that is most closely related to E. pasteuriana in human immunodeficiency virus (HIV)-infected adults in South Africa.
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Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review.
BMC Med
PUBLISHED: 09-03-2013
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The HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
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Procollagen III N-terminal propeptide and desmosine are released by matrix destruction in pulmonary tuberculosis.
J. Infect. Dis.
PUBLISHED: 08-06-2013
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Tuberculosis is transmitted by patients with pulmonary disease. Matrix metalloproteinases (MMPs) drive lung destruction in tuberculosis but the resulting matrix degradation products (MDPs) have not been studied. We investigate the hypothesis that MMP activity generates matrix turnover products as correlates of lung pathology.
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HIV-1 and the immune response to TB.
Future Virol
PUBLISHED: 05-09-2013
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TB causes 1.4 million deaths annually. HIV-1 infection is the strongest risk factor for TB. The characteristic immunological effect of HIV is on CD4 cell count. However, the risk of TB is elevated in HIV-1 infected individuals even in the first few years after HIV acquisition and also after CD4 cell counts are restored with antiretroviral therapy. In this review, we examine features of the immune response to TB and how this is affected by HIV-1 infection and vice versa. We discuss how the immunology of HIV-TB coinfection impacts on the clinical presentation and diagnosis of TB, and how antiretroviral therapy affects the immune response to TB, including the development of TB immune reconstitution inflammatory syndrome. We highlight important areas of uncertainty and future research needs.
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The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome.
Eur. J. Immunol.
PUBLISHED: 04-19-2013
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HIV-1 patients co-infected with some pathogens are at risk of developing the immune reconstitution inflammatory syndrome (IRIS) when initiating antiretroviral therapy (ART). IRIS is characterized by inflammation leading to the clinical worsening of a treated infection or the unmasking of a previously undiagnosed condition or infection. It is commonly associated with tuberculosis (TB), 8-43% of the HIV-TB co-infected patients prescribed with antitubercular treatment and ART develop TB-IRIS. Although IRIS has been recognized for over 20 years, relatively little was known until recently about its pathogenesis. Despite these advances in understanding IRIS, there remains no immune biomarker for diagnostic or prognostic purposes. Here, we review the risk factors associated with TB-IRIS, the challenges in studying this syndrome, and how T lymphocytes, dysregulated cytokine responses, and innate immunity may contribute to the development of TB-IRIS.
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Matrix metalloproteinases and tissue damage in HIV-tuberculosis immune reconstitution inflammatory syndrome.
Eur. J. Immunol.
PUBLISHED: 04-04-2013
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The HIV-TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) can complicate combined treatments for HIV-1 and TB. Little is known about tissue damage in TB-IRIS. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix and consequently may play a role in such immunopathology. Here we investigated the involvement of MMPs in TB-IRIS. We determined MMP transcript abundance and secreted protein in Mycobacterium tuberculosis stimulated PBMCs from 22 TB-IRIS patients and 22 non-IRIS controls. We also measured MMP protein levels in corresponding serum and the effect of prednisone - which reduces the duration of symptoms in IRIS patients - or placebo treatment on MMP transcript and circulating MMP protein levels. PBMCs from TB-IRIS had increased MMP-1, -3, -7, and -10 transcript levels when compared with those of controls at either 6 or 24 h. Similarly, MMP-1, -3, -7, and -10 protein secretion in stimulated cultures was higher in TB-IRIS than in controls. Serum MMP-7 concentration was elevated in TB-IRIS and 2 weeks of corticosteroid therapy decreased this level, although not significantly. TB-IRIS is associated with a distinct pattern of MMP gene and protein activation. Modulation of dysregulated MMP activity may represent a novel therapeutic approach to alleviate TB-IRIS in HIV-TB patients undergoing treatment.
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The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis.
J. Infect. Dis.
PUBLISHED: 03-14-2013
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Correlates of immune protection in patients with human immunodeficiency virus (HIV)-associated cryptococcal meningitis are poorly defined. A clearer understanding of these immune responses is essential to inform rational development of immunotherapies.
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Management of tuberculosis and latent tuberculosis infection in human immunodeficiency virus-infected persons.
Respirology
PUBLISHED: 03-08-2013
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The syndemic of human immunodeficiency virus (HIV)/tuberculosis (TB) co-infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics. The situation is particularly worrisome in countries with high or intermediate TB burden against the background of a variable HIV epidemic state. Early diagnosis of TB disease in an HIV-infected person is paramount but suffers from lack of sensitive and specific diagnostic tools. Enhanced symptom screening is currently advocated, and the wide application of affordable molecular diagnostics is urgently needed. Treatment of TB/HIV co-infection involves the concurrent use of standard antiretrovirals and antimycobacterials during which harmful drug interaction may occur. The pharmacokinetic interaction between rifamycin and antiretrovirals is a case in point, requiring dosage adjustment and preferential use of rifabutin, if available. Early initiation of antiretroviral therapy is indicated, preferably at 2 weeks after starting TB treatment for patients with a CD4 of <50 cells/?L. Development of TB-immune reconstitution inflammatory syndrome (TB-IRIS) is however more frequent with early antiretroviral therapy. The diagnosis of TB-IRIS is another clinical challenge, and cautious use of corticosteroids is suggested to improve clinical outcome. As a preventive measure against active TB disease, the screening for latent TB infection should be widely practiced, followed by at least 6-9 months of isoniazid treatment. To date tuberculin skin test remains the only diagnostic tool in high TB burden countries. The role of alternative tests, for example, interferon-? release assay, would need to be better defined for clinical application.
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Complications of antiretroviral therapy initiation in hospitalised patients with HIV-associated tuberculosis.
PLoS ONE
PUBLISHED: 02-08-2013
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HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.
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Role of the interleukin 10 family of cytokines in patients with immune reconstitution inflammatory syndrome associated with HIV infection and tuberculosis.
J. Infect. Dis.
PUBLISHED: 01-09-2013
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The interleukin 10 (IL-10) family comprises cytokines structurally related to IL-10 that share signaling receptors that have conserved signaling cascades. The immunopathogenesis of immune reconstitution inflammatory syndrome (IRIS) in patients with human immunodeficiency virus (HIV) infection and tuberculosis remains incompletely understood. We hypothesized that a deficiency of IL-10 and its homologs may contribute to the immunopathology of IRIS in these patients.
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Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa.
PLoS ONE
PUBLISHED: 01-01-2013
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Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM.
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Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis.
Clin. Infect. Dis.
PUBLISHED: 11-03-2011
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HIV-associated cryptococcal meningitis is associated with an estimated 600 000 deaths worldwide per year. Current standard initial therapy consists of amphotericin B (AmB) plus flucytosine (5-FC), but 5-FC remains largely unavailable in Asia and Africa. Alternative, more widely available, and/or more effective antifungal combination treatment regimens are urgently needed.
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Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis.
Clin. Infect. Dis.
PUBLISHED: 09-21-2011
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Many deaths from cryptococcal meningitis (CM) may be preventable through early diagnosis and treatment. An inexpensive point-of-care (POC) assay for use with urine or a drop of blood would facilitate early diagnosis of cryptococcal infection in resource-limited settings. We compared cryptococcal antigen (CRAG) concentrations in plasma, serum, and urine from patients with CM, using an antigen-capture assay for glucuronoxylomannan (GXM) and a novel POC dipstick test.
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Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.
Expert Rev Anti Infect Ther
PUBLISHED: 04-21-2011
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The risks of unmasking and paradoxical forms of immune reconstitution disease in HIV-infected patients starting antiretroviral therapy (ART) are fuelled by a combination of the late presentation of patients with advanced immunodeficiency, the associated high rates of opportunistic infections (OIs) and the need for rapid initiation of ART to minimize overall mortality risk. We review the risk factors and our current knowledge of the immunopathogenesis of immune reconstitution disease, leading to a discussion of strategies for prevention. Initiation of ART at higher CD4 counts, use of OI-preventive therapies prior to ART eligibility, intensified screening for OIs prior to ART initiation and optimum therapy for OIs are all needed. In addition, use of a range of pharmacological agents with immunosuppressive and immunomodulatory activity is being explored.
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Barriers to initiation of antiretrovirals during antituberculosis therapy in Africa.
PLoS ONE
PUBLISHED: 04-08-2011
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In the developing world, the principal cause of death among HIV-infected patients is tuberculosis (TB). The initiation of antiretroviral therapy (ART) during TB therapy significantly improves survival, however it is not known which barriers prevent eligible TB patients from initiating life-saving ART.
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Pulmonary manifestations of the immune reconstitution inflammatory syndrome.
Curr Opin Pulm Med
PUBLISHED: 02-25-2011
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Immune reconstitution inflammatory syndrome (IRIS) is a common occurrence in HIV patients starting antiretroviral therapy (ART), and pulmonary involvement is an important feature of tuberculosis-IRIS and pneumocystis-IRIS. Pulmonologists need an awareness of the timing, presentation and treatment of pulmonary IRIS.
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Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting.
PLoS ONE
PUBLISHED: 01-11-2011
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Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.
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Central nervous system disorders after starting antiretroviral therapy in South Africa.
AIDS
PUBLISHED: 11-04-2010
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To describe the spectrum of central nervous system (CNS) disease during the first year of antiretroviral therapy (ART) and to determine the contribution of neurological immune reconstitution inflammatory syndrome (IRIS).
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Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions.
Lancet Infect Dis
PUBLISHED: 10-30-2010
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Cryptococcal immune reconstitution inflammatory syndrome (IRIS) may present as a clinical worsening or new presentation of cryptococcal disease after initiation of antiretroviral therapy (ART), and is thought to be caused by recovery of cryptococcus-specific immune responses. We have reviewed reports of cryptococcal IRIS and have developed a consensus case definition specifically for paradoxical crytopcoccal IRIS in patients with HIV-1 and known cryptococcal disease before ART, and a separate definition for incident cryptococcosis developed during ART (termed ART-associated cryptococcosis), for which a proportion of cases are likely to be unmasking cryptococcal IRIS. These structured case definitions are intended to aid design of future clinical, epidemiological, and immunopathological studies of cryptococcal IRIS, to standardise diagnostic criteria, and to facilitate comparisons between studies. As for definitions of tuberculosis-associated IRIS, definitions for cryptococcal IRIS should be regarded as preliminary until further insights into the immunopathology of IRIS permit their refinement.
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Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.
AIDS
PUBLISHED: 09-03-2010
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Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4-week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events.
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Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: the role of inadequate secondary prophylaxis.
S. Afr. Med. J.
PUBLISHED: 06-08-2010
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Cryptococcal meningitis is the commonest cause of adult meningitis in Southern Africa. A sizeable proportion of this disease burden is thought to be due to symptomatic relapse of previously treated infection. We carried out a study to examine the contribution of inadequate secondary fluconazole prophylaxis to symptomatic relapses of cryptococcal meningitis.
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Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines.
PLoS Pathog.
PUBLISHED: 04-22-2010
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M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD) 11 (Rv2658C and Rv2659c), and one RD2 (Rv1986) absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-? response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61-80 and 161-180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains.
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Clinical deterioration during antituberculosis treatment in Africa: incidence, causes and risk factors.
BMC Infect. Dis.
PUBLISHED: 03-30-2010
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HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration.
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Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases.
BMC Infect. Dis.
PUBLISHED: 03-15-2010
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The presentation and causes of adult meningitis in South Africa have changed substantially as a result of HIV. Knowledge of aetiology and laboratory findings in patients presenting with meningitis are important in guiding management. We performed a retrospective study to determine these findings in a setting of high HIV and TB prevalence in Cape Town.
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Pulmonary cryptococcosis misdiagnosed as smear-negative pulmonary tuberculosis with fatal consequences.
Int. J. Infect. Dis.
PUBLISHED: 02-25-2010
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HIV-associated pulmonary cryptococcosis is under diagnosed, and may progress to fatal meningoencephalitis. We present a case of HIV-associated pulmonary Cryptococcus neoformans infection, initially mis-diagnosed as smear-negative pulmonary TB, which progressed to fatal cryptococcal meningitis. Autopsy series suggest that pulmonary cryptococcosis is common in African AIDS patients, and, due to limited diagnostic capacity, often mis-diagnosed as smear negative TB. Serum cryptococcal antigen testing may facilitate diagnosis in such cases.
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Reduced referral and case fatality rates for severe symptomatic hyperlactataemia in a South African public sector antiretroviral programme: a retrospective observational study.
AIDS Res Ther
PUBLISHED: 01-12-2010
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Interventions to promote prevention and earlier diagnosis of severe symptomatic hyperlactataemia (SHL) were implemented in the Western Cape provincial antiretroviral programme (South Africa) from 2004. Interventions included clinician education, point-of-care lactate meters, switch from stavudine to zidovudine in high risk patients and stavudine dose reduction. This study assessed trends in referral rate, severity at presentation and case fatality rate for severe SHL.
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Management of individuals requiring antiretroviral therapy and TB treatment.
Curr Opin HIV AIDS
PUBLISHED: 01-05-2010
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Globally, tuberculosis (TB) is the commonest opportunistic infection in people living with HIV. Many co-infected patients first present with advanced immunosuppression and require antiretroviral therapy (ART) initiation during TB treatment. The incidence of TB in patients established on ART remains high. Co-treatment presents several management challenges. Recent data on these management issues are reviewed.
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Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy.
Clin. Chest Med.
PUBLISHED: 11-21-2009
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The tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent early complication of antiretroviral therapy (ART), used to treat HIV-1 infection, especially in countries where TB is prevalent. TB-IRIS is characterized by an exaggerated inflammatory response toward the antigens of Mycobacterium tuberculosis that results in clinical deterioration in patients experiencing immune recovery during early ART. Two forms of TB-IRIS are recognized: paradoxical; and unmasking. Paradoxical TB-IRIS manifests with new or recurrent TB symptoms or signs in patients being treated for TB during early ART, and unmasking TB-IRIS is characterized by an exaggerated, unusually inflammatory initial presentation of TB during early ART. In this review the incidence, clinical features, risk factors, treatment, and prevention of TB-IRIS in adult and pediatric patients are discussed.
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Dissection of regenerating T-Cell responses against tuberculosis in HIV-infected adults sensitized by Mycobacterium tuberculosis.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 07-23-2009
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Combination antiretroviral treatment (cART) reduces the risk of tuberculosis in HIV-infected people. Therefore a novel approach to gain insight into protection against tuberculosis is to analyze the T cells that expand in people sensitized by Mycobacterium tuberculosis (MTB) during cART.
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Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients.
Clin. Infect. Dis.
PUBLISHED: 07-21-2009
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Progress in therapy for cryptococcal meningitis has been slow because of the lack of a suitable marker of treatment response. Previously, we demonstrated the statistical power of a novel endpoint, the rate of clearance of infection, based on serial quantitative cultures of cerebrospinal fluid, to differentiate the fungicidal activity of alternative antifungal drug regimens. We hypothesized that the rate of clearance of infection should also be a clinically meaningful endpoint.
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Management of patients with the immune reconstitution inflammatory syndrome.
Curr HIV/AIDS Rep
PUBLISHED: 07-11-2009
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A significant proportion of patients present with the immune reconstitution inflammatory syndrome (IRIS) after commencing antiretroviral therapy (ART). This syndrome is most frequently associated with infective causes. The lack of evidence-based treatment guidelines poses challenges in the management of these patients. Alternative causes for deterioration should be excluded, and optimization of treatment for the underlying opportunistic infection is essential. In addition, anti-inflammatory or immunomodulatory therapy may be considered, particularly in severe cases. Corticosteroids, the only treatment for which clinical trial data exist (for treating paradoxical tuberculosis-associated IRIS), are the treatment most frequently used in IRIS. Limited anecdotal reports of benefit exist for other agents, including NSAIDs, pentoxifylline, montelukast, thalidomide, and hydroxychloroquine. Therapeutic procedures (eg, aspiration of pus collections) play an important role in some patients. Interruption of ART may be considered in life-threatening forms of IRIS.
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Clinical and financial burdens of secondary level care in a public sector antiretroviral roll-out setting (G. F. Jooste Hospital).
S. Afr. Med. J.
PUBLISHED: 07-11-2009
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Antiretroviral therapy (ART) is being extended across South Africa. While efforts have been made to assess the costs of providing ART via accredited service points, little information is available on its downstream costs, particularly in public secondary level hospitals.
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Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series.
Clin. Infect. Dis.
PUBLISHED: 05-02-2009
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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.
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Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 04-15-2009
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Prospective data on incidence, characteristics, and risk factors for cryptococcal meningitis immune reconstitution inflammatory syndrome (CM-IRIS) are lacking.
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Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures.
AIDS
PUBLISHED: 03-13-2009
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To assess impact of serial lumbar punctures on association between cerebrospinal fluid (CSF) opening pressure and prognosis in HIV-associated cryptococcal meningitis; to explore time course and relationship of opening pressure with neurological findings, CSF fungal burden, immune response, and CD4 cell count.
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Early severe morbidity and resource utilization in South African adults on antiretroviral therapy.
BMC Infect. Dis.
PUBLISHED: 02-10-2009
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High rates of mortality and morbidity have been described in sub-Saharan African patients within the first few months of starting highly active antiretroviral therapy (HAART). There is limited data on the causes of early morbidity on HAART and the associated resource utilization.
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Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance.
Clin. Infect. Dis.
PUBLISHED: 02-05-2009
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Tuberculosis (TB) immune reconstitution inflammatory syndrome (IRIS) is emerging as an important early complication of combination antiretroviral therapy in patients with TB in developing countries. The differential diagnosis of TB IRIS includes deterioration caused by other human immunodeficiency virus-related morbidities and drug-resistant TB.
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Clinical deterioration during antitubercular treatment at a district hospital in South Africa: the importance of drug resistance and AIDS defining illnesses.
PLoS ONE
PUBLISHED: 01-13-2009
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Clinical deterioration on drug therapy for tuberculosis is a common cause of hospital admission in Africa. Potential causes for clinical deterioration in settings of high HIV-1 prevalence include drug resistant Mycobacterium tuberculosis (M.tb), co-morbid illnesses, poor adherence to therapy, tuberculosis associated-immune reconstitution inflammatory syndrome (TB-IRIS) and subtherapeutic antitubercular drug levels. It is important to derive a rapid diagnostic work-up to determine the cause of clinical deterioration as well as specific management to prevent further clinical deterioration and death. We undertook this study among tuberculosis (TB) patients referred to an adult district level hospital situated in a high HIV-1 prevalence setting to determine the frequency, reasons and outcome for such clinical deterioration.
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Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome.
Clin. Infect. Dis.
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Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART.
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Altered ratio of IFN-?/IL-10 in patients with drug resistant Mycobacterium tuberculosis and HIV- Tuberculosis Immune Reconstitution Inflammatory Syndrome.
PLoS ONE
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We have described a clinical relationship between HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and anti-tubercular drug resistance. Here we studied the immune response of TB-IRIS patients from whom a drug-resistant (n = 11) or drug-susceptible (n = 25) Mycobacterium tuberculosis (MTB) strain was isolated after presenting with TB-IRIS. ELISpot analysis and multiplex cytokine analysis of the supernatant collected from peripheral blood mononuclear cells stimulated overnight with the heat-killed H37Rv MTB laboratory strain was used. Although there was no statistical difference in IFN-gamma ELISpot responses between the two groups, the results point towards higher bacterial load in the drug-resistant patients, possibly due to failed therapy. The ratio between secreted IFN-gamma/IL-10 and IL-2/IL-10 was significantly lower in TB-IRIS patients in whom the cause of TB was a drug-resistant strain compared to those with a fully sensitive strain (p = 0.02). Since host immune responses are dependent on the bacterial load, we hypothesise that the impaired cytokine balance is likely to be caused by the poorly controlled bacterial growth in these patients.
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Cryptococcal antigen screening and preemptive therapy in patients initiating antiretroviral therapy in resource-limited settings: a proposed algorithm for clinical implementation.
J Int Assoc Physicians AIDS Care (Chic)
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HIV-associated cryptococcal meningitis (CM) is estimated to cause over half a million deaths annually in Africa. Many of these deaths are preventable. Screening patients for subclinical cryptococcal infection at the time of entry into antiretroviral therapy programs using cryptococcal antigen (CRAG) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with "preemptive" therapy to prevent the development of severe disease. Such CRAG screening programs are currently being implemented in a number of countries; however, a strong evidence base and clear guidance on how to manage patients with subclinical cryptococcal infection identified by screening are lacking. We review the available evidence and propose a treatment algorithm for the management of patients with asymptomatic cryptococcal antigenemia.
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Immune reconstitution inflammatory syndrome in a large multicenter cohort study: case definition and comparability.
Expert Rev Anti Infect Ther
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This study was nested within the HIV Outpatient Study cohort and investigated the incidence and risk factors for immune reconstitution inflammatory syndrome (IRIS) and the impact of IRIS on mortality. IRIS was defined as a new type B or C AIDS-defining condition or one of a range of mucocutaneous or autoimmune conditions diagnosed within 180 days of starting a new combination antiretroviral therapy regimen, provided there was a documented HIV viral load or CD4 response. IRIS occurred in 10.6% of the 2610 patients. Risk factors independently associated with IRIS included high HIV viral load and low CD4 count. IRIS related to type B or C AIDS-defining conditions was associated with subsequent mortality. Deaths among IRIS cases occurred over 3 years (median) after the IRIS event, making it unlikely that these deaths were directly attributable to IRIS. The IRIS case definition used has important differences when compared with previously published IRIS case definitions thereby affecting comparability of these findings, but this was a pragmatic definition for a large multicenter cohort study utilizing a central database.
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Failure to eradicate Isospora belli diarrhoea despite immune reconstitution in adults with HIV--a case series.
PLoS ONE
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Isospora belli causes diarrhoea in patients with AIDS. Most respond to targeted therapy and recommendations are that secondary prophylaxis can be stopped following immune reconstitution with ART. We report eight cases of chronic isosporiasis that persisted despite standard antimicrobial therapy, secondary prophylaxis, and good immunological and virological response to ART. Median CD4 nadir was 175.5 cells/mm(3) and median highest CD4 while symptomatic was 373 cells/mm(3). Overall 34% of stool samples and 63% of duodenal biopsy specimens were positive for oocytes. Four patients died, two remain symptomatic and two recovered. Possible explanations for persistence of symptoms include host factors such as antigen specific immune deficiency or generalised reduction in gut immunity. Parasite factors may include accumulating resistance to co-trimoxazole. Research is required to determine the optimum dose and duration of co-trimoxazole therapy and whether dual therapy may be necessary. Mortality was high and pending more data we recommend extended treatment with high-dose co-trimoxazole in similar cases.
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Improved survival and antiretroviral treatment outcomes in adults receiving community-based adherence support: 5-year results from a multicentre cohort study in South Africa.
J. Acquir. Immune Defic. Syndr.
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A large increase in lay health care workers has occurred in response to shortages of professional health care staff in sub-Saharan African antiretroviral treatment (ART) programs. However, little effectiveness data of the large-scale implementation of these programs is available. We evaluated the effect of a community-based adherence-support (CBAS) program on ART outcomes across 57 South African sites.
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Management of the immune reconstitution inflammatory syndrome.
Curr HIV/AIDS Rep
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The immune reconstitution inflammatory syndrome (IRIS) is a frequent early complication of antiretroviral therapy (ART) in patients with advanced HIV. Because there is no confirmatory diagnostic test, the diagnosis is based on clinical presentation and exclusion of alternative causes for deterioration, such as antimicrobial drug resistance. Opportunistic infection treatment should be optimized. Mild cases may require symptomatic therapy alone or nonsteroidal anti-inflammatory drugs. Corticosteroids have been used to treat more severe cases of IRIS associated with mycobacterial and fungal infections. There is evidence from a randomized controlled trial that prednisone reduces morbidity and improves symptoms in paradoxical tuberculosis (TB)-IRIS. Neurological TB-IRIS is potentially life-threatening; high-dose corticosteroids are indicated and ART interruption should be considered if level of consciousness is depressed. When considering corticosteroid treatment clinicians should be aware of their side effects and only use them when the diagnosis of IRIS is certain. In viral forms of IRIS corticosteroids are generally avoided.
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Assessment at antiretroviral clinics during TB treatment reduces loss to follow-up among HIV-infected patients.
PLoS ONE
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A South African township clinic where loss to follow-up during TB treatment may prevent HIV-infected TB patients from receiving life-saving ART.
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Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome.
Clin. Infect. Dis.
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Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients.
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Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome.
Am. J. Respir. Crit. Care Med.
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HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear.
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Reducing deaths from tuberculosis in antiretroviral treatment programmes in sub-Saharan Africa.
AIDS
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Mortality rates are high in antiretroviral therapy (ART) programmes in sub-Saharan Africa, especially during the first few months of treatment. Tuberculosis (TB) has been identified as a major underlying cause. Under routine programme conditions, between 5 and 40% of adult patients enrolling in ART services have a baseline diagnosis of TB. There is also a high TB incidence during the first few months of ART (much of which is prevalent disease missed by baseline screening) and long-term rates remain several-folds higher than background. We identify three groups of patients entering ART programmes for which different interventions are required to reduce TB-related deaths. First, diagnostic screening is needed in patients who have undiagnosed active TB so that timely anti-TB treatment can be started. This may be greatly facilitated by new diagnostic assays such as the Xpert MTB/RIF assay. Second, patients with a diagnosis of active TB need optimized case management, which includes early initiation of ART (with timing now defined by randomized controlled trials), trimethoprim-sulphamethoxazole prophylaxis and treatment of comorbidity. Third, all remaining patients who are TB-free at enrolment have high ongoing risk of developing TB and require preventive interventions, including optimized immune recovery (with ART ideally started early in the course of HIV infection), isoniazid preventive therapy and infection control to reduce infection risk. Further specific measures are needed to address multidrug-resistant TB (MDR-TB). Finally, scale-up of all these interventions requires nationally and locally tailored models of care that are patient-centred and provide integrated healthcare delivery for TB, HIV and other comorbidities.
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Immunological characterisation of an unmasking TB-IRIS case.
S. Afr. Med. J.
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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an early complication of combination antiretroviral therapy (cART). Two forms are recognised: (i) paradoxical - recurrent or new TB symptoms develop after cART initiation in patients receiving TB treatment prior to cART; and (ii) unmasking TB-IRIS - active TB presents within 3 months of cART in patients not receiving TB treatment at cART initiation. The latter has heightened clinical manifestations and a marked inflammatory presentation.
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Burden of antituberculosis and antiretroviral drug-induced liver injury at a secondary hospital in South Africa.
S. Afr. Med. J.
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G F Jooste Hospital (GFJH) is a secondary-level referral hospital in a high HIV and tuberculosis (TB) co-infection setting.
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Heart failure and cardiogenic shock associated with the TB-immune reconstitution inflammatory syndrome.
Cardiovasc J Afr
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Heart failure has not been described in the setting of TB-immune reconstitution inflammatory syndrome (IRIS). We describe a case of cardiogenic shock in the setting of TB-IRIS four weeks after commencement of antiretroviral therapy. Possible aetiologies and pathophysiology as well as suggested diagnostic and therapeutic approaches to this problem are discussed.
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The value of blood culture audits at peripheral hospitals.
S. Afr. Med. J.
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Knowledge of local antibiotic sensitivities is crucial to creating appropriate empiric antibiotic guidelines. The new National Health Laboratory Service (NHLS) Data Warehouse allows clinicians to access collated spreadsheets of culture isolates and antimicrobial susceptibility patterns for their facilities. We used this service to study the trends in blood culture (BC) results at GF Jooste Hospital from 2005 to 2010. We investigated the BC contamination rate and changes in the antibiotic sensitivity profiles of selected organisms, and estimated the proportion of infections that were hospital-acquired. Over 3000 BCs were performed per year in this period. A very high contamination rate was observed (7 - 9%) in 2005 - 2007, with a gratifying reduction by 2010. Ceftriaxone resistance increased from 16% to 62% in Klebsiella pneumoniae (p<0.0001), and from 33% to 100% in Enterobacter spp. (p=0.053).
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Adjunctive interferon-? immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial.
AIDS
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Interferon-gamma (IFN?) is of key importance in the immune response to Cryptococcus neoformans. Mortality related to cryptococcal meningitis remains high, and novel treatment strategies are needed. We performed a randomized controlled trial to determine whether addition of IFN? to standard therapy increased the rate of clearance of cryptococcal infection in HIV-associated cryptococcal meningitis.
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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases.
Am. J. Respir. Crit. Care Med.
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Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced, but underlying mechanisms are poorly defined and no current antituberculous therapy reduces host tissue damage.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.