A nurse-based algorithm for earlier diagnosis of smear-negative pulmonary tuberculosis in HIV-infected adults in Lesotho

Cape Town TB Conferenc

Treatment of Tuberculous Meningitis and Its Complications in Adults.

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is a global health problem. In this review, we systematically evaluate the evidence for current and emerging antimicrobials, host-directed therapies and supportive managements. RECENT FINDINGS: Current antimicrobial regimes do not factor the differing ability of drugs to cross the blood-brain barrier. Rifampicin may be more effective at higher doses yet the most recent clinical trial failed to demonstrate survival benefit at 15 mg/kg/day. Dose finding studies suggest that higher doses still may be safe and more effective. Fluoroquinolones are currently listed as important second-line agents in drug-resistant TBM; however, a survival benefit as a first-line agent has yet to be shown. Linezolid may be a promising antimicrobial with good central nervous system penetrance. Dexamethasone reduces mortality in HIV-uninfected individuals yet evidence for its use in HIV co-infection is lacking. Aspirin has anti-inflammatory and anti-thrombotic properties. Small studies have demonstrated efficacy in reducing stroke but further research is required to better understand its effect on controlling the host inflammatory response. Discovery of genetic polymorphisms may direct individualized immune therapies and mediators of the innate immune response may provide targets for the development of novel therapies. There is at present no significant evidence base to guide management of hydrocephalus in HIV co-infection. Further clinical trial data is required to improve treatment outcomes in TBM in particularly in regard to the value of high-dose rifampicin, newer antimicrobials with improved central nervous system penetration and host-directed therapies. Supportive measures in particular the management of hydrocephalus in HIV co-infection should be an area for future research

On the mass transfer in AE Aquarii

The observed properties of the close binary AE Aqr indicate that the mass transfer in this system operates via the Roche lobe overflow mechanism, but the material transferred from the normal companion is neither accreted onto the surface of the white dwarf nor stored in a disk around its magnetosphere. As previously shown, such a situation can be realized if the white dwarf operates as a propeller. At the same time, the efficiency of the propeller action by the white dwarf is insufficient to explain the rapid braking of the white dwarf, which implies that the spin-down power is in excess of the bolometric luminosity of the system. To avoid this problem we have simulated the mass-transfer process in AE Aqr assuming that the observed braking of the white dwarf is governed by a pulsar-like spin-down mechanism. We show that the expected H_alpha Doppler tomogram in this case resembles the tomogram observed from the system. We find that the agreement between the simulated and the observed tomograms is rather good provided the mean value of the mass-transfer rate ~5x10^16 g/s. Three spatially separated sources of H_alpha emission can be distinguished within this approach. The structure of the tomogram depends on the relative contributions of these sources to the H_alpha emission and is expected to vary from night to night.Comment: 12 pages, 3 figures (6 eps files). Published in A&A. The paper with high resolution images can be downloaded from http://urania.it.nuigalway.ie/papers/ae_aqr.ps.g

HIV-1 co-infection does not reduce exposure to rifampicin, isoniazid, and pyrazinamide in South African tuberculosis outpatients

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

Neutrophil-Associated Central Nervous System Inflammation in Tuberculous Meningitis Immune Reconstitution Inflammatory Syndrome.

Background. 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. Methods. We performed lumbar puncture at 3–5 time points in human immunodeficiency virus (HIV)–infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18). Results. At TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline. Conclusions. A high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS

Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL: a systematic review and meta-analysis.

Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg-positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001)

Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis.

BACKGROUND: 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. METHODS: GXM concentrations were determined in paired serum, plasma, and urine from 62 patients with active or recent CM, using a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). A dipstick lateral-flow assay developed using the same monoclonal antibodies for the sandwich ELISA was tested in parallel. Correlation coefficients were calculated using Spearman rank test. RESULTS: All patients had detectable GXM in serum, plasma, and urine using the quantitative ELISA. Comparison of paired serum and plasma showed identical results. There were strong correlations between GXM levels in serum/urine (r(s) = 0.86; P < .001) and plasma/urine (r(s) = 0.85; P < .001). Levels of GXM were 22-fold lower in urine than in serum/plasma. The dipstick test was positive in serum, plasma, and urine in 61 of 62 patients. Dipstick titers correlated strongly with ELISA. Correlations between the methods were 0.93 (P < .001) for serum, 0.94 (P < .001) for plasma, and 0.94 (P < .001) for urine. CONCLUSIONS: This novel dipstick test has the potential to markedly improve early diagnosis of CM in many settings, enabling testing of urine in patients presenting to health care facilities in which lumbar puncture, or even blood sampling, is not feasible

Cytotoxic Mediators in Paradoxical HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) frequently complicates combined antiretroviral therapy and antituberculosis therapy in HIV-1–coinfected tuberculosis patients. The immunopathological mechanisms underlying TB-IRIS are incompletely defined, and improved understanding is required to derive new treatments and to reduce associated morbidity and mortality. We performed longitudinal and cross-sectional analyses of human PBMCs from paradoxical TB-IRIS patients and non-IRIS controls (HIV-TB–coinfected patients commencing antiretroviral therapy who did not develop TB-IRIS). Freshly isolated PBMC stimulated with heat-killed Mycobacterium tuberculosis H37Rv (hkH37Rv) were used for IFN-γ ELISPOT and RNA extraction. Stored RNA was used for microarray and RT-PCR, whereas corresponding stored culture supernatants were used for ELISA. Stored PBMC were used for perforin and granzyme B ELISPOT and flow cytometry. There were significantly increased IFN-γ responses to hkH37Rv in TB-IRIS, compared with non-IRIS PBMC (p = 0.035). Microarray analysis of hkH37Rv-stimulated PBMC indicated that perforin 1 was the most significantly upregulated gene, with granzyme B among the top five (log(2) fold difference 3.587 and 2.828, respectively), in TB-IRIS. Downstream experiments using RT-PCR, ELISA, and ELISPOT confirmed the increased expression and secretion of perforin and granzyme B. Moreover, granzyme B secretion reduced in PBMC from TB-IRIS patients during corticosteroid treatment. Invariant NKT cell (CD3(+)Vα24(+)) proportions were higher in TB-IRIS patients (p = 0.004) and were a source of perforin. Our data implicate the granule exocytosis pathway in TB-IRIS pathophysiology. Further understanding of the immunopathogenesis of this condition will facilitate development of specific diagnostic and improved therapeutic options