Investigations into HIV-associated tuberculous meningitis

Includes bibliographical references.[Background] Tuberculous meningitis (TBM) is a common form of tuberculosis in high TB incidence settings. However, the burden of disease and outcome in affected adults is unknown in Cape Town. The diagnosis of TBM is often challenging, particularly in HIV co-infected patients and no standardized clinical case definition exists. An emerging complication that contributes to poor outcome in HIV-associated TBM is neurological TB immune reconstitution inflammatory syndrome (TB-IRIS). [Methods] A consensus clinical TBM case definition was developed following a TBM meeting that I co-ordinated. I led two observational studies that determined the burden of HIV-associated TBM and neurological TB-IRIS at a district-level hospital in Cape Town. Patients with HIV-associated TBM were prospectively enrolled in a third cohort study to determine the clinical and immunological characteristics of paradoxical TBM-IRIS. [Results] TBM accounted for 57% of meningitis cases over a 6-months period; 88% of these patients were HIV-infected. At six months follow-up, mortality in HIV-associated TBM patients was 48%. Neurological TB-IRIS accounted for 21% of patients who presented with central nervous system (CNS) deterioration during the first year of antiretroviral therapy (ART) over a one-year period. TBM-IRIS developed in 47% of HIV-associated TBM patients and associated with extensive cerebrospinal fluid (CSF) inflammation both at TBM diagnosis and at TBM-IRIS presentation. Patients who did not develop TBM-IRIS, but who were culture-positive for Mycobacterium tuberculosis from CSF at TBM diagnosis, showed an immunological phenotype similar to TBM-IRIS patients; however neutrophils were increased in TBM-IRIS patients compared to culture-positive TBM-non-IRIS patients, both at TBM diagnosis and two weeks after ART initiation. [Conclusions] HIV-associated TBM is a common cause of meningitis with a poor outcome in Cape Town. TBM-IRIS is a frequent complication of ART in HIV-associated TBM patients. CSF Mycobacterium tuberculosis culture positivity drives an inflammatory response that manifests as TBM-IRIS in most, but not all TBM patients. Neutrophils associate closely with the CNS inflammation that characterizes TBM-IRIS. An intensified TB treatment regimen with increased CSF penetration early during TB treatment may lead to improved mycobacterial clearance from the CNS, which may result in improved outcome during TBM treatment and a reduced frequency of TBM-IRIS. We aim to test this hypothesis in future studies

Reversible syndrome of extrapyramidal movement disorders with bilateral basal ganglia lesions in uremia: a case series and review of the literature

Background: The distinct clinicoradiological syndrome of reversible basal ganglia lesions associated with extrapyramidal movement disorders in uremic patients has rarely been described in the literature. There have been no reported cases from Africa.Methods: This study is a retrospective analysis of uremic patients presenting with extrapyramidal movement disorders in Durban, South Africa from 2003 to 2016. A review of all published studies was also undertaken.Results: Seven patients who presented with this syndrome were identified. An additional 41 cases were reported in the literature. Our seven cases showed similar characteristics to those previously reported. All patients were of Asian ethnicity and had dialysis dependent renal failure, 86% (6/7) due to diabetic nephropathy. The most frequent presentation was parkinsonism (5/7) followed by chorea (1/7) and dystonia (1/7). Typical neuroimaging findings included bilateral symmetrical basal ganglia abnormalities that were hypodense on computed tomography scan, and T1 hypointense and T2 hyperintense on magnetic resonance imaging. A key feature of this syndrome is its reversibility with supportive treatment; Clinical improvement was observed in 86% (6/7), which was accompanied by radiological regression of lesions in two patients who underwent follow-up imaging.Conclusions: The syndrome of acute extrapyramidal movement disorders in uremic patients with bilateral basal ganglia lesions presents with typical clinical and radiological findings. Awareness of this syndrome especially in Asian diabetic patients with renal failure is important for early recognition and appropriate supportive management to aid its resolution.Keywords: Basal ganglia, diabetic nephropathy, extrapyramidal, magnetic resonance imaging, renal failur

Overt hypoadrenalism is uncommon in patients with stage 3 and 4 bronchogenic carcinoma

Introduction. Lung cancer is the leading cause of cancer mortality in most countries. The adrenal glands are common sites of metastatic lung cancer as approximately 40% of subjects with stage 4 bronchogenic carcinoma have adrenal metastases. The prevalence of biochemical hypoadrenalism is, however, remarkably poorly documented. Objectives. Our study aimed to determine the prevalence of primary hypoadrenalism, as defined by a subnormal cortisol response to the 250 µg adrenocorticotrophic hormone (ACTH) stimulation test, in patients with stage 3 and 4 lung cancer. Methods. Thirty patients with stage 3 and 4 bronchogenic carcinoma were prospectively recruited from the bronchus clinic. Demographic data and electrolytes were recorded and each patient had a 250 µg ACTH stimulation test to determine the prevalence of overt adrenal insufficiency, defined as a +30 minute cortisol of less than 550 nmol/l. Results. The median age and quartile deviation was 62 (10) years and the median basal cortisol was 429.5 (321) nmol/l. The median peak cortisol was 828.5 (342) nmol/l (range 536 - 1 675 nmol/l). Twenty-eight patients (93.3%) had an appropriate rise of cortisol to greater than 550 nmol/l following 250 µg ACTH stimulation. Two patients (6.7%) had mild primary adrenal failure with a peak cortisol between 500 and 550 nmol/l associated with a raised plasma ACTH concentration (131.4 and 10.5 pmol/l, normal 2.2 - 10 pmol/l). Twenty-eight patients (92.9%) were normonatraemic, while the two hyponatraemic patients had biochemical evidence of the syndrome of inappropriate antidiuretic hormone secretion. Conclusion. In conclusion, despite evidence that the adrenal glands of patients with disseminated bronchogenic carcinoma are frequently affected by metastatic disease, biochemical evidence of clinically significant hypoadrenalism is relatively uncommon and is not accurately predicted by electrolyte abnormalities

Barriers to Initiation of Antiretrovirals during Antituberculosis Therapy in Africa

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.Setting. A South African township clinic with integrated tuberculosis and HIV services. Design. Logistic regression analyses of a prospective cohort of HIV-1 infected adults (≥18 years) who commenced TB therapy, were eligible for ART, and were followed for 6 months.Of 100 HIV-1 infected adults eligible for ART during TB therapy, 90 TB patients presented to an ART clinic for assessment, 66 TB patients initiated ART, and 15 TB patients died. 34% of eligible TB patients (95%CI: 25-43%) did not initiate ART. Male gender and younger age (<36 years) were associated with failure to initiate ART (adjusted odds ratios of 3.7 [95%CI: 1.25-10.95] and 3.3 [95%CI: 1.12-9.69], respectively). Death during TB therapy was associated with a CD4+ count <100 cells/µL.In a clinic with integrated services for tuberculosis and HIV, one-third of eligible TB patients--particularly young men--did not initiate ART. Strategies are needed to promote ART initiation during TB therapy, especially among young men

Burden of antituberculosis and antiretroviral drug-induced liver injury at a secondary hospital in South Africa

Background. G F Jooste Hospital (GFJH) is a secondary-level referral hospital in a high HIV and tuberculosis (TB) co-infection setting. Aims. To assess the proportion of significant drug-induced liver injury (DILI) due to tuberculosis treatment (TBT) and/or antiretroviral therapy (ART) among patients presenting with liver dysfunction at GFJH and to describe management and outcomes. Methods. A retrospective observational study was performed of all cases referred to GFJH with significant liver dysfunction from 1 January to 30 June 2009. Significant liver dysfunction was defined by alanine transaminase (ALT)≥200 U/l or total bilirubin (TBR)≥44 µmol/l. TBT- or ART-associated DILI was defined as significant liver dysfunction attributed to TBT and/or ART and which resulted in the halting of treatment or the adjustment thereof. Outcome measures included case numbers, descriptive data, and in-hospital and 3-month mortality. Results. A total of 318/354 cases of significant liver dysfunction were reviewed: 71 were classified as TBT- or ART-associated DILI, while liver dysfunction was attributed to other causes in the remainder. In-hospital and 3-month mortality of TBT- or ART-associated DILI patients was 27% (n=19) and 35% (n=25), respectively. The majority of deaths were related to sepsis or sepsis complicating liver dysfunction. Twenty-three patients (32%) were lost to follow-up; 23 (32%) were alive and in outpatient care 3 months after presentation. Conclusions. TBT- or ART-associated DILI is a common reason for presentation at a referral hospital in South Africa. In-hospital and 3-month mortality are high. Prospective studies are needed to define optimal management

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations

Management of intracranial tuberculous mass lesions : how long should we treat for? [version 3; peer review: 3 approved]

CITATION: Marais, S., et al. 2019. Management of intracranial tuberculous mass lesions : how long should we treat for? [version 3; peer review: 3 approved]. Wellcome Open Research, 4:158, doi:10.12688/wellcomeopenres.15501.3.The original publication is available at https://wellcomeopenresearch.orgTuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis (M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.https://wellcomeopenresearch.org/articles/4-158Publisher's versio