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Background: Good adherence to antiretroviral therapy (ART) and retention in care are essential for the effectiveness of an HIV care program. With the current increase in numbers of people living with HIV taking second-line ART in sub-Saharan Africa, there is a need to establish their treatment outcomes and the rate of loss to follow up. In this study, we determined the incidence and predictors of loss to follow up among patients taking second-line ART at an experienced HIV treatment center in southwestern Uganda. Methods: This was a retrospective review of an electronic database at Mbarara Regional Referral Hospital HIV clinic in southwestern Uganda. Second-line ART included at least two of the nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Loss to follow-up was defined as failure to return to the health facility for care or treatment refill for 180 days or more from the previous visit. After excluding children less than 15 years, we pooled data that included socio-demographic, clinical, and laboratory data for patients who started second-line ART between 2002 and 2017. Multiple imputation was done for variables with missing data. Variables that had a p < 0.05 in unadjusted bivariate analyses were included in a multivariate binomial regression model using a stepwise backward selection procedure to describe the factors that independently predicted loss to follow-up. Results: Between 2002 and 2017, 1121 patients had been initiated on second-line ART. We included data from 924 participants and of these, 518 (56.1%) were female, the mean age (SD) was 38.4 (± 10.5) years, and 433 (52.4%) had a CD4 count less than 100 cells/µl at the start of second-line ART. The incidence of loss to follow-up was 26.7 per 100 person-years. Male gender (Adjusted risk ratio (ARR) = 1.8, 95% CI 1.5–2.0) p < 0.001 and anemia ARR 1.4, 95% CI 1.1–1.6) p < 0.001 were strongly associated with loss to follow up. Conclusions: There is a high incidence of loss to follow up among patients taking protease-inhibitor based second-line ART at a tertiary HIV center in southwestern Uganda. There is a need to routinely measure hemoglobin during clinic reviews, and establish mechanisms to retain males initiated on second-line ART in care. The association of anemia and loss to follow up needs to be investigated. [ABSTRACT FROM AUTHOR]

Background: Pulmonary multi-drug-resistant tuberculosis (MDR TB) alters lung architecture and involves lengthy treatment duration, high pill burden, drug adverse effects, travel restrictions, and stigma. Literature about pulmonary function and health-related quality of life (QoL) of patients treated for MDR TB is limited. This study sought to determine the prevalence of chronic obstructive pulmonary disease (COPD) and QoL of patients who were treated for pulmonary MDR TB. Methods: Participants who completed 18 months of pulmonary MDR TB treatment and considered cured were eligible to be evaluated in a cross-sectional study. We performed post-bronchodilator spirometry to measure forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). COPD was defined as FEV1/FVC < 0.7; health-related QoL was assessed using the Medical Outcomes Survey for HIV (MOS-HIV) and St. George's Respiratory Questionnaire (SGRQ). Linear and logistic regression models were used to assess associations with COPD, health-related QoL, and other characteristics of the cohort. Results: A total of 95 participants were enrolled. Median age of the cohort was 39 years (interquartile range (IQR), 29–45), and 55 (58%) were HIV-positive. COPD prevalence was 23% (22/95). Median SGRQ score was normal at 7.8 (IQR, 3.1–14.8). Median mental and physical health summary scores were significantly impaired, at 58.6 (IQR, 52.0–61.5) and 52.9 (IQR, 47.8–57.9), respectively, on a scale of 0 to 100 where 100 represents excellent physical or mental health. In this sample, 19% (18/95) of participants were in the lowest relative socioeconomic position (SEP) while 34% (32/95) were in the highest relative SEP. Belonging in the lowest SEP group was the strongest predictor of COPD. Conclusion: Individuals who have completed MDR TB treatment have a high prevalence of COPD and low mental and physical health summary scores. Our study highlights the need for pulmonary rehabilitation programs in patients with a low socioeconomic position (SEP) after MDR TB treatment. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), is the latest virus to cause global health panic. Due to the rapidly escalating numbers of new infections outside China, COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11, 2020, in a message delivered by Dr. Tedros Adhanom Ghebreyesus, the WHO Director-General [1]. As of March 21, about 166 countries globally had recoded cases of the COVID-19 in only 4 months since its outbreak in Wuhan, Hubei Province, China [2-3]. With the Antarctic continent unaffected, Africa, in particular Sub-Saharan Africa (SSA), has recorded the least number of cases, despite the cited moderate-to-high risk of infection [4]. The biggest challenge is whether Sub-Saharan Africa is ready for this pandemic. [ABSTRACT FROM AUTHOR]

Background: WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis.Methods: We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test.Findings: From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24-68]; 10/22; p=0·0010) or culture (45% [24-68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014).Interpretation: Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis.Funding: National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation. [ABSTRACT FROM AUTHOR]

Background Mortality among adults diagnosed with HIV-associated cryptococcal meningitis remains high (24%–40%). We hypothesized that nutritional state, as measured by mid–upper arm circumference (MUAC), is a potentially modifiable risk factor for mortality. Methods Ugandan adults hospitalized with HIV-associated cryptococcal meningitis had MUAC measurements performed at baseline. We compared MUAC measurements with baseline clinical and demographic variables and investigated associations with survival using Cox regression. Results Of 433 participants enrolled, 41% were female, the median CD4 T-cell count (interquartile range [IQR]) was 15 (6–41) cells/μL, and 37% were antiretroviral therapy naïve. The median MUAC (IQR) was 24 (22–26) cm, the median weight (IQR) was 53 (50–60) kg, and MUAC correlated with weight (Pearson r = 0.6; P <.001). Overall, 46% (200/433) died during the 18-week follow-up. Participants in the lowest MUAC quartile (≤22 cm) had the highest mortality: 39% (46/118) at 2 weeks and 62% (73/118) at 18 weeks. A baseline MUAC ≤22 cm was associated with an 82% increased risk of 18-week mortality as compared with participants with an MUAC >22 cm (unadjusted hazard ratio, 1.82; 95% CI, 1.36–2.42; P <.001). Following adjustment for antiretroviral therapy status, CD4 count, hemoglobin, amphotericin dose, and tuberculosis status, the adjusted hazard ratio was 1.84 (95% CI, 1.27–2.65; P <.001). As a continuous variable, 18-week mortality was reduced by 10% for every 1-cm increase in MUAC. CSF Th17 immune responses were positively associated with MUAC quartile. Conclusions MUAC measurement is a simple bedside tool that can identify adults with HIV-associated cryptococcal meningitis at high risk for mortality for whom an enhanced bundle of care, including nutritional supplementation, should be further investigated. [ABSTRACT FROM AUTHOR]

Solar lighting is an alternative to polluting kerosene and other fuel‐based lighting devices relied upon by millions of families in resource‐limited settings. Whether solar lighting provides sustained displacement of fuel‐based lighting sources and reductions in personal exposure to fine particulate matter (PM2.5) and black carbon (BC) has not been examined in randomized controlled trials. Eighty adult women living in rural Uganda who utilized fuel‐based (candles and kerosene lamps) and/or clean (solar, grid, and battery‐powered devices) lighting were randomized in a 1:1 ratio to receive a home solar lighting system at no cost to study participants (ClinicalTrials.gov NCT03351504). Among intervention group participants, kerosene lamps were completely displaced in 92% of households using them. The intervention led to an average exposure reduction of 36.1 μg/m3 (95% CI −70.3 to −2.0) in PM2.5 and 10.8 μg/m3 (95% CI −17.6 to −4.1) in BC, corresponding to a reduction from baseline of 37% and 91%, respectively. Reductions were greatest among participants using kerosene lamps. Displacement of kerosene lamps and personal exposure reductions were sustained over 12 months of follow‐up. Solar lighting presents an immediate opportunity for achieving sustained reductions in personal exposure to PM2.5 and BC and should be considered in household air pollution intervention packages. [ABSTRACT FROM AUTHOR]

Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral meningitis. We measured CSF lactate in individuals with cryptococcal meningitis to determine its clinical significance. Methods We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of cryptococcal meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. Results Individuals with high CSF lactate >5 mmol/L at cryptococcal diagnosis more likely presented with altered mental status (P  < .0001), seizures (P  = .0005), elevated intracranial opening pressure (P  = .03), higher CSF white cells (P  = .007), and lower CSF glucose (P  = .0003) compared with those with mid-range (3.1 to 5 mmol/L) or low (≤3 mmol/L) CSF lactate levels. Two-week mortality was higher among individuals with high baseline CSF lactate >5 mmol/L (35%; 38 of 109) compared with individuals with mid-range (22%; 25 of 112) or low CSF lactate (9%; 9 of 97; P  =<.0001). After multivariate adjustment, CSF lactate >5 mmol/L remained independently associated with excess mortality (adjusted hazard ratio = 3.41; 95% confidence interval, 1.55–7.51; P  = .002). We found no correlation between baseline CSF lactate levels and blood capillary lactate levels. Conclusions Baseline point-of-care CSF lactate levels are a prognostic marker of disease severity and mortality in cryptococcal meningitis. Individuals with an elevated baseline CSF lactate level are more likely to present with altered mental status, seizures, and elevated CSF opening pressure and are at a greater risk of death. Future studies are needed to determine targeted therapeutic management strategies in persons with high CSF lactate. [ABSTRACT FROM AUTHOR]

Background: Active tuberculosis (TB) significantly increases the risk of cardiovascular disease, but the underlying mechanisms remain unclear. This study aimed to investigate the association between inflammation biomarkers and dyslipidemia in patients with drug-resistant TB (DR-TB). Methods: This was a secondary analysis of data from a cross-sectional multi-center study in Uganda conducted 2021. Participants underwent anthropometric measurements and laboratory tests included a lipid profile, full haemogram and serology for HIV infection. Dyslipidemia was defined as total cholesterol > 5.0 mmol/l and/or low-density lipoprotein cholesterol > 4.14 mmol/l, and/or triglycerides (TG) ≥ 1.7 mmol/l, and/or high density lipoprotein cholesterol (HDL-c) < 1.03 mmol/l for men and < 1.29 mmol/l for women. Biomarkers of inflammation were leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts, as well as neutrophil/lymphocyte (NLR), platelet/lymphocyte, and lymphocyte/monocyte (LMR) ratios, mean corpuscular volume (MCV), and the systemic immune inflammation index (SII) (neutrophil × platelet/lymphocyte). Modified Poisson Regression analysis was used for determining the association of the biomarkers and dyslipidemia. Results: Of 171 participants, 118 (69.0%) were co-infected with HIV. The prevalence of dyslipidemia was 70.2% (120/171) with low HDL-c (40.4%, 69/171) and hypertriglyceridemia (22.5%, 38/169) being the most common components. Patients with dyslipidemia had significantly higher lymphocyte (P = 0.008), monocyte (P < 0.001), and platelet counts (P = 0.014) in addition to a lower MCV (P < 0.001) than those without dyslipidemia. Further, patients with dyslipidemia had lower leucocyte (P < 0.001) and neutrophil (P = 0.001) counts, NLR (P = 0.008), LMR (P = 0.006), and SII (P = 0.049). The MCV was inversely associated with low HDL-C (adjusted prevalence ratio (aPR) = 0.97, 95% CI 0.94–0.99, P = 0.023) but was positively associated with hypertriglyceridemia (aPR = 1.04, 95% CI 1.00-1.08, P = 0.052). Conclusions: Individuals with dyslipidemia exhibited elevated lymphocyte, monocyte, and platelet counts compared to those without. However, only MCV demonstrated an independent association with specific components of dyslipidemia. There is need for further scientific inquiry into the potential impact of dyslipidemia on red cell morphology and a pro-thrombotic state among patients with TB. [ABSTRACT FROM AUTHOR]

Non-communicable diseases (NCDs) are a growing health burden in Sub-Saharan Africa and especially Uganda, where they account for over one third of all deaths. During the COVID-19 pandemic, public health control measures such as societal "lockdowns" had a significant impact on longitudinal NCD care though no studies have looked at the lived experience around NCD care during the pandemic. Our objective was to understand the experience of NCD care for both patients and providers in southwestern Uganda during the COVID-19 pandemic. We conducted in-depth, in-person qualitative interviews with 20 patients living with hypertension, diabetes, and/or cardiac disease purposefully selected from the outpatient clinics at Mbarara Regional Referral Hospital and 11 healthcare providers from public health facilities in Mbarara, southwestern Uganda. We analyzed transcripts according to conventional content analysis. We identified four major themes that emerged from the interviews; (1) difficulty accessing medication; (2) food insecurity; (3) barriers to the delivery of NCD clinical care and (4) alternative forms of care. Pre-existing challenges with NCD care were exacerbated during COVID-19 lockdown periods and care was severely disrupted, leading to worsened patient health and even death. The barriers to care were exacerbations of underlying systemic problems with NCD care delivery that require targeted interventions. Future work should leverage digital health interventions, de-centralizing NCD care, improving follow-up, providing social supports to NCD patients, and rectifying supply chain issues. [ABSTRACT FROM AUTHOR]

Introduction: Health workers' failure to adhere to guidelines for screening, diagnosis and management of HIV-associated cryptococcal meningitis (CM) remains a significant public health concern. We aimed to assess adherence to the standards of care and management of HIV patients at risk of CM per the MoH guidelines and assess stock management of CM supplies in the period of January to June 2021 at selected public health facilities (HFs) in Uganda. Methods: The study employed an observational cross-sectional design to assess the level of adherence of health workers to standards of clinical care and management of HIV positive patients at risk of CM as per the clinical guidelines for Uganda, and stock management of CM supplies in the period of January to June 2021in selected public health facilities. The study team used a survey guide designed by MoH to assess and score the screening, diagnosis and management practices of Health Facilities towards CM. Scoring was categorized as red (< 80%), light green (80%-95%), and dark green (˃95%) in the order from worst to best adherence. The data was transcribed into a spread sheet and analysed using STATA–v15. Results: The study team visited a total of 15 public health facilities including 5 general hospitals, 9 regional referral hospitals (RRHs) and 1 National Referral hospital (NRH). The mean score for adherence to screening and management of CM for all the combined facilities was 15 (64.7%) classified as red. 10 (66.7%) HFs had not performed a baseline CD4 test for eligible patients within 2 weeks of ART initiation. With regards to treatment, 9 (60%) of the HFs were scored as light green on knowledge of the procedure for reconstituting intravenous Liposomal Amphotericin B. None of the HFs visited had potassium chloride tablets in stock. Conclusion: Major MoH guidelines are generally not being adhered to by health workers while managing cryptococcal meningitis. It is vital that government and implementing partners regularly support HFs with training, mentorship, and support supervision on CM management to improve adherence to CM screening and treatment guidelines. [ABSTRACT FROM AUTHOR]

Background Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. Methods We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. Results 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9–76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4–85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47–142; WBC: 45 cells/μL; IQR: 8–128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. Conclusions Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. Clinical Trials Registration NCT01802385. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to determine associations between early (≤2 months) culture conversion (ECC) among people with HIV and drug‐resistant tuberculosis (DRTB) in Uganda. Methods: This was a countrywide retrospective cohort of people with bacteriologically confirmed DRTB and a positive baseline culture at 16 centres in Uganda between 2013 and 2019. Data were abstracted from treatment files and unit DRTB registers. Monthly sputum cultures were performed using the Lowenstein–Jensen solid medium. Results: We included 664 people with DRTB and a positive baseline culture, of whom 353 (53.4%) also had HIV. Among those living with HIV, 225 (63.7%) were male and 331 (94.3%) were on antiretroviral therapy. The median month of culture conversion was 2 (interquartile range [IQR] 1–3). ECC was observed among 226 people living with HIV (64.0%; 95% confidence interval [CI] 58.9–68.9). A DRTB treatment regimen of six or more drugs was associated with ECC among people living with HIV (adjusted odds ratio [aOR] 3.82; 95% CI 1.06–13.82; p = 0.041). Cure and overall treatment success was observed among 232 (65.7%) and 269 (76.2%) people living with HIV, respectively. However, ECC was not associated with cure (crude odds ratio [OR] 0.97; 95% CI 0.61–1.54; p = 0.901), death (OR 1.12; 95% CI 0.61–2.29; p = 0.610), or overall treatment success (OR 1.29; 95% CI 0.78–2.13; p = 0.326). Conclusion: The majority of people living with HIV and DRTB achieve ECC. However, ECC does not predict cure, death, or treatment success. Moreover, it may require six or more drugs to achieve ECC. ECC is not an excellent indicator of the effectiveness of DRTB regimens among people living with HIV. [ABSTRACT FROM AUTHOR]

Background It is unknown whether persons with symptomatic cryptococcal meningitis detected during routine blood cryptococcal antigen (CrAg) screening have better survival than persons presenting with overt meningitis. Methods We prospectively enrolled Ugandans with HIV and cryptocococcal meningitis from December 2018 to December 2021. Participants were treated with amphotericin-based combination therapy. We compared outcomes between persons who were CrAg screened then referred to hospital with those presenting directly to the hospital with symptomatic meningitis. Results Among 489 participants with cryptococcal meningitis, 40% (194/489) received blood CrAg screening and were referred to hospital (median time to referral 2 days; interquartile range [IQR], 1–6). CrAg-screened persons referred to hospital had lower 14-day mortality than non–CrAg-screened persons who presented directly to hospital with symptomatic meningitis (12% vs 21%; hazard ratio,.51; 95% confidence interval,.32–.83; P =.006). Fewer CrAg-screened participants had altered mental status versus non–CrAg-screened participants (29% vs 41%; P =.03). CrAg-screened persons had lower quantitative cerebrospinal fluid (CSF) culture burden (median [IQR], 4570 [11–100 000] vs 26 900 [182–324 000] CFU/mL; P =.01) and lower CSF opening pressures (median [IQR], 190 [120–270] vs 225 [140–340] mmH2O; P =.004) compared with non–CrAg-screened persons. Conclusions Survival from cryptococcal meningitis was higher in persons with prior CrAg screening than those without CrAg screening. Altered mental status was the most potent predictor for mortality in a multivariate model. We suggest that CrAg screening detects cryptococcal meningitis at an earlier stage, as evidenced by a favorable baseline risk profile and notably fewer persons with altered mental status. [ABSTRACT FROM AUTHOR]

Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal meningitis from November 2010 to May 2017. All persons were treated with amphotericin-based induction therapy. We grouped participants by tertile of baseline CSF quantitative Cryptococcus culture burden and compared clinical characteristics, CSF immune profiles, and 18-week mortality. We found 55 (7%) CSF CrAg-positive participants with sterile CSF cultures. Compared to the non-sterile groups, participants with sterile CSF cultures had higher CD4 counts, lower CSF opening pressures, and were more frequently receiving ART. By 18 weeks, 47% [26/55] died in the sterile culture group versus 35% [83/235] in the low culture tertile, 46% [107/234] in the middle tertile, and 56% [135/241] in the high tertile (p < 0.001). The sterile group had higher levels of CSF interferon-gamma (IFN-γ), IFN-α, interleukin (IL)-6, IL-17, G-CSF, GM-CSF, and chemokine CXCL2 compared with non-sterile groups. Despite persons with sterile CSF cultures having higher CD4 counts, lower CSF opening pressures, and CSF cytokine profiles associated with better Cryptococcus control (e.g., IFN-γ predominant), mortality was similar to those with higher fungal burdens. This unexpected finding challenges the traditional paradigm that increasing CSF fungal burdens are associated with increased mortality but is consistent with a damage-response framework model. [ABSTRACT FROM AUTHOR]

Background Although a third of people with tuberculosis (TB) are estimated to be coinfected with helminths, the prevalence is largely unknown among people with drug-resistant TB (DR-TB). We determined the prevalence of helminth coinfection among people with DR-TB in Uganda. Methods In a multicenter, cross-sectional study, eligible Ugandan adults with confirmed DR-TB were consecutively enrolled between July to December 2021 at 4 treatment centers. Sociodemographic data were collected using a questionnaire. Participants underwent anthropometric and blood pressure measurements, and blood samples were evaluated for random blood glucose, glycated hemoglobin, nonfasting lipid profile, human immunodeficiency virus (HIV) infection, and a complete blood count. Fresh stool samples were evaluated for adult worms, eggs, and larvae using direct microscopy after Kato-Katz concentration techniques. Results Of 212 participants, 156 (73.6%) were male, 118 (55.7%) had HIV, and 3 (2.8%) had malaria coinfection. The prevalence of intestinal helminth coinfection was 4.7% (10/212) (95% confidence interval, 2.6%–8.6%). The frequency of helminth infections was Ancylostoma duodenale (n = 4), Schistosoma mansoni (n = 2), Enterobius vermicularis (n = 2), Ascaris lumbricoides (n = 1), and Trichuris trichiura (n = 1). Conclusions The prevalence of helminth coinfection was low among people with DR-TB. More studies are needed to determine the clinical relevance of helminth/DR-TB coinfection. [ABSTRACT FROM AUTHOR]

Background Increased intracranial pressure (ICP) frequently complicates cryptococcal meningitis. Therapeutic lumbar punctures (LPs) have acute survival benefits in the first week, and we sought to understand the longer-term survival impact of therapeutic LPs. Methods We prospectively enrolled human immunodeficiency virus (HIV)–seropositive adults with cryptococcal meningitis from 2013 to 2017 in Uganda. We assessed the association between clinical characteristics, CSF parameters, and 14- and 30-day mortality by baseline ICP. We also assessed 30-day mortality by number of follow-up therapeutic LPs performed within 7 days. Results Our analysis included 533 participants. Participants with baseline ICP >350 mm H2O were more likely to have Glasgow Coma Scale (GCS) score <15 (P  < .001), seizures (P  < .01), and higher quantitative cryptococcal cultures (P  < .001), whereas participants with ICP <200 mm H2O were more likely to have baseline sterile CSF cultures (P  < .001) and CSF white blood cell count ≥5 cells/µL (P  = .02). Thirty-day mortality was higher in participants with baseline ICP >350 mm H2O and ICP <200 mm H2O as compared with baseline ICP 200–350 mm H2O (hazard ratio, 1.55 [95% confidence interval, 1.10–2.19]; P  = .02). Among survivors at least 7 days, the 30-day relative mortality was 50% higher among participants who did not receive any additional therapeutic LPs compared to those with ≥1 additional follow-up LP (33% vs 22%; P  = .04), irrespective of baseline ICP. Conclusions Management of increased ICP remains crucial in improving clinical outcomes in cryptococcal meningitis. Guidelines should consider an approach to therapeutic LPs that is not dictated by baseline ICP. [ABSTRACT FROM AUTHOR]

• CMV viremia was found in 36% of persons with HIV-associated meningitis. • Greater CMV viral load was positively associated with adjusted 18-week mortality. • It is uncertain whether CMV viremia is a marker of immune dysfunction or drives mortality. • Randomized controlled trials using CMV antivirals are needed to determine whether CMV is a modifiable risk factor. CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log 10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction. [ABSTRACT FROM AUTHOR]

Background Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. Methods We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus–infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <125, 125–129, and 130–145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival. Results Of 816 participants with CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3–4 hyponatremia (<125 mmol/L), 194 (26%) had grade 2 hyponatremia (125–129 mmol/L), and 426 (57%) had a baseline sodium of 130–145 mmol/L. Hyponatremia (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P  < .001), higher initial CSF opening pressure (P  < .01), lower baseline Glasgow Coma Scale score (P  < .01), and a higher percentage of baseline seizures (P  = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26–2.79]; P  < .01) compared to those with sodium 130–145 mmol/L. Conclusions Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested. [ABSTRACT FROM AUTHOR]

• TB survivors experienced a high mortality rate of 28.5 per 1000 person-years. • Deceased individuals lost a median of 23.8 years. • Hospitalization and unemployment at treatment initiation predicted mortality after cure. • Social protection measures and follow-up of TB survivors could improve survival. To determine the incidence of mortality and its predictors among pulmonary tuberculosis (PTB) survivors treated at a rural Ugandan tertiary hospital. We conducted a retrospective chart review of data between 2013 and 2023. We included all people that met the World Health Organisation's definition of tuberculosis cure and traced them or their next of kin to determine vital status (alive/deceased). We estimated the cumulative incidence of mortality per 1000 population, crude all-cause mortality rate per 1000 person-years, and median years of potential life lost for deceased individuals. Using Cox proportional hazard models, we investigated predictors of mortality. Of 334 PTB survivors enrolled, 38 (11.4%) had died. The cumulative incidence of all-cause mortality was 113.7 per 1000 population, and the crude all-cause mortality rate was 28.5 per 1000 person-years. The median years of potential life lost for deceased individuals was 23.8 years (IQR: 9.6-32.8). Hospitalization (adjusted hazard ratio (aHR): 4.3, 95% CI: 1.1-16.6) and unemployment (aHR: 7.04, 95% CI: 1.5-31.6) at TB treatment initiation predicted mortality. PTB survivors experience post high mortality rates after TB cure. Survivors who were hospitalized and unemployed at treatment initiation were more likely to die after cure. Social protection measures and long-term follow-up of previously hospitalized patients could improve the long-term survival of TB survivors. [ABSTRACT FROM AUTHOR]

Background: Gender differences among patients with drug resistant tuberculosis (DRTB) and HIV co-infection could affect treatment outcomes. We compared characteristics and treatment outcomes of DRTB/HIV co-infected men and women in Uganda.Methods: We conducted a retrospective chart review of patients with DRTB from 16 treatment sites in Uganda. Eligible patients were aged ≥ 18 years, had confirmed DRTB, HIV co-infection and a treatment outcome registered between 2013 and 2019. We compared socio-demographic and clinical characteristics and tuberculosis treatment outcomes between men and women. Potential predictors of mortality were determined by cox proportional hazard regression analysis that controlled for gender. Statistical significance was set at p < 0.05.Results: Of 666 DRTB/HIV co-infected patients, 401 (60.2%) were men. The median (IQR) age of men and women was 37.0 (13.0) and 34.0 (13.0) years respectively (p < 0.001). Men were significantly more likely to be on tenofovir-based antiretroviral therapy (ART), high-dose isoniazid-containing DRTB regimen and to have history of cigarette or alcohol use. They were also more likely to have multi-drug resistant TB, isoniazid and streptomycin resistance and had higher creatinine, aspartate and gamma-glutamyl aminotransferase and total bilirubin levels. Conversely, women were more likely to be unemployed, unmarried, receive treatment from the national referral hospital and to have anemia, a capreomycin-containing DRTB regimen and zidovudine-based ART. Treatment success was observed among 437 (65.6%) and did not differ between the genders. However, mortality was higher among men than women (25.7% vs. 18.5%, p = 0.030) and men had a shorter mean (standard error) survival time (16.8 (0.42) vs. 19.0 (0.46) months), Log Rank test (p = 0.046). Predictors of mortality, after adjusting for gender, were cigarette smoking (aHR = 4.87, 95% CI 1.28-18.58, p = 0.020), an increase in alanine aminotransferase levels (aHR = 1.05, 95% CI 1.02-1.07, p < 0.001), and history of ART default (aHR = 3.86, 95% CI 1.31-11.37, p = 0.014) while a higher baseline CD4 count was associated with lower mortality (aHR = 0.94, 95% CI 0.89-0.99, p = 0.013 for every 10 cells/mm3 increment).Conclusion: Mortality was higher among men than women with DRTB/HIV co-infection which could be explained by several sociodemographic and clinical differences. [ABSTRACT FROM AUTHOR]

Background: Gender differences among patients with drug resistant tuberculosis (DRTB) and HIV co-infection could affect treatment outcomes. We compared characteristics and treatment outcomes of DRTB/HIV co-infected men and women in Uganda. Methods: We conducted a retrospective chart review of patients with DRTB from 16 treatment sites in Uganda. Eligible patients were aged ≥ 18 years, had confirmed DRTB, HIV co-infection and a treatment outcome registered between 2013 and 2019. We compared socio-demographic and clinical characteristics and tuberculosis treatment outcomes between men and women. Potential predictors of mortality were determined by cox proportional hazard regression analysis that controlled for gender. Statistical significance was set at p < 0.05. Results: Of 666 DRTB/HIV co-infected patients, 401 (60.2%) were men. The median (IQR) age of men and women was 37.0 (13.0) and 34.0 (13.0) years respectively (p < 0.001). Men were significantly more likely to be on tenofovir-based antiretroviral therapy (ART), high-dose isoniazid-containing DRTB regimen and to have history of cigarette or alcohol use. They were also more likely to have multi-drug resistant TB, isoniazid and streptomycin resistance and had higher creatinine, aspartate and gamma-glutamyl aminotransferase and total bilirubin levels. Conversely, women were more likely to be unemployed, unmarried, receive treatment from the national referral hospital and to have anemia, a capreomycin-containing DRTB regimen and zidovudine-based ART. Treatment success was observed among 437 (65.6%) and did not differ between the genders. However, mortality was higher among men than women (25.7% vs. 18.5%, p = 0.030) and men had a shorter mean (standard error) survival time (16.8 (0.42) vs. 19.0 (0.46) months), Log Rank test (p = 0.046). Predictors of mortality, after adjusting for gender, were cigarette smoking (aHR = 4.87, 95% CI 1.28–18.58, p = 0.020), an increase in alanine aminotransferase levels (aHR = 1.05, 95% CI 1.02–1.07, p < 0.001), and history of ART default (aHR = 3.86, 95% CI 1.31–11.37, p = 0.014) while a higher baseline CD4 count was associated with lower mortality (aHR = 0.94, 95% CI 0.89–0.99, p = 0.013 for every 10 cells/mm3 increment). Conclusion: Mortality was higher among men than women with DRTB/HIV co-infection which could be explained by several sociodemographic and clinical differences. [ABSTRACT FROM AUTHOR]

Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P  = .002). The lowest EFA group had lower median CD4 T-cell counts (P  < .01) and lower proportion of patients with CSF pleocytosis (P  < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculous meningitis accounts for 1-5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis.Methods: In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard.Findings: From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5-87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6-96·2; 153 of 165), compared with 55·6% sensitivity (44·0-70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9-91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5-75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4-91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5-98·5; 39 of 42), higher than Xpert at 65·8% (48·6-80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9-86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture.Interpretation: Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required.Funding: Wellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo.Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385.Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity.Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations.Funding: National Institutes of Health and Medical Research Council, Wellcome Trust. [ABSTRACT FROM AUTHOR]

Background Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. Methods We evaluated 1201 human immunodeficiency virus–seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic–symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. Results We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P =.91). Conclusions Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus -negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. Clinical Trials Registration NCT01802385. [ABSTRACT FROM AUTHOR]

Background: The mortality from cryptococcal meningitis remains high, despite the availability of antiretroviral therapy (ART) and amphotericin-based fungal regimens. The role of neutrophils in cryptococcosis is controversial. Our objective was to examine the association between blood neutrophil counts and outcomes in terms of mortality, the incidence of bacterial infections (including Mycobacterium tuberculosis) and hospitalization among HIV-infected patients presenting with cryptococcal meningitis. Methods: We used data from participants from the Cryptococcal Optimal ART Timing (COAT) trial (2010–2012; Uganda and South Africa) and the Adjunctive Sertraline for Treatment of Cryptococcal Meningitis (ASTRO-CM) trial (2013–2017; Uganda). We estimated 30-day mortality risk with Cox proportional hazards models by baseline neutrophil counts (a) on a continuous scale and (b) with indicators for both relatively high (> 3,500 cells/mm3) and low (≤ 1,000 cells/mm3) counts. Follow-up neutrophil counts from the COAT trial were used to examine the time-dependent association of neutrophil counts with 12-month mortality and rehospitalization. Results: 801 participants had an absolute neutrophil value at meningitis diagnosis. The median baseline absolute neutrophil count was 2100 cells/mm3 (IQR, 1400 to 3300 cells/mm3). Baseline neutrophil count was positively associated with 30-day mortality (adjusted hazard ratio = 1.09, 95%CI, 1.04–1.13, per 1000 cells/mm3 increase; p<0.001). Baseline absolute neutrophil counts ≤ 1000 cells/mm3 did not have increased risk of 30-day mortality compared to those with baseline neutrophils of 1001–3500 cells/mm3; however, baseline >3500 cells/mm3 had significantly increased risk, with an adjusted hazard ratio of 1.85(95%CI, 1.40–2.44; p<0.001). Among the COAT participants with follow-up neutrophil data, there was a strong association between time-updated neutrophil count and 12-month mortality (adjusted hazard ratio = 1.16, 95% CI 1.09–1.24; p<0.001. Conclusion: Higher blood neutrophil counts in HIV-infected patients with cryptococcal meningitis were associated with mortality. Neutrophils role requires further investigation as to whether this may be a mediator directly contributing to mortality or merely a marker of underlying pathologies that increase mortality risk. [ABSTRACT FROM AUTHOR]

To compare cytogenetic abnormalities among people living with HIV (PLWH) with and without previous exposure to Mycobacterium tuberculosis (Mtb) (both latent tuberculosis infection [LTBI] and active tuberculosis [TB]). Adult PLWH (≥18 years) were randomly selected at three HIV clinics in Uganda. Previous active TB was confirmed in the clinics' TB records. LTBI was defined as a positive QuantiFERON-TB Gold Plus assay. Participants' buccal mucosal exfoliated cells were examined (per 2000 cells) using the buccal micronucleus assay for chromosomal aberrations (micronuclei and/or nuclear buds), cytokinetic defects (binucleated cells), proliferative potential (normal differentiated cells and basal cell frequency) and/or cell death (condensed chromatin, karyorrhexis, pyknotic and karyolytic cells). Among 97 PLWH, 42 (43.3%) had exposure to Mtb ;16 had previous successfully treated active TB and 26 had LTBI. PLWH with exposure to Mtb had a higher median number of normal differentiated cells (1806.5 [1757.0 – 1842.0] vs. 1784.0 [1732.0 – 1843.0], p = 0.031) and fewer karyorrhectic cells (12.0 [9.0 – 29.0] vs. 18.0 [11.0 – 30.0], p = 0.048) than those without. PLWH with LTBI had fewer karyorrhectic cells than those without (11.5 [8.0 – 29.0] vs. 18.0 [11 − 30], p = 0.006). We hypothesized that previous exposure to Mtb is associated with cytogenetic damage among PLWH. We found that exposure to Mtb is associated with more normal differentiated cells and less frequent karyorrhexis (a feature of apoptosis). It is unclear whether this increases the propensity for tumorigenesis. • Previous TB infection is associated with fewer karyorrhectic but more normal cells. • Previous Mtb might reduce cell apoptosis and increase proliferation. • Efavirenz, and advanced HIV were also associated with cytogenetic abnormalities. [ABSTRACT FROM AUTHOR]

The incorrect author name is: Anna Stadelmann The correct author name is: Anna M. Stadelman ORCID: 0000-0002-1457-0931 The author group and ORCID has been updated above and the original article [[1]] has been corrected. B Correction b B : b B BMC Infect Dis (2021) 21:1093 b https://doi.org/10.1186/s12879-021-06801-5 Following publication of the original article [[1]], the authors identified an error in the author name of Anna M. Stadelman. [Extracted from the article]

Background Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. Methods We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018–2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. Results We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13–102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%–30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83–2.49; P  = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13–28.5; P  = .04). Conclusions In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in advanced HIV disease. Data are limited on TB co-infection among individuals with cryptococcal meningitis. We performed a retrospective analysis of HIV-infected participants with cryptococcal meningitis from 2010–2017. Baseline demographics were compared between three groups: 'prevalent TB' if TB treated >14 days prior to cryptococcal meningitis diagnosis, 'concurrent TB' if TB treated ± 14 days from diagnosis, or 'No TB at baseline'. We used time-updated proportional-hazards regression models to assess TB diagnosis as a risk for death. Of 870 participants with cryptococcal meningitis, 50 (6%) had prevalent TB, 67 (8%) had concurrent TB, and 753 (86%) had no baseline TB. Among participants without baseline TB, 67 (9%) were diagnosed with incident TB (after >14 days), with a median time to TB incidence of 41 days (IQR, 22–69). The 18-week mortality was 50% (25/50) in prevalent TB, 46% (31/67) in concurrent TB, and 45% (341/753) in the no TB group (p = 0.81). However, TB co-infection was associated with an increased hazard of death (HR = 1.75; 95% CI, 1.33–2.32; p < 0.001) in a time-updated model. TB is commonly diagnosed in cryptococcal meningitis, and the increased mortality associated with co-infection is a public health concern. [ABSTRACT FROM AUTHOR]

Background Central nervous system (CNS) infections remain a major public health problem in Sub-Saharan Africa, causing 15%–25% of AIDS-related deaths. With widespread availability of antiretroviral therapy (ART) and the introduction of improved diagnostics, the epidemiology of infectious meningitis is evolving. Methods We prospectively enrolled adults presenting with HIV-associated meningitis in Kampala and Mbarara, Uganda, from March 2015 to September 2017. Participants had a structured, stepwise diagnostic algorithm performed of blood cryptococcal antigen (CrAg), CSF CrAg, Xpert MTB/RIF for tuberculous (TB) meningitis (TBM), Biofire multiplex polymerase chain reaction, and traditional microscopy and cultures. Results We screened 842 consecutive adults with HIV presenting with suspected meningitis: 57% men, median age 35 years, median CD4 26 cells/mcL, and 55% presented on ART. Overall, 60.5% (509/842) were diagnosed with first-episode cryptococcal meningitis and 7.4% (62/842) with second episode. Definite/probable TB meningitis was the primary diagnosis in 6.9% (58/842); 5.3% (n = 45) had microbiologically confirmed (definite) TB meningitis. An additional 7.8% (66/842) did not meet the diagnostic threshold for definite/probable TBM but received empiric TBM therapy. Bacterial and viral meningitis were diagnosed in 1.3% (11/842) and 0.7% (6/842), respectively. The adoption of a cost-effective stepwise diagnostic algorithm allowed 79% (661/842) to have a confirmed microbiological diagnosis at an average cost of $44 per person. Conclusions Despite widespread ART availability, Cryptococcus remains the leading cause of HIV-associated meningitis. The second most common etiology was TB meningitis, treated in 14.7% overall. The increased proportion of microbiologically confirmed TBM cases reflects the impact of new improved molecular diagnostics. [ABSTRACT FROM AUTHOR]

Background Increased antiretroviral therapy (ART) availability has been associated with more patients developing cryptococcosis after ART initiation. Despite this changing epidemiology, data regarding cryptococcal meningitis in those already receiving ART are limited. We compared clinical presentations and outcomes among ART-naïve and ART-experienced Ugandans. Methods We prospectively enrolled 605 HIV-infected persons with first-episode cryptococcal meningitis from August 2013 to May 2017 who received amphotericin-based combination therapy. We classified participants by ART status and ART duration and compared groups for 2-week survival. Results Overall, 46% (281/605) of participants were receiving ART at presentation. Compared with those not receiving ART, those receiving ART had higher CD4 counts (P <.001) and lower cerebrospinal fluid fungal burdens (P <.001). Of those receiving ART, 56% (156/281) initiated ART within 6 months, and 18% (51/281) initiated ART within 14 days. Two-week mortality did not differ by ART status (27% in both ART-naïve and ART-experienced%; P >.99). However, 47% (24/51) of those receiving ART for ≤14 days died within 2 weeks, compared with 19% (20/105) of those receiving ART for 15–182 days and 26% (32/125) of those receiving ART for >6 months (P <.001). Among persons receiving ART for >6 months, 87% had HIV viral loads >1000 copies/mL. Conclusions Cryptococcosis after ART initiation is common in Africa. Patients initiating ART who unmask cryptococcal meningitis are at a high risk of death. Immune recovery in the setting of central nervous system infection is detrimental, and management of this population requires further study. Implementing pre-ART cryptococcal antigen screening is urgently needed to prevent cryptococcal meningitis after ART initiation. [ABSTRACT FROM AUTHOR]