Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Association between biomarkers of inflammation and dyslipidemia in drug resistant tuberculosis in Uganda.

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.

Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda.

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.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

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.

Early culture conversion is a poor marker of treatment outcome among people with HIV and drug-resistant TB.

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.

Association of body mass index with left ventricular diastolic dysfunction among ambulatory individuals with diabetes mellitus in rural Uganda: a cross-sectional study.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is a recognized complication of diabetes mellitus that precedes and is a risk factor for heart failure. We aimed to determine the prevalence of LVDD and its association with body mass index in ambulatory adults with diabetes mellitus in rural Uganda. METHODS: We conducted a cross-sectional study, over 5 months, to enroll 195 ambulatory Ugandan adults living with diabetes mellitus for at least five years at Mbarara Regional Referral Hospital. We collected demographic, and clinical data and measured body mass index (BMI). Echocardiography was performed to determine LVDD by assessing the mitral inflow ventricular filling velocities (E/A and E/è ratios), tricuspid regurgitant jet peak velocity, and left atrium maximum volume index. We used logistic regression to estimate the odds ratio for the association of LVDD with BMI and evaluated the variation of associations by age and hypertension status. RESULTS: Of the 195 participants, 141 (72.31%) were female, the mean age was 62 [standard deviation, 11.50] years, and the median duration of diabetes diagnosis was 10 [interquartile range, 7, 15] years. Eighty-six percent (n = 168) had LVDD with the majority (n = 127, 65.1%) of participants in the grade 1 category of LVDD. In the adjusted model, the odds of LVDD for each 1 kg/m2 increase in BMI was 1.11 [95% confidence interval 1.00, 1.25, p = 0.04]. The adjusted odds of LVDD among individuals aged ≥ 50 years with BMI ≥ 25 kg/m2 was 13.82 times the odds of LVDD in individuals aged < 50 years with BMI < 25 kg/m2. CONCLUSION: LVDD is prevalent and positively associated with BMI among ambulatory Ugandan adults living with diabetes mellitus for at least five years. The association was higher for older overweight/obese than younger individuals with normal weight. Future studies should focus on the effect of weight loss on LVDD as a possible target for the prevention of heart failure.

Effect of a solar lighting intervention on fuel-based lighting use and exposure to household air pollution in rural Uganda: A randomized controlled trial.

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.

Cerebrospinal Fluid Lactate as a Prognostic Marker of Disease Severity and Mortality in Cryptococcal Meningitis.

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.

Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa.

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00-1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07-1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94-1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. LAY SUMMARY: We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

Gender differences among patients with drug resistant tuberculosis and HIV co-infection in Uganda: a countrywide retrospective cohort study.

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.

Incidence and predictors of early loss to follow up among patients initiated on protease inhibitor-based second-line antiretroviral therapy in southwestern Uganda.

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.

Incidence and risk predictors of acute kidney injury among HIV-positive patients presenting with sepsis in a low resource setting.

BACKGROUND: Acute kidney injury (AKI) is a frequently encountered clinical condition in critically ill patients and is associated with increased morbidity and mortality. In our resource-limited setting (RLS), the most common cause of AKI is sepsis and volume depletion. Sepsis alone, accounts for up to 62 % of the AKI cases in HIV-positive patients. OBJECTIVE: The major goal of this study was to determine the incidence and risk predictors of AKI among HIV-infected patients admitted with sepsis at a tertiary hospital in Uganda. METHODS: In a prospective cohort study, we enrolled adult patients presenting with sepsis at Mbarara Regional Referral Hospital (MRRH) in southwestern Uganda between March and July 2020. Sepsis was determined using the qSOFA criteria. Patients presenting with CKD or AKI were excluded. Sociodemographic characteristics, physical examination findings, and baseline laboratory values were recorded in a data collection tool. The serum creatinine and urea were done at admission (0-hour) and at the 48-hour mark to determine the presence of AKI. We performed crude and multivariable binomial regression to establish the factors that predicted developing AKI in the first 48 h of admission. Variables with a p < 0.01 in the adjusted analysis were considered as significant predictors of AKI. RESULTS: Out of 384 patients screened, 73 (19 %) met our inclusion criteria. Their median age was 38 (IQR 29-46) years and 44 (60.3 %) were male. The median CD4 T-cell count was 67 (IQR 35-200) cells, median MUAC was 23 (IQR 21-27) cm and 54 (74.0 %) participants were on a regimen containing Tenofovir Disoproxil Fumarate (TDF). The incidence of AKI in 48 h was 19.2 % and in the adjusted analysis, thrombocytopenia (Platelet count < 150) (adjusted risk ratio 8.21: 95 % CI: 2.0-33.8, p = 0.004) was an independent predictor of AKI. CONCLUSIONS: There is a high incidence of AKI among HIV-positive patients admitted with sepsis in Uganda. Thrombocytopenia at admission may be a significant risk factor for developing AKI. The association of thrombocytopenia in sepsis and AKI needs to be investigated.

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

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.

Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management.

Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7-1.0 mg/kg). Five were exposed to 200-800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis.

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.

Death after cure: Mortality among pulmonary tuberculosis survivors in rural Uganda.

OBJECTIVES: To determine the incidence of mortality and its predictors among pulmonary tuberculosis (PTB) survivors treated at a rural Ugandan tertiary hospital. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adverse drug reactions and associated factors in multidrug-resistant tuberculosis: A retrospective review of patient medical records at Mbarara Regional Referral Hospital, Uganda.

Objectives: The World Health Organization pragmatic guidelines recommend shorter duration drug regimens with newer, more efficacious agents for treatment of multidrug-resistant tuberculosis. However, adverse drug reactions associated with the use of newer, second-line agents may pose a major barrier to adequate management of multidrug-resistant tuberculosis. We therefore sought to investigate the prevalence and factors associated with adverse drug reactions among patients with multidrug-resistant tuberculosis. Methods: We retrospectively reviewed patient medical records at the tuberculosis treatment unit of Mbarara Regional Referral Hospital, between January 2013 and December 2020. Medical records were included in the study, if the patients were aged ⩾18 years, tested sputum positive for multidrug-resistant tuberculosis, with adequate pharmacovigilance data documented. We assessed all documented health-related patient complaints, deranged laboratory values, and clinician suspected adverse drug reactions for scientific/clinical plausibility. Adverse drug reactions were confirmed using published and manufacturer drug references materials. A multidisciplinary clinician team was involved to decide whether to exclude or include a suspected adverse drug reaction. Results: About 6 in 10 (67.4%; 120/178) patients experienced at least one adverse drug reactions during treatment, of which 18.3%, 14.6%, and 11.4% of adverse drug reactions affected the endocrine/metabolic, otic, and musculoskeletal body systems, respectively. Majority of the adverse drug reactions were probable and had a moderate severity. There was an upward trend in adverse drug reaction incidence between 2015 and 2019. Adverse drug reaction occurrence was associated with previous adverse drug reaction history (adjusted odds ratio = 2.85 (1.08, 7.53 at 95% confidence interval)); however, patients who were underweight (adjusted odds ratio = 0.34 (0.16, 0.69 at 95% confidence interval)) and those treated with bedaquiline-based drug regimens (adjusted odds ratio = 0.2 (0.07, 0.59 at 95% confidence interval)) were less likely to experience an adverse drug reaction. Conclusion: Majority of patients with multidrug-resistant tuberculosis experience at least adverse drug reaction during the course of treatment. The newer standard shorter duration drug regimens (9-12 months) may be associated with intolerable adverse drug reactions that hamper effective management of multidrug-resistant tuberculosis. There is need for more studies to assess the clinical adverse drug reaction burden associated with the implementation of shorter duration regimens.

Persistently elevated intracranial pressure in cryptococcal meningitis- 76 therapeutic lumbar punctures.

Cryptococcal meningitis still remains the most common form of adult meningitis in sub-Saharan Africa, due to the burden of HIV/AIDS. Increased intracranial pressure (ICP) is a major complication of cryptococcosis and requires aggressive management with therapeutic lumbar punctures (LPs). In this report, we describe a patient with persistently elevated ICP who underwent 76 LPs over 46 days with good outcome. While unusual, this highlights the importance of serial therapeutic LPs. 2012 Elsevier Ltd. All rights reserved.

Coinfection of COVID-19 and Tuberculosis in Uganda.

The clinical features and outcomes of tuberculosis (TB) and COVID-19 coinfection are not well established. This short report describes 11 people with TB/COVID-19 coinfection in Uganda. The mean age was 46.9 ± 14.5 years; eight (72.7%) were male and two (18.2%) were coinfected with HIV. All patients presented with cough whose median duration was 71.1 (interquartile range, 33.1, 109) days. Eight (72.7%) had mild COVID-19 whereas two (18.2%) died, including one with advanced HIV disease. All patients were treated with first-line anti-TB drugs and adjunct therapy for COVID-19 using national treatment guidelines. This report presents the possibility of the coexistence of the two diseases and calls for more vigilance, screening, and collective prevention measures for both COVID-19 and TB.