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

OBJECTIVE: To determine the incidence of mortality and its predictors among pulmonary TB (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 WHO'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 1,000 population, crude all-cause mortality rate per 1,000 person-years, and median years of potential life lost (YPLL) 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 1,000 population, and the crude all-cause mortality rate was 28.5 per 1,000 person-years. The median YPLL for deceased individuals was 23.8 years (IQR: 9.6-32.8). Hospitalization (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.

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.

Patient-provider experiences with chronic non-communicable disease care during COVID-19 lockdowns in rural Uganda: A qualitative analysis.

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.

Investigating Metabolic and Molecular Ecological Evolution of Opportunistic Pulmonary Fungal Coinfections: Protocol for a Laboratory-Based Cross-Sectional Study.

BACKGROUND: Fungal-bacterial cocolonization and coinfections pose an emerging challenge among patients suspected of having pulmonary tuberculosis (PTB); however, the underlying pathogenic mechanisms and microbiome interactions are poorly understood. Understanding how environmental microbes, such as fungi and bacteria, coevolve and develop traits to evade host immune responses and resist treatment is critical to controlling opportunistic pulmonary fungal coinfections. In this project, we propose to study the coexistence of fungal and bacterial microbial communities during chronic pulmonary diseases, with a keen interest in underpinning fungal etiological evolution and the predominating interactions that may exist between fungi and bacteria. OBJECTIVE: This is a protocol for a study aimed at investigating the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections through determining and characterizing the burden, etiological profiles, microbial communities, and interactions established between fungi and bacteria as implicated among patients with presumptive PTB. METHODS: This will be a laboratory-based cross-sectional study, with a sample size of 406 participants. From each participant, 2 sputa samples (one on-spot and one early morning) will be collected. These samples will then be analyzed for both fungal and bacterial etiology using conventional metabolic and molecular (intergenic transcribed spacer and 16S ribosomal DNA-based polymerase chain reaction) approaches. We will also attempt to design a genome-scale metabolic model for pulmonary microbial communities to analyze the composition of the entire microbiome (ie, fungi and bacteria) and investigate host-microbial interactions under different patient conditions. This analysis will be based on the interplays of genes (identified by metagenomics) and inferred from amplicon data and metabolites (identified by metabolomics) by analyzing the full data set and using specific computational tools. We will also collect baseline data, including demographic and clinical history, using a patient-reported questionnaire. Altogether, this approach will contribute to a diagnostic-based observational study. The primary outcome will be the overall fungal and bacterial diagnostic profile of the study participants. Other diagnostic factors associated with the etiological profile, such as incidence and prevalence, will also be analyzed using univariate and multivariate schemes. Odds ratios with 95% CIs will be presented with a statistical significance set at P<.05. RESULTS: The study has been approved by the Mbarara University Research Ethic Committee (MUREC1/7-07/09/20) and the Uganda National Council of Science and Technology (HS1233ES). Following careful scrutiny, the protocol was designed to enable patient enrollment, which began in March 2022 at Mbarara University Teaching Hospital. Data collection is ongoing and is expected to be completed by August 2023, and manuscripts will be submitted for publication thereafter. CONCLUSIONS: Through this protocol, we will explore the metabolic and molecular ecological evolution of opportunistic pulmonary fungal coinfections among patients with presumptive PTB. Establishing key fungal-bacterial cross-kingdom synergistic relationships is crucial for instituting fungal bacterial coinfecting etiology. TRIAL REGISTRATION: ISRCTN Registry ISRCTN33572982; https://tinyurl.com/caa2nw69. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48014.

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.

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.

Thirty-Day Outcomes of Young and Middle-Aged Adults Admitted with Severe COVID-19 in Uganda: A Retrospective Cohort Study.

Background: There is scarcity of data regarding young and middle-aged adults hospitalized with severe Corona Virus Disease 2019 (COVID-19) in Africa. In this study, we describe the clinical characteristics and 30-day survival among adults aged 18 to 49 years admitted with severe COVID-19 in Uganda. Methods: We reviewed treatment records of patients admitted with severe COVID-19 across five COVID-19 treatment units (CTU) in Uganda. We included individuals aged 18 to 49 years, who had a positive test or met the clinical criteria for COVID-19. We defined severe COVID-19 as having an oxygen saturation <94%, lung infiltrates >50% on imaging and presence of a co-morbidity that required admission in the CTU. Our main outcome was the 30-day survival from the time of admission. We used a Cox proportional hazards model to determine the factors associated with 30-day survival at a 5% level of significance. Results: Of the 246 patient files reviewed, 50.8% (n = 125) were male, the mean ± (standard deviation) age was 39 ± 8 years, majority presented with cough, 85.8% (n = 211) and median C-reactive protein (interquartile range) was 48 (47.5, 178.8) mg/L. The 30-day mortality was 23.9% (59/246). At admission, anemia (hazard ratio (HR): 3.00, 95% confidence interval (CI), 1.32-6.82; p = 0.009) and altered mental state (GCS <15) (HR: 6.89, 95% CI: 1.48-32.08, p = 0.014) were significant predictors of 30-day mortality. Conclusion: There was a high 30-day mortality among young and middle-aged adults with severe COVID-19 in Uganda. Early recognition and targeted management of anemia and altered consciousness are needed to improve clinical outcomes.

Mycobacterium tuberculosis infection and cytogenetic abnormalities among people with HIV.

OBJECTIVE: 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]). METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Adherence of health workers to guidelines for screening and management of cryptococcal meningitis in Uganda.

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.

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.

"If you have light, your heart will be at peace": A qualitative study of household lighting and social integration in southwestern Uganda.

Background: Expanding electrification and access to other clean and affordable energy, such as solar energy, is a critical component of the Sustainable Development Goals, particularly in sub-Saharan Africa where 70% of people are energy insecure. Intervention trials related to access or less polluting household energy alternatives have typically focused on air quality and biological outcomes rather than on how an intervention affects the end user's lived experiences, a key determinant of uptake and adoption outside of a research setting. We explored perceptions of and experiences with a household solar lighting intervention in rural Uganda. Methods: In 2019, we completed a one-year parallel group, randomized wait-list controlled trial of indoor solar lighting systems (ClinicalTrials.gov NCT03351504) in rural Uganda where participants are largely relying on kerosene and other fuel-based lighting received household indoor solar lighting systems. In this qualitative sub-study, we conducted one-on-one, in-depth qualitative interviews with all 80 female participants enrolled in the trial. Interviews explored how solar lighting and illumination impacted participants' lives. We applied a theoretical model linking social integration and health to analyse dynamic interactions across aspects of study participants' lived experiences. Sensors were used to measure daily lighting use before and after receipt of the intervention solar lighting system. Results: Introduction of the solar lighting system increased daily household lighting use by 6.02 (95% confidence intervals (CI) = 4.05-8.00) hours a day. The solar lighting intervention had far-reaching social implications with improved social integration and, consequently, social health. Participants felt that lighting improved their social status, mitigated the stigma of poverty, and increased the duration and frequency of social interactions. Household relationships improved with access to lighting because of reduced conflicts over light rationing. Participants also described a communal benefit of lighting due to improved feelings of safety. At the individual-level, many reported improved self-esteem, sense of well-being, and reduced stress. Conclusion: Improved access to lighting and illumination had far reaching implications for participants, including improved social integration. More empirical research, particularly in the light and household energy field, is needed that emphasizes the impacts of interventions on social health. Registration: ClinicalTrials.gov No. NCT03351504.

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.

Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis.

Background: Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear. Methods: We analysed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into ≥100 mg/dL (n=249) and <100 mg/dL (n=641). We described baseline clinical variables and mortality by CSF protein levels. Results: Approximately one-third of individuals had a baseline CSF protein ≥100 mg/dL. Those with CSF protein ≥100 mg/dL were more likely to present with Glasgow coma scale scores <15 (P<0.01), self-reported seizures at baseline (P=0.02), higher CD4 T-cells (p<0.001), and higher CSF white cells (p<0.001). Moreover, those with a baseline CSF protein ≥100 mg/dL also had a lower baseline CSF fungal burden (p<0.001) and a higher percentage of sterile CSF cultures at day 14 (p=0.02). Individuals with CSF protein ≥100 mg/dL demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules pro-inflammatory cytokines, type-1 T-helper cell cytokines, type-3 chemokines, and immune-exhaustion marker (p<0.05). 18-week mortality risk in individuals with a CSF protein <100 mg/dL was 34% higher, (unadjusted Hazard Ratio 1.34; 95% CI, 1.05 to 1.70; p=0.02) than those with ≥100 mg/dL. Conclusion: In cryptococcal meningitis, individuals with CSF protein ≥100 mg/dL more frequently presented with seizures, altered mental status, immune activation, and favourable fungal outcomes. Baseline CSF protein levels may serve as a surrogate marker of immune activation and prognosis.

Factors Associated with 30-Day in-Hospital Mortality Among Patients Admitted with Severe Covid-19 in Mbarara Regional Referral Hospital.

Background: COVID-19 has created a burden on the healthcare system globally. Severe COVID-19 is linked with high hospital mortality. Data regarding 30-day in-hospital mortality and its factors has not been explored in southwestern Uganda. Methods: We carried out a retrospective, single-center cohort study, and included all in-patients with laboratory-confirmed, radiological, or clinical severe COVID-19 admitted between April 2020 and September 2021 at Mbarara Regional Referral Hospital (MRRH). Demographic, laboratory, treatment, and clinical outcome data were extracted from patients' files. These data were described comparing survivors and non-survivors. We used logistic regression to explore the factors associated with 30-day in-hospital mortality. Results: Of the 283 patients with severe COVID-19 admitted at MRRH COVID-19 unit, 58.1% were male. The mean age ± standard deviation (SD) was 61±17.4 years; there were no differences in mean age between survivors and non-survivors (59 ± 17.2 versus 64.4 ±17.3, respectively, p=0.24) The median length of hospital stay was 7 (IQR 3-10) days (non-survivors had a shorter median length of stay 5 (IQR 2-9) days compared to the survivors; 8 (IQR 5-11) days, p<0.001. The most frequent comorbidities were hypertension (30.5%) and diabetes mellitus (30%). The overall 30-day in-hospital mortality was 134 of 279 (48%) mortality rate of 47,350×105 with a standard error of 2.99%. The factors associated with 30-day in-hospital mortality were age: 65 years and above (aOR, 3.88; 95% CI, 1.24-11.70; P =0.020) a neutrophil to lymphocyte ratio above 5 (aOR, 4.83; 95% CI, 1.53-15.28; P =0.007) and oxygen requirement ≥15L/min (aOR, 15.80; 95% CI, 5.17-48.25; P <0.001). Conclusion: We found a high 30-day in-hospital mortality among patients with severe forms of COVID-19. The identified factors could help clinicians to identify patients with poor prognosis at an early stage of admission.

Prevalence of Intestinal Helminth Coinfection in Drug-Resistant Tuberculosis in Uganda.

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.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Cigarette smoking is associated with an increase in blood monocytes in people with tuberculosis: A cross-sectional study.

The effect of smoking on immune responses in people with tuberculosis (TB) is not well elucidated. We aimed to compare peripheral blood counts of CD4+ and CD87 + T-lymphocytes, monocytes, and neutrophils and the CD4:CD8 ratio in TB patients with and without history of cigarette smoking. We further determined factors associated with current smoking. Participants with TB were consecutively enrolled in a cross-sectional study at a national TB treatment center in Uganda in 2018. We compared cell counts and the CD4:CD8 ratio using the median test among never smokers, past smokers (>6 months ago) and current smokers (≤6 months). Factors associated with current smoking were determined using logistic regression. A post hoc analysis for factors associated with an increase in the monocytes was also performed. Of 363 participants, there were 258 (71.1%) never smokers, 50 (13.8%) past smokers, and 55 (15.2%) current smokers. Most current smokers (49.1%) had a high sputum mycobacterial load. They also had the lowest body mass index and the highest axillary temperature. The median (interquartile range [IQR]) monocyte count among current smokers was 815 (540-1425) cells/mm3 and was significantly higher than that among past smokers (610 (350-900) cells/mm3, P = .017) and never smokers (560 [400-800] cells/mm3, P = .001). The monocyte counts positively correlated with the number of cigarettes smoked per day among current smokers (R = 0.43, P = .006). Current smokers also had higher neutrophil and CD4+ T-cell counts than never smokers. In a multivariable logistic regression model, an increase in the monocyte count was associated with current cigarette smoking (adjusted odds ratio [aOR] = 4.82, 95% confidence interval 1.61-14.39, P = .005). Similarly, current cigarette smoking was independently associated with an increase in the monocyte count (aOR = 1.80, 95% CI 1.39-2.32, P < .001). Cigarette smoking is associated with an increase in the blood monocytes in people with TB in a dose- and time-dependent manner. Further, current smoking is associated with an increase in neutrophils and CD4+ T-lymphocytes. The findings suggest that current smokers have systemic inflammation that is not necessarily beneficial to TB control in TB patients.