BACKGROUND:People living with HIV and hospitalised with sepsis in Africa are at risk of death due to tuberculosis but diagnostics for tuberculosis might be delayed or inaccessible for people presenting for critical care. We aimed to compare the effects of immediate empirical and high-dose antituberculosis therapy on 28-day mortality in adult people living with HIV with sepsis in east Africa. METHODS:ATLAS was a phase 3, open-label, randomised, controlled, 2 × 2 factorial, superiority trial conducted at four hospitals in Tanzania and Uganda. Participants were aged 18 years or older, living with HIV, and had been admitted to hospital with sepsis with two or more modified quick Sequential Organ Failure Assessment score criteria. Exclusion criteria were active tuberculosis or receipt of antituberculosis therapy within 6 months of hospitalisation, pregnancy or lactation, allergies to antituberculosis therapy, another investigational drug within the past month, chronic liver disease, heavy alcohol use, positive serum cryptococcal antigen, or anticipated significant drug-drug interaction with rifampicin. A computer-generated permuted-block algorithm with allocation concealment and random block sizes of four and eight randomly assigned participants (1:1) to receive either immediate or diagnosis-dependent antituberculosis therapy, and (1:1) to receive either high-dose or conventional WHO-recommended weight-based dose antituberculosis therapy. Allocation was stratified by country and the presence of altered mental status at the time of randomisation. Participants randomly assigned to conventional-dose antituberculosis therapy received fixed-dose combination tablets of rifampicin approximately 10 mg/kg, isoniazid approximately 5 mg/kg, pyrazinamide, and ethambutol, plus pyridoxine 50 mg orally. Participants randomly assigned to receive high-dose antituberculosis therapy received rifampicin approximately 30 mg/kg and isoniazid approximately 7·5 mg/kg as a combination of single formulation tablets and fixed-dose combination tablets that included WHO-recommended weight-based doses of pyrazinamide and ethambutol, plus pyridoxine. Participants continued immediate antituberculosis therapy for 28 days. All medications were administered daily. Participants in the diagnosis-dependent antituberculosis therapy groups received treatment based on a clinical or microbiological diagnosis of tuberculosis. All participants received 2 g intravenous ceftriaxone daily for 7 days. The primary endpoint was 28-day mortality analysed in the modified intention-to-treat population and in the subgroup with later confirmed tuberculosis. We defined the survival time for each participant as the time from randomisation until death, discharged (alive) by day 28, or censored (alive) at day 28. We graded adverse events according to recommendations from the National Institutes of Health Division of AIDS. This study was registered with ClinicalTrials.gov, NCT04618198, and is completed. FINDINGS:Between Jan 5, 2022, and Dec 9, 2024, 707 people were screened for eligibility and 437 were randomly assigned (110 to immediate conventional-dose, 112 to immediate high-dose, 107 to diagnosis-dependent conventional-dose, and 108 to diagnosis-dependent high-dose antituberculosis therapy). 395 patients (226 [57%] of whom were female and 169 [43%] were male; all participants were Black) received study intervention and were analysed for the primary outcome of 28-day mortality. We confirmed tuberculosis in 204 (52%) patients. There was no evidence of differences in 28-day mortality in immediate antituberculosis therapy groups (50 deaths [25%] in 198 patients) compared with diagnosis-dependent groups (50 deaths [25%] in 197 patients; adjusted hazard ratio [aHR] 0·99 [95% CI 0·67-1·46]; p=0·95), or in high-dose antituberculosis therapy groups (51 deaths [26%] in 199 patients) compared with conventional-dose groups (49 deaths [25%] in 196 patients; aHR 1·07 [0·72-1·59]; p=0·73). In patients with microbiologically confirmed tuberculosis, the 28-day mortality relative to the diagnosis-dependent conventional-dose group (18 deaths [34%] in 53 patients) was lower for the immediate conventional-dose group (six deaths [12%] in 51 participants; aHR 0·32 [95% CI 0·13-0·82]; p=0·015); for the diagnosis-dependent high-dose group (11 deaths [20%] in 56 patients) was 0·51 (0·24-1·08; p=0·079); and for the immediate high-dose group (11 deaths [26%] in 43 patients) was 0·63 (0·29-1·36; p=0·24). No significant differences in adverse events occurred between treatment groups but numerically more events of drug-induced liver injury occurred in the immediate high-dose group compared with any other group. INTERPRETATION:Among all participants with HIV-related sepsis, 28-day mortality was not significantly reduced with immediate or high-dose antituberculosis therapy. In the subgroup with later confirmed tuberculosis, immediate conventional-dose antituberculosis therapy significantly reduced 28-day mortality, suggesting, as in other forms of bacterial sepsis, that hours to active treatment might determine survival. FUNDING:US National Institutes of Health.

Background Sepsis in people living with HIV (PLWH) in East Africa has high mortality. Regionally, the etiology of sepsis is incompletely understood. We performed a planned analysis of the microbiological data obtained from a randomised clinical trial of early empiric anti-Mycobacterium tuberculosis (Mtb) therapy for sepsis (ATLAS) in Tanzania and Uganda. Methods We present a prespecified, secondary analysis of a phase three, open-label, multicentre, randomised, controlled trial conducted at four regional referral hospitals in Tanzania and Uganda. Participants were adults living with HIV admitted with concern for infection and a modified quick sepsis-related organ failure assessment (qSOFA) ≥2. Participants were randomised to (1) immediate or diagnosis-dependent antituberculosis therapy and to (2) high-dose or conventional-dose antituberculosis therapy. Tests for sepsis etiology included bacterial blood and urine cultures, multi-pathogen qPCR from blood, GeneXpert MTB/RIF Ultra from sputum and urine, urine lipoarabinomannan (LF-LAM), and Mtb cultures from sputum and blood. We used multivariable logistic regression analysis and random forest analysis to determine variables that predicted Mtb as the sepsis etiology. The trial is registered with ClinicalTrials.gov, NCT04618198. Findings From January 5, 2022 through December 9, 2024, we randomised 437 participants to receive immediate and/or high dose antituberculosis therapy. Mtb was the most common pathogen, detected in 229 (52%) of 437 participants, and in 54 (50%) of 108 participants with a bloodstream infection. Combined urine LF-LAM and sputum GeneXpert MTB/RIF testing missed 17 (32%) of 54 Mtb bloodstream infections. The most frequent non-mycobacterial bacteria were Klebsiella species and Escherichia coli, which were identified in 39 (9%) and 33 (8%) of 437 participants, respectively. We detected ceftriaxone resistance in 21 (64%) of 33 bacterial isolates. In a random forest prediction model (accuracy: 0.6; precision: 0.5; recall: 0.6; F1-score: 0.5), the best indicators of Mtb as a sepsis pathogen were a greater number of ill-days before presentation (mean decrease in accuracy [MDA] 10.1), younger age (MDA 8.7), a longer duration of cough (MDA 7.7), and low CD4+ T-cell concentration (MDA 3.7). Interpretation Mtb was the most common pathogen causing sepsis and bloodstream infection and was frequently missed by conventional rapid diagnostics. We also identified a high prevalence of non-mycobacterial pathogens resistant to ceftriaxone in blood and urine cultures. Limitations of our study included exclusion of cryptococcal antigen positive participants, non-systematic drug susceptibility testing, and potential regional differences in sepsis etiology and resistance patterns. Funding NIH.

Hospitalised adults with advanced HIV disease in sub-Saharan Africa experience high mortality, with tuberculosis, often disseminated and undiagnosed, being a leading cause. Despite this, initiation of antituberculous therapy is frequently delayed pending diagnostic confirmation, which may be unavailable in this population. Evidence from recent trials and cohort studies suggests that even short delays in antituberculous therapy are associated with substantial increases in mortality, whereas empiric therapy might improve survival in people at high risk. Applying the therapeutic threshold framework, the high pre-test probability of tuberculosis in severely ill inpatients with advanced HIV disease often exceeds the threshold at which treatment benefits outweigh risks, even in the absence of confirmatory testing. Although concerns regarding toxicity, drug interactions, and overtreatment are valid, short-term empiric antituberculous therapy appears safe and these risks might be outweighed by the consequences of untreated disease. We argue for a paradigm shift towards earlier empiric antituberculous therapy, with parallel diagnostic evaluation and structured reassessment in selected patients, and for adequately powered randomised controlled trials of empiric therapy powered for mortality.

In Uganda, the complete and timely reporting of priority disease data by health centers is critical for detecting outbreaks. However, all levels of health centers face significant reporting challenges, which compromise data fidelity and public health. To assess the efficacy of existing systems, we aimed to (i) compare reporting performance among districts in the Teso region of Eastern Uganda, (ii) ascertain the association between volume of outpatient department (OPD) visits and reporting rates at facilities, and (iii) characterize reporting challenges at public health facilities. We queried Uganda’s Electronic Health Management Information System database, DHIS2, regarding the completeness (reporting rate) and timeliness (reporting rate on time) of priority disease data submission within Teso from January 1st-April 30th, 2024. We selected the three lowest-performing districts in both metrics and assessed reporting at all health centers within these districts. We used linear regression to determine the relationship between the aggregate number of outpatient visits per health facility and their mean reporting rates. At seven health facilities across the three districts, we conducted focused group discussions to enumerate reporting challenges. Of all 11 districts in Teso, seven (64

In low- and middle-income settings, microbiologic evaluation of chemotherapy-associated febrile illness is limited by cost. Cost-effective diagnostic algorithms could streamline evaluation for chemotherapy-associated febrile illness where comprehensive testing is not possible, particularly in HIV- and tuberculosis (TB)-endemic settings. In this study, we created a decision analytic model to evaluate costs, diagnostic yield, and cost-effectiveness of diagnostic algorithms for adult inpatients with solid tumors who developed chemotherapy-associated febrile illness in Uganda. Given the high prevalence of HIV, TB, and malaria, diagnostics included serum cryptococcal antigen (CrAg) lateral flow assay, Alere TB urinary lipoarabinomannan (LAM), malaria rapid testing, and aerobic blood cultures. We considered the following testing algorithms: 1) a comprehensive approach where all tests were performed on all participants and 2) stepwise algorithms where tests were performed in series and stopped with the first positive result. Prevalence data and test performance were taken from the published literature. A comprehensive testing strategy yielded 32.2% correct diagnoses at a cost of $97.85 per correct diagnosis. Of the stepwise strategies, testing CrAg first yielded the cheapest strategy at a cost of $85.49 per correct diagnosis and the highest number of appropriate diagnoses (29.9%). The incremental cost-effectiveness ratio was $234 per additional correct diagnosis for the comprehensive strategy when compared with the sequential strategy. Although comprehensive diagnostic testing is optimal for patients who experience chemotherapy-associated febrile illness, if this strategy is unavailable, stepwise testing with CrAg first and then, TB LAM is optimal to maximize correct diagnosis and minimize costs.

With an estimated 5% of global cases, Uganda carries the third-largest burden of malaria. Despite years of focus on malaria by Uganda's Ministry of Health, the malaria incidence rate increased from 206 to 271 cases per 1,000 population between 2012 and 2022. We aimed to identify gaps in malaria prevention, detection, and response in the high-burden Elgon region of Uganda. We collected data from the Ugandan District Health Information Software 2 database to identify districts with the highest incidence of malaria within the Elgon region. We used a structured assessment tool to conduct key informant interviews of district health officers, malaria focal persons, and vector control officers within each district. Qualitative data were analyzed using immersion-crystallization methodology, with multiple independent reviewers extracting major and minor themes within the framework of prevention, detection, and response. Within the category of prevention, the main theme was a lapse in vector control strategies. The major themes in the detection and response categories were lack of timely logistical support and limited chemotherapeutics, respectively. Of the 10 districts assessed, 7 (70%) had inadequate access to insecticide-treated nets, 3 (30%) had no active indoor residual spraying program, and 8 (80%) had limited or no availability of rapid diagnostic tests at the time of the assessment. The mean (±SD) time since the last resupply for antimalarial medications from the central governmental supply was 117 (±9) days. The extracted themes highlight areas for intervention within high-burden districts in eastern Uganda.

Abstract Background Microbiology diagnostic tests are often prohibitively expensive in resource-limited settings. Cost-effective diagnostic algorithms could potentially guide diagnostic evaluation for chemotherapy-associated febrile illness in resource-limited settings where comprehensive testing is not possible. This is particularly true in sub-Saharan Africa, where the high prevalence of HIV and tuberculosis (TB) place patients at increased risk of developing opportunistic infections that do not frequently occur among patients receiving chemotherapy in the United States or Europe. Methods We created a decision analytic model to evaluate the costs, diagnostic yield, and cost-effectiveness of diagnostic algorithms for adult inpatients with solid tumors who developed fever within 30 days of receiving chemotherapy in Uganda. Since Uganda has a high prevalence of HIV and TB, diagnostics included serum cryptococcal antigen (CrAg) lateral flow assay, Alere TB urinary lipoarabinomannan (LAM), malaria rapid testing, and aerobic blood cultures. We considered the following testing algorithms: 1) a comprehensive approach where all tests were performed, and 2) various stepwise algorithms where tests were performed in series and stopped testing with the first positive result. We obtained prevalence data from a cohort of 100 patients with solid tumors who were admitted to the Uganda Cancer Institute (Kampala, Uganda) with fever. Test performance was taken from the published literature. Results A comprehensive diagnostic testing strategy yielded 64% of correct diagnoses at a cost of $97.85 per correct diagnosis. Of the stepwise strategies, testing CrAg first yielded the cheapest strategy, at a cost of $85.49 per correct diagnosis, and the highest number of appropriate diagnoses (59%). The incremental cost-effectiveness ratio was $234 per additional correct diagnosis for the comprehensive over this sequential strategy. Conclusion Comprehensive diagnostic testing is optimal for patients who experience post-chemotherapy febrile illness in resource-limited settings. If this strategy is not available, stepwise testing with CrAg then TB LAM is the optimal strategy to maximize correct diagnosis and minimize costs. Disclosures All Authors: No reported disclosures

BACKGROUND:Corticosteroids are recommended for the treatment of septic shock but are understudied in Africa. We aimed to determine (1) characteristics of patients with sepsis in Uganda who received corticosteroids, and (2) the association between receiving corticosteroids and outcomes. METHODS:We conducted a single centre retrospective observational cohort study of patients with sepsis at the Mbarara Regional Referral Hospital in Uganda. We included patients admitted from the emergency ward with suspected infection and ≥2 quick sequential organ failure assessment criteria. We determined predictors of receiving corticosteroids with logistic regression and predictors of 28-day mortality using Cox proportional hazards regression. We adjusted models for severity of illness using the Universal Vital Assessment (UVA) mortality risk score. RESULTS:Of the 300 patients analysed, 141 (47%) were female, and the median (IQR) age was 55 (43-66) years. Corticosteroids were received by 71 (23%) patients at a median (IQR) of 1 (0-2) day from admission. The UVA score (adjusted OR (aOR) 1.16, 95% CI 1.03 to 1.30) and meningitis (aOR 4.31, 95% CI 2.04 to 9.12) were predictors of receiving corticosteroids. The UVA score (adjusted HR (aHR) 1.14, 95% CI 1.02 to 1.26) and receiving corticosteroids (aHR 0.43, 95% CI 0.21 to 0.91) were predictors of increased and decreased 28-day mortality, respectively. Receiving corticosteroids remained an independent predictor of decreased 28-day mortality when entered into the model as a time dependent variable (aHR 0.33, 95% CI 0.13 to 0.83, p=0.02). In a sensitivity analysis adjusted for age, sex and severity of illness, receiving vasopressors (aHR 3.48, 95% CI 1.88 to 6.43, p<0.001) and receiving corticosteroids (aHR 0.40, 95% CI 0.19 to 0.85, p=0.02) were independent predictors of increased and decreased 28-day mortality, respectively. CONCLUSIONS:In patients with sepsis in Uganda, receiving corticosteroids was associated with severity of illness and meningitis, and receiving corticosteroids was associated with improved outcomes.

Within sub-Saharan Africa, Uganda carries the third largest burden of malaria with 5

Introduction:Sepsis causes high mortality among people living with HIV in Africa, yet immune response data are limited. We identified immune subphenotypes of adults with sepsis and a high prevalence of HIV in East Africa. Methods:We determined the association of serum cytokine and antibody concentrations with CD4+ T-cell and blood lactate concentration, tuberculosis, and 30-day mortality with K-means clustering, principal component analysis (PCA), and logistic regression. We validated results in a separate cohort of adults with sepsis in East Africa. Results:Of 208 participants in the discovery cohort, 117 (56%) were female and 175 (84%) were living with HIV, with a mean (±SD) age of 35 (±10) years. Participants with tuberculosis had higher concentrations of G-CSF, IFN-γ, IL-1β, IL-6, IL-8, and MCP1MCAF, whereas mortality was associated with higher concentrations of G-CSF, IL-6, IL-8, IL-10, and MIP-1β, and lower concentrations of IgM antibodies against oxidation-specific epidopes (IgM OSE ). PCA identified G-CSF, IL-5, IL-6, IL-8, and IL-13 as the main contributors to tuberculosis, and IL-4, IL-6, IL-8, IL-12, and IL-13 as the main contributors to mortality. Comprehensive biomarker and clinical and multivariable models accurately predicted tuberculosis (AUC = 0.84) and mortality (AUC = 0.78), which was replicated in the validation cohort. Cross-testing showed that the tuberculosis model delineated pathogen-specific immune activation, while the mortality model represented non-pathogen-specific immune dysregulation. Conclusions:In adults with sepsis and high HIV prevalence in East Africa, tuberculosis was associated with pathogen-specific inflammation, and mortality was associated with broader immune dysregulation and diminished IgM OSE antibody responses.

Sepsis remains a significant global health threat with a disproportionate burden in low-income countries including those in sub-Saharan Africa where case fatality rates are as high as 30% to 50%. Defined as a severe systemic response to infection, sepsis leads to widespread immune dysregulation and organ dysfunction, including adrenal insufficiency. Critical illness-related corticosteroid insufficiency (CIRCI) arises from dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids, all of which can occur during sepsis. Clinical trials of corticosteroids for the treatment of patients with sepsis and septic shock have shown improvements in shock reversal, and in some studies, patient survival; however, their role in the treatment of sepsis in sub-Saharan Africa is unknown. The incidence of sepsis in sub-Saharan Africa is compounded by high rates of human immunodeficiency virus (HIV) and co-infections, including tuberculosis (TB), which is the leading cause of sepsis. Both HIV and TB can cause immune dysregulation and adrenal insufficiency, which may exacerbate CIRCI and prolong shock. Existing sepsis research has been predominantly conducted in high-income countries and has largely excluded people living with HIV or TB. Therefore, there is a need to better understand sepsis and CIRCI pathophysiology in the context of specific regional host and pathogen characteristics. In this narrative review, we explored the pathophysiology of sepsis in sub-Saharan Africa including the existing literature on the immune response to sepsis and the prevalence of adrenal insufficiency in patients with HIV and TB, with a focus on the implications for corticosteroid management. We found a compelling need to further evaluate corticosteroids for the treatment of sepsis in Africa.

There are few data regarding clinical outcomes from COVD-19 from low-income countries (LICs) including Rwanda. Accordingly, we aimed to determine 1) outcomes of patients admitted to hospital with COVID-19 in Rwanda, and 2) the ability of the Universal Vital Assessment (UVA) score to predict mortality in patients with COVID-19 compared to sequential organ failure assessment (SOFA) and quick (qSOFA) scores. We conducted a retrospective study of patients aged ≥18 years hospitalized with laboratory-confirmed COVID-19 at the University Teaching Hospital of Butare (CHUB), Rwanda, April 2021-January 2022. For each participant, we calculated UVA, SOFA, and qSOFA risk scores and determined their area under the receive operating characteristic curve (AUC). We used logistic regression to determine predictors of mortality. Of the 150 patients included, 83 (55%) were female and the median (IQR) age was 61 (43-73) years. The median (IQR) length of hospital stay was 6 (3-10) days. Respiratory failure occurred in 69 (46%) including 34 (23%) who had ARDS. The case fatality rate was 44%. Factors independently associated with mortality included acute kidney injury (adjusted odds ratio [aOR] 7.99, 95% confidence interval [CI] 1.47-43.22, p = 0.016), severe COVID-19 (aOR 3.42, 95% CI 1.06-11.01, p = 0.039), and a UVA score >4 (aOR 7.15, 95% CI 1.56-32.79, p = 0.011). The AUCs for UVA, qSOFA, and SOFA scores were 0.86 (95% CI 0.79-0.92), 0.81 (95% CI 0.74-0.88), and 0.84 (95% CI 0.78-0.91), respectively, which were not statistically significantly different from each other. At a UVA score cut-off of 4, the sensitivity, specificity, positive predictive value, and negative predictive value for mortality were 0.58, 0.93, 0.86, and 0.74, respectively. Patients hospitalized with COVID-19 in CHUB had high mortality, which was accurately predicted by the UVA score. Calculation of the UVA score in patients with COVID-19 in LICs may assist clinicians with triage and other management decisions.

Background In sub-Saharan Africa, the provision of infection prevention and control (IPC) measures are often limited by resource constraints. Aim. To determine the association of supportive supervision activities with the availability of the WHO core components for IPC at health facilities in Southwestern Uganda. Methods We employed a before and after quality improvement study design. We conducted a baseline assessment of the availability of the WHO IPC core components and provided supportive supervision activities, which was followed by a second IPC assessment. We included health centers II-IV, which have increasing clinical care capacity, and regional hospitals. Findings. Of 244 regional health facilities, baseline assessment occurred at 111 (45%) of which 23 (21%) were reassessed. The number of facilities in the Red (<70%) category for each core component stayed the same or decreased at each facility type, but there was an increase from five to six health center III facilities scoring Red (<70%) for PPE. The number of facilities in the Green (>85%) category for each core component stayed the same or was increased at each facility type, but there was a decrease from four to two health center III facilities scoring Green (>85%) for instrument processing. There was an increase in the median (interquartile range [IQR]) overall score for all facilities (65 [54-72] vs 75 [68-83], p=0.0001). Conclusion Supportive supervision activities were associated with improved availability of the core components of IPC at health facilities in Southwestern Uganda. PPE should be prioritized in health care facilities in Southwestern Uganda.

Background Clinical severity scores can identify patients at risk of severe disease and death, and improve patient management. The modified early warning score (MEWS), the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA), and the Universal Vital Assessment (UVA) were developed as risk-stratification tools, but they have not been fully validated in low-resource settings where fever and infectious diseases are frequent reasons for health care seeking. We assessed the performance of MEWS, qSOFA, and UVA in predicting mortality among febrile patients in the Lao PDR, Malawi, Mozambique, and Zimbabwe. Methods We prospectively enrolled in- and outpatients aged >= 15 years who presented with fever (>= 37.5 degrees C) from June 2018-March 2021. We collected clinical data to calculate each severity score. The primary outcome was mortality 28 days after enrolment. The predictive performance of each score was determined using area under the receiver operating curve (AUC). Findings A total of 2797 participants were included in this analysis. The median (IQR) age was 32 (24-43) years, 38% were inpatients, and 60% (1684/2797) were female. By the time of follow-up, 7% (185/2797) had died. The AUC (95% CI) for MEWS, qSOFA and UVA were 0.67 (0.63-0.71), 0.68 (0.64-0.72), and 0.82 (0.79-0.85), respectively. The AUC comparison found UVA outperformed both MEWS (p < 0.001) and qSOFA (p < 0.001). Interpretation We showed that the UVA score performed best in predicting mortality among febrile participants by the time follow-up compared with MEWS and qSOFA, across all four study sites. The UVA score could be a valuable tool for early identification, triage, and initial treatment guidance of high-risk patients in resource-limited clinical settings.