John Kayiwa

Background: Seasonal influenza, commonly known as flu, is an acute respiratory, highly contagious illness caused by influenza viruses. A clear understanding of influenza seasonality is crucial for guiding prevention and treatment strategies, including decisions on vaccination timing to prevent outbreaks. While well documented in temperate regions, data on influenza epidemiology in tropical areas, particularly sub-Saharan Africa, remain limited. We described the types, subtypes and positivity rate of seasonal influenza in Uganda during 2019–2023. Methods: This study used descriptive statistics to understand the characteristics of the data, and then employed multivariable logistic regression to identify factors independently associated with a positive influenza test result. The regression analysis examined the impact of sex, sample type, time of year, and year on influenza positivity, quantifying these associations with odds ratios, confidence intervals, and p-values to assess their statistical significance. Results: Of 18035 samples, 938 (5.2%) tested positive for influenza, with a higher prevalence in Influenza-Like Illness (ILI) cases (5.7%) compared to Severe Acute Respiratory Infection (SARI) cases (3.7%). Influenza A was the predominant type (69.7%), followed by influenza B (29.7%, all B. Victoria), with rare co-infections. Among influenza A subtypes, A/H3N2 was most common (65.1%), followed by A/H1N1pdm09 (33.5%). Multivariable logistic regression revealed that the male gender, the month of March, and decreasing year were associated with increased influenza positivity, while SARI sampling and other months showed reduced positivity. Conclusion: The seasonal influenza positivity rates from 2019 to 2023 and the predominance of Influenza A and H3N2 highlight the need for sustained surveillance in Uganda. Given Influenza A’s high genetic variability and potential for novel strain emergence, monitoring circulating strains, informing vaccine development, and implementing targeted interventions for high-risk groups and regions are critical to controlling and preventing outbreaks.

OBJECTIVES: Severe tuberculosis (TB) is a major cause of critical illness and death in people living with HIV (PLWH) worldwide. Despite this, the immunopathology of severe HIV-associated TB (HIV/TB) is poorly understood. We aimed to identify an immunopathologic signature of severe HIV/TB in sub-Saharan Africa. DESIGN AND SETTING: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, n = 241) and a rural validation cohort (Tororo, n = 253). PATIENTS: Adults (age ≥ 18 yr) hospitalized with severe febrile illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, severe HIV/TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-d mortality of 22% in the discovery cohort and 60-d mortality of 26% in the validation cohort). Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort as a supervised feature-selection approach to identify proteins associated with progressive HIV/TB phenotype. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-d mortality of 42% in the discovery cohort and 60-d mortality of 52% in the validation cohort). An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (lysosome-associated membrane glycoprotein 3), natural killer cell and T-cell stimulation and cytotoxicity (cluster of differentiation 70, class I-restricted T-cell–associated molecule), B-cell activation (immunoglobulin lambda constant 2), protease-mediated tissue injury (protease, serine 2 [trypsin-2]), dysregulated coagulation (serpin peptidase inhibitor, clade A [alpha-1 antitrypsin], member 5), extracellular matrix remodeling (epidermal growth factor-containing fibulin-like extracellular matrix protein 1), and growth hormone/insulin-like growth factor axis dysregulation (insulin-like growth factor binding protein 3). CONCLUSIONS: We identified an immunologic signature of severe HIV/TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.

IMPORTANCE: Biologically defined sepsis subtypes have been identified in low- and middle-income countries (LMICs), but limited access to molecular diagnostics constrains broader evaluation and implementation in resource-limited settings. OBJECTIVES: To determine whether bedside-accessible variables could approximate molecular sepsis subtype assignments among Ugandan adults with sepsis. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of two prospective observational sepsis cohorts conducted at Tororo General Hospital (Research in the Epidemiology of Severe and Emerging Infections in Uganda-2-Tororo [RESERVE-U-2-TOR]) and Entebbe Regional Referral Hospital (Research in the Epidemiology of Severe and Emerging Infections in Uganda-1-Entebbe [RESERVE-U-1-EBB]), Uganda. Participants were adults 18 years old or older hospitalized with sepsis who underwent transcriptomic ( n = 355) and/or proteomic ( n = 495) profiling. MAIN OUTCOMES AND MEASURES: Prespecified clinical and clinico-microbiologic models were evaluated for discrimination and calibration against Uganda-derived transcriptomic and proteomic sepsis subtypes and, secondarily, high-income country (HIC)-derived sepsis subtypes and immune dysregulation frameworks. RESULTS: In RESERVE-U-2-TOR, clinical models incorporating demographic and physiologic variables showed moderate discrimination for transcriptomic and proteomic subtypes (area under the receiver operating characteristic curve [AUROC], 0.75 [95% CI, 0.69–0.81] and 0.73 [95% CI, 0.66–0.80], respectively), with generally acceptable calibration. Adding rapid HIV, malaria, and tuberculosis test results did not meaningfully improve performance. In RESERVE-U-1-EBB, discrimination was more variable (AUROC range, 0.63–0.75), with generally acceptable calibration. Performance was similarly modest for HIC-derived sepsis subtypes and immune dysregulation axes. CONCLUSIONS AND RELEVANCE: Bedside-accessible clinical variables, with or without rapid microbiologic testing, only partially approximated molecular sepsis frameworks in Uganda. Scalable molecular biomarker platforms are needed to advance precision medicine for sepsis in LMICs.

Background: Respiratory syncytial virus is an important cause of acute respiratory illness in older adults, yet data from sub-Saharan Africa remain scarce. Better understanding of its prevalence, coinfections, seasonal patterns, and risk factors in older populations is essential for strengthening surveillance systems and informing prevention strategies in low-resource settings. Methods: We conducted a retrospective cross-sectional study using Uganda’s national influenza-like illness and severe acute respiratory infection sentinel surveillance data from December 2010 to January 2025. Adults aged ≥65 years with real-time-PCR results for respiratory syncytial virus, influenza A and B, and SARS-CoV-2 were included. Descriptive analyses summarized prevalence, clinical characteristics, and temporal trends. Poisson regression with robust variance estimated adjusted prevalence ratios for factors associated with infection and hospitalization. Results: Among 545 illness episodes (mean age 73.2 years; 54.1% female), the period prevalence of respiratory syncytial virus across 2010–2025 was 4.8% (95% CI 3.3–6.9), comparable to influenza A (4.2%) and lower than SARS-CoV-2 (6.4%). Most RSV cases were mono-infections (92.3%), with rare respiratory syncytial virus–influenza coinfections (0.4%) and no respiratory syncytial virus–SARS-CoV-2 coinfections. Asthma and pneumonia were independent predictors of infection. Hospitalization was strongly associated with asthma, pneumonia, and heart disease. Activity showed seasonal peaks in March and June, with a marked decline during 2020–2021 and resurgence thereafter. Conclusions: RSV is a consistent contributor to medically attended respiratory illness among older Ugandan adults, with prevalence similar to influenza A. Although strong associations with asthma and pneumonia were observed, asthma-related findings are based on few cases and should be considered hypothesis-generating. Seasonal clustering and post-pandemic resurgence support integrating respiratory syncytial virus into routine respiratory surveillance and inform the targeted introduction of preventive interventions, including vaccination, in low- and middle-income settings.

Rift Valley fever (RVF) transmission has intensified in southwestern Uganda since 2016. To quantify human and livestock exposure and associated risks, we conducted a cross-sectional serosurvey in Isingiro, Kabale and Rubanda districts between October and November 2023. A total of 766 humans and 2383 livestock were sampled and tested for RVF antibodies using ELISA, with structured questionnaires capturing demographic, behavioral and environmental data. Human seroprevalence was 11.5% (88/766), varying by district (13.8% Isingiro, 11.8% Rubanda, 6.8% Kabale; p = 0.04). Independent predictors from the multivariate model included raw-meat consumption (aOR 6.11; 95% CI 1.16–27.80), cattle ownership (aOR 2.33; 95% CI 1.27–4.36), male sex (aOR 1.64; 95% CI 1.02–2.66) and younger age compared with ≥50 years (31–49 years: aOR 2.02; 95% CI 1.20–3.48; 18–30 years: aOR 2.37; 95% CI 1.04–5.14). Herd-level seroprevalence was 42.5% (204/480), associated with cattle presence (aOR 6.48; 95% CI 4.10–10.40), lack of carcass burial (aOR 15.70; 95% CI 4.23–63.60), on-farm slaughter (aOR 2.14; 95% CI 1.21–3.89) and increased mosquito activity (aOR 1.75; 95% CI 1.13–2.73). Animal-level seroprevalence was 14.6% (347/2383), highest in cattle (33.8%), with cattle having markedly higher odds than goats (aOR 6.73; 95% CI 4.96–9.14). These findings demonstrate substantial transmission and highlight cattle-centered interfaces as primary targets for control to humans.

OBJECTIVE: Severe infectious diseases are a leading cause of morbidity and mortality worldwide, particularly in sub-Saharan Africa (SSA), where young and middle-aged adults are disproportionately affected. Although age-related immune changes such as inflammaging and immunosenescence have been well characterized in high-income countries, their relevance to host responses during infection in SSA remains poorly understood. We aimed to characterize age-associated differences in immune, metabolic, and endothelial responses to severe infection in a prospective, multicenter cohort of adults in Uganda. DESIGN: Prospective cohort study. SETTING: Two public referral hospitals in Uganda. PATIENTS: Non-pregnant adults (18 yr old or older) hospitalized with severe, undifferentiated infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed clinical data and serum Olink proteomic profiles from 434 participants (median age: 45 yr old, interquartile range : 31–57). Clinically, illness severity and mortality were highest and comparable among adults 35–44, 45–59, and 60 years old or older, relative to younger adults. HIV prevalence peaked in the 35–44 and 45–59 age groups. Although most host responses were conserved across age groups after adjustment for sex and high-burden co-infections, patients 60 years old or older exhibited distinct immune dysregulation characterized by signs of Th1-predominant innate immune activation (increased CXCL9, CCL18, MCP1, and MCP4 expression, reduced interleukin-13 expression), dysregulated adaptive immunity (increased soluble CD27 and CD70 expression, reduced CD21 [CR2] expression), and increased cellular turnover and endothelial remodeling. CONCLUSIONS: Older age (60 yr old or older) is associated with distinct host responses to severe infection in SSA. These findings may inform development of age-stratified, host-directed treatment strategies for severe infectious diseases.

Background: Respiratory syncytial virus (RSV) is an important cause of acute respiratory illness in older adults, yet data from sub-Saharan Africa remain scarce. Understanding prevalence, coinfections, and risk factors in this age group is critical for guiding surveillance and prevention. Methods: We conducted a retrospective cross-sectional study using Uganda’s national influenza-like illness (ILI) and severe acute respiratory infection (SARI) sentinel surveillance data from December 2010 to January 2025. Adults aged ≥65 years with Real time-PCR (RT-PCR) results for RSV, influenza A/B, and SARS-CoV-2 were included. Descriptive analyses summarized period prevalence, clinical characteristics, and temporal trends. Poisson regression with robust variance estimated adjusted prevalence ratios (aPRs) for factors associated with RSV infection and hospitalization. Results: Among 545 illness episodes (mean age 73.2 years; 54.1% female), the period prevalence of RSV across 2010–2025 was 4.8% (95% CI: 3.3–6.9), comparable to influenza A (4.2%) and lower than SARS-CoV-2 (6.4%). Most RSV cases were mono-infections (92.3%), with rare RSV–influenza coinfections (0.4%) and no RSV–SARS-CoV-2 coinfections. Asthma (aPR 6.08, 95% CI: 1.18–31.26, p=0.031) and pneumonia (aPR 2.83, 95% CI: 1.06–7.56, p=0.038) were independent predictors of RSV infection. Hospitalization was strongly associated with asthma (aPR 21.69, 95% CI: 7.50–62.71, p<0.001), pneumonia (aPR 3.80, 95% CI: 1.51–9.56, p=0.005), and heart disease (aPR 3.50, 95% CI: 1.03–11.91, p=0.045). RSV activity showed seasonal peaks in March and June, with a marked decline during 2020–2021 (COVID-19 restrictions) and resurgence thereafter. Conclusions: RSV is a consistent contributor to respiratory illness among older Ugandan adults, with period prevalence estimates similar to influenza A and clinically important associations with asthma and pneumonia. Seasonal peaks during the dry season and post-pandemic resurgence emphasize the need for RSV integration into surveillance and the timely introduction of preventive interventions, including vaccination, in low- and middle-income settings.

Limited surveillance and laboratory testing for non-influenza viruses remains a challenge in Uganda. The World Health Organization (WHO) designated National Influenza Center (NIC) tested samples from patients with influenza-like illness (ILI) and severe acute respiratory infections (SARIs) during August 2022–February 2023. We leveraged the influenza sentinel surveillance system to detect other respiratory viruses (ORVs). Samples were tested using the US Centers for Disease Control and Prevention (CDC) influenza and SARS-CoV-2 multiplex and the FTD^TM Respiratory Pathogens 21 assays using real-time reverse transcription polymerase chain reaction (RT-qPCR). A total of 687 (ILI = 471 (68.6%) and SARI = 216 (31.4%) samples were tested. The median age was 2 years (IQR: 1–25) for ILI and 6 years (IQR: 1–18) for SARI case definitions (p-value = 0.045). One or more respiratory pathogens were detected in 38.7% (n = 266) of all samples; 33 (12.4%) were selected for metagenomics sequencing and 8 (3%) for SARS-CoV-2 targeted sequencing. Respiratory pathogens were detected by sequencing in 23 of 33 (69.7%) samples. Our study provides insight into the usefulness of this surveillance system in conducting virological testing for other viruses and provides tools and evidence to monitor patterns and characteristics of viruses causing ILI/SARI, which will guide public health decisions and interventions in Uganda.

Background: Chikungunya and Onyong’nyong viruses are mosquito-borne alphaviruses endemic to Africa, causing febrile illness with severe joint pain. While Chikungunya virus is known for its potential to cause life-threatening complications in neonates and vulnerable populations, Onyong’nyong virus remains vastly underreported due to weak surveillance and diagnostic overlap. As a result, Onyong’nyong virus’s true burden and epidemic potential remain dangerously underestimated. Methods: We conducted sentinel hospital-based surveillance in Uganda to assess the occurrence, geographical distribution, and clinical manifestation of Chikungunya and Onyong’nyong viruses. Serological and molecular diagnostic methods were employed to detect active and recent infections. Epidemiological data were analyzed to characterize clinical manifestations and determine risk factors for severe disease. Results: A total of 2,756 serum samples were collected from febrile patients across 63 districts in Uganda between 2018 and 2022. While no Chikungunya infection was detected by PCR, two cases tested positive for Onyong’nyong virus. Serological evidence of recent alphavirus infection was found in 8.79% of samples, with peak prevalence in 2020. Most positive cases reported fever, joint and muscle pain, and other non-specific symptoms. PRNT analysis revealed stronger neutralizing antibody responses to Onyong’nyong virus than Chikungunya virus, suggesting ongoing but under-recognized Onyong’nyong virus transmission across Uganda. Conclusion: This study underscores the endemic nature of Onyong’nyong virus in Uganda and the need for enhanced surveillance, improved diagnostic capacity, and targeted public health interventions. These findings will inform clinical management strategies and contribute to preparedness against future outbreaks.

: Scoring systems for organ dysfunction (e.g., the quick Sepsis-related Organ Failure Assessment [qSOFA], Modified Early Warning Score [MEWS], and Universal Vital Assessment [UVA]) are proposed as clinical criteria for sepsis. The content validity of these scoring systems is poorly understood in sub-Saharan Africa, where the global sepsis burden is concentrated. In a prospective cohort of 288 adults hospitalized with suspected sepsis in Uganda, we show that qSOFA, MEWS, and UVA scores were significantly associated with soluble mediators of innate and adaptive immune activation, endothelial dysfunction, and fibrinolysis. Results were consistent after adjustment for demographics, illness duration, and HIV or malaria coinfection. In resource-limited settings in sub-Saharan Africa, organ dysfunction scores may stratify patients at highest risk of poor outcomes and those with more dysregulated host responses. Further studies are needed to better define these relationships, including the temporal dynamics of dysregulated host responses and organ dysfunction in sepsis.