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The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.

Crimean-Congo Hemorrhagic Fever (CCHF) is endemic in Uganda, yet its epidemiology remains largely uncharacterized. To better understand its occurrence within Uganda, case reports of patients hospitalized with CCHF between 2013 and 2019 were reviewed. Further, genome sequences of CCHF-positive RNA obtained during this period were determined for phylogenetic comparisons. We found that a total of 32 cases (75% males; CFR, 31.2%), aged between 9 to 68 years, were reported during the study period. Most cases were detected during July to December of each outbreak year (81.2%; P < 0.01) and were located along the “cattle corridor” (68.7%, P = 0.03). The most common presenting symptoms were fever (93.8%), hemorrhage (81.3%), headache (78.1%), fatigue (68.8%), vomiting (68.8%), and myalgia (65.6%). In five patients for whom hematological data were available, varied abnormalities were observed including thrombocytopenia, leukopenia, anemia, lymphopenia, lymphocytosis, polycythemia, and microcytosis. About 56.3% (P = 0.47) of patients reported tick bites or exposure to livestock as their potential source of infection. Person-to-person transmission was suspected for two cases. Using unbiased metagenomics, we found that the viral S- and L- segments have remained conserved in Africa 2 clade since the 1950s. In contrast, the M segment split into two geographically interspersed clades; one that belongs to Africa 2 and another that is ancestral to Africa 1 and 2. Overall, this data summarizes information on the history and clinical presentation of human CCHF in Uganda. Importantly, it identifies vulnerable populations as well as temporal and geographic regions in Uganda where surveillance and control interventions could be focused.

After confirmation of two human cases of Rift Valley fever (RVF) in March 2016 in the Kabale district of Uganda, an entomological investigation was conducted with a focus on mosquito species composition and abundance of known and potential mosquito vector species, and virus testing to identify species most likely involved in Rift Valley fever virus transmission. This information could be used to forecast risk and facilitate improvement of prevention and response tools for use in preventing or controlling future outbreaks. From these collections, two virus isolates were obtained, one each from a pool of Aedes tricholabis and Ae. gibbinsi. Next-generation sequencing identified both isolates as Wesselsbron virus, family Flaviviridae, a neglected arbovirus of economic importance. These are the first reported Wesselsbron virus isolates from Uganda since 1966.

We evaluated the vector competence of three strains of Aedes aegypti formosus from Entebbe, Uganda, for Zika virus (ZIKV). The aim was to find out if these strains were competent or incompetent vectors for ZIKV, to explain the lack of ZIKV outbreaks in the city of Entebbe. We observed transmission rates ranging from 33% to 78%; however, these rates were not statistically significantly different, suggesting that there were no real differences among the strains. Nonetheless, this showed that populations of Ae. aegypti formosus in Entebbe are competent vectors for ZIKV. The reason why there is no detectable transmission of ZIKV to humans in Entebbe is currently unknown. The lack of detectable transmission despite Ae. aegypti formosus competence for ZIKV suggests that other parameters, such as preference for nonhuman blood, may be limiting its ability to serve as a vector.

Rift Valley fever (RVF) is caused by RVF virus (RVFV), a single-stranded RNA virus in the Bunyavirales order, Phenuiviridae family, and Phlebovirus genus. It is an emerging epidemic disease of humans and livestock and an important endemic problem in sub-Saharan Africa.1 Rift Valley fever virus is transmitted to livestock and humans by the bite of infected mosquitoes or exposure to tissues or blood of infected animals.2 Interepidemic virus maintenance is thought to occur either transovarially in Aedes species mosquitoes or through cycling of low-level transmission between domestic livestock or wild ungulates and mosquitoes.3 After periods of heavy rainfall, Aedes mosquitoes rapidly emerge, resulting in extensive amplification of the virus through infection of livestock.2 Presentation of RVF in animals can vary among species with a range of clinical severity. Livestock, particularly cattle, sheep, and goats are highly susceptible to RVFV and present with symptoms of fever, loss of appetite, weakness, low milk production, nasal discharge, vomiting, and diarrhea. During large epizootics, “abortion storms,” particularly in sheep and cattle, have been identified. High newborn mortality (80–100%) and adult mortality (5–20%) may also be observed.3 Humans infected with RVFV typically have mild, self-limited febrile illness, but can present in a small number of cases (< 8%) with severe jaundice, rhinitis, encephalitis, and hemorrhagic manifestations. Retinal degeneration (5–10% of cases), hemorrhagic fever (< 1%), or encephalitis (< 1%) may also develop.4,5 Outbreaks of RVF have been reported most frequently in East Africa, especially Kenya, Somalia, and Tanzania, with the last major outbreak in the region recorded in 1997–1998. However, outbreaks have also been reported in other African countries, including Egypt, South Africa, Madagascar, and Senegal.6 In 2000, the first RVF outbreak outside of Africa was reported in Saudi Arabia and Yemen.5,7 More recently, Kenya and Tanzania experienced a large epizootic of RVFV in 2006–2007 and Sudan in 2010.6 The emergence of RVFV in East Africa resulted in widespread livestock morbidity and mortality, with hundreds of laboratory-confirmed human cases, and likely thousands of asymptomatic or mild RVFV human infections going undetected.8,9 Rift Valley fever virus in Uganda was first detected in mosquitos collected in Semliki forest, Western Uganda, in 1944,10 and has since been detected several times by the East African Virus Research Institute (EAVRI), now the Uganda Virus Research Institute (UVRI). Human cases were recorded during outbreaks occurring near Entebbe in 1960 and 1962.11,12 Since then, serological evidence of human and livestock RVFV infections in Uganda have been intermittently reported,13,14 but the last published description of acute human RVFV infection was seven cases occurring near Entebbe in 1968.15 On March 10, 2016, UVRI and the Uganda Ministry of Health (MOH) received a report of a suspected viral hemorrhagic fever (VHF) case presenting to Kabale Regional Referral Hospital (KRRH) in Kabale district in southwestern Uganda. The initial case was of a 48-year-old male butcher who had been working in a local abattoir, where livestock were brought for slaughter. The patient presented with a history of fever, vomiting, diarrhea, headache, and hemorrhagic symptoms (bleeding gums, epistaxis, bloody urine, and stools). A blood sample was taken and sent to the UVRI VHF laboratory for testing. On March 11, a second suspected VHF case presented to KRRH with similar symptoms; a blood sample was collected for testing. This patient was a 16-year-old male student first reported by Kabale District Health Office from the Uganda–Rwanda border village of Katuna. Both samples were tested for hemorrhagic fever viruses, including Ebola viruses, Marburg virus, Crimean–Congo hemorrhagic fever virus, and RVFV. Both specimens were found to be positive for RVFV by reverse transcriptase polymerase chain reaction (RT-PCR) and IgM serology.

Among a prospective cohort of children and adults admitted to a national COVID-19 treatment unit in Uganda from March to December 2020, we characterized the epidemiology of and risk factors for severe illness. Across two epidemic phases differentiated by varying levels of community transmission, the proportion of patients admitted with WHO-defined severe COVID-19 ranged from 5% (7/146; 95% CI: 2–10) to 33% (41/124; 95% CI: 25–42); 21% (26/124; 95% CI: 14–29%) of patients admitted during the peak phase received oxygen therapy. Severe COVID-19 was associated with older age, male sex, and longer duration of illness before admission. Coinfection with HIV was not associated with illness severity; malaria or tuberculosis coinfection was rare. No patients died during admission. Despite low mortality, hospital incidence of severe COVID-19 during the first epidemic peak in Uganda was substantial. Improvements in vaccine deployment and acute care capacity, including oxygen delivery, are urgently needed to prevent and manage severe COVID-19 in sub-Saharan Africa.