Infectious Diseases Institute

Age is a key risk factor for morbidity in coronavirus disease 2019 (COVID-19). This study investigates how "inflammaging" predisposes older hosts to severe SARS-CoV-2 outcomes through systemic and localized metabolic shifts. SARS-CoV-2 infection experiments were conducted respectively on 8 week-old mice and 16 week-old mice. An integrated multiomics approach was employed to delineate age-dependent molecular signatures and metabolic-immune crosstalk. 16 week-old mice exhibited significantly exacerbated weight loss and pulmonary pathology, successfully recapitulating age-related susceptibility. Multiomics integration revealed a "systemic bioenergetic gap": suppressed plasma TCA cycle metabolites correlated with depleted pulmonary nucleotide pools (AMP, GMP, UMP and uracil). This metabolic failure led to a paradoxical proteomic profile: despite interferon pathway activation, key antiviral effectors (RSAD2, ISG15, IFIT3B) were downregulated, while stress markers (CYP1A1, MAPK8) increased. Furthermore, threonic acid, betaine, and d-ribose were identified as robust, age-dependent biomarkers of infection severity. Our findings suggest that COVID-19 severity in the aging host is driven by the failure of a systemic-to-local metabolic-immune axis. The exhaustion of circulating energetic precursors constrains localized pulmonary nucleotide metabolism, thereby impairing essential antiviral responses and tissue repair. This study identifies the "systemic bioenergetic gap" as a novel therapeutic target, suggesting that systemic metabolic resuscitation may improve clinical outcomes in elderly populations.

Limited data exist on temporal changes in antibiotic use in low and middle-income countries. We evaluated trends in antibiotic use at tertiary hospitals in Uganda. Retrospective trend analysis of a repeated point prevalence survey (PPS). This study utilised antibiotic use data from quarterly PPS conducted among inpatients at nine regional referral hospitals in Uganda between October 2020 and December 2023. We determined the proportions of antibiotic use, prescriptions guided by culture and sensitivity tests (CST), WHO AWaRe (Access, Watch and Reserve) categories, and prescriptions without documented indication. Linear regression was used to derive slope coefficients and 95% confidence interval (CI). Of 15,154 patients surveyed, 8,892 (58.7%) received systemic antibiotics. The median age was 23 years (IQR: 11-38), 5,338 (60.5%) were female, and 4,583 (51.5%) were on treatment for infectious syndromes, including sepsis (1,400, 15.7%) and pneumonia (867, 9.8%). The drug utilisation index (DU75) consisted of ceftriaxone, metronidazole, gentamicin and ampicillin, which accounted for 76.9% (12,291/15,989) of total antibiotic use. The distribution of prescribed antibiotics was 46.6% Access, 45.5% Watch, 0.1% Reserve and 7.7% unrecommended combinations. Overall, 5,402 (60.8%) prescriptions were aligned with national guidelines, 2,147 (24.1%) prescriptions were issued without an indication, and CST guided 271 (3%) prescriptions. Over time, there was no significant change in antibiotic prescription prevalence (slope=0.09, CI -0.93 to 1.10) and prescriptions without indication (slope=-0.70, CI -1.79 to 3.98). However, adherence to treatment guidelines (slope=2.06, CI 0.14 to 3.98) and prescriptions based on CST results (slope=0.62, CI 0.12 to 1.13) significantly increased, while 'Watch' antibiotics prescriptions decreased (slope=-0.40, CI -0.63 to -0.17). The antibiotic prescription rate remained high, with no significant change over time. Improvements were seen in adherence to treatment guidelines, use of CST and reduced use of 'Watch' antibiotics. Strengthening antibiotic stewardship is recommended to further improve practices.

Uganda implemented the antiretroviral therapy (ART) optimization program in July 2019, based on an eligibility rule. ART optimization targeted individuals with prior viral load (VL) < 1000 copies/mL, while those with VL ≥ 1000 copies/mL continued with non-optimized regimens. We assessed the effectiveness of ART optimization on VL suppression among children and adolescents with HIV (CAWH) in Uganda. We also assessed the compliance of human immunodeficiency virus (HIV) clinics with the eligibility rule and its effect on ART optimization. Therefore, we designed a quasi-experimental study using data from 21 urban and rural HIV clinics. The exposure was ART optimization, defined as the initiation or transition of CAWH on dolutegravir or a protease inhibitor (boosted lopinavir). Children and adolescents with HIV on an optimized ART regimen formed the exposed group, while those on a non-optimized ART regimen comprised the nonexposed group. The primary outcome was VL suppression, defined by VL < 1000 copies/mL after ≥6 months of ART optimization. We assessed the effectiveness of ART optimization on VL suppression using 2-stage least squares instrumental variable regression due to imperfect compliance with the eligibility rule across the clinics. We also established the effectiveness of the eligibility rule on ART optimization for individuals just below and just above the cutoff. Sensitivity analysis was performed using a noncausal approach. We analyzed data from 2999 CAWH aged ≤19 years and found an overall VL suppression of 76.1% (2282/2999). We found that ART optimization showed a trend toward improved VL suppression (risk ratio [RR] 1.81, 95% CI: 0.79-4.14). However, compliance with the rule was only for 2.6% of the participants, and the rule did not improve ART optimization (RR 0.96, 95% CI: 0.88-1.05). Overall, ART optimization, guided by an eligibility rule, did not achieve the target of ≥95% VL suppression among CAWH across the 21 public HIV clinics in Uganda, partly due to low compliance with the rule, although it showed a trend toward improvement. Addressing context-specific biological, behavioral, social, and structural barriers is needed to optimize VL outcomes.

Background Indoor residual spraying (IRS) remains one of the integral tools for malaria control and elimination globally. However, communities have mixed perceptions on the usefulness IRS and other malaria control measures. This study explored community perceptions on the effectiveness and safety of insecticides used in indoor residual spraying for malaria control in Uganda. Methods A qualitative study employing a phenomenological approach was used to collect data among adult (≥ 18 years) individuals in communities where indoor residual spraying was implemented. Household heads, IRS team leaders, spray operators, community leaders, and IRS field spray supervisors were purposively included in the study. In-depth interviews using an interview guide were used to collect data. Thematic data analysis was done using Nvivo ver 14.0 software. Results A total of 30 in-depth interviews were conducted. Study participants perceived IRS as effective from the observation of reduction in mosquito population and malaria cases following the spray. Most participants perceived IRS as safe causing only mild effects. The IRS killed other household insects including bed bugs, cockroaches, house flies and ants which helped enhance acceptance. Some of the insecticides used in the spray had strong smell and left stains on the walls. Individuals smeared sprayed walls remove the strong smell and the stains left behind. Participants reported discontinuation of use of bed nets among individuals in sprayed households. Conclusions The insecticides used in indoor residual spraying were perceived by participants as effective and safe. However, practices common in communities following IRS deployment such as discontinuation of use of bed nets and smearing of sprayed walls could potentially impact the effectiveness of IRS in malaria control. The Ministry of Health and implementing partners should strengthen community education and establish systems to help monitor implementation and effectiveness of indoor residual spraying for malaria control.

PurposeApplying standardized Brighton Collaboration (BC) case definitions retrospectively to heterogeneous real-world data (RWD) is challenging due to inconsistent clinical detail and data structures across settings. To address this, the Vaccine Monitoring Collaboration for Europe (VAC4EU) developed a structured validation pipeline that operationalizes BC case definitions for vaccine safety outcomes in RWD in a harmonized, scalable, and reusable manner.MethodsVAC4EU developed a systematic, stepwise approach to validate vaccine safety outcomes. BC case definitions were utilized when available, adapted for RWD as needed, and newly developed for outcomes without an existing BC definition. The approach involves: 1) Critical review and adaptation of BC definition by clinical and RWD experts; 2) Creation of dummy cases based on published reports; 3) Creation of REDCap electronic data collection forms (eDCF) incorporating decision logic to assigned levels of certainty (LOC); 4) Iterative testing of decision logic; and 5) comprehensive training of abstractors with real-time feedback. A dedicated task force assigned reference LOCs for dummy cases. Inter-rater reliability was measured using Fleiss’ kappa (κ) by comparing abstractor LOCs to the reference standard.ResultsThe pipeline was applied to 16 COVID-19 vaccine safety outcomes, of which 13 had existing BC definition. In total, 78 dummy case descriptions were developed across the outcomes for training of abstractors, and 15 REDCap eDCFs were created. Myocarditis and pericarditis shared an eDCF. Across 33 abstractors, 747 dummy case abstractions were completed. Agreement analysis showed 93 discrepancies (12.4%) and moderate overall concordance (κ = 0.55, across all outcomes), with the lowest for thrombosis with thrombocytopenia syndrome (κ = –0.05).ConclusionThe VAC4EU validation pipeline provides a standardized framework for training and validating vaccine safety outcome in RWD. By adapting BC case definitions and dedicated training of abstractors, we will reduce variability in outcome validation in post-authorization safety studies.

COVID-19 is a respiratory disease caused by the SARS-CoV-2 virus, which put the entire world on hold for two years from 2020 to March 2022 before the rapid roll-out of vaccines. This virus claimed many lives, 6,331,727 deaths globally, and 172,390 people in Africa died from the disease, while Uganda lost 3,620 people in the same period. The study aimed to analyse the spread patterns of SARS-CoV-2 in Uganda and neighbouring countries and understand the community transmission within Uganda. The study utilised genomic sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) repository. Bayesian Phylogeography methods were used via the BEAST software. The first case of COVID-19 in Uganda likely originated from Kenya. The virus spread from Kenya to other East African countries. Cross-border movements, especially by truck drivers and refugees, played a significant role in the spread. The study highlights the importance of cross-border collaborations to control infectious disease spread. The spread pattern was influenced by trade routes and the movement of people, emphasising the need for robust border control measures during pandemics. Understanding the origin and spread of SARS-CoV-2 can inform better public health strategies and preparedness for future pandemics.

IntroductionPre-exposure prophylaxis (PrEP) use among cisgender female sex workers (FSWs), a population at disproportionately high HIV acquisition risk in Uganda, remains suboptimal. Uptake and continued use are constrained by barriers, such as limited clinical hours, long distances to access facility-based PrEP services, and high mobility among FSWs. Community pharmacies may offer a more accessible PrEP delivery model due to extended operating hours and convenient locations. This study aims to evaluate the accessibility and capacity of pharmacies in Kampala, Uganda, to serve as potential sites for PrEP delivery.Methods and analysisWe will conduct a concurrent mixed-methods study combining geospatial mapping, structured surveys, a discrete choice experiment (DCE), and in-depth interviews (IDIs). First, the study will compare the reach and accessibility of PrEP services through community pharmacies versus public healthcare facilities. To highlight PrEP service reach, we will use geospatial analysis to map pharmacies, PrEP clinics, FSW hotspots (i.e., areas where sex is exchanged), and HIV incidence. We will also calculate a PrEP facility needs ratio (number of PrEP facilities/HIV incidence) for each of Kampala’s administrative divisions and estimate travel distance and time to access PrEP services using cost–distance analysis. Perceived accessibility of PrEP services will be assessed through FSW surveys (n=50) and IDIs (n=20–30), guided by Levesque’s framework. Then, we will evaluate pharmacy capacity via surveys (n=274) and IDIs (n=20–30), exploring infrastructure, resources, and staff perspectives, informed by the Consolidated Framework for Implementation Research. Additionally, a DCE will be embedded in the pharmacy survey to elicit staff preferences for delivery approaches and analysed using mixed logit models. Finally, we will integrate quantitative and qualitative findings to provide a broad assessment of whether pharmacies are suitable venues for PrEP delivery to FSWs in Kampala. Enrolment will begin by April 2026 for FSWs and July 2026 for pharmacy staff.Ethics and disseminationEthical approval has been obtained from the Infectious Diseases Institute Research Ethics Committee (IDI-REC-2025-175) and the Uganda National Council for Science and Technology (HS6178ES). Written informed consent will be obtained from all participants. We will disseminate study findings through stakeholder meetings, scientific conferences, and peer-reviewed publications.

Abstract Background Cryptococcal meningitis causes an estimated 19% of AIDS-related deaths globally and is the leading cause of meningitis in adults with HIV. Subclinical infection with cryptococcal antigen (CrAg) is detectable in plasma, and CrAg titer of &amp;gt;= 1:160 is associated with increased risk of meningitis or death. We evaluated if plasma CrAg titer changed over time in Uganda due to the expansion of national cryptococcal screening programs and increased access to antiretroviral therapy (ART). Baseline characteristics of participants by year of cryptococcal antigen screening. Data are presented as n (%) or median [IQR]. Fisher exact test was used to compare proportions and Kruskal-Wallis test was used for medians. Abbreviations: ART, antiretroviral therapy; CrAg, cryptococcal antigen; IQR, interquartile range. Trend in baseline median CrAg titer from 2017-2022 by quartiles. The blue line represents the estimated Sen's trend. Methods We prospectively screened adults with advanced HIV disease for plasma CrAg using the lateral flow assay and performed titers. We assessed median plasma CrAg titer and interquartile range by year and quartile from 2017 through 2022. We used Fisher’s exact test to compare the proportion with a high CrAg titer ( &amp;gt;= 1:160) over time in addition to other demographic characteristics. We applied the Mann-Kendall trend test with Sen’s estimate to analyze trends in median titers. Results From November 2017 to May 2022, 436 adults with advanced HIV disease had a positive plasma CrAg test. The median CD4+ cell count was 45 [IQR: 21,94] cells/µL, and median plasma CrAg titer was 1:80 [IQR: 10,1280]. Analysis of median quarterly CrAg titer from 2017-2022 demonstrated a non-statistically significant positive trend in CrAg titer (tau=0.385, p=0.086). The proportion of those on ART significantly decreased over time. No significant changes occurred in median CD4 count, proportion by sex, or duration of ART. Conclusion Despite expansion of CrAg screening programs and ART access in Uganda, median annual CrAg titer has not decreased between 2017 and 2022. Cryptococcosis persists in Uganda, and despite public health efforts, people are not presenting to care earlier in their disease course. In addition, the proportion on ART decreased over time. Continued expansion and refinement of CrAg screening programs and access to ART among individuals with HIV is needed in Uganda, to reduce and ultimately eliminate AIDS-related deaths. Further analysis of CrAg titer trends in other countries with a high burden of HIV would provide more insight into whether national screening programs result in earlier identification of CrAg-positive individuals, and lower plasma CrAg titer. Disclosures All Authors: No reported disclosures

Introduction: This study evaluated early treatment outcomes and the management of complications in patients with periprosthetic joint infection (PJI) of the hip and knee treated at a specialized centre using an algorithm-guided multidisciplinary team (MDT) approach. Methods: This prospective cohort includes all consecutive patients treated for acute or chronic PJI between December 2019 and December 2022, with a minimum 1-year follow-up. PJI was defined according to the criteria of the European Bone and Joint Infection Society (EBJIS). Surgical decisions were based on a published treatment algorithm. The primary outcome was treatment success at 1 year after the last PJI surgery. Results: 106 patients were included according to prespecified criteria, with a median age of 74 years (IQR 66-82) and follow-up of 24 months (IQR 15-28). 79 patients (75 %) were referred from other institutions. 44 patients (42 %) were treated with debridement, antibiotics, and implant retention (DAIR); 17 (16 %) were treated with one-stage revision; and 45 (42 %) were treated with two-stage revision. 9 patients (8 %) needed plastic surgery for soft tissue reconstruction. The 1-year infection-free survival (Delphi-based consensus criteria) was 69 % (95 % CI: 60 %-78 %). Within 1 year, 14 (13.2 %) septic and 12 (11.3 %) aseptic failures occurred after a median of 0.5 months (IQR 0.4-1) and were successfully treated in most patients. 12 patients (11 %) died after a median of 0.8 months (IQR 0.3-2.8). Conclusion: Our results demonstrate the value of an algorithm-driven MDT approach as an effective strategy for managing complex PJI patients and PJI-surgery-related complications in a specialized referral centre for bone and joint infections.