Open Forum Infectious Diseases

BackgroundEvidence supports the key role research mentors play in bolstering the success of early stage investigators (ESI). However, there are limited data about the impact of supplemental, cross-disciplinary career mentorship and professional development opportunities for ESIs seldom included during academic training. We assessed the perceived value of this approach among post-doctoral fellows and early career faculty who participated in a multi-component career mentoring program organized by the University of California, San Francisco Center for AIDS Research (UCSF CFAR). MethodsWe surveyed past program participants (2005-2020), assessing demographics, current career status, perceived impact of the program, and feedback on program elements. We performed thematic analysis on open-ended responses to explore program benefits. ResultsOf 146 program participants contacted, 102 responded (70% response rate). Over two thirds (65%) were female, and 38% self-identified as underrepresented minority (URM) investigators. A majority of respondents now dedicate >70% of their time to research. All would recommend the program to ESI colleagues, and over 80% reported that their CFAR mentors influenced their career trajectories in several ways, including help with grant writing, linkage to researchers sparking new collaborations, and support through personal challenges or navigating conflict with primary research mentors. While 90% of URM ESIs valued advice from CFAR mentors, only a third reported receiving specific support around challenges faced as minoritized investigators. ConclusionsA career mentoring program designed to complement the support offered by research mentors positively influenced the career trajectory of ESIs. Focused efforts are needed to support URM investigators who face ongoing structural barriers to success in academic settings.

Background: In sub-Saharan Africa where both tuberculosis (TB) and HIV are prevalent, empiric TB treatment in people living with HIV (PLHIV) persists due to limited sensitivity of sputum-based TB tests. We evaluated mortality among molecular test-negative presumptive TB adult PLHIV in a population where the majority are or have been on antiretroviral therapy (ART), comparing mortality between those who received empiric TB treatment and those who did not. Materials and Methods: From November 2017 to December 2020, Xpert-negative presumptive TB adult PLHIV were recruited at Mulago Referral Hospital and Kisenyi Health Centre-IV in Kampala, Uganda. Clinical data including TB symptoms, chest X-ray, and empiric TB treatment decision were collected. Laboratory investigations included CD4 cell count, serum cryptococcal antigen (CrAg), urine TB-lipoarabinomannan (TB-LAM), microbiological blood cultures, and sputum mycobacterial growth indicator tube (MGIT) cultures. Participants were followed monthly for 12 months to ascertain vital status. Results: Overall, 300 participants were enrolled; 61.3% inpatients, 55.7% female, median age 37 (IQR 29-45) years, 82.3% on ART, median CD4 206 cells/mm3 (IQR 36-507). Of the 300 participants, 68 (22.7%) received empiric TB treatment, of which 53 (77.9%) were inpatients. 12-month mortality was 31.0% (93/300); 91.4% among inpatients, 72% within three months post-enrolment. Mortality was higher among those who received empiric TB treatment (51.5 vs. 30.2 per 1,000 person-months; p=0.013) compared to those who did not. TB cultures were positive in 5.0% (15/300), of whom seven (46.7%) were also TB-LAM positive. CrAg was positive in 12.3% and 3.7% had positive blood culture. Conclusion: We found high mortality among Xpert-negative PLHIV, particularly those who received empiric TB treatment, despite high ART coverage. Cryptococcal antigenemia and bacteremia were not uncommon. In presence of negative Xpert results in PLHIV, clinicians should perform extensive laboratory evaluations to identify possible comorbidities or alternative non-TB diagnosis.

BackgroundHigh workload among healthcare workers has increasingly been correlated with poor patient outcomes, inefficient operational and financial outcomes, and burnout. Despite growing literature exploring causes of attending physician workload, there is limited understanding of trainee-specific measures. ObjectiveWe aimed to characterize elements contributing to trainee workload and perceived challenges and satisfiers to the trainee workday as a foundation for better understanding and measuring trainee work experience. MethodsInternal Medicine and Medicine-Pediatrics residents at an academic medical center were invited to participate in focus groups discussing contributors to inpatient workload and work experience between March and April 2024. A qualitative content analysis identified key metrics of trainee workload and work experience, which were then consolidated into overarching domains. A structured, multi-round rating process ranked the perceived relevance of each metric. ResultsTwenty residents participated across six focus groups. Analysis of focus groups yielded 297 workload metrics across 28 unique domains. Seventeen domains had metrics identified as highly relevant (median 6-7; IQR < 1) including autonomy, communication, disruptions, task switching, documentation, emotional burden, patient factors, professional fulfillment, rounding, teaming, and work-life balance. ConclusionsResident physicians highlighted complex interactions between clinical factors, work design, and psychosocial dynamics that contribute to their sense of workload. This creates opportunities to develop unique measures of workload to understand the trainee experience better. Further studies are needed to capture the generalizability of these findings and the relationship between these workload domains and patient, organizational, and trainee outcomes with the aim of implementing evidence-based work design.

Background: Oseltamivir is an antiviral medication for influenza that can reduce the duration of symptoms and may lower the risk of some complications. Recommendations for use of oseltamivir include in the outpatient setting for individuals at higher risk of developing influenza complications. Objectives: To describe oseltamivir initiation and treatment completion among influenza-positive outpatients and identify factors associated with each. Methods: In a U.S. outpatient household transmission study, index participants with laboratory-confirmed influenza provided up to 12 days of detailed information on medication use. We described oseltamivir initiation among index cases and treatment course completion of [&ge;] 10 doses among cases who initiated oseltamivir. We used unadjusted and adjusted logistic regression to identify factors associated with initiation and course completion. Results: Among 823 enrolled index cases, 324 (39%) initiated oseltamivir treatment. Of 406 persons at higher risk for influenza complications, 172 (42%) initiated treatment. Oseltamivir initiation was lowest among children aged 2 to < 5 years (19%) compared to all other age groups. Among 313 cases who initiated oseltamivir, 42% completed the recommended treatment course of [&ge;] 10 doses. Among 163 individuals at higher risk of influenza complications, 69 (42%) completed the recommended treatment course of [&ge;] 10 doses. Children < 2 years were significantly less likely to complete treatment compared to adults aged 18-50 years (aOR: 0.21, 95% CI: 0.04, 0.78, p= 0.030); reasons for discontinuation could not be determined. Conclusions: These findings reveal differences in oseltamivir treatment in an outpatient setting among groups at higher risk for influenza complications.

BackgroundDolutegravir (DTG)-based regimens are currently the preferred first-line therapy in many HIV programs; however, the influence of baseline advanced HIV disease (AHD) on virologic outcomes in routine national data in the DTG era remains unclear. MethodsWe conducted a retrospective cohort analysis using routinely collected data from Tanzanias National AIDS, STIs, and Hepatitis Control Programme (NASHCoP) database (2017-2021). A simple random sample of 50,000 patients was drawn from the de-duplicated national dataset, yielding 49,863 patients after data processing. The analytic cohort included 4,044 patients with baseline CD4 and endpoint viral load measurements. Viral load suppression was defined as <1000 copies/mL. Associations between baseline AHD, regimen status, and suppression were assessed using risk ratios and multivariable Poisson regression models, including an interaction term between AHD and DTG. ResultsOverall viral load suppression was 89.2% (3,607/4,044). Patients with baseline AHD had lower suppression than those without AHD (81.3% vs. 91.1%; RR 0.48, 95% CI 0.40-0.57). Suppression was higher among patients receiving DTG-based regimens than among those receiving non-DTG regimens (91.5% vs. 77.2%; RR 2.67, 95% CI 2.23-3.20). In the adjusted analysis, baseline AHD remained associated with reduced suppression (aRR 0.89, 95% CI 0.86-0.92), whereas DTG use was associated with improved suppression (aRR 1.15, 95% CI 1.10-1.20). A significant interaction between AHD and DTG was observed (aRR 1.40, 95% CI 1.20-1.63), indicating that the relative benefit of DTG was greater among patients with baseline AHD. ConclusionsAlthough viral load suppression was high in this Tanzanian routine-care cohort, patients with baseline AHD had poorer outcomes. DTG-based regimens were associated with improved overall suppression, with a greater relative benefit among patients with advanced disease. These findings support the continued prioritization of DTG-based therapy and reinforce the importance of early diagnosis and targeted management of patients with AHD.

Tuberculosis (TB) is a significant cause of morbidity and mortality in children and adolescents, causing 172,000 deaths in 2024 in children and adolescents worldwide. Diagnostic challenges are pronounced in pediatrics, in which collecting respiratory specimens is challenging and TB is often paucibacillary, leading to delayed diagnosis and increased mortality. We describe the protocol and methodology of the Pediatric TB Diagnostic (PDTBDx) cohort, a study with the primary aim of evaluating non-sputum-based TB diagnostics for diagnosis and treatment response in children. This is a prospective observational cohort study of >400 children recruited from inpatient and outpatient clinical sites in Nairobi, Kenya. Children <15 years presenting to study clinical sites with TB symptoms will be considered for enrollment as symptomatic participants. Enrolled participants will undergo rigorous clinical assessment and longitudinal follow-up to ensure appropriate diagnostic classification by NIH consensus statement guidelines for pediatric TB. Baseline evaluation includes symptom assessment, chest x-ray, HIV testing, respiratory TB culture and GeneXpert Ultra, and urine LAM. Subsequent visits occur at week 2, months 1, 2, 4, 6,12 and 24. Blood and urine specimens will be collected at baseline and at follow-up visits for storage for evaluation of novel diagnostic assays, including exosome-based and CRISPR-based TB biomarkers. This large, prospective cohort of pediatric participants with and without TB follows a consistent and rigorous protocol for diagnosing childhood TB, in concordance with internationally recognized guidelines. Assays evaluated in PDTBDx will guide improved diagnostic strategies for pediatric TB.

The A(H1N1)pdm09 virus remains a major global health threat. This study examined the burden of ICU admission, mortality, and associated predictors among patients with A(H1N1)pdm09 pneumonia in a leading center for infectious diseases in Vietnam. Information on demographic, clinical, and laboratory characteristics, and outcomes was retrieved from medical records of adults admitted with influenza A(H1N1)pdm09 during 2009-2019. Among 729 cases, 21.7% (158/729) developed pneumonia. Among 158 pneumonia cases, 36.7% (58/158) developed moderate-to-severe acute respiratory distress syndrome (ARDS), and 15.2% (24/158) received invasive ventilation. ICU admission and mortality rates were 48.7% (77/158, 95%CI 41.1-56.5%) and 8.2% (13/158, 95%CI 4.9-13.6%), respectively. Predictors of ICU admission included being >60 years old (adjusted OR [AOR] 13.864, 95%CI 2.185-87.956, P=0.005), comorbidities (AOR 6.527, 95%CI 1.710-24.915, P=0.006), AST (AOR 1.013, 95%CI 1.001-1.025, P=0.029), and moderate-to-severe ARDS (AOR 14.027, 95%CI 4.220-46.627, P<0.001). Predictors of mortality were invasive ventilation (AOR 55.355, 95%CI 1.486-2062.375, P=0.030) and double-dose oseltamivir or combination therapy (AOR 32.625, 95%CI 1.594-667.661, P=0.024). In conclusion, mortality is not rare in A(H1N1)pdm09 infection. Monitoring of older patients and those with comorbidities, liver enzyme elevation, or moderate-to-severe ARDS is essential for the timely detection of complications requiring intensive care.

Background: Induction of HIV envelope (Env)-specific broadly neutralizing antibodies (bnAbs) is considered a key objective for HIV-1 vaccine development. One approach is to vaccinate with HIV Env immunogens that initially target the naive B cell receptors of a bnAb type and boost with a series of HIV Env variants. We chose a priming immunogen, the CH505 transmitted/founder Env with high affinity for the naive B cell receptor of the prototype CD4 binding site (bs) bnAb lineage, CH103, as a candidate priming immunogen to induce the initial critical step in CD4bs bnAb development. Methods: HVTN 300 is a first-in-human, open-label Phase 1 study evaluating the safety and immunogenicity of a CH505 TF chimeric (ch) Trimer adjuvanted with 3M-052-AF (a TLR7/8 agonist) + Alum. The immunogen is a recombinant, stabilized chimeric Env trimer protein with the N-terminal sequence of CH505 TF gp120 Env transplanted into the BG505 SOSIP sequence. Participants received the adjuvanted protein administered in both deltoid muscles at months 0, 2, 4, 8, and 12. Results: Adults (n=18) aged 18 to 55 were screened at a single site in Boston, USA, and 13 were enrolled. Local and systemic reactogenicity was typically mild to moderate. One participant had severe pain/tenderness, and five participants reported transient severe systemic symptoms at least once. Five participants chose to stop further vaccination due to reactogenicity. No vaccine-related SAEs occurred. Vaccine-specific B-cell response rates reached 100% two weeks post third and fifth vaccinations. Antibody blocking experiments with monoclonal antibodies demonstrated that most participants had antibodies directed to the CD4bs. Four out of 11 participants had serum neutralization signatures for CD4bs bnAb precursors. Conclusions: No safety concerns were identified. The adjuvanted CH505 TF chTrimer elicited serum antibodies capable of CD4bs-mediated neutralization against strains designed to detect early precursors of the CD4bs B-cell lineages. Trial Registration: NCT04915768 Disclosure: Presented in part at HIVR4P 2024, Lima, Peru, October 6-10, 2024

Poor retention of physician-scientists in the work force is a major impediment to progress in biomedical research, and the leaky pipeline of junior physician-scientists was exacerbated after the COVID-19 pandemic. We report the results of a multi-institutional survey aimed at assessing hiring practice patterns among academic deans and department chairs, with 34 responses before and 70 responses after the COVID-19 pandemic. We found that private institutions tend to provide greater startup support across all areas of research, including basic science, translational, and clinical arenas, with NIH funding and publication volume predicting the level of support. We found that half of respondents provide research RVUs. The COVID-19 pandemic adversely impacted the availability of supplemental internal funding and bridge funding, which catalyzed institutions to support junior faculty through endowments. Yet, we found that junior faculty had to rearrange clinical schedules to increase clinical productivity. We also found that childcare policies were more robust at private institutions. These data highlight hiring practices across a cohort of academic deans and department chairs to improve transparency of the hiring process for junior faculty candidates approaching their first independent position. Providing greater transparency in hiring practices can help physician-scientist trainees find a good fit for their faculty position and can help stave off attrition from this pipeline.

ObjectiveTo quantify the seasonal burden of acute respiratory viral infections among healthcare workers (HCWs), characterize virologic etiologies, and identify predictors of symptomatic illness and sick leave. MethodsWe conducted a prospective cohort study of HCWs during winter 2024-2025, with weekly surveys capturing acute respiratory infections (ARI) and sick leave. Nasal-throat multiplex PCR swabs were self-collected during symptomatic episodes. Incidence rate ratios (IRRs) for symptomatic episodes and sick days were estimated using Poisson regression; presenteeism was assessed among febrile episodes. ResultsAmong 655 HCWs, 400 (61.1%) reported [&ge;]1 symptomatic episode. Over 70,861 person-days, incidence rates were 1.34 symptomatic episodes and 0.82 sick days per 100 person-days. Among PCR-confirmed episodes (n=112), rhinovirus (45.5%) and influenza (23.2%) predominated. Female sex was associated with higher rates of symptomatic episodes (IRR 1.38, 95% CI 1.11-1.72) and sick days (IRR 2.55, 95% CI 1.62-4.00), while age >56 years was associated with lower rates of both. During febrile episodes, 38.8% (95% CI 31.5%-46.6%) reported working despite fever. ConclusionsARIs were common among HCWs and frequently resulted in sick leave, yet febrile presenteeism remained substantial, underscoring the need for strengthened respiratory virus prevention and occupational health policies.

IntroductionDiagnostics have become the fundamental backbone of HIV prevention, treatment and long-term retention in care, and are critical to achieving the 95-95-95 UNAIDS targets. To effectively reach underserved and remote populations, diagnostic technologies must be cost-effective, robust, user-friendly and suitable for settings with limited infrastructure. Among available testing modalities, rapid diagnostic tests (RDTs) play a central role in expanding HIV testing coverage. Earlier generations of RDTs were limited by their inability to detect acute HIV, with limited ability to detect p24 antigen (Ag), an early marker of HIV infection, which is expected to shorten the diagnostic window to two-to-three weeks. The introduction of fourth-generation RDTs, which detects both chronic and acute HIV infection through p24 Ag detection, was designed to ensure that the traditional diagnostic window of two-to-three months is shortened to approximately two-to-three weeks. However, integrating these assays into existing testing algorithms requires clear evidence that they meet high standards of quality and performance. This systematic review aims to assess the performance of WHO-prequalified fourth-generation Ag/Ab RDTs. MethodsWe performed a systematic search across six databases to identify studies evaluating Ag/Ab RDTs against laboratory reference standards in individuals aged 12 years and older, spanning 1 January 2010 to 31 December 2025. Outcomes were limited to measures of diagnostic accuracy. A meta-analysis focusing exclusively on WHO-prequalified fourth-generation RDTs was performed using a bivariate random-effect model. Results1,932 records were screened, of which 31 diagnostic accuracy studies from 19 countries were included. 15 studies used US-only approved products, 12 used WHO-prequalified products and four used commercially discontinued products. The pooled sensitivity of WHO-prequalified Ag/Ab RDTs for acute HIV infection (AHI) was 94% (95% CI: 86%-99%). An RNA threshold of [&ge;] 1,000,000 copies/mL was used as a proxy for high viraemia and used as a cut-off for the following analyses. The cut-off based analysis is considered more suited to decision-making, as it focuses on cases most likely to be associated with higher viraemia and greater potential for detection during the p24 Ag window. When using enzyme immunoassay (EIA) as the reference standard, the pooled p24 Ag sensitivity was 76% (95% CI: 62%-88%), and the pooled p24 Ag sensitivity when using nucleic acid amplification test (NAAT) as the reference standard was 75% (95% CI: 41%-97%). In the general population, the pooled sensitivity for p24 antigen detection was 77% (95% CI: 60%-92%). Amongst risk populations, only three studies had available raw data, and the pooled sensitivity was 62% (95% CI: 10%-97%). In plasma and serum specimens, pooled p24 Ag sensitivity was 74% (95% CI: 57%-88). DiscussionCollectively, these findings indicate that WHO-prequalified fourth-generation Ag/Ab RDTs can function as a scalable frontline screening tool, particularly in low- and middle-income countries, while offering incremental holistic detection through p24 Ag. Their effective deployment, however, depends on maintaining standard algorithm safeguards, including repeat testing and targeted laboratory referral when acute infection is suspected. ConclusionsResults from this meta-analysis support the use of WHO-prequalified fourth-generation Ag/Ab RDTs for general population screening. From a programmatic perspective, the added value of WHO-prequalified fourth-generation RDTs lies in their ability to combine rapid, decentralized access to testing, with incremental yet impactful improvements in holistic detection.

Introduction Data on bloodstream infections (BSI) indicate a growth in incidence over time. This analysis utilised national data from England and the best available United States (US) evidence to predict BSI incidence over the years 2025 to 2029. The analysis utilised evidence on the cost-effectiveness of molecular rapid diagnostic tests (mRDT) to estimate the cost and mortality associated with BSI, and the potential for increased use of mRDT to save lives. Methods Data on BSI incidence by age group and sex for England in 2017 and the US (Minnesota) for 2003 to 2005 were combined with demographic projections over the years 2025 to 2029 to estimate the number of BSIs. Published costs and mortality associated with BSI, according to the method of identification of the pathogen, were used to estimate the lives saved and the cost impact of widespread use of mRDT in England and the US. Results BSI cases in England and the US are predicted to total 1.02 million and 6.24 million over the years 2025 to 2029, associated costs are GBP14.6 million and $221 million, respectively. Expanding the use of mRDT would save 2,219 and 7,554 lives in England and the US, respectively, over a 5-year period and would reduce healthcare expenditure in both countries. Conclusion There is a compelling argument to increase the uptake of mRDT to improve patient outcomes. This analysis demonstrates that expanded mRDT adoption can significantly reduce BSI burden, saving over 9,700 lives and decreasing healthcare expenditure in both countries.

Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.

BackgroundImmunocompromised (IC) individuals are at increased risk for persistent SARS-CoV-2 infections and can develop new viral mutations and lineages not seen in the community. In this case report, a persistent SARS-CoV-2 infection (330 days) in an IC patient is examined for viral mutations and mutations associated with cryptic lineages. Case PresentationThe patient was followed in a longitudinal study examining persistent SARS-CoV-2 in IC patients. The patient provided stool and nasal swab samples biweekly until 28 days post-enrollment, then monthly, and then quarterly after 12 month post enrollment until the participant was no longer positive for SARS-CoV-2. Staff performed RT-qPCR and viral sequencing on the samples. Viral mutations from the XBK lineage were already present in the initial sample. By the end of the infection period, there were 40 fixed consensus changes from XBK of which two mutations were typical for cryptic lineages. Mutations increased steadily over time, with most mutations fixed by day 253, including the cryptic typical mutations. ConclusionThis case demonstrates the potential for persistent SARS-CoV-2 infections to develop mutations and lineages in IC patients and highlights the need for continued SARS-CoV-2 monitoring and treatment in this vulnerable population.

BackgroundClostridium perfringens can cause life-threatening extraintestinal infections in immunocompromised patients, an area in which we have little information regarding strain factors that impact patient risks and outcomes. MethodsWe conducted genomic-epidemiologic analyses on C. perfringens isolates from 70 patients seen at Brigham and Womens Hospital over 2021-2024. Genomic analyses evaluated strain profiles within a broader context of 2,321 C. perfringens genomes from foodborne, veterinary, clinical, and environmental sources to identify factors associated with invasive infections. ResultsOf 70 patients with C. perfringens infections (mean age 67.6 years), 32 had invasive infections, of which two-thirds had active malignancies, and more than half were immunocompromised. Patients with invasive infections had a significantly higher 90-day mortality of 43.8% vs. 18.4% (p=0.035) and a higher median Charlson Comorbidity Index (6 vs. 3; p=0.003). Notably, no patient isolates were clonal, verifying the absence of hospital-based transmission. Patient isolates showed increased carriage of hyaluronidases (nagHIJKL), sialidases (nanIJ), and perfringolysin O (pfoA). Genomic-epidemiologic analyses identified a new independent association between the NagL hyaluronidase (OR 3.90, 95% CI 1.14 - 16.24) in highly morbid invasive infections. ConclusionWe present a comprehensive genomic analysis of C. perfringens and of strains infecting immunocompromised patients, including epidemiologic associations of the hyluronidase NagL, NanIJ sialidase, and perfringolysin O in highly morbid invasive infections. These genes provide potential markers to identify high morbidity strains that can infect these populations and to further elucidate their role in invasive infections.

ObjectiveThis study investigates the prevalence of human pegivirus (HPgV) in SARS-CoV-2-positive patients within the context of viral co-infections that may modulate COVID-19 outcomes and assesses whether HPgV co-infection is associated with COVID-19 severity. HPgV is a widely circulating but rarely monitored human virus with documented immunomodulatory effects in other viral infections, including HIV and Ebola. While HPgV prevalence is low in the general U.S. population (1-2%), it rises markedly in the setting of chronic viral co-infections, particularly HIV (15-40%). Given its immunologic effects and persistence, HPgV represents a biologically plausible but unexplored viral co-factor SARS-CoV-2 infection. MethodsWe analyzed four cohorts: SARS-CoV-2-positive individuals, ICU patients with respiratory symptoms but SARS-CoV-2-negative, HIV-positive individuals as a positive control for HPgV detection, and uninfected controls. ResultsHPgV prevalence in COVID-19 patients was low (2.1%) and comparable to population estimates. As expected, HPgV prevalence was substantially higher in the HIV cohort (34%), validating assay performance and cohort stratification. Among HPgV-positive COVID-19 cases, most experienced mild disease, with directional trends toward reduced severity despite high baseline risk factors. Healthcare workers in the control group showed unexpectedly elevated HPgV prevalence (9.6%). ConclusionsHPgV is an unmonitored but widely circulating viral co-infection in humans that may influence host responses to SARS-CoV-2. Although limited by small numbers, our findings support further investigation of HPgV and other immunomodulatory viral co-infections in COVID-19. This study suggests that HPgV co-infection may influence COVID-19 outcomes, warranting further investigation. HighlightsO_LISystematic screening of human pegivirus (HPgV), an unmonitored viral co-infection, in COVID-19 (n = 634). C_LIO_LIHPgV prevalence in COVID-19 mirrored population estimates but was markedly enriched in HIV (positive control). C_LIO_LIHPgV-positive COVID-19 cases showed trends toward milder clinical outcomes. C_LIO_LIFindings highlight the potential relevance of immunomodulatory viral co-infections in SARS-CoV-2 infection. C_LI Executive SummaryThis study evaluated the prevalence of human pegivirus (HPgV) co-infection among SARS-CoV-2-positive patients as part of a broader effort to understand how concurrent viral infections may influence COVID-19 severity. HPgV is a largely unmonitored, persistent human virus with well-described immunomodulatory effects in other viral infections, yet it has not been systematically evaluated in COVID-19. We therefore screened HPgV prevalence across COVID-19 cases, comparator cohorts, and an HIV-positive cohort as a positive control due to the well-established high prevalence of HPgV in HIV infection. Our findings indicate that HPgV prevalence in SARS-CoV-2-positive and -negative hospitalized individuals are consistent with the general U.S. population range (approximately 1-5%). Healthcare professionals exhibited a higher HPgV prevalence ([~]10%), suggesting that repeated occupational viral exposures may influence infection rates. While limited by small numbers, HPgV co-infection in COVID-19 cases was associated with directional trends toward reduced disease severity, warranting further longitudinal and mechanistic investigation. Editors summaryThis study identifies human pegivirus as a widely circulating, unmonitored viral co-infection in COVID-19 with potential relevance to disease severity.

Background: Human metapneumovirus (hMPV) is commonly associated with respiratory tract infections (RTIs) in young children. Methods: We estimated the annual hospital incidence of hMPV RTIs in children under 5 years in Scotland from 2017 to 2023 using national hospital and laboratory data. Incidence outside Lothian, where testing practices were uncertain, was extrapolated from Lothian laboratory data, where hMPV testing was advised for all RTI admissions. We also examined the severity and mortality of laboratory-confirmed hMPV cases. We developed similar estimates for RSV and Influenza A for comparison. Results: This analysis included 1,462 laboratory-confirmed hMPV hospitalisations in children aged under 5 years. The extrapolated hMPV hospital incidence ranged from 19 per 100,000 to 537 per 100,000 in children aged under 5 years. The extrapolated incidence was two to three times higher than that based on laboratory-confirmed data. Hospital incidence was higher in infants than in toddlers. hMPV incidence dropped substantially during the 2020/21 season, followed by a rebound during the 2021/22 season. About 10% of hMPV RTI hospital admissions required hospital stay [&ge;]5 days, but <1% required intensive care unit admissions or resulted in in-hospital death. RSV hospital incidence appeared substantially higher than the hMPV hospital incidence in this population. Conclusions: hMPV RTIs contribute to a substantial hospital burden in young children in Scotland. However, the RSV RTI burden is likely to be higher in the population unvaccinated against both viruses. Improved surveillance and diagnosis strategies are required to develop robust hospital burden estimates.

A number of vaccines and long-acting monoclonal antibodies have been shown to be effective in the prevention of respiratory syncytial virus (RSV) disease. However, an immune correlate of protection for RSV has not yet been identified. We conducted a systematic review to identify published reports of immunogenicity and/or efficacy in vaccines and long-acting monoclonal antibodies against RSV and performed a meta-analysis on extracted data to identify any relationship between antibody increase and protection against RSV disease. We identified 130 relevant reports which we classified into an open access evidence map of RSV immunisation products. We found a strong correlation between the immunisation induced rise in neutralising antibody titres and efficacy ({rho}>0.7 for all comparisons, Spearman). For infants, we estimated that each 10-fold increase in neutralising antibody titre rise provides an additional 31% [95% CI 10%-47%], 47% [95% CI 36%-56%] and 57% [95% CI 45%-66%] reduction in the relative risk of symptomatic, moderate and severe disease respectively. For older adults, a 10-fold rise in antibody levels was associated with a 34% [95% CI -2%-57%], 50% [95% CI 22%-67%] and 63% [95% CI 36%-79%] reduction in the relative risk of RSV disease with 1, 2 and 3 symptoms respectively. These results align extremely well with findings from natural history studies and individual-based analysis of correlates of protection studies. This work paves the way for use of neutralising antibodies as a correlate of protection to guide the development, approval, and deployment of RSV vaccines and monoclonal antibodies.

BackgroundRespiratory syncytial virus (RSV) is a leading cause of severe acute respiratory infection in infants, young children and vulnerable adults. Despite implications for designing interventions, our understanding of RSV infection/reinfection patterns during community outbreaks is incomplete. MethodsTo characterize respiratory virus infections regardless of symptom status, we performed a prospective cohort surveillance in coastal Kenya from August 2023 to August 2024. Nasopharyngeal/oropharyngeal (NP/OP) swabs were collected 1-2 times weekly regardless of symptom status for quantitative PCR testing followed by genomic analysis. RSV reinfections were defined as two positive tests separated by [&ge;]14 days and with intervening [&ge;]1 negative tests. ResultsOf 672 individuals screened, 74 tested positive (93/22,000 swabs; 0.4%). The median age among infections was 4.2 years (interquartile range (IQR): 1.8-9.4), 58.1% being female versus a median age of 14.3 years (IQR: 4.8-29.6) and 64.4% female among uninfected individuals. Overall incidence rate was 19.8 infections/100 person-years, highest incidence among infants (174.0/100 person-years, 95% CI:103.0-274.0). Infection episodes fell into seven viral lineages: A.D (n=1), A.D.1 (n=2), A.D.1.11 (n=21), A.D.2.1 (n=19), A.D.3 (n=30), A.D.5.2 (n=1), and B.D.E.1 (n=2). Six individuals (8.1%; 13.7/100 person-years) experienced reinfections, three involving same viruses with 0-3 nucleotide differences across the entire RSV genome, while other three had 20,78 and 200 nucleotide differences. The (suspect) reinfected individuals were all under 2 years of age, included both males and females, and had no reported chronic illnesses. ConclusionRSV community infections predominantly occur in children regardless of clinical presentation. Reinfections within the same season are rare. Key pointsO_LIIn a community cohort prospective study in coastal Kenya, RSV-A predominated the 2023/24 epidemic and seven lineages co-circulated. C_LIO_LIOverall incidence was 19.6 infections/100 person-years and highest in infants. C_LIO_LIMost reinfections (5/6) were asymptomatic and only half had amino acid changes. C_LI

BackgroundTuberculosis (TB) is a leading cause of morbidity and mortality among children living with HIV (CLHIV). Poor diagnostic performance is a significant contributor. Serological assays that determine levels of Mycobacterium tuberculosis reactive antibodies inconsistently detect TB. However, antigen-specific antibody Fc receptor engagement and effector functions are promising biomarkers of TB disease. MethodsThis study evaluated serum from a well-characterized cohort of Kenyan CLHIV via two orthogonal approaches: 1) longitudinally following over the course of TB treatment and 2) assessing a cross-section with and without clinical TB disease. For each individual sample, 13 antibody functional properties against 8 Mtb and 4 non-Mtb microbial antigens were measured and analyzed via univariate and multivariate machine-learning approaches. FindingsFcR/CD89 immune complex formation with antibodies reactive to four Mtb antigens including ESAT-6 & CFP-10, Fc{psi}RI/CD64 associated with one Mtb antigen, and HIV gp120 IgA1 levels decreased during the intensive and continuation/consolidation phases of TB therapy. This antibody signature also highlighted treatment non-responsiveness and distinguished children with from those without TB disease with predictive capacity similar to Xpert. InterpretationAn Mtb and HIV reactive peripheral blood antibody functional signature of FcR/CD89, Fc{psi}RI/CD64, and IgA1 has the potential to complement current clinical tools and those in development to diagnose pulmonary TB disease in CLHIV. FundingThis work is supported by UT Southwestern Disease Oriented Scholars Award (LLL), NIAID 5R01AI158858 (LLL), Burroughs-Wellcome Fund UTSW Training Resident Doctors as Innovators in Science (YJK), NICHD K12HD000850, NIAID K23AI143479 and R21AI192086 (LMC), NICHD R01 HD023412 (GJS), NIAID 75N93019C00071 (CW).