Clinical Infectious Diseases

BackgroundMultiple countries reported unprecedented increases in invasive group A streptococcal (iGAS) disease following widespread SARS-CoV-2 circulation. Whether this surge reflects reduced pathogen exposure during non-pharmaceutical interventions ("immunity debt") or effects of SARS-CoV-2 infection on host immunity remains unresolved. MethodsWe conducted a population-based time-series analysis of weekly iGAS incidence in central Ontario, Canada (population {approx}11 million) from March 2011 through March 2024 (676 weeks). Using negative binomial panel regression, we modeled acute (2-week lagged) and cumulative SARS-CoV-2 exposure while adjusting for seasonality, secular trends, age, and sex. Population attributable fractions (PAFs) were estimated by counterfactual prediction. Specificity was assessed through negative control analyses (influenza, RSV). The immunity debt hypothesis was evaluated using cumulative streptococcal exposure as a predictor of iGAS. ResultsAmong 2,906 iGAS episodes, 34.3% during the pandemic period were associated with acute SARS-CoV-2 effects (range by age group: 16.5-39.1%). Models incorporating cumulative SARS-CoV-2 burden showed markedly better fit ({Delta}AIC=-157.5); cumulative exposure was strongly associated with iGAS (IRR 1.193, 95% CI 1.151-1.235), increasing the estimated PAF to 66.7%. Cumulative effects were strongest in children (IRR 1.309). SARS-CoV-2 was comparably associated with non-invasive streptococcal disease, with no increase in invasion propensity. Cumulative streptococcal exposure was not protective (overall IRR 1.000, p=0.730); where significant, the association was positive, opposite to immunity debt predictions. ConclusionsCumulative SARS-CoV-2 burden was strongly associated with pandemic-era iGAS incidence. Cumulative streptococcal exposure did not support the immunity debt hypothesis. These ecological findings are consistent with SARS-CoV-2-associated immune dysregulation and warrant individual-level confirmation.

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.

Background: The 2024-25 influenza season was the most severe in the United States (US) since 2017-18, with co-circulation of both influenza A virus subtypes (H1N1 and H3N2). Influenza vaccine effectiveness (VE) has varied by season, setting, and patient characteristics. Methods: Using electronic healthcare encounter data from eight US states, we evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalizations and emergency department or urgent care (ED/UC) encounters from October 2024-April 2025 among children aged 6 months-17 years and adults aged 18+ years. Using a test-negative, case-control design, we compared the odds of influenza vaccination between acute respiratory illness (ARI) encounters with a positive (cases) versus negative (controls) test for influenza by molecular assay, adjusting for confounders. Results: Analyses included 108,618 encounters (5,764 hospitalizations and 102,854 ED/UC encounters) among children and 309,483 encounters (76,072 hospitalizations and 233,411 ED/UC encounters) among adults. Among children across care settings, 17.0% (6,097/35,765) of cases versus 29.4% (21,449/72,853) of controls were vaccinated. Among adults, 28.2% (21,832/77,477) of cases versus 44.2% (102,560/232,006) of controls were vaccinated. VE was 51% (95% confidence interval [95% CI]: 41-60%) against influenza-associated hospitalizations and 54% (95% CI: 52-55%) against influenza-associated ED/UC encounters among children. VE was 43% (95% CI: 41-46%) against influenza-associated hospitalizations and 49% (95% CI: 47-50%) against influenza-associated ED/UC encounters among adults. Conclusions: Influenza vaccination provided protection against influenza-associated hospitalizations and ED/UC encounters among children and adults in the US during the severe 2024-25 influenza season. These findings support influenza vaccination as an important tool to reduce influenza-associated disease.

Background: Rising antimicrobial resistance in Neisseria gonorrhoeae threatens the effectiveness of existing therapies. Resistance-guided treatment (RGT) may reduce treatment failures, complications, and inappropriate use of last-line agents while slowing resistance emergence. Methods and Findings: We developed an individual-level stochastic simulation model of gonorrhea diagnosis and treatment in the United States, incorporating infection prevalence, symptom status, diagnostic accuracy, resistance profiles, treatment pathways, and partner management (costs in 2025 USD). We evaluated three resistance testing strategies, ciprofloxacin-only, ciprofloxacin+ceftriaxone, and triple-target (including a novel drug A), across a wide range of resistance scenarios. We quantified economic value across three dimensions: (1) per-episode direct medical cost savings, (2) system-level costs attributable to ceftriaxone resistance emergence among MSM, and (3) avoided costs of new antibiotic development, estimating the maximum per-test price at which RGT remains cost-neutral. Per-episode cost-neutrality thresholds ranged from near $0 when ceftriaxone resistance was absent to up to $45/test at 15% ceftriaxone resistance. At 50% ciprofloxacin and 5% ceftriaxone resistance, the population-weighted threshold was $4 (95% UI:$3-$8) for a CIP-only test and $11 (95% UI:$5-$14) for a triple-target test. Among MSM, incorporating system-level resistance emergence costs and avoided antibiotic development costs increased the total per-test value to $35-$145 for a single-target test and $84-$128 for a triple-target test, depending on whether prescribing practices shift when ceftriaxone resistance reaches 5%. Conclusions: Resistance-guided therapy offers economic benefits across multiple dimensions even at relatively high diagnostic prices, supporting investment in gonorrhea resistance testing to improve partner outcomes, delay resistance emergence, and enhance the long-term cost-efficiency of gonorrhea management.

BackgroundWe assessed associations between antibody concentrations within 7 days of symptom onset and testing positive for influenza virus infection among outpatients enrolled in a test-negative study. MethodsFrom November 2018[boxh]May 2019, study sites in five states obtained serum and respiratory specimens from outpatients aged [≥]18 years presenting with acute respiratory illness. Respiratory specimens were tested for influenza virus, and viral clades were identified by genomic sequencing. We measured influenza antibody titers against vaccine and circulating viruses by hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase inhibition (NAI) assays. Percent of patients with HI, MN and NAI titers [≥]10 and [≥]40 were compared among patients with and without influenza-associated illness, and reduction in odds of confirmed influenza at increasing HI, MN and NAI antibody titers was estimated using logistic regression adjusting for influenza vaccination status and time since beginning of influenza season. ResultsAmong 175 patients with confirmed influenza virus infection, including 112 with influenza A(H1N1)pdm09 and 63 with A(H3N2) (44 clade 3C.3a), and 130 test-negative control patients, higher antibody titers against influenza hemagglutinin or neuraminidase proteins at enrollment were associated with lower odds of influenza virus infection. HI and MN antibody titers against circulating viruses were more strongly associated with protection than titers against vaccine reference viruses. Odds of A(H1N1)pdm09 infection were 44% and 54% lower for each two-fold increase in A(H1N1)pdm09 HI or NAI titer, respectively. Odds of A(H3N2) infection were 46% and 30% lower, respectively, for each two-fold increase in MN or NAI titer against circulating A(H3N2) virus clade. NAI titers were independently associated with lower odds of influenza A(H1N1)pdm09 and A(H3N2) after controlling for HI titer. ConclusionHigher influenza antibody titers against circulating viruses were associated with lower likelihood of influenza virus infection among adult patients with acute respiratory illness. SUMMARYFrom November 2018[boxh]May 2019, we assessed the association between antibody concentrations during acute illness and laboratory-confirmed influenza among adult patients enrolled in a test-negative study in five US states. We found that higher influenza antibody titers were associated with lower likelihood of symptomatic influenza virus infection.

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 [≥]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.

BackgroundHousehold contact investigation for tuberculosis (TB) is limited by referral for clinic-based testing services. We evaluated the performance of in-home tongue swab (TS) testing among symptom-agnostic household contacts (HHC) to inform HCI screening strategies. MethodsWe conducted a prospective cohort study among HHC of TB patients in Eastern Cape, South Africa. In-home testing of sputum and TSs, with TSs pooled from up to three HHCs, was performed using Xpert Ultra on portable GeneExpert devices. Outcomes included diagnostic performance of TS testing relative to sputum and linkage-to-care outcomes. FindingsBetween June 2021 and October 2024, 909 HHC were enrolled; 99{middle dot}1% provided s TS, 31{middle dot}6% provided sputum. Overall sensitivity and specificity of TS testing was 61{middle dot}9% (95% CI: 38{middle dot}4%-81{middle dot}9%) and 100% (98{middle dot}9%-100%), respectively; sensitivity was 100% (47{middle dot}8%-100%) for individually tested swabs. Among two-swab and three-swab pools where 21 individual was sputum positive, 55{middle dot}6% (21{middle dot}2%-86{middle dot}3%) and 42{middle dot}9% (9{middle dot}9%-81{middle dot}6%) tested positive, respectively; TS sensitivity declined with decreasing sputum Ultra semi-quantitative category. 27 of 439 (6{middle dot}2%) households had an indictation of secondary TB; 13 (3{middle dot}0%) by sputum and TS, 11 (2{middle dot}5%) by sputum only, 3 (0{middle dot}7%) by TS only. Sputum testing identified 29 HHC with TB (yield=3{middle dot}2%); 25/29 (86{middle dot}2%) linked to care (median 1 day [IQR 1-2]). InterpretationWhile in-home molecular testing of sputum supported rapid linkage-to-care, and TSs enabled near-universal testing of symptom-agnostic HHCs, efficiency gains through pooled TS testing must be balance against sensitivity trade-offs. FundingU.S. NIH; Australian Department of Foreign Affairs and Trade; UK Foreign, Commonwealth and Development Office RESEARCH IN CONTEXTO_ST_ABSEvidence Before This StudyC_ST_ABSHousehold contacts (HHCs) of people with TB are prioritized for active case-finding (ACF) strategies due to their increased risk of developing TB disease. Household contact investigation (HCI), a widely recommended ACF strategy, is constrained by attrition from referral-based cascades and sputum-based testing. We searched PubMed and Embase for studies published in English from January 1, 2010 to January 31, 2026, using combinations of the terms "tuberculosis" or "TB" with "household contact," "contact tracing," "contact investigation," "screening," "triage," "in-home testing," "molecular testing," and "tongue swab." We also reviewed references listed in relevant articles. There are limited data describing microbiological testing strategies targeting HHCs conducted outside clinic settings, and fewer still that explore the integration of HCI and in-home molecular TB testing. Tongue swabs have emerged as a promising non-invasive, non-sputum specimen type for molecular TB diagnosis. However, most tongue swab performance data have been generated in clinic-based or symptom-prompted populations, with a marked paucity of data generated in populations at high risk for asymptomatic or paucibacillary TB, including HHC. Before this study, published work exploring the use of tongue swabs within in-home TB testing strategies was limited to two papers, both from our group, which focused on acceptability, feasibility, and preliminary costing and modeling analyses. To date, no published studies have assessed the diagnostic performance of tongue swab-based molecular testing relative to sputum-based testing among HHC, the use of tongue swab specimens as part of in-home testing strategies, nor the implication of pooled tongue swab testing to inform household-level screening and diagnostic escalation strategies. In addition, evidence describing verified linkage to TB treatment services following in-home sputum molecular testing was limited to one pilot study paper. Added Value of This StudyThis study is the first to evaluate in-home molecular TB testing using tongue swab specimens, and to incorporate household-level pooling of tongue swabs from multiple household members as a primary screening strategy. Near-universal swab collection substantially expanded access to microbiological testing in a population with limited sputum production. Although pooled swab testing exhibited reduced sensitivity compared with individual-level sputum testing, stratified analyses of tongue swab tests by sputum Xpert Ultra semi-quantitative categories demonstrate that this reduction reflects a biological gradient associated with low mycobacterial burden. Importantly, pooled swab testing identified TB among contacts unable to produce sputum, increasing diagnostic yield beyond sputum-dependent approaches. The study also documents the increase in diagnostic yield when implementing a symptom-agnostic testing strategy among HHC, and rapid, verified linkage to clinic-based TB treatment services following in-home sputum testing. Implications of All the Available EvidenceCollectively, the available evidence supports reframing TB household contact investigation from individual-level referral for clinic-based testing toward in-home testing models, including the use of household-level screening with diagnostic escalation. Near-universal, in-home collection of tongue swab specimens enables substantially broader microbiological assessment than sputum-dependent strategies and facilitates detection of TB among asymptomatic and sputum-scarce HHCs, individuals frequently missed by referral-based approaches for clinic-based sputum collection and testing. Our findings show that the reduced sensitivity associated with pooled tongue swab testing follows a predictable biological gradient related to mycobacterial burden rather than a technical failure of pooling. Pooled swab testing should therefore be understood as a household-level screening strategy within a sequential diagnostic algorithm, not a replacement for individual diagnosis. For TB programs, efficiency gains and expanded coverage achieved through pooling must be balance against sensitivity trade-offs. Household-level screening using pooled specimens can focus downstream referrals and may improve programmatic efficiency without requiring universal individual testing. Future research should evaluate optimized diagnostic algorithms that integrate pooled, non-sputum testing with diagnostic escalation, assess impact on linkage-to-care and prevention outcomes, and define the role of pooled testing within scalable, community-based TB case-finding strategies.

Background: Infections of the central nervous system (CNS) in children remain a major cause of mortality and long-term disability globally, particularly in low- and middle-income countries (LMICs), where a high proportion of cases lack an identified pathogen. Sporadically, human parvovirus 4 (PARV4) has been detected in a small number of cerebrospinal fluid (CSF) from children with CNS infections, but its pathogenic role is unclear. We investigated the prevalence, clinical impact, and genomic characteristics of PARV4 in children with suspected meningitis. Methods: We retrospectively analyzed CSF samples collected from children with WHO-defined suspected meningitis at the largest pediatric hospital in Bangladesh between 2015-2022. All samples underwent routine diagnostics, including bacterial culture and serological testing. Additional testing for PARV4 and parvovirus B19 was performed using qPCR of samples with >9 white blood cell (WBC)/ul followed by metagenomic sequencing of a subset. Clinical and laboratory data were extracted from patient records. Associations between PARV4 detection and mortality were assessed using logistic regression, adjusting for age, WBC count, and co-infections. Genomic and phylogenetic analyses were conducted on PARV4-positive samples. Findings: Among 2,793 CSF samples with >9 WBC/ul, 526 (18.8%) were PARV4-positive. The median age of PARV4-positive cases was lower than that of PARV4-negative cases (4 vs 7 months, p<0.001). Co-infections were more common among PARV4-positive cases (49.6%) than PARV4-negative cases (16.4%). PARV4 positivity was independently associated with increased in-hospital mortality (adjusted odds ratio 2.09, 95%CI:1.46-2.96; p<0.001). Phylogenetic analysis indicated most strains belonged to genotype 2, with two sequences forming a distinct clade. Interpretation: PARV4 is frequently detected in the CSF of children with suspected meningitis and is associated with increased in-hospital mortality. Its high prevalence, detection early in life, and frequent co-infection with other pathogens highlight the need to investigate PARV4 as an emerging CNS pathogen in LMICs. Funding: Gates Foundation

Accurate vaccination status ascertainment is fundamental to valid vaccine effectiveness (VE) estimation. We evaluated the accuracy of current and prior seasons self-reported influenza vaccination status among outpatients with acute respiratory illness recruited by the Canadian Sentinel Practitioner Surveillance Network (SPSN) during the 2023-2024 season in Quebec, Canada. Vaccination status was self-reported at specimen collection for influenza virus testing and compared to the provincial vaccination registry. Self-report showed high registry agreement, including sensitivity, specificity, accuracy and kappa statistics for current (91%, 98%, 96%, 0.89) and prior (85%, 95%, 92%, 0.78) seasons vaccination status. Metrics were similar by influenza case status, age, sex and comorbidity with more variation for sensitivity than specificity. Test-negative design estimates of the crude association between influenza case status and current seasons self-reported or registry-based vaccination status did not meaningfully differ, with absolute difference of 2% overall. Findings support self-reported influenza vaccination for timely and valid VE estimation.

BackgroundSyphilis screening and treatment coverage remain lower than recommended among pregnant women in the US. ObjectiveWe estimated the prevalence and incidence of syphilis among pregnant women, incidence of congenital syphilis and the impact of improved prenatal care cascade by race and ethnicity. DesignCompartmental mathematical model of syphilis natural history, prenatal care, and syphilis screening and testing SettingUnited States ParticipantsPregnant women MeasurementsWomen were stratified by race and ethnicity and whether they received any prenatal care. The model was calibrated to epidemiological data for 2019. InterventionsWe evaluated improvements among women with any prenatal care and in all pregnant women, and we examined 100% treatment completion, first-trimester testing, first-trimester testing with 100% treatment, testing twice and testing twice with 100% treatment. ResultsWe estimated that, per 100,000 pregnant women, 110 (95% uncertainty interval [UI] 110-120) had syphilis at pregnancy onset, 13 (95% UI 10-15) acquired syphilis during pregnancy, and 13 (95% UI 12-14) had a syphilis-attributable stillbirth (95% UI 12-14). We estimated a 61% (95% UI 60-62) reduction in non-stillbirth-related congenital syphilis outcomes when at least two syphilis tests were provided and treatment was completed among women who receive prenatal care, and a 98% (95%UI 98- 99%) reduction if two tests were provided and treatment was completed for all pregnant women. The largest benefit of expanding testing and treatment to all pregnant women was seen in non-Hispanic Black and Hispanic populations. LimitationsResults represent national averages and do not account regional variation. ConclusionReaching women without prenatal care would substantially reduce congenital syphilis and racial and ethnic differences in congenital syphilis burden. Primary Funding sourceCenters for Disease Control and Prevention.

BackgroundInfluenza A(H1N1)pdm09 and A(H3N2) viruses predominated during the 2024-25 U.S. influenza season. We estimated influenza vaccine effectiveness (VE) in the United States against mild-to-moderate outpatient influenza illness by influenza type and subtype in the 2024-25 season. MethodsWe enrolled outpatients aged [&ge;]8 months with acute respiratory illness symptoms including cough in 7 states. Upper respiratory specimens were tested for influenza type/subtype by reverse-transcriptase polymerase chain reaction (RT-PCR). Influenza VE was estimated with a test-negative design comparing odds of testing positive for influenza among vaccinated versus unvaccinated participants controlling for age, study site, underlying health status, and month of illness onset. We also estimated VE of current season vaccination among adults stratified by prior season vaccination status. ResultsAmong 6,793 enrolled patients, 2,016 (30%) tested positive for influenza including 961 A(H3N2), 770 A(H1N1)pdm09, and 183 B/Victoria. Overall vaccine effectiveness against any influenza illness was 33% (95% Confidence Interval [CI]: 24 to 41): 27% (95% CI: 14 to 39) against influenza A(H3N2), 37% (95% CI: 24 to 48) against A(H1N1)pdm09, and 40% (95% CI: 12 to 59) against B/Victoria. VE did not differ based on whether or not participants had received influenza vaccine the previous season. ConclusionsInfluenza vaccination during the 2024-25 season protected against circulating influenza viruses, reducing the risk of outpatient medically attended influenza overall by approximately one-third among people who were vaccinated. Key PointsInfluenza vaccine reduced the risk of outpatient acute respiratory illness due to laboratory-confirmed influenza during the 2024-25 season by a third.

Background/ObjectivesThe trajectory of influenza hospitalization burden from pre-pandemic baseline through post-pandemic recovery remains poorly characterized at the national level. This study characterized phase-stratified burden and seasonal structure, quantified racial and ethnic disparities, and assessed whether post-pandemic seasons represent anomalous departures from pre-pandemic expectations. MethodsSixteen seasons of FluSurv-NET surveillance data (2009-2010 through 2024-2025; 509 observation weeks) were analyzed across pre-pandemic, disruption, and recovery phases using OLS regression with effect-size estimation, bootstrapped age-adjusted rate ratios, seasonal-trend decomposition (STL), Prophet time-series forecasting, and Isolation Forest anomaly detection. ResultsMean peak weekly hospitalization rate nearly doubled from pre-pandemic to recovery (5.1 to 11.1 per 100,000), cumulative seasonal burden increased from 46.3 to 87.0 per 100,000, and median peak timing advanced from MMWR week 9 to week 50. STL decomposition revealed a marked shift from weak pre-pandemic seasonality (Fs = 0.14) to substantially stronger annual regularity (Fs = 0.98) across three recovery seasons, with threefold amplitude increase. Non-Hispanic Black persons had rate ratios of 1.72, 2.16, and 1.99 relative to White persons across phases; American Indian and Alaska Native persons showed the highest disruption-phase ratio (2.24, 95% CI 1.90-3.53), based on two contributing seasons. A flat-growth Prophet model detected first exceedance in February 2020, outperforming a linear-growth specification on held-out validation. Isolation Forest identified 2017-2018, 2023-2024, and 2024-2025 as robust anomalies across all contamination thresholds. ConclusionsPost-pandemic influenza recovery is characterized by intensified and restructured seasonality, persistent racial and ethnic disparities, and anomalous burden exceeding pre-pandemic projections, identified independently by time-series forecasting and unsupervised anomaly detection.

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.

BackgroundPrimary amoebic meningoencephalitis (PAM) is a rapidly progressive and often fatal central nervous system infection caused by Naegleria fowleri. Despite widespread environmental exposure to this free-living amoeba, clinical disease is rare, suggesting that it requires not only exposure to the amoeba but also a host vulnerability. Yet, the immune mechanisms controlling protection vs. susceptibility to N. fowleri remain poorly understood. MethodsWe conducted comprehensive clinical, immunological, and genetic investigations in one of the few survivors of PAM. We performed high-dimensional immune profiling using Cytometry by Time-Of-Flight (CyTOF) to assess immune cell composition and activation state. We employed whole-exome sequencing (WES) to identify rare genetic variants that affect host responses. Functional immune assays were used to assess serum-mediated amoebicidal activity in vitro and to characterize key host defense pathways. ResultsA previously healthy pediatric patient was diagnosed with PAM. Contrary to other cases, her clinical course lasted for more than 2 months before she recovered with miltefosine treatment. Immunologic evaluation showed this patient had normal numbers and frequencies of major lymphoid and myeloid immune cells. WES revealed a homozygous deletion in the complement component 2 (C2) gene, resulting in a complete absence of circulating C2 protein and abolishing classical complement pathway activity. Normal human serum induced complement-mediated lysis of N. fowleri trophozoites in vitro, whereas complement-depleted normal human serum and serum from our patient both failed to deposit membrane attack complex (MAC) or kill N. fowleri. MAC deposition and amoebicidal activity were restored by supplementing the patients serum with purified human C2 protein. ConclusionOur study demonstrates that PAM can be caused by a monogenic inborn error of immunity (IEI) and that the complement system is critical for human immunity against Naegleria fowleri.

BackgroundCandidemia is a rare but life-threatening bloodstream infection that remains difficult to predict using conventional risk stratification approaches, highlighting the need for improved predictive strategies. As a result, empiric antifungal therapy is often delayed even in high-risk patients. MethodsWe developed a deep learning model (PyTorch_EHR) to predict 7-day candidemia risk by using electronic health record data from two large cohorts (Houston Methodist Hospital System [HMHS] and MIMIC-IV), including adult inpatients who underwent at least one blood culture. Model performance was compared with logistic regression (LR), LightGBM, and established intensive care unit candidemia scores. We further implemented a two-step prediction framework integrating candidemia and 30-day mortality risk models to inform empiric antifungal decision-making. ResultsAmong 213,404 and 107,507 patients in the HMHS and MIMIC-IV cohorts, candidemia occurred in fewer than 1% (851 [0.4%] and 634 [0.6%], respectively). PyTorch_EHR outperformed LR, LightGBM, and existing candidemia scores, particularly in terms of area under the precision-recall curve (AUPRC) in HMHS and MIMIC-IV. By integrating 30-day mortality risk, the two-step framework identified an additional 20 and 28 candidemia cases beyond the one-step model, increasing coverage to 61% (121/199) and 46% (68/147) in HMHS and MIMIC-IV, respectively. Many patients identified by the two-step framework had high mortality yet did not receive empiric antifungal therapy (61.1% HMHS; 82.6% MIMIC-IV). ConclusionA two-step deep-learning framework integrating candidemia and mortality risk may support early identification of high-risk patients and facilitate timely empiric antifungal therapy. Prospective studies are warranted to confirm the findings.

BackgroundMycoplasma genitalium (MG) is an emerging sexually transmitted infection (STI) associated with pelvic inflammatory disease and tubal factor infertility. Its relationship with impaired fecundity remains unclear and is rarely examined in the context of co-seropositivity with other STIs. MethodsWe conducted a secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a prospective preconception cohort of women with proven fecundity and prior pregnancy loss. MG serostatus was determined using Western blot-based IgG assays on 1146 stored serum specimens. Chlamydia trachomatis (CT) and other STIs were also measured. Associations between MG seropositivity and measures of impaired fecundity were assessed. Pregnancy loss and live birth were modeled using inverse-probability weighted quasi-Poisson and unweighted log-binomial models to calculate relative risks (RR). Fecundability-odds-ratio (FOR) was estimated using a discrete Cox proportional hazards model accounting for left truncation and right censoring. Propensity score (PS) weighted versions of these models assessed risks associated with CT co-seropositivity. Analyses were adjusted for demographic and reproductive history variables. ResultsOverall, 17.1% (n=210) of participants were MG seropositive, with 27.6% (n=58) co-seropositive with CT. Compared to STI-seronegative women, MG seropositivity was not associated with any outcome, although trends were observed for reduced fecundability (FORadj: 0.87, 95% CI 0.70-1.08) and live birth (RRadj: 0.94, 95% CI 0.79-1.11). Co-seropositivity with CT was associated with lower likelihood of live birth [Relative Risk (RR)PS-weighted: 0.82, 95% CI: 0.70-0.96]. Sensitivity analyses supported the robustness of these findings. ConclusionsBeing co-seropositive for MG and CT preconception may impair fecundity.

BACKGROUNDDiagnostic performance of tongue swab Mycobacterium tuberculosis PCR has been evaluated for facility-based triage of symptomatic tuberculosis (TB). It is unknown whether tongue swab performance differs for detection of asymptomatic TB in community-based screening. METHODSTongue swabs were collected from adult household contacts of TB patients (HHC Cohort), and symptomatic adults presenting to clinics with presumptive TB (Clinic Cohort), at eight South African sites. TB Cases were defined by positive sputum Xpert Ultra or liquid culture, performed in all participants; and matched [~]1:3 (HHC Cohort) or [~]1:2 (Clinic Cohort) to Controls without TB. Tongue swabs in both cohorts were tested by high-volume qPCR; and in the Clinic Cohort, also by sequence-specific magnetic capture (SSMaC) with qPCR. RESULTSThe Clinic Cohort included 217 TB Cases (100% symptomatic) and 437 Controls. The HHC Cohort included 44 TB Cases (84.1% asymptomatic) and 136 Controls. In the Clinic Cohort, sensitivity of SSMaC with qPCR was 73.2% (specificity 94.6%), but not significantly higher than high-volume qPCR (63.8%; p = 0.14) (specificity 94.4%). Sensitivity of high-volume qPCR in the Clinic Cohort (63.8%) was significantly higher than the HHC Cohort (34.1%; p = 0.0007) (specificity 91.9%). Among HHC, high-volume qPCR sensitivity was 35.1% for asymptomatic TB; 52.2% for TB with abnormal CXR; and 100% for TB with High sputum Xpert Ultra grade. CONCLUSIONSSensitivity of tongue swab high-volume qPCR for community-based, household screening for asymptomatic TB was low, approximately half that of facility-based triage for symptomatic TB, but increased with radiographic severity and sputum bacillary load. Key pointsSensitivity of tongue swab high-volume qPCR for community tuberculosis screening among primarily asymptomatic household contacts was low and approximately half that of facility-based triage for symptomatic tuberculosis. Sensitivity was lowest in individuals with normal chest radiography and low bacillary burden.

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.

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.

Influenza H3N2 subclade K (J.2.4.1) is a genetic branch of H3N2 with 11 mutations in hemagglutinin and currently represents the dominant circulating influenza strain. We evaluated antibody responses to H3N2 subclade K before and after influenza vaccination in 46 healthy individuals. Our data show that baseline antibody responses to two H3N2 subclade K variants were lower than to other H1N1 and H3N2 strains and that antibody responses following vaccination were also less robust to the H3N2 subclade K variants. These data indicate that the H3N2 subclade K strain partially evades both prior H3N2 immunity and the current inactivated influenza vaccine.