Clinical Infectious Diseases

ObjectiveLeukemic and hematopoietic cell transplant patients have one of the highest incidences of C. difficile infection (CDI). While CDI patients are considered the primary source of transmission, asymptomatic colonized patients (AC) can progress to CDI or contribute to in-unit transmission. We aim to quantify the roles of CDI and AC patients in C. difficile importation and transmission within oncological units. DesignProspective cohort study SettingTwo leukemia and HCT transplant units in a large tertiary care hospital in the US MethodsWe developed a stochastic, individual-based network model to simulate C. difficile acquisition and transmission. Data from cultures and nucleic acid amplification testing (NAAT) obtained at admission and weekly, and toxin enzyme immunoassay (EIA) tests used for CDI diagnosis were used to calibrate the model. Healthcare worker room assignments informed the network structure. Key parameters were estimated via particle filtering. ResultsThe model reproduced observed weekly test counts and transmission pairs. AC patients were the primary source of new colonizations: 51% were due to importation (of those, 88% were admitted as AC), and 49% were due to transmission (AC was the source in 92% of transmissions). Sensitivity analysis showed that these findings were most influenced by the colonization rate and rates of environmental contamination and cleaning. ConclusionsThese findings reinforce the role of AC, particularly via admission importation, in sustaining C. difficile transmission in high-risk hospital settings. Infection control focused on CDI effectively reduced onward transmission, as indicated by CDIs low contribution to new colonizations.

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: Isoniazid resistance is the most common form of drug-resistant tuberculosis (TB) globally. However, WHO-recommended molecular tests available to most TB patients worldwide detect rifampin resistance only, risking under-treatment of isoniazid-resistant, rifampin-susceptible TB (HR-TB) and subsequent emergence of rifampin resistance. Methods: This prospective study (2020-2024) aimed to collect and archive sputum specimens from all adults diagnosed with rifampin-susceptible pulmonary TB in Ho Chi Minh City, Vietnam. Cases were participants who developed rifampin-resistant recurrence; controls had rifampin-susceptible recurrence or no recurrence. Whole-genome sequencing of paired isolates distinguished acquired rifampin resistance from reinfection. The effect of pre-existing isoniazid resistance on rifampin resistance acquisition was estimated using inverse probability of treatment weighting, and the projected epidemiological impact of routine HR-TB testing was modelled. Results: 42,843 people were diagnosed with TB during the study period, from whom we archived 33,843 sputum samples. We enrolled 1,241 participants, 873 (70.4%) of whom had analysable data. 51/873 (5.8%) acquired rifampin resistance, of whom 49/51 (96.1%) had undetected isoniazid resistance. The weighted risk of acquired rifampin resistance was 2.98% (95% CI 2.08-4.50) with undetected isoniazid resistance, versus 0.03% (0.00-0.08) without (risk ratio105.42 (33.43-309.69)). Modelling projected that universal HR-TB diagnosis and treatment would reduce RR-TB incidence by 46% (35-61) over 10 years in Vietnam, with reductions of 26% (12-43) projected even where HR-TB prevalence was as low as 5%. Conclusions: Undetected, under-treated HR-TB confers a 100 fold increased risk of acquiring rifampin resistance. Routine isoniazid susceptibility testing combined with effective HR-TB treatment could substantially reduce the burden of RR-TB.

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.

BackgroundTuberculosis (TB) incidence in the United States has remained elevated above pre-pandemic levels since 2021, with over 85% of cases resulting from reactivation of Mycobacterium tuberculosis (Mtb) infection. New vaccines that would prevent TB in adults are under development, but the potential health impact of a program prioritizing non-U.S.-born persons and persons with medical comorbidities, including persons living with HIV (PLWH), has not been evaluated. MethodsWe developed a deterministic compartmental transmission model that simulates Mtb infection, transmission, and progression to TB in the U.S., both in the general population and in key high-risk groups. We calibrated the model to 2024 U.S. TB surveillance data and estimated annual cases prevented, percent reduction in annual TB cases, and number needed to vaccinate (NNV, a measure of vaccine program efficiency) at equilibrium conditions for targeted vaccination strategies under optimistic and plausible scenarios, varying assumptions of vaccine efficacy, duration of protection, and achieved vaccination coverage in high-risk groups. FindingsUnder an optimistic scenario, vaccinating PLWH, non-U.S.-born persons, and persons with medical comorbidities (all high-risk groups) prevented 5,385 cases per year (51{middle dot}8% reduction, NNV = 366). Under a more conservative plausible scenario, the same strategy prevented 1,348 cases per year (13{middle dot}0% reduction, NNV = 510). The efficiency and impact of targeting strategies we considered were preserved across all sensitivity and uncertainty analyses. InterpretationTargeted vaccination of persons with Mtb infection in population subgroups recognized to be at high-risk for TB can reduce incidence substantially. Strategies that include non- U.S.-born persons and PLWH are most efficient and impactful. FundingAmerican Lung Association, U.S. National Institutes of Health, and the Ferguson Fellowship.

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

Background Human challenge trials provide a unique opportunity to quantify pathogen infectivity in terms of the probability of infection given an inoculated dose. However, between-pathogen comparisons are often distorted by individual heterogeneity in host susceptibility and by differences in background immunity across trial populations. We examined how dose-dependent infection risks differ across common respiratory viruses when such heterogeneity is explicitly incorporated. Methods We conducted a systematic review of human challenge trials for four respiratory viruses: respiratory syncytial virus (RSV), influenza virus, rhinovirus, and adenovirus. Using the extracted data, we fitted dose-response models under different distributional assumptions, allowing both continuous susceptibility variation and discrete immune fractions. We compared alternative heterogeneity models and evaluated pathogen-specific dose-response patterns using original and scaled dose metrics. Results All four viruses showed substantial heterogeneity in host susceptibility, and models assuming homogeneous susceptibility were unsupported. RSV and influenza were best described by models with a distinct immune or effectively non-susceptible subgroup, and the estimated immune proportions were approximately 40% and 25%, respectively. In contrast, rhinovirus and adenovirus were better explained by continuously distributed susceptibility, with little evidence of a fully immune subgroup. On a scaled dose axis, rhinovirus and adenovirus showed steeper increases in infection risk with dose than RSV and influenza. Conclusions The structure of susceptibility heterogeneity differs across common respiratory viruses, which in turn shapes dose-dependent infection risks. Incorporating this heterogeneity is essential for valid cross-pathogen comparison and for interpreting human challenge data in epidemiologic and public health contexts.

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.

BackgroundProlonged SARS-CoV-2 infection in immunocompromised individuals may accelerate virus evolution within the host, raising concerns about the virus evading immunity, developing resistance, and forming novel variants of concern. However, the determinants and public health implications of within-host viral evolution in this population remain incompletely understood. MethodsWe performed longitudinal analyses of SARS-CoV-2 genomes from 91 patients with COVID-19 who were classified as being severely or moderately immunocompromised. Using serial measurements of viral RNA loads and infectious titers, we modeled the shedding dynamics of the virus and stratified the infected cases by upper respiratory virus shedding duration to assess associations with within-host evolutionary dynamics. ResultsShedding modeling identified two profiles of shedding duration: intermediate and long. The long shedding profile (shedding lasting >21 days) was found in 14.8% of moderately immunocompromised cases and 72.1% of severely immunocompromised cases. Frequent single-nucleotide variants accumulated specifically in severely immunocompromised individuals with the long shedding phenotype, correlating positively with shedding duration. By contrast, mutations remained limited in moderately immunocompromised individuals with the long shedding phenotype and in severely immunocompromised individuals with the intermediate shedding phenotype. We identified mutations in the spike receptor-binding domain associated with monoclonal antibody resistance; however, we found no fitness-enhancing mutations for inter-host transmission, and antiviral drug resistance mutations were rare. Instead, mutations were introduced frequently and randomly across the entire viral genome. ConclusionsProlonged upper respiratory virus shedding exceeding 21 days combined with severe immunocompromise is a risk factor of the accumulation of within-host SARS-CoV-2 mutations. Although no variants of concern emerged, the introduction of genome-wide random mutations suggests that the risk for novel variant generation cannot be excluded. These findings highlight the need for intensive antiviral strategies to limit shedding duration to less than 21 days in severely immunocompromised patients, and for immunological investigations to elucidate the host factors underlying residual shedding control in those who achieve clearance within this threshold.

BackgroundBacterial co-infection contributes substantially to influenza-associated morbidity and mortality. Patterns of viral circulation, diagnostic testing and antimicrobial use changed markedly during the COVID-19 pandemic, yet contemporary estimates of bacterial co-infection and antimicrobial use in influenza have not been synthesised. ObjectivesTo estimate the pooled prevalence of microbiologically confirmed bacterial co-infection among hospital-attended patients with laboratory-confirmed influenza. Secondary objectives were to characterise co-infecting bacterial pathogens, quantify antimicrobial prescribing overall and across key subgroups. This study was registered with PROSPERO (CRD420251072782). Data sources and eligibilityWe searched Embase (Ovid), MEDLINE, PubMed, Scopus, and Web of Science to 15th June 2025 for English-language studies including [&ge;]50 hospital-attended patients with laboratory-confirmed influenza and reporting bacterial co-infection. MethodsPooled prevalence estimates and antimicrobial prescription proportions were calculated using a generalised linear mixed model with logit link. Subgroup analyses included age group, clinical setting, and seasonal vs. pandemic influenza. Risk of bias was assessed using ROBINS-E and certainty of evidence using GRADE. ResultsNinety-three studies from 30 countries, comprising 111,889 patients with influenza, met inclusion criteria; 9,899 had confirmed bacterial co-infection. The pooled prevalence was 17.3% (95%CI 13.6-21.7%; I2=99.2%). Prevalence was higher in ICU compared to non-ICU settings (28.3% vs. 13.6%). The most frequently identified bacterial pathogens were Streptococcus pneumoniae (35.7%) and Staphylococcus aureus (30.3%). Antimicrobial use, reported in 38 studies, was high (pooled prevalence 88.1%, 95%CI 76.0-94.5%; I2=99.9%), and was more common in adults than children (97.8% vs 65.0%), and in ICU compared with non-ICU settings (96% vs 81%). ConclusionsBacterial co-infection was identified in approximately one in six hospital-attended influenza cases, yet antimicrobial prescribing is near-universal. Substantial heterogeneity and diagnostic variability constraint interpretation but underscore persistent challenges in clinical decision-making. These findings support strengthened diagnostic capacity and antimicrobial stewardship to optimise management of suspected influenza-associated bacterial co-infection.

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.

Background: Without tuberculosis preventive therapy (TPT), approximately 5% of individuals infected with M. tuberculosis progress to active tuberculosis (TB) disease. Recent studies have identified body mass index (BMI) < 25 kg/m2 as a predictor of TB progression, but additional markers are needed to better identify persons at increased risk. Methods: Close contacts of patients with culture-confirmed pulmonary TB were enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort from 2015 to 2019 and followed for up to 24 months. Analyses were restricted to interferon-{gamma} release assay (IGRA)-positive contacts who did not receive TPT or received <30 days of isoniazid. Prediction models to identify close contacts at increased TB risk were constructed using two complementary approaches: incremental models used BMI as the base predictor and evaluated whether baseline whole-blood transcriptomic signatures, human genetic polymorphism risk scores derived from low-pass whole-genome sequencing, and BMI-related plasma biomarkers improved model discrimination. Agnostic models did not impose BMI in the model and used penalized regression for predictor selection. Results: Among 285 close contacts, 15 (5%) progressed to TB. The model with BMI as unique predictor had a C-index of 0.66 (95% confidence interval [CI] 0.55; 0.77). Adding Rajan5 or Duffy9 transcriptomic signature scores to BMI improved discrimination compared with BMI alone, with C-indices of 0.78 (95% CI 0.62; 0.99) and 0.75 (95% CI 0.61; 0.89), respectively, but did not further improve discrimination after accounting for adiponectin. Adding adiponectin to BMI increased the C-index to 0.80 (95% CI 0.68; 0.91), while adiponectin alone captured most of the discriminatory performance in agnostic models (C-index, 0.80, 95% CI 0.69; 0.91). Genetic risk scores, leptin, and the adiponectin:leptin ratio did not improve model discrimination compared with the BMI-only model. In exploratory post hoc analyses, higher adiponectin was associated with increased risk of progression to TB, with each two-fold increase associated with a higher hazard of TB (HR 2.91, 95% CI 1.73; 4.91, p < 0.001). Conclusions: Baseline adiponectin strongly predicted progression to TB among close contacts and captured most of the discriminatory information contained in epidemiological and transcriptomic variables. Its consistent selection across modelling approaches supports adiponectin as a promising biomarker for TB risk stratification.

Background Tuberculosis remains the leading infectious cause of death worldwide. In the WHO African region, declining incidence has coincided with antiretroviral therapy (ART) scale-up, though whether this reflects reduced progression to disease or reduced transmission is unclear. We evaluated how ART and symptom status influence within-household Mycobacterium tuberculosis complex (MTBC) transmission risk. Methods We conducted a case-contact household study in rural South Africa, enrolling index adults with bacteriologically-confirmed pulmonary tuberculosis. MTBC immunoreactivity was measured in all child household contacts (aged 2-14 years) as a proxy measure of within-household transmission. We assessed the influence of index person ART status and symptom status, and explored effect-measure modification of the association between index person HIV status and transmission risk by sex. Results Among 755 child contacts of 296 index persons, effective ART was not associated with within-household MTBC transmission risk (risk ratio [RR], 1.07; 95% CI, 0.66-1.74). Among PLHIV engaged in ART care, WHO TB four-symptom screen (WHO4SS) status was not associated with transmission risk (RR, 0.80; 95% CI, 0.43-1.47), although absence of reported cough reduced risk (RR, 0.61; 95% CI, 0.38-0.96). A pronounced interaction between sex and HIV status was observed: HIV-negative women had the highest within-household MTBC transmission risk (30.5% vs. 14.3% in women with HIV) whereas risks were similar between HIV-positive and HIV-negative men. Conclusions We found no evidence that effective ART or WHO4SS status influenced within-household MTBC transmission risk, though confidence intervals were wide. Absence of reported cough was associated with lower risk, and transmission risk was highest among child contacts of HIV-negative women. These findings suggest reported cough is a useful marker of transmission risk and that routine tuberculosis screening within ART care may reduce transmission from PLHIV; intensified efforts are nonetheless needed to achieve earlier tuberculosis detection in HIV-negative individuals.

BackgroundPeripheral neuropathy frequently leads to linezolid dose reductions or interruptions during multidrug- or rifampicin-resistant tuberculosis treatment. The effect of these modifications to linezolid on treatment success is uncertain. MethodsWe conducted a target trial emulation using the endTB Observational Study among individuals who developed mild or moderate peripheral neuropathy while receiving linezolid 600 mg daily within 6 months of initiating an individualized regimen. We examined three linezolid management strategies: immediate change (suspension or dose reduction) during Weeks 1-7, deferred change during Weeks 8-26, and no change (i.e., continuing linezolid 600 mg daily) during Weeks 1-26. We used a clone-censor-weight approach to estimate the observational analog of the per-protocol effect on treatment success. ResultsAmong 303 eligible participants from 12 countries, peripheral neuropathy occurred a median (interquartile range) of 11 (4-18) weeks after treatment initiation. Weighted, standardized probabilities of treatment success were 85.8% (95% CI: 72.7%, 93.9%) for immediate change, 78.8% (95% CI: 66.1%, 87.1%) for deferred change, and 85.2% (95% CI: 80.5%, 89.1%) for no change. Compared with no change, treatment success ratios were 1.01 for immediate change (95% CI: 0.86, 1.11) and 0.93 for deferred change (95% CI: 0.78, 1.01) strategies. ConclusionsWe did not find evidence of a substantial negative impact of immediate modification to linezolid among people who developed mild or moderate peripheral neuropathy in the first six months of an individualized regimen. Our results support the clinical practice of cautiously adjusting linezolid when needed to manage non-severe peripheral neuropathy. Key pointsIn this target trial emulation, we found that immediate modifications to linezolid (dose reduction or suspension) in response to mild or moderate peripheral neuropathy during the first six months of MDR/RR-TB treatment did not substantially compromise MDR/RR-TB treatment success.

BackgroundFive-biomarker-defined hypervirulent Klebsiella pneumoniae (hvKp) causes invasive infections, but its burden in bloodstream infections versus classical K. pneumoniae (cKp) is unclear. MethodsThis retrospective cohort study at a tertiary hospital in Japan included K. pneumoniae bloodstream infection episodes from January 2022-December 2024. hvKp was defined by the presence of all 5 genotypic biomarkers (rmpA, rmpA2, iucA, iroB, and peg-344). The primary outcome was abscess complications, and secondary outcomes were length of stay and antibiotic duration. Whole-genome sequencing was performed for 164 isolates. ResultsAmong the 207 episodes, 28 (14%) were of hvKp. Abscess complication occurred in 17 (61%) hvKp versus 23 (13%) cKp episodes (adjusted odds ratio 10.7; 95% CI, 4.36-26.2). Median length of stay in hvKp versus cKp was 28 versus 14 days (adjusted ratio 1.60; 95% CI, 1.18-2.16) and median antibiotic duration was 43 versus 14 days (adjusted ratio 2.13; 95% CI, 1.64-2.77). These associations were attenuated after adjusting for abscess-related complications. No significant difference in 30-day mortality was observed, although the study was underpowered. Multidrug resistance was less frequent in hvKp strains than in cKp strains (11% vs. 30%; P = .040). Among the sequenced hvKp episodes, abscess rates varied across lineages, from 9 of 10 in ST23 to 1 of 4 in ST412. ConclusionsFive biomarker-defined hvKp strains delineated a bloodstream infection subgroup with frequent abscess complications and prolonged care. hvKp and cKp present distinct clinical challenges; diagnostic tools distinguishing these subgroups may aid abscess evaluation and source control.

Numerous factors may influence the optimal rollout of new gonococcal antibiotics. We compared eight rollout strategies using a gonorrhea transmission model and ranked strategies by the number of gonococcal infections and clinically useful antibiotic lifespan. Rankings were most sensitive to the starting ceftriaxone resistance prevalence and screening frequency.