Open Forum Infectious Diseases

Importance: Nirsevimab, a monoclonal antibody against RSV, was implemented in France in September 2023. Recently, rare resistance-associated substitutions were described in RSV but the effectiveness according to lineages remains unclear. Objective: We aimed to estimate the effectiveness of nirsevimab against hospitalization for RSV bronchiolitis according to RSV lineages. Design: We conducted a multicenter test-negative case-control study from October 15, 2023 to March 15, 2025. Setting: This study was based on data from three national multicentric prospective studies. The 12 participating centers were secondary or tertiary hospital with a pediatric department located in France. Participants: We included all children younger than 12 months who were hospitalized for RSV bronchiolitis in one of the participating centers in France during the two first RSV epidemic seasons following the implementation of nirsevimab (from October 15, 2023 to February 29, 2024, and from October 10, 2024 to March 15, 2025). Main outcomes and measures: The main outcome of the study was the RSV test result of bronchiolitis cases. RSV whole-genome sequencing was performed using a tiled amplicon approach covering the complete viral genome, as previously described in the POLYRES studies. We estimated the effectiveness of nirsevimab by a multivariable logistic regression model adjusted for potential confounders. We estimated the adjusted risk of immunization failure for each lineage by calculating relative odds ratio to a reference lineage. A range of sensitivity analyses were conducted. Results: We included 3019 infants with bronchiolitis among which 2273 had a positive RSV test (case patients) and 746 had a negative RSV test (control patients). Overall, 373/2273 (16.4%) case patients were immunized by nirsevimab versus 423/746 (56.7%) control patients. The adjusted effectiveness of nirsevimab against hospitalization for bronchiolitis was 88.4% (95% CI, 84.5-91.4) with RSV-B and 79.4% (95% CI, 73.7-83.8) with RSV-A. The risk of immunization failure was 3.2-fold (95% CI 1.8-5.7) higher for lineages derived from A.D.3 than for lineages derived from B.D.4.1. Conclusion and relevance: In this multicentric case-control study, we observed that nirsevimab effectiveness was variable across RSV lineages, with a lower effectiveness against A.D.3 lineages compare to others. Further surveillance is needed to confirm these findings and assess their implication on RSV lineages epidemiology as nirsevimab use expands.

Background: The relationship between recent viral infection and subsequent susceptibility to, or protection against, other viruses remains unclear, particularly across ages and symptom status. Methods: A prospective cohort study enrolled participants aged 6 months to 49 years in Washington and Oregon, USA, 2022-2024. Weekly nasal swabs were tested for SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A/B; additional swabs were collected during symptomatic illness and were also tested for parainfluenza (PIV) 1-4, endemic human coronaviruses (hCOV), adenovirus, human metapneumovirus, human rhinovirus (hRV), and enteroviruses. Proportional hazards regression models were used to characterize associations between incident symptomatic infection (illness) and history of recent illness due to other viruses (within 1-7, 8-14, 15-30, 31-60, 61-90, 91-180 days), adjusted for geographic region, age, sex, daycare/school/work attendance, household size, and number of children in the household. For SARS-CoV-2, influenza, and RSV, these analyses were repeated to study incidence of infection (including asymptomatic cases). Findings: Of 3,560 participants, 2,969 (83%) had [≥]1 illness over 4,299 person-years. Adjusted hazard ratios (aHRs) in the short term ([≤]2 weeks) after an illness were predominantly below 1, indicating that recent viral illness was often associated with lower risk of subsequent illness with other viruses. Across age groups, recent hRV illness was associated with lower risk of hCOV, PIV, and RSV illness (aHRs 0.07-0.27). SARS-CoV-2 illness was associated with a higher short-term risk of adenovirus and PIV illness (aHRs 3.20-3.33). In children aged 6 months-4 years, recent influenza illness was associated with higher short-term risk of SARS-CoV-2 illness. Including asymptomatic infections generally attenuated these associations. Interpretation: Some viral illnesses may alter short-term susceptibility to subsequent viral illnesses. Interactions may differ by age and symptom status. Funding: US Centers for Disease Control and Prevention; Washington State Department of Health.

Background: Host response and biomarker research to advance sepsis therapeutics requires well-characterized cohorts with longitudinal biospecimens across a range of hosts and infections. Automated screening based on SIRS criteria is sensitive but nonspecific and identifies more candidates than research teams can approach, sample, and follow longitudinally. We evaluated a structured enrichment review by non-physician study staff, done after automated screening in a hospital-wide prospective sepsis cohort. Methods: The CISID cohort is a prospective observational study of hospitalized patients with suspected sepsis, enrolling adults from the ED, inpatient wards, and ICUs at a tertiary academic medical center. Patients were identified through: (1) automated electronic health record screening for two or more SIRS criteria with a 24-hour lookback, documentation of microbiologic culture or PCR, and receipt of a new antibiotic; (2) a sepsis enrichment step of structured chart review by trained non-physician study staff; and (3) discussion with the primary clinical team. Enrolled patients underwent physician adjudication into four diagnostic categories. To evaluate the enrichment step, we analyzed all patients screened during a 9-week period, assigned a composite "sepsis-likely" variable (CDC Adult Sepsis Event criteria or ICD-10 code R65.20/R65.21 within 48 hours before or after screening), and assessed mortality across each stage of screening. We also assessed concordance of the composite with physician adjudication among enrolled patients. Results: From November 2023 through February 2026, 4,318 patients screened in through EHR-based automated screening; 1,220 (28%) were flagged for enrollment, and 288 were enrolled. Physician adjudication classified 209 (73%) as sepsis, 46 (16%) as infection without sepsis, 14 (5%) were classified as undifferentiated critical illness, and 19 (6.6%) as non-infectious sepsis mimics. Patients with sepsis were severely ill (median SOFA score, 9; ICU admission, 80%; shock, 48%), and 51% were immunocompromised; mortality was 14% in hospital and 27% at 90 days. In a 9-week sample of 907 screened encounters, 21% of those deferred and 70% of those flagged for enrollment met the sepsis-likely composite, a 3.3-fold increase in prevalence after structured study team review. Conclusions: A brief structured enrichment review after automated screening tripled the prevalence of EHR-based sepsis indicators among patients selected for enrollment, while concentrating enrollment efforts on roughly one-quarter of screened-in patients in this hospital-wide, all-source suspected-sepsis cohort. This approach may help prospective cohorts direct limited biospecimen resources toward patients most informative for host-response and biomarker research.

Typhoid intestinal perforation (TIP) is a late complication of Salmonella enterica serovar Typhi infection, and blood cultures, if available, are often negative at this stage, making etiologic confirmation challenging. In areas without access to blood culture diagnostics, TIP incidence can serve as a proxy for enteric fever burden. Antibodies against hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS) are promising serologic markers for typhoid, but their diagnostic utility for TIP remains unclear. In this study, we assessed the diagnostic accuracy of anti-HlyE and anti-LPS IgG and IgA antibodies measured by kinetic enzyme immunoassay in children undergoing emergency laparotomy for acute abdomen in Niger. Dried blood spots (DBS) were collected pre-operatively (baseline) and within 30 days post-hospital discharge (convalescence). Patients classified intraoperatively as TIP (n = 341) or as confirmed non-typhoid-related alternative etiology (i.e., controls, n = 48) were included in this serologic analysis. The primary analyses were conducted in a longitudinal sub-cohort of 122 TIP cases and 33 controls in whom all four anti-HlyE and anti-LPS IgA and IgG responses were measured at baseline and at convalescence. Anti-HlyE IgA and anti-LPS IgA were additionally measured at baseline in the full analytic cohort. In the primary analysis, all antigen-antibody isotype combinations distinguished TIP cases from controls with high accuracy: anti-HlyE IgA (AUC 0.94), anti-HlyE IgG (AUC 0.94), anti-LPS IgA (AUC 0.96), and anti-LPS IgG (AUC 0.96). Anti-HlyE IgA and anti-LPS IgA performed similarly in the full cohort (AUC 0.93 and 0.93, respectively), supporting the representativeness of the sub-cohort. Anti-LPS IgG showed the best overall performance (99% sensitivity, 94% specificity), exceeding that of all other individual markers, and combining markers did not improve diagnostic accuracy. Diagnostic performance at convalescence was similar to or lower than that observed at presentation. Overall, anti-HlyE and anti-LPS antibodies showed high diagnostic accuracy for TIP at presentation, extending the potential utility of these serologic markers for supporting the diagnosis of typhoid-associated intestinal perforation and improving surveillance of severe typhoid disease when patients present with late-stage complications. Our findings show that serologic testing could improve case detection and burden estimation of enteric fever and its complications in resource-limited settings.

Aim: Brucellosis remains endemic throughout the Mediterranean basin, the Middle East and Central Asia. Genitourinary involvement is an uncommon but clinically consequential focal complication that closely mimics urological emergencies and may precipitate unnecessary surgery. Contemporary data describing its frequency, laboratory signature and treatment outcomes in endemic settings remain limited. Material-Methods: We retrospectively screened all adults ([≥]18 years) with confirmed brucellosis managed at a tertiary infectious diseases unit between January 2008 and December 2020. Genitourinary involvement was defined as epididymo-orchitis, orchitis, epididymitis and/or brucellar pyelonephritis. Clinical, laboratory, ultrasonographic, therapeutic and outcome variables were abstracted using a standardised form. Proportions are reported with Wilson score 95% confidence intervals (CI). Reporting followed the STROBE statement. Result: Genitourinary involvement was identified in 18 of 125 patients with brucellosis (14.4%; 95% CI 9.3-21.6); 16 (88.9%) were men and the mean age was 35.2 years (range 22-62). Scrotal disease dominated the male presentation: epididymo-orchitis in 10 of 16 men (62.5%; 95% CI 38.6-81.5), orchitis in 4 (25.0%) and epididymitis in 2 (12.5%). Both women presented with pyelonephritis, one of whom developed a tubo-ovarian abscess requiring drainage. Constitutional features were near-universal (fatigue 100%, night sweats 88.9%, fever 77.8%). Leukocyte counts remained within the reference interval in every patient (mean 5,680/mm3), whereas erythrocyte sedimentation rate (mean 32 mm/h) and C-reactive protein (mean 24.2 mg/L) were only mildly to moderately raised. The Coombs anti-Brucella test was positive in 18 of 18 patients (100%) and the standard agglutination test in 17 of 18 (94.4%), whereas blood culture yielded Brucella melitensis in only 1 of 18 (5.6%). Concomitant extragenitourinary focal disease was present in 8 patients. All patients received doxycycline plus rifampicin; none required modification of the regimen or orchiectomy, and no treatment failure occurred (0 of 18; 95% CI 0-17.6). Median follow-up was 12 weeks (range 6-52) and no relapse was documented within this interval. Conclusions: In endemic regions, genitourinary brucellosis should be suspected in any patient with acute scrotal or flank symptoms accompanied by constitutional complaints, even when the leukocyte count is normal and acute-phase reactants are only marginally elevated. Coombs anti-Brucella serology rather than blood culture is the diagnostic cornerstone, and prompt doxycycline-rifampicin therapy averts surgical intervention.

Background: Pertussis has resurged in the post-COVID-19 era, yet diagnostic delay remains a barrier to timely treatment and transmission interruption, particularly among adults. Methods: Retrospective observational cohort study of 787 patients with confirmed pertussis from January 2016 through March 2026 across two South Carolina health systems. Electronic health record data from the 60 days preceding confirmation were used to characterize diagnostic timing (same-day vs. delayed), delay duration, and respiratory pathogen testing patterns including pertussis test modality. Results: Adults accounted for 48.4% of cases (median age 16 years [IQR 4-52]; 61.6% female). Same-day diagnosis was highest among children aged 1-4 years (75.4%) and lowest among adults aged 50 and older (approximately 50%). Among the 305 patients (38.8%) with delayed diagnosis, median delay ranged from 7-12 days in children to 22.5-26.5 days in adults aged 50 and older. Delay did not vary significantly by COVID-19 period, race, ethnicity, or insurance type. Testing breadth was greater in inpatient and emergency settings than outpatient. Pertussis testing was predominantly PCR-based in children but serologic in adults, potentially reflecting later clinical presentation relative to illness onset; however, the near-absence of PCR testing in older adults may contribute to missed diagnoses during the early illness window when PCR sensitivity is highest. Conclusions: Older adults experienced markedly delayed pertussis diagnoses compared with children. Earlier consideration of pertussis in adults with prolonged cough, including PCR testing early in illness before serologic conversion, may reduce diagnostic delay and facilitate timelier treatment and contact tracing.

Background: Child-friendly sample collection methods are needed to improve microbiological tuberculosis diagnosis in children. We assessed the feasibility, diagnostic yield, safety, tolerability, and acceptability of nasopharyngeal aspirates (NPA) and stool sample collection for XpertMTB/RIF Ultra (Ultra) testing in children <5 years with severe pneumonia in six high tuberculosis incidence countries. Methods: We conducted a cross-sectional mixed-methods study (10/2020-03/2021) nested within the TB-Speed Pneumonia trial (NCT03831906) in 15 tertiary hospitals. Uptake and diagnostic yield of NPA and stool, sampled by trained nurses, were computed. Nurses documented NPA feasibility and related adverse events. NPA tolerability was assessed through discomfort/distress/pain scales completed by nurses, parents/caregivers, and children >3 years. Individual interviews investigated nurses and parents/caregivers perceptions and experiences of both procedures. Results: Of 542 children enrolled, 541 (99.8%) and 423 (75.5%) had NPA and stool samples successfully collected, respectively; 8 (1.5%) had positive Ultra on any sample, 8 (1.5%) on NPA, and 3 (0.6%) on stool samples. Nurses reported that NPA was difficult to collect in 27 (5.0%) children. 130 (24%) children had bloodstained NPA samples and <5% experienced transient heart rate deceleration, digestive or respiratory distress during NPA. Median nurse-assessed tolerability scores were 1/10 [0,3] before and 5/10 [2,6] during NPA. Although most respondents perceived NPA as painful, all appreciated that NPA aimed to improve child health. Nurses reported that NPA and stool collection was quicker, less invasive than gastric aspiration. Parents/caregivers trusted nurses skills and valued the novelty of NPA. All respondents easily engaged in stool collection, but were frustrated to depend on children passing stool. Nurses underlined that continuous staff training and mentoring would sustain feasibility and self-efficacy in obtaining adequate samples. Conclusions: NPA and stool are viable specimen collection options for microbiological diagnosis of tuberculosis in young children <5 years with severe pneumonia in high tuberculosis incidence countries.

Abstract Background: Cyprus has transitioned into a high-alert zone for mosquito-borne viruses. This necessitates a proactive assessment of its future physicians. Following the 2022 re-establishment of Aedes aegypti in Larnaca and Aedes albopictus in Limassol, Cyprus, the island is now biologically primed for local outbreaks of dengue, Zika, and chikungunya, alongside Culex-borne West Nile virus. The study assessed medical students' knowledge and risk perception. Methods: A cross-sectional online survey administered the validated MosquitoWise Health Belief Model instrument to undergraduate-entry and graduate-entry students at a university in Cyprus in mid-2026. Results: Of 1023 students, 119 responded (11.6%), with pre-clinical students overrepresented (p<0.001). Mean knowledge was 5.43/9, stronger on mosquito biology (72.5%) than virus knowledge (54.2%). Median severity was 6.00/7 against susceptibility 4.25/7. Knowledge differed by study stage (p<0.001), correlated with severity (rs = 0.399) but not susceptibility. Conclusions: The study establishes a critical baseline for pre-clinical medical students in Cyprus. Overall, participants performed better on mosquito biology when compared to mosquito-borne viruses and how they spread. Our findings highlight the value of integrating theoretical microbiology with clinical practice in medical education to enhance physicians' preparedness for the changing landscape of newly emerging infections in Cyprus and across Europe as a whole. Key Words: Arboviruses, Cross-Sectional Studies, Cyprus, Health Belief Model, Medical Students, Risk Perception.

Background Mortality in sepsis is often considered a direct consequence of infection and organ dysfunction, although many deaths occur after withdrawal of life sustaining treatment. The clinical factors leading to these decisions and their implications for interpreting sepsis mortality are not well characterized. Methods We performed a secondary analysis of a prospective observational cohort of adults with physician adjudicated sepsis at a tertiary academic medical center. Patients who transitioned to comfort measures only (CMO) during the index hospitalization underwent structured chart review to characterize baseline health and functional status, clinical severity, care preferences, anticipated outcomes following survival, and the primary reason for CMO transition. Results Among 239 patients with adjudicated sepsis, 42 (17.6%) transitioned to CMO. These patients had substantial underlying disease, including malignancy in 76% and immunocompromised status in 62%. However, 88% lived at home before hospitalization, 52% were independent in activities of daily living, an additional 26% were partially independent, and 90% were full code on admission. Progressive multi organ failure (19%), refractory septic shock (19%), and irreversible respiratory failure (12%) accounted for half of CMO transitions, while advanced frailty (5%) and poor baseline functional status (2%) were infrequent primary reasons. Median time from admission to CMO was 16 days (IQR 7 to 33), and median time from admission to death was 18 days (IQR 11 to 35). Anticipated ventilator dependence (62%), dialysis dependence (36%), and cognitive impairment frequently influenced goals of care discussions. Overall, 38 patients died during the index hospitalization, and 35 (92%) of these deaths followed transition to CMO. Conclusions Most CMO transitions in this cohort occurred after an evolving course of severe sepsis and were driven primarily by progressive organ dysfunction and failure to recover rather than advanced frailty or poor baseline function. These findings identify failure to recover after the acute septic insult as an important clinical trajectory and highlight the need to account for treatment limitation when interpreting sepsis mortality. Understanding why some patients recover from sepsis associated organ dysfunction while others progress to irreversible organ failure may help identify patients and mechanisms for future therapeutic intervention.

PurposeLong COVID literature often describes new-onset symptoms or conditions following SARS-CoV-2 infection; however, Long COVID also encompasses the exacerbation of pre-existing conditions. We describe health conditions reportedly worsened by COVID-19 illness and associated concerns in U.S. adults. MethodsWe collected longitudinal data from adults 18 years and older participating in the Track Post COVID-19 Conditions, an active Long COVID cohort surveillance project. Respondents completed surveys 3-, 6-, and 12- months after COVID-19 illness, beginning in July 2023. In each survey, respondents were asked whether they had any health conditions or concerns that were made worse by COVID-19. Those with an affirmative response were asked to specify the worsening condition(s) via free text. Some respondents used this free text to describe challenges or experiences related to their worsening conditions. This report categorizes and quantifies reported conditions and concerns by body system categories and qualitatively describes associated challenges and experiences using direct quotes from respondents free text responses. ResultsAmong 2,227 adults, 263 (11.8%) respondents reported at least one worsening condition or concern following COVID-19 illness. Of these, nearly 32% reported a worsening respiratory condition or concern. Adults with worsening pre-existing conditions reported challenges accessing adequate care, completing daily activities, and managing their symptoms following COVID-19. DiscussionWhile Long COVID literature often focuses on the development of new-onset long-term symptoms, more than 1 in 10 adults reported worsening of a pre-existing condition following COVID-19. Reported challenges with accessing care and daily activities highlight potential need for accommodations or support for adults with Long COVID.

Background: Tuberculosis (TB) remains the leading infectious disease cause of mortality worldwide. A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) remain TST/IGRA-negative despite sustained exposure, termed "TB resisters". The biological mechanisms underlying this resistance remain poorly understood. We applied untargeted high-resolution metabolomics to determine whether systemic metabolic profiles differ between TB resisters and matched Mtb-infected close contacts. Methods: We compared untargeted high-resolution plasma metabolomics using liquid chromatography mass spectrometry between 269 TB resisters and 269 matched Mtb-infected close contacts, enrolled across Brazil, India, and South Africa. TB resisters were defined as highly exposed close contacts who slept in the same room or spent at least 5 hours indoors per day with an infectious pulmonary TB index patient, but remained TST/IGRA-negative. Mtb-infected close contacts were those who were TST/IGRA positive. Metabolome-wide association studies (MWAS) were conducted using paired t-tests. Results: There were 1,787 features with nominal differences between TB resisters and matched Mtb-infected contacts (p < 0.05). Pathway enrichment identified fructose and mannose metabolism and bile acid biosynthesis in the overall cohort, while lipid-related pathways were enriched in Brazil. Among metabolites with confirmed chemical identities, glyceric acid concentrations were higher in TB resisters by 0.53 uM, whereas hydroxyproline was lower by 0.90 uM, butyrobetaine was lower by 0.06 uM, and homogentisate was lower by 0.0036 uM at false discovery rate of 0.2. Conclusions: Plasma metabolomic profiles differed between TB resisters and matched Mtb-infected close contacts. These findings indicate that systemic metabolic differences are associated with resistance to Mtb infection.

Background: Parenthood in medicine is an experience fraught with challenges that begin in the pre-conception phase and persist as physician-parents navigate their dual role. Methods: This study aims to understand the experiences of physician-parents (both childbearing and non-childbearing) returning to work after parental leave. Physicians, including residents, affiliated with the University of Toronto Department of Medicine internal medicine division who had a child within the last ten years were invited to participate in a self-administered electronic survey from June2022 to 30June 2023. Data were summarized using descriptive statistics. Results: Twenty-nine respondents took part in the survey; 79% were staff physicians while the remaining were trainees at the time of the survey. At the time their first child was born, 48% were staff members and 52% were trainees. The median duration of parental leave was 5 months (range 1-12 months). Among those for whom lactation was applicable, 76% reported that they continued their lactation efforts on returning to work, while 24% chose not to. Thirty five percent (35%, n=6/17) of respondents cited that they were not provided with duty hour modifications when required. Many respondents (46%) felt guilty about burdening their co-workers for requesting accommodations for childcare. When requested to rate their experiences of balancing their personal and professional lives on a scale of 1-10 (1 being impossible to maintain and 10 being extremely easy to maintain), most respondents (66%) chose a rating of 5 or less. Conclusion: This study supports previous findings that physician-parents face a myriad of challenges integrating their roles in medicine and parenthood. A change in culture is required to support and normalize parenthood for physicians and foster sustainability and productivity in academic medicine.

Background: Common variable immunodeficiency is frequently underrecognized due to its heterogeneous clinical presentation, resulting in diagnostic delays that increase disease-related complications, with each year of delay increasing mortality risk by 4% for the most common inborn error of immunity. Objective: In individuals with established common variable immunodeficiency, we sought to recognize patterns in patient diagnostic trajectories to identify opportunities for interventions to reduce time to diagnosis. Methods: We analyzed retrospective electronic health records data from 139 individuals with physician-confirmed common variable immunodeficiency across five academic health systems representing >10million patients. We evaluated diagnosing specialties and international classification of disease code trajectories in the two years prior to and at common variable immunodeficiency confirmation. Additionally, we construct specialty-specific prediction on a 1:50 case: control cohort using a gradient boosting algorithm. Results: The leading diagnoses at common variable immunodeficiency determination were respiratory (35% of individuals), and individuals with respiratory symptoms were more likely to be diagnosed by Allergy / Immunology than by other specialties (odds ratio 2.9, standard error 0.35, p-value 1.9x10-3) and had a higher frequency of visits to pulmonary disease in the two years prior to diagnosis. Individuals with neoplasms were 50% more likely than other patients (OR 2.0, SE 0.29, p-value 0.02) to receive a diagnosis at each visit, reducing their diagnostic delay by up to a year. We find that a larger ratio of number of specialties visited to the total number of visits is significantly correlated with an increased time to diagnosis. A trajectory-informed specialty-specific prediction improved detection with an area under the precision-recall curve of fifty times the value expected under the null. Conclusions: Individuals referred to Allergy / Immunology have shorter time to diagnosis, and a specialty-specific prediction could improve detection of common variable immunodeficiency. Clinical Implications: Overall, we find that phenotype-specialty interactions may inform targeted interventions to improve common variable immunodeficiency recognition across specialties, reducing diagnostic odyssey and disease-related complications.

Interferon-gamma release assays detect Mycobacterium tuberculosis infection but cannot distinguish infection from active tuberculosis (TB). We evaluated the diagnostic information provided by QuantiFERON-TB Gold Plus (QFT-Plus) among adults investigated for active TB in Brazil and South Africa. Adults with presumptive TB were prospectively enrolled by convenience sampling. QFT-Plus was the index test, and diagnostic classification required microbiological confirmation of TB or an established alternative diagnosis. QFT-Plus results did not inform diagnostic classification. Accuracy was assessed among participants with determinate results, primarily using likelihood ratios. Of 723 participants tested, 48 (6.6%) had indeterminate results, all due to low mitogen responses. Among 675 participants with determinate results, 147 (21.8%) had confirmed TB. Sensitivity was 68.0% (95% CI, 60.1-75.0), specificity was 59.3% (95% CI, 55.0-63.4), and the negative likelihood ratio was 0.54 (95% CI, 0.42-0.69). At the observed prevalence, a negative result left a 13.1% probability of active TB. Negative likelihood ratio confidence intervals included 1 in both South African HIV strata. Specificity was higher among participants with HIV in both countries. Adding TB2 to TB1 alone identified 15 additional TB cases and generated 18 additional positive results among participants without active TB. HIV and active TB were independently associated with indeterminate results in exploratory regression. A negative QFT-Plus result provided insufficient information to exclude active TB. Higher negative predictive values among participants with HIV reflected lower disease prevalence and higher specificity rather than greater sensitivity. Negative or indeterminate results should not terminate diagnostic evaluation.

Background: Filoviruses, specifically Ebola virus (EBOV), Bundibugyo virus (BDBV), and Marburg virus (MARV), have been the etiologic agents of multiple outbreaks of severe disease in the Democratic Republic of the Congo (DRC). Two EBOV-specific vaccine regimens have been approved for use in outbreak scenarios, including the Ad26.ZEBOV/MVA-BN-Filo (Zabdeno/Mvabea) two-dose vaccine, where the MVA-BN-Filo booster dose contains EBOV, MARV, and Sudan (SUDV) virus glycoproteins (GPs) and the nucleoprotein from Tai Forest virus. While long-term immunogenicity of up to two years has been found in clinical trial settings, limited real-world data exists. Methods: Using a multiplexed immunoassay, samples (n=698 at baseline) collected in Mbandaka, Equateur province, DRC, between September 2023 and October 2024 were assessed for seroreactivity to six filovirus antigens (1 BDBV, 2 EBOV, 2 MARV, and 1 SUDV) at three distinct periods: baseline/pre-vaccination, 6-8 weeks post-first dose (Zabdeno), at booster administration (Mvabea), and one-year post-boost dose. Results: Substantial filovirus seroreactivity was found at baseline, with 48.7% (n=340/698) of individuals being seroreactive to at least one virus antigen. High baseline seroreactivity was found against BDBV GP (31.1%, n=217/698), with lower baseline seroreactivity to EBOV GP (15.5%, n=106/698), comparatively. Overall EBOV GP seroreactivity increased to 66.8% (n=376/563) at one year-post vaccine boost and 57.6% (n=250/434) of participants were seroreactive. Despite the booster dose inclusion of SUDV GP and MARV GP, there were no substantial increases in reactivity against either antigen at subsequent timepoints. Overall filovirus seroreactivity increased at all timepoints for the entire cohort, although filovirus reactivity decreased over the study period for those who were seroreactive at baseline. Findings: These data highlight detection of significantly elevated seoreactivity to EBOV GP following first-dose administration of Ad26.ZEBOV, which remained relatively stable one-year post-booster dose administration. Additionally, this study identifies high levels of baseline seroreactivity to BDBV GP despite no previous documented outbreaks in this region of DRC. These data suggest that vaccination with the Ad26.ZEBOV-MVA-BN-Filo vaccine induces stable seroreactivity against EBOV GP, but not to other filovirus antigens.

Background State-level estimates of hepatitis C virus (HCV) prevalence are needed to guide resource allocation and to provide a baseline against which to measure progress toward elimination goals. Population prevalence is not directly observable, requiring estimation from indirect data sources. Methods We adapted a Bayesian spatial integrated abundance model to estimate state-level HCV prevalence during 2017-2020 across 48 states and the District of Columbia. The model integrated six HCV-related outcomes: acute and chronic surveillance cases, HCV-related deaths, observations of HCV in [MarketScan] administrative claims data, diagnoses of HCV in Medicaid recipients, and treatment with direct-acting antivirals in Medicaid recipients. Estimates were anchored to a national prevalence estimate, and the model accounted for data source-specific selection, heterogeneity in HCV risk factors across states, and geospatial correlation. Results Estimated average prevalence was 1.32% (95% credible interval [CrI]: 0.94%-1.80%), corresponding to 3.33 million (95% CrI: 2.37-4.65 million) adults with HCV infection across 48 states and DC. State estimates ranged from 0.74% in North Dakota to 2.22% in Oklahoma (median state-specific prevalence, 1.27%), with higher prevalence concentrated in South Central states, Appalachia, and the West, and the lower prevalence in the upper Midwest, Southeast, and New England. Ten states accounted for 56% of estimated infections. Estimates were stable in sensitivity analyses (most differences <1 percentage point). Conclusions These estimates quantify state-level HCV burden prior to the 2021 federal expansion of HCV surveillance funding, providing a baseline for monitoring elimination progress. Geographic variation indicates that resource needs will differ by jurisdiction.

Background: Age is an important determinant of tuberculosis (TB) risk, but population-level age patterns in TB prevalence have not been systematically quantified across settings. We conducted a systematic review of surveys conducted in low- and middle-income countries to quantify trends in TB prevalence across age groups. Methods: We collated age-stratified TB prevalence data for individuals aged 15+ years, from population-based surveys reported between 1993 and 2025. We analyzed data using Bayesian meta-regression models, estimating trends in bacteriologically confirmed pulmonary TB prevalence across age groups. We extended models to understand how age trends varied with alternative outcome definitions and data subsets, and examined correlations between TB age trends and sociodemographic determinants. We also estimated age-stratified notification-to-prevalence ratios as a measure of diagnostic delays for untreated TB. Findings: We included 82 unique surveys reporting age-stratified TB prevalence, spanning 30 countries and 4.6 million participants. These data demonstrated a pattern of increasing bacteriologically confirmed TB prevalence with older age, with each 10-year increase associated with a 30% (95% credible interval: 22, 38) increase in prevalence. TB prevalence for the oldest age group (75+: 796 per 100,000 [522, 1178]) was 6.4 (4.0, 10.4) times higher than the youngest (15-19: 127 per 100,000 [79, 186]), and positive age gradients were estimated for all countries (interquartile range: 23-40% increase per 10-year increase in age). Age gradients were lower in Africa compared to other regions, and for smear-positive compared to bacteriologically confirmed TB. Countries with HIV prevalence [&ge;]5% had flatter age gradients above 40 years of age. Age gradients declined slowly over the study period. Notification-to-prevalence ratios demonstrated a negative age gradient, declining by 10% (7, 14) per 10-year increase in age. Interpretation: The prevalence of untreated TB disease increases substantially throughout adulthood, and lower notification-to-prevalence ratios suggest poorer case detection among older individuals.

BackgroundSevere community-acquired pneumonia (CAP) remains a leading cause of mortality in children under five. The PediCAP trial evaluated oral step-down therapy using dispersible amoxicillin or amoxicillin/clavulanate tablets in African children hospitalised with severe CAP. Dispersible tablet formulations are preferred in children; however, pharmacokinetic data for oral amoxicillin/clavulanate in paediatric populations remain limited. We characterised the pharmacokinetics of 4:1, 7:1, and 14:1 dispersible amoxicillin/clavulanate tablets in children enrolled in the PediCAP trial and predicted target attainment under different dosing schemes. MethodsChildren were randomised within 24 hours of starting intravenous antibiotics to oral step-down therapy with weight-banded dosing of twice-daily amoxicillin/clavulanate (4:1, 7:1, or 14:1). Plasma concentrations were quantified following intensive sampling and analysed using nonlinear mixed-effects modelling with allometric scaling and postmenstrual age-dependent clearance maturation. Pharmacodynamic indices included %fT>MIC for amoxicillin and %fT>Ct for clavulanate. ResultsA total of 157 children (median [range] age, 12 [2-70] months; weight, 8.4 [4.0-22.0] kg) contributed 707 paired concentrations. Amoxicillin was described by a two-compartment model and clavulanate by a one-compartment model, both with sequential zero-and first-order absorption. Typical clearance for an 8-kg individual at full maturation was 11.8L/h for amoxicillin and 6.1L/h for clavulanate. Pharmacokinetics were similar between the formulation ratios. Weight-banded dosing achieved balanced exposures across weight groups. Amoxicillin achieved 40%fT>MIC for MICs[&le;]2mg/L. A proposed clavulanate target of 20%fT>0.5mg/L was achieved in most children even at the lowest amoxicillin/clavulanate ratio. ConclusionWeight-banded dosing using dispersible amoxicillin/clavulanate tablets provide consistent exposure profiles in African children with severe CAP. SUMMARYPopulation pharmacokinetic modelling of dispersible amoxicillin/clavulanate tablets (4:1, 7:1, 14:1) in 157 African children with severe pneumonia showed weight-banded dosing achieved consistent and adequate amoxicillin and clavulanate exposures across formulations.

Morganella morganii is an opportunistic pathogen with intrinsic and acquired antimicrobial resistance, but its genomic epidemiology remains poorly characterized in Bangladesh. We sequenced and compared genomes of 47 stool-derived M. morganii isolates from hospital (n = 29) and community (n = 18) participants in urban Dhaka. Susceptibility testing showed frequent resistance to imipenem (70.2%) and cefuroxime (97.9%), while all isolates were resistant to colistin. Resistance to meropenem (6.4%) and ertapenem (2.1%) was uncommon. Based on acquired non-susceptibility across tested antimicrobial categories, 18/47 (38.3%) isolates were multidrug-resistant, including 15/29 (51.7%) hospital-derived and 3/18 (16.7%) community-derived isolates. Genomic analysis identified 17 {beta}-lactamase alleles including Morganella-associated chromosomal {beta}-lactamases and acquired resistance determinants, with blaOXA-1, blaDHA-21, blaCTX-M-15, and blaTEM-1 predominating. However, no recognized acquired carbapenemase genes were detected. Among 44 non-{beta}-lactam resistance genes, tetB was most frequent. Phylogenomic and average nucleotide identity analyses classified 31 isolates as M. morganii subsp. morganii and 16 as the subsp. intermedius lineage. Considerable population diversity was observed, with 33 distinct sequence types among the 47 isolates and no clear clustering by hospital or community origin. The subsp. intermedius isolates showed greater genomic heterogeneity than subsp. morganii, with a minimum within-group average nucleotide identity of 94.2%. Single nucleotide variant (SNV) analysis identified several closely related isolate groups, including an ST1 pair differing by 10 SNVs and collected three days apart within the same hospital, although direct transmission could not be established. Virulence-associated gene profiles differed between subspecies, with hemolysin- and toxin-associated genes predominantly detected among subsp. morganii isolates and largely absent from subsp. intermedius. Overall, these findings reveal substantial genomic diversity, a considerable burden of multidrug resistance, and subspecies-associated differences in virulence gene content among M. morganii circulating in Dhaka, while the frequent imipenem-non-susceptible but carbapenemase-negative phenotype highlights the need to investigate alternative carbapenem resistance mechanisms.

Background Killed whole-cell oral cholera vaccines require multiple doses and have reduced efficacy in young children, limiting their utility. PanChol is a single-dose, oral live-attenuated cholera vaccine engineered from a current seventh pandemic El Tor O1 Vibrio cholerae strain. PanChol was shown to be safe and immunogenic in a previous phase 1a trial. In participants from this first-in-human trial, we aimed to assess the durability of the initial PanChol dose and the safety and immunogenicity of a second dose. Methods This open-label phase 1a booster study was conducted at Brigham and Women's Hospital (Boston, MA). Eligible participants were healthy adults aged 18-55 years without a history of cholera or gastrointestinal disorders and had received a PanChol dose ranging from 105-1010 colony-forming units (CFU) within the previous 322-1111 days. All participants received a booster dose of 2x107 CFU. The primary outcome was safety, including solicited, unsolicited, and serious adverse events following the second dose of PanChol. Secondary endpoints were the magnitude of pre- and post-vaccination serum vibriocidal titers to both Inaba and Ogawa V. cholerae, including seroconversion (4-fold rise in titers over baseline), and stool shedding of PanChol organisms using quantitative and qualitative stool cultures. Comparisons of the amount of vaccine shedding in stool following primary and secondary immunization were used to assess the intestinal mucosal immunity elicited by the initial PanChol dose. All outcomes were assessed in all participants. This trial is registered with ClinicalTrials.gov, NCT05657782, and is complete. Findings Between Aug 25, 2025, and Feb 20, 2026, 20 healthy adults who previously received a single oral dose of PanChol were enrolled to receive a booster dose of 2x107 CFU. Eleven (55%) of 20 participants were male and the median age was 43{middle dot}6 (IQR 30{middle dot}2-49{middle dot}5). Ten (50%) were White and 17 (85%) were not Hispanic or Latino. Nine (45%) of 20 boost recipients reported at least one solicited adverse event; 13 (93%) of 14 events were mild, and all were transient. The most common solicited adverse event was nausea, reported by 4 (20%) participants; all cases were mild. Most unsolicited adverse events were mild; one was grade 3 and was deemed unrelated to vaccination. Two unsolicited adverse events were deemed related to vaccination (mild gassy sensation and heartburn, both of which occurred on day 1 and resolved the same day). In most participants, vibriocidal antibody titers measured on the day of boosting exceeded baseline titers prior to the initial dose (17 (85%) for Inaba and 14 (70%) for Ogawa). Fifteen (75%) of 20 boost recipients seroconverted vibriocidal antibody titers to both serotypes. After the boost, 17 (85%) participants had no or self-limited vaccine shedding, compared with 10% after the first PanChol dose. Interpretation A second oral dose of PanChol had a favorable safety profile and induced vibriocidal seroconversion to both serotypes in 75% of boost recipients. Intestinal colonization of PanChol following the boost serves as a proxy for measuring mucosal immunity targeting V. cholerae. The decrease in in the abundance of PanChol fecal shedding following the second dose, compared with the first, suggests that a single dose of PanChol is sufficient to confer durable protective immunity against a cholera challenge. These observations underscore the need for further clinical development of PanChol. Funding Wellcome Trust.