The Lancet Respiratory Medicine

BackgroundWe explored the efficacy of AS01E-adjuvanted respiratory syncytial virus prefusion F protein-based vaccine (adjuvanted RSVPreF3) in subpopulations of participants with underlying medical conditions in the multi-country, phase 3 AReSVi-006 trial (conducted May/2021-May/2024). MethodsMedically stable [≥]60-year-olds were 1:1-randomised to receive one adjuvanted RSVPreF3 or placebo dose pre-RSV season 1. In exploratory post-hoc analyses in subgroups of participants with underlying conditions (including COPD, asthma, diabetes, obesity [BMI[≥]30 kg/m2]), we evaluated efficacy of one vaccine dose against RSV-related lower respiratory tract disease (RSV-LRTD), acute respiratory illness (RSV-ARI), and RSV-ARI-related complications (e.g., pneumonia, COPD/asthma exacerbation, cardiovascular events). We also evaluated (post-hoc) RSV-ARI-related systemic corticosteroid and antibiotics use in participants with COPD or asthma. ResultsThe efficacy analyses comprised 12,468 vaccine and 12,498 placebo recipients. Efficacy against RSV-LRTD over three RSV seasons was similar among participants with COPD (75.1%, 95% CI: 40.2-91.4), asthma (65.8%, 31.0-84.7), diabetes (69.8%, 37.5-87.1), and obesity (74.1%, 56.4-85.5) as in the overall study population (62.9%, 97.5% CI: 46.7-74.8). Efficacy was also observed against RSV-ARI in these subgroups. Efficacy against RSV-ARI-related complications was 74.4% (95% CI: 11.2-95.2) in participants with COPD and 60.8% (-9.9-88.7) in those with asthma. Among participants with COPD, 15.4% (1.9-45.4) of RSV-ARI episodes in vaccine vs 22.4% (12.5-35.3) in placebo recipients were treated with systemic corticosteroids, and 46.2% (19.2-74.9) vs 56.9% (43.2-69.8) with antibiotics. ConclusionsPost-hoc analyses of the AReSVi-006 trial suggest that adjuvanted RSVPreF3 may help prevent RSV-ARI, RSV-LRTD, and RSV-related complications in medically stable older adults with underlying medical conditions like COPD and asthma. Trial registrationClinicalTrials.gov: NCT04886596 SummaryPost-hoc analyses of the AReSVi-006 trial suggest that 1 dose of adjuvanted RSVPreF3 may help prevent RSV-related illness and complications over 3 consecutive RSV seasons in subgroups of [≥]60-year-olds with chronic medical conditions, e.g., COPD and asthma.

IntroductionPublic and regulatory scrutiny of immunization safety has intensified in recent years. The COVID-19 pandemic has been instrumental in this. The accelerated timeline of COVID-19 vaccine development combined with the amplification of resultant side effects have proven corrosive to confidence. Unsurprisingly, COVID-19 vaccine uptake has declined year-on-year. This conflicts with the threat that infection still presents: predictors and prognoses of post-acute complications remain uncertain. Restoring public trust in these technologies will require meaningful progress in the availability and accessibility of clinical safety and pharmacovigilance data. MethodsExpanding upon recent comparisons of COVID-19 vaccine reactogenicity, we present a post-hoc safety analysis of adintrevimab, an intramuscular (IM) anti-SARS-CoV-2 spike recombinant investigational monoclonal antibody (mAb) for the pre-exposure and post-exposure prophylaxis of COVID-19, as assessed by the multi-center, double-blind, Phase 2/3 randomized placebo-controlled EVADE study (NCT04859517). Exploratory endpoints included the incidence of [≥]1 systemic symptoms within 7 days of study drug administration as well as symptom number, duration and severity. Safety reporting encompassed solicited and unsolicited treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, and clinical laboratory assessments. ResultsEVADE study participants (n=2582) were randomized between April 2021 - January 2022. Baseline characteristics were balanced across treatment groups. Within the 7 day post-dose period, 25/1241 (2.0%) of adintrevimab recipients and 12/1242 (1.0%) of placebo recipients reported at least one systematic TEAE. Multiple systemic TEAEs were less prevalent, with 0.3% and 0.1% reporting two systemic TEAEs, and 0.1% and 0.1% reporting three TEAEs in adintrevimab and placebo groups, respectively. The majority of TEAEs reported were mild to moderate in severity, primarily involving headache (0.4% adintrevimab, 0.8% placebo), fatigue (adintrevimab 0.4%, placebo 0.2%), and nausea/vomiting (adintrevimab 0.4%, placebo 0.1%). For those participants who experienced any TEAEs in the 7 day post-dose period, mean (+/-standard deviation) number of systemic symptoms was 1.2 (0.5) for adintrevimab and 1.3 (0.6) for placebo with symptoms consistently resolving within 3 days. ConclusionsIncreased expectations for pharmaceutical safety data generation are to be welcomed, offering patients the information they need to appropriately weigh the benefits and risks of any novel therapeutic. These analysis results support the high tolerability of IM-administered adintrevimab, with reactogenicity data broadly comparable to placebo. While the co-administration of vaccines and monoclonal antibodies limit direct comparisons between historical safety reports, findings such as these demonstrate the potential clinical value of controlled head-to-head studies such as the anticipated LIBERTY trial.

BackgroundIn extensively drug-resistant and pre-extensively drug-resistant TB, bacteriology-based monitoring often fails to capture structural lung recovery and patient-reported functional health. We aimed to characterize multidomain treatment response and examine host inflammatory and transcriptional features associated with incomplete recovery. MethodsWe conducted an ancillary analysis of a prospective, open-label, pilot study evaluating adjunctive ibuprofen in XDR-TB (NCT02781909). Participants were assessed at baseline and during treatment using TBS, chest radiography, sputum culture, SGRQ, blood cell indices, plasma cytokines, and whole-blood transcriptomic profiling. Clinical and laboratory measures were compared across outcome groups, and blood transcriptional profiles were analyzed in relation to treatment outcomes. ResultsHere we show that microbiological and symptomatic improvement occurred earlier than radiological and functional recovery. Higher baseline systemic inflammation, including elevated NLR, SII, and IL-6, as well as increased expression of interferon-related genes such as CD274 and GBP5, were associated with poorer radiological and SGRQ outcomes at 6 months. In contrast, transient elevations of IL-8 and IL-4 were associated with early bacteriological clearance. IL-8 was the only plasma biomarker consistently correlated with symptom severity, radiological findings, and functional health. ConclusionsTreatment response in drug-resistant TB is asynchronous across biological domains. Integrated host profiling identifies inflammatory and transcriptional features associated with incomplete structural and functional recovery, supporting the use of multidimensional endpoints to better capture long-term outcomes and inform individualized patient management. Plain Language SummaryPeople with highly drug-resistant tuberculosis can clear the infection but still experience lung damage and reduced quality of life after treatment. In this study, we examined recovery using several measures, including symptoms, chest X-rays, blood markers of inflammation, and gene activity, in addition to tests for tuberculosis bacteria. We analyzed data and stored samples from a small clinical trial to see how these measures changed over time. We found that lung structure and quality of life improved more slowly than bacterial clearance. People with higher levels of inflammation before treatment were more likely to have ongoing lung changes and poorer quality of life later. These results suggest that tuberculosis care should look beyond bacterial clearance and include monitoring inflammation to better support long-term recovery.

ABSTRACT Background: Corticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19. Methods: We utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support. Results: This emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated). Conclusions: In this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.

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.

Adjunctive therapies that enhance the efficacy of existing antitubercular drugs are needed for drug-resistant tuberculosis. We evaluated the efficacy of intranasally administered recombinant D29 LysB, a mycobacteriophage-derived mycolylarabinogalactan esterase, in murine and guinea pig models of pulmonary tuberculosis. BALB/c mice and guinea pigs were aerosol-infected with Mycobacterium tuberculosis H37Rv and treated for 4 weeks with LysB alone or with standard antitubercular therapy (ATT: rifampicin, isoniazid, pyrazinamide). Outcomes included pulmonary and extrapulmonary bacterial burden (CFU), lung and spleen histopathology, cytokine profiling, and humoral immune responses. LysB monotherapy produced modest pulmonary CFU reductions. When given adjunctively with ATT, LysB produced an additional 0.6-0.7 log10 reduction in lung CFU compared with ATT alone and decreased splenic dissemination in both species. Combination therapy improved tissue pathology, reducing granulomatous involvement and preserving pulmonary architecture. LysB treatment increased TNF- with a moderate rise in IL-10, a profile consistent with enhanced antibacterial immunity without excessive inflammatory damage. Repeated intranasal administration was well tolerated; no IgE-mediated hypersensitivity was detected. LysB-specific IgG developed but did not diminish therapeutic efficacy. These results show that intranasal D29 LysB augments the bactericidal and histopathological effects of standard ATT in vivo and support further development of inhaled phage-derived lysins as adjunctive therapies for drug-resistant tuberculosis. ImportanceTuberculosis remains a major cause of infectious mortality worldwide, and the increasing burden of multidrug-resistant and extensively drug-resistant disease continues to challenge effective treatment. New therapeutic approaches that complement conventional antibiotics are urgently needed. In this study, intranasally delivered recombinant mycobacteriophage-derived LysB was well tolerated and enhanced treatment efficacy in experimental pulmonary tuberculosis. Adjunctive LysB improved bacterial clearance, reduced tissue pathology, and modulated host immune responses in both murine and guinea pig models. These findings highlight phage-derived endolysins as promising inhalable adjunctive therapeutics for drug-resistant tuberculosis.

Introduction: A prominent symptom of post-acute sequelae of SARS-CoV-2 infection (i.e., Long COVID) is exercise intolerance with or without post-exertional malaise (PEM). PEM is characterized by the worsening of both symptoms and function following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. Individualized, supervised cardiopulmonary rehabilitation is considered a safe and effective intervention for many cardiac and pulmonary conditions, and has been effective in gradually improving function in previously hospitalized and nonhospitalized patients with severe COVID-19. While traditional cardiopulmonary rehabilitation approaches appear helpful in some situations, the exercise intolerance symptoms experienced by many individuals with Long COVID may require a different approach, especially when attempts to increase physical activity result in PEM. No clear consensus exists on the optimal treatment of PEM, and no major studies have evaluated the efficacy in individuals with Long COVID of either carefully supervised, individualized cardiopulmonary rehabilitation programs for exercise intolerance without significant PEM or activity pacing interventions designed to treat or prevent PEM. Methods and Analysis: The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative funded by the National Institutes of Health (NIH) included a prospective, multicenter, randomized controlled platform trial (RECOVER-ENERGIZE) designed to assess two interventions in patients with Long COVID and exercise intolerance: (1) cardiopulmonary rehabilitation for patients without significant PEM and (2) structured activity pacing to prevent or reduce PEM in participants who experience the symptom. The intervention duration will be 12 weeks. The primary endpoints for the trial include the Endurance Shuttle Walk Test as a measure of endurance capacity for the cardiopulmonary rehabilitation intervention and a modified version of the DePaul Symptom Questionnaire - Post-Exertional Malaise for the pacing intervention. Assessments will be completed at baseline, middle of intervention, end of intervention, and 12 weeks after completion of the intervention, and include physical performance measures and patient-reported surveys. Ethics and Dissemination: The RECOVER-ENERGIZE trial protocol has been approved by an institutional review board (Advarra), and written informed consent will be obtained from all participants prior to enrollment. The trial is registered on ClinicalTrials.gov (NCT06404047). Formally assessing PEM and developing a structured activity pacing intervention delivered by local pacing coaches are novel features of this trial. Results will be disseminated through peer-reviewed publications, presentations at scientific conferences, and communication with participants, patient advocacy organizations, and the broader Long COVID community. De-identified participant data will be made available through the NIH RECOVER data repository in accordance with NIH data-sharing policies. If successful, this protocol will provide accessible tools that clinicians can use to address exercise intolerance and PEM in patients with Long COVID.

Background High-risk subgroups among household contacts of persons with tuberculosis (TB) might benefit from additional interventions. However, the significance of an abnormal baseline chest radiograph (CXR) suggestive of TB, despite negative sputum microbiology, is uncertain. Methods Adults ([≥]18 years) with recent household TB exposure were enrolled at three South African sites (April 2021-September 2022). All participants underwent symptom screening, CXR, and sputum Xpert Ultra and MGIT culture. Pulmonary TB diagnosis was microbiologically-confirmed. Participants without prevalent TB were followed for symptomatic incident TB through 12 months. Multivariable logistic regression identified factors associated with abnormal CXR suggestive of TB. Poisson regression estimated adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95%CI). Results Baseline CXR were available for 795/846 (94.0%) participants without prevalent TB and were abnormal in 157/795 (19.7%); associated with older age (adjusted odds ratio, aOR=1.04, 95%CI 1.02-1.05); prior TB (aOR=6.39, 95%CI 4.18-9.78); and current smoking (aOR=1.61, 95%CI 1.00-2.62). Symptomatic incident TB developed in 8/795 (1.0%) participants, including 7/8 (87.5%) who were asymptomatic and 4/8 (50.0%) with abnormal CXR at baseline. TB incidence was higher in those with abnormal versus normal CXR (aIRR=4.11, 95%CI 1.29-13.09), but after median 12.1 (IQR 11.1-13.1) months follow-up, 153/157 (97.5%) had not progressed to incident TB. Conclusions Adult household contacts with CXR abnormalities, but without prevalent TB, had a four-fold higher incidence of TB within one year, compared to those with normal CXR. This additional risk warrants targeted preventive treatment and extended surveillance, but since most remained TB-free, therapeutic TB treatment is not justified.

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations, effective for use in both Drug Susceptible (DS)- and Drug Resistant (DR)- TB patients. Towards this aim, bactericidal and sterilizing activity of 25 priority 4-drug combinations was evaluated at doses targeting clinically relevant exposures, in the BALB/c relapsing mouse model of TB. The combinations comprised 8 PAN-TB drugs and candidates: bedaquiline (B), pretomanid (Pa), delamanid (Del), quabodepistat (Q), sutezolid (Sut), GSK2556286 (286), GSK3211830 (830) and ganfeborole (GSK3036656, (656)). Combination PK studies in infected mice enabled dose selection and a population-PK approach guided dosing so that compounds should achieve mean AUC0-24 within 2-fold of their clinical target exposures during the efficacy studies. All test combinations showed time-dependent bactericidal activity, with six regimens reducing lung bacterial burdens below the limit of detection with 8 weeks treatment, similar to the comparator BPaMZ (M is moxifloxacin and Z as pyrazinamide). Cure/Relapse data were modelled to derive population time to cure 90% mice (T90) values. Fifteen PAN-TB combinations had T90s of less than 5 months, sterilizing mice faster than the standard of care for drug susceptible TB, RHZE/RH. The best-performing PAN-TB combinations, BPa830Sut, BPa286Sut and BQSut286, cured 90% of mice in less than 3 months. These 3 top-ranked 4-drug combinations are all centered on a diarylquinoline (B)/oxazolidinone (Sut) core, together with the nitroimidazole (Pa) or a DprE1 inhibitor (Q) plus a novel agent such as the LeuRS inhibitor (830) or the Rv1625c agonist (286).

Background Erythema nodosum leprosum (ENL) is a severe inflammatory complication of leprosy that often requires prolonged corticosteroid therapy which is associated with adverse effects. Methotrexate is an affordable immunomodulatory agent with limited evidence for its use in ENL treatment. We evaluated whether weekly oral methotrexate in additional to prednisolone reduces the need for additional prednisolone in adults with severe ENL. Methods and Findings We performed an international, multicentre, double-blind, randomised, placebo-controlled trial conducted at five leprosy referral centres in Ethiopia, India, Indonesia, and Nepal. Adults aged 18-60 years with severe ENL were randomised to receive oral methotrexate and prednisolone, or matching placebo and prednisolone. All participants received an identical prednisolone regime over 20 weeks and were followed for 60 weeks. The primary outcome was time to first ENL flare requiring additional prednisolone, assessed over 24 and 48 weeks. Between January 2023 and June 2024, 231 individuals were screened and 137 were randomised (68 methotrexate and prednisolone; 69 placebo and prednisolone). By 24 weeks, 85/137 (62.0%) participants experienced an ENL flare requiring additional prednisolone; the adjusted hazard ratio (HR) for methotrexate versus placebo was 0.98 (95% CI 0.62-1.54). By 48 weeks, 102/137 (74.5%) experienced an ENL flare; adjusted HR 0.95 (95% CI 0.62-1.43). Secondary outcomes were similar: methotrexate did not reduce ENL severity at first flare, flare frequency, or severity of subsequent flares. Health-related quality of life improved substantially in both groups with no evidence of a differential treatment effect. Methotrexate was generally well tolerated. The trial was registered at ClinicalTrials.gov (NCT03775460). Conclusions Oral methotrexate added to prednisolone did not reduce the requirement for additional prednisolone or delay ENL flares compared to placebo and prednisolone, and our study does not support the use of methotrexate for severe ENL.

Background Erythema nodosum leprosum (ENL) is a severe inflammatory complication of lepromatous leprosy characterised by recurrent inflammatory episodes often requiring prolonged immunosuppression. The severity of ENL can be quantified using the validated and reliable ENLIST ENL Severity Scale (EESS). The longitudinal course of ENL and how it is captured using standardised severity measures has not been well described. We prospectively evaluated the changes in ENL severity over time using the EESS in a randomised clinical trial. Methods We conducted a post-hoc analysis of participants enrolled in the Methotrexate and Prednisolone Study in ENL, an international multicentre randomised controlled trial conducted in Ethiopia, India, Indonesia, and Nepal. Adults with severe ENL (EESS score [&ge;]9) were followed for 60 weeks with repeated EESS assessments. Longitudinal trajectories were analysed using mixed-effects regression models. Item-level analyses characterised the clinical phenotype captured by the scale. Associations between EESS score, prednisolone exposure, and dermatology-specific health-related quality of life measured using the Dermatology Life Quality Index (DLQI) were examined. Findings A total of 135 participants contributed 1,958 EESS assessments. Mean EESS declined rapidly during the first four weeks of treatment (-2.10 points/week; 95% CI -2.36 to -1.84; p<0.001), increased modestly during reduction in corticosteroid dose (weeks 4-20), and gradually declined thereafter. Severe ENL (EESS score [&ge;]9) occurred in 20.6% of visits and was characterised primarily by pain and cutaneous inflammatory manifestations. Participants who required additional prednisolone had persistently higher EESS scores and showed limited improvement compared with those who did not receive additional prednisolone. Longitudinal EESS scores were strongly correlated with the DLQI score (Spearmans {rho}=0.75; p<0.001). Conclusion The EESS captures clinically meaningful changes in ENL severity, aligns with treatment decisions, and reflects patient-reported severity over time. These findings support the use of the EESS as a robust tool for monitoring ENL severity in both clinical research and routine care.

We evaluated 2024/25 KP.2 vaccine effectiveness (VE) against COVID-19 hospitalization among adults >60 years old eligible for publicly-funded vaccination during fall and/or spring campaigns in the province of Quebec, Canada. We included Quebec residents tested for COVID-19-compatible symptoms in an acute-care hospital between October 13, 2024 (epi-week 2024-42) and August 23, 2025 (2025-34), linking vaccine, hospital, chronic diseases and laboratory administrative records to assess VE through test-negative design. We compared the odds of being COVID-19 test-positive versus test-negative among vaccinated versus non-vaccinated participants, adjusting for sex, age, comorbidities, place of residence, and epidemiological week. Overall, 49,949 (43%) participants were vaccinated. Over an analysis period spanning up to ten months, including median time since vaccination of 16 weeks (interquartile range 9-24 weeks), VE was 34% overall, declining from 43% <8 weeks to negligible by the 32nd week post-vaccination. Findings confirm meaningful but short-lived COVID-19 vaccine protection against hospitalization in older adults.

Background Rifampicin-resistant tuberculosis (RR-TB) is a major threat to public health in Viet Nam, with nearly 10,000 incident cases estimated annually. It is uncertain whether these cases are driven by transmission of resistant strains or de novo resistance acquisition during treatment. Methods We undertook dense, city-wide sampling of adults newly diagnosed with pulmonary RR-TB in Ho Chi Minh City, Viet Nam's largest city, between March 2020 and April 2024. Participants provided sputum for culture and whole-genome sequencing (WGS), and demographic and clinical data were collected at enrolment. Phylogenetic analyses were combined with clinical histories to infer transmitted versus acquired rifampicin resistance. Estimates were corrected for sampling coverage using simulation-extrapolation (SIMEX). Temporal emergence of rifampicin resistance was reconstructed by lineage using Bayesian phylogenetic dating, and the geographic and demographic structure of transmission networks was assessed using geocoded residential data and commute time-based analyses. Findings Among 2,319 RR-TB cases diagnosed during the study period, 1,491 (64%) isolates were successfully sequenced. After accounting for sampling and phylogenetic uncertainty, we estimated that between 72% and 87% of all RR-TB arose through transmission of already-resistant strains with the remainder due to de novo acquired resistance. Bayesian dating analyses revealed that resistance emergence events occurred repeatedly from the 1980s to the present, with early events seeding long-lived, city-wide transmission networks. Transmission networks were geographically dispersed across the city, with limited household clustering, and only weakly structured by host demographics, consistent with diffuse, city-wide transmission rather than localised or assortative spread. Interpretation RR-TB in Ho Chi Minh City is driven predominantly by ongoing transmission, but a substantial minority of cases arise from newly acquired resistance. Alongside promoting early diagnosis and treatment to interrupt transmission, the main drivers of acquired resistance need to be identified to control RR-TB.

Background Community-wide active case-finding (ACF) is being increasingly implemented as a tuberculosis (TB) elimination intervention. However, conventional site selection strategies may result in low yields from screening. We evaluated whether an artificial intelligence (AI) software guided targeting strategy could improve detection of TB during screening activities (called camps) relative to routine approaches to site selection in the programmatic setting in Pakistan. Methods We conducted a stepped-wedge cluster-randomised trial embedded within Global Fund supported ACF activities implemented by Pakistan s National TB Program and private sector partners. Thirty mobile X-ray van teams operating in 68 districts were randomly assigned to transition from routine site selection approaches (based on field-staff experience and historical data) to an AI-guided targeting strategy, using the software MATCH-AI. We assessed the effect of the intervention on the primary outcome, Camp Positivity Yield, defined as the number of individuals diagnosed with bacteriologically confirmed TB per camp, using generalised linear mixed models. The primary analysis was by intention to treat. Camps conducted within a 5-km radius of the AI selected locations were included in a validated per-protocol analysis. We conducted several district-level subgroup analyses. This trial is registered, number NCT06017843. Findings Between August 2023 and September 2024, 3,936 screening camps were conducted (2,046 control, 1,890 intervention), screening 269,254 individuals. In the intention-to-treat analysis, Camp Positivity Yield was 7% higher in the intervention group relative to the control group, however this difference was not statistically significant (adjusted risk ratio [RR] 1.07, 95% CI: 0.94 -1.22). In the validated per-protocol analysis, Camp Positivity Yield was 32% higher in the intervention group relative to the control group (adjusted RR 1.32, 95% CI: 1.12-1.54). Yields were highest in districts that had moderate baseline yields of 0.5-1% per population screened prior to the trial (adjusted RR: 1.57, 95% CI: 1.13 - 2.18) and in rural districts (adjusted RR 1.43, 95% CI: 1.23 -1.65). Interpretation The use of an AI-guided targeting strategy significantly increased detection of bacteriologically confirmed TB during active case-finding in the validated per-protocol analysis, relative to conventional site-selection approaches employed by field-staff. This software may be considered as a supportive tool to improve the efficiency of community-based TB case-finding interventions in other high burden countries.

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.

BackgroundExtreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. MethodsWe conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. ResultsDNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [&ge;]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. ConclusionsThe first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.

ObjectiveThe objective of this study was to compare hospital length-of-stay and other clinical outcomes between intact fish skin graft (IFSG; Graftguide, Kerecis, Arlington, VA) and synthetic/biosynthetic dermal substitutes (SSS; Integra Dermal Regeneration Template and NovoSorb Biodegradable Temporizing Matrix) in propensity score-matched burn patients using the American Burn Association Burn Care Quality Platform. MethodsThis retrospective cohort study identified adult patients treated with a single dermal substitute product during hospitalization for acute burn injury. Patients receiving IFSG (n = 93) were matched 1:4 to patients receiving SSS (n = 372) using nearest-neighbor propensity score matching on the logit scale. Matching covariates included total body surface area burned (TBSA), patient age, sex), burn severity classification, inhalation injury, and trauma diagnosis. The primary outcome was hospital length of stay (LOS), analyzed using a gamma generalized linear mixed model (GLMM). Secondary outcomes included the incidences of sepsis, graft loss, venous thromboembolism (VTE), and hospital-acquired pressure injury (HAPI). A prespecified sensitivity analysis was performed using a broader mixed-product cohort. ResultsA total of 93 IFSG-treated patients from 17 burn centers admitted between the years 2019 and 2025 were matched 1:4 to 372 SSS-treated patients from 44 centers. Unadjusted mean LOS was 24.1 days (median 20, IQR 11-32) in the IFSG-treated group and 36.7 days (median 31, IQR 17-52) in the SSS-treated group representing a 12.6-day reduction. GLMM-adjusted estimated marginal mean LOS was 24.2 days (95% CI, 20.0-29.4) for IFSG versus 33.5 days (95% CI, 30.0-37.6) for SSS (ratio 0.723; p = 0.00245), representing a 9.3-day reduction. Sepsis (1.1% vs 4.6%), graft loss (3.2% vs 8.3%), VTE (2.2% vs 2.7%), and HAPI (2.2% vs 3.8%) were all numerically lower in the IFSG-treated arm; although GLMM-adjusted odds ratios were not statistically significant for any individual complication. The mixed-cohort sensitivity analysis (n = 229 IFSG vs 458 SSS across 67 centers) confirmed the primary finding with GLMM-adjusted LOS ratio 0.716 (p = 0.0001). ConclusionsIn this propensity score-matched analysis of the ABA registry, IFSG was associated with a statistically significant and clinically meaningful reduction in hospital length of stay compared with synthetic/biosynthetic dermal substitutes, in requiring dermal substitution and autografting, with all complication rates, sepsis, graft loss, VTE, and HAPI, numerically lower in the IFSG-treated arm. The shorter hospitalization was not achieved at the expense of safety. These findings support IFSG as a viable alternative to synthetic dermal substitutes in burns requiring dermal substitution and autografting. Prospective studies are warranted particularly in larger burns requiring staged reconstruction.

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.

BackgroundThe World Health Organisation (WHO) recommends digital chest radiography (dCXR) with computer-aided detection (CAD) for tuberculosis (TB) screening of individuals >15 years of age. MethodologyAdults ([&ge;]18 years) were enrolled (March 2021-December 2022) in South Africa into a community-based Screening Cohort (household contacts) and a facility-based Triage Cohort (symptomatic clinic attendees). Microbiologically-confirmed pulmonary TB required positive sputum culture and/or Xpert Ultra. Asymptomatic TB was diagnosed in participants without TB symptoms. dCXR were read by blinded human readers and qXR CAD (0.5 threshold; Qure.AI, India). ResultsdCXR from 1,353 participants (886 Screening Cohort; 467 Triage Cohort) were analysed. Microbiologically-confirmed TB occurred in 48 (5.4%) Screening Cohort [9 symptomatic (19%) and 39 asymptomatic (81%)]; and 116 (24.8%) Triage Cohort (all symptomatic) participants. dCXR sensitivity (human readers) for asymptomatic TB in the Screening Cohort was 56.4%, vs. 72.4% for symptomatic TB in the Triage Cohort (difference -16%; 95%CI -2.9 to -29.1); with specificities 94.1% and 81.2%, respectively. Corresponding qXR CAD sensitivities were 69.2% vs. 83.6% (difference -14.4%; 95%CI -26 to -2.8), with specificities 89.3% and 73.5%, respectively. The difference in dCXR sensitivity and specificity for asymptomatic TB between qXR CAD and human readers was 12.8% (95%CI -0.48 to 26.1) and -4.8% (95%CI -12.4 to 28.2), respectively. ConclusionSensitivity of community-based dCXR screening for microbiologically-confirmed asymptomatic TB among household contacts was lower than for facility-based triage of symptomatic TB, but approached 70% with CAD. Neither human reader nor qXR CAD evaluation met WHO targets for a TB screening test (90% sensitivity; 80% specificity). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe World Health Organisation (WHO) recommends digital chest radiography (dCXR) with computer-aided detection (CAD) for tuberculosis (TB) screening of individuals >15 years of age, based on data from prevalence surveys and facility-based studies. Performance data for community-based screening of asymptomatic TB are lacking. We searched PubMed for literature published in English between January 1, 2000, and November 1, 2025, for community-based, active case-finding studies of adolescents and adults aged 15 years and older that used dCXR CAD for asymptomatic TB screening. We used the following search terms: "Tuberculosis" AND ("asymptomatic" OR "subclinical") AND ("computer aided diagnosis" OR "artificial intelligence") AND "community-based screening" AND "chest radiography" AND ("diagnostic performance" OR "sensitivity"). We identified five studies reporting on microbiologically-confirmed asymptomatic TB and dCXR CAD performance. Three of five studies tested sputum only in those who were symptomatic and/or had abnormal CXR. One study did measure prevalence of asymptomatic TB by universal sputum testing of all participants, but did not report sensitivity and specificity for asymptomatic TB separately. One case-control study of CAD4TB (v7), which pooled data from five active case-finding cohorts, reported sensitivity of 61.4% and specificity of 86.7% for asymptomatic TB. However, the case-control design and inclusion of two cohorts using prevalence survey methodology and three cohorts enrolling high TB risk groups, two of which did not perform CXR on all participants, suggest potential for selection bias. Added value of this studyWe evaluated discriminatory performance of dCXR screening for asymptomatic TB among adult household contacts of TB patients, using human readers and qXR CAD (QURE.AI, India), in three communities in South Africa (Screening Cohort). Performance was benchmarked against that for symptomatic TB among adult clinic attendees (Triage Cohort), to enable comparison with traditional published approaches. All participants underwent universal sputum testing, regardless of symptom status or dCXR results. Sensitivity of human readers for asymptomatic TB in the Screening Cohort was 56.4%, compared to 72.4% for symptomatic TB in the Triage Cohort, with specificity 94.1% and 81.2%, respectively. The corresponding sensitivity of qXR CAD for asymptomatic TB, using the manufacturers 0.5 threshold score, was 69.2%, compared to 83.6% for symptomatic TB, with specificity 89.3% and 73.5%, respectively. The difference in dCXR sensitivity and specificity for asymptomatic TB between qXR CAD and human readers was 12.8% and -4.8%, respectively. The adjusted qXR threshold score (0.007) required to achieve 90% sensitivity for asymptomatic TB reduced specificity to 18.9%; and did not meet the WHO Target Product Profile (TPP) for a high sensitivity (90%), high specificity (80%) TB screening test. Implications of all the available evidenceSensitivity of community-based dCXR screening of household contacts for asymptomatic TB was low, compared to facility-based triage of symptomatic TB. Neither human reader nor qXR CAD evaluation of dCXR met the minimal WHO TPP for a high sensitivity (90%), high specificity (80%) TB screening test. Although dCXR CAD community screening would detect more than two-thirds of all people with previously undiagnosed, microbiologically-confirmed asymptomatic TB, the significant proportion of people with TB that would remain undetected, and untreated, might allow ongoing Mycobacterium tuberculosis transmission and hinder elimination efforts.

Soil-transmitted helminths (STH) are a plausible but under-characterized comorbidity in tuberculosis. In this prospective South Indian cohort, multiplex stool PCR detected STH in 43% of 137 adults with pulmonary tuberculosis and 34% of 230 household contacts. Food insecurity independently predicted co-infection. Current adult deworming gaps warrant evaluation.