Daily Respiratory Research Analysis

BACKGROUND: Long-term survival of lung transplant recipients remains limited by chronic lung allograft dysfunction (CLAD). CLAD is only diagnosed following a persistent and substantial decline in lung function, after which irreversible damage to the lungs has occurred, limiting opportunities to effectively intervene at an early stage. There is a critical need for earlier detection prior to its clinical manifestation. The immunological drivers of CLAD remain unclear, limiting the development of predictive biomarkers and new therapies. METHODS AND FINDINGS: In this hypothesis-generating, prospective cohort study, we profiled the microbial, metabolic, lipidomic, and gene expression dynamics of longitudinally collected broncho-alveolar lavages (BALs) from 56 CLAD-free lung transplant recipients up to 30 months post-transplant, and compared BALs from 13 CLAD-free patients to BALs from 13 patients who developed CLAD. In CLAD-free patients, the first 6 months post-transplant were hallmarked by diminished microbial diversity and increased abundance of Staphylococcus and Candida, coupled with upregulated innate and adaptive immune responses, and elevated nitric oxide metabolism (FDR < 0.05). This was superseded by homeostatic tissue repair and by the reactivation of T-cell genes such as CD3, GZMA, IL2RB, CD28, CD40LG, and LCK, after tapering of maintenance immunosuppression (FDR < 0.05). In patients who developed CLAD, disease onset was preceded by the increased abundance of sphingolipids and the upregulation of glycocalyx and immune cell recruitment genes such as HAPLN3, HS3ST3B1, SULF2, CHST2, CSGALNACT1, CXCR1, CSF3R, SELL, CXCL2, and CEACAM1 (FDR < 0.05), suggesting increased vascular dysfunction and immune cell graft infiltration prior to CLAD onset. Scoring against a publicly available lung single-cell dataset showed our bulk gene transcriptomics signature to be expressed by monocytes, endothelial, and T cells. In contrast to CLAD-free patients, this signature persisted after 1.5 months post-transplant and increased in intensity upon the start of lung function decline. Multi-omics integration highlighted sphingolipid molecules and genes involved in immune cell recruitment and endothelial function as candidate biomarkers associated with the onset of CLAD. This study is limited by its small sample size. CONCLUSIONS: We have identified immunological processes, metabolites, lipids, and genes associated with the onset of CLAD. Our findings are to be considered associative and not aimed at establishing causality. Future studies employing a targeted approach in independent validation cohorts, using, for example, quantitative polymerase chain reaction (PCR) and targeted mass-spectrometry, will be required to confirm these findings.

IMPORTANCE: The 2025-2026 COVID-19 vaccine, targeting JN.1 and JN.1-derived sublineages, became available in the US in September 2025. OBJECTIVE: To assess the estimated interim effectiveness of 2025-2026 COVID-19 vaccines against medically attended COVID-19 among immunocompetent adults aged 18 years or older in the US. DESIGN, SETTING, AND PARTICIPANTS: This case-control study used a test-negative design to investigate patient encounters captured in the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network, an electronic medical record-based network of health care systems (253 emergency departments/urgent cares [ED/UCs] and 179 hospitals in 7 states) from September 3, 2025, to December 31, 2025. Patient encounters with COVID-19-like illness and a molecular or antigen SARS-CoV-2 test 10 days before to 3 days after the encounter date were included. EXPOSURE: 2025-2026 COVID-19 vaccination regardless of prior COVID-19 vaccination. MAIN OUTCOMES AND MEASURES: The main outcomes were COVID-19-associated ED/UC encounters and COVID-19-associated hospitalizations. Cases were defined as encounters with a positive molecular or antigen SARS-CoV-2 test and controls as encounters with a negative molecular SARS-CoV-2 test. The odds of 2025-2026 COVID-19 vaccination among cases and controls, adjusting for confounders, were compared and used to estimate vaccine effectiveness (VE) as (1 - adjusted odds ratio) × 100%. RESULTS: In 85 725 ED/UC encounters among adults aged 18 years and older (51 841 [60%] aged 18-64 years; 51 775 female [60%]), 206 of 3941 cases (5%) and 9453 of 81 784 controls (12%) received a 2025-2026 COVID-19 vaccination. Estimated VE against COVID-19-associated ED/UC encounters was 50% (95% CI, 42%-57%; median [IQR] time since 2025-2026 COVID-19 vaccine dose receipt, 47 [27-69] days). In 26 073 hospitalizations with a COVID-19-like illness (17 530 [67%] aged ≥65 years; 13 985 female [54%]), 60 of 1022 cases (6%) received a 2025-2026 COVID-19 vaccination compared with 3080 of 25 051 controls (12%). Estimated VE against COVID-19-associated hospitalization was 55% (95% CI, 41%-66%; median [IQR] time since 2025-2026 COVID-19 vaccine dose receipt, 46 [26-68] days). Among patients aged 65 years or older, estimated VE against ED/UC encounters was 48% (95% CI, 37%-56%; median [IQR] time since dose receipt, 48 [27-69] days; 33 884 encounters) and against hospitalization was 53% (95% CI, 37%-65%; median [IQR] time since dose receipt, 46 [26-69] days; 17 530 hospitalizations). CONCLUSIONS AND RELEVANCE: In this study, receipt of 2025-2026 COVID-19 vaccination was associated with additional protection beyond existing immunity in adults against medically attended COVID-19, including ED/UC encounters and hospitalizations, compared with no receipt of a 2025-2026 vaccine dose. These findings suggest that adults can reduce their likelihood of severe COVID-19-associated outcomes by obtaining a 2025-2026 COVID-19 vaccination.

BACKGROUND: Lung transplantation (LT) is the definitive treatment for selected end-stage lung diseases, yet some recipients fail to achieve normal pulmonary function posttransplant, a condition known as baseline lung allograft dysfunction (BLAD). Its causes and long-term outcomes remain incompletely understood. METHODS: We retrospectively analyzed all adult bilateral LT performed between 2014 and 2019, with follow-up through December 2024. BLAD was defined as failure to achieve forced expiratory volume in 1 s and/or forced vital capacity ≥80% predicted within the first post-LT year. Multivariable logistic regression identified risk factors, and Cox and linear mixed-effects models assessed associations with survival, chronic lung allograft dysfunction (CLAD), and lung function trajectories. RESULTS: Among 325 recipients, BLAD occurred in 65.5% and was independently associated with reduced survival (hazard ratio, 5.25; 95% confidence interval, 3.84-7.18; P < 0.001). BLAD was associated with increased CLAD risk in the overall cohort (hazard ratio, 1.42; 95% confidence interval, 1.00-2.00; P = 0.047), although this association was attenuated after excluding recipients with structural or mechanical causes of reduced spirometry. Risk factors included higher body mass index, longer intensive care unit stay, bronchial stenosis, and older donor age. Over 5 y, BLAD recipients exhibited slower spirometry decline than recipients achieving normal baseline function, whereas CLAD was the main determinant of long-term functional deterioration. CONCLUSIONS: BLAD is common after LT and is associated with increased mortality and lower long-term pulmonary function. The BLAD-CLAD association may be partly confounded by structural or mechanical causes of reduced spirometry, supporting BLAD as a heterogeneous early post-LT phenotype.