SUMMARY Background Patients with hypersensitivity pneumonitis (HP) may develop lung fibrosis, which is associated with reduced survival. Families with pulmonary fibrosis can present with members diagnosed with idiopathic pulmonary fibrosis (IPF) or chronic HP (cHP), suggesting that fibrotic HP may share risk factors with IPF. Methods In an observational study of two independent cohorts of patients with cHP (UCSF n=145, UTSW n=72), we measured two common single nucleotide polymorphisms associated with IPF (MUC5B rs35705950 & TOLLIP rs5743890) and peripheral blood leukocyte telomere length and evaluated their associations with cHP disease, survival, and clinical-radiograph-pathologic features. Findings The frequency of the MUC5B minor allele, but not the TOLLIP minor allele, was significantly increased in cHP patients in both cohorts (UCSF MAF 24.4% & UTSW MAF 32.3%) compared to healthy controls (MAF 10.7%; p-values for comparison = <0.0001 for both cohorts) and similar to IPF (UCSF MAF 33.3% & UTSW MAF 32.0%, p-values for comparison=0.10 & 0.95, respectively). The MUC5B minor allele (adjusted OR 1.91, p=0.045) and shorter telomere length (adjusted OR 0.23, p=0.002) were associated with extent of radiographic fibrosis and other measures of lung remodeling and fibrosis in the combined cHP cohorts. Shorter telomere length had a significant association (adjusted HR 0.18, p=0.001) with reduced survival in the combined cHP cohorts. Interpretation The MUC5B promoter polymorphism rs35705950 and shorter telomere length are associated with extent of fibrosis in cHP. Shorter telomere length is associated with histopathology findings typical of usual interstitial pneumonia and reduced survival in cHP. Funding NIH grants KL2TR001870, T32HL098040, UL1TR001105, R01HL093096, and the Nina Ireland Program for Lung Health.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (b-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1 F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated b-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airwaycentric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

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SARS–CoV–2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS–CoV–2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS–CoV–2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay–at–home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID–19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay–at–home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS–CoV–2 transmission. Overall, our findings suggest a role for local–scale phylodynamics in understanding the heterogeneous transmission landscape.