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Introduction: We assessed the prognostic utility of circulating levels of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry. Methods: MMP and TIMP concentrations were quantified by ELISA in plasma from 300 patients. A Cox proportional hazard regression model was used to assess associations between select MMPs and TIMPs and death and disease progression (absolute decline in forced vital capacity ≥10% predicted, death, or lung transplant). Results: Over a median follow-up of 30.4 months, 98 patients died and 182 patients had disease progression. In unadjusted analyses, higher concentrations of MMPs 2, 3, 8 and 9 and TIMPs 1, 2 and 4 were associated with an increased risk of death. MMPs 2 and 8 and TIMP1 remained associated with death after adjustment for clinical factors. In unadjusted analyses, higher concentrations of MMPs 8 and 9 and TIMPs 1 and 4 were associated with an increased risk of disease progression. MMPs 8 and 9 and TIMP1 remained associated with progression after adjustment for clinical factors. Conclusion: Circulating levels of MMP8 and TIMP1 may provide information on the risk of outcomes in patients with IPF not captured by clinical measures. [ABSTRACT FROM AUTHOR]

Background: To assess the characteristics of patients enrolled in the ILD-PRO Registry. Methods: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months. Patient characteristics were analysed based on the number of patients with available data. Results: Of the first 491 patients enrolled, the majority were white (75.4%) and female (60.6%); 47.4% had a history of smoking. Reported ILDs were autoimmune disease-associated ILDs (47.2%), hypersensitivity pneumonitis (17.5%), idiopathic non-specific interstitial pneumonia (9.1%), interstitial pneumonia with autoimmune features (8.9%), unclassifiable ILD (7.6%), other ILDs (9.7%). At enrolment, median (Q1, Q3) FVC % predicted was 62.2 (49.4, 72.4) and DLco % predicted was 39.2 (30.2, 49.2). Median (Q1, Q3) total score on the St. George's Respiratory Questionnaire was 50.8 (35.9, 64.7). The most common comorbidities were gastroesophageal reflux disease (61.1%) and sleep apnoea (29.6%). Overall, 64.5% of patients were receiving immunosuppressive or cytotoxic therapy, 61.1% proton-pump inhibitors, 53.2% oral steroids, 19.8% nintedanib and 3.6% pirfenidone. Conclusions: Patients enrolled into the ILD-PRO Registry have a variety of ILD diagnoses, marked impairment in lung function and health-related quality of life, and high medication use. Longitudinal data from this registry will further our knowledge of the course of progressive pulmonary fibrosis. Trial Registration: ClinicalTrials.gov, NCT01915511; registered August 5, 2013. [ABSTRACT FROM AUTHOR]

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, 23.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, 22.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. [ABSTRACT FROM AUTHOR]

Rationale: Meta-analyses have suggested the risk of cardiovascular disease (CVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, many of these studies have included a broad array of CVD events or have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. Objectives and Methods: We assessed the risk of atherosclerotic cardiovascular disease (ASCVD) hospitalizations after COPD hospitalization compared with before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016 to 2019 in the United States. The primary outcome was risk of an ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, stroke, or transient ischemic attack) in the 30 days and 1 year after COPD hospitalization relative to the same time period before COPD hospitalization. Time in the before and after COPD hospitalization time periods to a composite ASCVD hospitalization outcome were modeled using an extension of the Cox proportional hazards model, the Anderson-Gill model, with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups associated with the composite ASCVD hospitalization outcome. Results: Among 920,550 patients in the 30-day and 1-year cohorts (mean age, 73-74 yr) the hazard ratio estimate (95% confidence interval) for the composite ASCVD hospitalization outcome after COPD hospitalization versus before COPD hospitalization for the 30-day cohort was 0.99 (0.93, 1.05; P  = 0.67), and for the 1-year cohort, it was 0.99 (0.97, 1.02; P  = 0.53) after adjustment. We observed three subgroups that were significantly associated with higher risk for ASCVD hospitalizations 1 year after COPD hospitalization: 76+ years old, women, and COPD hospitalization severity. Conclusions: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalization was not significantly increased 30 days or 1 year after COPD hospitalization relative to before COPD hospitalization. In subgroup analyses, we identified age 76+ years old, female sex, and COPD hospitalization severity as high-risk subgroups with increased risk of ASCVD events 1 year after COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Rationale: Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain., Objectives: Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort., Methods: Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD., Measurements and Main Results: Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar., Conclusions: Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

Background: Few tools exist for early identification of patients at risk for chronic lung allograft dysfunction (CLAD). We previously showed hyaluronan (HA), a matrix molecule that regulates lung inflammation and fibrosis, accumulates in bronchoalveolar lavage fluid (BALF) and blood in CLAD. We aimed to determine if early posttransplant HA elevations inform CLAD risk., Methods: HA was quantified in 3080 BALF and 1323 blood samples collected over the first posttransplant year in 743 adult lung recipients at 5 centers. The relationship between BALF or blood HA and CLAD was assessed using Cox models with a time-dependent binary covariate for "elevated" HA. Potential thresholds for elevated HA were examined using a grid search between the 50th and 85th percentile. The optimal threshold was identified using fit statistics, and the association between the selected threshold and CLAD was internally validated through iterative resampling. A multivariable Cox model using the selected threshold was performed to evaluate the association of elevated HA with CLAD considering other factors that may influence CLAD risk., Results: BALF HA levels >19.1ng/mL (65th percentile), had the largest hazard ratio for CLAD (HR 1.70, 95% CI 1.25-1.31; p<0.001), optimized fit statistics, and demonstrated robust reproducibility. In a multivariable model, the occurrence of BALF HA >19.1 ng/mL in the first posttransplant year conferred a 66% increase in the hazards for CLAD (adjusted HR 1.66, 95% CI 1.19-2.32; p=0.003). Blood HA was not significantly associated with CLAD., Conclusions: We identified and validated a precise threshold for BALF HA in the first posttransplant year that distinguishes patients at increased CLAD risk., (Copyright © 2024. Published by Elsevier Inc.)

Background: Poor agreement among lung transplant pathologists has been reported in the assessment of rejection. In addition to acute rejection (AR) and lymphocytic bronchiolitis (LB), acute lung injury (ALI) and organizing pneumonia (OP) were recently identified as histopathologic risk factors for chronic lung allograft dysfunction (CLAD). Therefore, maximizing inter-rater reliability (IRR) for identifying these histopathologic risk factors is important to guide individual patient care and to support incorporating them in inclusion criteria for clinical trials in lung transplantation., Methods: Nine pathologists across eight North American lung transplant centers were surveyed for practices in the assessment of lung transplant transbronchial biopsies. We conducted seven diagnostic alignment sessions with pathologists discussing histomorphologic features of CLAD high-risk histopathology. Then, each pathologist blindly scored 75 digitized slides. Fleiss' kappa, accounting for agreement across numerous observers, was used to determine IRR across all raters for presence of any high-risk finding and each individual entity., Results: IRR (95% confidence intervals) and % agreement for any high-risk finding (AR, LB, ALI and/or OP) and each individual finding is as follows: Any Finding, k = 0.578 (0.487, 0.668), 78.9%; AR, k = 0.582 (0.481, 0.651), 79.1%; LB, k = 0.683 (0.585, 0.764), 83.5%; ALI, k = 0.418 (0.312, 0.494), 70.9%; OP, k = 0.621 (0.560, 0.714), 81.0%., Conclusions: After pre-study diagnostic alignment sessions, a multi-center group of lung transplant pathologists seeking to identify histopathology high-risk for CLAD achieved good IRR., (Copyright © 2024 International Society for the Heart and Lung Transplantation. All rights reserved.)