The primary factor that limits long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD continues to evolve. Consensus definitions of CLAD and the major CLAD phenotypes were recently updated and clarified, but it remains to be seen whether the current definitions will lead to advances in management or impact care. Understanding the potential differences in pathogenesis for each CLAD phenotype may lead to novel therapeutic strategies, including precision medicine. Recognition of CLAD risk factors may lead to earlier interventions to mitigate risk, or to avoid risk factors all together, to prevent the development of CLAD. Unfortunately, currently available therapies for CLAD are usually not effective. However, novel therapeutics aimed at both prevention and treatment are currently under investigation. We provide an overview of the updates to CLAD-related terminology, clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential strategies to treat and prevent CLAD.
Background. Chronic lung allograft dysfunction (CLAD) phenotype determines prognosis and may have therapeutic implications. Despite the clarity achieved by recent consensus statement definitions, their reliance on radiologic interpretation introduces subjectivity. The Center for Computer Vision and Imaging Biomarkers at the University of California, Los Angeles (UCLA) has established protocols for chest high-resolution computed tomography (HRCT)-based computer-aided quantification of both interstitial disease and air-trapping. We applied quantitative image analysis (QIA) at CLAD onset to demonstrate radiographic phenotypes with clinical implications. Methods. We studied 47 first bilateral lung transplant recipients at UCLA with chest HRCT performed within 90 d of CLAD onset and 47 no-CLAD control HRCTs. QIA determined the proportion of lung volume affected by interstitial disease and air-trapping in total lung capacity and residual volume images, respectively. We compared QIA scores between no-CLAD and CLAD, and between phenotypes. We also assigned radiographic phenotypes based solely on QIA, and compared their survival outcomes. Results. CLAD onset HRCTs had more lung affected by the interstitial disease ( P = 0.003) than no-CLAD controls. Bronchiolitis obliterans syndrome (BOS) cases had lower scores for interstitial disease as compared with probable restrictive allograft syndrome (RAS) ( P < 0.0001) and mixed CLAD ( P = 0.02) phenotypes. BOS cases had more air-trapping than probable RAS ( P < 0.0001). Among phenotypes assigned by QIA, the relative risk of death was greatest for mixed (relative risk [RR] 11.81), followed by RAS (RR 6.27) and BOS (RR 3.15). Conclusions. Chest HRCT QIA at CLAD onset appears promising as a method for precise determination of CLAD phenotypes with survival implications.
Higher-dose mRNA booster vaccines have not been well studied for transplant recipients. This study evaluated the safety, reactogenicity and immunogenicity of higher dose mRNA-1273 booster vaccines among lung transplant recipients (LTRs). This phase 1/2 open-label randomized clinical trial of higher-dose mRNA-1273 booster vaccination enrolled nineteen adult LTRs into the 50 ug (n=8) vs. 100 ug (n=11) groups before enrollment was terminated due to the availability of the bivalent mRNA-1273.222 vaccine. Local and systemic reactogenicity was predominantly mild or moderate in severity for both dose groups, mostly limited to pain at the injection site, fatigue and headache. Humoral and cellular immune responses were weak. Overall, 75% and 64% of the 50 ug and 100 ug groups had detectable neutralizing antibodies on Day 30 (vs. 63% and 55% on Day 1), respectively. On Day 30, 50% and 55% had detectable spike-specific CD4+ IFN responses (vs. 29% and 36% on Day 1), and 50% and 36% had detectable CD8+ IFN responses (vs. 29% and 45% on Day 1) for the two groups, respectively. LTRs have reactogenicity and immune responses that are attenuated compared with the non-immunocompromised population. Administration of higher doses in solid organ transplant patients may be warranted. Clinical trial NCT05280158.
Importance Elevated ambient fine particulate matter (PM 2.5 ) air pollution exposure has been associated with poor health outcomes across several domains, but its associated outcomes among lung transplant recipients are poorly understood. Objective To investigate whether greater PM 2.5 exposure at the zip code of residence is associated with a higher hazard for mortality and graft failure in patients with lung transplants. Design, Setting, and Participants This retrospective cohort study used panel data provided by the United Network for Organ Sharing, which includes patients receiving transplants across all active US lung transplant programs. Adult patients who received lung transplants between May 2005 and December 2016 were included, with a last follow-up of September 10, 2020. Data were analyzed from September 2022 to May 2023. Exposure Zip code–level annual PM 2.5 exposure was constructed using previously published North American estimates. Main Outcomes and Measures The primary outcome was time to death or lung allograft failure after lung transplant. A gamma shared frailty Cox proportional hazards model was used to produce unadjusted and adjusted hazard ratios (HRs) to estimate the association of zip code PM 2.5 exposure at the time of transplant with graft failure or mortality. Results Among 18 265 lung transplant recipients (mean [SD] age, 55.3 [13.2] years; 7328 female [40.2%]), the resident zip code’s annual PM 2.5 exposure level was greater than or equal to the Environmental Protection Agency (EPA) standard of 12μg/m 3 for 1790 patients (9.8%) and less than the standard for 16 475 patients (90.2%). In unadjusted analysis, median graft survival was 4.87 years (95% CI, 4.57-5.23 years) for recipients living in high PM 2.5 areas and 5.84 years (95% CI, 5.71-5.96 years) for recipients in the low PM 2.5 group. Having an annual PM 2.5 exposure level greater than or equal to the EPA standard 12 μg/m 3 was associated with an increase in the hazard of death or graft failure (HR, 1.11; 95% CI, 1.05-1.18; P &lt; .001) in the unadjusted analysis and after adjusting for covariates (HR, 1.08; 95% CI, 1.01-1.15; P = .02). Each 1 μg/m 3 increase in exposure was associated with an increase in the hazard of death or graft failure (adjusted HR, 1.01; 95% CI, 1.00-1.02; P = .004) when treating PM 2.5 exposure as a continuous variable. Conclusions and Relevance In this study, elevated zip code–level ambient PM 2.5 exposure was associated with an increased hazard of death or graft failure in lung transplant recipients. Further study is needed to better understand this association, which may help guide risk modification strategies at individual and population levels.
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.
