Machine Learning of Plasma Proteomics Classifies Diagnosis of Interstitial Lung Disease.

RATIONALE: Distinguishing connective tissue disease associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging. OBJECTIVES: Identify proteins that separate and classify CTD-ILD from IPF patients. METHODS: Four registries with 1247 IPF and 352 CTD-ILD patients were included in analyses. Plasma samples were subjected to high-throughput proteomics assays. Protein features were prioritized using Recursive Feature Elimination (RFE) to construct a proteomic classifier. Multiple machine learning models, including Support Vector Machine, LASSO regression, Random Forest (RF), and imbalanced-RF, were trained and tested in independent cohorts. The validated models were used to classify each case iteratively in external datasets. MEASUREMENT AND MAIN RESULTS: A classifier with 37 proteins (PC37) was enriched in biological process of bronchiole development and smooth muscle proliferation, and immune responses. Four machine learning models used PC37 with sex and age score to generate continuous classification values. Receiver-operating-characteristic curve analyses of these scores demonstrated consistent Area-Under-Curve 0.85-0.90 in test cohort, and 0.94-0.96 in the single-sample dataset. Binary classification demonstrated 78.6%-80.4% sensitivity and 76%-84.4% specificity in test cohort, 93.5%-96.1% sensitivity and 69.5%-77.6% specificity in single-sample classification dataset. Composite analysis of all machine learning models confirmed 78.2% (194/248) accuracy in test cohort and 82.9% (208/251) in single-sample classification dataset. CONCLUSIONS: Multiple machine learning models trained with large cohort proteomic datasets consistently distinguished CTD-ILD from IPF. Identified proteins involved in immune pathways. We further developed a novel approach for single sample classification, which could facilitate honing the differential diagnosis of ILD in challenging cases and improve clinical decision-making.

Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

RATIONALE: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood. OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control. METHODS: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization. MEASUREMENTS AND MAIN RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P < 0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P < 0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P < 0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21). CONCLUSIONS: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.

IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control.

CMV remains an important opportunistic pathogen in solid organ and hematopoietic cell transplantation, particularly in lung transplant recipients (LTRs). LTRs mismatched for CMV (donor(+)/recipient(-); D(+)R(-)) are at high risk for active CMV infection and increased mortality; however, the immune correlates of viral control remain incompletely understood. We prospectively studied 27 D(+)R(-) LTRs during primary CMV infection to determine whether acute CD4(+) T cell parameters differentiated the capacity for viral control during early chronic infection. Unexpectedly, the T-box transcription factor, T-bet, was expressed at low levels in CD4(+) compared with CD8(+) T cells during acute primary infection. However, the capacity for in vitro CMV phosphoprotein 65-specific proliferation and CD4(+)T-bet(+) induction differentiated LTR controllers from early viremic relapsers, correlating with granzyme B loading and effector multifunction. Furthermore, impaired CMV-specific proliferative responses from relapsers, along with T-bet, and effector function could be significantly rescued, most effectively with phosphoprotein 65 Ag and combined exogenous IL-2 and IL-12. Acute CD4(+) T cell CMV-specific proliferative and effector responses were highly IL-12-dependent in blocking studies. In addition, we generated monocyte-derived dendritic cells using PBMC obtained during primary infection from relapsers and observed impaired monocyte-derived dendritic cell differentiation, a reduced capacity for IL-12 production, but increased IL-10 production compared with controls, suggesting an APC defect during acute CMV viremia. Taken together, these data show an important role for CMV-specific CD4(+) effector responses in differentiating the capacity of high-risk LTRs to establish durable immune control during early chronic infection and provide evidence for IL-12 as a key factor driving these responses.

The Lung Transplant Candidate, Indications, Timing, and Selection Criteria.

Lung transplantation can be lifesaving for patients with advanced lung disease. Demographics are evolving with recipients now sicker but determining candidacy remains predicated on one's underlying lung disease prognosis, along with the likelihood of posttransplant success. Determining optimal timing can be challenging, and most programs favor initiating the process early and proactively to allow time for patient education, informed decision-making, and preparation. A comprehensive, multidisciplinary evaluation is used to elucidate disease progrnosis and identify risk factors for poor posttransplant outcomes. Candidacy criteria vary significantly by center, and close communication between referring and transplant providers is necessary to improve access to transplant and outcomes.

Influence of broader geographic allograft sharing on outcomes and cost in smaller lung transplant centers.

OBJECTIVE: On November 24, 2017, Organ Procurement and Transplantation Network implemented a change to lung allocation replacing donor service area with a 250 nautical mile radius around donor hospitals. We sought to evaluate the experience of a small to medium size center following implementation. METHODS: Patients (47 pre and 54 post) undergoing lung transplantation were identified from institutional database from January 2016 to October 2019. Detailed chart review and analysis of institutional cost data was performed. Univariate analysis was performed to compare eras. RESULTS: Similar short-term mortality and primary graft dysfunction were observed between groups. Decreased local donation (68% vs 6%; P < .001), increased travel distance (145 vs 235 miles; P = .004), travel cost ($8626 vs $14,482; P < .001), and total procurement cost ($60,852 vs $69,052; P = .001) were observed postimplementation. We also document an increase in waitlist mortality postimplementation (6.9 vs 31.6 per 100 patient-years; P < .001). CONCLUSIONS: Following implementation of the new allocation policy in a small to medium size center, several changes were in accordance with policy intention. However, concerning shifts emerged, including increased waitlist mortality and resource utilization. Continued close monitoring of transplant centers stratified by size and location are paramount to maintaining global availability of lung transplantation to all Americans regardless of geographic residence or socioeconomic status.

Lung Transplantation for Patients With COVID-19.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

Lung Transplantation for Severe Post-coronavirus Disease 2019 Respiratory Failure.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in >72 million cases and 1.6 million deaths. End-stage lung disease from COVID-19 is a new and growing entity that may benefit from lung transplant; however, there are limited data on the patient selection, perioperative management, and expected outcomes of transplantation for this indication. METHODS: A systematic review of the literature was performed with searches of MEDLINE and Web of Science databases as well as the gray literature. All manuscripts, editorials, commentaries, and gray literature reports of lung transplantation for COVID-related respiratory failure were included. A case from the University of Virginia is described and included in the review. RESULTS: A total of 27 studies were included: 11 manuscripts, 5 commentaries, and 11 gray literature reports. The total number of transplantations for COVID-related lung disease was 21. The mean age was 55±12 years, 16 (76%) were male individuals, and the acuity was high, with 85% on extracorporeal membrane oxygenation preoperatively. There was a 95% early survival rate, with 1 additional late death. There is growing histopathologic evidence for permanent structural damage with no replicating virus at the time of transplantation. CONCLUSIONS: Bilateral lung transplantation is an effective treatment option with reasonable short-term outcomes for patients with end-stage lung failure secondary to COVID-19. However, specific considerations in this new population require a multidisciplinary approach. As we move into the second wave of the COVID-19 global pandemic, lung transplantation will likely have a growing role in management of these complex patients.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements.

Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Adenosine A2A receptor agonist (regadenoson) in human lung transplantation.

BACKGROUND: Currently, there are no clinically approved treatments for ischemia-reperfusion injury after lung transplantation. Pre-clinical animal models have demonstrated a promising efficacy of adenosine 2A receptor (A2AR) agonists as a treatment option for reducing ischemia-reperfusion injury. The purpose of this human study, is to conduct a Phase I clinical trial for evaluating the safety of continuous infusion of an A2AR agonist in lung transplant recipients. METHODS: An adaptive, two-stage continual reassessment trial was designed to evaluate the safety of regadenoson (A2AR agonist) in the setting of lung transplantation. Continuous infusion of regadenoson was administered to lung transplant recipients that was started at the time of skin incision. Adverse events and dose-limiting toxicities, as pre-determined by a study team and assessed by a clinical team and an independent safety monitor, were the primary end-points for safety in this trial. RESULTS: Between January 2018 and March 2019, 14 recipients were enrolled in the trial. Of these, 10 received the maximum infused dose of 1.44 µg/kg/min for 12 hours. No dose-limiting toxicities were observed. The steady-state plasma regadenoson levels sampled before the reperfusion of the first lung were 0.98 ± 0.46 ng/ml. There were no mortalities within 30 days. CONCLUSIONS: Regadenoson, an A2AR agonist, can be safely infused in the setting of lung transplantation with no dose-limiting toxicities or drug-related mortality. Although not powered for the evaluation of secondary end-points, the results of this trial and the outcome of pre-clinical studies warrant further investigation with a Phase II randomized controlled trial.