Lung Transplantation For Idiopathic Pulmonary Fibrosis Research Articles

Lung Transplant Outcomes for Idiopathic Pulmonary Fibrosis: Are We Improving?

Following implementation of the Lung Allocation Score in 2005, idiopathic pulmonary fibrosis (IPF) emerged as the most common indication for lung transplant (LT) in the United States. The age and comorbidity of patients receiving LT have since increased and the indications for LT have evolved. However, limited data have analyzed more recent outcomes among the IPF population. We analyzed LTs for the primary indication of IPF using the United Network for Organ Sharing database. We performed an eras-based analysis, comparing patient characteristics, survival, and related outcomes during 2005-2009 (Era 1) and 2010-2014 (Era 2) with Chi square, Wilcoxon rank sum, and Kaplan-Meier analyses. We compared 1-year survival from 2005-2020 and survival at milestones ranging from 1-month to 5-years. We conducted two adjusted Cox proportional hazards models: 5-year survival by era and 1-year survival annually from 2010-2020. From Era 1 (n=1818) to Era 2 (n=3227), the median age of LT recipients increased from 61 to 63 years old (p<0.001). Patients in the intensive care unit prior to LT climbed from 7.7% to 12.1% (p<0.001), and patients with diabetes grew from 17.9% to 19.4% (p=0.003). Despite increased severity of illness, 5-year survival increased from 51.9% in Era 1 to 55.2% in Era 2 (p=0.02). Adjusted modeling indicated that LT during Era 2 featured a 17% hazard reduction compared to Era 1 (Hazard Ratio = 0.83, 95% CI: 0.76-0.91). Survival is improving for patients undergoing LT for IPF, despite the challenges of transplantation patients with progressively higher risk profiles.

Lung transplant recipients with telomere-mediated pulmonary fibrosis have increased risk for hematologic complications

Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.

Frailty and aging-associated syndromes in lung transplant candidates and recipients.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and posttransplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

Idiopathic Pulmonary Fibrosis Lung Transplant Recipients are at Increased Risk for Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorder

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a seven-year period. All LTRs transplanted from 2010 to 2016 were included. LTRs who died within 3 months or were lost to follow-up were excluded. Sex, age, EBV serostatus, induction agent, indication agent, and survival were collected via chart review. The primary outcome was development of PTLD. Secondary endpoints were early and late PTLD and survival. Primary and secondary outcomes were assessed using Kaplan-Meier methods and Cox proportional hazards models. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed an increased rate of PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (p<0.02). Multivariable Cox proportional hazards modeling found IPF (HR 3.51, 95% CI 1.33-8.21, p=0.01), alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, p=0.03), and EBV mismatch (HR: 34.43, 95% CI: 15.57-76.09, p<0.0001) as risk factors for PTLD. Early PTLD (first-year) was associated with alemtuzumab use (p=0.04), whereas IPF was a predictor for late PTLD (after first-year) (p=0.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF-LTRs compared to other LTRs (p=0.04). The use of alemtuzumab in EBV-mismatch was found to particularly increase PTLD risk. IPF-LTRs are at increased susceptibility for PTLD compared to non-IPF LTRs. LTRs who received alemtuzumab induction were at increased risk for PTLD, particularly those who were EBV mismatches. Ongoing studies are being conducted to understand the mechanisms driving PTLD in IPF-LTRs and develop strategies to mitigate risk.

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival.

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P<.02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P=.01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P=.03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P<.0001). Early PTLD (first year) was associated with alemtuzumab use (P=.04), whereas IPF was a predictor for late PTLD (after first year) (P=.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P=.04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

INCIDENTAL PULMONARY ADENOCARCINOMA DETECTED ONLY IN ONE EXPLANTED LYMPH NODE OF A LUNG TRANSPLANT RECIPIENT WITH OLIGO-METASTATIC RECURRENCE ONE YEAR AFTER TRANSPLANT

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: The most common indications for lung transplant (LT) in the post-lung allocation score (LAS) era are idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Unexpected neoplasms are detected in between 1-4% of LT recipients upon pathological review of explants. CASE PRESENTATION: We present a rare case of incidental adenocarcinoma of the lung detected only on an explanted lymph node after LT. A 73-year-old man underwent bilateral sequential LT for IPF. Explant pathology revealed a 0.2 cm focus of pulmonary adenocarcinoma in one out of 21 lymph nodes (strongly positive for TTF-1) without a parenchymal primary focus. The explanted lungs were re-reviewed to confirm the absence of a primary focus (pathological stage pT0, pN1). The patient was subsequently followed with serial imaging including computed tomography (CT) and positron emission tomography (PET) scans. One year after LT he suffered a compression fracture at L1 and was hospitalized for hyponatremia. Workup revealed lesions in the T10 vertebra, right second rib and in the left acetabulum that showed mild uptake on PET scans. He underwent a CT-guided biopsy of the acetabular lesion, which was consistent with adenocarcinoma of pulmonary origin (strongly positive for keratin AE1/AE3 and CK7, while focally positive for TTF-1) – all consistent with a diagnosis of oligometastatic disease. His immunosuppression was lowered but given his leucopenia, he was thought to be a poor candidate for systemic therapy. After multidisciplinary discussions with the patient it was decided the best course of action for this patient would be stereotactic body radiation therapy (SBRT). He was treated with one dose of 20Gy radiation to each of the three sites of metastasis. The patient tolerated the treatment well and had no complications. Four months after initial therapy, repeat PET scan revealed a new FDG avid in the left pubic body concerning for metastasis and showed stable uptake in the three previously treated lesions. After additional discussions the patient and medical team again opted for SBRT to the lesion. He underwent single dose 20Gy radiation without complications. The patient tolerated all procedures well and continues to do well post treatment. DISCUSSION: Diagnosis and management of incidental neoplasms post-LT is challenging. This case highlights the importance of in depth pathological evaluation of lung explants and lymph nodes to look for foci of malignancy not detected on prior clinical evaluation. CONCLUSIONS: High clinical suspicion, lowering immunosuppression and multidisciplinary management are key in managing patients with incidental malignancies detected on lung explants. The incidence of such tumors will likely increase given the higher number of LT for IPF in the post-LAS era. Reference #1: Panchabhai TS, Arrossi AV, Patil PD, Bandyopadhyay D, Budev MM, McCurry KR, Farver C. Unexpected Neoplasms in Lungs Explanted From Lung Transplant Recipients: A Single-Center Experience and Review of Literature. Transplant Proc. 2018;50(1):234-240. DISCLOSURES: No relevant relationships by Hesham Abdelrazek, source=Web Response No relevant relationships by Sreeja Biswas Roy, source=Web Response No relevant relationships by Thomas Luzny, source=Web Response No relevant relationships by Tanmay Panchabhai, source=Web Response no disclosure on file for Nitika Thawani; Speaker/Speaker's Bureau relationship with Genentech Please note: $5001 - $20000 Added 03/18/2019 by Rajat Walia, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: $5001 - $20000 Added 03/18/2019 by Rajat Walia, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Grifols Please note: $5001 - $20000 Added 03/18/2019 by Rajat Walia, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Shire Please note: $1001 - $5000 Added 03/18/2019 by Rajat Walia, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Astellas Please note: $5001 - $20000 Added 03/18/2019 by Rajat Walia, source=Web Response, value=Honoraria

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

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. 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. 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. 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). 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.

TIMING OF LUNG TRANSPLANT IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS

SESSION TITLE: Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis SESSION TYPE: Original Investigations PRESENTED ON: 10/08/2018 07:30 am - 08:30 am PURPOSE: Idiopathic pulmonary fibrosis (IPF) is one of the leading indications for lung transplant. The timing of lung transplant in IPF varies due to the general nature of the guidelines from the ISHLT and center-specific implementation practices. More data are needed to describe the time from diagnosis of IPF to transplant in clinical practice and the characteristics of patients who undergo transplant. METHODS: Patients with IPF enrolled in the ongoing Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry in the US from its inception on 5 June 2014 to 7 June 2017 comprised the analysis cohort. Individuals enrolled in the registry had newly diagnosed IPF or were newly confirmed with IPF by the enrolling center, and were not listed for lung transplant at the time of enrollment. Time from confirmed diagnosis of IPF at the enrolling center to lung transplant, and clinical characteristics at the time of confirmed diagnosis of IPF, were evaluated descriptively in patients who subsequently received a transplant, who died and who did not receive a transplant and had not died. RESULTS: Of 563 patients in this analysis cohort, 15 (2.7%) had received a lung transplant and 482 (85.6%) did not receive a lung transplant and were alive. Median (Q1, Q3) time from confirmed diagnosis of IPF to lung transplant was 11.0 (5.7, 15.0) months, with Kaplan-Meier estimated transplant rates (95% CI) of 2.5% (1.3%, 4.7%) at 1 year and 6.0% (3.3%, 10.8%) at 2 years post-diagnosis. At the time of confirmed diagnosis of IPF, patients who went on to receive a lung transplant had lower median FVC % predicted (53.8% vs 70.6%), lower median DLco % predicted (36.0% vs 42.6%) and lower median 6-minute walk test distance (350 m vs 383 m) than patients who did not receive a lung transplant and were alive. A greater proportion of patients who went on to receive a lung transplant were using supplemental oxygen with activity than patients who did not receive a lung transplant and were alive (66.7% vs 30.1%). CONCLUSIONS: Data from the IPF-PRO Registry suggest that in patients not listed for lung transplant at enrollment, a low proportion of patients had a transplant within 2 years. Those that underwent transplant had more severe disease. CLINICAL IMPLICATIONS: Further analyses of data from the ongoing IPF-PRO Registry will provide valuable insights into clinical practices around lung transplant for IPF in the US. DISCLOSURES: Employee relationship with Boehringer Ingelheim Please note: >$100000 Added 03/01/2018 by Shaun Bender, source=Web Response, value=Salary Employee relationship with Boehringer Ingelheim Pharmaceuticals Please note: >$100000 Added 03/01/2018 by Craig Conoscenti, source=Web Response, value=Salary Consultant relationship with Boehringer Ingelheim Please note: $20001 - $100000 Added 03/15/2018 by Kevin Flaherty, source=Web Response, value=Consulting fee Consultant relationship with Roche/Genentech Please note: $1001 - $5000 Added 03/15/2018 by Kevin Flaherty, source=Web Response, value=Consulting fee Consultant relationship with Sanofi Genzyme Please note: $1001 - $5000 Added 03/15/2018 by Kevin Flaherty, source=Web Response, value=Consulting fee Consultant relationship with Veracyte Please note: $5001 - $20000 Added 03/15/2018 by Kevin Flaherty, source=Web Response, value=Consulting fee Employee relationship with Boehringer-Ingelheim Pharmaceuticals Inc Please note: >$100000 Added 03/01/2018 by Thomas Leonard, source=Web Response, value=Salary No relevant relationships by Megan Neely, source=Web Response PI relationship with BI Please note: $1001 - $5000 Added 03/15/2018 by Scott Palmer, source=Web Response, value=Consulting fee PI relationship with BI Please note: >$100000 Added 03/15/2018 by Scott Palmer, source=Web Response, value=Grant/Research Support No relevant relationships Added 02/28/2018 by Laurie Snyder, source=Web Response, value=Consulting feeRemoved 02/28/2018 by Laurie Snyder, source=Web Response No relevant relationships Added 02/28/2018 by Laurie Snyder, source=Web Response, value=Consulting feeRemoved 02/28/2018 by Laurie Snyder, source=Web Response No relevant relationships by Eric Yow, source=Web Response

Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis.

The receptor for advanced glycation end products (RAGE) is underexpressed in idiopathic pulmonary fibrosis (IPF) lung, but the role of RAGE in human lung fibrosis remains uncertain. To examine (1) the association between IPF risk and variation at rs2070600, a functional missense variant in AGER (the gene that codes for RAGE), and (2) the associations between plasma-soluble RAGE (sRAGE) levels with disease severity and time to death or lung transplant in IPF. We genotyped the rs2070600 single-nucleotide polymorphism in 108 adults with IPF and 324 race-/ethnicity-matched control subjects. We measured plasma sRAGE by ELISA in 103 adults with IPF. We used generalized linear and additive models as well as Cox models to control for potential confounders. We repeated our analyses in 168 (genetic analyses) and 177 (sRAGE analyses) adults with other forms of interstitial lung disease (ILD). There was no association between rs2070600 variation among adults with IPF (P = 0.31). Plasma sRAGE levels were lower among adults with IPF and other forms of ILD than in control subjects (P < 0.001). The rs2070600 allele A was associated with a 49% lower sRAGE level (95% confidence interval [CI], 11 to 71%; P = 0.02) among adults with IPF. In adjusted analyses, lower sRAGE levels were associated with greater disease severity (14% sRAGE decrement per 10% FVC decrement; 95% CI, 5 to 22%) and a higher rate of death or lung transplant at 1 year (adjusted hazard ratio, 1.9 per logarithmic unit of sRAGE decrement; 95% CI, 1.2-3.3) in IPF. Similar findings were observed in a heterogeneous group of adults with other forms of ILD. Lower plasma sRAGE levels may be a biological measure of disease severity in IPF. Variation at the rs2070600 single-nucleotide polymorphism was not associated with IPF risk.

(113) - Lung Allocation Score Does Not Predict Survival Among Idiopathic Pulmonary Fibrosis Lung Transplant Recipients

(113) - Lung Allocation Score Does Not Predict Survival Among Idiopathic Pulmonary Fibrosis Lung Transplant Recipients

Age-Dependent Gender Disparities in Post Lung Transplant Survival Among Patients With Idiopathic Pulmonary Fibrosis

The influence of age and gender on survival after lung transplant in patients with idiopathic pulmonary fibrosis (IPF) is not well defined. The United Network for Organ Sharing database was queried to identify IPF patients receiving lung transplant between 2005 and 2015. There were 6,677 patients receiving lung transplant between May 2015 and June 2015 who met the inclusion criteria, predominantly males (n= 4,769, 71%). Within 1 year posttransplant, the survival curves of male and female recipients diverged, with male recipients having significantly worse survival (log-rank test p= 0.008). Univariate Cox proportional hazards regressions demonstrated no gender difference in survival below age 65 years (HR= 1.051; 95% CI= 0.945, 1.168; p= 0.362) but a significant increase in mortality hazard associated with male gender among patients age 65 years and older (HR= 1.161; 95% CI= 1.000, 1.347; p= 0.049). Multivariable Cox regression accounting for age modulation of the gender effect further demonstrated the emergence of a male disadvantage in post-transplant survival above age 65 years at transplantation. In patients with IPF receiving lung transplant at greater than 65 years of age, male gender is associated with significantly increased risk for death, so referral for lung transplant in IPF should be considered early in the disease course.

Age-Dependent Gender Disparities in Post-Lung Transplant Survival Among Patients With Idiopathic Pulmonary Fibrosis

Background The influence of age and gender on survival after lung transplant in patients with idiopathic pulmonary fibrosis (IPF) is not well defined. Methods The United Network for Organ Sharing database was queried to identify IPF patients receiving lung transplant between 2005 and 2015. Results There were 6,677 patients receiving lung transplant between May 2015 and June 2015 who met the inclusion criteria, predominantly males (n = 4,769, 71%). Within 1 year posttransplant, the survival curves of male and female recipients diverged, with male recipients having significantly worse survival (log-rank test p = 0.008). Univariate Cox proportional hazards regressions demonstrated no gender difference in survival below age 65 years (HR = 1.051; 95% CI = 0.945, 1.168; p = 0.362) but a significant increase in mortality hazard associated with male gender among patients age 65 years and older (HR = 1.161; 95% CI = 1.000, 1.347; p = 0.049). Multivariable Cox regression accounting for age modulation of the gender effect further demonstrated the emergence of a male disadvantage in post-transplant survival above age 65 years at transplantation. Conclusions In patients with IPF receiving lung transplant at greater than 65 years of age, male gender is associated with significantly increased risk for death, so referral for lung transplant in IPF should be considered early in the disease course.

Timing of Lung Transplantation for Patients with Fibrotic Lung Diseases

Idiopathic pulmonary fibrosis (IPF) is typically a fatal disease that fails to respond to medical therapy. For these patients lung transplantation offers the promise of improved quality and duration of life. The initial reports of successful transplantation for IPF date back to the mid-1980s although recent data suggest IPF patients make up nearly 20% of all single lung transplants. The survival rates following lung transplantation for IPF are estimated at 67% for 1 year, 52% for 3 years, and 35% for 5 years. Mortality rates following lung transplantation for IPF are higher than emphysema, but are generally comparable to primary pulmonary hypertension. Given the relatively high mortality following transplant the decision of when to transplant a patient is of paramount importance. Although individual patients differ, generalizations predicting a poor prognosis include the diagnosis of usual interstitial pneumonia (UIP), a forced vital capacity or total lung capacity of less than 65% predicted, a diffusion capacity for carbon monoxide (DL(CO)) less than 45% of predicted, and the presence of extensive honeycombing on high-resolution computed tomographic scans. The presence of any of these features should prompt the patient and physician to consider lung transplantation as a potential therapeutic modality. Patients with interstitial lung disease related to collagen vascular diseases or other causes need to be considered on an individual basis; their prognosis is usually better than patients with IPF, and the potential for systemic involvement may preclude listing for lung transplantation.