Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival

Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease.This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival.Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1–3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03–1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01–1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05–15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27–7.01, p=0.70).Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.

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Profiles and predictors of the course of psychological distress across four years after heart transplantation

Psychological Medicine ◽

10.1017/s0033291705004563 ◽

2005 ◽

Vol 35 (8) ◽

pp. 1215-1227 ◽

Cited By ~ 45

Author(s):

MARY AMANDA DEW ◽

LARISSA MYASKOVSKY ◽

GALEN E. SWITZER ◽

ANDREA F. DiMARTINI ◽

HERBERT C. SCHULBERG ◽

...

Keyword(s):

Psychological Distress ◽

Heart Transplantation ◽

Social Supports ◽

Psychological Needs ◽

Physical Impairment ◽

Transplant Recipients ◽

Post Transplant ◽

High Distress ◽

Clinically Significant ◽

Over Time

Background. Like individuals exposed to other life stressors, patients undergoing organ transplantation typically show elevated psychological distress initially post-transplant, with improvement thereafter. However, this ‘average’ pattern may conceal subgroups with differing profiles of psychological response. We sought to identify unique temporal distress profiles, and their predictors, after heart transplantation.Method. A total of 156 transplant recipients (refusal rate, 6%) were enrolled and assessed at 2, 7, 12, 36, and 42 months post-transplant. Cluster analysis was used to identify distinct distress profiles over time. Multivariate analyses examined health and psychosocial predictors of the profiles.Results. Five groups were identified, with either: (a) low distress at all time-points (45% of the sample), (b) high, clinically significant distress at all times (21%), (c) high distress over several years with low distress only at final assessment (12%), (d) high distress during the first several months with decline thereafter (6%), or (e) fluctuating distress levels (16%). Patients showing any distress (versus none) were more likely to have a pre-transplant psychiatric history, poorer social supports and more physical impairment early post-transplant, and continued physical impairment over time. Among distressed patients, those with persistent (versus declining) distress were most likely to be female, waited more briefly for transplant, and were most physically impaired early post-transplant. While persistently distressed patients had better social supports early post-transplant, these supports subsequently worsened.Conclusions. Individuals differ in whether and when psychological distress abates after heart transplantation. Findings regarding distress profiles and their predictors may inform the design of interventions to address each transplant recipient's unique psychological needs.

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Longitudinal assessment of interstitial lung disease in single lung transplant recipients with scleroderma

Rheumatology ◽

10.1093/rheumatology/kez341 ◽

2019 ◽

Vol 59 (4) ◽

pp. 790-798

Author(s):

Alicia M Hinze ◽

Cheng T Lin ◽

Amira F Hussien ◽

Jamie Perin ◽

Aida Venado ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Lung Transplant ◽

Transplant Recipients ◽

Longitudinal Assessment ◽

Hounsfield Units ◽

Lung Density ◽

Native Lung ◽

Single Lung Transplant ◽

Lung Transplant Recipients

Abstract Objective To investigate the natural history of fibrotic lung disease in recipients of a single lung transplant for scleroderma-associated interstitial lung disease (ILD). Methods Global ILD (including ground glass, nodular opacities and fibrosis) was categorized into severity quintiles on first and last post-transplant CT scans, and percent fibrosis by manual contouring was also determined, in nine single lung transplant recipients. Quantitative mean lung densities and volumes for the native and allograft lungs were also acquired. Results In the native lung, global ILD severity quintile worsened in two cases and percent fibrosis worsened in four cases (range 5–28%). In the lung allograft, one case each developed mild, moderate and severe ILD; of these, new fibrotic ILD (involving <10% of lung) occurred in two cases and acute cellular rejection occurred in one. The average change in native lung density over time was +2.2 Hounsfield Units per year and lung volume +1.4 ml per year, whereas the allograft lung density changed by –5.5 Hounsfield Units per year and total volume +27 ml per year (P = 0.011 and P = 0.039 for native vs allograft density and volume comparisons, respectively). Conclusions While the course of ILD in the native and transplanted lungs varied in this series, these cases illustrate that disease progression is common in the native lung, suggesting that either the immune process continues to target autoantigens or ongoing fibrotic pathways are active in the native lung. Mild lung disease may occur in the allograft after several years due to either allograft rejection or recurrent mild ILD.

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Telomere length and genetic variant associations with interstitial lung disease progression and survival

European Respiratory Journal ◽

10.1183/13993003.01641-2018 ◽

2019 ◽

Vol 53 (4) ◽

pp. 1801641 ◽

Cited By ~ 29

Author(s):

Chad A. Newton ◽

Justin M. Oldham ◽

Brett Ley ◽

Vikram Anand ◽

Ayodeji Adegunsoye ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Function ◽

Lung Disease ◽

Disease Progression ◽

Telomere Length ◽

Hazard Ratio ◽

Lung Function Decline ◽

Free Survival ◽

Genomic Markers ◽

Observational Cohort

Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of −0.05±0.29 and −0.04±0.25, respectively) is longer than that of IPF patients (−0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (−6.43% per year versus −0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70–5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8–28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18–3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (−0.14±0.27 versus −0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4–46.3 versus 14.1, 95% CI 9.8–20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.

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Exacerbation of Pulmonary Fibrosis Following Single Lung Transplantation

Canadian Respiratory Journal ◽

10.1155/2012/258485 ◽

2012 ◽

Vol 19 (1) ◽

pp. e3-e4 ◽

Cited By ~ 5

Author(s):

Dawei Yang ◽

Jennifer M Wilson ◽

Chunxue Bai ◽

John Yee ◽

Pearce G Wilcox ◽

...

Keyword(s):

Heart Failure ◽

Pulmonary Fibrosis ◽

Lung Transplantation ◽

Lung Disease ◽

Acute Exacerbation ◽

Thromboembolic Disease ◽

Single Lung Transplantation ◽

Maintenance Immunosuppression ◽

Native Lung ◽

Acute Exacerbations

Acute exacerbations of interstitial lung disease present as clinical deteriorations, with progressive hypoxemia and parenchymal consolidation not related to infection, heart failure or thromboembolic disease. Following single lung transplantation, patients receive maintenance immunosuppression, which could mitigate the development of acute exacerbations in the native lung. A 66-year-old man with fibrotic, nonspecific interstitial pneumonitis presented with fever, hypoxemia and parenchymal consolidation limited to the native lung four years after single lung transplantation. Investigations were negative for infection, heart failure and thromboembolic disease. The patient worsened over the course of one week despite broad-spectrum antimicrobial therapy, but subsequently improved promptly with augmentation of prednisone dosed to 50 mg daily and addition of N-acetylcysteine. Hence, the patient fulfilled the criteria for a diagnosis of an acute exacerbation of pulmonary fibrosis in his native lung. Clinicians should consider acute exacerbation of parenchymal lung disease of the native lung in the differential diagnosis of progressive respiratory deterioration following single lung transplantation for pulmonary fibrosis.

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Stereotactic body radiation therapy (SBRT) for the treatment of primary lung cancer in recipients of lung transplant

Radiology and Oncology ◽

10.2478/raon-2020-0022 ◽

2020 ◽

Vol 54 (2) ◽

pp. 227-232

Author(s):

Assaf Moore ◽

Mordechai R. Kramer ◽

Dror Rosengarten ◽

Osnat Shtraichman ◽

Alona Zer ◽

...

Keyword(s):

Lung Cancer ◽

Radiation Therapy ◽

Lung Transplantation ◽

Lung Transplant ◽

Stereotactic Body Radiation Therapy ◽

Tumor Board ◽

Transplant Recipients ◽

Stereotactic Body Radiation ◽

Native Lung ◽

Lung Transplant Recipients

AbstractBackgroundLung transplantation is a life-saving treatment for patients with end stage lung disease. There may be a higher incidence of lung cancer in lung transplant recipients, and these cancers tend to be diagnosed at a more advanced stage. There is very little data on the safety and efficacy of stereotactic body radiation therapy (SBRT) for lesions in the native lung in lung-transplant recipients.Patients and methodsA retrospective chart review of all patients who have undergone lung transplantation and were treated with SBRT for lung cancer in the native lung in the Davidoff Cancer Center was performed.ResultsFour patients who were treated with SBRT to a total of 5 lesions were included. Two patients were treated without histological confirmation of malignancy. All cases were discussed in a multidisciplinary tumor board before being referred for radiotherapy. Standard SBRT dosing was used. Responses were assessed by imaging. Three lesions exhibited a complete response and two lesions had a partial response. The patients who had partial responses developed distant metastases and died shortly. No patient developed measurable toxicity.ConclusionsSBRT is effective and safe for the management of lung cancer in lung-transplant patients. Standard dose and fractionation can be used.

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1136. Universal Prophylaxis for Prevention of Invasive Aspergillus in Lung Transplant Recipients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.969 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S341-S341

Author(s):

Alexis Guenette ◽

A Adrian Gonzalez ◽

Amir Emtiazjoo

Keyword(s):

Early Diagnosis ◽

Bronchoalveolar Lavage ◽

Lung Transplantation ◽

Lung Transplant ◽

Clinical Signs ◽

Diagnostic Methods ◽

Transplant Recipients ◽

Ischemic Time ◽

Post Transplant ◽

Lung Transplant Recipients

Abstract Background Invasive aspergillosis (IA) is a significant complication status post lung transplantation with an incidence of 6% to 16%. Because early diagnosis of IA in lung transplant is hampered by the lack of specific clinical signs and by the low sensitivity of culture-based diagnostic methods, the efficacy of bronchoalveolar lavage galactomannan (BAL GM) for early diagnosis is explored in this study. Methods A retrospective analysis was performed on 45 consecutive lung transplant recipients between January 2015 and February 2016 at UF Health Shands Hospital. All patients were placed on prophylactic itraconazole post-transplant. Surveillance bronchoscopies were performed at 2 weeks, 1 month, 3 months, 6 months, 9 months, and 12 months post-transplant. During each bronchoscopy, bacterial, fungal, and acid-fast bacterial cultures along with BAL GM [an optical density (OD) index of ≥0.5 considered positive] were obtained. If BAL GM ≥1.0, the patient was switched to voriconazole for further treatment. CT Chest was also evaluated. If BAL GM remained ≤1.0 at the 6 month interval, then prophylaxis was complete. IA was defined using the EORTC/MSG criteria for invasive fungal disease (i.e., patient classified as either having proven, probable or possible IA). Results There was a total of 225 observations from the 45 patients. Two patients (4.4%) had proven IA with a mean GM of 4.153 (SE, 0.629) and seven patients (15%) had probable IA with a mean of 2.169 (SE, 0.409). There was no correlation of cold ischemic time (P = 0.88), primary graft dysfunction (PGD, P = 0.38), presence of Candida species (P =0.048) or non-tuberculous mycobacteria (NTM) in bronchoalveolar lavage (P = 0.044), and viral pneumonitis (P = 0.047) with a positive BAL GM. All nine patients with GM >1 were switched to voriconazole from itraconazole which resulted in negative GM levels on follow-up bronchoscopy. Conclusion Our data suggest that the implementation of universal antifungal prophylaxis with itraconazole may not be efficacious in preventing IA in lung transplant recipients. On the other hand, surveillance with BAL GM is a strategy that can lead to early detection of IA in patients during the first year after lung transplantation. Disclosures All authors: No reported disclosures.

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Single-breath test in lateral decubitus reflects function of single lungs grafted for emphysema

Journal of Applied Physiology ◽

10.1152/japplphysiol.01307.2005 ◽

2006 ◽

Vol 100 (3) ◽

pp. 834-838 ◽

Cited By ~ 8

Author(s):

Alain Van Muylem ◽

Pietro Scillia ◽

Christiane Knoop ◽

Manuel Paiva ◽

Marc Estenne

Keyword(s):

Lung Transplantation ◽

Computerized Tomography ◽

Breath Test ◽

Transplant Recipients ◽

Single Lung Transplantation ◽

Single Breath ◽

Native Lung ◽

Single Breath Test ◽

Lateral Decubitus ◽

Normal Controls

The slope of alveolar plateau for nitrogen derived from the single-breath test is useful to assess the function of bilateral lung grafts, but this technique is not applicable to patients with single-lung grafts due to the confounding influence of the native lung. We tested the hypothesis that the nitrogen slope measured in lateral decubitus with the graft in nondependent position may primarily reflect the distribution of ventilation in this lung. Fifteen patients with single-lung transplantation for emphysema, 10 healthy controls, and 7 patients with advanced emphysema performed single-breath washouts in right and left lateral decubitus; nitrogen slope was measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in the two postures by computerized tomography. Nitrogen slope was unaffected by posture in normal controls and emphysema patients. On the other hand, nitrogen slope in transplant recipients was invariably smaller, with the graft in nondependent vs. in dependent position. Values of nitrogen slope with the graft in nondependent position were similar to those obtained in normal controls but significantly smaller than those obtained in emphysema patients. Computerized tomography studies in this position indicated that the volume expired below functional residual capacity was exclusively contributed by the graft. We conclude that, in patients with single-lung transplantation for emphysema, 1) measuring nitrogen slope in lateral decubitus allows to distinguish between the graft and the native lung, and 2) nitrogen slope obtained with the graft in nondependent position reflects ventilation distribution in this lung.

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Late-onset “acute fibrinous and organising pneumonia” impairs long-term lung allograft function and survival

European Respiratory Journal ◽

10.1183/13993003.02292-2019 ◽

2020 ◽

Vol 56 (3) ◽

pp. 1902292 ◽

Cited By ~ 1

Author(s):

Arno Vanstapel ◽

Stijn E. Verleden ◽

Birgit Weynand ◽

Eric Verbeken ◽

Laurens De Sadeleer ◽

...

Keyword(s):

Lung Transplantation ◽

Graft Survival ◽

Median Survival ◽

Free Survival ◽

Specific Antibodies ◽

Blood Eosinophilia ◽

Post Transplant ◽

Restrictive Allograft Syndrome ◽

Donor Specific Antibodies ◽

New Onset

Acute fibrinous and organising pneumonia (AFOP) after lung transplantation is associated with a rapid decline in pulmonary function. However, the relation with chronic lung allograft dysfunction (CLAD) remains unclear. We investigated the association between detection of AFOP in lung allograft biopsies with clinically important endpoints.We reviewed lung allograft biopsies from 468 patients who underwent lung transplantation at the University Hospitals Leuven (2011–2017). AFOP was categorised as early new-onset (≤90 days post-transplant) or late new-onset (>90 days post-transplant); and associated with CLAD-free survival, graft survival, donor-specific antibodies, airway and blood eosinophilia.Early and late AFOP was detected in 24 (5%) and 30 (6%) patients, respectively. CLAD-free survival was significantly lower in patients with late AFOP (median survival 2.42 years; p<0.0001) compared with patients with early or without AFOP and specifically associated with development of restrictive allograft syndrome (OR 28.57, 95% CI 11.34–67.88; p<0.0001). Similarly, graft survival was significantly lower in patients with late AFOP (median survival 4.39 years; p<0.0001) compared with patients with early AFOP or without AFOP. Late AFOP was furthermore associated with detection of circulating donor-specific antibodies (OR 4.75, 95% CI 2.17–10.60; p=0.0004) compared with patients with early or without AFOP, and elevated airway and blood eosinophilia (p=0.043 and p=0.045, respectively) compared with early AFOP patients.Late new-onset AFOP is associated with a worse prognosis and high risk of CLAD development, specifically restrictive allograft syndrome. Our findings indicate that late new-onset AFOP might play a role in the early pathogenesis of restrictive allograft syndrome.

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Lung transplantation for interstitial lung disease

European Respiratory Review ◽

10.1183/16000617.0017-2021 ◽

2021 ◽

Vol 30 (161) ◽

pp. 210017

Author(s):

Siddhartha G. Kapnadak ◽

Ganesh Raghu

Keyword(s):

Interstitial Lung Disease ◽

Lung Transplantation ◽

Lung Disease ◽

Hypersensitivity Pneumonitis ◽

Clinical Findings ◽

Cardiac Complications ◽

Optimal Timing ◽

Post Transplant ◽

Improved Outcomes ◽

Telomere Biology

Lung transplantation (LTx) can be a life-extending treatment option for patients with advanced and/or progressive fibrotic interstitial lung disease (ILD), especially idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, sarcoidosis and connective tissue disease-associated ILD. IPF is now the most common indication for LTx worldwide. Several unique features in patients with ILD can impact optimal timing of referral or listing for LTx, pre- or post-transplant risks, candidacy and post-transplant management. As the epidemiology of LTx and community practices have evolved, recent literature describes outcomes and approaches in higher-risk candidates. In this review, we discuss the unique and important clinical findings, course, monitoring and management of patients with IPF and other progressive fibrotic ILDs during pre-LTx evaluation and up to the day of transplantation; the need for co-management with clinical experts in ILD and LTx is emphasised. Some post-LTx complications are unique in these patient cohorts, which require prompt detection and appropriate management by experts in multiple disciplines familiar with telomere biology disorders and infectious, haematological, oncological and cardiac complications to enhance the likelihood of improved outcomes and survival of LTx recipients with IPF and other ILDs.

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