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

Courtwright, Andrew; Lamattina, Anthony M.; Takahashi, Masakazu; Trindade, Anil J.; Hunninghake, Gary M.; Rosas, Iván O.; Agarwal, Suneet; Raby, Benjamin A.; Goldberg, Hilary J.; El–Chemaly, Souheil

doi:10.1183/23120541.00003-2020

Cited by 35 publications

(24 citation statements)

References 41 publications

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“…Hence, increasing the knowledge about when and why each complication appears would set specific prevention and management strategies in order to tip the balance in favor of survival benefits. Pre-transplant work-up considerations should include telomere disorders in order to establish variations in care (48). However, wider evidence is clearly needed to identify interventions that work best for this subset of ILD patients.…”

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confidence: 99%

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

et al. 2021

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Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology.Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life.Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal.Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.

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Section: Figure 3 |mentioning

confidence: 99%

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

et al. 2021

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“…These patients appear more susceptible to the effects of immunosuppression with more frequent cytopenia (7,20), an increased susceptibility to infective insults, in particular cytomegalovirus disease (20,27) and extrapulmonary organ dysfunction (25). Reduced CLAD-free survival has been noted for this group of patients (20). These findings suggest that the effect of recipient telomere length is greatest in extrapulmonary organs, particularly the recipient immune system.…”

Section: Discussionmentioning

confidence: 85%

“…Patients with pulmonary fibrosis related to such mutations, with extreme telomere shortening, may be more prevalent in the transplant population, owing to their earlier age of onset and worse prognosis. Inferior posttransplant outcomes are noted in this group (20,(25)(26)(27)(28). These patients appear more susceptible to the effects of immunosuppression with more frequent cytopenia (7,20), an increased susceptibility to infective insults, in particular cytomegalovirus disease (20,27) and extrapulmonary organ dysfunction (25).…”

Section: Discussionmentioning

confidence: 87%

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Airway Telomere Length in Lung Transplant Recipients

et al. 2021

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IntroductionChronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality.MethodsThis prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020.ResultsIn total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively).ConclusionsIn this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.

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“…46 Although short telomere length has been associated with CLAD, no association was found with ACR. [47][48][49] Finally, pretransplant circulating anti-HLA antibodies (not necessarily specific to the donor) in recipients have been found to be associated with a higher risk of posttransplant ACR. 5,50…”

Section: Pretransplant Recipient Characteristicsmentioning

confidence: 99%

Acute Rejection in the Modern Lung Transplant Era

Renaud-Picard

Koutsokera

Cabanero

et al. 2021

Semin Respir Crit Care Med

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Acute cellular rejection (ACR) remains a common complication after lung transplantation. Mortality directly related to ACR is low and most patients respond to first-line immunosuppressive treatment. However, a subset of patients may develop refractory or recurrent ACR leading to an accelerated lung function decline and ultimately chronic lung allograft dysfunction. Infectious complications associated with the intensification of immunosuppression can also negatively impact long-term survival. In this review, we summarize the most recent evidence on the mechanisms, risk factors, diagnosis, treatment, and prognosis of ACR. We specifically focus on novel, promising biomarkers which are under investigation for their potential to improve the diagnostic performance of transbronchial biopsies. Finally, for each topic, we highlight current gaps in knowledge and areas for future research.

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

Cited by 35 publications

References 41 publications

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction

Airway Telomere Length in Lung Transplant Recipients

Acute Rejection in the Modern Lung Transplant Era

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