Clinical outcomes of lung transplant recipients with telomerase mutations

Tokman, Sofya; Singer, Jonathan P.; Devine, Megan S.; Westall, Glen P.; Aubert, John‐David; Tamm, Michael; Snell, Gregory I; Lee, Joyce; Goldberg, Hilary J.; Kukreja, Jasleen; Golden, Jeffrey A.; Leard, Lorriana E.; Garcia, Christine Kim; Hays, Steven R.

doi:10.1016/j.healun.2015.05.002

Cited by 86 publications

(88 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Over 50% of affected individuals had a diagnosis other than IPF. Other studies of ILD patients with short telomere lengths have also found high percentages of non-IPF diagnoses, including hypersensitivity pneumonitis, unclassified interstitial pneumonia and combined pulmonary fibrosis and emphysema [30, 31]. We found discordant diagnoses among affected individuals with the same inherited rare mutation in 80% of kindreds.…”

Section: Discussionsupporting

confidence: 58%

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

et al. 2016

View full text Add to dashboard Cite

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals. 115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed. Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year−1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis. Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.

show abstract

Section: Discussionsupporting

confidence: 58%

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Thrombocytopenia and a need for platelet transfusion were frequent, and myelodysplastic syndrome and/or bone-marrow failure occurred in some patients. Acute kidney failure requiring dialysis support seemed unexpectedly frequent in two series (0-50%) [58][59][60]. The prevalence of infections and acute/chronic rejections did not differ from historical data, but there was no control group.…”

Section: Pulmonary Involvementmentioning

confidence: 80%

“…Three retrospective series recently reported the outcome of lung transplantation in 26 patients with TERT and TERC mutations [58][59][60]. Almost all patients required adjustment of immunosuppression because of haematological toxicity.…”

Section: Pulmonary Involvementmentioning

confidence: 99%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

View full text Add to dashboard Cite

At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

show abstract

“…Sequencing of telomere-related genes was not systematically performed. Five subjects with telomere-related gene mutations (all with telomere lengths <10 th percentile) were included in other studies(8, 11). …”

Section: Methodsmentioning

confidence: 99%

“…Heterozygous mutations in these genes are associated with short telomere lengths and a rapidly-progressive form of pulmonary fibrosis, which is most commonly characterized as idiopathic pulmonary fibrosis (IPF)(8). Small observational studies have found that pulmonary fibrosis patients with TERT or TERC mutations have high rates of bone marrow failure, infection, renal dysfunction, and allograft dysfunction after lung transplant(9–11). However, these studies were limited by small numbers of patients and the absence of a comparison cohort.…”

Section: Introductionmentioning

confidence: 99%

Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post–lung transplantation survival

Newton

Kozlitina

Lines

et al. 2017

The Journal of Heart and Lung Transplantation

View full text Add to dashboard Cite

Background Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes by leukocyte telomere length. Methods We conducted an observational cohort study of all pulmonary fibrosis patients who underwent lung transplantation at a single center between January 1, 2007 and December 31, 2014. Leukocyte telomere length was measured from a sample of blood collected prior to lung transplantation and subjects were stratified into two groups (telomere length <10th versus ≥10th percentile). The primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction and infection. Results Approximately one-third (32%) of subjects had a telomere length below the 10th percentile. Telomere length <10th percentile was independently associated with worse survival (HR 10.9, 95% CI 2.7–44.8, p=0.001). Telomere length <10th percentile was also independently associated with a shorter time to the onset of chronic lung allograft dysfunction (CLAD) (HR 6.3, 95% CI 2.0–20.0, p=0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared to the ≥10th percentile group (28% vs 7%, p=0.034). There was no difference in the incidence of acute cellular rejection, cytopenias, infection or renal dysfunction in the two groups. Conclusions Telomere length <10th percentile was associated with worse survival and shorter time to onset of CLAD, and thus represents a biomarker that may aid in the risk stratification of pulmonary fibrosis patients prior to lung transplantation.

show abstract

Clinical outcomes of lung transplant recipients with telomerase mutations

Cited by 86 publications

References 29 publications

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

Management of suspected monogenic lung fibrosis in a specialised centre

Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post–lung transplantation survival

Contact Info

Product

Resources

About