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Running Short on TimeTransplant for Telomere-Related Pulmonary Fibrosis: Lung Transplant Evaluation for Telomere-Related Pulmonary Fibrosis FREE TO VIEW

Christine Kim Garcia, MD, PhD
Author and Funding Information

From the McDermott Center for Human Growth and Development and the Department of Internal Medicine, University of Texas Southwestern Medical Center.

CORRESPONDENCE TO: Christine Kim Garcia, MD, PhD, University of Texas Southwestern Medical Center, McDermott Center for Human Growth and Development and the Department of Internal Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-8591; e-mail: christine.garcia@utsouthwestern.edu


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):1450-1452. doi:10.1378/chest.15-0077
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Published online

Idiopathic pulmonary fibrosis (IPF) is the most common subtype of interstitial lung disease (ILD) and disproportionately affects older adults.1 The pathogenesis of IPF in some patients has been linked to shortening of chromosomal ends, or telomeres, which is regulated by both genetic and environmental factors.2,3 Since telomeres erode with each cycle of cell replication, this genomic timepiece provides a surrogate measure of molecular age and, thus, provides a biologic explanation for the increased incidence of IPF in older patients.

Most studies of telomere-related pulmonary fibrosis have focused on families in which one of several different telomere-associated ailments cosegregate with rare genetic mutations. Kindreds fall into two broad categories. First, for those with a diagnosis of dyskeratosis congenita, pulmonary fibrosis develops after the appearance of characteristic mucocutaneous features, usually following bone marrow failure during childhood or young adulthood.4 These patients have extremely short age-adjusted telomere lengths, usually less than the first percentile of normal. Second, patients with familial pulmonary fibrosis have lung disease as the dominant and presenting clinical feature, with an age of onset typically 50 years or older.5,6 For the latter group, hematologic abnormalities are mild or nonexistent and blood telomere lengths are not quite so short, usually within the lower 10th percentile. Although families with Mendelian single-gene telomeropathies have been well studied, prospective evaluations of cohorts of patients presenting with severe ILD and short telomere lengths are few.

In this issue of CHEST (see page 1549), George et al7 report the prospective evaluation of pulmonary and extrapulmonary clinical phenotypes of 13 patients with ILD and short telomere lengths referred for lung transplantation. Telomere lengths of blood leukocytes were considered to be short if they fell below the 10th percentile of age-matched control subjects. From an original cohort of 127 patients, 30 were selected because of features suggestive of telomere shortening, and 22 of the 30 underwent telomere length measurement. Of the 15 who were found to have short telomere lengths, 13 underwent a bone marrow biopsy, and seven underwent a liver biopsy.

Detailed extrapulmonary phenotypes by examination of bone marrow and liver biopsies represent a key strength of this single-site study. Approximately one-third of those who underwent bone marrow biopsy (four of 13 patients) were deemed to be not suitable for lung transplantation because of an uncovered hematologic disorder. Another one-third (four of 13 patients) were listed for lung transplantation, but the findings of hypocellular marrow seen on bone marrow biopsy led to a change in the planned immunosuppression by avoiding induction at the time of lung transplant. Although minor abnormalities in liver biopsies from seven of the 13 patients were seen, these findings did not affect candidacy for lung transplantation or lead to adjustment of transplant-associated immunosuppressant medications. These results suggest that stratification of patients with ILD and short telomere lengths based upon bone marrow, but not liver, biopsy results may affect lung transplant candidacy and management.

This study also highlights the considerable overlap of pulmonary and extrapulmonary phenotypes observed in this cohort and other patients with familial pulmonary fibrosis and telomerase (TERT) mutations.8,9 Nearly one-half of the individuals with ILD and short telomere lengths in this study had a family history of interstitial pneumonia or early graying of hair. Although most patients (60%) with short telomere lengths had a diagnosis of IPF, other diagnoses of hypersensitivity pneumonitis, combined pulmonary fibrosis and emphysema, and unclassified interstitial pneumonitis were also represented, consistent with the broad spectrum of lung phenotypes seen in patients with telomerase (TERT) mutations. Similarly, only mild peripheral blood count abnormalities were observed in patients prior to transplant. Mildly larger mean corpuscular volumes and reduced platelet counts were found in the cohort evaluated for telomere length testing.

Shortcomings of the current study include a lack of telomere length measurement for the entire cohort. Testing was restricted to those with a clinical suspicion of short telomere lengths and was not performed for those without a blood count abnormality or those who presented with sporadic (nonfamilial) disease. The true percentage of patients with short telomere lengths referred for lung transplantation at this site is unknown. The other major shortcoming is a lack of longitudinal follow-up. It will be important to determine in the future if increased scrutiny for subclinical bone marrow and liver abnormalities results in better outcomes or post-lung transplant survival.

This article falls on the heels of two reports of post-lung transplantation complications of telomerase mutation carriers with end-stage pulmonary fibrosis.10,11 Most adverse events were hematologic and led to transfusion support as well as adjustment of immunosuppressive medication dosages. It appears that the environmental effect of the immunosuppressant therapies can unmask a dyskeratosis congenita-like bone marrow failure in these patients. Therefore, short telomere lengths may be a clinically useful biomarker that demands a high suspicion and close vigilance for telomere-associated ailments, especially those affecting the bone marrow, after lung transplantation.

Since 2007, older patients with IPF compose an increasingly larger proportion of those undergoing lung transplantation in the United States. Because telomere length is associated with survival in IPF,12 short telomere lengths may identify those who should be referred for earlier transplantation evaluation. This study suggests that short telomere lengths may also predict subclinical bone marrow abnormalities, thus affecting candidacy for lung transplantation and leading to personalized immunosuppressant treatments. Future studies are needed to determine the generalizability of these findings. Thus, telomere length testing may lead to a new categorization of ILD that supervenes conventional histopathologic diagnoses, predicting extrapulmonary disease and resulting in a personalized approach to lung transplantation.

References

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-816. [CrossRef] [PubMed]
 
Cronkhite JT, Xing C, Raghu G, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178(7):729-737. [CrossRef] [PubMed]
 
Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13051-13056. [CrossRef] [PubMed]
 
Giri N, Lee R, Faro A, et al. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: case report and systematic literature review. BMC Blood Disord. 2011;11:3. [CrossRef] [PubMed]
 
Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-1326. [CrossRef] [PubMed]
 
Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557. [CrossRef] [PubMed]
 
George G, Rosas IO, Cui Y, et al. Short telomeres, telomeropathy, and subclinical extrapulmonary organ damage in patients with interstitial lung disease. Chest. 2015;147(6):1549-1557.
 
Diaz de Leon A, Cronkhite JT, Yilmaz C, et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest. 2011;140(3):753-763. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE. 2010;5(5):e10680. [CrossRef] [PubMed]
 
Borie R, Kannengiesser C, Hirschi S, et al. Severe hematological complications after lung transplantation in patients with telomerase complex mutations [published online ahead of print November 13, 2014]. J Heart Lung Transplant. doi:10.1016/j.healun.2014.11.010.
 
Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur Respir J. 2014;44(1):178-187. [CrossRef] [PubMed]
 
Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2(7):557-565. [CrossRef] [PubMed]
 

Figures

Tables

References

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-816. [CrossRef] [PubMed]
 
Cronkhite JT, Xing C, Raghu G, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178(7):729-737. [CrossRef] [PubMed]
 
Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13051-13056. [CrossRef] [PubMed]
 
Giri N, Lee R, Faro A, et al. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: case report and systematic literature review. BMC Blood Disord. 2011;11:3. [CrossRef] [PubMed]
 
Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-1326. [CrossRef] [PubMed]
 
Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104(18):7552-7557. [CrossRef] [PubMed]
 
George G, Rosas IO, Cui Y, et al. Short telomeres, telomeropathy, and subclinical extrapulmonary organ damage in patients with interstitial lung disease. Chest. 2015;147(6):1549-1557.
 
Diaz de Leon A, Cronkhite JT, Yilmaz C, et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest. 2011;140(3):753-763. [CrossRef] [PubMed]
 
Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE. 2010;5(5):e10680. [CrossRef] [PubMed]
 
Borie R, Kannengiesser C, Hirschi S, et al. Severe hematological complications after lung transplantation in patients with telomerase complex mutations [published online ahead of print November 13, 2014]. J Heart Lung Transplant. doi:10.1016/j.healun.2014.11.010.
 
Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur Respir J. 2014;44(1):178-187. [CrossRef] [PubMed]
 
Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2(7):557-565. [CrossRef] [PubMed]
 
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