Chest
Volume 147, Issue 6, June 2015, Pages 1549-1557
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Original Research: Transplantation
Short Telomeres, Telomeropathy, and Subclinical Extrapulmonary Organ Damage in Patients With Interstitial Lung Disease

https://doi.org/10.1378/chest.14-0631Get rights and content

BACKGROUND

Human telomere disease consists of a wide spectrum of disorders, including pulmonary, hepatic, and bone marrow abnormalities. The extent of bone marrow and liver abnormalities in patients with interstitial lung disease (ILD) and short telomeres is unknown.

METHODS

The lung transplant clinic established a prospective protocol to identify short telomeres in patients with ILD not related to connective tissue disease or sarcoidosis. Patients with short telomeres underwent bone marrow biopsies, liver biopsies, or both as part of the evaluation for transplant candidacy.

RESULTS

One hundred twenty-seven patients met ILD categorization for inclusion. Thirty were suspected to have short telomeres, and 15 had the diagnosis confirmed. Eight of 13 (53') patients had bone marrow abnormalities. Four patients had hypocellular marrow associated with macrocytosis and relatively normal blood counts, which resulted in changes to planned immunosuppression at the time of transplant. Four patients with more severe hematologic abnormalities were not listed because of myelodysplastic syndrome (two); monoclonal gammopathy of unclear significance (one); and hypocellular marrow, decreased megakaryocyte lineage associated with thrombocytopenia (one). Seven patients underwent liver biopsies, and six had abnormal liver pathology. These abnormalities did not affect listing for lung transplant, and liver biopsies are no longer routinely obtained.

CONCLUSIONS

Subclinical bone marrow and liver abnormalities can be seen in patients with ILD and short telomeres, in some cases in the absence of clinically significant abnormalities in peripheral blood counts and liver function tests. A larger study examining the implication of these findings on the outcome of patients with ILD and short telomeres is needed.

Section snippets

Subjects

In September 2011, the lung transplant program at Brigham and Women's Hospital established clinical guidelines designed to increase the index of suspicion for short telomeres and associated disease(s) in patients referred for consideration of candidacy. Here, we report the results of this intervention. All patients with ILD and two or more visits to the program were included in the study cohort. Patients with sarcoidosis or connective tissue disease (CTD)-associated ILD were excluded. Patients

Diagnosis of ILD and Clinical Information

A review of medical records including CT scanning and existing surgical lung biopsy results was used to determine the diagnosis of ILD. Hematology, chemistry, and pathology results were obtained through a review of the computerized medical records.

Telomere Length by Flow Fluorescence In Situ Hybridization

Telomere length analysis in peripheral blood lymphocytes was performed with a Clinical Laboratory Improvement Amendments-approved test performed at Repeat Diagnostics Laboratory, Vancouver, Canada.16, 17 The control population for this test consisted of 835 subjects identified only by age and sex; no other demographic or medical information was available.17 The age distribution of the control population was as follows: 0 to 40 years, 398; 41 to 50 years, 80; 51 to 70 years, 155; and > 70 years,

Sequencing and Mutation Analysis

Seven subjects consented to genetic testing. Sequencing and mutational analysis for TERT and TERC were performed in a Clinical Laboratory Improvement Amendments-approved laboratory.

Statistical Analysis

Results are expressed as mean ± SD for n number of samples. Analysis of difference between groups was conducted using an analysis of variance, t test, or Fisher exact test as appropriate. A two-sided P value < .05 was used for statistical significance. All analysis was done using GraphPad Prism software (GraphPad 5.0).

Results

From September 2011 until December 2013, 127 patients met our preestablished inclusion criteria of ILD without evidence of sarcoidosis or CTD and at least two visits to our lung transplant clinic (Fig 1, Table 1). Most patients (60.6') were diagnosed with IPF. Based on our predefined screening criteria, 30 patients (23.6') were suspected of having short telomeres, and 22 of 127 (17.3') patients underwent telomere length testing. Eight patients did not undergo telomere testing for the following

Discussion

We report significant subclinical marrow and liver abnormalities in our cohort of patients with ILD and short telomeres referred for lung transplantation. This group of patients showed important bone marrow abnormalities, in some cases in the absence of clinically significant changes in peripheral blood counts.

Others have shown that short telomere syndrome can present with lower RBC counts, leukopenia, thrombocytopenia, abnormal liver function, increased MCV, and early graying.14 We used these

Conclusions

In summary, our study shows that predetermined noninvasive testing can identify a subset of patients with ILD who should be tested for short telomeres. Further, seemingly mild peripheral blood abnormalities were associated with significant bone marrow pathology and regenerative changes on liver biopsy. These results increase our understanding of telomeropathies and have potentially important implications for patients with interstitial lung disease. A larger study is indicated to further examine

Acknowledgments

Author contributions: S. E.-C. is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article. I. O. R., P. C. C., H. J. G., and S. E.-C. contributed to conception and design; G. G., Y. C., C. M., G. M. H., B. A. R., and S. E.-C. contributed to analysis and interpretation; and G. G., I. O. R., Y. C., C. M., P. C. C., B. A. R., H. J. G., and S. E.-C. contributed to drafting the manuscript for important intellectual content.

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    FOR EDITORIAL COMMENT SEE PAGE 1450

    Drs Goldberg and El-Chemaly contributed equally to this manuscript.

    FUNDING/SUPPORT: Dr El-Chemaly is funded by the National Institutes of Health (NIH) [Grant R21 HL119902-01] and the American Thoracic Society/American Lung Association foundation grant. Drs Hunninghake and Rosas are supported by the NIH [Grant R01 HL111024 to Dr Hunninghake and Grants U01HL105371 and P01HL114501 to Dr Rosas].

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

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