Short Telomeres in Familial and Sporadic Fibrotic Interstitial Lung Diseases in Israel

Scientific Background Interstitial lung diseases (ILD) comprise a large heterogenic group of conditions which involve the lung parenchyma by inflammation, fibrosis, or both. Fibrotic ILD (FILD), which are characterized by evidence of lung fibrosis by either imaging studies (chest CT), and/or histopathology, may result from known exposures or association, or be idiopathic. Management of FILD depends on specific diagnosis, patient characteristics, and disease behavior. Some conditions may respond favorably to immunosuppression, while in others, such as idiopathic pulmonary fibrosis (IPF), such treatment may be harmful. Antifibrotic therapy may attenuate the progression of various FILD, including IPF, yet in many cases, disease progression ultimately leads to a fatal outcome or need for lung transplantation.

Telomeres are repetitive 6-nucleotide sequences which cap the end of chromosomes, and are essential in stabilizing chromosomes [1]. While they shorten with each cell replication, telomeres are maintained by complex mechanisms which can add nucleotide repeats (telomerase), and protect chromosomal ends by other mechanisms. Shortened telomeres may result from mutations in telomere related genes. Short telomeres have also been associated with single nucleotide polymorphism in those genes. Telomeres shorten with age, and are also shorter among males. Additional acquired factors also contribute to shortening, including harmful exposures, cigarette smoking, obesity, stress, lack of physical activity, and others [3-4].

Short leukocyte telomere length (LTL), i.e. <10th percentile adjusted for age, are common in patients with various FILD, with or without identifiable mutations in telomere related genes, both in familial and sporadic cases [5-6]. Short LTL has been associated with worse prognosis among subjects with several FILD, including faster deterioration of pulmonary functions tests, quicker disease progression, and shorter transplant-free survival [7-11]. In addition, IPF patients with short LTL had worse prognosis when exposed to immunosuppressive treatment [12], as were patients with other FILD commonly treated with immunosuppression [13]. Antifibrotic therapy, on the other hand, seems to be safe and effective [14].

This accumulating data has implications on the management of patients. Experts suggest testing for LTL in patients with familial pulmonary fibrosis, early age of disease onset, or with personal or family history of relevant extrapulmonary disease [8, 15]. Prompt initiation of antifibrotics, early referral for lung transplant and avoidance of immunosuppression have also been recommended [8, 16].

However, the prevalence of short LTL varies among ethnically diverse cohorts of FILD patients [7] and have never been assessed in the Israeli population.