A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?

Ageing and replicative senescence of alveolar epithelial stem cells are critical factors driving the development of idiopathic pulmonary fibrosis (IPF).¹ At birth, all stem cells in the human body have a pre-determined and finite capacity to divide and produce daughter cells. With every cell division this capacity is diminished until stem cells finally reach senescence. In the distal lung, senescent alveolar epithelial stem cells lack the capacity to repopulate damaged and denuded basement membrane and instead adopt a secretory phenotype, releasing growth factors that promote healing by fibrogenesis.²

Genetics and the environment influence the onset of cellular senescence. Individuals who work in dusty or smoky environments will, over a lifetime, experience an increased frequency of alveolar epithelial damage through the direct effect of inhaled injurious agents.³ Injury to the alveolus requires stem cells to undergo cell division to restore the damaged epithelial barrier, thus accelerating the onset of replicative senescence. Genes, primarily through their effect on the telomere complex (a length of repeating DNA found at the end of chromosomes, which interacts with a series of proteins that function to ensure integrity of DNA replication during cell division) determine the pre-ordained capacity of stem cells for replication.⁴ Broadly speaking, the longer an individual's telomeres, the greater the capacity of their stem cells to divide over a lifetime before reaching senescence. Genes and environment interact; an individual born with short telomeres at birth might develop IPF despite a healthy life, lacking any relevant exposures or injury to the lung. By contrast, an individual with long telomeres but, for instance, a history of occupational dust exposure might still develop pulmonary fibrosis.

Individuals with IPF have shorter telomeres in both lung epithelial cells and circulating leucocytes compared with unaffected individuals and frequently have telomeres that tend to lie in the lowest decile of length when assessed by age.^5-7 Furthermore, in genetic studies of patients with sporadic IPF, approximately 7%–10% of those studied have single-nucleotide polymorphisms affecting genes coding for telomere complex proteins.^{4, 8} IPF patients with telomere-related polymorphisms tend to have an earlier age of diagnosis and more rapidly progressive disease.⁸ Dyskeratosis congenita (DC), a genetic disorder characterized by mucocutaneous abnormalities, bone marrow failure and a predisposition to cancer, is now known to be caused by abnormalities affecting any of at least 18 genes related to telomere biology.⁹ Pulmonary fibrosis is recognized to occur in individuals with DC. Studies of DC family pedigrees have identified pulmonary fibrosis occurring in family members in the absence of other features of DC itself. The observation that abnormalities in telomere biology can trigger a range of organ manifestations across individuals has led to the adoption of the term ‘telomeropathies’ to describe this cluster of related disorders.

These insights have the potential to improve the diagnosis and management of individuals with IPF. Measurement of telomere length is technically challenging and remains predominantly in the research domain. Genotyping of patients with pulmonary fibrosis is becoming increasingly practical; however, access to genetic testing varies across territories and in many countries is not routinely reimbursed. In a recent publication in Respirology, Hoffman et al. explored the feasibility of using clinical features suggestive of telomeropathies to predict outcomes in a cohort of 409 patients with IPF.¹⁰ The features assessed included those related to the patient themselves (e.g., premature greying of the hair, liver cirrhosis, nail dystrophy, etc.), those related to family history (e.g., dyskeratosis congenita, bone marrow failure or liver cirrhosis, etc., occurring in up to a third degree relative) and laboratory features (e.g., anaemia, thrombocytopaenia, macrocytosis). Overall, 27% of the subjects assessed had one of these features and was judged to have a suspicion of having a telomeropathy. When telomere lengths were measured across the cohort, 26% of the individuals with suspicion for a telomeropathy had a telomere length below the first centile compared with only 10% in those without clinical suspicion. Furthermore, suspicion of a telomere syndrome was associated with poorer survival even after correcting for baseline differences in lung function.

Hoffman and colleagues are to be congratulated for developing a pragmatic clinical approach for identifying patients at high likelihood of having a telomeropathy and a consequently poorer prognosis. Their approach can be easily translated into clinical practice and has the potential for selecting patients in whom genetic screening should be performed and a cohort requiring closer follow-up and earlier assessment for transplant. The study does have some weaknesses; it was a single-centre retrospective study and it is possible that some clinical histories were incomplete. It is conceivable that a protocolized assessment of clinical details germane to telomere-related disease might have further improved the identification of at-risk individuals. The study lacked a validation cohort; thus, some caution should be applied in interpreting the results. The authors did not assess the impact of a suspicion of a telomeropathy on response to anti-fibrotic therapy; it therefore remains unknown whether identification of individuals at risk of a telomeropathy should trigger an alternative approach to therapy.

Premature telomere shortening and telomere-related genetic abnormalities are an important contributor to the development of disease in a sizeable minority of patients with IPF. In the absence of molecular tests, detailed clinical assessment combined with simple laboratory testing is sufficient to identify individuals at a higher likelihood of having a telomeropathy and a poorer prognosis. Prospective clinical studies are now needed to assess whether tailored therapy might improve outcomes for this group of individuals with poor prognosis disease.

CONFLICTS OF INTEREST

Toby M. Maher reports consulting fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Roche/Genentech, Theravance, Trevi and Veracyte; and speaking fees from Boehringer Ingelheim, Roche/Genentech and United Therapeutics.

LINKED CONTENT

This publication is linked to a related article. To view this article, visit https://doi.org/10.1111/resp.14264