FPF is estimated to account for at least 20% of patients with F-ILD [1]. A subset of FPF associates with short telomere length and genetic alterations in telomere-related (e.g., TERT, TERC, and RTEL1) and surfactant protein genes (e.g., SFTPA1, SFTPA2, SFTPB, and SFTPC). Conditions like IPF, chronic hypersensitivity pneumonitis (CHP), combined pulmonary fibrosis and emphysema, and PPFE are among some of the F-ILD associated with telomere biology disorders (TBD) and surfactant protein genetic alterations. These entities are indistinguishable from those with no genetic abnormalities. Furthermore, similar radiographic and histological findings may be the result of very different genetic alterations. Despite increasing recognition of the importance of genetic testing in F-ILD, its use is inconsistent. Increasing awareness and availability of clinical testing is therefore crucial.

In our study, we identified 6 patients (8%) with PPFE among a cohort of 70 individuals evaluated for FPF or early-onset lung fibrosis (manuscript under preparation), highlighting the prevalence of PPFE in this population. These PPFE patients were predominantly females, exhibited a lower FVC % predicted value, and had a higher likelihood of undergoing lung transplantation compared with the non-PPFE group. Although no significant differences were observed in the age at diagnosis, DLCO % predicted, or age at transplantation between the groups, the PPFE patients appeared to have more severe disease manifestations. However, due to the small sample size of the PPFE group, further research is necessary to validate these findings. The selection bias toward patients with a history of FPF or early lung fibrosis might have also influenced the observed severity of the disease.

Additionally, we found that five out of the six PPFE patients had evidence of TBD, either through shortened telomere length in peripheral lymphocytes or granulocytes (below the 10th percentile) or through the identification of pathogenic or likely pathogenic variants in telomere-associated genes. This is consistent with prior reports [9, 10]. Nunes et al. for example, described PPFE in 10.4% of patients with genetic-related pulmonary fibrosis [10]. Our findings underscore the variability in clinical presentation and the necessity for heightened clinical vigilance to identify TBD, as hallmark features like bone marrow failure, liver fibrosis, and early graying of hair may only manifest in a minority of affected individuals [11].

Interestingly, patient #6 in Table 2 who had a lung biopsy consistent with PPFE had a heterozygous pathogenic variant in the SFTPA2 gene. This genetic variant was also found in the patient's maternal first cousin. Although they shared the same genetic mutation, the cousin's lung biopsy revealed UIP, a diagnosis supported by lung histology. However, the radiographic pattern observed in the cousin was atypical for UIP, suggesting variability in the clinical presentation and radiological findings associated with the SFTPA2 variant. This case highlights the genetic complexity and phenotypic diversity of interstitial lung diseases, particularly within familial contexts. The presence of the same genetic variant in relatives, manifesting in different pulmonary pathologies and radiographic patterns, underscores the importance of genetic testing and comprehensive clinical evaluation in the diagnosis and management of familial pulmonary fibrosis and related conditions. Pathogenic variants in SFTPA1 and SFTPA2 are also associated with lung malignancy, like in this case, with the risk of lung cancer in this group estimated to be as high as 36% as compared to 13% for individuals with IPF [12].

Genetic evaluation in cases of PPFE provides additional insights into the pathophysiology of the disease and can guide management since patients with TBD and surfactant protein abnormalities have a worse decline in FVC, reduced transplant-free survival, and poorer outcomes than those with normal telomere length or absence of genetic abnormalities [3, 4, 13, 14]. Avoidance of immunosuppressive agents and radiation exposure is also important, especially for those with TBD, as they are associated with worse outcomes [13, 14]. While the role of antifibrotics (nintedanib and pirfenidone) in TBD needs further investigation, newer data suggest that antifibrotics can be used safely and help reduce FVC declined in patients with TBD-associated lung fibrosis [15].

In summary, the presence of PPFE, especially in patients with premature lung fibrosis or familial disease, should prompt telomere length analysis and genetic evaluation to identify potentially pathogenic variants in telomere and surfactant protein-related genes. Genetic testing provides additional insight beyond radiological and histological findings and could avoid unnecessary testing and invasive procedures such as lung biopsy. It also has an impact on patients’ management and outcomes, as patients with TBD are sensitive to immunosuppression and radiotherapy and may need specific screening for other disease manifestations like liver cirrhosis and hematological disorders in patients with TBD and lung cancer in those with surfactant protein abnormalities [14] Identifying pathogenic genetic variants also leads to appropriate genetic counseling for patients and at-risk relatives.