Present and future perspectives in early diagnosis and monitoring for progressive fibrosing interstitial lung diseases

Abstract

Progressive fibrosing interstitial lung diseases (PF-ILDs) represent a group of conditions of both known and unknown origin which continue to worsen despite standard treatments, leading to respiratory failure and early mortality. Given the potential to slow down progression by initiating antifibrotic therapies where appropriate, there is ample opportunity to implement innovative strategies for early diagnosis and monitoring with the goal of improving clinical outcomes. Early diagnosis can be facilitated by standardizing ILD multidisciplinary team (MDT) discussions, implementing machine learning algorithms for chest computed-tomography quantitative analysis and novel magnetic-resonance imaging techniques, as well as measuring blood biomarker signatures and genetic testing for telomere length and identification of deleterious mutations in telomere-related genes and other single-nucleotide polymorphisms (SNPs) linked to pulmonary fibrosis such as rs35705950 in the MUC5B promoter region. Assessing disease progression in the post COVID-19 era also led to a number of advances in home monitoring using digitally-enabled home spirometers, pulse oximeters and other wearable devices. While validation for many of these innovations is still in progress, significant changes to current clinical practice for PF-ILDs can be expected in the near future.

Familial pulmonary fibrosis: Defining inherited fibrotic lung disease in the era of clinical genetic testing

“…In comparison, Cutting et al 5 conducted a similar multi‐site registry‐based study and reported that 25.1% met their definition of fPF, with others reporting similarly higher estimates (summarized in Table 1). These variable estimates largely arise from: (1) the varying and evolving criteria used to define fPF, which range from the requirement for a definitive diagnosis of IPF in a family member (Froidure et al 3 ) to a broader set of criteria encompassing other interstitial lung diseases (ILDs) and related syndromic conditions 5,9 ; (2) the necessary reliance on the presenting patient's knowledge of detailed medical histories of their family members; and to a lesser extent; (3) the inevitable variability introduced by differences in study design, ascertainment and population differences. Further, we know that of patients presenting with ‘sporadic’ PF, ~10% are subsequently reclassified as fPF, as familial medical histories are re‐visited over time.…”

“…Highlighting the heterogenous nature of fPF, there are conflicting reports regarding whether fPF patients experience a more rapid decline in lung function and poorer transplant‐free survival 5,9 . Froidure et al 3 report that despite fPF patients being younger, with less exposure to smoke and more likely to be prescribed antifibrotic therapies, their lung function decline and transplant‐free survival were similar to that observed in sporadic IPF patients.…”

“…Froidure et al 3 report that despite fPF patients being younger, with less exposure to smoke and more likely to be prescribed antifibrotic therapies, their lung function decline and transplant‐free survival were similar to that observed in sporadic IPF patients. Evidence is emerging that the nature of the underlying pathogenic variant influences age at diagnosis and disease course; however, further research is required to understand how the underlying genetic aetiology interacts with environmental exposures to drive the heterogeneity in patient presentation, prognosis and response to therapy 6,9 …”

“…Evidence is emerging that the nature of the underlying pathogenic variant influences age at diagnosis and disease course; however, further research is required to understand how the underlying genetic aetiology interacts with environmental exposures to drive the heterogeneity in patient presentation, prognosis and response to therapy. 6,9 The take home message is that, for the foreseeable future, clinicians are likely to be reliant on obtaining detailed family medical histories to deliver a diagnosis of fPF, with age at diagnosis on its own, of limited value. The average age of diagnosis even for those with pathogenic variants in telomere biology pathway genes is >50 years.…”

“…The average age of diagnosis even for those with pathogenic variants in telomere biology pathway genes is >50 years. 9,17 The European Respiratory Society has recently released a Statement on Familial Pulmonary Fibrosis 18 defining familial PF as 'any fibrotic ILD in at least two blood relative first-or seconddegree family members' signalling a shift towards capturing a broader spectrum of disease under the fPF umbrella. Zhang et al 15 and Terwiel et al 8 have also advocated the importance of generating detailed medical histories of relatives of patients focussing on both fPF-associated pulmonary disease, including lung cancer, in addition to extrapulmonary conditions in an effort to better identify fPF patients, but also to assist in the interpretation of genetic testing results.…”