The first patient-centered scientific congress in the field of Greek respiratory medicine, Bridges of Pulmonology 2023, took place on June 2023, in Patras. The congress welcomed over 1000 participants on its hybrid platform ‘bridging’ specialized professionals from different medical fields and highlighting the importance of a modern holistic approach in the management of the respiratory patient. A wide spectrum of topics was discussed, some of which were focused on interstitial lung diseases (ILDs). We aim to summarize the scientific highlights of Bridges of Pulmonology 2023 in the field of ILDs, enriched with the latest literature review.

Despite their similar clinical presentation, fibrotic lung diseases of different cause may have different prognosis and management. Grouping ILDs with progressive fibrosing behavior remains challenging, given that the response to treatment and the risk of further progression may differ according to the underlying disease entity¹. On the other hand, splitting pulmonary fibrosis in order to apply personalized medicine has been hampered by the lack of clinically applicable molecular biomarkers linking endotypes with clinical phenotypes. Shedding light on the cellular and molecular mechanisms that generate and regulate fibrosis would be of great importance². Recently, single cell profiling data have revealed cellular changes and immune aberrations in the usual interstitial pneumonia (UIP) lung. Several cell populations, such as alveolar epithelial cells and endothelial capillary cells, are substantially reduced in the fibrotic lung parenchyma samples³. In contrast, aberrant basaloid cells, a previously unknown cell type co-expressing epithelial, basal, mesenchymal and senescence genes and highly expressing genes typically related to idiopathic pulmonary fibrosis (IPF), have been identified in the fibroblastic foci, but not in control donor lungs³. Ectopic bronchial vascular endothelial cells abound in the affected alveolar regions of remodeling in IPF, while these cells are limited to the normal airway circulation. This finding is consistent with the already described histological observation of ‘proximalization’ of the distal airways in IPF³. Moreover, peripheral blood and lung single-cell RNA data from patients with IPF demonstrated that the immune elements and the chemokine signaling pathways could differentiate progressors from non-progressors. Classical monocytes and regulatory T-cells are increased, while other lymphocytic populations are decreased in progressive IPF compared to stable. Combined evidence from lung and blood samples, associated specific cytokines receptors (CCR) and their ligands (CCL) with the accumulation of these cell types, such as CCR2/CCL7 for monocytes and CCR4/CCL17 and CCR8/CCL18 for regulatory T-cells, and a mechanism of lung-blood recruitment has been suggested⁴. Despite promising data, the future taxonomy of pulmonary fibrosis based on sequencing technology is still in its infancy.

The recently-introduced term ‘progressive pulmonary fibrosis’ (PPF) encompasses certain non-IPF ILDs that develop a progressive phenotype, as defined by clinical, functional and radiological criteria⁵. Both anti-fibrotic agents can decelerate disease progression, as measured by forced vital capacity (FVC) decline from baseline, but only nintedanib has received conditional recommendation for the treatment of PPF⁶. The identification of the predictors of disease progression, to integrate an individually tailored management approach in the context of personalized medicine is of paramount importance. UIP pattern is an independent predictor of acute exacerbations and disease progression in non-IPF ILDs⁷. In a cohort of 167 patients with rheumatoid arthritis-ILD (RA-ILD), the gradual decline of pulmonary function is worse in UIP pattern than nonspecific interstitial pneumonia⁸. Moreover, the extent of fibrotic features, the presence of honeycombing and traction bronchiectasis, as well as the elevated systolic pulmonary artery pressure >36.5 mmHg, are independent risk factors for mortality in IPF and other fibrosing ILDs^9,10. A substantial minority of patients with scleroderma-related-ILD (SSc-ILD) may present with a rapid, continuous pattern of FVC decline with several consecutive episodes of deterioration. The phenotype of rapid progressors includes early-onset diffuse cutaneous SSc, with elevated acute-phase markers and topoisomerase I antibody positivity¹¹.

With regard to recent advances in non-IPF ILDs treatment, both mycophenolate mofetil (MMF) and cyclophosphamide presented favorable results in lung function, imaging, and clinical presentation in symptomatic/progressive SSc-ILD, while MMF had a better toxicity profile¹². Additionally, improvement of skin thickening and FVC measurements were noticed in patients with SSc treated with rituximab¹³. Towards this direction, the RECITAL study showed non-superiority of rituximab compared to cyclophosphamide in progressive connective-tissue disease-ILDs (CTD-ILDs), and therefore, rituximab may be an alternative therapeutic choice in severe CTD-ILDs¹⁴; yet, the majority of these patients displayed an inflammatory imaging phenotype based on HRCT pattern. In the FOCUSSCED trial, tocilizumab stabilized lung function in a population of patients with early SSc-ILD with diffuse skin involvement, active disease and high inflammatory markers or platelet count¹⁵. Among anti-fibrotics, only nintedanib has been proved to reduce the annual rate of FVC decline in patients with SSc-ILD. Moreover, a subgroup analysis of SENSCIS trial suggests a possible benefit of nintedanib on top of MMF in SSc, along with a good safety profile¹⁶. Nintedanib’s safety profile and efficacy were also assessed on SENSCIS-ON trial favoring its long-term use¹⁷. On the other hand, there is a pressing need for further research about pirfenidone, as the unclassifiable ILD and RELIEF trials were limited by their small sample size and the non-significance level of their primary endpoint^18,19. These results may indicate pitfalls in current clinical practice, where treatment initiation occurs after FVC decline and thus, irreversible lung damage has already been installed.

Ongoing clinical trials could hopefully broaden the therapeutic horizons of ILDs by identifying potential molecular targets and novel effective agents. However, drug development can take years for a single asset, and therefore, acceleration of these processes could be a game-changer. Growing interest has been noted in enhanced methods to bring robust evidence particularly in heterogenous diseases requiring multiple concomitant therapies. A new approach to trial design, which is known as Randomized, Embedded, Multifactorial, Adaptive Platform (REMAP), will favor the assessment of multiple concurrent therapies. A flagship study designed before COVID-19 pandemic for the assessment of community acquired pneumonia (CAP), REMAP-CAP, successfully showed the effectiveness of various treatment options for COVID-19 patients as well. Towards this direction, the aim of REMAP-ILD, detailly presented in this congress, is to create an international platform for clinical trials that can accelerate the assessment of therapies for individuals with ILD²⁰. The primary endpoint is the FVC trajectory incorporating data from baseline, 12-month follow-up and any time points in between, indicating it as a better marker due to its easiness and frequency of measurement. The numerous medications that could be assessed simultaneously, the lower risk of individuals receiving ineffective therapy and the spectrum of patients with different types and stages of the disease, including rare forms, highlight a promising global modular adaptive trial.

In the era of personalized medicine, genetic screening could be a strong asset. During the last decades, intense research has elucidated pulmonary fibrosis genetic predisposition by the detection of numerous gene variants related to sporadic or familial fibrotic lung diseases²¹. Fibrogenic variants may reflect disease clinical characteristics, natural history and prognosis and may provide timely therapeutic approaches. Mutations in telomerase reverse transcriptase (TERT) and telomerase RNA(TERC) have been associated with multisystemic clinical syndromes, the telomeropathies, with concurrent hepatic, cutaneous or hematological disorders. Moreover, carriers of TERT and TERC pathogenic variations present pulmonary fibrosis of early onset and rapidly progressive course, with worse prognosis and worse outcomes after lung transplantation compared to non-carriers^22,23. Interestingly, the prognostic significance of the telomere related gene (TRG) variants is higher than the histopathological and clinical features²⁴. Additionally, higher incidence of lung cancer, usually adenocarcinomas, has been noticed in patients carrying pathogenic surfactant-related gene (SRG) variants. In carriers of SFTPA mutations, lung cancer is diagnosed more frequently and in younger ages than expected and coexists with pulmonary fibrosis in two-thirds of cases. The possible underlying mechanisms include promotion of necroptosis without apoptosis and deficit surfactant protein-A-associated anti-neoplastic properties²⁵. The mucin 5B promoter polymorphism has been associated with UIP pattern and may contribute to the early recognition of subclinical RA-ILD as part of a scoring system²⁶. Regarding the therapeutic implications, recent data suggest that antifibrotic agents are beneficial for patients with pathogenic TRG alleles²⁷. Clinical trials investigating the potential effect of the synthetic androgen Danazol in telomere related syndromes are currently in process²⁸. Gene-based strategies of restoring surfactant function or telomere length are in the development pipeline with growing therapeutic potential, and may present favorable clinical outcomes in the future^29,30.

The recently published European Respiratory Society statement on familial pulmonary fibrosis (FPF), suggests that genetic testing and counselling may be beneficial for: 1) patients with FPF, defined as having more than one relative of first or second degree with pulmonary fibrosis; 2) asymptomatic individuals with a recognized disease-causing allele in their family; 3) patients aged under 50 years with pulmonary fibrosis of unknown cause; and 4) patients with clinical characteristics suggestive of telomeropathy³¹. In the appropriate setting, genetic testing could be an option for patients with interstitial lung abnormalities, pretransplant patients or members of families where pulmonary fibrosis or lung adenocarcinoma appear through generations^32,33. The routinely analyzed gene panel includes SRGs and TRGs, while screening for single nucleotide polymorphisms is not currently suggested³¹. Considering the current lack of official guidelines, the implementation of genetic testing in clinical practice still presents major challenges. The availability of techniques, the funding requirements and the different legislation rules among countries comprise significant hurdles^33,34. Expertise in the field, along with a multidisciplinary approach, are prerequisites for the accomplishment and evaluation of the genetic analysis, and therefore, it can only be performed in highly specialized and fully equipped institutions^33,34. The psychosocial impact of ILD diagnosis or predisposition must be taken into consideration. Therefore, it is necessary that genetic testing be accompanied by genetic counselling and follow-up of the patients and relatives³³. The discovery of more genetic culprits, the elucidation of possible clinical and therapeutic implications of pathogenic variants in asymptomatic individuals and the demarcation of the role of genetic screening in the personalized management of pulmonary fibrosis, are anticipated future perspectives.

A multidisciplinary team approach will improve the management of the ILD patient. Of note, ongoing efforts to promote personalized medicine will hopefully enrich this effort. The presented findings and proposals for further research may inspire both senior and young investigators to create ‘bridges’ in order to better understand the upcoming challenges, prolonging survival, and improving patients’ quality of life.