Geographical, institutional and workplace variability in genetic evaluation, screening practices, multidisciplinary care, and lung transplantation management for familial interstitial lung disease

Abstract

Background

Advances in genetics have improved the understanding of risk factors for interstitial lung diseases (ILDs). However, geographical and institutional differences in genetic evaluation may affect clinical practice. We aimed to investigate how such variability influences access to genetic testing and screening, awareness of telomerase mutation–related symptoms, and the management of lung transplantation in familial ILD.

Methods

An expert panel of pulmonologists working in the field of ILD developed an international survey targeting pulmonologists involved in ILD care. The survey comprised 74 questions addressing diagnosis, screening, genetic testing methods, lung transplantation, and future research needs in familial ILD.

Results

In total, 237 pulmonologists representing 50 countries participated in the survey. Respondents from Europe, Oceania, and North America reported significant better access to genetic testing compared to the other continents. European respondents more often had a standardized screening program for first degree relatives than respondents from other continents. Having access to genetic testing significantly increased the likelihood of asking for a family history of early gray hair, liver cirrhosis, and bone marrow disease if a family history of ILD was present and in patients with idiopathic ILD younger than 50 years. Respondents from academic centers were significantly more likely than those from ILD centers to consider telomere length below the 10th percentile as a contraindication for lung transplantation. Respondents from non-academic centers were significantly less likely to treat patients with antifibrotic therapy compared to respondents from academic and ILD centers.

Conclusion

This study demonstrated significant differences in access to genetic testing, screening and genetic multidisciplinary teams as well as differences in the management of lung transplantation and antifibrotic therapy in familial ILD. These findings highlight the need for international collaboration to develop evidence-based guidelines for the management of familial ILD.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12890-026-04471-0.

Introduction

The pathology and risk of developing idiopathic pulmonary fibrosis (IPF) and other fibrotic interstitial lung diseases (fILDs) is incompletely understood; however, a genetic predisposition has been confirmed in some patients that have what is referred to as familial pulmonary fibrosis (FPF) [1–3]. It is estimated that up to 10–20% of patients suffering from IPF and fILD fulfill the criteria for FPF [2, 4–7]. Telomere-related genes (TRGs) and surfactant-related genes (SRGs) have been identified as the most common genetic variants associated with developing FPF and are usually the genes tested in FPF [3, 8]. In parallel, common variants such as the MUC5B promoter is associated with the risk of developing fibrotic ILD, including IPF, hypersensitivity pneumonitis, and rheumatoid arthritis-associated ILD [3, 8–10]. The MUC5B promoter variant is however not especially associated with familial fibrotic ILD. Consequently, the European Respiratory Society statement on FPF does not currently recommend MUC5B testing as part of the routine genetic evaluation of FPF [3]. Nevertheless, some experts advocate testing for MUC5B, particularly when no pathogenic variants are identified in TRG or SRG and FPF is suspected [3, 5]. Especially younger patients with pathogenic variants in TRG or SRG have an overall worse prognosis compared to patients without genetic background [3, 11–13]. Patients carrying pathogenic variants in TRGs may have a higher risk of infections on immunosuppressive treatment, particularly after lung transplantation [12, 14–16]. However, genetic testing is not incorporated in all ILD centers [3, 4]. Studies on these differences are lacking, and expert task forces have indicated a need for a standardized approach for genetic testing in FPF [3, 4].

Two recent international surveys found that pulmonologists and patients were in favor of genetic testing and screening for FPF but also discovered a lack of access to genetic testing and genetic multidisciplinary team meetings (MDT) [17, 18]. Studies investigating FPF and genetic MDTs found these meetings to strongly influence the patient treatment and management [19, 20]. Importantly, studies addressing potential barriers, reasons, and differences in availability for genetic testing are needed.

This study aimed, across regions, workplace settings, ILD expertise levels, and availability of genetic testing, to assess differences in:

1. Access to genetic testing, screening, and MDT involvement, as well as

2. Awareness of telomerase mutation–related symptoms and

3. Variations in lung transplantation management for FPF.

Methods

Survey design

The questions for the survey were created by an expert panel of pulmonologists working within the field of ILD based on the known literature of FPF. The survey was available online via SurveyMonkey from May to October 2023. Potential respondents were identified by the expert panel and invited via email. Before taking part, the participants were informed on the purpose of the study, confidentiality agreement, and gave their consent to be included in the study. Only limited data about the participants were collected to ensure anonymity.

The questions of the survey were divided into 8 topics: Respondent demographics, diagnosis of FPF, diagnosis and screening, screening tools, genetic testing, lung transplantation, treatment related to testing, and ethical concerns. Respondents were permitted to skip any question. Survey questions were structured in different formats (multiple-choice, closed- and open-ended questions, and the possibility to elaborate an answer in free writing). We have previously published the questionnaire used in this study and reported on the general results of the survey [18].

Data analysis

Respondents were divided into groups according to (1) workplace (non-academic center, academic center, or ILD center), (2) continent (Europe, North America, South America, Asia, or Oceania (Australia and New Zealand)), (3) ILD experience (≤ 10 years, 11–20 years, > 20 years), and (4) access to genetic testing. If a respondent worked in more than one center, the center with the highest level of specialization was chosen for the analyses.

For continuous variables not following a normal distribution, the following tests were used: (1) the Wilcoxon Mann-Whitney test for comparison of two groups, and (2) the Kruskal-Wallis test for comparison of several groups. For binary variables, the Chi-square test and the Spearman rank correlation were used as appropriate. Furthermore, odds ratios were calculated when comparing two binary outcomes.

P-values < 0.05 were considered statistically significant. Data were analyzed using STATA 14.2 (StataCorp, College Station, Texas). For selected questions prevalences are found in supplementary file 1.

Results

Study population

A total of 870 pulmonologists were invited to participate from 50 different countries, and 244 of these answered the survey, resulting in a response rate of 28%. Seven respondents were excluded (six did not work with ILD, and one respondent did not answer this question), resulting in 237 respondents eligible for analysis. Respondents were from Europe (50%), North America (19%), Asia (14%), Oceania (4%), and Africa (0.4%). Due to the low number of respondents from Africa, they were excluded from the analyses.

Many respondents had more than one workplace. Based on the workplace with the highest level of specialization, 37 (15.6%) worked at a non-academic center, 126 (53.2%) worked at an academic center, and 74 (31.2%) worked at an ILD Center.

Access to genetic testing, screening, and MDT involvement

Respondents from Europe and Oceania reported better access to genetic testing. Respondents from North America reported access levels in line with the overall average, whereas respondents from South America and Asia reported lower access (Table 1). When addressing access to genetic ILD MDTs, we found significant differences based on continent. Respondents from Europe had more frequent access, whereas respondents from North America had less access. Statistically significant differences were found for access to genetic ILD MDTs based on availability to genetic testing. Among those who had access to genetic testing, 61% had access to a genetic ILD MDT corresponding to an OR of 2.8 (95% CI 1.5–5.4). Furthermore, having access to genetic testing significantly increased the likelihood of a standardized screening program with an OR of 4.5 (95% CI 1.7–12.5). Similarly, European respondents more often had a standardized screening program for first degree relatives than respondents from other continents.

Table 1.

Differences in testing, screening and ethical concerns

	Workplacea	Continentb	Experiencec	Accessd
Do you have access to genetic testing?	0.12	< 0.001*	0.44	NA
Do you have access to genetic ILD multidisciplinary meetings?	0.90	0.010*	0.72	0.002*
Do you have a standardized screening program for a first degree relative with a pathogenic variant?	0.56	0.001*	0.52	0.001*
Will you refer ILD patients with otherwise unexplained ILD < 50 years of age without a family history of an interstitial lung disease for genetic testing and counseling?	0.10	0.0001*	0.98	< 0.001*
In case a pathogenic variant in the telomere-related gene or surfactant protein gene is found in the index patient, do you suggest genetic testing and counselling for first degree relatives?	0.95	0.001*	0.84	0.030*
How often do you discuss ethical concerns with patients before referral for genetic testing?	0.15	0.041*	0.33	< 0.001*
Do you perform a somatic evaluation as part of the screening program according to the nature of the mutation/syndrome? **	0.26	0.033*	0.16	0.001*

All results in the table are presented as p-values

NA Not appicable

* Statistically significant result (p-value below 5%)

** Cutaneous examination, premature greying of hair, nail dystrophy, oral leukoplakia, abnormal skin pigmentation and signs of liver cirrhosis

^a Non-academic center, academic center, or ILD center.

^b Europe, North America, South America, Asia, or Oceania (Australia and New Zealand).

^c ILD experience (< 10 years, 11–20 years, > 20 years)

^d Access to genetic testing (yes/no)

Respondents from Europe and Asia would significantly more often refer ILD patients with otherwise unexplained ILD < 50 years of age without a family history of an ILD for genetic testing and counseling than respondents from the other continents. This difference was also statistically significant based on access to genetic testing. Similar results were discovered when investigating if respondents would suggest genetic testing for first degree relatives to patients with a TRG or SRG mutation.

We found a significant difference in discussion of potential ethical concerns before referral to genetic testing. Respondents from South America almost never engaged in such discussions whereas most respondents from all other continents initiated these discussions prior to referral for genetic testing. Ethical concerns were more often discussed with patients if respondents had access to genetic testing. Significantly more respondents from Europe performed a somatic evaluation as part of their screening program and in contrast, fewer from South America performed a somatic evaluation. Respondents with access to genetic testing performed somatic evaluations significantly more frequently than those without access, corresponding to an OR of 2.7 (95% CI 1.5–4.8).

Awareness of telomerase mutation–related symptoms

When asking ILD patients in general for a family history of early gray hair, no differences were observed regarding workplace, continent, experience or access to generic testing among the respondents (Table 2). However, respondents more often asked for a family history of liver cirrhosis and bone marrow disease if they had access to genetic testing compared to those without access. Similarly, significantly more respondents with access to genetic testing asked for a family history of early gray hair, liver cirrhosis, and bone marrow disease if a family history of ILD was present.

Table 2.

Differences in questions indicating extrapulmonary symptoms associated with telomerase complex mutations

	Workplacea	Continentb	Experiencec	Accessd
In general, for ILD patients. How often do you:
Ask about a family history of early grey hair?	0.63	0.13	0.74	0.11
Ask about a family history of liver cirrhosis?	0.75	0.15	0.77	0.0075*
Ask about a family history of bone marrow disease?	0.46	0.54	0.92	0.0039*
If a family history of ILD is present. How often do you:
Ask about a family history of early grey hair?	0.10	0.09	0.42	0.0018*
Ask about a family history of liver cirrhosis?	0.26	0.12	0.94	0.0035*
Ask about a family history of bone marrow disease?	0.15	0.20	0.15	0.0025*
For newly referred patients with an idiopathic ILD < 50 years. How often do you:
Ask about early grey hair?	0.20	0.0191*	0.38	0.0097*
Ask about unexplained liver cirrhosis?	0.37	0.0291*	0.17	0.0011*
Ask about bone marrow disease?	0.14	0.17	0.27	0.0026*

All results in the table are presented as p-values

* Statistically significant result (p-value below 5%)

^a Non-academic center, academic center, or ILD center

^b Europe, North America, South America, Asia, or Oceania (Australia and New Zealand)

^c ILD experience (< 10 years, 11–20 years, > 20 years),

^d Access to genetic testing (yes/no)

Approximately half of the respondents from Asia asked patients under 50 years with idiopathic ILD about early grey hair. In contrast, the majority of respondents from other continents inquired about early grey hair in these patients. Similarly, while most respondents from Europe, North America, and Oceania asked patients under 50 years with idiopathic ILD about unexplained liver cirrhosis, less than half of respondents from South America and Asia did so. Respondents with access to genetic testing significantly more often asked patients with idiopathic ILD < 50 years of age about early grey hair, unexplained liver cirrhosis, and bone marrow disease than those who did not have access.

Variations in lung transplantation management

Respondents from non-academic centers were less prone to treating patients with antifibrotic therapy compared to respondents from academic and ILD centers. Likewise, respondents from South America were less likely to treat patients with genetic mutations with antifibrotic therapy than respondents from Europe and Oceania who were more willing to treat with antifibrotics (Table 3).

Table 3.

Questions addressing lung transplantation and familial ILD drug treatment

	Workplacea	Continentb	Experiencec	Accessd
Lung transplantation and genetic variants
Will identification of a telomere-related gene mutation prevent the patient from lung transplantation at your center/collaborating transplant center?	0.77	0.297	0.86	NA
If telomere length is below the 10th percentile, will this prevent the patient from lung transplantation at your center/collaborating transplant center?	0.0375*	0.280	0.80	NA
Will identification of peripheral blood leukocyte telomere length below the 10th percentile, or a telomere-related gene mutation modify the protocol of treatment after lung transplantation at your center/collaborating transplant center?	0.14	0.048*	1.00	NA
Drug treatment of patients with genetic variants
Do you treat patients with a pathogenic variant in the telomere-related genes with immunomodulatory drugs?	0.62	0.309	0.57	NA
Do you treat patients with a pathogenic variant in the telomere-related or surfactant protein genes with antifibrotic therapy?	0.0112*	0.031*	0.25	NA .

All results in the table are presented as p-values

NA Not applicable

* Statistically significant result (p-value below 5%)

^a Non-academic center, academic center, or ILD center

^b Europe, North America, South America, Asia, or Oceania (Australia and New Zealand)

^c ILD experience (< 10 years, 11–20 years, > 20 years)

^d Access to genetic testing (yes/no)

Discussion

Our study demonstrated significant differences in access to genetic testing, screening, and genetic multidisciplinary teams, as well as in the management of lung transplantation and antifibrotic therapy among patients with FPF.

Studies have found that pulmonologists are generally positive towards implementation of genetic testing in ILD [17, 18], but that access to genetic testing and even more to genetic MDTs remains limited [18, 21]. We found respondents from Europe, Oceania, and North America reported better access to genetic testing compared to other continents. Potential explanations for this disparity could be socioeconomic differences, national legislation, and health insurance issues, prioritization in the different countries, different cultural backgrounds, and ultimately reflecting inequities in healthcare access. Expert statements and consensus guidelines recommend genetic testing and MDT involvement in the management of FPF patients [3, 4, 22], our findings may suggest that implementation of these guidelines in routine clinical practice remains challenging. Moreover, underrepresentation of certain regions in guideline development may further limit their feasibility and applicability in clinical settings worldwide and is an important area to further explore in future research projects.

Inequality in healthcare is recognized by the World Health Organization as a global issue of concern [23]. Selection bias in respondents, if based on access to genetic testing, might even lead to an underestimation of inequities in our findings.

Given the growing complexity of genetic contribution in ILD, genetic MDTs have been proposed to better advise patients with FPF and their relatives [19]. Therefore, it is concerning that among respondents with access to genetic testing, only 61% also reported access to a genetic MDT. This emphasizes the need for easier access, potentially to international MDTs, more research, and international collaboration on optimal management of these patients. In the analysis of standardized screening programs for first-degree relatives, both access to genetic testing and European respondent status were significantly associated with a higher likelihood of program implementation. This association may indicate an interaction effect, as respondents from Europe reported greater access to genetic testing.

It is well recognized that FPF patients tend to be younger and have a poorer prognosis [3, 24–26]. Furthermore, up to 75% of FPF cases lack an identifiable pathogenic gene variant, and this highlights an important challenge where FPF patients have negative testing results despite fulfilling the definition of FPF [3, 22]. This emphasizes the need for follow up, and standardized screening of first-degree relatives to facilitate early disease detection and to reassess genetic testing, as new gene variants are detected.

The genetics behind FPF is complex and may be part of broader syndromes, such as those caused by pathogenic variants in TRGs leading to telomere biology disorders [1, 3]. Extrapulmonary manifestations such as early grey hair, liver cirrhosis, and bone marrow disease, are well established indicators of TRGs and awareness of these signs is critical [14, 27, 28]. Overall, we found respondents significantly more frequently inquired about a family history of symptoms indicative of TRGs if they had access to genetic testing, both for ILD patients in general and in those with a family history of ILD. Similar results were seen for patients diagnosed with idiopathic ILD before the age of 50. However, we found no significant difference in how often respondents asked for a family history of early grey hair for ILD patients in general, regardless of working place, continent, experience, or access to genetic testing. These findings support the need for further education, guidelines, and improved knowledge on symptoms indicating telomere disease.

It is well established that FPF patients should be considered as potential lung-transplantation candidates, also when carrying a TRG mutation, as outcomes have been shown to be comparable to ILD patients without such mutations [3, 29–32]. In a previous study, we found 6–8% of respondents considered pathogenic genetic variants as a potential contraindication for transplantation [18]. Other studies have suggested that telomere length below the 10th percentile may negatively affect lung transplantation prognosis [31, 33]. FPF patients with short telomere syndrome may require adjusted immunosuppressive regimes to reduce hematological and renal complications post-transplant [3, 14, 15, 30].

Respondents from academic centers were more likely than those from ILD centers to consider telomere length below the 10th percentile as a contraindication for lung transplantation. These findings highlight the urgent need for global education efforts and formalized guidelines in this area and confirm the importance of the ongoing and awaited consensus statement on this topic from the International Society of Heart and Lung Transplantation.

We found respondents from academic and ILD centers were more inclined to treat FPF patients with antifibrotic therapy than those from non-academic centers. These findings are consistent with previous studies in ILD populations, which have similarly reported an association between workplace setting and the use of antifibrotic therapy [34, 35]. Notably, respondents from Europe and Oceania were more willing to treat FPF patients with antifibrotics. This is concerning, as international guidelines and recommendations recommend FPF patients to be managed with antifibrotic treatment similarly to patients with IPF or progressive pulmonary fibrosis [3, 36].

As previously stated, our survey has several limitations [18]. To ensure respondent confidentiality and privacy, all responses were collected anonymously, precluding verification of respondents’ identities and reported practices. Geographical representation was uneven, with relatively few responses obtained from Oceania and Africa. In addition, participants were recruited through the authors’ professional networks, and participation was voluntary. This recruitment strategy may have introduced selection bias by preferentially attracting clinicians and researchers with a particular interest in FPF and genetic testing. Consequently, the reported practices may not be representative of the broader global ILD community and may overestimate the implementation and availability of genetic testing in routine clinical practice.

Furthermore, as with all self-reported surveys, social desirability bias cannot be excluded. Respondents may have reported practices that are more closely aligned with perceived best practice recommendations than with actual clinical practice. Therefore, our findings should be interpreted as reflecting the perspectives and experiences of participating experts rather than providing an objective estimate of the global use of genetic testing in FPF. Although substantial geographic and institutional variation was identified, the study design does not allow robust assessment of the true worldwide prevalence of genetic testing practices. Such questions would be better addressed through registry-based, population-based, or other systematic data collection approaches.

Despite these limitations, the survey provides valuable international insights into current expert perspectives and reported practices regarding genetic testing in FPF and highlights important areas of variation, unmet needs, and opportunities for future harmonization of care.

Conclusions

In conclusion, we identified significant differences in access to genetic testing, screening, and genetic MDTs as well as in the management of lung transplantation and antifibrotic treatment in FPF patients. The result from our study calls for international collaborations to strengthen research, education, clinical guidelines, and access to genetic testing in ILD patients and relatives.

Abbreviations

ILD

Interstitial lung disease

MDT

Multidisciplinary team

IPF

Idiopathic pulmonary fibrosis

FPF

Familial pulmonary fibrosis

TRG

Telomere-related gene

SRG

Surfactant-related gene

Authors’ contributions

EVM: Conceptualization (lead); data curation (lead); project administration (lead); formal analysis (lead); investigation (lead); methodology (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). TP: Conceptualization (equal); data curation (lead); formal analysis (lead); methodology (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal). MK: Conceptualization (equal); formal analysis (equal); investigation (equal), methodology (equal); writing – review and editing (equal). WAW: Conceptualization (equal); formal analysis (equal); investigation (equal), methodology (equal); writing – review and editing (equal). MMM Conceptualization (equal); formal analysis (equal); investigation (equal), methodology (equal); writing – review and editing (equal). MW: Conceptualization (equal); formal analysis (equal); investigation (equal), methodology (equal); writing – review and editing (equal). JMØ: Conceptualization (equal); data curation (lead); formal analysis (lead); methodology (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal). SKW: Conceptualization (equal); data curation (lead); formal analysis (lead); methodology (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal). NMØ: Conceptualization (equal); data curation (lead); formal analysis (lead); methodology (equal); visualization (equal); writing – original draft (equal); writing – review and editing (equal) AM: Investigation (equal), writing – review and editing (equal). AT: Investigation (equal), writing – review and editing (equal). CJR: Investigation (equal), writing – review and editing (equal). FC: Investigation (equal), writing – review and editing (equal). IB: Investigation (equal), writing – review and editing (equal). JM Investigation (equal), writing – review and editing (equal). JL: Investigation (equal), writing – review and editing (equal). JMO: Investigation (equal), writing – review and editing (equal). LKT: Investigation (equal), writing – review and editing (equal). MFC: Investigation (equal), writing – review and editing (equal). MLA: Conceptualization (equal); formal analysis (equal); investigation (equal), methodology (equal); writing – review and editing (equal). RB: Investigation (equal), writing – review and editing (equal). SLW: Investigation (equal), writing – review and editing (equal). SR: Investigation (equal), writing – review and editing (equal). YK: Investigation (equal), writing – review and editing (equal). YHK: Investigation (equal), writing – review and editing (equal). EB: Conceptualization (lead); data curation (lead); supervision (lead); formal analysis (lead); investigation (lead); methodology (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). All authors approved the final manuscript to be published and were involved in critically drafting or assessing the content of this paper.

Funding

None do declare.

Data availability

The data that supports the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted in Denmark, and was a health science survey questionnaire, and was not subject to medical research involving human biological material. According to Danish Legislation no registration details were therefore required [37]. In this study, participants were not subject to procedures and participated voluntarily. To ensure the anonymity of the participants no email addresses were collected, participants were issued a code number, and limited data were collected. It was therefore exempted from research ethics approval according to Danish legislation [37]. Prior to participating in the survey, the respondents were informed on the study, handling of the data, and gave consent to participate when accepting to participate in the survey. All respondents were free to participate in the survey and skip any questions. The study was conducted in accordance with the Declaration of Helsinki, but was exempted for research ethics approval according to Danish legislation since this study was a health science survey questionnaire, and was not subject to medical research involving human biological material and all participants gave consent prior to participating and were kept anonymous [37].

Consent for publication

Not applicable.

Competing interests

Thomas Prior has received honoraria for steering committee of scientific meetings from Boehringer Ingelheim, support for attending international meetings from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim. Michael Kreuter has received grants and fees for consulting and lectures from BI, Roche, GSK and AstraZeneca. Wim A Wuyts has received grants or consultancy or speaker fees from Boehriner Ingelheim, Roche, Galapagos, Sanofi, Alentis, Pliant, Insilico, all payed to the institution. Maria Molina-Molina has received grants and fees for scientific advises from Boehringer, Roche, Ferrer and Chiesi. Marlies Wijsenbeek has received grants and fees for consulting and lectures from Astra Zeneca, Bristol Myers Squibb, Boehringer Ingelheim, Galapagos, Galecto, GSK, Hoffman la Roche, Horizon therapeutics, Kinevant Sciences, Molecure, Nerre Therapeutics, Novartis, PureTech Health, Thyron, Trevi, Vicore. Janne Møller has received honoraria for lectures and support for attending international meetings from Boehringer Ingelheim. Sissel Kronborg-White has received grants from Roche and fees for lectures from Boehringer Ingelheim, Daichii-Sankyo, AstraZeneca and travel support from Boehringer Ingelheim, Nanna Makholm Østergård has received grants and fees for consulting and lectures from Chiesi and Boehringer Ingelheim. Antonió Morias has received grants and fees for scientific advice or speaker fees from Roche, Boehringer Ingelheim, Bial, GSK and Sanofi-Aventis. Christopher J. Ryerson has received consulting fees from Boehringer-Ingelheim, Pliant Therapeutics, Astra Zeneca, Trevi Therapeutics, Veracyte and honoraria for lectures from Hofmann-La Roche and Boehringer-Ingelheim. Jesper Magnusson has received research grants from Boehringer-Ingelheim and consulting fees from Boehringer Ingelheim, AstraZeneca, Takada Pharma, Vicore Pharma Mallinckrodt, Chiesi Pharma and Unimedic Pharma. Joyce Lee has received grants from the NIH and Boehringer-Ingelheim, unrestricted research gift from Pliant and consulting fees from Blade, Boehringer Ingelheim, United Therapeutics, Astra Zeneca, Elima and Eleven P15. Justin Oldham have received consulting fees from Boehringer-Ingelheim and Roche. Lauren K. Troy have received speaker fees from Boehringer-Ingelheim and grant support from the NHMRC Centre of Research Excellence in Pulmonary Fibrosis. Manuela Funke-Chambour has received research support from BI, BMS, AstraZeneca, advisory board, consultancy fees from BI, MSD, GSK, Pfizer, Roche, Sanofi. Presentations: BI, Astra, GSK. Raphael Borie has received consulting fees from Boehringer-Ingelheim, Ferrer and Sanofi. Honoria for lectures from Boehringer-Ingelheim. Yasuhiro Kondoh serves as a consultant to Asahi Kasei Pharma Corp., Shionogi & Co.Ltd., Boehringer Ingelheim Co., Ltd., Janssen Pharmaceutical K.K., Healios K.K., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., received lecture fees from Asahi Kasei Pharma Corp., Shionogi & Co.Ltd., and Boehringer Ingelheim Co., Ltd., AstraZaneca K.K, Eisai inc., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Novartis Pharma K.k., outside the presentation work. Yet. H Khor has received grants from NHMRC Investigator Grant during the conduct of the study and non-financial support from the Air Liquide Healthcare outside the submitted work. Elisabeth Bendstrup has received fees for presentations for Boehringer-Ingelheim, Bristol Myers Squibb, AstraZeneca, Novartis. Advisory board meeting Boehringer-Ingelheim, travel support from Boehringer-Ingelheim. The other authors have nothing to disclose.