Original article

Idiopathic pulmonary fibrosis in a Swiss interstitial lung disease reference centre

DOI: https://doi.org/10.4414/smw.2018.14577
Publication Date: 04.01.2018
Swiss Med Wkly. 2018;148:w14577

Guler Sabina A.a, Zumstein Pascala, Berezowska Sabinab, Poellinger Alexanderc, Geiser Thomasa, Funke-Chambour Manuelaa

a Department of Pulmonary Medicine, University Hospital and University of Bern, Switzerland

b Institute of Pathology, University of Bern, Switzerland

c Department of Diagnostic, Interventional and Paediatric Radiology, University Hospital and University of Bern, Switzerland

Summary

BACKGROUND

Idiopathic pulmonary fibrosis (IPF) differs substantially from other idiopathic interstitial pneumonias regarding disease trajectory and the appropriate management strategies, making meticulous diagnosis essential. However, patient characteristics and clinical practice vary between clinical trials, and real life and registries provide the opportunity to critically analyse current clinical practices in order to ultimately improve patient care.

METHODS: We aimed to identify characteristics of our baseline IPF cohort at initiation of a web-based registry for patients with idiopathic interstitial pneumonia. Baseline and 6-month follow-up data from all consecutive IPF patients consulting at our centre over 2 years were analysed.

RESULTS

Forty IPF patients were included for baseline and 23 for longitudinal analysis. Besides many similarities to other IPF populations, our cohort included considerably fewer women. Forced vital capacity impairment in our cohort was more severe and mortality prediction poorer than in clinical trials, which emphasises the importance to confirm the applicability of clinical trial results with data from real life settings.

CONCLUSION

Registries for rare diseases such as IPF are a valuable resource for studying the course of the disease under current compliance with diagnostic and treatment guidelines and to appreciate local epidemiological particularities.

Keywords: idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, registry, real life practice, gender differences, cohort study

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonia (IIP) [1, 2]. Prompt and correct diagnosis of IPF is crucial, since antifibrotic drugs are approved for IPF only and its management differs from that of non-IPF IIPs [3, 4]. Although guidelines and national recommendations for diagnosis and treatment are available, real-life standards often diverge and information about regional discrepancies is sparse [58]. Specifically, in rare diseases, critical review of current standards by use of registry data can elucidate clinical reality and guide real-life practices.

The aim of this brief communication is to report characteristics of our baseline IPF cohort revealed at initiation of our web-based registry for patients with IIP.

Methods and results

We retrospectively analysed all consecutive IPF patients consulting at our Swiss reference centre over 2 years. Clinical data were collected and stored directly by means of electronic case report forms, with automatic plausibility checks, on a web-based platform (ALABUS®, Alabus AG, Zug, Switzerland).

Data on demographics, risk factors, comorbidities, medication, symptoms, physical examinations, pulmonary function tests, 6-minute walk tests, arterial blood gas analysis, chest computed tomography (CT) scans, bronchoscopy (including bronchoalveolar lavage), surgical lung biopsy, multidisciplinary discussion and current therapy (including oxygen) were assessed. For the 6-month longitudinal observation, we collected those parameters again, plus rate of hospitalisations, exacerbations, and death. Approval by the local ethics committee was obtained for data acquisition (Swiss Ethics Committee, Bern, approval number KEK 246/15 PB_2016-01524).

Forty patients met the inclusion criteria. Longitudinal data 6 months after the first data entry were available for 23 patients. Seventeen patients were referred only for a second opinion or were lost to follow up for other reasons. Patient characteristics including exposures, symptoms at presentation, diagnostic tests, comorbidities and ILD severity are reported in table 1.

Table 1

Patient characteristics at baseline including pulmonary function tests at follow-up.

DemographicsSex, male39 (98)
Race, Caucasian37 (88)
Age, years70 (43 to 85)
ExposuresEver smokers32 (80)
Smoked pack-years32.9 ± 16.6
Farming4 (10)
Welding4 (10)
Asbestos4 (10)
Birds (droppings/feather)3 (7.5)
Dust2 (5)
SymptomsDyspnoea only8 (20)
Cough only8 (20)
Dyspnoea and cough19 (47.5)
InvestigationsMultidisciplinary discussion20 (50)
Bronchoalveolar lavage19 (48)
Transbronchial biopsy6 (15)
Surgical lung biopsy19 (48)
Composite IndexGAP Index4.45 ± 1.72
GAP Stage I10 (26.3)
GAP Stage II20 (52.6)
GAP Stage III8 (21.1)
ComorbiditiesLung cancer3 (7.5)
Pulmonary hypertension7 (17.5)
Pulmonary embolism3 (7.5)
Arterial hypertension13 (32.5)
Coronary artery disease12 (30)
Obesity10 (25)
Obstructive sleep apnoea9 (22.5)
Gastroesophageal reflux8 (20)
Depression2 (5)
 BaselineFollow-upp-value#
FVC, L2.60 ± 0.832.46 ± 0.820.09
FVC, % predicted65.1 ± 17.460.5 ± 16.90.12
FEV1, L2.17 ± 0.672.08 ± 0.680.05
FEV1, % predicted70.7 ± 18.466.3 ± 18.60.09
FEV1/FVC, %84.1 ± 5.285.1 ± 7.20.58
DLCO3.89 ± 1.63.69 ± 1.20.09
DLCO, % predicted43.3 ± 17.940.7 ± 11.20.12

DLCO = diffusion capacity of the lung for carbon monoxide (ml/min/mm Hg/l); FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second; GAP = gender, age, physiology (FVC, DLCO)
Data are presented as n (%) or mean ± standard deviation/median (range)
* Pulmonary function data from our clinic available for 38 patients (2 tested externally).
# Paired t-test comparing baseline and 6-month follow-up in 23 patients with available data

Discussion

Interestingly, we found, that our IPF patients were almost exclusively men (98%), whereas other studies report a proportion of male patients ranging from 57% in Northern Italy, to 78% in Germany [917]. Compared with women, men are at greater risk of developing IPF, and have faster disease progress and an increased mortality [2, 18, 19]. Traditionally men more frequently chose occupations that are associated with dust exposures. Exposure to agricultural, wood, stone and several metal dusts has been shown to increase IPF risk, more so in male smokers [20, 21]. Nearly half of our patients reported occupational exposures and the majority were previous smokers. In Switzerland even now 30% of men and 24% of women smoke [22], although in the past this gender difference was more pronounced. Besides these exposure differences between genders, there are diverging theories hypothesising that the male predominance in IPF is due to differences in sex hormones, which has also been suggested by animal studies using the bleomycin model of lung fibrosis [23]. So far, no clinical studies on sex hormones as modulators of pulmonary fibrosis in humans are available. However, evidence on sex hormone receptor expression in fibrotic lung tissue is evolving [24]. The reason for the small number of women in our IPF population remains unclear; possible explanations are a regional underdiagnosis [25] or a more thorough exclusion of secondary causes of interstitial lung disease in women. Reasons for sex differences in IPF prevalence warrant further investigation.

Our IPF population had more severe lung function impairment (mean forced vital capacity [FVC] 65% predicted) compared with other registries and large clinical trial cohorts (FVC 71–82% predicted) [3, 9, 11, 26, 27]. Compared with our and other registries [9], the populations of the phase III pharmacological trials included more patients with GAP stage I (40%) and fewer with GAP stage III (9%) (GAP score based on gender, age, physiology) [26]. This indicates that patients in clinical trials have less severe disease and better prognosis compared with real life, and might suggest that our patients were diagnosed at later disease stages. Clinical trials on safety and efficacy of antifibrotic agents in real-world settings are emerging [28, 29] and further studies will hopefully confirm the benefit of antifibrotic medications in the general IPF population.

Age- and smoking-related comorbidities in IPF are highly prevalent and their management is challenging [30]. Comorbidities have a significant impact on quality of life, morbidity, and mortality, and even though IPF is a fatal disease every fifth IPF patient dies from unrelated causes [31]. In contrast to our observations, studies that specifically screen for comorbidities in their populations report higher prevalences [30, 3237], which highlights the importance of specific screening in populations at risk.

We diagnose IPF according to the current ATS/ERS guidelines [5] and as previously described in our interstitial lung disease centre [38]. We found only 50% of our IPF cases were diagnosed by formal multidisciplinary team discussion. Even though this team approach is considered the gold standard for diagnosis [5, 6], in real-life practice it is still implemented poorly with only about 20% of cases diagnosed in multidisciplinary conferences [9, 11]. Possible reasons are the high demand on time and resources, and the current lack of clear guidance on the format of an ideal multidisciplinary team discussion [3840].

Conclusion

We briefly summarised initial data from our local IPF cohort and the pilot study for an open-end, multicentre prospective observational cohort study including patients with IIP referred to specialised centres in Switzerland. Our data show that patient characteristics, diagnostic standards and treatments are mostly, but not in every aspect, consistent with international data and recommendations. Most strikingly, there are almost no women diagnosed with IPF in our cohort. Registries for rare diseases offer opportunities to evaluate the real-life situation and contribute to more effective care for our patients.

Acknowledgements

We thank Liselotte McEvoy and Sandra Mathier for the contribution to collection of registry data.

Author contributions

SG and PZ contributed equally to this manuscript. MF designed the study. SG, PZ, and MF made substantial contributions to conception of the study and contributed to acquisition of data, analysis and interpretation of data acquired, analyzed data and prepared the manuscript. SB, AP, and TG contributed substantially by critical revision for important intellectual content; all authors have given final approval of the version to be published.

Financial disclosure

Set up of the Bernese registry was initially financed with unrestricted grants from Intermune, Roche and Boehringer Ingelheim.

Competing interests

MF has received travel support, advisory board and speaker fees as well as research funding from Boehringer Ingelheim, Roche and Intermune. TG has received advisory and speaker fees from BI and Roche. SB received travel support and advisory board fees from MSD, Roche and Bristol-Myers Squibb outside the submitted work, and grants from AstraZeneca outside the submitted work.

Correspondence

Manuela Funke-Chambour, MD, Department of Pulmonary Medicine, Inselspital, University Hospital Bern, CH-3010 Bern, manuela.funke-chambour[ar]insel.ch

References

1 Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, et al.Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;157(1):199–203. doi:. http://dx.doi.org/10.1164/ajrccm.157.1.9704130 PubMed

2 Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431–40. doi:. http://dx.doi.org/10.1164/rccm.201006-0894CI PubMed

3 King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al.; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–92. doi:. http://dx.doi.org/10.1056/NEJMoa1402582 PubMed

4 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al.; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82. doi:. http://dx.doi.org/10.1056/NEJMoa1402584 PubMed

5 Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al.; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788–824. doi:. http://dx.doi.org/10.1164/rccm.2009-040GL PubMed

6 Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, Nicholson AG, et al.; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733–48. doi:. http://dx.doi.org/10.1164/rccm.201308-1483ST PubMed

7 Behr J, Günther A, Ammenwerth W, Bittmann I, Bonnet R, Buhl R, et al.S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose [German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. Pneumologie. 2013;67(2):81–111. Article in German. PubMed

8 Cottin V, Crestani B, Valeyre D, Wallaert B, Cadranel J, Dalphin JC, et al., Societe de Pneumologies de Langue Francaise. Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique. Élaborées par le centre national de référence et les centres de compétence pour les maladies pulmonaires rares sous l’égide de la Société de pneumologie de langue française [French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis. From the National Reference and the Competence centers for rare diseases and the Société de Pneumologie de Langue Française]. Rev Mal Respir. 2013;30(10):879–902. Article in French. doi:. http://dx.doi.org/10.1016/j.rmr.2013.09.007 PubMed

9 Behr J, Kreuter M, Hoeper MM, Wirtz H, Klotsche J, Koschel D, et al.Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. Eur Respir J. 2015;46(1):186–96. doi:. http://dx.doi.org/10.1183/09031936.00217614 PubMed

10 Moodley Y, Goh N, Glaspole I, Macansh S, Walters EH, Chapman S, et al.; Australian IPF Registry Steering Committee. Australian Idiopathic Pulmonary Fibrosis Registry: vital lessons from a national prospective collaborative project. Respirology. 2014;19(7):1088–91. doi:. http://dx.doi.org/10.1111/resp.12358 PubMed

11 Ferrara G, Carlson L, Palm A, Einarsson J, Olivesten C, Sköld M; for the Swedish Idiopathic Pulmonar. Idiopathic pulmonary fibrosis in Sweden: report from the first year of activity of the Swedish IPF-Registry. Eur Clin Respir J. 2016;3(1):31090. doi:. http://dx.doi.org/10.3402/ecrj.v3.31090 PubMed

12 Musellim B, Okumus G, Uzaslan E, Akgün M, Cetinkaya E, Turan O, et al.; Turkish Interstitial Lung Diseases Group. Epidemiology and distribution of interstitial lung diseases in Turkey. Clin Respir J. 2014;8(1):55–62. doi:. http://dx.doi.org/10.1111/crj.12035 PubMed

13 Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, et al.Interstitial Lung Disease in India. Results of a Prospective Registry. Am J Respir Crit Care Med. 2017;195(6):801–13. doi:. http://dx.doi.org/10.1164/rccm.201607-1484OC PubMed

14 Alhamad EH. Interstitial lung diseases in Saudi Arabia: A single-center study. Ann Thorac Med. 2013;8(1):33–7. doi:. http://dx.doi.org/10.4103/1817-1737.105717 PubMed

15 Hyldgaard C, Hilberg O, Muller A, Bendstrup E. A cohort study of interstitial lung diseases in central Denmark. Respir Med. 2014;108(5):793–9. doi:. http://dx.doi.org/10.1016/j.rmed.2013.09.002 PubMed

16 Harari S, Madotto F, Caminati A, Conti S, Cesana G. Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy. PLoS One. 2016;11(2):e0147072. doi:. http://dx.doi.org/10.1371/journal.pone.0147072 PubMed

17 Jo HE, Glaspole I, Grainge C, Goh N, Hopkins PM, Moodley Y, et al.Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry. Eur Respir J. 2017;49(2):1601592. doi:. Correction in: Eur Respir J 2017;49:1651592. doi:. http://dx.doi.org/10.1183/13993003.01592-2016 PubMed

18 Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994;150(4):967–72. doi:. http://dx.doi.org/10.1164/ajrccm.150.4.7921471 PubMed

19 Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol. 2013;5:483–92. doi:. http://dx.doi.org/10.2147/CLEP.S54815 PubMed

20 Baumgartner KB, Samet JM, Coultas DB, Stidley CA, Hunt WC, Colby TV, et al.; Collaborating Centers. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Am J Epidemiol. 2000;152(4):307–15. doi:. http://dx.doi.org/10.1093/aje/152.4.307 PubMed

21 Ekström M, Gustafson T, Boman K, Nilsson K, Tornling G, Murgia N, et al.Effects of smoking, gender and occupational exposure on the risk of severe pulmonary fibrosis: a population-based case-control study. BMJ Open. 2014;4(1):e004018. doi:. http://dx.doi.org/10.1136/bmjopen-2013-004018 PubMed

22 Keller R, Radtke T, Krebs H, Hornung R. Der Tabakkonsum der Schweizer Wohnbevölkerung in den Jahren 2001 bis 2010. Tabakmonitoring – Schweizerische Umfrage zum Tabakkonsum. Psychologisches Institut der Universität Zürich, Sozial- und Gesundheitspsychologie. 2011.

23 Tofovic SP, Zhang X, Jackson EK, Zhu H, Petrusevska G. 2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats. Vascul Pharmacol. 2009;51(2-3):190–7. doi:. http://dx.doi.org/10.1016/j.vph.2009.06.002 PubMed

24 Mehrad M, Trejo Bittar HE, Yousem SA. Sex steroid receptor expression in idiopathic pulmonary fibrosis. Hum Pathol. 2017;66:200–5. doi:. http://dx.doi.org/10.1016/j.humpath.2017.02.012 PubMed

25 Ancochea J, Miravitlles M, García-Río F, Muñoz L, Sánchez G, Sobradillo V, et al.Underdiagnosis of chronic obstructive pulmonary disease in women: quantification of the problem, determinants and proposed actions. Arch Bronconeumol. 2013;49(6):223–9. PubMed

26 Ley B, Bradford WZ, Vittinghoff E, Weycker D, du Bois RM, Collard HR. Predictors of Mortality Poorly Predict Common Measures of Disease Progression in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2016;194(6):711–8. doi:. http://dx.doi.org/10.1164/rccm.201508-1546OC PubMed

27 Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al.Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. 2016;113:74–9. doi:. http://dx.doi.org/10.1016/j.rmed.2016.02.001 PubMed

28 Cottin V, Maher T. Long-term clinical and real-world experience with pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev. 2015;24(135):58–64. doi:.. Corrected in: Eur Respir Rev. 2015;24(137):545. http://err.ersjournals.com/content/24/137/545.1. http://dx.doi.org/10.1183/09059180.00011514 PubMed

29 Hughes G, Toellner H, Morris H, Leonard C, Chaudhuri N. Real World Experiences: Pirfenidone and Nintedanib are Effective and Well Tolerated Treatments for Idiopathic Pulmonary Fibrosis. J Clin Med. 2016;5(9):78. doi:. http://dx.doi.org/10.3390/jcm5090078 PubMed

30 Kreuter M, Ehlers-Tenenbaum S, Palmowski K, Bruhwyler J, Oltmanns U, Muley T, et al.Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis. PLoS One. 2016;11(3):e0151425. doi:. http://dx.doi.org/10.1371/journal.pone.0151425 PubMed

31 King TE, Albera C, Bradford WZ, Costabel U, du Bois RM, Leff JA, et al.; Implications for the Design and Execution of Clinical Trials. All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. Am J Respir Crit Care Med. 2014;189(7):825–31. doi:. http://dx.doi.org/10.1164/rccm.201311-1951OC PubMed

32 Akhtar AA, Ali MA, Smith RP. Depression in patients with idiopathic pulmonary fibrosis. Chron Respir Dis. 2013;10(3):127–33. doi:. http://dx.doi.org/10.1177/1479972313493098 PubMed

33 Ozawa Y, Suda T, Naito T, Enomoto N, Hashimoto D, Fujisawa T, et al.Cumulative incidence of and predictive factors for lung cancer in IPF. Respirology. 2009;14(5):723–8. doi:. http://dx.doi.org/10.1111/j.1440-1843.2009.01547.x PubMed

34 Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu JH. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest. 2007;131(5):1448–53. doi:. http://dx.doi.org/10.1378/chest.06-2784 PubMed

35 Mermigkis C, Stagaki E, Tryfon S, Schiza S, Amfilochiou A, Polychronopoulos V, et al.How common is sleep-disordered breathing in patients with idiopathic pulmonary fibrosis?Sleep Breath. 2010;14(4):387–90. doi:. http://dx.doi.org/10.1007/s11325-010-0336-5 PubMed

36 Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al.High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136–42. doi:. http://dx.doi.org/10.1183/09031936.06.00037005 PubMed

37 Holland AE, Fiore JF, Bell EC, Goh N, Westall G, Symons K, et al.Dyspnoea and comorbidity contribute to anxiety and depression in interstitial lung disease. Respirology. 2014;19(8):1215–21. doi:. http://dx.doi.org/10.1111/resp.12360 PubMed

38 Guler SA, Berezowska SA, Christe A, Geiser T, Funke-Chambour M. Multidisciplinary discussion for diagnosis of interstitial lung disease in real life. Swiss Med Wkly. 2016;146:w14318. Available at: https://smw.ch/en/article/doi/smw.2016.14318/. PubMed

39 Flaherty KR, King TE, Raghu G, Lynch JP, Colby TV, Travis WD, et al.Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?Am J Respir Crit Care Med. 2004;170(8):904–10. doi:. http://dx.doi.org/10.1164/rccm.200402-147OC PubMed

40 Tomassetti S, Piciucchi S, Tantalocco P, Dubini A, Poletti V. The multidisciplinary approach in the diagnosis of idiopathic pulmonary fibrosis: a patient case-based review. Eur Respir Rev. 2015;24(135):69–77. doi:. http://dx.doi.org/10.1183/09059180.00011714 PubMed