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. 2022 Jan 24;8(1):00597-2021.
doi: 10.1183/23120541.00597-2021. eCollection 2022 Jan.

Epidemiology of interstitial lung diseases and their progressive-fibrosing behaviour in six European countries

Ole Hilberg  1 , Anna-Maria Hoffmann-Vold  2 , Vanessa Smith  3 , Demosthenes Bouros  4   5 , Maritta Kilpeläinen  6 , Julien Guiot  7 , Antonio Morais  8 , Susana Clemente  9 , Zoe Daniil  10 , Despina Papakosta  11 , Havard Fretheim  2 , Sofia Neves  12 , Tiago M Alfaro  13 , Katerina M Antoniou  14 , Neus Valveny  15 , Guus Asijee  16 , Stéphane Soulard  16 , Wim Wuyts  17
Affiliations

Epidemiology of interstitial lung diseases and their progressive-fibrosing behaviour in six European countries

Ole Hilberg et al. ERJ Open Res. .

Abstract

The PERSEIDS study aimed to estimate incidence/prevalence of interstitial lung diseases (ILDs), fibrosing interstitial lung diseases (F-ILDs), idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated ILD (SSc-ILD), other non-IPF F-ILDs and their progressive-fibrosing (PF) forms in six European countries, as current data are scarce. This retrospective, two-phase study used aggregate data (2014-2018). In Phase 1, incident/prevalent cases of ILDs above were identified from clinical databases through an algorithm based on codes/keywords, and incidence/prevalence was estimated. For non-IPF F-ILDs, the relative percentage of subtypes was also determined. In Phase 2, a subset of non-IPF F-ILD cases was manually reviewed to determine the percentage of PF behaviour and usual interstitial pneumonia-like (UIP-like) pattern. A weighted mean percentage of progression was calculated for each country and used to extrapolate incidence/prevalence of progressive-fibrosing ILDs (PF-ILDs). In 2018, incidence/105 person-years ranged between 9.4 and 83.6 (ILDs), 7.7 and 76.2 (F-ILDs), 0.4 and 10.3 (IPF), 6.6 and 71.7 (non-IPF F-ILDs), and 0.3 and 1.5 (SSc-ILD); and prevalence/105 persons ranged between 33.6 and 247.4 (ILDs), 26.7 and 236.8 (F-ILDs), 2.8 and 31.0 (IPF), 22.3 and 205.8 (non-IPF F-ILDs), and 1.4 and 10.1 (SSc-ILD). Among non-IPF F-ILDs, sarcoidosis was the most frequent subtype. PF behaviour and UIP-like pattern were present in a third of non-IPF F-ILD cases each and hypersensitivity pneumonitis showed the highest percentage of progressive behaviour. Incidence of PF-ILDs ranged between 2.1 and 14.5/105 person-years, and prevalence between 6.9 and 78.0/105 persons. To our knowledge, PERSEIDS is the first study assessing incidence, prevalence and rate of progression of ILDs across several European countries. Still below the threshold for orphan diseases, the estimates obtained were higher and more variable than reported in previous studies, but differences in study design/population must be considered.

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Conflict of interest statement

Conflict of interest: O. Hilberg has nothing to disclose. Conflict of interest: A-M. Hoffmann-Vold had a consultancy and medical writing relationship with Boehringer Ingelheim; received unrestricted grants from Bayer and Boehringer Ingelheim; received consulting fees from Actelion, Boehringer Ingelheim, ARXX and Medscape; received honoraria for lectures and presentations from Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly and Medscape; received support for attending meetings and/or travel from Actelion, Boehringer Ingelheim, Roche and Medscape; and was board member of EUSTAR and Nordic PH group. Conflict of interest: V. Smith received grants to research support, as senior clinical investigator from Research Foundation Flanders and Boehringer Ingelheim, research grant from Belgian Fund for Scientific Research in Rheumatic Diseases and educational grant from Janssen-Cilag; received consultancy fees from Boehringer Ingelheim; received honoraria for lectures, presentations, and speaker fees from Accord Healthcare, UCB, Boehringer Ingelheim and Janssen-Cilag; received support for attending meetings and/or travel from Celgene and Boehringer Ingelheim; and was chair (unpaid) to EULAR Study group on Microcirculation in Rheumatic Diseases, co-chair (unpaid) to ACR Study Group on Microcirculation and SCTC working group, and steering committee member (unpaid) to ERN-ReCONNET. Conflict of interest: D. Bouros received consulting fees from Boehringer Ingelheim; received honoraria from Boehringer Ingelheim, Roche and AstraZeneca; received support for attending meetings and/or travel from Boehringer Ingelheim and Roche; and received other financial or nonfinancial interests from Chiesi and ELPEN. Conflict of interest: M. Kilpelainen has nothing to disclose. Conflict of interest: J. Guiot has nothing to disclose. Conflict of interest: A. Morais has nothing to disclose. Conflict of interest: S. Clemente received payment for lectures and presentations and manuscript writing from Boehringer Ingelheim; and was ad hoc expert member of EMEA (January 2020). Conflict of interest: Z. Daniil has nothing to disclose. Conflict of interest: D. Papakosta has nothing to disclose. Conflict of interest: H. Fretheim has nothing to disclose. Conflict of interest: S. Neves has nothing to disclose. Conflict of interest: T.M. Alfaro received consulting fees from Boehringer Ingelheim and Roche; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and Roche; received support for attending meetings and/or travel from Boehringer Ingelheim and Roche; and participated on a Data Safety Monitoring Board or Advisory Board of Boehringer Ingelheim and Roche. Conflict of interest: K.M. Antoniou received consulting fees from Boehringer Ingelheim and Roche; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and Roche; received support for attending meetings and/or travel from Boehringer Ingelheim and Roche; and had leadership or fiduciary role in ERS Assembly 12 Secretary (unpaid). Conflict of interest: N. Valveny received funding to TFS for study conduction and medical writing from Boehringer Ingelheim and is employee of TFS. Conflict of interest: G. Asijee is employee of Boehringer Ingelheim. Conflict of interest: S. Soulard is employee of Boehringer Ingelheim. Conflict of interest: W. Wuyts received grants from Boehringer Ingelheim, Roche and Galapagos.

Figures

FIGURE 1
FIGURE 1
Study design. Grey squares correspond to primary outcomes and light blue squares to secondary outcomes. CTD-ILD: connective tissue disease-associated interstitial lung disease; F-ILD: fibrosing interstitial lung disease; HP: hypersensitivity pneumonitis; ILD: interstitial lung disease; iNSIP: idiopathic nonspecific interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; non-IPF F-ILD: fibrosing interstitial lung disease other than idiopathic pulmonary fibrosis; PF-ILD: progressive-fibrosing interstitial lung disease; RA-ILD: rheumatoid arthritis-associated interstitial lung disease; SSc-ILD: systemic sclerosis-associated interstitial lung disease; PPV: positive predictive value; IIP: idiopathic interstitial pneumonia; UIP: usual interstitial pneumonia. #: secondary outcomes of Phase 1 also included the relative percentage of each non-IPF F-ILD subtype. : unspecified ILDs and other ILDs with fibrosis, including ICD-10 codes J84.10 (Pulmonary fibrosis, unspecified) and J84.89 (Other specified interstitial pulmonary diseases), ICD-9 codes 515 (Postinflammatory pulmonary fibrosis) and 516.9 (Unspecified alveolar and parietoalveolar pneumonopathy) and keywords such as “interstitial pulmonary disease”, “lung fibrosis”, “fibrotic lung”, among others (see supplementary material Section A). +: also in Phase 2, a weighted mean percentage of PF behaviour was calculated for each country and used to extrapolate incidence and prevalence of PF-ILD. §: the PPVs obtained in each country were used to adjust the incidence and prevalence estimates obtained in Phase 1 and Phase 2.
FIGURE 2
FIGURE 2
Annual prevalence (per 105 persons) of ILDs in the participating countries during the study period (2014–2018). Areas show the widest variability observed in the primary plus sensitivity analyses. In Belgium, Greece, Norway and Portugal, this means the range between the minimum adjusted and the maximum crude estimates. In Denmark and Finland, there was only one participating centre that searched a national or regional database (respectively), so there were no reference and extended populations, but a single population (i.e. no maximum–minimum estimates, but a single estimate). In both countries, the area shows the range between the single crude and adjusted estimates. In Portugal, only one of the participating centres reported an extended population, and only for 2018. Therefore, minimum estimates could not be obtained for 2014–2017. For these years, the area shows the range from 0 to maximum crude estimates. ILDs: interstitial lung diseases; NA: not available.
FIGURE 3
FIGURE 3
Annual prevalence (per 105 persons) of F-ILDs in the participating countries during the study period (2014–2018). Areas show the widest variability observed in the primary plus sensitivity analyses. In Belgium, Greece, Norway and Portugal, this means the range between the minimum adjusted and the maximum crude estimates. In Denmark and Finland, there was only one participating centre that searched a national or regional database (respectively), so there were no reference and extended populations, but a single population (i.e. no maximum–minimum estimates, but a single estimate). In both countries, the area shows the range between the single crude and adjusted estimates. In Portugal, only one of the participating centres reported an extended population, and only for 2018. Therefore, minimum estimates could not be obtained for 2014–2017. For these years, the area shows the range from 0 to maximum crude estimates. F-ILDs: fibrosing interstitial lung diseases; NA: not available.
FIGURE 4
FIGURE 4
Annual prevalence (per 105 persons) of IPF in the participating countries during the study period (2014–2018). Areas show the widest variability observed in the primary plus sensitivity analyses. In Belgium, Greece, Norway and Portugal, this means the range between the minimum adjusted and the maximum crude estimates. In Denmark and Finland, there was only one participating centre that searched a national or regional database (respectively), so there were no reference and extended populations, but a single population (i.e. no maximum–minimum estimates, but a single estimate). In both countries, the area shows the range between the single crude and adjusted estimates. In Portugal, only one of the participating centres reported an extended population, and only for 2018. Therefore, minimum estimates could not be obtained for 2014–2017. For these years, the area shows the range from 0 to maximum crude estimates. IPF: idiopathic pulmonary fibrosis; NA: not available.
FIGURE 5
FIGURE 5
Annual prevalence (per 105 persons) of non-IPF F-ILDs in the participating countries during the study period (2014–2018). Areas show the widest variability observed in the primary plus sensitivity analyses. In Denmark and Finland, there was only one participating centre that searched a national or regional database (respectively), so there were no reference and extended populations, but a single population (i.e. no maximum–minimum estimates, but a single estimate). In both countries, the area shows the range between the single crude and adjusted estimates. In Belgium, Greece, Norway and Portugal, this means the range between the minimum adjusted and the maximum crude estimates. In Portugal, only one of the participating centres reported an extended population, and only for 2018. Therefore, minimum estimates could not be obtained for 2014–2017. For these years, the area shows the range from 0 to maximum crude estimates. F-ILDs: fibrosing interstitial lung diseases; IPF: idiopathic pulmonary fibrosis; NA: not available.
FIGURE 6
FIGURE 6
a) Incidence and b) prevalence of non-IPF F-ILD subtypes in 2018 (all countries). Minimum and maximum values show the widest variability observed in the primary plus sensitivity analyses (i.e. minimum adjusted–maximum crude) and across all participating countries. Countries where these minimum and maximum values were observed are indicated alongside data labels. CTD-ILD: connective tissue disease-associated interstitial lung disease; F-ILDs: fibrosing interstitial lung disease; HP: hypersensitivity pneumonitis; iNSIP: idiopathic nonspecific interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; RA-ILD: rheumatoid arthritis-associated interstitial lung disease; SSc-ILD: systemic sclerosis-associated interstitial lung disease; uIIP: unclassifiable idiopathic interstitial pneumonia.
FIGURE 7
FIGURE 7
a) Absolute number and b) relative percentage in each non-IPF F-ILD subtype, and c) relative percentage in total non-IPF F-ILDs of cases with PF behaviour only, UIP-like pattern only, both and none (all countries). Percentages were calculated based on the total number of cases for each subtype (a and b) or the total number of cases of non-IPF F-ILDs (c). Only centres participating in Phase 2 and reporting complete data were considered (number of cases reviewed in Phase 2 at each centre are shown in parentheses): Belgium – Leuven (100); Denmark – Lillebælt (100); Finland – Turku (166); Greece – Larissa (118) and Thessaloniki (100); Portugal – São João (131) and Beatriz Angelo (159). CI: confidence interval; CTD-ILD: connective tissue disease-associated interstitial lung disease; F-ILDs: fibrosing interstitial lung disease; HP: hypersensitivity pneumonitis; iNSIP: idiopathic nonspecific interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; PF: progressive-fibrosing; RA-ILD: rheumatoid arthritis-associated interstitial lung disease; SSc-ILD: systemic sclerosis-associated interstitial lung disease; uIIP: unclassifiable idiopathic interstitial pneumonia; UIP: usual interstitial pneumonia.
FIGURE 8
FIGURE 8
Annual prevalence (per 105 persons) of PF-ILDs in the participating countries during the study period (Primary analysis). Areas show the widest variability observed in the primary plus sensitivity analyses. In Belgium, Greece, Norway and Portugal, this means the range between the minimum adjusted and the maximum crude estimates. In Denmark and Finland, there was only one participating centre that searched a national or regional database (respectively), so there were no reference and extended populations, but a single population (i.e. no maximum–minimum estimates, but a single estimate). In both countries, the area shows the range between the single crude and adjusted estimates. In Portugal, only one of the participating centres reported an extended population, and only for 2018. Therefore, minimum estimates could not be obtained for 2014–2017. For these years, the area shows the range from 0 to maximum crude estimates. NA: not available; PF-ILDs: progressive-fibrosing interstitial lung diseases.
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