Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 https://doi.org/10.1186/s12931-019-1084-0 RESEARCH Open Access Demographic and clinical profile of idiopathic pulmonary fibrosis patients in Spain: the SEPAR National Registry Estrella Fernández-Fabrellas1, María Molina-Molina2* , Joan B. Soriano3, José Antonio Rodríguez Portal4, Julio Ancochea3, Claudia Valenzuela3, Antoni Xaubet5ˆ and on behalf of the SEPAR-IPF National Registry Abstract Background: Little is known on the characteristics of patients diagnosed with idiopathic pulmonary fibrosis (IPF) in Spain. We aimed to characterize the demographic and clinical profile of IPF patients included in the IPF National Registry of the Spanish Respiratory Society (SEPAR). Methods: This is a prospective, observational, multicentre and nationwide study that involved 608 IPF patients included in the SEPAR IPF Registry up to June 27th, 2017, and who received any treatment for their disease. IPF patients were predominantly males, ex-smokers, and aged in their 70s, similar to other registries. Results: Upon inclusion, mean ± SD predicted forced vital capacity was 77.6% ± 19.4, diffusing capacity for carbon monoxide was 48.5% ± 17.7, and the 6-min walk distance was 423.5 m ± 110.4. The diagnosis was mainly established on results from the high-resolution computed tomography in the proper clinical context (55.0% of patients), while 21.2% of patients required invasive procedures (surgical lung biopsy) for definitive diagnosis. Anti-fibrotic treatment was prescribed in 69.4% of cases, 51.5% pirfenidone and 17.9% nintedanib, overall with a good safety profile. Conclusions: The SEPAR IPF Registry should help to further characterize current characteristics and future trends of IPF patients in Spain and compare/pool them with other registries and cohorts. Keywords: Anti-fibrotic treatment, Idiopathic pulmonary fibrosis, National registry, Spain, SEPAR Background shorter survival time, such as older age, smoking sta- Idiopathic pulmonary fibrosis (IPF) is a fatal, chronic tus (smokers and ex-smokers), lower body mass fibrosing interstitial pneumonia, of unknown aeti- index, more impaired pulmonary function (mainly on ology, which affects primarily adults older than 50 forced vital capacity, FVC, total lung capacity, TLC, [1–3]. Although there is a great variability in the oc- and diffusing capacity for carbon monoxide, DLCO), currence of IPF, possibly due to geographic and radiological findings (usual interstitial pneumonia, demographic differences, the most reliable data esti- UIP), a pattern or greater extent of fibrosis, and the mate a prevalence ranging approximately 13–20 per development of acute exacerbations or comorbidities, 100,000 inhabitants in women and men, respectively especially pulmonary hypertension and emphysema [4]. The IPF mean survival ranges between 2 and 4 [6–10]. The diagnosis of IPF requires the collabor- years from diagnosis for patients not receiving anti- ation of a multidisciplinary team of specialists to inte- fibrotic treatment [5]. Some factors have been identi- grate and interpret complex clinical information [11, fied to be associated with poorer prognosis and 12]. Anti-fibrotic treatments for IPF aim to slow down the disease progression and increase the sur- * Correspondence: mariamolinamolina@hotmail.com vival time [13, 14]. To date, there are two effective ˆDeceased 2 Interstitial Diseases Unit, Respiratory Department, Hospital Universitario de disease-modifying therapies, pirfenidone and ninteda- Bellvitge, Carrer de la Feixa Llarga, S/N, 08907 – L’Hospitalet de Llobregat, nib [2]. Besides the performance of clinical trials for Barcelona, Spain investigating the efficacy and safety of novel drugs, Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 2 of 10 observational studies from routine clinical practice are of predicted) at diagnosis, DLCO at diagnosis, anti-fibrotic also required for understanding the natural course of treatment (yes/no), proton-pump inhibitors (yes/no), re- the disease, and identifying differential patterns of ported comorbidities such as pulmonary emphysema (yes/ diagnosis and treatments [15–17]. Several national no) or pulmonary hypertension (yes/no), and smoking IPF registries have been created worldwide; however habits. The patient comorbidities were reported by each par- published results are still scarce [18–24]. The Spanish ticipant and the Charlson comorbidity index was calculated Society of Pneumology and Thoracic Surgery after including the data in the Registry. All statistical proce- (‘Sociedad Española de Neumología y Cirugía Torá- dures were performed by using SAS 9.4 software. cica’, SEPAR) started in 2012 a National IPF Registry aimed to know the clinical characteristics of IPF pa- Results tients, procedures for diagnosis, and the evolution of From 713 patients included in the SEPAR IPF National patients in Spain. The primary objective of the Registry, 105 were finally excluded (Fig. 1). Therefore, present study was to characterize the demographic the number of patients evaluable for the primary end- and clinical profile of IPF patients included in the point was 608. Regarding participating centres, 18 were SEPAR IPF National Registry, regardless of any re- interstitial lung disease (ILD) academic centres, and 10 ceived treatment. non-ILD academic centres [26]. Methods Registry patients Study design Demographics This prospective, observational, multicentre and nation- Patients were predominantly male (80.8%), with a mean age wide study involved patients with IPF who were included of 70.2 years (SD 9.2), a mean body mass index of 28.2 kg/ in the SEPAR IPF National Registry and received any m2 (SD 4.2), and ex-smokers (63.7%). Demographic and clin- treatment for their disease. A total of 28 public hospitals, ical characteristics of patients are shown in Table 1. Time widely distributed through Spain, participated in the from the onset of symptoms to diagnosis was 20.4 months study by including patients in the Registry. Patients were (SD 21.4). eligible if confirmed diagnosis of IPF. The diagnosis of IPF was based on criteria from international clinical Comorbidities guidelines [10]. Those cases receiving pirfenidone for at The Charlson comorbidity index was 3.5 (SD 1.7). Dia- least 12 months were analysed to evaluate treatment ef- betes mellitus with no target organ damage (15.8% of fects in the real-world clinical practice. Procedures were patients), chronic respiratory disease (15.6%), arterial in accordance with guidelines established in the Declar- hypertension (14%), gastroesophageal reflux (12.8%), ation of Helsinki, and with the principles of Good Clin- pulmonary emphysema (12.1%), and coronary artery dis- ical Practices. We have followed and endorsed the ease (8.6%) were the most frequent comorbidities. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidance for reporting observa- IPF characteristics tional evidence [24]. Each participating hospital obtained Regarding symptoms or signs indicative of IPF at the the ethic approval from the Human Research Ethics time of diagnosis, 89.6% of patients had inspiratory Committee. bibasilar crackles, 84.7% dyspnoea (mainly grade 2 or 1), 62.8% non-productive cough, and 29.4% digital Data collection and statistical analysis clubbing. The mean FVC was 77.6% of predicted (SD All pulmonologists from SEPAR were invited to partici- 19.4), mean DLCO was 48.5% of predicted (SD 17.7), pate in this IPF Registry. They collected the information mean TLC was 72.5% of predicted (SD 16.5), and the during routine visits, and uploaded data to the SEPAR 6-min walk distance (6MWD) was 423.5 m (SD 110.4; website, up to June 27th 2017 [25]. The first patient in- Table 2). cluded was in January 10th, 2012. Database lock oc- curred in October 5th, 2017. Continuous variables are Diagnostic procedures expressed as the mean, standard deviation (SD), whereas The high-resolution computed tomography (HRCT) was categorical variables as absolute and relative frequencies the most frequent procedure performed at diagnosis (%). Median survival time was determined including the (99.2% of patients), followed by pulmonary function tests corresponding 95% confidence interval (95% CI). Signifi- (98.3%), autoimmune serology (91.8%), chest radiog- cant prognostic factors associated with mortality were identi- raphy (81.7%), and the 6-min walking test (71.2%). The fied by using a backward Cox regression analysis (Hazard confident radiological UIP pattern was found in 65.4% of ratio, HR). Survival was analysed by Kaplan-Meier method- cases (Table 3). The definitive diagnosis of IPF was ology. Variables included in the analysis were: age, FVC (% established in the 55% of cases by the results of the Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 3 of 10 Fig. 1 Flowchart of patients. 608 patients were evaluable for the main objective of the study (IPF Spanish patient characterization). 231 patients that received pirfenidone for at least 12 months were analysed to evaluate safety of treatment and clinical features of this subgroup of cases HRCT in the proper clinical context (after evaluation by such as rehabilitation and lung transplant were performed ILD clinical and radiological experts). A multidisciplin- in 10.1 and 3.1%, respectively. ary discussion with the whole ILD committee was re- quired for definitive IPF diagnosis in 45% of cases; 21.2% Survival of patients that underwent surgical lung biopsy (surgical A total of 108 patients (17.8%) died during the follow- or transbronchial cryobiopsy), and 23.8% without biopsy. up, 88 male (81.48%) and 20 females (18.51%) (HR 1.5; 95% 0.94–2.3, p = 0.092) (Fig. 2a). The causes of death were: disease progression (45.4%), disease exacerbation Treatment approach (15.7%), lung cancer (5.6%), post-lung transplantation Patients were receiving pirfenidone (51.5%) or nintedanib (3.7%), and others /unknown (29.6%). The median sur- (17.9%) as disease-modifying therapies for IPF at inclusion vival time was 5.8 years (95 CI 4.8–6.6) since diagnosis. in the Registry. Main concurrent treatments were: proton- The DLCO at diagnosis was the only prognostic factor as- pump inhibitors (68.9%), oxygen therapy (21.5%), or oral sociated with mortality (HR 0.609; 95%CI 0.525–0.706). corticosteroids (17.8%). From 30.6% of cases not anti- A patient had 39.1% lower risk of death per 10 units of fibrotic treatment: 8.5% were > 85 years, 43.5% presented DLCO (%) increased. an FVC > 80%. Of those treated patients, 24.7% experi- enced at least one adverse event, such as gastrointestinal discomfort (14.0% of patients), anorexia/weight loss (5.9%), Patients receiving pirfenidone alteration of liver enzymes (3.3%), and photosensitivity A total of 231 patients received pirfenidone for at least (2.6%). The adverse event (AE) was the reason for discon- 12 months. Patients were predominantly male (79.7%), tinuing the treatment in 27 patients (4.4% of total): pirfeni- with a mean age of 68.2 years (SD 9.2), and ex-smokers done (n = 15), nintedanib (n = 11), or oral corticosteroids (68.4%; Table 4). In these patients, the definitive diagno- (n = 1). Recommended non-pharmacological treatment sis was established by results of the HRCT (52.2%), after Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 4 of 10 Table 1 Demographic and clinical characteristics of patients with idiopathic pulmonary fibrosis N available Total Gender (male/female), n 608 491 (80.8)/ 117 (19.2) Age, mean years (SD) 608 70.2 (9.2) a Weight mean kg (SD) 549 77.0 (14.2) Height mean cm (SD) b 547 165.0 (8.9) 2 b Body mass index, Kg/m (SD) 547 28.2 (4.2) Smoking habits, n (%) 608 Never-smoker 164 (27.3) Ex-smoker 382 (63.7) Smoker 54 (9.0) Charlson comorbidity index, mean (SD) c 563 3.5 (1.7) d Estimated 10-year survival, mean % (SD) 607 59.8 (29.6) Occupational exposure to, n (%) 608 Inorganic particles 131 (23.2) Organic particles 120 (21.4) Potentially harmful aerosols 63 (11.3) Family history, n (%) 608 IPF 57 (9.7) Other DILD 23 (4.2) Time from diagnosis to inclusion in the registry, mean years (SD) 608 1.7 (2.2) Months from the onset of symptoms to diagnosis, mean (SD) e 547 20.4 (21.4) Main comorbidities, n (%) 608 Diabetes mellitus with no target organ damage 89 (15.8) Other chronic pulmonary disease 88 (15.6) Gastroesophageal reflux 74 (12.8) Pulmonary emphysema 70 (12.1) Coronary artery disease 50 (8.6) Myocardial infarction 46 (8.2) Pulmonary hypertension 36 (6.2) Malignancies 30 (5.3) Sleep apnoea-hypopnea syndrome 29 (5.0) Peripheral vascular disease 24 (4.3) SD standard deviation, IPF idiopathic pulmonary fibrosis, DILD diffuse interstitial lung disease. Calculated over: a 549 patients, b 547 patients, c 563 patients, d 607 patients, e 547 patients undergoing the surgical lung biopsy (27.6%), or by multi- Safety profile disciplinary discussion (20.2%). Of patients receiving pirfenidone, 23.4% experienced at least one adverse event (Table 4). Of 231 patients receiv- ing pirfenidone, 15.2% had to modify the treatment dur- Changes in IPF characteristics ing the follow-up period. Reasons of treatment Patients receiving pirfenidone showed a stable lung modification (dose reduction n = 10, discontinuing the function in FVC (71.5% of predicted, SD 16.7) and treatment n = 9) were as follows: clinical worsening of DLCO (47.2% of predicted, SD 17.6) after 12 months disease (3.5%), AEs (2.2%) and requiring concomitant of treatment (compared with baseline, 74.1% of pre- medications (1.3%). dicted, SD 15.5 for FVC; and 47.4% of predicted, SD 16.9 for DLCO). The mean 6MWT distance was simi- Survival lar after 12 months of treatment (429.9 m, SD 117.4) Eight patients receiving pirfenidone (3.5%) died during than at baseline (425.5 m, SD 114.7). the first 12-month period of treatment. A total of 55 Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 5 of 10 Table 2 Clinical and laboratory findings of patients with Discussion idiopathic pulmonary fibrosis Limited information is available about the demographic n available Total and clinical profile of IPF patients in Spain, the diagnostic Pulmonary function tests, mean (SD) decision-making, and treatments for IPF in real-life set- FVC, L 580 2.6 (0.8) ting. To our knowledge, data from 7 national IPF registries have published so far [18–24]. While some IPF features FVC, % of predicted 584 77.6 (19.4) are common in all countries such as male predominance, FEV1, L 574 2.1 (0.6) mean age, and smoking history, other demographic and FEV1, % of predicted 578 81.8 (19.6) clinical data differ from other registries, especially mean FEV1/FVC, % of predicted 569 82.0 (9.5) FVC, DLCO and 6MWD at inclusion, or the basis for the Total lung capacity, L 416 4.4 (1.2) final diagnosis (Table 5). Probably, the heterogeneity of Total lung capacity, % of predicted 451 72.5 (16.5) data among registries would depend on the different methodology and type of centres. Some authors have thus DLCO adjusted for haemoglobin 285 8.8 (14.2) suggested creating a global IPF registry, or connecting DLCO, % of predicted 523 48.5 (17.7) current IPF networks, such as the ARIANE-IPF pan- kCO, % of predicted 458 74.9 (23.1) European IPF registry and biobank [28]. The goal of the PaO2, mmHg 215 68.0 (15.8) present study is to publish for the first time results from PaCO2, mmHg 213 38.6 (6.7) the Spanish IPF national registry on the profile of patients DA-aO2, mmHg 213 77.2 (15.7) with IPF in routine clinical practice. In agreement with international consensus, in most Oxygen saturation, % 416 94.9 (2.4) cases the diagnosis was based on typical HRCT images 6-min walking test, mean (SD) in the clinical context [11, 12, 29–32]. 45% of cases re- Distance, m 419 423.5 (110.4) quired a case-discussion by the whole ILD multidiscip- Autoantibodies in serum, n (%) 500 28 (5,6) linary committee. Walsh and colleagues showed a good Anti-dsDNA 482 27 (5.6) agreement for the IPF diagnosis between pulmonolo- Rheumatoid factor 500 18 (3.6) gists, independently of the type of centre (academic or non-academic centres), with higher concordance in ANCAs 500 10 (2.0) those cases with ILD MDT availability (32). The Fleisch- Anti-Sm 437 7 (1.6) ner Society recently stated that a confident IPF diagnosis Anti-SCL-70 429 3 (0.7) can be achieved when HRCT shows a typical or probable SD standard deviation, FVC forced vital capacity, FEV1 forced expiratory volume UIP pattern [12]. On the other hand, the MDT discus- in 1 s, DLCO diffusing capacity for carbon monoxide, kCO carbon monoxide transfer coefficient, PaO2 partial pressure of arterial oxygen, PaCO2 partial sion of each potential IPF case with probable, possible or pressure of arterial carbon dioxide, DA-aO2 difference in the alveolar-to-arterial inconsistent UIP pattern is recommended in the updated O2 gradient, anti-dsDNA anti-double-stranded DNA, ANCAs anti-neutrophil cytoplasmic antibodies IPF guideline (11). Once made the diagnosis of IPF, the treatment with anti-fibrotics should start as soon as possible [33]. In our study 51.5 and 17.9% of the partici- pants were receiving pirfenidone or nintedanib, respect- patients (23.8%) died during the follow-up. 87.3% ively. Besides this, some pulmonologists seem reluctant were male and 12.7% female (Fig. 2b). The median to treat patients with “mild” or “stable” disease, and thus survival time was 5.8 years (95 CI 4.2–9.2) since diag- they perform a wait and see approach, probably for nosis (Fig. 2c). Causes of death were: disease progres- avoiding potential AEs or due to misunderstanding by sion (32 patients, 58.2%), disease exacerbation (8 pulmonologists [34, 35]. An international survey re- patients, 14.5%), lung cancer (5 patients, 9.1%), and vealed that only 40% of patients with a confirmed diag- others /unknown (10 patients, 18.2%). nosis will receive anti-fibrotic treatment; and among Table 3 Results of different diagnostic procedures regarding usual interstitial pneumonia (UIP) pattern Confident UIP pattern Probable UIP pattern Indeterminate UIP pattern Alternative or no suggestive HRCT 65.4 (391/598) 25.3 (151/598) 7.7 (46/598) 1.6 (10/598) Possible UIP Probably UIP Surgical lung biopsy 85.5 (135/158) 8.2 (13/158) 2.5 (4/158) 0.6 (1/158) Lung cryobiopsy 51.2 (21/41) 14.6 (6/41) 9.8 (4/41) 12.2 (5/41) HRCT high-resolution computed tomography, UIP usual interstitial pneumonia Data are presented as percentage of patients (n/ N available) Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 6 of 10 Fig. 2 Mortality and survival analyze depending on gender and pirfenidone treatment. a No statistically significant higher mortality was observed in males (HR 1.5; 95% 0.94–2.3, p = 0.092). b There was no statistically significant difference in mortality among pirfenidone treated patients depending on gender (HR 1.6; 95% 0.86–3, p = 0.139. c Survival time (weeks) analyzed by gender and pirfenidone treatment was not statistically different untreated patients, 45% receive no treatment at all [34]. patients had family history of IPF, and 55.9% of pa- Another survey has recently shown that pulmonologists tients experienced occupational exposures (inorganic, who initiated the anti-fibrotic treatment after more than organic particles, or potentially harmful aerosols). In 4 months of patient’s diagnosis (46% of total) saw fewer this line, diverse studies have reported an increased patients and had less confidence in the treatment than risk of UIP in workers exposed to fumes, metal or or- those who initiated it in ≤4 months [36]. On the other ganic dust [42, 43]. hand, patients with IPF have a higher risk of developing We aimed to describe pirfenidone in clinical practice be- comorbidities [37]. In our study, 12.8% of our patients cause it was the first anti-fibrotic available in Spain (more had gastro-oesophageal reflux, 12.1% pulmonary emphy- than 2 years before nintedanib). In our Registry, up to 313 sema, 8.6% coronary artery disease, and 6.2% pulmonary patients (51.5%) received treatment with pirfenidone. Des- hypertension. It is interesting to note the low number of pite the proven effectiveness of pirfenidone [34], when re- cases of gastro-oesophageal reflux or cardiovascular dis- ceiving treatment, there is always a subgroup of patients ease, compared with literature. Previous studies have who experience inadequate response to therapy. Patients shown a prevalence of 87 and 66% for gastro- who continue treatment with pirfenidone after having dis- oesophageal reflux and coronary artery disease in IPF, ease progression by month 6 of treatment have a lower respectively [38, 39]. Some studies have demonstrated an risk of FVC decline or death during the subsequent 6 association between decreased disease progression and months of treatment [44]. For this reason, it seems recom- longer survival time and the treatment of gastro- mendable to maintain the treatment with pirfenidone for, oesophageal reflux with antacid [40]; whereas other have at least, 12 months. In our study 8 patients (3.5%) experi- not so [41]. In our study, the high percentage of patients enced clinical worsening during the treatment with pirfe- receiving proton-pump inhibitors (65.3%) does contrast nidone, and 9 patients (3.9%) discontinued treatment. with the low percentage of patients diagnosed with This percentage of discontinuation is slightly lower than symptomatic gastro-oesophageal reflux. One explanation previous studies, such as CAPACITY (7.5 and 5.8% of pa- is that these treatments were prescribed at the time of tients), or ASCEND (16%) [45, 46]. It is interesting to note IPF diagnosis, before the beginning of the “anti-fibrotic” that in our study the median survival rate of total patients era. Furthermore, in our study, approximately one in ten and those receiving pirfenidone was similar (5.8 years). Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 7 of 10 Table 4 Demographic and clinical characteristics of patients with idiopathic pulmonary fibrosis receiving pirfenidone N available Total Gender (male/female), n (%) 231 184 (79.7)/ 47 (20.3) Age mean years (SD) 231 68.9 (8.4) Smoking habits, n (%) 231 Never-smoker 59 (25.9) Ex-smoker 156 (68.4) Smoker 13 (5.7) Time from diagnosis to inclusion in the registry, mean years (SD) 231 1.7 (2.1) Disease progression since onset of symptoms, mean months (SD) 211 22.7 (23.7) Time of treatment with pirfenidone, mean years (SD) 231 1.5 (1.1) FVC, mean % of predicted (SD) At baseline 226 74.1 (15.5) After 12 months of treatment 181 71.5 (16.7) DLCO, mean % of predicted (SD) At baseline 200 47.4 (16.9) After 12 months of treatment 150 47.2 (17.6) 6-min walk distance mean m (SD) At baseline 158 425.5 (114.7) After 12 months of treatment 55 429.0 (117.4) Diagnostic procedures, n (%) 231 High-resolution computed tomography 229 (99.6) Pulmonary function test 228 (98.7) Autoimmune serology 213 (94.2) 6-min walk test 173 (77.2) Surgical lung biopsy 78 (34.2) Lung cryobiopsy 14 (6.4) Adverse events related to pirfenidone, n (%) 231 54 (23.4) Gastrointestinal discomfort 22 (9.5) Anorexia/weight loss 18 (7.8) Photosensitivity 13 (5.6) Fatigue 10 (4.3) Dizziness 3 (1.3) Alteration of liver enzymes 2 (0.9) Others 9 (3.9) SD standard deviation, FVC forced vital capacity, DLCO diffusing capacity for carbon monoxide This result is in disagreement with other studies, such as pirfenidone. Finally, DLCO at diagnosis was the only factor the European Registry (EurIPFreg) which reported a sig- significantly associated with mortality. In our study, a pa- nificant improvement in survival rate in patients receiving tient had 39.1% lower risk of death per 10 units of DLCO anti-fibrotic treatment (mean 123.1 months; 83% of cases (%) increased. The impact of DLCO on survival has already with pirfenidone and 17% with nintedanib) after 7 years of been described in previous studies [47, 48]. In fact, some follow-up, comparing with patients not receiving it (mean indices combine DLCO together with FVC (the Gender 68.3 months) [24]. Although no definitive explanation can Age Physiology score) and with forced expiratory volume be provided, we suppose it is because pirfenidone has in 1 s (the Composite Physiological Index) for predicting been only available to patients with FVC < 80% for a long mortality [49, 50]. time in most of Spanish hospitals. This fact might have Main limitations of our study were intrinsically related limited the rate of survival in patients receiving to the retrospective nature of data collection in the first Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 8 of 10 Table 5 Main sociodemographic and clinical characteristics of patients from other National Registries Ω SEPAR IPF National INSIGHTS-IPF Finnish IPF Swedish IPF Indian IPF Australian IPF EMPIRE IPF EurIPFreg Registry [17] [18] [19] [20] [21] [22] [23] Country Spain Germany Finland Sweden India Australia Czech part Europe b Number of patients, n 608 502 111 71 148 647 514 525 Males, % 80.8 77.9 60.4 70.4 73.6 67.7 69.8 73.7 Age mean years 70.2 68.7 73.5 70.0 64.7 70.9 67.0 68.1 BMI mean Kg/m2 28.2 27.6 28.1 27.0 – 28.7 28.7 27.2 Ex-smoker, % 63.7 60.2 45.9 56.4 – 71.7 – 65.4 6MWD, mean m 423.5 267.6 – – 420 388 FVC, mean % of predicted 77.6 72.2 80.4 72.3 57.5 81.0 80.0 68.4 DLCO, mean % of predicted 48.5 35.5 57.3 52.1 – 48.4 45.6 42.1 Symptoms indicative of IPF at diagnosis, % Dyspnoea 84.7 85.9 44.7 a – – – – 90.1 Inspiratory bibasilar crackles 89.6 79.0 – – – – – 95.5 Cough 62.8 74.9 46.6 a – – – – 53.2 Procedures for definitive diagnosis, % HRCT 99.2 90.2 – 72 – – – – Surgical lung biopsy 26.5 34.1 – 14 – – – 32 → 8 c Multidisciplinary discussion 23.8 21.8 – 20 – – – – a From patients with available data; b EurIPFreg, the European IPF Registry has collected information of hospitals from Germany, France, United Kingdom, Italy, Spain, Hungary, and Czech Republic; c 32% in 2009 and 8% in 2016; Ω IPF patients are part of the interstitial lung disease registry completed in India SD standard deviation, BMI body mass index, 6MWD 6-min walk distance, FVC forced vital capacity, DLCO diffusing capacity of the lung for carbon monoxide, HRCT high-resolution computed tomography participants in the Registry (those diagnosed before patients in clinical trials (an exclusion factor for the 2011). Presumably, no available data would improve the present study) or prescribe antifibrotic medication. Re- knowledge in management of IPF in clinical practice. garding the 5.6% (19 male/9 female) of cases with low For example, we only collected information of treat- titter of non-specific positive auto-antibodies, all of them ments at the time of inclusion. There is thus a lack of in- had been evaluated by an expert rheumatologist, exclud- formation regarding when they actually received the ing the association with connective tissue diseases. Al- treatment or whether or not the patient received a new beit, only pulmonologists from ILD and non- ILD treatment during the follow-up. Another limitation de- specialist centres recruited the patients. Furthermore, rived from the heterogeneity of patients (including mild, this database was not established to evaluate the safety moderate and severe disease) and some uncertainty as- profile or effectiveness of pirfenidone, thus conclusions sociated with the diagnostic process, i.e. integrating in- given with reference to this should be made carefully. formation from different healthcare professionals, such Although a higher number of centres would strength re- as clinicians, thoracic radiologists, and pathologists; with sults and conclusions, our cohort of patients is represen- varying degrees of experience; and different sites (univer- tative of the whole population of patients with IPF in sity or non-university facilities, with or without access to Spain. This valuable information can be used in subse- multidisciplinary team meetings) [32]. Furthermore, we quent studies to build prediction models for Spanish pa- couldn’t identify those cases diagnosed based on disease tients with IPF. Another goal of the study is that all behaviour (working diagnosis), which probably could be patients derived from public hospitals, having the same part of the IPF cases without lung biopsy that required (free) access to procedures and medications. multidisciplinary discussion. In this regard, SEPAR has recently created a registry of Spanish hospitals according Conclusions to level of ILD expertise [27]. Differences in the access Demographic characteristics of patients from the to medications among Spanish regions may also contrib- SEPAR IPF National Registry are in accordance with ute to heterogeneity. Another limitation was that the other national registries. In agreement with inter- type of centre of recruitment (ILD specialist or non- ILD national guidelines, the diagnosis is mainly based on specialist academic centres) may have biased the results HRCT in the proper clinical context. A low percent- as ILD specialist centres could preferentially enrol age of patients require invasive procedures for the Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 9 of 10 definitive diagnosis. The treatment with pirfenidone Competing interests is generally safe and well tolerated, and most cases EF-F received funding for research grants and advisory boards from Hoffman-La Roche, Boeringher Ing., GSK, Chiesi, Esteve Teijin Healthcare. do not present disease progression after 12 months. Additional studies, including more patients and cen- Author details 1 tres to the Registry, are required to corroborate Pulmonology Department, Consorcio Hospital General Universitario, Valencia, Spain. 2Interstitial Diseases Unit, Respiratory Department, Hospital these results. This SEPAR IPF Registry should help Universitario de Bellvitge, Carrer de la Feixa Llarga, S/N, 08907 – L’Hospitalet to further characterize current characteristics and fu- de Llobregat, Barcelona, Spain. 3Pulmonology Department, Hospital ture trends of IPF patients in Spain, and compare/ Universitario de La Princesa, Madrid, Spain. 4Pulmonology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain. 5Pulmonology pool them with other registries and cohorts. Department, Hospital Clinic, Barcelona, Spain. Abbreviations Received: 7 February 2019 Accepted: 24 May 2019 95% CI: 95% confidence interval; AE: Adverse Event; DLCO: Diffusing Capacity for Carbon Monoxide; FVC: Forced Vital Capacity; HR: Hazard ratio; HRCT: The high-resolution computed tomography; ILD: Interstitial Lung Disease; IPF: Idiopathic pulmonary fibrosis; SD: Standard Deviation; SEPAR: National References Registry of the Spanish Respiratory Society; STROBE: The Strengthening the 1. Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty Reporting of Observational studies in Epidemiology; TLC: Total lung capacity; KR, Schwartz DA, Noble PW, Raghu G, et al. The clinical course of patients UIP: Usual Interstitial Pneumonia with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–7. 2. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017;389:1941–52. Acknowledgements 3. Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic Authors would like to thank to A. Xaubet for his contribution to the IPF pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19:32. Registry initiation. Authors would also like to express their gratitude to Roche 4. Ley B, Collard HR. Epidemiology of idiopathic pulmonary fibrosis. Clin Farma and Meisys for assisting in the preparation of the manuscript. The list Epidemiol. 2013;5:483–92. of additional researchers participating in the present SEPAR National Registry 5. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in is as follows (in alphabetical order): Aburto Barrenetxea, M. (Hospital idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431–440. Galdakao-Usansolo, Bizkaia); Alfageme Michavila, I. (Hospital Universitario 6. Erbes R, Schaberg T, Loddenkemper R. Lung function tests in patients with Virgen de Valme, Sevilla); Bollo de Miguel, E. (Complejo Asistencial idiopathic pulmonary fibrosis. Are they helpful for predicting outcome? Universitario de León, León); Cano, E. (Hospital Universitario Lucus Augusti, Chest. 1997;111:51–7. Lugo); Casanova Espinosa, A. (Hospital Universitario del Henares, Madrid); 7. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting Castillo Villegas, D. (Hospital de la Santa Creu i Sant Pau, Barcelona); Figuerola survival in idiopathic pulmonary fibrosis. Scoring system and survival model. Mendal, J.A. (Hospital Clínico Universitario Lozano Blesa, Zaragoza); García Am J Respir Crit Care Med. 2001;164:1171–81. Sevila, R. (Hospital General Universitario de Alicante, Alicante); Gaudó Navarro, 8. Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu JH. Body mass J.I. (Hospital Universitario Ramón y Cajal, Madrid); Gómez Carrera, L. (Hospital index and mortality in patients with idiopathic pulmonary fibrosis. Chest. Universitario La Paz, Madrid); González, J.M. (Hospital Universitario de 2007;131:1448–53. Salamanca, Salamanca); Herrera Lara, S. (Hospital Universitario Doctor Peset, 9. Sumikawa H, Johkoh T, Colby TV, Ichikado K, Suga M, Taniguchi H, Kondoh Valencia); Laporta Hernández, R. (Hospital Universitario Puerta de Hierro Y, Ogura T, Arakawa H, Fujimoto K, et al. Computed tomography findings in Majadahonda, Madrid); Marín González, M. (Hospital Clínico Universitario de pathological usual interstitial pneumonia: relationship to survival. Am J Valencia, Valencia); Nieto Barbero, M.A. (Hospital Clínico San Carlos, Madrid); Respir Crit Care Med. 2008;177:433–9. Portillo, K. (Hospital Universitari Germans Trias i Pujol, Barcelona); Romero, 10. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, A.D. (Hospital Universitario Virgen de las Nieves, Granada); Sánchez Simón- Cordier JF, Flaherty KR, Lasky JA, et al. An official ATS/ERS/JRS/ALAT Talero, R. (Hospital Universitario Nuestra Señora del Perpetuo Socorro, statement: idiopathic pulmonary fibrosis: evidence-based guidelines for Albacete); Sancho Chust, J.N. (Hospital Universitari Sant Joan d’Alacant, diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. Alicante); Sellarés Torres, J. (Hospital Clínic de Barcelona. Instituto del Tórax, 11. Raghu G, Remy-Jardin M, Myers J, Richeldi L, Ryerson C, Lederer D, Behr J, Barcelona); Soler Sempere, M.J. (Hospital General Universitario de Elche, Cottin V, Danoff S, Morell F, et al. Diagnosis of idiopathic pulmonary fibrosis. Alicante); Sauleda Roig, J. (Hospital Universitari Son Espases, Palma, Illes An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Balears); Tomás López, L. (Hospital Universitario de Araba. Txagorritxu. Álaba); Care Med. 2018;198:e44–68. Villanueva Montes, M. (Hospital San Agustin, Asturias). 12. Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, Goldin JG, Hansell DM, Inoue Y, Johkoh T, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Authors’ contributions Fleischner society white paper. Lancet Respir Med. 2018;6:138–53. EF-F, MM-M and JB participated in the study design. All authors contributed 13. Center for Drug Evaluation and Research (CDER), U.S. Food and Drug in the data acquisition. JB, JAR, JA and CV analysed the data. EFF and JB did Administration (FDA). The voice of the patient: a series of reports from the U.S. the manuscript drafting; and EFF and MMM performed the critical manuscript Food and Drug Administration's (FDA's) patient-focused drug development revision. All authors read and approved the final manuscript. initiative. [Accessed 03 June 2018]. Available from URL: http://www.fda.gov/ downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM440829.pdf. Funding 14. European Medicines Agency. Esbriet (Pirfenidone). CHMP assessment report. This study was funded by Roche Farma SA Spain. [Accessed 03 June 2018]. Available from URL: http://www.ema.europa.eu/ docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/ 002154/WC500103073.pdf. Availability of data and materials 15. Antoniou KM, Margaritopoulos GA, Siafakas NM. Pharmacological treatment The datasets used and/or analysed during the current study are available of idiopathic pulmonary fibrosis: from the past to the future. Eur Respir Rev. from the corresponding author on reasonable request. 2013;22:281–91. 16. Wuyts WA, Agostini C, Antoniou KM, Bouros D, Chambers RC, Cottin V, Egan Ethics approval and consent to participate JJ, Lambrecht BN, Lories R, Parfrey H, et al. The pathogenesis of pulmonary Each participating hospital obtained the ethic approval from the Human fibrosis: a moving target. Eur Respir J. 2013;41:1207–18. Research Ethics Committee. 17. Cordier JF, Cottin V. Neglected evidence in idiopathic pulmonary fibrosis: from history to earlier diagnosis. Eur Respir J. 2013;42:916–23. Consent for publication 18. Behr J, Kreuter M, Hoeper MM, Wirtz H, Klotsche J, Koschel D, Andreas S, Not applicable. Claussen M, Grohé C, Wilkens H, et al. Management of patients with Fernández-Fabrellas et al. Respiratory Research (2019) 20:127 Page 10 of 10 idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. 38. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE Eur Respir J. 2015;46:186–96. 2nd, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in 19. Kaunisto J, Kelloniemi K, Sutinen E, Hodgson U, Piilonen A, Kaarteenaho R, idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:136–42. Mäkitaro R, Purokivi M, Lappi-Blanco E, Saarelainen S, et al. Re-evaluation of 39. Nathan SD, Basavaraj A, Reichner C, Shlobin OA, Ahmad S, Kiernan J, Burton diagnostic parameters is crucial for obtaining accurate data on idiopathic N, Barnett SD. Prevalence and impact of coronary artery disease in pulmonary fibrosis. BMC Pulm Med. 2015;15:92. idiopathic pulmonary fibrosis. Respir Med. 2010;104:1035–41. 20. Ferrara G, Carlson L, Palm A, Einarsson J, Olivesten C, Sköld M. Idiopathic 40. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, pulmonary fibrosis in Sweden: report from the first year of activity of the Raghu G, Investigators IPF. Anti-acid treatment and disease progression in Swedish IPF-registry. Eur Clin Respir J. 2016;3:31090. idiopathic pulmonary fibrosis: an analysis of data from three randomised 21. Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, Singh N, Ho L, controlled trials. Lancet Respir Med. 2013;1:369–76. Samaria JK, Bhattacharya P, et al. Interstitial lung disease in India. Results of 41. Kreuter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, Weycker D, Spagnolo a prospective registry. Am J Respir Crit Care Med. 2017;195:801–13. P, Kirchgaessler KU, Herth FJ, et al. Antacid therapy and disease outcomes in 22. Jo HE, Glaspole I, Grainge C, Goh N, Hopkins PM, Moodley Y, Reynolds PN, idiopathic pulmonary fibrosis: a pooled analysis. Lancet Respir Med. 2016;4:381–9. Chapman S, Walters EH, Zappala C, et al. Baseline characteristics of idiopathic 42. Barber CM, Fishwick D. Importance of past occupational exposures in pulmonary fibrosis: analysis from the Australian idiopathic pulmonary fibrosis the rising incidence of idiopathic pulmonary fibrosis in the U.K. registry. Eur Respir J. 2017;49(2). https://doi.org/10.1183/13993003.01592-2016. Thorax. 2012;67:264–5. 23. Doubková M, Švancara J, Svoboda M, Šterclová M, Bartoš V, Plačková M, Lacina 43. Paolocci G, Folletti I, Torén K, Ekström M, Dell'Omo M, Muzi G, Murgia N. L, Žurková M, Binková I, Bittenglová R, et al. EMPIRE registry, Czech part: impact Occupational risk factors for idiopathic pulmonary fibrosis in southern of demographics, pulmonary function and HRCT on survival and clinical course Europe: a case-control study. BMC Pulm Med. 2018;18:75. in idiopathic pulmonary fibrosis. Clin Respir J. 2018;12:1526–35. 44. Nathan SD, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, 24. Guenther A, Krauss E, Tello S, Wagner J, Paul B, Kuhn S, Maurer O, Fishman RS, Glaspole I, Glassberg MK, Glasscock KF, et al. Effect of Heinemann S, Costabel U, Barbero MAN, et al. The European IPF registry continued treatment with pirfenidone following clinically meaningful (eurIPFreg): baseline characteristics and survival of patients with idiopathic declines in forced vital capacity: analysis of data from three phase 3 trials in pulmonary fibrosis. Respir Res. 2018;19:141. patients with idiopathic pulmonary fibrosis. Thorax. 2016;71:429–35. 25. STrengthening the reporting of OBservational studies in epidemiology (STROBE) 45. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, guidance for reporting observational research. [Accessed 03 June 2018]. Available King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, et al. Pirfenidone in patients from URL: http://strobe-statement.org/index.php?id=strobe-home. with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. 26. SEPAR Website. [accessed 03 June 2018]. Available from URL: https://www. Lancet. 2011;377:1760–9. separ.es/?q=node/233. 46. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg 27. Spanish Society of Pneumology and Thoracic Surgery (SEPAR). [Unidades MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, et al. A phase 3 trial of acreditadas de enfermedades pulmonares intersticiales difusas]. [Accessed pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 03 June 2018]. Available from URL: https://www.separ.es/?q=node/826. 2014;370:2083–92. 28. Ryerson CJ, Corte TJ, Collard HR, Richeldi L. A global registry for idiopathic 47. Kim HJ, Perlman D, Tomic R. Natural history of idiopathic pulmonary fibrosis. pulmonary fibrosis: the time is now. Eur Respir J. 2014;44:273–6. Respir Med. 2015;109(6):661-70. 29. Xaubet A, Ancochea J, Bollo E, Fernández-Fabrellas E, Franquet T, Molina- 48. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, Molina M, Montero MA, Serrano-Mollar A. Sociedad Española de King TE Jr, Lancaster L, Noble PW, Sahn SA, et al. Forced vital capacity in Neumología y Cirugía Torácica (SEPAR) research group on diffuse patients with idiopathic pulmonary fibrosis: test properties and minimal pulmonary diseases. Guidelines for the diagnosis and treatment of clinically important difference. Am J Respir Crit Care Med. 2011;184:1382–9. idiopathic pulmonary fibrosis. Sociedad Española de Neumología y Cirugía 49. Wells AU, Desai SR, Rubens MB, Goh NS, Cramer D, Nicholson AG, Colby TV, Torácica (SEPAR) research group on diffuse pulmonary diseases. Arch du Bois RM, Hansell DM. Idiopathic pulmonary fibrosis: a composite Bronconeumol. 2013;49:343–53. physiologic index derived from disease extent observed by computed 30. Raghu G, Lynch D, Godwin JD, Webb R, Colby TV, Leslie KO, Behr J, Brown tomography. Am J Respir Crit Care Med. 2003;167:962–9. KK, Egan JJ, Flaherty KR, et al. Diagnosis of idiopathic pulmonary fibrosis 50. Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli with high-resolution CT in patients with little or no radiological evidence of M, Elicker BM, Jones KD, et al. A multidimensional index and staging system for honeycombing: secondary analysis of a randomised, controlled trial. Lancet idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156:684–91. Respir Med. 2014;2:277–84. 31. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, McKean Publisher’s Note DF, Brown KK, Fingerlin TE, Schwarz MI, et al. CT scan findings of probable Springer Nature remains neutral with regard to jurisdictional claims in usual interstitial pneumonitis have a high predictive value for histologic published maps and institutional affiliations. usual interstitial pneumonitis. Chest. 2015;147:450–9. 32. Walsh SLF, Maher TM, Kolb M, Poletti V, Nusser R, Richeldi L, Vancheri C, Wilsher ML, Antoniou KM, Behr J, et al. Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case-cohort study. Eur Respir J. 2017;50(2). https://doi.org/10.1183/13993003.00936-2017. 33. Antoniou KM, Symvoulakis EK, Anyfantakis D, Wells AU. New treatments for idiopathic pulmonary fibrosis: ‘die another day’ if diagnosed early? Respiration. 2015;90:352. 34. Maher TM, Molina-Molina M, Russell AM, Bonella F, Jouneau S, Ripamonti E, Axmann J, Vancheri C. Unmet needs in the treatment of idiopathic pulmonary fibrosis-insights from patient chart review in five European countries. BMC Pulm Med. 2017;17:124. 35. Torrisi SE, Pavone M, Vancheri A, Vancheri C. When to start and when to stop antifibrotic therapies. Eur Respir Rev. 2017;26(145). https://doi.org/10. 1183/16000617.0053-2017. 36. Maher TM, Swigris JJ, Kreuter M, Wijsenbeek M, Cassidy N, Ireland L, Axmann J, Nathan SD. Identifying barriers to idiopathic pulmonary fibrosis treatment: a survey of patient and physician views. Respiration. 2018;96:514–24. 37. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J. 2015;46:1113–30.