The Benefits of a Rapid Diagnostic Primary Care Circuit for Interstitial Lung Disease

The Benefits of a Rapid Diagnostic Primary Care Circuit for Interstitial Lung Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Benefits of a Rapid Diagnostic Primary Care Circuit for Interstitial Lung Disease G Bermudo, P Rivera-Ortega, V Vicens-Zygmunt, B Del Rio, S Bolivar, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7224984/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in npj Primary Care Respiratory Medicine → Version 1 posted 9 You are reading this latest preprint version Abstract Interstitial lung diseases (ILDs) are complex rare diseases that associate a delay in diagnosis and eventually poor prognosis. Early and accurate diagnosis could be crucial. This study aimed to evaluate the feasibility and benefits of a rapid diagnostic circuit for ILD. Methods : A training program for ILD identification and a direct referral diagnostic circuit to the ILD Unit of University Hospital of Bellvitge were established in primary care centers in the southern metropolitan area of Barcelona (Spain). ILD patients were diagnosed and followed-up until study completion, death or lung transplantation. Diagnostic, therapeutic and prognostic outcomes were compared to patients referred through the common circuit during the same period of time. Results : Of 123 patients referred directly from the primary care, 112 had ILD. The most common diagnosis were idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis. The main reasons for suspecting ILD were interstitial radiological features (74%) and abnormal lung auscultation (67%). Eighteen patients were asymptomatic. Compared with patients referred through the common circuit, there was a statistically significant reduction in the time from symptom onset to diagnosis (6 vs. 22.1 months, p < 0.01) and in the percentage of fibrosing ILD (55.9 vs 63.9%, p 0.36). Although patients from rapid circuit were older, they had better forced vital capacity and diffusing capacity for carbon monoxide at diagnosis (p 0.04) and lung biopsies were performed more frequently. More patients were elegible for lung transplant. Conclusions : Identifying potential patients with fibrotic ILD through rapid circuit working with primary care physicians is feasible and useful. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research primary care rapid circuit diagnostic delay interstitial lung disease pulmonary fibrosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Interstitial lung diseases (ILDs) represent a group of rare and complex conditions of both known and unknown origin. Fibrotic ILDs may progress despite standard treatments, leading to respiratory failure and early mortality [ 1 ]. The common fibrotic ILD is idiopathic pulmonary fibrosis (IPF), which is characterized by chronic, progressive and irreversible scarring of the lung. Main symptoms and signs of IPF and non-IPF progressive pulmonary fibrosis (PPF) include dyspnea, dry cough, inspiratory crackles, and finger clubbing [ 2 , 3 ]. A confident diagnosis is challenging and requires expert multidisciplinary teams which are not available in all hospitals [ 2 , 4 , 5 ]. The natural history varies considerably between patients but involves a decline in lung function and quality of life, eventually leads to death [ 6 ]. A delay of 1–3 years between symptom onset and diagnosis is frequently observed in fibrotic ILDs, mainly due to the limited awareness of primary care physicians about these types of rare diseases [ 5 – 10 ]. Delayed diagnosis of IPF and other fibrotic ILDs is associated with worse survival [ 5 , 7 , 11 , 12 ]. Furthermore, misdiagnosis of other respiratory diseases, such as asthma, and the futility of most empirical treatments initiated before diagnosis impact on the patient’s emotional state and healthcare resources. Finally, early intervention is crucial to improve ILD prognosis. Avoiding risk factors or identified causes and initiating antifibrotic drugs when necessary may modify the natural history of the disease, reducing mortality, and even preventing irreversible changes in induced fibrotic ILDs [ 12 – 16 ]. Although there are no specific biomarkers with predictive diagnostic or prognostic value, several studies are currently testing molecular, genetic, and epigenetic markers that will be useful even in the early stages of the disease [ 9 , 10 ]. Therefore, early diagnosis and optimal therapeutic management of fibrotic ILDs are more relevant than ever [ 4 , 5 , 9 ]. In this regard, lung auscultation for velcro-like crackles, which are strongly associated with the presence of pulmonary fibrosis, has been proposed as a feasible and sensitive measure to improve early detection [ 3 ]. However, most cases report a patient’s journey that starts receiving symptomatic treatment, including inhalers, in primary care centers [ 17 ]. After worsening despite treatment, patients are referred to a pulmonologist, who performs additional respiratory tests [ 5 , 6 , 7 ]. Once ILD is identified and the patient continues to worsen, referral to an ILD Unit at a tertiary center allows for multidisciplinary diagnosis [ 3 – 5 , 17 , 18 , 19 ]. Therefore, definitive diagnosis and therapeutic management usually take more than a year [ 6 , 7 ]. Although the time required for ILD diagnosis varies considerably by geographic area, delays occur at every stage of the diagnostic process, even after raising awareness about these rare diseases among the general population and healthcare workers [ 20 , 21 , 22 ]. Therefore, considering the relevance of existing rapid diagnostic pathways for oncological diseases to reduce diagnostic delay, a pilot program for rapid ILD diagnosis was established and analyzed in collaboration with primary care centers in our area. Methods Population and study design Our multicenter, observational, retrospective study included consecutive patients with newly diagnosed ILD between 2012 and 2015, with follow-up until 2022 at the ILD Unit of University Hospital of Bellvitge (HUB). Diagnosis and treatment were performed according to the American Thoracic Society/European Respiratory Society criteria by the multidisciplinary committee (MDT) [ 2 ]. This study was approved by the HUB Ethics Committee (PR413/18). It was conducted in accordance with the ethical principles of the Declaration of Helsinki and local legislation laws. Informed consent was obtained from each participant by the study investigator prior to data collection. Initially, a training program for clinical suspicion and identification of ILD patients was performed in 10 primary care centers staffed by general practitioners (GPs) focused on respiratory diseases. Chest radiologists from these centers were connected to the ILD radiological team at the HUB. As online clinical and radiological network was established. All ILD patients diagnosed through this circuit were recruited and followed-up until study completion, death or lung transplantation. Outcomes were compared wich those of patients referred through the common patient diagnostic circuit during the same period. These patients were referred from 12 hospitals for which the HUB is the referral center for complex diagnostic and therapeutic procedures, including rare respiratory rare diseases. The rapid diagnostic circuit was established through an ILD Unit’s email account that was reviewed every weekday. In addition, GPs faxed the case referral and information. If a primary care radiologist identified the case after evaluating a chest x-ray or high-resolution computed tomography (HRCT), they contacted the GP to activate the rapid diagnostic referral circuit. The common respiratory diagnostic circuit included email contact with the ILD Unit and an administrative referral by fax. Cases were referred by pulmonologists, internal medicine physicians, rheumatologists, thoracic surgeons, and emergency physicians from various hospitals. Collected data Baseline demographic and clinical characteristics were collected at diagnosis, including age, gender, smoking status/history, occupational and environmental exposures, respiratory symptoms and signs (crackles and nail clubbing), time to symptom onset, comorbidities, radiological high-resolution computed tomography (HRCT) pattern, final diagnosis, and treatment received. HRCT findings and radiological pattern were interpreted according to the recommendations of the Fleischner Society nomenclature commite [ 23 ]. Fibrotic ILD was defined radiologically as the presence of fibrosing features on chest HRCT that exceeded 5% of the total lung area. The lung function characteristics, such as forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO), 6-minute walk test (6MWT) and oxygen desaturation were also included. During the follow-up, clinical, functional and radiological data and use of antifibrotic treatment were recorded. Mortality, survival and lung transplantation were also recorded. Data from patients referred using both referral process (rapid and common diagnostic circuit) were compared. Statistical analysis Categorical data are described as frequency and percentages, and differences were evaluated using chi-squared test or Fisher’s exact test when required. For descriptive analysis, continuous and normally distributed variables are expressed as mean and standard deviation (SD). Differences in continuous variables were analyzed with ANOVA tests or Student’s t test, or their corresponding non-parametrical tests when required (Kruskal-Wallis and Mann-Whitney U tests). Time to event data (time to lung transplantation and/or death) were analyzed using Kaplan-Meier survival analysis and Cox proportional hazard regression for multivariable analyses. A p-value < 0.05 was considered statistically significant. Data were analyzed by using SPSS 27 (SPSS, IBM Corp). The recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative were followed [ 24 ]. Results Patient features at diagnosis A total of 726 new patients were referred to the HUB ILD Unit between 2012 and 2015. Of the 123 patients referred directly from primary care, 112 patients (91.05%) had ILD and 11 had other respiratory diseases such as cylindrical bronchiectasis or pulmonary edema (Fig. 1 ). These patients showed a mean age of 66.3 years (IQR 9.5), and 55.9% (SD 5.92) had fibrotic ILD. The main reasons for suspecting ILD in primary care were interstitial radiological features (74%) and auscultation of lung crackles (67%). A chest HRCT was performed before arrival to the ILD Unit in 81.05% patients. No invasive procedures were performed during the patient’s journey. The time from symptom onset (when present) to diagnosis was 6 months (SD 5) (Fig. 2 ). No respiratory symptoms were identified in 18 patients, although 2 of them presented with fibrosing ILD. The main diagnoses were IPF and fibrotic hypersensitivity pneumonitis (fHP) (Table 1 ). The median FVC was 89.61% (IQR 17.23) and DLCO was 68.72% (SD 17.89). Up to 34.82% cases showed oxygen desaturation below 90% in the 6MWT. The predominant radiological pattern on HRCT was indeterminate usual interstitial pneumonia (UIP) (41.90%) and probable UIP (36.61%). Thirty-four patients (30.35%) underwent bronchoscopy and surgical lung biopsy was necessary to reach a diagnosis in 43 patients (38.39%) (Table 1 ). Interstitial lung abnormality (ILA) was identified in 3 patients, of whom 2 progressed to fibrotic ILD during follow-up. Table 1 Characteristics of patients in the rapid referral circuit and common referral circuit at the time of diagnosis. Rapid diagnostic circuit (n 112) Common diagnostic circuit (n 564) p-value ILD Subtypes (n, %) IPF 27 (24.1%) 98 (17.38%) 0.29 HP 18 (16.1%) 86 (15.25%) 0.64 CTD-ILD 14 (12.5%) 80 (14.18%) 0.83 OP 8 (7.1) 74 (13.12%) 0.24 Sarcoidosis 15 (13.4%) 59 (10.46%) 0.66 Occupational 7 (6.3%) 36 (6.38%) 0.76 Drug/Radiation-induced ILD 4 (3.6%) 6 (1.06%) 0.62 Unclassifiable 13 (11.5%) 78 (13.83%) 0.73 Others 1 (0.9%) 6 (1.06%) 0.86 ILA 3 (2.7%) 8 (1.42%) 0.87 Age (years), median (IQR) 66.3 (9.5) 62.3 (3.18) 0.035* Gender (male), n (%) 62 (60.78%) 379 (67.19%) 0.488 Fibrosing ILD, mean (SD) 55.9% (5.92) 63.9% (3.67) 0.046* FVC percentage of predicted, median (IQR) 89.61 (17.23) 76.14 (15.78) 0.0084* DLCO percentage of predicted, mean ± SD 68.72 ±17.89 56.26 ± 18.45 0.0139* Desaturation on 6MWT below 90%, n (%) 39 (34.82%) 327 (57.98%) 0.021* Chest HRCT pattern, n (%) Definite UIP Probable UIP Indeterminate UIP 24 (21.43%) 41 (36.61%) 47 (41.96%) 247 (43.79%) 169 (29.96%) 148 (26.24%) 0.016* 0.202 0.019* Surgical lung biopsy, n (%) 43 (38.39) 186 (32.97) 0.004* Time (months) from onset of symptoms to diagnosis, mean (SD) 6 (5) 22.1 (9.9) < 0.001* Asymptomatic, n (%) 18 (16.07) 62 (10.99) 0.082 Antifibrotic treatment (only in IPF), n (%) 21 (18.75) 85 (15.07) 0.622 Lung transplant median, n (%) 13 (11.61) 48 (8.51) <0.001* Transplant-free survival at 7 years follow-up median, n (%) 64 (57.14) 241 (42.73) 0.043* IPF (Idiopathic Pulmonary Fibrosis); HP (Hypersensitivity Pneumonitis); CTD-ILD (Connective Tissue Disease associated Interstitial Lung Disease); OP (Organizing Pneumonia); ILA (interstitial lung abnormalities). FVC: Forced vital capacity; DLCO: Diffusing capacity for carbon monoxide; HRCT: High resolution computed tomography; UIP: Usual interstitial pneumonia; 6MWT: 6-minute walk test; IQR: Interquartile range; SD: Standard deviation. Of the 603 patients referred through the common circuit, 39 (6.46%) had other non-ILD respiratory diseases such as cylindrical bronchiectasis, pulmonary edema or asthma and 564 ILD patients were diagnosed and followed-up. The median age was 62.3 years and the majority were men (67.19%). Most patients presented with fibrotic ILD (63.9%) and 43.79% had a definite UIP pattern on chest HRCT. The main diagnoses were IPF and fibrotic hypersensitivity pneumonitis (fHP). Most patients were referred after ILD was identified on chest HRCT (87.21%) and 79% had crackles on auscultation. Sixty-two patients had no respiratory symptoms, and of these, 4 (6.45%) had fibrosing ILD. The median FVC was 76.14% (IQR 15.78) and DLCO was 56.26% (SD 18.45%). A total of 57.98% cases showed oxygen desaturation below 90% in 6MWT. The time from symptom onset (when present) to diagnosis was 22.1 (SD 9.9) months (Fig. 1 ). During the patient’s journey, chest HRCT was performed at least once in all patients, and 210 (37.23%) before the final diagnostic procedures at the ILD Unit. The diagnoses were variable but the proportion of each ILD did not differ from the rapid referral circuit cohort (Table 1 ). Interstitial lung abnormalities (ILAs) were initially identified in 8 patients, and 5 of them progressed to ILD during follow-up. Surgical lung biopsy was performed for diagnosis in 32.97% of patients. The delay in diagnosis (time from symptom onset) and the number of non-diagnostic tests during the patient’s journey were significantly lower in those patients referred from primary care centers (Fig. 1 and Table 1 ). Disease outcomes Regarding the subgroup of patients with IPF who presented symptoms at the time of diagnosis, patients from the rapid diagnostic circuit had a higher FVC than those from the common circuit. The time elapsed from of symptom onset to diagnosis was defined as the "FVC diagnostic FVC pitfall”: $$\:\varvec{F}\varvec{V}\varvec{C}\:\varvec{d}\varvec{i}\varvec{a}\varvec{g}\varvec{n}\varvec{o}\varvec{s}\varvec{t}\varvec{i}\varvec{c}\:\:\varvec{p}\varvec{i}\varvec{t}\varvec{f}\varvec{a}\varvec{l}\varvec{l}=\frac{FVC\:\left(\%\right)onset\:of\:symptoms-FVC\:\left(\%\right)at\:diagnosis}{\nabla\:FVC\:\left(\%\right)/year}$$ \(\:\nabla\:\) decrease Figure 3 , shows the progressive decline in predicted FVC (%) over a 7-year follow-up period for patients with IPF and respiratory symptoms can be observed. We highlight the area referred to as the "Diagnostic FVC pitfall," which is defined as the interval between the onset of symptoms and the time of diagnosis, delineated by the annual progressive decline of the predicted FVC. No significant difference was observed in the percentage of IPF patients treated with antifibrotics between the two groups. However, antifibrotic drugs were only available in a clinical trial (nintedanib) or for compassionate use (pirfenidone) for selected IPF patients at the time of referral (Table 1 ). Lung transplantation was more common in patients in the rapid referral group (11.61% vs 8.51%, p < 0.001) (Table 1 ). The differences in 7-year transplant-free survival between both groups were statistically significant (57.14% and 42.73%, (p = 0.043) (Table 1 , Fig. 4 ). Discussion The results of our study suggest that a rapid referral circuit from primary care centers to an ILD Unit is feasible and improves ILD patient’s journey by reducing the delay in diagnosis and the number of additional tests performed, the latter compared to the standard pathway used in Spain and other countries [ 5 ]. Furthermore, it allows to identify a greater number of patients with fibrotic ILDs at early stages and is associated with a higher likelihood of lung transplantation and better survival after transplantation. Different strategies have been suggested to achieve early diagnosis of ILDs, including awareness among primary care physicians, lung cancer screening programs, and the use of artificial intelligence (AI) to analyze computed tomography (CT) images [ 25 , 26 , 27 ]. An early diagnosis of IPF may lead to timely pharmacological and non-pharmacological treatment and, therefore, better disease outcomes [ 28 ]. Furthermore, the European Commission seek to achieve sustainable proposed actions and implementations into national plans and strategies for rare diseases such as ILDs. However, ILDs can be difficult to diagnose in early stages due to overlapping symptoms with other more common conditions that may be attributed to ageing, smoking or cardiovascular conditions [ 29 ]. Moreover, patients with early disease may present minimal symptoms or subtle clinical signs. Patients with IPF frequently endure a significant delay to diagnosis [ 22 , 30 ]. Furthermore, an accurate diagnosis requires a specialized multidisciplinary ILD team [ 2 , 4 , 31 ], available in some tertiary centers [ 5 , 18 , 32 ]. The pivotal role played by primary care physicians play in the early diagnosis of diseases highlights the need for educational interventions to raise awareness of ILDs. This, in turn, could result in rapid referral of patients to specialized centers and in on-going dialogue between pulmonologists and primary care physicians during patient follow-up and at the end of life. A retrospective study conducted in two specialist ILD clinics from UK and Ireland investigated patients’ outcomes in relation to the time from primary care visit to ILD specialist center referral [ 33 ]. The study showed that patients evaluated at an ILD clinic within 12 months had a longer time to death and a longer duration of antifibrotic medication compared with those evaluated later [ 33 ]. Silva et al. evaluated primary care physicians’ awareness of the major ILD subtypes, including IPF. Their questionnaire assessed respondents’ degree of awareness of the basic diagnosis and management of the main ILD conditions in five healthcare centers. Participants performed acceptably on sections related to hypersensitivity pneumonitis, connective tissue disease associate with ILD, sarcoidosis and drug-induced ILD; but, their level of awareness of IPF was considered poor [ 34 ]. Several models of rapid diagnostic circuits for ILD have been proposed [ 10 , 35 , 36 ]. A rapid diagnosis more frequently identifies early or mild- stages ILD cases, allowing for an optimal therapeutic approach that may impact on the natural history of the disease [ 37 , 38 ]. An analysis from the Australian IPF registry found that patients with IPF with mild physiological impairment (FVC ≥ 80%) had better survival than patients with moderate-to-severe disease (FVC < 80%). However, the overall rate of disease progression was comparable, suggesting that better survival in early stages simply reflects an earlier point in the natural history of IPF [ 39 ]. Other studies have indicated that patients with IPF in mild functional stages experience fewer episodes of acute exacerbation than those with advanced disease [ 29 , 40 ]. However, preserved FVC may reflect different types of IPF patients and is not sufficient to indicate early IPF. This observation may have prognostic and therapeutic implications when considering the initiation of antifibrotic treatment or evaluating lung transplantation. Decreased DLCO or definite UIP pattern of diagnosis is associated with a poor prognosis [ 40 ]. Therefore, IPF patients with preserved FVC would allow a broader spectrum of treatment options [ 41 – 46 ]. The main limitations of this work are associated with the retrospective nature of the study, which impacts the comparison between both groups. However, the diagnostic, treatment and follow-up process was the same for all patients due to the standardized protocols of the ILD Unit in clinical practice. Another limitation of the study is the difficulty in extrapolating these results to regions or countries that do not have established rapid diagnostic circuit or do not have the option of training GPs and radiologists in specific diseases or conditions. Nevertheless, the established training program and rapid diagnostic circuit are feasible, so an international validation would be possible for implementing these procedures in ILD clinical practice. Conclusions Early identification of fibrotic ILDs is possible through a rapid referral circuit, a training program, and networking with primary care centers. Furthermore, rapid referral from primary care centers improves the patient’s journey, optimizes healthcare resources, and is associated with increased survival. Declarations Disclosures: Guadalupe Bermudo (GB) has received for research projects from Boehringer Ingelheim, Hoffmann La Roche, not related with the present study. Funding: Medical writing and editorial assistance were funded by FUCAP (Catalan Foundation of Pneumology), through an unrestricted grant from Boehringer Ingelheim (BI) Spain. BI had no role in the design, analysis, or interpretation of the results in this study. Author Contribution Guadalupe Bermudo (GB) has received for research projects from Boehringer Ingelheim, Hoffmann La Roche, not related with the present study.Pilar Rivera-Ortega (PRO) has received speaker and consultations fees from Boehringer Ingelheim, The Limbic, Chiesi, Cipla, Tecnofarma, and Hoffmann La Roche, none of them related to this study. PRO has also received research honoraria from Boehringer Ingelheim, Hoffmann La Roche, CSL Behring, FibroGen, Vicore Pharma AB, Gilead Sciences, Galecto, and Chiesi; not related to the present study.V.Vicens-Zygmunt (VVZ) has received for research projects from Boehringer Ingelheim, not related with the present study.María Molina-Molina (MM) has received grants and fees for scientific advice, not related with the present study, from Boehringer Ing, Ferrer, Janssen, Roche, Raffo.B.Del Río (BDR), S.Bolivar (SB), E.Serra (ES), F.Ferrer (FF), R.Llatjós (RL), F. Rivas (FR), R.López-Lisbona (RLL), L.García (LG), S.Santos (SS) and P.Luburich (PL); have nothing to disclose. Data Availability The datasets generated and analyzed during the current study are not publicly available due to contain sensitive personal information of hospital patients and are subject to strict confidentiality agreements and data protection laws. 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Multidiscip Respir Med. 2022;17(1):848. doi: 10.4081/mrm.2022.848 Bermudo G, Roman-Rodriguez M, Molina-Molina M. Interstitial lung diseases: never forget to think about it in primary care. Respiratory Medicine, 2024; 18: 1–2, 9–15. doi: 10.1080/17476348.2024.2331763 Schoenheit G, Becattelli I, Cohen AH. Living with idiopathic pulmonary fibrosis: an in depth qualitative survey of European patients. Chron Respir Dis. 2011;8(4): 225–31. doi: 10.1177/1479972311416382 Spagnolo P, Ryerson C, Putman R, Oldham J, Salisbury M, et al. Early diagnosis of fibrotic intertitial lung disease: challenges and opportunities. The Lancet Resp Medicine. September 2021; 9: 1065–1076. doi: 10.1016/S2213-2600(21)00017-5 Aiello M, Bertorelli G, Bocchino M, Chetta A, Donati A, et al. The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis. Pulmonary Pharmacology and Therapeutics. June 2017; 44: 7–15. doi: 10.1016/j.pupt.2017.02.005 Jo HE, Glaspole I, Moodley Y, Chapman S, Ellis S, et al. Disease progression in idiopathic pulmonary fibrosis with mild physiological impairment: analysis from the Australian IPF registry. BMC Pulm Med. 2018;18 (1):19. doi: 10.1186/s12890-018-0575-y Song JW, Hong S-B, Lim C-M, Koh Y, Kim D-S. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011;37(2):356–63. doi: 10.1183/09031936.00159709 Bermudo G, Suarez-Cuartin G, Rivera-Ortega P, Rodríguez-Portal JA, et al. Different Faces of Idiopathic Pulmonary Fibrosis With Preserved Forced Vital Capacity. Arch Bronconeumol. 2022; 58(2): 135–141. doi: 10.1016/j.arbres.2021.03.018 Molina-Molina M, Aburto M, Acosta O, Ancochea J, et al. Importance of early diagnosis and treatment in idiopathic pulmonary fibrosis, Expert Review of Respiratory Medicine, 2018; 12:7, 537–539. doi: 10.1080/17476348.2018.1472580 Alsomali, H., Palmer, E., Aujayeb, A, Funston W. Early Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis: A Narrative Review. Pulm Ther, 2023; 9, 177–193. doi: 10.1007/s41030-023-00216-0 Maher TM, Strek ME. Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat. Respir Res. 2019;20(1):205. doi: 10.1186/s12931-019-1161-4 Pleasants R, Tighe RM. Management of Idiopathic Pulmonary Fibrosis. Ann Pharmacother, 2019 Dec, 53 (12): 1238–1248. doi: 10.1177/1060028019862497 . Salisbury ML, et al. Antifibrotic drug use in patients with idiopathic pulmonary fibrosis. Data from the IPF-PRO Registry. Ann Am Thorac Soc. 2020;17(11): 1413–23. doi: 10.1513/AnnalsATS.201912-880OC Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in npj Primary Care Respiratory Medicine → Version 1 posted Editorial decision: Revision requested 08 Sep, 2025 Reviews received at journal 08 Sep, 2025 Reviewers agreed at journal 31 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviewers agreed at journal 13 Aug, 2025 Reviewers invited by journal 05 Aug, 2025 Editor assigned by journal 28 Jul, 2025 Submission checks completed at journal 28 Jul, 2025 First submitted to journal 27 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7224984","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":497338698,"identity":"c0dd1272-8839-487b-99e1-0a9c18c96b06","order_by":0,"name":"G Bermudo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACPiBmhjATgLgCxGVuwKuFDVXLGRCXkRQtjG0gBiEtErkHHxdU3Is2OJ587MHHebXR/O1ALT8qtuHRkpdsPONMce6GM8/SDWduO5474zBjA2PPmdt4tOSYSfO2JeRuuAFibDuW2wDUwszYhleL+W/ef1Atf+ccy51PhBYzZt4GqBbGhprcDQS18LxLlp5xLCF3JsgvPccO5G4EajmIzy/87LkHPxfUJOT2gULsR01d7rzzhw8++FGBWwsDAw/CRiA+DGYdwKMeQ0sdfsWjYBSMglEwIgEA/2JdFHYeUNsAAAAASUVORK5CYII=","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":true,"prefix":"","firstName":"G","middleName":"","lastName":"Bermudo","suffix":""},{"id":497338699,"identity":"fd428377-071f-49fc-8b96-b93325f0d533","order_by":1,"name":"P Rivera-Ortega","email":"","orcid":"","institution":"Royal Devon University Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"P","middleName":"","lastName":"Rivera-Ortega","suffix":""},{"id":497338700,"identity":"39196cc2-97d3-4720-af25-6fe970a6de50","order_by":2,"name":"V Vicens-Zygmunt","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"V","middleName":"","lastName":"Vicens-Zygmunt","suffix":""},{"id":497338701,"identity":"5e1e7608-ce3a-4c97-8ceb-bd85875b1644","order_by":3,"name":"B Del Rio","email":"","orcid":"","institution":"University Hospital of Bellvitge","correspondingAuthor":false,"prefix":"","firstName":"B","middleName":"Del","lastName":"Rio","suffix":""},{"id":497338702,"identity":"bf595bd4-4bb7-4a71-9322-e5fe71204ddc","order_by":4,"name":"S Bolivar","email":"","orcid":"","institution":"University Hospital of Bellvitge","correspondingAuthor":false,"prefix":"","firstName":"S","middleName":"","lastName":"Bolivar","suffix":""},{"id":497338703,"identity":"130ae82f-37ca-49c2-a7db-8ccd7f30c3c2","order_by":5,"name":"E Serra","email":"","orcid":"","institution":"ABS Centre Hospitalet de Llobregat","correspondingAuthor":false,"prefix":"","firstName":"E","middleName":"","lastName":"Serra","suffix":""},{"id":497338704,"identity":"162a761b-48f0-43c0-849e-8ee65dce1176","order_by":6,"name":"F Ferrer","email":"","orcid":"","institution":"ABS El Prat, El Prat de Llobregat","correspondingAuthor":false,"prefix":"","firstName":"F","middleName":"","lastName":"Ferrer","suffix":""},{"id":497338705,"identity":"b62e6bd6-f2c0-4d07-afe6-d5039766972b","order_by":7,"name":"R. Llatjós","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL)","correspondingAuthor":false,"prefix":"","firstName":"R.","middleName":"","lastName":"Llatjós","suffix":""},{"id":497338706,"identity":"bc95b8f5-215a-4f92-a255-9e0934842de4","order_by":8,"name":"F Rivas","email":"","orcid":"","institution":"Hospital Universitari de Bellvitge, IDIBELL. Barcelona","correspondingAuthor":false,"prefix":"","firstName":"F","middleName":"","lastName":"Rivas","suffix":""},{"id":497338707,"identity":"65a66186-feed-4edf-9366-633c1f513ad3","order_by":9,"name":"R López-Lisbona","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"R","middleName":"","lastName":"López-Lisbona","suffix":""},{"id":497338708,"identity":"a8f158b3-998d-4f1f-b95b-e0bcbe12b71d","order_by":10,"name":"L García","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"L","middleName":"","lastName":"García","suffix":""},{"id":497338709,"identity":"75648412-d51e-40e1-bdbb-dac2f7cf3415","order_by":11,"name":"S Santos","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"S","middleName":"","lastName":"Santos","suffix":""},{"id":497338712,"identity":"09d04141-42ac-4b7d-aa20-adaa6b942af3","order_by":12,"name":"P Luburich","email":"","orcid":"","institution":"University Hospital of Bellvitge","correspondingAuthor":false,"prefix":"","firstName":"P","middleName":"","lastName":"Luburich","suffix":""},{"id":497338713,"identity":"63e78eba-62c8-4d0e-a79c-e39ad594995b","order_by":13,"name":"M Molina-Molina","email":"","orcid":"","institution":"University Hospital of Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"M","middleName":"","lastName":"Molina-Molina","suffix":""}],"badges":[],"createdAt":"2025-07-27 08:23:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7224984/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7224984/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41533-025-00462-6","type":"published","date":"2025-11-26T15:56:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88773657,"identity":"c66b3e2d-c4ed-4b25-8345-c029e0500b86","added_by":"auto","created_at":"2025-08-11 09:58:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81849,"visible":true,"origin":"","legend":"\u003cp\u003eRapid circuit diagnostic algorithm for patients with ILD that avoids the typical ILD patient journey.\u003c/p\u003e\n\u003cp\u003eThere are four types of patients with a suspected diagnosis of ILD in Primary Care.\u003c/p\u003e\n\u003cp\u003eSubclinical cases are patients with few respiratory symptoms, patients at risk of developing ILD (for example, due to family history or environmental or occupational exposures) and incidental cases (diagnosis of ILD by chance, extension study, abdominal CT scan and suspicion of ILD in thoracic sections, etc). Finally, there are clinical cases, which are the most frequent (those with respiratory symptoms such as dry cough and/or dyspnea).\u003c/p\u003e\n\u003cp\u003eAll these patients should undergo a through physical examination to rule out the presence of finger clubbing, complete respiratory semiology to rule out the presence of crackles on auscultation, and a detailed medical history. Subsequently, complementary examinations are performed, such as a chest X-ray and/or chest CT scan, spirometry and, if ILD is diagnosed in Primary Care, the patient is referred is made to the Tertiary Care Centre, specifically to the ILD Unit, to confirm and study the diagnosis of ILD through the Multidisciplinary Expert Committee.\u003c/p\u003e\n\u003cp\u003eOnce the patient is diagnosed with ILD, depending on the severity, they will continue to be monitored at the Expert Unit or may be referred back to Primary Care.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7224984/v1/bb67bfa87698c32bdb99be66.jpg"},{"id":88777617,"identity":"1583353e-52bf-46e0-9e26-6b575fcdad2d","added_by":"auto","created_at":"2025-08-11 10:14:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22923,"visible":true,"origin":"","legend":"\u003cp\u003etime from onset of symptoms to diagnosis in the Rapid Diagnostic Circuit and Common Diagnostic Circuit.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7224984/v1/39a0fdc1a4503776f24a2c7d.jpg"},{"id":88775590,"identity":"ca57b91c-c60e-4d9a-ab73-ecfb10360db6","added_by":"auto","created_at":"2025-08-11 10:06:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39692,"visible":true,"origin":"","legend":"\u003cp\u003eevolutionary decrease in predicted FVC over 7 years of follow-up of patients in the rapid diagnostic circuit and in the common diagnostic circuit.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7224984/v1/7bc34a6285dd7479b492a1b4.jpg"},{"id":88773659,"identity":"0d12ace6-7b6b-47b4-b930-c77e1da63cdb","added_by":"auto","created_at":"2025-08-11 09:58:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40460,"visible":true,"origin":"","legend":"\u003cp\u003eTransplant- free survival at 7 years follow-up in the rapid and common diagnostic circuit.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7224984/v1/105f94262555c14456466f08.jpg"},{"id":97179342,"identity":"b50396dd-e036-4c09-a13f-824b971d7710","added_by":"auto","created_at":"2025-12-01 16:14:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":749083,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7224984/v1/f59dab05-5cef-41db-855d-766d66fa4acc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Benefits of a Rapid Diagnostic Primary Care Circuit for Interstitial Lung Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInterstitial lung diseases (ILDs) represent a group of rare and complex conditions of both known and unknown origin. Fibrotic ILDs may progress despite standard treatments, leading to respiratory failure and early mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The common fibrotic ILD is idiopathic pulmonary fibrosis (IPF), which is characterized by chronic, progressive and irreversible scarring of the lung. Main symptoms and signs of IPF and non-IPF progressive pulmonary fibrosis (PPF) include dyspnea, dry cough, inspiratory crackles, and finger clubbing [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A confident diagnosis is challenging and requires expert multidisciplinary teams which are not available in all hospitals [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The natural history varies considerably between patients but involves a decline in lung function and quality of life, eventually leads to death [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA delay of 1–3 years between symptom onset and diagnosis is frequently observed in fibrotic ILDs, mainly due to the limited awareness of primary care physicians about these types of rare diseases [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Delayed diagnosis of IPF and other fibrotic ILDs is associated with worse survival [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, misdiagnosis of other respiratory diseases, such as asthma, and the futility of most empirical treatments initiated before diagnosis impact on the patient’s emotional state and healthcare resources. Finally, early intervention is crucial to improve ILD prognosis. Avoiding risk factors or identified causes and initiating antifibrotic drugs when necessary may modify the natural history of the disease, reducing mortality, and even preventing irreversible changes in induced fibrotic ILDs [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Although there are no specific biomarkers with predictive diagnostic or prognostic value, several studies are currently testing molecular, genetic, and epigenetic markers that will be useful even in the early stages of the disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, early diagnosis and optimal therapeutic management of fibrotic ILDs are more relevant than ever [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this regard, lung auscultation for velcro-like crackles, which are strongly associated with the presence of pulmonary fibrosis, has been proposed as a feasible and sensitive measure to improve early detection [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, most cases report a patient’s journey that starts receiving symptomatic treatment, including inhalers, in primary care centers [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. After worsening despite treatment, patients are referred to a pulmonologist, who performs additional respiratory tests [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Once ILD is identified and the patient continues to worsen, referral to an ILD Unit at a tertiary center allows for multidisciplinary diagnosis [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, definitive diagnosis and therapeutic management usually take more than a year [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough the time required for ILD diagnosis varies considerably by geographic area, delays occur at every stage of the diagnostic process, even after raising awareness about these rare diseases among the general population and healthcare workers [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, considering the relevance of existing rapid diagnostic pathways for oncological diseases to reduce diagnostic delay, a pilot program for rapid ILD diagnosis was established and analyzed in collaboration with primary care centers in our area.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003ePopulation and study design\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOur multicenter, observational, retrospective study included consecutive patients with newly diagnosed ILD between 2012 and 2015, with follow-up until 2022 at the ILD Unit of University Hospital of Bellvitge (HUB). Diagnosis and treatment were performed according to the American Thoracic Society/European Respiratory Society criteria by the multidisciplinary committee (MDT) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This study was approved by the HUB Ethics Committee (PR413/18). It was conducted in accordance with the ethical principles of the Declaration of Helsinki and local legislation laws. Informed consent was obtained from each participant by the study investigator prior to data collection.\u003c/p\u003e\u003cp\u003eInitially, a training program for clinical suspicion and identification of ILD patients was performed in 10 primary care centers staffed by general practitioners (GPs) focused on respiratory diseases. Chest radiologists from these centers were connected to the ILD radiological team at the HUB. As online clinical and radiological network was established. All ILD patients diagnosed through this circuit were recruited and followed-up until study completion, death or lung transplantation. Outcomes were compared wich those of patients referred through the common patient diagnostic circuit during the same period. These patients were referred from 12 hospitals for which the HUB is the referral center for complex diagnostic and therapeutic procedures, including rare respiratory rare diseases.\u003c/p\u003e\u003cp\u003e The rapid diagnostic circuit was established through an ILD Unit’s email account that was reviewed every weekday. In addition, GPs faxed the case referral and information.\u003c/p\u003e\u003cp\u003eIf a primary care radiologist identified the case after evaluating a chest x-ray or high-resolution computed tomography (HRCT), they contacted the GP to activate the rapid diagnostic referral circuit.\u003c/p\u003e\u003cp\u003eThe common respiratory diagnostic circuit included email contact with the ILD Unit and an administrative referral by fax. Cases were referred by pulmonologists, internal medicine physicians, rheumatologists, thoracic surgeons, and emergency physicians from various hospitals.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCollected data\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBaseline demographic and clinical characteristics were collected at diagnosis, including age, gender, smoking status/history, occupational and environmental exposures, respiratory symptoms and signs (crackles and nail clubbing), time to symptom onset, comorbidities, radiological high-resolution computed tomography (HRCT) pattern, final diagnosis, and treatment received. HRCT findings and radiological pattern were interpreted according to the recommendations of the Fleischner Society nomenclature commite [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Fibrotic ILD was defined radiologically as the presence of fibrosing features on chest HRCT that exceeded 5% of the total lung area. The lung function characteristics, such as forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO), 6-minute walk test (6MWT) and oxygen desaturation were also included. During the follow-up, clinical, functional and radiological data and use of antifibrotic treatment were recorded. Mortality, survival and lung transplantation were also recorded. Data from patients referred using both referral process (rapid and common diagnostic circuit) were compared.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eCategorical data are described as frequency and percentages, and differences were evaluated using chi-squared test or Fisher’s exact test when required. For descriptive analysis, continuous and normally distributed variables are expressed as mean and standard deviation (SD). Differences in continuous variables were analyzed with ANOVA tests or Student’s t test, or their corresponding non-parametrical tests when required (Kruskal-Wallis and Mann-Whitney U tests). Time to event data (time to lung transplantation and/or death) were analyzed using Kaplan-Meier survival analysis and Cox proportional hazard regression for multivariable analyses. A p-value \u0026lt; 0.05 was considered statistically significant. Data were analyzed by using SPSS 27 (SPSS, IBM Corp). The recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative were followed [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient features at diagnosis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 726 new patients were referred to the HUB ILD Unit between 2012 and 2015. Of the 123 patients referred directly from primary care, 112 patients (91.05%) had ILD and 11 had other respiratory diseases such as cylindrical bronchiectasis or pulmonary edema (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These patients showed a mean age of 66.3 years (IQR 9.5), and 55.9% (SD 5.92) had fibrotic ILD. The main reasons for suspecting ILD in primary care were interstitial radiological features (74%) and auscultation of lung crackles (67%). A chest HRCT was performed before arrival to the ILD Unit in 81.05% patients. No invasive procedures were performed during the patient\u0026rsquo;s journey. The time from symptom onset (when present) to diagnosis was 6 months (SD 5) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No respiratory symptoms were identified in 18 patients, although 2 of them presented with fibrosing ILD. The main diagnoses were IPF and fibrotic hypersensitivity pneumonitis (fHP) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median FVC was 89.61% (IQR 17.23) and DLCO was 68.72% (SD 17.89). Up to 34.82% cases showed oxygen desaturation below 90% in the 6MWT. The predominant radiological pattern on HRCT was indeterminate usual interstitial pneumonia (UIP) (41.90%) and probable UIP (36.61%). Thirty-four patients (30.35%) underwent bronchoscopy and surgical lung biopsy was necessary to reach a diagnosis in 43 patients (38.39%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Interstitial lung abnormality (ILA) was identified in 3 patients, of whom 2 progressed to fibrotic ILD during follow-up.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of patients in the rapid referral circuit and common referral circuit at the time of diagnosis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRapid diagnostic circuit (n 112)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCommon diagnostic circuit (n 564)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eILD Subtypes\u003c/p\u003e\u003cp\u003e(n, %)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (24.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e98 (17.38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (16.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e86 (15.25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCTD-ILD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e80 (14.18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.83\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e74 (13.12%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSarcoidosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (13.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e59 (10.46%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOccupational\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36 (6.38%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrug/Radiation-induced ILD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (1.06%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnclassifiable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (11.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e78 (13.83%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (1.06%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eILA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (2.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8 (1.42%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.87\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.3 (9.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62.3 (3.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.035*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender (male), n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62 (60.78%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e379 (67.19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.488\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFibrosing ILD, mean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.9% (5.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e63.9% (3.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.046*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFVC percentage of predicted, median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89.61 (17.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e76.14 (15.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0084*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDLCO percentage of predicted, mean \u0026plusmn; SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.72 \u0026plusmn;17.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56.26 \u0026plusmn; 18.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0139*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDesaturation on 6MWT below 90%, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (34.82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e327 (57.98%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.021*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChest HRCT pattern, n (%)\u003c/p\u003e\u003cp\u003eDefinite UIP\u003c/p\u003e\u003cp\u003eProbable UIP\u003c/p\u003e\u003cp\u003eIndeterminate UIP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (21.43%)\u003c/p\u003e\u003cp\u003e41 (36.61%)\u003c/p\u003e\u003cp\u003e47 (41.96%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e247 (43.79%)\u003c/p\u003e\u003cp\u003e169 (29.96%)\u003c/p\u003e\u003cp\u003e148 (26.24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.016*\u003c/p\u003e\u003cp\u003e0.202\u003c/p\u003e\u003cp\u003e0.019*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical lung biopsy, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (38.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e186 (32.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime (months) from onset of symptoms to diagnosis, mean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.1 (9.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsymptomatic, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (16.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62 (10.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.082\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntifibrotic treatment (only in IPF), n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (18.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e85 (15.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.622\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLung transplant median, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (11.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e48 (8.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTransplant-free survival at 7 years follow-up median, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64 (57.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e241 (42.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.043*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eIPF (Idiopathic Pulmonary Fibrosis); HP (Hypersensitivity Pneumonitis); CTD-ILD (Connective Tissue Disease associated Interstitial Lung Disease); OP (Organizing Pneumonia); ILA (interstitial lung abnormalities).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eFVC: Forced vital capacity; DLCO: Diffusing capacity for carbon monoxide; HRCT: High resolution computed tomography; UIP: Usual interstitial pneumonia; 6MWT: 6-minute walk test; IQR: Interquartile range; SD: Standard deviation.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOf the 603 patients referred through the common circuit, 39 (6.46%) had other non-ILD respiratory diseases such as cylindrical bronchiectasis, pulmonary edema or asthma and 564 ILD patients were diagnosed and followed-up. The median age was 62.3 years and the majority were men (67.19%). Most patients presented with fibrotic ILD (63.9%) and 43.79% had a definite UIP pattern on chest HRCT. The main diagnoses were IPF and fibrotic hypersensitivity pneumonitis (fHP). Most patients were referred after ILD was identified on chest HRCT (87.21%) and 79% had crackles on auscultation. Sixty-two patients had no respiratory symptoms, and of these, 4 (6.45%) had fibrosing ILD. The median FVC was 76.14% (IQR 15.78) and DLCO was 56.26% (SD 18.45%). A total of 57.98% cases showed oxygen desaturation below 90% in 6MWT. The time from symptom onset (when present) to diagnosis was 22.1 (SD 9.9) months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the patient\u0026rsquo;s journey, chest HRCT was performed at least once in all patients, and 210 (37.23%) before the final diagnostic procedures at the ILD Unit. The diagnoses were variable but the proportion of each ILD did not differ from the rapid referral circuit cohort (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Interstitial lung abnormalities (ILAs) were initially identified in 8 patients, and 5 of them progressed to ILD during follow-up. Surgical lung biopsy was performed for diagnosis in 32.97% of patients.\u003c/p\u003e\u003cp\u003eThe delay in diagnosis (time from symptom onset) and the number of non-diagnostic tests during the patient\u0026rsquo;s journey were significantly lower in those patients referred from primary care centers (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eDisease outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRegarding the subgroup of patients with IPF who presented symptoms at the time of diagnosis, patients from the rapid diagnostic circuit had a higher FVC than those from the common circuit. The time elapsed from of symptom onset to diagnosis was defined as the \"FVC diagnostic FVC pitfall\u0026rdquo;:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\varvec{F}\\varvec{V}\\varvec{C}\\:\\varvec{d}\\varvec{i}\\varvec{a}\\varvec{g}\\varvec{n}\\varvec{o}\\varvec{s}\\varvec{t}\\varvec{i}\\varvec{c}\\:\\:\\varvec{p}\\varvec{i}\\varvec{t}\\varvec{f}\\varvec{a}\\varvec{l}\\varvec{l}=\\frac{FVC\\:\\left(\\%\\right)onset\\:of\\:symptoms-FVC\\:\\left(\\%\\right)at\\:diagnosis}{\\nabla\\:FVC\\:\\left(\\%\\right)/year}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\nabla\\:\\)\u003c/span\u003e\u003c/span\u003e\u003c/strong\u003e\u003cp\u003e\u003cem\u003edecrease\u003c/em\u003e\u003c/p\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, shows the progressive decline in predicted FVC (%) over a 7-year follow-up period for patients with IPF and respiratory symptoms can be observed. We highlight the area referred to as the \"Diagnostic FVC pitfall,\" which is defined as the interval between the onset of symptoms and the time of diagnosis, delineated by the annual progressive decline of the predicted FVC.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNo significant difference was observed in the percentage of IPF patients treated with antifibrotics between the two groups. However, antifibrotic drugs were only available in a clinical trial (nintedanib) or for compassionate use (pirfenidone) for selected IPF patients at the time of referral (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eLung transplantation was more common in patients in the rapid referral group (11.61% vs 8.51%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe differences in 7-year transplant-free survival between both groups were statistically significant (57.14% and 42.73%, (p\u0026thinsp;=\u0026thinsp;0.043) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of our study suggest that a rapid referral circuit from primary care centers to an ILD Unit is feasible and improves ILD patient\u0026rsquo;s journey by reducing the delay in diagnosis and the number of additional tests performed, the latter compared to the standard pathway used in Spain and other countries [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, it allows to identify a greater number of patients with fibrotic ILDs at early stages and is associated with a higher likelihood of lung transplantation and better survival after transplantation.\u003c/p\u003e\u003cp\u003eDifferent strategies have been suggested to achieve early diagnosis of ILDs, including awareness among primary care physicians, lung cancer screening programs, and the use of artificial intelligence (AI) to analyze computed tomography (CT) images [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. An early diagnosis of IPF may lead to timely pharmacological and non-pharmacological treatment and, therefore, better disease outcomes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Furthermore, the European Commission seek to achieve sustainable proposed actions and implementations into national plans and strategies for rare diseases such as ILDs. However, ILDs can be difficult to diagnose in early stages due to overlapping symptoms with other more common conditions that may be attributed to ageing, smoking or cardiovascular conditions [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Moreover, patients with early disease may present minimal symptoms or subtle clinical signs. Patients with IPF frequently endure a significant delay to diagnosis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Furthermore, an accurate diagnosis requires a specialized multidisciplinary ILD team [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], available in some tertiary centers [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The pivotal role played by primary care physicians play in the early diagnosis of diseases highlights the need for educational interventions to raise awareness of ILDs. This, in turn, could result in rapid referral of patients to specialized centers and in on-going dialogue between pulmonologists and primary care physicians during patient follow-up and at the end of life. A retrospective study conducted in two specialist ILD clinics from UK and Ireland investigated patients\u0026rsquo; outcomes in relation to the time from primary care visit to ILD specialist center referral [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The study showed that patients evaluated at an ILD clinic within 12 months had a longer time to death and a longer duration of antifibrotic medication compared with those evaluated later [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Silva et al. evaluated primary care physicians\u0026rsquo; awareness of the major ILD subtypes, including IPF. Their questionnaire assessed respondents\u0026rsquo; degree of awareness of the basic diagnosis and management of the main ILD conditions in five healthcare centers. Participants performed acceptably on sections related to hypersensitivity pneumonitis, connective tissue disease associate with ILD, sarcoidosis and drug-induced ILD; but, their level of awareness of IPF was considered poor [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Several models of rapid diagnostic circuits for ILD have been proposed [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA rapid diagnosis more frequently identifies early or mild- stages ILD cases, allowing for an optimal therapeutic approach that may impact on the natural history of the disease [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. An analysis from the Australian IPF registry found that patients with IPF with mild physiological impairment (FVC\u0026thinsp;\u0026ge;\u0026thinsp;80%) had better survival than patients with moderate-to-severe disease (FVC\u0026thinsp;\u0026lt;\u0026thinsp;80%). However, the overall rate of disease progression was comparable, suggesting that better survival in early stages simply reflects an earlier point in the natural history of IPF [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Other studies have indicated that patients with IPF in mild functional stages experience fewer episodes of acute exacerbation than those with advanced disease [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, preserved FVC may reflect different types of IPF patients and is not sufficient to indicate early IPF. This observation may have prognostic and therapeutic implications when considering the initiation of antifibrotic treatment or evaluating lung transplantation. Decreased DLCO or definite UIP pattern of diagnosis is associated with a poor prognosis [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Therefore, IPF patients with preserved FVC would allow a broader spectrum of treatment options [\u003cspan additionalcitationids=\"CR42 CR43 CR44 CR45\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe main limitations of this work are associated with the retrospective nature of the study, which impacts the comparison between both groups. However, the diagnostic, treatment and follow-up process was the same for all patients due to the standardized protocols of the ILD Unit in clinical practice. Another limitation of the study is the difficulty in extrapolating these results to regions or countries that do not have established rapid diagnostic circuit or do not have the option of training GPs and radiologists in specific diseases or conditions. Nevertheless, the established training program and rapid diagnostic circuit are feasible, so an international validation would be possible for implementing these procedures in ILD clinical practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eEarly identification of fibrotic ILDs is possible through a rapid referral circuit, a training program, and networking with primary care centers. Furthermore, rapid referral from primary care centers improves the patient\u0026rsquo;s journey, optimizes healthcare resources, and is associated with increased survival.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDisclosures:\u003c/h2\u003e\n\u003cp\u003eGuadalupe Bermudo (GB) has received for research projects from Boehringer Ingelheim, Hoffmann La Roche, not related with the present study.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eMedical writing and editorial assistance were funded by FUCAP (Catalan Foundation of Pneumology), through an unrestricted grant from Boehringer Ingelheim (BI) Spain.\u003c/p\u003e\n\u003cp\u003eBI had no role in the design, analysis, or interpretation of the results in this study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eGuadalupe Bermudo (GB) has received for research projects from Boehringer Ingelheim, Hoffmann La Roche, not related with the present study.Pilar Rivera-Ortega (PRO) has received speaker and consultations fees from Boehringer Ingelheim, The Limbic, Chiesi, Cipla, Tecnofarma, and Hoffmann La Roche, none of them related to this study. PRO has also received research honoraria from Boehringer Ingelheim, Hoffmann La Roche, CSL Behring, FibroGen, Vicore Pharma AB, Gilead Sciences, Galecto, and Chiesi; not related to the present study.V.Vicens-Zygmunt (VVZ) has received for research projects from Boehringer Ingelheim, not related with the present study.María Molina-Molina (MM) has received grants and fees for scientific advice, not related with the present study, from Boehringer Ing, Ferrer, Janssen, Roche, Raffo.B.Del Río (BDR), S.Bolivar (SB), E.Serra (ES), F.Ferrer (FF), R.Llatjós (RL), F. Rivas (FR), R.López-Lisbona (RLL), L.García (LG), S.Santos (SS) and P.Luburich (PL); have nothing to disclose.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to contain sensitive personal information of hospital patients and are subject to strict confidentiality agreements and data protection laws. However, anonymized data may be accessed by qualified researchers upon reasonable request and with approval from the University Hospital Bellvitge Ethics Committee (PR413/18).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStanel S, Rivera-Ortega P. Present and future perspectives in early diagnosis and monitoring for progressive fibrosing interstitial lung diseases. Front. Med. 2024. 10:1114722. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fmed.2023.1114722\u003c/span\u003e\u003cspan address=\"10.3389/fmed.2023.1114722\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaghu, G, Remy-Jardin, M, Richeldi, L, Thomson, CC, Inoue, Y, Johkoh, T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. 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Ann Am Thorac Soc. 2020;17(11): 1413\u0026ndash;23. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1513/AnnalsATS.201912-880OC\u003c/span\u003e\u003cspan address=\"10.1513/AnnalsATS.201912-880OC\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-primary-care-respiratory-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjpcrm","sideBox":"Learn more about [npj Primary Care Respiratory Medicine](https://www.nature.com/npjpcrm/)","snPcode":"41533","submissionUrl":"https://submission.springernature.com/new-submission/41533/3","title":"npj Primary Care Respiratory Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"primary care, rapid circuit, diagnostic delay, interstitial lung disease, pulmonary fibrosis","lastPublishedDoi":"10.21203/rs.3.rs-7224984/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7224984/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInterstitial lung diseases (ILDs) are complex rare diseases that associate a delay in diagnosis and eventually poor prognosis. Early and accurate diagnosis could be crucial. This study aimed to evaluate the feasibility and benefits of a rapid diagnostic circuit for ILD.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMethods\u003c/span\u003e: A training program for ILD identification and a direct referral diagnostic circuit to the ILD Unit of University Hospital of Bellvitge were established in primary care centers in the southern metropolitan area of Barcelona (Spain). ILD patients were diagnosed and followed-up until study completion, death or lung transplantation. Diagnostic, therapeutic and prognostic outcomes were compared to patients referred through the common circuit during the same period of time.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eResults\u003c/span\u003e: Of 123 patients referred directly from the primary care, 112 had ILD. The most common diagnosis were idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis. The main reasons for suspecting ILD were interstitial radiological features (74%) and abnormal lung auscultation (67%). Eighteen patients were asymptomatic. Compared with patients referred through the common circuit, there was a statistically significant reduction in the time from symptom onset to diagnosis (6 vs. 22.1 months, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and in the percentage of fibrosing ILD (55.9 vs 63.9%, p 0.36). Although patients from rapid circuit were older, they had better forced vital capacity and diffusing capacity for carbon monoxide at diagnosis (p 0.04) and lung biopsies were performed more frequently. More patients were elegible for lung transplant.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eConclusions\u003c/span\u003e: Identifying potential patients with fibrotic ILD through rapid circuit working with primary care physicians is feasible and useful.\u003c/p\u003e","manuscriptTitle":"The Benefits of a Rapid Diagnostic Primary Care Circuit for Interstitial Lung Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-11 09:58:15","doi":"10.21203/rs.3.rs-7224984/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-08T12:29:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T10:12:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"310842738416237834296999034816417913565","date":"2025-08-31T08:12:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-16T01:38:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225186989892083716388118798239114961057","date":"2025-08-13T08:15:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-05T16:18:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-29T00:14:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-29T00:12:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Primary Care Respiratory Medicine","date":"2025-07-27T08:11:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-primary-care-respiratory-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjpcrm","sideBox":"Learn more about [npj Primary Care Respiratory Medicine](https://www.nature.com/npjpcrm/)","snPcode":"41533","submissionUrl":"https://submission.springernature.com/new-submission/41533/3","title":"npj Primary Care Respiratory Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a82253f-2752-4bb9-a462-fc450c75f015","owner":[],"postedDate":"August 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":52833004,"name":"Health sciences/Diseases"},{"id":52833005,"name":"Health sciences/Health care"},{"id":52833006,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-12-01T16:10:05+00:00","versionOfRecord":{"articleIdentity":"rs-7224984","link":"https://doi.org/10.1038/s41533-025-00462-6","journal":{"identity":"npj-primary-care-respiratory-medicine","isVorOnly":false,"title":"npj Primary Care Respiratory Medicine"},"publishedOn":"2025-11-26 15:56:52","publishedOnDateReadable":"November 26th, 2025"},"versionCreatedAt":"2025-08-11 09:58:15","video":"","vorDoi":"10.1038/s41533-025-00462-6","vorDoiUrl":"https://doi.org/10.1038/s41533-025-00462-6","workflowStages":[]},"version":"v1","identity":"rs-7224984","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7224984","identity":"rs-7224984","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}