ORIGINAL RESEARCH published: 27 September 2021 doi: 10.3389/fmed.2021.699644 Management of Acute Exacerbation of Idiopathic Pulmonary Fibrosis in Specialised and Non-specialised ILD Centres Around the World Markus Polke 1 , Yasuhiro Kondoh 2 , Marlies Wijsenbeek 3 , Vincent Cottin 4 , Simon L. F. Walsh 5 , Harold R. Collard 6 , Nazia Chaudhuri 7 , Sergey Avdeev 8 , Jürgen Behr 9,10 , Gregory Calligaro 11 , Tamera J. Corte 12 , Kevin Flaherty 13 , Manuela Funke-Chambour 14 , Martin Kolb 15 , Johannes Krisam 16 , Toby M. Maher 17,18 , Maria Molina Molina 19,20 , Antonio Morais 21 , Catharina C. Moor 3 , Julie Morisset 22 , Edited by: Carlos Pereira 23 , Silvia Quadrelli 24,25 , Moises Selman 26 , Argyrios Tzouvelekis 27 , Sinéad Weldon, Queen’s University Belfast, Claudia Valenzuela 28 , Carlo Vancheri 29 , Vanesa Vicens-Zygmunt 30 , Julia Wälscher 1,31 , United Kingdom Wim Wuyts 32 , Elisabeth Bendstrup 33 and Michael Kreuter 1,10* Reviewed by: 1 Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, Heidelberg, Germany, Michael Keane, 2 Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan, 3 Department of Respiratory Medicine, University College Dublin, Ireland Centre for Interstitial Lung Diseases and Sarcoidosis, Erasmus University Medical Centre, Rotterdam, Netherlands, 4 National Corey Kershaw, Coordinating Reference Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, University University of Texas Southwestern Claude Bernard Lyon 1, Lyon, France, 5 Imperial College, National Heart and Lung Institute, London, United Kingdom, Medical Centre, United States 6 Department of Medicine, University of California, San Francisco, San Francisco, CA, United States, 7 North West Interstitial Riitta Kaarteenaho, Lung Disease Unit, Manchester University NHS Foundation Trust, Wythenshawe, Manchester, United Kingdom, 8 Sechenov University of Oulu, Finland First Moscow State Medical University, Moscow, Russia, 9 Medizinische Klinik und Poliklinik V, LMU Klinikum, University of *Correspondence: Munich, Munich, Germany, 10 German Center for Lung Research (DZL), Marburg, Germany, 11 Division of Pulmonology, Michael Kreuter Department of Medicine, University of Cape Town, Cape Town, South Africa, 12 Royal Prince Alfred Hospital, University of kreuter@uni-heidelberg.de Sydney, Sydney, NSW, Australia, 13 Department of Medicine, University of Michigan, Ann Arbor, MI, United States, 14 Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland, 15 Department of Medicine, Firestone Institute for Respiratory Health, Research Institute at St Joseph’s Healthcare, McMaster Specialty section: University, Hamilton, ON, Canada, 16 Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, This article was submitted to Germany, 17 Hastings Centre for Pulmonary Research and Division of Pulmonary, Critical Care, and Sleep Medicine, Keck Pulmonary Medicine, School of Medicine, University of Southern California, Los Angeles, CA, United States, 18 Interstitial Lung Disease Unit, a section of the journal Imperial College London, National Heart and Lung Institute, Royal Brompton and Harefield NHS Foundation Trust, London, Frontiers in Medicine United Kingdom, 19 Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), University Hospital of Bellvitge, L’Hospitalet de Received: 23 April 2021 Llobregat, Barcelona, Spain, 20 Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, Accepted: 26 August 2021 Spain, 21 Department of Pneumology, Faculdade de Medicina, Centro Hospitalar São João, Universidade do Porto, Porto, Published: 27 September 2021 Portugal, 22 Département de Médecine, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada, 23 Lung Disease Department, Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil, 24 Hospital Británico, Citation: Buenos Aires, Argentina, 25 Sanatorio Güemes, Buenos Aires, Argentina, 26 Instituto Nacional de Enfermedades Respiratorias Polke M, Kondoh Y, Wijsenbeek M, Ismael Cosío Villegas, Mexico City, Mexico, 27 Department of First Academic Respiratory, Sotiria General Hospital for Thoracic Cottin V, Walsh SLF, Collard HR, Diseases, University of Athens, Athens, Greece, 28 ILD Unit, Pulmonology Department Hospital Universitario de La Princesa, Chaudhuri N, Avdeev S, Behr J, Universidad Autonoma de Madrid, Madrid, Spain, 29 Regional Referral Centre for Rare Lung Diseases, A.O.U. Calligaro G, Corte TJ, Flaherty K, Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy, 30 Unit of Interstitial Lung Diseases, Department of Funke-Chambour M, Kolb M, Pneumology, Pneumology Research Group, IDIBELL, L’Hospitalet de Llobregat, University Hospital of Bellvitge, Barcelona, Krisam J, Maher TM, Molina Molina M, Spain, 31 Department of Pulmonary Medicine, Centre for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital Morais A, Moor CC, Morisset J, Essen, Essen, Germany, 32 Unit for Interstitial Lung Diseases, Department of Respiratory Diseases, University Hospitals Pereira C, Quadrelli S, Selman M, Leuven, Leuven, Belgium, 33 Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus C, Denmark Tzouvelekis A, Valenzuela C, Vancheri C, Vicens-Zygmunt V, Wälscher J, Wuyts W, Bendstrup E Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is and Kreuter M (2021) Management of Acute Exacerbation of Idiopathic a severe complication associated with a high mortality. However, evidence Pulmonary Fibrosis in Specialised and and guidance on management is sparse. The aim of this international Non-specialised ILD Centres Around the World. Front. Med. 8:699644. survey was to assess differences in prevention, diagnostic and treatment doi: 10.3389/fmed.2021.699644 strategies for AE-IPF in specialised and non-specialised ILD centres worldwide. Frontiers in Medicine | www.frontiersin.org 1 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians’ institutions. Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods. Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF. Keywords: idiopathic pulmonary fibrosis, acute exacerbation, questionnaire, pulmonologists, specialised ILD centres, non-specialised ILD centres INTRODUCTION this survey. Then, an expert panel was created, comprising pulmonologists with expertise in the diagnosis and management Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive of ILD working in specialist ILD centres and a track fibrosing interstitial lung disease associated with a poor prognosis record of publication in this field, to participate in an with a five-year survival rate of 20–40% and a median survival email-based interview to structure the survey. The final time of 2–5 years (1, 2). An acute exacerbation of IPF questionnaire consisted of 20 questions regarding diagnosis, contributes to the dismal prognosis and disease progression treatment and prevention of AE-IPF and suggested future and is defined as an acute, clinically significant respiratory perspectives in AE-IPF research (10). To identify working deterioration characterised by evidence of new widespread place (specialised and non-specialised ILD centres), country alveolar abnormality in patients with IPF and after the exclusion of origin, number of patients with IPF under care, and of cardiac failure or fluid overload (3). The annual incidence estimated number of AE-IPF seen, additional questions were is up to 20%, depending on the population analysed (4, included into this survey. From July 1 2017 to November 5). AE-IPF is associated with a median survival of ∼3– 30 2017 pulmonologists worldwide with interest in ILD 4 months (6, 7) and may account for more than 40% of were identified, including the European Respiratory Society all death in patients with IPF (8). The aetiology is still assembly on Diffuse Parenchymal Lung Disease, the American obscure, but AE-IPF might be triggered e.g. by infection or Thoracic Society assembly on Clinical Problems, the Japanese procedures/operation, or may occur idiopathic (6). Evidence Respiratory Society assembly on Diffuse Parenchymal Lung on prevention, diagnosis and therapy of AE-IPF is sparse Disease and participants of the IPF Project Consortium and no international guidelines exist (3, 9). Accordingly, there (www.theipfproject.com) (11). Nationality, academic status is a huge variability with regards to preventive, diagnostic (working at a university hospital or not) or subspecialist and therapeutic approaches worldwide (10). It is unknown interests within respiratory medicine did not influence whether these different strategies are partially explainable by inclusion eligibility. The questionnaire was provided by the differences between specialised and non-specialised ILD centres. online survey tool SurveyMonkey R from December 2017 to Therefore, this study aimed to compare preventive, diagnostic April 2018. and therapeutic strategies for AE-IPF between specialised and non-specialised ILD centres. Statistical Analysis For questions with categorical answers, absolute and relative MATERIALS AND METHODS frequencies were calculated and chi-squared tests were used to assess differences between specialised and non-specialised Questionnaire and Participating Physicians ILD centres. For questions with answers on a continuous As described previously (10), as a first step we conducted a scale, median, first and third quartile, minimum and maximum literature research on diagnostics, therapy, prevention and were determined and differences between continents were management of AE-IPF to identify items to be included in assessed using Kruskal–Wallis tests. Due to the exploratory Frontiers in Medicine | www.frontiersin.org 2 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management nature of this survey, all resulting p-values are solely to be more frequent in non-specialised ILD centres (22 vs. 12%, p = interpreted descriptively and no adjustment for multiple testing 0.0106). Conversely, pathogen testing in urine was performed was conducted. p-values smaller than 0.05 were regarded as significantly more often in specialised ILD centres than in statistically significant. All analyses were conducted using R non-specialised ILD centres (42 vs. 28%, p = 0.0068). 50% of v.3.4.2 (http://r-project.org). specialised ILD centres screened for RSV (respiratory syncytial virus), compared to only 33% in non-specialised ILD centres (p = 0.0024). The use of biomarker KL-6 was higher in non- RESULTS specialised ILD centres than in specialised ILD centres (24 vs. Participants 15%, p = 0.0313). The most relevant diagnostic procedures Overall, 509 pulmonologists from 66 countries responded. Three applied for AE-IPF are shown in Figure 2. Other diagnostic hundred and thirty four (65.9%) of the participants worked in procedures such as laboratory parameters or specific pathogens a specialised ILD centre, 142 (28.0%) in non-specialised ILD are shown in Supplementary 1. centres i.e. in a general pulmonology department, 4 (0.8%) on an intensive care unit and 27 (5.3%) did not indicate their Treatment Approaches for AE-IPF institution. Physicians working on an intensive care unit or who The majority of participating pulmonologists treated AE-IPF did not indicate their institution were excluded from the analysis. with methylprednisolone or equivalent with a dosage of 500– A total of 436 pulmonologists working in a specialised or non- 1,000 mg per day for 3 days followed by a slow tapering similarly specialised ILD centre were included in this analysis. On average in both types of institutions (63 vs. 66%). 331 cases of AE-IPF were seen in specialised ILD centres and 139 Other immunosuppressive therapies such as cyclosporine, in non-specialised ILD centres. Figure 1 shows the place of work cyclophosphamide (i.v. bolus), tacrolimus and rituximab were (continent) of the respondents in specialised and non-specialised rarely used in both specialised and non-specialised ILD centres, ILD centres. but cyclosporine was significantly more frequently used in non- specialised ILD centres (13 vs. 6%, p = 0.0288). Diagnostic Procedures for AE-IPF Other therapies such as polymyxin B hemoperfusion (7 vs. Most diagnostic tools, including multi-slice thin-section 10%), and plasmapheresis/plasma exchange (4 vs. 5%) were computer tomography without contrast media (HRCT), CT with also less commonly used in specialised and non-specialised ILD contrast media in the absence of clinical suspicion of pulmonary centres. However, significantly more pulmonologists treated their embolism, bronchoalveolar lavage (BAL), echocardiography, patients with recombinant thrombomodulin in non-specialised assessment for pathogens, NT-proBNP/BNP, D-Dimer and ILD centres than in specialised ILD centres (15 vs. 8%, p troponins were used similarly between specialised and non- = 0.0342). specialised ILD centres. The main difference was the sampling Differences between institutions in the use of treatment of sputum for microbiology (induced sputum) which was strategies are shown in Figure 3. See also Supplementary 1. FIGURE 1 | Number of participants in specialised and non-specialised ILD centres from different continents. Frontiers in Medicine | www.frontiersin.org 3 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management Antifibrotic Therapy Management During significantly more physicians in specialised ILD centres would AE-IPF start diuretic therapy than in non-specialised ILD centre (54 vs. In patients without antifibrotic therapy, the majority of the 41%, p = 0.0210). Only a minority in both institutions would survey participants see a reason to initiate an antifibrotic therapy perform right heart catheterization in AE-IPF in suspected PH in the event of an AE-IPF in specialised and non-specialised ILD (6 vs. 7%). Seven percentage would start a PH specific treatment centres (66 vs. 69%). after an established PH diagnosis in a specialised ILD centre, The choice of the antifibrotic drug did also not differ significantly more (14%) would do so in a non-specialised ILD significantly between specialised and non-specialised centres centre (p = 0.0494). Only 3% of physicians in a specialised (nintedanib 20 vs. 20%, pirfenidone 11 vs. 19%, no preference for ILD centre and 1% in a non-specialised centre would start specific anti-fibrotic drug 35 vs. 28%). a PH specific treatment without a confident diagnosis. After For patients already on antifibrotic therapy at the time of AE- stabilisation of AE-IPF, more than 50% of physicians would IPF, there was no significant difference in the approach: 80% evaluate a PH specific treatment by subsequently performing of respondents in specialised ILD centres would continue and right heart catheterization (56 vs. 55%). A quarter of all 5% would discontinue antifibrotic therapy, compared to 70% participating pulmonologists in specialised and non-specialised continuing (p = 0.0513) and 7% discontinuing therapy (p = ILD centres saw no indication for a PH treatment during or after 0.5491) in non-specialised ILD centres. The dose was reduced by AE-IPF (Supplementary 1). 1 % in specialised ILD centres compared to 5% in non-specialised ILD centres (p = 0.0301), 9% would switch to the alternative Intensive Care Unit (ICU) and Palliative antifibrotic therapy in specialist ILD centres and similarly 10% Care in AE-IPF would switch in non-specialised ILD centres (p = 0.999). With regards to the care for critically ill patients with AE, Different strategies in this situation are also shown in Figure 4. there were no differences in specialised and non-specialised For further strategies see Supplementary 1. ILD centres for the use of high-flow oxygen (84 vs. 78%) and non-invasive ventilation (NIV) (72 vs. 77%). 9% of specialised Management of Pulmonary Hypertension and 11% of non-specialised ILD centres use invasive ventilation (PH) During AE-IPF for all critical ill patients, whereas 48 vs. 39% respectively In the case of suspected PH on clinical investigations (e.g. would only use invasive ventilation in patients suitable for lung echocardiography, BNP, clinical signs) during an AE-IPF, transplantation (LTX) as a bridge to LTX or in very selected cases. FIGURE 2 | The main diagnostic procedures applied for AE-IPF in specialised and non-specialised ILD centres. Statistically significant differences are labelled with a * (p-value = <0.05). Frontiers in Medicine | www.frontiersin.org 4 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management FIGURE 3 | Different treatment strategies towards AE-IPF in specialised and non-specialised ILD centres. Statistically significant differences are labelled with a * (p-value = <0.05). FIGURE 4 | Different strategies in AE-IPF concerning an antifibrotic treatment in specialised and non-specialised ILD centres. Statistically significant differences are labelled with a * (p-value = <0.05). Significantly more physicians in specialised ILD centres Institutional differences in these approaches are shown in offered extracorporeal membrane oxygenation (ECMO) to Figure 5 (Supplementary 1). patients suitable for LTX as a bridge to LTX than in non- specialised ILD centres (49 vs. 36%, p = 0.0287). Preventive Strategies for AE-IPF Palliative care was considered similarly in both types of Measures aimed at preventing the occurrence of AE-IPF was institutions (65 vs. 62%). equal amongst specialised and non-specialised ILD centres Frontiers in Medicine | www.frontiersin.org 5 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management FIGURE 5 | Different management strategies in critically ill patients with AE-IPF in specialised and non-specialised ILD centres. Statistically significant differences are labelled with a * (p-value = <0.05). and included vaccinations, antifibrotic therapy and pulmonary who saw a need of improvement in multidisciplinary strategies rehabilitation or other forms of structured exercise therapy. for diagnosing and discussions than in specialised ILD centres Antacid drugs were prescribed significantly more in non- (67 vs. 53%, p = 0.0088). specialised ILD centres than in specialised ILD centres (61 vs. 50%, p = 0.0438) in all IPF patients. Long-term azithromycin, low dose steroids (≤10 mg) and anticoagulation (to prevent DISCUSSION AE-IPF) were only used by a minority in both types Despite the fact that AE-IPF is one of the most common causes of institutions. of death in IPF (3), evidence on prevention, additional diagnostic In terms of planned surgical procedures, significantly more approaches besides HRCT and treatment of this complication physicians in specialised ILD centres favoured preventive is sparse and differs significantly worldwide (10). No particular anaesthetic measures such as low tidal volume and avoidance evidence-based guidance exists. Here we report analyses on of hyperoxygenation compared to physicians in non-specialised similarities and differences in the management of AE-IPF in ILD centres (72 vs. 61%, p=0.0368). specialised vs. non-specialised ILD centres. The strength of our Institutional differences in preventive strategies are shown in report was the significant number of physicians who replied Figure 6. See also Supplementary 1. to our survey representing both specialised and non-specialised ILD centres. Unmet Needs in AE-IPF Diagnostic procedures were almost identical in both Pulmonologists in both specialised and non-specialised ILD specialised and non-specialised ILD centres, including radiology centres advocate more intensive collaboration between different and screening for infections. Molyneaux et al. have showed that ILD specialists; improved education and training of physicians; there is an increased bacterial load in the BAL of IPF patients education of patients and caregivers as well as enhanced research with AE-IPF compared to stable IPF patients (12) suggesting to improve the understanding of the pathophysiology, diagnosis a potential causative role in AE-IPF. There is evidence for the and management of AE-IPF. Physicians working in specialised contribution of lung microbiota in disease progression and in ILD centres saw a stronger need for intensified research and acute exacerbation (13, 14). Microbiological confirmation may projects on the treatment of AE-IPF (90 vs. 80%, p = 0.0101). therefore play an important role in the diagnostic process and There were more pulmonologists in non-specialised ILD centres may be useful for future therapeutic and preventive strategies. Frontiers in Medicine | www.frontiersin.org 6 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management FIGURE 6 | Different preventive strategies in AE-IPF in specialised and non-specialised ILD centres. Statistically significant differences are labelled with a * (p-value = <0.05). The majority of physicians in specialised and non-specialised Other immunosuppressants and strategies are used ILD centres screen for pathogens in sputum, deemed a safer less frequently. Very few pulmonologists never use method to screen for pathogens compared to bronchoscopy. A immunosuppression for AE-IPF. Although there is only recent study supports this approach as a positive bronchoscopy low evidence base for the use of more potent anti-inflammatory only affected management in 13% of patients and resulted in treatment approaches such as cyclosporine A, intravenous a change of treatment in <5% (15). Furthermore, in the same cyclophosphamide or tacrolimus (20–24), they are used by some study, a significant number of patients required intubation pulmonologists in non-specialised and specialised ILD centres. A and transfer to the ICU with poor extubation success post randomised, double-blinded clinical trial of cyclophosphamide in bronchoscopy (15). Conversely, a study has demonstrated AE-IPF with 120 patients was completed and results are eagerly the feasibility and safety of performing BAL aided by NIV awaited (https://clinicaltrials.gov/ct2/show/NCT02460588). as a useful tool for differentiating or confirming triggered The international guidelines recommend avoiding ICU in AE (16). patients with AE-IPF (weak recommendation) (25) because the Furthermore, there is a similarity in therapeutic approaches. mortality of patients with AE-IPF admitted to ICU, particularly The majority of pulmonologists in specialised and non- in ventilated patients, is high (26). Some patients who do not specialised ILD centres use antibiotic therapy, namely broad- respond to conventional oxygen therapy benefit from high flow spectrum antibiotic combined with macrolide. High dose steroids oxygen (27). NIV may be a reasonable option for some critically are widely administered in non-specialised and specialised ill patients (28). Trudzinski et al. showed that ECMO is only ILD centres in AE-IPF. High dose long-term steroid use was an option for patients who are suitable for LTX, as it conferred associated with an increased mortality in the PANTHER trial (17) limited impact on the poor prognosis for those who were not and a history of previous immunosuppression before AE-IPF has LTX candidates (29). This might be a reason for pulmonologists a negative impact on mortality (18). Recently, a retrospective in no matter what kind of institution to prefer NIV and high-flow study with 82 AE-IPF patients showed that subjects receiving oxygen in patients with AE-IPF. Data on this is however limited. corticosteroids were more likely to require ICU level care In non-specialised and specialised ILD centres prevention and mechanical ventilation and therefore did not benefit from strategies towards AE-IPF were performed to the same extent. treatment with corticosteroids (19). However, future studies with Vaccinations were most frequently used; although their use is larger cohorts are necessary to prove the deleterious effects of recommended by the international guideline, there is a lack of steroid therapy. evidence to support this recommendation (30). Frontiers in Medicine | www.frontiersin.org 7 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management The approach by physicians to utilise antifibrotic drugs as meetings are widely used in the process of diagnostic and a form of preventive strategy is supported by recent data patient management (48) and they improve confidence in ILD of controlled trials that suggest nintedanib may prolong the diagnostics (49). MTD meetings are officially recommended (50). time to the first AE-IPF (31) and reduces mortality after AE- Arguably, MTD are more available in specialised ILD centres. IPF (32). Pirfenidone reduces the risk for respiratory related Many of the differences observed underscore the high and hospitalisation in post-hoc analyses (33). Data proving a reduced still unmet need for intensive research in AE-IPF. However, frequency of AE-IPF with pirfenidone is sparse: In a Phase 2 trial others might be associated with strategies applied outside current of 107 patients Azuma et al. found a significant reduction of AE- evidence. This demonstrates how important education in rare IPF in patients using pirfenidone (34). A larger trial could not diseases and their complications is. prove this (35). Our survey has some limitations: The survey was not designed While a Japanese study suggested a role for anticoagulants for a data driven assessment of management practises but to prevent AE-IPF (Kubo et al.), a more recent study did not mainly to evaluate attitudes towards different aspects of AE- support this (36). This is in line with the results shown here: only IPF. Participation was voluntarily and biased by involvement a minority use anticoagulants to prevent AE-IPF. This is further i.e. non-participating centres may have answered differently. supported by data suggesting a negative impact of anticoagulants Additionally, there was an imbalance between the number on survival in IPF in general (37, 38). of specialised and non-specialised ILD institutions. Moreover, Besides many similarities in the approach towards AE-IPF, the number of ILD centres and patient numbers and thus there are also some differences in ILD specialised and non- experiences of diagnosis and management of AE-IPF may vary specialised ILD centres. from country to country. Arguably, the number of IPF patients PH is common in patients with IPF (39). Its prevalence at and cases of AE-IPF are higher in Japan as an example, than baseline means a higher risk for a subsequent AE-IPF, it is in other countries (51). Therefore, non-specialised ILD centres associated with a poorer overall survival but until now no specific in Japan may have a higher number of patients to treat and PH treatment could show a benefit for IPF patients (40, 41). thus greater experience than other non-specialised ILD centres Significantly more pulmonologists in specialised ILD centres elsewhere. More experienced physicians in the field of AE- start diuretics compared to non-specialised ILD centres, and in IPF might have influenced the results of this questionnaire. line with the lack of benefits for specific PH treatment, most Furthermore, the availability of treatments differs clearly between physicians do not use a specific PH treatment. countries/continents, e.g., recombinant thrombomodelin is used Many physicians use antacid drugs as a preventive strategy almost exclusively in Asia and here by a quarter of all physicians for AE-IPF, significantly more in non-specialised ILD centres. (10). This might explain the fact that thrombomodulin is used Lee et al. reported a higher pepsin level in the BAL of patients more often in non-specialised ILD centres. The same applies for with AE-IPF compared to patients with stable disease (42) and a the use of KL-6 in the diagnostic process of AE-IPF. Finally, not retrospective analysis showed a positive impact of antacid drugs all aspects of approaches to AE-IPF could be addressed in the on the course of IPF (43, 44). Other studies could not repeat questionnaire. The current COVID-19 pandemic was not part of this effect and suggested potentially higher rates of respiratory the questionnaire because it was sent out before. This situation infections (45) and AE-IPF (46). The reason for the difference might have a huge impact on how AE-IPF is managed and this in the use of anti-acid drugs remains unclear, maybe because was not assed in the survey. specialised ILD centres treat patients who are more ill or In conclusion, specialised and non-specialised ILD centres receive palliative treatment. Also different prescription rules in throughout the world do only differ in some aspects in different countries or the fact that an old statement published by the management of AE-IPF. Due to scant evidence and international societies from 2011 recommended their use (9) may missing focused guidelines basic research and clinical trials be responsible. have to be performed to establish optimal approaches to this Only a few pulmonologists use low dose steroids as a deadly complication. preventive strategy for AE-IPF, most of them in non-specialised ILD centres. This approach is in line with the international DATA AVAILABILITY STATEMENT guideline where it is not recommended to use steroids beyond AE-IPF (17, 25). Furthermore, the use of corticosteroids has a The original contributions presented in the study are included negative effect on the outcome of IPF patients who received in the article/Supplementary Material, further inquiries can be nintedanib (47). directed to the corresponding author. Both pulmonologists in specialised and non-specialised ILD centres saw a high requirement for improved research strategies ETHICS STATEMENT for AE-IPF. Significantly more non-specialised ILD centres saw the need for improvement in multidisciplinary strategies Ethical review and approval was not required for the study for diagnosing and discussion compared to pulmonologists on human participants in accordance with the local legislation in specialised ILD centres. Multidisciplinary team (MTD) and institutional requirements. Written informed consent Frontiers in Medicine | www.frontiersin.org 8 September 2021 | Volume 8 | Article 699644 Polke et al. Differences of AE-IPF Management from the participants was not required to participate in this ACKNOWLEDGMENTS study in accordance with the national legislation and the institutional requirements. We would like to thank all participants who generously agreed to participate in this study. AUTHOR CONTRIBUTIONS SUPPLEMENTARY MATERIAL MP and MK contributed mainly to the conception and design of the study. MP wrote the first draft of the manuscript. JK The Supplementary Material for this article can be found performed the statistical analysis. All authors contributed to online at: https://www.frontiersin.org/articles/10.3389/fmed. manuscript revision, read, and approved the submitted version. 2021.699644/full#supplementary-material REFERENCES acute exacerbation of pulmonary fibrosis. Nat Commun. (2020) 11:1539. doi: 10.1038/s41467-020-15344-3 1. 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