Open Respiratory Archives 4 (2022) 100211 Open Respiratory Archives www.elsevier.es/ora Original article Systematic Review of Systemic Corticosteroids for Treatment of Organizing Pneumonia Laia Cendon a,1 , Albert Rafecas Codern a,1 , David de la Rosa a,b , Ivan Castellví b,c , Paolo Spagnolo d , Diego Castillo a,b,∗ a Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain b Sant Pau Institute for Biomedical Research (IIB-Sant Pau), Barcelona, Spain c Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain d Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy a r t i c l e i n f o a b s t r a c t Article history: Introduction: Regardless corticosteroids are recommended for the treatment of organizing pneumo- Received 27 June 2022 nia there is limited evidence supporting this practice. Thus, we performed a systematic review of the Accepted 16 August 2022 literature on systemic corticosteroid treatment for organizing pneumonia. Available online 19 September 2022 Methods: A search was implemented in the PubMed database (Medline) for articles published in the last 20 years. Those studies with incomplete or insufficient data and case reports were excluded. We collected Keywords: data including: demographics, clinical data, diagnostic procedures, aetiology, treatment regimen (drug, Organizing pneumonia posology, duration, response) and evolution. Corticosteroids Steroids Results: A total of 135 publications were selected and finally 13 studies with 849 patients were included in Treatment the review: 12 retrospective observational studies and a single prospective observational study. Most of the patients were started on treatment with systemic corticosteroids – a total of 627 (30–100% depending on the series), but there was a great heterogeneity regarding drug, doses and duration. On those that started treatment, 226 (36%) presented a relapse of the disease during follow-up. Only one study provided information regarding treatment side-effects. Conclusion: The findings of this systematic review show the low quality data supporting the use of corti- costeroids for the treatment of organizing pneumonia. This highlights a need to undertake appropriately designed studies to investigate which is the most appropriate treatment regimen that trades off benefits and risks of prolonged corticosteroid administration. © 2022 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Revisión sistemática de los corticosteroides para el tratamiento de la neumonía organizativa r e s u m e n Palabras clave: Introducción: Aunque los corticosteroides están recomendados para tratar la neumonía organizada, hay Neumonía organizada pocos datos que respalden esta práctica, por lo cual efectuamos una revisión sistemática de la bibliografía Corticosteroides sobre el tratamiento con corticosteroides sistémicos para la neumonía organizada. Esteroides Métodos: Se hizo una búsqueda en la base de datos PubMed (Medline) de artículos publicados en los Tratamiento últimos 20 años. Se descartaron los estudios con datos y casos clínicos incompletos o insuficientes. Los datos que recabamos abarcaron: datos demográficos, datos clínicos, técnicas diagnósticas, etiología, pauta terapéutica (fármaco, posología, duración, respuesta) y evolución. ∗ Corresponding author. E-mail address: dcastillo@santpau.cat (D. Castillo). 1 Contributed equally. https://doi.org/10.1016/j.opresp.2022.100211 2659-6636/© 2022 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). L. Cendon, A. Rafecas Codern, D. de la Rosa et al. Open Respiratory Archives 4 (2022) 100211 Resultados: Se eligieron 135 publicaciones en total y se incorporaron finalmente a la revisión 13 estudios con 849 pacientes: 12 estudios observacionales retrospectivos y un solo estudio observacional prospec- tivo. La mayor parte de los pacientes habían comenzado el tratamiento con corticosteroides sistémicos, un total de 627 (30%-100% en función de la serie), pero la duración, las dosis y el fármaco manifestaron una gran heterogeneidad. Entre los que habían empezado el tratamiento, 226 (36%) presentaron una recidiva de la enfermedad durante el seguimiento. Solo en un estudio se ofreció información sobre los efectos adversos del tratamiento. Conclusión: Los resultados de esta revisión ponen de manifiesto la escasa calidad de los datos sobre el tratamiento de la neumonía organizada con corticosteroides. Este hecho destaca la necesidad de empren- der estudios diseñados correctamente para investigar la pauta terapéutica más adecuada que compense los riesgos y beneficios de la administración prolongada de corticosteroides. © 2022 Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR). Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Introduction Data extraction Organizing pneumonia (OP) is an interstitial lung disease Retrieved publications on OP treated with systemic corticos- (ILD) initially described as bronchiolitis obliterans with organizing teroids were evaluated for inclusion in this systematic review by pneumonia,1 a label currently in disuse because the bronchiolitis two authors (LC and AR). Due to the heterogeneity of the informa- is a minor finding.2 OP is histologically characterized by intra- tion retrieved, we excluded from the analysis those studies with alveolar buds of granulation tissue composed of myofibroblasts and incomplete or insufficient data and case reports. fibroblasts intermixed with connective tissue.3 It is thought of as a nonspecific response to a local or distant injury triggered in the Data analysis lung.4,5 Clinical manifestations include an influenza-like syndrome – consisting of fever, cough, asthenia, and weight loss – that evolves Data extracted from the selected articles and compiled in a to dyspnoea and different degrees of hypoxaemia. The typical clin- Microsoft Excel 2010 document included: demographics (age, sex), ical picture is non-specific, so a delay in diagnosis is frequent.2,6 clinical data (comorbidities, symptoms, OP extension), procedures Cryptogenic organizing pneumonia (COP) is the idiopathic form performed to obtain the diagnosis, suspected cause/s, treatment of OP, while OP with a known trigger is referred to as secondary (drug, posology, duration, response), and relapse. organizing pneumonia (SOP). Triggers for SOP include systemic autoimmune disease (SAD), infection, malignancy, drug, radia- Results tion, transplant, and aspiration. COP is diagnosed after ruling out known causes of OP in a compatible clinical, radiological, and The bibliography search flowchart is depicted in Fig. 1. The sys- histopathological setting.3 While there is no evidence of histolog- tematic search resulted in 135 publications. Of these, 13 were not ical differences between COP and SOP,7 classification is important included in the study because either the full text was unavailable because appropriate management requires identification of the or they were unrelated to the aim of the review. Then 122 articles underlying cause or trigger of SOP.3 Pharmacological treatment were selected for reading.2,4–8,12–126 The most frequent exclusion for OP is based on the use of systemic corticosteroids, mainly – criterion was sample size, as most publications were case reports. given the possibility of spontaneous remission – for symptomatic Finally 13 studies with 849 patients were included in the review: and progressive forms of OP.8 Corticosteroid treatment rapidly 12 retrospective observational studies and a single prospective improves the clinical and radiological picture. However, dosage observational study (Table 1).2,6,12–14,54,120–126 Sample size ranged and treatment duration are not well established and relapse is between 19 and 176 patients. Clinical findings are summarized in common.5 Therapeutic recommendations vary widely between Table 2. Radiological and laboratory data and diagnostic procedures studies, which highlights the great heterogeneity in OP manage- are shown in the supplementary data (Tables A1 and A2). ment. Most of the 849 patients were started on treatment, 627 (74%) In this study, we performed a systematic review of the evidence with systemic corticosteroids (30–100% depending on the series) on systemic corticosteroid treatment for OP in the last 20 years. (Fig. 2). A detail review of each study is shown in the supplementary data (Table A2). Overall, the studies reported a favourable initial Materials and methods response to the treatment in the majority of cases, including partial or complete resolution. Basarakodu et al.12 found full resolution in Search strategy 38 cases (67%), Yoo et al. in 40 cases (40%),121 while Okada et al. reported completed resolution in all patients treated with CS.14 A systematic literature search was implemented in May 2020 The most widely prescribed corticosteroid was prednisone (5 in the PubMed database (Medline) for articles published between studies), followed by methylprednisolone, although the corticos- January 1st 2000 and May 31st 2020. We decided to set our start teroid type was not specified in 6 studies. Moreover, as the majority date agreeing with the publication of international guidelines that of the studies were retrospective the period of treatment and the specified the definition of OP in the context of other ILD.9,10 Arti- timing of steroid tapering were not unified, which resulted in a huge cles were limited to those published in English and Spanish. The variability regarding CS total dose and duration (Fig. 2). Altogether, MeSH terms used for the search were “cryptogenic organizing patients were treated initially with high CS doses, with regimens pneumonia” (which includes the term “organizing pneumonia” and superior to 0.5 mg/kg/day, at least 4 weeks, followed by gradual “bronchiolitis obliterans with organizing pneumonia”) and “corti- tapering in the following 6–12 months (Table A2). costeroids”. Additional articles were sought in the reference lists About other therapies, spontaneous OP resolution was observed of articles retrieved from PubMed. We followed the PRISMA guide- in 31 patients (3.6%), reported as asymptomatic or mild involve- lines for reporting systematics reviews.11 ment cases, who received no specific treatment. Lung resection 2 L. Cendon, A. Rafecas Codern, D. de la Rosa et al. Open Respiratory Archives 4 (2022) 100211 Fig. 1. Study selection flowchart. Table 1 Articles included in the systematic review. Author, year Country Patients Design 54 1 Cazzato, 2000 Italy 78 Retrospective observational 2 Lazor, 200013 France 48 Retrospective observational 3 Basarakodu, 200712 USA 57 Retrospective observational 4 Barroso, 2007120 Spain 33 Retrospective observational 5 Drakopanagiotakis, 20116 Greece/USA 61 Prospective observational 6 Yoo, 2011121 South Korea 100 Retrospective observational 7 Nishino, 2014122 USA 26 Retrospective observational 8 Okada, 201614 Japan 19 Retrospective observational 9 Onishi, 2016123 Japan 75 Retrospective observational 10 Baha, 20182 Turkey 56 Retrospective observational 11 Saito, 2019124 Japan 33 Retrospective observational 12 Zhou, 2019125 China 87 Retrospective observational 13 Zhang, 2020126 China 176 Retrospective observational Total patients 849 surgery was the only treatment in 99 cases (11.6%), while antibi- (31.5 ± 39.4 mg/L vs 17.5 ± 32.2 mg/L, p = 0.038) and DLCO lower otics (anti-inflammatory treatment with macrolides) were used in (45.9 ± 14.2% vs 57.6 ± 18.5%, p = 0.05) in the relapse group.125 In 14 cases (1.6%). Information regarding other cytotoxic drugs is very other study, BAL neutrophilia (OR 1.07, CI 1.02–1.13, p = 0.012) and limited, as only in one study half of the patients were under this high levels of fibrin deposits (OR 17.4, CI 1.89–160.9, p = 0.012) were regimen.121 independent predictors of relapse.123 Among the 849 patients included in the analysis, 66 deaths With reference to CS side effects, it was not described in the (7.7%) were reported. In 9 cases were documented as in-hospital, majority of studies. Lazor et al. reported a rate of adverse effects whereas for the remaining occurred during follow-up. The rela- as high as 25%,13 Barroso et al. up to 17 of 32 cases (53%),120 while tion of this event with the diagnosis of OP was not described in all Onishi et al. described one or more adverse effects of corticosteroid studies. Yoo et al. showed 23 deaths among 100 cases (23%), while therapy in 39 of the 75 patients (52%).123 The most frequent side- disease-related was limited to 14 patients (14%).121 effects were weight gain, myopathy, osteoporosis, hypertension, or A non-negligible number of patients (240 of 849) experienced systemic infection. one or more relapses at some point during their follow-up: 28% of patients with OP, and 36% of patients treated with corticos- Discussion teroids. Most relapses occurred when corticosteroids were tapered or suspended. The period of time until the event was wide. In The thirteen studies analyzed in this systematic review reveal a Okada et al. relapses occurred at between 3 months and 14 years widespread use of systemic corticosteroids to treat OP, with most of (mean 5.3 years) after OP diagnosis,14 and in Lazor et al. at between the 849 patients responding favourably in terms of their symptoms 2 and 46 months (mean 5 months) after starting treatment for and radiological abnormalities. However, our analysis also shows the first OP episode.13 In this study, the subgroup with multiple that there is currently no consensus regarding the most appropriate relapses (≥3) was characterized by delayed treatment of the first corticosteroid, its dose, and the duration of treatment. A significant OP episode and mild cholestasis in laboratory tests.13 Saito et al. number of relapses were reported during follow-up, even in those found that radiographic findings, such as bilateral shadow pattern, that had been treated with CS. However, key clinical questions as traction bronchiectasis, and partial remission, may have possibil- causes of non-response to steroids, recurrence and the usefulness ity of predictive factors for COP relapse.124 Zhou et al. showed that of other drugs in OP remain answered with the information derived fever was more common (65% vs 32%, p = 0.04), serum CRP higher from these articles. 3 L. Cendon, A. Rafecas Codern, D. de la Rosa et al. Table 2 Characteristics and symptoms of patients with organizing pneumonia (n = 849). Cazzato, Lazor, Basarakodu, Barroso, Yoo, Drakopan- Nishino, Onishi, Okada, Baha, Saito, Zhou, Zhang, 2000,54 2000,13 2007,12 2007,120 2011,121 agiotakis, 2014,122 2016,123 2016,14 2018,2 2019,124 2019,125 2020,126 n = 78 n = 48 n = 57 n = 33 n = 100 2011,6 n = 26 n = 75 n = 19 n = 56 n = 33 n = 87 n = 176 n = 61 Mean (SD) 61 ± 12 61 ± 11 63 ± 15 62 ± 10 54.8 ± 12.3 60.5 ± 13.6 62.5 69.9 ± 10.3 61.9 ± 8 57.1 ± 12.7 Relapse: 56.1 ± 10.4 Unilateral age (COP) (CTD- (39–78) 71 ± 10; (31–75) 55.9 ± 9.4 (years) 59 ± 15 OP)/56.0 ± 11.5 No Bilateral (SOP) (COP) relapse: 55.8 ± 10.0 74 ± 14 Sex (F) 36 (46%) 31 (65%) 26 (46%) 18 (55%) 65 (65%) 34 (56%) 8 (31%) 32 (43%) 12 (63%) 27 (48%) 15 (45%) 42 (48%) 73 (41%) Smokers 53 (68%) 14 (29%) – 10 (30%) 15 (15%) 33 (54%) 1 (4%) – 7 (37%) 33 (59%) 14 (42%) 24 (28%) 55 (31%) Lung – – 12 (21%) – – – – – 4 (21%) – – – – disease Fever 49 (63%) – 16 (28%) 26 (76%) – 39 (64%) – 42 (56%) 15 (79%) 24 (43%) 22 (67%) 40 (46%) – Cough 41 (53%) – 26 (46%) 29 (88%) – 40 (66%) – 44 (59%) 8 (42%) 40 (71%) 27 (82%) 73 (84%) – Dyspnoea 45 (58%) – 45 (79%) 19 (58%) 85 (85%) 38 (62%) – 17 (23%) 6 (32%) 37 (66%) 20 (61%) 54 (32%) – Asthenia 30 (38%) – 16 (28%) – – 44 (72%) – – – 36 (64%) – – – Weight loss 10 (13%) – 8 (14%) 14 (42%) – 17 (28%) – – – 14 (25%) – 9 (10%) – 4 Flu-like 21 (27%) – 2 (3.5%) 7 (21%) – 15 (26%) – – – – – – – symp- arthralgia toms Chest pain 2 (3%) – 16 (28%) 18 (52%) – 18 (30%) – – – 7 (12.5%) 1 (3%) 4 (5%) – Haemoptysis 1 (1%) – – 12% – – – – – 4 (7%) – 5 (6%) – Asymptomatic 10 (13%) – – – – – 7 (9%) – – – – Aetiology 53 (68%) 48 (100%) 30 (53%) 33 (100%) 76 (76%) 40 (66%) 26 (100%) 40 (53%) 19 (100%) 37 (66%) 33 (100%) 87 (100%) 176 COP COP COP COP COP COP COP COP; SOP: COP COP COP (100%) 25 (32%) 27 (47%) 24 (24%) 21 (34%) 35 (47%) 18 (95%) 19 (34%) COP SOP: SOP: CTD–OP. SOP: SOP: RA SOP: 7 (9%) 8 (14%) 7 (7%) RA 6 (10%) 18 (24%) 1 (5%) 4 (7%) RA, drugs infec- 6 (6%) SS drugs SAD, bacterial 3 (5%) SS, 5 (6%) tions 3 (3%) PM 5 (8%) 6 (8%) infection 1 (4%) radio- 7 (12%) solid infec- SLE, therapy CTD tumours tions, 2 (4%) 5 (6%) 7 (12%) 4 (7%) 11 (15%) lym- Open Respiratory Archives 4 (2022) 100211 CTD drugs CTD others phoma COP: cryptogenic organizing pneumonia; COPD: chronic obstructive pulmonary disease; CTD: connective tissue disease; F, female; HBV: hepatitis B virus; IBD: inflammatory bowel disease; ILD: interstitial lung disease; M, male; OSAS: obstructive sleep apnoea syndrome; PMR: polymyalgia rheumatica; POEMS: peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma-cells proliferative disorder and skin change syndrome; RA: rheumatoid arthritis; SAD: systemic autoimmune disease; SS: Sjögren syndrome; PM: polymyositis; SLE: systemic lupus erythematosus; SOP: secondary organizing pneumonia. L. Cendon, A. Rafecas Codern, D. de la Rosa et al. Open Respiratory Archives 4 (2022) 100211 Fig. 2. Summary of corticosteroids prescription and response for the treatment of organizing pneumonia. T: therapy; D: initial dose; E: death; R: relapse; CS: corticosteroids; PDN: prednisone; MTP: methylprednisolone; COP: cryptogenic organizing pneumonia; CTD-OP: connective tissue disease-organizing pneumonia. Based on the reviewed studies, OP is characterized by a regimens tended to last at least 6 months and corticosteroid dose non-specific clinical picture with respiratory and constitutional was progressively tapered off to minimize the risk of relapse. This symptoms, radiological images of bilateral multifocal lung con- is confirmed by the reviewed studies, which reported relapse rates solidation, and in the absence of any infectious processes. For as high as 21–66% depending on the study. Lazor et al. concluded diagnostic purposes as a first option, before considering more that a delay in initiating treatment increased the risk of relapse, invasive techniques such as surgical biopsy, most authors used a although prolonged treatment did not seem to have any effect on combination of BAL (which typically shows lymphocyte predomi- the incidence of relapses.13 nance) and transbronchial biopsy. In most cases, a triggering factor There is a scarcity of data to identify patients at greater was not detected and the condition was classified as COP. risk of experiencing a relapse. In Lazor et al.,13 the relapse rate The studies showed that most patients with organizing pneu- was 68% during treatment (primarily (96%) with prednisone at monia respond favourably to corticosteroids in the short-term, doses of ≤20 mg/day) and 32% after treatment discontinuation. which support the value of this therapy for this entity. This corre- In Drakopanagiotakis et al.,6 the relapse rate was 37.8%, with lates with current clinical practise and guidelines.10 Some authors no differences between COP and SOP, and with no correlation have proposed a regimen based on oral prednisone at a dose of with hypoxaemia, hypoalbuminemia, BAL lymphocytosis, or a 1 mg/kg/day, tapered off over 12 months, given the risk of relapse reticulonodular pattern on high-resolution CT. In another study, after dose reduction or treatment discontinuation.127–130 However, radiographic findings were not independently associated with the interpretation of the efficacy is limited because the hetero- the risk of relapse in multivariate analysis.124 Conversely, 90% geneity of the data collected, as each study assesses different of patients in Baha et al. achieved complete remission, mostly outcomes. Prednisone is the most widely used corticosteroid for patients with ground glass opacity on high-resolution CT.2 Some treatment of OP. There is less experience with other drugs, like authors, including Cazzato et al.,54 have suggested that elevated methylprednisolone, and none of the reviewed studies used dex- BAL lymphocytosis might predict a good response to corticosteroid amethasone. This is probably due to the safety profile of prednisone treatment, although subsequent studies have reported different and its common use in other chronic respiratory diseases. Regard- results.6,13 In short, although relapse is clinically crucial in the nat- ing the dose, the majority of the studies used a regimen higher than ural history of OP, to date no clinical data enables identification of 0.5 mg/kg/day, but with a high variability within the same studies. treatment responders. This would avoid potential adverse effects The doses might have been adjusted based on patient’s comorbidi- of unnecessary corticosteroid treatment. ties and weight, but this was not clearly stated in the study methods. Surprisingly, the issue of the adverse effects of corticosteroid This highlights the significant heterogeneity in the corticosteroids treatment was only reflected in a minority of studies, that reported regimens to treat OP in clinical practise. a rate of adverse effects as high as 53%, mainly weight gain, myopa- An issue of interest is that the prolonged corticosteroid use thy, and osteoporosis. Undoubtedly, in addition to avoidance of has traditionally been justified by the risk of relapse. Treatment relapse, reduced mortality may be a justification for the acceptance 5 L. Cendon, A. Rafecas Codern, D. de la Rosa et al. Open Respiratory Archives 4 (2022) 100211 of such high adverse effect rates. In the reviewed studies, while Acknowledgement mortality ranged between 0% and 23%, it is not known which patient profiles was associated with a poorer response to corticosteroids Mrs. Ailish for English editing. and worse outcomes. The conclusions of this review of OP studies are clearly lim- Appendix A. Supplementary data ited by the poor quality of currently available studies. Indeed, most existing studies are case reports, while larger studies have limita- Supplementary data associated with this article can be found, in tions in terms of the reported data, with insufficient details on the the online version, at doi:10.1016/j.opresp.2022.100211. drugs used, effectiveness, treatment duration, and rates of adverse effects. There is both a lack of studies specifically designed to eval- uate this issue and a large heterogeneity in treatment, irrespective References of OP aetiology (cryptogenic or secondary). All these unanswered 1. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis oblit- questions highlight the need to undertake appropriately designed erans organizing pneumonia. N Engl J Med. 1985;312:152–8. studies and to develop a consensus on the most appropriate treat- 2. 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