Abstract
Background
Organising pneumonia is an interstitial lung disease linked to infections and other conditions. Cryptogenic organising pneumonia is a rarer, idiopathic form. Organising pneumonia has become one of the most frequent respiratory complications following severe acute respiratory syndrome coronavirus 2 pneumonia. Standard treatment involves the use of glucocorticoids. The objective of the study is to determine the optimal dosage of oral corticosteroids for the treatment of this disease.
Methods
Randomised, open-label, assessor-blinded, parallel-group, single-centre, noninferiority clinical trial with an active control group comparing two oral prednisone regimens. The control group received prednisone 0.75 mg·kg−1·day−1 for 4 weeks; 0.5 mg·kg−1·day−1 for 4 weeks; 20 mg·day−1 for 4 weeks; 10 mg·day−1 for 6 weeks; or 5 mg·day−1 for 6 weeks (total treatment duration 6 months) and the experimental group prednisone 0.5 mg·kg−1·day−1 for 3 weeks; 20 mg·day−1 for 3 weeks; 15 mg·day−1 for 2 weeks; 10 mg·day−1 for 2 weeks; and 5 mg·day−1 for 2 weeks (total treatment duration 3 months). Visits were carried out at baseline and at 3, 6 and 12 months, recording clinical history, physical examination, pulmonary function tests and chest computed tomography. The primary outcome was noninferiority with a margin of 10% in diffusing capacity of the lung for carbon monoxide (DLCO) at 6 months.
Results
79 patients were randomised according to intention-to-treat group, 40 to the experimental group and 39 to the control group. Mean±sd baseline DLCO was 59.3±16.7% in the experimental group and 55.5±16.5% in the control group, with mean improvements at 6 months of 11.7% (95% CI 7.18–16.17%) and 12.8% (95% CI 8.57–17.11%) respectively. The difference between groups at 6 months was 1.23% (95% CI −5.13–7.59%), the experimental regimen being noninferior to the control group with the margin of 10%. Patients in the experimental group had fewer than half as many adverse effects as controls: nine (23%) versus 22 (56%) (p=0.0027).
Conclusions
Treatment with oral corticosteroids lasting 3 months (initial dose of prednisone 0.5 mg·kg−1·day−1) may be recommended in patients with post-COVID organising pneumonia.
Shareable abstract
A 3-month prednisone regimen (starting at 0.5 mg·kg−1·day−1) is as effective as the standard 6-month course for post-COVID-19 organising pneumonia, with significantly fewer adverse effects https://bit.ly/46TxwQX
Introduction
Organising pneumonia is an interstitial lung disease (ILD) characterised by a pattern of lung tissue repair following injury. The pathogenesis of organising pneumonia involves inflammation in which the bronchioles and alveoli are filled with granulation tissue, disrupting the normal lung architecture [1, 2].
This inflammatory response is a nonspecific lung reaction to damage, although it may also occur without a known cause, in which case it is termed “cryptogenic”. Cryptogenic organising pneumonia (COP) is a rare condition with an undetermined incidence and prevalence. While it was previously estimated that ∼50% of organising pneumonia cases were COPs, the majority are now considered secondary. Indeed, <15% are classified as cryptogenic, probably due to advances in the diagnosis of secondary causes [3, 4]. Secondary causes of organising pneumonia include infectious diseases, rheumatological diseases, radiotherapy, drugs, organ transplantation, haematological cancer and inflammatory bowel disease, with post-infectious aetiologies being the most prevalent [1, 2]. Although it is well known that certain viral or bacterial infections can cause organising pneumonia, the prevalence in these conditions is not well established and depends on the type of infection and its severity. Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a wide spectrum of pulmonary complications has been described. Among them, organising pneumonia has been increasingly recognised as a prominent inflammatory sequela following acute infection [5, 6]. Several studies have reported a prevalence ranging from 12% to 32%, particularly in patients who experienced a more severe initial course of COVID-19 [7, 8]. Organising pneumonia represents one of the most relevant post-acute inflammatory patterns and is frequently associated with persistent respiratory symptoms, functional impairment, and prolonged radiological abnormalities, highlighting its clinical significance in the follow-up of patients recovering from COVID-19 [5–8].
To date, no randomised controlled trials evaluating potential therapies for organising pneumonia have been published. Spontaneous remission is uncommon. Systemic glucocorticoid therapy is the preferred treatment for symptomatic patients [1, 9]. However, recommended corticosteroid regimens for organising pneumonia are usually prolonged and largely based on expert opinion rather than comparative evidence [1, 9]. Prolonged systemic corticosteroid therapy is associated with well-known adverse effects, including metabolic complications, increased susceptibility to infections, osteoporosis, myopathy and adrenal suppression, which may substantially impact patient safety and quality of life [10]. Therefore, defining the shortest effective corticosteroid regimen represents a clinically important goal to balance efficacy and treatment-related toxicity.
The typical initial dosage of prednisone is 0.5–1 mg·kg−1 of ideal bodyweight per day, up to 60 mg, given once daily. This dose is maintained for 2–4 weeks, then gradually reduced to 0.25 mg·kg−1·day−1 over 4–6 months. If the patient improves, the dose is tapered to zero over the next 6–12 months [1]. Alternative treatment options, although supported by limited evidence, include macrolides, due to their anti-inflammatory properties, as well as immunosuppressive therapies such as cyclophosphamide, azathioprine, mycophenolate and rituximab [1].
The objective of the present study was two-fold: first, to evaluate the efficacy of oral corticosteroid therapy in treating organising pneumonia secondary to SARS-CoV-2 infection, and second, to determine whether a less intensive corticosteroid regimen yields a therapeutic effect that is noninferior to the standard recommended regimen for this condition.
Methods
Trial design
The trial was a randomised, open-label, assessor-blinded, parallel-group, single-centre, noninferiority clinical trial with an active control group comparing two oral prednisone regimens. The trial was open-label for patients and treating physicians; however, outcome assessors were blinded to treatment allocation. Pulmonary function tests were performed by trained technicians unaware of group assignment, and chest computed tomography (CT) scans were evaluated by a radiologist blinded to treatment arm.
The control group received prednisone 0.75 mg·kg−1·day−1 for 4 weeks, followed by 0.5 mg·kg−1·day−1 for 4 weeks, 20 mg·day−1 for 4 weeks, 10 mg·day−1 for 6 weeks and 5 mg·day−1 for 6 weeks (total treatment duration: 6 months). The experimental group received prednisone 0.5 mg·kg−1·day−1 for 3 weeks, followed by 20 mg·day−1 for 3 weeks, 15 mg·day−1 for 2 weeks, 10 mg·day−1 for 2 weeks and 5 mg·day−1 for 2 weeks (total treatment duration: 3 months). Upon diagnosing organising pneumonia, the patients were randomised to one of the two treatment arms. Subsequent visits were held at 1, 3, 6 and 12 months. Study outcome variables were assessed by trained hospital nurses and a radiologist who were blinded to the patient's treatment allocation. Patients had telephone contact with two of the investigators (X. Muñoz, D. Espejo-Castellanos), and could thus report any incidents immediately (figure 1).
FIGURE 1.
Diagram of the treatment groups in the clinical trial. CT: computed tomography.
The trial was conducted in compliance with the principles of the Declaration of Helsinki [11] and the Harmonised Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation [12]. It was approved by local authorities and registered as www.clinicaltrials.gov (identifier number NCT04534478), and it is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement [13]. All patients provided written informed consent before trial entry.
Trial oversight
The trial was designed by the last two authors in collaboration with the Academic Research Organisation Unit at the Vall d'Hebron Hospital (Barcelona, Spain). Trial data were collected by the clinical investigators and analysed by the group's statistician (F. Torres). The first and second authors vouch for the accuracy and completeness of the data and analyses, and for the fidelity of the trial to the protocol (supplementary material). The patients were visited by some of the authors (D. Espejo-Castellanos, M-F. Pilia, G. Granados, C. Romero-Mesones, I. Ojanguren, X. Muñoz) and by all members of the Se-COVID group. All authors reviewed the data. The manuscript was written by all the authors and reviewed by all members of the Se-COVID group. This is an institutional clinical trial with competitive public funding from Instituto de Salud Carlos III (PI21/01046), but no support from any pharmaceutical company.
Participants and randomisation
All patients aged >18 years who had been diagnosed with organising pneumonia at a post-COVID respiratory sequelae outpatient clinic at Vall d'Hebron Hospital were assessed. This clinic systematically reviewed all patients who had required hospitalisation for SARS-CoV-2 pneumonia between March 2020 and December 2021. The diagnosis of organising pneumonia was established by a multidisciplinary committee based on clinical and radiological data, pulmonary function, and biopsy evaluations (supplementary table S1). All patients included met the inclusion criteria, and none met the exclusion criteria. A complete list of the inclusion and exclusion criteria is provided in supplementary table S2.
Patients were randomised in a 1:1 ratio to the two treatment arms. Randomisation codes were generated using the PROC PLAN of the SAS system. The randomisation of patients was managed through the electronic case report form and was concealed until the confirmation of the randomisation for each patient. To minimise missing data, patients who withdrew from the trial regimen prematurely were asked to attend all visits and undergo all examinations as originally planned. For patients who did not attend all visits, vital status at the end of the study was determined.
Interventions
Patients received oral prednisone in the morning with breakfast, adjusted for weight and based on the treatment arm assigned. All patients were also treated with omeprazole 20 mg·day−1 while taking prednisone, and trimethoprim/sulfamethoxazole 80/400 mg·day−1 to prevent opportunistic infections as long as the prednisone dose exceeded 10 mg·day−1. Additionally, calcium and alendronic acid were given to prevent bone-related complications. At the end of the prednisone treatment, before discontinuation, plasma cortisol levels were determined to assess for adrenal insufficiency.
Procedures and assessments
For all patients included, demographic data were collected along with information obtained from the clinical interview, physical examination, blood tests, pulmonary function tests (spirometry and carbon monoxide transfer test), the 6-min walk test, and chest CT (figure 1). All these procedures are described in supplementary table S3. All initial visit variables are described in supplementary table S4.
During follow-up, clinical progress, pulmonary function tests and chest CT scans, adverse events, and treatment adherence were assessed. Variables and definitions are detailed in supplementary table S5.
End-points
The primary efficacy end-point was the comparison between treatment groups in the change in pulmonary diffusion capacity. This was assessed by the baseline-adjusted predicted diffusing capacity of the lung for carbon monoxide (DLCO) (%) from baseline to 6 months, using a noninferiority design with a 10% margin. DLCO was selected as the primary end-point as it is a clinically meaningful measure of gas-exchange impairment in organising pneumonia and interstitial lung diseases, and is sensitive to treatment-related changes over time.
The secondary variables analysed included the percentage of patients with DLCO values <80% predicted, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC% from forced spirometry, the 6-min walk distance (6MWD), the need to increase the oral corticosteroid dose or to start a new treatment period, parenchymal involvement on the chest CT, complications related to prednisone treatment (both severe and nonsevere), complications of any type (both severe and nonsevere), all-cause mortality, and the ordinal clinical improvement (the clinical variable recommended by the World Health Organization (WHO) R&D Blueprint for Epidemics expert group for the acute phase). This variable was assessed at each visit, and the worst score obtained during the study was recorded as a summary measure.
Sample size
60 patients per group were planned to be randomised to ensure an 80% statistical power for demonstrating the noninferiority of the less-intensive prednisone regimen compared to the established regimen for the predicted DLCO. This calculation was based on a noninferiority margin of 10% and a standard deviation of 14.3% and accounted for a potential imbalance of up to 2.5% against the experimental treatment, with a one-sided α-value of 2.5%.
Statistical analysis
Two efficacy populations were pre-defined: the modified full analysis set (mFAS) based on the intention-to-treat principle and the per-protocol (PP) population (supplementary figure S1). For the primary efficacy end-point of noninferiority, both mFAS and PP were co-primary, while mFAS was primary for the remaining end-points.
Categorical variables were summarised using frequencies and percentages, and continuous variables were reported as mean±sd or median and interquartile range, as appropriate.
The primary efficacy variable and Gaussian longitudinal continuous variables were analysed using a mixed model for repeated measures (MMRM), which deals appropriately with observations missing at random. The MMRM model included treatment, visit, treatment-by-visit interaction and a continuous baseline variable, with a common unstructured covariance structure to model within-patient errors. Other variables were analysed using Fisher's exact test for categorical data, t-test for Gaussian variables, and the Mann–Whitney test for non-Gaussian continuous and ordinal variables.
Analyses were performed using SAS 9.2 software (SAS Institute, Cary, NC, USA), with a significance level of 0.05 (two-sided).
Results
Patients
In this study the intention was to randomise 120 patients, but recruitment was halted after randomisation of 82 patients (41 per group) due to a critically slow recruitment rate. Among the patients who were randomised and included in the mFAS population, 79 (96.34%) completed the trial regimen, and 74 (90.24%) finished the trial (supplementary figure S1).
In the mFAS population, the mean±sd age was 61.5±10.9 years, and 56 (70.9%) were men. 55 (69.6%) patients had histopathology consistent with organising pneumonia, while the others were diagnosed based on clinical and radiological criteria. Baseline clinical characteristics of the mFAS population are displayed in table 1, and details on the protocol population in supplementary table S6. Although a numerically higher proportion of patients in the control group had required noninvasive respiratory support during the acute phase of COVID-19, baseline pulmonary impairment at the time of organising pneumonia diagnosis was comparable between groups, and the primary analysis was adjusted for baseline DLCO. Comorbidities are outlined in supplementary table S7.
TABLE 1.
Demographic data and clinical characteristics of the modified full analysis set population
| Control | Experimental | Total | |
|---|---|---|---|
| Subjects | 39 | 40 | 79 |
| Age years | 62.7±11.3 | 60.3±10.6 | 61.5±10.9 |
| Male | 29 (74.4) | 27 (67.5) | 56 (70.9) |
| BMI kg·m−2 | 28.1 (3.6) | 28.8 (3.8) | 28.5 (3.7) |
| Tobacco exposure | |||
| Smoker | 0 (0) | 2 (5) | 2 (2.5) |
| Former smoker | 13 (33.3) | 15 (37.5) | 28 (35.4) |
| Nonsmoker | 26 (66.6) | 23 (57.5) | 49 (62) |
| COVID-19 severity | |||
| No oxygen required | 3 (7.7) | 5 (12.5) | 8 (10.1) |
| Oxygen therapy FIO2 <40% | 8 (20.5) | 13 (32.5) | 21 (26.6) |
| NIV or HFNC | 13 (33.3) | 5 (12.5) | 18 (22.8) |
| IMV or ECMO | 15 (38.5) | 17 (42.5) | 32 (40.5) |
| Post-COVID control | |||
| Diagnosis of organising pneumonia with biopsy | 27 (69.2) | 28 (70) | 55 (69.6) |
| Symptoms | |||
| Cough | 6 (15) | 6 (15) | 12 (15) |
| Expectoration | 0 (0) | 2 (5) | 2 (2.5) |
| Fever | 0 (0) | 0 (0) | 0 (0) |
| Dyspnoea | 37 (95) | 39 (98) | 76 (96) |
| mMRC | |||
| 0 | 2 (5.1) | 1 (2.5) | 3 (3.8) |
| 1 | 14 (35.9) | 11 (27.5) | 25 (31.6) |
| 2 | 21 (53.8) | 23 (57.5) | 44 (55.7) |
| 3 | 2 (5.1) | 5 (12.5) | 7 (8.9) |
| Arthromyalgia | 0 (0) | 1 (2.5) | 1 (1.3) |
| Chest pain | 8 (20.5) | 3 (7.5) | 11 (13.9) |
| Respiratory function tests | |||
| FVC % of the theoretical value | 76.9±24.7 | 78.7±21.6 | 77.8±2 |
| FEV1 % of the theoretical value | 80.8±25.9 | 83.2±22.9 | 82±24.3 |
| DLCO % of the theoretical value | 55.5±16.5 | 59.31±16.7 | 57.5±16.6 |
| DLCO /VA % of the theoretical value | 76.9±17.5 | 79.2±19.2 | 78±18.3 |
| Chest CT | |||
| With abnormalities | 39 (100) | 40 (100) | 79 (100) |
| Parenchymal involvement | |||
| Linear opacities | 1 (2.6) | 0 (0) | 1 (1.3) |
| Mixed type# | 32 (82.1) | 30 (75) | 62 (78.5) |
| Reticulation | 2 (5.1) | 1 (2.5) | 3 (3.8) |
| Ground-glass opacity | 4 (10.3) | 9 (22.5) | 13 (16.5) |
Data are presented as n, mean±sd, or n (%). BMI: body mass index; FIO2: inspiratory oxygen fraction; NIV: noninvasive ventilation; HFNC: high-flow nasal cannula; IMV: invasive mechanical ventilation; ECMO: extracorporeal membrane oxygenation; mMRC: modified Medical Research Council dyspnoea scale; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of the lung for carbon monoxide; VA: alveolar volume; CT: computed tomography. #: patient presents two of the other conditions listed. All patients with consolidations exhibited additional findings and were therefore classified under the mixed pattern.
Primary end-point
The mean±sd initial DLCO was 59.3±16.7% in the experimental group and 55.5±16.5% in the control group, with mean (95% CI) increases at 6 months of 11.7% (7.18–16.17%) and 12.8% (8.57–17.11%), respectively. The difference between groups at 6 months was 1.16% (−5.06–7.38%) in the mFAS population and 1.23% (−5.13–7.59%) in the protocol population; the experimental regimen being noninferior to the control group within a margin of 10%. At 12 months, the mean (95% CI) increases were 15.5% (10.28–20.73%) and 22.26% (17.01–27.51%), respectively. The difference between groups at 12 months was 6.75% (−0.66–14.17%), with a p-value of 0.074. Table 2 shows the evolution of the diffusion test in the mFAS population and the per-protocol populations in table 2 and supplementary table S8, respectively. Exploratory analyses among DLCO tertile levels did not show a differential treatment effect (p=0.1450) (supplementary figures S2–S5).
TABLE 2.
Evolution of the diffusion test
| Patients | Baseline# | Baseline-adjusted changes from baseline | ||||
|---|---|---|---|---|---|---|
| At 6 months# | p-value | At 12 months# | p-value | |||
| DLCO SB (% of the theoretical value) | ||||||
| Control | 39 | 55.54±16.48 | 12.84 (8.57–17.11) | 22.26 (17.01–27.51) | ||
| Experimental | 40 | 59.31±16.65 | 11.68 (7.18–16.17) | 15.50 (10.28–20.73) | ||
| Difference between control and experimental groups | 1.16 (−5.06–7.38) | 0.711 | 6.75 (−0.66–14.17) | 0.074 | ||
| Difference between control and experimental groups (per-protocol) | 1.23 (−5.13–7.59) | 0.701 | 7.12 (−0.58–14.82) | 0.069 | ||
| Patients with DLCO <80% predicted | ||||||
| Control | 38 | 54.66±15.77 | 13.78 (9.52–18.05) | 23.09 (17.76–28.42) | ||
| Experimental | 36 | 55.87±13.54 | 12.41 (7.68–17.13) | 17.01 (11.46–22.56) | ||
| Difference between control and experimental groups | 1.38 (−4.99–7.75) | 0.668 | 6.08 (−1.61–13.77) | 0.120 | ||
Data are presented as n, mean±sd or mean (95% CI), unless otherwise stated. All analyses are presented for modified full analysis set population, except for the sensitivity analyses of the main per-protocol variable, as noted in the table. DLCO: diffusing capacity of the lung for carbon monoxide; SB: single-breath. #: inferential results are based on mixed models for repeated measures.
Secondary end-points
In the subgroup of patients with an initial DLCO <80%, the noninferiority criterion between the two corticosteroid treatment protocols was also met (table 2). Regarding spirometry, the control group showed greater increases in FVC and FEV1 than the experimental group. The difference in FEV1 between the groups reached statistical significance, with a p-value of 0.033; however, no significant differences were observed between the groups in the FEV1/FVC ratio (p=0.607) or in the 6-min walk test results (table 3).
TABLE 3.
Progression of secondary end-points
| Patients | Baseline | Changes from baseline at 6 months | p-value | ||
|---|---|---|---|---|---|
| FVC % of theoretical value# | |||||
| Control | 37 | 76.88±24.72 | 9.51 (4.93–14.09) | ||
| Experimental | 38 | 78.69±21.58 | 3.69 (−1.00–8.37) | ||
| Difference between control and experimental groups | 5.82 (−0.73–12.38) | 0.081 | |||
| FEV1 % of theoretical value# | |||||
| Control | 37 | 80.7±25.9 | 9.51 (5.23–13.79) | ||
| Experimental | 38 | 83.15±22.9 | 2.76 (−1.7–7.21) | ||
| Difference between control and experimental groups | 6.75 (0.57–12.93) | 0.033 | |||
| FEV1/FVC % of theoretical value# | |||||
| Control | 37 | 82.48±5.67 | 82.24 (80.75–83.72) | ||
| Experimental | 38 | 82.96±6.37 | 81.68 (80.13–83.23) | ||
| Difference between control and experimental groups | 0.56 (−1.59–2.70) | 0.607 | |||
| 6MWD¶ m | |||||
| Control | 27 | 375 (316–450) | 30 (−9–53) | ||
| Experimental | 27 | 405 (346–465) | 45 (6104) | ||
| Median difference between control and experimental groups | 32.5 (−10– 75) | 0.148 | |||
| Chest CT | 0.149 | ||||
| Control | 39 | 39 (100) | |||
| Deterioration | 1 (2.6) | ||||
| Stability | 17 (43.6) | ||||
| Improvement | 18 (46.2) | ||||
| Resolution | 3 (7.7) | ||||
| Experimental | 40 | 40 (100) | |||
| Deterioration | 0 (0) | ||||
| Stability | 13 (32.5) | ||||
| Improvement | 21 (52.5) | ||||
| Resolution | 6 (15) | ||||
| WHO Clinical Progression Scale | 0.646 | ||||
| Control | 38 | ||||
| 1 (not hospitalised, no limitations on activities) | 9 (23.7) | 22 (57.9) | |||
| 2 (not hospitalised, limitation on activities) | 26 (68.4) | 16 (42.1) | |||
| 3 (hospitalised, not requiring supplemental oxygen) | 2 (5.3) | 0 | |||
| 4 (hospitalised, requiring supplemental oxygen) | 1 (2.6) | 0 | |||
| Experimental+ | 38 | ||||
| 1 (not hospitalised, no limitations on activities) | 5 (13.2) | 19 (51.4) | |||
| 2 (not hospitalised, limitation on activities) | 31 (81.6) | 18 (48.6) | |||
| 3 (hospitalised, not requiring supplemental oxygen) | 2 (5.3) | 0 | |||
| 4 (hospitalised, requiring supplemental oxygen) | 0 (0.0) | 0 | |||
Data are presented as n, mean±sd or n (%), unless otherwise stated. FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; 6MWD: 6-min walk distance; CT: computed tomography; WHO: World Health Organization. #: baseline-adjusted changes from baseline (95% CI) and for 6-month visit; inferential results are based on mixed models for repeated measures; ¶: median (interquartile range) percentiles for descriptive data and median difference (95% CI) for inference using the Hodges–Lehmann estimator; +: one missing value for one patient.
Chest CT abnormalities were present in all patients, with ground-glass opacity in 13 (16.5%), reticulation in three (3.8%), linear opacities in one (1.3%), and a mixed pattern in 62 (78.5%). All patients with consolidations exhibited additional findings and were therefore classified under the mixed pattern. When comparing the chest CT at 6 months to the baseline CT, no patients in the experimental group showed worsening; 32.5% remained unchanged, 52.5% showed improvement and 15% achieved resolution of abnormalities. In the control group, 2.6% worsened, 43.6% remained stable, 46.2% improved and 7.7% achieved resolution. No significant differences were observed between groups (table 3).
Baseline symptoms are summarised in table 1. Clinical progression was assessed using the WHO Clinical Progression Scale. Initially, 23.7% of the control group and 13.2% of the experimental group were not hospitalised and did not present activity limitations. At 12 months, these rates rose to 85.7% and 75.7%, respectively, with no significant differences (p=0.3755; table 3).
Of all the patients who completed the treatment regimen, three in the experimental group and two in the control group presented relapses.
Safety and side-effect profile
Nonsevere complications of any type were more frequent in the control group (22 cases, 56.4%) than in the experimental group (nine cases, 22.5%) (p=0.003). No differences between the groups were observed in severe complications or in complications of any degree related to prednisone treatment (table 4). During the trial, one patient in the control group succumbed to disseminated cryptococcosis caused by Cryptococcus neoformans. Additionally, two patients developed pulmonary thromboembolism, one experienced deep vein thrombosis, and another developed adrenal insufficiency. Table 5 details the primary corticosteroid-related adverse effects, while the total number of adverse events during the trial is provided in supplementary table S9.
TABLE 4.
Adverse effects
| Control | Experimental | p-value | |
|---|---|---|---|
| Patients | 39 | 40 | |
| Complications of prednisone treatment (severe) | 1 (2.56) | 0 (0) | 0.494 |
| Complications of prednisone treatment (nonsevere) | 8 (20.51) | 5 (12.5) | 0.378 |
| Complications of any type (severe) | 1 (2.56) | 2 (5) | >0.999 |
| Complications of any type (nonsevere) | 22 (56.4) | 9 (22.5) | 0.003 |
Data are presented as n or n (%), unless otherwise stated. Bold type represents statistical significance.
TABLE 5.
Description of adverse effects related to treatment
| Serious | Control occurrences/ subjects |
Experimental occurrences/ subjects |
Total occurrences/ subjects |
|
|---|---|---|---|---|
| Patients | 40 | 40 | 40 | |
| Endocrine disorders | ||||
| Adrenal insufficiency | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| General disorders | ||||
| Swelling | No | 2/2 (5) | 0/0 (0) | 2/2 (2.5) |
| Investigations | ||||
| Cortisol decreased | No | 0/0 (0) | 1/1 (2.5) | 1/1 (1.3) |
| Weight increased | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Metabolism and nutrition disorders | ||||
| Hyperglycaemia (mild) | No | 2/2 (5.0) | 1/1 (2.5) | 3/3 (3.8) |
| Hyperglycaemia (moderate) | No | 0/0 (0) | 1/1 (2.5) | 1/1 (1.3) |
| Musculoskeletal and connective tissue | ||||
| Musculoskeletal pain | No | 0/0 (0) | 1/1 (2.5) | 1/1 (1.3) |
| Myalgia | No | 0/0 (0) | 1/1 (2.5) | 1/1 (1.3) |
| Nervous system disorders | ||||
| Dizziness | No | 0/0 (0) | 1/1 (2.5) | 1/1 (1.3) |
| Paraesthesia | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Tremor | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Psychiatric disorders | ||||
| Insomnia | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Respiratory, thoracic and mediastinal | ||||
| Pulmonary embolism | Yes | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Skin and subcutaneous tissue disorders | ||||
| Erythematous rash | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Skin lesion | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
| Vascular disorders | ||||
| Hypertension | No | 1/1 (2.5) | 0/0 (0) | 1/1 (1.3) |
Data are presented as n or n/N (%). Patients may be in multiple categories.
Discussion
This study is the first clinical trial conducted on patients with organising pneumonia since the first description of this condition in the 1970s [14]. It has demonstrated that a 3-month treatment regimen, starting with a dose of 0.5 mg·kg−1·day−1, is as effective as longer treatments with higher initial doses and halves the rate of adverse effects.
Systemic glucocorticoids are the preferred treatment for symptomatic patients with respiratory impairment due to organising pneumonia [1, 9]. Although they have proven effective, they are not free from side-effects, especially when administered at the high doses and extended durations currently proposed for the treatment of this condition [10]. Only 23% of patients treated with the experimental regimen experienced any adverse side-effects, compared to 56% of those treated with the conventional regimen. For the treatment of patients with any post-COVID-19 respiratory sequelae, a low-dose prednisone regimen can be as effective as one with a higher dose, and also presents fewer adverse effects [15].
Although some patients with post-COVID organising pneumonia may show residual fibrotic-like changes on imaging [16, 17], the present study was not designed to assess long-term fibrotic progression. Our results should therefore be interpreted mainly in the context of an inflammatory and potentially reversible lung process, which is the hallmark of organising pneumonia. In fact, from a pathobiological perspective, organising pneumonia is characterised by an inflammatory process with intra-alveolar fibroblastic plugs and largely preserved lung architecture, which is typically responsive to anti-inflammatory therapy [9]. These features provide biological plausibility for the effectiveness of shorter corticosteroid regimens while minimising treatment-related toxicity. Until now, studies on organising pneumonia, including cryptogenic and secondary forms, have reported substantial heterogeneity in corticosteroid regimens, with treatment durations ranging from a few weeks to 6–12 months or longer [1, 9, 18]. Most available data derive from retrospective series, in which prolonged courses are commonly used to reduce the risk of relapse [18–21], despite the lack of randomised comparative evidence defining the optimal treatment duration.
DLCO is one of the parameters that can be monitored in both the management and follow-up of these patients. Reductions in DLCO are common in patients with diffuse ILD, as in the case of idiopathic pulmonary fibrosis (IPF), and are associated with increased mortality [22]. Changes in DLCO values over time may indicate stabilisation, improvement, or worsening of the disease and can thus guide therapeutic decisions [23]. DLCO has already been analysed in various clinical trials investigating interstitial lung diseases, primarily in the context of assessing the response to antifibrotic drugs, immunosuppressants, or corticosteroids themselves. Thus, in patients with IPF, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, or even in patients with systemic sclerosis with lung involvement, stable increased DLCO was associated with a favourable response to treatment [24–28]. In most of these studies, changes >15% were considered significant [28, 29]. The fact that a change of 10% was established as significant in the present study may reinforce the value of the observed results. It is important to emphasise that, in these trials, DLCO served not only to assess the response to treatment, but also the progression of the disease, as a DLCO that remains stable or improves indicates a slowing or reversal of interstitial damage. In this context, when analysing the subgroup of patients with DLCO <80%, similar increases were observed in both treatment groups.
Chest CT is an essential component for both the diagnosis and follow-up of organising pneumonia. As described in multiple studies, the majority of patients included in this clinical trial exhibited a mixed pattern with peripheral consolidations, reticulation and ground-glass opacities [6, 30, 31]. <20% of the patients presented any of these alterations in isolation. This variable was analysed as secondary since a significant proportion of patients show only a partial resolution of alveolar opacities, while reticular opacities tend to persist despite treatment [32]. Indeed, only 15% and 7.7% of patients in the experimental and control groups respectively showed complete resolution of changes in CT at the end of the study. No differences were observed in the degree of improvement between the treatment regimens. Nor were there significant differences in other secondary variables such as FVC, 6MWD or quality of life.
As recommended by the WHO, particularly in patients with infection and/or post-COVID-19 sequelae, in the study variables we included the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. This scale was created to facilitate data pooling across cohort studies and clinical trials, with the objective of expediting the exchange of knowledge to benefit patients infected with SARS-CoV-2 and to guide optimal resource planning [33]. Again, no differences were observed between the groups.
This study is not without limitations. First, it is an open-label, single-centre clinical trial, a circumstance that may introduce biases and limit the generalisability of the results to other populations and clinical settings. However, the raters responsible for measuring all the study outcomes were blinded to patient allocation, thereby reducing the risk of this detection bias. Second, the study was prematurely terminated after recruiting 66% (79 out of 120) of the planned sample size due to a critical decline in patient enrolment. Although the reduced sample size may have affected the statistical power for certain secondary outcomes, the 95% confidence intervals calculated from the recruited sample provide adequate precision to support the conclusion of noninferiority for both mFAS and per-protocol analyses of the primary end-point. Consequently, this reduction did not compromise the study's primary objectives. Third, the use of clinical interviews with patients to assess treatment adherence, without additional verification methods, may also have introduced a bias. The lack of a placebo group could also be seen as a limitation, as it makes it impossible to determine whether the observed improvements are solely due to corticosteroid treatment or to the natural progression of the disease. However, given that all patients included were symptomatic and had both radiological and pulmonary function abnormalities, it would have been unethical to leave any patients untreated. Finally, the fact that up to 30% of the patients were diagnosed without histological tests to confirm the diagnosis could be considered a limitation. Nonetheless, it should be stressed that all patients, with or without histology, were diagnosed by consensus in a multidisciplinary committee consisting of clinicians, radiologists and pathologists. In fact, having access to histopathological studies in up to 70% of the patients is considered extraordinarily valuable, given the challenges of conducting such studies during peak pandemic waves.
Despite these limitations, we believe that a 3-month course of prednisone starting at a dose of 0.5 mg·kg−1·day−1 in patients with post-COVID-19 organising pneumonia may be as effective as the longer standard regimen, with the additional advantage of a lower cumulative corticosteroid exposure and potentially fewer adverse effects. Taken together, these findings suggest that a shorter course of corticosteroids may be sufficient for the treatment of post-COVID organising pneumonia and may also have implications for the management of organising pneumonia from other aetiologies, including noninfectious forms.
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/23120541.00469-2026
Se-COVID-19 team: Marta Arjona (Vall d'Hebron University Hospital, Barcelona, Spain), Miriam Barrecheguren (Vall d'Hebron University Hospital, Barcelona, Spain), Cristina Berastegui (Vall d'Hebron University Hospital, Barcelona, Spain), José Cardoso (Vall d'Hebron University Hospital, Barcelona, Spain), David Clofent (Vall d'Hebron University Hospital, Barcelona, Spain), Almudena Felipe (Vall d'Hebron University Hospital, Barcelona, Spain), María Angeles Jiménez (Vall d'Hebron University Hospital, Barcelona, Spain), Manuel Lopez (Vall d'Hebron University Hospital, Barcelona, Spain), Jeisson Osorio (Vall d'Hebron University Hospital, Barcelona, Spain), Mercedes Pallero (Vall d'Hebron University Hospital, Barcelona, Spain), Eva María Revilla (Vall d'Hebron University Hospital, Barcelona, Spain), Berta Saez (Vall d'Hebron University Hospital, Barcelona, Spain), Maria Saéz (Vall d'Hebron University Hospital, Barcelona, Spain), Júlia Sampol (Vall d'Hebron University Hospital, Barcelona, Spain), Eduardo Vélez (Vall d'Hebron University Hospital, Barcelona, Spain) and Ana Villar (Vall d'Hebron University Hospital, Barcelona, Spain).
Provenance: Submitted article, peer reviewed.
This clinical trial is prospectively registered with ClinicalTrials.gov as NCT04534478.
Ethics statement: This study was approved by local authorities and is reported in accordance with the CONSORT statement.
Conflict of interest: D. Espejo-Castellanos reports payment or honoraria from AstraZeneca, GSK, BIAL and Chiesi; and support for attending meetings from Sanofi, Menarini and Chiesi. M-F. Pilia reports payment or honoraria from Sanofi and GSK; and support for attending meetings from Sanofi, Boehringer and Chiesi. G. Granados reports payment or honoraria from GSK, Zambon and AstraZeneca; and support for attending meetings from Sanofi and Chiesi. C. Romero-Mesones reports payment or honoraria from AstraZeneca, GSK and Chiesi; and support for attending meetings from Sanofi and Chiesi. I. Ojanguren reports consultancy fees from AstraZeneca, GSK, Sanofi and Chiesi; payment or honoraria from AstraZeneca, GSK, Sanofi and Chiesi; support for attending meetings from Sanofi; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Sanofi. M-J. Cruz is an associate editor of this journal. X. Muñoz reports grants from AstraZeneca, GSK and Sanofi; consultancy fees from AstraZeneca, GSK and Novartis; payment or honoraria from AstraZeneca, GSK, Sanofi, Boehringer and Chiesi; and support for attending meetings from AstraZeneca, GSK, Novartis, Menarini and FAES. F. Torres reports consultancy fees from Archivel, LEO Pharma, FAES, Ferrer and Boehringer Ingelheim; and participation on a data safety monitoring or advisory board for Argenx BV, Archivel, Connecta and RemAb Therapeutics. The remaining authors have nothing to disclose.
Support statement: D. Espejo-Castellanos is a researcher supported by the Rio Hortega programme from Instituto de Salud Carlos III (CM23/00174). M-F. Pilia is a researcher supported by the Contratos Predoctorales de Formación en Investigación en Salud programme from Instituto de Salud Carlos III (FI22/00262). This project received funding from Instituto de Salud Carlos III (PI21/01046) and Fondo Europeo de Desarrollo Regional. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding information for this article has been deposited with the Open Funder Registry.
Contributor Information
the Se-COVID-19 team:
Marta Arjona, Miriam Barrecheguren, Cristina Berastegui, José Cardoso, David Clofent, Almudena Felipe, María Angeles Jiménez, Manuel Lopez, Jeisson Osorio, Mercedes Pallero, Eva María Revilla, Berta Saez, Maria Saéz, Júlia Sampol, Eduardo Vélez, and Ana Villar
Data availability
Individual participant data will not be available. The study protocol, tables and figures will be available immediately after publication.
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01552-2025.SUPPLEMENT
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Data Availability Statement
Individual participant data will not be available. The study protocol, tables and figures will be available immediately after publication.