Abstract
Background:
Cryptogenic organizing pneumonia (COP) is classified as a subtype of idiopathic interstitial pneumonia (IIP), which has a good prognosis. Relapse remains one of the most challenging and intriguing aspects of COP. This study aimed to characterize the clinical features, prognosis, and relapse patterns of COP.
Methods:
In this prospective cohort study, patients diagnosed with COP between March 1, 2004 and June 30, 2022 at China-Japan Friendship Hospital and Beijing Chao-Yang Hospital were enrolled after a comprehensive multidisciplinary review. Patients were followed up through regular clinical visits every 3–6 months until October 30, 2023. Data collected included demographic characteristics, clinical presentation, laboratory findings, radiologic features, and prognostic outcomes. The primary outcome measure was relapse. Cox regression analyses were performed to explore factors related to the presence of relapse.
Results:
This study included 268 patients with a final diagnosis of COP based on multidisciplinary discussion. After diagnosis, the one-year survival rate was 99.6%, decreasing to 97.7% at 3 years, 94.5% at 5 years, and 81.7% at 10 years. Relapses occurred in 20.9% (56/268) of patients, with a median time to relapse of 12 months. Of these relapses, 28.6% (16/56) occurred when prednisone was tapered to below 10 mg/day, and 62.5% (35/56) occurred after discontinuation of prednisone therapy; fewer than 10% of relapses occurred at prednisone doses above 15 mg/day. Ground-glass opacities (GGOs) (225/268, 84.0%) and consolidations (212/268, 79.1%), predominantly with bilateral lung distribution, were the most common computed tomography (CT) features at diagnosis. No patient developed residual lung fibrosis on high-resolution CT, regardless of relapse status. Furthermore, no deaths were attributable to COP progression or relapse, and all-cause mortality was unrelated to COP itself.
Conclusion:
This study indicated that patients with COP had a good prognosis with favorable survival outcomes. However, relapse was relatively common, occurring in more than 20% of patients. Therefore, close follow-up is essential for early detection of relapses, particularly during corticosteroid tapering or after treatment discontinuation.
Keywords: Cryptogenic organizing pneumonia (COP), Relapse, Risk factors, Prognosis
Introduction
Organizing pneumonia (OP) represents a reparative response of lung tissue following injury, characterized histologically by polypoid granulation tissue within the lumens of bronchioles and alveolar ducts.[1] When no identifiable cause is present, OP is termed cryptogenic organizing pneumonia (COP), which is classified as a subtype of idiopathic interstitial pneumonia (IIP).[1–4] A retrospective study from Iceland reported a mean annual incidence of COP of 1.10 per 100,000 individuals over a 20-year period.[5] In Spain, registry data indicated that approximately 10% of patients with interstitial lung disease (ILD) were diagnosed with COP,[6] whereas a Greek registry reported a prevalence of about 5% among ILD patients.[7] In our previous study, COP accounted for 8.8% of ILD cases.[8]
Relapse remains one of the most challenging and intriguing aspects of COP. Approximately 25% of patients with COP have been reported to experience relapse, most commonly within the first year after diagnosis.[1] Numerous factors have been associated with relapse, including delayed diagnosis and initiation of treatment,[9] increased inflammatory markers,[10] hypoxemia,[11,12] reduced pulmonary diffusing capacity,[10] gastroesophageal reflux,[13] computed tomography (CT) findings of multifocal opacities[14] and involvement of multiple lobes,[15] as well as, in some cases, traction bronchiectasis and architectural distortion accompanied by increased serum levels of Krebs von den Lungen-6 (KL-6).[16] Histopathological features, such as fibrin deposition in biopsy specimens,[15,17] and evidence of lung scarring and remodeling have also been implicated.[18] However, findings across studies have been inconsistent, and reliable predictors of relapse in COP have yet to be established.
Hence, this study aimed to improve understanding of the clinical characteristics of COP and to explore factors associated with relapses, with the goal of identifying patients at high risk of recurrence.
Methods
Study population
Based on a prospective ILD-China cohort established by our group, this multicenter observational study was conducted by the China-Japan Friendship Hospital (ClinicalTrials.gov ID: NCT04370158). This study involving human participants was approved by the China-Japan Friendship Hospital Clinical Research Ethics Committee (approval number: 2017-25) and the Beijing Chaoyang Hospital of Capital Medical University Clinical Research Ethics Committee (approval number: 13-k-19). Patients diagnosed with COP were enrolled between March 1, 2004 and June 30, 2022, at two centers: China-Japan Friendship Hospital and Beijing Chao-Yang Hospital. The inclusion criterion was that all diagnoses met the 2013 American Thoracic Society/European Respiratory Society (ATS/ERS) standards.[4] All diagnoses were confirmed through multidisciplinary discussion (MDD), incorporating clinical features, CT findings, bronchoalveolar lavage fluid (BALF) analyses, and pathological results. The multidisciplinary team comprised at least one respiratory physician, one pathologist, and one radiologist. Patients without available chest high-resolution computed tomography (HRCT) images from the participating hospitals at admission, as well as those lacking follow-up data, were excluded. Written informed consent was obtained from all participants.
Data collection
We collected the following data from patients: clinical characteristics, laboratory test results, HRCT images, arterial blood gas analyses, pulmonary function parameters, treatment strategies, and treatment responses. Patients were followed up through regular clinical visits every 3–6 months until October 30, 2023. For those unable to attend in-person visits, follow-up was conducted via telephone interviews. The follow-up period was defined as the time from diagnosis to death or the end of follow-up.
Definition of relapse
COP relapse was defined as the emergence of new characteristic infiltrates on chest imaging consistent with the disease, accompanied by compatible clinical features and supported, when available, by bronchoalveolar lavage (BAL) and/or lung biopsy findings, in the absence of any other identifiable causes. Infection was rigorously excluded based on clinical presentation; laboratory tests (including complete blood count, C-reactive protein, and procalcitonin); imaging studies; microbiological evaluations (including sputum smear and/or culture, blood culture, BALF smear and culture, and/or metagenomic next-generation sequencing of blood or BALF); and assessment of the response to anti-infective therapy. Meanwhile, conditions, such as pulmonary tumors, pulmonary edema, atelectasis, and pulmonary embolism—whose clinical manifestations and CT findings may mimic relapse—were carefully excluded. Histopathological confirmation was not required for the diagnosis of relapses when the clinical and radiological presentation was typical.[9] However, for imaging-atypical relapses, biopsy was considered particularly important.
Chest HRCT review and scoring
Two experts in ILD radiology independently evaluated the chest HRCT scans, resolving any discrepancies through consensus. The assessed imaging features included ground-glass opacities (GGOs), consolidations, nodules, reticular or interlobular septal thickening, traction bronchiectasis, and reverse halo signs. Interobserver agreement between the two reviewers was strong, as measured by kappa analysis (κ = 0.788; 95% CI: 0.734–0.839; P <0.001).
A semi-quantitative method was employed to assess the extent of parenchymal infiltrates. Four key anatomical levels were selected for evaluation: the aortic arch, the tracheal bifurcation, 2 cm above the diaphragm, and 2 cm below the diaphragm. The extent of GGOs and consolidations was scored on a six-point scale: 0, no involvement; 1, ≤5%; 2, 6–24%; 3, 25–49%; 4, 50–74%; and 5, ≥75%. For each feature, scores from the four levels were averaged, and the combined scores from both reviewers were further averaged. The total CT score was calculated as the sum of the averaged GGO and consolidation scores.
Pattern changes and disease progression during follow-up were classified as either complete resolution or residual abnormality. Baseline CT scans were categorized as typical COP or other forms of COP. Typical COP was defined by consolidations, with or without GGOs, distributed along peribronchial or subpleural regions. Other forms of COP were characterized by the presence of interstitial shadows superimposed on alveolar consolidations.[19,20] Detailed examples of these two CT patterns are presented in Supplementary Figure 1, http://links.lww.com/CM9/C985.
Statistical analysis
Data with a normal distribution were presented as mean ± standard deviation, while non-normally distributed data were expressed as median and interquartile range (IQR). Categorical variables were reported as counts and percentages. The study population was divided into relapsed and non-relapsed groups. Comparisons between these groups were performed using the Student’s t-test or Mann–Whitney U test for continuous variables and the chi-squared test or Fisher’s exact test for categorical variables, as appropriate. Cumulative survival and relapse-free survival were analyzed using Kaplan–Meier curves and compared with the log-rank test. Missing data were addressed using multiple imputations. Variables with P <0.1 in univariable Cox analysis, along with those considered clinically relevant, were included in the multivariable Cox models. Statistical analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA) and R software (version 3.5.0, http://www.R-project.org). A P-value of <0.05 was considered statistically significant.
Results
Clinical characteristics of COP and COP relapse
A total of 303 patients diagnosed with COP were initially enrolled. During follow-up, secondary causes were identified in 13 patients [Supplementary Table 1, http://links.lww.com/CM9/C985], and 22 patients without available chest CT data were excluded. Ultimately, 268 patients with a confirmed diagnosis of COP were included in the study [Figure 1]. Lung biopsy was performed in 242 cases: 151 via transbronchial lung biopsy (TBLB), 18 via transbronchial cryobiopsy (TBCB), 67 via B-mode ultrasound or CT-guided percutaneous needle biopsy, 3 via video-assisted thoracoscopic surgery, and 3 via open lung biopsy. The remaining 26 patients did not undergo biopsy due to severe clinical conditions, patient refusal, or inability to discontinue antiplatelet/anticoagulant therapy. There was no significant difference in the proportion of patients diagnosed with biopsy between the relapsed and non-relapsed groups (89.3% [50/56] vs. 90.6%[192/212], P = 0.800).
Figure 1.
Flow diagram of screening and inclusion of patients with COP in this analysis. COP: Cryptogenic organizing pneumonia; CT: Computed tomography.
The median age of the study population was 58.0 years (IQR: 50.0–67.0 years), and 50.4% (135/268) were male. Approximately two-thirds of patients were non-smokers. The median duration from symptom onset to diagnosis was 6.0 weeks (IQR: 4.0–8.0 weeks). The most common symptoms were cough (203/268, 75.7%), dyspnea (166/268, 61.9%), and sputum production (136/268, 50.7%), followed by fever (99/268, 36.9%) and flu-like symptoms (44/268, 16.4%), including headache, nasal congestion, chills and sweats, and sore throat. On physical examination, similar proportions of patients presented with moist rales (63/268, 23.5%) and crackles (71/268, 26.5%) [Table 1].
Table 1.
Baseline characteristics of patients with relapsed COP and non-relapsed COP.
| Characteristics | Total COP (n = 268) | Relapsed group (n = 56) | Non-relapsed group (n = 212) | Statistics | P values |
|---|---|---|---|---|---|
| Age (years), median (IQR) | 58.0 (50.0–67.0) | 56.0 (48.0–63.8) | 59.5 (51.0–67.0) | –1.906* | 0.024 |
| Male, n (%) | 135 (50.4) | 27 (48.2) | 108 (50.9) | 0.132† | 0.716 |
| Smoking status | 1.240† | 0.538 | |||
| Non-smokers, n (%) | 182 (67.9) | 35 (62.5) | 147 (69.3) | ||
| Smokers, n (%) | 86 (32.1) | 21 (37.5) | 65 (30.7) | ||
| Symptoms duration (weeks), median (IQR) | 6.0 (4.0–8.0) | 6.0 (3.0–8.0) | 7.0 (4.0–12.0) | –0.958* | 0.302 |
| Symptoms | |||||
| Fever, n (%) | 99 (36.9) | 23 (41.1) | 76 (35.8) | 0.519† | 0.471 |
| Cough, n (%) | 203 (75.7) | 39 (69.6) | 164 (77.4) | 1.435† | 0.231 |
| Sputum, n (%) | 136 (50.7) | 22 (39.3) | 114 (53.8) | 3.720† | 0.054 |
| Dyspnea, n (%) | 166 (61.9) | 39 (69.6) | 127 (59.9) | 1.782† | 0.182 |
| Flu-like syndrome, n (%) | 44 (16.4) | 8 (14.3) | 36 (17.0) | 0.235† | 0.628 |
| Physical examination | |||||
| Moist rales, n (%) | 63 (23.5) | 13 (23.2) | 50 (23.6) | 0.003† | 0.954 |
| Crackles, n (%) | 71 (26.5) | 15 (26.8) | 56 (26.4) | 0.003† | 0.955 |
| Laboratory testing | |||||
| WBC (×109/L), median (IQR) | 6.7 (5.5–8.7) | 8.3 (6.3–9.6) | 6.4 (5.3–8.2) | 3.427* | 0.001 |
| N (%), median (IQR) | 65.8 (58.3–73.3) | 68.7 (62.5–73.6) | 65.2 (57.5–72.0) | 2.167* | 0.041 |
| L (%), median (IQR) | 23.0 (16.1–29.6) | 20.1 (13.6–25.9) | 23.7 (17.5–30.8) | –2.781* | 0.004 |
| PLT (×109/L), median (IQR) | 250.0 (197.0–319.0) | 281.0 (212.0–344.0) | 235.5 (193.8–305.8) | 2.642* | 0.008 |
| NLR, median (IQR) | 2.9 (1.9–4.3) | 3.2 (2.4–5.4) | 2.8 (1.9–4.0) | 2.635* | 0.008 |
| PLR, median (IQR) | 165.8 (115.8–237.6) | 196.8 (119.6–269.6) | 162.2 (114.0–223.7) | 1.722* | 0.085 |
| ESR (mm/h), median (IQR) | 25.0 (9.0–50.0) | 26.0 (12.5–53.5) | 21.5 (8.0–49.8) | 1.117* | 0.264 |
| CRP | 0.939† | 0.322 | |||
| Normal, n (%) | 87 (46.8) | 16 (40.0) | 71 (48.6) | ||
| High, n (%) | 99 (53.2) | 24 (60.0) | 75 (51.4) | ||
| ALP (IU/L), median (IQR) | 77.0 (61.0–94.5) | 71.0 (58.0–90.0) | 78.0 (62.0–95.0) | –0.834* | 0.404 |
| GGT (IU/L), median (IQR) | 28.0 (19.0–47.3) | 31.5 (21.0–52.8) | 27.5 (19.0–46.8) | 0.722* | 0.470 |
| LDH (IU/L), median (IQR) | 182.0 (156.0–224.5) | 191.0 (162.5–224.5) | 179.0 (153.5–224.5) | 1.009* | 0.313 |
| D-dimer (mg/L), median (IQR) | 0.5 (0.3–1.0) | 0.6 (0.3–1.0) | 0.5 (0.3–1.0) | 0.497* | 0.619 |
| CEA (ng/mL), median (IQR) | 1.8 (1.3–3.1) | 1.8 (1.2–3.3) | 1.8 (1.3–3.1) | –0.212* | 0.832 |
| CYFRA21-1 (ng/mL), median (IQR) | 3.0 (2.1–4.4) | 3.0 (2.1–4.9) | 3.0 (2.2–4.4) | 0.206* | 0.837 |
| ANA positive, n (%)‡ | 19 (10.2) | 4 (10.0) | 15 (10.2) | – | 1.000§ |
| Low titer (<1:160), n (%) | 11 (5.9) | 2 (5.0) | 9 (6.1) | ||
| High titer (≥1:160), n (%) | 8 (4.3) | 2 (5.0) | 6 (4.1) | ||
| BAL fluid cellular analysis | |||||
| Lymphocytes (%), median (IQR) | 43.0 (21.0–57.5) | 43.0 (24.3–69.0) | 44.0 (20.8–57.5) | 0.607* | 0.544 |
| Eosinophils (%), median (IQR) | 1.5 (0.5–6.0) | 2.5 (0–9.3) | 1.5 (0.5–5.5) | 0.462* | 0.644 |
| Neutrophils (%), median (IQR) | 18.0 (6.5–36.0) | 12.0 (5.5–29.0) | 20.0 (7.9–37.1) | –1.113* | 0.266 |
| Macrophages (%), median (IQR) | 24.0 (11.5–41.5) | 24.0 (10.0–50.0) | 24.0 (12.0–40.0) | 0.091* | 0.927 |
| CD4/CD8, median (IQR) | 0.5 (0.3–0.9) | 0.5 (0.3–0.8) | 0.5 (0.3–1.0) | –1.993* | 0.801 |
| ABG and PFTs | |||||
| PaO2 (mmHg), median (IQR) | 77.0 (68.0–86.0) | 79.0 (68.0–85.1) | 76.0 (67.9–86.1) | 0.508* | 0.612 |
| OI (mmHg), median (IQR) | 357.0 (319.0–405.0) | 371.0 (319.0–405.0) | 357.0 (314.0–406.3) | 0.283* | 0.827 |
| FEV1 pred (%), median (IQR) | 79.9 (61.6–95.7) | 77.9 (60.1–88.6) | 80.7 (62.3–97.9) | –1.189* | 0.339 |
| FVC pred (%), median (IQR) | 84.4 (65.1–101.5) | 80.7 (60.6–89.5) | 86.7 (65.4–103.2) | –1.912* | 0.085 |
| TLC pred (%), median (IQR) | 79.9 (63.4–89.4) | 76.0 (61.2–85.3) | 81.3 (63.5–89.8) | –1.138* | 0.255 |
| DLCO pred (%), median (IQR) | 58.7 (45.0–72.4) | 50.5 (40.1–69.0) | 61.2 (49.2–72.6) | –1.993* | 0.040 |
*Z values. †χ2 values. ‡The number of cases is 187, with 40 in the relapsed group and 147 in the non-relapsed group. §Calculated using the Fisher’s exact test. ABG: Arterial blood gas; ALP: Alkaline phosphatase; ANA: Antinuclear antibody; BAL: Bronchoalveolar lavage; CEA: Carcinoembryonic antigen; COP: Cryptogenic organizing pneumonia; CRP: C-reactive protein; CYFRA21-1: Cytokeratin 19 fragment antigen 21-1; DLCO: Diffusion of the lung for carbon oxide; FEV1: Forced expiratory volume in 1 s; ESR: Erythrocyte sedimentation rate; FVC: Forced vital capacity; GGT: Gamma-glutamyl transferase; IQR: Interquartile range; L: Lymphocyte; LDH: Lactate dehydrogenase; N: Neutrophil; NLR: Neutrophil to lymphocyte ratio; OI: Oxygenation index; PaO2: Partial pressure of arterial oxygen; PFT: Pulmonary function test; PLR: Platelet to lymphocyte ratio; PLT: Platelet; TLC: Total lung capacity; WBC: White blood cell; –: Not available.
Most laboratory test results were within normal limits. However, C-reactive protein and the erythrocyte sedimentation rate were increased in approximately half of the patients. Nineteen patients (19/186, 10.2%) tested positive for antinuclear antibody (ANA). BALF analysis showed a marked increase in the percentage of lymphocytes and neutrophils, with a mild elevation in the percentage of eosinophils. Hypoxemia and low oxygenation index were common. Pulmonary function tests revealed median values of 79.9% (IQR: 61.6–95.7%) for forced expiratory volume in 1 s (FEV1)% predicted, 84.4% (IQR: 65.1–101.5%) for forced vital capacity (FVC)% predicted, and 79.9% (IQR: 63.4–89.4%) for total lung capacity (TLC)% predicted [Table 1]. GGOs were the most frequently observed CT feature (225/268, 84.0%), followed by consolidations (212/268, 79.1%), reticulation or interlobular septal thickening (80/268, 29.9%), and nodules (39/268, 14.6%). Approximately 90% of patients had bilateral lung involvement, with lesions affecting all five lobes most commonly. The median CT score was 2.0 (1.5–3.0) [Table 2]. CT features in COP patients were heterogeneous, and imaging patterns and lesion locations at relapse could either be similar to or completely different from baseline findings [Figure 2]. No patient showed residual lung fibrosis on HRCT, regardless of relapse status.
Table 2.
Comparison of CT features between patients with relapsed COP and non-relapsed COP.
| CT features | Total COP (n = 268) | Relapsed group (n = 56) | Non-relapsed group (n = 212) | Statistics | P values |
|---|---|---|---|---|---|
| Lesion type | |||||
| Ground-glass opacity, n (%) | 225 (84.0) | 52 (92.9) | 173 (81.6) | 4.165* | 0.041 |
| Consolidations, n (%) | 212 (79.1) | 45 (80.4) | 167 (78.8) | 0.067* | 0.795 |
| Nodules, n (%) | 39 (14.6) | 8 (14.3) | 31 (14.6) | 0.004* | 0.949 |
| Reticulation/Interlobular septal thickening, n (%) | 80 (29.9) | 19 (33.9) | 61 (28.8) | 0.562* | 0.453 |
| Traction bronchiectasis, n (%) | 62 (23.1) | 16 (28.6) | 46 (21.7) | 1.177* | 0.278 |
| Reversed halo sign, n (%) | 33 (12.3) | 10 (17.9) | 23 (10.8) | 2.015* | 0.156 |
| Distribution | 0.741† | 0.389 | |||
| Unilateral, n (%) | 19 (7.1) | 2 (3.6) | 17 (8.0) | ||
| Bilateral, n (%) | 249 (92.9) | 54 (96.4) | 195 (92.0) | ||
| Number of lobes involved | 0.170* | 0.762 | |||
| Less than 5 lobes, n (%) | 63 (23.5) | 12 (21.4) | 51 (24.1) | ||
| 5 lobes, n (%) | 205 (76.5) | 44 (78.6) | 161 (75.9) | ||
| CT score, median (IQR) | 2.0 (1.5–3.0) | 2.6 (1.8–3.3) | 2.0 (1.5–2.9) | 2.474§ | 0.013 |
*χ2 values. †χ2 values (Yates continuity correction). §Z values. COP: Cryptogenic organizing pneumonia; CT: Computed tomography; IQR: Interquartile range.
Figure 2.
Dynamic changes of HRCT scan in relapsed patients with COP. (A–C) HRCT of a 48-years old female patient. (A) Imaging at first onset shows peripheral and multifocal consolidations. (B) One month after (A), complete resolution of the lesions. (C) Three months after (B), new areas of GGOs developed. (D–F) HRCT of a 70-years old female patient. (D) Imaging at first onset shows subpleural consolidations. (E) Six months after (D), almost complete resolution of the lesions was observed. (F) Six months after (E), new areas of GGOs developed at other locations. (G–I) HRCT of a 77-year-old female patient. (G) Imaging at first onset shows subpleural consolidations, ground glass abnormality, and reticular pattern. (H) Four months after (G), the lesions have resolved. (I) Two months after (H), new areas of consolidations developed at other locations. COP: Cryptogenic organizing pneumonia; GGOs: Ground glass opacities; HRCT: High-resolution computed tomography.
Glucocorticoid (GC) therapy was administered to around 80% of patients, with a median starting dose of 0.5 mg·kg–1·day–1 of prednisone or equivalent (typically 0.5–1.0 mg·kg–1·day–1, up to a maximum of 60 mg/day). The dose was tapered by 5 mg every two weeks initially, and at longer intervals once reduced to 15–20 mg/day. The median treatment duration was 8.0 months (IQR: 4.0–12.0 months), with no significant difference between the relapsed and non-relapsed COP groups [Table 3].
Table 3.
Comparison of follow-up and treatment between patients with relapsed COP and non-relapsed COP.
| Characteristics | Total COP (n = 268) | Relapsed group (n = 56) | Non-relapsed group (n = 212) | Statistics | P values |
|---|---|---|---|---|---|
| Follow-up period (months), median (IQR) | 73.0 (43.3–136.8) | 69.0 (47.0–134.8) | 74.0 (42.3–138.8) | –0.499* | 0.788 |
| GC therapy, n (%) | 224 (83.6) | 52 (92.9) | 172 (81.1) | 4.438† | 0.035 |
| Initial dose of GC (mg·kg–1·day–1), median (IQR) | 0.540 (0.460–0.650) | 0.535 (0.470–0.660) | 0.540 (0.460–0.650) | –0.036* | 0.972 |
| Duration of GC treatment (months), median (IQR) | 8.0 (4.0–12.0) | 8.0 (6.0–12.0) | 7.0 (3.0–13.5) | 0.667* | 0.300 |
*Z values. †χ2 values. COP: Cryptogenic organizing pneumonia; GC: Glucocorticosteroid; IQR: Interquartile range.
Clinical outcomes of patients with COP
Follow-up duration varied from 16 months to over 19 years, with a median follow-up of 73.0 months [Table 3]. Overall survival was analyzed using Kaplan–Meier curves, showing survival rates of 99.6% at 1 year, 97.7% at 3 years, 94.5% at 5 years, and 81.7% at 10 years after diagnosis [Figure 3]. During follow-up, 26 patients (26/268, 9.7%) died. Of these, five deaths were attributed to malignant tumors, including two liver cancers, one gynecological cancer, one hematological malignancy, and one urinary system cancer. Eleven patients died from pulmonary infection or respiratory failure, four of whom had coronavirus disease 2019 (COVID-19) pneumonia. One patient died from pulmonary embolism, and another from pulmonary heart disease, while the cause of death was unknown for eight patients. Importantly, no deaths were attributable to the progression or relapse of COP [Supplementary Table 2, http://links.lww.com/CM9/C985]. A multivariable Cox model, treating relapse as a time-dependent covariate and adjusting for other factors affecting survival, including age, CT score, and baseline diffusion of the lung for carbon oxide on single breath (DLCO SB), showed that COP relapse was not associated with an increased risk of death (P = 0.269) [Supplementary Table 2, http://links.lww.com/CM9/C985].
Figure 3.
Kaplan–Meier curves showing the survival probability of patients with COP. CI: Confidence interval; COP: Cryptogenic organizing pneumonia; HR: Hazard ratio.
Comparison of characteristics between patients with and without relapse
A total of 56 patients (56/268, 20.9%) experienced relapse. Of these, 21 underwent BAL at the time of recurrence, with no evidence of bacterial or fungal infection or colonization. Survival probability did not differ significantly between relapsed and non-relapsed groups (P = 0.470) [Figure 3]. Compared with non-relapsed patients, those who relapsed were younger (56.0 [48.0–63.8] years vs. 59.5 [51.0–67.0] years, P = 0.024), more likely to receive GC therapy (92.9% [52/56] vs. 81.1% [172/212], P = 0.035), had a higher neutrophil-to-lymphocyte ratio (3.2 [2.4–5.4] vs. 2.8 [1.9–4.0], P = 0.008), and lower DLCO% predicted (50.5% [40.1–69.0%] vs. 61.2% [49.2–72.6%], P = 0.040) [Tables 1 and 3]. In addition, GGOs were more frequent (92.9% [52/56] vs. 81.6% [173/212], P = 0.041), and CT scores were higher (2.6 [1.8–3.3] vs. 2.0 [1.5–2.9], P = 0.013) in the relapse group [Table 2].
Among the 56 relapsed patients, the time from diagnosis to first relapse ranged from 2 months to 48 months, with a median of 12 months [Supplementary Figure 2, http://links.lww.com/CM9/C985]. Most patients (80.4% [45/56]) experienced a single relapse [Supplementary Figure 3A, http://links.lww.com/CM9/C985]. At the time of first relapse, 35 patients (62.5%) had discontinued therapy, 4 (7.1%) were receiving prednisone at 2.5 mg/day, 12 (21.4%) at 5–10 mg/day, 3 (5.4%) at 15–20 mg/day, and 2 (3.6%) at 25 mg/day [Supplementary Figure 3B, http://links.lww.com/CM9/C985]. The timing of the first relapse was within 6 months for 14.3% (8/56) of patients, between 6 months and 12 months for 32.1% (18/56), and more than 1 year for 53.6% (30/56) [Supplementary Figure 3C, http://links.lww.com/CM9/C985].
We performed Kaplan–Meier survival analyses based on initial GC dose, baseline CT pattern, CT score, and changes in CT findings during follow-up to assess their impact on COP relapse. As illustrated in Supplementary Figure 4, http://links.lww.com/CM9/C985, relapse-free survival only differed significantly between patients with CT score <3.13 and ≥3.13.
Factors associated with the relapse in patients with COP
We performed Cox regression analyses to identify factors associated with relapses in patients with COP. In the multivariable Cox proportional-hazards model, independent risk factors for relapse were younger age (HR: 0.97, 95% CI: 0.95–0.99, P = 0.007), platelet count >350 × 109/L (HR: 1.89, 95% CI: 1.12–1.86, P = 0.048), and higher CT score (HR: 1.44, 95% CI: 1.12–1.86, P = 0.005). [Table 4].
Table 4.
Univariable and multivariable Cox regression analysis of factors associated with relapsed COP.
| Variables | Unadjusted HR (95% CI) | P values | Adjusted HR (95% CI) | P values | Variables | Unadjusted HR (95% CI) | P values | Adjusted HR (95% CI) | P values |
|---|---|---|---|---|---|---|---|---|---|
| Age (years) | 0.98 (0.96–1.00) | 0.033 | 0.97 (0.95–0.99) | 0.007 | PLR | 1.00 (1.00–1.00) | 0.194 | ||
| ALP (IU/L) | 1.00 (0.99–1.01) | 0.885 | |||||||
| Male | 0.93 (0.55–1.57) | 0.757 | GGT (IU/L) | 1.00 (1.00–1.00) | 0.704 | ||||
| Smoking status | LDH (IU/L) | 1.00 (1.00–1.00) | 0.964 | ||||||
| Non-smokers | 1.00 | D-dimer (mg/L) | |||||||
| Smokers | 0.74 (0.43–1.27) | 0.270 | Normal | 1.00 | |||||
| BMI (kg/m2) | 0.97 (0.88–1.06) | 0.463 | High | 1.31 (0.67–2.59) | 0.430 | ||||
| Corticosteroid therapy | 2.83 (1.02–7.82) | 0.045 | CEA (ng/mL) | ||||||
| Duration of GCs treatment (months) | 1.00 (0.96–1.04) | 0.892 | Normal | 1.00 | |||||
| High | 0.49 (0.12–2.02) | 0.321 | |||||||
| Follow-up period (months) | 1.00 (0.99–1.00) | 0.362 | CYFRA21-1 (ng/mL) | ||||||
| Symptoms | Normal | 1.00 | |||||||
| Fever | 1.17 (0.69–2.00) | 0.558 | High | 0.89 (0.44–1.82) | 0.747 | ||||
| Cough | 0.76 (0.43–1.34) | 0.342 | ANA positive | 0.92 (0.33–2.60) | 0.880 | ||||
| Sputum | 0.62 (0.36–1.06) | 0.079 | BAL fluid cellular analysis | ||||||
| Dyspnea | 1.45 (0.82–2.56) | 0.203 | Lymphocytes (%) | 1.01 (0.99–1.02) | 0.371 | ||||
| Flu-like syndrome | 0.84 (0.40–1.78) | 0.653 | Eosinophils (%) | 1.01 (0.98–1.05) | 0.551 | ||||
| Symptoms duration (weeks) | 0.99 (0.97–1.01) | 0.286 | Neutrophils (%) | 0.99 (0.98–1.01) | 0.326 | ||||
| Physical examination | Macrophages (%) | 1.00 (0.99–1.02) | 0.698 | ||||||
| Coarse breath sounds | 0.90 (0.51–1.59) | 0.719 | CD4/CD8 | 0.92 (0.63–1.33) | 0.647 | ||||
| Low breath sounds | 0.81 (0.25–2.59) | 0.721 | ABG&PFT | ||||||
| Moist rales | 1.00 (0.54–1.87) | 0.990 | PaO2 (mmHg) | 1.00 (0.99–1.02) | 0.711 | ||||
| Crackles | 0.99 (0.55–1.79) | 0.969 | OI (mmHg) | 1.00 (1.00–1.00) | 0.644 | ||||
| Laboratory findings | FEV1 pred (%) | 1.00 (0.98–1.01) | 0.513 | ||||||
| WBC (×109/L) | FVC pred (%) | 0.99 (0.98–1.01) | 0.286 | ||||||
| Normal | 1.00 | TLC pred (%) | 1.00 (0.98–1.01) | 0.703 | |||||
| High | 2.12 (1.18–3.79) | 0.011 | 0.66 (0.35–1.25) | 0.203 | DLCO pred (%) | 0.98 (0.97–1.00) | 0.016 | 0.99 (0.98–1.00) | 0.217 |
| N (%) | CT features | ||||||||
| Normal | 1.00 | Lesion type | |||||||
| High | 1.23 (0.65–2.33) | 0.528 | Ground–glass opacity | 2.76 (1.00–7.63) | 0.050 | ||||
| L (%) | Consolidations | 1.07 (0.55–2.06) | 0.850 | ||||||
| Normal | 1.00 | Nodules | 1.00 (0.47–2.11) | 0.997 | |||||
| Low | 1.75 (1.03–2.98) | 0.037 | 0.81 (0.45–1.43) | 0.462 | Reticulation/Interlobular septal thickening | 1.31 (0.75–2.28) | 0.338 | ||
| PLT (×109/L) | Traction bronchiectasis | 1.43 (0.80–2.56) | 0.225 | ||||||
| Normal | 1.00 | Reversed halo sign | 1.58 (0.80–3.12) | 0.193 | |||||
| High | 1.99 (1.07–3.72) | 0.030 | 1.89 (1.12–1.86) | 0.048 | Distribution | ||||
| Unilateral | 1.00 | ||||||||
| ESR (mm/1 h) | Bilateral | 2.20 (0.54–9.02) | 0.274 | ||||||
| Normal | 1.00 | Number of lobes involved | |||||||
| High | 1.27 (0.71–2.29) | 0.425 | Less than 5 lobes | 1.00 | |||||
| CRP (mg/L) | 5 lobes | 1.13 (0.60–2.14) | 0.710 | ||||||
| Normal | 1.00 | CT scores | 1.41 (1.11–1.79) | 0.005 | 1.44 (1.12–1.86) | 0.005 | |||
| High | 1.42 (0.75–2.67) | 0.281 | |||||||
| NLR | 1.05 (0.97–1.12) | 0.214 | Initial GCs dose (mg·kg–1·day–1) | 0.83 (0.16–4.29) | 0.833 |
ABG: Arterial blood gas; ALP: Alkaline phosphatase; ANA: Antinuclear antibody; BAL: Bronchoalveolar lavage; BMI: Body mass index; CEA: Carcinoembryonic antigen; CHE: Cholinesterase; CI: Confidence interval; COP: Cryptogenic organizing pneumonia; CRP: C-reactive protein; CT: Computed tomography; CYFRA21-1: Cytokeratin 19 fragment antigen 21-1; DLCO: Diffusion of the lung for carbon oxide; ESR: Erythrocyte sedimentation rate; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; GCs: Glucocorticosteroids ; GGT: Gamma-glutamyl transferase; HR: Hazard ratio; L: Lymphocyte; LDH: Lactate dehydrogenase; N: Neutrophil; NLR: Neutrophil to lymphocyte ratio; OI: Oxygenation index; PaO2: Partial pressure of arterial oxygen; PFT: Pulmonary function test; PLR: Platelet to lymphocyte ratio; PLT: Platelet; TLC: Total lung capacity; WBC: White blood cell.
Discussion
This prospective study describes the clinical characteristics and outcomes of patients with COP at two ILD centers in China. In this cohort, the median age was 58 years, the sex distribution was balanced, and approximately two-thirds of patients were non-smokers. The most common symptoms were cough, dyspnea, and sputum production, followed by fever and flu-like symptoms. The median time from symptom onset to diagnosis was 6 weeks. HRCT mainly revealed GGOs and consolidations, and BALF analysis commonly showed lymphocytosis.
This study demonstrated that patients with COP had a highly favorable prognosis, with survival rates of 99.6% at 1 year, 97.7% at 3 years, 94.5% at 5 years, and 81.7% at 10 years after diagnosis. The overall relapse rate was 20.9% (56/268), with the interval from diagnosis to first relapse ranging from 2 months to 48 months and a median of 12 months. Among those who relapsed, nearly 80% experienced only a single relapse. For almost 50% of patients, the first relapse occurred within 12 months of diagnosis, including 14.3% (8/56) within the first 6 months. Approximately 30% of relapses occurred when prednisone was tapered below 10 mg/day, while over 60% occurred after discontinuation of therapy; fewer than 10% of relapses occurred at doses above 15 mg/day. No patient developed residual lung fibrosis on HRCT, regardless of relapse status, and no deaths were attributable to COP progression or relapse, with all-cause mortality unrelated to the disease.
The disease burden of ILD is gradually increasing.[21,22] Among the IIPs, COP generally has a favorable prognosis, with reported 5-year survival rates ranging from 73.0% to 98.3%.[9,23,24] Fewer than 10% of patients with COP died, and in most of these cases, death was attributable to causes other than COP.[2–4,14,25,26] Our findings are consistent with previous studies, showing a 5-year survival rate of 94.5%. Notably, extended follow-up in our cohort demonstrated a 10-year survival rate of 81.7%, markedly higher than that reported for most other IIPs.
Relapses have long been a challenging aspect of COP, occurring during or after steroid therapy. Repeated relapses and subsequent courses of treatment can increase the side effects of corticosteroids, with both physical and psychological consequences for patients. Accordingly, we focused on relapses in COP patients. In our study, 20.9% of patients experienced a relapse, consistent with previously reported rates ranging from 13% to 58%.[9–12,14,15,23] Survival did not differ between the relapsed and non-relapsed groups, indicating that relapse did not impact the overall survival in COP. Additionally, our results suggested that the likelihood of relapses decreased with longer disease duration from the time of diagnosis.
We found that younger age, particularly under 52 years, was a risk factor for COP relapses. A similar finding was reported in patients with organizing pneumonia associated with rheumatoid arthritis (RA-OP), where age under 66 years predicted a higher likelihood of relapse.[27] However, previous studies in COP have not consistently identified age as a risk factor. We speculate that younger age may predict relapses due to a more active immune response. In addition, higher platelet counts were associated with COP relapse. Drakopanagiotakis et al[28] reported that platelet counts were significantly higher in patients with COP compared with those with secondary OP. The reason for increased platelet counts in COP is not fully understood. The association of platelet count with relapses suggests a potential link between coagulation or platelet activation and the pathophysiology of COP relapse. Platelets are increasingly recognized as active participants in inflammation,[29,30] releasing various growth factors and cytokines that may contribute to the abnormal tissue repair characteristic of COP. Increased platelet counts may therefore reflect a greater degree of systemic inflammation, predisposing patients to relapse. Similarly, the positive correlation between higher CT scores and relapse risk is clinically intuitive. Greater radiographic involvement, as reflected by the CT score, likely indicates more severe initial inflammation and a larger burden of COP. Previous studies have suggested that CT findings of multifocal shadows[14] and involvement of multiple lobes[15] are associated with relapse. Both factors reflect the extent of lesion involvement on CT, which aligns with our findings. In summary, these three factors—age, platelet count, and CT score—constitute a simple yet powerful clinical profile for stratifying COP patients by relapse risk. For patients identified as high-risk using this model, individualized management may be warranted, including closer monitoring, slower prednisone tapering, or consideration of adjunctive or alternative immunosuppressive therapies at treatment initiation. Future studies should aim to externally validate this model and investigate the underlying biological mechanisms, ultimately supporting more personalized and effective approaches to COP management.
Relapses in COP commonly occur during prednisone tapering or after discontinuation. A retrospective study reported that COP patients are at risk of relapse during the course of treatment.[9] Another study observed that among 23 patients receiving prednisone, 2 relapsed after discontinuation, while 6 experienced relapse during tapering to doses below 5–10 mg/day.[31] These findings highlight the importance of gradual prednisone reduction in COP management. In our study, however, there was no significant difference in the initial prednisone dose or the duration of corticosteroid therapy between patients who relapsed and those who did not. We typically initiate treatment with 0.5 mg·kg–1·day–1 of prednisone or equivalent and taper by 5 mg every two weeks, followed by longer intervals once the dose reaches 15–20 mg/day. In our study, over 90% of relapses occurred when prednisone was tapered below 10 mg/day or discontinued, with an additional 5% occurring at 15–20 mg/day. Randomized controlled trials and evidence-based guidelines for COP treatment are currently lacking. In clinical practice, the steroid tapering regimen is tailored to each patient based on clinical symptoms, CT findings, and recovery of lung function. Our study recommends initiation of prednisone or equivalent glucocorticoids at a dosage of 0.5 mg·kg–1·day–1. The dose is tapered by 5 mg every two weeks until it is reduced to 15–20 mg/day. A slower tapering regimen is adopted thereafter to gradually decrease the dose to 10 mg/day, especially after the daily dose drops below 15 mg/day. Patients receive maintenance therapy at a daily dose below 10 mg/day, with an overall treatment course spanning 6 to 12 months. Clinically, the regimen should be individualized for each patient to balance treatment efficacy with minimization of side effects, including effects on blood pressure, blood glucose, blood lipids, bone density, and immune function.
This study has several limitations. First, both centers were located in Beijing, which may introduce selection bias and limit the generalizability of the findings. However, these are large ILD centers that treat over half of the ILD patients from outside Beijing. Therefore, this study represents one of the largest prospective COP cohorts, with thorough exclusion of secondary causes such as connective tissue disease (CTD) during follow-up. Second, most patients were pathologically diagnosed via TBLB, TBCB, or B-mode ultrasound/CT-guided percutaneous needle biopsy. While these biopsy methods mainly demonstrate features of OP, the combination of pathological findings with HRCT patterns and other clinical and laboratory data enabled a confident COP diagnosis through MDD. This study remains the large cohort in which COP was diagnosed via MDD, particularly with pathological confirmation. Third, approximately 10% of patients did not undergo lung tissue biopsy due to various reasons, particularly severe disease, which could introduce a risk of misdiagnosis. However, their COP diagnoses were established through MDD and clinically confirmed during follow-up. This approach allowed inclusion of more complex and severe cases, making the results more representative of the overall COP population. There was no significant difference in the proportion of patients diagnosed with biopsy between the relapsed and non-relapsed groups (89.3% vs. 90.6%, P = 0.800). Fourth, only about half of the relapsed patients underwent BAL to exclude infection and confirm relapses, which could potentially lead to over- or underestimation of the relapse rate. Nevertheless, BAL is not mandatory for relapse confirmation, as all relapses were diagnosed through MDD and clinically verified during follow-up.
In conclusion, this study indicates that patients with COP generally have a favorable prognosis and good survival. However, relapses are common, occurring in over 20% of patients. Close follow-up is essential for the early detection of relapses, particularly during steroid tapering or after discontinuation. Future larger, prospective, multi-center studies and translational research are needed to better understand the clinical profiles and pathogenesis of COP and its relapses, which may also provide insights into the development of lung fibrosis.
Funding
This study was supported by grants from the Capital’s Funds for Health Improvement and Research (No. 2024-1-4062), and the National Key Technologies Research & Development Program of China (Nos. 2021YFC2500700 and 2016YFC0901100).
Conflicts of interest
None.
Supplementary Material
Footnotes
How to cite this article: Meng WQ, Xie BB, Zhang S, Zhang XR, Geng J, Hu YN, Chen XY, Zhao L, Ren YH, Guo XJ, Liu M, Xie S, Dai HP. Characteristics, prognosis, and risk factors for relapse in patients with cryptogenic organizing pneumonia: A prospective cohort study in China. Chin Med J 2026;139:2750–2759. doi: 10.1097/CM9.0000000000004247
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