Introduction
In the 1980s, Davison et al. [1] and Epler et al. [2] described a condition characterized by cold-like symptoms persisting for 4 to 10 weeks with a histologic pattern of alveolar and alveolar duct organization. Although this condition responded well to steroids, it was prone to recurrence. They named this condition cryptogenic organizing pneumonia (COP) and bronchiolitis obliterans organizing pneumonia (BOOP), respectively. By 1997, idiopathic BOOP was recognized as an independent entity within the classification of idiopathic interstitial pneumonias (IIPs) by Muller and Colby. In 2002, a decision was made by the American Thoracic Society (ATS) and European Respiratory Society (ERS) to uniformly name it COP due to concerns that the term BOOP could be confused with airway diseases and that ‘organizing pneumonia (OP)’ was a generic term potentially applicable to various etiologies [3]. This classification was reaffirmed in the 2013 revision by the same societies, where COP continued to be the preferred term and secondary OP was described to be associated with specific causative conditions (e.g., rheumatoid arthritis-related OP) to differentiate it from idiopathic forms [4]. Diverse causes of secondary OP necessitate its exclusion before diagnosing COP.
Epidemiology
The precise incidence and prevalence of COP are unknown. However, a retrospective 20-year study in Iceland reported an incidence of 1.1 cases per 100,000 population [5] and a major teaching hospital in Canada observed a cumulative prevalence of 6.5 cases per 100,000 hospital admissions [6]. In interstitial lung disease (ILD) registries, the prevalence of COP was reported to be 5% in one study [7] and 10% in another [8]. A 2008 nationwide survey by the Korean Academy of Tuberculosis and Respiratory Diseases found that COP accounted for 8.5% of 2,186 patients with IIP, making it the third most common form of IIP in Korea [9]. With increasing recognition of various conditions that can cause OP, the diagnostic rate for COP is decreasing [10,11]. The average age at diagnosis of COP ranged from 50 to 60 years based on 37 studies involving 1,490 confirmed cases [9]. Reports have indicated no gender predominance, although some data suggest a slightly higher incidence in males. However, three studies on COP in Korea found a female predominance at approximately 60% [12-14]. Less than 15% were smokers and 54% were non-smokers, suggesting a low likelihood of association between COP and smoking [15,16].
Clinical Characteristics
COP should be considered in patients presumed to have infectious pneumonia when they do not respond to antibiotic treatment [15]. Clinically, symptoms manifest acutely or subacutely over weeks to months, usually beginning 2 months prior to diagnosis. The most common symptoms include a dry cough (71%) and dyspnea on exertion (62%). These symptoms can be accompanied by fever (44%), fatigue, malaise, and weight loss. Influenza-like symptoms such as nasal congestion, headache, chills, sweating, sore throat, cough, myalgia, and fever have been reported in 10% to 15% of cases, while the occurrence of hemoptysis is very rare (<5%). Some patients may rapidly progress to acute respiratory failure. Inspiratory crackles are detected in 60% of patients during auscultation, although some patients may present with normal breathing sounds [15,17-22].
Diagnosis
When diagnosing COP, it is crucial to differentiating it from other diseases with similar clinical presentations and to exclude potential causes of OP (Table 1) [15,16]. Community-acquired pneumonia is the most common and significant differential diagnosis. COP should be suspected if there is no response to antibiotic treatment. Radiologically, if multiple areas of pulmonary consolidation are observed, differential diagnoses such as hypersensitivity pneumonitis (HP), eosinophilic pneumonia, pulmonary hemorrhage, and vasculitis should be considered. When nodular consolidations with air bronchograms are observed, the possibility of pulmonary lymphoma or invasive mucinous adenocarcinoma should be considered. In cases where OP and nonspecific interstitial pneumonia (NSIP) occur concurrently or sequentially, differentiation is required for underlying causes such as connective tissue diseases (CTD), anti-synthetase syndrome, HP, and drug toxicity. A previous report has suggested an increased risk of disease progression when patterns of OP coexist with NSIP [23].
COP can be diagnosed and treated clinically without a tissue biopsy. However, if the diagnosis is ambiguous, a lung biopsy is necessary for confirmation. Such decision should be made through multidisciplinary discussion (Figure 1). In certain cases, causes of secondary OP, such as aspiration, vasculitis, and infection, may be identified through histological examination of lung biopsy sample. If treatment is initiated without a biopsy and if the clinical course and follow-up observations do not align with COP, a re-evaluation of the diagnosis is required, potentially necessitating a tissue biopsy [15,16].
1. Laboratory findings
Laboratory findings are nonspecific, with approximately half of patients showing elevated peripheral white blood cell counts, C-reactive protein, and erythrocyte sedimentation rate [18-22,24]. In cases of CTD, secondary OP can precede onset of the underlying disease by weeks to months. Therefore, when a CTD is clinically suspected, diagnostic tests for the underlying condition (e.g., antinuclear antibody, rheumatoid factor, anti-cyclic citrullinated peptide antibody, anti-dsDNA, CK, anti-centromere Ab, anti-Scl-70, and anti-Jo-1) should be considered [21].
2. Pulmonary function tests
Pulmonary function tests generally reveal restrictive ventilatory defects, with the forced vital capacity demonstrating a mild to moderate decrease ranging from 60% to 70%. Although airflow limitation is uncommon, it might be observed in ever-smokers. Approximately 25% of patients have normal lung volumes, while most exhibit a reduction in diffusing capacity of the lungs for carbon monoxide (DLco), which ranges from 50% to 70% of the predicted value. Even if pulmonary function is compromised at diagnosis, a good response to treatment can lead to normalization of these parameters [17,18,25].
3. Radiologic findings
The most common finding on chest high-resolution computed tomography (HRCT) is patchy pulmonary consolidation occurring peripherally (80% to 95%), typically without any signs of parenchymal destruction (Figure 2) [2,17,19,20,25-27]. These consolidations can occur in any pulmonary regions. They might affect either one lung or both, predominantly appearing subpleural or in the lower zones of the lungs. Consolidations often coincide with air bronchograms. They might be accompanied by ground-glass opacities and nodular patterns (Figure 3). Spontaneous resolution of pulmonary lesions and emergence of new lesions may coexist. The reverse halo sign, or atoll sign, characterized by a sclerotic rim surrounding a central area of transparency or ground-glass opacity, is observed in less than 5% of cases (Figure 4). Mediastinal lymph node enlargement is rare. A small amount of pleural effusion may occasionally be present [10,22,26,28-33]. Progressive fibrosis and honeycombing are exceedingly rare manifestations [33,34].
4. Bronchoscopy
Lymphocytes, plasma cells, and macrophages variably populate the interstitium. Bronchoalveolar lavage (BAL) fluid cytology commonly reveals an increase in the lymphocyte fraction exceeding 25%. Although CD4/CD8 ratio is usually decreased, this finding is nonspecific. Increases in neutrophils and eosinophils can also occur. An increase in neutrophils necessitates ruling out infectious diseases, while an increase in eosinophils suggests a need to differentiate eosinophilic pneumonia Furthermore, BAL is recommended to exclude infectious diseases, pulmonary hemorrhage, and other conditions [12,13,25,28,35-38].
5. Lung biopsy and histologic features
Histologically, granulation tissue (Masson’s bodies) is typically observed within the alveoli, alveolar ducts, and occasionally in small bronchioles, sometimes accompanied by intraluminal bronchiolar polyps (Figure 5). These features are characteristic of OP, which often displays a patchy distribution without significant alteration of lung architecture [39]. Interstitial fibrosis, granulomas, necrosis, vasculitis, and hyaline membranes are rare findings that might suggest other diseases [38]. While surgical lung biopsy remains the standard, studies have also diagnosed OP using transbronchial lung biopsy. A study involving 37 subjects reported a diagnostic sensitivity of 64% and a specificity of 86% for this method [40]. Several retrospective studies have reported improvement after steroid therapy by observing the pattern of OP through transbronchial lung biopsy [19]. Some studies have suggested that a diagnosis can also be made through percutaneous transthoracic needle biopsy [41]. Recent advancements in transbronchial lung cryobiopsy (TBLC) have shown high concordance with surgical lung biopsies in diagnosing ILD [42], suggesting that TBLC could be beneficial for diagnosing COP. Further validation of TBLC in COP is warranted.
Treatment
1. Expert recommendation
- Steroids may be utilized in the treatment of COP (voting result: strong recommendation from five out of six experts)
- In patients with COP, immunosuppressive therapy may be considered in cases of progression or recurrence despite steroid monotherapy (voting result: conditional recommendation from six out of six experts).
2. Steroid
To date, there are no controlled studies comparing steroids with placebo in the treatment of COP. However, many studies have reported rapid clinical improvement with steroid therapy in COP [15]. The initial dosing starts at prednisone 0.5-1 mg/kg per day, with a maximum of 60 mg daily for 2 to 4 weeks as a single oral dose. Depending on the clinical response, the dosage is gradually tapered over 4 to 6 months. Although not well studied, treatment duration is generally recommended to be between 6 months and 1 year [17,27]. Patients who respond well to treatment often show clinical improvement within 24-72 hours. Complete remission may be confirmed after 3 months [27]. For patients using more than 20 mg/day of prednisone, prophylaxis against Pneumocystis jirovecii is recommended [15]. In cases of severe and rapidly progressing disease where respiratory failure is emergent, high-dose steroid pulse therapy with methylprednisolone 500 to 1,000 mg intravenously for 3 to 5 days may be necessary, with a switch to oral therapy within a few days as the patient improves [31].
To reduce the risk of cumulative steroid dosage and side effects, a previous study has introduced a regimen starting with prednisone at 0.75 mg/kg/day for 4 weeks, followed by 0.5 mg/kg/day for another 4 weeks, then 20 mg/day for 4 weeks, 10 mg/day for 6 weeks, and finally 5 mg/day for another 6 weeks, totaling 24 weeks. At this dose regimen, the disease course did not differ compared to patients treated with other regimens, while the cumulative steroid dosage was reduced by 50% [16].
Recurrences also respond well to steroids. A study comparing outcomes between increasing the dose to 20 mg/day of prednisone when relapses occur under a dose of 20 mg/day or less versus increasing to higher doses (average 40 mg/day) found no difference in clinical outcomes, with higher doses leading to more side effects [27]. Based on this, it could be reasonable to reinitiate treatment with prednisone at 20 mg/day and taper the dose in case of recurrence.
3. Macrolide antibiotics
Small retrospective observational studies have reported that macrolide antibiotics (erythromycin, azithromycin, or clarithromycin), known for their anti-inflammatory properties, can serve as adjuvants to oral steroids [21,35]. It has been reported that macrolides could be an alternative to steroids in patients with mild COP who have normal lung function due to their shorter treatment durations, lower side effects (such as upper respiratory infections and weight gain), and lower relapse rates than steroids [43]. In one of these studies, clarithromycin was administered orally at a dose of 500 mg twice daily for 3 months. The steroid group used prednisone, with an average initial dose of 0.67±0.24 mg/kg/day, administered over an average of 8.59±3.05 months [43]. Other studies have compared the combined therapy of macrolides and steroids to steroid monotherapy [21,43,44]. The combination treatment (clarithromycin 100 mg/day for 1 week, 500 mg/day for 3 weeks, 250 mg/day for 8 weeks, total 12 weeks, accompanied by prednisone 0.75 mg/kg/day for 2 weeks, 0.5 mg/kg/day for 2 weeks, 20 mg/day for 2 weeks, 10 mg/day for 3 weeks, 5 mg/day for 3 weeks, total 12 weeks) did not demonstrate superiority over steroid monotherapy (prednisone 0.75 mg/kg/day for 4 weeks, 0.5 mg/kg/day for 4 weeks, 20 mg/day for 4 weeks, 10 mg/day for 6 weeks, 5 mg/day for 6 weeks, total 24 weeks), showing a lower response rate and a higher relapse rate. Therefore, the role of macrolides in the treatment of COP has not yet been conclusively determined [16].
4. Other medications
Immunoglobulin [45], rituximab [46], cyclophosphamide [47], and mycophenolic acid [48] are being explored as alternatives or for their steroid-sparing effects in severe cases of COP that do not respond to steroids. However, their effectiveness remains unclear as it has only been documented in case reports.
Natural Course and Prognosis
In some cases, COP improves naturally without pharmacological treatment and generally responds well to steroid therapy, with most patients achieving complete recovery. Improvement is usually rapid within days after starting steroids, although occasionally it can take more than 10 days, with most imaging findings showing improvement after 3 months [13,14,28]. Follow-up HRCT shows that while pulmonary consolidation may partially or completely resolve, reticular opacities may persist or progress, potentially leading to fibrotic sequelae. One study has reported that initial poor responses to treatment are associated with cases showing traction bronchiectasis or extensive pulmonary consolidation affecting more than 10% of the lung area on initial chest computed tomography scans, with secondary OP typically showing poorer responses than idiopathic cases [13].
Progressive respiratory failure is rare. Most retrospective studies have reported that mortality due to COP occurs in less than 10% of cases, with a 5-year survival rate of over 90%. Most deaths are due to underlying diseases in cases of secondary OP [12,14,23,24,27-29,49]. Cohen et al. [34] have analyzed outcomes of 10 patients with BOOP showing progressive pulmonary fibrosis and found that most of them have drug or environmental exposures or secondary OP due to CTD [24,34].
Recurrences are relatively common, with reported relapse rates ranging from 13% to 70% [16]. Most recurrences occur within the first year of treatment, often upon tapering or discontinuation of steroids. Risks of relapse are higher if treatment is delayed after symptom onset, if initial steroid doses are low or the duration of use is short, or if pulmonary consolidation is extensive [23,24,27-29,43]. If relapse occurs while taking more than 20 mg of prednisone or after 18 months from the onset, the diagnosis of COP should be reconsidered and the possibility of CTD, HP, and drug-induced secondary OP should be evaluated [16].
Acute Fibrous and Organizing Pneumonia
Acute fibrous and organizing pneumonia (AFOP) was first described in 2002 by Beasley et al. [50] as a histological subtype of IIP. Unlike diffuse alveolar damage, which exhibits similar rapid and progressive lung injury, or OP, AFOP is characterized by distinctive intra-alveolar fibrin deposition, alongside acute and chronic inflammation of the adjacent pulmonary parenchyma and proliferation of type II pneumocytes (Figure 6) [50,51]. Radiographically, it often presents as bilateral pulmonary consolidations, predominantly in the lower lobes, with reticular and reticulonodular interstitial shadow (Figure 7) [52]. In 2013, the ATS/ERS guidelines on ILD recognized AFOP as a rare type of IIP [4].
AFOP has been reported in patients with a wide age range from 38 to 80 years. It is clinically characterized by rapidly progressive respiratory failure [51,53,54]. Its mortality rate is approximately 50%, with about 30% of cases requiring mechanical ventilation. However, some cases of AFOP have shown a favorable prognosis [50,55,56]. A recent study found that among 15 patients with surgically confirmed AFOP, nine (60%) required mechanical ventilation and eight (53%) died [57]. Among survivors, five showed significant improvement [57]. Rapidly progressing dyspnea, severe hypoxemia, and bilateral pulmonary infiltrates should prompt differential diagnosis between acute interstitial pneumonia (AIP) and AFOP, with consideration for a lung biopsy for confirmation. Initially, fever may accompany symptoms, making it challenging to differentiate it from infectious diseases such as pneumonia. Like COP, secondary AFOP has been frequently associated with various causes, including infections, CTD, hematological malignancies, and drugs (e.g., programmed death-ligand 1 inhibitors, amiodarone), making it crucial to identifying triggering factors [50,58].
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