What is the definition, diagnosis, signs and symptoms, pathophysiology, and treatment of Cryptogenic Organising Pneumonia (COP)?

Cryptogenic Organising Pneumonia: Clinical Overview

Definition

Cryptogenic Organising Pneumonia (COP) is a clinicopathological syndrome characterized by fibroblast proliferation and inflammatory cells embedded in extracellular matrix within small airways and alveoli, forming polypoid masses called Masson bodies, where no underlying cause can be identified after exhaustive testing. 1, 2

• The organizing pneumonia pattern involves a patchy process affecting alveolar ducts and alveoli with or without bronchiolar intraluminal polyps 1, 2
• COP is distinguished from secondary organizing pneumonia by the absence of identifiable triggers such as infection, connective tissue disease, malignancy, radiotherapy, drug reactions, or immunodeficiency 1
• This is a rare disease with an annual incidence of approximately 1:100,000 1

Pathophysiology

The pathological hallmark is an aberrant healing response to injury within the small airways and alveolar spaces, characterized by three key histological features: 2, 3

• Cellular interstitial pneumonia 2
• Cellular bronchiolitis 2
• Poorly formed nonnecrotizing granulomas 2
• The presence of Masson bodies (buds of granulation tissue containing fibroblasts and connective matrix within alveolar lumens) confirms the diagnosis and predicts excellent corticosteroid response 2, 4

Signs and Symptoms

COP typically presents as a subacute illness with median duration less than 3 months, characterized by: 1, 5, 3

Respiratory Symptoms

• Dyspnea and cough (60% of patients) 6
• Cough alone (40% of patients) 6
• Progressive breathlessness over weeks to months 1

Constitutional Symptoms

• Fever (60% of patients) 1, 6
• Myalgia 1, 3
• Fatigue 7

Physical Examination Findings

• New focal chest signs including crackles, diminished breath sounds, dull percussion note, or pleural rub in discrete lung regions 3
• Tachypnea and tachycardia 3
• Elevated blood inflammatory markers (C-reactive protein, ESR) 1, 5

Diagnosis

High-resolution computed tomography (HRCT) is the primary imaging modality, with histological confirmation typically required via open lung biopsy or transbronchial biopsy. 5, 6

Imaging Characteristics (HRCT)

• Patchy and often migratory consolidation in subpleural, peribronchial, or bandlike pattern 1, 5, 3
• Ground-glass opacity (present in 63.6% of cases) 1, 8
• Reversed halo (atoll) sign - characteristic but present in only 6.8% of cases 1, 8
• Perilobular opacities 1
• Small unilateral or bilateral pleural effusion (10-30% of patients) 1, 5
• Nodules (39.8% of cases) 8

Pulmonary Function Tests

• Combined restrictive and obstructive pattern 3, 6
• Impaired gas transfer (reduced DLCO) 1, 5

Histopathological Confirmation

• Definitive diagnosis requires three features: cellular interstitial pneumonia, cellular bronchiolitis, and poorly formed nonnecrotizing granulomas 2
• Open lung biopsy provides definitive diagnosis in most cases, though transbronchial biopsy may be sufficient 6, 7
• Correlation of biopsy findings with HRCT findings is essential 2

Exclusion of Secondary Causes (Critical Step)

Before diagnosing COP, systematically exclude: 2, 5, 3

• Collagen vascular diseases (rheumatoid arthritis, systemic sclerosis) 2, 5
• Infections (bacterial, viral, fungal) 5, 7
• Malignancies 5, 3
• Drug reactions 2, 3
• Hypersensitivity pneumonitis 5, 3
• Immunotherapy-related pneumonitis (anti-PD-1/PD-L1 therapy can cause organizing pneumonia in 4.6% of patients) 3

Diagnostic Biomarkers

• Procalcitonin may help differentiate COP from community-acquired pneumonia, as it remains low in COP despite elevated CRP 9

Treatment

Oral corticosteroids are the treatment of choice for non-remitting or progressive COP, with typical initial dosing of prednisone approximately 50 mg/day. 2, 3

Treatment Response

• The majority of patients recover completely with oral corticosteroids 1, 5, 3
• Response to corticosteroids is rapid and complete, usually without sequelae 4
• Complete recovery occurs in the majority of patients 3

Natural History Considerations

• Spontaneous remission occurs in many untreated cases (37 of 90 patients with bilateral lesions in one series achieved spontaneous remission) 1, 8
• Patients with unilateral lesions may not require glucocorticoid therapy 8

Macrolide Antibiotics

Long-term macrolide antibiotics should NOT be used for COP management. 1

• There is insufficient evidence to recommend macrolide therapy 1, 5
• The natural history of untreated COP is often self-resolution, and in the absence of placebo-controlled trials, no conclusions can be made about macrolide efficacy 1

Treatment Duration and Relapse

• Prolonged corticosteroid treatment is often necessary due to frequent relapses 4
• Relapse is common, reported in up to two-thirds of cases 2, 3
• After steroid therapy is reduced or stopped, 66% of patients experience recurrence 8
• Risk factors for relapse include fever at presentation, elevated CRP levels, and reduced DLCO % predicted 3

Refractory Cases

• Some cases do not completely resolve despite prolonged treatment, characterized by residual or progressive interstitial fibrosis with or without recurrent episodes of organizing pneumonia 1, 5

Prognosis

The prognosis of COP is excellent, with 5-year survival of 73% for cryptogenic cases compared to 44% for secondary organizing pneumonia. 1, 2, 3

• Overall 5-year survival rate is 98.3% in recent series 8
• Prognosis is particularly good when consolidation is the primary pattern on CT 1
• Prognosis is more guarded when COP is associated with lymphoproliferative or connective tissue disease 6

Clinical Pitfalls to Avoid

• Do not delay diagnosis: COP is frequently misdiagnosed as community-acquired pneumonia; consider COP in patients with bilateral airspace disease who fail to respond to antibiotics 6, 7
• Do not skip histological confirmation: Definite confirmation via biopsy is warranted as corticosteroid therapy is usually needed for months 6
• Do not miss secondary causes: 86.9% of pathologically diagnosed organizing pneumonia cases are secondary; continuous follow-up is key for accurate COP diagnosis 8
• Do not stop steroids prematurely: Prolonged treatment is often necessary due to high relapse rates 4