Cryptogenic Organising Pneumonia (COP) — MD Examination Answer

Definition & Nomenclature

• Historical term: Idiopathic bronchiolitis obliterans organising pneumonia (BOOP) — coined by Epler et al. (1985)
• Preferred term: COP, since "bronchiolitis obliterans" is a misnomer — the dominant process is in the air spaces, not the airways
• First described as a clinicoradiological entity by Davison et al. (1983) in eight patients with bilateral consolidation, polypoid fibrosis in alveoli, and striking corticosteroid response
• "Organising pneumonia" = histological pattern; "Cryptogenic" = only when no cause is identified

Classification

Aetiology / Causes of OP Pattern

• Unknown → COP
• Infections (bacterial, viral — including COVID-19)
• Toxic fume exposure
• Drugs — antibiotics, chemotherapeutics (bleomycin, amiodarone, nitrofurantoin), anti-inflammatory drugs
• Connective tissue diseases — especially polymyositis/dermatomyositis, RA, Sjögren's syndrome
• Vasculitis — Churg–Strauss, Wegener's granulomatosis
• Immunological disorders — common variable immunodeficiency, mixed cryoglobulinaemia
• Organ transplantation — bone marrow, lung, renal
• Radiation pneumonitis
• Malignancy — particularly lymphoma

Epidemiology

• Affects patients typically in their 50s–60s (range 40–70 years)
• Equal sex incidence; no association with smoking
• Incidence: ~2–7 per 100,000 population

Pathogenesis

1. Initial injury (unknown trigger in COP) → damage to alveolar epithelial cells
2. Exudation of fibrin into alveolar spaces
3. Migration of fibroblasts and myofibroblasts into fibrin matrix
4. Formation of polypoid granulation tissue buds (Masson bodies) in alveolar ducts and alveoli
5. Inflammatory infiltrate of lymphocytes, plasma cells, macrophages in alveolar walls
6. Architecture preserved — no honeycombing or significant fibrosis
7. The process is potentially reversible with treatment (unlike UIP/IPF)

Pathology (Histology)

• Masson bodies (polypoid buds of loose connective tissue / fibroblastic plugs) in alveolar spaces, alveolar ducts, and respiratory bronchioles
• Inflammatory infiltrate in alveolar walls — lymphocytes, plasma cells, occasional eosinophils
• Alveolar architecture preserved (no destructive fibrosis)
• Patchy and temporally uniform (unlike UIP)
• Foamy macrophages may fill adjacent alveoli
• No hyaline membranes, no eosinophilic infiltrates, no granulomas (distinguishes from other IIPs)

Histopathologic findings include patchy regions of organizing pneumonia with granulation tissue commonly involving small airways, alveolar ducts, and alveoli with surrounding inflammation that can involve alveolar walls — Harrison's 22E, Fig. 304-3C

Clinical Features

• Symptoms present for 4–10 weeks before diagnosis (average 3 months)
• Multiple failed courses of antibiotics → should raise suspicion
• Non-productive cough + dyspnoea + constitutional symptoms in middle-aged non-smoker

Investigations

Pulmonary Function Tests

• Restrictive pattern — reduced TLC, FVC, DLCO
• FEV1/FVC normal or increased
• Hypoxaemia at rest or on exertion
• Mild obstruction occasionally (due to bronchiolar involvement)

Blood Tests

• Elevated ESR and CRP (often markedly)
• Mild leukocytosis
• Autoantibody screen (ANA, anti-Jo-1, RF) — to exclude secondary causes (CTD)

Bronchoalveolar Lavage (BAL)

• Lymphocytosis (CD8 > CD4) — most characteristic
• Also: neutrophilia, eosinophilia (mixed cellularity)
• CD4:CD8 ratio decreased
• BAL pattern alone not diagnostic but supportive

Chest X-Ray Findings

• Bilateral patchy areas of consolidation — mid and lower zone predominance (though any zone can be affected)
• Subpleural and/or peribronchovascular distribution in ~2/3 of patients
• Migrating (fleeting) opacities — highly characteristic
• Nodules (up to 1 cm) — may be the sole manifestation
• Cavitation is NOT a feature

HRCT Findings (most important investigation)

A perilobular distribution of consolidation, unlike a multitude of other radiological signs, may be regarded as pathognomonic of an organising pneumonia pattern — Grainger & Allison's Diagnostic Radiology

Diagnosis

Diagnostic Criteria

1. Infectious causes
2. Drug-induced OP
3. CTD-associated OP
4. Post-radiation OP

• Transbronchial biopsy — sufficient in typical cases (shows Masson bodies); avoids surgical biopsy
• Surgical lung biopsy (VATS) — when diagnosis remains uncertain; gold standard for histology
• CT-guided — for peripheral nodular lesions

1. Typical clinical + HRCT findings → MDT discussion
2. BAL to support (lymphocytosis)
3. Transbronchial biopsy if clinical picture not clear
4. VATS/surgical biopsy if diagnosis still uncertain

Differential Diagnosis

Treatment

Corticosteroids — First-line

• Response is typically dramatic and rapid — symptomatic improvement within days to weeks
• Radiological improvement within 4–8 weeks

Second-line / Steroid-sparing

Evidence is growing that alternate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic (e.g., rituximab) therapies can be helpful in both treating the disease and reducing the need for steroids — Harrison's 22E

Spontaneous resolution

• Mild/asymptomatic cases may resolve spontaneously
• Watchful waiting acceptable only in very mild disease

Prognosis & Relapse

• Overall prognosis: Excellent — most patients respond well to corticosteroids
• Relapse rate: 30–58% — usually on steroid taper or after discontinuation
• Relapses respond to re-initiation of steroids
• Factors predicting relapse:
  • Short duration of initial treatment
  • Rapid steroid taper
  • Secondary forms (CTD-associated)
• Progression to respiratory failure is rare
• Chronic fibrosing course seen in a minority (termed "fibrotic OP" or progression to NSIP/UIP pattern)
• Mortality: <5% in COP; higher in secondary forms

COP vs. Secondary OP — Key Distinction

Summary / High-Yield Points for MD Exam

1. COP = organising pneumonia without identifiable cause — diagnosis of exclusion
2. Masson bodies = pathological hallmark (polypoid fibroblastic plugs in alveoli/alveolar ducts)
3. Classic presentation: middle-aged non-smoker, subacute flu-like illness, bilateral consolidation failing antibiotic therapy
4. HRCT: bilateral peripheral consolidation ± GGO ± reversed halo sign ± perilobular pattern
5. Reversed halo/atoll sign and perilobular consolidation = near-pathognomonic CT signs
6. BAL: mixed cellularity with lymphocytosis (CD4:CD8 ratio decreased)
7. PFTs: restrictive pattern with reduced DLCO
8. Treatment: Prednisolone 0.75–1 mg/kg/day for minimum 6–12 months
9. Dramatic response to steroids is both diagnostic and therapeutic
10. Relapse in 30–58% — especially on steroid taper; re-treat with steroids

• Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 304
• Grainger & Allison's Diagnostic Radiology, Chapter 11
• Murray & Nadel's Textbook of Respiratory Medicine
• Fishman's Pulmonary Diseases and Disorders