What is granulomatous disease?

Granulomatous Disease: Definition, Types, and Management

Granulomatous disease is characterized by the formation of granulomas, which are organized collections of macrophages and other immune cells that form in response to chronic inflammation, often with a perilymphatic distribution pattern and distinctive histopathological features. 1

Types of Granulomatous Disease

Sarcoidosis

• Most common systemic granulomatous disease
• Characterized by non-necrotizing granulomas with a perilymphatic distribution 2, 1
• Clinical features:
  • Bilateral hilar lymphadenopathy (highly characteristic) 2
  • Pulmonary involvement in >90% of cases 1
  • Extrapulmonary manifestations: skin (lupus pernio), eyes (uveitis, optic neuritis), nervous system, bones 2
  • Laboratory findings: hypercalcemia, elevated serum angiotensin-converting enzyme (sensitivity 60%, specificity 70%) 2, 1

Infectious Granulomatous Diseases

• Tuberculosis and non-tuberculous mycobacterial infections
• Fungal infections (Aspergillus, Candida)
• Characterized by central necrosis in granulomas 1
• Diagnosis confirmed by special stains and cultures 1

Vasculitic Granulomatous Diseases

• Granulomatosis with polyangiitis (GPA, formerly Wegener's)

  • Necrotizing granulomatous vasculitis affecting upper/lower respiratory tract and kidneys 2
  • Associated with c-ANCA/PR3 antibodies
  • Presents with cough, hemoptysis, and respiratory symptoms in >95% of patients 2

• Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

  • Characterized by asthma, eosinophilia, and granulomatous inflammation 2
  • ANCA-positive in ~40% of cases (usually MPO-ANCA) 2
  • Three phases: allergic phase (asthma, rhinosinusitis), eosinophilic phase, and vasculitic phase 2

Chronic Granulomatous Disease (CGD)

• Primary immunodeficiency of phagocyte function due to defective NADPH oxidase 3, 4
• Characterized by recurrent bacterial and fungal infections 5, 3
• Associated with inflammatory complications, particularly inflammatory bowel disease 6
• Genetic forms: X-linked (most common) and autosomal recessive 3

Diagnostic Approach

Imaging

• High-resolution CT (HRCT) of the chest is essential to evaluate distribution patterns 1
  • Perilymphatic pattern suggests sarcoidosis
  • Random pattern suggests infection
  • In sarcoidosis: nodularity of mucosal thickening, osteoneogenesis, bone erosion may be seen 2

Histopathology

• Key features to assess: 1
  • Presence/absence of necrosis (necrotizing in infections, non-necrotizing in sarcoidosis)
  • Distribution and organization of granulomas
  • Presence of fibrosis
  • In sarcoidosis: well-formed, concentrically arranged layers of immune cells with central macrophage aggregates and multinucleated giant cells 2

Laboratory Tests

• Serum angiotensin-converting enzyme (SACE) - elevated in sarcoidosis but not diagnostic (sensitivity 60%, specificity 70%) 2, 1
• ANCA testing - positive in vasculitic granulomatous diseases 2
• Special stains and cultures for mycobacteria and fungi 1
• For CGD: dihydrorhodamine (DHR) assay to assess neutrophil oxidative burst 3

Treatment Approaches

Sarcoidosis

• Many cases (particularly Stage 1) undergo spontaneous remission within two years 2
• Systemic corticosteroids are the mainstay of treatment when required 2
• Steroid-sparing agents: methotrexate, azathioprine, hydroxychloroquine 2
• For refractory disease: TNF-alpha antagonists like infliximab 2

Vasculitic Granulomatous Diseases

• GPA: combination of systemic corticosteroids and cyclophosphamide initially 2
• EGPA: treatment based on disease severity and organ involvement 2

Chronic Granulomatous Disease

• Antimicrobial, antifungal, and interferon-γ prophylaxis 3
• Immunomodulators for inflammatory manifestations 6
• Hematopoietic stem cell transplantation is curative with >84-90% survival 3
• Gene therapy approaches are under investigation 3

Differential Diagnosis

When evaluating granulomatous disease, consider: 2

• Sarcoidosis
• Tuberculosis and other mycobacterial infections
• Fungal infections
• Vasculitic disorders (GPA, EGPA)
• Berylliosis
• Hypersensitivity pneumonitis
• Chronic granulomatous disease
• Drug-induced granulomatous reactions

Understanding the distribution pattern, histopathological features, and clinical presentation is crucial for distinguishing between these entities and establishing the correct diagnosis.