What are common granulomatous diseases?

Common Granulomatous Diseases

Granulomatous diseases are broadly categorized into infectious and non-infectious etiologies, with the most common being tuberculosis and fungal infections (infectious), and sarcoidosis, hypersensitivity pneumonitis, and granulomatosis with polyangiitis (non-infectious). 1

Infectious Granulomatous Diseases

Mycobacterial Infections

• Tuberculosis is the leading infectious cause of granulomatous disease worldwide, characterized by robust, frequent necrotizing granulomas with central acellular necrosis 2, 1
• Atypical mycobacteria can also produce granulomatous inflammation, particularly in immunocompromised patients 3

Fungal Infections

• Histoplasma capsulatum produces large acellular necrotizing granulomas and is endemic to Ohio and Mississippi River valleys 1, 4
• Other endemic fungi (Coccidioides, Blastomyces) and opportunistic fungi (Aspergillus, Cryptococcus) cause granulomatous disease in specific geographic regions or immunocompromised hosts 1
• Rhinosporidiosis occurs in specific geographic areas 1

Other Infectious Causes

• Brucellosis presents with non-caseating granulomas similar to sarcoidosis but is distinguished by positive cultures/serology and exposure to livestock or unpasteurized dairy 4
• Leishmania and other parasitic infections can trigger cutaneous granulomatous reactions 3

Non-Infectious Granulomatous Diseases

Sarcoidosis

• Sarcoidosis is characterized by well-formed, non-necrotizing granulomas in a perilymphatic distribution with minimal surrounding lymphocytic inflammation 2, 1
• Bilateral hilar adenopathy and perilymphatic nodules on chest CT are highly characteristic imaging features 2, 1
• Extrapulmonary manifestations include lupus pernio, uveitis, cardiac involvement, and bone lesions 2, 5
• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) is a highly probable clinical presentation 2, 4

Hypersensitivity Pneumonitis

• Hypersensitivity pneumonitis features poorly formed, non-necrotizing granulomas with extensive surrounding lymphocytic alveolitis in a small airway distribution 2, 1
• The inflammation consists mostly of lymphocytes with cellular bronchiolitis and interstitial pneumonia patterns 2
• Foamy macrophages, cholesterol clefts, and organizing pneumonia may be present as minor features 2

Vasculitis-Associated Granulomatous Disease

• Granulomatosis with polyangiitis (GPA, formerly Wegener's) shows necrotizing granulomatous inflammation with vasculitis affecting small-to-medium vessels 1, 6
• Upper respiratory tract involvement occurs in approximately 3-4% of patients with generalized disease 5
• ANCA testing is essential when vasculitis is suspected 1

Inflammatory Bowel Disease-Associated

• Crohn's disease can present with granulomatous interstitial lung disease mimicking parenchymal sarcoidosis 2, 7
• Bronchopulmonary involvement includes bronchiectasis, chronic bronchitis, and organizing pneumonia 2
• Drug-induced granulomatous reactions from 5-ASA, methotrexate, or anti-TNF agents must be excluded 2

Immunodeficiency-Related

• Common variable immunodeficiency (CVID) and chronic granulomatous disease (CGD) are major inborn errors of immunity presenting with granulomas 7, 8
• The estimated prevalence of granulomas in inborn errors of immunity ranges from 1-4% 8
• These conditions carry significant morbidity and mortality 8

Other Non-Infectious Causes

Occupational/Environmental

• Berylliosis (chronic beryllium disease) presents with well-formed granulomas indistinguishable from sarcoidosis; diagnosis requires blood lymphocyte proliferation testing 2
• Talc granulomatosis occurs from intravenous drug use or occupational exposure 6

Cutaneous Granulomatous Diseases

• Granuloma annulare and necrobiosis lipoidica (more frequent in diabetics) present as palisaded granulomas 3
• Foreign body granulomas result from retained material triggering chronic inflammation 9, 3
• Interstitial granulomatous dermatitis represents a disseminated cutaneous form 3

Drug-Induced

• Immune checkpoint inhibitors, anti-TNF agents, and other immunotherapeutics can trigger sarcoidosis-like granulomatous reactions 2

Malignancy-Associated

• Lymphoma can present with granulomatous inflammation and must be excluded through immunohistochemistry showing monoclonal B-cell populations 4, 9

Critical Diagnostic Principle

Special stains must be performed on all biopsy specimens to exclude mycobacteria and fungi before diagnosing any non-infectious granulomatous disease, as this distinction has profound treatment implications. 2, 1