What is granulomatous disease?

What is Granulomatous Disease?

Granulomatous disease refers to a diverse group of conditions characterized by the formation of granulomas—focal, compact collections of inflammatory cells (predominantly mononuclear cells) that develop in response to persistent non-degradable antigens or active cell-mediated hypersensitivity. 1

Two Distinct Categories

Granulomatous diseases fall into two fundamentally different categories that must not be confused:

1. Chronic Granulomatous Disease (CGD)

CGD is a rare inherited primary immunodeficiency (occurring in approximately 1:250,000 individuals) caused by defects in the NADPH oxidase system of phagocytic cells, resulting in defective intracellular killing of pathogens. 2

• Pathophysiology: Mutations in any of the five components of NADPH oxidase prevent phagocytes from generating superoxide, leading to inability to kill certain bacteria and fungi 3, 2
• Clinical presentation: Recurrent, life-threatening bacterial and fungal infections affecting skin, airways, lymph nodes, liver, brain, and bones 2
• Common pathogens: Staphylococcus aureus, Aspergillus species, Burkholderia cepacia, Serratia marcescens, Salmonella species, Nocardia species, and Candida albicans 4, 2
• Inflammatory complications: Paradoxically, CGD patients develop excessive granuloma formation and inflammatory reactions (including IBD-like colitis) due to hyper-activation of NF-κB and inflammasomes 3, 5
• Diagnosis: Nitroblue tetrazolium (NBT) test as primary screening, followed by dihydrorhodamine (DHR) flow cytometry for confirmation 6

2. Granulomatous Disorders (General)

These encompass a broad spectrum of infectious and non-infectious conditions that share the common histological feature of granuloma formation but have entirely different etiologies than CGD. 1

Classification of Granulomatous Disorders

Infectious Causes (Must Be Excluded First)

The American Thoracic Society mandates that infectious etiologies must be systematically excluded before considering non-infectious diagnoses, as infections are the most common cause worldwide. 7

• Tuberculosis: Produces robust, frequent necrotizing granulomas with central acellular necrosis; leading cause globally 7, 8
• Fungal infections: Histoplasma capsulatum creates large acellular necrotizing granulomas; endemic fungi vary by geography 7, 8
• Other infections: Syphilis, rhinoscleroma, leprosy, cat scratch fever 9

Non-Infectious Causes

Sarcoidosis

Well-formed, non-necrotizing granulomas arranged in a perilymphatic distribution (around bronchovascular bundles and pleura) with minimal surrounding lymphocytic inflammation are pathognomonic for sarcoidosis. 9, 7

• Imaging: Bilateral hilar adenopathy with perilymphatic nodules on chest CT 9
• Clinical features: May present as Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis); lupus pernio, uveitis 9
• Laboratory: Elevated ACE (>50% above upper limit), hypercalcemia with abnormal vitamin D metabolism 9

Hypersensitivity Pneumonitis

Poorly formed, non-necrotizing granulomas with extensive surrounding lymphocytic alveolitis in a small airway distribution (bronchioles and alveolar ducts) distinguish HP from sarcoidosis. 9, 7

• Key difference from sarcoidosis: Uniform cellular interstitial inflammation, predominantly lymphocytic, with less compact granulomas 9

Granulomatosis with Polyangiitis (GPA)

Necrotizing granulomatous inflammation combined with vasculitis affecting small-to-medium vessels characterizes GPA. 9, 7

• Laboratory: PR3-ANCA (proteinase-3) highly specific; Staphylococcus aureus colonization found in 72% of cases 9
• Clinical: Upper and lower airway involvement, renal disease 9

Other Non-Infectious Causes

• Vasculitis: ANCA-associated vasculitides, Behçet's disease 9, 1
• Occupational: Berylliosis (mimics sarcoidosis; diagnosed by blood lymphocyte proliferation test) 9
• Drug-induced: 5-ASA, methotrexate, anti-TNF agents (paradoxical sarcoid-like reactions) 9
• Malignancy-related: Sarcoid-like reactions to tumors, lymphomas 9
• Immunologic: IgG4-related disease, common variable immunodeficiency 9

Critical Diagnostic Algorithm

The American Thoracic Society recommends this stepwise approach: 7, 8

1. Obtain tissue biopsy with special stains: Perform AFB and fungal stains on ALL specimens to exclude mycobacteria and fungi—never diagnose sarcoidosis without this step 7
2. Assess granuloma morphology: Necrotizing vs. non-necrotizing; compact vs. poorly formed; distribution pattern 9
3. Chest CT imaging: Evaluate for bilateral hilar adenopathy, perilymphatic nodules (sarcoidosis), cavitation (infection), small airway distribution (HP) 7, 8
4. Targeted laboratory testing:
   • Mycobacterial: AFB smear/culture, interferon-gamma release assay 8
   • Fungal: Histoplasma antigen, fungal cultures 8
   • Sarcoidosis: Serum ACE, calcium levels 9, 8
   • Vasculitis: ANCA testing if clinically suspected 7
5. Consider geographic/occupational exposures: Histoplasmosis (Ohio/Mississippi River valleys), TB-endemic travel, livestock exposure (brucellosis) 8

Common Pitfalls to Avoid

• Never assume sarcoidosis without excluding infection: Necrotizing granulomas can occur in sarcoidosis variants (nodular pulmonary sarcoidosis), but infection must still be ruled out 9, 7
• Do not confuse CGD with granulomatous disorders: CGD is a specific immunodeficiency with recurrent infections; granulomatous disorders are inflammatory conditions that form granulomas 4, 1
• Early GPA may show non-specific findings: Initial biopsies may lack obvious vasculitis features, showing only mucosal inflammation 7
• Drug-induced granulomas are reversible: Cessation of offending agent (anti-TNF, methotrexate, 5-ASA) with or without steroids typically resolves lesions 9