Chronic Inflammation and Granulomatous Disease

Transition from Acute to Chronic Inflammation

• Persistent injury or ineffective acute inflammation resolution perpetuates inflammatory cell recruitment
• Shift in mediators: IL-1, TNF-α, and chemokines (CCL2, CXCL10) recruit mononuclear cells rather than neutrophils
• Failure of pathogen clearance, continuous antigen presentation, and chronic tissue injury maintain the inflammatory state
• Macrophage activation by IFN-γ (from Th1 cells) and TNF-α sustains chronic inflammation

Granuloma Formation—Core Mechanism

• Antigen presentation by dendritic cells activates Th1 and Th17 CD4+ T cells
• IL-2 and IFN-γ production drives macrophage activation and differentiation into epithelioid cells (activated macrophages with elongated nuclei and reduced phagocytic capacity)
• TNF-α from macrophages is critical for granuloma cohesion and maintenance; TNF-α-deficient animals cannot form granulomas
• Multinucleated giant cells (Langhans-type or foreign body-type) form through fusion of epithelioid macrophages; nuclei arrange peripherally in Langhans giant cells
• Central necrosis (caseating or non-caseating) results from macrophage antimicrobial products (ROS, TNF-α, nitric oxide) and cytotoxic T cell-mediated killing

Chronic Inflammatory Cell Infiltrate

• CD4+ T cells and CD8+ T cells maintain persistent antigen-specific immune responses
• Plasma cells produce antibodies contributing to immune complex-mediated inflammation
• Fibroblasts proliferate in response to TGF-β, PDGF, and FGF, producing collagen and leading to fibrosis
• Neovascularization via VEGF and FGF supports the chronic inflammatory infiltrate

Molecular Perpetuation

• Continuous antigen presentation in lymphoid aggregates maintains Th1/Th17 responses
• Persistent pathogens or their antigens (in tuberculosis, histoplasmosis) or autoantigens (in sarcoidosis) sustain granuloma formation
• Defective regulatory T cell (Treg) function or reduced IL-10/TGF-β signaling fail to suppress inflammation
• Oxidative stress from macrophage-derived ROS perpetuates tissue damage and fibrosis

Infectious Causes of Granulomatous Inflammation

• Mycobacterium tuberculosis (most common granulomatous disease worldwide)—intracellular pathogen resisting phagolysosomal killing
• Atypical mycobacteria (MAC in AIDS, M. marinum)
• Fungal infections: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus species
• Bacterial infections: Brucella, Bartonella henselae (cat-scratch disease), Tropheryma whipplei (Whipple disease), Syphilis (gummas)
• Parasitic infections: Schistosomiasis, toxoplasmosis
• Viral: Some reports in CMV colitis

Non-Infectious Causes

• Sarcoidosis (idiopathic, most common non-infectious granulomatous disease in developed countries)—unknown antigen
• Crohn disease (GI tract)—dysregulated immune response to commensal bacteria
• Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)—autoimmune destruction with granulomatous features
• Chronic granulomatous disease (CGD) and Job syndrome—primary immunodeficiencies affecting neutrophil and macrophage oxidative burst
• Hypersensitivity pneumonitis—IgG-mediated immune response to inhaled antigens (occupational/environmental)
• Granulomatosis with polyangiitis (GPA, formerly Wegener) and microscopic polyangiitis—ANCA-associated vasculitis
• Talcosis, silicosis, berylliosis—occupational/environmental mineral exposure
• Foreign body granulomas—sutures, splinters, retained foreign material
• Drug reactions—sulfonamides, allopurinol
• Chronic granulomatous disease of childhood (CGD)—defects in NADPH oxidase complex (X-linked gp91phox, autosomal recessive p22phox, p47phox, p67phox)

Risk Factors for Chronic Inflammation

• Persistent pathogen burden (especially mycobacteria, fungi)
• Immunosuppression (HIV/AIDS, medications)
• Genetic predisposition (HLA associations in sarcoidosis and CGD)
• Occupational exposure (silica, asbestos, beryllium)
• Smoking (impairs macrophage function)
• Environmental/dietary triggers (in sarcoidosis, Crohn disease)

Systemic Manifestations of Chronic Inflammation

• Fever (often low-grade, persistent)—due to continued IL-1 and TNF-α production
• Constitutional symptoms: fatigue, malaise, weight loss—result of cachexia from TNF-α, IL-1, IFN-γ
• Night sweats—particularly in tuberculosis and lymphomas
• Anemia of chronic disease—from hepcidin upregulation by IL-6, iron sequestration in macrophages

Granulomatous Disease-Specific Presentations

• Pulmonary TB: productive cough with hemoptysis, cavitary disease on imaging
• Extrapulmonary TB: lymphadenitis, miliary spread, Pott disease (spine), CNS involvement
• Gross appearance: cheese-like (caseous) necrotic center with surrounding epithelioid granuloma

• Hilar lymphadenopathy with pulmonary infiltrates (asymptomatic or with cough, dyspnea)
• Erythema nodosum (painful nodules, particularly on shins)
• Ocular involvement: anterior uveitis, posterior synechiae
• Hypercalcemia and hypercalciuria (from calcitriol production by macrophages)
• Constitutional symptoms, arthralgias
• Non-caseating granulomas without central necrosis

• Abdominal pain, diarrhea, rectal bleeding
• Fistula and abscess formation (from transmural inflammation)
• Apthous ulcers, perianal disease
• Extraintestinal manifestations: arthritis, erythema nodosum, pyoderma gangrenosum
• Skip lesions with cobblestone appearance

• Geographic/occupational history crucial
• Histoplasmosis: pulmonary infection with dissemination in immunocompromised
• Coccidioidomycosis: respiratory symptoms, erythema nodosum
• Blastomycosis: pulmonary/cutaneous disease

• Recurrent bacterial and fungal infections (Staphylococcus aureus, Serratia, Aspergillus, Nocardia)
• Granulomas in unusual sites: liver abscesses, osteomyelitis, rectal strictures
• Inflammatory complications: dermatitis, inflammatory bowel disease-like colitis
• Early-onset (often by age 5); X-linked form more severe

Morphological Correlates

• Caseating granulomas (TB, some fungi) = central acellular debris with epithelioid cells at periphery
• Non-caseating granulomas (sarcoidosis, Crohn) = tightly cohesive epithelioid cells without necrosis
• Foreign body granulomas = giant cells surrounding foreign material without epithelioid differentiation

Histopathology—Gold Standard

• Epithelioid cells: activated macrophages with elongated nuclei, pale cytoplasm, reduced lysosomes
• Multinucleated giant cells:
• Langhans giant cells: nuclei arranged in peripheral horseshoe pattern (associated with infectious causes, sarcoidosis)
• Foreign body giant cells: randomly distributed nuclei (associated with foreign material)
• Central necrosis:
• Caseating necrosis (tuberculous granuloma)—acellular eosinophilic debris with sharp demarcation
• Non-caseating necrosis (sarcoidosis, Crohn)—tightly cohesive without central acellular zone
• Surrounding lymphocytic infiltrate: CD4+ T cells predominate, plasma cells present
• Fibrosis at periphery (indicates chronicity and healing phase)

Gross Pathology

• Tuberculosis: cheese-like (caseous) yellow-tan nodules with cavitation in upper lobes
• Sarcoidosis: granular appearance without necrosis, hilar lymph node enlargement
• Crohn disease: transmural inflammation, skip lesions, fistulas, cobblestone mucosa
• Foreign body: visible foreign material at center of granuloma

Laboratory Investigations

• ACE level (angiotensin-converting enzyme): elevated in sarcoidosis (produced by epithelioid macrophages)
• Serum calcium and 1,25-dihydroxyvitamin D: elevated in sarcoidosis (hypercalcemia in ~10%)
• Inflammatory markers: ESR and CRP elevated (non-specific)
• Tissue fungal/mycobacterial stains:
• Ziehl-Neelsen or auramine-rhodamine for acid-fast bacilli (TB)
• GMS (Gomori methenamine silver) for fungi
• PAS (periodic acid-Schiff) for some fungi
• Culture: mycobacterial culture (gold standard for TB) takes 2-8 weeks; molecular methods (TB-PCR) faster
• Mantoux test (tuberculin skin test): delayed hypersensitivity reaction (positive in TB infection)
• Interferon-gamma release assays (IGRAs): more specific for TB than TST
• Biopsy confirmation: essential for diagnosis—histology showing granulomas in appropriate clinical context

Imaging

• Chest X-ray: hilar lymphadenopathy, apical-posterior infiltrates (TB), cavitary disease
• CT chest: better detail of nodules, lymph node distribution, bronchiectasis
• 18F-FDG PET: hypermetabolic uptake in active granulomas (used in sarcoidosis, TB)

Diagnostic Criteria

• Tuberculosis: positive culture/molecular testing + histology + clinical/radiologic correlation
• Sarcoidosis (Scadding staging):
• Stage 0: No radiographic findings
• Stage 1: Hilar lymphadenopathy without parenchymal involvement
• Stage 2: Hilar lymphadenopathy + parenchymal infiltrates
• Stage 3: Parenchymal infiltrates without hilar adenopathy
• Stage 4: Pulmonary fibrosis
• Crohn disease: CDEIS (Crohn Disease Endoscopic Index), histology with non-caseating granulomas, imaging (MR enterography)
• CGD: Nitroblue tetrazolium (NBT) test negative (cells cannot produce respiratory burst), dihydrorhodamine flow cytometry abnormal

Tuberculosis (Caseating Granulomas)

• First-line: 6-month regimen—isoniazid, rifampin, pyrazinamide, ethambutol for 2 months, then isoniazid + rifampin for 4 months
• Rationale: Multi-drug therapy prevents resistance; pyrazinamide penetrates macrophages and caseous lesions
• Directly observed therapy (DOT) improves adherence
• Rifampin: induces CYP450 (drug interactions critical)
• Monitoring: monthly sputum smears, clinical response, liver function tests (especially with isoniazid hepatotoxicity risk)

Sarcoidosis (Non-Caseating Granulomas)

• Corticosteroids (first-line for symptomatic disease)—prednisone 20-40 mg daily, tapered over weeks to months
• Rationale: Inhibit TNF-α, IL-6, IL-17 production and suppress Th1/Th17 cells
• Target: remission of pulmonary and extrapulmonary manifestations
• Asymptomatic disease: observation (up to 20% remit spontaneously)
• Second-line/steroid-sparing agents:
• Methotrexate (TNF-α inhibition)
• Mycophenolate mofetil (inhibits lymphocyte proliferation)
• TNF-α inhibitors (infliximab, adalimumab) for refractory cases or when steroids contraindicated
• Hydroxychloroquine: for hypercalcemia and skin manifestations

Crohn Disease (Non-Caseating Granulomas)

• Induction therapy:
• Corticosteroids (prednisone 40-60 mg daily) for moderate-severe disease
• 5-ASA compounds (mesalamine) for mild-moderate colonic disease
• Maintenance therapy:
• Azathioprine or 6-mercaptopurine (immunosuppression)
• TNF-α inhibitors (infliximab, adalimumab, certolizumab): gold standard, particularly effective with concurrent immunosuppressive therapy
• Biologic agents:
• Anti-TNF-α agents: mechanism—block TNF-α production and induce regulatory T cells
• Anti-α4β7 integrin (vedolizumab): blocks lymphocyte homing to gut
• Surgical intervention: resection for refractory disease, severe strictures, or fistulas
• Monitoring: disease activity scores, endoscopy for mucosal healing assessment, TNF-α inhibitor drug levels

Hypersensitivity Pneumonitis

• Antigen avoidance (first-line)—remove from occupational/environmental exposure
• Corticosteroids for acute/subacute symptomatic disease
• Immunosuppressants for progressive fibrotic disease (mycophenolate, azathioprine)

Chronic Granulomatous Disease (CGD)

• Prophylactic antibiotics: trimethoprim-sulfamethoxazole (prevents Pneumocystis and bacterial infections)
• IFN-γ supplementation: enhances macrophage activation and oxidative burst (modest benefit)
• Aggressive treatment of active infections (prolonged courses, combination therapy)
• Antifungal prophylaxis (itraconazole) in some centers
• **Gene therapy and

Disease-related — structural sequelae of persistent macrophage activation

• Progressive fibrosis: TGF-β/PDGF-driven collagen deposition replaces granulomas, giving restrictive physiology with a reduced DLCO; in sarcoidosis this is Scadding stage 4, in TB it produces upper-lobe scarring and traction bronchiectasis.
• Cavitation and massive hemoptysis: caseous material liquefies and drains into a bronchus; erosion of a pulmonary artery branch coursing through the cavity wall produces a Rasmussen aneurysm. Most massive hemoptysis, however, arises from hypertrophied bronchial arteries — hence bronchial artery embolization after airway protection and positioning the bleeding lung dependent. Emergency.
• Miliary/disseminated disease and TB meningitis: hematogenous seeding when granulomas fail to contain organisms; new headache, cranial neuropathies, or basilar meningeal enhancement is an emergency. Obtain neuroimaging before LP if focal deficits or altered mental status suggest raised ICP; treat with four-drug therapy plus adjunctive dexamethasone and extend total duration to 9–12 months per the ATS/CDC/IDSA tuberculosis guidelines.
• Cardiac sarcoidosis: granulomas in the basal septum interrupt conduction — unexplained high-grade AV block or VT in a young adult is an emergency and, per Heart Rhythm Society consensus, prompts cardiac MRI/FDG-PET and ICD consideration.
• Hypercalcemia: unregulated macrophage 1α-hydroxylase raises calcitriol, causing nephrolithiasis, nephrocalcinosis, and AKI; severe symptomatic hypercalcemia is an emergency (saline plus glucocorticoids).
• Secondary (AA) amyloidosis: chronic IL-6-driven serum amyloid A production; signaled by new nephrotic-range proteinuria after years of inflammation.
• Anemia of chronic disease: IL-6 → hepcidin → iron sequestration; low serum iron with normal-to-high ferritin and low TIBC.
• Crohn complications: transmural inflammation yields strictures with obstruction, fistulas, and abscess; free perforation is an emergency. Ileal disease/resection causes B12 deficiency, bile-salt diarrhea, and calcium-oxalate stones; long-standing colitis raises colorectal cancer risk (surveillance colonoscopy per ACG).

Treatment-related

• Isoniazid: hepatitis and pyridoxine-responsive peripheral neuropathy — rising transaminases with symptoms mandates stopping.
• Ethambutol: optic neuritis — loss of red-green discrimination.
• Rifampin: CYP450 induction (oral contraceptive and warfarin failure), orange secretions. Pyrazinamide: hyperuricemia, hepatotoxicity.
• TNF-α inhibitors: TNF-α maintains granuloma integrity, so blockade causes reactivation of latent TB and disseminated histoplasmosis — screen with TST/IGRA and chest imaging first.
• Glucocorticoids: hyperglycemia, osteoporosis, and adrenal insufficiency on abrupt withdrawal (emergency).
• Thiopurines: TPMT/NUDT15 deficiency → profound myelosuppression; test before starting.

• Caseating = think infection: a granuloma with central cheesy acellular debris means mycobacteria or endemic fungi until proven otherwise. Non-caseating granulomas point to sarcoidosis, Crohn disease, berylliosis, or foreign body. The single best next step on any granuloma is stains and culture (AFB/Ziehl-Neelsen, GMS) before immunosuppression — steroids given to undiagnosed TB disseminate it.
• TNF-α is the glue: it maintains granuloma architecture, which is why anti-TNF biologics reactivate latent TB. Examiners test this as "screen with TST or IGRA and chest radiograph before infliximab/adalimumab" — a high-yield and frequently tested association.
• Sarcoid hypercalcemia comes from 1α-hydroxylase in epithelioid macrophages, giving high 1,25-(OH)₂ vitamin D with a suppressed PTH — the mechanistic mirror of PTH-driven hypercalcemia. Glucocorticoids, not bisphosphonates, are the mechanistic answer.
• ACE level is a distractor: it may be elevated as noted in the diagnostic workup above, but per the ATS sarcoidosis guideline it is neither sensitive nor specific and does not establish the diagnosis. Tissue biopsy showing non-caseating granulomas plus exclusion of alternatives does.
• Langhans giant cell = nuclei in a peripheral horseshoe; foreign body giant cell = haphazard nuclei around refractile material. Asteroid and Schaumann bodies are classic for sarcoid but are not specific — do not diagnose on them alone.
• Berylliosis is the perfect sarcoid mimic: identical non-caseating granulomas and hilar adenopathy. The discriminator is the occupational history (aerospace, ceramics, electronics) and a beryllium lymphocyte proliferation test.
• CGD: NADPH oxidase failure → abnormal dihydrorhodamine flow cytometry (has replaced the NBT test) and infections with catalase-positive organisms — S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus. Prophylaxis is TMP-SMX plus an azole, with interferon-γ.
• Anemia of chronic disease vs iron deficiency is a recurring stem: IL-6 → hepcidin → iron trapped in macrophages, so ferritin is normal-to-high and TIBC/transferrin is low — the opposite of true iron deficiency.
• Löfgren syndrome (erythema nodosum, bilateral hilar adenopathy, arthralgia, fever) carries a good prognosis and often needs only NSAIDs and observation, not steroids.