Sarcoidosis
Multisystem non-caseating granulomatous disease most commonly involving lungs and lymph nodes.
Also known as: sarcoid, sarcoidosis, noncaseating granuloma, Löfgren syndrome, Heerfordt syndrome
Overview
Idiopathic multisystem disorder characterized by formation of non-caseating epithelioid granulomas in affected organs — most commonly lung and intrathoracic lymph nodes, but virtually any organ can be involved.
Epidemiology
Incidence varies by race: highest in African Americans (35-80 per 100,000) and northern Europeans. Female predominance. Peak onset ages 20-40, with second peak in women 50-60. African American patients more often present with severe/multiorgan disease.
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Risk factors
- African American ancestry (highest US incidence)
- Scandinavian ancestry
- Female sex
- Family history
- Occupational exposures (uncertain causal role): silica, mold, agricultural dust
- Genetic associations: HLA-DRB1, BTNL2
Pathophysiology
Hypothesized antigen-driven T-helper 1 / Th17 response leading to non-caseating granuloma formation with epithelioid macrophages and CD4+ T cells. Activated macrophages produce 1-alpha-hydroxylase → 1,25-dihydroxyvitamin D → hypercalcemia in some patients. Exact triggering antigen unknown.
Clinical presentation
Symptoms
- Pulmonary: dry cough, dyspnea, chest discomfort (~90% have lung involvement at some point)
- Constitutional: fatigue, fever, weight loss, night sweats
- Skin: erythema nodosum, lupus pernio (chronic violaceous facial plaques), papules, plaques
- Ocular: anterior uveitis (most common), posterior uveitis, conjunctival nodules, dry eyes
- Cardiac: heart block, arrhythmias, cardiomyopathy, sudden death
- Neurologic (neurosarcoidosis): cranial neuropathies (CN VII most common), aseptic meningitis, hypothalamic/pituitary involvement (diabetes insipidus, hypopituitarism)
- Renal: nephrolithiasis (hypercalciuria), interstitial nephritis
- Hepatic/splenic involvement (often asymptomatic), peripheral lymphadenopathy
- Löfgren syndrome (acute, good prognosis): bilateral hilar lymphadenopathy + erythema nodosum + arthralgia ± fever
- Heerfordt syndrome (uveoparotid fever): uveitis + parotitis + facial palsy + fever
Signs / physical exam
- Crackles uncommon despite extensive parenchymal involvement
- Skin lesions (erythema nodosum on shins, lupus pernio on face/nose)
- Lymphadenopathy (cervical, supraclavicular)
- Hepatosplenomegaly
- Eye exam: uveitis, conjunctival nodules
Classic findings
Bilateral hilar lymphadenopathy on CXR in young African American or northern European patient; Löfgren triad; lupus pernio; bell's-like facial palsy.
Differential diagnosis
- Tuberculosis — Caseating granulomas (sarcoid is non-caseating), positive AFB, upper-lobe cavitation, exposure history
- Lymphoma — B symptoms, bulky asymmetric lymphadenopathy, biopsy required
- Hypersensitivity pneumonitis — Exposure history (birds, mold), upper-lobe centrilobular nodules, BAL with lymphocytosis (CD4:CD8 <1, opposite of sarcoid)
- Berylliosis — Indistinguishable histology — requires beryllium exposure history and BeLPT (lymphocyte proliferation test)
- Fungal infections (histoplasmosis, coccidioidomycosis) — Endemic exposures, serologic and fungal cultures
- Granulomatosis with polyangiitis — Upper airway involvement, glomerulonephritis, c-ANCA positive
- Common variable immunodeficiency (granulomatous-lymphocytic interstitial lung disease) — Recurrent infections, hypogammaglobulinemia
Diagnostic workup
Diagnostic criteria
Clinical/radiographic presentation + biopsy showing non-caseating granulomas + exclusion of alternative causes. Löfgren syndrome and asymptomatic Stage I CXR in a young patient may be diagnosed clinically without biopsy.
Labs
- ACE level — elevated in ~60%, neither sensitive nor specific (poor diagnostic value)
- CBC (lymphopenia, mild anemia), CMP (hypercalcemia in ~10%, elevated alk phos)
- 1,25-dihydroxyvitamin D (elevated; reflects granuloma alpha-hydroxylase activity)
- 24-hour urine calcium (often elevated even with normal serum calcium)
- Quantiferon / PPD to exclude TB before steroids
- ECG for cardiac involvement; echocardiogram if suspected
Imaging
- Chest radiograph — Scadding stage (0-IV): 0 normal; I bilateral hilar adenopathy; II hilar adenopathy + parenchymal disease; III parenchymal only; IV fibrosis
- HRCT chest — perilymphatic micronodular pattern (along bronchovascular bundles, fissures, subpleural), bilateral symmetric hilar/mediastinal adenopathy
- PET/CT — identifies occult active disease for biopsy targeting and cardiac sarcoid evaluation
- Cardiac MRI with gadolinium for suspected cardiac sarcoid; FDG-PET for inflammatory activity
Other studies
- Tissue biopsy showing non-caseating granulomas — preferred site: enlarged lymph node via EBUS-TBNA (high yield, low risk); skin lesion or peripheral node if accessible; transbronchial lung biopsy
- Always exclude TB and fungi on cultures before attributing granulomas to sarcoid
- PFTs: restrictive pattern with reduced DLCO; can also have obstruction from endobronchial involvement
- Slit-lamp eye exam at diagnosis (uveitis can be asymptomatic)
- Baseline ECG and consider Holter for cardiac involvement
Diagnostic algorithm
| Scadding Stage | CXR Findings | Approx. % at Diagnosis | 5-Yr Spontaneous Remission |
|---|---|---|---|
| 0 | Normal | ~5-10% | — |
| I | Bilateral hilar lymphadenopathy | ~50% | ~75% |
| II | Hilar lymphadenopathy + parenchymal infiltrates | ~25-30% | ~50% |
| III | Parenchymal infiltrates without adenopathy | ~10-15% | ~30% |
| IV | Pulmonary fibrosis (irreversible) | ~5% | 0% |
Treatment
First-line
- Many patients require no treatment — spontaneous remission in ~50% within 2-5 years
- Indications for systemic therapy: progressive pulmonary disease, symptomatic Stage II/III, cardiac involvement, neurosarcoidosis, ocular disease unresponsive to topical therapy, hypercalcemia, severe constitutional symptoms
- Corticosteroids — first-line: prednisone 20-40 mg/day initial, then slow taper over 6-12 months; minimum 1 year of therapy typical
- Topical/local steroids for limited skin or ocular disease
- Hydroxychloroquine 200-400 mg/day for cutaneous disease and hypercalcemia
- NSAIDs for arthralgias of Löfgren syndrome (often self-limited)
Second-line / adjunct
- Steroid-sparing immunosuppressants for chronic disease or steroid intolerance: methotrexate (15-25 mg weekly + folic acid), azathioprine, mycophenolate, leflunomide
- TNF-alpha inhibitors: infliximab, adalimumab — for refractory disease, neurosarcoid, cardiac sarcoid
- Cardiac sarcoid: corticosteroids + immunosuppressant; ICD for high-grade block or VT; pacemaker for AV block
- Pulmonary hypertension complicating sarcoid — referral to specialist; phosphodiesterase-5 inhibitors or endothelin antagonists in select cases
- Lung transplantation for end-stage Stage IV fibrotic disease
- AVOID vitamin D and calcium supplementation (worsens hypercalcemia); sun exposure precautions
Complications
- Pulmonary fibrosis (Scadding stage IV), pulmonary hypertension, aspergilloma in old cavities
- Sudden cardiac death from arrhythmia or heart block (cardiac sarcoid)
- Neurosarcoidosis: cranial neuropathies, hypothalamic dysfunction, seizures
- Vision loss from chronic uveitis
- Hypercalcemia, nephrolithiasis, AKI
- Steroid-related adverse effects from chronic therapy
PANCE pearls
- Löfgren syndrome (erythema nodosum + bilateral hilar adenopathy + arthralgia ± fever) carries an excellent prognosis with spontaneous remission in most patients.
- Cardiac sarcoid and neurosarcoidosis are leading causes of sarcoid mortality — low threshold for cardiac MRI/PET when symptoms suggest involvement.
- Hypercalcemia in sarcoid is mediated by granuloma alpha-hydroxylase converting 25-OH-D to 1,25-OH-D — treat with steroids and AVOID vitamin D supplementation.
- ACE level is too insensitive and nonspecific to diagnose or monitor sarcoid — do not rely on it.
- Biopsy is essential to confirm non-caseating granulomas and exclude TB, fungi, and lymphoma before committing to immunosuppression.
References
- ATS 2020 — Diagnosis and Detection of Sarcoidosis: An Official ATS Clinical Practice Guideline (Crouser et al., Am J Respir Crit Care Med 2020)
- ERS 2021 — ERS Clinical Practice Guidelines on Treatment of Sarcoidosis (Baughman et al., Eur Respir J 2021)
- WASOG — World Association of Sarcoidosis and Other Granulomatous Disorders — Cardiac Sarcoidosis Expert Consensus (Birnie et al., Heart Rhythm 2014)
- ACCESS Study — Clinical Characteristics of Patients in a Case Control Study of Sarcoidosis (Baughman et al., Am J Respir Crit Care Med 2001)
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