Pulmonary · PANCE / PANRE

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%

Scadding radiographic staging of pulmonary sarcoidosis — predicts prognosis and likelihood of spontaneous remission.

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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