What is the recommended diagnostic workup and treatment for a patient with suspected sarcoidosis?

Diagnostic Workup and Treatment for Suspected Sarcoidosis

For patients with suspected sarcoidosis, obtain tissue confirmation of noncaseating granulomas from the most accessible site (unless presenting with Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome), perform baseline laboratory screening including serum calcium, creatinine, alkaline phosphatase, and ECG, and initiate corticosteroid therapy (prednisone 20-40 mg daily) for symptomatic disease with parenchymal infiltrates and abnormal pulmonary function testing. 1, 2, 3, 4

Diagnostic Criteria

The diagnosis of sarcoidosis requires three essential components 1, 5:

• Compatible clinical and radiologic presentation - typically bilateral hilar lymphadenopathy with or without parenchymal infiltrates 5
• Histopathologic confirmation - noncaseating (non-necrotizing) epithelioid granulomas on tissue biopsy 1, 5
• Exclusion of alternative diagnoses - rule out infections (especially tuberculosis), malignancy, berylliosis, hypersensitivity pneumonitis, and drug-induced reactions 5

Exceptions to Tissue Diagnosis

Do NOT perform lymph node sampling in patients with highly specific clinical syndromes 1:

• Löfgren's syndrome (bilateral hilar adenopathy, erythema nodosum, arthritis, fever)
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears)
• Heerfordt's syndrome (parotid enlargement, uveitis, facial nerve palsy, fever)

These patients require close clinical follow-up without biopsy 1

Initial Imaging Workup

Chest Imaging

• High-resolution CT (HRCT) chest without IV contrast is the preferred initial imaging modality 5, 6
• HRCT detects bilateral hilar adenopathy, perilymphatic nodules, and parenchymal infiltrates characteristic of pulmonary sarcoidosis 5
• HRCT has higher accuracy than chest X-ray for detecting early-stage disease and narrowing differential diagnosis 7

Advanced Imaging for Multiorgan Assessment

• FDG-PET/CT should be obtained when multiorgan involvement is suspected or to guide biopsy site selection 5, 7
• PET/CT is particularly valuable for detecting extrapulmonary disease in inaccessible locations 8

Tissue Sampling Strategy

EBUS-guided lymph node sampling is the preferred method with 87% diagnostic yield, 98% confirmation rate for sarcoidosis, and <0.1% complication rate 5

Target the most accessible involved lymph node for biopsy 2. Look for noncaseating epithelioid granulomas comprised of macrophage aggregates with multinucleated giant cells and minimal surrounding lymphocytic inflammation 5

Baseline Laboratory Screening

Mandatory Tests

• Serum calcium - STRONG recommendation to screen for abnormal calcium metabolism (present in up to 42% of untreated patients) 1, 2
• Serum creatinine - screen for renal sarcoidosis and hypercalcemia-induced renal insufficiency 1, 2
• Serum alkaline phosphatase - screen for hepatic sarcoidosis 1, 2
• Complete blood count - evaluate for cytopenias from bone marrow or splenic involvement 2

Vitamin D Assessment

• If vitamin D assessment is needed, measure BOTH 25-OH and 1,25-OH vitamin D levels before any replacement 1, 2, 5
• Sarcoidosis granulomas produce excess 1α-hydroxylase, converting 25-OH to 1,25-OH vitamin D, causing hypercalcemia 2
• Avoid vitamin D supplementation as this will worsen hypercalcemia 2

Optional Tests

• Serum ACE level may be elevated and correlates with calcium levels, but lacks sensitivity/specificity for diagnosis 2
• No recommendation for or against baseline serum transaminase testing 1

Cardiac Screening Protocol

All patients with suspected sarcoidosis require baseline cardiac screening because cardiac involvement can be fatal 2, 5:

• Baseline ECG for all patients, even without cardiac symptoms 1, 2, 5
• Do NOT perform routine transthoracic echocardiography (TTE) or 24-hour Holter monitoring in asymptomatic patients without ECG abnormalities 1, 5

If Cardiac Involvement Suspected

When ECG shows abnormalities or patient has cardiac symptoms 2:

• Cardiac MRI is the preferred first-line imaging modality 1, 5
• If cardiac MRI unavailable: use dedicated PET scan rather than echocardiography 1, 2
• Refer to cardiologist for management 5

Pulmonary Hypertension Screening

When pulmonary hypertension is suspected (exertional chest pain/syncope, prominent P2 or S4, reduced 6-minute walk distance, desaturation with exercise, reduced DLCO, increased PA diameter on CT, elevated BNP, or fibrotic lung disease) 1:

• Initial testing with transthoracic echocardiography 1, 5
• Right heart catheterization if TTE suggests pulmonary hypertension to definitively confirm or exclude 1, 5
• Up to 70% of stage IV fibrocystic sarcoidosis patients develop precapillary pulmonary hypertension 4

Treatment Approach

First-Line Therapy: Corticosteroids

Oral glucocorticoids (prednisone) are the mainstay of treatment for symptomatic patients with parenchymal infiltrates and abnormal pulmonary function testing 3, 4:

• Starting dose: Prednisone 20-40 mg daily for 2 weeks to 2 months 4
• Taper over 6-18 months if symptoms, spirometry, PFTs, and radiographs improve 4
• Prolonged prednisone may be required to stabilize disease 4
• Prednisone is FDA-approved for symptomatic sarcoidosis 3

Indications for Treatment

• Symptomatic disease (cough, dyspnea) with parenchymal infiltrates on imaging 4
• Abnormal pulmonary function testing 4
• Hypercalcemia (urgent indication requiring prompt treatment) 2
• Serious extrapulmonary organ involvement (cardiac, neurologic, ocular, renal) 3, 9

Second and Third-Line Therapies

For patients requiring prolonged prednisone ≥10 mg/day or those with adverse effects from glucocorticoids 4:

• Second-line: Immunosuppressive agents (methotrexate, azathioprine) 4
• Third-line: Anti-TNF medications 4

Treatment Outcomes and Prognosis

Prognosis varies by Scadding stage 4:

• Stages I-II: 30-80% radiographic remission
• Stage III: 10-40% chance of resolution
• Stage IV: No chance of resolution; 10-40% of patients progress to stage IV with fibroplasia, bronchiectasis, and fibrocystic disease

Mortality considerations 4:

• 5-year mortality rate approximately 7%
• 60% of deaths are sarcoid-related, with up to 80% from advanced cardiopulmonary failure
• Stage IV disease with >20% fibrosis on HRCT or precapillary pulmonary hypertension has >40% mortality at 5 years
• Relapse rates range from 13-75% depending on stage, organ involvement, and socioeconomic factors

Specialist Referrals Based on Organ Involvement

• Cardiologist - for ECG abnormalities, cardiac symptoms, or imaging findings suggesting cardiac involvement 5
• Ophthalmologist - for baseline eye exam (uveitis screening) and any ocular symptoms 2, 5
• Nephrologist - if creatinine remains elevated or worsens despite treatment 2, 5
• Neurologist - for neurological symptoms, especially cranial nerve palsies 5
• Dermatologist - for skin manifestations (lupus pernio, erythema nodosum, maculopapular lesions) 5
• Hepatologist - for significant liver abnormalities (alkaline phosphatase >3x normal) 5

Monitoring and Follow-Up

• Serial serum calcium levels to assess treatment response 2
• Serial creatinine to monitor renal function 2
• Follow-up CT should be clinically driven based on symptoms, pulmonary function changes, or treatment decisions rather than predetermined schedule 6
• HRCT to assess disease progression, stability, or reversibility and discriminate active inflammation from irreversible fibrosis 6

Critical Pitfalls to Avoid

• Failure to exclude alternative diagnoses - always rule out infections (especially tuberculosis), malignancy, berylliosis, hypersensitivity pneumonitis, and drug-induced sarcoid-like reactions 5, 9
• Relying solely on ACE levels - they lack sensitivity and specificity 5
• Missing cardiac involvement - can be fatal and requires specific imaging beyond routine echocardiography 5
• Inadequate screening for hypercalcemia - causes renal insufficiency in 42% of untreated patients and requires urgent treatment 2
• Performing unnecessary biopsies in patients with highly specific clinical syndromes (Löfgren's, lupus pernio, Heerfordt's) 1, 5