What investigations are recommended to rule out sarcoidosis?

Testing to Rule Out Sarcoidosis

The diagnosis of sarcoidosis requires three essential components: compatible clinical and radiologic presentation, histopathologic evidence of noncaseating granulomas, and rigorous exclusion of alternative diagnoses—particularly infections, malignancy, and other granulomatous diseases. 1, 2

Initial Clinical and Imaging Assessment

High-Probability Clinical Features

Start by identifying features that make sarcoidosis highly probable, which may obviate the need for tissue sampling 1:

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) is highly specific 1, 2
• Lupus pernio on physical examination 1, 2
• Bilateral hilar adenopathy on chest X-ray, CT, or PET imaging 1, 2
• Perilymphatic nodules on chest CT 1

For patients with Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome, the American Thoracic Society suggests NOT performing lymph node biopsy, though close clinical follow-up is mandatory. 1

Essential Imaging Studies

Obtain chest imaging as the first-line diagnostic test 2:

• Chest CT scan to identify bilateral hilar lymphadenopathy, perilymphatic nodules, and peribronchial thickening 1, 2
• Look for upper lobe or diffuse infiltrates 1
• Assess for two or more enlarged extrathoracic lymph nodes 1

Tissue Confirmation

Biopsy Strategy

Tissue biopsy showing noncaseating granulomas is essential for definitive diagnosis unless high-probability clinical syndromes are present. 3, 2

• Select the most accessible site based on clinical manifestations 2
• Options include lung (via bronchoscopy), lymph node, or skin lesions 3
• Bronchoalveolar lavage (BAL) can show lymphocytosis or elevated CD4:CD8 ratio and helps exclude infections or malignancy 1, 2

Histopathologic Requirements

The pathology must demonstrate 1, 4:

• Noncaseating granulomas (minimal focal necrosis acceptable) 4
• Negative stains and cultures for microorganisms 4
• Compatible features distinguishing sarcoidosis from mimics 1

Mandatory Exclusion of Alternative Diagnoses

Critical Infections to Rule Out

Inadequate exclusion of infections is the most common cause of misdiagnosis. 3, 2

Perform microbiological testing for 5, 6:

• Tuberculosis (especially in endemic regions—this is the leading differential diagnosis) 5, 6
• Nontuberculous mycobacterial infections 5
• Fungal infections (histoplasmosis, others) 5
• Cultures and special stains on all tissue specimens 4

Other Granulomatous Conditions to Exclude

Rule out 1, 5:

• Chronic beryllium disease (obtain lymphocyte proliferation test with beryllium if occupational exposure) 5
• Hypersensitivity pneumonitis (assess environmental/occupational exposures) 5
• Drug-induced granulomatosis from TNF-α antagonists, immune checkpoint inhibitors, interferons 1, 5
• Granulomatosis with polyangiitis (check MPO and PR3 ANCA antibodies) 1
• IgG4-related disease (measure serum IgG4 levels and IgG4:IgG ratio) 1
• Common variable immune deficiency 1
• Malignancy-associated granulomatosis 5

Baseline Laboratory Screening

Once sarcoidosis is diagnosed or strongly suspected, obtain baseline tests to screen for organ involvement 1:

Strongly Recommended

• Serum calcium (strong recommendation—screen for abnormal calcium metabolism even without hypercalcemia symptoms) 1, 2
• Serum creatinine (screen for renal involvement) 1
• Serum alkaline phosphatase (screen for hepatic involvement) 1

Additional Useful Tests

• ACE level (elevated >50% above upper limit of normal supports diagnosis, but has limited sensitivity/specificity—do not overrely on this) 1, 2
• Vitamin D metabolism (measure both 25-OH and 1,25-OH vitamin D if replacement considered) 1
• ECG (screen for cardiac involvement in extracardiac sarcoidosis without cardiac symptoms) 1

Cardiac Screening Protocol

Insufficient monitoring for cardiac involvement is a critical pitfall, as cardiac sarcoidosis carries significant mortality risk. 3, 2

For patients with extracardiac sarcoidosis without cardiac symptoms 1:

• Perform baseline ECG 1
• The American Thoracic Society suggests NOT routinely performing TTE or Holter monitoring for screening, though these should be considered case-by-case given their low risk 1

If cardiac involvement is suspected 1:

• Cardiac MRI with gadolinium is the preferred test 1, 3
• If MRI unavailable, use dedicated PET scan rather than TTE 1

Common Diagnostic Pitfalls to Avoid

• Never assume all neurologic or other symptoms in sarcoidosis patients are due to sarcoidosis—always exclude alternative causes 3
• Do not rely solely on ACE levels due to limited sensitivity and specificity 2
• Do not overlook drug-induced sarcoid-like reactions in patients on immunotherapeutics 1
• Do not miss cardiac involvement—new-onset third-degree AV block in young/middle-aged adults is a probable feature 1
• Ensure adequate follow-up for patients diagnosed without tissue confirmation 1