What is sarcoidosis and how is it diagnosed and treated in adults?

Sarcoidosis: A Comprehensive Overview

Definition and Pathophysiology

Sarcoidosis is a chronic multisystem granulomatous disease of unknown etiology characterized by noncaseating granulomas that can affect virtually any organ, though pulmonary involvement dominates in over 90% of cases. 1

The disease involves an abnormal immune response with several key features:

• Granuloma formation consists of well-formed, concentrically arranged layers of immune cells with a central core of macrophage aggregates and multinucleated giant cells, surrounded by loosely organized T lymphocytes (predominantly CD4+ cells) 1
• T-cell accumulation drives the pathology through release of IL-2 and other pro-inflammatory cytokines, creating a state of chronic inflammation 2
• Granulomas are typically nonnecrotizing, though variants (particularly nodular pulmonary sarcoidosis) can present with mixed necrotic and nonnecrotic patterns 1
• Fibrosis may develop beginning at the granuloma periphery and extending centrally, with or without calcification 3

Epidemiology

The disease affects all races and ages but shows marked demographic variations:

• Age-adjusted incidence is approximately 11 cases per 100,000 in Caucasians, with higher prevalence in northern Europe and Scandinavians 2
• African Americans experience higher prevalence, greater morbidity, and significantly elevated mortality (2.4 times higher in African American women compared to matched cohorts) 2
• Peak incidence occurs in adults between 20-50 years of age, though presentation after age 50 is common and clinically similar to younger patients 4, 5
• Women experience higher rates of extrapulmonary involvement and worse outcomes 2
• Over 50% of patients diagnosed by radiographic screening are asymptomatic 1

Clinical Manifestations

Highly Probable Features (Diagnostic Confidence)

Certain clinical presentations are so characteristic that they may not require histological confirmation: 1

• Löfgren's syndrome (acute presentation with bilateral hilar adenopathy, erythema nodosum, arthritis, and fever) 1, 6
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, and ears) 1
• Uveitis and optic neuritis (ocular involvement) 1
• Heerfordt's syndrome (uveoparotid fever) 5

Pulmonary Manifestations

Respiratory involvement is the dominant feature:

• Cough (dry, persistent) occurs in 40-80% of symptomatic patients, often with scant mucoid sputum 1
• Dyspnea and constitutional symptoms (fatigue, weight loss, night sweats) are common 7, 8
• Bilateral hilar adenopathy is the hallmark radiographic finding 1, 3
• Perilymphatic nodules on chest CT are highly characteristic 1
• Small airway involvement with physiologic airflow limitation occurs in over 50% of patients, independent of smoking status 1
• Bronchial hyperresponsiveness can be demonstrated in >50% of patients depending on disease stage 1
• Reduced diffusing capacity is the most prevalent pulmonary function abnormality 4

Extrapulmonary Manifestations

Skin involvement (25-50% of patients): 2, 5

• Maculopapular, erythematous, or violaceous lesions 1
• Erythema nodosum 1
• Subcutaneous nodules 1

Ocular involvement (25-50%): 2, 5

• Anterior and posterior uveitis 1
• Scleritis and retinitis 1
• Lacrimal gland swelling 1

Cardiac involvement (<10% but life-threatening): 2, 5

• Cardiomyopathy with reduced LVEF 1
• Atrioventricular block (new-onset third-degree AV block in young/middle-aged adults is highly suggestive) 1
• Spontaneous or inducible ventricular tachycardia 1

Neurologic involvement (<10%): 2, 5

• Seventh cranial nerve paralysis 1
• CNS lesions with gadolinium enhancement on MRI 1

Other systems: 1, 2

• Hepatosplenomegaly (25-50%) 1
• Peripheral and abdominal lymphadenopathy (25-50%) 2, 5
• Symmetrical parotid enlargement 1
• Hypercalcemia/hypercalciuria with abnormal vitamin D metabolism 1
• Renal involvement with treatment-responsive renal failure 1
• Bone involvement with osteolysis and cystic lesions 1
• Upper respiratory tract involvement (3-4% of generalized disease) 2

Diagnosis

The diagnosis of sarcoidosis requires three essential criteria: 1, 8, 5

1. Compatible clinical and radiologic presentation
2. Pathologic evidence of noncaseating granulomas
3. Exclusion of alternative causes of granulomatous disease

Diagnostic Algorithm

Step 1: Assess for highly probable clinical features 1, 6

• If Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome is present with characteristic imaging, lymph node sampling may be avoided 3, 6
• These patients require close clinical follow-up but may not need tissue confirmation 6

Step 2: Obtain baseline imaging 6

• Chest radiography and CT are essential first-line investigations 6
• Bilateral hilar adenopathy on CXR, CT, or PET is highly supportive 1, 3
• Perilymphatic nodules on chest CT are highly characteristic 1
• Upper lobe or diffuse infiltrates, peribronchial thickening 1

Step 3: Tissue sampling (when needed) 1, 6

• Biopsy from accessible involved organs (lung, lymph nodes, skin) to demonstrate noncaseating granulomas 6, 2
• Histology shows compact collections of epithelioid histiocytes and multinucleated giant cells 1, 3
• Avoid biopsy in patients with highly suggestive clinical characteristics (conditional recommendation) 6

Step 4: Bronchoalveolar lavage (BAL) 1, 6

• BAL lymphocytosis or elevated CD4:CD8 ratio supports the diagnosis 1, 6
• BAL is insufficient alone but useful for excluding infections, malignancy, or identifying patterns suggestive of alternative diagnoses (eosinophilic pneumonitis, hypersensitivity pneumonitis) 1

Step 5: Baseline laboratory testing 6

• Serum calcium (strong recommendation) to screen for abnormal calcium metabolism 6
• Serum creatinine (conditional recommendation) for renal involvement 6
• Alkaline phosphatase (conditional recommendation) for hepatic involvement (>3x upper limit of normal is probable feature) 1, 6
• Baseline ECG to screen for cardiac involvement 6
• Complete blood count to detect hematologic alterations (anemia of chronic disease, reactive thrombocytosis, leukocytosis) 2

Step 6: Advanced imaging for specific organ involvement 6

• Cardiac MRI is preferred for suspected cardiac involvement 6, 2
• Transthoracic echocardiogram initially for suspected pulmonary hypertension, followed by right heart catheterization if suggestive 6, 2
• PET scanning can identify parotid uptake, inflammatory activity in heart, and extrathoracic nodes 1
• MRI for CNS involvement (gadolinium enhancement), bone lesions 1

Critical Exclusions

Alternative diagnoses that MUST be ruled out: 1, 3, 6

• Infectious causes (tuberculosis represented 38% of alternative diagnoses in suspected stage 1 sarcoidosis): 3

  • Tuberculosis (most important differential) 3
  • Fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis) 3, 6
  • Atypical mycobacteria 6

• Malignancy (lymphoma represented 25% of alternative diagnoses): 3

  • Lymphoma 3
  • Malignancy-associated sarcoid-like reactions 6

• Other granulomatous diseases: 1, 6

  • Chronic beryllium disease (use blood lymphocyte proliferation test for diagnosis) 1
  • Hypersensitivity pneumonitis 1, 6
  • ANCA-associated vasculitides 6
  • IgG4-related disease 6
  • Silicosis, amyloidosis 3

• Drug-induced sarcoid-like reactions: 1

  • Immune checkpoint inhibitors 1
  • Anti-TNF-α agents 1

Perform microorganism stains and cultures to exclude infections 6

Common Diagnostic Pitfalls

Avoid these errors: 6

• Do NOT rely solely on elevated ACE levels for diagnosis—this finding is not specific to sarcoidosis 1, 6
• Do NOT fail to exclude infectious causes, particularly tuberculosis and fungal infections 3, 6
• Do NOT assume calcified lymph nodes are specific to sarcoidosis—they require exclusion of TB, fungal infections, silicosis 3
• Do NOT diagnose sarcoidosis as the cause of chronic cough without first excluding upper airway cough syndrome, asthma, and GERD, as these may coexist or mimic sarcoidosis 1

Treatment

General Principles

Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease and do not require treatment. 2

Corticosteroids remain the mainstay of therapy for symptomatic or progressive disease: 9, 8

• Prednisone is FDA-approved for symptomatic sarcoidosis 9
• Indications for treatment include significantly symptomatic or progressive pulmonary disease, serious extrapulmonary disease (cardiac, neurologic, ocular, renal, hypercalcemia) 9, 8
• Treatment should be dictated by the specific organ involvement and prognostic implications 1

Treatment Considerations for Specific Scenarios

For pulmonary sarcoidosis with cough: 1

• Before treating cough as sarcoidosis-related, exclude UACS (upper airway cough syndrome), asthma, and GERD as these are common causes that may coexist 1
• Therapy directed at the underlying diagnosis is often beneficial when cough is part of the disease manifestations 1

For idiopathic pulmonary fibrosis (IPF) with cough: 1

• Corticosteroids may lead to symptomatic improvement in cough severity and capsaicin sensitivity 1
• However, corticosteroids have NOT been shown to prolong survival or improve quality of life in IPF and carry significant side effects 1
• Use requires individualized risk-benefit analysis given the dismal prognosis of IPF 1

For refractory or complex cases: 8

• Immunosuppressive therapy may be required for patients not responding to corticosteroids 8

For end-stage disease: 8

• Lung or heart transplantation may be necessary for eligible patients with life-threatening pulmonary or cardiac complications 8

Monitoring During Treatment

Routine monitoring should include: 2

• Platelet counts as part of complete blood count (reactive thrombocytosis resolves with control of inflammation) 2
• Calcium levels to monitor for hypercalcemia 6
• Renal and hepatic function 6
• Cardiac monitoring with ECG and advanced imaging as indicated 6

Prognosis

Prognosis is highly variable and depends on: 8

• Epidemiologic factors (race, age, sex) 2, 8
• Mode of onset (Löfgren's syndrome has excellent prognosis) 5
• Initial clinical course (asymptomatic vs. symptomatic presentation) 1, 8
• Specific organ involvement (cardiac and neurologic involvement portend worse outcomes) 2, 8

Despite aggressive treatment, some patients develop life-threatening complications from severe, progressive pulmonary, cardiac, or neurologic disease 8