Sarcoidosis

Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Acutely, sarcoidosis presents with lymphadenopathy, fever, malaise, joint pains, a panniculitis on the shins known as erythema nodosum, and occasionally cough and shortness of breath. Chronic pulmonary sarcoidosis presents with an insidious onset of dyspnea, cough, chest pain, and a variety of other symptoms depending on the organ systems involved. Diagnosis often requires a biopsy of the granulomas. Management includes observation, NSAIDs, glucocorticoids, and potentially one of several steroid-sparing agents. Acute sarcoidosis is usually self-limiting with an excellent prognosis, but chronic sarcoidosis can lead to severe pulmonary fibrosis.

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Overview

Definition

Sarcoidosis is a multisystem inflammatory disease characterized by the formation of noncaseating granulomas that are most likely caused by a cell-mediated immune reaction of unknown etiology.

Pulmonary sarcoidosis is a restrictive interstitial lung disease with granuloma formation in the:

  • Lungs (90% of patients)
  • Thoracic lymph nodes (hilar and mediastinal)

Extrapulmonary sarcoidosis is characterized by granuloma formation in:

  • Eyes
  • Skin
  • Joints
  • Heart
  • Kidney
  • CNS and peripheral nervous system
  • Exocrine glands

Sarcoidosis may be acute or chronic:

  • Löfgren syndrome: an acute presentation of sarcoidosis lasting weeks to months:
    • Usually resolves spontaneously without treatment
    • Typically in younger adults
  • Chronic disease: insidious onset, often progressive, may wax and wane

Categorization of interstitial lung diseases
ILD: interstitial lung disease

Image by Lecturio.

Epidemiology

  • Most common interstitial lung disease
  • Estimated prevalence: 
    • 34 per 100,000 in African Americans
    • 10 per 100,000 in Caucasians 
  • Age at onset: 
    • Incidence peaks at 20–40 years of age.
    • Second peak in incidence for women between 45 and 65 
  • Sex bias: women > men
  • Racial/ethnic bias: African American > other races
  • Most cases are sporadic, but about 5% are familial.

Etiology

Etiology is undetermined but is most likely multifactorial.

Theory: An infectious or environmental agent triggers a cell-mediated inflammatory immune response in a genetically susceptible host, leading to granuloma formation.

Potential triggering exposures:

  • Inhalation of talc, aluminum, beryllium, or zirconium
  • Exposure to dust and debris at the collapsed World Trade Center after 9/11
  • Infectious agents: 
    • Mycobacterium tuberculosis
    • Cutibacterium (previously Propionibacterium) acnes

Genetic predispositions:

  • Antigens of the major histocompatibility complex (MHC), especially the HLA-DR alleles:
    • HLA-DRB1*1101
    • HLA-DQB1*0201
  • Possible association with ACE variants
  • Ongoing studies looking at gene networks

Pathophysiology

Sarcoidosis is the result of a cell-mediated immune reaction. 

  • Phagocytosis of a new antigen by antigen-presenting cells (e.g., macrophages and dendritic cells)
  • Activated macrophages present the antigen to helper T cells via the HLA-CD4 complex.
  • Activated T cells and macrophages release inflammatory mediators (Th1 response):
    • Interleukin 2 (IL-2)
    • Interferon gamma
    • Tumor necrosis factor (TNF)
    • Other cytokines and chemokines
  • Inflammatory mediators cause macrophages to fuse into multinucleated giant cells.
  • Unable to destroy the antigens, the multinucleated giant cells wall them off → noncaseating granuloma formation
  • Fibroblasts are recruited and surround granulomas.
  • Granulomas may progress to fibrosis; the mechanism is poorly understood.

Noncaseating granuloma

Image: “Granuloma 20x” by Mutleysmith. License: Public Domain

Clinical Presentation

Sarcoidosis usually progresses slowly, with few symptoms initially. Symptoms appear as an increasing number of granulomas begin to affect organ function.

Clinical manifestations of sarcoidosis by organ system
Organ systemClinical presentation of sarcoidosis
Systemic symptoms (typically in acute presentations)
  • Fever
  • Myalgias
  • Weight loss
  • Fatigue and exhaustion
Pulmonary
  • Chest pain
  • Dry cough
  • Dyspnea on exertion
  • Severe complications: pulmonary hypertension or cor pulmonale (as consequences of pulmonary fibrosis)
Lymph
  • Intrathoracic lymphadenopathy
    • Hilar and mediastinal
    • Bilateral involvement (differentiates sarcoidosis from tuberculosis and malignancy)
  • Peripheral lymph node enlargement
Ocular
  • Uveitis (most common)
  • Granulomas may involve:
    • Orbit
    • Anterior and posterior segments of the eye
    • Conjunctiva
    • Lacrimal glands
    • Extraocular muscles
    • Eyelids
  • Symptoms include dry eye, blurred vision, photophobia, redness, and pain.
Cutaneous
  • Erythema nodosum:
    • A panniculitis (inflammation of the subcutaneous fat)
    • Painful inflammatory nodules, usually on the shins
  • Lupus pernio:
    • Violaceous or erythematous indurated papules, plaques, and nodules
    • Primarily on the face: nose, cheeks, chin, and ears
    • Accompanied by significant scar formation
Musculoskeletal
  • Polyarthritis (joint pain and swelling)
  • Granulomatous myositis
Cardiac
  • Cardiac arrhythmia with ↑ risk of sudden cardiac death
  • Conduction defects (heart block)
  • Heart failure
  • Restrictive cardiomyopathy
Nervous system
  • Lymphocytic meningitis
  • Facial paralysis (cranial nerve palsy)
  • Hypothalamic–pituitary dysfunction:
    • Diabetes insipidus
    • Hypopituitarism
    • Amenorrhea
  • Spinal cord involvement
  • Peripheral neuropathies
Other potential sites of involvement
  • Upper respiratory tract: larynx, pharynx, nares, and sinuses
  • Kidney
  • Liver and spleen
  • GI tract
  • Exocrine glands: parotid and salivary

Löfgren syndrome

An acute presentation of sarcoidosis with a classic triad of symptoms:

  • Erythema nodosum
  • Hilar adenopathy
  • Migratory polyarthralgia

Diagnosis

Diagnosing sarcoidosis typically requires: 

  1. Compatible clinical and radiologic manifestations
  2. Noncaseating granulomas on pathology
  3. Exclusion of other conditions

Imaging

  • Chest X-ray:
    • Best initial test
    • Findings:
      • Bilateral hilar lymphadenopathy (classic finding)
      • Bilateral reticulonodular infiltrates (often upper lobes)
      • Honeycombing (end-stage disease)
  • High-resolution CT (HRCT):
    • Higher sensitivity than X-ray
    • Indications:
      • Confirm findings from suspicious X-ray
      • Further evaluate lungs in patient with pulmonary symptoms but normal X-ray
    • Findings:
      • Bilateral hilar and mediastinal lymphadenopathy
      • Small centrilobular parenchymal nodules
      • Mid–upper zone predominance of lung parenchymal changes
      • Fine nodularity
      • Ground-glass opacification
      • Fibrosis with lung distortion and traction bronchiectasis

Bronchoscopy

  • Bronchoalveolar lavage (BAL)
    • Obtained primarily to exclude alternative diagnosis (e.g., infections, malignancy)
    • Lymphocytosis ≥ 25% suggests a granulomatous process.
    • Findings consistent with pulmonary sarcoidosis:
      • ↓ CD8 cells
      • ↑ CD4 cells, activated T cells, and IgG-secreting cells
      • ↑ CD4:CD8 ratio > 4:1
  • Allows for less invasive pulmonary tissue sampling:
    • Endobronchial biopsy
    • Transbronchial lung biopsy
    • Transbronchial needle aspiration

Biopsy

  • Gold standard for diagnosis
  • Biopsy the most accessible affected site (e.g., skin lesions).
  • Lung biopsies can be obtained via bronchoscopy or surgically (more invasive).
  • Key finding: well-defined noncaseating granulomas 
    • Noncaseating: no central necrosis
    • Multinucleated giant cells
  • Other histopathologic findings: 
    • Asteroid bodies
    • Schaumann bodies

Spirometry

Obtained to assess severity of respiratory involvement and monitor disease; less helpful in actually establishing diagnosis

  • Sarcoid usually demonstrates a restrictive pattern:
    • ↓ Forced vital capacity (FVC; total forced exhaled volume)
    • ↓ Total lung capacity (TLC; total volume in lungs at the end of a maximal inspiration)
    • ↓ Compliance (lungs have difficulty expanding)
  • Mixed restrictive/obstructive patterns are also possible in severe disease:
    • Mixed patterns have both restrictive and obstructive findings.
    • Obstructive findings:
      • ↓ Forced expiratory volume in 1 second (FEV1):FVC ratio
      • ↓ Airflow (airways are partially obstructed by inflammation and fibrosis)
  • Impaired gas diffusion across the alveolar membrane: ↓ diffusing capacity of the lung for carbon monoxide (DLCO)

Other testing

  • Electrocardiography: to assess for cardiac involvement
  • Ophthalmologic examination: to assess for eye involvement
  • Tuberculin skin test: to rule out tuberculosis
  • Other testing guided by clinical presentation

Laboratory testing

These tests are important in assessing and monitoring the extent of disease rather than making the diagnosis. The following findings are often seen in sarcoidosis.

  • CBC:
    • Leukopenia
    • Lymphopenia
    • Anemia (uncommon)
  • CMP:
    • Hypercalcemia
    • ↑ Liver function tests if liver involvement
    • ↑ BUN and creatinine if renal involvement
  • Urinalysis:
    • Hypercalciuria
  • Inflammatory markers:
    • ↑ ESR
    • ↑ CRP
  • Others:
    • ↑ ACE
    • ↑ IgG

Staging

Table: Staging schema according to presence or absence of bilateral hilar lymphadenopathy and by the presence or absence of lung infiltrates
StageChest X-raySymptomsFrequency
0Extrapulmonary disease onlyNone10%
1BHL onlyNone or mild cough50%
2BHL plus parenchymal infiltratesNone, dyspnea, or cough25%
3Parenchymal infiltrates onlyDyspnea10%
4Advanced pulmonary fibrosisDyspnea5%
BHL: bilateral hilar lymphadenopathy

Management

Management is based on stage and location of disease and includes:

  • Observation: 
    • Indicated in patients with high rates of spontaneous resolution:
      • Acute sarcoidosis 
      • Stage 1 chronic sarcoidosis
    • NSAIDs for treatment of pain if needed
  • Corticosteroids: 1st-line therapy in patients with:
    • ≥ Stage 2 disease with simultaneously restricted pulmonary function
    • Renal insufficiency (hypercalcemia and hyperuricemia) 
    • Extrapulmonary involvement
    • Severe systemic symptoms
    • Severe arthritis (Löfgren syndrome)
    • Localized symptoms including uveitis and skin lesions → administered locally
  • Steroid-sparing agents: 2nd-line therapy:
    • Azathioprine
    • Methotrexate
    • Mycophenolate
    • Hydroxychloroquine
    • Leflunomide
    • Infliximab (anti-TNF agent)
  • Lung transplantation: in cases of advanced pulmonary fibrosis

Prognosis

Table: Remission rates
StageRemission rate
0
190%
270%
320%
4< 5%

Differential Diagnosis

  • Pneumoconiosis: occupational disease that consists of a group of restrictive interstitial lung diseases caused by inhalation of toxic dust, including silica, asbestos, beryllium, and others: Pneumoconiosis presents with cough and progressive dyspnea. Diagnosis is by occupational history, imaging, and histology. Management is largely supportive.
  • Histoplasmosis: infection caused by the fungus Histoplasma capsulatum: Histoplasmosis presents with symptoms of pneumonia, including fever, headache, myalgias, cough, and chest pain that develop 2–4 weeks after exposure. In immunocompromised individuals, the infection may be fatal. Both sarcoidosis and histoplasmosis can cause pulmonary infiltrates, mediastinal lymphadenopathy, and erythema nodosum. Histoplasmosis tends to form caseating granulomas, while sarcoidosis causes noncaseating granulomas. Treatment involves antifungal medications.
  • Tuberculosis: disease caused by Mycobacterium tuberculosis: The bacteria usually attacks the lungs, but it can also damage other parts of the body. Tuberculosis presents with a chronic cough with hemoptysis. The diagnosis is made with a tuberculin skin test, sputum cultures, and lung imaging. Biopsies show caseating granulomas (central necrosis), whereas sarcoid granulomas are noncaseating. Management is with antimycobacterial drugs. 
  • Idiopathic pulmonary fibrosis: interstitial lung disease, characterized by irreversible pulmonary fibrosis and impaired pulmonary function: Idiopathic pulmonary fibrosis presents with exertional dyspnea, persistent dry cough, and fatigue. Diagnosis is by chest X-ray or CT, along with pulmonary function tests. Management is supportive, along with therapy targeting the underlying cause. 
  • Lymphoma: cancers originating from lymphocytes, including B cells, T cells, and natural killer (NK) cells: Lymphomas often present with constitutional signs and/or painless lymphadenopathy. Similar to sarcoidosis, imaging findings may include thoracic lymphadenopathy. Management is based on the specific stage and type of cancer and is usually chemotherapy.

References

  1. King T (2020). Clinical manifestations and diagnosis of pulmonary sarcoidosis. UpToDate. Retrieved March 2, 2021 from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-pulmonary-sarcoidosis
  2. Kamanger N (2020). Sarcoidosis. Emedicine. Retrieved March 2, 2021 from https://emedicine.medscape.com/article/301914-overview
  3. Jameson, J, Fauci A, Kasper S, Hauser D, Jameson J, Loscalzo J (2018). Harrison’s Principles of Internal Medicine (20th ed., vol. 2. chapter 390). 
  4. Fontenot A, King T (2020). Pathology and pathogenesis of sarcoidosis. In Hollingsworth H (Ed.). UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/pathology-and-pathogenesis-of-sarcoidosis
  5. King T (2020). Extrapulmonary manifestations of sarcoidosis. In Hollingsworth H (Ed.). UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/extrapulmonary-manifestations-of-sarcoidosis
  6. King T (2020). Treatment of pulmonary sarcoidosis: Disease refractory to glucocorticoid therapy. In Hollingsworth H (Ed.). UpToDate. Retrieved March 5, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-sarcoidosis-disease-refractory-to-glucocorticoid-therapy

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