Sarcoidosis

Sarcoidosis is a multisystem disorder characterized by noncaseating granulomatous inflammation. It is classified as either acute or chronic; chronic sarcoidosis is not necessarily preceded by acute sarcoidosis. Acute sarcoidosis has an abrupt onset with constitutional symptoms (e.g., fever, malaise) as well as cough, dyspnea, anterior uveitis, erythema nodosum, and arthralgia, and it is self-limiting after a few years. Chronic sarcoidosis has an insidious onset and is often asymptomatic in its early stages. It primarily affects the lungs, although other systemic manifestations are also possible. The first symptoms of chronic sarcoidosis usually include exertional dyspnea and a dry cough with mild rales on pulmonary examination. A chest x-ray is the most appropriate initial test in a patient with suspected sarcoidosis. An x-ray may show parenchymal disease with bilateral hilar lymphadenopathy, but these features are not always evident. A biopsy is the gold standard for diagnosis. The most common histopathological finding is noncaseating granulomas with giant cells. Glucocorticoid therapy is indicated with disease progression or if certain organs, such as the eyes or heart, are affected. While spontaneous remission rates are high during the early stages of sarcoidosis, irreversible lung fibrosis may develop as the disease recurs or progresses.

• Bimodal distribution: 25–35 years old with a second peak for females 45–65 years old
• Sex: ♀ > ♂ (2:1)
• Prevalence: 10 times higher among African Americans than whites in the US. African Americans are also more likely to have chronic and more severe disease courses.

Sarcoidosis most frequently affects young African American women in the US!
References:^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of noncaseating granulomas.

• T-cell dysfunction and increased B-cell activity result in local immune hyperactivity and inflammation.
• Formation of non-caseating granulomas within the lungs and the lymphatic system (see granulomatous inflammation for details)
  • Macrophages activate Th1 cells.
  • Th1 cells stimulate the formation of epithelioid cells and multinucleated giant cells by releasing IFN-γ.
  • Epithelioid cells produce angiotensin-converting enzyme (ACE) and release cytokines, which recruit more immune cells.
  • A mature granuloma is composed of epithelioid cells and macrophages in the center, which are surrounded by lymphocytes and fibroblasts.
• Fibrosis and subsequent damage of organs and tissue: Epithelioid cells secrete cytokines to recruit fibroblasts, which cause fibrosis.
• Calcium dysregulation: activated macrophages produce 1-α hydroxylase → ↑ 1,25 hydroxyvitamin D (hypervitaminosis D) → hyperphosphatemia, hypercalcemia, and possibly renal failure

References:^[4][5]

Acute sarcoidosis and chronic sarcoidosis are two distinct manifestations of the disease, where acute sarcoidosis does not necessarily precede chronic sarcoidosis.

Acute sarcoidosis (approx. ⅓ of cases)

• Typically has a sudden onset and remits spontaneously within approx. 2 years
• Progression to chronic sarcoidosis is rare.
• General: fever, malaise, lack of appetite, weight loss
• Pulmonary: dyspnea, cough, chest pain
• Extrapulmonary: arthritis, anterior uveitis, erythema nodosum

Chronic sarcoidosis (approx. ⅔ of cases)

• In rare cases, preceded by acute sarcoidosis
• Gradual disease course; may be recurrent or progressive

Pulmonary (most common)

• Often asymptomatic in the early stages
• Dry cough, exertional dyspnea
• Mild rales on pulmonary auscultation

Extrapulmonary

• Common
  • Peripheral lymph nodes are the most frequent site of extrapulmonary manifestation (40%).
  • Eyes (25%): granulomatous uveitis; blurred vision (ocular sarcoidosis)
  • Skin (25%)
    • Lupus pernio: pathognomonic, extensive, purple skin lesions (violaceous skin plaques) on the nose, cheeks, chin, and/or ears; also referred to as epithelioid granulomas of the dermis
    • Scar sarcoidosis: inflamed, purple skin infiltration and elevation of old scars or tattoos
• Other manifestations
  • Musculoskeletal ; bone lesions
  • Nervous system (neurosarcoidosis): cranial nerve palsy (7^th cranial nerve palsy is the most common), diabetes insipidus, meningitis, hypopituitarism
  • Heart
  • Liver
  • Kidneys
  • Spleen

Features of sarcoidosis are GRUELING: Granulomas, aRthritis, Uveitis, Erythema nodosum, Lymphadenopathy, Interstitial fibrosis, Negative TB test, and Gammaglobulinemia.

References:^{[6][7][1][8][9][10]}

Lofgren syndrome

• Highly acute clinical presentation with fever and the following triad of symptoms
  • Migratory polyarthritis: symmetrical arthritis that primarily affects the ankles
  • Erythema nodosum: primarily affects the extensor surface of the lower legs
  • Bilateral hilar lymphadenopathy

Heerfordt syndrome

• Chronic clinical presentation with fever and the following triad of symptoms
  • Parotitis
  • Uveitis (iridocyclitis)
  • Facial palsy

A chest x-ray (which may reveal parenchymal disease with hilar lymphadenopathy) is the most appropriate initial test for a patient with suspected sarcoidosis. Laboratory tests may support the diagnosis of sarcoidosis, but a biopsy is the gold standard. Additional tests can help determine the severity of the disease, possible complications, and prognosis.

Chest x-ray

• Best initial test
• Sarcoidosis is frequently an incidental finding detected on chest x-ray
• Findings: hilar lymphadenopathy with or without bilateral reticular opacities
• Chronic sarcoidosis is categorized according to chest x-ray findings (see “Stages” above).

Patients with chronic sarcoidosis often have moderate clinical manifestations but radiographic findings of extensive disease!

Laboratory tests

• Acute sarcoidosis
  • ↑ Inflammatory markers
  • Findings typical for sarcoidosis are absent (e.g., ↑ ACE, ↑ IgG, ↑ calcium)
• Chronic sarcoidosis
  • ↑ Calcium due to elevated levels of 1,25-(OH)₂-vitamin D₃
  • ↓ CD4⁺ T cells; : T helper cells are consumed during granuloma formation → CD4⁺ levels are low in serum and high in bronchoalveolar lavage.
  • ↑ IgG (approx. 50% of patients)
  • ↑ Angiotensin-converting enzyme (ACE) blood levels; may be used to monitor disease activity and therapy
  • ↑ Inflammatory markers, possible lymphopenia
  • Urine analysis: hypercalciuria

Bronchoscopy

• Biopsy: the gold standard for diagnosis
  • Origin of specimen: lung tissue and lymph nodes
  • Findings: non-caseating granulomas with giant cells
    • Asteroid bodies, Schaumann bodies

• Bronchoalveolar lavage (BAL): : increased CD4⁺/CD8⁺ ratio

Pulmonary function tests

• Restrictive or obstructive pattern (see restrictive lung disease and obstructive lung disease)

References:^{[12][7][13][1][9]}

Differential diagnosis of granulomatous disease
	Risk factors	Clinical presentation	Biopsy	Other laboratory findings
Sarcoidosis	African American females in the US	Dry cough Erythema nodosum Lupus pernio Anterior (and possibly posterior) uveitis	Non-caseating granulomas Giant cells	↑ CD4+/CD8+ ratio in bronchoalveolar lavage
Tuberculosis (TB)	Immunocompromised individuals Previous TB and/or recent TB exposure	Fever, weight loss, and night sweats Productive cough that does not respond to conventional antibiotic therapy Hemoptysis	Caseating granulomas Langhans giant cells, epithelioid macrophages, and lymphocytes Acid-fast M. tuberculosis	M. tuberculosis or its DNA
Hodgkin lymphoma	History of infectious mononucleosis	Pel-Ebstein fever Alcohol-induced pain Pruritus	Non-caseating granulomas Reed-Sternberg cells Inflammatory cell infiltrate (e.g., eosinophils, fibroblasts, plasma cells)	Single or combined cytopenias (i.e., anemia, leukopenia, and/or thrombocytopenia)
Non-Hodgkin lymphoma	Infections (e.g., EBV infection or Helicobacter pylori) Cell damage (caused by toxic substances, immunosuppressive drugs, cytostatic therapy, radiation)	Indolent lymph node enlargement Splenomegaly Evidence of bone marrow suppression (i.e., pallor, infections) Possible large abdominal mass (in Burkitt lymphoma)	Non-caseating granulomas without Reed-Sternberg cells B-lymphocytes or T-lymphocytes Inflammatory cell infiltrate	Single or combined cytopenias
Pneumoconiosis	Exposure to mineral dust (e.g., silica)	Often, patients are asymptomatic and the physical examination is unremarkable. In symptomatic patients Progressive exertional dyspnea Chronic cough (possibly with sputum) Auscultatory findings (e.g., rales, crackles) Signs of respiratory failure (e.g., digital clubbing)	Non-caseating granulomas Silica/asbestos bodies	Positive beryllium lymphocyte proliferation test (BeLPT)
Granulomatosis with polyangiitis	Caucasian individuals aged 65–74 years	Chronic rhinitis/sinusitis with thick purulent/bloody discharge Treatment-resistant pneumonia Glomerulonephritis	Non-caseating granulomas	Positive cytoplasmic ANCA
Histoplasmosis	AIDS Exposure to bird or bat excrement	Pulmonary (e.g., dry cough, oral ulcers) or extrapulmonary (e.g., splenomegaly) manifestations	Caseating granulomas Identification of H. capsulatum yeast with silver stain	Positive polysaccharide urine and serum antigen test

References:^[14][15][16]

The differential diagnoses listed here are not exhaustive.

• Isolated pulmonary sarcoidosis: In most cases, no treatment is required. The disease is often asymptomatic, non‑progressive, and has a high rate of spontaneous remission.
• Symptomatic or extrapulmonary sarcoidosis
  • First line: glucocorticoids
  • Second line: alternative immunosuppressive therapy (e.g., methotrexate or azathioprine), possibly in combination with glucocorticoids
  • Antimalarial drugs (e.g., chloroquine, hydroxychloroquine)
  • Last resort in severe pulmonary disease: lung transplantation
  • NSAIDs are always indicated for symptom relief.

References:^[1][11]

• Patients with sarcoidosis have an increased risk of malignant changes (esp. within the lungs and lymph nodes).
• Pulmonary complications
  • Bronchiectasis
  • Lung fibrosis; : Irreversible fibrotic remodeling together with compression of large pulmonary arteries due to bilateral hilar lymphadenopathy may increase pulmonary vascular resistance, resulting in pulmonary hypertension (PH).
• Chronic renal failure (see “Clinical features” above)

References:^[6]

We list the most important complications. The selection is not exhaustive.

• Increased calcium is associated with a poorer prognosis
• Acute sarcoidosis: spontaneous remission > 95%
• Chronic sarcoidosis (% remission rate)
  • Type IV: Life expectancy is limited because of severely impaired lung function.
  • Type III: approx. 20%
  • Type II: approx. 50%
  • Type I: approx. 70%

The spontaneous remission rates in acute sarcoidosis are extremely high. In chronic sarcoidosis, the remission rates vary depending on the type!

References:^[1][11]