Sarcoidosis

Sarcoidosis is a multisystem disorder characterized by non-caseating granulomatous inflammation. It is classified as either acute or chronic – the former does not necessarily precede the latter form. Acute sarcoidosis has an abrupt onset, with constitutional symptoms (e.g., fever, malaise) but is self-limiting after a few years. Other manifestations include cough, dyspnea, anterior uveitis, erythema nodosum, and arthralgia. Chronic sarcoidosis has a gradual onset and is often asymptomatic in the early stages although it primarily affects the lungs. Other characteristic systemic manifestations are also possible. The first symptoms 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. Although chest x-ray may show classic parenchymal disease with bilateral hilar lymphadenopathy, it is important to note these features are not always evident. A biopsy is the gold standard to confirm the diagnosis. Typical histopathological findings include the presence of non-caseating 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 is frequent 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: higher among African-Americans in the US; chronic and fatal disease courses more likely

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 both T-cell dysfunction and increased B-cell activity with subsequent local immune hyperactivity and inflammation. This leads to the formation of non-caseating granulomas commonly within the lungs and the lymphatic system. The granulomatous inflammation resolves in the majority of patients but, in some cases, it may develop into pulmonary fibrosis.

References:^[4]

Acute sarcoidosis and chronic sarcoidosis generally represent different forms of the disease.

Acute sarcoidosis (approx. ⅓ of the cases)

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

Chronic sarcoidosis (approx. ⅔ of the cases)

• In rare cases, preceded by acute sarcoidosis
• Gradual course of disease; 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 (40%): most frequent site of manifestation
  • Eyes (25%): iridocyclitis
  • 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 as part of systemic sarcoidosis.
• Other manifestations
  • Musculoskeletal , bone lesions
  • Nervous system
  • Heart
  • Liver , kidney , spleen

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

References:^{[5][6][1][7][8][9]}

Lofgren's syndrome

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

Heerfordt syndrome

• Chronic clinical presentation with fever and the following triad of symptoms:
  1. Parotitis
  2. Uveitis (iridocyclitis)
  3. Facial palsy

Jungling's disease

• Special form of chronic sarcoidosis
• Cystic bone lesions of the acral regions (fingers)

Staging of chronic sarcoidosis

Chronic sarcoidosis	Chest x-ray findings
Type 0	Normal findings
Type I	Bilateral hilar lymphadenopathy (reversible)*
Type II	Bilateral reticular or ground glass opacities with hilar lymphadenopathy → disseminated, reticulonodular infiltrates
Type III	Bilateral reticular or ground glass opacities without hilar lymphadenopathy
Type IV	Lung fibrosis
* The majority of patients are still able to undergo spontaneous resolution at this point

References:^[6][8][10]

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

Chest x-ray

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

Chronic sarcoidosis is characterized by a divergence between highly developed radiological findings and moderate clinical presentation!

Laboratory tests

• Acute sarcoidosis
  • ↑ Inflammatory markers
  • Usually no findings typical for sarcoidosis
• Chronic sarcoidosis
  • Soluble interleukin-2 receptor (S-IL-2R), neopterin: parameters that also correlate with disease activity
  • ↑ Alkaline phosphatase level
  • ↑ 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% 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: Gold standard
  • Origin of specimen: lung tissue and lymph nodes
  • Findings: presence of non-caseating granulomas with giant cells Histopathological verification is unnecessary in the following cases: a typical clinical presentation (e.g., Lofgren's syndrome) and further findings (e.g., increased CD4+/CD8+ ratio in bronchoalveolar lavage) are present or the patient is asymptomatic with incidental findings.
    • Asteroid bodies, Schaumann bodies
  • Specimens should be used for histology and culture with special stains for fungus and mycobacteria

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

Pulmonary function tests

• Restrictive or obstructive pattern (see restrictive lung disease and obstructive lung disease)
• Early reduction of diffusion capacity and lung compliance
• Diffusing capacity of the lung for carbon monoxide (DLco): sensitive parameter for disease activity

Other tests

• Indications:
  • Exclusion of differential diagnosis, particularly granulomatous diseases
  • Suspicion of extrapulmonary manifestations
• Procedures:
  • ECG and echocardiography (e.g., AV Block, arrhythmias, cardiomyopathy)
  • Eye examination (e.g., slit lamp detection of uveitis)
  • TB skin test (TST) (exclusion of lung tuberculosis (alternatively QuantiFERON test))

References:^{[11][6][12][1][8]}

Differential diagnosis of granulomatous disease
		Sarcoidosis	Tuberculosis (TB)	Hodgkin lymphoma	Non-Hodgkin lymphoma	Pneumoconiosis	Granulomatosis with polyangiitis	Histoplasmosis
History		African-American females in the US	Immunocompromised individual History of previous TB and/or recent TB exposure	History of infectious mononucleosis	Certain infections (e.g., EBV infection or Helicobacter pylori) Cell damage (caused by toxic substances, immunosuppressive and/or cytostatic therapy or radiation)	Exposure to mineral dust (e.g., silica)	-	AIDS Exposure to bird or bat excrements
Clinical presentation		Dry cough Erythema nodosum Lupus pernio Anterior (possibly with posterior) uveitis	Fever, weight loss and night sweats Productive cough, not responding to conventional antibiotic therapy Hemoptysis	Pel-Ebstein fever Alcohol-induced pain Pruritis	Indolent lymph node enlargement Splenomegaly Evidence of bone marrow suppression (i.e. pallor, infections) Possible large abdominal mass (in Burkitts lymphoma)	Patients are often asymptomatic and the physical examination is often 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)	Chronic rhinitis/sinusitis with thick purulent/bloody discharge Treatment-resistant pneumonia Glomerulonephritis	Pulmonary (e.g., dry cough, oral ulcers) or extrapulmonary (e.g., splenomegaly) manifestations
Biopsy		Non-caseating granuloma Giant cells	Caseating granulomas Polynuclear Langhans giant cells, epithelioid macrophages, and lymphocytes Acid-fast M. tuberculosis	Non-caseating granuloma Reed-Sternberg cells Inflammatory cell infiltrate (e.g., Eosinophils, fibroblasts, plasma cells)	Non-caseating granuloma without Reed-Sternberg cells B-lymphocytes or T-lymphocytes Inflammatory cell infiltrate	Non-caseating granuloma Silica/asbestos bodies	Non-caseating granuloma	Caseating granuloma Identification of H.capsulatum yeast with silver stain
Other laboratory findings		↑ CD4+/CD8+ ratio in bronchoalveolar lavage	M. tuberculosis or its DNA	Single or combined cytopenias (i.e., anemia, leukopenia and/or thrombocytopenia)	Single or combined cytopenias	Positive Beryllium lymphocyte proliferation test (BeLPT)	Positive cytoplasmic ANCA	Positive polysaccharide urine and serum antigen test

References:^[13][14]

The differential diagnoses listed here are not exhaustive.

• Isolated pulmonary sarcoidosis: usually no treatment required, as the disease is often asymptomatic and non‑progressive with a high rate of spontaneous remissions
• 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][10]

• Patients with sarcoidosis are at an increased risk of malignant changes (esp. within the lung 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). PH may lead to respiratory insufficiency and/or pulmonary heart disease (cor pulmonale).
• Chronic renal failure (see “Symptoms/clinical findings” above)

References:^[5]

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

• ↑ Calcium is accompanied with a poorer prognosis
• Acute sarcoidosis: spontaneous remission: > 95%
  • Progression to chronic sarcoidosis is possible
• Chronic sarcoidosis:
  • 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][10]