- Clinical science
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!
Epidemiological data refers to the US, unless otherwise specified.
The cause of sarcoidosis is still unknown; . Current hypotheses suggest that the etiology is multifactorial:
- Environmental agent exposure
- Infectious agents
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.
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, ,
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
- 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
Highly acute clinical presentation with fever and the following triad of symptoms:
- Migratory polyarthritis: symmetrical arthritis which primarily affects the ankles
- : primarily affects the extensor surface of the lower legs
- Bilateral hilar lymphadenopathy
- Chronic clinical presentation with fever and the following triad of symptoms:
- Uveitis (iridocyclitis)
- Facial palsy
- 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|| |
|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|| |
|* The majority of patients are still able to undergo spontaneous resolution at this point|
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.
- 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!
- ↑ Inflammatory markers
- Usually no findings typical for 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
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.
- Specimens should be used for histology and culture with special stains for fungus and mycobacteria
- Restrictive or obstructive pattern (see and )
- Early reduction of diffusion capacity and lung compliance
- Diffusing capacity of the lung for carbon monoxide (DLco): sensitive parameter for disease activity
- Exclusion of differential diagnosis, particularly granulomatous diseases
- Suspicion of extrapulmonary manifestations
|History|| || || || || |
|Biopsy|| || || || |
|Other laboratory findings|| || |
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., , )
- Last resort in severe pulmonary disease: lung transplantation
- NSAIDs are always indicated for symptom relief
- Patients with sarcoidosis are at an increased risk of malignant changes (esp. within the lung and lymph nodes)
- Pulmonary complications
- (see “Symptoms/clinical findings” above)
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
- Type IV: Life expectancy is limited because of severely impaired lung function.
- Type III: Approx. 20%
- Type II: Approx. 50%
- Type I: Approx. 70%