• Clinical science

Sarcoidosis

Summary

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. If the disease progresses or if certain organs, such as the eyes or heart, are affected, 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.

Epidemiology

  • 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.

Etiology

The cause of sarcoidosis is still unknown; . Current hypotheses suggest that the etiology is multifactorial.

  • Genetic
  • Environmental agent exposure
  • Infectious agents

References:[3]

Pathophysiology

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

References:[4][5]

Clinical features

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)

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

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]

Subtypes and variants

Lofgren syndrome

  • Highly acute clinical presentation with fever and the following triad of symptoms

Heerfordt syndrome

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

Stages

Stages of chronic sarcoidosis

Chronic sarcoidosis Chest x-ray findings
Stage 0

Normal findings

Stage I

Bilateral hilar lymphadenopathy (reversible)*

Stage II

Bilateral reticular or ground-glass opacities with hilar lymphadenopathy → disseminated, reticulonodular infiltrates

Stage III

Bilateral reticular or ground-glass opacities without hilar lymphadenopathy

Stage IV

Lung fibrosis

* In most cases, the disease resolves spontaneously at this stage.

References:[7][9][11]

Diagnostics

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

Pulmonary function tests

References:[12][7][13][1][9]

Differential diagnoses

Differential diagnosis of granulomatous disease

Sarcoidosis Tuberculosis (TB) Hodgkin lymphoma Non-Hodgkin lymphoma Pneumoconiosis Granulomatosis with polyangiitis Histoplasmosis
Risk factors
  • African American females in the US
  • Exposure to mineral dust (e.g., silica)
  • -Caucasian individuals aged 65–74 years
  • AIDS
  • Exposure to bird or bat excrement
Clinical presentation
  • Often, patients are asymptomatic and the physical examination is unremarkable.
  • In symptomatic patients
  • Pulmonary (e.g., dry cough, oral ulcers) or extrapulmonary (e.g., splenomegaly) manifestations
Biopsy
  • Non-caseating granulomas
  • Giant cells
  • Non-caseating granulomas
Other laboratory findings
  • CD4+/CD8+ ratio in bronchoalveolar lavage
  • Single or combined cytopenias

References:[14][15][16]

The differential diagnoses listed here are not exhaustive.

Treatment

References:[1][11]

Complications

References:[6]

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

Prognosis

  • 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]