• Clinical science

Sarcoidosis

Abstract

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.

Epidemiology

  • 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.

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 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]

Clinical features

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

Acute sarcoidosis (approx. ⅓ of the cases)

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

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]

Subtypes and variants

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

Stages

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]

Diagnostics

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.
    • 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

Other tests

References:[11][6][12][1][8]

Differential diagnoses

Differential diagnosis of granulomatous disease

Sarcoidosis Tuberculosis (TB) Hodgkin's lymphoma

Non-Hodgkin's lymphoma

Pneumoconiosis Granulomatosis with polyangiitis Histoplasmosis
History
  • African-American females in the US
  • Exposure to mineral dust (e.g., silica)
  • AIDS
  • Exposure to bird or bat excrements
Clinical presentation
  • Patients are often asymptomatic and the physical examination is often unremarkable
  • In symptomatic patients
  • Pulmonary (e.g., dry cough, oral ulcers) or extrapulmonary (e.g., splenomegaly) manifestations
Biopsy
  • Non-caseating granuloma
  • Giant cells
  • Non-caseating granuloma
  • Silica/asbestos bodies
  • Non-caseating granuloma
  • Non-caseating granuloma
  • Identification of H.capsulatum yeast with silver stain
Other laboratory findings
  • CD4+/CD8+ ratio in bronchoalveolar lavage
  • Single or combined cytopenias

References:[13][14]

The differential diagnoses listed here are not exhaustive.

Treatment

References:[1][10]

Complications

References:[5]

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

Prognosis

  • ↑ Calcium is accompanied with a poorer prognosis
  • Acute sarcoidosis: spontaneous remission: > 95%
  • 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]