Approach

Sarcoidosis is a diagnosis of exclusion of granulomatous lung diseases, including tuberculosis and histoplasmosis. Typical history is essential and biopsy from affected organs is often required to establish the diagnosis.[30][31]

Diagnostic goals are as follows:[14]​​

  • Histologic confirmation (may be necessary for nontypical clinical presentation or computed tomography [CT] appearance)

  • Assessment of the extent and severity of organ involvement

  • Assessment of likelihood of progression

  • Determination of whether therapy will benefit the patient.

Certain clinical features are highly specific for the disease and are considered diagnostic, including Löfgren syndrome, lupus pernio, and Heerfordt syndrome.[31][32][33][34]​​​

History

Diagnosis is more common among those with a family history of sarcoidosis.[19][20][21]​​​ There is a higher incidence in people of Scandinavian origin.​[8][9][14]

Pulmonary symptoms such as cough and dyspnea predominate. Costochondritis may also occur, resulting in chest wall pain.

Constitutional symptoms are common and include chronic fatigue, weight loss, and low-grade fever.[30]​ Other symptoms include photophobia and skin lesions.[30][35]​​​ Musculoskeletal manifestations, including arthralgia (affecting the knees, ankles, elbows, and wrists) occur in up to one third of people with sarcoidosis.[36][37]​​

Many patients are, however, asymptomatic and sarcoidosis is only suspected on the basis of radiographic testing for an unrelated reason.

Chronic beryllium exposure and hypersensitivity pneumonitis should be considered in patients with a history of relevant occupational and/or environmental exposures.[31]

Physical exam

Chest signs may include wheezing/rhonchi due to airway involvement, mimicking asthma.[30]

Lymph nodes are enlarged and nontender. Cervical, submandibular nodes are often involved. Rarely, lymphadenopathy is generalized.

Cardiac manifestations occur in 5% to 10% of cases and may present with arrhythmias or heart block.[3][38]​​ Pulmonary hypertension and congestive heart failure occur later in the course of the condition.[38]

Palpable hepatomegaly occurs in 20% of people.[39]​ The liver is usually nontender.

Erythema nodosum and lupus pernio are typical skin manifestations of sarcoidosis. Erythema nodosum presents as tender erythematous nodules on the lower extremities and is a predictor of a good prognosis. Lupus pernio presents as indurated plaques with discoloration of the nose, cheeks, lips, and ears. It is more common in black women and is a predictor of a poor prognosis.[14][40]

Other skin lesions have been described, including scaly erythematous rash, and smooth papules.

Ocular sarcoidosis may present as anterior uveitis, optic neuritis, or conjunctival nodules. Anterior uveitis usually presents with red, painful eyes and blurred vision.[41]

Neurosarcoidosis occurs in <15% of cases and may present with facial palsy and signs of pituitary lesions (e.g., diabetes insipidus). Headaches and seizures can also occur.[5]

Joint exam does not usually reveal synovial thickening.

Initial tests

There are several initial tests to perform in people with suspected sarcoidosis.[14]​​[30][31]

  • Chest x-ray: typically shows bilateral hilar and right paratracheal adenopathy, although isolated bilateral hilar adenopathy is more frequent. May show bilateral pulmonary infiltrates, predominantly in the upper lobes.

  • CBC: may reveal modest leukopenia or lymphopenia and anemia.

  • BUN and serum creatinine: may be elevated in the uncommon event of renal involvement.

  • Liver enzymes: liver function tests screen for hepatic sarcoidosis; US guidelines recommend baseline serum alkaline phosphatase testing.

  • Serum calcium: baseline serum calcium testing to screen for abnormal calcium metabolism. Hypercalcemia occurs due to the dysregulated production of calcitriol by activated macrophages and granulomas.

  • PFTs (including spirometry and gas transfer analysis): measure baseline lung function. Obstructive and restrictive defects in lung function may be found. PFTs are used to monitor any decline in lung function over time.

  • ECG: may show conduction abnormalities if there is any cardiac involvement.

  • Eye exam: baseline eye exam can help to identify ocular involvement, including in those without ocular symptoms.

  • Interferon gamma release assay: tuberculosis and atypical mycobacterial infections can mimic sarcoidosis. Interferon gamma release assay is used for screening, and preferable to tuberculin skin testing due to anergy. Interferon gamma release assays cannot distinguish between latent infection and active disease.

  • Serum ACE: a marker of active disease, elevated in many patients. ACE levels cannot be used for diagnosis and may not reflect disease activity. Utility is unreliable and controversial.[14]

Seek specialist advice if there is major extrapulmonary organ involvement, including ophthalmic review for patients with ocular symptoms, neurology review for central or peripheral nervous symptoms, and dermatology review for patients with skin lesions.[30][Figure caption and citation for the preceding image starts]: Bilateral hilar adenopathyFrom the collection of Dr M.P. Muthiah; used with permission [Citation ends].com.bmj.content.model.Caption@20b9881a

Subsequent tests

Chest CT scan

Not necessary in the routine evaluation or management of sarcoidosis. Indications include atypical presentation or evaluation of complications (bronchiectasis, aspergilloma, pulmonary fibrosis, or a superimposed infection or malignancy).[42]

Scans with contrast and high-resolution images show hilar and/or paratracheal adenopathy with predominantly upper lobe bilateral infiltrates. The infiltrates are classically in a perilymphatic distribution.

Endobronchial ultrasound bronchoscopy

Most patients with pulmonary symptoms, with no histologic diagnosis of sarcoidosis from extrathoracic sites, require bronchoscopy. In patients with suspected pulmonary sarcoidosis, diagnostic yield is superior with endobronchial ultrasound (EBUS)-guided transbronchial node aspiration (EBUS-TBNA) compared with conventional transbronchial lung biopsy.[43][44]​​ EBUS-TBNA is standard of care and routine practice for the diagnosis of mediastinal lymphadenopathy, with high sensitivity (88%) and specificity (100%).[45][46][47][Figure caption and citation for the preceding image starts]: Photomicrograph showing well-formed granulomas typical for sarcoidosisFrom the collection of Dr M.P. Muthiah; used with permission [Citation ends].com.bmj.content.model.Caption@7853aaa6

Bronchoalveolar lavage (BAL) is a useful adjunct; BAL may reveal lymphocytosis with a CD4-to-CD8 ratio >3.5.

Endobronchial biopsy and transbronchial biopsy can be performed. Transthoracic biopsy may be considered for peripheral lesions not accessible by bronchoscopy.

Biopsy shows noncaseating granulomas, with negative stains for acid-fast bacillus and fungi.

Skin lesion biopsy

Performed in people with lesions that are suspected to be manifestations of cutaneous sarcoidosis; reveals classic noncaseating granulomas.

24-hour urine calcium

May be ordered in patients with a history of renal calculi to rule out hypercalciuria, which, when present, can cause nephrocalcinosis with progressive renal insufficiency.

Gallium-67 scintigraphy

May be used when the diagnosis is in doubt. Serial images sometimes require 48 hours to complete. The clinical value of this test remains controversial.[30]​ Gallium scans can show typical uptake patterns. These include the panda sign (lacrimal and parotid gland uptake) or the lambda sign (parahilar, infrahilar, and right paratracheal or azygos node uptake). Gallium-67 scintigraphy lacks specificity.

Vitamin D metabolism

If assessment of vitamin D metabolism is deemed necessary (e.g., to determine whether vitamin D replacement is indicated) measure both 25- and 1,25-OH vitamin D levels before vitamin D replacement.[31]

Magnetic resonance imaging (MRI)

May be used to identify areas of sarcoidosis involvement including the heart and the brain.[48][Figure caption and citation for the preceding image starts]: A) Gadolinium-enhanced MRI scan of the heart (short axis) showing delayed enhancement in the anteroseptal myocardiumAdapted from https://casereports.bmj.com/content/2009/bcr.2006.070805.full [Citation ends].com.bmj.content.model.Caption@2d25948e

(18)F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)

Demonstrates a characteristic pattern of uptake in sarcoidosis and may aid in the diagnosis of cardiac sarcoidosis.[38]​[49][50]​​​​​ This test is much less invasive than endomyocardial biopsy, with minimal to no complications from the procedure.[51][Figure caption and citation for the preceding image starts]: B) 18F-FDG PET scan of the heart (short axis) showing focal uptake in the anteroseptal wall corresponding to granulomatous inflammation. (C) 18F-FDG PET scan of the heart (short axis) from the base to the apex (from left to the right) showing focal uptake in the anteroseptal wall at baseline (upper series) and disappearance of the uptake after treatment (lower series)Adapted from https://casereports.bmj.com/content/2009/bcr.2006.070805.full [Citation ends].com.bmj.content.model.Caption@1e04634d

Emerging tests

​Newer applications of PET include 3'-deoxy-3'-[18F]-fluorothymidine or 4' [methyl-11C]-thiothymidine imaging.[52][53] Unlike 18F-FDG PET, these imaging techniques do not require any dietary restriction.

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