Sarcoidosis -15 Interesting Facts

Sarcoidosis -15 Interesting Facts

1. Sarcoidosis is a multisystem granulomatous disease with widely varied presentation. In the United States, onset is typically in young or middle-aged adults, with higher prevalence in the black and female subpopulations
2. Presentations with the most diagnostic specificity include asymptomatic bilateral hilar adenopathy, acute onset of Löfgren syndrome (ie, fever, arthralgia, erythema nodosum, bilateral hilar adenopathy), and acute onset of Heerfordt syndrome (ie, fever, uveitis, parotitis with or without cranial nerve VII palsy)
3. Any organ system can be affected; most commonly lungs, followed by skin (lupus pernio and various other lesions) and eyes (uveitis). Multisystem involvement is common; lung is nearly always involved in such cases. Pulmonary symptoms are typically limited to mild cough and dyspnea on exertion unless granulomatous inflammation has progressed to pulmonary fibrosis
4. Diagnosis is based on a compatible clinical presentation, supportive imaging findings, histopathologic confirmation of nonnecrotizing granulomas, and exclusion of other causes of granulomatous disease (eg, mycobacterial infections, fungal infections, autoimmune diseases, exposures to allergens or beryllium, adverse drug reactions). There is no gold standard diagnostic test
5. Cardiac sarcoidosis is rare, but it can be life-threatening (eg, malignant ventricular arrhythmia, complete heart block, ventricular dysfunction). All patients must be screened with a careful review of cardiac symptoms, an ECG, and (in some cases) Holter monitoring and echocardiography
6. Not all patients with sarcoidosis require treatment. Treat patients with disease that is causing organ dysfunction or is progressive. Refer patients with ocular, neurologic, or cardiac sarcoidosis to an appropriate specialist for consideration of treatment, even if asymptomatic
7. Immunosuppressive drugs are the primary treatment. Corticosteroids are usually the initial treatment for acute symptoms or organ dysfunction. Steroid-sparing drugs (eg, methotrexate, azathioprine) are indicated for long-term management. Anti-TNF-α drugs are third line treatment
8. Complications of sarcoidosis depend on the organ systems involved. Cardiac sarcoidosis may require an implantable cardioverter-defibrillator for malignant arrhythmias. Advanced pulmonary disease can result in pulmonary fibrosis and pulmonary hypertension with eventual need for lung transplant
9. Prognosis varies. Pulmonary sarcoidosis improves spontaneously in up to half of patients, and most patients who require corticosteroid treatment have a favorable response, although relapse is common after drug discontinuation
10. Sarcoidosis rarely results in death, but when deaths occur, they usually result from cardiac sarcoidosis or advanced pulmonary sarcoidosis
11. Multisystemic granulomatous disorder of unclear etiology, affecting both the central and peripheral nervous systems
12. Characterized pathologically by the presence of noncaseating granulomas
13. Involves fatigue, weight loss, anorexia, malaise, peripheral neuropathy, cranial nerve palsies, visual disturbances, myopathy, and dry, nonproductive cough or dyspnea
14. Diagnosis requires biopsy in most cases; transbronchial biopsy via fiberoptic bronchoscopy has a high diagnostic yield
15. Differentiated with biopsy results showing noncaseating granulomas with special stains negative for fungus and mycobacteria

Pitfalls

• Sarcoidosis is known as a great imitator/mimicker; a detailed exposure history is necessary to exclude other potential causes of granulomatous disorders, such as mycobacterial infection, endemic fungal infection, hypersensitivity pneumonitis, autoimmune granulomatous disease, occupational exposure to beryllium, and exposure to an implicated drug
• Hypercalcemia and hypercalciuria complicate up to 10% of cases, owing to altered vitamin D metabolism. Lethargy, constipation, urolithiasis, or mental status changes may be manifestations of this process ¹
• Ocular involvement is fairly common but may be asymptomatic. All patients with suspected sarcoidosis should be referred to an ophthalmologist for a complete eye examination

Sarcoidosis derives from the Greek words “ sarco ”, meaning flesh, “ eidos ” meaning like, and “ osis ,” meaning condition. The first case was described in 1877 by Dr. Jonathan Hutchinson at King’s College Hospital, London. It is a systemic inflammatory disorder characterized by noncaseating granulomas that classically involve the lungs but can affect any organ. Since there is no specific test for sarcoidosis, the diagnosis is established when the following criteria are met:

• • A consistent clinical and radiographic presentation.
• • Histologic evidence of noncaseating epithelioid granulomas in more than one organ.
• • Exclusion of other granulomatous diseases caused by mycobacterial infection, fungal infection, berylliosis, drugs, and local reactions to tumors or lymphoma.

Although diagnosis relies on tissue biopsy, there are certain situations in which a presumptive diagnosis can be made based on clinical and radiographic findings, such as the presence of asymptomatic bilateral hilar adenopathy, Lofgren syndrome, or Heerfordt syndrome.

Terminology

Clinical Clarification

• Sarcoidosis is a multisystem granulomatous disease that most commonly affects hilar and mediastinal lymph nodes and lung parenchyma, but it may also cause disease in any other organ, including the skin, eyes, liver, heart, and nervous system
• Once formed, granulomas either resolve spontaneously, persist as chronic inflammation, or progress, leading to fibrosis and organ dysfunction
• Variation in the trigger, the host immune response, and the organs involved allow for many phenotypic presentations of sarcoidosis
• Term for sarcoidosis involving intrathoracic lymph nodes with or without lung parenchymal involvement is pulmonary sarcoidosis 

Classification

• No clinical classification of sarcoidosis is in widespread use to date, although various proposals have been made ²

Diagnosis

Clinical Presentation

History

• Presentation varies widely
  • Presentations with high diagnostic specificity:
    • Asymptomatic, with incidental finding of bilateral hilar adenopathy on chest radiograph done for unrelated reasons (95% diagnostic specificity for sarcoidosis) ³
      • Often described as classic presentation
    • Acute presentation as Löfgren syndrome (95% diagnostic specificity for sarcoidosis) ³
      • Fever
      • Ankle arthralgia (some descriptions of Löfgren syndrome describe polyarthralgia as opposed to ankle arthralgia)
      • Erythema nodosum (tender nodules along anterior lower extremity)
      • Chest radiograph showing bilateral hilar lymphadenopathy
    • Acute presentation as Heerfordt syndrome (rare) ³
      • Fever
      • Uveitis
      • Parotitis, with or without cranial nerve VII palsy
  • Other symptomatic, nonsyndromic presentations of sarcoidosis vary
    • Fatigue is common
    • Symptoms (or objective evidence of disease) in more than 2 organ systems that are commonly involved in sarcoidosis increases confidence in the diagnosis ³
      • Most commonly involved organs (within the first 6 months)
        • Lung parenchyma, including involvement of hilar or mediastinal lymph nodes (about 95% of patients) ⁴
          • Nonspecific symptoms, including cough and dyspnea on exertion
        • Skin (about 16%) ⁴
          • Variety of skin lesions, including nodules, plaques, and papules
        • Eyes (about 12%) ⁴
          • Symptoms vary; any part of the eye can be involved
          • Uveitis (eg, anterior, posterior, panuveitis) is the most frequent manifestation, with symptoms of acute bilateral eye pain, redness, photophobia, floaters, and blurry vision
        • Liver (about 12%) ⁴
          • Often asymptomatic. If symptomatic, most common presentation is with a chronic intrahepatic cholestasis syndrome
            • Symptoms include jaundice and pruritus; typically alkaline phosphatase level is elevated
      • Less common presentations
        • Nearly any organ can be affected, including the nervous system, heart, musculoskeletal system, adnexa of eye, salivary glands, ear, nose, throat, and genitourinary tract
        • Most patients with such involvement also have radiographic pulmonary disease, often asymptomatic
        • Neurologic and cardiac sarcoidosis can cause serious morbidity; a high index of suspicion is needed so that these are not missed
          • Neurologic involvement (seen in 10%) is rarely the initial presentation ¹
            • Cranial nerve mononeuropathy, with either a unilateral or bilateral facial nerve palsy (most common nerve affected)
            • Less commonly, involvement of other cranial nerves (eg, blurry vision, diplopia, blindness [optic neuritis], slurred speech, alterations in taste and smell, or difficulty swallowing)
            • Peripheral nerve involvement, with focal numbness, tingling, or weakness
            • Parenchymal brain disease, with seizures, headaches, or cognitive/behavioral changes
          • Cardiac sarcoidosis
            • May be asymptomatic
            • Initial presentation may be arrhythmias, conduction defects (including complete heart block), heart failure with progression to cardiomyopathy, or (rarely) sudden cardiac death
            • Unexplained syncope or presyncope is suggestive of cardiac sarcoidosis in the appropriate setting
        • Symptomatic skeletal muscle involvement is rare, but when it is present it can be associated with pain or weakness
        • Bone involvement may accompany lupus pernio (pigmented cutaneous plaques), especially the phalanges of hands, feet, or both. Axial skeleton may also be affected in those unaffected by lupus pernio, causing bone or joint pain
        • Lacrimal gland involvement presents as chronic discomfort and swelling over the eyelid
        • Salivary gland sarcoidosis often presents as acute bilateral painless swelling (parotid swelling may be accompanied by uveitis and fever to comprise the rare but diagnostically specific presentation of Heerfordt syndrome)
        • Otolaryngologic disease presents with symptoms of rhinosinusitis, nasal obstruction, epistaxis, and dysphonia
        • Dysregulated production of calcitriol by the action of activated macrophages within granulomas can result in symptoms related to hypercalcemia and hypercalciuria
          • Patients may have symptoms of hypercalcemia (eg, lethargy, mental status changes, constipation, renal dysfunction)
          • Hypercalciuria can result in urolithiasis. Colicky flank pain is sometimes the presenting symptom of sarcoidosis
    • Constitutional symptoms may be present with involvement of any organ, with mild weight loss and fever
  • Course of disease over time varies. May have spontaneous resolution, stable chronic disease, or severe disease progressing to organ failure
• Because sarcoidosis is a diagnosis of exclusion, question carefully for past exposures that may have caused nonsarcoid granulomatous disease with similar symptoms or radiographic appearance
  • Tuberculosis history (active or latent) or known exposure
  • Travel to fungal endemic regions
  • Occupational exposure to beryllium, found in aerospace, telecommunication, automotive, dental, x-ray tube manufacturing, and defense industries. Beryllium disease mimics radiographic appearance of sarcoidosis
  • Exposure to hot tubs, birds, molds, or other relevant environmental factors that can result in subacute or chronic hypersensitivity pneumonitis
• Family history is also significant; familial clustering is seen

Physical examination

• There are no pathognomonic clinical findings
  • Pulmonary examination
    • At time of initial diagnosis (before any progression to pulmonary fibrosis), examination findings may be normal
    • Although sarcoidosis is an interstitial disease, wheezing can be the most prominent pulmonary finding; this reflects endobronchial granuloma formation
    • Pulmonary hypertension due to sarcoidosis can result in signs of right-sided heart failure
  • Certain physical findings are very supportive of the diagnosis in the appropriate clinical setting, while the presence of others suggests consideration of an alternative diagnosis ³
    • Supportive findings:
      • Lupus pernio skin lesions
        • Brown to violaceous plaques of face and neck, most commonly involving the nose
        • May involve nares and nasal mucosa
      • Ophthalmologic examination findings consistent with uveitis
        • Decreased visual acuity
        • Small or constricted pupil
        • Pupils may react poorly when iris is adherent to anterior lens capsule (synechiae)
        • Difficulty visualizing iris owing to corneal edema or suspension of cells and protein in aqueous humor
        • Ciliary flush (perilimbal redness)
        • Refer to ophthalmologist for slit lamp examination if suspected
      • Facial nerve palsy (especially if bilateral)
        • Neurosarcoidosis is uncommon, but when it is present it is the most suggestive physical manifestation
    • Findings that are not common at diagnosis of sarcoidosis (although some may be present in later stages if pulmonary fibrosis develops) and suggest need to exclude an alternative diagnosis:
      • Pulmonary crackles
      • Digital clubbing
      • Weight loss of more than 10%
      • Tender lymphadenopathy
• Depending on the organs involved, a variety of other physical findings may be present
  • Skin lesions other than lupus pernio
    • Papules and maculopapular lesions: discrete lesions (up to 1 cm) on face, eyelids, nasolabial folds, red to brown to violaceous. Common in acute disease ⁵
    • Plaques: discrete lesions that range from solid, round lesions to ring-shaped lesions. Flesh-colored to erythematous and commonly on extensor surfaces of limbs or on buttocks or back. Associated with chronic disease
    • Infiltrative scars: scar sarcoidosis may develop in old scars, new incisions, tattoos, and other lesions. Color change to violaceous may indicate reactivation of sarcoidosis in a patient with quiescent disease
  • Hepatomegaly or hepatosplenomegaly
  • Cranial neuropathies (facial nerve palsy is most common)
  • Irregular pulse or examination findings consistent with heart failure with cardiac sarcoidosis (however, cardiac examination findings are more typically completely normal)
  • Upper eyelid edema with lacrimal gland involvement
  • Swollen, nontender parotid glands bilaterally

Causes and Risk Factors

Causes

• Specific cause is uncertain
• Postulated that exposure to environmental trigger results in HLA-mediated activation of immune system, leading to formation of nonnecrotizing granulomas

Risk factors and/or associations

Age

• Onset is typically in young to middle-aged adults ¹

Sex

• Women are affected more frequently than men

Genetics

• Polygenic disease without any specific gene variant being predominantly responsible
  • Both susceptibility to sarcoidosis and disease phenotype have been linked to several genes, including HLA genes and some related to immune function
    • HLA-DRB1*11:01 allele is associated with sarcoidosis in both African Americans (attributable risk of 16%) and white Americans (attributable risk of 9%) ⁶
  • Tends to cluster in families, with higher prevalence in first-degree relatives

Ethnicity/race

• Incidence and prevalence vary by race, ethnicity, and geography worldwide
  • In the United States, as follows: ⁷
    • Incidence in black people is about 3 times higher than in white people
      • Black females have the highest incidence
      • Disease occurs later in life in black people compared with white people, peaking in the fourth decade
    • Organ involvement and severity varied between black and white cohorts in a large cohort study ⁸
      • Black patients had more organs involved, had higher radiographic stage of disease, and required treatment more frequently
  • More common among persons of Scandinavian, Irish, German, and West Indian descent ³
  • Rare in Japan, Spain, and Portugal ³

Other risk factors/associations

• Sarcoidosis triggers identified in an etiologic study include: ⁹
  • Occupational environment
    • Agriculture
    • Health care
    • Bird breeding
    • Automotive
    • Education (middle and high school teachers)
  • Exposures
    • Insecticides
    • Mold and mildew
    • Musty odors in the workplace
    • Home central air conditioning
• Several bacteria have been postulated to act as triggers, but sarcoidosis is not an active infectious disease ¹
  • Mycobacterium tuberculosis
  • Cutibacterium acnes
• Obesity increases risk ¹⁰
• Lower incidence of sarcoidosis in smokers; nicotine may be protective ¹⁰

Diagnostic Procedures

Primary diagnostic tools

• Make the diagnosis based on compatible clinical presentation, supportive imaging findings, and tissue confirmation of noncaseating granulomas ¹
  • Caveats
    • There is no gold standard diagnostic test for sarcoidosis
    • Other potential causes of symptoms and abnormal imaging must be considered and ruled out, as sarcoidosis is historically known as a great imitator (great mimicker) ¹
    • A tissue finding of nonnecrotizing granulomas is, in and of itself, nonspecific
      • Carefully consider exposure history and overall clinical picture to rule out infectious, hypersensitivity-related, autoimmune, occupational exposure–related, malignancy-related, immunodeficiency-related, and drug-related granulomatous disease
• Diagnostic work-up varies depending on clinical presentation
  • As part of initial evaluation, for all patients with suspected sarcoidosis, obtain the following: ^11 12
    • Laboratory tests (eg, CBC, chemistry panel, liver enzyme levels)
      • Consider serum ACE level; some experts do not recommend this test because it is insensitive and nonspecific
      • If assessment of vitamin D metabolism is indicated (eg, presence of hypercalcemia, radiographic evidence of bone resorption), measure both 25(OH) and 1,25(OH)₂ vitamin D levels before beginning vitamin D replacement ¹¹
    • Pulmonary screening with chest radiograph
      • Asymptomatic pulmonary sarcoidosis often exists in patients who present with sarcoidosis of another organ; therefore, screening is required for all patients
    • Cardiac screening, usually with ECG
      • Cardiac sarcoidosis is uncommon but can be life-threatening even if asymptomatic; therefore, screening is required
      • Common approach is to screen with ECG and to follow up with additional functional testing if findings are abnormal ^11 12 13
      • Presence of cardiac symptoms has a higher sensitivity as an individual screening tool than ECG, echocardiography, or Holter monitoring ¹³
      • In addition to presence of cardiac symptoms, performing ECG, echocardiography, or Holter monitoring minimally raises the sensitivity for detecting cardiac sarcoidosis ¹³
      • Among ECG, echocardiography, and Holter monitoring, Holter monitoring raises the sensitivity for detecting cardiac sarcoidosis to the greatest degree; however, it does not reach a diagnostic threshold ¹³
      • American Thoracic Society guideline suggests against routinely performing echocardiography and Holter monitoring in patients without cardiac signs or symptoms ¹¹
  • Further evaluation of respiratory symptoms and/or abnormal chest radiograph findings includes pulmonary function tests and high-resolution CT of chest ¹²
    • Other causes of abnormal chest radiograph findings should be considered at this point, given that sarcoidosis is a diagnosis of exclusion
      • Tuberculosis testing (tuberculin skin test or interferon-γ release assay) is indicated in most patients ¹²
      • Depending on patient history and possible exposures, fungal serologies (eg, for histoplasmosis, blastomycosis, or coccidioidomycosis) may be helpful ¹²
  • Further evaluation of cardiac symptoms (eg, palpitations, syncope) or of abnormal screening ECG findings requires additional cardiac function testing (eg, Holter monitor and/or echocardiogram) and/or diagnostic imaging (eg, cardiac MRI or PET) ^12 13
    • American Thoracic Society guideline favors cardiac MRI over transthoracic echocardiography or PET scanning as initial test; if cardiac MRI is not available, PET scanning is recommended ¹¹
  • Additional 3-dimensional imaging may be required for suspected multiorgan involvement
  • After initial evaluation, most patients with suspected sarcoidosis require biopsy for tissue confirmation from the most safe and accessible site (usually a skin lesion, an intrathoracic lymph node, or the lungs) ¹²
    • Exceptions:
      • Many experts do not obtain tissue confirmation for presentations that are associated with high likelihood of sarcoidosis, including the following: ^3 11 12
        • Asymptomatic patient with typical chest radiograph findings of bilateral hilar adenopathy ³
        • Presentation as Löfgren syndrome ³
        • Presentation as Heerfordt syndrome ³
        • Presentation as lupus pernio ¹¹
      • When there is no low-risk biopsy site available and treatment is not contemplated ¹²

Laboratory

• General routine laboratory testing; some abnormal results are frequent but nonspecific
  • CBC
    • Leukopenia (in particular, lymphopenia) is common
  • Serum chemistry panel, including levels of calcium, creatinine, and alkaline phosphatase, with or without transaminase levels
    • Hypercalcemia can occur
      • Results from dysregulated production of calcitriol by granulomas and activated macrophages
    • Elevated creatinine level may be due to renal involvement
    • Elevated alkaline phosphatase level suggests diffuse hepatic granulomas; hepatic transaminase levels are less commonly elevated
• Serum ACE level ¹²
  • Sometimes ordered routinely, but this is controversial for diagnostic purposes
    • Most patients have an elevated level, although it is not diagnostic
    • Value more than twice the upper reference limit is suggestive ¹⁴
    • Levels vary based on additional patient factors
      • ACE genotype
      • Use of ACE inhibitors
    • Sensitivity is poor
      • Normal value does not exclude the diagnosis
    • Specificity is suboptimal
  • Sometimes used for monitoring disease

Imaging

• Chest radiograph ¹²
  • Routine for all patients, including those with nonpulmonary presentations of sarcoidosis
  • Classic finding is bilateral hilar lymphadenopathy (radiographic term for enlargement of the mediastinal lymph nodes on chest radiograph) ¹⁵
    • Unilateral adenopathy is atypical
    • Calcification may be present
      • Amorphous or cloud-like pattern is most typical calcification pattern; if present, it can be helpful, because it is not associated with other forms of granulomatous adenopathy ¹⁵
  • Chest radiograph appearance is used to determine the radiographic stage of pulmonary sarcoidosis ^15 16
    • Clinical relevance: stage correlates poorly with symptoms and need for therapy (inter-reader agreement is not high)
    • Stages
      • Stage 0: normal initial chest radiograph
      • Stage 1: hilar or mediastinal adenopathy
      • Stage 2: adenopathy and pulmonary opacities
      • Stage 3: pulmonary opacities without adenopathy
      • Stage 4: pulmonary fibrosis and bullous changes in upper lobes
• High-resolution CT of chest ¹²
  • Indicated if patient has respiratory symptoms and abnormal findings on chest radiograph or pulmonary function tests
  • Useful for determining severity of parenchymal involvement
    • Common pattern in prefibrotic stages is nodules in a bilateral upper or mid-lung distribution
      • Typical distribution of nodules is peribronchovascular or lymphatic and along fissures
      • Nodules are typically 2 to 5 mm ¹⁵
      • Upper lobe predilection for nodules
    • In advanced, fibrotic stage (20% eventually develop this stage), findings include: ¹⁵
      • Reticular opacities
      • Volume loss
      • Traction bronchiectasis
      • Fibrotic perihilar conglomerate masses
      • Architectural distortion of airways
      • Cavitations
      • Evidence of pulmonary hypertension (dilatation of pulmonary trunk and dilatation of left and right pulmonary arteries)
    • Portion of spleen and liver captured with imaging may show granulomas (scattered hypoattenuated lesions)
  • Can identify adenopathy (eg, supraclavicular, mediastinal) and identify the best target lymphatic tissue for tissue sampling
    • Typical pattern is bilateral mediastinal adenopathy
    • Calcification can develop over time
• Imaging for confirmation of cardiac sarcoidosis
  • Indicated when confirmation of cardiac sarcoidosis (beyond the level of screening tests) would be beneficial to patient ¹³
    • Useful to confirm cardiac involvement before beginning potentially toxic therapies or placing an automated implantable cardioverter-defibrillator
    • Cardiac MRI
      • High diagnostic sensitivity and specificity for cardiac sarcoidosis ¹³
      • Patchy areas of T2 hyperintensity (midmyocardial or subepicardial with sparing of endocardium) are suggestive ¹⁵
      • Gadolinium-enhanced T1 images typically demonstrate patchy midmyocardial and subepicardial areas ¹⁵
      • Identifies area of myocardial damage (eg, scarring), which is often a nidus for arrhythmias, and can help to identify patients who will benefit from an implantable cardioverter‐defibrillator ¹⁷
    • Cardiac PET ¹⁵
      • Useful for patients who have a contraindication to MRI, however, should be performed in centers with specific expertise in nuclear imaging of sarcoidosis
      • Shows any heterogeneous areas of myocardial uptake of fludeoxyglucose F 18
      • Identifies areas of active inflammation (as opposed to scar tissue) and may help to identify patients who are likely to benefit from steroid therapy 

Functional testing

• Pulmonary function tests, including diffusing capacity ¹²
  • Indicated for patients with respiratory symptoms and/or any abnormalities on pulmonary imaging
  • Decreases in vital capacity, diffusing capacity, and PaO₂ are noted in 20% to 40% of patients with radiographic stage 1 disease; abnormalities are present in most patients with higher-stage radiographic disease ¹⁸
  • Typically a restrictive spirometry pattern, but varying degrees of airflow obstruction (indicating endobronchial involvement) may also be present even in asymptomatic patients, resulting in a mixed restrictive/obstructive picture
  • Restrictive pattern is present in advanced, fibrotic stage of disease
  • Disproportionate reduction in diffusing capacity for carbon monoxide may indicate development of pulmonary hypertension
• ECG ¹²
  • Indicated for all patients with presumptive or confirmed diagnosis of sarcoidosis
  • Cardiac sarcoidosis may be silent until life-threatening presentation with arrhythmia, sudden cardiac death, or heart failure
  • 5% of patients screened at baseline have abnormal ECG findings ¹⁹
• Additional cardiopulmonary functional evaluation is not routine, but it should be performed in the appropriate circumstances (eg, if there are cardiac symptoms or abnormal ECG findings, or if pulmonary hypertension is suspected)
  • Referral to a cardiologist is recommended to direct such testing ¹²
  • For cardiac symptoms or abnormal ECG findings, obtain Holter monitoring and echocardiogram ¹²
  • If pulmonary hypertension is suspected, obtain an echocardiogram; right-sided heart catheterization should be considered 

Procedures

Biopsy

General explanation

• Tissue is obtained from the most easily accessible affected site, with lowest risk to patient ¹⁴
  • A peripheral site is preferred (eg, skin lesion, if present)
    • Punch biopsy is required because pathologic alteration is in dermis and/or subcutaneous tissue ⁵
    • Macular lesions may require repeated biopsy to obtain granulomas
  • Most commonly involved and accessible sites are lung parenchyma and intrathoracic lymph nodes, which can be sampled bronchoscopically
    • Intrathoracic lymph nodes are accessible via endobronchial ultrasonography–guided transbronchial needle aspiration biopsy; procedure of choice when bronchoscopy is performed ¹¹
    • Pulmonary parenchymal tissue can be sampled by transbronchial biopsy
    • Bronchoalveolar lavage is often performed to obtain cultures to rule out infectious causes of pulmonary granulomatous disease and to perform cellular analysis ¹

Indication

• Pathologic confirmation of granulomatous inflammation is recommended unless the clinical presentation is a classic presentation highly associated with sarcoidosis

Contraindications

• When the affected site cannot easily be biopsied (eg, heart, brain) or biopsy is likely to be nondiagnostic ¹⁴
  • Endomyocardial biopsy is rarely performed, because it has low sensitivity given that myocardial involvement is patchy rather than confluent
    • Cardiac sarcoidosis can be considered probable with suggestive findings on cardiac MRI or PET scan
  • PET or gallium 67 scan can sometimes identify an alternative biopsy site
  • In some cases, the diagnosis must remain in the category of possible, rather than probable or highly probable

Other diagnostic tools

Differential Diagnosis

Most common

• Differential diagnosis of sarcoidosis is initially extremely broad and depends on clinical manifestations at presentation
  • When histologic examination finds granulomas, other conditions that involve pulmonary or multisystem granulomas must be considered
  • These granulomatous conditions can be due to infection (mycobacteria, fungi), hypersensitivity reactions to organic substances, autoimmune disease, environmental or occupational exposures (eg, beryllium), or use of specific drug therapies (primarily immunotherapies)
  • In general, granulomas in sarcoid pulmonary specimens should be located in the airway mucosa or the peribronchiolar interstitium. Findings of granulomas in the airspace or any nonlymphatic distribution are more suggestive of infection or other alternative diagnoses
  • Infectious causes of pulmonary granulomas
    • Infectious causes typically produce necrotizing granulomas (eg, the caseating necrotizing granulomas of tuberculosis in immunocompetent patients), but nonnecrotizing granulomas may also be present, especially in patients with immunodeficiency
    • Mycobacterial infection
      • Mycobacterium tuberculosis
        • Active tuberculosis (primary progressive disease or reactivation) typically manifests with constitutional symptoms, respiratory tract symptoms, and chest radiograph abnormalities, which may overlap with some presentations of pulmonary sarcoidosis
        • As opposed to patients with pulmonary sarcoidosis (in prefibrotic stage), patients with active pulmonary tuberculosis have night sweats, productive cough with purulent or bloody sputum for longer than 3 weeks, and abnormal lung examination findings (Related: Tuberculosis)
        • Chest radiograph appearance of active tuberculosis varies by stage of disease; bilateral hilar adenopathy can be present in both tuberculosis and sarcoidosis (Related: Tuberculous lymphadenitis)
        • Differentiate the conditions by stepwise testing to identify active tuberculosis
          • Tuberculin skin test or interferon-γ release assay is usually performed early in evaluation of suspected sarcoidosis
          • Obtain acid-fast bacilli sputum microscopy (serial specimens) and/or sputum nucleic acid amplification test to make a presumptive diagnosis of pulmonary tuberculosis
          • Positive Mycobacterium tuberculosis sputum or tissue culture is required for definitive diagnosis
      • Nontuberculous mycobacteria
        • Various bacterial species that are ubiquitous in the environment (water, soils, aerosols). Most are much less pathogenic than Mycobacterium tuberculosis
        • Infection primarily affects lungs. Impaired immunity and underlying pulmonary disease are the main risk factors, but these bacteria may also affect persons with normal immune function and otherwise normal lungs
        • May present similar to pulmonary tuberculosis, with cavitary disease; as a pulmonary hypersensitivity syndrome; or in disseminated form with an immunodeficient host
        • Differentiate the condition with sputum cultures to identify the causative mycobacteria. Requires at least 2 positive culture results or a positive bronchoalveolar lavage specimen or compatible histopathology (granulomatous inflammation) with a positive culture result
      • Histology may not always differentiate sarcoidosis (nonnecrotizing granulomas) from mycobacterial infection
        • While mycobacterial infection typically produces necrotizing granulomas in immunocompetent patients, they may coexist with nonnecrotizing granulomas, especially when the patient has immunodeficiency
    • Granulomatous fungal infection
      • Diverse clinical manifestations (subclinical and self-limiting pulmonary disease to disseminated disease). Suspect in persons with a compatible clinical presentation and residence or travel to an endemic area. Can progress to necrotizing granulomas, especially in the setting of underlying cavitary lung disease, emphysema, and immunodeficiency
        • Histoplasmosis
          • Primarily in southeastern, mid-Atlantic, and central United States (especially in the Mississippi and Ohio river valleys) and in Rio de Janeiro state in Brazil
          • Histopathology: granulomas may be necrotizing or nonnecrotizing. Special stains can identify specific pattern of yeast forms
          • Additional diagnostic testing may be required to confirm the diagnosis, including culture (low yield), serology, and antigen detection methods
        • Blastomycosis
          • In the United States, southeastern and south central states bordering the Mississippi and Ohio rivers and upper midwestern states bordering the Great Lakes. In Canada, Manitoba and Ontario (bordering the Great Lakes) and Quebec (along the St Lawrence River)
          • Histopathology: mixture of acute inflammation with microabscess formation and granulomas. Special stains identify budding yeast compatible with Blastomyces dermatitidis 
          • Culture, nucleic acid test, and antigen detection test to confirm the diagnosis
        • Coccidioidomycosis
          • Primarily in semiarid desert regions of North, South, and Central America
          • Histopathology: granulomas are present; Coccidioides spherules are directly observed
          • Serology, culture, and in some cases antigen testing to confirm the diagnosis
  • Noninfectious causes of granulomas
    • Hypersensitivity pneumonitis (extrinsic allergic alveolitis)
      • Results from repeated inhalation of a variety of microbial agents, animal proteins, and chemical sensitizers
      • Most common causes of hypersensitivity pneumonitis are inhaled bioaerosols from hot tubs and birds
      • Exists in acute, subacute, or chronic form, and overlap is possible. Presentation depends on mode and frequency of exposure
      • Diagnosis depends on a strong clinical index of suspicion, a careful exposure history, and consideration of compatible imaging and histopathologic findings, if tissue is obtained
      • Histopathology varies by antigen and acuity of disease
        • With subacute disease, scattered small nonnecrotizing granulomas are present
        • Additional histologic factors that are useful for differentiating from sarcoidosis include the following:
          • Hypersensitivity pneumonitis granulomas tend to be smaller, less numerous, and more loosely organized than sarcoid granulomas
            • An exception to this is “hot-tub lung,” which is associated with well-formed granulomas
          • Hypersensitivity pneumonitis granulomas do not hyalinize, and they may therefore completely resolve after removal of antigen exposure
    • Autoimmune granulomatous diseases
      • Granulomatosis with polyangiitis (Wegener granulomatosis)
        • Primarily involves upper and/or lower respiratory tract and kidneys; may also affect skin, eyes, central nervous system, joints, and (rarely) heart or gastrointestinal tract in adults older than 55 years
        • Histopathology: necrotizing granulomatous inflammation with necrotizing vasculitis affecting predominantly small to medium vessels
        • Does not have the well-formed granulomas typical of sarcoidosis
      • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss disease)
        • Associated with asthma and eosinophilia
        • Histopathology: necrotizing granulomatous inflammation with marked eosinophil infiltration in the respiratory tract, predominantly affecting small to medium vessels
    • Chronic beryllium disease (berylliosis)
      • Occupational exposure (often accidental) to high level of beryllium can cause a toxic pneumonitis; beryllium is found in aerospace, telecommunication, automotive, dental, x-ray tube manufacturing, and defense industries
      • Beryllium persists in lung tissue, so disease can appear and progress after cessation of exposure
      • Beryllium disease mimics radiographic appearance of sarcoidosis with multiple nodular opacities and hilar adenopathy; radiographic signs may appear before respiratory symptoms develop
      • Histopathologic findings mimic sarcoidosis, with lymphangitic distribution of nonnecrotizing granulomas and hilar lymph node involvement
      • Differentiate from sarcoidosis by the positive history of exposure to beryllium and a positive beryllium lymphocyte transformation test on blood or bronchoalveolar lavage fluid
    • Drug-induced granulomatous disease
      • Interstitial lung disease can be associated with use of immune checkpoint inhibitors (ie, pembrolizumab, nivolumab), antiretroviral therapy, interferons (α and β), and anti-TNF-α drugs ¹
      • Hilar or mediastinal adenopathy may also be present
      • Histopathology shows granulomas, which are typically nonnecrotizing
      • Exposure history is critical for consideration of the diagnosis, as it cannot be distinguished from sarcoidosis by tissue examination
    • Foreign body granulomatosis
      • Caused by aspiration or IV injection of foreign materials (eg, IV injection of crushed pills made with talc or microcrystalline cellulose as a filler)
      • Histopathology typically shows perivascular fibrosis and granulomas with prominent multinucleated giant cells
      • Because talc and microcrystalline cellulose are strongly birefringent, examination under polarized light facilitates the diagnosis
    • Common variable immunodeficiency
      • Acquired primary hypogammaglobulinemia is within a family of disorders that exhibit a common phenotype
      • Usual presentation is with recurrent respiratory tract infections. Definitive diagnosis of common variable immunodeficiency requires the demonstration of a low serum level of IgG, low serum level of IgA and/or IgM, impaired capacity to make specific antibodies in response to immunization or infection, and the exclusion of other primary or secondary antibody deficiencies
      • Granulomatous, sarcoidlike pulmonary disease develops in a subset of patients with common variable immunodeficiency
      • Consider when sarcoidosis is suspected in patients with recurrent respiratory infection and hypogammaglobulinemia

Treatment

Goals

• For patients with symptomatic, organ-threatening, or progressive disease:
  • Improve symptoms
  • Prevent organ dysfunction
  • Stop disease progression
• For asymptomatic patients, without critical organ involvement and in the absence of disease progression:
  • Observation without treatment is usually appropriate

Disposition

Admission criteria

Acute sarcoidosis may require admission to complete diagnostic evaluation and to start corticosteroids or other immunosuppressive therapies

Criteria for ICU admission

• Cardiac sarcoidosis with ventricular arrhythmias, heart block, or ventricular dysfunction and heart failure
• Severe presentations of neurologic sarcoidosis may require an intensive care environment (eg, parenchymal brain involvement with seizures or cognitive/behavioral changes)

Recommendations for specialist referral

• Refer to a pulmonologist when biopsy confirmation of intrathoracic disease is needed to establish the diagnosis, and for treatment decisions and management
• Consult a cardiologist for symptoms (eg, syncope, palpitations) or ECG findings (eg, evidence of conduction delay) suggestive of cardiac sarcoidosis
• An ophthalmologist should perform a baseline eye examination on every patient with suspected or diagnosed sarcoidosis and should be consulted for rapid evaluation of visual symptoms ¹¹
• When suspected cutaneous lesions of sarcoidosis are present, consult a dermatologist for biopsy. A skin lesion may be the best site for obtaining tissue in multiorgan involvement
• Consultation with other specialists may be appropriate, depending on presentation, given that sarcoidosis is a multisystem disease

Treatment Options

Not all patients with sarcoidosis require treatment, as many patients will have spontaneous remission within several years of disease onset and be left with no long-term sequelae ¹

• Treat symptomatic patients based on individualized, patient-centered decision making
• Treat patients who have organ dysfunction or progressive disease
• Treat patients who have critical organ involvement ¹
  • Patients with ocular, neurologic, or cardiac sarcoidosis require referral to a specialist in these organ systems (even if the diagnosis of sarcoidosis in these organs is made based on physical examination or screening test and the patient has no symptoms referable to these sites)
  • Some, but not all, patients with these organ involvements require immediate treatment
  • Ophthalmic involvement requires urgent attention and management, because irreversible vision impairment can occur

Various immunosuppressive drugs are used; the following general themes apply: ¹

• For rapid treatment of acute symptoms or organ dysfunction, critical organ involvement, or hypercalcemia/hypercalciuria, corticosteroids are indicated
• For long-term management, use steroid-sparing agents such as methotrexate, azathioprine, mycophenolate mofetil, or leflunomide. Hydroxychloroquine may be effective to manage hypercalcemia/hypercalciuria and cutaneous disease
• For disease unresponsive to steroid-sparing agents, use anti-TNF-α drugs (infliximab and adalimumab)
  • Sometimes used as a first line treatment in cases of critical organ involvement
• Consider potential complications of long-term immunosuppressive therapy when selecting treatment

Drug therapy

• Corticosteroids
  • Prednisone
    • For rapid treatment of acute symptoms, organ dysfunction, critical organ involvement (eg, eyes, heart, nervous system), or hypercalcemia
    • For pulmonary sarcoidosis of radiographic stage 2 and 3, there is evidence for radiographic improvement as well as improvement in FVC and diffusing capacity of lung for carbon monoxide ²⁰
    • Optimal dose and duration of treatment are uncertain
    • Prednisone Oral tablet; Adults: Initial dose is usually 15 to 40 mg PO daily ²¹; however, many patients improve with a dose of 20 mg/day. Titrate to response. ²⁰
    • Duration of treatment typically ranges from 3 to 8 months before tapering off ²¹
      • 30% to 80% of patients will have relapse if steroids are withdrawn after 6 to 24 months ²⁰
      • However, there is no clear benefit regarding disease progression from extending treatment beyond 24 months ²²
      • Treatment-limiting adverse effects (eg, weight gain, hypertension, glucose intolerance) may require switch to a steroid-sparing therapy
• Steroid-sparing immunosuppressive therapies
  • Second line therapies with evidence supporting their use for disease control when steroids have been ineffective, or to allow dose reductions/discontinuation of corticosteroids when there are treatment-related toxicities ²⁰
  • More data to support methotrexate than other second line therapies, but the evidence base is limited by a lack of randomized controlled trials and by variation in trial design and dosage in observational studies ²⁰
  • Choice of drug depends on patient characteristics and contraindications
  • Most of these drugs require laboratory test monitoring for adverse effects (eg, CBC, liver function tests)
  • Methotrexate
    • A randomized controlled trial found a primary outcome of significant reductions in corticosteroid requirement, but no difference in FVC ²³
    • Methotrexate Sodium Oral tablet; Adults: Doses used in clinical trials have ranged from 5 to 15 mg PO once weekly; may also be given as a weekly injection. ²⁰
    • About 20% of patients discontinue the drug owing to adverse effects (eg, gastrointestinal symptoms, infection, elevation of liver enzyme levels) ²⁰
  • Azathioprine
    • Similar response rate as with methotrexate ²⁴
      • If no response to corticosteroids, azathioprine is also likely to be ineffective, however, it is useful for allowing steroid dose reduction or discontinuation ²⁵
      • Can take 6 months to reach therapeutic effect ²⁰
    • Azathioprine Oral tablet; Adults: Clinical trials have used doses of 2 mg/kg/day orally, up to 100 to 150 mg/day ^20 24
    • Higher rate of adverse event–related discontinuation than methotrexate (primarily gastrointestinal symptoms) ²⁴
  • Additional steroid-sparing therapies include leflunomide and mycophenolate mofetil
• Anti-TNF-α drugs (TNF-α inhibitors)
  • For disease unresponsive to steroid-sparing agents, use monoclonal antibodies against tumor necrosis factor α
  • Systematic review of anti-TNF-α drugs (which included 5 small randomized controlled trials versus placebo as well as data from nonrandomized studies) suggests the following: ²⁶
    • Infliximab
      • Efficacy and safety for pulmonary, cutaneous, ocular, neurologic, and multisystem sarcoidosis
      • Infliximab (Murine) Solution for injection; Adults: Doses used in included randomized controlled trials ^27 28 were either 3 or 5 mg/kg IV at weeks 0, 2, and 6, continuing on a variable maintenance regimen thereafter. ²⁶
    • Adalimumab
      • Efficacy and safety for cutaneous and ocular sarcoidosis
      • Adalimumab Solution for injection; Adults: Dose used in the single small randomized controlled trial of adalimumab ²⁹ was 80 mg subcutaneously at week 0, then 40 mg subcutaneously weekly for 12 weeks ²⁶
    • Relapse is common after discontinuation of anti-TNF-α drugs ²⁶
• Antimalarial agents
  • Hydroxychloroquine ¹
    • Useful for management of hypercalcemia/hypercalciuria and skin involvement ²⁰
    • Requires baseline and follow-up ophthalmologic examinations to screen for retinal damage
    • Hydroxychloroquine Sulfate Oral tablet; Adults: 200 mg (155 mg base) to 400 mg (310 mg base) PO per day, given as a single dose or in 2 divided doses. ³⁰

Nondrug and supportive care

• Some experts recommend Pneumocystis jirovecii pneumonia prophylaxis if corticosteroids are required for more than 4 weeks ¹²
• Patients with cardiac sarcoidosis and arrhythmias (or a cardiac MRI suggestive of potentially arrhythmogenic scar tissue) often require an implantable cardioverter‐defibrillator ¹⁷
• Avoid precipitating hypercalcemia/hypercalciuria by recommending avoidance of the following: ¹
  • Excessive sun exposure
  • Excessive dairy intake
  • Vitamin D supplementation

Special populations

• Children
  • Disease is extremely rare in this population, although probably underreported ³¹
  • Children are more likely to present with constitutional signs (eg, fever, fatigue, weight loss) than adults with sarcoidosis
  • Respiratory symptoms are often but not always present (eg, cough, dyspnea, chest pain), and multisystem disease is possible
  • Care should be delivered by a multispecialty team at a sarcoidosis center of excellence
  • Corticosteroids are the mainstay of treatment, with immunosuppressive drugs (primarily methotrexate) used as second line therapy ³¹

Monitoring

• There are no specific monitoring recommendations for patients with sarcoidosis
• Patients receiving corticosteroids or immunosuppressive therapies require more frequent follow-up
• Asymptomatic patients or those with stable disease should receive follow-up for disease progression, development of organ dysfunction, and development of multisystem disease
• Patients with history of sarcoidosis-related uveitis should have regular ophthalmologic monitoring ³²

Complications and Prognosis

Complications

• Pulmonary
  • Progression to pulmonary fibrosis occurs in some patients
    • These patients may not respond to immunosuppressive therapy and should be referred for possible lung transplant ¹²
    • Lung transplant may also be required in some patients with minimal fibrosis; suspect in patients with dyspnea or hypoxemia disproportionate to degree of parenchymal lung involvement
  • Pulmonary hypertension
  • Aspergilloma can develop with advanced pulmonary fibrosis, especially with immunosuppressive therapy (Related: Aspergillosis)¹⁴
• Ocular
  • If uveitis becomes chronic, complications are common; they include cataract formation, cystoid macular edema, and ocular hypertension (related to both corticosteroid therapy and the underlying disease process) ³²
• Cardiac
  • Granulomas may result in life-threatening conditions, especially if scarring occurs in critical conduction pathways
    • Complete heart block
    • Ventricular tachyarrhythmias and sudden cardiac death
    • Heart failure and cardiomyopathy
• Systemic
  • Hypercalcemia occurs in about 5% to 10% of patients and hypercalciuria (more than 300 mg/day) is also common, owing to altered vitamin D metabolism ¹
  • Hypercalcemia may result in lethargy, mental status changes, or constipation
  • Urolithiasis and renal dysfunction can occur with persistent hypercalciuria (Related: Nephrolithiasis)

Prognosis

• Pulmonary sarcoidosis improves spontaneously in up to half of patients ¹²
• Patients who present with asymptomatic bilateral hilar adenopathy or Löfgren syndrome have good prognosis
• Among patients with primarily pulmonary sarcoidosis, 50% to 90% of those treated with corticosteroids have a favorable response, although relapse often occurs after discontinuation ¹²
• Prognosis of cutaneous sarcoidosis depends on extent of systemic sarcoidosis ⁵
• Acute uveitis due to sarcoidosis may be a self-limiting anterior uveitis or may become an insidious chronic intraocular inflammation. In the latter case, relapses are frequent ³²
• Sarcoidosis rarely results in death. Such deaths are primarily due to cardiac sarcoidosis or advanced pulmonary sarcoidosis ¹³
  • Cardiac sarcoidosis may result in sudden death even before a diagnosis is made clinically; this can occur when a small granuloma develops in a vulnerable area of the cardiac conduction system
  • Deaths from pulmonary sarcoidosis are due to severe pulmonary fibrosis, which develops over 5 to 25 years ^13 33

REFERENCES

1. Llanos O et al: Sarcoidosis. Med Clin North Am. 103(3):527-34, 2019 View In Article | Cross Reference