Clinical manifestations and diagnosis of sarcoidosis

INTRODUCTION — Sarcoidosis is a multisystem granulomatous disorder that affects individuals worldwide. The disease was historically thought to present mainly in young or middle-aged adults, but more recent data suggest that it may also occur in the sixth and seventh decade of life, especially in females. Accumulation of non-necrotizing granulomas and subsequently fibrosis in the lungs and other organs accounts for the clinical manifestations, which may be symptomatic or discovered incidentally when testing is ordered for other purposes. Clinical manifestations vary widely, depending on organ involvement. Some of the most common presentations include:

●Bilateral hilar adenopathy

●Pulmonary reticular and/or nodular opacities

●Skin, joint, or eye lesions

An overview of the typical clinical manifestations and diagnosis of sarcoidosis is presented here. Organ-specific clinical manifestations involving the heart, neurologic system, gastrointestinal tract, skin, bone, joint, and other extrapulmonary tissues are discussed in more detail separately.

●(See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●(See "Neurologic sarcoidosis".)

●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

●(See "Cutaneous manifestations of sarcoidosis".)

●(See "Sarcoidosis of bone".)

●(See "Sarcoid arthropathy".)

●(See "Extrapulmonary manifestations of sarcoidosis".)

The pathogenesis of sarcoidosis and treatment of pulmonary sarcoidosis are also presented elsewhere.

●(See "Pathology and pathogenesis of sarcoidosis".)

●(See "Treatment of pulmonary sarcoidosis: Initial approach".)

●(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

EPIDEMIOLOGY — Sarcoidosis risk varies by age, sex, race, and ethnic background, leading to widely varying worldwide incidence and prevalence.

Estimated sarcoidosis prevalence is 60 per 100,000 persons in the United States [1,2], but worldwide prevalence estimates range from 2.2 per 100,000 in Taiwan to 160 per 100,000 in Sweden [2,3]. Sarcoidosis incidence is likewise quite variable and difficult to determine with high confidence [1-3]. Estimates of yearly incidence range from 0.5 to 1.3 per 100,000 persons in East Asia to 11.5 per 100,000 in Scandinavian countries; incidence is approximately 7 to 11 per 100,000 in the United States and Canada [1-5].

Individual risk for sarcoidosis is strongly associated with certain demographic characteristics, including sex, race, and ethnicity [6-11]. In a large United States database study of adults over the age 18 years, females were twice as likely to have sarcoidosis than males [1]. The estimated lifetime risk of sarcoidosis among Black Americans is 2.4 percent, compared with an estimated lifetime risk of 0.85 percent among White Americans [7,8]. Black Americans also tend to develop symptoms earlier, more acutely, and more severely than White Americans, who frequently present with asymptomatic and indolent disease [9,12].

Sarcoidosis typically presents in patients 20 to 60 years of age. Although the disease was initially described in young adults, in modern practice, more than half of cases are diagnosed in patients older than age 40 years [1,13]. Female patients are more frequently older at the time of diagnosis [11,14].

Individual immunogenetic background also likely plays a role in the clinical manifestations of sarcoidosis and may account for illness heterogeneity. (See "Pathology and pathogenesis of sarcoidosis".)

ETIOLOGY — The exact etiology and pathogenesis of sarcoidosis remain unknown. There are multiple proposed triggers of the underlying granulomatous inflammation, including environmental exposures, infectious agents, and endogenous proteins. According to one hypothesis, different underlying causes of sarcoidosis may result in different patterns of illness. (See "Pathology and pathogenesis of sarcoidosis".)

TYPICAL PRESENTATIONS

Patients presenting due to abnormal chest imaging — Clinical experience suggests that nearly half of all patients with sarcoidosis present with disease incidentally detected by chest imaging performed for an unrelated indication [15]. This proportion may vary based on individual population characteristics and clinical resource utilization. (See 'Epidemiology' above.)

Patients presenting with isolated chest imaging abnormalities are more likely to have radiographic stage I or II disease with hilar adenopathy, although asymptomatic stage III disease may be present in a small minority (table 1). Pulmonary examination is usually normal. (See 'Chest radiograph' below.)

Previously unidentified systemic and extrapulmonary manifestations of disease may also be present in this group. These may include fatigue, malaise, weight loss, exertional dyspnea, skin rashes, peripheral lymphadenopathy, nephrolithiasis, uveitis, palpitations, and syncope and Bell palsy, among others. In one series, 33 of 73 patients with extrapulmonary sarcoidosis had chest imaging abnormalities alongside their earliest extrapulmonary symptoms [16]. Most of the remainder (35 of 40 patients) developed subsequent pulmonary disease [16].

Patients with pulmonary symptoms — Lung or thoracic lymph node involvement occurs in approximately 90 to 95 percent of patients with sarcoidosis [13,15,17]. For those with symptoms due to thoracic disease, common presenting complaints include cough, dyspnea, fatigue, and chest pain. The chest pain is usually constant and can be localized to substernal, subcostal, or infrascapular areas [15]. The location and severity of chest pain are not generally related to the location or extent of granulomatous lesions or lymph node enlargement.

Pulmonary symptoms are frequently accompanied by systemic manifestations such as fatigue, malaise, fever, and weight loss, particularly in the elderly [18,19]. Systemic inflammation may also contribute to muscle weakness and exercise intolerance [20-22].

Even in the presence of lung parenchymal sarcoidosis, crackles are rarely heard on chest examination [23]. Wheezing may be present when there is airway hyperreactivity, endobronchial involvement, massive mediastinal lymphadenopathy with bronchial compression, or traction bronchiectasis due to scarring. Digital clubbing is rare and typically associated with advanced pulmonary fibrosis. Additional extrapulmonary manifestations may be present at diagnosis (table 2). (See 'Common extrapulmonary findings and pathognomonic syndromes' below.)

Common extrapulmonary findings and pathognomonic syndromes — Although sarcoidosis frequently involves the lung, approximately 50 percent of patients on careful review also have extrathoracic manifestations at presentation (table 2) [13,15-17,24]. It should be noted that more sensitive testing, such as 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scan will reveal an even higher proportion with clinically silent extrapulmonary disease, but 18F-FDG-PET scanning is not recommended for routine evaluation of patients with sarcoidosis [25]. Some patients may also present with only extrathoracic findings; except for cutaneous disease, this group is significantly less likely to be successfully diagnosed early in their course [16]. The most frequent early extrapulmonary manifestations include skin lesions (eg, erythema nodosum, facial rashes including lupus pernio and papular sarcoidosis, nodular sarcoidosis lesions, and sarcoidosis hypopigmentation), peripheral lymph node enlargement, and visual changes (especially uveitis and dry eyes) [17]. Hypercalciuria and mild hypercalcemia are common and can manifest as nephrolithiasis or azotemia. In addition, sarcoidosis is a relatively common cause of parotid or salivary gland swelling and facial nerve palsies. Sarcoidosis should also be considered in the differential diagnosis of patients with cardiac syncope, unexplained heart failure, and conduction delays. Other extrapulmonary symptoms such as neuropathies, myopathy, polyuria, arthritis, and cytopenia are rarely suggestive of the diagnosis unless other features are also present.

Some extrapulmonary manifestations are less common but highly specific for sarcoidosis. These pathognomonic presentations include:

●Löfgren syndrome – Approximately 5 to 10 percent of patients with sarcoidosis present with Löfgren syndrome, which is defined by acute-onset fever, hilar adenopathy, and variable proportions of erythema nodosum or bilateral ankle inflammation.

Löfgren syndrome is more common in the third and fourth decades of life and is seen more frequently in females than in males [15]. Among those presenting with Löfgren syndrome, erythema nodosum is a more common manifestation in female patients, and ankle arthropathy is more common in male patients [26]. The arthropathy is most frequently due to periarticular inflammation involving soft tissue and tenosynovitis rather than true arthritis and can also involve knees, wrists, and elbow joints. Of note, erythema nodosum lesions should not be biopsied because the histopathology will demonstrate panniculitis and not granulomas regardless of the underlying etiology [27]. Löfgren syndrome and erythema nodosum are discussed in greater detail separately. (See "Erythema nodosum" and "Sarcoid arthropathy", section on 'Acute arthritis and Lofgren syndrome'.)

The presence of Löfgren syndrome has a high diagnostic specificity for sarcoidosis [28,29]. The other clinical entities that may result in Löfgren syndrome include acute tuberculosis and acute presentations of endemic fungal infections including histoplasmosis, blastomycosis, and coccidioidosis [30,31]. (See 'Testing for tuberculosis and other infections' below.)

●Uveoparotid fever – This combination of anterior uveitis, bilateral parotid gland enlargement, facial nerve palsy, and fever (also known as Heerfordt syndrome) is an uncommon acute presentation of sarcoidosis [32]. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Ocular'.)

●Lupus pernio – Lupus pernio is characterized by violaceous or erythematous indurated, infiltrative plaques distributed on the central face, particularly the nose and cheeks (picture 1 and picture 2). It is more common in Black and female patients. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)

Greater detail regarding extrapulmonary manifestations of sarcoidosis may be found elsewhere:

●(See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●(See "Neurologic sarcoidosis".)

●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

●(See "Cutaneous manifestations of sarcoidosis".)

●(See "Sarcoidosis of bone".)

●(See "Sarcoid arthropathy".)

●(See "Extrapulmonary manifestations of sarcoidosis".)

Presentation in children — Symptomatic sarcoidosis is rare in children. In general, children between the ages of 8 and 15 years develop multisystem disease like that described in adults [33]. Younger children often present with skin rash, arthritis, and uveitis without apparent lung involvement [34].

In a series of Danish children with sarcoidosis, the most common presenting manifestations were erythema nodosum and iridocyclitis [35]. Ninety percent of the children had an abnormal chest radiograph.

ATYPICAL MANIFESTATIONS OF PULMONARY DISEASE — Although sarcoidosis most often results in bronchovascular inflammatory and fibrotic changes, nodular sarcoidosis, necrotizing granulomatosis, or pleural effusions may also be seen.

●Nodular sarcoidosis and necrotizing sarcoid granulomatosis – Nodular sarcoidosis presents with multiple, usually peripheral, pulmonary masses that are almost always accompanied by mediastinal lymphadenopathy. Patients may be asymptomatic or may have mild cough and dyspnea. Case series suggest that this subtype may be seen in 2 to 4 percent of patients with sarcoidosis and is most likely to occur in Black females between 20 and 40 years of age [36,37]. Very rarely, sarcoidosis is diagnosed as part of the work-up for solitary pulmonary nodules.

Necrotizing sarcoid granulomatosis is a rare variant that may overlap radiographically with nodular sarcoidosis. It exhibits the same symptoms as other sarcoidosis manifestations. Radiographically, it appears as one or more areas of consolidation, usually extending to the pleural surface. Histology demonstrates areas of bland necrosis, but there are always nearby well-formed granulomas in a pattern typical of sarcoidosis granulomas. Despite the histologic appearance, the prognosis and indications for treatment are no different than for other forms of pulmonary sarcoidosis.

●Pleural effusions – Pleural effusions are rare in patients with sarcoidosis (less than 3 percent of patients) and often arise from unrelated conditions [38]. Pleural effusions caused by sarcoidosis are typically lymphocytic predominant and exudative without elevated lactate dehydrogenase concentrations. Rarely, chylothorax may be seen due to granulomatous inflammation preventing lymphatic drainage of the thoracic duct [39,40].

INITIAL EVALUATION

History and physical examination — The initial evaluation of a patient with suspected sarcoidosis focuses on assessment of pulmonary and common extrapulmonary symptoms as well as a thorough occupational, travel, and infection history to identify potential alternative etiologies [23].

When patients are symptomatic, the most common presenting symptoms include cough, dyspnea, and chest pain; these are frequently accompanied by fatigue, malaise, fever, and weight loss. These manifestations may arise acutely (typically with inflammatory symptoms) or more insidiously. Patients with sarcoidosis may also present with new skin lesions (particularly around tattoos or scars), visual changes, dry eyes or mouth, parotid swelling, palpitations, syncope, and joint pain or swelling. (See 'Typical presentations' above.)

All patients with suspected pulmonary sarcoidosis require an occupational and environmental history to assess for alternative etiologies of diffuse micronodular lung disease and hilar lymphadenopathy. A thorough history should address possible silicosis (sand-blasting, quarry work, other mining), chronic beryllium disease (CBD; metal and metal-alloy machine shops, electronics, defense industry work, and beryllium extraction), hypersensitivity pneumonitis (farming, bird and poultry handling, grain processing, milling, construction, organic chemical exposures) (table 3), and environmental exposure to mycobacteria and fungi (indoor hot tub use, exposure to persons with tuberculosis, spelunking, and travel or habitation in areas with endemic histoplasmosis, blastomycosis, or coccidiomycosis). (See "Silicosis" and "Chronic beryllium disease (berylliosis)" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on 'Etiologic agents' and "Clinical manifestations and diagnosis of blastomycosis" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Primary pulmonary coccidioidal infection".)

Sarcoidosis-like reactions may occur as a complication of certain medications, neoplasms or in the setting of immunodeficiency syndromes. We review ongoing and recent medications with careful attention to immunosuppressant, antitumor necrosis factor, antiretroviral, and chemotherapeutic agents. Assessing the status of known malignancies and of age-appropriate cancer screening is also warranted (see 'Differential diagnosis' below). When immunodeficiency syndromes (eg, common variable immune deficiency) lead to pulmonary presentations similar to sarcoidosis, there is usually splenomegaly and either a history of recurrent infections or of autoimmune diseases. (See "Pulmonary complications of primary immunodeficiencies".)

Any evidence of a new cardiac abnormality (eg, a history of palpitations, presyncope or syncope, unexplained heart failure, or conduction delays) in patients with suspected sarcoidosis requires immediate attention. (See 'Electrocardiogram' below and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Key manifestations'.)

Chest examination of patients presenting with pulmonary sarcoidosis is rarely revealing [23]. Wheezing may be heard with more severe airway disease or extrinsic airway narrowing from lymphadenopathy. Crackles are very unusual, and their presence should prompt reconsideration of the diagnosis, although they can be occasionally present in advanced disease. Other findings of advanced lung disease (hypoxemia, clubbing) are rare.

Additional examination should be performed routinely to assess for extrathoracic disease. A thorough skin exam may reveal characteristic findings (eg, erythema nodosum, lupus pernio). Assessment of lymphadenopathy may identify more accessible tissue for biopsy. Neurologic examination for cranial and peripheral nerve sensory and motor neuropathies can be informative. Targeted musculoskeletal evaluation is appropriate based on symptoms. Additional physical examination findings of extrapulmonary sarcoidosis are discussed separately. (See "Extrapulmonary manifestations of sarcoidosis" and "Cutaneous manifestations of sarcoidosis" and "Sarcoid arthropathy" and "Neurologic sarcoidosis".)

Chest imaging — Thoracic imaging is essential in the diagnosis of sarcoidosis because intrathoracic lymph node and/or lung involvement occurs in over 90 percent of patients [17,41]. In patients with suspected sarcoidosis who have not already received chest imaging, we prioritize imaging before conducting additional noninvasive work-up. Diagnostic imaging begins with a chest radiograph, followed by high-resolution computed tomography (HRCT). Other imaging tests, such as 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET), magnetic resonance imaging (MRI), gallium-67, thallium-201, and technetium sestamibi (MIBI-Tc) single-photon emission computed tomography (SPECT), may be used for specific indications, as described below.

Chest radiograph — All patients undergoing evaluation for possible sarcoidosis should receive a chest radiograph. Most patients present with bilateral hilar adenopathy, with or without additional pulmonary involvement.

The hila are symmetrically enlarged in approximately 50 percent of cases, with the right side slightly more prominent in most of the remainder [42]. Unilateral adenopathy is uncommon (<5 percent of cases). Lung parenchymal findings are more varied and include nodular, reticular, or ground-glass opacities, consolidations, and cystic changes. When localized, these abnormalities typically involve the mid or upper lung zones.

Chest radiographic findings have been organized into patterns (Scadding patterns) (table 1). Although these "stages" give an anatomic guide to lung involvement and imaging pattern, they do not reflect disease activity or functional deficits. They are not applicable to interpretation of chest computed tomography (CT). Patients do not necessarily progress to higher radiographic stages in the course of the disease, and radiographic resolution may occur at any stage except for stage IV. The radiographic stages are as follows:

●Stage I – Stage I is defined by the presence of bilateral hilar adenopathy, which is often accompanied by right paratracheal node enlargement (image 1). Fifty percent of affected patients exhibit bilateral hilar adenopathy as the first expression of sarcoidosis. Regression of hilar nodes within one to three years occurs in 75 percent of such patients, while 10 percent develop chronic enlargement that can persist for 10 years or more.

●Stage II – Stage II disease consists of bilateral hilar adenopathy and parenchymal involvement, most commonly reticular and nodular opacities. These findings are present at initial diagnosis in 25 percent of patients (image 2). Two-thirds of such patients undergo spontaneous resolution, while the remainder either have progressive disease or display little change over time. Patients with stage II disease usually have mild to moderate symptoms, most commonly cough, exertional dyspnea, and/or easy fatigue.

●Stage III – Stage III consists of parenchymal involvement without lymphadenopathy (image 3).

●Stage IV – Stage IV disease is characterized by fibrosis, manifested as reticular opacities with or without associated cystic changes, typically involving mainly the upper lung zones (image 4). Conglomerated masses with marked traction bronchiectasis may also be seen. Extensive calcifications, cavitation, or cyst formation may occur in this disease stage [43]. Inter-reader agreement for the diagnosis of stage IV disease is poor [44].

Calcification of hilar or mediastinal lymph nodes becomes more common with longer disease duration; the pattern is nonspecific [42].

Less commonly, the chest radiograph may show multiple, bilateral lung nodules or consolidative mass-like opacities (nodular sarcoidosis), findings that may mimic metastatic disease. Pleural involvement is unusual (<5 percent of patients), but can result in lymphocytic exudative effusion, chylothorax, hemothorax, and pneumothorax [38,45,46]. (See 'Atypical manifestations of pulmonary disease' above and "Pleural fluid analysis in adults with a pleural effusion".)

HRCT scan — HRCT of the chest is typically obtained to evaluate abnormalities seen on a chest radiograph or to evaluate unexplained dyspnea or cough in a patient with a clear chest radiograph. HRCT can detect parenchymal and mediastinal abnormalities that are not well delineated on the chest radiograph [36,43,47,48], including:

●Subtle hilar and mediastinal lymphadenopathy

●Beaded (nodular or micronodular) or irregular thickening of the bronchovascular bundles

●Nodules along bronchi, vessels, and subpleural areas

●Bronchial wall thickening

●Ground-glass opacifications

●Parenchymal masses or nodular consolidation, occasionally with cavitation

●Parenchymal bands

●Cysts

●Fibrotic changes

●Traction bronchiectasis

●Mycetoma

The characteristic HRCT feature of sarcoidosis is the presence of small nodules (2 to 5 mm) in a perilymphatic distribution. This distribution includes the peribronchovascular interstitium, the costal pleura and interlobar fissures, and, to a lesser extent, interlobular septa and centrilobular regions (image 5 and image 6) [49-51]. Micronodules surrounding a large nodule or conglomerate mass, also called the "galaxy sign," are a pattern highly suggestive of sarcoidosis (image 7) [52,53].

Other common parenchymal findings include large nodules and masses, patchy bilateral consolidation, and ground-glass opacities typically with a mid to upper zone predominance (image 8 and image 9) [51] One small histologic case series found that ground-glass abnormalities in patients with sarcoidosis were frequently conglomerated tiny sarcoid granulomas rather than alveolitis [54]. Although lymphocytic alveolitis may occur, it is rare [55]. (See "High resolution computed tomography of the lungs".)

Hilar lymph node involvement tends to be bilateral and symmetric. The finding of faint "icing" or "frosting" calcifications in lymph nodes is highly suggestive of the diagnosis (image 10). In areas with endemic fungal infections, the presence of calcifications in lymph nodes without a calcified nodule in the lung parenchyma and/or calcifications in the spleen or liver is highly suggestive of sarcoidosis rather than resolved fungal infection.

Fibrotic changes manifest as irregular linear opacities and traction bronchiectasis typically involving mainly the peribronchovascular regions of the upper lobes and resulting in cephalad displacement of the hila (image 11). Fibrosis may also result in conglomerate masses, paracicatricial emphysema, subpleural honeycombing, large cystic spaces (due to traction bronchiectasis or formation of bullae), and development of intracavitary mycetomas (image 12) [51].

Uncommon imaging manifestations of sarcoidosis include incidentally found ring-like dense airspace consolidations surrounding normal lung (described as "fairy-ring," "reverse-halo," or "atoll" signs), as well as pleural thickening or pneumothorax [15].

Less commonly needed imaging — 18F-FDG-PET imaging and MRI imaging can be helpful in select patients. Other radiotracers have been used historically, and several new radiotracers are under active investigation.

●18F-FDG-PET – 18F-FDG-PET is sometimes helpful to identify occult lesions that are more accessible to biopsy than intrathoracic lesions; dedicated cardiac positron emission tomography (PET) scanning is also used in the evaluation of cardiac sarcoidosis [56-59]. This test does not differentiate sarcoidosis from malignancy or infection, as 18F-FDG-PET may be positive in any of these processes (image 13). (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'FDG-PET'.)

●MRI – The main role for MRI scanning is in the evaluation of extrapulmonary sarcoid, such as cardiac sarcoidosis and neurosarcoidosis, as discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Cardiovascular magnetic resonance' and "Neurologic sarcoidosis", section on 'Neurodiagnostic testing'.)

●Other radiotracers – In the future, the use of other tracers may improve the utility of PET imaging for diagnosing sarcoid.

•In a small study (24 patients with sarcoidosis, 17 with lung cancer), the combination of 18F-FDG and fluorine-18-methyltyrosine (18F-FMT) PET scanning was able to differentiate sarcoidosis from malignancy; sarcoidosis lesions were positive only on 18F-FDG PET, but cancers had uptake of both radiotracers [60].

•Somatostatin receptor scintigraphy (SRS) is being explored as a method to improve localization of disease in sarcoidosis based on the observation that somatostatin receptor subtype 2 is highly expressed in sarcoid granulomas [61]. Somatostatin analogs, such as ⁶⁸Gallium-DOTA-tyrosine-octreotide and ¹¹¹Indium octreotide PET/CT scanning, may be particularly useful for imaging cardiac sarcoidosis [62-64].

Due to its greater sensitivity, 18F-FDG-PET has largely replaced older radiotracer-based imaging methods, such as ⁶⁷Gallium scintigraphy and ²⁰¹Thallium or ⁹⁹Technitium SPECT.

Laboratory testing — Laboratory testing is neither sufficiently sensitive nor specific to secure a diagnosis. As an initial approach, we test for other granulomatous disorders in select situations and look for evidence of clinically silent extrapulmonary sarcoidosis.

Testing for tuberculosis and other infections — Some patients with suspected sarcoidosis should be tested for mycobacterial and relevant endemic fungal diseases. The type of testing and interpretation of testing depends on the specific presentation and on the local prevalence of infections.

In areas with endemic tuberculosis, unless a patient has a well-documented positive tuberculin skin test, tuberculin skin testing or an interferon-gamma release assay is necessary to help exclude Mycobacterium tuberculosis infection. Diminished skin test reactivity is expected in sarcoidosis, so a positive test is strong evidence of latent or active disease. (See "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Endemic fungal infections may mimic the clinical presentation of sarcoidosis. For those with chronic symptoms who live in (or have previously lived in) endemic areas, it is reasonable to perform antibody testing for histoplasmosis. For patients with travel to the southwestern United States and more acute or subacute presentations (over weeks), serologic testing for coccidiomycosis is also appropriate.

For similar reasons, patients who are producing sputum should have their sputum tested for Mycobacterium tuberculosis, atypical mycobacterial, and fungal infections both by smear and culture. Inducing sputum for testing is reasonable when moderate or high clinical suspicion exists for active mycobacterial or fungal infection.

Assessing immunodeficiency and autoimmunity — We suggest routine testing for human immunodeficiency virus (HIV) and evaluation for primary immunodeficiencies in patients with a suggestive history of recurrent infections or risk factors for HIV.

HIV itself can lead to mediastinal lymphadenopathy and increases the risk for mycobacterial and fungal infections. In addition, patients with sarcoidosis and HIV require close monitoring because immunosuppression can impact HIV control, and active HIV treatment can lead to worsening of sarcoidosis. (See "Immune reconstitution inflammatory syndrome", section on 'Miscellaneous syndromes possibly associated with IRIS'.)

Some antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis) can demonstrate lung parenchymal abnormalities and granulomatous inflammation difficult to distinguish from sarcoidosis on biopsy [65]. Because significant false-positives may occur, we reserve ANCA testing for patients with increased clinical suspicion for ANCA-positive vasculitis based on other symptoms and clinical features. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Evaluation' and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Evaluation'.)

Although rare, primary immunodeficiencies may present with clinical features that mimic sarcoidosis. Patients with sarcoidosis-like symptoms and imaging as well as a strong history of recurrent infections should be further evaluated for these disorders. (See "Pulmonary complications of primary immunodeficiencies".)

Testing for occult extrapulmonary disease — Our typical testing includes a complete blood count and differential, liver function tests, blood urea nitrogen, creatinine, glucose, electrolytes, serum calcium, electrocardiogram (ECG), and ophthalmologic examination [25,66].

Although uncommon, sarcoidosis may result in anemia due to chronic inflammation (ie, anemia of chronic disease), hypersplenism, bone marrow involvement, or autoimmune hemolysis [56,67,68]. Leukopenia (5 to 10 percent) [68], eosinophilia (3 percent) [69], and thrombocytopenia (rare) can be seen [42]. Peripheral lymphopenia is common, observed in up to 50 percent; some reports suggest it may be associated with a worse prognosis [70,71].

Chronic granulomatous inflammation may lead to hypercalcemia, although hypercalciuria is more common. A substantial elevation in the serum alkaline phosphatase concentration suggests granulomatous hepatic involvement. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)

Proposed activity tests, including angiotensin converting enzyme (ACE) level — Although multiple serum markers of sarcoidosis have been studied, none are very helpful clinically [72]. We do not recommend routinely obtaining ACE levels as a diagnostic tool.

●Serum angiotensin converting enzyme – Although the ACE level is elevated in 75 percent of untreated patients with sarcoidosis, serum ACE has limited utility as a diagnostic test due to poor sensitivity and insufficient specificity (almost a 10 percent rate of false-positive results) [41,73-75]. Multiple other disease processes are associated with elevated serum ACE levels (table 4). When ACE level is more than twice the upper limit of normal, the specificity increases to more than 90 percent [76].

●Other serum markers – Nonspecific inflammatory markers (eg, erythrocyte sedimentation rate and C-reactive protein) are occasionally elevated, but nonspecific. Adenosine deaminase, serum amyloid A levels, and soluble interleukin (IL)-2 levels are also elevated in the serum of patients with sarcoidosis but have not been shown to be clinically useful for diagnosis [77,78]. Chitotriosidases (chitinase family) are produced by activated macrophages and correlate with sarcoidosis disease activity [72,79,80]; however, chitotriosidase testing is not widely available.

●Intradermal (Kveim) testing – The Kveim test uses a suspension of heat-sterilized splenic or lymph node homogenate cells from patients with sarcoidosis (the Kveim-Siltzbach reagent) in an intradermal skin test (similar to a tuberculin skin test) to evoke a sarcoid granulomatous response over approximately three weeks [81]. The Kveim test is primarily a historic research tool due to limited availability of the reagent and concerns about disease transmission with testing.

Electrocardiogram — All patients with suspected sarcoidosis should receive an ECG to evaluate for evidence of cardiac involvement. Cardiac sarcoidosis and its complications account for a significant proportion of sarcoidosis overall mortality. Atrioventricular block is the most common ECG manifestation of cardiac sarcoidosis, followed by frequent ventricular premature beats, supraventricular tachycardias (atrial fibrillation, atrial flutter, and atrial tachycardia), and sinus arrest. Any of these abnormalities on ECG in a patient with suspected sarcoidosis merit prompt further evaluation. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Key manifestations'.)

INVASIVE DIAGNOSTIC TESTING

Diagnostic approach — A definitive diagnostic test for sarcoidosis does not exist. Instead, the diagnosis of sarcoidosis generally requires three elements:

●Compatible clinical and radiographic manifestations

●Exclusion of other diseases that may present similarly

●In many cases, histopathologic detection of non-necrotizing granulomas (picture 3A-B)

Although confirmation of sarcoidosis usually requires diagnostic tissue sampling, invasive testing may be deferred in patients with clinical presentations that overwhelmingly favor the diagnosis (table 5). A sarcoidosis diagnosis score has been developed that can aid in determining whether multiple manifestations in different systems carry sufficient specificity to preclude further work-up [65]. (See 'Multiple suggestive manifestations' below.)

When selecting a site for biopsy, we prefer to use the least invasive methods that are likely to achieve a diagnostic sample. Skin lesions and subcutaneous nodules or glandular tissue offer excellent biopsy sites for those with extrathoracic manifestations. Patients with only intrathoracic disease should generally undergo biopsy using an endoscopic approach, with surgical biopsy reserved for those with nondiagnostic endoscopic sampling.

Conditions in which invasive testing can be avoided — We do not perform invasive testing for pathognomonic presentations of sarcoidosis, for certain patients with asymptomatic hilar lymphadenopathy at low risk for alternative etiologies, and for patients with high clinical diagnostic certainty based on manifestations across several organ systems.

Pathognomonic presentations — Patients with certain pathognomonic syndromes highly suggestive of sarcoidosis can often defer biopsy after completion of the noninvasive work-up. (See 'Common extrapulmonary findings and pathognomonic syndromes' above.)

After negative testing for relevant mimickers, including infection, patients with Löfgren syndrome do not need additional diagnostic evaluation. In patients with uveoparotid fever, parotid gland or nasolacrimal tissue containing noncaseating granulomas are frequently obtained during work-up and treatment. However, the stereotypical presentation does not require additional testing. In the case of lupus pernio, a skin biopsy revealing noncaseating granulomas may be performed, but these lesions can be distinctive enough that biopsy may be deferred in the setting of other strong evidence for sarcoidosis (eg, bilateral hilar lymphadenopathy) (table 5).

Asymptomatic bilateral hilar lymphadenopathy — Patients with sarcoidosis who present with asymptomatic bilateral hilar lymph node involvement (radiographic stage I) (table 1) generally have self-limited disease that can be monitored to ensure stability or resolution [23,25]. These patients do not typically require a biopsy in the absence of likely alternative explanations, but we recommend engaging in shared decision making with each patient. The diagnostic guidelines from the American Thoracic Society describe clinical equipoise between biopsy and close observation [25].

Despite the favorable prognosis, the finding of enlarged hilar and mediastinal lymph nodes during radiographic testing is often alarming to health care providers and patients alike, primarily out of concern for occult malignancy or latent infection. In one systematic review of 16 studies and 556 patients with suspected asymptomatic stage I sarcoidosis who received invasive testing, biopsy confirmed sarcoidosis in 85 percent, was nondiagnostic in 11 percent, and led to an alternative diagnosis in 1.9 percent [25]. Among the alternative diagnoses, tuberculosis and lymphoma were most common, present in 38 and 25 percent of patients, respectively.

Factors we consider when discussing biopsy with this patient group include:

●The presence of symptoms, cytopenias, or abnormal physical examination findings that indicate a higher chance of alternative diagnoses [82]

●Regional prevalence of potential infectious etiologies (particularly tuberculosis and endemic fungal infections)

●Stability versus worsening of the lymphadenopathy (if known)

●Patient-specific risks for infection and malignancy

●Patient comorbidities that may increase procedural risk

●Likelihood of obtaining close follow-up

●Patient preference

Spontaneous remission of bilateral hilar adenopathy occurs within two years in most of these patients. Appropriate monitoring is discussed elsewhere. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Approach to asymptomatic patients'.)

Multiple suggestive manifestations — In patients with suggestive clinical signs, symptoms, and imaging across multiple organ systems, a high clinical sarcoidosis diagnosis score (≥10) may be considered sufficiently diagnostic to preclude biopsy.

Based on several observational cohort studies over the past three decades, a sarcoidosis organ assessment tool and a clinical diagnosis tool have been developed to help determine the likelihood of sarcoidosis utilizing noninvasive measures only [12,65,83]. In a worldwide validation cohort of approximately 1000 patients with sarcoidosis and 1000 referred patients diagnosed with other diseases, a sarcoidosis diagnosis score ≥10 was seen in approximately 10 percent of patients and demonstrated a specificity of more than 99 percent [65]. In this group, a high diagnosis score only failed to distinguish between sarcoidosis and other systemic noninfectious granulomatous diseases (antineutrophil cytoplasmic antibody [ANCA]-vasculitides, chronic beryllium disease [CBD], and granulomatous complications of common variable immunodeficiency). Importantly, biopsy may also not always be able to distinguish between sarcoidosis and CBD.

Patients with accessible extrathoracic disease — Biopsies should be performed on the most accessible lesion, which may include cutaneous lesions (other than erythema nodosum), subcutaneous nodules, palpable lymph nodes, enlarged parotid glands, conjunctival lesions, enlarged lacrimal glands, or certain other ocular lesions [23]. 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) may be helpful in identifying potential extrathoracic lesions (eg, subcutaneous nodules or mildly enlarged lymph nodes) likely to be involved. Serologic testing, antigen testing, and histopathologic assessment for tuberculosis and relevant endemic fungi should always be performed on biopsy samples.

When combined with clinical evidence suspicious for sarcoidosis elsewhere (table 5), an extrathoracic biopsy demonstrating non-necrotizing granulomas with negative infectious staining allows for a confident diagnosis of sarcoidosis. In contrast, isolated granulomatous lesions in only one tissue may arise from other, localized granulomatous diseases, which vary by tissue type affected.

Some patients with non-necrotizing granulomas documented at extrapulmonary sites may still require bronchoscopic evaluation or intrathoracic biopsies for atypical thoracic findings. For example, patients with cavitary lung disease may require bronchoscopy to exclude mycobacterial and fungal infection prior to initiation of immunosuppressive therapy. Similarly, patients with unilateral mediastinal adenopathy may require sampling of their mediastinal nodes to rule out infections and malignancies.

Biopsies of other internal organs such as the heart, kidney, liver, neurologic system, or spleen are generally less safe or have a lower diagnostic yield than intrathoracic biopsy, so they are rarely performed to establish the diagnosis of sarcoidosis.

Patients without accessible extrathoracic disease — If the patient does not have extrathoracic involvement in accessible tissues or if a biopsy would be less preferable than a bronchoscopy, the next choice is usually a biopsy or transbronchial needle aspiration (TBNA) of radiographically enlarged intrathoracic lymph nodes or lung parenchyma. An endobronchial procedure is usually the most appropriate first step for patients with high suspicion for sarcoidosis.

For patients with enlarged intrathoracic lymph nodes and high suspicion for sarcoidosis, endobronchial ultrasound-guided TBNA has an excellent yield and is less invasive than mediastinoscopy [25]. Bronchoalveolar lavage (BAL) should be performed concomitantly to assess for infectious etiologies and for differential cell count.

For patients with parenchymal lung disease but no apparent mediastinal adenopathy or extrapulmonary disease (after a careful search), the decision between a transbronchial lung biopsy and a thoracoscopic biopsy depends on the degree of suspicion for sarcoidosis. Because transbronchial lung biopsy has a high yield in sarcoidosis, it is an appropriate choice for a patient in whom sarcoidosis is strongly suspected (eg, a young patient with high-resolution computed tomography [HRCT] showing beading of the bronchovascular bundles). In contrast, a thoracoscopic biopsy is preferred for patients with a lower likelihood of sarcoidosis and a greater likelihood of an alternative diagnosis that would require a larger specimen (eg, an idiopathic interstitial pneumonia). (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Endobronchial approach (preferred) — Endobronchial diagnostic approaches include endoscopic ultrasound-guided fine-needle aspiration or cryobiopsy of mediastinal lymph nodes and endobronchial biopsy or transbronchial biopsy of the lung. These procedures should be accompanied by bronchoscopy with BAL to rule out infectious and eosinophilic processes and to provide additional support for the diagnosis of sarcoidosis.

Bronchoscopy with BAL — The main purpose of BAL in this setting is to exclude alternative diagnoses, such as CBD, eosinophilic lung disease, infections (eg, actinomycosis, mycobacterial, fungal), and malignancy. BAL lymphocytosis greater than 15 percent, especially when accompanied by an elevated CD4:CD8 ratio >3.5, confers 93 to 96 percent specificity for the diagnosis of sarcoidosis [84]. In patients with any history of possible beryllium exposure, a beryllium-specific lymphocyte proliferation test should be performed using the BAL cells. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL' and "Chronic beryllium disease (berylliosis)", section on 'Bronchoalveolar lavage'.)

Several studies examining the patterns of lymphocyte subsets in sarcoidosis have reported a reduced number of CD8 cells, an elevated CD4:CD8 ratio, and increased proportions of activated T cells, CD4 cells, immunoglobulins (Ig), and IgG-secreting cells [81,82,85-91]. While the American Thoracic Society guidelines advise against routine assessment of lymphocyte subsets, for patients with suspected sarcoidosis and BAL lymphocytosis ≥16 percent, a CD4:CD8 ratio greater than 3.5:1 provides support for sarcoidosis. As an example, one study evaluated 128 untreated patients with BAL lymphocytosis ≥16 percent due to a variety of causes [82]. Although there were limitations to this study, several results were of particular interest:

●The triad of a CD4:CD8 ratio >4:1, a lymphocyte percentage ≥16 percent, and a transbronchial biopsy demonstrating noncaseating granulomas was the most specific test for sarcoidosis. This combination of findings was associated with a 100 percent positive predictive value (PPV) for distinguishing sarcoidosis from other interstitial lung diseases and an 81 percent PPV for distinguishing sarcoidosis from all other diseases.

●A CD4:CD8 ratio less than one had a 100 percent negative predictive value for sarcoidosis. However, this finding should be interpreted with caution, as other series have found low CD4:CD8 ratios in a small percentage of patients [92].

Endoscopic ultrasound-guided needle aspiration or cryobiopsy — Endoscopic ultrasound-guided needle aspiration of intrathoracic lymph nodes via esophageal endoscopic ultrasound (EUS) or endobronchial ultrasound (EBUS) has a diagnostic yield of approximately 80 to 90 percent in patients with mediastinal adenopathy and a clinical suspicion of sarcoidosis [25,93]. The addition of ultrasound-guided cryobiopsy of lymph nodes following needle aspiration may further increase the diagnostic yield for granulomatous diseases, including sarcoidosis [94]. The choice of procedure depends on the available expertise and equipment and the location of enlarged thoracic lymph nodes. These techniques and their diagnostic yield in sarcoidosis are discussed in greater detail separately. (See "Endoscopic ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications, and complications" and "Endobronchial ultrasound: Technical aspects" and "Endobronchial ultrasound: Indications, contraindications, and complications", section on 'Mediastinal lymphadenopathy of unclear etiology'.)

Endobronchial and transbronchial biopsy — Endobronchial and transbronchial biopsy are most frequently performed in patients with parenchymal disease without mediastinal lymphadenopathy (radiographic stage III sarcoidosis) (table 1).They can also be used in addition to endoscopic ultrasound-guided lymph node sampling in patients with lymphadenopathy to improve diagnostic yield. For example, these techniques are commonly used in settings where rapid-onsite cytology examination is available and is negative for a specific diagnosis after EBUS-TBNA. Newer endoscopic techniques may allow better targeting of involved lung and improve diagnostic yield. The specimens obtained should be used for both culture and histologic stains, including stains for acid-fast bacilli and fungi [95].

●Traditional transbronchial lung biopsy – Transbronchial lung biopsy has a relatively high yield (50 to 75 percent) among patients suspected of having sarcoidosis on the basis of bilateral hilar adenopathy or compatible lung parenchymal findings on HRCT (eg, beaded or irregular thickening along bronchovascular bundles) (image 5) [96,97]. Six to eight adequate specimens are generally obtained to maximize the yield. (See 'HRCT scan' above and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy'.)

●Endobronchial biopsy – For all patients undergoing flexible bronchoscopy, an airway survey should be performed looking for endobronchial lesions, such as erythema or a nodular, granular, or cobblestone appearance (picture 4) [98,99]. Endobronchial disease occurs in approximately 40 percent of patients with radiographic stage I disease and approximately 70 percent of patients with stages II or III disease (table 1) [98]. Most interventionalists obtain four to six endobronchial biopsies, ideally from a site where the mucosa appears erythematous or, alternatively, from the first and secondary carinas [100]. Endobronchial mucosal biopsies are frequently positive in sarcoidosis and may increase the diagnostic yield compared with transbronchial biopsies alone [101]. For example, in one series of 34 patients with sarcoidosis, endobronchial biopsies had a diagnostic yield of 62 percent and increased the yield over transbronchial biopsy alone by 20 percent [102]. However, the reported yield for endobronchial biopsy is highly variable, with other studies indicating a yield as low as 24 percent [103].

●Transbronchial needle aspiration – In addition to its use in obtaining cellular or core biopsy tissue from mediastinal nodes (see 'Endoscopic ultrasound-guided needle aspiration or cryobiopsy' above), TBNA can also be used for sampling of pulmonary nodules. The technique of TBNA and its role in the diagnosis of sarcoidosis are described separately. (See "Bronchoscopy: Transbronchial needle aspiration", section on 'Technical considerations' and "Bronchoscopy: Transbronchial needle aspiration", section on 'Sarcoidosis'.)

●Transbronchial cryobiopsy – Transbronchial cryobiopsy (TBCB), which requires specialized equipment and specific training, may be a useful alternative to avoid thoracoscopy in a minority of suspected sarcoidosis cases where an initial bronchoscopic procedure is inconclusive and no other accessible biopsy sites can be identified [104,105]. TBCB had a diagnostic yield of 93 percent in one series of 32 patients with suspected sarcoidosis [106]; five patients sustained a pneumothorax, and one patient had moderate bleeding. The technique, complications, and diagnostic yield are described separately. In general, sarcoidosis is typically easily diagnosed with less risky conventional bronchoscopic techniques, and we therefore do not recommend routine use of TBCB to diagnose sarcoidosis. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)

Surgical biopsy of mediastinum and lung — Mediastinal lymph node biopsy via mediastinoscopy or lung biopsy via thoracoscopy or thoracotomy can establish the diagnosis of sarcoidosis when less invasive tests are inconclusive. EBUS-TBNA is preferred when the clinical scenario suggests sarcoidosis is the leading diagnostic consideration [25]. (See "Surgical evaluation of mediastinal lymphadenopathy" and "Overview of minimally invasive thoracic surgery".)

Lymph node biopsy via cervical mediastinoscopy is positive in over 90 percent of patients with bilateral hilar adenopathy and a clear chest radiograph [107]. In a series of 229 patients who underwent mediastinoscopy for the evaluation of non-lung cancer lymphadenopathy, 100 (44 percent) had sarcoidosis, while alternative diagnoses were identified in the remaining patients [108]. All biopsy specimens should undergo histopathologic analysis as well as special staining and cultures for mycobacteria and fungi.

Sometimes, a mediastinal lymph node biopsy can be examined by frozen section while the patient remains under anesthesia. The patient can be spared additional procedures if the frozen tissue reveals a clear diagnosis (eg, noncaseating granulomas); otherwise, a lung biopsy may be obtained by thoracoscopy or thoracotomy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

HISTOPATHOLOGY — The characteristic morphologic feature of sarcoidosis is the non-necrotizing granuloma. The sarcoidosis granuloma is a focal, chronic inflammatory reaction formed by the accumulation of epithelial cells, monocytes, lymphocytes, macrophages, and fibroblasts [109]. Multinucleated giant cells are frequently found among the epithelioid cells within the granuloma follicle and often have cytoplasmic inclusions, such as asteroid bodies, Schaumann bodies, and birefringent crystalline particles (calcium oxalate and other calcium salts) (picture 5 and picture 6 and picture 7) [110]. These inclusions are not specific for sarcoidosis. Small amounts of central fibrinoid necrosis may be seen, but large amounts of necrosis suggest an alternate diagnosis or necrotizing sarcoid granulomatosis [111,112]. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Sarcoidosis'.)

In the lung, granulomas are usually found in the alveolar septa, the walls of bronchi, and along the pulmonary arteries and veins. Granulomas in the airspace, or poorly formed granulomas, suggest an alternative diagnosis such as infection or hypersensitivity pneumonitis. Sarcoidosis granuloma formation is probably preceded by an interstitial accumulation of monocytes, macrophages, and lymphocytes [113,114]. (See "Pathology and pathogenesis of sarcoidosis".)

Sarcoid-like histopathologic changes can be seen in lymph nodes from patients with neoplastic diseases such as Hodgkin lymphoma, lymphoproliferative disorders, germ cell testicular tumors, breast cancer, renal cell carcinoma, leiomyosarcoma, and ovarian mucinous cystadenoma, among others [115-119]. Lymph nodes in sarcoidosis patients are typically effaced by granulomatous inflammation ("wall-to-wall"), whereas granulomatous reactions to malignancy or medications are generally more focal. Occasionally, draining lymph nodes may exhibit granulomas after surgical procedures or trauma; these should not be misinterpreted as sarcoidosis. Thus, caution is advised when patients present with sarcoid-like granulomas in a lymph node but without other typical features of sarcoidosis. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — Although it is the most common noninfectious cause of granulomatous inflammation, sarcoidosis remains a diagnosis of exclusion among granulomatous disorders. Mycobacterial and endemic fungal infections should be considered in all patients. Suspicion for alternative etiologies should be particularly high among those patients with atypical presentations, such as those without either mediastinal lymphadenopathy or extrapulmonary disease. The presence of immunodeficiency (including HIV), a history of exposure to potential occupational or environmental agents (eg, beryllium, aluminum, titanium. zirconium, organic dusts), or the use of illicit substances (by inhalation or injection) each increase the likelihood of other granulomatous conditions [120,121]. Prominent systemic symptoms (eg, fever, night sweats, weight loss, and/or fatigue), although sometimes present in sarcoidosis, prompt concern for infection or malignancy. For the latter patients, a lymph node biopsy showing non-necrotizing granulomas needs to be carefully examined to exclude the presence of malignant cells [122-124].

Patients with non-necrotizing granulomas by biopsy at extrathoracic sites may have a tissue-specific differential diagnosis for localized granulomatous inflammation. A confident diagnosis of sarcoidosis is bolstered by additional signs of probable disease at other sites (table 5). (See 'Patients with accessible extrathoracic disease' above.)

The differential diagnosis for intrathoracic granulomatous processes includes sarcoidosis and the following alternative etiologies (see "Interpretation of lung biopsy results in interstitial lung disease", section on 'Granulomatous lung diseases'):

●Mycobacterial infection – Tuberculosis and atypical mycobacterial infections may cause pulmonary, mediastinal, and systemic granulomatous inflammation. Although classically the granulomas arising from Mycobacterium tuberculosis infection are necrotizing, non-necrotizing granulomas may be seen. Non-necrotizing granulomas are even more frequent in nontuberculous mycobacterial (NTM) disease. Nontuberculous mycobacteria more frequently exhibit granulomas in the airspace, as well as concomitant organizing pneumonia. Mycobacterial stains are insensitive for NTM in this setting. All biopsy specimens of patients with suspected sarcoidosis should be examined with special stains for mycobacteria, and cultures should be obtained whenever possible. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Overview of nontuberculous mycobacterial infections".)

●Fungal infection – Fungal infections (eg, histoplasmosis, blastomycosis, coccidioidomycosis, and rarely Pneumocystis jirovecii) may result in non-necrotizing granulomatous inflammation in the lung and mediastinal lymph nodes, with invasive infections occasionally leading to erythema nodosum and disseminated disease. Biopsy specimens in those with suspected sarcoidosis should be routinely examined with special stains for fungal pathogens. Serologic testing should be performed on patients from endemic areas, and cultures of bronchoalveolar lavage (BAL) fluid should be obtained prior to initiation of immunosuppressant therapy. Antigen testing is mainly useful for disseminated fungal disease. (See 'Testing for tuberculosis and other infections' above and "Diagnosis and treatment of pulmonary histoplasmosis" and "Clinical manifestations and diagnosis of blastomycosis", section on 'Pulmonary involvement' and "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)

●Hypersensitivity pneumonitis – Hypersensitivity pneumonitis (HP; also called extrinsic allergic alveolitis) can be misdiagnosed as sarcoidosis if the history of exposures to potential antigens is missed or characteristic radiologic and pathologic features are not appreciated. HP granulomas are generally located near respiratory or terminal bronchioles, while sarcoidosis granulomas have a lymphatic pattern around bronchovascular structures. Compared with sarcoidosis granulomas, HP granulomas are smaller, less well-formed, and associated with greater chronic interstitial inflammation. (See 'History and physical examination' above and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy' and 'Histopathology' above.)

●Pneumoconiosis – Certain pneumoconioses, especially chronic beryllium disease (CBD), can mimic sarcoidosis radiographically and pathologically. The diagnosis of chronic beryllium disease is based on a careful occupational history and, when needed, a blood and/or BAL beryllium lymphocyte proliferation test. (See 'History and physical examination' above and "Chronic beryllium disease (berylliosis)".)

●Drug-induced sarcoid-like reactions – Drug hypersensitivity reactions with granuloma formation, also known as drug-induced sarcoid-like reactions, have been described with several classes of pharmaceuticals, especially checkpoint inhibitors, highly active antiretroviral therapy, interferons, and tumor necrosis factor-alpha antagonists [125]. Specific agents described in case reports include etanercept, infliximab, adalimumab, azacytidine, oxaliplatin, amoxicillin, sirolimus, fluoxetine, immune checkpoint inhibitors, antiretroviral agents, and interferons [125-132]. Such reactions tend to improve or resolve with discontinuation of the agent [125].

Granulomatous inflammation can occur in the setting of methotrexate-induced pneumonitis, with 35 percent of cases affected in one literature review [133]. (See "Methotrexate-induced lung injury".)

Acute pulmonary granulomatosis with or without alveolar damage has also been seen due to hypersensitivity reaction or frank infection after intracavitary Bacillus Calmette-Guérin therapy [134,135]. (See "Infectious complications of intravesical BCG immunotherapy".)

●Pulmonary histiocytic disorders – Pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, another histiocytic proliferation, are causes of upper lung zone inflammation and scarring that can have a nodular pattern. They are differentiated based on biopsy results, which prominently feature histocytes and more rarely reveal granulomas. Langerhans cells are S-100 and CD1a-positive on staining. Erdheim-Chester disease cells express the histiocyte marker CD68 but (unlike Langerhans cell histiocytosis) do not express CD1a or S100. (See "Pulmonary Langerhans cell histiocytosis" and "Erdheim-Chester disease".)

●Foreign body granulomatosis – Foreign body granulomatosis (FBG) can be caused by aspiration or intravenous injection of foreign materials. The histopathology of FBG typically consists of perivascular fibrosis and aggregates of multinucleated giant cells and granulomas. Polarizable material may be seen within the granulomas and giant cells or may be found extracellularly in the vessel wall. (See "Foreign body granulomatosis".)

●Diseases associated with vascular inflammation – Granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and pulmonary lymphomatoid granulomatosis can be differentiated from sarcoidosis by their angiocentric pattern and associated evidence of vasculitis. The "granulomas" seen in vasculitis are not compact structures seen in sarcoidosis, but rather are focal collections of histiocytes and multinucleate giant cells involving the vasculature, usually with disruption of the elastica. Whether to label these features as granulomas is controversial. Measurement of a serum antineutrophil cytoplasmic antibody (ANCA) test may be helpful in identifying systemic vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Pulmonary lymphomatoid granulomatosis".)

●Bronchocentric granulomatosis – Bronchocentric granulomatosis is characterized by peribronchial and peribronchiolar necrotizing granulomatous inflammation. Approximately half of all cases are associated with asthma and allergic bronchopulmonary aspergillosis. (See "Bronchocentric granulomatosis".)

●Primary immunodeficiencies – Patients with chronic granulomatous disease typically develop granulomas in response to infectious agents, but they can also develop noninfectious pulmonary granulomas. A sarcoid-like disorder, called granulomatous and lymphocytic interstitial lung disease (GLILD), can present with granulomatous disease in the liver and lungs of patients with common variable immunodeficiency (CVID). Therefore, patients with apparent sarcoidosis who are hypogammaglobulinemic and have recurrent infections and/or autoimmune diseases should be evaluated for CVID. These disorders are discussed separately. (See "Pulmonary complications of primary immunodeficiencies", section on 'Chronic granulomatous disease' and "Pulmonary complications of primary immunodeficiencies", section on 'Severe combined immunodeficiency'.)

●Sarcoid-like reaction to malignancy – Sarcoid-like reactions in patients with neoplastic disease (eg, lymphoma and breast, lung, renal cell, and colon cancers) may be found in or around the tumor or in regional lymph nodes [115-119,136-146]. 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) can show increased uptake suspicious for the primary tumor [136]. In one report of a sarcoid-like reaction to breast cancer in the lung and mediastinal nodes, granulomas were admixed with clusters of malignant cells [142]. However, nonnecrotizing granulomas can also be present in affected lymph nodes that do not contain metastatic tumor [146]. Because this diagnosis is difficult to rule out completely, maintaining a high clinical suspicion is critical, particularly for those whose disease does not respond typically to observation or treatment. Sarcoidosis-like granulomatous tumor reactions can sometimes present prior to radiographically evident malignancy [147].

POSTDIAGNOSTIC ASSESSMENT OF DISEASE SEVERITY AND EXTENT — Once the diagnosis of sarcoidosis is confirmed, the functional severity of pulmonary disease should be determined and additional screening for occult extrathoracic disease is warranted. Additional detailed evaluation of potential extrapulmonary disease depends on clinical manifestations and the results of screening. The extrapulmonary organ systems that may be affected by sarcoidosis are described separately. (See "Extrapulmonary manifestations of sarcoidosis".)

Pulmonary function testing — Pulmonary function tests (PFTs), including spirometry and diffusing capacity for carbon monoxide (DLCO) are obtained in patients with pulmonary sarcoidosis to assess the severity of respiratory impairment and to monitor the course of disease. PFTs are not a reliable means for detecting the presence or extent of lung parenchymal involvement, but impairments do tend to correlate with dyspnea. Lung volumes, bronchoprovocation testing, six-minute walk test, and cardiopulmonary exercise test may be obtained on a case-by-case basis, but we do not recommend routinely performing these tests in all patients.

Approximately 20 percent of patients with stage I sarcoidosis have abnormal PFTs (table 1) [42]. In contrast, PFTs are abnormal in 40 to 70 percent of patients with stage II to IV disease. When abnormal, PFTs characteristically reveal a restrictive pattern (reduced vital capacity and total lung capacity) and a reduction in DLCO [23,148]. In parallel, endobronchial sarcoidosis, airways distortion from peribronchial fibrosis, or extrinsic compression of intrathoracic airways may lead to impairment of airflow and obstructive respiratory physiology. Overall, obstructive physiology may be seen in approximately 25 percent of patients with sarcoidosis; of these, 40 percent have mixed obstruction and restriction [149]. Some of these patients exhibit bronchial hyperreactivity during bronchoprovocation testing.

We typically obtain pulse oximetry with exertion in patients with dyspnea or impaired DLCO. Exercise-related desaturation tends to correlate with impairments in resting DLCO [150] and may be an indicator of pulmonary hypertension [151-153]. We reserve arterial blood gases for patients with evidence of advanced disease, whom we assess for hypercapnia and verify pulse oximetry findings. The evaluation and management of pulmonary hypertension due to lung disease are discussed separately.

Ophthalmologic examination — Patients with confirmed sarcoidosis should undergo visual acuity testing, tonometry, slit lamp, and fundoscopy to assess for ocular involvement [23]. Although most patients with ophthalmologic involvement are symptomatic, the high prevalence of ophthalmologic findings (25 to 50 percent) and potentially severe consequences of untreated disease merit screening of asymptomatic patients as well [25]. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Ocular'.)

Additional tests of endocrine and kidney function — Basic laboratory assessment of extrapulmonary organ involvement for all patients with suspected sarcoidosis includes a complete blood count, serum creatinine, serum calcium, and serum alkaline phosphatase, as recommended by the American Thoracic Society [25]. (See 'Testing for occult extrapulmonary disease' above.)

For treatment of fatigue and a more thorough evaluation of calcium homeostasis in patients requiring treatment, we suggest additional postdiagnostic testing with evaluation of both 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (figure 1) [154]. Deficiency of 25-hydroxyvitamin D is nearly universal among patients with sarcoidosis, although 1,25-dihydroxyvitamin D is sufficient in 70 percent. Prevention of glucocorticoid-induced bone loss is a complicated issue in patients with sarcoidosis compared with other glucocorticoid-requiring diseases due to both the production of vitamin D by sarcoidosis granulomas and the risk of hypercalcemia and hypercalciuria with calcium supplementation. (See "Overview of vitamin D" and "Hypercalcemia in granulomatous diseases" and "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis' and "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Adverse effects'.)

To evaluate for renal dysfunction in those with established sarcoidosis, we obtain a calcium level and creatinine. For patients with abnormal findings, a urinalysis and 24-hour urine are obtained to assess urinary calcium excretion, protein excretion, and creatinine clearance. (See "Kidney disease in sarcoidosis".)

NATURAL HISTORY — Dyspnea, need for systemic therapy, radiographic stage, demographic factors, and multiorgan involvement have all been associated with sarcoidosis prognosis. In one large study, (A Case Control Etiologic Study of Sarcoidosis [ACCESS]), the presence of dyspnea modified medical research council (mMRC) grade ≥2 (table 6) and a requirement for systemic treatment within the first six months were the only two independent variables associated with ongoing need for treatment at two years [155]. Older age, Black race, lower socioeconomic status, female sex, and higher Scadding stage (table 1) have all been associated with fewer chances for remission and higher chances for clinically bothersome disease [156]. A strong driver of overall outcome is the number of overtly involved organs: in a Japanese series of 295 patients, those with severe sarcoidosis had a higher frequency of ≥3 organ system involvement (70 percent) compared with those with mild disease (43 percent) [157].

The natural history of pulmonary sarcoidosis depends significantly on the degree of organ involvement:

●Patients with mild pulmonary involvement – Most patients presenting with isolated imaging abnormalities or mild pulmonary symptoms will experience spontaneous remission without treatment. Spontaneous remission, including radiographic resolution, occurs in an estimated 60 to 80 percent of patients with radiographic stage I disease, 50 to 60 percent with stage II disease, but in less than 30 percent with stage III disease (table 1) [9]. Even among patients who do not have remission, many have indolent disease without progression over time; this is particularly common in those with isolated lymphadenopathy or mild lung involvement (ie, normal pulmonary function). The relatively benign disease course in these groups has implications for monitoring and treatment. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Assessing disease severity and progression' and "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Approach to asymptomatic patients' and "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Symptomatic patients with mild lung involvement'.)

●Patients with extensive pulmonary involvement – Patients with more substantial pulmonary symptoms, decrements in lung function, and widespread granulomatous pulmonary inflammation are more likely to develop fibrocystic scarring (stage IV radiographic disease) over time [158]. Fibrocystic scarring increases the risk of progressive fibrosis, pulmonary hypertension, chronic pulmonary aspergillosis (CPA), and respiratory failure.

Much like fibrotic lesions in other interstitial lung diseases, fibrocystic sarcoidosis may progress despite anti-inflammatory treatment [15]. Although it is not uncommon for patients with fibrocystic changes to enter a quiescent phase or to stabilize with treatment, most respiratory deaths due to sarcoidosis involve this patient group [158].

Due to a frequent predilection for the airways and/or bronchial distortion from peribronchial fibrosis, inflammation in advanced pulmonary sarcoidosis may also result in significant airflow obstruction. This manifests with wheezing, prolonged exhalation, air-trapping, and hyperinflation not typically seen in patients with other fibrotic interstitial diseases. Chronic hypersensitivity pneumonitis may exhibit many of the same auscultatory and radiographic findings.

Pulmonary hypertension is a life-threatening complication of sarcoidosis that manifests clinically with progressive exertional dyspnea and hypoxemia. Although typically a result of advanced lung fibrosis and hypoxemia, pulmonary hypertension may also arise from granulomatous inflammation in the pulmonary vascular tree or complications of cardiac sarcoidosis. The evaluation and management of pulmonary hypertension due to lung disease are discussed separately.

CPA complicates approximately 2 percent of sarcoidosis and 10 percent of patients with advanced fibrotic disease [159,160]. The most common presentation involves mycetoma formation in fibrocystic spaces. Mycetomas can also complicate cavitary sarcoidosis [43,161]. Life-threatening hemoptysis occurs in more than one-half of individuals with pulmonary mycetomas, and concomitant sarcoidosis is a poor prognostic factor [162]. The diagnosis and treatment of pulmonary aspergillosis is described separately. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis" and "Chronic pulmonary aspergillosis: Treatment".)

The natural history of extrapulmonary disease is highly variable and end-organ specific. It is discussed separately. (See "Management and prognosis of cardiac sarcoidosis" and "Neurologic sarcoidosis" and "Extrapulmonary manifestations of sarcoidosis" and "Sarcoid myopathy" and "Kidney disease in sarcoidosis" and "Sarcoidosis of bone".)

ONGOING MONITORING — The indications for specific tests and optimal frequency of monitoring of disease activity in sarcoidosis have not been well established [25,163]. We suggest different testing strategies for those with active versus inactive disease (table 7).

●Pulmonary disease – Patients with more significant initial symptoms will need more frequent follow up; those who have minimal or no symptoms need less frequent evaluation. For example, patients who are started on prednisone for active disease will need to be reevaluated at four- to eight-week intervals, but patients who are asymptomatic may be seen in three- to four-month intervals for the first year and less frequently (usually yearly) thereafter (table 7). (See "Treatment of pulmonary sarcoidosis: Initial approach" and "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

●Extrapulmonary disease – Routine monitoring of sarcoidosis includes evaluation for the types of extrapulmonary involvement that can lead to organ or life-threatening disease. This monitoring begins with broad questions about new symptoms that could indicate extrapulmonary disease followed by laboratory testing and imaging based on elicited symptoms. For patients with new disease manifestations after biopsy-proven sarcoidosis in one organ and no evidence of an alternative diagnosis, a clinical instrument (World Association of Sarcoidosis and other Granulomatous Disorders [WASOG] Organ Assessment Instrument) can serve as a surrogate for tissue confirmation of sarcoidosis involving other organs [25,83,164]. In the absence of new symptoms, sarcoidosis centers vary in the selection of routine screening tests [25]; our suggestions are summarized in the table (table 7).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sarcoidosis (The Basics)")

●Beyond the Basics topics (see "Patient education: Sarcoidosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Sarcoidosis is a multisystem disorder of unknown etiology that is characterized pathologically by the presence of noncaseating granulomas (picture 3A-B) in involved organs. (See 'Introduction' above and 'Etiology' above.)

●Epidemiology – Sarcoidosis affects primarily young and middle-aged adults and is more common among females than males. In the United States, Black Americans have approximately 3-fold higher lifetime risk of sarcoidosis than White Americans and more commonly present with acute and severe disease. (See 'Epidemiology' above.)

●Clinical manifestations – Common presenting symptoms include cough, dyspnea, chest pain, and eye or skin lesions (table 5). Many other extrapulmonary manifestations may occur (table 2). In approximately one-half of patients, the disease is suspected due to incidentally discovered hilar lymphadenopathy and/or pulmonary infiltrates. (See 'Typical presentations' above.)

●Evaluation – A comprehensive evaluation for suspected sarcoidosis includes a history, physical examination, chest radiograph, peripheral blood counts, serum chemistries, and electrocardiogram (ECG). This evaluation focuses on eliminating alternative diagnoses, including mycobacterial and endemic fungal infections, hypersensitivity pneumonitis, and pneumoconioses. (See 'Initial evaluation' above.)

●Imaging – Patients with suspected sarcoidosis should receive a chest radiograph, followed by high-resolution computed tomography (HRCT) in those with pulmonary infiltrates. Chest radiographic findings have been organized into stages (table 1). These give an anatomic guide to lung involvement and imaging pattern but do not reflect disease activity or functional deficits. (See 'Chest imaging' above.)

●Diagnosis – The diagnosis of sarcoidosis requires compatible clinical and radiographic manifestations, exclusion of other diseases that may present similarly, and usually histopathologic detection of non-necrotizing granulomas (table 5). (See 'Diagnostic approach' above.)

•Deferred biopsy – Patients who present with asymptomatic bilateral hilar adenopathy, pathognomonic presentations (Löfgren syndrome, uveoparotid fever, or lupus pernio), or a sarcoidosis diagnosis score ≥10 based on multiple organ manifestations do not require biopsy unless there are atypical features or an unusual clinical course. (See 'Conditions in which invasive testing can be avoided' above.)

•Extrathoracic biopsy – Biopsy of accessible peripheral lesions (eg, cutaneous lesions, palpable lymph nodes, glandular tissues) is preferable over more invasive procedures. (See 'Patients without accessible extrathoracic disease' above.)

•Intrathoracic biopsy – If an accessible peripheral lesion cannot be identified, most patients should undergo intrathoracic biopsy using an endoscopic approach. (See 'Patients without accessible extrathoracic disease' above.)

If endoscopic biopsies cannot be performed or are nondiagnostic, the next step is usually surgical mediastinal lymph node biopsy followed (if necessary) by surgical lung biopsy via thoracoscopy or thoracotomy. (See 'Surgical biopsy of mediastinum and lung' above.)

●Differential diagnosis – The differential diagnosis of granulomatous lung diseases includes many conditions; it is particularly important to exclude infections and malignancy. (See 'Histopathology' above and 'Differential diagnosis' above.)

●Post-diagnostic testing – Once the diagnosis of pulmonary sarcoidosis is confirmed, the extent of involvement of the lung and other organs should be determined. We recommend pulmonary function testing (spirometry and diffusing capacity [DLCO]), as well as an ophthalmologic examination for all patients. (See 'Postdiagnostic assessment of disease severity and extent' above.)

●Ongoing monitoring – The specific testing and optimal frequency of disease monitoring in sarcoidosis have not been established. Monitoring should include broad questions about respiratory complaints and other new or worsening symptoms that could indicate extrapulmonary disease. Suggested routine testing frequency varies based on disease activity (table 7). (See 'Ongoing monitoring' above.)