Clinical manifestations and diagnosis of pulmonary sarcoidosis

INTRODUCTION — Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that affects individuals worldwide and is characterized pathologically by the presence of noncaseating granulomas in involved organs. It typically affects young adults and initially presents with one or more of the following abnormalities:

●Bilateral hilar adenopathy

●Pulmonary reticular opacities

●Skin, joint, and/or eye lesions

An overview of the clinical manifestations and diagnosis of pulmonary sarcoidosis is presented here. Issues relating to extrapulmonary sarcoidosis and the pathogenesis and treatment of sarcoidosis are discussed separately. (See "Pathology and pathogenesis of sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial approach to treatment" and "Treatment of pulmonary sarcoidosis refractory to initial therapy" and "Extrapulmonary manifestations of sarcoidosis".)

EPIDEMIOLOGY — The prevalence of sarcoidosis varies greatly depending on the region of the world and is estimated at 50 to 160 per 100,000 population [1-3].

The annual incidence of sarcoidosis is not known with certainty [1,2] and appears to vary among geographical regions and genetic backgrounds, eg, being two to three times more common in Black Americans than White Americans [1,4]. The incidence of sarcoidosis ranges from 0.5 to 1.3 per 100,000 in East Asia, 11.5 per 100,000 in Scandinavian countries and about 7 to 11 per 100,000 in the United States and Canada. [1-3,5,6]. It has been estimated that the lifetime risk of sarcoidosis among Black Americans is 2.4 percent, compared with a lifetime risk of 0.85 percent in White Americans [7,8]. Also, epidemiological studies show significant heterogeneity in disease presentation and severity occurs among different ethnic racial groups [9,10]. For example, Black Americans tend to be affected more acutely and with more severe disease than White Americans, who tend to present with asymptomatic and chronic disease [9].

In a large United States database study of adults over age 18, females were twice as likely to have sarcoidosis compared with males [1], with the highest prevalence of sarcoidosis being in Black American females.

Sarcoidosis is a disease commonly seen in young adults, however the age at diagnosis of sarcoidosis has increased steadily over the past 75 years such that more than half of cases are diagnosed over age 40 years [1,11]. Women tend to be older at the age they develop sarcoidosis [12,13]. The patient's immunogenetic background may play a role in the clinical manifestations of sarcoidosis and may underlie the heterogeneity of the illness [14,15]. The rate of hospitalization is higher among patients with sarcoidosis than patients without sarcoidosis (rate ratio [RR] of 1.37 [95% confidence interval (CI) 1.24–1.52]), especially among women with sarcoidosis [16].

There are numerous reports of familial clustering of sarcoidosis. The most prominent finding is linkage to a section within MHC on the short arm of chromosome 6. It appears that several alleles confer susceptibility to disease (HLA DR 11, 12, 14, 15, 17) and others seem to be protective (eg, HLA DRI, DR4, and possibly DQ*0202) [14].

ETIOLOGY — Despite an extensive research effort, the exact etiology and pathogenesis of sarcoidosis remain unknown. According to one widely held hypothesis, there are multiple causes of sarcoidosis, and different patterns of illness may in part be related to different underlying causes. (See "Pathology and pathogenesis of sarcoidosis".)

CLINICAL MANIFESTATIONS

Adolescents and adults — Sarcoidosis typically presents in patients between 20 and 60 years of age; disease onset is approximately 10 years earlier in Black Americans than in White Americans [17]. In approximately one-half, the disease is detected incidentally by radiographic abnormalities (eg, bilateral hilar adenopathy, reticular opacities) on a routine chest radiograph prior to the development of symptoms. (See 'Chest radiograph' below.)

Sarcoidosis most frequently involves the lung, but up to 30 percent of patients present with extrathoracic manifestations of sarcoidosis (table 1) [11,18-21]. Diffuse interstitial lung disease is the classic type of lung involvement; other less common pulmonary manifestations include pneumothorax, pleural thickening, chylothorax, and pulmonary hypertension. The extrapulmonary manifestations of sarcoidosis are described separately. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Diagnostic approach'.)

Common presenting respiratory symptoms include cough, dyspnea, and chest pain; these are frequently accompanied by fatigue, malaise, fever, and weight loss [22]. Patients over the age of 70 years appear to be more likely to present with systemic symptoms, such as fatigue and anorexia; however, dyspnea and cough are generally present at the same time [23]. Systemic inflammation may contribute to muscle weakness and exercise intolerance [24-26]. Patients should also be asked about new skin lesions (particularly around tattoos or scars), visual changes, dry eyes or mouth, parotid swelling, palpitations, syncope, joint pain or swelling, or muscle weakness.

Even in the presence of lung parenchymal sarcoidosis, crackles are not commonly heard on chest examination [27]. Wheezing may be present when there is endobronchial involvement or traction bronchiectasis due to scarring. Digital clubbing is rare and typically associated with advanced pulmonary fibrosis. The physical exam findings of extrapulmonary sarcoidosis are discussed separately. (See "Extrapulmonary manifestations of sarcoidosis" and "Cutaneous manifestations of sarcoidosis" and "Sarcoid arthropathy" and "Neurologic sarcoidosis".)

Children — Symptomatic sarcoidosis is rare in children. Black children appear to have more severe and extensive disease compared with other populations. Children between the ages of 8 and 15 develop multisystem disease similar to that described in adults [28]. Younger children often present with skin rash, arthritis, and uveitis without apparent lung involvement [29]. African American children tend to have higher incidences of lymph node involvement, hyperglobulinemia, and hypercalcemia.

In a series of Danish children with sarcoidosis, the most common presenting manifestations were erythema nodosum and iridocyclitis [30]. Ninety percent of the children had an abnormal chest radiograph.

EVALUATION — A comprehensive initial evaluation should be performed in all patients with suspected sarcoidosis. The purpose of this initial evaluation is to obtain additional data supporting the diagnosis of sarcoidosis while eliminating alternative diagnoses, characterize the severity of pulmonary impairment, and identify extrapulmonary organ involvement that may be amenable to biopsy or require immediate therapy.

Suggested elements of the evaluation include the following [31]:

●History, including occupational and environmental exposure

●Full physical examination

●Laboratory testing

●Tuberculin skin test

●Posteroanterior chest radiograph and often high resolution computed tomography (HRCT)

●Pulmonary function tests

●Electrocardiogram

●Ophthalmologic examination

Laboratory testing — Laboratory testing usually includes a complete blood count and differential, liver function tests, blood urea nitrogen, creatinine, glucose, electrolytes, serum calcium, and urinalysis [32]. Serologic testing for HIV infection should be considered when evaluating a patient for sarcoidosis. The erythrocyte sedimentation rate and C-reactive protein are nonspecific measures of inflammation and are variably obtained. The serum angiotensin converting enzyme (ACE) level and Kveim tests have limited clinical use, as described below.

A variety of laboratory abnormalities may be seen in patients with sarcoidosis:

●Anemia is uncommon. When present, it usually results from the anemia of chronic disease, although hypersplenism, bone marrow involvement, or autoimmune hemolytic anemia can occur in some patients [33-35].

●Leukopenia (5 to 10 percent) [35], eosinophilia (3 percent) [36], and thrombocytopenia (rare) can be seen [37].

●Hypercalciuria is more commonly observed than hypercalcemia.

●A moderate elevation in the serum alkaline phosphatase concentration suggests diffuse granulomatous hepatic involvement. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)

●Hypergammaglobulinemia (30 to 80 percent) and a positive rheumatoid factor may be present, but are not usually obtained.

●The erythrocyte sedimentation rate is frequently elevated, but is not useful in assessing disease activity.

●C-reactive protein (CRP) is mildly elevated in about one-third to one-half of patients with sarcoidosis, but does not differentiate sarcoidosis from other causes of inflammation and shows only a variable correlation with fatigue among patients with sarcoidosis [38,39]. The relationship between CRP and response to therapy is an area of research [40].

Serum markers — Serologic markers, such as serum angiotensin converting enzyme (ACE), adenosine deaminase, serum amyloid A, soluble interleukin-2 receptor, and D-dimer, have been examined for potential roles in diagnosis or monitoring disease activity, but without clear evidence of utility [41].

●Serum angiotensin converting enzyme – The ACE level is elevated in 75 percent of untreated patients with sarcoidosis [42]. However, serum ACE has limited utility as a diagnostic test, due to poor sensitivity (false negative results) and insufficient specificity (almost a 10 percent rate of false positive results) [42-45]. Other disease processes that have been associated with an elevated serum ACE are listed in the table (table 2). Tissue levels of ACE are typically very high, but are not used clinically. The value of monitoring the ACE level to assess the course of the disease remains unclear.

●Adenosine deaminase – Elevated adenosine deaminase (ADA) levels may be found in serum and bronchoalveolar lavage (BAL) fluid in sarcoidosis patients [41]. However, given the low sensitivity and specificity, the clinical utilization of ADA is limited.

●Serum amyloid A – Serum amyloid A (SAA) has also been found to be increased in sarcoidosis, but it has also not been shown to be clinically useful [41].

●Serum soluble interleukin-2 receptor – Serum soluble interleukin-2 receptor (sIL2R) has been suggested as a useful marker for determination of extrapulmonary involvement in sarcoidosis patients [41,46].

●Serum chitotriosidase – Chitotriosidases (chitinase family) are produced by activated macrophages, and substantially higher levels are present in serum from patients with sarcoidosis compared with healthy controls [47,48]. Serum chitotriosidase is increased in patients with greater disease activity and has promise as a biomarker of disease activity and response to therapy [47,49].

●D-dimer in bronchoalveolar lavage – The identification of D-dimer in BAL fluid supports the diagnosis of sarcoidosis, although this is largely a research tool. One observational study found that 8 out of 10 patients with sarcoidosis had detectable D-dimer in their BAL fluid (defined as >78 ng D-dimer per mL of concentrated BAL fluid), compared with none of 18 healthy controls [50]. Among patients with sarcoidosis, Black Americans appear more likely to have D-dimer in their BAL fluid than White Americans [51].

Kveim test — The Kveim test uses a suspension of heat-sterilized splenic 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 [52]. The Kveim test is essentially a research tool due to limited availability of the reagent and concerns about disease transmission with testing.

Testing for tuberculosis — Unless a patient has a well-documented positive tuberculin skin test, tuberculin skin testing or an interferon gamma release assay is performed to help exclude Mycobacterium tuberculosis infection. Diminished skin test reactivity is expected in sarcoidosis, so a positive test is strong evidence in favor of mycobacterial disease. (See "Use of interferon-gamma release assays for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Pulmonary imaging — Lung involvement occurs in over 90 percent of patients with sarcoidosis [18,43]. Pulmonary imaging plays an essential role in the diagnosis of sarcoidosis, starting with a chest radiograph, which is often followed by high resolution computed tomography. Other imaging tests, such as fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET), gallium-67, thallium-201, and technetium sestamibi (MIBI-Tc) single photon emission computed tomography (SPECT) are used for particular indications, as described below.

Chest radiograph — All patients being evaluated for possible sarcoidosis should have a chest radiograph. Bilateral hilar adenopathy is a classic finding in sarcoidosis, and the hila may be symmetrically enlarged (in approximately 50 percent of cases) or the right may be slightly more prominent [37]. True unilateral adenopathy is uncommon (<5 percent of cases). The lung parenchymal findings are more varied and include normal, nodular, reticular, reticulonodular, or ground-glass opacities, consolidation, and cystic changes. The abnormalities mainly involve the upper lung zones. Chest radiographic findings have been organized into stages, which give an anatomic guide to lung involvement, but do not reflect disease activity or functional deficits.

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. When bilateral hilar adenopathy is associated with erythema nodosum (EN), migratory polyarthralgias, and fever, the diagnosis of Lofgren syndrome is highly likely.

●Stage II – Stage II consists of bilateral hilar adenopathy and parenchymal involvement, most commonly reticulonodular 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, dyspnea, fever, and/or easy fatigue.

●Stage III – Stage III consists of parenchymal involvement without lymphadenopathy (image 3 and image 4).

●Stage IV – Stage IV disease is characterized by fibrosis, manifested as reticular opacities with or without associated cystic changes, predominantly distributed in the upper lung zones (image 5). Conglomerated masses with marked traction bronchiectasis may also be seen. Extensive calcification and cavitation or cyst formation may also be seen [53].

Less commonly, the chest radiograph may show multiple, bilateral lung nodules or consolidative mass-like opacities and minimal hilar adenopathy, findings that may simulate metastatic disease.

Calcification of hilar or mediastinal lymph nodes becomes more common with longer disease duration; the pattern is nonspecific [37]. Pleural involvement is unusual (<5 percent of patients), but can result in lymphocytic exudative effusion, chylothorax, hemothorax, and pneumothorax [54-56]. (See "Pleural fluid analysis in adults with a pleural effusion".)

HRCT scan — High resolution computed tomography (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 seen on the plain chest radiograph [53,57-59]:

●Hilar and mediastinal lymphadenopathy

●Beaded or irregular thickening of the bronchovascular bundles

●Nodules along bronchi, vessels, and subpleural regions

●Bronchial wall thickening

●Ground glass opacification

●Parenchymal masses or nodular consolidation, occasionally with cavitation

●Parenchymal bands

●Cysts

●Fibrosis with distortion of the lung architecture and traction bronchiectasis

The characteristic HRCT feature of sarcoidosis is the presence of small nodules (2 to 5 mm) in a perilymphatic distribution, predominantly in the peribronchovascular interstitium, but also along the costal pleura and interlobar fissures, and, to lesser extent, interlobular septa and centrilobular regions (image 6) [60-62]. HRCT scanning typically reveals a mid-to-upper zone predominance of the lung parenchymal abnormalities.

Other findings may include large nodules and masses, patchy bilateral consolidation, and ground-glass opacities (image 7) [62]. The correlation between HRCT findings and histologic abnormalities was examined in a small series that found an association between ground-glass opacities and sarcoid granulomas rather than alveolitis [63]. Although lymphocytic alveolitis can occur, it is rarely identified in those with clinically significant sarcoidosis [64]. (See "High resolution computed tomography of the lungs".)

Fibrosis manifests as irregular linear opacities and traction bronchiectasis typically involving mainly the peribronchovascular regions of the upper lobes with associated cephalad displacement of the hila (image 8). Fibrosis may also result in conglomerate masses, paracicatricial emphysema, large cystic spaces due to traction bronchiectasis or bullae, subpleural honeycombing, and development of intracavitary aspergillomas [62].

FDG-PET scan — Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is sometimes helpful to identify occult lesions that are more accessible to biopsy than lung lesions, as well as in the evaluation of cardiac sarcoidosis [33,65-67]. This test does not differentiate sarcoidosis from malignancy or infection, as FDG-PET may be positive in all of these processes. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'FDG-PET'.)

The use of other tracers may, in the future, improve the utility of PET imaging in diagnosing sarcoid. In a small study (24 sarcoid, 17 lung cancer), the combination of 18F-FDG and fluorine-18-methyltyrosine (18F-FMT) PET scanning was able to differentiate sarcoidosis from malignancy; sarcoid lesions were positive on 18F-FDG PET, but negative on 18F-FMT PET (both scans are positive in patients with cancer) [68]. Additional studies are needed for confirmation. The 18F-FMT tracer may not be available at all institutions.

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

Other radiotracer scanning — FDG-PET has largely replaced older imaging methods, such as ⁶⁷Gallium scintigraphy and ²⁰¹Thallium or ⁹⁹Technicium SPECT, due to greater sensitivity. (See 'FDG-PET scan' above.)

⁶⁷Gallium localizes in inflammatory foci and gallium scans were used in the past to identify foci of sarcoidosis. As an example, the so-called "panda" sign occurs when bilateral uptake in the lacrimal and parotid glands is superimposed on the normal uptake of the nasopharyngeal mucosa [69]. The "lambda" sign refers to gallium uptake by the right paratracheal and bilateral hilar lymph nodes results in a pattern similar to the Greek "lambda" symbol. The combination of these signs was felt to be strong evidence in favor of sarcoidosis, although the panda sign alone could be seen in Sjögren disease and lymphoma. The sensitivity of ⁶⁷Ga scintigraphy ranges between 60 and 90 percent, with a low specificity of approximately 50 percent [69,70].

Somatostatin receptor scintigraphy (SRS) is being explored as a method to improve localization of disease in sarcoidosis, based on the observation that the somatostatin receptor subtype 2 is highly expressed in sarcoid granulomas [71]. Somatostatin analogs, such as ⁶⁸Gallium-DOTA-tyrosine-octreotide and ¹¹¹Indium octreotide, can be used in PET/CT scanning instead of FDG and may be particularly useful for imaging cardiac sarcoid, although additional studies are needed [72-74].

Pulmonary function testing — Pulmonary function tests (PFTs), including spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and six-minute walk test (6MWT), are obtained in patients with pulmonary sarcoidosis to assess the severity of respiratory impairment and to monitor the course of disease with sequential measurements. However, PFTs are not a reliable means for detecting lung parenchymal sarcoidosis (an HRCT is better), nor do they provide an accurate estimate of the extent of parenchymal disease. In addition, the clinician cannot predict the natural course of lung involvement or the response to therapy solely on the basis of these tests.

Approximately 20 percent of patients with stage I sarcoid have abnormal PFTs [37]. In contrast, PFTs are abnormal in 40 to 70 percent of patients with stage II to IV disease. (See 'Chest radiograph' above.)

PFTs characteristically reveal a restrictive pattern (reduced vital capacity and total lung capacity) associated with a reduction in the DLCO, although it is not unusual for lung function to be normal [27,75]. Endobronchial sarcoidosis may lead to impairment of airflow and obstructive respiratory physiology.

The 6MWT distance is reduced in the majority of patients with sarcoidosis and correlates with reductions in forced vital capacity and ambulatory pulse oxygen saturation [76]. It is thought that the 6MWT provides an integrated assessment of sarcoidosis as it is affected by extrapulmonary factors such as muscle strength, fatigue, and cardiac function [76]. (See "Overview of pulmonary function testing in adults".)

Oxygenation is typically assessed by pulse oximetry at rest and often with exertion. Arterial blood gases in patients with sarcoid may reveal hypoxemia and hypocapnia (hyperventilation) or hypoxemia with hypercapnia (acute or chronic respiratory failure) in advanced disease. Hypoxemia is often an indicator of pulmonary hypertension [76-78]. Exercise may accentuate these abnormalities [79]. Exercise-related arterial desaturation (PaO₂ decrease) tends to correlate with degree of impairment in resting DLCO.

Bronchoscopy — Flexible bronchoscopy with BAL, endobronchial biopsy, and transbronchial biopsy are traditional methods for the minimally invasive diagnosis of sarcoidosis.

●Bronchoalveolar lavage – The main purpose of BAL in this setting is to exclude alternative diagnoses, such as chronic beryllium disease, eosinophilic lung disease, infections (eg, actinomycosis, mycobacteria, fungal), and malignancy. While the finding of BAL lymphocytosis ≥25 percent suggests a granulomatous process, the finding of BAL lymphocytosis is neither sensitive nor specific for the diagnosis of sarcoidosis. It therefore has the potential for diagnostic misinterpretation. (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'.)

A number of studies have examined the patterns of lymphocyte subsets in sarcoidosis and reported a reduced number of CD8 cells, an elevated CD4 to CD8 ratio (eg, >4:1), and increased proportions of activated T cells, CD4 cells, immunoglobulins, and IgG-secreting cells [50-52,80-85]. 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 4:1 provides support for sarcoidosis. As an example, one study evaluated 128 untreated patients with BAL lymphocytosis 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 to 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 to CD8 ratio less than one had a 100 percent negative predictive value for sarcoidosis. However, this finding should be interpreted with caution in light of case reports of CD8-predominant sarcoidosis.

•BAL fluid with >2 percent neutrophils or >1 percent eosinophils suggested that sarcoidosis was not the correct diagnosis.

●Endobronchial and transbronchial lung biopsy – Endobronchial and transbronchial biopsies may enable the patient to avoid a surgical biopsy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung 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 1) [86,87]. Endobronchial disease exists in approximately 40 percent of patients with stage I disease and approximately 70 percent of patients with stages II or III disease [86]. Four to six endobronchial biopsies are usually obtained, preferably from a site where the mucosa appears erythematous or from the first and secondary carinas if the mucosa appears normal [88]. In sarcoidosis, endobronchial mucosal biopsies are frequently positive and may increase the diagnostic yield, compared with transbronchial biopsies alone [89]. In a series of 37 patients with sarcoidosis, endobronchial biopsies had a diagnostic yield of 24 percent and increased the yield over transbronchial biopsy alone by 8 percent.

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 high resolution computed tomography (eg, beaded or irregular thickening along bronchovascular bundles) [90,91]. The specimens obtained should be used for both culture and histologic stains, including stains for acid-fast bacilli and fungi [92]. (See 'HRCT scan' above and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy'.)

●Transbronchial needle aspiration – Transbronchial needle aspiration (TBNA) can be performed during the same procedure and with the same bronchoscope as transbronchial lung biopsy to obtain cellular or core biopsy tissue from pulmonary nodules and mediastinal nodes. Alternatively, TBNA can be performed with ultrasound guidance (see 'Endoscopic ultrasound guided needle aspiration' below). As noted above, samples should be sent for pathologic and microbiologic analysis. 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 (cryo-TBB), which requires specialized equipment and specific training, may become a useful alternative in a minority of atypical suspected cases of sarcoidosis (ie, those without marked adenopathy) where bronchial or transbronchial biopsies are inconclusive and no other accessible sites for biopsy are identified [93,94]. Cryo-TBB had a diagnostic yield of 93 percent in a series of 32 patients with suspected sarcoidosis [95]; five patients sustained a pneumothorax and one patient had moderate bleeding. The technique, complications, and diagnostic yield are described separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)

Endoscopic ultrasound guided needle aspiration — 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 [96,97]. The choice between these procedures depends on the available expertise and equipment and the location of enlarged thoracic lymph nodes based on computed tomography (CT). 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'.)

DIAGNOSIS

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

●Compatible clinical and radiographic manifestations

●Exclusion of other diseases that may present similarly

●For most patients, histopathologic detection of noncaseating granulomas (picture 2A-B)

These elements are achieved by a comprehensive evaluation in all patients with suspected sarcoidosis, followed by a diagnostic procedure in most cases. In general, involvement of more than one organ system is needed for a diagnosis of sarcoidosis (table 3) [31], although biopsy of a second site is not always needed. As an example, the combination of noncaseating granulomas in one organ (eg, skin, lung) and clinical evidence of sarcoid in another (eg, hypercalcemia, bilateral hilar enlargement) would generally be sufficient to make a diagnosis of sarcoidosis.

●When a biopsy can be deferred – The main exceptions to the need for a biopsy are the presence of bilateral hilar adenopathy in an asymptomatic patient (Stage I) who can be monitored to ensure stability or resolution; classical Lofgren syndrome with fever, erythema nodosum, arthralgias, and bilateral hilar lymphadenopathy; Heerfordt syndrome of uveoparotid fever; and lupus pernio (picture 3 and picture 4) [27,96,98]. These patients typically do not require a biopsy if no alternative explanation for the constellation of findings exists and if the abnormalities resolve quickly and spontaneously. Spontaneous remissions of bilateral hilar adenopathy occur within 6 to 12 months from the onset of symptoms in 15 to 40 percent of patients and by 24 months in 85 percent. Of note, erythema nodosum lesions should not be biopsied, because the histopathology will demonstrate panniculitis and not granulomas, even if sarcoidosis exists [31]. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Löfgren syndrome' and "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)

Choice of biopsy site — Biopsies should be performed on the most accessible lesion that appears to be affected, which may include cutaneous lesions, subcutaneous nodules, palpable lymph nodes, enlarged parotid gland, conjunctival lesions, enlarged lacrimal gland, or certain other ocular lesions. If the patient does not appear to have involvement of one of these sites, the next choice is usually to obtain a biopsy or fine needle aspirate of radiographically enlarged intrathoracic lymph nodes or lung parenchyma.

Some patients with noncaseating granulomas documented at extrapulmonary sites still require bronchoscopy, such as those with constitutional symptoms suggestive of infection or atypical clinical or radiographic findings. As an example, patients with cavitary lung disease may require bronchoscopy to exclude mycobacterial and fungal infection prior to initiation of any immunosuppressive therapy. Similarly, patients with an atypical pattern of mediastinal adenopathy often need sampling of their mediastinal nodes.  

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 versus a thoracoscopic biopsy depends on the degree of suspicion for sarcoidosis. As transbronchial lung biopsy has a high yield in sarcoidosis, it would be an appropriate choice for a patient in whom sarcoidosis is strongly suspected (eg, a young patient with high resolution computed tomography 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 for diagnosis. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Surgical biopsy of mediastinum and lung — Mediastinal lymph node biopsy via mediastinoscopy or lung biopsy via thoracoscopy or thoracotomy may be required if less invasive tests are unable to provide a diagnosis. (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 [99]. In a series of 229 patients who underwent mediastinoscopy for the evaluation of nonlung cancer lymphadenopathy, 100 (44 percent) had sarcoidosis, while alternative diagnoses were identified in the remaining patients [100]. All biopsy specimens should undergo histopathologic analysis, special staining for mycobacteria and fungi, and culture for mycobacteria and fungi. Sometimes, a mediastinal lymph node biopsy is examined by frozen section while the patient remains under anesthesia. If the lymph node does not reveal granulomas, a lung biopsy is obtained by thoracoscopy or thoracotomy, but the patient is spared the lung biopsy if the lymph node reveals noncaseating granulomas. However, if the lung parenchymal findings are atypical for sarcoidosis, both procedures may be necessary. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Histopathology — The characteristic morphologic feature of sarcoidosis is the noncaseating granuloma. In the lung, granulomas are most commonly found in the alveolar septa, the walls of bronchi, and along the pulmonary arteries and veins. Sarcoid granuloma formation is probably preceded by an alveolitis that involves the interstitium more than the alveolar spaces and is characterized by the accumulation of inflammatory cells, including monocytes, macrophages, and lymphocytes [101,102]. (See "Pathology and pathogenesis of sarcoidosis".)

The sarcoid granuloma is a focal, chronic inflammatory reaction formed by the accumulation of epithelial cells, monocytes, lymphocytes, macrophages, and fibroblasts [103]. 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) [104]. Most sarcoid granulomas gradually resolve and leave few or no residual manifestations of previous inflammation. Small amounts of central fibrinoid necrosis may be seen, but large amounts of necrosis suggest an alternate diagnosis or necrotizing sarcoid granulomatosis [105,106]. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Sarcoidosis'.)

Sarcoid-like histopathologic changes can be seen in lymph nodes from patients with neoplastic diseases such as Hodgkin disease and other lymphoproliferative disorders, germ cell testicular tumors, breast cancer, renal cell carcinoma, leiomyosarcoma, and ovarian mucinous cystadenoma, among others [107-111]. 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 — An essential part of the diagnosis of sarcoidosis is the exclusion of alternative possibilities, and several settings are particularly prone to diagnostic difficulty. As an example, diagnosis may be difficult in the absence of extrapulmonary manifestations, bilateral hilar lymphadenopathy, or mediastinal lymphadenopathy. Similarly, the presence of HIV infection, a history of exposure to potential occupational or environmental agents (eg, beryllium, zirconium, organic dusts), and/or prominent systemic symptoms may make the diagnosis more challenging [112,113]. Prominent systemic symptoms (eg, fever, night sweats, weight loss, and/or fatigue) increase the concern for infection or malignancy. For the latter patients, a lymph node biopsy showing noncaseating granulomas needs to be carefully examined to exclude concomitant malignancy [114-116]. (See 'Histopathology' above.)

The list of granulomatous lung diseases to be considered in the differential diagnosis of sarcoidosis includes the following (see "Interpretation of lung biopsy results in interstitial lung disease", section on 'Granulomatous lung diseases'):

●Mycobacterial infection – Tuberculosis and atypical mycobacterial infections are in the differential of sarcoidosis and granulomatous lung disease. Thus, all biopsy specimens should be examined with special stains for mycobacteria, and cultures obtained whenever possible. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Overview of nontuberculous mycobacterial infections".)

●Fungal infection – Fungal infections (eg, histoplasmosis, blastomycosis, Pneumocystis jirovecii) are in the differential of sarcoidosis. Thus, all biopsy specimens should be examined with special stains for fungus and cultures of bronchoalveolar lavage fluid obtained whenever possible. In areas endemic for histoplasmosis, antigen testing of urine, serum, and bronchoalveolar lavage fluid should also be performed. (See "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. A detailed history of occupational exposures will help to exclude many causes of hypersensitivity pneumonitis. HP granulomas are generally located near respiratory or terminal bronchioles, while sarcoid granulomas have a lymphatic pattern around bronchovascular structures. Compared with sarcoid granulomas, HP granulomas are smaller, less discrete, and associated with greater interstitial chronic inflammation. (See 'Histopathology' above and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy'.)

●Pneumoconiosis – Certain pneumoconioses, especially chronic beryllium disease, 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 bronchoalveolar lavage beryllium lymphocyte proliferation test. (See "Chronic beryllium disease (berylliosis)".)

●Drug-induced sarcoid-like reactions – Drug-induced sarcoid-like reactions (drug hypersensitivity with granuloma formation) have been described with a number of agents, including methotrexate, etanercept, infliximab, adalimumab, azacytidine, oxaliplatin, amoxicillin, sirolimus, fluoxetine, immune checkpoint inhibitors, antiretroviral agents, interferons, and intravesicular Bacillus Calmette-Guerin (BCG) [117-125]. Such reactions tend to improve or resolve with discontinuation of the agent [123].

●Pulmonary histiocytic disorders – Pulmonary Langerhans cell histiocytosis (eosinophilic granuloma) and Erdheim-Chester disease, another histiocytic proliferation, are causes of upper lung zone inflammation and scarring. They are differentiated based on biopsy results. 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 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. Measurement of a serum antineutrophil cytoplasmic antibody test (ANCA) 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 can develop noninfectious pulmonary granulomas. A sarcoid-like disorder, called granulomatous and lymphocytic interstitial lung disease (GLILD), can present with granulomatous infiltration of the liver and lungs and variable elevations in ACE levels in patients with common variable immunodeficiency (CVID). Therefore, patients with apparent sarcoidosis who are hypogammaglobulinemic and have recurrent infections 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'.)

●Immune reconstitution inflammatory syndrome (IRIS) – The occurrence of sarcoidosis several months after initiation of potent combination antiretroviral therapy (ART) for AIDS suggests that immune reconstitution may "trigger" the reactivation or appearance of preexisting subclinical sarcoidosis. Indeed some but not all patients with IRIS-associated sarcoidosis had preexisting known sarcoidosis that became inactive years earlier. (See "Immune reconstitution inflammatory syndrome", section on 'Miscellaneous syndromes possibly associated with IRIS'.)

●Sarcoid-like reaction to malignancy – Sarcoid-like reactions in patients with neoplastic disease (eg, breast, lung, renal cell, and colon cancer and lymphoma) may be found in or around the tumor or in regional lymph nodes (eg, hilar, mediastinal, axillary) [107-111,126-136]. FDG-PET can show increased uptake suspicious for the primary tumor [126]. 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 [132]. On biopsy affected lymph nodes, nonnecrotizing granulomas can be present without metastatic tumor [136].

INITIAL ASSESSMENT OF DISEASE EXTENT — Once the diagnosis of pulmonary sarcoidosis is confirmed, the extent of involvement of other organs should be determined. For patients with biopsy-proven sarcoidosis in one organ and no evidence of an alternative diagnosis, a clinical instrument (ACCESS) can serve as a surrogate for tissue confirmation of sarcoidosis involving other organs [96,137,138]. The extrapulmonary organ systems that may be affected by sarcoidosis are described separately. (See "Extrapulmonary manifestations of sarcoidosis".)

In addition to clinical and laboratory assessment for extrapulmonary sarcoidosis, all patients with a new diagnosis of sarcoid should have an electrocardiogram [96]. Additional studies, such as 24 hour Holter monitoring and echocardiography, are performed based on symptoms, signs, and results of the electrocardiogram. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

Patients should also undergo visual acuity, tonometry, slit lamp, and fundoscopic testing to assess for ocular involvement [27]. (See "Extrapulmonary manifestations of sarcoidosis", section on 'Ocular'.)

In addition to assessing extrapulmonary organ involvement, we obtain serum testing for vitamin D deficiency by measuring both 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (figure 1) [139]. Deficiency of 25-hydroxyvitamin D is nearly universal among patients with sarcoidosis, although 1,25-dihydroxyvitamin D is sufficient in 70 percent. The cause of low levels of 25-hydroxyvitamin D in sarcoidosis is not known. (See "Overview of vitamin D".)

A serum calcium should be obtained, as hypercalcemia is present in approximately 6 percent of patients with sarcoidosis who undergo routine testing [96]. We also obtain a spot urine for calcium and creatinine, to assess for hypercalcuria. For patients with an elevated serum calcium, a 24 hour urine is obtained to assess urinary calcium excretion and creatinine clearance. If the urinalysis shows protein, then urinary protein is also assessed in the 24 hour specimen. (See "Kidney disease in sarcoidosis".)

MONITORING — The indications for specific tests and optimal frequency of monitoring of disease activity in sarcoidosis have not been established [96,140]. 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 in 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.

Routine monitoring of sarcoidosis also includes evaluation for the types of extrapulmonary involvement that can lead to organ or life-threatening disease, which begins with broad questions about new symptoms that could indicate extrapulmonary disease. Laboratory testing is largely based on symptoms; sarcoidosis centers vary in the selection of routine screening tests [96]. A general guideline and list of tests is provided in the table (table 4) and discussed separately. (See "Extrapulmonary manifestations of sarcoidosis".)

Any on-going medications used to treat active disease will also influence follow up testing. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy" and "Treatment of pulmonary sarcoidosis: Initial approach to treatment".)

COMPLICATIONS — Pulmonary sarcoidosis is occasionally associated with complications such as venous thromboembolic disease (VTE), development of aspergilloma, and pulmonary hypertension.

An increased risk of VTE has been reported in patients with sarcoidosis. In a population-based study of 345 incident cases of sarcoidosis and 345 sex, age, and calendar year-matched comparator subjects, an increased risk was noted among patients with sarcoidosis (HR 3.04, 95% CI 1.47-7.48) and (HR 4.29, 95% CI 1.21-15.23) for deep venous thrombosis and pulmonary embolism, respectively [141]. This observation was supported by an analysis of the Explorys, IBM Watson Health data set with more than 20 million patients of whom more than 53 thousand had a diagnosis of sarcoidosis [142]. After adjusting for sex, age, and race, the odds ratio was 3.06 (95% CI 2.94-3.18) for DVT and 3.96 (95% CI 3.80-4.13) for PE.

Chronic pulmonary aspergillosis (CPA) complicates approximately 2 percent of sarcoidosis, most commonly presenting as an aspergilloma in fibrocystic sarcoidosis [143,144]. Aspergillomas can also complicate cavitary sarcoidosis [53,145]. The diagnosis and treatment of aspergilloma are described separately. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Aspergilloma' and "Treatment of chronic pulmonary aspergillosis", section on 'Aspergilloma'.)

In patients with sarcoidosis, pulmonary hypertension is generally a complication of advanced lung fibrosis. Pulmonary hypertension correlates with the need for supplemental oxygen, but not spirometric results. The evaluation and management of pulmonary fibrosis due to lung disease are discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)

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 2A-B) in involved organs. (See 'Introduction' above and 'Etiology' above.)

●Epidemiology – The estimated prevalence of sarcoidosis is 50 to 160 per 100,000 population. Sarcoidosis affects young adults more often than children or older adults and is more common among Black Americans than White Americans and more common among females than males. Black Americans more commonly present with acute, severe disease, while White Americans more commonly present with mild, chronic disease. (See 'Epidemiology' above.)

●Clinical manifestations – Common presenting symptoms include cough, dyspnea, chest pain, eye lesions, and/or skin lesions (table 3). Other extrapulmonary manifestations are listed in the table (table 1). In approximately one-half of the patients, the disease is detected incidentally on a chest radiograph obtained for other reasons (eg, bilateral hilar adenopathy, reticular opacities). (See 'Clinical manifestations' above.)

●Evaluation – A comprehensive evaluation should be performed in all patients with suspected sarcoidosis, including history, physical examination, a chest radiograph, pulmonary function tests, peripheral blood counts, serum chemistries, urinalysis, electrocardiogram, ophthalmologic examination, and a tuberculin skin test. The purpose of this evaluation is to obtain additional data supporting the diagnosis of sarcoidosis and to assess disease severity and extent, while eliminating alternative diagnoses. (See 'Evaluation' above.)

●Imaging – Pulmonary imaging plays an essential role in the diagnosis of sarcoidosis, starting with a chest radiograph, which is often followed by high resolution computed tomography. Other imaging tests, such as fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) and other radiotracer scans are used on a case-by-case basis. The "classic" chest radiograph reveals bilateral hilar adenopathy. This finding, however, may be absent or, if present, may occur in combination with parenchymal opacities. (See 'Pulmonary imaging' above.)

●Pulmonary function tests – Pulmonary function tests (spirometry, lung volumes, diffusing capacity, and six-minute walk test) are obtained in all patients with suspected sarcoidosis to assess for respiratory impairment and characteristically demonstrate a restrictive defect with reduced gas exchange and reduced functional status. (See 'Pulmonary function testing' above.)

●Diagnosis – The diagnosis of sarcoidosis requires compatible clinical and radiographic manifestations, exclusion of other diseases that may present similarly, and histopathologic detection of noncaseating granulomas (table 3). (See 'Diagnostic approach' above.)

•Biopsy can be deferred – Patients who present with asymptomatic bilateral hilar adenopathy or a classical Lofgren syndrome (fever, erythema nodosum, arthralgias, and bilateral hilar lymphadenopathy), Heerfordt syndrome with uveoparotid fever, or lupus pernio do not require biopsy if the abnormalities resolve quickly and spontaneously. (See 'Diagnostic approach' above.)

•Biopsy needed – Biopsy should be performed in most other cases of suspected sarcoidosis. Biopsy of accessible peripheral lesions (eg, cutaneous lesions, palpable lymph nodes, conjunctival lesions) is preferred to an invasive procedure. If an accessible lesion cannot be identified, the choice of procedure depends on the pattern and location of lung parenchymal abnormalities, the presence and location of enlarged thoracic lymph nodes, and also the available expertise and equipment. Endoscopic ultrasound guided needle aspiration techniques have a high diagnostic yield (80 to 90 percent) in patients with mediastinal adenopathy and a clinical suspicion of sarcoidosis, while the yield from transbronchial lung biopsy is slightly lower (50 to 75 percent). (See 'Diagnosis' above and 'Endoscopic ultrasound guided needle aspiration' above.)

If ultrasound-guided endoscopy or flexible bronchoscopy cannot be performed or are nondiagnostic, the next step is usually surgical mediastinal lymph node biopsy (mediastinoscopy), followed by surgical lung biopsy via thoracoscopy or thoracotomy. (See 'Surgical biopsy of mediastinum and lung' above.)

●Post-diagnostic testing – Once the diagnosis of pulmonary sarcoidosis is confirmed, the extent of involvement of other organs should be determined. All patients with a new diagnosis of sarcoid should have an electrocardiogram. Additional studies (eg, 24-hour Holter monitoring and echocardiography) depend on symptoms, signs, and results of the electrocardiogram. Patients should undergo ophthalmologic testing to assess for ocular involvement. We also obtain a serum calcium and measure both 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D. (See 'Initial assessment of disease extent' 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 'Diagnostic approach' above.)

●Monitoring – The specific tests and optimal frequency of monitoring of disease activity in sarcoidosis have not been established and vary among sarcoidosis centers. Monitoring should include broad questions about respiratory symptoms and other new or worsening symptoms that could indicate extrapulmonary disease. Laboratory testing is largely based on reported symptoms. A general guideline and list of tests is provided in the table (table 4). (See 'Monitoring' above.)