CONTENTS

• Basics
• Epidemiology
• Pulmonary sarcoidosis
  • Clinical presentation
  • Radiographic staging (Scadding stage)
  • Chest CT scan
    • Lymphadenopathy ➡️
    • Nonfibrotic parenchymal abnormalities
    • Fibrotic parenchymal abnormalities
    • Necrotizing sarcoid granulomatosis
  • Pulmonary function tests
    • Reduced DLCO
    • Restriction
    • Obstruction
  • Pleural involvement
  • Pulmonary hypertension
  • Large airway involvement
  • Treatment of pulmonary sarcoid
  • Approach to sarcoidosis patient with cardiopulmonary deterioration
• Extrapulmonary sarcoidosis
  • Skin
    • Erythema nodosum & Lofgren syndrome
    • Granulomatous skin lesions
  • Eyes
  • Joints
  • Neurosarcoidosis (& Heerfordt syndrome)
  • Cardiac sarcoidosis
  • Kidney
    • Interstitial nephritis
    • Hypercalcemia
  • Liver
  • Gastrointestinal tract
• Diagnosis
  • Laboratory studies
    • ACE level
  • Tissue diagnosis
    • Site of biopsy
    • Bronchoscopy
    • Histopathology
    • DDx of granulomas
• Differential diagnoses of note
  • Drug-induced sarcoid-like reaction
  • Sarcoid-like reaction to malignancy
  • GLUS (granulomatous lesions of unknown significance)
• Treatment (& multi-organ staging evaluation)
  • Treatment of pulmonary sarcoid
• Prognosis and clinical course
• Questions & discussion

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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basics

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• Sarcoidosis is an immune-mediated granulomatous disease which may manifest with inflammation in various organs, including the lungs (90%), eye (~20%), skin (~15%), and nervous system (~10%). (34607912)

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epidemiology

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• Age:
  • The average age at diagnosis is ~35-50 years old. (31485575)
  • Onset in a patient >50 years old should be approached with skepticism. (31891305) Very few cases begin in the elderly. (32424017) With increasing age, alternative diagnoses such as sarcoid-like reaction to malignancy may become more likely. 📖
• A first-degree relative with sarcoidosis increases the risk of disease. (Murray 2022)
• Rates of sarcoidosis in the United States varies with race: (31485575)
  • African American: 17-35 per 100,000.
  • White: 5-12 per 100,000.
  • Asian or Hispanic American: 1-3 per 100,000.
• The effect of sex on disease incidence may vary between countries.
• Rates of sarcoidosis vary dramatically between various countries (figure below).

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clinical presentation of pulmonary sarcoidosis

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epidemiology

• 90% of sarcoidosis patients have some intrathoracic involvement.

clinical manifestations may include

• Patients may be asymptomatic (with incidental diagnosis based on imaging).
  • Asymptomatic radiographic abnormalities may be especially suggestive of sarcoidosis.
• Constitutional symptoms may occur, including fatigue. However, prominent systemic symptoms may increase concern for infection or malignancy.
• Dry cough is common and potentially severe.
• Exertional dyspnea may occur. Dyspnea is the most worrisome symptom since it suggests loss of respiratory function. (Shah 2019)
• Hypoxemia is uncommon in early disease. If hypoxemia is seen this may suggest the possibility of severe, fibrocystic sarcoidosis and/or pulmonary hypertension. (BTS 2020 guidelines)

less common symptoms

• Chest pain or vague retrosternal discomfort may occur, often with features of musculoskeletal chest wall pain. (Shah 2019)
• Wheeze and chest tightness can occur (discussed further below 📖).
• Fibrocystic sarcoidosis with bronchiectasis may cause sputum production and hemoptysis.

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staging of pulmonary sarcoidosis

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The following staging system applies only to disease visible on chest radiograph. For example, if a patient had bulky hilar lymphadenopathy (visible on chest radiograph) and subtle interstitial infiltrates visible only on CT scan, they would be classified as Stage-1 disease.

stage 0 (~5% of patients)

• Normal chest radiograph.

stage I (~40% of patients at presentation)

• Radiology: Mediastinal and hilar lymphadenopathy (usually bilateral) without pulmonary infiltrates.
• Clinically:
  • Most patients are asymptomatic.
  • About 10% of patients may have extrapulmonary involvement (arthralgia, erythema nodosum, ophthalmic involvement). This includes patients with Lofgren syndrome (discussed further below 📖).
• Prognosis: Up to 80% will spontaneously regress, with a low rate of developing chronic respiratory dysfunction. (31485575)

stage II (~35% of patients at presentation)

• Radiology: Mediastinal and hilar lymphadenopathy (usually bilateral) with pulmonary infiltrates.
• Clinically: Patients may have pulmonary symptoms.
• Prognosis: About half of patients may have spontaneous remission.

stage III (~10% of patients at presentation)

• Radiology: Pulmonary infiltrates without lymphadenopathy (which has regressed).
• Clinically: Respiratory symptoms are common.
• Prognosis: Spontaneous remission in only ~15% of patients.

stage IV (~5% of patients at presentation)

• Radiology: Advanced fibrosis with volume loss and architectural distortion.
• Clinically: Patients have respiratory symptoms (which may include hemoptysis, dyspnea, recurrent bacterial infections). Aspergilloma formation may occur, potentially causing severe hemoptysis.
• Prognosis: Remission is impossible.

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chest CT findings in sarcoidosis

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lymphadenopathy – discussed here 📖

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nonfibrotic parenchymal findings 

Nonfibrotic findings reflect micronodules or conglomerations of micronodules that form macronodules and/or consolidation. These findings correlate with active granulomatous inflammation that may improve (either spontaneously or following therapy). 

micronodules

• Micronodules are distributed in a perilymphatic distribution. 📖
  • Nodules are typically most notable along bronchi, vessels, and the pleura (with less involvement of interlobular septa). (Walker 2019) This may generate a beaded appearance of blood vessels, airways, and interlobar fissures that is highly suggestive of sarcoidosis. (34314343)
• Usually there is a mid and upper lung predominance.
• Nodules may cluster in some areas, with sparing of other regions.
• Nodules are generally small (2-5 mm), but range up to 1 cm in size. (Shepard 2019)
• Differential diagnosis: other conditions where nodules tend to predominate in the peribronchovascular and subpleural regions include Berylliosis and IgG4-related lung disease. (Walker 2019)

aggregated micronodules

• Micronodules may combine to form several patterns:
  • Large nodules or masses often ranging from 1-4 cm in size. (Walker 2019) The galaxy sign 📖 refers to a large nodule surrounded by small satellite nodules. (34314343) 
  • Consolidation(s) may occur, often in the perihilar regions.
  • Stippled or textured GGO (ground glass opacity) may occur. This is sometimes referred to as a “cluster sign” 📖. Over time, ground glass opacity may resolve, or it may progress towards fibrosis (so GGO may reflect fine fibrosis, as discussed below). (Mostard 2022)
• These lesions may masquerade as alveolar filling processes (e.g., community-acquired pneumonia). However, some clues may help assist with the diagnosis of sarcoidosis:
  • (1) Lesions are usually associated with mediastinal lymphadenopathy.
  • (2) Lesion edges may have a micronodular configuration, or there may be small satellite nodules nearby.
  • (3) Perilymphatic nodules are present elsewhere on the CT scan.

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fibrotic sarcoidosis 

distribution

• Usually upper lobe predominant (especially the apical and posterior portions of the upper lobes and the superior segments of the lower lobes).
• This often causes upwards and posterior retraction of the hila. (Shepard 2019)

features of fibrosis may include:

• Reticulation and fibrous bands.
• Traction bronchiectasis.
• Irreversible diffuse ground glass opacification may occur (ground glass opacification is due to fibrosis below the resolution of CT scanning, so it won't improve with steroid therapy).
• Mass-like areas of fibrosis may occur centrally along the perihilar bronchi and vasculature. (Shepard 2019)
• Bullae may develop (contraction of fibrotic tissue causes adjacent, normal tissue to be stretched).
• Honeycombing can occur in some patients, but this isn't a prominent feature of the fibrosis.

cavitation

• Cavitation may rarely occur (~4% of cases), usually in the context of advanced fibrotic disease.
• Cavitary lesions are usually multiple and bilateral (alternatively, isolated lung cavitation might suggest an infectious process, such as tuberculosis).
• Cavitation is overall uncommon in sarcoidosis, so alternative diagnoses should also be considered (e.g., infection or granulomatosis with polyangiitis). (Mostard 2022)
• Aspergilloma formation may eventually develop within cavities.

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necrotizing sarcoid granulomatosis

basics

• Necrotizing sarcoid granulomatosis is an extremely rare entity, which combines some clinical features of sarcoidosis and some clinical features of GPA (granulomatosis with polyangiitis). (28756634)
• It's not entirely clear whether this represents a distinctive entity from sarcoidosis, or a specific form of sarcoidosis. Necrotizing sarcoid granulomatosis may represent a late stage of nodular sarcoidosis, during which vascular obstruction has led to necrosis. (28756634)

clinical presentation

• Most frequent symptoms are cough, fever, dyspnea, and chest pain. (28756634)
• Extrapulmonary involvement occurs in ~1/3 of cases, most frequently involving the eyes.

imaging features

• (1) Multiple nodules or masses are usually present. Unlike most nodules seen in patients with sarcoidosis, these have smooth edges (resembling malignancy). Cavitation may occur.
• (2) Mediastinal lymphadenopathy is seen in ~1/3 of patients. (28756634)

diagnosis

• Differential diagnosis includes:
  • Infection (e.g., tuberculosis).
  • GPA (granulomatosis with polyangiitis).
  • Malignancy.
  • Malignancy combined with sarcoid-like reaction to malignancy.
• Due to its rareness and close resemblance to malignancy, the diagnosis of necrotizing sarcoid granulomatosis almost always requires a lung biopsy. (James 2022)

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pulmonary function tests

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Pulmonary function test abnormalities are seen in nearly all patients with symptomatic pulmonary sarcoidosis.

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reduced DLCO (diffusion of carbon monoxide)

• This is the most sensitive abnormality, and typically the first abnormality detected.
• A disproportionately reduced DLCO (as compared to other pulmonary function tests) may reflect sarcoidosis-associated pulmonary hypertension. (Murray 2022)
• DLCO impairment is less severe than in IPF (idiopathic pulmonary fibrosis).

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restrictive pattern (30-60% of patients)

• Changes in vital capacity and DLCO are usually concordant.
• FVC (forced vital capacity) is the most reliable parameter for disease monitoring over time. (34314343) For example, FVC is the most sensitive indicator of disease progression (DLCO is more variable).
• Extent of disease on CT scan usually correlates with the level of restriction. (34314343)

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obstructive pattern (20% of patients) & clinical correlates

basics of airflow obstruction in sarcoidosis

• Airflow obstruction may result from a variety of different mechanisms:
  • (1) Endobronchial involvement of large airways.
  • (2) Diffuse granulomas in the small airways.
  • (3) Fibrotic disease causing airway distortion.
  • (4) Lymphadenopathy may occasionally cause extrinsic compression of large airways.

symptomatology

• Clinically, patients may experience cough, wheezing and dyspnea. (30732704)

pulmonary function tests

• Airway hyperresponsiveness is present in ~20% of patients with sarcoidosis. (BTS 2020 guidelines) Usually this is associated with endobronchial involvement. (BTS 2020 guidelines)

imaging

• Small airway obstruction can occasionally cause mosaic attenuation. (Shah 2019) 
  • Expiratory air trapping on CT scan may be seen in 90% of patients. (Walker 2019)

management implications

• Sorting out sarcoidosis versus asthma can be challenging. Serum IgE and exhaled nitric oxide measurements may help evaluate for the presence of atopic asthma. (James 2022) To further complicate matters, some patients may have both conditions. When in doubt, it may be reasonable to perform a therapeutic trial of medical therapy for asthma (e.g., bronchodilators and inhaled steroid). (30732704)
• Use of inhaled steroid in sarcoidosis:
  • Among heterogeneous groups of patients with pulmonary sarcoidosis, inhaled steroid does not appear to be effective. (8077885) Consequently, inhaled steroid is not generally recommended by guidelines. (33268456) 
  • However, inhaled steroid may be a rational therapy for individual patients who display clinical and physiological features of dynamic airflow obstruction (especially if the patient may have an asthma-sarcoidosis overlap syndrome). The goal of therapy is symptomatic benefit (noting that inhaled steroid doesn't appear to alter the disease course of sarcoidosis).

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pleural involvement

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epidemiology

• Pleural involvement is rare, but may occur in ~1-2% of patients.
• Patients with pleural involvement usually have extensive parenchymal and frequently extraparenchymal sarcoidosis. (Murray 2022)

clinical presentation

• Effusions can be symptomatic (causing pleuritic chest pain or dyspnea).

radiology

• Unilateral or bilateral effusions can occur, which are generally small to moderate in size.

pleural fluid analysis

• Most effusions are exudative, but transudative effusions also have been described. (Fishman 2023)
• The differential cell count is usually lymphocytic.

differential diagnosis: pleural effusion in the context of sarcoidosis

• More common causes of pleural effusion: (33611981)
  • Left heart failure.
  • Superimposed infection (e.g., pneumonia).
• Diagnosis of the effusion as caused by sarcoidosis requires evaluation for alternative causes of a lymphocytic exudate (especially tuberculosis or malignancy). Pleural effusions in sarcoidosis are extremely rare, so be cautious when attributing a lymphocytic effusion to sarcoidosis. (James 2022)

treatment

• Effusions may resolve spontaneously over 1-2 months, or require steroid therapy. (Murray 2022)

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pulmonary hypertension due to sarcoidosis

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epidemiology & clinical features

• The prevalence of pulmonary hypertension may be ~10%. (Fishman 2023)
• Some predictors of pulmonary hypertension:
  • Advanced fibrocystic sarcoidosis (where the prevalence may approach 50%), severe physiological restriction.
  • Exertional dyspnea that is otherwise unexplained (e.g., inconsistent with pulmonary function tests).
  • Disproportionate reduction in DLCO (diffusion capacity of carbon monoxide) as compared to other abnormalities in pulmonary function.
  • Desaturation >90% with ambulation (e.g., during a 6-minute walk test).
  • Imaging features of pulmonary hypertension on CT scan (e.g., dilated pulmonary artery).

potential mechanisms of pulmonary hypertension

• Extensive parenchymal lung disease (most common mechanism).
  • Loss of pulmonary capillary bed.
  • Fibrosis may distort pulmonary arteries.
• Compression of pulmonary arteries by lymphadenopathy.
• Primary granulomatous vasculopathy (may predominantly involve the pulmonary veins).
• Pulmonary hypertension due to left ventricular failure, as a result of myocardial involvement from sarcoidosis.

management

• Treatment may vary, since different patients may have different hemodynamic profiles. Specific therapy for PH is predominantly useful for patients with precapillary pulmonary hypertension. Treatment options for such patients may include one or more of the following:
  • Ambrisentan or bosentan.
  • Sildenafil or tadalafil.
  • Prostacyclins (e.g., intravenous epoprostenol or inhaled iloprost).
• The basic supportive management for pulmonary hypertension is discussed further here: 📖

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large airway involvement

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pathogenesis

• Various mechanisms of airway stenosis may occur:
  • Usually: intrinsic granulomatous infiltration of the trachea.
  • Less often: extrinsic compression from mediastinal lymphadenopathy.

clinical presentation

• Symptoms may include wheeze, dyspnea, and cough.

radiology & anatomic distribution

• Laryngeal involvement may be the most common site. (Fishman 2023)
• Tracheal involvement is rare, occurring in 1-3% of patients.
  • The proximal third of the trachea is most often involved.
  • Diffuse tracheal stenosis may occur.
• Involvement of the main, lobar, and segmental bronchi is more common.
• Wall thickening may be smooth, irregular, or nodular.

bronchoscopy is discussed below 📖

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treatment of pulmonary sarcoidosis

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when to treat pulmonary sarcoidosis

situations where treatment may be deferred

• Most patients do not require treatment for pulmonary involvement.
• Stage I disease should generally be observed, since it will often spontaneously regress.
• Mild parenchymal disease with stability on pulmonary function tests over ~6-12 months may be observed carefully without treatment. This may spontaneously resolve over time (~50% with Stage II disease and ~30% with Stage III disease). (Shah 2019)

indication #1/2: preventing loss of lung function

• Disease severity alone isn't necessarily an indication for therapy (if sarcoidosis is quiescent). However, limited pulmonary reserve function should lower the threshold for treatment. Moderate to severe disease may be considered as a DLCO <65% predicted, or spirometric volumes <70% predicted. (Shah 2019)
• Evidence of active disease may include the following: (Shah 2019; 31485575) 
  • Progressive decline in lung function:
    • >10% reduction in forced vital capacity. (BTS 2020 guidelines)
    • >15% reduction in the diffusing capacity for carbon monoxide. (BTS 2020 guidelines)
  • Progression on thoracic imaging.
  • Progressive symptomatic disease.

indication #2/2: improved quality of life

• Some patients have relatively low risk of functional decline (e.g., preserved pulmonary function tests), but they experience pulmonary symptoms that impair their quality of life. Patients may wish to trial steroid therapy, with a goal of symptom improvement.
• Careful discussion with patients is required regarding risks of systemic steroid therapy, the likelihood that steroid will actually improve symptoms, and the likelihood that disease may spontaneously remit. The decision to treat hinges on shared decision-making.

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how to treat pulmonary sarcoidosis

steroid is first-line therapy

• Initial steroid dose:
  • The initial dose is 20 mg/day of prednisone for patients at high risk of disease progression. (ERS 2021 guidelines) The SARCORT trial demonstrated that 20 mg/day was equally as effective as 40 mg/day. (37690784)
  • For patients with worsening quality of life from pulmonary disease but only intermediate risk of disease progression, an initial dose of 5-10 mg/day prednisone may be trialed. (ERS 2021 guidelines)
• Weaning steroid to a maintenance dose of 5-10 mg/day:
  • If steroid initiation causes clinical improvement, then patients may be monitored while undergoing a very gradual steroid taper. (Alternatively: failure to improve may raise the possibility of either an alternative diagnosis or fibrotic sarcoidosis, since active sarcoidosis would usually be expected to respond to steroid.)
  • After 4-6 weeks at 20 mg/day, the dose may be decreased by 5 mg every two weeks. Patients can usually be weaned down to a maintenance dose between 5-10 mg/day. (BTS 2020 guidelines)
  • About a third of patients may relapse during taper. This may be managed by increasing the steroid dose and adding a steroid-sparing agent (usually methotrexate). Low-dose steroid is often needed in combination with a steroid-sparing agent. (Fishman 2023)
• Trial of withdrawal of steroid:
  • In patients with controlled disease, attempting withdrawal of steroid is typically performed after 6-12 months. The steroid dose is gradually tapered off over months, to allow for recovery of endogenous hypothalamic-pituitary-adrenal axis function. (BTS 2020 guidelines)
  • Steroid withdrawal symptoms may occur even when the dose is still within the supra-physiologic range (>7.5 mg/day), but these should stabilize over time. Differentiating steroid withdrawal from sarcoidosis can be challenging. (BTS 2020 guidelines)

steroid-sparing agent

• Indications for a steroid-sparing agent include: (BTS 2020 guidelines)
  • Progression of pulmonary disease or an unacceptable symptom burden despite adequate steroid therapy.
  • Intolerable steroid side effects.
  • Inability to taper steroid below 10-15 mg/day.
  • Major comorbidities likely to be adversely affected by steroid therapy (e.g., severe obesity, diabetes, osteoporosis, hypertension).
  • A strong patient aversion to steroid (in which case, a second-line agent may occasionally be used as initial therapy).
• Options include: methotrexate (used most frequently), azathioprine, mycophenolate, and hydroxychloroquine. These are discussed further below:

steroid sparing agent #1/4: methotrexate

• Methotrexate is a front-line steroid-sparing agent for pulmonary sarcoidosis.
• Usual dosing: (BTS 2020 guidelines)
  • The initial dose is usually 5-10 mg/week orally.
  • Dose may be increased every two weeks.
  • Target dose is 15-20 mg/week as tolerated.
• The range of doses is roughly 10-25 mg weekly.
• Folic acid should be prescribed (5 mg weekly) to reduce the risk of myelosuppression. (BTS 2020 guidelines)
• Reversible hepatotoxicity may occur, so liver function tests require monitoring.
• Methotrexate is renally cleared, with contraindication in cases of renal dysfunction.
• Methotrexate pneumonitis is rare in the context of sarcoidosis (more on this here 📖).

steroid sparing agent #2/4: azathioprine

• Overall, azathioprine and methotrexate seem to have similar efficacy. (ERS 2021 guidelines, BTS 2020 guidelines) However, it is possible than an individual patient may respond better to one agent or the other.
• Further discussion of azathioprine here, including dosing regimens: 💉

steroid sparing agent #3/4: mycophenolate

• Data on mycophenolate is limited, so it's generally considered a third-line agent (after methotrexate and azathioprine).
• One retrospective study suggested that mycophenolate could be beneficial for patients who failed an initial second-line treatment. (25301291)
• Further discussion of mycophenolate here, including dosing regimens: 💉

steroid sparing agent #4/4: hydroxychloroquine

• Hydroxychloroquine is utilized mostly for treatment of fatigue, joint, and skin sarcoidosis – but it may be used as a steroid-sparing agent for pulmonary sarcoidosis as well. (BTS 2020 guidelines)
• The usual dose is 200 mg once or twice daily.
• Retinal and cardiac toxicities (QT prolongation) are rare but potentially serious.
  • Ophthalmologic examination should be undertaken at baseline, and then yearly after five years of therapy. However, patients with sarcoidosis should be receiving ophthalmologic examinations anyway. (BTS 2020 guidelines)
  • QTc intervals should be monitored.

antifibrotic therapy

• The INBUILD study did find improvement from nintedanib in patients with sarcoidosis. (BTS 2020 guidelines)
• For patients with progressive deterioration in pulmonary function tests despite immunosuppressive therapy, antifibrotic therapy should be considered (within the generalized rubric of progressive pulmonary fibrosis, as discussed further here: 📖).

Further discussion: ERS 2021 guidelines page #6: 📄

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approach to sarcoidosis patient with cardiopulmonary deterioration

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differential diagnosis

• Worsening of sarcoidosis:
  • Parenchymal lung tissue inflammation.
  • Airway involvement.
  • ⚠️ Note that sarcoidosis itself rarely causes rapidly progressive diffuse lung disease leading to respiratory failure (within days to a few weeks). (31365383) Thus, the presence of ARDS should prompt consideration for alternative or superimposed diagnoses other than sarcoidosis.
• Infection:
  • Usual infections (e.g., community acquired pneumonia).
  • Bronchiectasis:
    • If substantial bronchiectasis is present due to sarcoidosis, this may increase the risk of pseudomonas colonization and invasive infection.
    • Patients may experience exacerbations of bronchiectasis (similar to other groups of patients with bronchiectasis). Management is similar to other patients with bronchiectasis, as described here: 📖
  • Opportunistic infection related to immunosuppression, especially:
    • Pneumocystis (primarily a consideration among patients on ≧20 mg/day prednisone for >1 month, but combination therapy involving anti-TNF agents may also present a risk). (33611981)
    • CCPA (chronic cavitary pulmonary aspergillosis). (33611981)
    • Tumor necrosis factor inhibitors may increase the risk of endemic fungal infections.
• Pulmonary hypertension / right ventricular failure:
  • Pulmonary embolism.
  • Decompensated right ventricular failure within the context of sarcoidosis-associated pulmonary hypertension.
• Left ventricular failure:
  • Heart failure that isn't sarcoidosis-related.
  • Myocardial or conduction dysfunction due to sarcoidosis.
• Neuromuscular dysfunction:
  • Steroid-related myopathy.
  • Myopathy or radiculopathy due to sarcoidosis.
• Drug-induced lung disease:
  • Methotrexate-induced pneumonitis.
• Adrenal crisis:
  • Patients on chronic steroid therapy will experience adrenal suppression. Adrenal crisis may occur in the following situations:
    • Moderate-to-high dose steroid is abruptly discontinued (e.g., due to gastroenteritis).
    • Patient on low-dose steroid is exposed to acute physiologic stress (leading to relative adrenal insufficiency, since the adrenal glands are unable to respond properly).

evaluation may often include:

• CT angiogram of the chest.
• Transthoracic echocardiogram.
• Infectious evaluation.
• Bedside pulmonary mechanics to evaluate diaphragmatic strength (forced vital capacity, negative inspiratory force).
• Creatinine kinase and aldolase.

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skin

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Skin involvement is the most common extrathoracic manifestation, present in up to a third of patients. (31485575) It is often helpful in securing the diagnosis of sarcoidosis. 

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erythema nodosum & Lofgren syndrome

erythema nodosum

• This is the most common skin finding in sarcoidosis.
• Painful erythematous nodules are often located on the anterior legs.
• Biopsy will not reveal granulomata, but rather merely nonspecific panniculitis.
• This is usually associated with Stage I-II pulmonary sarcoidosis; for example, as a component of Lofgren syndrome.

Lofgren syndrome

• Lofgren syndrome is defined as bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis. (32293205) 
• Lofgren syndrome is the presenting manifestation of sarcoidosis in ~15% of patients.
• Clinical features: (18996998)
  • (1) Bilateral hilar lymphadenopathy.
  • (2) Erythema nodosum and/or polyarthralgia. Typically 2-6 joints are involved, often beginning in the feet and ankles, with subsequent spreading in an additive fashion to involve the knees and upper extremities.
  • (3) Constitutional symptoms (fever, malaise) often occur.
• Differential diagnosis includes acute histoplasmosis or coccidioidomycosis, which may cause bilateral hilar lymphadenopathy (although usually asymmetric), arthralgias, and erythema nodosum.
• Evaluation:
  • PPD and fungal serologies should be obtained.
  • Tissue biopsy isn't needed to make the working diagnosis of Lofgren syndrome, if alternative diagnoses can be excluded (especially coccidiomycosis).
• Management:
  • Steroid isn't indicated, since there is a very high rate of spontaneous remission (~90%) within 3-6 months. (31485575) Note that Lofgren syndrome is a subgroup of Scadding Stage I sarcoidosis (a stage that typically remits spontaneously). 📖
  • NSAIDs or colchicine may be used to provide symptomatic relief. Acetaminophen has limited anti-inflammatory properties, so it may not be sufficient to treat the arthritis. (Bloch 2022)
  • Follow-up is required. If the disease progresses or clinical illness persists, then biopsy should be considered to exclude lymphoma or infection.

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granulomatous skin lesions

• These occur in ~20% of patients, usually in association with chronic and persistent lung disease (Stage III pulmonary sarcoidosis).
• Maculopapular eruptions may involve the nose, eyelids, lips, forehead, back of neck or hairline, or prior sites of trauma (e.g., scars or tattoos).
• Nodular waxy, pink lesions can occur on the face, trunk, and extensor surface of extremities.
• Plaque-like lesions may involve the nose, cheeks, earlobes, fingers, toes, or knees.

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eyes

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epidemiology

• Ocular involvement is the second most common extrapulmonary site (after skin).
• ~10-25% of patients may have ocular involvement. Ocular involvement may occur early or late within the overall course of the patient's sarcoidosis. (31485575)

presentations

• Anterior uveitis may cause pain, erythema, photophobia, tearing, and visual loss.
• Posterior uveitis may cause painless visual loss and floaters.
• Less common manifestations include scleritis, episcleritis, conjunctivitis, orbital masses, and optic neuritis (although optic neuritis may be considered a component of neurosarcoidosis).

management

• All sarcoidosis patients should undergo evaluation by an ophthalmologist following initial diagnosis.
• Uveitis requires treatment, as this may threaten vision.
• Initial therapy may often involve local steroid (eye drops for anterior uveitis, or intravitreal injection for posterior uveitis).

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joints

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• Joint involvement occurs in ~10% of patients, often as an early manifestation of sarcoidosis.
• Typically acute oligoarthritis involves the large joints, especially the ankle. This may occur simultaneously with erythema nodosum, as part of Lofgren syndrome. 📖
• Enthesitis (especially Achilles tendinitis) may occur in ~5% of patients. (31485575)
• Arthropathy is usually self-limited and may be treated supportively.

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neurosarcoidosis

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epidemiology & relationship to systemic sarcoidosis

• Neurologic involvement is seen in ~10% of patients with sarcoidosis. When this occurs, it usually begins within a couple years of the initial sarcoidosis diagnosis. (34607912)
• In ~75% of patients with neurosarcoidosis, neurologic symptoms are the initial manifestations of sarcoidosis.
• Most neurosarcoidosis patients eventually develop other organ involvement from sarcoidosis (especially the lungs). However, ~15% of patients with neurosarcoidosis persistently lack involvement of other organs. (34607912)

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neurological manifestations

cranial neuropathy (~60% of neurosarcoidosis)

• Sarcoidosis may affect various cranial nerves, most commonly those listed below. Neurosarcoidosis may be suggested by numerous concurrent or serial cranial neuropathies.
  • Facial nerve involvement (Bell palsy) is most common. It is somewhat unusual, in that it usually resolves spontaneously.
  • Optic neuritis is the second most commonly involved nerve.
  • Vestibulocochlear nerve involvement may cause hearing loss.
  • Trigeminal nerve involvement may cause facial pain/sensory changes. (Tavee 2022)
• MRI often shows enhancement of nearby leptomeninges. Thus, nerve involvement may be a manifestation of basilar meningitis.
• Heerfordt syndrome may involve cranial neuropathy:
  • Heerfordt syndrome is defined as a combination of: (34607912, 32424017)
    • Cranial nerve palsy, usually involving the facial nerve (Bell palsy).
    • Anterior uveitis.
    • Parotitis
    • Fever.
  • If this constellation is recognized, the diagnosis of sarcoidosis may be made without a tissue biopsy.

meningitis (~15% of neurosarcoidosis)

• Sarcoidosis may cause a subacute or chronic basilar meningitis.
• Clinical manifestations may include:
  • Headache.
  • Cranial nerve dysfunction (discussed above).
  • Hydrocephalus (usually communicating hydrocephalus), which may associate with gait disturbance, cognitive impairment, and even obtundation.
  • Less frequently: seizures.

myelopathy (~15% of neurosarcoidosis)

• There may be a combination of motor, sensory, and bowel/bladder symptoms. (Louis 2021)

parenchymal disease (up to 50% of neurosarcoidosis)

• May manifest with seizure, mass lesions, or encephalopathy.
• Mass-like lesions (~15%) may cause seizures and focal deficits.
• Cerebrovascular involvement may cause stroke or venous sinus thrombosis.

hypothalamic/pituitary axis (~5% of neurosarcoidosis)

• Hypopituitarism.
• Diabetes insipidus, reset osmostat, or even SIADH (syndrome of inappropriate ADH production).

neuropathy

• Small fiber neuropathy may cause pain and paresthesias.
• Dysautonomia may cause palpitations, orthostasis, hyperhidrosis, gastrointestinal dysmotility, dry eyes and mouth, or bladder dysfunction. (31485575)
  • Dysautonomia often accompanies neuropathic symptoms, but rarely occurs alone.

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CSF analysis

• CSF can be normal in up to a third of patients with neurosarcoidosis. (Tavee 2022)
• Protein elevation is the most common abnormality. Protein elevation may correlate with hydrocephalus. (32424017)
• Mild pleocytosis is typically seen (usually <100 cells/uL) with lymphocytic predominance.
  • Neutrophils may be present, especially acutely.
• Glucose is usually normal, but is reduced in ~20% of patients. (31485575) However, glucose levels <20 mg/dL should raise concern for an alternative diagnosis (e.g., fungi, mycobacteria, or malignancy). (34607912)
• Oligoclonal bands may be seen in about a third of patients with neurosarcoidosis. (34314343)
• CSF ACE levels lack sensitivity or specificity. (32777849)

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neuroimaging findings may include

brain

• Leptomeningeal enhancement (may resemble leptomeningeal carcinomatosis or other causes of basilar meningitis) is often seen, especially along the skull base.
• Optic nerve enhancement may be seen.
• Focal lesions may resemble malignancy, albeit usually with some meningeal component. Alternatively, parenchymal lesions may resemble those seen in multiple sclerosis. Contrast enhancement implies more active disease.
• Pituitary gland thickening and enhancement may be seen.
• Dural masses may occur, along with pachymeningeal (dural) enhancement. These can mimic a meningioma.

spinal cord

• Intraparenchymal T2 hyperintensity usually occurs in a longitudinally extensive transverse myelitis pattern (LETM; involving three or more vertebral segments). However, a short tumefactive myelitis pattern may also occur.
• A dorsal cord subpial pattern of enhancement is characteristic. The combination of central canal plus dorsal subpial enhancement may produce the classic “trident” appearance on axial MRI.
• The thoracic region is most commonly involved, followed by cervical disease. (Louis 2021)
• Leptomeningeal enhancement is often seen. Mass-like dural and leptomeningeal lesions can occur.

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investigation for systemic sarcoidosis

• About half of patients with neurosarcoidosis have an abnormal chest radiograph. Sensitivity of thoracic CT scan should be higher.
• If no obvious systemic sarcoidosis is present, whole body PET/CT has a reasonable yield for detecting occult sites of involvement (which may be safer to biopsy than the brain). Skin examination may occasionally reveal a site amenable to safe biopsy as well (although cutaneous granulomas aren't entirely specific for sarcoidosis).

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diagnosis

challenges in neurosarcoidosis diagnosis: 

• There is no specific test to rule sarcoidosis in or out. Even the presence of non-necrotizing granulomas doesn't prove the diagnosis (depending on the tissue, there are often a variety of causes of granuloma formation).
• The presence of systemic sarcoidosis doesn't necessarily prove that neurologic disease is caused by sarcoidosis (for example, neurologic disease could be a complication of therapeutic immunosuppression).
• Tissue biopsy of the nervous system may be difficult or prohibitively dangerous.
• Even if a patient definitely has neurosarcoidosis, it can be difficult to differentiate chronic/stable disease from active disease.

useful principles:

• A broad differential diagnosis should be considered, with careful exclusion of competing diagnoses (especially infection).
• Avoid premature diagnostic closure. It's difficult to ever be 100% certain that a specific symptom is due to sarcoidosis. If treatment isn't successful, reconsider the diagnosis.

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management of neurosarcoidosis

• Treatment is virtually always warranted in active neurosarcoidosis, as this is unlikely to regress spontaneously (with the exception of facial nerve palsy). (32777849, 31485575)
• Glucocorticoids are standard front-line therapy.
  • A 3-5 day pulse of 500-1,000 mg/day IV methylprednisolone may be considered initially for patients with severe disabling manifestations (e.g., altered mental status, visual loss, paralysis) or rapid deterioration. (31485575; Tavee 2022) 
  • Isolated facial nerve palsy may be treated with ~0.5 mg/kg/day prednisone. (31485575)
  • Otherwise, CNS involvement is usually treated with prednisone 1 mg/kg/day. (31485575)
  • Once control is achieved, steroid may be very slowly tapered over a period of several months. An exception is facial nerve palsy, which may require only 1-2 months of therapy. (31485575)
• Neurosarcoidosis tends to relapse while tapering off steroids, so steroid-sparing agents are often needed (with a preference for methotrexate). Methotrexate and hydroxychloroquine might lower the relapse rate of neurosarcoidosis more than mycophenolate or azathioprine. (35838355)
• Other supportive management:
  • Hydrocephalus may require a ventriculoperitoneal shunt. (Louis 2021)
  • Seizures may require anti-seizure medication.
• Small-fiber neuropathy:
  • Tends to be refractory to steroid or steroid-sparing agents.
  • Intravenous immunoglobulin or TNF-inhibitors might be more effective in this situation.

Further discussion: ERS 2021 guidelines page #16: 📄

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cardiac sarcoidosis

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epidemiology

• Reported rates of cardiac involvement vary, perhaps including ~10% of patients with sarcoidosis.
• Most patients with cardiac sarcoidosis have low levels of extracardiac disease. (Birnie 2022) Cardiac sarcoidosis may occur in the absence of other organ involvement.

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clinical manifestations

conduction disease

• Most common manifestation of cardiac sarcoidosis.
• Variations include:
  • LBBB.
  • RBBB.
  • Hemi-blocks.
  • Complete heart block.
• Sarcoidosis may be reasonably common (e.g., ~20%) among some populations of patients <55-60 years old presenting with unexplained heart block. The Heart and Rhythm Society guidelines recommend screening of such patients with thoracic CT scan and either cardiac MRI or PET scan. (Birnie 2022)

ventricular tachycardia

• The mechanism of VT is reentry within patchy areas of fibrosis.
• VT may have either an LV or RV origin. (Hurst 15e)

cardiomyopathy

• May be the initial manifestation of cardiac sarcoidosis.
• 3% of patients with cardiac sarcoidosis present with acute heart failure or shock. (37014337)
• This includes either reduced ejection fraction or restrictive cardiomyopathy.

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diagnostic studies

echocardiography

• Interventricular thinning (especially basal) is the most common feature (highly specific for sarcoidosis). However, increased myocardial wall thickness may also occur, mimicking hypertrophic cardiomyopathy. (Birnie 2022)
• Other abnormalities may include dysfunction of the left and/or right ventricle, isolated wall motion abnormalities, and aneurysms. (Birnie 2022)

cardiac MRI

• MRI is generally the diagnostic tool of choice for cardiac sarcoidosis (sensitivity of 97% and specificity close to 100%). (BTS 2020 guidelines)
• Findings may include:
  • (1) Edema on T2 sequences implies active myocardial inflammation.
  • (2) Late gadolinium enhancement reflects myocardial fibrosis. This may appear similar to a prior myocardial infarction, but the distribution is inconsistent with coronary anatomy.
• Sarcoidosis often involves the basal septum, left ventricular basal segment, left ventricular lateral wall, and papillary muscles (with sparing of the subendocardium). (31365383; 37031986)

cardiac PET

• PET scan is useful for the detection of active myocardial inflammation (reflected by the presence of diffuse or patchy uptake in the myocardium).
• PET is highly sensitive, but less specific than cardiac MRI. (37031986)

myocardial biopsy

• Tissue biopsy revealing sarcoidosis involving other organs may be extremely useful (and safer than biopsy of the heart).
• Endomyocardial biopsy is invasive and has low sensitivity (~25%), due to patchy involvement. (37031986) In practice this is seldom performed. (BTS 2020 guidelines) 

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diagnostic criteria for cardiac sarcoidosis 

There are two pathways to a diagnosis of cardiac sarcoidosis: (Birnie 2022)

(1) Histological diagnosis from myocardial tissue requires:

• Noncaseating granuloma on histological examination of myocardial tissue.
• No alternative cause identified.

(2) Clinical diagnosis from invasive and noninvasive studies requires:

• (a) Histological diagnosis of extracardiac sarcoidosis.
• (b) One or more of the following:
  • Steroid +/- immunosuppressant-responsive cardiomyopathy or heart block.
  • Unexplained left ventricular ejection fraction <40%.
  • Unexplained sustained (spontaneous or induced) ventricular tachycardia.
  • Mobitz type II second-degree heart block or third-degree heart block.
  • Patchy uptake on dedicated cardiac PET scan (in a pattern consistent with sarcoidosis).
  • Late gadolinium enhancement on cardiac MRI (in a pattern consistent with sarcoidosis).
• (c) Other causes of cardiac manifestation(s) have been reasonably excluded.

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management

indications for therapy

• Suggested indications for immunosuppression are as follows (noting that care should be made to differentiate between active myocarditis versus chronic scar tissue): (31485575)
  • Hypermetabolic activity on cardiac PET scan.
  • Conduction deficit (heart block is often an early sign of cardiac involvement, and it may improve with therapy). (ERS 2021 guidelines)
  • Ventricular arrhythmia.
  • Left ventricular dysfunction.
  • Right ventricular dysfunction in the absence of pulmonary hypertension.
• Increasing data suggests that PET scans may be a helpful indicator of disease activity to guide therapy (figure below). (Birnie 2022)
• Poor prognostic variables that may influence treatment decisions for cardiac sarcoidosis: (ERS 2021 guidelines)
  • Age >50 years old.
  • Left ventricular ejection fraction <40%.
  • New York Heart Association Functional class III-IV.
  • Increased left ventricular end-diastolic diameter.
  • Late gadolinium enhancement on cardiac MRI.
  • Ventricular tachycardia.
  • Cardiac inflammation identified by cardiac PET scan.
  • Echocardiographic evidence of abnormal global longitudinal strain.
  • Interventricular septal thinning.
  • Elevated troponin or brain natriuretic peptide.

initial therapy

• Front-line therapy is usually prednisone dosed at ~30-40 mg/day. (Birnie 2022) European Respiratory Society guidelines note that a retrospective analysis suggested that prednisolone doses >0.5 mg/kg were not more effective than a starting dose of 0.5 mg/kg/day. (ERS 2021 guidelines)
• Early initiation of steroid-sparing medications should be considered (e.g., methotrexate, azathioprine, or mycophenolate). (35838355)
• Serial cardiac PET scans may evaluate for response to therapy. If steroid fails or isn't tolerated, methotrexate is the second-line therapy. 
• Supportive therapy:
  • Heart failure should be managed using standard guideline-directed medical therapy.
  • Electrophysiology may be consulted for consideration of permanent pacemaker, AICD, and/or ventricular tachycardia ablation. Malignant arrhythmia is a significant cause of death in the context of cardiac sarcoidosis, so AICD insertion may be critical.

Further discussion: ERS 2021 guidelines page #13: 📄

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interstitial nephritis

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clinical manifestations

• Granulomatous interstitial nephritis occurs in <3% of patients. It usually occurs in the context of active sarcoidosis in other organs. (31485575)
• Manifestations include renal dysfunction and urinalysis abnormalities (aseptic pyuria, microscopic hematuria, proteinuria).

diagnosis

• Kidney biopsy may yield evidence of noncaseating granulomas in only about half of cases, possibly reflective of sampling error.

treatment

• Most experts agree that treatment is indicated to prevent progressive renal injury.
• Initial therapy with steroid may be reasonable, followed by the addition of steroid-sparing agents in refractory cases. (31485575)

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hypercalcemia

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basics

• Hypercalcemia occurs in 5-10% of patients. (30955519)
• Sarcoidosis may lead to excess activation of vitamin D (conversion from 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol). This “rogue hydroxylation” may cause hypercalcemia and hypercalciuria.
• Typically, patients will have the following laboratory pattern:(31365383)
  • Hypercalcemia.
  • Low 25-hydroxycholecalciferol (25-hydroxy vitamin D).
  • High or inappropriately normal 1,25-hydroxycholecalciferol (1,25-hydroxy vitamin D).
  • Low parathyroid hormone level.
• Symptoms of hypercalcemia may include fatigue, delirium, abdominal discomfort, and renal dysfunction (discussed further in the chapter on hypercalcemia: 📖).

treatment

• Other causes of hypercalcemia should be evaluated 📖 (including excess calcium and/or vitamin D intake).
• Symptomatic hypercalcemia due to sarcoidosis is an indication for steroid therapy. (30955519)
• ~20 mg/day prednisone should usually improve hypercalcemia within a week.
• Relatively rapid tapering may be attempted (over 4-6 weeks), with frequent monitoring. Hypercalcemia has a tendency to recur. Hydroxychloroquine may be useful for the management of hypercalcemia.

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liver

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• The prevalence of liver involvement is unclear, as this is often asymptomatic. Symptoms may include pruritus, jaundice, or abdominal pain.
• Hepatic infiltration may cause elevation of alkaline phosphatase and gamma-glutamyl transferase levels.
• Imaging studies may reveal hypodense nodules (~20% of patients) or hepatomegaly (~15% of patients).
• Prognosis is generally favorable, but it is possible to progress to cirrhosis.
• ⚠️ Most experts recommend against treatment of asymptomatic abnormalities in liver function tests. (31485575)

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gastrointestinal tract

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• Clinically relevant involvement is rare (occurring in <1% of patients). (31485575)
• Any part of the alimentary canal may be involved. Manifestations can include mucositis, ulceration, obstruction, or stricturing.
• Gastric involvement is most common (which may cause epigastric pain, nausea, vomiting, and weight loss).

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diagnosis

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some principles of diagnosing sarcoidosis

• It's rarely possible to diagnose or exclude sarcoidosis with 100% certainty.
  • If patients aren't responding as expected to therapy, the diagnosis needs to be reevaluated.
• Sarcoidosis diagnosis often involves four components:
  • (1) Clinical and radiographic presentation compatible with sarcoidosis.
  • (2) Exclusion of alternative diagnoses (often focusing on: tuberculosis, lymphoma, silicosis, berylliosis, combined variable immunodeficiency).
  • (3) Evidence of systemic involvement (usually present, but not always).
  • (4) Tissue biopsy showing noncaseating granulomas (not always necessary).
• Sarcoidosis is less likely if the disease course is very rapid. Specifically, sarcoidosis is unlikely if any of the following are seen: (31365383)
  • Rapid improvement (days to a few weeks) without therapy.
  • Rapid organ damage (days to a few weeks) involving organs other than the heart or nervous system.
  • Rapid onset (days to a few weeks) of diffuse lung disease with respiratory failure.

clinical presentations that may be diagnosed as sarcoidosis, without a tissue biopsy

• ⚠️ Patients who don't undergo a tissue biopsy should undergo close follow-up to further ensure that an infectious or malignant process isn't developing.
• (1) Bilateral hilar lymphadenopathy that is typical of sarcoidosis (discussed in #3 below) plus a clinical context that is highly suggestive of sarcoidosis:
  • Lofgren syndrome. 📖
  • Heerfordt syndrome. 📖
  • Bilateral hilar lymphadenopathy with uveitis. (34314343)
  • Bilateral hilar lymphadenopathy with lupus pernio. (32293205)
  • Bilateral hilar lymphadenopathy without symptoms (no fever, night sweats, or weight loss). (34314343, 34496176) This remains controversial, with the most recent ATS guidelines making no recommendation either for or against biopsy. (32293205)
• (2) Typical CT scan findings plus a typical clinical presentation may allow for a confident clinical diagnosis, according to the British Thoracic Society guidelines. However, this remains controversial and should ideally be decided within a multidisciplinary conference. These guidelines describe typical CT features as follows: (BTS 2020 guidelines)
  • Lymph node enlargement:
    • Hilar +/- mediastinal.
    • Bilateral and symmetric
    • Well-defined, homogeneous.
    • Calcification may be present in an eggshell configuration, or an “icing sugar” configuration.
  • Nodules:
    • Well-defined 2-5 mm nodules.
    • Paraseptal predominance.
    • Fissural beading/peribronchovascular nodularity.
    • Nodules may coalesce into larger nodules or perihilar consolidation.
  • Fibrosis:
    • Reticular opacity.
    • Volume loss/architectural distortion.
    • Traction bronchiectasis.
    • Peribronchovascular fibrosis.

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laboratory studies

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laboratory tests to consider obtaining in suspected sarcoidosis:

• Labs that may reflect granulomatous inflammation:
  • ACE level (discussed below).
  • Serum calcium and ionized calcium, PTH level, 25-hydroxy vitamin D, and 1,25-dihydroxy vitamin D.
• Infection evaluation may include:
  • IGRA (interferon gamma release assay for tuberculosis).
  • Induced sputum for acid-fast bacilli culture/smear and tuberculosis PCR.
  • Fungal antigens (e.g., beta-D-glucan, serum cryptococcal antigen, urine Blastomyces and histoplasmosis antigens).
• Evaluation for CVID (combined variable immunodeficiency syndrome): quantitative serum immunoglobulin levels (IgG, IgA, IgM).
• Evaluation for GPA (granulomatosis with polyangiitis): ANCA titer, testing for anti-MPO and anti-PR3 autoantibodies.
• Evaluation for berylliosis: Beryllium Lymphocyte Proliferation Test (BeLPT) 📖
• Evaluation for IgG4-related disease: IgG4 levels.

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ACE level

basics

• Angiotensin-converting enzyme (ACE) is produced by macrophages within a granuloma, so it is increased in granulomatous diseases.
• Normally ACE levels are <40 mcg/L.
• ACE level may have some utility for the initial diagnosis of sarcoidosis. However, this remains controversial.
• ⚠️ ACE levels may be confounded by the therapeutic use of ACE-inhibitors.

sensitivity

• ACE level >40 mcg/L has a sensitivity of ~75% for sarcoidosis. (Murray 2022) 
• ACE elevation may be more sensitive for patients with hepatic or splenic involvement, with less sensitivity for cardiac or neurologic involvement.
  • In neurosarcoidosis, ACE levels are elevated only in about a third of cases. (Tavee 2022)

specificity – causes of elevated ACE level include: 

• Granulomatous inflammatory disorders:
  • Sarcoidosis.
    • ACE level >40 mcg/L has a specificity of ~85% for sarcoidosis. (31485575)
    • ACE level >80 mcg/L has a higher specificity for sarcoidosis (with a likelihood ratio of ~7). (24476436) 
  • Berylliosis.
  • CVID (combined variable immunodeficiency syndrome) & GLILD (granulomatous lymphocytic interstitial lung disease). (33447267)
  • HP (hypersensitivity pneumonitis).
  • Pneumoconiosis:
    • Silicosis.
    • Asbestosis.
• Infectious diseases that cause granulomatous inflammation:
  • Tuberculosis.
  • Fungal infection, especially coccidiomycosis. (37407005)
• Malignancy:
  • Hodgkin lymphoma.
  • Lung cancer.
• Miscellaneous other:
  • Hyperthyroidism.
  • Primary biliary cholangitis.

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tissue diagnosis

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site of biopsy

safer biopsy sites may include:

• Skin (but not erythema nodosum – which won't yield granulomas).
• Peripheral lymphadenopathy.
• Cervical lymph nodes (via ultrasound-guided core needle biopsy; seems to have high yield). (32678668)
• Bone marrow (e.g., among patients with multiple cytopenias).
• Conjunctival nodules, enlarged lacrimal gland.
• Bronchoscopic biopsy (discussed below).
• 💡 Total body PET scan may be considered to identify organ involvement that may be a safe site for biopsy.

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bronchoscopy in sarcoidosis

airway inspection & endobronchial biopsy

• Airway inspection may reveal a variety of abnormalities:
  • Erythematous inflammation.
  • Mucosal nodules or plaques (classically 2-3 mm waxy yellow mucosal lesions, sometimes described as cobblestone mucosa). (BTS 2020 guidelines)
  • Bronchial stenosis, airway compression.
• Endobronchial biopsy may show granulomatous inflammation. (ERS handbook 3rd ed.)
  • Diagnostic yield may be roughly ~50%, with higher yield if there is visually abnormal bronchial mucosa (e.g., erythematous and/or thickened airways, and especially a nodular/cobblestone appearance). (28210300)
  • For patients with visual bronchial abnormalities, endobronchial biopsy is a safer alternative to transbronchial biopsy. (28210300)

BAL (bronchoalveolar lavage) in sarcoidosis

• Roles of BAL in sarcoidosis:
  • (1) Might provide supportive evidence regarding sarcoidosis, based on cell count.
  • (2) Primary role is to help exclude alternative diagnoses (especially infection).
• Differential cell count in sarcoidosis::
  • Lymphocytosis (>15%) is ~90% sensitive, but poorly specific.
    • Lymphocyte count of 15-25% supports granulomatous disease (including sarcoidosis). (BTS 2020 guidelines)
    • Lymphocytosis >50% suggests hypersensitivity pneumonitis or cellular nonspecific interstitial pneumonia. (BTS 2020 guidelines)
  • CD4/CD8 ratio >3.5-4 can be strongly supportive of the diagnosis. 📖
  • Eosinophilia suggests an alternative diagnosis.
  • Neutrophilia generally suggests an alternative diagnosis, but can occur in severe disease.

EBUS-TBNA (endobronchial ultrasound – transbronchial lymph node aspiration) 

• Diagnostic yield is ~75% (which is higher than transbronchial biopsy or endobronchial biopsy). (BTS 2020 guidelines)
• EBUS-TBNA is generally the preferred technique for obtaining a tissue biopsy among patients with lymphadenopathy.
• Rapid on-site evaluation of cytopathology (ROSE) may help determine if diagnostic material has been obtained (while the procedure is underway).

transbronchial lung biopsy

• Performance:
  • The diagnostic yield is ~60%. However, when parenchymal lung disease is absent on CT scan, the diagnostic yield is low. (Trisolini 2022)
  • Transbronchial biopsy carries the highest risk of pneumothorax (~5%) or clinically significant hemoptysis.
• Transbronchial biopsy is most useful for patients with parenchymal lung disease who lack significant lymphadenopathy. (BTS 2020 guidelines)
• Transbronchial biopsy may not offer a favorable risk/benefit ratio for patients who have other suitable biopsy targets. If both nodal and parenchymal disease is present, EBUS is the preferred initial diagnostic test. (BTS 2020 guidelines)

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histologic findings

• Non-necrotizing (aka, noncaseating) granulomas are typically associated with sarcoidosis or other inflammatory disorders. Alternatively, necrotizing granulomas are typically associated with infection or possibly vasculitis. (31365383) 
  • The distinction between necrotizing and non-necrotizing granulomas is not completely reliable. For example, sarcoidosis may occur with necrotizing granulomas. Alternatively, tuberculosis may present with non-necrotizing granulomas.
• Pathological staining to detect mycobacteria or fungal pathogens should be performed whenever possible. This may help exclude infection.
• Yellow-brown bodies (Hamazaki-Wesenberg bodies) may be seen in patients with sarcoidosis. This is nonspecific and of unknown precise significance, but it may support the diagnosis of sarcoidosis. These bodies react with GMS (Gomori methenamine silver) stain, so they can mimic a fungal infection. (35526899)

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differential diagnosis of granulomatous inflammation

granulomas involving the lung

• Infection: (usually necrotizing granulomas)
  • Mycobacteria (note that pathologic examination of tissue won't always reveal acid-fast bacilli; cultures and/or PCR may be additionally needed).
    • Tuberculosis.
    • Nontuberculous mycobacteria.
    • Mycobacterium bovis due to therapy with BCG (bacille Calmette-Guerin) for urological malignancy (illness may develop following a latency period of months to years). (26605931)
  • Fungi, for example:
    • Endemic mycoses.
    • Cryptococcus neoformans.
    • Aspergillus.
    • Pneumocystis.
  • Herpes zoster.
  • Chronic granulomatous disease.
• Inflammatory: (usually non-necrotizing granulomas)
  • Sarcoidosis or berylliosis.
  • Inflammatory bowel disease.
  • CVID (common variable immunodeficiency syndrome)
    • May cause inflammatory granuloma formation even in the absence of active infection. This constitutes the diagnosis of GLILD (granulomatous and lymphocytic interstitial lung disease).
  • ANCA-associated vasculitides:
    • GPA (granulomatosis with polyangiitis).
    • EGPA (eosinophilic granulomatosis with polyangiitis).
  • Bronchocentric granulomatosis. 📖
• Malignancy/lymphoproliferative:
  • Primary pulmonary lymphoma.
  • Lymphomatoid granulomatosis.
  • Sarcoid-like reaction to malignancy.
  • IgG4-related disease.
• Exposure-related:
  • HP (hypersensitivity pneumonitis):
    • HP is usually associated with scattered, small, poorly-formed non-necrotizing granulomas centered around bronchioles.
    • HP due to Mycobacterium avium complex (“hot tub lung”) may cause large, well-formed granulomas to develop. (26605931)
  • Pneumoconiosis: Beryllium, aluminum, titanium, talc, zirconium, cobalt, etc.
  • Foreign body granulomatosis:
    • Aspiration (e.g., chronic aspiration bronchiolitis).
    • Aspirated talc.
    • Injected talc (incipient lung disease).
  • PLCH (pulmonary Langerhans cell histiocytosis).
  • Drug-induced sarcoidosis-like reactions.* (32293205)

lymph node

• Infection:
  • Tuberculosis.
  • Nontuberculous mycobacteria.
  • Brucellosis.
  • Histoplasmosis.
  • Toxoplasmosis.
  • Brucellosis.
  • Bartonella henselae (cat-scratch disease).
  • Tularemia.
• Malignancy:
  • Hodgkin and non-Hodgkin lymphoma.
  • Germ cell tumor.
  • Sarcoid-like reaction to malignancy in regional draining lymph nodes.
• Inflammatory:
  • Sarcoidosis, berylliosis.
  • HP (hypersensitivity pneumonitis).
  • GLILD associated with CVID (granulomatous and lymphocytic interstitial lung disease associated with combined variable immunodeficiency syndrome).
• Exposure-related:
  • Langerhans cell histiocytosis.
  • Pneumoconiosis: Beryllium, aluminum, titanium, talc, zirconium, cobalt, etc.
  • Foreign body granulomatosis (e.g., aspirated or injected talc).
  • Drug-induced sarcoidosis-like reactions.*
• Other:
  • IgG4-related disease.
  • GLUS (granulomatous lesions of unknown significance).
  • Histiocytic necrotizing lymphadenitis (Kikuchi disease). (32293205)

skin

• Infection:
  • Tuberculosis.
  • Atypical mycobacteria.
  • Brucellosis.
  • Tularemia.
  • Bartonella henselae (Cat scratch disease).
  • Fungi.
    • Aspergillus
    • Histoplasmosis.
    • Blastomycosis
    • Cryptococcus.
  • Herpes zoster.
  • Toxoplasmosis.
• Malignancy:
  • Lymphoma.
  • Sarcoid-like reaction to tumor.
  • Lymphomatoid granulomatosis.
• Inflammatory:
  • Sarcoidosis.
  • Inflammatory bowel disease.
  • ANCA-associated vasculitis.
  • Rheumatoid nodules.
• Exposure related:
  • Pneumoconiosis: Beryllium, aluminum, titanium, talc, zirconium, cobalt, etc.
  • Reaction to foreign bodies (metals, tattoos, paraffin, etc.).
  • Drug reactions, including drug-induced sarcoidosis-like reactions.*
• Other:
  • IgG4-related disease.
  • GLUS (granulomatous lesions of unknown significance). (32293205)

liver

• Infection:
  • Tuberculosis, nontuberculous mycobacteria.
  • Brucellosis.
  • Coxiella burnetii.
  • Cryptococcus.
  • Toxoplasmosis.
  • Schistosomiasis.
  • Leishmaniasis.
  • Echinococcosis.
• Malignancy:
  • Hodgkin and non-Hodgkin lymphoma.
  • Sarcoid-like reaction to malignancy.
• Inflammatory:
  • Sarcoidosis.
  • Inflammatory bowel disease, primary biliary cholangitis, primary sclerosing cholangitis.
• Other:
  • GLUS (granulomatous lesions of unknown significance).
  • Langerhans cell histiocytosis.
  • IgG4-related disease.
  • Steatosis (lipogranulomas)
  • Drug reactions, including drug-induced sarcoidosis-like reactions.* (32293205)

bone marrow

• Infection:
  • Tuberculosis.
  • Histoplasmosis.
  • Brucellosis.
  • Aspergillus, histoplasmosis, coccidiomycosis, cryptococcus.
  • Infectious mononucleosis.
  • Cytomegalovirus.
  • Coxiella burnetii.
• Malignancy:
  • Hodgkin and non-Hodgkin lymphoma.
  • Sarcoid-like reaction to tumor.
• Other:
  • Sarcoidosis.
  • Granulomatous lesions of unknown significance (GLUS).
  • Langerhans cell histiocytosis.
  • IgG4-related disease.
  • Drug reactions, including drug-induced sarcoidosis-like reactions.* (32293205)

renal biopsy

• Tuberculosis.
• Fungal infection.
• Foreign body reaction.
• Granulomatosis with polyangiitis.
• Crohn disease.
• Medications.* (31485575; 32293205)

*Medications that may cause granulomatous inflammation include:

• Antiretroviral therapy.
• Immune checkpoint inhibitors.
• Interferons.
• Methotrexate.
• TNF-alpha inhibitors. (30955519, 34314343)

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differential diagnoses of note

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drug-induced sarcoidosis-like reaction

• May closely mimic sarcoidosis.
• Exposure history and timing are the crux of diagnosis.
• Causative medications include:
  • Interferons.
  • Highly active antiretroviral therapy.
  • Immune checkpoint inhibitors.
  • Tumor necrosis factor alpha antagonists.

checkpoint inhibitor-related sarcoidosis-like reaction

• This is less common than checkpoint inhibitor-induced pneumonitis in general.
• In addition to pulmonary involvement, this may involve other organs (ocular, myocardial, neurologic, hypercalcemia). (29162153)
• Treatment is not necessarily required, especially if the condition is asymptomatic. (35332071)

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sarcoid-like reaction to malignancy

basics

• Tumor antigens incite a non-caseating granulomatous reaction, leading to lymphadenopathy (that mimics sarcoidosis).
• This is generally asymptomatic. The primary importance of sarcoid-like reaction to malignancy is that it may function as a diagnostic red herring. For example:
  • (1) Sarcoid-like reactions may cause benign lymphadenopathy that can mimic malignant lymphadenopathy, thereby making it appear that the malignancy has a higher stage than it actually does.
  • (2) If the underlying malignancy hasn't yet been diagnosed, there is a risk that the entire clinical presentation could be incorrectly attributed to sarcoidosis (thereby missing the underlying cancer diagnosis). (31891305)

epidemiology

• Clinically this usually develops in the context of known malignancy (sometimes triggered by immunotherapy). However, it can occur as the original presentation of malignancy. (31699233)
• Lymphoma is the most common trigger, with a fairly high incidence on postmortem autopsy studies: (31891305)
  • ~14% of patients with Hodgkin lymphoma.
  • ~7% of non-Hodgkin lymphoma.
• Solid tumors may also cause a sarcoid-like reaction (e.g., breast cancer, testicular cancer, lung cancer, renal cell carcinoma, cervical carcinoma, gastric carcinoma, skin cancer). (31699233)

clinical presentation

• Lesions are usually located near the primary tumor or metastatic tumor sites. However, in Hodgkin lymphoma granulomas may be found at distant sites throughout the reticuloendothelial system (e.g., liver, spleen, bone marrow, and distant lymph nodes). (31891305)
• There is usually little functional lung impairment. (Fishman 2023)
• There usually aren't systemic symptoms. (31891305)

clues to the presence of sarcoid-like reaction to malignancy may include:

• Atypical presentation of sarcoidosis.
• Lack of steroid response.
• Patient aged >50 years old. (31891305)

treatment

• Treatment focuses on management of the underlying malignancy.
• Treatment of the sarcoid-like reaction is generally unnecessary.

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granulomatous lesions of unknown significance (GLUS)

• Histologically, patients with GLUS may have a greater number of B-lymphocytes than those with sarcoidosis.
• Typically involves the liver, bone marrow, spleen, and/or lymph nodes (but not the lung).

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treatment

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general principles of treatment

• Spontaneous remission is frequent.
• Indications for treatment:
  • Severe symptoms that impair quality of life.
  • Progressive organ damage/dysfunction.
• Management depends considerably on the specific manifestation of sarcoidosis.
  • (1) This begins with a systematic evaluation for involvement of various organs, as listed below.
  • (2) Specific management of various organ systems is detailed further above.

initial multi-organ staging evaluation for sarcoidosis:

• History and physical examination.
• Pulmonary evaluation:
  • Chest radiograph +/- chest CT scan.
  • PFTs (pulmonary function tests).
• Laboratory studies:
  • Complete blood count.
  • Electrolytes and renal function.
  • Calcium level, 25-hydroxyvitamin D3.
  • Liver function tests.
  • Urinalysis (to evaluate for interstitial nephritis).
• Cardiac examination: 📖
  • EKG for everyone.
  • Low threshold to obtain echocardiogram and/or Holter monitor if concerning symptoms.
• Eye examination by ophthalmology.

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prognosis and clinical course

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• Organ involvement usually defines itself early in the disease (within the first 2-3 years following diagnosis). An exception is cardiac sarcoidosis, which may manifest years after the initial diagnosis (even among patients who initially didn't require therapy). (Fishman 2023, Culver 2022)
• Patients who undergo remission usually do so within <2-3 years. This defines different patterns of disease progression: (Fishman 2023)
  • (a) After long-standing remission, recurrence is rare (with the exception of neurologic or ocular involvement). (Fishman 2023) 
  • (b) Patients with chronic active disease usually have a progressive and unremitting course (rather than a waxing/waning course). (Fishman 2023)
• Relapse following steroid discontinuation:
  • Relapse may occur in roughly a third of patients.
  • About half of relapses occur within six months, and nearly all relapses occur within <36 months. Thus, if disease is inactive for >3 years then it may be labeled as being in remission (with subsequent relapse being unlikely). (Culver 2022)
  • Most relapses involve the same organs that were originally involved. (Culver 2022)
• Prognosis as related to radiographic staging is discussed above: 📖.

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questions & discussion

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Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.