Sarcoidosis: Pulmonary Disorders: Merck Manual Professional

Sarcoidosis is characterized by noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but sarcoidosis may affect any organ. Pulmonary symptoms range from none (limited disease) to exertional dyspnea and, rarely, respiratory or other organ failure (advanced disease). Diagnosis usually is first suspected because of pulmonary involvement and is confirmed by chest x-ray, biopsy, and exclusion of other causes of granulomatous inflammation. First-line treatment is corticosteroids. Prognosis is excellent for limited disease but poor for more advanced disease.

Sarcoidosis primarily affects people aged 20 to 40 but occasionally affects children and older adults. Worldwide, prevalence is greatest in black Americans and northern Europeans, especially Scandinavians. Disease presentation varies widely by racial and ethnic background, with black Americans and Puerto Ricans demonstrating more frequent extrathoracic manifestations. Sarcoidosis is slightly more prevalent in women. Incidence increases in winter and early spring, for unknown reasons.

Sarcoidosis is thought to be due to an inflammatory response to an environmental exposure in a genetically susceptible person. Although uncertain, proposed triggers include viral, bacterial, and mycobacterial infections and inhalation of inorganic (eg, aluminum, zirconium, talc) or organic (eg, pine tree pollen, clay) agents. The unknown antigen triggers a cell-mediated immune response characterized by the accumulation of T lymphocytes and macrophages, release of cytokines and chemokines, and organization of responding cells into granulomas. Clusters of disease in families and communities suggest a genetic predisposition, shared exposures, or, less likely, person-to-person transmission.

The result of the inflammatory process is formation of noncaseating granulomas, the hallmark of sarcoidosis. Granulomas are collections of mononuclear cells and macrophages that are differentiated into epithelioid and multinucleated giant cells, surrounded by lymphocytes, plasma cells, mast cells, fibroblasts, and collagen. Granulomas occur most commonly in the lung and lymph nodes but can involve many other sites, including the liver, spleen, eyes (see Uveitis: Sarcoidosis), sinuses, skin, bones, joints, skeletal muscle, kidney, reproductive organs, heart, salivary glands, and nervous system. The granulomas in the lung are distributed along lymphatics, with most found in peribronchiolar, subpleural, and perilobular regions.

Symptoms and signs depend on the site and degree of involvement and vary over time, ranging from spontaneous remission to chronic indolent illness. Therefore, frequent reassessment for new symptoms in different organs is needed. Most cases are probably asymptomatic and thus go undetected. Pulmonary disease occurs in > 90% of adult patients.

Symptoms and signs may include dyspnea, cough, chest discomfort, and crackles on examination. Fatigue, malaise, weakness, anorexia, weight loss, and low-grade fever are also common; sarcoidosis is an unusual cause of fever of unknown origin. Nontender lymphadenopathy is often the only sign. Systemic involvement causes various symptoms (see Table 1: Sarcoidosis: Systemic Involvement in Sarcoidosis

), which vary by race, sex, and age. Blacks are more likely than whites to have involvement of the eye, liver, bone marrow, peripheral lymph nodes, and skin other than erythema nodosum. Women are more likely to have erythema nodosum and eye or nervous system involvement. Men and older patients are more likely to be hypercalcemic.

In children < 4 yr, arthritis, rash, and uveitis are the most common presentations. Sarcoidosis may be confused with juvenile RA in this age group.

Sarcoidosis is most often suspected when hilar adenopathy is incidentally detected on chest x-ray. These changes are the most common abnormality, and x-ray appearance is roughly predictive of the likelihood of spontaneous remission (see Table 2: Sarcoidosis: Staging Sarcoidosis

) in patients with pulmonary involvement. Therefore, a chest x-ray should be the first test if it has not already been obtained in patients suspected of having sarcoidosis.

Because pulmonary involvement is so frequent, a normal chest x-ray generally excludes the diagnosis. In cases in which the disease is highly suspected despite a normal chest x-ray, high-resolution chest CT is more sensitive for detecting hilar and mediastinal lymphadenopathy; CT findings in more advanced stages (II to IV) include thickening of the bronchovascular bundles and bronchial walls; beading of the interlobular septa; ground-glass opacification; parenchymal nodules, cysts, or cavities; and/or traction bronchiectasis.

When imaging suggests sarcoidosis, the diagnosis is confirmed by demonstration of noncaseating granulomas on biopsy and exclusion of alternative causes of granulomatous disease (see Table 3: Sarcoidosis: Differential Diagnosis of Sarcoidosis

). The diagnostic evaluation, therefore, requires selection of a biopsy site; exclusion of other causes of granulomatous disease; and assessment of the severity and extent of disease to determine if therapy is indicated.

Sites for biopsy may be obvious from physical examination and initial assessment: peripheral lymph nodes, skin lesions, and conjunctivae are all easily accessible. However, bronchoscopic transbronchial biopsy is the diagnostic procedure of choice in patients with intrathoracic involvement, because the sensitivity is as high as 90% in experienced hands. Video-assisted thoracoscopy can provide access to lung tissue when bronchoscopic transbronchial biopsy is nondiagnostic. Mediastinoscopy is sometimes performed when hilar or mediastinal lymphadenopathy exists in the absence of pulmonary infiltrates, especially if lymphoma is in the differential diagnosis. However, even in patients with only mediastinal adenopathy on x-ray or CT, transbronchial biopsies are often diagnostic. Open lung biopsy provides another way to obtain tissue but requires general anesthesia and is now rarely necessary. Clinical and x-ray findings may be accurate enough for diagnosis in stage I disease or in stage II disease when biopsy is not possible.

Exclusion of other diagnoses is critical, especially when symptoms and x-ray signs are minimal, because many other diseases and processes can cause granulomatous inflammation (see Table 3: Sarcoidosis: Differential Diagnosis of Sarcoidosis

). Biopsy tissue should be cultured for fungi and mycobacteria. Exposure history to occupational (silicates, beryllium), environmental (moldy hay, birds, and other antigenic triggers of hypersensitivity pneumonitis), and infectious (TB, coccidioidomycosis, histoplasmosis) antigens should be explored. PPD skin testing should be performed early in the assessment along with anergy controls.

Pulmonary function tests and exercise pulse-oximetry assess disease severity. Pulmonary function test results are often normal in early stages but demonstrate restriction and reduced diffusing capacity for carbon monoxide (DLco) in advanced disease. Airflow obstruction also occurs and may suggest involvement of the bronchial mucosae. Pulse oximetry is often normal when measured at rest but may show effort desaturation with more extensive lung involvement. ABG analysis at rest and during exercise is more sensitive than pulse oximetry.

Recommended screening tests for extrapulmonary disease include ECG, slit-lamp ophthalmologic examination, and routine renal and liver function testing. Echocardiography, neuroimaging, lumbar puncture, bone films or MRI, and electromyography may be appropriate when symptoms suggest cardiac, neurologic, or rheumatologic disease. Abdominal CT with radiopaque dye is not routinely recommended but can provide evidence of hepatic or splenic involvement with enlargement and hyperlucent lesions.

Laboratory testing plays an adjunctive role in establishing the diagnosis and extent of organ involvement. CBC, electrolytes (including calcium), BUN, creatinine, and liver function tests generally provide useful information in screening for extrathoracic involvement. CBC may show anemia, eosinophilia, or leukopenia. Serum Ca may be elevated because of production of vitamin D analogs by activated macrophages. BUN, creatinine, and liver function tests may be elevated in renal and hepatic sarcoidosis. Total protein may be elevated because of hypergammaglobulinemia. Elevated ESR is nonspecific. Measurement of Ca in a urine specimen collected over 24 h is recommended to exclude hypercalciuria, even in patients with normal serum Ca levels. Elevated serum ACE levels also suggest sarcoidosis but are nonspecific and may be low in patients taking ACE inhibitors or elevated in patients with a variety of other conditions (eg, hyperthyroidism, Gaucher's disease, silicosis, mycobacterial disease, hypersensitivity pneumonitis). ACE levels may be useful for following disease activity and therapeutic response in patients with confirmed sarcoidosis. Increased ACE levels in CSF may be useful for diagnosing CNS sarcoidosis.

Sarcoidosis—Stage I

Sarcoidosis—Stage II

Sarcoidosis—Stage III

Sarcoidosis—Stage IV

Other adjunctive tests include bronchoalveolar lavage and gallium scanning. The findings on bronchoalveolar lavage vary considerably, but lymphocytosis (lymphocytes > 10%) and/or a CD4+/CD8+ ratio of > 3.5 in the lavage fluid cell differential suggests the diagnosis in the proper clinical context. Absence of these findings does not exclude sarcoidosis, however.

Whole-body gallium scanning may provide useful supportive evidence in the absence of tissue confirmation. Symmetrical increased uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid, and salivary glands (panda sign) are patterns highly suggestive of sarcoidosis. A negative result in patients taking prednisone Some Trade Names
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is unreliable.

Although spontaneous improvement is common, the severity and manifestations of disease are highly variable, and many patients require courses of corticosteroids some time during the course of their disease. Thus, serial monitoring for evidence of relapse is imperative. About 90% of patients who have spontaneous remission do so within the first 2 yr after diagnosis; < 10% of these patients have relapses after 2 yr. Those patients who do not experience remission within 2 yr are likely to have chronic disease.

Sarcoidosis is thought to be chronic in up to 30% of patients, and 10 to 20% experience permanent sequelae. The disease is fatal in 1 to 5% of patients. Pulmonary fibrosis with respiratory failure is the most common cause of death worldwide, followed by pulmonary hemorrhage from aspergilloma. In Japan, however, infiltrative cardiomyopathy causing heart failure and arrhythmias is the most common cause of death.

Prognosis is worse for patients with extrapulmonary sarcoidosis and for blacks. Recovery occurs in 89% of whites and 76% of blacks with no extrathoracic disease and in 70% of whites and 46% of blacks with extrathoracic disease. The presence of erythema nodosum and acute arthritis are good prognostic signs. Uveitis, lupus pernio, chronic hypercalcemia, neurosarcoidosis, nephrocalcinosis, myocardial disease, and extensive pulmonary involvement are all poor prognostic signs. However, little difference is demonstrable in long-term outcome between treated and untreated patients, and relapse is common when treatment ends.

Because sarcoidosis often spontaneously resolves, asymptomatic patients and those with mild symptoms do not require treatment, although they should be monitored for signs of deterioration. These patients can be followed with serial x-rays, pulmonary function tests (including diffusing capacity), and markers of extrathoracic involvement (eg, routine renal and liver function testing). Patients who require treatment regardless of stage include those with worsening symptoms; limitation of activity; markedly abnormal or deteriorating lung function; worrisome x-ray changes (cavitation, fibrosis, conglomerate masses, signs of pulmonary hypertension); heart, nervous system, or eye involvement; renal or hepatic insufficiency or failure; or disfiguring skin and joint disease.

Treatment is with corticosteroids. A standard protocol is prednisone Some Trade Names
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0.3 to 1mg/kg po once/day depending on symptoms and severity of findings. Alternate-day regimens are also used (eg, prednisone Some Trade Names
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40 to 60 mg po once every other day). It is rare to exceed 40 mg/day; however, higher doses may be needed to reduce complications in patients with ocular, myocardial, or neurologic disease. Response usually occurs within 2 to 4 wk, so symptoms and results of chest x-ray and pulmonary function tests may be reassessed between 4 and 12 wk. Chronic, insidious cases may respond more slowly. The drug is tapered to a maintenance dose (eg, prednisone Some Trade Names
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≤ 10 mg every other day if possible) after evidence of response and is continued for a minimum of 12 mo if improvement occurs. The optimal duration of treatment is unknown. Premature taper can result in relapse. The drug is slowly stopped if response is absent or equivocal. Corticosteroids can ultimately be stopped in most patients, but because relapse occurs up to 50% of the time, monitoring should be repeated, usually every 3 to 6 mo. Corticosteroid treatment should be resumed for recurrence of symptoms and signs, including dyspnea, arthralgia, fever, hepatic insufficiency, cardiac arrhythmia, CNS involvement, hypercalcemia, ocular disease uncontrolled by local drugs, and disfiguring skin lesions.

Data on use of inhaled corticosteroids for pulmonary sarcoidosis are not definitive, but some evidence suggests that this route of administration can relieve cough in patients with endobronchial involvement. Topical corticosteroids may be useful in some cases of dermatologic and ocular disease.

About 10% of patients requiring therapy are unresponsive to tolerable doses of a corticosteroid and should be given a 6-mo trial of methotrexate Some Trade Names
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starting at 2.5 mg po once/wk and increasing in increments of 2.5 mg/wk to a total of 10 to 15 mg/wk as tolerated to keep WBC > 3000/μL. Initially, methotrexate Some Trade Names
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and corticosteroids are both given; over 8 wk, the corticosteroid dose can be tapered and, in many cases, stopped. The maximal response to methotrexate Some Trade Names
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, however, may take 6 to 12 mo. In such cases, prednisone Some Trade Names
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must be tapered more slowly. Serial blood counts and liver enzyme tests should be performed every 1 to 2 wk initially and then every 4 to 6 wk once a stable dose is achieved. Folic acid (1 mg po once/day) is recommended for patients treated with methotrexate Some Trade Names
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.

Hydroxychloroquine Some Trade Names
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200 mg po bid to tid can be as effective as corticosteroids for treatment of disfiguring skin sarcoidosis and in treatment of hypercalciuria. Although immunosuppressants are often more effective in refractory cases, relapse is common after cessation.

Lung transplantation is an option for patients with end-stage pulmonary involvement, although disease may recur in the transplanted organ.