Presentations of sarcoidosis vary with the sites of granulomatous inflammation. The most common presentation, especially in young adults, is bilateral hilar adenopathy, which occurs in 50% of patients with sarcoidosis and is often detected on routine chest radiography. About 25% of patients present with bilateral hilar adenopathy and pulmonary infiltrates, and 15% present with infiltrates alone. Disease in the hilum is not associated with invasion or compression of the bronchi or nodal calcification. Erythema nodosum may accompany bilateral hilar adenopathy. This combination is known as Lofgren syndrome. Less common is Heerfordt syndrome: parotid gland enlargement, fever, uveitis, and cranial nerve palsies. Some patients exhibit cough, shortness of breath, wheezing, or chest discomfort in addition to constitutional symptoms of fever, malaise, and fatigue. Although pulmonary symptoms are the most frequent, sarcoidosis may present with extrathoracic disease, including hepatomegaly, splenomegaly, or uveitis (manifested by red, watery eyes). Other presenting manifestations include fever of unknown origin, granulomatous hepatitis, salivary and lacrimal gland enlargement, arthritis, peripheral adenopathy, and skin lesions. Diagnosis is delayed longer among patients who present with nonspecific pulmonary symptoms than among those who present with skin findings. Lofgren syndrome is the combination of hilar adenopathy and erythema nodosum.

Hypercalcemia as a consequence of increased sensitivity to vitamin D is reported in 10% to 30% of patients but is sustained in only 2% to 3%. Recent data suggest that it is more frequent in white people and those older than 40 years of age. Cardiac conduction abnormalities, such as heart block, and neurologic abnormalities, including facial palsies, are each seen in about 5% of cases. In addition, many unusual presentations have been reported.

Patients with clear lungs and asymptomatic hilar adenopathy have an excellent prognosis. In one large series of untreated cases, complete remission occurred in more than 75% of patients within 5 years. In 50% of patients with untreated pulmonary parenchymal involvement, complete resolution was seen within 2 years. In one third of those in whom clearing did not occur, severe fibrosis developed. Overall, at 5 years, 87% were clinically well, 10% had died of respiratory failure, and 3% were disabled by pulmonary disease. Patients with Lofgren syndrome also have a very favorable prognosis.

Most natural history data derive from referral centers. In a report from a nonreferral setting, 86 patients were followed for 10 years in a primary care practice; pulmonary fibrosis developed in 12, and none experienced respiratory failure or cor pulmonale. This latter study suggests that the course of sarcoidosis may be more benign than has been reported from referral centers, which are more likely to attract complicated cases. There is also a striking 10-fold difference in mortality rates derived from series of patients seen in referral centers (5% mortality) and those that are population based (0.5% mortality). One study raised the question of whether frequent and sustained use of corticosteroids in referral centers contributes to higher mortality.

In general, patients with stage I disease have an 80% chance of spontaneous remission, those with stage II disease have about a 50% remission rate, and those with stage III disease have about a 20% to 40% chance of spontaneous remission. Stage IV represents irreversible, advanced disease.

Extrathoracic complications are infrequent. Hepatic granulomas are often present, but the development of clinically symptomatic granulomatous hepatitis is much less common; hepatic failure and portal hypertension are rare. Cranial and peripheral neuropathies tend to occur early in the disease and are usually transient; however, in some patients, significant neurologic damage is seen. Uveitis affects about 15% of patients, comes on acutely, and often resolves spontaneously. More worrisome is chronic iridocyclitis; it presents as pain and blurring of vision, and cataracts, secondary glaucoma, and blindness may eventually develop. As noted earlier, hypercalcemia persists in about 2% to 3% of cases, although it may be found transiently in up to 30%. Cardiac granulomas are found in 20% of sarcoidosis cases that come to autopsy, but fewer than 5% of patients experience difficulties with conduction or impulse formation. Rarely, infiltration of the myocardium produces pump failure.

The course of patients with sarcoidosis may occasionally be complicated by infections such as tuberculosis, Aspergillus fungus balls, candidiasis, and cryptococcosis, attributable in part to the disease and in part to the use of long-term steroid therapy.

The chest x-ray is an essential component of the diagnostic assessment. The use of imaging other than chest x-ray on a routine basis in sarcoidosis is controversial. There are findings on chest computed tomography (CT) that are characteristic of sarcoidosis, including hilar and mediastinal adenopathy, lung disease with upper lobe predominance, peribronchial irregularities, and subpleural micronodules. None of these findings, however, is specific enough to confirm a diagnosis and necessitate its use, but the increased sensitivity of the chest CT for detection of hilar adenopathy makes it a reasonable consideration when plain film of the chest is unrevealing, but clinical suspicion remains high. Abdominal adenopathy and hepatic and splenic nodules may be present on abdominal CT, but these findings too are nonspecific. Positron emission tomography (PET) has been used to help detect sites of active disease that might be useful targets for biopsy; the test is highly sensitive, but specificity is low. The same is true for gallium-67 radionuclide scanning, which has also been helpful in identifying extrathoracic disease. Plain films of the bones of the hands may reveal changes suggestive of sarcoidosis.

Serum levels of angiotensin-converting enzyme (ACE) are elevated in about 70% of patients with active sarcoidosis, but ACE determinations lack both sensitivity and specificity for establishing a diagnosis of sarcoidosis. ACE levels have been studied as markers of disease activity and therapeutic responsiveness, but results have proved disappointing in clinical practice (see later discussion).

Other abnormalities that may be present in patients with sarcoidosis include cutaneous anergy, hyperglobulinemia, abnormal serum liver chemistries, and elevated levels of lysozyme; none of these findings is specific, but together, they are supportive of the diagnosis.

A decision to perform a biopsy must be made by viewing the potential for discovering treatable conditions and balancing this probability against the risks associated with the procedure. For the tissue diagnosis of hilar adenopathy, mediastinoscopy is the most direct approach, but its invasiveness, need for general anesthesia, and risks of serious complications make it a problematic procedure. A less invasive approach to hilar node biopsy has emerged utilizing endosonography (esophageal or endobronchial); yields are high (80%), and complication rates are low compared to mediastinoscopy, obviating the need for the latter procedure in many instances.

For the documentation of pulmonary sarcoidosis, fiberoptic bronchoscopy with transbronchial biopsy has been the standard procedure, with a reported sensitivity of 60% to 80%. In addition, bronchoscopy allows direct visualization of the bronchial tree, so it can be helpful in ruling out tumor and obtaining samples of secretions by bronchoalveolar lavage for laboratory study (e.g., flow cytometry), which can provide additional diagnostic information (test sensitivity in the 50% to 60% range, but 10% false positives). The major complications of transbronchial lung
biopsy are pneumothorax and bleeding (usually minor); these are infrequent in the hands of experienced bronchoscopists.

Nonetheless, alternatives to endobronchial biopsy have been sought. In a large European randomized trial comparing endosonographic hilar node biopsy with transbronchial lung biopsy, the former provided a significantly higher yield (80% vs. 53%) with fewer complications. More study is needed to confirm this emerging technology as an alternative to endobronchial lung biopsy.

In patients with extrathoracic sarcoidosis, accessible sites for biopsy include skin lesions and enlarged peripheral lymph nodes. Biopsy of conjunctivae, salivary glands, and liver may reveal noncaseating granulomas, even if clinical evidence of sarcoid in these tissues is absent. Because of the low morbidity associated with salivary gland and conjunctival biopsies, these may be particularly useful. It must be remembered that the histologic appearance of sarcoid granulomas is not etiologically specific. Therefore, the other known causes of noncaseating granulomas must be ruled out, including tuberculosis, syphilis, berylliosis, brucellosis, Q fever, biliary cirrhosis, Wegener granulomatosis, drug reactions, and local sarcoid reactions in nodes draining solid tumors. Hodgkin disease is particularly difficult to exclude with mediastinoscopy in patients presenting with unilateral or asymmetric hilar adenopathy.

The Kveim test was previously used, but the antigen for this skin test is no longer available, and the test’s diagnostic performance was mediocre.

Intrathoracic sarcoidosis can be divided into four stages based on symptoms and results of chest x-ray and pulmonary function tests. In stage 0, the chest radiographic appearance is normal. In stage I, only bilateral hilar adenopathy is present; most patients are asymptomatic, the lung parenchyma appears normal on chest x-ray film, and pulmonary function tests show normal mechanics, although the carbon monoxide diffusion capacity may be impaired. In stage II, both hilar adenopathy and pulmonary infiltrates are present; pulmonary function tests show predominantly restrictive defects. In stage III disease, pulmonary infiltrates are present, accompanied by obstructive and restrictive defects; however, hilar adenopathy has resolved. Stage IV disease is marked by advanced fibrosis, bullae, and cysts.

The principal treatment for sarcoidosis remains systemic corticosteroid therapy. The great variability in the clinical course of the disease and the previous lack of sensitive indicators of disease activity have made it difficult rigorously to document the efficacy of steroid therapy, and not surprisingly, consensus on when to start treatment remains elusive. Older studies relied on such crude measures of disease activity as symptoms, radiographic findings, and pulmonary function test values. Recent evaluations examining the effect of corticosteroids on more direct indicators of the disease process (see later discussion) have found marked suppression of the alveolitis but little influence on anatomic abnormalities present before the initiation of steroid therapy.

Although recommendations for when to start steroid therapy differ among experts, most authorities recommend commencing with a substantial program of oral glucocorticosteroids (e.g., prednisone, 30 to 40 mg/d), given on a daily basis for 2 weeks and then tapering every 2 weeks by 5 mg/d until a minimum baseline level that controls symptoms (e.g., 10 to 20 mg/d) is reached; it is then continued for 6 to 9 months. Improvement is usually evident by 2 to 3 weeks. Steroid therapy is most effective if it is instituted before the development of pulmonary fibrosis. However, there is no evidence that prophylactic treatment is worth the adverse effects of long-term steroid use (see Chapter 105).

Steroids consistently produce subjective improvement in dyspneic patients with early sarcoidosis and may even reduce pulmonary infiltrates when they are secondary to alveolitis or granulomatous changes. Lung volumes usually improve, but not necessarily the diffusion capacity, which may be permanently altered by destructive changes. Relapses after cessation of therapy are frequent, so close monitoring is necessary for at least 12 months after discontinuation of treatment. Alternateday steroid therapy (e.g., 15 to 25 mg every other day) has proved successful as a maintenance program in some patients, controlling disease when given after an initial course of daily steroids; this approach minimizes the adverse effects of long-term steroid therapy (see Chapter 105). Nevertheless, it must be kept in mind that it remains unproven that the long-term outcomes of sarcoidosis are improved by corticosteroid treatment.

Adrenal corticosteroids are also indicated for active ocular disease. Every patient with sarcoidosis should have an ophthalmologic examination, especially if visual symptoms develop. Topical steroids may be used, but systemic therapy is usually added. Treatment is also indicated in the presence of significant or progressive involvement of any other organ. The onset of hepatitis, facial nerve palsies, meningitis, myocardial conduction defects, hypercalcemia, and persistent constitutional symptoms (fever, fatigue) are all indications for treatment.

In an effort to improve treatment outcomes or to avoid or minimize the toxic effects of prolonged steroid therapy, other approaches have been tried. Inhaled steroids have been used in several randomized trials, either alone or after a course of systemic steroids. The evidence does not support a role for inhaled steroids in achieving improvement in lung function. There may be a reduction in symptoms, but clear evidence is lacking.

Advances in understanding the immunopathogenesis of sarcoidosis have suggested additional approaches to treatment. Attention has been focused on agents that can modulate CD4 T_H1 helper cells and TNF, which appear to play central roles in the granulomatous inflammatory process.