Harwood-Nuss' Clinical Practice of Emergency Medicine, 6 ed.

CHAPTER 81
Sarcoidosis

Sanjay Bhatt

Sarcoidosis is a multisystem, chronic granulomatous disease with diverse manifestations and a variable clinical course. It is characterized by a heightened cellular immune response at the site of disease activity; the lungs are the primary target organ and are involved in 90% of cases (1,2). Other organs of lesser involvement include the skin, lymphatic system, and eyes. While no single etiology has been identified, a number of them have been postulated. These include exposure to infectious agents, including Mycobacterium tuberculosis, Propionibacterium acnes, and HHV 8, and noninfectious occupational and environmental agents, including beryllium, and autoantigens. Until 1995, only nine patients infected with human immunodeficiency virus (HIV) had coexistent sarcoidosis (3,4) with a resulting postulation that a low CD4 count is “protective” against the granuloma formations seen in sarcoidosis (5).

In the United States, the prevalence of sarcoidosis is 10 per 100,000 in Caucasians and 40 per 100,000 in African Americans (6). Among African-American patients, women outnumber men two to one in the prevalence of disease. Curiously, sarcoidosis is virtually unknown on the continent of Africa, giving credit to an environmental etiology. While the peak incidence of diagnosis and symptoms are between 20 and 40 years of age, the disease has been reported in children and the elderly. Sarcoidosis has also been identified in twins, husband–wife pairs, and in coworker firefighters (7,8).

With or without treatment, most cases of sarcoidosis resolve spontaneously. Indicators of a favorable prognosis include acute manifestations of inflammation including erythema nodosum, polyarthritis, fever, and bilateral lymphadenopathy. Poor prognostic indicators include African-American race, lupus pernio, and chronic bone, lung, or nasopharyngeal involvement (2,6,7).

CLINICAL PRESENTATION

In the United States, approximately 50% of patients with sarcoidosis are asymptomatic and diagnosed on routine radiograph that shows hilar lymphadenopathy (6,7). Those with suspected sarcoidosis can be referred for follow-up and confirmation of the disease. In the emergency department (ED), however, the more important issue revolves around when to suspect and how to treat active disease (Table 81.1).

TABLE 81.1

Characteristics at Clinical Presentation

In 20% to 40% of cases, acute sarcoidosis develops over a period of several weeks. The symptoms are usually mild and may include fever, malaise, anorexia, and weight loss (7,9). Those with chronic sarcoidosis develop a more indolent form over months. Most have vague respiratory complaints and are likely to have symptomatic relapses. It is the group with a slow evolution of symptoms that is more likely to develop chronic disease and organ damage.

As sarcoidosis is a multisystem disease, it can present as a multitude of symptoms. The lungs, however, are almost always (90%) involved, and the clinical presentation is consistent with the presence of interstitial lung disease. Patient often present with exertional dyspnea and a dry cough. The physical examination may reveal dry rales or wheezing, suggestive of reactive airway. Airway hyperreactivity is especially prominent in patients with endobronchial involvement (10). Ninety percent of patients have an abnormal chest radiograph and some may develop pulmonary hypertension related to decreased lung volumes (11,12).

There are four stages of sarcoidosis; these stages are classified by the Scadding scale. Radiographic evaluation is helpful to define pulmonary involvement and also stage the disease. These four stages of involvement are shown on chest films (Table 81.2). Stage I is defined by the presence of bilateral hilar adenopathy and can often be accompanied by right paratracheal node enlargement (Fig. 81.1). Stage II is characterized by bilateral hilar adenopathy and reticular opacities. Stage III consists of reticular opacities, which are generally distributed in the upper lung zones with shrinking hilar nodes. Finally, stage IV is defined by reticular opacities in the upper lung zones with general lung volume loss (2,8).

TABLE 81.2

Radiographic Stage and Prognosis in Sarcoidosis

FIGURE 81.1 Typical type I radiograph. (Courtesy of Murray K. Dalinka, MD, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia.)

Radiographic staging has limited prognostic significance. While staging provides a guide to lung involvement, it does not assess functional ability or disease activity. Stage I changes of bilateral hilar adenopathy may resolve whereas changes in stage II to IV are generally chronic. It is important to recognize that these are not stages of the disease but rather represent different radiographic manifestations (7).

While pulmonary manifestations of sarcoidosis account for 90% of disease, extrapulmonary manifestations account for the remaining 10%. These extrapulmonary manifestations can involve most organs including the skin, lymph nodes, and heart. Although myocardial involvement of sarcoidosis is found in 25% of autopsied cases, only 10% of those patients without cardiac symptoms have an abnormal electrocardiogram. Granulomatous involvement of the conduction system and ventricular walls can lead to dysrhythmias including complete heart block and sudden cardiac death. Life-threatening ventricular dysrhythmias may be related to QT prolongation (13). As many as 25% of patients with cardiac manifestations of sarcoidosis die as a result of congestive heart failure (CHF) (7). CHF may be due to local infiltration of the mitral valve or diffuse granulomatous disease (1). Myocardial magnetic resonance imaging may be a useful modality for tracking the clinical course of disease (14).

Abnormalities related to calcium are the most common renal and electrolyte abnormalities among patients with sarcoidosis. The defect in calcium metabolism is due to increased intestinal calcium absorption owing to overproduction of 1,25-dihydroxyvitamin D3 by activated macrophages. Hypercalciuria (30%) and hypercalcemia (10%) are common presentations of sarcoidosis; patients may present with renal colic from nephrolithiasis, hypertension, and renal arteritis; primary renal infiltration with sarcoid granulomas is rare (7).

While severe hypercalcemia is unusual, corticosteroids can control hypercalcemia by inhibiting the action of 1,25-dihydroxyvitamin D3. Before corticosteroids are considered, treatment begins with conservative measures including intravenous (IV) fluids and decreasing oral calcium intake (15).

Ocular involvement of sarcoidosis involves approximately 25% of patients; 5% of patients initially present with ocular symptoms. The most common ocular presentation is anterior uveitis. Uveitis may develop rapidly and can become chronic eventually leading to glaucoma, cataracts, and blindness (9). Other ocular diagnoses include posterior uveitis, conjunctivitis, cataracts, and retinal hemorrhages.

Skin lesions occur in about one of every four patients. Cutaneous manifestations include lupus pernio (Fig. 81.2), plaques, and symmetric maculopapular eruptions. In addition, erythema nodosum is a hypersensitivity reaction that may be seen in women of childbearing age. While a nonspecific finding (7,8), erythema nodosum is often considered the hallmark of the disease (8).

FIGURE 81.2 Lupus pernio. (Courtesy of Gerald S. Lazarus GS, MD, Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia.)

Musculoskeletal presentations of sarcoidosis are common with 10% to 20% of patients presenting with chronic arthritis or acute polyarthritis. Acute polyarthritis is associated with erythema nodosum and can be incapacitating, requiring corticosteroid therapy. Chronic arthritis is associated with chronic persistent disease and is most frequently seen in black patients (7).

Sarcoidosis that involves the upper respiratory tract should be suspected in all patients with systemic sarcoidosis and upper respiratory tract symptoms. The granulomatous disease can involve the larynx, pharynx, nares, and sinuses. Nasal and laryngeal involvement occurs in up to 16% of patients with sarcoidosis; extensive disease may cause severe airway compromise (9).

Less than 10% of patients have neural involvement. While the initial manifestations of neural involvement are central nervous system (CNS) related, peripheral nerve and skeletal muscle involvement is characteristically seen in the later stages. The granulomatous component of sarcoidosis can compress local structures. Patients can present with cranial neuropathy, especially seventh nerve palsy from brainstem compression, central diabetes insipidus from pituitary and hypothalamic lesions, and seizures from hydrocephalus. Neurologic symptoms usually improve with corticosteroid therapy (7,16).

Two other syndromes have been described. Löfgren syndrome includes the triad of erythema nodosum, bilateral hilar adenopathy, and arthralgias. Löfgren syndrome is associated with a good prognosis with over 90% of patients experiencing disease resolution within 2 years. A second syndrome, Heerfordt–Waldenström, also referred to as uveoparotid fever, is a rare presentation of sarcoidosis. The symptoms include chronic fever, anterior uveitis, facial nerve palsy, and parotid enlargement (9,17).

Symptomatic sarcoidosis is rare in children. It has been shown that children of African descent have more severe disease than Caucasian and Asian counterparts. There are two distinct forms of pediatric sarcoidosis. Children under the age of 4 years, those with an early onset of disease, are likely to present with the triad of rash, uveitis, and arthritis. Children between the ages of 8 and 15 develop multisystem disease similar to that described in adults with lymphadenopathy, pulmonary involvement, and the typical generalized signs and symptoms of fever and malaise (18).

DIFFERENTIAL DIAGNOSIS

While there is no classic presentation of sarcoidosis, a common presentation entails a young adult who presents with a fever, subjective shortness of breath, blurry vision, and erythema nodosum; the chest radiograph shows bilateral hilar adenopathy. Most cases, of course, are not this typical. As sarcoidosis is a multisystem disease, the differential diagnosis is broad. Sarcoidosis can be confused with tuberculosis, or other mycobacterial infections, lymphoma, and some fungal disorders including coccidioidomycosis. Other systemic diseases to be considered include leprosy, berylliosis, and hypersensitivity pneumonitis.

HIV infection must also be considered in patients suspected of having sarcoidosis. Patients with HIV commonly have several of the features found in sarcoidosis, including chest radiograph abnormalities and lymphocytopenia. Only a small number of patients with concurrent HIV and sarcoidosis have been recorded. It has been postulated because CD4 cells are required for clinical expression of sarcoidosis, they may be “protective,” against the viral illness. Although the clinical suspicion may be high, a definitive diagnosis of sarcoidosis cannot be made with certainty on initial clinical presentation. A patient who carries a diagnosis of sarcoidosis, however, may present with a complication of the disease.

ED EVALUATION

On presentation to the ED, a physician should direct the initial patient history to determine the duration and severity of symptoms, a previous diagnosis of sarcoidosis, and any previous need for corticosteroid therapy.

The major complications of systemic sarcoidosis include upper airway obstruction from laryngeal involvement (19,6), cardiac dysrhythmias and conduction disturbances including complete heart block, CHF, advanced pulmonary fibrosis with cor pulmonale (20), superimposed tuberculosis or bacterial infection (7), sudden loss of vision from ocular complications (1), incapacitating arthritis or arthralgias (11), space-occupying lesions of the brain and hydrocephalus (21), and hypercalcemia with its cardiac, neurologic, and renal sequelae. In the proper clinical setting, abrupt corticosteroid withdrawal may cause signs and symptoms of adrenal insufficiency (15,22).

The physical examination should first focus on airway and cardiopulmonary systems. As sarcoidosis is a multisystem disease, attention should be given to all potentially involved organ systems. Ocular, neurologic, skin, and joint complaints necessitate more specialized examination and testing. Like all patients who present with altered mental status or abnormal neurologic findings, a funduscopic examination may be useful.

Diagnostic studies in the ED should be directed toward detecting both current and potential sarcoidosis-related problems. Patients may benefit from a 12-lead electrocardiogram and outpatient Holter monitoring. Chest radiography, pulse oximetry, and arterial or venous blood gas analysis may be indicated in those with respiratory complaints. Benefit may be realized from renal function studies, electrolytes, and calcium and platelet counts.

Strict criteria must be satisfied to diagnose sarcoidosis. They include compatible clinical and radiographic findings (6,19), histologic finding of noncaseating granulomas, and exclusion of other diseases with similar findings (20,21,23,24). It is unlikely that an emergency physician will establish that a patient meets these exacting criteria. A diagnosis based on only one of these features may be misleading. Definitive diagnosis requires specialty assistance.

Additional evaluation often includes cerebrospinal fluid (CSF) and isotopic imaging studies, extrapulmonary biopsy, and bronchoalveolar lavage. The ATS Sarcoidosis Consensus Group believes that transbronchial biopsy should be performed on patients suspected of sarcoidosis (2). Fine-needle biopsy is an important diagnostic tool (21), and bronchoalveolar lavage may be performed at the same time as biopsy. An elevated CD4:CD8 ratio in the fluid confirms the diagnosis and occurs in the majority of those with pulmonary disease (2,21,22). Advances in gallium scanning have improved diagnostic accuracy; however, this test is not diagnostic of sarcoidosis. Likewise, although CT scanning may be helpful to rule out other diseases, it cannot establish a definitive diagnosis (21). Most patients will eventually have a 24-hour urinary calcium level (7) and serum and CSF angiotensin–converting enzyme levels.

KEY TESTING

• CXR and pulse oximetry for respiratory complaints

• ECG to detect conduction abnormalities

• Calcium level, electrolytes, BUN, creatinine, if suspected hypercalcemia

• CT head if altered mental status

ED MANAGEMENT

Most patients with sarcoidosis do not require treatment. This is especially true as most patients have asymptomatic disease. For those individuals who have more severe pulmonary or extrapulmonary symptoms, treatment is aimed at reducing the burden of granulomatous inflammation. While no specific treatment exists, oral glucocorticoids have been most widely used to control symptoms. Incapacitating disease that interferes with normal life activities merits consideration for corticosteroid therapy. Conversely, mildly symptomatic disease warrants conservative management without corticosteroids. In those who require treatment, systemic corticosteroids of prednisone 40 mg/d remain an effective and safe form of treatment (16,19).

Indications for treatment with corticosteroids in patients with pulmonary sarcoidosis include progressive and worsening radiographic imaging, pulmonary symptoms, and deteriorating lung function as measured by pulmonary function testing. Therapy is generally withheld in all asymptomatic patients despite the stage of therapy. Lung transplantation is a final option for end-stage pulmonary disease (7,23).

Treatment of extrapulmonary sarcoidosis is based on the affected organ and the degree of damage. As a general rule, treatment of neurologic, ocular, myocardial, or renal sarcoidosis and hypercalcemia is indicated. Treatment is generally started to prevent further complication leading to loss of vision, sudden cardiac death and fatal arrhythmias, or renal failure.

Because of mortality rates approaching 10%, patients with neurosarcoidosis require treatment with prednisone 1 mg/kg/d followed by a taper. For severe or fulminant cases, IV steroids (1 g/d methylprednisolone) are administered for 2 to 3 days (16). Topical corticosteroids are used for anterior ocular and dermatologic disease (7,15,19).

Patients with cardiac conduction abnormalities resulting from granulomatous infiltration are usually refractory to conventional pharmacotherapy and often need to be admitted to the hospital to determine the most appropriate pharmacologic or electrical therapy. Cardiac transplantation has been performed successfully in younger patients with severe heart failure. Refractory dysrhythmias may require resection of a ventricular aneurysm (19,23). Hypercalcemia, if severe or symptomatic, may be treated as per conventional treatment. High-dose corticosteroid therapy may be required. Milder elevations of serum calcium levels may be treated with corticosteroids and frequent monitoring (15,19).

Although corticosteroids remain the mainstay of treatment, other agents have also been used. These agents include methotrexate, azathioprine, cyclophosphamide, chlorambucil, cyclosporine, nonsteroidal anti-inflammatory agents, chloroquine, infliximab, and hydroxychloroquine.

CRITICAL INTERVENTIONS

• Obtain a serum calcium level in patients with suspected or diagnosed sarcoidosis

• Treat hypercalcemia as an inpatient; aggressive treatment is warranted, especially in patients with significant signs and symptoms of hypercalcemia

• Obtain an electrocardiogram to diagnose cardiac conduction abnormalities

• Begin corticosteroid therapy in selected cases in conjunction with the appropriate primary care physician or consultant

DISPOSITION

The ED physician may require the assistance of specialty consultants in diagnosing and managing a patient with suspected sarcoidosis. Pulmonary, ophthalmologic, dermatologic, and neurologic consultation may be necessary before definitive therapy is undertaken.

In those patients who carry a diagnosis of sarcoidosis, hospital admission is indicated for patients with cardiac or neurologic symptoms, hypercalcemia, severe thrombocytopenia, or any degree of airway compromise.

Because long-term care is usually required, the family physician, internist, or pulmonary specialist is most commonly called on to provide primary outpatient therapy for sarcoidosis.

Common Pitfalls

• Sarcoidosis is frequently asymptomatic; it should be considered in patient with eye findings, suggestive skin lesions, hypercalcemia, persistent cough or dyspnea, or unexplained fever and weight loss

• The emergency physician should arrange follow-up so that a definitive diagnosis can be made and an appropriate treatment plan begun

• Specialty consultation should be obtained before treating with systemic corticosteroids and when dealing with cardiac, neurologic, or ocular disease

• Children can develop sarcoidosis

• The presence of wheezing may incorrectly suggest reactive airway disease. Corticosteroids may not be indicated in this setting

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