Emergent Management of Acute Complications of Sarcoidosis 

Emergency medicine physicians may diagnose sarcoidosis de novo or provide emergent management of its exacerbations, recurrences, and/or acute complications. Sarcoidosis is a chronic noncaseating granulomatous disease of unknown etiology that affects many organs and tissues, most commonly the lungs. Although sarcoidosis may be suspected by a patient's history, it usually is diagnosed by using chest radiography and histology. (See the images below.)

In the emergency department (ED), a patient may present with nonspecific complaints or be diagnosed incidentally by radiograph and/or other findings. Approximately 50% of patients are asymptomatic at diagnosis. Patients may present to the ED with a known diagnosis of sarcoidosis and complain of symptoms consistent with a recurrence. Because sarcoidosis is a multiorgan disease, patients may complain of a variety of symptoms that may complicate diagnosis.

The organs most affected are as follows:

• Lungs - 90% with abnormal chest radiographic findings at some point
• Lymphatics - 75% of pulmonary and 60% of peripheral
• Skin - 25%
• Eyes - 25%
• Bone marrow - 30%
• Liver - 60-90%
• Spleen - 40%
• Upper respiratory tract - Nose, tonsils in 20%
• Salivary glands - Parotitis
• Musculoskeletal - Acute or chronic arthritis; see Lofgren syndrome, below
• Kidney - Mainly as a kidney stone secondary to hypercalcemia; hypercalcemia is produced by calcitriol hyperactivity of macrophages
• Central nervous system - 5%
• Joint - 25%
• Heart - 5%; can present as a conduction defect; also, in advanced cases, pulmonary hypertension causes cor pulmonale
• Endocrine system
• Gastrointestinal system

Patients may present with the following:

• No symptoms; diagnosed incidentally because of chest radiographic findings
• Abrupt onset of signs and symptoms evolving over 1-3 weeks; occurs in 40% of cases and consists of constitutional complaints and/or other findings
• Chronic onset that evolves over a few months and is observed in 60% of patients; respiratory signs and symptoms predominate
• Recurrences

Constitutional symptoms

Constitutional symptoms include the following:

• Fever/night sweats
• Malaise
• Fatigue
• Weight loss
• Arthritis, uveitis, cranial nerve VII involvement, and parotid enlargement (ie, Heerfordt-Waldenström syndrome)

Pulmonary symptoms

Approximately 90% of patients have an abnormal radiographic finding at some stage of the disease; 10% have pulmonary fibrosis. Pulmonary symptoms include the following:

• Dry cough
• Dyspnea that worsens upon or with exertion
• Occasional hemoptysis
• Pleural effusion and pneumothorax (rare)

Lymph nodes

These are found in hilar and peripheral locations, such as cervical, axillary, and inguinal.

Dermatologic symptoms

Dermatologic symptoms include the following:

• Maculopapular eruptions involving the nares, lips, eyelids, and previous trauma areas
• Lupus pernio (specific for sarcoidosis), a plaquelike lesion of violaceous discoloration of the nose, cheeks, chin, and ears
• Erythema nodosum (EN), the most common skin manifestation, referred to as Lofgren syndrome when it occurs with radiographic findings of bilateral hilar or paratracheal adenopathy and joint involvement (EN is associated with a good prognosis)
• Subcutaneous nodules

Ocular lesions

Ocular lesions can manifest with the following:

• Uveitis
• Retinal vasculitis
• Keratoconjuctivitis

Neurologic symptoms

Given the wide a range of neurologic involvement, patients may present with virtually any neurologic complaint. Neurologic symptoms include the following:

• Facial numbness and dysphagia
• Hoarseness
• Decreased gag reflex
• Headache
• Visual deficit
• Polydipsia
• Deafness
• Involvement of cranial nerves VII, VIII, IX, and X
• Basal granulomatous meningitis with involvement of optic chiasm and optic nerve
• Signs of meningitis - Aseptic meningitis that, on cerebrospinal fluid (CSF) examination, shows decreased glucose, increased protein, increased lymphocytes
• Involvement of the hypothalamic-pituitary axis - Manifests with pituitary insufficiency, optic chiasm compression, DI
• Seizures
• Vasculitis
• Stroke or transient ischemic attack
• Peripheral neuropathy - Possibly manifesting with paresthesias and decreased deep tendon reflexes (DTRs)

Dermatologic symptoms

Clinical examination of the skin may reveal the following:

• Maculopapular eruptions
• Lupus pernio - Violaceous lesions on the face and/or extremities
• Erythema nodosum – Red, painful lesion on the extensor surface of the lower extremities; considered to be the most common skin lesion in sarcoidosis
• Granuloma formation in old scar or tattoo and subcutaneous nodules

Neurologic symptoms

Neurologic manifestations include cranial nerve VII involvement (unilaterally or bilaterally), Bell palsy, basal granulomatous meningitis (ie, aseptic meningitis), or peripheral neuropathies; each presenting with the proper constellation of symptoms

Ocular symptoms

Patients may present with ophthalmologic or neuro-ophthalmologic findings before the systemic manifestations of sarcoidosis are seen. Ocular symptoms include the following:

• Uveitis - Presents with blurry vision, tearing, and photophobia
• Conjunctiva - May present with infiltration that has the appearance of a yellowish nodule
• Keratitis sicca - Presents with complaints of dry eyes.

Musculoskeletal symptoms

Musculoskeletal symptoms include myositis, bony lesions, and polyarthritis. Regarding the third symptom, it has been found, for example, that spondyloarthropathy has a higher incidence and prevalence in patients with sarcoidosis (6.6%) than in the general population (1.9%). An association with positive HLA-B27 has been determined, suggesting an association between sarcoidosis and spondyloarthropathy. Thus, a patient with sarcoidosis may present with back pain or sacroiliac pain. Note that Lofgren syndrome includes arthritis.^[1]

Head, neck, and upper respiratory tract symptoms

Symptoms involving the head, neck, and upper respiratory tract include the following:

• Dry cough
• Rales
• Tonsillitis, parotitis (Heerfordt syndrome), and epiglottitis that presents as hoarseness, stridor, or cough
• Nasal involvement - May present as damage to the septum and turbinates

Cardiac symptoms

Cardiac symptoms include the following:

• Cor pulmonale (most common cardiac complication) - Caused by pulmonary fibrosis
• Complete heart block, ventricular tachycardia (most common arrhythmia), bundle-branch block (BBB), ventricular aneurysm, myocarditis, pericarditis, and congestive heart failure (CHF)

Additional symptoms

Patients with sarcoidosis may also demonstrate the following:

• Painless, nonadherent lymph nodes
• Splenomegaly - Occurs in 10% of cases; presents with hematologic and general complications (eg, rupture)
• Hepatomegaly - Occurs in 25% of cases, with elevation in liver function tests [LFTs]; usually not clinically significant
• Nephrolithiasis - May be caused by hypercalcemia and hypercalciuria secondary to increase in 1,25-dihydroxyvitamin D and calcitriol production by activated macrophages
• Clinically significant renal failure (uncommon)

Consider the possibility of other life-threatening conditions (eg, pulmonary embolism) if no evidence of sarcoidosis is documented in the ED and a patient complains of dyspnea.

Conditions to consider in the differential diagnosis of sarcoidosis include the following (tuberculosis and lymphoma are particularly important in the United States):

• Rheumatoid arthritis
• Multiple sclerosis
• Pericarditis and cardiac tamponade
• Pneumothorax
• Pulmonary embolism
• Systemic lupus erythematosus
• Tuberculosis
• Angina
• Bronchitis
• Fungal pneumonia
• Histiocytosis X
• Leprosy
• Lymphoma
• Lung cancer
• Pulmonary alveolar proteinosis (PAP)
• Pneumoconiosis (eg, silicosis, berylliosis)

A complete blood count (CBC) should be performed. Studies may reveal the following:

• Leukocytosis - With or without eosinophilia; elevated erythrocyte sedimentation rate (ESR)
• Elevated serum angiotensin-converting enzyme (ACE) level - Elevated in 75% of cases; the value of monitoring ACE levels remains unclear
• Increased serum PO₄ and alkaline phosphatase levels
• Increased calcium levels- May be revealed with a 24-hour urinalysis assessment

Immunologic studies can show falsely elevated antinuclear antibodies (ANA) and rheumatoid factor (RF) levels and hypergammaglobulinemia.

Hypercalcemia is observed in 10-15% of cases. (It may be helpful to remember the mnemonic "Pam P. Schmidt," in which P represents parathyroid hormone [PTH], A represents Addison, M represents multiple myeloma, P represents Paget, S represents sarcoidosis [or other granulomatous disease], C represents cancer [lungs, multiple myeloma, breast], M represents milk-alkali syndrome, I represents immobilization, D represents vitamin D, and T represents thiazides.)

Although hypercalcemia is present by definition, it is rarely clinically significant. If other organs are involved, such as the liver, kidney, or endocrine organs, laboratory results pertinent to these organs are abnormal.

Patients with sarcoidosis may have myocardial involvement and elevated creatine kinase (CK) and CK-MB levels.

Studies also include slit lamp examination; this is generally is obtained periodically, even if the patient is asymptomatic.

Radiography

Chest radiography is an integral part of the diagnosis and staging. In addition, the radiograph may demonstrate pleural involvement, such as a pneumothorax or pleural effusion. Stages of sarcoidosis, as identified through imaging, are as follows (see also the images below):

• Stage O - No findings
• Stage I - Bilateral hilar adenopathy
• Stage II - Bilateral hilar adenopathy and parenchymal involvement (reticular opacities)
• Stage III - Parenchymal involvement (reticular opacities) with shrinking adenopathy
• Stage IV - Parenchymal involvement turns into volume loss (pulmonary fibrosis); cavitations and calcifications may also be seen Stage II sarcoidosis. Courtesy of Anthony Notino, MD, New York Hospital, Department of Radiology, Cornell Medical Center. Stage II sarcoidosis. Courtesy of Anthony Notino, MD, New York Hospital, Department of Radiology, Cornell Medical Center.

Radiotracer scanning

Gallium-67 scanning is used for staging of disease and for detecting extrapulmonary sarcoidosis. Gallium bound by inflammatory tissue and not by fibrotic tissue can distinguish areas of fibrosis from inflammation.

Other types of radiotracer scanning may be available. Technetium-labeled depreotide that binds somatostatin receptors has been used with good results in some cases.

Bronchoalveolar lavage (BAL) shows increases in the CD4/CD8 ratio, lymphocytes, and cytokines. Studies performed to correlate the presence of these markers with prognosis were not conclusive.

However, a study by Bacha et al showed that a high CD4/CD8 ratio seems to be predictive of a poor prognosis in patients with multiple extrathoracic organ involvement. Their study of 40 patients with clinically and histologically evident sarcoidosis showed that, before corticosteroid treatment, total cell count was increased with a T lymphocytosis and an increase in the CD4/CD8 ratio, as shown in BAL fluid. After corticosteroid treatment, a significant decrease in CD4/CD8 ratio and lymphocyte proportion was noted in BAL fluid. Patients with multiple extrathoracic lesions had significantly higher CD4/CD8 ratios than did those with only intrathoracic involvement.^[2]

Skin anergy with purified protein derivative (PPD) is common in patients with sarcoidosis but obviously not specific. With regard to cardiac assessment, a Holter monitor may be indicated to detect arrhythmias.

Biopsy

Biopsy is an integral part of the diagnosis and is of very high yield. The site of biopsy is dictated by clinical presentation of the organ involved. The sensitivity is highest from lung parenchyma, and 5-10 biopsy specimens generally are needed.

Pulmonary function tests

Pulmonary function tests (PFTs) are not required for diagnosis, but results may range from reference range to findings consistent with restrictive lung disease.

Kveim-Stilzbach test

A suspension from the spleen or a lymph node of a patient with a confirmed diagnosis of sarcoidosis is injected intradermally into a patient suspected to be affected by the disease. Test results are considered positive if a nodule appears within 2-7 weeks. A biopsy sample is then taken from the nodule to find similarities to sarcoid granuloma. The time required for this test, the incidence of false-negative and false-positive results, and the availability of more timely diagnostic tests make this procedure unpopular in the United States.

Electrocardiography

Electrocardiography may reveal the following:

• Signs of hypercalcemia (eg, decreased QT interval)
• Ventricular tachycardia
• Bundle-branch block or complete heart blocks
• ST elevation, PR depression caused by pericarditis, or ST elevation caused by ventricular aneurysm

Focus prehospital care on immediate or potential life threats. Initial assessment of the patient always begins with attention to airway, breathing, and circulation (the ABCs). Focus on respiratory support and ensuring adequacy of oxygenation, because patients generally present with respiratory complaints.

Provide supplemental oxygen to all patients. Patients with signs of impending respiratory failure should have ventilatory assistance with bag-valve-mask and high-flow oxygen. Consider intubation if a patient's condition continues to deteriorate. Perform continuous pulse oximetry if available.

Obtain intravenous access for all patients except those who have minimal complaints. Provide judicious fluid boluses to patients with evidence of dehydration. Monitor cardiac function of all patients with a history of sarcoidosis because the potential for cardiac involvement exists.

Because many patients with sarcoidosis are treated with steroids, consider the possibility of altered glucose metabolism and perform blood glucose determinations.

Perform a primary evaluation of the ABCs. Because pulmonary complaints predominate, pay attention to respiratory effort, monitor oxygenation, and evaluate for evidence of respiratory failure.

Provide supplemental oxygen for all patients. Patients with impending or obvious respiratory failure should have ventilatory assistance with bag-valve-mask and high-flow oxygen. Patients with respiratory failure should be intubated and placed on ventilator control.

Perform pulse oximetry tests. Hypoxemic patients and those with evidence of respiratory failure should have arterial blood gas determination. With the possibility of cardiac involvement, cardiac monitoring is generally indicated. Consider intravenous access and administration of fluid boluses to patients with evidence of volume depletion.

Because patients with sarcoidosis may have taken long courses of steroids, consider alteration in glucose metabolism and the possibility of secondary adrenal insufficiency. Blood glucose determination, urinalysis, and serum chemistries may be indicated.

Sarcoidosis generally is treated with steroids, but this is not endorsed by all physicians. The dosage and duration of treatment varies among institutions and studies; the prognosis of sarcoidosis is difficult to determine, because the course of the disease varies from one individual to another. However, a consensus exists among most physicians to treat symptomatic patients and patients who show signs of deterioration from baseline. These guidelines are discussed below and are arbitrarily classified into pulmonary and extrapulmonary.

Pulmonary symptoms may vary from dyspnea on exertion to severe respiratory failure. Patients require supplemental oxygen, pulse oximetry, arterial blood gas (ABG) assessment, chest radiography, and intubation when indicated. Note that endotracheal disease is present in 40% of cases in stage I and in 70% of patients in stage II and III. Nevertheless, significant stenosis is uncommon and intubation should not be a problem.

For patients in stage I-III, if the individual is asymptomatic and PFT results are normal, he or she is monitored for a few weeks with radiography and PFTs. If symptoms worsen, steroids are begun.

Patients in stage IV are symptomatic and are treated with steroids. Even though stage IV stands for pulmonary fibrosis, patients taking steroids show improvement, probably because the steroids act on ongoing inflammation.

Other agents, mainly cytotoxic medications, also have been used in the treatment of sarcoidosis; however, success has been variable. Consider a lung transplant if the disease does not respond to standard therapy or the disease is in the end stage.

Review of the patient's medication is mandatory. If the patient is not taking any medications or if the patient's medication dosage was recently changed, starting or restarting the patient on medications is reasonable.

In most cases, when symptoms are severe, 60 mg of prednisone daily is prescribed. In moderate cases, 40-60 mg of prednisone every other day is sufficient, and the drug is tapered by 5 mg per month after 6 months. Many patients are treated with a maintenance dose of 20 mg.

Ruling out other pulmonary pathologies, such as pneumonia (eg, bacterial, fungal, Pneumocystis carinii pneumonia [PCP]), CHF, or pulmonary hypertension, is mandatory.

Cardiac care

The heart can manifest with mechanical and/or conduction defects. Standard treatment is indicated. Holter monitoring is indicated in the outpatient setting. Central nervous system (CNS) or peripheral neuropathy is treated with systemic steroids.^[3]

Patients may present with CHF (diuretics and/or inotropics are the mainstays of therapy) or arrhythmias (eg, bundle-branch blocks, atrioventricular [AV] blocks). Electrocardiography, chest radiography, and telemetry are indicated. Cardiac manifestations are treated in the usual fashion with diuretics and inotropics, as indicated. Steroids and other immunosuppressive treatments have shown an improvement in 87% of patients and a cure in 54% of patients from a clinical and laboratory point of view.

Ocular care

The eye is commonly involved in sarcoidosis. Topical steroids may be sufficient. Ocular manifestations can present with uveitis or conjunctivitis. A slit lamp examination and/or ophthalmologic consultation are mandatory. Treatment is with local or systemic steroids.

Neurologic care

CNS manifestations may present with cranial nerve symptoms (eg, VII, IX, X), with signs of optic chiasm involvement (eg, papilledema, blurred vision), meningeal symptoms caused by aseptic meningitis (requires a lumbar puncture [LP] for confirmation), symptoms of stroke/transient ischemic attack, decreased DTR, and paresthesias (caused by peripheral neuropathies).

Computed tomography (CT) scanning of the head, magnetic resonance imaging (MRI), and neurologic consultation are appropriate. Once it is established that neurologic symptoms are secondary to sarcoidosis, systemic steroids are started.

Hypercalcemia treatment

Hypercalcemia is generally responsive to intravenous hydration. If this is not sufficient or electrocardiographic manifestations are present, systemic steroids are indicated. In the outpatient setting, a decrease in sunlight exposure and, sometimes, ketoconazole (decreases 1,25-dihydroxyvitamin D) are helpful in minimizing hypercalcemia and hypercalciuria.

Additional therapies

Skin manifestations are treated with topical or systemic steroids. Methotrexate and retinoids are used occasionally. A dermatologic consultation is suggested. Arthritis generally is treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Steroids and occasionally colchicine are reserved for severe cases. Asymptomatic elevation of LFTs does not require treatment.

Prednisone is an oral steroid and the mainstay of medical treatment. Base dosage on the patient's symptoms.

Patients with severe pulmonary and/or extrapulmonary symptoms must be admitted to the hospital. When failure of steroid treatment and progression of disease is evident, other empiric treatments, such as cytotoxics (eg, methotrexate) are tried. Lung transplant is an option when the patient is refractory to medical therapy and end-stage pulmonary failure is present. However, cases of new-onset sarcoidosis in transplanted lungs have been documented.

Prednisone treatment is instituted as discussed earlier. If symptoms are refractory to treatment, if multiorgan involvement occurs because of concomitant failure, or if infection is present, placing the patient in the intensive care unit (ICU) is prudent.

In the hospital, patients may benefit from pulmonary physical therapy (PT). This decision must be made in conjunction with the PT department. PT can involve energy conservation, incentive spirometry, segmental breathing exercises, demonstration of positions to relieve breathlessness, and interval exercise training to improve aerobic capacity.

Transfer

Consider transfer to a specialized center for patients who are not responding to standard therapy or if lung transplant is entertained. Before transfer, ensure that the patient has stable vital signs and a good or acceptable oxygen saturation level, electrocardiogram (ECG) finding, and mental status.

Consultations

Consider consultations with other services, such as pulmonology, neurology, dermatology, ophthalmology, gastroenterology, and rheumatology, for all patients, except those with minimal findings. Patients considered for discharge should meet with a specialist in managing sarcoidosis for appropriate follow-up treatment.

Follow-up

Emphasize the need for follow-up treatment. Explain the complications and symptoms that require immediate medical attention. Discuss compliance with medications and medical follow-up.