TOC | Pulm

SARCOIDOSIS                                 sarcoidosis2007.pdf   
SX  |  LAB | DX |  Diff. Dx  | RX                                                                                                                      
Sarcoidosis, a multisystem disease, is characterized by the formation of epithelioid granulomas in response to an unknown antigen(s). The lung is involved in more than 90% of cases, but scarring and the chance for permanent loss of function occur in 15% to 20%. Patients usually present in the third to fourth decade of life. The most characteristic pathologic feature of established sarcoidosis is the presence of noncaseating granulomas composed of epithelioid and multinucleated giant cells. Asteroid or Schaumann's bodies are frequently seen, and some central fibrinoid necrosis may occur

A. Symptoms and Signs     

1. General.  Approximately 80% of patients have symptoms at the time of diagnosis, the remainder being diagnosed from an incidental finding on chest x-ray. Constitutional symptoms (fever, weight loss, fatigue, malaise) develop insidiously in approximately one-third of patients. Patients presenting acutely with spiking fevers and erythema nodosum usually resolve most rapidly.

2. Pulmonary. Although over 90% of patients have pulmonary involvement, respiratory symptoms occur in 40-60% of patients and include shortness of breath, dry cough, substernal chest discomfort, and occasionally blood-streaked sputum. The physical findings are variable (depending on the stage) and nonspecific, consisting of tachypnea, crackles (diffuse or basilar), and sometimes wheezing (indicating endobronchial involvement).

3. Extrapulmonary. Adenopathy (32%), hepatomegaly (27%), skin lesions (23%), uveitis (17%), peripheral nerve involvement (15%), splenomegaly (13%), arthritis (10%), arrhythmias (5%), salivary gland enlargement resulting in pain and/or dry mouth (5%), nasal mucosal edema (5%), and facial nerve palsy (2%) are seen clinically but most are more commonly found on biopsy or at autopsy. All patients suspected of having sarcoidosis should have a careful slit-lamp examination to rule out uveitis.

B. Laboratory findings    

Serum angiotensin converting enzyme (ACE) levels are elevated in 60-75% of all cases and in as many as 90% of active cases.   IT is is relatively nonspecific, being present in other infectious and noninfectious granulomatous lung diseases. Although persistent elevation of this value indicates active disease, a rapid fall following corticosteroid treatment does not necessarily indicate nonprogressive disease.
Erythrocyte sedimentation rate is usually elevated in active disease.
Leukopenia is common, anemia is unusual.
Polyclonal hypergammaglobulinemia is present in 50% of cases.
with or without hypercalcemia may be present and appears to be due to secretion of 1,25-dihydroxy-vitamin D3 by the granuloma.
Cutaneous anergy may be present. The Kveim test is an intradermal injection of sarcoid spleen suspension that results in a typical noncaseating granuloma in 4-6 weeks in affected patients. The Kveim test is not commonly used because of a lack of a standardized, specific antigen and concern about transmission of infection.
Gallium scanning is of value in determining the extent as well as the activity of disease but is not a practical test for longitudinal followup because of its cost and radiation exposure.

C. Radiographic and nuclear medicine findings

Stage 0: A normal chest x-ray occurs in 5-10% of patients on presentation.

Stage I: Bilateral hilar lymphadenopathy without infiltrates is found in 35-45% of presenting patients.

Stage II: Linear and reticulonodular infiltrates with bilateral hilar lymphadenopathy and

Stage III parenchymal infiltrates alone are each observed in 25% of patients on presentation.

Stage IV End-stage patients develop fibrosis, hilar retraction, bronchiectasis, and bullae formation, which are irreversible . Rarely pneumothorax, unilateral pleural effusion, single or multiple cavities or nodules, or calcification of lymph nodes can be present.

While computed tomography (CT) may be more sensitive at detecting granulomas and lymphadenopathy, it may not add anything to the diagnosis and management of sarcoidosis. Gallium scintigraphy detects pulmonary inflammation of any etiology and correlates poorly with disease activity, limiting its usefulness.

D. Pulmonary function tests

Pulmonary function tests commonly show a restrictive ventilatory defect with a decrease in vital capacity, total lung capacity, and diffusing capacity. If endobronchial sarcoidosis is present, an obstructive ventilatory defect may also occur.

Diagnostic approach                
A. Criteria

The diagnosis requires three primary criteria:

  1. A compatible clinical and radiographic presentation.
  2. Histologic evidence of a noncaseating granuloma from tissue biopsy.
  3. Careful exclusion of other disease processes, especially infectious diseases.

B. Biopsy

Choice of biopsy site depends both on clinical presentation and ease or risk of obtaining tissue from a particular site. All biopsies should be stained and cultured to exclude tuberculous and fungal infections.

  1. Lung. Four to six transbronchial biopsies as obtained through a fiberoptic bronchoscope yield a positive diagnosis in 85-90% of cases, and is the procedure of choice for obtaining pulmonary tissue. Transbronchial biopsies are often positive even without clinical or radiologic evidence of pulmonary disease. Open lung biopsy is rarely necessary.
  2. Reticuloendothelial sites. Palpable lymph nodes (80% yield), liver (70%, especially if alkaline phosphatase is elevated), and spleen (50%) are more invasive sites for biopsy. Mediastinoscopy is usually diagnostic in cases with mediastinal adenopathy but is rarely necessary.
  3. Other sites. Skin lesions, lacrimal and minor salivary glands, skeletal muscle, conjunctiva, and nasal mucosa all may yield positive biopsies with or without clinical involvement.

C. Differential diagnosis

Noncaseating granulomas are nonspecific and are seen in tuberculosis, fungal infections, lymphoma, foreign-body reactions, berylliosis, hypersensitivity pneumonitis, primary biliary cirrhosis, leprosy, brucellosis, tertiary syphilis, granulomatous arteritis, and lymph nodes draining malignant tumors. Serum angiotensin converting enzyme (ACE) levels are not specific and can be elevated in hyperthyroidism (81%), leprosy (53%), cirrhosis of the liver (28.5%), diabetes mellitus (24-32%), silicosis (21%), Lennert's lymphoma, and berylliosis. Ordinarily, neither mycobacterial nor fungal infections are associated with elevated levels of ACE, but exceptions have been reported. Sarcoidosis is a diagnosis of exclusion, and it is crucial to exclude these other diagnoses.

V. Treatment         

A. Indications of Rx

Sarcoidosis is associated with both a variable clinical course and a high spontaneous remission rate, making assessment of therapeutic regimens difficult. It is appropriate to follow asymptomatic patients with bilateral hilar adenopathy and no extrapulmonary lesions with chest x-rays at 6-month intervals. Patients with symptomatic pulmonary disease, progressive or persistent parenchymal disease after 2 years, posterior ocular disease, persistent systemic findings, or clinically significant extrapulmonary disease are candidates for systemic corticosteroid therapy.

B. Corticosteroids

1. Local. Acute iridocyclitis or uveitis responds well to topical corticosteroids (triamcinolone acetonide 1%). Skin lesions may respond to intralesional corticosteroid injections.

2. Oral prednisone (40-60 mg/day in divided doses [1-2 mg/kg in children]), should be given for 4-6 months and then gradually tapered to 10-20 mg/day, if possible. Therapy should continue for another 6-12 months with periodic attempts to further reduce the dosage or discontinue the drug. Alternate day therapy (40 mg every other day) may also be an effective maintenance therapy and may be tapered by 10 mg every 3 months as tolerated. Lower doses and/or more rapid tapering may be possible in selected cases. Frequently, interruption or premature discontinuation of therapy results in relapse, which generally responds to increased doses of prednisone. Oral corticosteroids may or may not be effective in preventing fibrosis.
Corticosteroids, on the other hand, are effective for hypercalcemia and uveitis, but it is less clear if they are effective in cardiac and neurologic sarcoidosis.
Alternate therapies for chronic progressive disease include methotrexate, chloroquine, azathioprine, and chlorambucil.

Corticosteroid Therapy in Pulmonary Sarcoidosis  
JAMA, March 13, 2002 - VOl 287, No 10: 1301 - Shanthi Paramothayan, Paul W. Jones  
Conclusions: Oral corticosteroids improved results on the chest radiograph following 6 to 24 months of treatment and produced a small improvement in vital capacity and diffusing capacity. Trials of inhaled corticosteroids were small and results too inconsistent to make firm conclusions concerning their efficacy. There are no data to suggest that corticosteroid therapy alters long-term disease progression.

C. Monitoring of response

No one test is optimal for following the response to therapy. The clinical picture in conjunction with some combination of objective tests (pulmonary function tests, diffusing capacity, ACE levels, chest x-rays) relevant to the patients clinical situation is optimal. Lack of response may be present in inactive, fixed pulmonary fibrosis. Lung transplantation should be considered in patients with end stage fibrosis.

VI. Prognosis

As many as 60% of patients have spontaneous clinical and physiologic resolution within 2 years. A further 20% resolve with therapy. About 10-20% fail to resolve even with corticosteroid therapy, and a few present with irreversible disease. Cases with rapid onset of disease, especially those with erythema nodosum, generally resolve most quickly and completely. Chronic extrathoracic and central nervous system sarcoidosis tend to respond poorly.

Manual of Allergy & Immunology - Glenn Lawlor, etc.
NEJM 4/24/1997;336:1224 Lee Newman (Review of Sarcoidosis)
ACP Library on Disk 2- (c) 1997 - American College of Physicians


ATS Sarcoidosis 1998