You are in: eMedicine Specialties > Rheumatology > Vasculitis Serum SicknessArticle Last Updated: Nov 7, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Hassan M Alissa, MD, Fellow in Rheumatology, Department of Internal Medicine, Loyola University Medical Center Hassan M Alissa is a member of the following medical societies: American College of Physicians Coauthor(s): Elaine Adams, MD, Chief of Medical Service, Chief of Rheumatology Section, Hines Veterans Affairs Hospital; Associate Chief, Associate Professor, Department of Internal Medicine, Loyola University School of Medicine Editors: John Varga, MD, Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital Author and Editor Disclosure Synonyms and related keywords: serum sickness, hypersensitivity vasculitis, drug-induced vasculitis, immune complex disease, foreign serum, serum protein, serum disease, serum reaction, foreign proteins, haptens, serum syndrome, antigens, leukocytoclastic vasculitis, secondary serum sickness, antirabies serum, tetanus antitoxin INTRODUCTIONSection 2 of 11
  BackgroundHistorically, the term serum sickness connotes a self-limited immune complex disease caused by exposure to foreign proteins or haptens. Von Pirquet and Shick first described the syndrome in 1905. Approximately 8-13 days after injection with equine diphtheria antitoxin, patients developed a skin rash, fever, and to a lesser extent, facial edema, arthralgia, regional lymphadenopathy, and albuminuria. Later, physicians reported a similar clinical picture after the injection of other equine-based antitoxins and antivenins. Certain medications (eg, penicillin, nonsteroidal anti-inflammatory drugs [NSAIDs]) have also been associated with serum sickness–like disease. Identifying serum sickness was a landmark observation in understanding immune complex diseases. PathophysiologyThe antigen molecular size, charge, structure, amount, and valence influence the type of immune complexes that are formed. Typically, patients have immunoglobulin (Ig) antibodies of IgG type. IgM complexes are less common and elicit immune complexes more readily removed by the reticuloendothelial system. IgE-mediated vasoactive amines may cause the urticarial skin rash and may further initiate complement activation. After a single injection of a foreign protein, the antigen equilibrates between blood and tissues. A primary antibody response develops, with small immune complexes formed in antigen excess. These complexes are easily filtered from the circulation without triggering further inflammation. In the next phase of slight antigen excess, intermediate-sized immune complexes form and deposit in small vessels and activate complement (see Image 1). Endothelial cells increase expression of adhesion molecules and proinflammatory cytokines are released by monocytes and macrophages. Subsequently, more inflammatory cells are recruited, and necrosis of the small vessels develops. This clinicopathological syndrome usually develops within 1-2 weeks of antigen injection. The pathological hallmark in the skin is a leukocytoclastic vasculitis. Serum cryoglobulins, which in effect are circulating immune complexes in vivo, may be present in some patients with serum sickness. Free antigen continues to clear from the blood, leading to antibody excess and the formation of large immune complexes, which are quickly removed by circulating macrophages. Finally, the antigen is no longer detectable, and the level of circulating antibodies continues to rise. Clinical recovery is usually apparent after 7-28 days, as intermediate-sized immune complexes are cleared by the reticuloendothelial system. Secondary serum sickness is the result of antigen recognition by presensitized cells of the immune system, and this disorder is characterized by a shorter latent period, exaggerated symptoms, and a brief clinical course. FrequencyUnited StatesIncidence is decreasing as the administration of foreign antigens in medical therapeutics is refined. In a recent clinical trial to evaluate the efficacy and safety of recombinant murine monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis, serum sickness reactions were noted in 15 (2.3%) of 645 patients in the treatment group. The frequency of serum sickness is dose related. In one study, 10% of patients receiving 10 mL of tetanus antitoxin developed serum sickness; the administration of 80 mL or more produced the disease in almost all patients. The frequency also varies by antigen type. Antirabies serum produced a higher incidence (16.3%) of serum sickness than tetanus antitoxin (2.5-5%). InternationalSerum sickness occurs worldwide, in proportion to the therapeutic use of foreign antigens and drugs. Mortality/MorbidityAlthough occasional reports show mortality resulting from progressive glomerulonephritis or severe neurological complications, serum sickness is usually self-limited and recovery is the rule. AgeIn one study, the disease was more common in patients older than 15 years who were given antirabies serum. Antibiotic-associated serum sickness–like disease, however, is more frequently described in children younger than 5 years. CLINICALSection 3 of 11
History
Physical
Causes
DIFFERENTIALSSection 4 of 11
Cryoglobulinemia Glomerulonephritis, Poststreptococcal Hepatitis, Viral Hypersensitivity Reactions, Immediate Infectious Mononucleosis Infective Endocarditis Kawasaki Disease Leukocytoclastic Vasculitis Sickle Cell Anemia Systemic Lupus Erythematosus
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| Drug Name | Ibuprofen (Motrin, Ibuprin) |
|---|---|
| Description | Decreases inflammation by blocking prostaglandin synthesis and reduces fever by acting on the hypothalamic temperature-regulating center. Usually administered for mild symptoms of arthralgia, myalgia, or fever. |
| Adult Dose | 200-800 mg PO qid; not to exceed 3200 mg |
| Pediatric Dose | <12 years: 5-10 mg/kg PO qid >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding |
| Interactions | Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Category D in third trimester of pregnancy; caution in congestive heart failure, asthma, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy |
These agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression and cardiac arrhythmias.
| Drug Name | Diphenhydramine HCL (Benadryl) |
|---|---|
| Description | Blocks histamine H1 receptors on the target tissue. For urticarial rash. |
| Adult Dose | 25-50 mg PO/IM qid |
| Pediatric Dose | 5 mg/kg/d PO/IV/IM divided tid/qid |
| Contraindications | Documented hypersensitivity; MAOIs |
| Interactions | Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patient taking medications that can cause disulfiramlike reactions |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in neonates and nursing mothers; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, urinary tract obstruction, asthma |
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Orasone, Sterapred) |
|---|---|
| Description | Acts by altering the number and availability of leukocytes, reducing vascular permeability, and suppressing cytokines. Mainstays of treatment in severe cases; usually administered in moderate doses for 1-2 weeks. This or other oral forms of corticosteroids (eg, prednisolone) are useful in managing mild-to-moderate serum sickness treated in an outpatient setting. |
| Adult Dose | 20-40 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve |
| Pediatric Dose | 0.2-0.5 mg/kg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve |
| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease |
| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
| Media file 1: Antigen, antibody, and complement serum levels after injection of a foreign protein. | |
 | View Full Size Image | Media type: Graph |
Article Last Updated: Nov 7, 2006
