You are in: eMedicine Specialties > Pediatrics: General Medicine > Allergy and Immunology Serum SicknessArticle Last Updated: Oct 17, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Robyn Siperstein, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School Coauthor(s): Philip J Cohen, MD, Chief, Section of Dermatology, New Jersey Veterans Affairs Medical Center; Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology and Immunology, Associate Professor, Department of Pediatrics, Creighton University School of Medicine Editors: Ann O'Neill Shigeoka, MD †, Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals; David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville; Harumi Jyonouchi, MD, Associate Professor, Department of Pediatrics, Division of Pulmonary Allergy/Immunology and Infectious Diseases, UMDNJ-New Jersey Medical School Author and Editor Disclosure Synonyms and related keywords: serum sickness, serum disease, serum reaction, serum sickness–like reactions, type III reaction, immune complex–mediated allergic disease, type III hypersensitivity INTRODUCTIONSection 2 of 11
  BackgroundSerum sickness is an immune complex–mediated hypersensitivity reaction characterized by fever, rash, arthritis, arthralgia, and other systemic symptoms. von Pirquet and Schick first described and popularized the term serum sickness at the turn of the 20th century, using it to describe patients who had received injections of heterologous (nonhuman) antitoxins for the treatment of diphtheria and scarlet fever (von Pirquet, 1951). Classic serum sickness is now rarely seen because the use of foreign proteins is limited to antitoxins such as those used to treat botulism, gas gangrene, diphtheria, rabies, and snake and spider venom (Gamarra, 2006). However, the recent use of equine and murine antisera as antilymphocyte or antithymocyte globulins and as monoclonal antibodies for immunomodulation and cancer treatment has created a new group of medications that may cause serum sickness. Serum sickness–like reaction (SSLR) is clinically similar to the classic or primary form described above and is attributed to many nonprotein drugs, including beta-lactam antibiotics, ciprofloxacin, sulfonamides, bupropion, streptokinase, metronidazole, allopurinol, carbamazepine, and others (Ornetti, 2004; Platt, 1988; Heckbert, 1990; Brucculeri, 2006; Kunnamo, 1986; Vial, 1992). This term has been used to describe the syndrome of a rash, arthritis, and fever within several days to weeks after drug administration. PathophysiologySerum sickness is a type III hypersensitivity reaction mediated by immune complex deposition with subsequent complement activation. The classic syndrome is caused by immunization of the host by heterologous serum proteins. Shortly after the injection of the foreign protein, the host mounts a specific antibody response to clear the foreign substance. Immunoglobulin M (IgM) antibodies usually develop 7-14 days after immunization with the antigen. When the antigen and antibody molecules are present in approximately equal molar ratios (slight antigen excess), called the zone of equivalence, cross-linking and lattice formation occur. This results in a large mass of aggregates of immune complexes deposited in various tissues such as the internal elastic lamina of arteries and in perivascular regions. These tissue-deposited immune complexes activate complements, which lead to the clinical manifestation of the disease (eg, inflammatory changes in the renal glomeruli and in the skin; Lawley, 1984). Antigen cross-linking of immunoglobulin E (IgE) molecules that are bound to specific cell surface receptors and/or binding of complement split products, such as iC3b, to complement receptors (CR3/CR4) may activate mast cells and basophils, resulting in the release of the inflammatory mediators, including histamine, causing skin symptoms (urticaria). Large amounts of antigen exposure can lead to widespread deposition of complement-fixing immune complexes and the clinical presentation of serum sickness. A patient with agammaglobulinemia lacks the ability to produce a specific antibody to antigenic challenge, including heterologous serum, and is incapable of developing serum sickness. Antithymocyte globulin (ATG) is generated by immunization of horses with human thymus tissue. The immune serum is partially purified through multiple steps, including fractionation by ion-exchange chromatography (Lawley, 1984). However, ATG, as well as other immunosuppressive foreign proteins such as chimeric monoclonal antibodies that consist of murine-derived fragment antigen-binding (Fab) and human-derived crystallizable fragment (Fc) portions of antibodies have been reported to be sufficiently immunogenic to cause serum sickness. The mechanism of many of the drugs responsible for SSLR is not well known. The medications may act as haptens that bind to carrier proteins (albumin or other serum proteins) that act as antigens, while others may create metabolites that have direct toxic effects on cells, leading to idiosyncratic delayed-type drug reactions with symptoms similar to those of serum sickness. Cefaclor has been studied for this mechanism, and its metabolites have been found to be lymphotoxic (Knowles, 1997; Kearns, 1994). FrequencyUnited StatesThe incidence of serum sickness decreased with declining use of heterologous serum sources of antitoxin to treat conditions such as diphtheria and scarlet fever. Twenty to thirty percent of patients who receive antisera for diphtheria and scarlet fever develop serum sickness; however, most individuals develop the disease only when larger doses of the antisera are administered (Von Pirquet, 1951). Similarly, higher doses of equine botulinum toxin and anti–snake venom antiserum are more likely to produce serum sickness than lower doses (Black, 1980). In separate studies, serum sickness developed after antivenin for snake bites in 17% (Offerman, 2002), 44% (Shemesh, 1998), 50% (Jurkovich, 1988), and 57% (LoVecchio, 2003) of patients. Biologic agents such as monoclonal antibodies and ATG are also associated with this reaction. The use of ATG in bone marrow transplantation and in patients with aplastic anemia resulted in serum sickness in 86-92% of recipients (Bielory, 1988; Lawley, 1984). Infliximab, a monoclonal chimeric antibody against tumor necrosis factor (TNF)–a, has also been shown to produce serum sickness. In the ACCENT I (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) trial, 3 of 88 patients (2%) developed serum sickness after receiving infliximab as a maintenance treatment for Crohn disease (Hanauer, 2002). Rituximab is another chimeric monoclonal antibody on the market and is directed at CD20 expressed on B cells. In 2 studies that used rituximab to treat immune thrombocytopenic purpura (ITP) in children, the incidence of serum sickness was 12.5% (Bennet, 2006) and 5.6% (Wang, 2005). Serum sickness caused by monoclonal antibodies will likely increase given the dramatic rise in the use of immunomodulators. However, the use of humanized monoclonal antibodies with less murine-derived component will help reduce this risk. Many nonprotein drugs, including beta-lactam antibiotics, ciprofloxacin, sulfonamides, bupropion, streptokinase, metronidazole, allopurinol, carbamazepine, and others, have been reported to cause SSLR (Ornetti, 2004; Platt, 1988; Heckbert, 1990; Brucculeri, 2006; Kunnamo, 1986; Vial, 1992). However, the incidence is much lower for antibiotics than for heterologous serum. For example, Kunnamo et al estimated that the annual incidence of drug-induced SSLR with acute arthritis and detectable immune complexes was 4.7 cases per 100,000 children younger than 16 years. Literature surveys report a higher incidence of SSLR in children treated with cefaclor compared with children treated with other antibiotics. Reviews suggest an incidence of serum sickness of 2 cases per 100,000 children for cefaclor and less than 1 case per 10 million children for cephalexin and amoxicillin (Vial, 1992; Heckbert, 1990; Platt, 1988). Mortality/MorbiditySerum sickness is usually a self-limited disorder, and symptoms resolve with time as the immune complexes are cleared from the system. The use of antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids helps to ameliorate the symptoms. Repeated and continual administration of the offending agents may lead to an immediate accelerated reaction, including cardiovascular collapse (von Pirquet, 1951). Vasculitis, nephropathy, and respiratory complications are usually associated with the use of heterologous animal protein (antitoxin, ATG, streptokinase) and are not usually observed with drugs and other agents. SSLR is usually self-limited, with symptoms lasting only 1-2 weeks. AgeWhile serum sickness may occur in individuals of any age in response to the introduction of heterologous protein, the incidence of SSLR due to antibiotics, especially cefaclor, is higher in children than in adults (Vial, 1992). CLINICALSection 3 of 11
HistoryThe onset of symptoms usually occurs 7-10 days after administration of the offending agent and correlates with the peak of circulating immune complexes. Fever, malaise, and headache are the earliest symptoms. Rash, joint pain, edema, GI symptoms, and other symptoms follow. PhysicalThe major physical findings include fever, rash, arthritis, arthralgia, and lymphadenopathy.
Causes
DIFFERENTIALSSection 4 of 11
[Reiter Syndrome] Agammaglobulinemia Kawasaki Disease Lymphoproliferative Disorders Meningococcal Infections Rheumatic Heart Disease Systemic Lupus Erythematosus
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| Drug Name | Diphenhydramine (Benadryl) |
|---|---|
| Description | An antihistamine with anticholinergic and sedative adverse effects. It is used for treatment of allergic reactions. |
| Adult Dose | 10-50 mg q6-8h PO/IV/IM; not to exceed 400 mg/d |
| Pediatric Dose | 5 mg/kg/d or 150 mg/m2/d PO divided q6-8h; not to exceed 300 mg/d |
| Contraindications | Documented hypersensitivity; MAOIs; administration to newborns and premature infants |
| Interactions | Potentiates effect of CNS depressants; because of alcohol content, do not administer in syrup form to patients taking medications that can cause disulfiramlike reactions |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Possible impaired mental alertness in some patients; possible CNS stimulation in young children |
This class of drugs acts by inhibiting cyclooxygenase, thereby blocking the production of prostaglandins, which are powerful mediators of inflammation. These drugs are useful in relieving fever and musculoskeletal pain.
| Drug Name | Ibuprofen (Motrin) |
|---|---|
| Description | Member of the propionic acid group of NSAIDs, it has moderate efficacy and good safety profile and is used in children for various conditions, including fever, arthritis, and others. To avoid GI complications, should be taken with food. |
| Adult Dose | 400 mg PO q4-6h; not to exceed 3200 mg/d |
| Pediatric Dose | 10-40 mg/kg/d PO divided q6h |
| Contraindications | Documented hypersensitivity; hypersensitivity to related NSAIDs, including acetylsalicylic acid |
| Interactions | Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (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 with congestive heart failure or hypertension; risk of GI ulceration and perforation due to inhibition of COX-1 activity; can inhibit platelet aggregation, resulting in prolonged bleeding (therefore, caution with coagulation defects); possible hepatic dysfunction; possible renal toxicity because reduction of prostaglandins may lead to reduced renal blood flow and subsequent renal decompensation (use with extreme caution, if at all, with renal insufficiency); may aggravate inflammatory bowel disease |
These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Orasone) |
|---|---|
| Description | Corticosteroid with salt-retention properties used for its potent anti-inflammatory effects. Because of its well-known adverse effects, only used in cases in which the systemic symptoms are severe. |
| Adult Dose | Up to 60-80 mg/d PO; taper downward over 2 wk as symptoms resolve |
| Pediatric Dose | 1-2 mg/kg/d PO; taper downward 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 bleeding |
| Interactions | Coadministration with estrogens may decrease prednisone 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 | Adrenal insufficiency with long-term corticosteroid use may persist for months after discontinuation (implement corticosteroid replacement in time of stress during that period); avoid exposure to chickenpox and measles; possibility of impaired growth in children with long-term use; possible electrolyte and fluid disturbances, myopathy, osteoporosis, vertebral fractures, aseptic necrosis of femoral and humeral heads, peptic ulcer, pancreatitis, esophagitis, facial erythema, skin fragility, impaired wound healing, headache, vertigo, depression, overexcitation, menstrual irregularities, cushingoid features, decreased carbohydrate tolerance, cataracts, or glaucoma |
| Media file 1: Urticarial rash in a child 10 days after cefaclor was administered for sore throat. Associated findings included fever, arthralgia of knees and ankles, and eosinophilia. | |
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Article Last Updated: Oct 17, 2006
