eMedicine Specialties > Emergency Medicine > Allergy & Immunology

Serum Sickness

Susan M Chen, MD, Clinical Assistant Professor, Department of Emergency Medicine, University of Pennsylvania Health System, Penn Presbyterian Medical Center

Updated: Jul 9, 2009

Introduction

Background

Serum sickness is a type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum. Reactions secondary to the administration of nonprotein drugs are clinically similar to serum sickness reactions.

Pathophysiology

Not all substances that are recognized as foreign by the immune system elicit an immune response. The antigen must be of characteristic size or have specific antigenic determinants and physiological properties to be an effective stimulator of the immune system. After an appropriate antigen is introduced, an individual's immune system responds by synthesizing antibodies after 4-10 days. The antibody reacts with the antigen, forming soluble circulating immune complexes that may diffuse into the vascular walls, where they may initiate fixation and activation of complement. Complement-containing immune complexes generate an influx of polymorphonuclear leukocytes into the vessel wall, where proteolytic enzymes that can mediate tissue damage are released. Immune complex deposition and the subsequent inflammatory response are responsible for the widespread vasculitic lesions seen in serum sickness.

Frequency

United States

The incidence of serum sickness is decreasing as a result of public health vaccination programs that have decreased the need for specific antitoxins. Also, many horse serum antitoxins have been refined of the antigenic components that cause serum sickness. Products derived from human serum have replaced the most frequently used antitoxins, which are rabies and tetanus horse serum antitoxins. When these were used, the incidences of serum sickness were 2-5% in patients receiving tetanus antitoxin and 16% in patients receiving rabies antitoxin. The frequency and severity of reactions were directly related to the amount and type of antiserum administered.

Currently, nonprotein drugs are the most common causes of serum sickness–like reactions. The incidence of serum sickness–like reactions caused by nonprotein drugs is difficult to determine. From 1972-1985, the adverse drug reactions reported to the US Food and Drug Administration (FDA) included 10 cases of serum sickness related to amoxicillin (Amoxil, Polymox), 638 cases related to cefaclor (Ceclor), 28 cases related to cephalexin (Keflex), and 51 cases related to trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra, Sulfatrim).

Mortality/Morbidity

Symptoms usually last 1-2 weeks before spontaneously subsiding. Long-lasting sequelae generally do not occur. Fatalities are rare and usually are due to continued administration of the antigen.

Age

Individuals older than 15 years may experience more frequent and more severe disease because they receive larger volumes of antitoxin.

Clinical

History

Primary serum sickness occurs 6-21 days after the administration of the inciting antigen. The onset may be more rapid with subsequent exposures to the same antigen, with symptoms occurring 1-4 days after exposure.

• The classic clinical manifestations consist of fever, arthralgia, lymphadenopathy, and skin eruption.
• Pain, pruritus, and erythematous swelling at the injection site usually precede the onset of disease.
• Patients also may report joint and muscle aches, chest pain, and difficulty breathing.

Physical

Physical examination may reveal cutaneous symptoms; fever; lymphadenopathy; arthritis or arthralgias; edema; and renal, cardiovascular, neurologic, or pulmonary manifestations.

• Cutaneous symptoms (95%) may include the following:
  • Urticaria
  • Scarlatiniform rash
  • Maculopapular or purpuric lesions
  • Erythema multiforme
  • Characteristic serpiginous, erythematous, and purpuric eruption at the junction of the palmar or plantar skin with the dorsolateral surface of the hands, feet, fingers, and toes
• Fever (temperature of 101-104°F) is invariably present and may precede rash in 10-20% of cases.
• Lymphadenopathy (10-20%) may be generalized or may involve tenderness in the nodes that drain the injection site; splenomegaly may occur.
• Arthritis or arthralgias (10-50%) usually affects multiple large joints, but occasionally, small joints and joints of spine and temporomandibular joint may be inflamed. Myalgias or myositis also may occur.
• Edema may occur, particularly about the face and neck.
• Renal manifestations include proteinuria, microscopic hematuria, and oliguria; however, significant disease usually does not result.
• Cardiovascular findings may include myocardial and pericardial inflammation. Generalized vasculitis occurs rarely.
• Neurologic manifestations include peripheral neuropathy, brachial plexus neuritis, optic neuritis, cranial nerve palsies, Guillain-Barré syndrome, and encephalomyelitis.
• Pulmonary manifestations, such as pleurisy, are rare. However, dyspnea and cyanosis are not uncommon.

Causes

Drugs that have been implicated in the development of serum sickness–like reactions include the following: allopurinol (Zyloprim), arsenicals and mercurial derivatives, barbiturates, bupropion^1,2 (Zyban, Wellbutrin SR), captopril (Capoten), cephalosporins, furazolidone (Furoxone), gold salts, griseofulvin (Fulvicin, Grifulvin), halothane, hydralazine (Apresoline), infliximab (Remicade),³ iodides, methyldopa, omalizumab,⁴ para-aminosalicylic acid, penicillamine, penicillins, phenytoin (Dilantin), piperazine, procainamide (Procan SR, Procanbid, Pronestyl-SR), quinidine (Quinaglute, Quinalan, Quinidex, Quinora), streptokinase (Streptase, Kabikinase), sulfonamides, and thiouracils.

Other causes of serum sickness may include the following:

• Heterologous serum used in the prophylaxis and/or treatment of botulism, diphtheria, gas gangrene, organ transplant rejection, and snake and spider bites
• Allergen extracts
• Blood products
• Hormones
• Hymenopteran venom⁵
• Infectious agents
• Vaccines

Differential Diagnoses

Erythema Multiforme
Mononucleosis
Polymyositis
Systemic Lupus Erythematosus
Tick-Borne Diseases, Rocky Mountain Spotted Fever
Toxic Epidermal Necrolysis

Other Problems to Be Considered

Dermatomyositis
Drug-related exanthema
Drug-induced arthritis and arthralgias
Leukemia
Leukocytoclastic vasculitis
Lymphoma
Urticarial vasculitis

Workup

Laboratory Studies

Although laboratory studies are not helpful in establishing a diagnosis of serum sickness, certain laboratory findings have been reported.

• Complement levels (determined outside the ED) vary.
• CBC and differential tests may reveal leukocytosis or leukopenia with or without eosinophilia.
• The erythrocyte sedimentation rate usually is slightly elevated.
• Serum protein electrophoresis (performed outside the ED) may reveal hypergammaglobulinemia with free circulating light chains.
• Urinalysis may reveal proteinuria and/or hematuria.

Treatment

Emergency Department Care

ED care for those with serum sickness includes cessation of therapy involving the suspected antigen and initiation of supportive and symptomatic therapy as described below.

Medication

The goal of therapy is to treat the clinical syndrome resulting from the effects of soluble circulating immune complexes that form under conditions of antigen excess. These immune complexes can originate from the administration of either heterologous antisera or drugs known to cause serum sickness.

Antihistamines

These agents are used for symptomatic treatment of pruritus and may prevent the deposition of immune complexes. Prophylactic antihistamines may decrease the incidence of serum sickness by negating the action of vasoactive amines and preventing the increased vascular permeability that they induce.

Diphenhydramine (Benadryl)

For symptomatic relief of symptoms caused by the release of histamine in allergic reactions.

Dosing

Adult

Initial dose: 50-100 mg PO/IV/IM
Maintenance dose: 10-50 mg PO/IV/IM q6-8h; not to exceed 400 mg/d

Pediatric

12.5-25 mg PO tid/qid, 5 mg/kg/d or 150 mg/m²/d IV/IM divided tid/qid; not to exceed 300 mg/d

Interactions

Potentiates effect of CNS depressants; alcohol in syrup form may interact with medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; concurrent administration with MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction

Antipyretics

Bed rest and mild analgesic-antipyretic therapy are often helpful in relieving fever, arthralgias, and myalgias associated with the syndrome.

Aspirin (Anacin, Bayer Aspirin, Bufferin, and Ecotrin)

Lowers elevated body temperature by causing peripheral vasodilatation, thereby enhancing dissipation of excess heat; also acts on the heat-regulating center of the hypothalamus to reduce fever.

Dosing

Adult

325-650 mg PO q4-6h; not to exceed 4 g/d

Pediatric

10-15 mg/kg/dose PO q4-6h; not to exceed 60-80 mg/kg/d

Interactions

Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; <16 y with flu (because of association with Reye syndrome)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid in severe anemia, blood coagulation defects, or anticoagulant use

Corticosteroids

These agents have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties and cause profound and varied metabolic effects. These agents modify the immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for the treatment of autoimmune disorders.

Dosing

Adult

0.05-2 mg/kg/d PO divided bid/qid; alternatively, up to 80 mg/d qd or divided bid/qid; taper over 2 wk as symptoms resolve

Pediatric

4-5 mg/m²/d PO; alternatively, 1-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve

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

Contraindications

Documented hypersensitivity; viral, fungal, tubercular skin, or connective tissue infections; peptic ulcer disease; hepatic dysfunction; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Follow-up

Further Inpatient Care

• Admit the patient if any significant comorbidities are present (advanced or very young age, immunocompromised), if any severe symptoms or hemodynamic instability/hypotension is present, or if the diagnosis is unclear.

Deterrence/Prevention

• Avoidance of the offending agent is the best way to prevent serum sickness. However, in some circumstances, avoidance is not possible.
• Skin tests are indicated before antiserum administration, particularly in patients with a history of allergy to horse dander or in those who have previously received the material. Skin tests reveal the presence of immunoglobulin E antibodies and, thus, help to identify individuals at risk of anaphylaxis. However, these tests are not reliable in the identification of individuals with an increased risk for serum sickness.
• If rapid administration of antiserum is necessary, establish intravenous access in each arm (one access for the infusion of antiserum and the other for the treatment of complications) and premedicate the patient with 50-100 mg of diphenhydramine (Benadryl). If a reaction occurs, temporarily discontinue the infusion, and administer epinephrine and other necessary medications. Once the adverse reaction is halted, resume slow infusion.

Complications

• Vasculitis
• Neuropathy
• Glomerulonephritis (rare)
• Anaphylaxis
• Shock
• Death

Prognosis

• Most cases are mild and resolve within a few days. However, subjective complaints and objective findings may persist for several weeks.

Miscellaneous

Medicolegal Pitfalls

• The primary medical legal pitfall is not considering serum sickness in the differential diagnosis. Cessation of the offending antigen is important in the treatment of serum sickness.

References

1. Benson E. Bupropion-induced hypersensitivity reactions. Med J Aust. Jun 18 2001;174(12):650-1. [Medline].

2. Wooltorton E. Bupropion (Zyban, Wellbutrin SR): reports of deaths, seizures, serum sickness. CMAJ. Jan 8 2002;166(1):68. [Medline].

3. Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med. Jan 2006;30(1):41-4. [Medline].

4. Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol. Oct 2007;120(4):972-3. [Medline].

5. Lazoglu AH, Boglioli LR, Taff ML, Rosenbluth M, Macris NT. Serum sickness reaction following multiple insect stings. Ann Allergy Asthma Immunol. Dec 1995;75(6 Pt 1):522-4. [Medline].

6. Berman BA, Ross RN. Acute serum sickness. Cutis. Nov 1983;32(5):420, 422. [Medline].

7. Bigby M, Stern RS, Arndt KA. Allergic cutaneous reactions to drugs. Prim Care. Sep 1989;16(3):713-27. [Medline].

8. Erffmeyer JE. Serum sickness. Ann Allergy. Feb 1986;56(2):105-9. [Medline].

9. Hart FD. Drug-induced arthritis and arthralgia. Drugs. Oct 1984;28(4):347-54. [Medline].

10. Heckbert SR, Stryker WS, Coltin KL, Manson JE, Platt R. Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population. Am J Epidemiol. Aug 1990;132(2):336-42. [Medline].

11. Lawley TJ, Bielory L, Gascon P, Yancey KB, Young NS, Frank MM. Human serum sickness. Trans Assoc Am Physicians. 1984;97:49-55. [Medline].

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13. Parker CW. Allergic reactions in man. Pharmacol Rev. Mar 1982;34(1):85-104. [Medline].

14. Platt R, Dreis MW, Kennedy DL, Kuritsky JN. Serum sickness-like reactions to amoxicillin, cefaclor, cephalexin, and trimethoprim-sulfamethoxazole. J Infect Dis. Aug 1988;158(2):474-7. [Medline].

15. Reynolds JS. Serum sickness: an old problem with new implications. Ann Allergy. Jul 1966;24(7):337-44. [Medline].

Keywords

serum sickness, hypersensitivity reaction, type III hypersensitivity reaction, serum sickness reactions, foreign protein injection, antitoxin, tetanus horse serum, rabies horse serum, heterologous serum

Contributor Information and Disclosures

Author

Susan M Chen, MD, Clinical Assistant Professor, Department of Emergency Medicine, University of Pennsylvania Health System, Penn Presbyterian Medical Center
Susan M Chen, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Francis Counselman, MD, Program Director, Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School
Francis Counselman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Association of Academic Chairs of Emergency Medicine (AACEM), Norfolk Academy of Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Matthew M Rice, MD, JD, FACEP, Senior Vice President, Chief Medical Officer, Northwest Emergency Physicians; Assistant Clinical Professor of Medicine, University of Washington at Seattle
Matthew M Rice, MD, JD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, Society for Academic Emergency Medicine, and Washington State Medical Association
Disclosure: Team Health  Salary Employment

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Erik D Schraga, MD, Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous editor, Charles V Pollack, Jr, MD, to the development and writing of this article.

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