AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 (Zyban, Wellbutrin SR), captopril (Capoten), cephalosporins, furazolidone (Furoxone), gold salts, griseofulvin (Fulvicin, Grifulvin), halothane, hydralazine (Apresoline), infliximab (Remicade), iodides, methyldopa, 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 venom
• Infectious agents
• Vaccines

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Although laboratory studies are not helpful in establishing a diagnosis, 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

ED care includes cessation of therapy involving the suspected antigen and supportive and symptomatic therapy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: 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.

Drug Category: Antipyretics

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

Drug Category: 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit the patient if serum sickness is severe 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Benson E. Bupropion-induced hypersensitivity reactions. Med J Aust. Jun 18 2001;174(12):650-1. [Medline].
• Berman BA, Ross RN. Acute serum sickness. Cutis. Nov 1983;32(5):420, 422. [Medline].
• Bigby M, Stern RS, Arndt KA. Allergic cutaneous reactions to drugs. Prim Care. Sep 1989;16(3):713-27. [Medline].
• Erffmeyer JE. Serum sickness. Ann Allergy. Feb 1986;56(2):105-9. [Medline].
• 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].
• Hart FD. Drug-induced arthritis and arthralgia. Drugs. Oct 1984;28(4):347-54. [Medline].
• 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].
• Lawley TJ, Bielory L, Gascon P, Yancey KB, Young NS, Frank MM. Human serum sickness. Trans Assoc Am Physicians. 1984;97:49-55. [Medline].
• 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].
• Naguwa SM, Nelson BL. Human serum sickness. Clin Rev Allergy. Feb 1985;3(1):117-26. [Medline].
• Parker CW. Allergic reactions in man. Pharmacol Rev. Mar 1982;34(1):85-104. [Medline].
• 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].
• Reynolds JS. Serum sickness: an old problem with new implications. Ann Allergy. Jul 1966;24(7):337-44. [Medline].
• Wooltorton E. Bupropion (Zyban, Wellbutrin SR): reports of deaths, seizures, serum sickness. CMAJ. Jan 8 2002;166(1):68. [Medline].

Article Last Updated: Aug 14, 2007