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:

• In the US: 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 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.

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 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 affect 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, captopril (Capoten), cephalosporins, furazolidone (Furoxone), gold salts, griseofulvin (Fulvicin, Grifulvin), halothane, hydralazine (Apresoline), 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