Etiology

Immune complexes involving heterologous (animal) serum proteins and complement activation are important pathogenic mechanisms in serum sickness. Antibody therapies derived from the horse are available for treatment of envenomation by the black widow spider and a variety of snakes, for treatment of botulism, and for immunosuppression (antithymocyte globulin). The availability of alternative medical therapies, modified or bioengineered antibodies, and biologics of human origin have supplanted the use of nonhuman antisera, reducing the risk of serum sickness. Reactions described as “serum sickness–like” are often attributed to drug allergy, triggered in particular by antibiotics (e.g., cefaclor). In contrast to a true immunologic reaction, serum sickness–like reactions do not exhibit the immune complexes, hypocomplementemia, vasculitis, and renal lesions that are seen in serum sickness reactions.

Pathogenesis

Serum sickness is a classic example of a type III hypersensitivity reaction caused by antigen-antibody complexes. In the rabbit model using bovine serum albumin as the antigen, symptoms develop with the appearance of antibody against the injected antigen. As free antigen concentration falls and antibody production increases over days, antigen-antibody complexes of various sizes develop in a manner analogous to a precipitin curve. Whereas small complexes usually circulate harmlessly and large complexes are cleared by the reticuloendothelial system, intermediate-sized complexes that develop at the point of slight antigen excess may deposit in blood vessel walls and tissues. There the immune microprecipitates induce vascular and tissue damage through activation of complement and granulocytes.

Complement activation (C3a, C5a) promotes chemotaxis and adherence of neutrophils to the site of immune complex deposition. The processes of immune complex deposition and of neutrophil accumulation may be facilitated by increased vascular permeability, owing to the release of vasoactive amines from tissue mast cells. Mast cells may be activated by binding of antigen to immunoglobulin (Ig) E or through contact with anaphylatoxins (C3a). Tissue injury results from the liberation of proteolytic enzymes and oxygen radicals from the neutrophils.

Clinical Manifestations

The symptoms of serum sickness generally begin 7-12 days after injection of the foreign material but may appear as late as 3 wk afterward. The onset of symptoms may be accelerated if there has been earlier exposure or previous allergic reaction to the same antigen. A few days before the onset of generalized symptoms, the site of injection may become edematous and erythematous. Symptoms usually include fever, malaise, and rashes (Chapter 637.1). Urticaria and morbilliform rashes are the predominant types of skin eruptions, and pruritus is common. In a prospective study of serum sickness induced by administration of equine antithymocyte globulin, an initial rash was noted in most patients. It began as a thin serpiginous band of erythema along the sides of the hands, fingers, feet, and toes at the junction of the palmar or plantar skin with the skin of the dorsolateral surface. In most patients, the band of erythema was replaced by petechiae or purpura, presumably because of low platelet counts or local damage to small blood vessels. Additional symptoms include edema, myalgia, lymphadenopathy, arthralgia or arthritis involving multiple joints, and gastrointestinal complaints, including pain, nausea, diarrhea, and melena. The disease generally runs a self-limited course, with recovery in 1-2 wk. Carditis, glomerulonephritis, Guillain-Barré syndrome, and peripheral neuritis are rare complications. Serum sickness–like reactions from drugs are characterized by fever, pruritus, urticaria, and arthralgias that usually begin 1-3 wk after drug exposure. The urticarial skin eruption becomes increasingly erythematous as the reaction progresses and can evolve into dusky centers with round plaques.

Diagnosis

Circulating immune complexes are usually detectable, with peak levels at 10-12 days. Serum complement levels (C3 and C4) are generally decreased and reach a nadir at about day 10. C3a anaphylatoxin may be increased. The erythrocyte sedimentation rate (ESR) is usually elevated, and thrombocytopenia is often present. Mild proteinuria, hemoglobinuria, and microscopic hematuria may be seen. Direct immunofluorescence studies of skin lesions often reveal immune deposits of IgM, IgA, IgE, or C3.

Treatment

Treatment is primarily supportive, consisting of antihistamines and analgesics. When the symptoms are especially severe, systemic corticosteroids can be used. High doses are given and rapidly reduced as the patient improves. The utility of extracorporeal removal of circulating immune complexes via plasmapheresis requires further study.

Prevention

The primary mode of prevention of serum sickness is to seek alternative therapies. In some cases, non–equine-derived formulations may be available (human-derived botulinum immune globulin). Other emerging alternatives are partially digested antibodies of animal origin and engineered (humanized) antibodies. The potential of these therapies to elicit serum sickness–like disease appears low. When only equine antitoxin/antivenom is available, skin tests should be performed before administration of serum, but this procedure indicates the risk only of anaphylaxis, not of serum sickness. Testing generally begins with prick-puncture using a 1 : 100 dilution of the serum with positive (histamine) and negative (saline) controls and proceeds through increasingly higher doses until a positive response is seen or a top dose of 0.02 mL of a 1 : 100 dilution injected intracutaneously is reached. A negative response to the strongest solution indicates that anaphylactic sensitivity to horse serum is unlikely.

For patients who have evidence of anaphylactic sensitivity to horse serum, a risk-to-benefit assessment must be made to determine the need to proceed with treatment. If needed, the serum can usually be successfully administered by a process of rapid desensitization using protocols of gradual administration outlined by the manufacturers. Desensitization is transient, and the patient may regain the previous anaphylactic sensitivity. Serum sickness is not prevented by desensitization or by pretreatment with corticosteroids.