Pediatric Serum Sickness 

Serum 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. (See Differentials, History and Physical Examination.)^[1]

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.^[2] However, the use of equine and murine antisera as antilymphocyte or antithymocyte globulins and murine monoclonal antibodies for immunomodulation and cancer treatment has created a new group of medications that may cause serum sickness. (See Etiology.)

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.^{[3, 4, 5, 6, 7, 8]} This term has been used to describe the syndrome of a rash, arthritis, and fever within several days to weeks after drug administration. (See Etiology.)

With regard to patient education, the patient and his or her family should be advised of the nature of the offending agent.

Serum 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).^[9]

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 thymic tissue. The immune serum is partially purified through multiple steps, including fractionation by ion-exchange chromatography.^[9] However, ATG, as well as other immunosuppressive foreign proteins, such as chimeric monoclonal antibodies that consist of murine-derived antigen-binding fragment (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 serum sickness–like reaction is not well known. The medications may act as haptens that bind to carrier proteins (albumin or other serum proteins) that act as antigens, whereas 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.^{[10, 11]}

Agents that cause serum sickness

The causes of serum sickness include the following:

• Heterologous serum proteins - Antitoxin, antivenin, ATG, and monoclonal antibodies used in the treatment and management of various medical disorders
• Antibiotics - Cephalosporins, ciprofloxacin, griseofulvin, penicillins, sulfonamides, tetracyclines, metronidazole, and others
• Other drugs - Allopurinol, barbiturates, captopril, indomethacin, phenylbutazone, procainamide, quinidine, and thiouracil
• Biologic agents – Streptokinase

Serum sickness develops in 20-30% of patients who receive antisera for diphtheria and scarlet fever; however, most individuals develop the disease only when larger doses of the antisera are administered.^[1]

Similarly, higher doses of equine botulinum toxin and anti–snake venom antiserum are more likely to produce serum sickness than are lower doses.^[12] Serum sickness developed after antivenin for snake bites in 17% of patients,^[13] 44% of patients,^[14] 50% of patients,^[15] and 57% of patients^[16] in previously reported studies. In a subsequent review of redback spider antivenom, 3 of 32 patients who were observed for 2 weeks (10%) developed serum sickness.^[17]

Biologic agents such as monoclonal antibodies and ATG can also cause serum sickness. The use of ATG in bone marrow transplantation and in patients with aplastic anemia resulted in serum sickness in 86-92% of recipients.^{[9, 18]} Infliximab, a monoclonal chimeric antibody against tumor necrosis factor (TNF)–α, has also been shown to produce serum sickness. As reported in A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I), 3 of 88 patients (2%) developed serum sickness after receiving infliximab as a maintenance treatment for Crohn disease.^[19]

Rituximab is another chimeric monoclonal antibody on the market and is directed at CD20 expressed on the cell surface of B cells. In 2 studies that used rituximab to treat immune thrombocytopenic purpura (ITP) in children, the incidences of serum sickness were 12.5%^[20] and 5.6%.^[21] Other reviews have shown that serum sickness is not limited in the treatment of ITP; persons using rituximab for autoimmune diseases are also at risk.^{[22, 23]}

The humanized monoclonal antibody natalizumab (Tysabri) is a new therapeutic option for treating relapsing forms of multiple sclerosis. Humanized antibody contains murine-derived, antibody-binding portion integrated into human antibodies by recombinant deoxyribonucleic acid (DNA) technology. Natalizumab is a monoclonal antibody directed to the α₄ integrin, including α₄ ß₁ and α₄ ß₇. In one study, a delayed-infusion serum sickness–like reaction (type III reaction) occurred in 4 of 40 patients (10%).^[24]

In the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) trial, one patient who developed a delayed serum sickness–like reaction tested positive for antinatalizumab antibodies 5 weeks after initiation of this therapy; his symptoms persisted 12 weeks later.^[25] However, the symptoms completely resolved with a short course of oral glucocorticosteroids.

One case report detailed the use of omalizumab (Xolair), a humanized monoclonal antibody that blocks IgE, which caused a severe serum sickness–like reaction in a patient using this medication to treat asthma.^[26] Serum sickness caused by monoclonal antibodies will likely increase because of the dramatic rise in the use of immunomodulators of this kind. 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 serum sickness–like reactions.^{[3, 4, 5, 6, 7, 8]} 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 serum sickness–like reaction with acute arthritis and detectable immune complexes was 4.7 cases per 100,000 children younger than 16 years.^[7]

Literature surveys report a higher incidence 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.^{[5, 4, 8]}

As previously mentioned, 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.^[2] Although serum sickness may occur in individuals of any age in response to the introduction of heterologous protein, the incidence of serum sickness–like reactions due to antibiotics, especially cefaclor, is higher in children than in adults.^[8]

The prognosis is excellent in most cases of serum sickness, with resolution of signs and symptoms occurring in a few days. Serum sickness may recur if reexposure to the offending antigen occurs. Subsequent reactions may be more severe, with an escalating time frame compared with the original reaction. Anaphylaxis and shock from reexposure to the offending agent are possibilities.

Serum 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.^[1]

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. Serum sickness–like reaction is usually self-limited, with symptoms lasting only 1-2 weeks.