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, diphtheria, rabies, and snake, scorpion, and spider venom. 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. ^[2] (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, and others. ^{[3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]} 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 on serum sickness, 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 administration 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), known as the zone of equivalence, cross-linking and lattice formation occur forming intermediate and large immune complexes. These are usually cleared by the mononuclear phagocyte system; however, this is not the case in the presence of a high concentration of immune complexes or if the removal system is not functioning well.

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). ^[14]

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. This results in the release of the inflammatory mediators, including a 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.

Since the development of serum sickness is dependent on the host’s ability to produce antibodies to the inciting antigen, patients who are incapable of producing antibodies, such as patients with Bruton agammaglobulinemia, will not develop serum sickness.

Classic serum sickness can be induced by antithymocyte globulin (ATG), a heterologous serum protein generated by immunization of horses or rabbits with human thymic tissue. The immune serum is partially purified through multiple steps, including fractionation by ion-exchange chromatography. ^[14] 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. ^{[15, 16, 17]}

Agents that cause serum sickness and serum sickness-like reactions

The causes of serum sickness include the following:

• Heterologous serum proteins - Antitoxin, antivenom, ATG

• Biologic agents - Chimeric monoclonal antibodies, humanized monoclonal antibodies, human monoclonal antibodies used in the treatment and management of various medical disorders, streptokinase, pneumococcal vaccine

The causes of serum sickness–like illness include the following:

• Antibiotics - Cephalosporins, ciprofloxacin, griseofulvin, penicillins, sulfonamides, tetracyclines, metronidazole, and others

• Other drugs - Carbamezapine, bupropion, and others

Serum sickness has been reported to develop in 20-30% of patients who receive antisera for diphtheria and scarlet fever; however, most individuals develop the disease only with larger doses of antisera. ^[1] Similarly, higher doses of equine botulinum toxin and anti–snake venom antiserum are more likely to produce serum sickness than are lower doses. ^[18]

The incidence of serum sickness after antivenom for snake bites seems to have decreased from 44-50% with equine-derived whole-immunoglobulin G antivenom ^{[19, 20]} to 5-7% with ovine polyvalent immune Fab approved by the US Food and Drug Administration in 2000. ^{[21, 22]} A prospective case series of scorpion envenomations in central Arizona identified 49 patients (57%) with serum sickness, defined as rash 1-21 days afterward the envenomation. ^[23] A retrospective study of redback spider antivenom use in Australia identified a 10% incidence of “symptoms consistent with serum sickness.” ^[24] In these references, the definition of serum sickness is variable, often defined as rash post treatment or not defined, which makes the reported incidence less reliable.

Biologic agents such as chimeric monoclonal antibodies and ATG can also cause serum sickness or serum sickness–like reaction. The use of ATG in bone marrow transplantation and in patients with aplastic anemia resulted in serum sickness in 65-100% of recipients. ^{[14, 25, 26]} Infliximab, a chimeric murine/human monoclonal 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), 14 (2%) of 573 patients developed serum sickness after receiving infliximab as a maintenance treatment. ^[27] Follow-up studies regarding use of infliximab with inflammatory bowel disease have reported a subsequent incidence of serum sickness–like reaction to be 0.7-4%. ^{[28, 29, 30]}

Rituximab is another chimeric murine/human monoclonal antibody 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 3 (12.5%) of 24 children ^[31] and 2 (5.6%) of 36 children. ^[32] 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. ^[33] Serum sickness after rituximab administration in patients with rheumatoid arthritis and systemic lupus erythematosus has also been reported. ^{[34, 35]} Some reports of serum sickness or serum sickness–like reaction describe it in association with elevated human antichimeric antibody (HACA) after the administration of rituximab. ^{[33, 36]}

Humanized antibody contains murine-derived, antibody-binding portion integrated into human antibodies by recombinant deoxyribonucleic acid (DNA) technology. The humanized monoclonal antibody natalizumab (Tysabri) is a therapeutic option for treating relapsing forms of multiple sclerosis. Natalizumab is directed to the α₄ integrin, including α₄ ß₁ and α₄ ß₇. In one study, a delayed-infusion reaction with fever, headache, arthralgia, edema, and lymphadenopathy resembling serum sickness occurred in 4 (10%) of 40 patients, 2 of whom were positive for antinatalizumab antibodies and 2 of whom were not. ^[37]

One case report detailed severe serum sickness-like reaction in a 67-year old individual following use of omalizumab (Xolair), a humanized monoclonal antibody that blocks IgE for management of asthma. ^[38]

Adalimumab is a human monoclonal antibody to TNF–α. In one retrospective study of adalimumab use for maintenance therapy in Crohn disease, a 1 (1.6%) in 61 incidence of serum sickness–type reaction was reported. ^[39]

Serum sickness was described in a case report of a child aged 9 months after treatment with intravenous immunoglobulin (IVIg) for Kawasaki disease. ^[40] A male aged 16 years developed a serum sickness-like syndrome after being treated with immunoglobulin M-enriched polyclonal immunoglobulin for acute myeloid leukemia. ^[41]

Postlicensure safety surveillance for pneumococcal vaccine identified 6 cases of serum sickness after vaccine administration between 2000-2002, with an incidence of about 1.9 in 1 million, although causation cannot be verified. ^[42] A case report described severe serum sickness in an adult after immunization with the H1N1 influenza vaccine. ^[43]

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, diphtheria, rabies, and snake and spider venom. ^[2] Serum sickness caused by monoclonal antibodies will likely increase because of the dramatic rise in the use of immunomodulators of this kind. However, the increasing use of humanized monoclonal antibodies with less nonhuman component will likely reduce this risk.

Many nonprotein drugs, including beta-lactam antibiotics, ciprofloxacin, sulfonamides, bupropion, streptokinase, metronidazole, carbamazepine, insulin detemir, and others, have been reported to cause serum sickness–like reactions. ^{[11, 7, 4, 10, 13, 44]} However, the incidence is much lower for antibiotics and other drugs 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. ^[10]

A higher incidence of serum sickness-like reaction has been reported 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. ^{[7, 9, 11, 13]} This may be related to increased intestinal mucosal permeability and/or by direct effect on the integrity of the intestinal mucosa. ^[45]

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, has been reported to be higher in children than in adults. ^[13] In addition, one study found that equine and human rabies immunoglobulin hypersensitivity reactions, including serum sickness, were more common in females than in males. ^[46]

See Etiology for information on incidence and prevalence rates for specific causes.

The prognosis is excellent in most cases of serum sickness, with resolution of signs and symptoms 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 may occur.

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 can help to ameliorate the symptoms. Repeated and continual administration of the offending agent(s) 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, antivenom, ATG) 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.