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] 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).[13]

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.[13] 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.[14, 15]

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.[16]

The incidence of serum sickness after antivenom for snake bites seems to have decreased from 44-50% with equine-derived whole-immunoglobulin G antivenom[17, 18] to 5-7% with ovine polyvalent immune Fab approved by the US Food and Drug Administration in 2000.[19, 20] 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.[21] A retrospective study of redback spider antivenom use in Australia identified a 10% incidence of “symptoms consistent with serum sickness.”[22] 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.[13, 23, 24] 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.[25] 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%.[26, 27, 28]

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[29] and 2 (5.6%) of 36 children.[30] 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.[31] Serum sickness after rituximab administration in patients with rheumatoid arthritis and systemic lupus erythematosus has also been reported.[32, 33] 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.[31, 34]

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.[35]

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.[36]

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.[37]

Serum sickness was described in a case report of a child aged 9 months after treatment with intravenous immunoglobulin (IVIg) for Kawasaki disease.[38] A male aged 16 years developed a serum sickness-like syndrome after being treated with immunoglobulin M-enriched polyclonal immunoglobulin for acute myeloid leukemia.[39]

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.[40] A case report described severe serum sickness in an adult after immunization with the H1N1 influenza vaccine.[41]

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.[10, 6, 3, 9, 12, 42] 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.[9]

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.[6, 8, 10, 12] This may be related to increased intestinal mucosal permeability and/or by direct effect on the integrity of the intestinal mucosa.[43]

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.[12] In addition, one study found that equine and human rabies immunoglobulin hypersensitivity reactions, including serum sickness, were more common in females than in males.[44]

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.

The onset of serum sickness symptoms usually occurs 1-2 weeks after administration of the offending agent and correlates with the peak of circulating immune complexes. Fever, malaise, and headache are the earliest symptoms. Rash, joint pain, edema, gastrointestinal (GI) symptoms, arthralgia, and other symptoms follow.

A rash is often the first clinical symptom and is frequently pruritic. If the causal agent was injected, the rash typically starts at the site of injection. Otherwise, the rash starts on the abdomen and spreads outward. Mucous membranes are not involved. Eruption over the rest of the body is usually symmetric and may take any of the following forms:

• Urticaria (see image below)

• Scarlatiniform rash

• Morbilliform rash

• Polymorphous exanthema

• Erythema, petechiae, or purpura with a serpiginous border at the margin of palmar plantar skin with the use of ATG[13]

Approximately two thirds of patients experience joint discomfort.[45] In order of decreasing frequency, the affected joints include the knees, ankles, shoulders, wrists, spine, and temporomandibular joint. Joint fluid usually yields a moderately high number of white cells. Myalgias in the arms and thighs may also occur.

Lymphadenopathy coincides with the onset of other symptoms of serum sickness. Lymph nodes that receive drainage from the injection site may enlarge and become tender. Other lymph nodes may also enlarge, sometimes to several centimeters in diameter.

Proteinuria, microscopic hematuria, and hyaline casts may be observed. Serum creatinine levels may transiently rise, and the creatinine clearance may decrease. Edema may be due to proteinuria or rash.

Nausea, vomiting, and abdominal pain are usually mild but may be confused with appendicitis and other GI disorders in children. Other, rare symptoms include:

• Headache and blurred vision

• Uveitis[46]

• Cardiovascular problems - Pericardial effusion

• Respiratory problems - Dyspnea, wheezing, cyanosis

Since this condition is associated with immune complex-based bascular inflammation, in severe cases, involvement of other organs such as the kidney, brain, lung, GI tract, etc. can occur. For example, severe cases of serum sickness with sulfonamide can manifest as Stevens-Johnson syndrome.

The following studies are indicated in patients with serum sickness:

• CBC with differential - Leukocytosis or leukopenia, eosinophilia, or mild thrombocytopenia

• Erythrocyte sedimentation rate and C-reactive protein levels - Usually slightly elevated

• Urinalysis - Proteinuria, hematuria, active sediment

• Blood urea nitrogen (BUN) and creatinine levels - May be transiently elevated

• C3, C4, CH50 - Depressed complement levels due to complement consumption

• Quantitative immunoglobulins - Hypergammaglobulinemia that results from prolonged course of antithymocyte globulin (ATG)

• Immune complexes - C1q binding or Raji cell assays for elevated levels of immune complexes (These test can be confirmatory but are not essential for diagnosis.)

Skin biopsy is usually not indicated for serum sickness but may be considered to further evaluate for vasculitis if the etiology is unclear.

Biopsy of serum sickness skin lesions reveals a perivascular lymphohistiocytic infiltrate and may show edema of perivascular stroma.[13] Immune deposits (IgM, IgE, C3, and IgA) are found in superficial small blood vessels and renal glomeruli with direct immunofluorescence (DIF).

Results from biopsy of skin lesions in serum sickness–like reactions have noted interstitial inflammatory infiltrate with neutrophils and eosinophils, perivascular lymphocytic, eosinophilic, histiocytic, or neutrophilic infiltrate, typically consistent with urticaria without evidence of vasculitis.[47]

Because of the high rate of blood flow and the filtration effect at the renal glomeruli, the immune complexes with serum sickness are deposited at the glomerular basement membrane. These deposits can be visualized with electron microscopy in the subendothelial and mesangial areas. These deposits lead to the activation of the complement system and the recruitment of neutrophils. Inflammatory mediators are released, resulting in a histologic picture of glomerulonephritis.[48]

The primary therapy in patients with serum sickness is discontinuation of the offending agent. Therefore, the identification of the offending agent is of the utmost importance. Although the use of heterologous protein, such as antithymocyte globulin (ATG), is easily identified, other more common medications, may not be as obvious. Follow-up care is needed until symptoms resolve.

Treatment also includes:

• Supportive care

• Antihistamines - For urticaria

• Nonsteroidal anti-inflammatory drugs (NSAIDs) - For arthritis, arthralgia, or both (but be cautious if renal involvement is present)

• Steroids - Particularly if heterologous antiserum is necessary for management of the underlying condition

 

 

Tanriover et al investigated the therapeutic effects of plasma exchange as an alternative treatment for patients who developed severe serum sickness that was unresponsive to systemic steroids after receiving a polyclonal antibody (ATG [thymoglobulin] or lymphocyte immune globulin/antithymocyte globulin [Atgam]) for renal transplantation.[49] Five renal transplantation patients with serum sickness experienced complete resolution of all symptoms after receiving 1 or 2 courses of therapeutic plasma exchange.

If the cause of serum sickness is clear and the patient is stable, inpatient care is unnecessary. However, in cases in which the etiology of the constitutional symptoms is uncertain or symptoms are worsening, further inpatient evaluation and management may be indicated.

In patients whose symptoms do not follow the typical course of spontaneous resolution consultation with an allergist/immunologist to rule out an immunoglobulin E (IgE)–mediated reaction may be helpful. Rheumatology consultation can evaluate for other causes of arthritis or vasculitis. Infectious disease specialists can help choose alternative antibiotic therapy.

No restriction of activity is necessary, although arthritis, arthralgia, or both may limit the child's activity for several days to weeks.

The patient and family should be instructed to avoid using the offending agent in the future as well as drugs in the same class as the offending agent.

The objective of medical therapy is to ameliorate the symptoms that result from deposition of the immune complexes in the various tissues. Antihistamines are useful in controlling urticarial lesions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat fever and minor musculoskeletal symptoms. Corticosteroids are necessary to treat the more severe symptoms.

Class Summary

These agents are used to treat urticaria and pruritus. Classic H1-blocker antihistamines block the histamine-mediated increase in vascular permeability. Some second-generation antihistamines may also reduce the release of vasoactive amines.

Diphenhydramine (Benadryl, Anti-Hist, Aler-Tab, Diphen)

Diphenhydramine is an antihistamine with anticholinergic and sedative adverse effects. It is used for treatment of allergic reactions.

Class Summary

This class of drugs acts by inhibiting cyclooxygenase, thereby blocking the production of prostaglandins, which are powerful mediators of inflammation. These drugs are useful in relieving fever and musculoskeletal pain.

Ibuprofen (Motrin, Advil, Provil)

Ibuprofen is a member of the propionic acid group of NSAIDs. It has moderate efficacy and a good safety profile and is used in children for various conditions, including fever and arthritis. To avoid gastrointestinal (GI) complications, it should be taken with food.

Class Summary

These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is a corticosteroid with salt-retention properties that is used for its potent anti-inflammatory effects. Because of its well-known adverse effects, it is used only in cases in which the systemic symptoms are severe.