AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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.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 recent 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.

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.

Pathophysiology

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}

Frequency

United States

The incidence of serum sickness decreased with declining use of heterologous serum antitoxins for treating conditions such as diphtheria and scarlet fever. 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 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 patients¹⁶ in previously reported studies. In a more recent 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.^{18, 9} 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 (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 incidence of serum sickness was 12.5%²⁰ and 5.6%,²¹ respectively.

Other reviews have shown that serum sickness is not limited in the treatment of ITP; those using rituximab for auto-immune diseases are also at risk.²²

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.^{8, 5, 4}

Mortality/Morbidity

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.

Age

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

CLINICAL

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History

The onset of serum sickness symptoms usually occurs 7-10 days 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, GI symptoms, and other symptoms follow.

Physical

The major physical findings include fever, rash, arthritis, arthralgia, and lymphadenopathy.

• Fever: The elevated temperature fluctuates from 37.5-40°C.
• Rash: 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. Eruption over the rest of the body is usually symmetrical and may take any of the following forms:
• • Urticaria
  • 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 antithymocyte globulin (ATG)⁹
• Arthralgia/arthritis: Approximately two thirds of patients experience joint discomfort.²⁶ 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: Lymphadenopathy coincides with the onset of other symptoms of serum sickness. The lymph nodes that receive drainage from the injection site enlarge and become tender. Other lymph nodes may also enlarge, sometimes to several centimeters in diameter.
• Renal involvement: Albuminuria, microscopic hematuria, and hyaline casts are observed. Serum creatinine levels may transiently rise, and the creatinine clearance may decrease.
• Edema: Edema may be due to albuminuria or rash.
• GI symptoms: Nausea, vomiting, and abdominal pain are usually mild but may be confused with appendicitis and other GI disorders in children.
• Headache: Headache and blurred vision may develop.
• Other, rare symptoms
• • Cardiovascular problems - Pericardial effusion
  • Respiratory problems - Dyspnea, wheezing, cyanosis

Causes

• 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

DIFFERENTIALS

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Other Problems to be Considered

Systemic-onset juvenile arthritis
Infectious mononucleosis
Postviral synovitis
Henoch-Schönlein purpura
Urticarial vasculitis
Hypersensitivity vasculitis
Appendicitis
GI disorders
Chronic idiopathic urticaria
Viral exanthem
Other drug reactions

WORKUP

Section 5 of 11  

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Lab Studies

The following studies are indicated in patients with serum sickness:

• CBC count with differential - Leukocytosis or leukopenia, eosinophilia, or mild thrombocytopenia
• Erythrocyte sedimentation rate and C-reactive protein levels - Usually slightly elevated
• Urinalysis - Albuminuria, hematuria, active sediment
• 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 are possibly confirmatory but not essential for diagnosis.)

Procedures

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

Histologic Findings

• Skin lesions reveal a perivascular lymphohistiocytic infiltrate and possible edema of perivascular stroma.⁹
• Immune deposits (IgM, IgE, C3, and immunoglobulin A [IgA]) seen with direct immunofluorescence (DIF) are found in superficial small blood vessels and renal glomeruli.
• Because of the high rate of blood flow and the filtration effect at the renal glomeruli, the immune complexes 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 the neutrophils. Inflammatory mediators are released, resulting in a histologic picture of glomerulonephritis.²⁷

TREATMENT

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Medical Care

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, others such as medications may not be as obvious.

• Medical care
• • Discontinuation of the offending agent
  • Supportive care
  • Antihistamines for urticaria
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) for arthritis, arthralgia, or both
  • Steroids (when the heterologous antiserum is necessary for management of the basic disorder)
• Experimental treatment: Tanriover et al investigated the therapeutic effects of plasma exchange as an alternative treatment for patients who underwent renal transplant and developed severe serum sickness that persisted despite systemic steroids after receiving a polyclonal antibody (ATG [Thymoglobulin] or lymphocyte immune globulin/antithymocyte globulin [Atgam]).²⁸ All 5 patients experienced complete resolution of all symptoms after receiving 1 or 2 courses of therapeutic plasma exchange.

Consultations

• Consult an allergist/immunologist to rule out an immunoglobulin E (IgE)–mediated reaction.
• Consult a rheumatologist to rule out other causes for arthritis or vasculitis.
• Consult an infectious disease specialist to choose alternative antibiotic therapy.

Activity

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

MEDICATION

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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.

Drug Category: Antihistamines

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.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

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.

Drug Category: Corticosteroids

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.

FOLLOW-UP

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Further Inpatient Care

• In patients with serum sickness, if the cause of the symptoms is clear, inpatient care is unnecessary. However, in cases in which the etiology of the constitutional symptoms is uncertain, further inpatient diagnostic studies may be indicated.

Further Outpatient Care

• Follow-up care is needed until symptoms resolve.

In/Out Patient Meds

• See Medication section.

Deterrence/Prevention

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

Complications

• Anaphylaxis and shock from reexposure to the offending agent are possibilities.

Prognosis

• Prognosis is excellent in most cases, 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.

Patient Education

• The patient and the family should be advised of the nature of the offending agent.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Inform patients and their families that serum sickness is a complication of therapeutic use of heterologous serum.
• In cases of drug-related serum sickness, the reaction is idiosyncratic, but the family should be informed.
• In the event that serum sickness–like reaction (SSLR) has resulted from the use of the medication, the family should be advised against the use of that agent or drugs of the same class in the future.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Urticarial rash in a child 10 days after cefaclor was administered for sore throat. Associated findings included fever, arthralgia of knees and ankles, and eosinophilia.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Oct 15, 2008