Introduction
Background
Historically, the term serum sickness connotes a self-limited immune complex disease caused by exposure to foreign proteins or haptens. Immune complex formation is a common event and does not typically cause symptoms. However, an immune reaction can occur, as in the case of serum sickness.1
Von Pirquet and Shick first described the syndrome in 1905, describing fever, skin eruptions (mainly consisting of urticaria), joint pain, and lymphadenopathy in regions draining the site of injection after patients were given antitoxin in the form of horse serum. Later, physicians reported a similar clinical picture after the injection of other equine-based antitoxins and antivenins.2 Certain medications (eg, penicillin, nonsteroidal anti-inflammatory drugs [NSAIDs]) have also been associated with serum sickness–like disease.
Identifying serum sickness was a landmark observation in understanding immune complex diseases.
Pathophysiology
Serum sickness is an example of the type III, or immune complex–mediated, hypersensitivity disease. The molecular size, charge, structure, amount, and valence of the antigen involved influence the type of immune complexes formed.2
After the initial exposure to a foreign antigen in the absence of a preexisting antibody, serum sickness can develop within 1-2 weeks. Upon subsequent exposure, however, serum sickness develops sooner. The disease appears as the antibody formation begins, and the pathogenesis of serum sickness is related to protracted interaction between antigen and antibody in the circulation, with antigen-antibody complex formation in an environment of antigen excess.
The immunological interactions observed in serum sickness occur when antigens capable of remaining in the circulation for long periods incite antibody formation.3 Typically, serum protein molecules are removed from the circulation by nonimmune processes that are not yet completely understood. Small complexes usually circulate without triggering inflammation, and large complexes are cleared by the reticuloendothelial system. However, intermediate-sized complexes that develop in the context of slight antigen excess may deposit in blood vessel walls and tissues, where they induce vascular and tissue damage resulting from activation of complement and granulocytes.4
Endothelial cells increase the expression of adhesion molecules, and proinflammatory cytokines are released by monocytes and macrophages. Subsequently, addition inflammatory cells are recruited, and necrosis of the small vessels develops. Complement activation promotes chemotaxis and adherence of neutrophils to the site of immune complex deposition. This may be facilitated by increased vascular permeability due to release of vasoactive amines from tissue mast cells.4 At this point, complement levels fall to half their levels prior to the antibody response.3 This clinicopathological syndrome usually develops within 1-2 weeks of antigen injection.
Free antigen continues to clear from the blood, leading to antibody excess and the formation of large immune complexes, which are quickly removed by circulating macrophages. Finally, the antigen is no longer detectable, and the level of circulating antibodies continues to rise. Clinical recovery is usually apparent after 7-28 days, as intermediate-sized immune complexes are cleared by the reticuloendothelial system.
Secondary serum sickness is the result of antigen recognition by presensitized cells of the immune system and is characterized by a shorter latent period, exaggerated symptoms, and a brief clinical course.
Why immune complex disease occurs under certain circumstances is not known. Possible factors may include high levels of immune complexes and a relative deficiency of some complement components leading to a decreased ability to eliminate immune complexes.1
Frequency
United States
The annual incidence of serum sickness is decreasing as the administration of foreign antigens in medical therapeutics is refined.5
The likelihood of developing serum sickness is dose-related. In one study, 10% of patients who received 10 mL of tetanus antitoxin developed serum sickness; the administration of 80 mL or more produced the disease in almost all patients.5
The likelihood also varies by antigen type. Antirabies serum were associated with a higher likelihood (16.3%) of serum sickness than tetanus antitoxin (2.5%-5%).5 The reported rate of serum sickness–like reaction per course of cefaclor in United States children is 0.2%.6
In a clinical trial conducted to evaluate the efficacy and safety of recombinant murine monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis, serum sickness reactions were noted in 15 (2.3%) of 645 patients in the treatment group.7
International
Serum sickness occurs worldwide, in proportion to the therapeutic use of foreign antigens and drugs.
Mortality/Morbidity
Although occasional reports show mortality resulting from progressive glomerulonephritis or severe neurological complications, serum sickness is usually self-limited, and recovery is the rule.
Age
In one study, serum sickness was more common in patients older than 15 years who were given antirabies serum.8 Antibiotic-associated serum sickness–like disease, however, is more frequently described in children younger than 5 years.
Clinical
History
Serum sickness develops 1-3 weeks after administration of the causative agent (in many cases a medication) is initiated but can occur within 12-36 hours in individuals who have been previously sensitized through an antecedent exposure.9
- Symptoms described in serum sickness include the following:10
- Fever/malaise - 100%
- Cutaneous eruptions - 93%
- Arthralgias - 77%
- Gastrointestinal complaints - 67%
- Headaches - 57%
- Myalgias - 37%
- Blurred vision - 37%
- Dyspnea/wheezing - 20%
- Lymphadenopathy - 17%
- Specific GI symptoms may include abdominal pain, nausea, vomiting, or diarrhea.2
- Chest pain or breathlessness due to pleuritis, pericarditis, or myocarditis is possible but rare.
Physical
- Fever: This develops in almost all patients with serum sickness, preceding skin rash in 20% of cases. The fever is characterized by high spikes that normalize within the same day.4
- Skin symptoms
- Rash (92% are urticarial2 ): Most rashes associated with serum sickness are urticarial and/or serpiginous. They typically start on the anterior lower trunk or the periumbilical or axillary regions and spread to the back, upper trunk, and extremities.4
- Morbilliform or scarlatiniform rash, palpable purpura, erythema simplex or multiforme (less common)
- Possible pruritus and erythema at injection site
- Arthritis (10%-50%), usually in the metacarpophalangeal and knee joints and usually symmetrical5
- Edema, which can be limited to site of injection but can also be observed in the face2
- Regional lymphadenopathy2
- Carditis
- Acute renal failure (rare), proteinuria, hemoglobinuria2
- Neurologic complications5
- Peripheral neuritis
- Brachial plexus neuritis
- Optic neuritis
- Cranial nerves palsies
- Guillain-Barré syndrome
- Myelitis
- Encephalitis (rare)
Causes
- Currently, the most common cause of serum sickness is hypersensitivity reaction to drugs.9
- Proteins of other species, such as antitoxins, antivenins, hormones from other species, and streptokinase
- Antibiotics and other antimicrobials, such as cephalosporins, ciprofloxacin, griseofulvin, lincomycin, metronidazole, penicillins, streptomycin, sulfonamides, and tetracyclines
- Other drugs, such as allopurinol, barbiturates, carbamazepine, fluoxetine, hydantoins, indomethacin, iron dextran, methimazole, phenylbutazone, procarbazine, propranolol, and thiouracil
- Polyclonal and monoclonal antibodies prepared from horse, rabbit, or mouse serum (eg, antithymocyte globulin, OKT-3) have also been found to cause serum sickness.11
- Omalizumab, a monoclonal antibody used to treat allergy-related asthma, has recently been reported to cause serum sickness–like syndrome.12
- Various different case studies (20 cases in the literature as of August 2007) have linked serum sickness–like syndromes to rituximab therapy used to treat various diseases, including autoimmune diseases, mixed cryoglobulinemia, and lymphoma.13
- Stings from insects in the order Hymenoptera (eg, bees, mosquitoes) and tick bites may cause serum sickness.
- Infectious diseases involving circulating immune complexes (eg, hepatitis B, infectious endocarditis) may cause serum sickness–like reactions. These conditions are often associated with circulating cryoglobulins.
More on Serum Sickness |
 Overview: Serum Sickness |
| Differential Diagnoses & Workup: Serum Sickness |
| Treatment & Medication: Serum Sickness |
| Follow-up: Serum Sickness |
| References |
| Next Page » |
References
Pichler, WJ. Drug hypersensitivity. In: Rich RR, ed. Clinical Immunology Principles and Practice. 3rd ed. St Louis, Mo: Mosby/Elsevier; 2008:714.
Mannik M. Serum sickness and pathophysiology of immune complexes. In: Rich RR, ed. Clinical Immunology Principles and Practice. St. Louis, Mo: Mosby; 1996:1062-71.
Dixon FJ, Cochrane CC. Immune complex injury. In: Samter M, ed. Immunological Diseases. 4th ed. New York, NY: Little, Brown and Company; 1988:233.
Sicherer SH, Leung DYM. Serum sickness. In: Kliegman, ed. Nelson Textbook of Pediatrics. 18th ed. Online Edition, Chapter 149.
Erffmeyer JE. Serum sickness. Ann Allergy. Feb 1986;56(2):105-9. [Medline].
King BA, Geelhoed GC. Adverse skin and joint reactions associated with oral antibiotics in children: the role of cefaclor in serum sickness-like reactions. J Paediatr Child Health. Dec 2003;39(9):677-81. [Medline].
Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. Mar 22-29 1995;273(12):934-41. [Medline].
Karliner JS, Belaval GS. Incidence of reactions following administration of antirabies serum; study of 526 cases. JAMA. Aug 2 1965;193:359-62. [Medline].
Frank, MM, Lawley TJ. Immune complexes and allergic disease. In: Middleton E Jr, ed. Allergy Principles and Practice. 5th ed. St Louis, Mo: Mosby; 1998:704-6.
Lawley TJ, Frank MM. Immune complexes and allergic diseases. In: Middleton E Jr, ed. Allergy Principles and Practice. 4th ed. St. Louis, Mo: Mosby; 1993:990.
Lawley TJ, Bielory L, Gascon P, Yancey KB, Young NS, Frank MM. A prospective clinical and immunologic analysis of patients with serum sickness. N Engl J Med. Nov 29 1984;311(22):1407-13. [Medline].
Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol. Oct 2007;120(4):972-3. [Medline].
Disperati P, Hicks LK, Buckstein R. Rituximab-induced serum sickness in a patient with follicular lymphoma. Leuk Lymphoma. Aug 2007;48(8):1633-5. [Medline].
Further Reading
Keywords
serum sickness, hypersensitivity vasculitis, drug-induced vasculitis, immune complex disease, foreign serum, serum protein, serum disease, serum reaction, foreign proteins, haptens, antigens, leukocytoclastic vasculitis, secondary serum sickness, antirabies serum, tetanus antitoxin
