eMedicine Specialties > Rheumatology > Vasculitis

Serum Sickness

Hassan M Alissa, MD, Fellow in Rheumatology, Department of Internal Medicine, Loyola University Medical Center
Elaine Adams, MD, Chief of Medical Service, Chief of Rheumatology Section, Hines Veterans Affairs Hospital; Associate Chief, Associate Professor, Department of Internal Medicine, Loyola University School of Medicine; Rochella Abaygar Ostrowski, MD, Assistant Professor, Department of Medicine, Division of Rheumatology, Loyola University Medical Center; Staff Physician, Department of Medicine, Division of Rheumatology, Edward Hines Jr Veterans Affairs Hospital; Richard Hariman, MD, Fellow, Department of Rheumatology, Loyola University Medical Center

Updated: Jun 22, 2009

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.

Differential Diagnoses

Other Problems to Be Considered

Dermatitis herpetiformis
Guillain-Barré syndrome
Henoch-Schönlein purpura
Microscopic polyangiitis
Shunt nephritis
Still disease

Workup

Laboratory Studies

• Patients with serum sickness may have leukopenia or mild leukocytosis, with or without eosinophilia. Plasma cells may be observed on a peripheral blood smear.²
• The erythrocyte sedimentation rate is usually elevated.²
• Patients may have polyclonal gammopathy or a transient monoclonal immunoglobulin G (IgG) spike.⁵
• Urinalysis may reveal mild proteinuria or hematuria, and serum creatinine levels may be transiently elevated.
• Complement levels (C3, C4) are often decreased.²
• Cryoglobulins, often of the mixed (IgM-IgG) type, may be present.

Histologic Findings

Numerous histological changes may be found in serum sickness, depending on the organ involved and, possibly, the nature of the antigen. The tissues most commonly involved include those of the heart, arteries, joints, and kidneys. Arteritic lesions are focal, necrotizing, and inflammatory processes usually involving all layers of the artery. Acute inflammatory exudate, necrosis of the arterial wall, fibrinoid material, or primarily a mononuclear reaction may be observed. Joints may have focal mononuclear infiltrates with edema and fibrinoid formation in the synovial tissues. Kidneys develop endothelial proliferation of the glomerular capillaries with slight basement membrane thickenings.³

Treatment

Medical Care

Withdrawal of the offending agent is the mainstay of treatment in serum sickness. Anti-inflammatories and antihistamines provide symptomatic relief. Severe cases (multisystem involvement with significant symptomatology⁵ ) may warrant a brief course of corticosteroids.

In some cases, plasmapheresis can attenuate serum sickness.⁹

Consultations

The presenting features of fever, rash, and joint pain may be observed in numerous infectious and autoimmune diseases. Consider a consultation with an allergist or a rheumatologist.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Nonsteroidal anti-inflammatory drugs

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Ibuprofen (Motrin, Ibuprin)

Decreases inflammation by blocking prostaglandin synthesis and reduces fever by acting on the hypothalamic temperature-regulating center. Usually administered for mild symptoms of arthralgia, myalgia, or fever.

Dosing

Adult

200-800 mg PO qid; not to exceed 3200 mg

Pediatric

<12 years: 5-10 mg/kg PO qid
>12 years: Administer as in adults

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, asthma, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Antihistamines

agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine HCL (Benadryl)

Blocks histamine H1 receptors on the target tissue. For urticarial rash.

Dosing

Adult

25-50 mg PO/IM qid

Pediatric

5 mg/kg/d PO/IV/IM divided tid/qid

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patient taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in neonates and nursing mothers; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, urinary tract obstruction, asthma

Corticosteroids

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

Prednisone (Deltasone, Orasone, Sterapred)

Acts by altering the number and availability of leukocytes, reducing vascular permeability, and suppressing cytokines. Mainstays of treatment in severe cases; usually administered in moderate doses for 1-2 weeks. This or other oral forms of corticosteroids (eg, prednisolone) are useful in managing mild-to-moderate serum sickness treated in an outpatient setting.

Dosing

Adult

20-40 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Pediatric

0.2-0.5 mg/kg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Follow-up

Further Outpatient Care

• Reconsider the diagnosis of serum sickness if symptoms persist beyond 3-4 weeks.
• Symptoms may reappear in severe cases if steroids are tapered too quickly; this recurrence is usually responsive to another course of treatment.

Deterrence/Prevention

• Withhold further use of the offending agent.
• To identify patients who are at risk of anaphylactic reactions, test their skin using prick and intradermal testing at 1:1000 and then at 1:100 dilutions. However, these tests are not helpful for predicting which patients are at risk for developing serum sickness.
• Premedication with steroids is not protective.

Complications

• Severe progressive glomerulonephritis (rare)
• Irreversible neurologic damage (rare)

Prognosis

• Serum sickness is typically self-limited and resolves within days.⁹
• The prognosis of serum sickness in the absence of internal organ involvement is good.¹

Patient Education

• After identifying the causative agent, inform the patient and advise that future exposure may cause a similar or more severe response.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider serum sickness in the differential diagnoses and to stop the offending agent
• Readministration of an agent that has caused serum sickness in the past

References

1. Pichler, WJ. Drug hypersensitivity. In: Rich RR, ed. Clinical Immunology Principles and Practice. 3^rd ed. St Louis, Mo: Mosby/Elsevier; 2008:714.

2. 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.

3. Dixon FJ, Cochrane CC. Immune complex injury. In: Samter M, ed. Immunological Diseases. 4^th ed. New York, NY: Little, Brown and Company; 1988:233.

4. Sicherer SH, Leung DYM. Serum sickness. In: Kliegman, ed. Nelson Textbook of Pediatrics. 18^th ed. Online Edition, Chapter 149.

5. Erffmeyer JE. Serum sickness. Ann Allergy. Feb 1986;56(2):105-9. [Medline].

6. 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].

7. 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].

8. Karliner JS, Belaval GS. Incidence of reactions following administration of antirabies serum; study of 526 cases. JAMA. Aug 2 1965;193:359-62. [Medline].

9. Frank, MM, Lawley TJ. Immune complexes and allergic disease. In: Middleton E Jr, ed. Allergy Principles and Practice. 5^th ed. St Louis, Mo: Mosby; 1998:704-6.

10. Lawley TJ, Frank MM. Immune complexes and allergic diseases. In: Middleton E Jr, ed. Allergy Principles and Practice. 4^th ed. St. Louis, Mo: Mosby; 1993:990.

11. 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].

12. 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].

13. 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].

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

Contributor Information and Disclosures

Author

Hassan M Alissa, MD, Fellow in Rheumatology, Department of Internal Medicine, Loyola University Medical Center
Hassan M Alissa, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Elaine Adams, MD, Chief of Medical Service, Chief of Rheumatology Section, Hines Veterans Affairs Hospital; Associate Chief, Associate Professor, Department of Internal Medicine, Loyola University School of Medicine
Elaine Adams, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Nothing to disclose.

Rochella Abaygar Ostrowski, MD, Assistant Professor, Department of Medicine, Division of Rheumatology, Loyola University Medical Center; Staff Physician, Department of Medicine, Division of Rheumatology, Edward Hines Jr Veterans Affairs Hospital
Rochella Abaygar Ostrowski, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Nothing to disclose.

Richard Hariman, MD, Fellow, Department of Rheumatology, Loyola University Medical Center
Richard Hariman, MD is a member of the following medical societies: American College of Rheumatology
Disclosure: Nothing to disclose.

Medical Editor

John Varga, MD, Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University
John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical Research, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

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