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Serum Sickness

  • Author: Hassan M Alissa, MD; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Feb 15, 2016
 

Background

Serum sickness is a type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum. Reactions secondary to the administration of nonprotein drugs are clinically similar to serum sickness reactions.

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.

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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 immunologic 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 monocytes and macrophages release proinflammatory cytokines. Subsequently, additional 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. It 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]

Not all substances that are recognized as foreign by the immune system elicit an immune response. The antigen must be of characteristic size or have specific antigenic determinants and physiological properties to be an effective stimulator of the immune system.

After an appropriate antigen is introduced, an individual's immune system responds by synthesizing antibodies after 4-10 days. The antibody reacts with the antigen, forming soluble circulating immune complexes that may diffuse into the vascular walls, where they may initiate fixation and activation of complement.

Complement-containing immune complexes generate an influx of polymorphonuclear leukocytes into the vessel wall, where proteolytic enzymes that can mediate tissue damage are released. Immune complex deposition and the subsequent inflammatory response are responsible for the widespread vasculitic lesions seen in serum sickness.

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Etiology

Currently, the most common cause of serum sickness is hypersensitivity reaction to drugs.[5] Drugs containing proteins of other species include the following:

  • Antitoxins
  • Antivenins
  • Hormones from other species
  • Streptokinase
  • Vaccines

Polyclonal and monoclonal antibodies prepared from horse, rabbit, or mouse serum (eg, antithymocyte globulin, OKT-3) have also been found to cause serum sickness.[6]

Antibiotics and other antimicrobials that can cause serum sickness include the following:

  • Cephalosporins
  • Ciprofloxacin
  • Furazolidone (Furoxone)
  • Griseofulvin
  • Lincomycin
  • Metronidazole
  • Para-aminosalicylic acid
  • Penicillins
  • Streptomycin
  • Sulfonamides
  • Tetracyclines

Other drugs associated with serum sickness include the following:

  • Allopurinol
  • Barbiturates
  • Bupropion (Zyban, Wellbutrin SR) [7, 8]
  • Captopril (Capoten),
  • Carbamazepine
  • Fluoxetine
  • Gold salts
  • Halothane
  • Hydantoins (eg, phenytoin)
  • Hydralazine (Apresoline)
  • Indomethacin
  • Iodides
  • Iron dextran
  • Methimazole
  • Methyldopa
  • Penicillamine
  • Procainamide
  • Procarbazine
  • Propranolol
  • Thiouracil

Several monoclonal antibodies have been reported to cause serum sickness–like syndrome. These include infliximab (Remicade), which is used to treat Crohn disease and rheumatoid arthritis[9, 10] ; omalizumab, which is used to treat allergy-related asthma[11, 12] ; and rituximab, which is used to treat various diseases, including rheumatologic disorders, mixed cryoglobulinemia, and lymphoma.[13, 14, 15]

Stings from insects in the order Hymenoptera (eg, bees, wasps), mosquitoes, and tick bites may cause serum sickness.[16]

Infectious diseases involving circulating immune complexes (eg, hepatitis B, infective endocarditis) may cause serum sickness–like reactions. These conditions are often associated with circulating cryoglobulins.

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Epidemiology

The annual incidence of serum sickness is decreasing as the administration of foreign antigens in medical therapeutics is refined.[17] 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.[17]

The likelihood also varies by antigen type. Antirabies serum is associated with a higher likelihood (16.3%) of serum sickness than tetanus antitoxin (2.5%-5%).[17] The reported rate of serum sickness–like reaction per course of cefaclor in United States children is 0.2%.[18]

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.[19]

In one study, serum sickness was more common in patients older than 15 years who were given antirabies serum.[20] Antibiotic-associated serum sickness–like disease, however, is more frequently described in children younger than 5 years.

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Prognosis

Serum sickness is typically self-limited and resolves within days.[5] The prognosis of serum sickness in patients without internal organ involvement is good.[1] Although occasional reports show mortality resulting from progressive glomerulonephritis or severe neurological complications.

Complications of serum sickness may include the following:

  • Vasculitis
  • Neuropathy
  • Acute renal failure
  • Glomerulonephritis (rare)
  • Anaphylaxis
  • Shock
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Contributor Information and Disclosures
Author

Hassan M Alissa, MD Rheumatologist, Multispecialty Group, San Marcos, Texas

Hassan M Alissa, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Francis Counselman, MD, FACEP Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School

Francis Counselman, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Norfolk Academy of Medicine, Association of Academic Chairs of Emergency Medicine, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Susan M Chen, MD Clinical Assistant Professor, Department of Emergency Medicine, University of Pennsylvania Health System, Penn Presbyterian Medical Center

Susan M Chen, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Elaine Adams, MD Associate Chief of Staff, Chief of Rheumatology Section, Hines Veterans Affairs Hospital; Professor of Medicine, Loyola University School of Medicine

Elaine Adams, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Richard Hariman, MD Assistant Professor, Division of Rheumatology, Medical College of Wisconsin

Richard Hariman, MD is a member of the following medical societies: 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, American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; 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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Matthew M Rice, MD, JD, FACEP Senior Vice President, Chief Medical Officer, Northwest Emergency Physicians of TeamHealth; Assistant Clinical Professor of Medicine, University of Washington School of Medicine Pending Approval

Matthew M Rice, MD, JD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, Society for Academic Emergency Medicine, Washington State Medical Association

Disclosure: Nothing to disclose.

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

  2. Mannik M. Serum sickness and pathophysiology of immune complexes. Rich RR, ed. Clinical Immunology Principles and Practice. St. Louis, Mo: Mosby; 1996. 1062-71.

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

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

  5. Frank MM, Hester CG. Immune Complex–Mediated Diseases. Adkinson NF Jr, Bochner BS, Burks W, et al, Eds. Middleton's Allergy Principles and Practice. 8th ed. Philadelphia PA: Saunders; 2014. 602-16.

  6. 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. 1984 Nov 29. 311(22):1407-13. [Medline].

  7. Benson E. Bupropion-induced hypersensitivity reactions. Med J Aust. 2001 Jun 18. 174(12):650-1. [Medline].

  8. Wooltorton E. Bupropion (Zyban, Wellbutrin SR): reports of deaths, seizures, serum sickness. CMAJ. 2002 Jan 8. 166(1):68. [Medline]. [Full Text].

  9. Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med. 2006 Jan. 30(1):41-4. [Medline].

  10. Vermeire S, Van Assche G, Rutgeerts P. Serum sickness, encephalitis and other complications of anti-cytokine therapy. Best Pract Res Clin Gastroenterol. 2009. 23(1):101-12. [Medline].

  11. Pilette C, Coppens N, Houssiau FA, Rodenstein DO. Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol. 2007 Oct. 120(4):972-3. [Medline].

  12. Harrison RG, MacRae M, Karsh J, Santucci S, Yang WH. Anaphylaxis and serum sickness in patients receiving omalizumab: reviewing the data in light of clinical experience. Ann Allergy Asthma Immunol. 2015 Jul. 115 (1):77-8. [Medline].

  13. Disperati P, Hicks LK, Buckstein R. Rituximab-induced serum sickness in a patient with follicular lymphoma. Leuk Lymphoma. 2007 Aug. 48(8):1633-5. [Medline].

  14. Meijer JM, Pijpe J, Vissink A, Kallenberg CG, Bootsma H. Treatment of primary Sjogren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment. Ann Rheum Dis. 2009 Feb. 68(2):284-5. [Medline].

  15. Karmacharya P, Poudel DR, Pathak R, Donato AA, Ghimire S, Giri S, et al. Rituximab-induced serum sickness: A systematic review. Semin Arthritis Rheum. 2015 Dec. 45 (3):334-40. [Medline].

  16. Lazoglu AH, Boglioli LR, Taff ML, Rosenbluth M, Macris NT. Serum sickness reaction following multiple insect stings. Ann Allergy Asthma Immunol. 1995 Dec. 75(6 Pt 1):522-4. [Medline].

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

  18. 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. 2003 Dec. 39(9):677-81. [Medline].

  19. 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. 1995 Mar 22-29. 273(12):934-41. [Medline].

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

  21. Fajt ML, Petrov AA. Desensitization protocol for rituximab-induced serum sickness. Curr Drug Saf. 2014. 9(3):240-2. [Medline].

 
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A 29-year-old woman with RA presented with fever, a diffuse skin rash, and arthralgia approximately 10 days after receiving intravenous rituximab. Diagnosis was rituximab-associated serum sickness. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
 
 
 
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