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Serum sickness

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, 2009.

Table of contents

What is serum sickness?

Serum sickness is a self-limited allergic reaction following exposure to foreign proteins. Serum sickness is sometimes called a type III hypersensitivity reaction. The resulting immune complex of the patient's antibodies bound to the foreign protein is deposited in small blood vessels and stimulates the complement cascade and hence an inflammatory reaction. It presents with a classic triad:

  • Fever
  • Skin rash
  • Joint symptoms.

Who gets serum sickness?

Serum sickness typically followed exposure to foreign, non-human proteins, especially antivenoms and antitoxins made in horse, for example, rattlesnake antivenom used in the USA. More recently, reactions have been reported with the increasing use of thymoglobulin and chimeric monoclonal antibody therapy (biological response agents).

Thymoglobulin (anti-thymocyte globulin) is made in rabbits. It is used particularly in the perioperative period following solid organ transplants to reduce the post-operative doses of immunosuppressive drugs. The incidence of serum sickness due to thymoglobulin in renal transplant recipients has been estimated to be between 7 and 27%. There is an increased risk of developing serum sickness to thymoglobulin if there has been significant past exposure to rabbits or horses.

Chimeric monoclonal antibodies are a group of biologic agents that are being used with increasing frequency for many immunological disorders such as rheumatoid arthritis, psoriasis and in cancer therapies.

What are the clinical features of serum sickness?

The typical triad of serum sickness comprises fever, rash and joint pain/swelling (arthritis or arthralgia). There is also often facial swelling and lymph node enlargement. The kidneys are commonly affected.

The classical rash is similar to hives (urticaria), but following thymoglobulin this may be absent or a brief erythematous morbilliform rash may be visible at the onset.

How is serum sickness diagnosed?

In classic serum sickness, immune complexes deposit in small blood vessels, activating the complement cascade and resulting in inflammation. This is recognised by typical clinical features. Blood tests may detect these immune complexes or the antibodies against the foreign protein and may reveal that complement levels (C3, C4) are reduced.

Skin biopsy of the rash will show a leukocytoclastic vasculitis (inflammation of blood vessels) with immune complex deposits composed of a combination of complement, IgG, IgM and IgA.

Serum sickness due to thymoglobulin can be confirmed by a blood test for antiheterologous antibodies against rabbit immunoglobulin G by enzyme-linked immunosorbent assay (ELISA).

Proposed criteria for making the diagnosis of thymoglobulin-induced serum sickness
Major Criteria
  • More than seven days since starting thymoglobulin therapy
  • Persistent high fevers
  • Persistent joint pain or swelling
  • Presence of antibodies
Minor Criteria
  • +/- Acute kidney failure
  • +/- Skin rash
  • +/- Restricted mouth opening
  • +/- Low blood complement levels

What is the treatment of serum sickness?

If possible the triggering therapy should be ceased.

High dose IV corticosteroids should be given for three days then reducing doses of oral steroids following clinical response.

If there has been no response, then plasma exchange can be used to remove the immune complexes, antibodies and protein.

Serum sickness usually resolves without long-term complications.



  • Lundquist AL, Chari RS, Wood JH, Miller GG, Schaefer HM, Raiford DS, Wright KJ, Gorden DL. Serum Sickness Following Rabbit Antithymocyte-Globulin Induction in a Liver Transplant Recipient: Case Report and Literature Review. Liver Transpl. 2007; 13: 647–50. PubMed

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