Serum Sickness



  • A disorder resulting from antibody-antigen complexes (typically a protein and IgG/IgM) that are formed after exposure to a foreign antigen
  • An acute type III hypersensitivity reaction
    • With first-dose reactions, symptoms tend to develop in 4 to 21 days after contact.
    • With subsequent exposures, symptoms can occur within hours.
    • Most common cause is exposure to nonprotein drugs, such as antiepileptic drugs and antibiotics, especially penicillins, cephalosporins, and trimethoprim/sulfamethoxazole (TMP/SMX).
    • Can occur even if drug was previously tolerated
  • No sex or age predominance
  • Serum sickness–like reaction (SSLR): a specific drug reaction not associated with immune complexes (see “Commonly Associated Conditions”)
  • System(s) affected: hematologic/lymphatic/immunologic, musculoskeletal, skin/exocrine, cardiovascular, gastrointestinal, genitourinary



  • More common with β-lactam antibiotics
  • Rate of cefaclor SSLR has been estimated at ~0.024–0.2% per course prescribed (1)[C].
  • Infusion-associated reactions to rituximab noted in patients with multiple sclerosis, non-Hodgkin lymphoma, and rheumatoid arthritis

Etiology and Pathophysiology

  • IgM antibodies develop 7 to 14 days after exposure to protein antigen.
  • IgG antibodies develop a few days after IgM.
  • IgG antibodies form immune complexes with circulating antigen.
  • Complexes deposit in tissue causing activation of mast cells, monocytes, polymorphonuclear leukocytes, and platelets, leading to cytokine release and subsequent clinical illness.
  • Immune complexes and vasculitis are absent.
  • Complement activation causes
    • Release of inflammatory mediators
    • Recruitment of leukocytes
    • Vascular leak
  • Potential antigens include:
    • Antithymocyte globulin
    • Antimicrobials
      • Cephalosporins, especially cefaclor (antibodies form against side chains)
      • Minocycline
      • TMP/SMX
      • Rifampin
      • Penicillins
      • Streptokinase
      • Meropenem
    • Monoclonal antibodies, especially rituximab
    • SSRIs
    • Bupropion
    • Propranolol
    • Vaccines, has been reported after H1N1 vaccine
    • Equine diphtheria antiserum
    • Rabies and rabbit antiserum
    • Crotalidae antivenin

In genetically susceptible hosts, a reactive cefaclor metabolite forms and can bind with tissue proteins (2)[C].

Risk Factors

  • Prior exposure to high-risk medications or serum
  • In children, the risk of SSLR is greater with cefaclor than other antibiotics (2)[C].
  • Large dose of immunoglobulin followed by an antigen (e.g., a vaccine) can trigger precipitation of antibody/antigen complexes (1)[C].

Commonly Associated Conditions


  • Typically occurs 1 to 3 weeks after initiation of certain drugs, especially antibiotics
  • In SSLR, immune complex formation and complement fixation do not occur; instead, in genetically susceptible patients, reactive drug metabolites bind to host proteins, eliciting an inflammatory response.
  • Reactions may be dose related; higher doses produce more metabolites to bind host proteins.
  • Reactions may be related to the drug itself (e.g., insulin detemir) or additives/preservatives (e.g., myristic acid or mannitol) (3)[C].

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