Serum Sickness

Description

• 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

Epidemiology

Incidence

• 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

Genetics
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

SSLR

• 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].