Serum Sickness
Basics
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
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
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].
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Citation
Domino, Frank J., et al., editors. "Serum Sickness." 5-Minute Clinical Consult, 33rd ed., Wolters Kluwer, 2025. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816110/all/Serum_Sickness.
Serum Sickness. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2025. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816110/all/Serum_Sickness. Accessed December 4, 2024.
Serum Sickness. (2025). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (33rd ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816110/all/Serum_Sickness
Serum Sickness [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2025. [cited 2024 December 04]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816110/all/Serum_Sickness.
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