Serum sickness is an often overlooked entity when considering the differential diagnosis of a febrile patient. This is a brief overview on the history and management of a patient who presents with signs and symptoms of this disorder:


In the late 1800’s in Germany diphtheria was rampant and many children were dying. Thankfully, a physiologist named Emil von Behring developed diphtheria antitoxin serum from the serum of horses inoculated with diphtheria. He won a Nobel Prize for his efforts. In some patients, however, injection of antitoxin caused a systemic reaction which involved fever, rash, and joint pain. This was described in 1905 by Austrian pediatricians Clemens E. von Pirquet and Bela Schick in their thesis entitled Die Serumkrankheit (The Serum Sickness). What they noted was patients developed the above symptoms 8-12 days after administration of their first dose of antitoxin and subsequent doses elicited a more rapid onset of illness. It was postulated that something in the foreign horse serum was causing a violent immune response.


Then, in 1953 it was discovered that serum sickness was the likely result of a type III hypersensitivity reaction (immune-complex mediated). This was confirmed by assessing complement levels, antigen levels, and antibody levels throughout the illness. What they found was as antigen levels fell free antibody levels rose, indicating antibodies had previously been bound to antigens. During this fall in antigen level, patients (or rabbits in this case) were displaying more severe symptoms.

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After the advent of manufactured corticosteroids in 1948, it was found that symptoms of serum sickness were alleviated with administration. Since that time, it has remained the mainstay of treatment of serum sickness.


Serum sickness is a Type III immune complex mediated hypersensitivity reaction. In this type of reaction complement attaches to these immune complexes facilitating the release of anaphylotoxins C3a and C5a. These mediate histamine release from mast cells and recruitment of inflammatory cells which explains symptoms associated with serum sickness.


Serum sickness typically presents 1-2 weeks after administration of a medication. Symptoms include rash (which can be highly variable), fever, and severe arthralgias. Symptoms mimic sepsis which is typically how these patients are treated.

Offending Agents

Essentially, any injectable protein can cause serum sickness. This includes antitoxins, antivenom, certain vaccines, streptokinase, monoclonal antibodies for immune modulation. There have also been case reports of insect bites causing serum sickness.


Laboratory findings may include neutropenia, mild thrombocytopenia, elevated ESR/CRP, mild proteinuria, AKI, and decreased complement levels. One should also still have a high suspicion for sepsis and as such patients should undergo infectious workup.


The offending agent should be immediately stopped. Given patients typically meet SIRS criteria, these patients are treated as presumed sepsis with empiric antibiotics. Systemic steroids (1-2mg/kg/day divided into 2 doses of methylprednisolone) and antihistamines, however, are the only medications which have been shown to benefit patients with serum sickness. In severe disease that is refractory to the above treatments, plasmaphoresis is also an option.


Serum sickness typically lasts 1-2 weeks. Assuming the offending agent has been removed and the patient does not develop an anaphylactic reaction, the prognosis is excellent.

Wener, M. Serum sickness and serum sickness-like reactions. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2015.

Bela Schick and Serum Sickness. Circulating Now. February 25, 2014. Accessed October 9, 2015.

Germuth FG Jr. A comparative histologic and immunologic study in rabbits of induced hypersensitivity of the serum sickness type. J Exp Med 97:257–282, 1953

von Pirquet C, Schick B. Die Serumkrankheit. Leipzig; Wien: Franz Deuticke; 1905.

May 2024