Serum sickness is an immune system reaction, most commonly triggered by medications or biological products containing foreign proteins. It is not an infection, but a delayed, systemic reaction where the body mistakenly identifies a therapeutic substance as a threat. This condition causes a generalized illness involving multiple body systems and typically appears days or weeks after the initial exposure. Though the name suggests involvement with blood serum, the term is historical, originating from early treatments using animal-derived antitoxins.
Understanding the Immune Reaction
Serum sickness is classified as a Type III hypersensitivity reaction, meaning its mechanism involves the formation of immune complexes. The process begins when the immune system creates antibodies, primarily Immunoglobulin G (IgG), to neutralize the foreign proteins, known as antigens. These antibodies bind to the circulating foreign proteins, forming large structures called immune complexes.
These immune complexes circulate in the bloodstream, eventually depositing in the walls of small blood vessels in various tissues, including the joints, kidneys, and skin. Once deposited, the complexes activate the complement system, triggering a cascade of inflammatory responses. This intense local inflammation results in the tissue damage and symptoms characteristic of serum sickness. The delayed onset, typically 7 to 14 days after the first exposure, is due to the time needed for antibody production and complex formation.
Substances That Can Trigger Serum Sickness
The original cases of serum sickness were caused by the injection of animal-derived serum, such as horse or rabbit antitoxins. Today, the most frequent triggers are modern pharmaceutical agents and biological therapies that contain non-human proteins.
A significant number of cases are now associated with monoclonal antibodies, which are biological agents used to treat autoimmune diseases and cancers. Examples include rituximab and infliximab, which are known to cause true serum sickness. Certain antibiotics, such as penicillin, cephalosporins, and sulfonamides, can also trigger a similar clinical presentation, often termed a serum sickness-like reaction. Other substances, including antivenoms, streptokinase (a clot-busting agent), and some vaccines, have also been documented as potential causes.
Recognizing the Signs and Symptoms
The clinical presentation of serum sickness is characterized by a triad of systemic symptoms: rash, fever, and painful joints. These symptoms usually begin simultaneously or shortly after one another. The rash is one of the most common signs, often presenting as hives (urticaria) or a measles-like eruption that can be intensely itchy. It frequently starts around the injection site before spreading across the body, though the hands and feet are often involved early.
Fever is a universal symptom, often high and sometimes exceeding 104°F, and is accompanied by a general feeling of illness or malaise. Joint pain, known as arthralgia, affects a majority of patients and can involve multiple joints, especially the knees, ankles, and fingers. The joint pain is typically symmetrical and can be severe enough to limit movement.
Other symptoms can occur as the immune complexes deposit elsewhere in the body. Swollen lymph nodes (lymphadenopathy) are often observed, particularly those draining the site where the causative agent was administered. Less commonly, patients may experience swelling in the face and extremities, abdominal discomfort, or signs of mild kidney involvement such as protein in the urine.
Diagnosis, Treatment, and Outlook
Diagnosis relies on linking the onset of the classic symptoms to a recent exposure to a known causative agent within the typical 7- to 21-day window. Doctors will take a detailed history of all medications and biological products received in the weeks leading up to symptom onset. Blood tests may be ordered to confirm the inflammatory process, sometimes showing low levels of complement proteins C3 and C4, which are consumed during the immune reaction.
The primary step in treatment is the immediate discontinuation of the medication or substance suspected of causing the reaction. For mild to moderate symptoms, treatment focuses on supportive care to manage discomfort. Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed to relieve fever and joint pain, while antihistamines help control the rash and itching.
For more severe cases involving significant joint pain or systemic inflammation, a short course of corticosteroids, such as prednisone, may be necessary to suppress the immune response. Serum sickness is a self-limiting condition with an excellent prognosis. Once the body clears the offending foreign proteins, symptoms typically resolve completely within a few days to a few weeks, and long-term complications are rare.