In United States, serum Sickness is managed by allergy & immunologists. Serum sickness is a type III hypersensitivity reaction caused by circulating immune complexes that deposit in skin, joints, kidneys, and other tissues, producing fever, urticaria, arthralgia, lymphadenopathy, and proteinuria roughly 7-21 days after exposure to a foreign protein or drug. Originally described after horse serum was used as antitoxin in diphtheria and tetanus, the classical form is now rare.
Serum sickness (ICD-10: T80.6 anaphylactic reaction due to serum; T80.61 other serum reaction following blood and blood products; T80.69 other serum reaction) is a delayed, immune complex-mediated systemic reaction occurring 7-21 days after first exposure or 1-7 days after re-exposure to a foreign protein or hapten-protein. Antibodies (typically IgM and IgG) form against the foreign antigen and combine to produce circulating immune complexes that activate complement, deposit in small vessels of skin, joints, kidneys, and other tissues, and trigger neutrophil-mediated vasculitis. Coombs and Gell classified this as type III hypersensitivity. Classical serum sickness, named in 1905 by Clemens von Pirquet after his observations on horse-derived diphtheria antitoxin, includes fever, urticarial rash (often serpiginous), polyarthralgia, lymphadenopathy, glomerulonephritis, and decreased serum complement (C3, C4, CH50).
The key symptoms of Serum Sickness are: Fever (38-40 °C), often spiking and accompanied by rigors, beginning 7-21 days after exposure or 1-7 days after re-exposure., Urticarial or serpiginous rash, classically beginning at the site of injection (in injectable therapies) and spreading centrally, often along the lateral feet and hands, palms, and soles., Symmetrical arthralgia and arthritis affecting hands, wrists, knees, and ankles, ranging from mild aching to disabling joint pain., Generalized lymphadenopathy in 10-20%, particularly affecting cervical and axillary chains adjacent to the exposure site., Generalized malaise, fatigue, headache, and myalgia., Edema of the hands, feet, and face — sometimes with peri-orbital involvement., Pruritus, ranging from mild itching to severe disturbance of sleep..
Diagnosis rests on the characteristic clinical pattern of fever, urticarial rash, arthralgia, and lymphadenopathy appearing 7-21 days after exposure to a foreign protein or drug. History identifies the specific exposure, prior similar reactions, and any concurrent medications. Physical examination documents the rash distribution (especially serpiginous lesions on the lateral feet and hands), joint involvement, lymph nodes, and edema. Routine investigations include complete blood count (often shows neutrophilia, eosinophilia, and mild anemia), urinalysis (proteinuria, hematuria, red cell casts in classical disease), creatinine and electrolytes (renal involvement), liver function tests, ESR and CRP (elevated), and serum complement (C3, C4, CH50 reduced in classical serum sickness but normal in SSLR). Complement consumption is the single most useful test to distinguish true serum sickness (low) from serum sickness-like reaction (normal). Anti-drug antibody testing can confirm immune response to specific monoclonal antibodies. Skin biopsy of fresh lesions shows leukocytoclastic vasculitis or perivascular neutrophilic infiltrate with immune complex deposits on direct immunofluorescence. Renal biopsy is reserved for unclear cases with severe glomerulonephritis. The differential diagnosis includes drug-induced lupus, hypersensitivity vasculitis, Stevens-Johnson syndrome, DRESS, acute viral exanthem (parvovirus, hepatitis B, EBV, hepatitis C), Henoch-Schonlein purpura, Kawasaki disease (in children), and acute rheumatic fever. Drug allergy testing is generally not performed during the acute reaction but can confirm sensitization 4-6 weeks later if rechallenge is considered.
Most patients recover completely within 1-2 weeks of stopping the offending agent and beginning supportive care; mortality is under 0.1% in modern series, and major organ damage is rare. Cefaclor-induced serum sickness-like reactions in children have an excellent prognosis with full recovery in over 95% of cases. Severe classical serum sickness with glomerulonephritis or vasculitis has a more variable course but rarely produces lasting renal damage when treated with high-dose corticosteroids. Recurrence with re-exposure to the same antigen is common and typically more rapid in onset. Long-term immunologic consequences are limited; patients retain memory B-cells against the offending antigen but do not have ongoing autoimmune disease. Avoidance of the responsible agent prevents future episodes in nearly all cases.
Any patient with suspected serum sickness should be evaluated by allergy and immunology, both to confirm the diagnosis and to plan safe future therapy. Nephrology, neurology, or cardiology input is warranted when organ involvement is present. Rheumatology assessment helps distinguish serum sickness from drug-induced lupus or systemic vasculitis.
Find specialists →Symptom resolution typically begins within 24-72 hours of stopping the offending agent. Rash and arthralgia improve over 7-14 days; lymphadenopathy and laboratory abnormalities (low complement, proteinuria) resolve over 2-6 weeks. Severe cases with renal or neurological involvement may take 2-3 months to fully recover.
Rest during the acute phase. Gentle activity (walking, light stretching) can resume once fever and joint pain settle. Return to vigorous exercise after symptoms have fully resolved, usually 2-4 weeks. Avoid contact sports during corticosteroid taper if myocarditis was suspected.
Choose an allergy specialist with experience in drug allergy, biologics, and antivenom-related reactions. Tertiary centers with multidisciplinary biologics clinics offer the best combination of immunology, rheumatology, and nephrology expertise for severe or rare presentations.
Medically reviewed by AIHealz Medical Editorial Board · May 13, 2026
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