Serum sickness–like reaction

Overview

Serum sickness–like reaction (SSLR) is a hypersensitivity response that mimics classic serum sickness but differs in its underlying mechanism and severity. Unlike true serum sickness, which is an immune complex-mediated Type III hypersensitivity reaction triggered by exposure to non-human proteins, SSLR is often drug-induced and not associated with circulating immune complexes. SSLR is most commonly observed in children and young adults and typically occurs one to three weeks after exposure to the triggering agent. While the condition is self-limited and non-life-threatening, it can cause significant discomfort and requires prompt identification and management to avoid recurrence.

Causes

Serum sickness–like reaction is most commonly triggered by certain medications, especially antibiotics. Unlike true serum sickness, SSLR is not caused by foreign proteins but by drug hypersensitivity reactions that do not involve immune complex deposition. Common drugs associated with SSLR include:

• Cefaclor: The most frequently reported antibiotic linked to SSLR, especially in children

• Amoxicillin and other penicillins

• Trimethoprim-sulfamethoxazole

• Barbiturates

• Phenytoin

Vaccinations and viral infections have also occasionally been implicated. Genetic susceptibility and prior sensitization to the drug may increase the risk of developing SSLR.

Symptoms

Symptoms of serum sickness–like reaction typically begin 7 to 21 days after the initiation of the offending drug. Unlike classic serum sickness, systemic immune complex involvement such as nephritis or vasculitis is usually absent. Common symptoms include:

• Fever: Low-grade or moderate, typically transient

• Rash: Often urticarial or maculopapular, usually starting on the trunk and spreading outward

• Arthralgia or arthritis: Joint pain or swelling, commonly affecting knees, ankles, and wrists

• Lymphadenopathy: Swollen lymph nodes, especially in the cervical region

• Fatigue and malaise

Unlike classic serum sickness, symptoms such as proteinuria, nephritis, and hypocomplementemia are typically absent in SSLR.

Diagnosis

Diagnosis of SSLR is clinical and based on history and symptomatology. There are no specific laboratory tests to confirm SSLR, but certain evaluations can help support the diagnosis and rule out other conditions:

• Detailed medication history: Identifying recent exposure to high-risk drugs (especially cefaclor or penicillins)

• Physical examination: Noting characteristic rash, joint findings, and lymphadenopathy

• Blood tests:

  • Normal or slightly elevated white blood cell count

  • Normal complement levels (distinguishing from classic serum sickness)

  • Absence of significant proteinuria or hematuria

Other diagnoses to consider include viral exanthems, autoimmune disorders (e.g., juvenile idiopathic arthritis, systemic lupus erythematosus), and true serum sickness. Referral to a specialist may be warranted in unclear or recurrent cases.

Treatment

Treatment of serum sickness–like reaction is supportive and focused on relieving symptoms while eliminating the causative agent.

• Discontinue the offending drug: This is the most important step in management

• Antihistamines: For relief of rash and itching (e.g., diphenhydramine, cetirizine)

• NSAIDs: For joint pain and fever (e.g., ibuprofen or naproxen)

• Corticosteroids: For more severe or persistent symptoms; short courses of oral prednisone are usually sufficient

• Rest and hydration: Supportive care for systemic symptoms

Hospitalization is rarely needed unless the reaction is unusually severe or complicated by misdiagnosis.

Prognosis

The prognosis of serum sickness–like reaction is excellent. Most cases resolve completely within 1 to 2 weeks after stopping the offending drug and initiating symptomatic treatment. Recurrence can be avoided by identifying and avoiding the causative medication in the future. Unlike true serum sickness, SSLR does not cause long-term organ damage or serious complications.

Patients and caregivers should be educated about the condition and advised to inform healthcare providers about the drug allergy in future medical settings. Medical alert bracelets and documentation in electronic health records can help prevent re-exposure.