Continuing Education Activity
Serum sickness is a rare but important cause of fever, arthritis, and rash in both children and adults. This activity reviews the differences between the pathophysiology, clinical presentation, diagnosis and management of serum sickness versus serum-sickness-like-reaction. This activity highlights the role of the interprofessional team in caring for patients affected by serum sickness.
- Describe the pathophysiology of serum sickness and compare it to that of serum sickness-like-reaction.
- Review the clinical presentation of serum sickness and serum sickness-like-reaction.
- Describe the diagnostic evaluation of a patient with serum sickness.
- Explain interprofessional team strategies for improving care coordination and communication in the management of serum sickness.
Serum sickness is an immune-complex-mediated hypersensitivity reaction that classically presents with fever, rash, polyarthritis or polyarthralgias. It was first recognized as an entity in the early 1900s in patients who had received heterologous antisera, which was historically used to treat infectious diseases. The symptoms typically occur one to two weeks after exposure to an offending agent and resolve within several weeks of discontinuation.  It is a self-limited disease process with an excellent prognosis.
The symptoms of serum sickness arise as a result of the formation of immune complexes between human proteins and heterologous (nonhuman) proteins. Medications containing heterologous antigens are the most common cause of serum sickness and include vaccinations (i.e., Rabies), immune modulating agents (i.e., rituximab, infliximab) and anti-venoms. 
Serum sickness is not to be confused with a serum sickness-like reaction, which results in a similar clinical presentation but does not involve the formation of immune complexes. The most common offending medications include penicillins, cephalosporins (most commonly cefaclor), sulfonamides, bupropion, fluoxetine, and thiouracil.  Also, several infections can lead to the development of serum sickness-like reaction, including streptococcus and hepatitis B. 
Although considered a rare overall entity, serum sickness is more common in adults than in children. One study of 72,000 patients found that serum sickness was found in less than 0.5 percent of children under ten years who received human and equine anti-rabies globulins.  Certain patient populations are considered to be at a higher risk for developing serum sickness following rituximab infusion, including those with hypergammaglobulinemia and Hepatitis C-related cryoglobulinemia vasculitis. 
When a patient is exposed to a foreign serum protein, it takes approximately 6-10 days for antibodies to develop and form antigen-antibody complexes and is considered a Type III immune-mediated hypersensitivity reaction.  If the macrophage activating system is not functioning properly, these complexes will become saturated in the circulation, leading to immune complex deposition, most commonly in parenchymal tissues and synovial joint fluid. The deposition of immune complexes may also activate the classical complement pathway, leading to lower levels of circulating C3 and C4. These levels can be used to differentiate serum sickness from a serum sickness-like reaction, which will have normal complement levels.  Also, the activation of the complement system will trigger histamine release and increase vascular permeability, which leads to an inflammatory response in the tissues and joints. It is the process of clearing these immune complexes and the subsequent inflammatory reaction that coincides with the onset of clinical symptoms.  Note that in patients previously sensitized to the antigen, symptoms may develop within a few days of re-exposure to the causative agent.
History and Physical
A thorough history and physical exam are essential in the evaluation of suspected serum sickness. The history should focus on identification of an offending agent within the two weeks before the onset of symptoms, or, in the case of potential repeat exposure, within the few days before presentation. Also, a complete review of systems, with a focus on each organ system and severity of symptoms, should be performed to evaluate for other potential causes of the patient's presentation.
The physical exam should be carefully undertaken to determine the severity of symptoms and signs of systemic illness. A close inspection of the rash may reveal an urticarial, maculopapular or vasculitic (purpuric) eruption. Importantly, the mucous membranes are not involved and can be helpful in distinguishing serum sickness from Stevens-Johnson syndrome or toxic epidermal necrolysis. If associated with subcutaneous injection, the rash may first appear around the site of the injection. The rash typically takes days to weeks to resolve once the offending agent is discontinued. Arthralgias are more common than frank arthritis, but either may occur. The hands, feet, ankles, knees, and shoulders are most commonly affected. Less common findings on the physical exam include edema (i.e., of the hands, feet, and face), lymphadenopathy, headache or blurry vision, splenomegaly, anterior uveitis, peripheral neuropathy, nephropathy, and vasculitis.  Of note, these systemic symptoms are less likely in serum sickness-like reaction, which is usually limited to fever, arthralgias, rash/urticaria, and pruritis.
The evaluation of well-appearing patients with suspected serum sickness can be limited to urinalysis to determine the presence of renal involvement, which would require close follow-up. However, if the patient is ill-appearing or if there is any degree of diagnostic uncertainty based on the history or physical exam, further testing should be performed. The clinician should consider the following laboratory tests to evaluate for other etiologies and multi-organ system involvement: complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, total hemolytic complement (CH50), C3, C4, basic metabolic panel, liver transaminases, antinuclear antibody, and rheumatoid factor.  Depending on the clinical history, testing for infectious diseases may include hepatitis B screen and heterophile antibody testing for EBV. If carditis is suspected, an electrocardiogram should be obtained. Stool hematocrit should be obtained in any patient with gastrointestinal symptoms. Neuroimaging with a computed tomography scan should be considered in patients with neurological complaints.
Laboratory results in serum sickness may be widely variable. The complete blood count can show leukopenia or mild leukocytosis. Serum creatinine may be elevated, but typically returns to baseline within days-weeks of discontinuing the offending agent. Inflammatory markers will be elevated in serum sickness. Complement levels including CH50, C3, and C4, will be decreased, reflecting activation and consumption of complement.
Recall that patients with serum sickness-like reaction will generally not manifest with additional multi-organ system symptoms as outlined above. Also, the lab results in a serum sickness-like reaction will not show hypocomplementemia or renal dysfunction. 
Treatment / Management
Serum sickness is a self-limited entity that will usually resolve upon discontinuation of the offending agent, with or without additional treatment. Thus, treatment is generally aimed at reducing symptom severity and removing the agent, or reducing exposure to it if complete removal is not possible (for example, potentially life-saving anti-thymocyte globulin in the treatment of aplastic anemia).  For mild or moderate presentations, symptomatic relief can be achieved with NSAIDs and/or antihistamines. The patient should be counseled that the rash and pruritis should stop progressing within 48 hours of initiation of these medications. For more severe symptoms, a 7 to 10-day course of 0.5 - 2 mg/kg of systemic glucocorticoids can be helpful.  Most children can be safely treated as outpatients, but inpatient hospitalization should be considered for those with severe symptoms, multi-organ system involvement or evidence of an underlying infection or more serious etiology.
The differential diagnosis of serum sickness and serum sickness-like reaction is broad and requires a thorough evaluation to narrow the lens of focus. In general, the differential should include viral illnesses with exanthems (i.e. Chikungunya, Dengue fever), acute rheumatic fever, Scarlet fever, Kawasaki disease, meningococcemia, systemic juvenile idiopathic arthritis, Lyme disease, hypersensitivity vasculitis (i.e. IgA vasculitis, Sweet syndrome, Stevens-Johnson syndrome) and other types of drug reactions (i.e. drug reaction with eosinophilia and systemic symptoms, or DRESS). Specific disease characteristics and laboratory evaluation can help to distinguish between these entities.
The prognosis of serum sickness and serum sickness-like reaction is excellent. Patients generally experience resolution of symptoms within 1-2 weeks following discontinuation of the offending agent. Those with severe symptoms, recurrent serum sickness, or ongoing exposure to the causative agent may experience a prolonged course of illness.
Generally, serum sickness resolves on its own and does not lead to any long-term complications. To date, there have been no large-scale studies demonstrating any long-standing consequences of serum sickness. However, repeat exposure to a causative agent leading to multiple episodes of serum sickness has caused renal failure and death in animal models.  However, studies of patients receiving anti-thymocyte globulin in the treatment of aplastic anemia, who developed serum sickness, have demonstrated more favorable outcomes. 
Deterrence and Patient Education
Following an episode of serum sickness or serum sickness-like reaction, patients should be counseled to avoid the offending agent indefinitely. The patient should be educated on the generic and brand names of the medication to ensure proper avoidance. Patients should understand that, after a single episode of serum sickness, re-exposure to the same agent can result in a more severe course of illness. It is currently unclear whether or not patients can safely be medicated with agents of the same class following an episode of serum sickness, but some experts argue that structurally-related medications should be avoided. 
Enhancing Healthcare Team Outcomes
Serum sickness is a self-limited disease process that is generally alleviated by the discontinuation of the offending agent. However, the differential diagnosis of serum sickness includes potentially life-threatening disease entities that need to be considered and excluded. It is the responsibility of the entire treatment team, including the physician or advanced practice provider, nurses and pharmacists, to ensure that the correct diagnosis is identified and the offending medication is discontinued indefinitely. Adjunctive therapies including NSAIDs, antihistamines, and corticosteroids may help alleviate symptom severity. For those patients in whom discontinuation of the causative agent is not possible, an interprofessional care team including, but not limited to, specialty trained nurses, assisting an allergist/immunologist, rheumatologist, and oncologist, is essential in the management of ongoing treatment and mitigation of side effects.  (Level V)