Are You Confident of the Diagnosis?

Serum sickness, serum sickness-like reactions (SSLR), and DRESS (drug rash with eosinophilia and systemic symptoms) fall into this category. The first two topics will be discussed here; the latter subject may be found in its own chapter, see DRESS.

  • What you should be alert for in the history

Onset of symptoms in serum sickness is 8 to 14 days after administration of the culprit protein. For SSLR, the syndrome appears 1 to 3 weeks after drug initiation. Clinically, serum sickness and SSLR share the features of fever, rash and arthralgias. Frank arthritis may eventuate in a minority of cases. Patients with true serum sickness may have, in addition, renal, gastrointestinal, and neurologic symptoms and signs. Both subsets of patients may manifest lymphadenopathy.

  • Characteristic findings on physical examination

In serum sickness, the eruption begins acrally, usually on the lateral aspects of the fingers and toes and then spreads to the hands and more generally. A serpiginous band of erythema along the borders between dorsal and palmar hands and dorsal and plantar feet is also described. The eruption may be exanthematous (morbilliform), scarlatiniform or urticaria-like. A targetoid appearance has also been reported. An injection site reaction may be seen in cases of subcutaneous or intramuscular injection. In SSLR, the eruption is urticarial. Pruritus is a feature in both reactions.

The diagnosis is made based on the typical foreign protein/drug history and the constellation of signs and symptoms. Hypocomplementemia (low C3 and C4) is a feature in serum sickness, but not in SSLR. Heterologous antibodies have been found to be present in most patients with serum sickness when they have been tested. Patients with SSLR may show a peripheral eosinophilia.

  • Expected results of diagnostic studies

Histopathologically, there is a perivascular infiltrate of lymphocytes with or without eosinophils or neutrophils. In urticarial cases, dermal edema is prominent (Figure 1). The following differential diagnoses needs to be considered.

Figure 1.

  • Urticarial vasculitis. This is an immune-complex-mediated vasculitis that occurs in the absence of an offending agent. The eruption is urticarial, but plaques last longer than 24 hours and may leave a post-inflammatory hyperpigmentation as they fade. Arthralgias are a feature, but fever is typically absent. An autoimmune background, such as the presence of systemic lupus erythematosus, may be present.

  • Viral exanthems, especially those that typically present with arthralgias, such as rubella and parvovirus B19, may be diagnostic considerations.

  • Schnitzler’s syndrome is the presence of non-pruritic urticaria, bone pain, arthralgias and an IgM monoclonal gammopathy. Fever is absent.

  • Adult-onset Still’s disease. This is an uncommon acute or subacute systemic illness that presents with a high spiking fever, a sore throat and a rash. The characteristic eruption consists of salmon-pink macules that wax and wane with the fever. The eruption is usually more prominent in sites of pressure. The Koebner phenomenon may be a feature. Arthralgias may also occur.

Who is at Risk for Developing this Disease?

Serum sickness

On the whole, the incidence rates of serum sickness are declining as a result of human-derived antitoxins replacing those that are animal-derived, as well as the widespread use of vaccines that then limit the need for antitoxins. In a recent study of patients who received purified equine rabies immunoglobulin, females were more likely to develop serum sickness. In this study, children under 10 years were less likely to develop serum sickness. Incidence rates vary with the foreign protein that has been administered: 1.13% of more than 72,000 patients developed serum sickness to the rabies immunoglobulin in the study mentioned above.

Serum sickness to anti-thymocyte globulin is reported to develop in 7% to 27% of patients. Prior sensitization via previously being exposed to rabbits has been shown to be an important risk factor with the rabbit-derived preparation. The reaction to many foreign proteins is also dose dependent.

SSLR

The incidence of SSLR from cefaclor is estimated to be 0.024% to 0.2% per course of cefaclor. Cefaclor-induced SSLR is usually seen in children. This may reflect prescribing patterns of the drug. The frequency of SSLR from other drugs is unknown. With monoclonal antibodies, rituximab and infliximab have been implicated most frequently. Reaction rates to rituximab are higher in those receiving the drug for autoimmune conditions than malignancies. An SSLR has been reported after influenza vaccination.

What is the Cause of the Disease?

  • Etiology

Serum sickness is induced by the presence of foreign antigens (proteins derived from other species) that have usually been parenterally administered. The reaction is seen in the setting of administration of snake and spider antivenins, equine antitoxins and horse- or rabbit-derived anti-thymocyte globulins (used for induction immunosuppressive treatment in solid organ transplantation and as a first-line drug in immune-mediated bone marrow failure).

The most commonly implicated agent in SSLR is cefaclor. Other cephalopsorins, penicillins, sulphonamides, streptokinase, propanolol, minocycline, buproprion and, more recently, murine monoclonal or chimeric antibodies (such as rituximab and infliximab among others) have also been reported as offending agents.

  • Pathophysiology

In serum sickness, the foreign antigen stimulates an antibody response. The resultant antigen-antibody complex activates complement in small vessels in target organs. This leads to neutrophil recruitment and tissue inflammation. In SSLR to cefaclor, it is thought that a reactive metabolite of the culprit drug binds to tissue proteins and inflammation is initiated. In other cases, drug-haptens binding to albumin and stimulating an antibody response and a subsequent type III hypersensitivity (similar to serum sickness) are thought to be responsible.

Systemic Implications and Complications

In serum sickness and SSLR, arthralgia is reported in up to half of cases. The large joints are commonly affected. In serum sickness, lymphadenopathy may be generalized or localized to the lymph nodes draining the site of injection. In serum sickness, immune complexes may deposit renally, giving rise to nephritis with proteinuria, hematuria and oliguria. The nephritis is usually not severe. Gastrointestinal tract involvement (giving rise to nausea, vomiting, diarrhea, abdominal pain and rarely melena), serositis, myocarditis and neurologic manifestations (such as peripheral neuropathy and optic neuritis) can rarely occur.

Treatment Options

Table I. Medical treatment

Table I.
Medical treatment
Discontinue offending agent; supportive care
Potent topical steroids
Antihistamines
Oral corticosteroids

Optimal Therapeutic Approach for this Disease

Discontinuation of the offending drug is a vital first step. Potent or ultrapotent topical steroids (such as betamethasone diproprionate 0.05% or equivalent, or clobetasol 0.05% or equivalent) along with oral antihistamines can be used for symptom control. Antipyretics can be used for relief of fever and arthralgias. In severe cases of serum sickness, oral corticosteroids, such as oral prednisone at 1mg/kg/day, can be given.

Patient Management

An in-depth discussion may be needed with the patient to identify the offending drug. This drug should be discontinued promptly. The patient and his or her family can be reassured that the syndrome will resolve within 7 to 14 days.

The option of systemic corticosteroids may need to be considered in cases of nephritis or other internal organ involvement. The side effects of this treatment need to be balanced with the benefits to the patient.

In patients with internal organ involvement who have been treated with anti-thymocyte globulin in the setting of organ transplantation or immune-mediated bone marrow failure, or in those with underlying severe comorbidities, a discussion regarding the need for intravenous corticosteroids or possibly plasmapheresis should be held. Management decisions in these patients should be made after consultation with the primary transplantation team, the hematology team or the intensivist team.

It is important for the patient to know that reactions will recur if the same drug is given again. The risk of cross-reaction of cefaclor to beta-lactams is small, however, some clinicians recommend avoiding the entire beta-lactam class in the future.

Unusual Clinical Scenarios to Consider in Patient Management

As stated above, intravenous corticosteroids or plasmapheresis may be indicated in patients with internal organ involvement who have been treated with anti-thymocyte globulin in the setting of organ transplantation or immune-mediated bone marrow failure, or in those with underlying severe comorbidities.

What is the Evidence?

Boothpur, R, Hardinger, KL, Skelton, RM, Lluka, B, Koch, MJ, Miller, BW. “Serum sickness after treatment with rabbit antithymocyte globulin in kidney transplant recipients with previous rabbit exposure”. Am J Kidney Dis. vol. 55. 2010. pp. 141-3. (A case series and review of the literature of serum sickness to anti-thymocyte globulin in liver transplant patients.)

Chiong, FJ, Loewenthal, M, Boyle, M, Attia, J. “Serum sickness-like reaction after influenza vaccination”. BMJ Case Rep. 2015. (SSLR after influenza vaccine.)

Gamarra, RM, McGraw, SD, Drelichman, VS, Maas, LC. “Serum sickness-like reactions in patients receiving intravenous infliximab”. J Emerg Med. vol. 30. 2006. pp. 41-4. (A review of SSLR from infliximab.)

Knowles, SR, Shear, NH. “Recognition and management of severe cutaneous drug reactions”. Dermatol Clin. vol. 25. 2007. pp. 245-53. (A classic review article on severe cutaneous drug reactions, including serum sickness and SSLR.)

Roujeau, JC, Stern, RS. “Severe cutaneous reactions to drugs”. N Engl J Med. vol. 331. 1994. pp. 1272-85. (An outstanding review of severe drug eruptions, including serum sickness.

Suwansrinon, K, Jaijareonsup, W, Wilde, H, Benjavongkulchai, M, Sriaroon, C, Sitprija, V. “Sex- and age-related differences in rabies immunoglobulin hypersensitivity”. Trans R Soc Trop Med Hyg. vol. 101. 2007. pp. 206-8. (A retrospective review of reactions in over 72,000 patients who received rabies immunoglobulin.)

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