A 26-year-old man returns to the emergency department after developing a fever and skin rash. The patient was discharged from the hospital 10 days ago after treatment for a copperhead snake bite to his left leg. He received multiple doses of polyvalent Fab antivenom therapy and other supportive care during hospitalization. The patient's bite site pain, swelling, and ecchymosis have resolved; however, he has developed fever, pain in multiple extremity joints, and pruritic rash over the past 2 days. He has no chronic medical conditions. Temperature is 38.5 C (101.3 F), blood pressure is 128/70 mm Hg, pulse is 98/min, and respirations are 17/min. Physical examination shows a diffuse urticarial rash. No mucous membrane lesions are present. There is tenderness to palpation of the bilateral metacarpophalangeal joints, wrists, and ankles with no redness or swelling. Blood cell counts, serum chemistry studies, and coagulation parameters are within normal limits. Which of the following is the most likely underlying mechanism of this patient's current condition?

Question

A 26-year-old man returns to the emergency department after developing a fever and skin rash.  The patient was discharged from the hospital 10 days ago after treatment for a copperhead snake bite to his left leg.  He received multiple doses of polyvalent Fab antivenom therapy and other supportive care during hospitalization.  The patient's bite site pain, swelling, and ecchymosis have resolved; however, he has developed fever, pain in multiple extremity joints, and pruritic rash over the past 2 days.  He has no chronic medical conditions.  Temperature is 38.5 C (101.3 F), blood pressure is 128/70 mm Hg, pulse is 98/min, and respirations are 17/min.  Physical examination shows a diffuse urticarial rash.  No mucous membrane lesions are present.  There is tenderness to palpation of the bilateral metacarpophalangeal joints, wrists, and ankles with no redness or swelling.  Blood cell counts, serum chemistry studies, and coagulation parameters are within normal limits.  Which of the following is the most likely underlying mechanism of this patient's current condition?

Quizplus · Accepted Answer

Polyclonal fab antivenom is a collection of immunoglobulin fragments from the plasma of venom-inoculated animals (eg, horses). Because the antivenom contains foreign proteins, exposure triggers the adaptive immune response to form high-affinity IgG antibodies against the foreign components of the antivenom. This typically takes 1-2 weeks due to time lag between antigen processing, antigen presentation, CD4 T-lymphocyte activation, and T-cell-mediated B-cell activation/differentiation. Once formed, IgG then binds to the free-circulating antivenom, which creates immune complexes (ICs). The Fc portion of the IgG triggers clearance of the ICs by activating the classical complement system and by directly binding to the Fc receptor on mononuclear phagocytes in the reticuloendothelial system. Clearance of ICs generally proceeds without issue when there is minimal antigen because the phagocytic system has a large capacity. However, the administration of multiple antivenom doses can overwhelm the phagocytic system, leading to the aggregation of ICs in the bloodstream. Aggregated ICs then deposit in tissue (eg, skin, joints), activate the complement cascade, and cause a type III hypersensitivity reaction called serum sickness. Serum sickness generally presents with fever, urticarial rash, and arthralgia 1-2 weeks after exposure to nonhuman proteins in antivenom, antitoxins, monoclonal antibodies, or vaccinations. Most cases resolve spontaneously over several days as the ICs are cleared. (Choices A and D) Antivenom administration can cause IgE antibodies to form against the nonhuman portions of the protein, which then triggers a type I hypersensitivity reaction upon reexposure. Although these reactions often cause urticaria due to mast cell degranulation, symptoms typically arise within seconds or minutes of reexposure, not a week or two after initial exposure. (Choice B) Superantigens directly activate polyclonal populations of T cells, leading to acute-onset fever, hypotension, sunburn-like rash, and organ failure. Fab fragments in antivenom are unlikely to activate T cells directly; they are processed by antigen-presenting cells and lead to the generation of antibodies. (Choice C) The phagocytic Fc receptor can only bind antivenom that has bound IgG or IgM antibody. Unbound antivenom cannot attach to phagocytic receptors. Educational objective: Serum sickness is an immune complex-mediated type III hypersensitivity reaction that occurs 1-2 weeks after exposure to nonhuman protein in antitoxins (eg, antivenom), monoclonal antibodies (eg, rituximab), or vaccines (eg, rabies antigens). Deposition of immune complexes in tissue leads to complement activation and subsequent self-limited fever, arthralgia, and urticarial rash. __________ References: Adverse reactions to snake antivenom, and their prevention and treatment. (http://www.ncbi.nlm.nih.gov/pubmed/26256124)

A 26-Year-Old Man Returns to the Emergency Department After Developing