Serum Sickness After Antithymocyte Globulin Administration in a Cardiac Transplant Patient

Serum sickness (SS) after antithymocyte globulin (ATG) administration is documented in liver, pancreas, and renal transplants along with aplastic anemia (1–4). To our knowledge, although a few SS cases in the adult cardiac transplant population are reported online, none have been previously documented in the scientific literature. CLINICAL HISTORY A 57-year-old gentleman with allo-geneic heart transplantation for nonischemic cardiomyopathy developed nonspecific graft dysfunction 3 years posttransplant. He had no documented cellular or antibody-mediated rejection, graft vasculopathy, and donor-specific antibodies on panel reactive antibody testing. Plasmapheresis and IV immunoglobulin infusions were initiated in addition to increases in maintenance immuno-suppression therapy with no significant impact on his reduced ejection fraction. Because of recurrent presentations of decompensated heart failure despite escalation of care, ATG therapy was initiated with 75 mg of IV rabbit ATG daily for 3 days followed by 50 mg IV for 1 day. Nine days after IV thymoglobulin therapy, he presents with fever, chills, lip swelling, and myalgias. Physical examination revealed mild congestive heart failure and an erythematous and pruritic maculopapular rash. He had tender polyarthritis in his extremities with significant restriction to active and passive range of motion (Fig. 1). Laboratory investigations revealed mild leukocytosis, elevated C-reactive protein, and acute renal insufficiency with no evidence of active sediments on urinalysis. Cytomegalovirus testing was unremarkable. Based on this inflammatory presentation and clinical context, he was diagnosed with SS secondary to IV ATG and started on IV methylprednisolone 1 g daily for 6 days. Failing to show significant improvement at 48 hours, plasmapheresis was initiated for 5 days with marked symptomatic relief after the first exchange. He was discharged home on his 10th day of admission with complete resolution of his presenting symptoms.FIGURE 1: A, Maculo-papular-pruritic rash. B, Limited range of motion on hand grip secondary to arthritis. C, Inflammatory effacement of metacarpophalangeal joints.DISCUSSION Antithymocyte globulins are antibodies used in immunosuppression against human T cells and typically derived from the injection of human thymocytes into animals such as horses and rabbits. Exposure to such heterologous proteins may precipitate SS by the generation of host immunoglobulins and activation of the complement cascade (5). Antithymocyte globulin has been used in human transplantation since the late 1960s and has many inherent benefits (6). It is thought to protect the allograft by dampening inflammatory damage, allorecognition processes, and development and intensity of immune response and may increase the sensibility to oral maintenance immunosuppressive agents (7). The administration of rabbit or horse ATG has been associated with SS in 1% to 10% of cases. Risk factors for developing SS include older age, greater levels of heterologous protein, type of preparation, prior exposure to the antigen or source animal, along with a history of hypergammaglobulinemia and cryoglobulinemia (8–11). Serum sickness is characterized by fever, lymphadenopathy, pruritic rash, polyarthralgias, and polyarthritis, which can develop 7 to 10 days after administration of the exogenous antigen. The maculopapular or urticarial rash is usually the first sign, and in severe cases, patients may develop glomerulonephritis as a conglomeration of immune-complex mediated small vessel vasculitis and tissue injury. Angioedema may also be present (5). The polyarthritis commonly involves large joints, but occasionally, the spine or the temporal-mandibular joint may be affected (8). Laboratory investigations may mirror the clinical inflammatory processes with elevated markers such the ESR and leukocytosis along with hypocomplementemia. The urinalysis may show evidence of glomerulonephritis with hematuria,proteinuria, and red cell casts (5). The clinical presentation of SS can be nonspecific and confused for common conditions, such as acute infections or rheumatism, leading to therapeutic delay (1). Serum sickness is a clinical diagnosis, and therapy should not be delayed for any supportive laboratory results (8). Serum sickness is typically self-limited, resolving spontaneously when the trigger for the immune-inflammatory processes is cleared (5). Given the rarity of this condition, all current treatment recommendations are based on clinical experience and case-based reports. Discontinuation or avoidance of re-exposure to the offending agent is paramount when SS is suspected. In mild cases, treatment can be symptom directed with nonsteroidal anti-inflammatory drugs for arthralgias and fevers, along with antihistamines and topical corticosteroids for the pruritic rash. High-dose oral or IV corticosteroids are reserved for severe forms especially with evidence of disabling symptoms, hemodynamic compromise, glomerulonephritis, and other manifestations of vasculitis (5). High-dose steroids can be administered for 3 days, followed by a rapid prednisone taper with anticipated symptom resolution within 10±2 days (1). Plasma exchange is another treatment modality considered an adjuvant to corticosteroids especially in refractory cases (1, 4). It is often initiated for 1 to 2 exchanges when patients remain symptomatic with minimal improvement after 3 days of corticosteroid use (1). Some investigators even advocate plasma exchange as the initial and only treatment modality for SS (8). Jacques Rizkallah Francisco Cordova Amrit Malik Shelley Zieroth Section of Cardiology Department of Medicine St Boniface Hospital University of Manitoba Winnipeg, Manitoba, Canada.