BacteriologyInfections after the use of alemtuzumab in solid organ transplant recipients: a comparative study
Introduction
Major advances in transplantation techniques and understanding of transplant biology have greatly improved the survival of renal transplant recipients. Each year, approximately 15 000 renal transplants are performed in the United States, with a 5-year survival exceeding 80% (http://www.unos.org [United Network for Organ Sharing, n.d.]). However, infection remains a major challenge in the solid organ transplant recipient and now exceeds rejection as the precipitating factor for hospitalization in patients in the first 2 years after a solid organ transplant (Dharnidharka et al., 2004).
In recent years, lymphocyte depletion has been used with increasing frequency as an induction strategy after transplantation and for treatment of rejection (Shapiro et al., 2005a, Shapiro et al., 2005b). Alemtuzumab (Campath-IH; Berlex, Montville, NJ) is a humanized monoclonal antibody directed against CD52, a cell surface antigen expressed on B and T lymphocytes, monocytes, and natural killer (NK) cells (Ferrajoli et al., 2001, Flynn and Byrd, 2000). It is a powerful cytolytic agent and is used therapeutically in bone marrow transplantation (Dumont, 2002, Hale, 2002) and several autoimmune diseases (Marsh and Gordon-Smith, 2001). Infusion of alemtuzumab results in marked decrement in circulating levels of NK cells, B cells, T lymphocytes, macrophages, and monocytes. Although numbers of NK cells, B cells, and monocytes typically return to normal levels within 3 to 6 months of alemtuzumab use, CD4+ and CD8+ T cells may remain low for years (Ferrajoli et al., 2001). In a trial of alemtuzumab in patients with rheumatoid arthritis, there was profound and persistent peripheral blood lymphopenia in the alemtuzumab-treated patients, affecting predominantly the CD4+ subset. Median CD4+ and CD8+ peripheral blood lymphocyte counts at 73 to 84 months after therapy were 185 and 95 cells/μL, respectively (Issacs et al., 2001). More recently, alemtuzumab has come into use for induction immunosuppression and treatment of rejection for solid organ transplantation in some transplantation centers (Gourishankar et al., 2002, Magliocca and Knechtle, 2006, Morris and Russell, 2006, Shapiro et al., 2005a, Shapiro et al., 2005b). Long-lasting lymphopenia has been confirmed in patients treated with alemtuzumab for induction of immunosuppression in solid organ transplantation administered maintenance mycophenolate mofetil or sirolimus in addition to calcineurin inhibitors (Knechtle et al., 2003, Knechtle et al., 2004).
Depletion of lymphocytes would be expected to result in an increased risk of opportunistic infections. Some series have found that alemtuzumab use was associated with an increase in the frequency of unusual infections (Abad et al., 2003, Magliocca and Knechtle, 2006, Martin et al., 2006, Nath et al., 2005, Silveira et al., 2007). However, others have not confirmed these findings (Barth et al., 2006), and thus, whether or not alemtuzumab use translates into an increased risk of infection in solid organ transplant recipients is unclear.
We performed a retrospective cohort study to determine the risk of infection in patients receiving alemtuzumab induction compared with basiliximab/daclizumab or antithymocyte/antilymphocyte globulin at time of transplantation. We focused particularly on fungal infections as the main outcome.
Section snippets
Sources of data
Using data from a prospectively maintained transplant database, supplemented by chart review and pharmacy billing records, we identified all 1738 patients who had undergone renal, liver, and kidney–pancreas transplantation at the University of Wisconsin, Madison, WI, between January 1, 2002, and December 31, 2005. For this retrospective cohort study, the cohort was constructed by including patients who received at least 1 dose of alemtuzumab as the alemtuzumab group. For retransplanted
Patient demographics
The patients were followed longitudinally at our institution for a mean of 13 months (SD, 8.3). Patient demographics and clinical features are shown in Table 2. There were 215 patients in the basiliximab/daclizumab group (henceforth called basiliximab group, 9 patients received daclizumab), 726 patients in the alemtuzumab group, and 85 in the ATG or OKT3 group (henceforth called ATG group, 1 patient received OKT3). Because of limitations in data availability, we were not able to obtain an equal
Discussion
Our study shows that although the overall risk of infection was not increased with the use of alemtuzumab and was lower than that with basiliximab, the infections that did occur were more severe and were more likely to be disseminated. Our interest was particularly in fungal infections, and we found that disseminated fungal infection and CMV viremia occurred more commonly in the alemtuzumab-treated group. However, patients who were given alemtuzumab were also more likely to receive
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