COMPLICATIONS OF TRANSPLANTATION Infection
Fungal Infections in Transplant Recipients Receiving Alemtuzumab D.S. Nath, R. Kandaswamy, R. Gruessner, D.E.R. Sutherland, D.L. Dunn, and A. Humar ABSTRACT Recently, we have used an anti-T-cell agent, alemtuzumab, as induction or conversion therapy to achieve a calcineurin (CNI) and steroid-free immunosuppressive regimen. We identified recipients who developed systemic fungal infections after the initiation of alemtuzumab and looked at their outcomes. The study population consisted of all pancreas transplant recipients who received alemtuzumab. Only invasive fungal infections were included in the analysis (eg, fungemia, meningitis, or pneumonia; fungal urinary tract infections were excluded). The organism was confirmed by culture, histopathology, or latex antigen test. Between February 2003 and February 2004, a total of 121 pancreas transplant recipients received alemtuzumab-56 as part of induction, and 65 as part of conversion. Of these, 8 (6.6%) developed an invasive fungal infection; 2 (3.6%) recipients as part of induction therapy and 6 (9.2%) as part of conversion therapy. Mean recipient age was 42.1 years. The mean length of time from alemtuzumab administration (first dose) to the diagnosis of the fungal infection was 115.9 days (range 5 to 318). The organisms identified initially were: Cryptococcus, Histoplasma, Aspergillus, and Candida. Overall, 3 (38%) of the eight patients died during ongoing treatment of their fungal infection: two from sepsis, one due to myocardial infarction. The other five recipients were treated successfully and have functioning grafts. The initial therapeutic agents used included: amphotericin B/liposomal AMB (n ⫽ 6), voriconazole (n ⫽ 3), capsofungin (n ⫽ 2), and fluconazole (n ⫽ 1). The use of alemtuzumab as induction or conversion therapy in pancreas transplant recipients may predispose patients to the development of systemic fungal infections. It would be important to determine what the most appropriate prophylaxis regimen would be for these patients.
ANCREAS TRANSPLANTS have proven efficacy in establishing normoglycemia and insulin independence in patients with type 1 diabetes mellitus. Much of the success can be attributed to improvements in immunosuppression protocols that have typically relied upon the use of calcineurin inhibitors (CNIs) and steroids. CNIs such as cyclosporine and tacrolimus, however, can adversely affect native or transplant renal function and hence there is 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.01.054 934
continued interest in developing a regimen that can diminish or eliminate the use of nephrotoxic agents. This is one of From the Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA. Address reprint requests to Abhinav Humar, MD, Department of Surgery MMC 195 Mayo, University of Minnesota, 420 Delaware St SE, Minneapolis, Min 55455. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 934 –936 (2005)
FUNGAL INFECTION IN TRANSPLANT RECIPIENTS
the reasons for the increasing interest in immunosuppressive regimens that are not CNI-based. Alemtuzumab (Campath 1-H) is a humanized monoclonal antibody that targets CD 52, an antigen that is expressed on B-cells, T-cells, monocytes, and natural killer cells.1,2 By rapidly depleting lymphocytes and monocytes but not affecting neutrophils and hematopoietic stem cells, alemtuzumab prevents an aggressive lymphocyte-based immune response soon after transplantation.3,4 Since these cells remain suppressed for a period of months before gradually resurfacing, it is possible that a relatively low dose of other immunosuppressive agents can be used in conjunction with alemtuzumab.5,6 Initially approved for the use of chronic lymphocytic leukemia, this T-cell– directed monoclonal antibody has been used to treat patients with autoimmune diseases such as rheumatoid arthritis and mycosis fungoides. Infectious complications, including fungal infections, arising from the use of alemtuzumab have been previously documented, particularly in the nontransplant population.7,8 What has not been well described is the incidence, management, and outcome of pancreas transplant recipients who have received alemtuzumab and developed an invasive fungal infection. The objective of this review was to study the clinical characteristics of such patients and describe the means of diagnosis, examine the subsequent management of these recipients, and determine their eventual outcome. METHODS The records of pancreas transplant recipients who received alemtuzumab at the University of Minnesota between February 01, 2003, and February 01, 2004, were examined to identify cases of invasive fungal infections. An invasive fungal infection was defined as one where fungemia, meningitis, or pneumonia was diagnosed and confirmed by culture, histopathology, or latex antigen tests. Excluded were patients who developed fungal urinary tract infections. Data was obtained in a retrospective fashion from the University of Minnesota medical records. These included the (1) recipient age, (2) basis of alemtuzumab use, (3) length of time from first administered dose to diagnosis of fungal infection, (4) presenting symptoms, (5) classification of organism, (5) site of infection, (6) management, and (7) graft and patient outcome.
Of the 121 pancreas transplant recipients who received alemtuzumab in this period, 56 patients received it as part of induction therapy. The remaining recipients were transplanted patients on CNI maintenance therapy, and alemtuzumab was used in a protocol to withdraw the CNI. A total of eight recipients were identified who developed a systemic fungal infection and met the study criteria (6.6%). The incidence of invasive fungal infections following alemtuzumab use for induction therapy was 3.6% (2 of 56) and for conversion therapy, 9.2% (6 of 65; P ⫽ .21). The mean recipient age was 42.1 years. The category of transplant was as follows: SPK (n ⫽ 3, 38%) and PAK (n ⫽ 5, 72%). The mean length of time from first dose of alemtuzumab to the
diagnosis of initial fungal infection was 115.9 days (range ⫽ 5 to 318). The organisms identified were Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida glabrata, and Aspergillus. Three patients were identified with cryptococcal infections. Patient 1 presented with fevers, chills, and lower extremity pain. The organism was first identified in the lower extremity soft tissues, for which she underwent extensive debridement followed by amputation to achieve source control. While receiving treatment, she died from a myocardial infarction likely unrelated to the fungal infection. Patients 2 and 3 presented with fevers, nausea, and hypotension. In both cases, the organism was first cultured in the bloodstream and subsequently in the cerebrospinal fluid. The antifungal regimen in all three cases consisted of intravenous liposomal amphotericin B by followed by oral fluconazole. Two patients were identified with histoplasmosis. Patient 4 presented with fevers, a productive cough, and shortness of breath. The organism was cultured in the bloodstream. The antibiotic regimen consisted of intravenous capsofungin and voriconazole. During the initial treatment, she died secondary to sepsis. Patient 5 similarly presented with fevers, chills, and shortness of breath. The fungus was identified through a bronchial lavage. Treatment consisted of intravenous amphotericin B followed by oral voriconazole. Two patients were identified with candidiasis. Patient 6 presented with weight loss and fatigue. Further evaluation revealed abnormalities on chest radiographs that did not resolve over time. A bronchial lavage was performed and Candida albicans and Candida glabrata were cultured. She was successfully treated with voriconazole. Patient 7 presented with fevers and peritonitis 5 days after his pancreas transplant. He underwent an exploratory laparatomy that did not reveal any gross intra-abdominal pathology. Peritoneal fluid cultures were significant for Candida glabrata and the patient was successfully treated with capsofungin, fluconazole, and voriconazole. Nearly 15 weeks later, he presented with persistent oral apthous ulcers. Further evaluation revealed chest radiographic abnormalities and a subsequent bronchial culture grew aspergillus. He was treated with intravenous liposomal amphotericin B followed by oral voriconazole. Two patients were identified with aspergillosis. Patient 7 is described above. Patient 8 presented with fevers, chills, nausea, and subsequently seizures. He was being treated for a previously diagnosed buccal actinomycosis (an anaerobic bacterial infection) with penicillin. At this time, computed tomographic images and cerebral spinal fluid cultures were obtained, which were consistent with aspergillosis. Treatment with amphotericin B was initiated but the patient died secondary to sepsis a few days after diagnosis. Three of the eight patients (38%) died during treatment of the invasive fungal infection. The cause of death was fungemia in two cases and a myocardial infarction in one case. The other five patients were successfully treated with
antifungal agents and are alive with a functioning graft at a mean follow-up of 295 days. DISCUSSION
In solid-organ transplantation, alemtuzumab was initially used to reverse steroid-resistant rejection episodes in kidney allograft recipients.9 A high incidence of associated CMV-related infectious complications was noted; since there was no effective antiviral treatment available at the time, this immunosuppressive agent was not widely used. More recently, the benefits of using this T-cell–mediated antibody as induction therapy to permit a lower dose of maintenance immunosuppression was demonstrated.5,10 At present, there is evidence that the inclusion of alemtuzumab in immunosuppression protocols can effectively lower the dose of required maintenance therapy and reduce the incidence of acute rejection episodes.4,11 What is less clear is the risk associated with this agent, with its efficacy based on lymphocyte depletion, in the development of malignancies and opportunistic infections. There are anecdotal reports of lymphoproliferative disorders occurring following alemtuzumab use in patients with chronic lymphocytic leukemia.12 However, there is no discernable evidence to suggest that there is an increased incidence of malignancies noted in patients with solid-organ transplants or those with autoimmune disorders due to alemtuzumab administration.6 There is some evidence that alemtuzumab therapy leads to a high incidence of infectious complications. In a study designed to test the efficacy and safety of this agent in patients with chronic lymphocytic leukemia, 10 of 24 (41.7%) patients developed an opportunistic infection; of these, 3 (12.5%) patients developed a fungal infection.7 These patients did not consistently receive both antiviral and antibacterial prophylaxis therapy. None of the patients received prophylactic antifungal therapy. In a similar study conducted in patients with advanced mycosis fungoides, a cutaneous T-cell lymphoma, 11 of 22 (50%) patients had an infectious complication, of which a reactivation of cytomegalovirus infection was most common. A fatal fungal infection was identified in 1 (4.5%) patient. Fungal infections have been noted in solid-organ trans-
NATH, KANDASWAMY, GRUESSNER ET AL
plant recipients who have received alemtuzumab. In one instance, 4 of 16 (25%) recipients with intestinal and multivisceral transplants developed fungal infections related to central venous access.4 We found that the use of alemtuzumab as induction or conversion therapy in pancreas transplant recipients is associated with a relatively high (6.6%) incidence of invasive fungal infections. While prompt and appropriate antifungal therapy can successfully treat such infections and preserve long-term graft function, we noted that it can be a fatal complication in up to a third of the cases. It will be important to determine an appropriate prophylactic regimen for such patients. REFERENCES 1. Reichman L, Clark M, Waldmann H, et al: Reshaping human antibodies for therapy. Nature 332:323, 1998 2. Salisbury JR, Rapson NT, Codd JD, et al: Immunohistochemical analysis of CD 52 antigen expression in non-Hodgkin’s lymphomas. J Clin Pathol 47:313, 1994 3. Gilleece MH, Dexter TM: Effect of Campath I-H antibody on human hematopoietic progenitors in vitro. Blood 82:807, 1993 4. Tzakis A, Kato T, Nishida S, et al: Alemtuzumab (Campath1H) combined with tacrolimus in intestinal and multivisceral transplantation. Transplantation 75:1512, 2003 5. Calne R, Friend P, Moffatt S, et al: Prope tolerance, perioperative Campath-1H, and low-dose cylosporine monotherapy in renal allograft recipients. Lancet 351:1701, 1998 6. Knechtle SJ: Present experience with Campath-1H in organ transplantation and its potential use in pediatric recipients. Pediatr Transplantation 8:106, 2004 7. Rai KR, Freter CE, Mercier RJ, et al: Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Onco 20:3891, 2002 8. Lundin J, Hagberg H, Repp R, et al: Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 101:4267, 2003 9. Friend PJ, Waldmann H, Hale G, et al: Reversal of allograft rejection using the monoclonal antibody, Campath-1G. Transplant Proc 23:2253, 1991 10. Calne R, Moffatt SD, Friend PJ, et al: Campath 1H allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 68:1613, 1999 11. Farmer DG, McDiarmid SV, Yersiz H, et al: Outcome after intestinal transplantation: results from one center’s 9-year experience. Arch Surg 136:1027, 2001 12. Ghobrial IM, Otteman LA, White WI: An EBV-positive lymphoproliferative disorder after therapy with alemtuzumab. N Engl J Med 349:2570, 2003