Curr Infect Dis Rep (2015) 17:25 DOI 10.1007/s11908-015-0482-9
TRANSPLANT AND ONCOLOGY (M ISON AND N THEODOROPOULOS, SECTION EDITORS)
Infectious Complications of Pancreatic Islet Transplantation: Clinical Experience and Unanswered Questions Stephanie M. Pouch
# Springer Science+Business Media New York 2015
Abstract Pancreatic islet transplantation is an evolving treatment modality for type I diabetes mellitus. While the field has advanced significantly over the course of the past three decades, our understanding of the infectious complications of pancreatic islet transplantation remains quite limited. This review aims to describe the current literature relating to infectious complications of pancreatic islet transplantation, including the role of microbiologically contaminated islet preparations in disease pathogenesis, our current understanding of the epidemiology and outcomes of cytomegalovirus and other infectious complications of pancreatic islet transplantation, and infectious concerns related to the use of porcine pancreatic islet cell xenografts. This review also highlights unanswered clinical questions and suggests areas of future research to mitigate infectious complications in recipients of islet transplantation. Keywords Pancreatic islet transplantation . Infection . Microbial contamination . Cytomegalovirus (CMV) . Xenotransplantation
Introduction The incidence of type I diabetes mellitus (DM) continues to increase globally [1–3]. While intensive insulin therapy reduces the risk of nephropathy and retinopathy and decreases cardiovascular events , glycemic control with medical This article is part of the Topical Collection on Transplant and Oncology S. M. Pouch (*) Transplant Infectious Diseases Service, Division of Infectious Diseases, Ohio State University Wexner Medical Center, 410 W. 10th Avenue, N1123 Doan Hall, Columbus, OH 43210, USA e-mail: [email protected]
therapy alone remains difficult for many patients. Over the past several decades, whole pancreas transplantation has proven effective in restoring normoglycemia in those with DM, but carries with it the inherent risks of intra-abdominal surgery and management of pancreatic exocrine secretions . Efforts to achieve insulin independence in a less invasive manner and by utilizing only the endocrine components of the pancreas led to the advent of pancreatic islet transplantation. The first pancreatic islet transplant was performed with concomitant use of azathioprine and corticosteroids in 1977 . Through 1999, however, <10 % of those who had undergone pancreatic islet transplantation achieved more than 1 year of insulin independence . Through the use of a steroidsparing immunosuppressive regimen (daclizumab, tacrolimus, and sirolimus), outcomes improved to greater than 1 year of insulin independence in seven consecutive patients with type I DM who underwent pancreatic islet transplantation utilizing islets from at least two donors . Since that time, insulin independence at 3 years following pancreatic islet transplantation has increased from 27 % from 1999 to 2002 to 44 % from 2007 to 2010; this has been partially attributed to improved islet isolation and changes in immunosuppression, with trends towards decreased use of daclizumab and sirolimus and more frequent use of polyclonal T celldepleting antibodies and mycophenolic acid . Despite advances in pancreatic islet transplantation over the past few decades, the procedure is classified as experimental and is largely limited to those with labile type I DM or recurrent severe hypoglycemia , though pancreatic islet autotransplantation after pancreatectomy has also been reported for the management of chronic pancreatitis [11–13]. Current challenges in pancreatic islet transplantation include a limited islet donor supply and the need for improved islet cell isolation technology, optimization of immunosuppressive protocols, mediation of the post-transplant inflammatory response, and delineation of the optimal site of transplantation.
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Additionally, there is a relative paucity of data describing the epidemiology and outcomes of infectious complications of pancreatic islet transplantation, and the optimal approach to the prevention of infectious complications unique to pancreatic islet transplantation remains unclear. This review aims to describe the current literature relating to infectious complications of pancreatic islet transplantation, highlight unanswered clinical questions, and suggest areas of future research to mitigate infectious complications in pancreatic islet transplant recipients. Microbial Contamination of Islet Cell Preparations The process of pancreatic islet preparation from cadaveric donors has improved over the past several decades. While the exact methodology may vary slightly from center to center, the explanted pancreas and portion of the duodenum are transported to an islet isolation laboratory in a transport medium. There, the pancreatic duct is cannulated, and a collagenase blend enzyme solution is perfused transductally. The pancreas is then mechanically and enzymatically degraded using a Ricordi chamber  and subsequently purified via continuous density gradient separation using Ficoll or Bicoll solution . Islet preparations are placed in culture, during which time microbiological testing of the isolate may occur . The complexity of this islet cell preparation process allows for microbial contamination at several steps, and optimizing the sterility of the final pancreatic islet preparations is necessary to decrease the potential of donor-derived or process-mediated infection. Epidemiology of Microbial Contamination During Islet Cell Isolation Previous studies have reported microbial contamination rates of 19 to 84 % in pancreatic transport media, with coagulasenegative Staphylococci, Streptococcus spp., Eschericia coli and other Enterobacteriaceae, and Candida spp. representing the most commonly isolated pathogens [17–20]. Microbial contamination of transport media is thought largely due to the donor pancreas and, in particular, the retrieved segment of donor duodenum [18, 21]. The variable rates of transport media contamination may also be due to institutional differences in sampling, culture techniques, or use of antibiotics within the transport solution itself [19, 20]. Cold ischemic time greater than 4 h has also been implicated as a risk factor for microbial contamination of transport media . While contamination of the transport media from cadaveric donors is not uncommon, the processes of purification and subsequent cryopreservation appear to eliminate the majority of microbial contaminants from the transport media [18, 20, 21], and the rates of contaminated final pancreatic islet preparations range from 0 to 16 % [18, 21, 22••]. Further, pancreas
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decontamination prior to collagenase digestion appears to decrease the rate of contamination of final islet preparations by up to 92 % [18, 21]. De novo contamination during islet isolation is rare and is likely attributed to the use of contaminated reagents or violations of standard operating procedures [18, 20]. Little is known about microbial contamination occurring during pancreatic islet isolation for autologous transplantation. In a study of 28 patients with chronic pancreatitis undergoing total or completion pancreatectomy and autologous pancreatic islet transplantation, 25 (89 %) patients had contaminated transport and/or final transplant media; 9 patients (32 %) had the same bacterial species isolated from both media . The apparent higher incidence of microbial contamination in autologous islet cell transplantation media compared to deceased donor media may be related to pancreatic immune dysfunction or endoscopic biliary tract manipulation for the management of chronic pancreatitis .
Clinical Impact of Contaminated Pancreatic Islet Transplant Preparations The consequences of receiving contaminated deceased donor pancreatic islets in the setting of potent immunosuppression remain uncertain. To date, most literature suggests that the infectious risk of using contaminated pancreatic islet preparations is low, though not clearly documented, and the majority of studies report no infections directly related to islet infusion, particularly in the context of negative Gram stain and endotoxin content of <5 endotoxin units/kg of recipient’s body weight [17, 18, 22••]. Further, the use of peri-procedural antimicrobial prophylaxis appears to vary by center, and the role of these agents in preventing infections due to microbiologically contaminated islets is unknown. While the liver is presently the preferred site for pancreatic islet transplantation  and may protect against infection due to the presence of large numbers of phagocytic Kuppfer cells , infectious complications of microbiologically contaminated islets have been described. In one report, 2 of 7 consecutive cryopreserved pancreatic islet transplant recipients who developed Enterobacter cloacae bacteremia within hours of islet infusion; no other source of Enterobacter sepsis could be found in either patient. Cultures of 4 of 47 previously cryopreserved islet lots were grown E. cloacae, suggesting that transplantation of contaminated cryopreserved pancreatic islets was responsible for the 2 cases of bacteremia . Little is known about the impact of microbial contamination of final pancreatic islet products on long-term graft survival. However, in the largest single-center series evaluating the outcomes of microbiologically contaminated pancreatic islet transplant preparations to date, there was no difference in the maintenance of C-peptide levels or graft survival in
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patients who did and did not receive contaminated islet preparations [22••]. In the first series of infectious complications in autologous pancreatic islet transplant recipients , all patients received perioperative prophylaxis with cefazolin, cefazolin plus metronidazole, moxifloxacin, or clindamycin plus gentamicin. Sixteen patients’ final isolates grew bacterial pathogens not susceptible to the antimicrobial prophylaxis received. Seven of these patients developed postoperative infections, two of whom had infections related to their islet cultures. Nine patients received antimicrobial prophylaxis to which microbial isolates were susceptible, but two developed an infection correlating to the islet cultures. The four infections related to microbiologically contaminated islets included two bloodstream infections (one alpha-hemolytic Streptococcus and one Staphylococcus epidermidis) and two urinary tract infections (one Klebsiella oxytoca and one Pseudomonas aeruginosa), though the relationship between administered antimicrobial prophylaxis, microbiologic isolate, and site of infection remain unclear. Immunosuppression-Related Infectious Complications of Pancreatic Islet Transplantation Cytomegalovirus The risk of cytomegalovirus (CMV) transmission and disease following solitary pancreatic islet transplantation remains undefined. Several small-case series initially suggested that the incidence of CMV seroconversion or disease in pancreatic islet transplant recipients was low and was uncommonly associated with tissue-invasive disease, even in the context of donor-recipient mismatch (D+/R−) [8, 27–32]. The lower risk of CMV disease relative to other solid organ transplantation procedures, including simultaneous or sequential kidney-islet transplantation, has been attributed to the use of corticosteroid-sparing immunosuppressive regimens, effective 90-day CMV prophylaxis with ganciclovir or valganciclovir, and the low numbers of passenger leukocytes and small volume of islet tissue transplanted [28, 33, 34]. The largest study to date evaluating the epidemiology and outcomes of CMV infection and disease in pancreatic islet transplant recipients included recipients over an 11-year period (1999–2010) [35••]. During this time, immunosuppressive protocols evolved to include mycophenolate mofetil and potent lymphocyte-depleting agents such as alemtuzumab or thymoglobulin. Ninety days of CMV prophylaxis with oral ganciclovir or valganciclovir was provided to 68 % of islet recipients, a group comprised of those who were either D+/R− or were CMV seropositive and had received thymoglobulin. CMV infection occurred in 12 % of pancreatic islet transplant recipients, and graft-associated CMV transmission complicated approximately 10 % of D+/R− procedures. CMV disease
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occurred in two patients, including an individual who received a D+/R− graft. Viremia occurred at a median of 306 days posttransplant, well outside the timing of CMV prophylaxis. Compared to anti-interleukin-2 receptor monoclonal antibodies, lymphocyte depletion with alemtuzumab or thymoblobulin increased the risk of post-transplant CMV viremia. Further, while not statistically significant, CMV infection appeared to negatively impact long-term pancreatic islet graft survival. Other Reported Infectious Complications of Pancreatic Islet Transplantation Previous case series have reported a number of additional infectious complications following pancreatic islet transplantation, though the true incidence and timing of these infections remain unknown. In a report of 26 pancreatic islet transplant recipients (4 islet after kidney, 16 islet alone, and 6 islet alone in conjunction with CD34+ enriched bone marrow infusion), the most commonly encountered infections within 18 months of transplantation included upper respiratory infection (69 %), bronchitis (23 %), bacterial skin infection (23 %), urinary tract infection (19 %), dental infection (15 %), fungal skin infection (12 %), and pneumonia (12 %). Less frequently encountered infections included herpetic whitlow (4 %), oral thrush (4 %), influenza (4 %), Clostridium difficile diarrhea (4 %), diarrhea secondary to Giardia lamblia and Entamoeba spp. (4 %), and Campylobacter jejuni-associated diarrhea (4 %). Additionally, one parvovirus-seronegative patient developed parvovirus B19 infection 3 months following pancreatic islet transplantation, requiring Epoetin-α and multiple blood transfusions. Administration of intravenous immunoglobulin resulted in aseptic meningitis, but the parvovirus infection ultimately resolved following withdrawal of immunosuppression . In a report of 65 islet transplant recipients, three patients developed pneumonia within 5 years of transplant; one case was presumed fungal and required discontinuation of sirolimus . A case of hepatitis E virus-related chronic hepatitis has also been reported in a solitary pancreatic islet transplant recipient. This patient developed elevated transaminases after each of two islet cell infusions and again from 8 months through 4 years post-transplant, accompanied by depressed graft function. He was found to have a positive hepatitis E IgM, as well as detectable hepatitis E viremia, which ultimately cleared with reduction in immunosuppression; graft function also partially recovered. There was no evidence of hepatitis E in the patient’s blood prior to transplant nor in the blood of either donor, and it was ultimately felt that hepatitis E infection resulted from chronic carriage or new acquisition in the face of immunosuppression . Myonecrosis of the neck complicated by staphylococcal septic arthritis of the first costovertebral articulation and C7-T1 vertebral osteomyelitis has also been reported in a patient 3 weeks following islet cell transplantation . All of the aforementioned patients
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received sirolimus and tacrolimus maintenance immunosuppression [29, 36, 37]. Previously reported infectious complications of autologous pancreatic islet transplantation have included intra-abdominal abscess, urinary tract infections, central line infections, and bacteremia . However, the incidence of and risk factors for infections following autologous pancreatic islet transplantation remain undefined. To date, no cases of Pneumocystis jirovecii pneumonia have been reported in pancreatic islet transplant recipients . This may relate to the use of trimethoprimsulfamethoxazole (TMP-SMX) prophylaxis, though the optimal duration of TMP-SMX prophylaxis remains unknown. Additionally, since acquisition of Epstein-Barr virus (EBV) infection following transplantation has been associated with a greater risk of post-transplant lymphoproliferative disease (PTLD), only EBV-seropositive subjects are currently included in pancreatic islet transplantation protocols . The incidence of EBV reactivation and PTLD in pancreatic islet transplant recipients remains unknown.
preparations from decreased donors, the impact of alternate sites of transplantation on infectious risk, and the impact of microbiologically contaminated islets on long-term patient and graft survival. Additionally, collaborative efforts are required to improve our understanding of the epidemiology and outcomes CMV and EBV infection in pancreatic islet transplant recipients, risk factors for and epidemiology of bacterial and fungal infections in this patient population, and duration of prophylactic antimicrobials, including valganciclovir and TMP-SMX. Future clinical trials will also provide insight into the infectious risk of xenotransplantation and optimal strategies for monitoring of potentially xenotropic infections. Compliance with Ethics Guidelines Conflict of Interest Stephanie Pouch declares that she has no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animals performed by the author.
Xenotransplantation may serve as a potentially viable solution for the current shortage of organ donors, and phase I and II trials of porcine pancreatic islet transplantation for patients with type I DM have been completed . The infectious risk of xenotransplantation is of concern, and pathogens that may be transmitted from pigs to humans include Streptococcus suis, Brucella spp., Salmonella spp., Leptospira spp., Erysipelotrix rhusiopathiae, methicillin-resistant Staphylococcus aureus, influenza, and hepatitis E virus [40–43]. Additionally, porcine endogenous retroviruses (PERVs), which are integrated in the porcine genome and have been shown to infect human cells in vitro, are also of potential concern [41, 44]. However, small reports of humans who have undergone porcine pancreatic islet xenotransplantation suggest no evidence of PERV transmission up to 9 years following transplantation [45–47].
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
Conclusion The field of pancreatic islet transplantation has advanced significantly over the course of the past three decades. However, our understanding of the infectious complications of pancreatic islet transplantation remains quite limited. Moving forward, larger multicenter studies are required to address the optimal antimicrobial prophylaxis prior to pancreatic islet transplantation, the need for and duration of targeted antimicrobial therapy in recipients of microbiologically contaminated islet preparations, the role of immunosuppressive regimens in the development of infections related to contaminated islet
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