- Email: [email protected]
Three Cases of Cytomegalovirus Infection Following Pancreatic Islet Transplantation
Three Cases of Cytomegalovirus Infection Following Pancreatic Islet Transplantation N. Yakubovich, M.A. Fung, and D.M. Thompson ABSTRACT Transmission of cytomegalovirus (CMV) is uncommon in patients transplanted with CMV-mismatched pancreatic islets, and CMV-seropositive recipients rarely experience reactivation of the virus or reinfection from a CMV-positive graft. This study describes three cases of CMV infection following islet transplantation for type 1 diabetes despite prophylaxis with valganciclovir. Further studies are needed to evaluate risk factors for CMV transmission and reactivation in this patient population.
C
YTOMEGALOVIRUS (CMV) accounts for significant morbidity and mortality in solid-organ transplant recipients. It has been shown to cause retinitis, pneumonitis, colitis, hepatitis, encephalitis, and CMV syndrome, which is defined by the presence of CMV viremia, fever, malaise, leukopenia, thrombocytopenia, or transaminitis. Cytomegalovirus lowers the state of immunosuppression, predisposes to further opportunistic infections, and is associated with increased risk of graft rejection and lymphoproliferative disease.1–3 Risk of development of CMV disease is dependent on the CMV serological status of the donor and the recipient, type of organ transplanted, specific immunosuppressive agents used, and the overall intensity of immunosuppression.3,4 Antiviral prophylaxis has been shown to delay CMV transmission, reduce severity of disease, and improve graft survival.5,6 Cytomegalovirus infection has been rarely reported in recipients of solitary islet transplants. Several reasons previously postulated for negligible risk of CMV transmission and reactivation observed in islet transplantation include the small volume of tissue with low number of contaminating leukocytes transplanted, and, therefore, low viral load transmitted, as well as unique immunosuppressive regimens and effective CMV prophylaxis.7 However, patients with type 1 diabetes may be at higher risk for CMV mismatch during transplantation than other organ transplant recipients. The prevalence of positive CMV serology among 362 type 1 diabetic patients who were candidates for islet transplantation was reported to be only 38%, compared to 67% prevalence among 1042 potential organ donors representative of the general population.7 In this study, the presence of type 1 diabetes mellitus was negatively associated with CMV positivity even after adjusting for age, gender, and race.
We searched the Medline database between 1966 and July 2006 for “islet transplant” mapped to subject and “cytomegalovirus,” “CMV,” “infection,” or “virus” keywords, and found only one report of CMV disease seen in solitary islet transplant recipients. The islet transplant group in Miami described a 42-year-old female who developed CMV infection with colitis 15 months after the second intrahepatic islet infusion from a CMV-positive donor. Colitis and viremia completely resolved on administration of antiviral treatment and mesalamine.8 The researchers also reported a patient who seroconverted with no CMV disease 6.4 months after islet transplantation. Twelve of 29 islet transplant recipients at this center were recipientnegative, donor-positive for CMV. There have been only two cases of CMV seroconversion without overt CMV disease in the Edmonton islet transplantation program among 65 islet transplant recipients followed for up to 5 years despite 43 CMV mismatches (donor-seropositive, recipient-seronegative for CMV).9 At both centers, patients received CMV prophylaxis for 3 months posttransplantation. CASE SERIES Between March 2003 and May 2006, a total of 23 patients with type 1 diabetes received solitary islet transplantation at Vancouver Hospital, Vancouver, British Columbia. The CMV status of the transplanted patients was as follows: 13 of 23 donor⫹/recipient⫺, 8 of 23 donor⫹/recipient⫹, 1 of 23 donor⫺/recipient⫹, and 1 of 23 donor⫺/recipient⫺. Patients receiving islets from at least one From the Division of Endocrinology, University of British Columbia, Vancouver, Canada. Address reprint requests to Dr. Michelle Anne Fung, Division of Endocrinology, Diamond Health Care Center, 2775 Laurel St., 4th floor, Vancouver, BC V5Z 1M9. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.01.074
Transplantation Proceedings, 39, 1599 –1603 (2007)
1599
Case 1
Age and Gender Duration of type 1 diabetes Diabetes complications
41-year-old male 22 years Microalbuminuria, retinopathy
Number of islet transplants Recipient CMV status Donor CMV status
One CMV⫺ CMV⫹
Induction immunotherapy
ATG
Maintenance immunotherapy CMV prophylaxis
Tacrolimus, MMF Ganciclovir IV with islet transplant. Oral valganciclovir started 8 days later and continued until presentation
Other medications
TMP/SMX, insulin, aspirin, quinapril, amitriptyline, gabapentin. High-dose oral prednisone for left brachial plexus neuritis. Hypertension
Significant past history Symptoms and CMV Ag level on presentation*
Case 3
58-year-old male 48 years Microalbuminuria, neuropathy, retinopathy Two, 52 days apart CMV⫹ Transplant #1: CMV⫹ Transplant #2: CMV⫺ Transplant #1: ATG Transplant #2: Basiliximab Tacrolimus MMF Ganciclovir IV with transplant #1, followed by valganciclovir orally until presentation TMP/SMX, insulin, aspirin, ramipril, pantoprazole
WBC 3.4 ⫻ 109/L (4.0 –11.0), neutrophils 3.0 ⫻ 109/L (2.0 – 8.0), Hb 97 g/L (115–155), platelets 443 ⫻ 109/L (150 – 400). Electrolytes, creatinine, amylase, bilirubin, and liver enzymes normal. Stool culture negative for bacterial pathogens and Clostridium difficile toxin.
WBC 3.0 ⫻ 109/L (4.0 –11.0), neutrophils 2.2 ⫻ 109/L (2.0 – 8.0), Hb 111 g/L (135–170). ALT107 U/L (25– 80). Platelets, electrolytes, creatinine, amylase, bilirubin, and other liver enzymes normal.
Irritable bowel syndrome, hypertension Long-standing alternating diarrhea and constipation, discomfort in left upper quadrant, and occasional nausea and vomiting. CMV Ag ⫽ 3 two weeks after transplant #2 followed by Ag ⫽ 13 two weeks later.
YAKUBOVICH, FUNG, AND THOMPSON
Significant laboratory investigations
Presentation 1: Intermittent loose stools, CMV Ag ⫽ 8 three and a half weeks posttransplant rising to 24 three weeks later. Prednisone rapidly tapered, MMF dose decreased by 50%, and IV ganciclovir administered for 2 weeks. CMV Ag level decreased to 7, and patient restarted on oral valganciclovir. Presentation 2: CMV Ag ⫽ 405 three weeks after ganciclovir course completed. Initially asymptomatic. Two days after immunosuppression withdrawn and IV ganciclovir restarted, fevers, intermittent diarrhea, dyspnea, headaches, generalized weakness. On admission to hospital 12 days later, fever 39.7°C, CMV Ag ⫽ 112. Presentation 1: WBC 3.2 ⫻ 109/L (normal range 4.0 –11.0), neutrophils 2.5 ⫻ 109/L (2.0 – 8.0), lymphocytes 0.4 ⫻ 109/ L (1.2–3.0), Hb 112 g/L (135–175). Liver enzymes normal. Presentation 2 (on admission to hospital): WBC 3.1 ⫻ 109/L (4.0 –11.0), neutrophils 1.1 ⫻ 109/L (2.0 – 8.0), Hb 85 g/L (135–175). AST 61 U/L (10 –38). Platelets, electrolytes, creatinine, bicarbonate, amylase, bilirubin, and other liver enzymes normal. On cerebrospinal fluid analysis, normal WBC 2 ⫻ 106/L (1–10) (91% lymphocytes, 9% monocytes), normal glucose, and elevated protein 615 mg/L (150 – 450). Urine culture and blood cultures on days 1, 4, and 5 negative. Nasopharyngeal wash negative for respiratory virus pool Ag stain†, and negative on CMV
Case 2
54-year-old woman 53 years Microalbuminuria, neuropathy, retinopathy Two, 9 days apart CMV⫹ Transplant #1: CMV⫹ Transplant #2: CMV⫺ Transplant #1: ATG Transplant #2: Basiliximab Tacrolimus, MMF Ganciclovir IV with transplant #1, followed by valganciclovir orally until presentation TMP/SMX, insulin, aspirin, telmisartan/ hydrochlorothiazide, venlafaxine, bupropion Irritable bowel syndrome, gastroesophageal reflux disease Intermittent watery diarrhea and lower abdominal cramping started 3 weeks posttransplant. CMV Ag ⫽ 3 six weeks posttransplant #2.
1600
Table 1. Clinical Presentation and Outcome of 3 Cases of CMV Antigenemia Following Islet Transplantation for Type 1 Diabetes
Case 1
Other investigations
Therapeutic intervention
Clinical outcome
rapid culture, respiratory, and influenza cultures. CSF negative on bacterial and fungal cultures, and negative for Cryptococcus Ag on latex agglutination. CT scan of chest showed no evidence of pulmonary CMV infection. CT scan of head normal. Transthoracic echocardiogram showed normal biventricular systolic function and no vegetations.
Presentation 1: See clinical presentation Presentation 2: Immunosuppression withdrawn as graft rejection evident. Ganciclovir IV for 5 weeks, followed by oral valganciclovir for 3 weeks. Five doses of CMV immune globulin given during 2 weeks of hospital admission. Diarrhea resolved prior to admission to hospital. Two weeks after admission, headache and fever resolved and the patient was discharged home. The patient had no further symptoms, and repeated CMV Ag levels were negative for 1.5 months.
Case 2
Case 3
Sigmoidoscopy revealed normal distal colonic mucosa. Distal colon biopsy negative for CMV on rapid culture.
Endoscopy revealed gastric stasis consistent with gastroparesis, and normal small bowel mucosa. Small bowel mucosa biopsy negative for CMV on rapid culture. Tacrolimus dose reduced by 60%, trough levels maintained within target 5–10 ng/mL range. Ganciclovir IV for 4 weeks, followed by valganciclovir orally for 1.5 months. Abdominal discomfort improved with laxatives and motility agents. Repeated CMV Ag levels tested weekly were negative for 1.5 months.
MMF dose reduced by 50%. Oral valganciclovir for 5 weeks.
Diarrhea and abdominal cramping resolved in 1 week. Repeated CMV Ag levels tested weekly for 1 month, then monthly for 2 months were negative.
CYTOMEGALOVIRUS INFECTION
Table 1. (continued)
Abbreviations: antigen (Ag); alanine aminotransferase (ALT); aspartate aminotransferase (AST); anti-thymocyte globulin (ATG); cytomegalovirus (CMV); cerebrospinal fluid (CSF); intravenous (IV); hemoglobin (Hb); mycophenolate mofetil (MMF); trimethoprim sulfamethoxazole (TMP/SMX); white blood cell (WBC). *Cytomegalovirus antigen (CMV Ag) level: expressed as number of positive cells per 200,000 peripheral blood leukocytes. The DiaSorin CMV-vue FITC cytomegalovirus antigenemia assay was used to detect the CMV early structural protein pp65 in peripheral blood leukocytes via indirect immunocytochemistry. † Respiratory virus pool Ag stain: detects influenza A and B, parainfluenza 1, 2, and 3, adenovirus, and respiratory syncytial virus.
1601
1602 CMV-positive donor were included in the donor-positive subgroups. Three of 23 patients developed CMV antigenemia following islet transplantation despite receiving prophylaxis with oral valganciclovir (Table 1).
DISCUSSION
The three cases of CMV infection observed in our islet transplant recipients warrant close analysis. Case 1 was a CMV-seronegative recipient who received a CMV-positive graft. He developed CMV antigenemia within 12 days of being started on prednisone 75 mg daily for brachial plexus neuritis while receiving CMV prophylaxis. When the patient’s CMV antigen (Ag) status turned positive, he was asymptomatic apart from occasional loose stools. Prednisone was rapidly tapered and mycophenolate mofetil (MMF) dose cut in half. Intravenous (IV) ganciclovir was administered for 2 weeks followed by oral valganciclovir. The decision to withdraw immunosuppression was made in view of rising levels of CMV antigen following completion of ganciclovir treatment and strong evidence of graft rejection. The patient developed symptoms of fever, chills, headache, diarrhea, malaise, and fatigue within 2 days of withdrawal of immunosuppression. By that time, the CMV Ag level decreased significantly. Because the workup for bacterial and other viral infections was negative, it was believed that this patient developed CMV disease and/or immune reconstitution syndrome on withdrawal of immunosuppression. The CMV antigenemia eventually cleared on IV ganciclovir and CMV immune globulin treatment, and patient’s symptoms resolved. The graft loss was not attributed to CMV infection as C-peptide levels dropped to pretransplant levels 3 weeks posttransplantation just prior to the first detection of CMV antigenemia, which was tested weekly. In cases 2 and 3, CMV reactivation or reinfection occurred in CMV-seropositive recipients who received a CMV-positive graft as evident by CMV antigenemia. It was believed that neither of the two patients had CMV disease. Diarrhea and abdominal discomfort observed in both patients were more likely to be explained by irritable bowel syndrome, gastroparesis, and/or MMF use, and in both cases bowel biopsies were negative for CMV. In case 2, CMV antigenemia cleared when MMF dose was reduced in an attempt to alleviate diarrhea. No change in antiviral therapy was implemented. In case 3, tacrolimus dose was reduced by 60% while maintaining trough levels within target 5 to 10 ng/mL range. Intravenous ganciclovir was then administered for 4 weeks when levels of CMV Ag continued to rise despite oral valganciclovir. The CMV antigenemia rapidly resolved in this patient on initiation of ganciclovir treatment. In all three cases, CMV infection occurred during the 3-month period of ongoing CMV prophylaxis with oral valganciclovir posttransplantation. The reasons behind this are unclear. Oral valganciclovir was used for CMV prophylaxis in our patients at a dose of 900 mg daily, which is similar to the prophylactic regimens utilized in other islet transplant
YAKUBOVICH, FUNG, AND THOMPSON
centers.7 All three cases also received IV ganciclovir prophylaxis during induction therapy with anti-thymocyte globulin (ATG). The Edmonton group used a CMV prophylactic regimen of oral ganciclovir 1 g three times a day for 3 months after transplantation.10 The Miami group reported using either oral ganciclovir 1 g three times daily or oral valganciclovir 450 mg twice daily.7 The efficacy of using oral valganciclovir as the only agent for CMV prophylaxis has been previously demonstrated in a large randomized controlled trial on 372 solid-organ transplant recipients. The rates of CMV disease and CMV infection at 6 and 12 months posttransplant were not significantly different between patients receiving valganciclovir 900 mg daily or oral ganciclovir 1 g three times daily.11 Interestingly, valganciclovir was found to be more effective than ganciclovir in preventing CMV disease in recipients of certain solid-organ types, and the incidence of CMV viremia during prophylaxis was significantly lower with valganciclovir. The optimal duration of prophylaxis remains controversial; however, a prophylactic agent is generally administered for 3 months. The choice of immunosuppressive regimen may be a significant factor influencing the rates of CMV infection posttransplantation, yet the exact relationship in islet transplant recipients is unclear. Since the Edmonton group demonstrated successful islet transplantation in patients with type 1 diabetes, most other islet cell transplant centers have adopted similar immunosuppressive protocols. This protocol consists of induction with anti-interleukin-2-receptor monoclonal antibody daclizumab for a total of five doses, and maintenance therapy with sirolimus and low-dose tacrolimus.12 The Miami group utilized almost identical protocols.7 The immunosuppressive regimen used in our three patients included induction with a lymphocyte-depleting agent antithymocyte globulin and maintenance therapy with tacrolimus and MMF. In two patients, induction therapy with interleukin-2-receptor antagonist basiliximab was also used during the second islet transplantation. With such low incidence of CMV infection and different CMV detection techniques, it is difficult to compare the rates of CMV transmission/reactivation between centers. However, it will be important to study CMV infection rates as different immunosuppressive protocols are tested in these patients in an attempt to improve islet graft survival. CMV disease appears to be rare postislet transplantation; however, it should be considered in islet transplant recipients presenting with an acute illness. Prompt intervention is required if CMV viremia is detected on screening tests. Further studies are needed to evaluate risk factors for CMV transmission and reactivation in this patient population and to test the efficacy of prophylactic and therapeutic regimens. REFERENCES 1. Schnitzler MA, Lowell JA, Hardinger KL, et al: The association of cytomegalovirus sero-pairing with outcomes and costs following cadaveric renal transplantation prior to the introduction of oral ganciclovir CMV prophylaxis. Am J Transplant 3:445, 2003
CYTOMEGALOVIRUS INFECTION 2. Freeman RB, Paya C, Pescovitz MD, et al: Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients. Transplantation 78: 1765, 2004 3. Preiksaitis JK, Brennan DC, Fishman J, et al: Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant 5:218, 2005 4. Mourad G, Rostaing L, Legendre C, et al: Sequential protocols using basiliximab versus antithymocyte globulins in renaltransplant patients receiving mycophenolate mofetil and steroids. Transplantation 78:584, 2004 5. Lo A, Stratta RJ, Egidi MF, et al: Patterns of cytomegalovirus infection in simultaneous kidney–pancreas transplant recipients receiving tacrolimus, mycophenolate mofetil, and prednisone with ganciclovir prophylaxis. Transpl Infect Dis 3:8, 2001 6. Opelz G, Dohler B, Ruhenstroth A: Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant 4:928, 2004
1603 7. Hafiz MM, Poggioli R, Caulfield A, et al: Cytomegalovirus prevalence and transmission after islet allograft transplant in patients with type 1 diabetes mellitus. Am J Transplant 4:1697, 2004 8. Cure P, Pileggi A, Faradji RN, et al: Cytomegalovirus infection in a recipient of solitary allogeneic islets. Am J Transplant 6:1089, 2006 9. Ryan EA, Paty BW, Senior PA, et al: Five-year follow-up after clinical islet transplantation. Diabetes 54:2060, 2005 10. Ryan EA, Lakey JRT, Paty BW, et al: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148, 2002 11. Paya C, Humar A, Dominguez E, et al: Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 4:611, 2004 12. Ryan EA, Lakey JRT, Rajotte RV, et al: Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710, 2001
C
YTOMEGALOVIRUS (CMV) accounts for significant morbidity and mortality in solid-organ transplant recipients. It has been shown to cause retinitis, pneumonitis, colitis, hepatitis, encephalitis, and CMV syndrome, which is defined by the presence of CMV viremia, fever, malaise, leukopenia, thrombocytopenia, or transaminitis. Cytomegalovirus lowers the state of immunosuppression, predisposes to further opportunistic infections, and is associated with increased risk of graft rejection and lymphoproliferative disease.1–3 Risk of development of CMV disease is dependent on the CMV serological status of the donor and the recipient, type of organ transplanted, specific immunosuppressive agents used, and the overall intensity of immunosuppression.3,4 Antiviral prophylaxis has been shown to delay CMV transmission, reduce severity of disease, and improve graft survival.5,6 Cytomegalovirus infection has been rarely reported in recipients of solitary islet transplants. Several reasons previously postulated for negligible risk of CMV transmission and reactivation observed in islet transplantation include the small volume of tissue with low number of contaminating leukocytes transplanted, and, therefore, low viral load transmitted, as well as unique immunosuppressive regimens and effective CMV prophylaxis.7 However, patients with type 1 diabetes may be at higher risk for CMV mismatch during transplantation than other organ transplant recipients. The prevalence of positive CMV serology among 362 type 1 diabetic patients who were candidates for islet transplantation was reported to be only 38%, compared to 67% prevalence among 1042 potential organ donors representative of the general population.7 In this study, the presence of type 1 diabetes mellitus was negatively associated with CMV positivity even after adjusting for age, gender, and race.
We searched the Medline database between 1966 and July 2006 for “islet transplant” mapped to subject and “cytomegalovirus,” “CMV,” “infection,” or “virus” keywords, and found only one report of CMV disease seen in solitary islet transplant recipients. The islet transplant group in Miami described a 42-year-old female who developed CMV infection with colitis 15 months after the second intrahepatic islet infusion from a CMV-positive donor. Colitis and viremia completely resolved on administration of antiviral treatment and mesalamine.8 The researchers also reported a patient who seroconverted with no CMV disease 6.4 months after islet transplantation. Twelve of 29 islet transplant recipients at this center were recipientnegative, donor-positive for CMV. There have been only two cases of CMV seroconversion without overt CMV disease in the Edmonton islet transplantation program among 65 islet transplant recipients followed for up to 5 years despite 43 CMV mismatches (donor-seropositive, recipient-seronegative for CMV).9 At both centers, patients received CMV prophylaxis for 3 months posttransplantation. CASE SERIES Between March 2003 and May 2006, a total of 23 patients with type 1 diabetes received solitary islet transplantation at Vancouver Hospital, Vancouver, British Columbia. The CMV status of the transplanted patients was as follows: 13 of 23 donor⫹/recipient⫺, 8 of 23 donor⫹/recipient⫹, 1 of 23 donor⫺/recipient⫹, and 1 of 23 donor⫺/recipient⫺. Patients receiving islets from at least one From the Division of Endocrinology, University of British Columbia, Vancouver, Canada. Address reprint requests to Dr. Michelle Anne Fung, Division of Endocrinology, Diamond Health Care Center, 2775 Laurel St., 4th floor, Vancouver, BC V5Z 1M9. E-mail: [email protected]
© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.01.074
Transplantation Proceedings, 39, 1599 –1603 (2007)
1599
Case 1
Age and Gender Duration of type 1 diabetes Diabetes complications
41-year-old male 22 years Microalbuminuria, retinopathy
Number of islet transplants Recipient CMV status Donor CMV status
One CMV⫺ CMV⫹
Induction immunotherapy
ATG
Maintenance immunotherapy CMV prophylaxis
Tacrolimus, MMF Ganciclovir IV with islet transplant. Oral valganciclovir started 8 days later and continued until presentation
Other medications
TMP/SMX, insulin, aspirin, quinapril, amitriptyline, gabapentin. High-dose oral prednisone for left brachial plexus neuritis. Hypertension
Significant past history Symptoms and CMV Ag level on presentation*
Case 3
58-year-old male 48 years Microalbuminuria, neuropathy, retinopathy Two, 52 days apart CMV⫹ Transplant #1: CMV⫹ Transplant #2: CMV⫺ Transplant #1: ATG Transplant #2: Basiliximab Tacrolimus MMF Ganciclovir IV with transplant #1, followed by valganciclovir orally until presentation TMP/SMX, insulin, aspirin, ramipril, pantoprazole
WBC 3.4 ⫻ 109/L (4.0 –11.0), neutrophils 3.0 ⫻ 109/L (2.0 – 8.0), Hb 97 g/L (115–155), platelets 443 ⫻ 109/L (150 – 400). Electrolytes, creatinine, amylase, bilirubin, and liver enzymes normal. Stool culture negative for bacterial pathogens and Clostridium difficile toxin.
WBC 3.0 ⫻ 109/L (4.0 –11.0), neutrophils 2.2 ⫻ 109/L (2.0 – 8.0), Hb 111 g/L (135–170). ALT107 U/L (25– 80). Platelets, electrolytes, creatinine, amylase, bilirubin, and other liver enzymes normal.
Irritable bowel syndrome, hypertension Long-standing alternating diarrhea and constipation, discomfort in left upper quadrant, and occasional nausea and vomiting. CMV Ag ⫽ 3 two weeks after transplant #2 followed by Ag ⫽ 13 two weeks later.
YAKUBOVICH, FUNG, AND THOMPSON
Significant laboratory investigations
Presentation 1: Intermittent loose stools, CMV Ag ⫽ 8 three and a half weeks posttransplant rising to 24 three weeks later. Prednisone rapidly tapered, MMF dose decreased by 50%, and IV ganciclovir administered for 2 weeks. CMV Ag level decreased to 7, and patient restarted on oral valganciclovir. Presentation 2: CMV Ag ⫽ 405 three weeks after ganciclovir course completed. Initially asymptomatic. Two days after immunosuppression withdrawn and IV ganciclovir restarted, fevers, intermittent diarrhea, dyspnea, headaches, generalized weakness. On admission to hospital 12 days later, fever 39.7°C, CMV Ag ⫽ 112. Presentation 1: WBC 3.2 ⫻ 109/L (normal range 4.0 –11.0), neutrophils 2.5 ⫻ 109/L (2.0 – 8.0), lymphocytes 0.4 ⫻ 109/ L (1.2–3.0), Hb 112 g/L (135–175). Liver enzymes normal. Presentation 2 (on admission to hospital): WBC 3.1 ⫻ 109/L (4.0 –11.0), neutrophils 1.1 ⫻ 109/L (2.0 – 8.0), Hb 85 g/L (135–175). AST 61 U/L (10 –38). Platelets, electrolytes, creatinine, bicarbonate, amylase, bilirubin, and other liver enzymes normal. On cerebrospinal fluid analysis, normal WBC 2 ⫻ 106/L (1–10) (91% lymphocytes, 9% monocytes), normal glucose, and elevated protein 615 mg/L (150 – 450). Urine culture and blood cultures on days 1, 4, and 5 negative. Nasopharyngeal wash negative for respiratory virus pool Ag stain†, and negative on CMV
Case 2
54-year-old woman 53 years Microalbuminuria, neuropathy, retinopathy Two, 9 days apart CMV⫹ Transplant #1: CMV⫹ Transplant #2: CMV⫺ Transplant #1: ATG Transplant #2: Basiliximab Tacrolimus, MMF Ganciclovir IV with transplant #1, followed by valganciclovir orally until presentation TMP/SMX, insulin, aspirin, telmisartan/ hydrochlorothiazide, venlafaxine, bupropion Irritable bowel syndrome, gastroesophageal reflux disease Intermittent watery diarrhea and lower abdominal cramping started 3 weeks posttransplant. CMV Ag ⫽ 3 six weeks posttransplant #2.
1600
Table 1. Clinical Presentation and Outcome of 3 Cases of CMV Antigenemia Following Islet Transplantation for Type 1 Diabetes
Case 1
Other investigations
Therapeutic intervention
Clinical outcome
rapid culture, respiratory, and influenza cultures. CSF negative on bacterial and fungal cultures, and negative for Cryptococcus Ag on latex agglutination. CT scan of chest showed no evidence of pulmonary CMV infection. CT scan of head normal. Transthoracic echocardiogram showed normal biventricular systolic function and no vegetations.
Presentation 1: See clinical presentation Presentation 2: Immunosuppression withdrawn as graft rejection evident. Ganciclovir IV for 5 weeks, followed by oral valganciclovir for 3 weeks. Five doses of CMV immune globulin given during 2 weeks of hospital admission. Diarrhea resolved prior to admission to hospital. Two weeks after admission, headache and fever resolved and the patient was discharged home. The patient had no further symptoms, and repeated CMV Ag levels were negative for 1.5 months.
Case 2
Case 3
Sigmoidoscopy revealed normal distal colonic mucosa. Distal colon biopsy negative for CMV on rapid culture.
Endoscopy revealed gastric stasis consistent with gastroparesis, and normal small bowel mucosa. Small bowel mucosa biopsy negative for CMV on rapid culture. Tacrolimus dose reduced by 60%, trough levels maintained within target 5–10 ng/mL range. Ganciclovir IV for 4 weeks, followed by valganciclovir orally for 1.5 months. Abdominal discomfort improved with laxatives and motility agents. Repeated CMV Ag levels tested weekly were negative for 1.5 months.
MMF dose reduced by 50%. Oral valganciclovir for 5 weeks.
Diarrhea and abdominal cramping resolved in 1 week. Repeated CMV Ag levels tested weekly for 1 month, then monthly for 2 months were negative.
CYTOMEGALOVIRUS INFECTION
Table 1. (continued)
Abbreviations: antigen (Ag); alanine aminotransferase (ALT); aspartate aminotransferase (AST); anti-thymocyte globulin (ATG); cytomegalovirus (CMV); cerebrospinal fluid (CSF); intravenous (IV); hemoglobin (Hb); mycophenolate mofetil (MMF); trimethoprim sulfamethoxazole (TMP/SMX); white blood cell (WBC). *Cytomegalovirus antigen (CMV Ag) level: expressed as number of positive cells per 200,000 peripheral blood leukocytes. The DiaSorin CMV-vue FITC cytomegalovirus antigenemia assay was used to detect the CMV early structural protein pp65 in peripheral blood leukocytes via indirect immunocytochemistry. † Respiratory virus pool Ag stain: detects influenza A and B, parainfluenza 1, 2, and 3, adenovirus, and respiratory syncytial virus.
1601
1602 CMV-positive donor were included in the donor-positive subgroups. Three of 23 patients developed CMV antigenemia following islet transplantation despite receiving prophylaxis with oral valganciclovir (Table 1).
DISCUSSION
The three cases of CMV infection observed in our islet transplant recipients warrant close analysis. Case 1 was a CMV-seronegative recipient who received a CMV-positive graft. He developed CMV antigenemia within 12 days of being started on prednisone 75 mg daily for brachial plexus neuritis while receiving CMV prophylaxis. When the patient’s CMV antigen (Ag) status turned positive, he was asymptomatic apart from occasional loose stools. Prednisone was rapidly tapered and mycophenolate mofetil (MMF) dose cut in half. Intravenous (IV) ganciclovir was administered for 2 weeks followed by oral valganciclovir. The decision to withdraw immunosuppression was made in view of rising levels of CMV antigen following completion of ganciclovir treatment and strong evidence of graft rejection. The patient developed symptoms of fever, chills, headache, diarrhea, malaise, and fatigue within 2 days of withdrawal of immunosuppression. By that time, the CMV Ag level decreased significantly. Because the workup for bacterial and other viral infections was negative, it was believed that this patient developed CMV disease and/or immune reconstitution syndrome on withdrawal of immunosuppression. The CMV antigenemia eventually cleared on IV ganciclovir and CMV immune globulin treatment, and patient’s symptoms resolved. The graft loss was not attributed to CMV infection as C-peptide levels dropped to pretransplant levels 3 weeks posttransplantation just prior to the first detection of CMV antigenemia, which was tested weekly. In cases 2 and 3, CMV reactivation or reinfection occurred in CMV-seropositive recipients who received a CMV-positive graft as evident by CMV antigenemia. It was believed that neither of the two patients had CMV disease. Diarrhea and abdominal discomfort observed in both patients were more likely to be explained by irritable bowel syndrome, gastroparesis, and/or MMF use, and in both cases bowel biopsies were negative for CMV. In case 2, CMV antigenemia cleared when MMF dose was reduced in an attempt to alleviate diarrhea. No change in antiviral therapy was implemented. In case 3, tacrolimus dose was reduced by 60% while maintaining trough levels within target 5 to 10 ng/mL range. Intravenous ganciclovir was then administered for 4 weeks when levels of CMV Ag continued to rise despite oral valganciclovir. The CMV antigenemia rapidly resolved in this patient on initiation of ganciclovir treatment. In all three cases, CMV infection occurred during the 3-month period of ongoing CMV prophylaxis with oral valganciclovir posttransplantation. The reasons behind this are unclear. Oral valganciclovir was used for CMV prophylaxis in our patients at a dose of 900 mg daily, which is similar to the prophylactic regimens utilized in other islet transplant
YAKUBOVICH, FUNG, AND THOMPSON
centers.7 All three cases also received IV ganciclovir prophylaxis during induction therapy with anti-thymocyte globulin (ATG). The Edmonton group used a CMV prophylactic regimen of oral ganciclovir 1 g three times a day for 3 months after transplantation.10 The Miami group reported using either oral ganciclovir 1 g three times daily or oral valganciclovir 450 mg twice daily.7 The efficacy of using oral valganciclovir as the only agent for CMV prophylaxis has been previously demonstrated in a large randomized controlled trial on 372 solid-organ transplant recipients. The rates of CMV disease and CMV infection at 6 and 12 months posttransplant were not significantly different between patients receiving valganciclovir 900 mg daily or oral ganciclovir 1 g three times daily.11 Interestingly, valganciclovir was found to be more effective than ganciclovir in preventing CMV disease in recipients of certain solid-organ types, and the incidence of CMV viremia during prophylaxis was significantly lower with valganciclovir. The optimal duration of prophylaxis remains controversial; however, a prophylactic agent is generally administered for 3 months. The choice of immunosuppressive regimen may be a significant factor influencing the rates of CMV infection posttransplantation, yet the exact relationship in islet transplant recipients is unclear. Since the Edmonton group demonstrated successful islet transplantation in patients with type 1 diabetes, most other islet cell transplant centers have adopted similar immunosuppressive protocols. This protocol consists of induction with anti-interleukin-2-receptor monoclonal antibody daclizumab for a total of five doses, and maintenance therapy with sirolimus and low-dose tacrolimus.12 The Miami group utilized almost identical protocols.7 The immunosuppressive regimen used in our three patients included induction with a lymphocyte-depleting agent antithymocyte globulin and maintenance therapy with tacrolimus and MMF. In two patients, induction therapy with interleukin-2-receptor antagonist basiliximab was also used during the second islet transplantation. With such low incidence of CMV infection and different CMV detection techniques, it is difficult to compare the rates of CMV transmission/reactivation between centers. However, it will be important to study CMV infection rates as different immunosuppressive protocols are tested in these patients in an attempt to improve islet graft survival. CMV disease appears to be rare postislet transplantation; however, it should be considered in islet transplant recipients presenting with an acute illness. Prompt intervention is required if CMV viremia is detected on screening tests. Further studies are needed to evaluate risk factors for CMV transmission and reactivation in this patient population and to test the efficacy of prophylactic and therapeutic regimens. REFERENCES 1. Schnitzler MA, Lowell JA, Hardinger KL, et al: The association of cytomegalovirus sero-pairing with outcomes and costs following cadaveric renal transplantation prior to the introduction of oral ganciclovir CMV prophylaxis. Am J Transplant 3:445, 2003
CYTOMEGALOVIRUS INFECTION 2. Freeman RB, Paya C, Pescovitz MD, et al: Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients. Transplantation 78: 1765, 2004 3. Preiksaitis JK, Brennan DC, Fishman J, et al: Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant 5:218, 2005 4. Mourad G, Rostaing L, Legendre C, et al: Sequential protocols using basiliximab versus antithymocyte globulins in renaltransplant patients receiving mycophenolate mofetil and steroids. Transplantation 78:584, 2004 5. Lo A, Stratta RJ, Egidi MF, et al: Patterns of cytomegalovirus infection in simultaneous kidney–pancreas transplant recipients receiving tacrolimus, mycophenolate mofetil, and prednisone with ganciclovir prophylaxis. Transpl Infect Dis 3:8, 2001 6. Opelz G, Dohler B, Ruhenstroth A: Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant 4:928, 2004
1603 7. Hafiz MM, Poggioli R, Caulfield A, et al: Cytomegalovirus prevalence and transmission after islet allograft transplant in patients with type 1 diabetes mellitus. Am J Transplant 4:1697, 2004 8. Cure P, Pileggi A, Faradji RN, et al: Cytomegalovirus infection in a recipient of solitary allogeneic islets. Am J Transplant 6:1089, 2006 9. Ryan EA, Paty BW, Senior PA, et al: Five-year follow-up after clinical islet transplantation. Diabetes 54:2060, 2005 10. Ryan EA, Lakey JRT, Paty BW, et al: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148, 2002 11. Paya C, Humar A, Dominguez E, et al: Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 4:611, 2004 12. Ryan EA, Lakey JRT, Rajotte RV, et al: Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50:710, 2001