Cytomegalovirus Immune Globulin Research Articles

Invasive Cytomegalovirus Disease in a Low Risk CMV Serostatus, D-/R- Lung Transplant Recipient

<h3>Introduction</h3> Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality among transplant patients. Here, we report a case of lung transplant patient with low risk CMV serostatus (D-/R-) who developed invasive CMV disease. <h3>Case Report</h3> A 64-year-old lady with COPD underwent bilateral lung transplant. CMV serostatus was donor IgG negative / recipient IgG negative. Basiliximab was used for induction and was maintained on tacrolimus, mycophenolate and prednisone. Intraoperatively, she received 2 leucoreduced PRBC's. 15 days post-transplant she developed CMV viremia and was started on treatment dose valganciclovir. No mutations noted on the resistance panel. 2 weeks on therapy, there was no reduction in the CMV PCR. Chest CT showed a right pleural effusion which was exudative in nature. Microbiology testing was negative. Fluid cytology showed CMV cytopathic changes. Valganciclovir was changed to iv ganciclovir because of her GI absorption concerns. With 6 weeks of iv ganciclovir and monthly CMV Immune globulin, CMV PCR log values steadily declined. <h3>Summary</h3> Lung transplant patients with low risk CMV serostatus can have a minor risk of transfusion acquired (TA) or community acquired (CA) CMV infection. A single center retrospective study of low-risk organ transplant patients did not identify any cases of TA CMV infection in patients receiving leucoreduced PRBC. Another study showed 2.4% risk of TA CMV infection in patients receiving non-leucoreduced PRBC. CA CMV risk is greater than TA CMV, with the incidence being higher in children (3/100 patient years) compared to adults (0.46/100 patient years). Currently no guidelines exist to recommend CMV prophylaxis in low risk CMV serostatus transplant patients. Hence measures need to be taken to monitor such patients who are at increased risk for TA or CA CMV. Recipients whose IgG was negative during transplant work up should be retested at the time of transplant. CMV PCR monitoring should be considered if the donor or recipient received extensive transfusions.

Cytomegalovirus Immune Globulin (CMV-Ig): An Old Drug with Fewer Tricks - Removal of Prophylactic CMV-Ig Administration in CMV Mismatched Lung Transplant Recipients

The routine use of cytomegalovirus immune globulin (CMV-Ig) to provide passive immunity to cytomegalovirus (CMV) in patients is not supported in published literature. International guidelines do not advocate for the use of CMV-Ig alone in thoracic transplant and provide only weak recommendations for its role in combination with antiviral therapy for prevention of CMV. The utilization of CMV-Ig incurs significant cost, and carries the potential for infusion related toxicities. Furthermore, in 2012, an international survey reported only 38 % of thoracic transplant centers utilized CMV-Ig as part of a universal prophylaxis protocol. We evaluated the safety and cost efficiency of the removal of CMV-Ig from standard practice. Prior to September 2018, CMV-Ig 150mg/kg x1 was given to all CMV high-risk lung transplant recipients on postoperative day two in conjunction with intravenous ganciclovir (GCV) followed by prophylaxis with oral valganciclovir (vGCV) for 12 months per institution protocol. After September 2018, CMV-Ig was removed from our institution protocol and high-risk patients received GCV/vGCV prophylaxis alone. Serum CMV PCRs were monitored per institution protocol. All patients post-intervention were retrospectively reviewed for occurrence of CMV viremia, seroconversion, and a cost savings analysis was performed. Twelve CMV high-risk lung transplant recipients were observed after the removal of CMV-Ig administration from standard practice. None of these patients experienced a detectable serum CMV PCR. Median follow up time was 163 days (IQR 111-301) post-transplant. All patients received antiviral prophylaxis immediately post-operatively, and had at least 8 weeks of follow up. Seroconversion was observed in three patients at post-operative day 7, 76, and 80 respectively. Using average wholesale price, the calculated cost savings was approximately $5,700 per patient and $68,400 across the entire cohort. Our results demonstrate that removal of CMV-Ig administration from standard practice, even in CMV high-risk patients, did not increase the risk of CMV viremia and led to significant cost savings. These data allude to the decreasing utility of CMV-Ig for CMV prophylaxis in the GCV/vGCV era.

Utilization of PHS Increased Risk for Transmission of Infectious Disease Donor Organs in Lung Transplantation: One Center's 7-year Experience

Over the past several years 37 to 41% of all deceased donor organs in Region 1 were designated as Public Health Service increased risk for infectious disease transmission compared to 25-27% nationally. Limited by the number of standard donors our Center sought to develop guidelines for utilizing these donors and implement a system for follow-up testing for disease transmission. We reviewed our single-center 7-year experience utilizing PHS donor organs in our lung transplant program. Our Center developed a protocol based on the PHS Guidelines to guide the lung transplant program in the management of recipients. Transplant recipients of PHS donor organs had blood testing (serology and viral load) for HIV, HBV and HCV performed on the day of transplant; 1-3 months and 6-12 months after transplant. A QAPI project was implemented to ensure medical record documentation and follow-up testing was conducted. From 2013 to October 2019 there were 66 lung transplants performed from PHS donor organs. A retrospective analysis revealed one false positive HIV antibody test; and 15 recipients (23%) converted their HBV core antibody from negative to positive at the 1-3 month time frame after surgery. Of the 15, 11 converted back to HBV core antibody negative within a year after transplant; 2 patients did not have testing performed/expired; and 2 patients were still within the first year after surgery and remained HBV core antibody positive. Although the etiology of the conversion remains unclear it was attributed to the administration of cytomegalovirus immune globulin in the recipients. Of note, 8 of the 66 PHS organs (12%) were also HCV positive and were transplanted under an IRB protocol. The recipients of HCV NAT positive donor organs were started on direct acting anti-viral agents. All of these patients remained HCV viral load negative after transplant. In addition to these donors, there was one HCV antibody/NAT positive donor organ that did not meet PHS criteria that was tracked and the recipient was HCV viral load negative after transplant. Our Center experience suggests that there is limited risk to using PHS donor organs in lung transplantation. Special considerations may be warranted in tracking recipients of HCV positive donor organs that may not meet PHS donor organ criteria.

Safety of Cytomegalovirus Prophylaxis on Engraftment in Pediatric Umbilical Cord Blood Transplant Following Reduced Intensity Conditioning

Background Reduced intensity conditioning (RIC) transplant carries the advantage of decreased transplant related morbidity and mortality, however comes with an increased risk of viral infections, particularly cytomegalovirus (CMV) in the setting of serotherapy and umbilical cord blood (UCB) grafts. Given this, the use of prophylaxis is considered, though with hesitation given associated myelosuppression and nephrotoxicity. We report outcomes of CMV prophylaxis with ganciclovir and foscarnet on engraftment and viremia in the setting of RIC umbilical cord blood transplant (UCBT). Methods A retrospective chart review was conducted reviewing patients with non-malignant disease who underwent UCBT on an institutional protocol between 2016 - 2019. A RIC regimen was administered using alemtuzumab (Day -14), hydroyxurea (Day -14 to -5), fludarabine (Day -9 to -5), melphalan (split Day -4 & -3), and thiotepa (Day -2). ClinicalTrials.gov: NCT01962415. The patients were divided into 3 groups: patients who did not receive CMV prophylaxis (Group 1), patients who did (Group 2), and patients who received preemptive treatment prior to Day 0 due to CMV DNAemia (Group 3). CMV prophylaxis included ganciclovir 5 mg/kg/d (Day -10 to -2) followed by foscarnet 90 mg/kg daily (from Day +1) to reduce marrow suppression. Results Group 1 included 14 patients. Neutrophil engraftment occurred in all patients [median: 16 days; range: 11 – 33]. Platelet engraftment (> 50k) occurred at a median of 45.5 days (range: 33 – 79). Of the 14 patients, 1 patient received acyclovir as CMV prophylaxis while the remaining 13 received ganciclovir/foscarnet. 5 developed CMV viremia (max copies of 95,000 IU/mL); one of whom had graft rejection attributed to CMV. These patients were treated preemptively following detection of DNAemia. Group 2 included 6 patients. Neutrophil engraftment occurred in all patients [median: 15 days; range: 13 – 18]. Platelet engraftment occurred at a median of 32 days (range: 26 – 39). 5 patients developed CMV viremia (max copies of 3290 IU/mL). Similar to Group 1, these patients were also escalated to treatment doses of ganciclovir and switched to foscarnet and/or human CMV immune globulin (CytoGAM) with treatment failure. Group 3 included 2 patients who were found to have CMV DNAemia prior to Day 0 therefore received preemptive treatment. Neutrophil and platelet engraftment occurred at a median of 14 and 42 days, respectively. In all groups, no patient developed end-organ disease. Conclusion In our single-institution pediatric UCB transplant dataset, there is no suggestion that pre-engraftment exposure to CMV prophylaxis with ganciclovir and foscarnet impacted the kinetics of either neutrophil or platelet engraftment. Therefore, CMV prophylaxis in seropositive patients undergoing UCB transplant could be considered alongside preemptive therapy as an option for management of viral reactivation.

Resource utilization of cytomegalovirus immune globulin in prevention and treatment of cytomegalovirus infection in pediatric heart transplantation.

There is debate whether cytomegalovirus immunoglobulin (CMV-Ig) is also needed for CMV prevention in heart transplant recipients in the era of good anti-viral drugs. We conducted a cost-savings quality initiative on CMV-Ig eventually leading to discontinuation of routine use of CMV-Ig for CMV prevention. Subsequently, a retrospective cohort study was conducted, comparing patients in cohort I (CMV-Ig plus anti-viral drugs, 2013-2015) to cohort II (anti-virals alone, 2015-2017). The medication acquisition costs and outcomes of CMV infection were assessed. There were 39 total patients: 22/39(56%) in cohort I, with mean follow-up of 35.14±17.38months and 17/39(44%) in cohort II, mean follow-up of 19.12±7.08months. In cohort I, 5/22(22.7%) patients died from causes unrelated to CMV and 0/17 in cohort II died. There were 5/22(22.7%) patients in cohort I, and 2/17(9%) patients in cohort II that developed CMV infection (P=.508). Freedom from rejection was 81.8% (18/22) in cohort I, and 71% (12/17) in cohort II (P=.46), and 100% for allograft vasculopathy. There was significant reduction in medication acquisition cost following the protocol change of $260839 or $15343 per patient. Our study demonstrated an acquisition cost savings with similar clinical outcomes utilizing anti-viral CMV prophylaxis alone vs anti-viral prophylaxis plus CMV-Ig.

Cytomegalovirus Induced Thrombocytopenia with No Platelets in an Immunocompetent Young Male

Introduction Immune thrombocytopenic purpura (ITP) is a common cause of acquired thrombocytopenia in an otherwise asymptomatic adult. It is generally believed to be caused by auto- antibodies against platelet antigens that destroy platelets peripherally and autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production. Cytomegalovirus (CMV) is a known cause of cause of morbidity and mortality in patients with immunosuppressed states, whereas in immunocompetent patients, it commonly manifest as asymptomatic or mononucleosis like syndrome. We are presenting a case of CMV induced thrombocytopenia with severe epistaxis and platelet count of 0 x10 9 in an otherwise healthy immunocompetent male who failed to improve after standard treatments with high dose steroids and intra venous immune globulin (IVIG). Case Description A 36-year-old Caucasian male without any past medical history presented to emergency room (ER) with flu like symptoms for five days associated with subjective fevers, anorexia, nausea, cough and weight loss of 15 lb. in two weeks. He also reported possible tick bite while working in the yard two days prior to admission. No dizziness, vomiting, diarrhea or any bleeding were reported. Denied any smoking, alcohol use or any illicit drug use. No significant family history was reported. On evaluation he was afebrile, normotensive with normal heart rate and respiratory rate. Physical examination was unremarkable. Initial laboratory data revealed hemoglobin of 11.2, platelet count 4 x109, white cell count of 13,100 with 4.5% atypical lymphocytes, aspartate aminotransferase of 41, alanine aminotransferase of 49, and creatinine of 1.4. He tested positive for Influenza A, CMV Immune globulin (Ig)M and IgG antibody. Serological tests for tick panel including anaplasma, babesia, Lyme disease and ehrlichia were negative. Epstein-Barr virus (EBV) antibody, parvo virus antibody, hepatitis screen, HIV screen, auto antibodies including anti-nuclear antibody and anti-double stranded DNA were negative. Coombs test was negative. Further work up includes ADAMTS13 activity was normal. No laboratory evidence of ADAMTS13 deficiency. After excluding all other causes, diagnosis of ITP was made. He was started on Tamiflu for Influenza A and high dose intra venous (IV) methyl prednisone for ITP. After platelet transfusion and two days of IV steroids platelet count improved 43 x 109 and he was discharged home with prolonged prednisone taper. Five days later, he presented to ER with severe epistaxis. Laboratory data revealed platelet count of 0 x109. Serum CMV-DNA was determined by PCR showed viral load of 8,790 copies/ml. Ultrasound abdomen showed mild splenomegaly. He received three doses of IVIG (1g/kg). Platelet count failed to improve after administration of IVIG. Bone marrow biopsy revealed hyper cellular marrow with trilineage hematopoiesis with no increase in CD 34 blasts. Per infectious disease and hematology recommendations, he was started on valganciclovir (900 mg PO BID). One month later, platelet count improved to 150 x 109 and CMV viral load dropped to 413 with subsequent resolution of patient's symptoms. Discussion Secondary ITP is an acquired thrombocytopenia caused by autoantibodies against platelets. Many patients with ITP are asymptomatic. For those who do have symptoms, initial presentations of ITP are petechiae, purpura and epistaxis, with a more severe progression to intracranial hemorrhage or gastrointestinal bleeding leading to a fatal outcome, if treatment is not started on a promptly manner. CMV induced thrombocytopenia in immunocompetent adults seems to be rare. we are presenting a case of CMV induced ITP which failed to improve after standard treatment with high dose steroids and IVIG but responded to anti-viral therapy with valganciclovir. In conclusion, it may be worthwhile to test for CMV infection in patients presenting with ITP. Further research is needed in order to establish treatment guidelines for CMV induced ITP in immunocompetent adults. Disclosures No relevant conflicts of interest to declare.

Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients.

BackgroundThe rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.MethodsUsing stored serial serum specimens from renal (n = 59) and liver (n = 35) transplant recipients (D+R-; CMV-seropositive donors, CMV-seronegative recipients) from 2 prospective, randomized, controlled, interventional prophylaxis trials of CMV immune globulin (CMVIG), CMV viral load was measured using the COBAS quantitative polymerase chain reaction assay and the World Health Organization CMV standard. Patients with severe CMV-associated disease were classified according to trial definitions. Pairwise comparisons of mean viral load among deceased, surviving diseased, and nondiseased patients were analyzed by 2-way analysis of variance. To determine if viral load could predict mortality, receiver operating characteristic (ROC) curves were constructed using area under the curve (AUC) of the viral load and peak viral concentration (Vmax).ResultsViral load (mean log10 [AUC], peak viral load [Vmax]) for patients with severe CMV disease was significantly higher compared with nondiseased patients (P < .001). Similarly, higher viral burden was significantly associated with mortality (P < .001). Viral load AUC and Vmax AUROCs for predicting mortality were 0.796 and 0.824, respectively, for renal patients, and 0.769 and 0.807, respectively, for liver patients.ConclusionsUsing specimens from studies preceding the antiviral prophylaxis era, CMV viral load was associated with severe CMV disease and death, supporting CMV viral load quantification as a proxy for CMV disease severity and disease-associated mortality end points in solid organ transplantation.

A Novel Cytomegalovirus Prophylaxis Protocol in Cytomegalovirus (CMV) D+/R- Heart Transplant Recipients: A Single-Center Experience

Background We previously reported that after completion of 3 months of prophylactic treatment with valganciclovir in cytomegalovirus (CMV) donor positive, recipient negative (D+/R-) heart transplant patients, there was a high incidence of CMV disease, with six out of seven recipients (86%) developing CMV disease within the next 6 months. A novel, three-tiered CMV prophylactic strategy for D+/R-heart transplant recipients was thus implemented at our center in 2010. The efficacy of this strategy is unknown. Methods We retrospectively reviewed consecutive heart transplants between September 2010 and December 2013. The novel 3-tiered CMV protocol administered to D+/R- patients consisted of: 1) Renally-dosed valganciclovir, starting on post-operative day 5 and continuing for 12 months, if tolerated; 2) CMV Immune Globulin administration through 16 weeks; and 3) Azathioprine rather than mycophenolate mofetil for immunosuppression. The diagnosis of CMV disease, consisting either of the CMV syndrome or tissue-invasive CMV infection, was established according to American Society of Transplantation Guidelines for clinical CMV infection. Results Of seventy-five heart transplant recipients, 17 (23%) were CMV D+/R-. Three of the 17 died of non-CMV causes within the first year. Among the remaining 14 recipients, CMV disease occurred in the first year in 3 (21%) recipients. Following cessation of valganciclovir at one year, another 4 (29%) recipients developed CMV disease within the next 6 months. Conclusion CMV D+/R- heart transplant recipients appear to have a lower incidence of CMV disease in the first year using a novel prophylactic regimen as compared to a historical group at our program. CMV D+/R- patients remain at risk of developing CMV disease with valganciclovir discontinuation, even after a full year of prophylactic treatment. Figure 1

Binding and neutralizing anti-cytomegalovirus activities in immune globulin products

Congenital infection as well as infection of immunocompromised individuals by cytomegalovirus (CMV) can be associated with significant morbidity, mortality, and long-term adverse health outcomes. Assessment of anti-viral activity using appropriate assays is essential for ensuring safe and efficacious use of therapeutic CMV immune globulin (IG) products. In this study, we used commercial ELISA kits to compare anti-CMV antibody binding activity and avidity for lots of CMV-specific and normal IG products available in the US market. Additionally, neutralizing activity of IG products was measured against CMV strains (AD169wt131 or TB40E-GFP) in MRC-5 human fibroblasts and ARPE-19 human epithelial cells. Our data revealed that, regardless of the method, anti-CMV activity was higher in CMV IG lots we tested compared with normal IG lots; CMV binding activity was at least 4-fold higher, and neutralizing activity at least 2- and 3-fold higher for epithelial and fibroblast cells, respectively, in CMV IG lots compared with normal IG lots. Furthermore, anti-CMV activity values from all three methods (ELISA, neutralization in MRC-5 cells, and neutralization in ARPE-19 cells) were highly correlated, whereas avidity, although higher in CMV IG lots, did not correlate well with either binding or neutralizing activities.

Potential role of plasmapheresis in severe cytomegalovirus infection with ongoing immunemediated hemolysis and low complement level

Symptomatic cytomegalovirus (CMV) infections are rare in patients with no previous history of immunosuppressive therapy or condition. A 33-year-old woman with type-2 diabetes, endstage renal disease (ESRD) and unexplained lower extremity weakness was admitted with failure to thrive, ongoing hemolysis, low haptoglobin and C3 levels and suppressed IgM and IgG globulin fractions. Multiple cultures and serologic workup for autoimmune disorders remained negative. CMV viral titer by serum polymerase chain reaction (PCR) revealed massive elevation at 9.2 million copies/mL. Initial CMV IgG titer was positive, IgM titer remained consistently negative and CMV was recovered from cerebrospinal fluid, as well. She received treatment with I.V. ganciclovir, CMV immune globulin (CytoGam) and three sessions of plasmapheresis (PLEX). The extreme viremia without neutropenia, lack of IgM antibody reconversion and CMV-mediated hemolysis with a low complement level were all very unusual features. Timely initiation of PLEX may have contributed to recovery

Treatment of Cytomegalovirus Infection with Cidofovir and CMV Immune Globulin in a Lung Transplant Recipient.

Cytomegalovirus (CMV) infection after lung transplantation is associated with increased risk for pneumonitis and bronchiolitis obliterans as well as allograft rejection and opportunistic infections. Ganciclovir is the mainstay of prophylaxis and treatment but CMV infections can be unresponsive. Apart from direct antiviral drugs, CMV immunoglobulin (CMVIG) preparations may be considered but are only licensed for prophylaxis. A CMV-seronegative 42-year-old man with cystic fibrosis received a lung from a CMV-seropositive donor. Intravenous ganciclovir prophylaxis was delayed until day 12 due to acute postoperative renal failure and was accompanied by five doses of CMVIG (10 g). By day 16, CMV-DNA was detectable and rising; CMV-specific T-cells were undetectable. Switch from ganciclovir to foscarnet prompted a transient decrease in CMV viral load, but after increasing again to reach 3600 copies/mL foscarnet was changed to intravenous cidofovir and CMVIG was restarted. CMV load continued to fluctuate and declined slowly, whereas CMV-specific T-cells were detected five months later and increased thereafter. At last follow-up, the patient was in very good clinical condition with no evidence of bronchiolitis obliterans. No side effects of this treatment were observed. In this hard-to-treat case, the combination of cidofovir with off-label use of CMVIG contributed to a successful outcome.

Desensitization With Plasmapheresis and Anti-Cd20 for ABO Incompatible Kidney Transplantation From Living Donor: Experience of a Single Center in Italy

ObjectiveBlood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP. Patients and MethodsFrom July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP + cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline® (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant. ResultsAfter a mean follow-up of 11.6 ± 10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48 ± 0.29, 1.47 ± 0.18, 1.47 ± 0.27, and 1.5 ± 0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection. ConclusionsDesensitization with rituximab, PP, and anti–cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.

Efficacy of Valganciclovir Plus Cytomegalovirus Immune Globulin for Prevention of Cytomegalovirus Disease in High-Risk Renal Transplant Recipients

Efficacy of Valganciclovir Plus Cytomegalovirus Immune Globulin for Prevention of Cytomegalovirus Disease in High-Risk Renal Transplant Recipients

Characteristics and Cost of Treatment of Acute Rejection within 1 Year after Pediatric Heart Transplant: A Multi-Institutional Study

Purpose To characterize and trend in-hospital therapy, outcomes and cost of children admitted with acute rejection within 1y after heart transplantation (TX) over the last 10 y. Methods and Materials Retrospective study of PHIS database(national database with inpatient data from 43 not-for-profit, tertiary-care pediatric hospitals in the USA) from 2002-2010. Inclusion criteria: ICD-9 code for heart TX, and readmission with a code for acute rejection within 1y of heart TX. Results 478 patients (57% male) were readmitted for acute rejection a median of 51d (IQR 12-162d) after TX. Median age was 7y (IQR 1.6-13.5y) 69% were Caucasian. Median length of stay was 4d (IQR 3-9d) and overall mortality was 5%. 31% were admitted to the intensive-care unit and 16% were mechanically ventilated. ECMO was used in 4% and 0.6% received a VAD. Patients received: calcineurin inhibitors (98%), corticosteroids (93%), mycophenolate (70%), azathioprine (21%), immune globulins (21%), monoclonal antibodies (10%), cytomegalovirus immune globulin (8%), and methotrexate (0.6%). Time to readmit went from 29.5 d (13-136) in 2002 to 121d (28-258) in 2012 (p figure1 ] Conclusions The cost of treatment and in-hospital mortality of acute humoral or cellular rejection in children has increased over time. Time to readmission has increased, potentially signifying changes in early management.

Treatment Update of Sensitized Pediatric Kidney Transplant Recipients: A Review

Sensitization of recipients is an increasing problem in children. Some case series in children exist comparing the diverse desensitizing protocols. These protocols include intravenous immunoglobulin, cytomegalovirus immune globulin, plasmapheresis, and some adjunctive therapies such as rituximab. Desensitizing protocols have advantages and disadvantages. Clinical trials are required to determine suitable protocols for sensitized pediatric recipients. We performed a systematic review of these protocols in children. A massive search was done in PubMed, Embase, and the Cochrane library system. The results of these studies are compared.

The association between cytomegalovirus immune globulin and long‐term recipient and graft survival following liver transplantation

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and long-term clinical outcomes has not been well defined. We examined the association between CMVIG and long-term recipient and graft survival in liver transplant recipients. Data were from the Scientific Registry of Transplant Recipients and included recipients transplanted between January 1995 and October 2008; follow-up was through March 2009. All recipients≤80 years of age with primary, single-organ liver transplants, given CMVIG with (n=2350) or without antivirals (n=455), antivirals without CMVIG (n = 32,939), or no CMV prophylaxis (n=28,508) before discharge were included. Kaplan-Meier analysis was used to examine rates of acute rejection (AR), graft loss, and death, over 7 years post transplantation. The adjusted risk of AR, graft loss, and death associated with CMVIG with and without antivirals vs. no prophylaxis was estimated using the Cox proportional hazards regression. In the univariate analysis, CMVIG, with and without antivirals, was associated with increased AR rates, but decreased mortality; CMVIG with antivirals was also associated with decreased graft loss compared with no prophylaxis. From the multivariable model, CMVIG with antivirals was associated with increased risk for AR, but decreased risk for graft loss and death; after adjustment, the association between CMVIG alone and mortality was not significant. CMVIG with antivirals is associated with increased risk of AR but greater long-term patient and graft survival after liver transplantation.

Successful ABO Incompatible Kidney Transplant After an Isolated Intestinal Transplant

To our knowledge, we herein report the first case in the literature of a living unrelated ABO incompatible (ABOi) renal transplantation after successful isolated small bowel and colon transplantation. This case illustrates several interesting immunologic findings. The patient is a 50-year-old woman with a history of hypertension and cholecystectomy who suffered with complicated endometriosis, which lead to multiple intestinal resections for recurrent obstruction and enterocutaneous fistulae. These ultimately led to short gut syndrome and total parenteral nutrition dependence for 5 years. The patient underwent an ABO identical isolated intestinal transplant (small bowel and right colon) with systemic venous drainage and basiliximab and steroid induction. Posttransplant maintenance included tacrolimus, sirolimus, and prednisone. No rejection was encountered, parenteral nutrition was discontinued, and her ileostomy was reversed 18 months later. Because of poor wound healing and wound infection, sirolimus was discontinued thereafter. One year after small bowel transplantation, the patient experienced progressive renal insufficiency presumed because of tacrolimus toxicity. Despite diuretic therapy, volume management ultimately led to hemodialysis 16 months after transplant. Her only potential live kidney donor was ABOi; the patient was blood group O; and her donor was blood group A. She subsequently underwent an ABOi renal transplant 24 months after her intestinal transplant. The desensitization protocol consisted of pretransplant and posttransplant tacrolimus and mycophenolate mofetil with four preoperative and two postoperative rounds of plasmapheresis and intravenous cytomegalovirus immune globulin. Induction therapy also included 1.5 mg/kg rabbit antithymocyte globulin intraoperatively and on the first 4 postoperative days along with methylprednisolone. Her baseline anti-A antibody titer was 1:64. After plasmapheresis, it decreased to 1:8 below the threshold of 1:32, necessary for successful ABOi renal transplantation (1). It is now 46 months after intestinal transplant and 26 months after her kidney transplant. She continues on a low fat diet with no nutritional support. In addition, she has a good kidney function and a serum creatinine level of 1.8. She is maintained on tacrolimus, mycophenolate mofetil, and prednisone for immunosuppression. The patient has had no evidence of rejection of graft or opportunistic infection. DISCUSSION Intestinal transplantation has improved in the past decade, achieving 1-year patient and graft survival rates in excess of 90% at several centers (2). It has been associated with a 30% to 40% risk of rejection in the first 3 months (3). Ojo et al. (4) report rates of renal failure as high as 21.3% in recipients of intestinal transplants, likely related to aggressive immunosuppression protocols. In this case, we successfully performed an isolated intestinal transplant with an excellent functional outcome using an aggressive immunosuppressive protocol including rabbit antithymocyte globulin induction and maintenance tacrolimus, sirolimus, and prednisone. Eventually the patient developed chronic renal failure, and we followed up this with an ABOi living donor kidney transplant. Despite the exposure to a second set of non-self-human leukocyte antigens and crossing the ABO barrier, there was no episode of rejection of either allograft. We hypothesize that her previous immunosuppression and our desensitization protocol would decrease the likelihood of such an occurrence. At our center, we use sirolimus as a part of our strategy for maintenance immunosuppression for intestinal transplantation, because this has been shown to be of benefit in combating acute rejection (5). She did not have evidence of rejection but did develop a wound infection and poor wound healing necessitating discontinuation of sirolimus. After 1 year, the patient ultimately developed progressive chronic renal failure and required hemodialysis. We believed that this occurred because of tacrolimus toxicity and recurrent dehydration because of high ileostomy output. At her kidney transplantation evaluation, we considered both deceased donor and living donor; ABOi or entering her into a paired kidney donor exchange. Because of a long expected wait time for a deceased donor organ, we opted for a living donor. Her only living donor was ABOi. The patient had no donor-specific antibody and a low ABOi titer to her donor. Such a donor recipient phenotype (O recipient and A donor) have less than 20% chance of a match in a paired kidney donation pool with long projected waiting times (6). Thus, we believed that an ABOi transplant was achievable in a short period of time with less morbidity on hemodialysis. The current shortage of deceased donor kidneys necessitate the use of all strategies to increase the donor pool for patients with end-stage renal disease. This case demonstrates the effective use of ABOi kidney transplantation for end-stage renal disease after intestinal transplantation with the absence of both rejection and opportunistic infection. Lee S. Cummings1 Jason S. Hawksworth1 Juan-Francisco Guerra1 Chirag S. Desai2 Raffaele Girlanda1 Cal S. Matsumoto1 Thomas M. Fishbein1 Lynt B. Johnson3 Joseph K. Melancon1 1Division of Transplantation and Hepatobiliary Surgery Georgetown University Hospital WA 2University of Arizona College of Medicine Tucson, AZ 3Department of Surgery Georgetown University Hospital WA

Cytomegalovirus Prevention and Long-Term Recipient and Graft Survival in Pediatric Heart Transplant Recipients

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and clinical outcomes in pediatric heart transplantation has not been evaluated. Long-term recipient and graft survival were compared between pediatric heart recipients who received CMV prophylaxis with CMVIG (with or without antivirals), antivirals without CMVIG, and no prophylaxis. CMVIG (with or without antivirals) versus no prophylaxis was also assessed in the CMV-positive donor/CMV-negative recipient cohort. Data from the Scientific Registry of Transplant Recipients included patients with a transplant date between January 1995 and October 2008; follow-up data were through March 2009. All pediatric (younger than 18 years) recipients of primary, single-organ heart transplants were included. Kaplan-Meier analysis was used to examine rates of recipient death and graft loss at 7 years posttransplantation. Cox proportional hazards regression was used to estimate adjusted risk for graft loss and death. CMVIG (with or without antivirals) and antivirals without CMVIG were both associated with significantly (P≤0.05) lower rates of graft loss and death versus no prophylaxis. After adjustment, CMVIG was associated with a significantly decreased adjusted risk for graft loss and a borderline (P=0.09) decreased adjusted mortality risk; antiviral prophylaxis was associated with decreased adjusted risk for graft loss and mortality. In the CMV-positive donor/CMV-negative recipient cohort, CMVIG (with or without antivirals) was associated with decreased adjusted risk for graft loss and death. CMV prophylaxis with CMVIG or antivirals seems to offer long-term clinical outcome benefits. Determination of optimal regimen, dosage, and duration remains to be examined.

Invited Commentary: Human Cytomegalovirus, Inflammation, Cardiovascular Disease, and Mortality

Human cytomegalovirus (CMV) is a human herpesvirus, and infection is widespread in the human population. Prevalence of seropositivity for human CMV increases with age. CMV establishes persistent infection in vascular arterial and venous endothelial tissue. It has been associated with atherosclerosis and graft rejection in heart transplant recipients. The antiviral drug ganciclovir prevents CMV disease in heart transplant patients, and valganciclovir and CMV immune globulin reduce rejection rates and cardiovascular disease. Human CMV infection has been associated with proinflammatory cytokine increases and nonresponsiveness to antiinfluenza vaccine in the elderly. Enhanced expression of proinflammatory cytokines has also been associated with enhanced mortality in the elderly. In this issue of the Journal, Roberts et al. (Am J Epidemiol. 2010;000(00):000-000) report that, in a large population-based cohort of elderly Sacramento area Latino subjects in California followed from 1998 to 2008, more than 95% were seropositive for human CMV. In that study, Kaplan-Meier survival curves suggested worse cardiovascular disease survival for individuals in the highest quartile of human CMV immunoglobulin G antibody titers over 9 years of follow-up. Theirs is the first study known to report a relation between high human CMV antibody levels and mortality.

144: The Association between Cytomegalovirus Immune Globulin (CMVIG) Use and Long-Term Recipient and Graft Survival in Pediatric and Adult Heart Transplantation Recipients

144: The Association between Cytomegalovirus Immune Globulin (CMVIG) Use and Long-Term Recipient and Graft Survival in Pediatric and Adult Heart Transplantation Recipients