Peripheral Blood Epstein–Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk

Several viruses, such as Epstein–Barr virus, are now known to be associated with several human cancers, but not all patients with these viral infections develop cancer. In transplantation, such viruses often have a prolonged time gap from infection to cancer development, and many are preceded by a period of circulating and detectable nucleic acids in the peripheral blood compartment. The interpretation of a viral load as a measure of posttransplant risk of developing cancer depends on the virus, the cancer and associated pathogenic factors. This review describes the current state of knowledge regarding the utility and limitations of peripheral blood nucleic acid testing for Epstein–Barr virus in surveillance and risk prediction for posttransplant lymphoproliferative disorders.     

Transplant Infectious Diseases: A Review of the Scientific Registry of Transplant Recipients Published Data

The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection‐related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein‐Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti‐HBV core antibody–positive donor organs and stable reporting of HCV‐positive donor organs and HIV‐positive recipients.     

Preventive Strategies Against Cytomegalovirus and Incidence of α‐Herpesvirus Infections in Solid Organ Transplant Recipients: A Nationwide Cohort Study

We assessed the impact of antiviral preventive strategies on the incidence of herpes simplex virus (HSV) and varicella‐zoster virus (VZV) infections in a nationwide cohort of transplant recipients. Risk factors for the development of HSV or VZV infection were assessed by Cox proportional hazards regression. We included 2781 patients (56% kidney, 20% liver, 10% lung, 7.3% heart, 6.7% others). Overall, 1264 (45%) patients received antiviral prophylaxis (ganciclovir or valganciclovir, n = 1145; acyclovir or valacyclovir, n = 138). Incidence of HSV and VZV infections was 28.9 and 12.1 cases, respectively, per 1000 person‐years. Incidence of HSV and VZV infections at 1 year after transplant was 4.6% (95% confidence interval [CI] 3.5–5.8) in patients receiving antiviral prophylaxis versus 12.3% (95% CI 10.7–14) in patients without prophylaxis; this was observed particularly for HSV infections (3% [95% CI 2.2–4] versus 9.8% [95% CI 8.4–11.4], respectively). A lower rate of HSV and VZV infections was also seen in donor or recipient cytomegalovirus‐positive patients receiving ganciclovir or valganciclovir prophylaxis compared with a preemptive approach. Female sex (hazard ratio [HR] 1.663, p = 0.001), HSV seropositivity (HR 5.198, p < 0.001), previous episodes of rejection (HR 1.95, p = 0.004), and use of a preemptive approach (HR 2.841, p = 0.017) were significantly associated with a higher risk of HSV infection. Although HSV and VZV infections were common after transplantation, antiviral prophylaxis significantly reduced symptomatic HSV infections.     

The Impact of EBV Status on Characteristics and Outcomes of Posttransplantation Lymphoproliferative Disorder

We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV‐negative; 118 [67%] EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.     

Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus–Associated Membranoproliferative Glomerulonephritis

Recurrence of hepatitis C virus (HCV)–associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct‐acting antiviral agents (DAAs) allow a highly effective and interferon‐free treatment option for chronic HCV‐infected patients. Data on the therapeutic safety and efficacy in HCV‐infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63‐year‐old female HCV‐positive renal transplant patient with biopsy‐proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti‐HCV–directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy‐associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis‐dependent renal transplant failure after treatment of recurrent HCV‐associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.     

Dual blockade of the PI3K/Akt/mTOR pathway inhibits posttransplant Epstein‐Barr virus B cell lymphomas and promotes allograft survival

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation that often manifests as Epstein‐Barr virus (EBV)‐associated B cell lymphomas. Current treatments for PTLD have limited efficacy and can be associated with graft rejection or systemic toxicities. The mTOR inhibitor, rapamycin, suppresses tumor growth of EBV+ B cell lymphoma cells in vitro and in vivo; however, the efficacy is limited and clinical benefits of mTOR inhibitors for PTLD are variable. Here, we show constitutive activation of multiple nodes within the PI3K/Akt/mTOR pathway in EBV+ PTLD‐derived cell lines. Inhibition of either PI3K or Akt, with specific inhibitors CAL‐101 and MK‐2206, respectively, diminished growth of EBV+ B cell lines from PTLD patients in a dose‐dependent manner. Importantly, rapamycin combined with CAL‐101 or MK‐2206 had a synergistic effect in suppressing cell growth as determined by IC₅₀ isobolographic analysis and Loewe indices. Moreover, these combinations were significantly more effective than rapamycin alone in inhibiting tumor xenograft growth in NOD‐SCID mice. Finally, both CAL‐101 and MK‐2206 also prolonged survival of heterotopic cardiac allografts in C57BL/6 mice. Thus, combination therapy with rapamycin and a PI3K inhibitor, or an Akt inhibitor, can be an efficacious treatment for EBV‐associated PTLD, while simultaneously promoting allograft survival.     

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital‐based registry, we identified biopsy‐proven cases of PTLD among children during a 15‐year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow‐up after the diagnosis of PTLD. We studied 82 patients with first‐episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2‐12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan‐Meier survival curves showed that T/A PTLD was associated with decreased all‐cause mortality compared with PTLD at other sites (log‐rank 0.004), even after adjustment for histological subtype (P = .047). PTLD‐related mortality was also decreased among T/A PTLD (log‐rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.     

Solid Organ Transplantation From Hepatitis B Virus–Positive Donors: Consensus Guidelines for Recipient Management

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.     

An Interventional Study Using Cell‐Mediated Immunity to Personalize Therapy for Cytomegalovirus Infection After Transplantation

Cell‐mediated immune responses predict clinical cytomegalovirus (CMV) events but have not been adopted into routine practice due to lack of interventional studies. Our objective was to demonstrate the safety and feasibility of early discontinuation of antivirals based on the real‐time measurement of CMV‐specific cell‐mediated immunity (CMI) in patients with CMV viremia. Transplant patients were enrolled at the onset of CMV viremia requiring antiviral therapy. CD8 T cell responses were determined using the Quantiferon‐CMV assay, and results were used to guide subsequent management. A total of 27 patients (median viral load at onset 10 900 International Units/mL) were treated until viral load negative. At end of treatment, 14/27 (51.9%) had a positive CMV‐CMI response and had antivirals discontinued. The remaining 13/27 (48.1%) patients had a negative CMV‐CMI response and received 2 months of secondary antiviral prophylaxis. In those with a positive CMI and early discontinuation of antivirals, only a single patient experienced a low‐level asymptomatic recurrence. In contrast, recurrence was observed in 69.2% of CMI‐negative patients despite more prolonged antivirals (p = 0.001). In conclusion, this is the first study to demonstrate the feasibility and safety of real‐time CMV‐specific CMI assessment to guide changes to the management of CMV infection.     

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases

We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44‐year‐old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high‐dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58‐year‐old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein–Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.     

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199–1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751–6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077–0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.     

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV‐associated posttransplant lymphoproliferative disorder and worse survival

Epstein‐Barr virus (EBV)–associated posttransplant lymphoproliferative disorder (EBV‐PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single‐center retrospective study to evaluate the risks for PTLD in LTRs over a 7‐year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan‐Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)‐LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33‐8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10‐6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57‐76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan‐Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.     

Combination Drug Products for HIV—A Word of Caution for the Transplant Clinician

Modern‐day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed‐dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV‐infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction–induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat‐containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV‐positive transplant recipients and their providers.