Incidence and antiviral treatment of cytomegalovirus infection in infants with biliary atresia.

PURPOSE: Patients with biliary atresia (BA) and cytomegalovirus (CMV) infection may have poorer outcomes after Kasai portoenterostomy (KPE) than uninfected patients, suggesting a rationale for antiviral treatment (AVT). We aimed to describe the incidence of CMV infection and of AVT in BA patients, and to detect any differences between infected and uninfected patients to conclude if AVT is of use. METHODS: Data on BA patients who underwent KPE 2004-2020 were retrospectively collected, and the outcome was analyzed with regard to CMV status. RESULTS: Fifteen out of forty-six (33%) BA patients had signs of ongoing CMV infection. They did not differ significantly from the CMV-negative patients regarding rate of prematurity, birth weight, or biochemical markers but were slightly older at KPE. All patients received steroids postoperatively and all patients with ongoing CMV infection received AVT with very good effect on viremia and without major side effects. The AVT consisted of oral valganciclovir (10-40 (- 58) mg/kg/d) or intravenous ganciclovir (5.3-11 mg/kg/d). CONCLUSION: Ongoing CMV infection is common in this group of patients. The viremia can effectively be treated with AVT without any major side effects. Larger, randomized studies are needed to clarify the possible effect on clinical outcome.

The use of organs from hepatitis C virus-viremic donors into uninfected recipients.

PURPOSE OF REVIEW: There has been an ongoing disparity between the number of organs available for solid organ transplantation (SOT) relative to the need. This has resulted in significant waitlist mortality, may affect transplant outcomes due to transplants being performed on sicker patients and may even increase healthcare costs due to extended hospital stays. Transplanting organs from hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-) is now a reality, due to the advent of highly affective direct-acting antivirals (DAAs) which not only have very high efficacy, but also a favorable side effect and drug-drug interaction profile. RECENT FINDINGS: Data from multiple centers reporting outcomes of kidney, liver, heart, lung and liver-kidney transplant during the past few years reveal that SOT from HCV-infected donors into noninfected recipients is safe, efficacious and can result in excellent recipient outcomes, with an opportunity to decrease the time on the waitlist, waitlist mortality and to improve outcomes after transplant due to less morbidity at the time of surgery. When livers are the transplanted organ, 8-12 weeks of DAA treatment will be required. For other organs, 2-4 weeks is likely sufficient. The available DAAs have profiles such that patients with all genotypes, with or without renal insufficiency an on renal replacement therapy and those who fail treatment may be successfully treated, with a sustained virologic response rate of more than 95%. Based upon the available data, starting DAAs shortly after transplant will likely limit posttransplant complications. that This will require cooperation between the transplant team, transplant hospital and insurer providing medication coverage. SUMMARY: SOT from HCV infected recipients is safe, is associated with excellent outcomes and should be considered for recipients who would benefit from receiving an organ earlier than they would if they waited for an organ from an uninfected donor.

Heart Transplantation for Hepatitis C Virus Non-Viremic Recipients From Hepatitis C Virus Viremic Donors.

Multiple strategies have been implemented to increase the donor pool to avoid transplant wait-list mortality. The approval of highly effective direct-acting antiviral regimens for the treatment of hepatitis C virus (HCV) has enabled expansion of the donor pool by allowing the transplantation of organs from HCV-viremic donors to HCV-negative recipients. Multiple centers have recently published data on outcomes of heart transplantation from HCV-viremic heart donors to HCV-negative recipients, with acceptable posttransplant outcomes. However, areas of uncertainty remain, particularly in the long-term risks of intentional HCV transmission, as well as the possibility that sustained virologic response may not be achieved. In this article, we review the literature illustrating both the risks and benefits of transplantation of organs from HCV-viremic donors to HCV-negative recipients. We also present the data collected at our institution regarding this special patient population.

Increasing Utilization and Excellent Initial Outcomes Following Liver Transplant of Hepatitis C Virus (HCV)-Viremic Donors Into HCV-Negative Recipients: Outcomes Following Liver Transplant of HCV-Viremic Donors.

Direct-acting antiviral (DAA) therapy has altered the frequency and outcome of liver transplantation (LT) for hepatitis C virus (HCV). The high efficacy and tolerability of DAA therapy has also created a rationale for utilizing HCV-viremic (HCV-RNA-positive) donors, including into HCV-negative recipients. We examined trends in frequency of organ utilization and graft survival in recipients of HCV-viremic donors (HCV-RNA positive as measured by nucleic acid testing [NAT]). Data were collected from the Scientific Registry of Transplant Recipients (SRTR) on adult patients who underwent a primary, single-organ, deceased donor LT from January 1, 2008 to January 31, 2018. Outcomes of HCV-negative transplant recipients (R- ) who received an allograft from donors who were HCV-RNA positive (DNAT+ ) were compared to outcomes for R- patients who received organs from donors who were HCV-RNA negative (DNAT- ). There were 11,270 DNAT- /R- ; 4,748 DNAT- /R+ ; 87 DNAT+ /R- ; and 753 DNAT+ /R+ patients, with 2-year graft survival similar across all groups: DNAT- /R- 88%; DNAT- /R+ 88%; DNAT+ /R- 86%; and DNAT+ /R+ 90%. Additionally, there were 2,635 LTs using HCV antibody-positive donors (DAb+ ): 2,378 DAb+ /R+ and 257 DAb+ /R- . The annual number of DAb+ /R- transplants increased from seven in 2008 to 107 in 2017. In the post-DAA era, graft survival improved for all recipients, with 3-year survival of DAb+ /R- patients and DAb+ /R+ patients increasing to 88% from 79% and to 85% from 78%, respectively. Conclusion: The post-DAA era has seen increased utilization of HCV-viremic donor livers, including HCV-viremic livers into HCV-negative recipients. Early graft outcomes are similar to those of HCV-negative recipients. These results support utilization of HCV-viremic organs in selected recipients both with and without HCV infection.

Epstein-Barr virus and renal transplantation.

Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease.

fMRI evaluation of cochlear implant candidacy in diffuse cortical cytomegalovirus disease.

Congenital cytomegalovirus infection is the most frequent nongenetic cause of pediatric hearing loss in the United States, affecting approximately 8,000 children each year. Due in part to variable cytomegalic involvement of the auditory cortex, cochlear implantation outcomes have varied widely. Functional magnetic resonance imaging (fMRI) has the potential to assist in determining candidacy for cochlear implantation through the detection of intact auditory pathways including the cortex. We report a case of a 21-month-old girl with cytomegalovirus-related deafness and diffuse white matter involvement in which fMRI was a determining factor for cochlear implantation and side selection.

BK viremia in critically ill surgical patients with hemorrhagic or septic shock.

BACKGROUND: Infections with polyomavirus BK virus (BKV) are a common cause of renal dysfunction after renal transplantation and may also be harmful in surgical patients with shock. The aim of the present study was to determine the frequency of BKV viremia in critically ill surgical patients with septic or hemorrhagic shock, and, if viremia is detectable, whether viremia may be associated with renal dysfunction. FINDINGS: A total of 125 plasma samples from 44 critically ill surgical patients with septic or hemorrhagic shock were tested by real-time polymerase chain reaction (PCR) for BKV DNA during their stay on the intensive care unit (ICU). BKV viremia occurred in four patients, i.e. in three of the septic and in one of the hemorrhagic shock group. There was no association between viremia and renal dysfunction. All positive samples contained a low viral load (< 500 copies/ml). CONCLUSIONS: Since BK viremia was rarely found and with low viral load only in critically ill surgical patients with shock, it is very unlikely that BK viremia results in BK nephropathy later on.

Unrelated bone marrow transplantation induced long-term remission in a patient with life-threatening Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

We present a case of life-threatening Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) with severe hepatitis that was successfully treated by allogeneic stem cell transplantation from an unrelated donor. A 26-year-old woman was admitted to hospital with a high fever and liver dysfunction. Laboratory tests, including bone marrow aspiration, revealed severe HLH that occurred after EBV infection. High-dose methylprednisolone and etoposide therapy did not control the disease. We could control the HLH, but the EBV viremia continued following the CHOPE (cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide) chemotherapy regimen. Therefore, the patient underwent allogeneic bone marrow transplantation from an HLA-matched, unrelated donor. The patient has remained in good condition without disease recurrence for 2 years after bone marrow transplantation. Although there is no consensus regarding allogeneic stem cell transplantation for EBV-HLH, it is the treatment of choice for aggressive EBV-HLH when the patient is refractory to intensive chemotherapy.

Rising antigenemia levels may be misleading in pre-emptive therapy of human cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients.

BACKGROUND AND OBJECTIVES: Hematopoietic stem cell transplant (HSCT) recipients after show rising levels of antigenemia during pre-emptive ganciclovir treatment of human cytomegalovirus (HCMV) infection. This raises some doubts about the therapeutic decisions to be taken. DESIGN AND METHODS: Three groups of HSCT recipients with HCMV infection undergoing anti-viral treatment were identified: group A, showing increasing antigenemia and decreasing viremia and DNAemia; group B, with simultaneous increases in antigenemia, viremia, and DNAemia; and group C, with decreasing levels of all 3 viral markers. Viral load, determined as levels of antigenemia, viremia and DNAemia, was monitored for 3 months post-transplantation in all groups. RESULTS: Group A HSCT recipients showed antigenemia peaks 2-11 days after the onset of treatment, reaching negative levels only 25-30 days thereafter, whereas viremia and DNAemia started to drop earlier. Group B patients, mainly including HSCT recipients with grade II-IV acute GvHD treated with steroids prior to and during antiviral treatment, showed increasing levels of all three viral parameters until 5-10 days after the start of treatment; the levels dropped to negative values 25-30 days thereafter. Group C patients, who acted as controls, progressively cleared virus from blood as an early result of antiviral therapy. INTERPRETATION AND CONCLUSIONS: Antigenemia is not the best assay to guide pre-emptive therapy. Group A patients, who have an isolated increase of antigenemia, do not require a change of the ongoing antiviral therapy. Whether better control of infection could be obtained in group B patients by either reducing immunosuppressive therapy (when possible) or adopting combination therapy remains to be determined.

Quantification of hepatitis C virus-infected peripheral blood mononuclear cells by in situ reverse transcriptase-polymerase chain reaction.

Hepatitis C virus (HCV) is known to infect peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis C, but the proportion of HCV-infected circulating cells is not detectable by conventional reverse transcriptase-polymerase chain reaction (RT-PCR) and the pathogenic significance of HCV lymphotropism is still unclear. Therefore, we have devised an in situ RT-PCR technique using fluorescein-labeled HCV-specific primers revealed by flow cytometry. PBMC were isolated from 28 patients with chronic HCV-related liver disease; of these, 6 had previously received an orthotopic liver transplantation (OLT) and were on immuno-suppressive treatment. Fourteen patients (50%) were found positive for HCV genome within PBMC by in situ RT-PCR, the proportion of HCV-infected cells ranging from 0.2% to 8.1%. All 6 OLT patients tested positive. The fluorescent signal, corresponding to the HCV-specific 340-bp amplicon, was confined to part of the cytoplasmic compartment of scattered PBMC. Of these 14 patients, 12 had also negativestrand HCV RNA within PBMC detected by "tagged" RT-PCR. We conclude that HCV may infect a significant proportion of PBMC in chronic hepatitis C patients, especially immunosuppressed OLT cases, and that viral replication within PBMC is a common occurrence. Over time, the persistence of HCV-infected immune system cells might interfere with normal immunologic mechanisms and play a role in the pathogenic processes leading to extrahepatic disorders such as mixed cryoglobulinemia and B-cell malignant lymphoma.