Impact of cytomegalovirus infection on biliary disease after liver transplantation-maybe an essential factor

BACKGROUND Cytomegalovirus(CMV)infection is common in liver transplant(LT)_recipients,and biliary complications occur in a large number of patients.It has been reported that CMV-DNA is more detectable in bile than in blood.AIM To investigate the effects of CMV infection on biliary complications by comparing the levels of CMV-DNA in the bile and blood of patients after LT.METHODS We conducted a retrospective analysis of 57 patients who underwent LT,10 of these patients had no biliary complications and 47 patients had biliary complications.We also compared the levels of CMV-DNA in patients’bile and blood,which were sampled concurrently.We used RNAscope technology to identify CMV in paraffin-embedded liver sections.RESULTS CMV-DNA was not detected in bile samples and was detected in 2 blood samples from patients without biliary complications.In the 47 patients with biliary complications,CMV-DNA was detected in 22 bile samples and 8 blood samples,both bile and blood samples were positive for CMV-DNA in 6 patients.The identification rate of CMV-DNA in blood was 17.0%,and was 46.8%in bile.Moreover,tissue samples from 4 patients with biliary complications tested positive using RNAscope technology but were negative with hematoxylin and eosin staining.During the follow-up period,graft failure occurred in 13 patients with biliary complications,8 of whom underwent retransplantation,and 3 died.CMV-DNA in bile was detected in 9 of 13 patients with graft failure.CONCLUSION In patients with biliary complications,the identification rate of CMV-DNA in bile was higher than that in blood.Blood CMV-DNA negative patients with biliary complications should still be monitored for CMV-related biliary tract diseases.Potential occult CMV infection may also be a contributing etiological factor in the development of graft failure.

Impact of cytomegalovirus reactivation just before liver transplantation:A prospective cohort study

BACKGROUND Cytomegalovirus(CMV)is the most common viral pathogen after liver transplantation(LT).Although reactivation of CMV infection is generally described in the context of immunosuppression,it has also been described in critically ill immunocompetent patients including cirrhotic patients.AIM To determine the incidence of reactivated CMV prior to LT.METHODS This was a prospective cohort study evaluating adult patients who underwent LT between 2014 and 2016.A plasma sample was obtained from all patients for CMV quantitative real-time PCR testing right before transplantation.Patients were followed for at least 1 year to assess the following outcomes:Incidence of CMV infection,organ rejection and overall mortality.RESULTS A total of 72 patients were enrolled.Four patients died before transplantation,thus 68 patients were followed up for a median of 44 mo(20-50 mo).In 23/72 patients(31.9%)CMV was reactivated before transplantation.Post-transplantation,16/68(23.5%)patients had CMV infection and that was significantly associated with the recipient being CMV negative and a CMV-positive donor.Pretransplant CMV reactivation was not associated with overall mortality(log rank:0.9).CONCLUSION This study shows that CMV infection is common in patients with chronic liver disease just before LT,but the clinical impact of this infection seems to be negligible.

An Evaluation of the Benefit of Cytomegalovirus Prophylaxis with Acyclovir on Post-Transplant Cytomegalovirus Infection Prevention in a Population of Renal Transplant Recipients in Nigeria

Background: Cytomegalovirus (CMV) is an important infection in renal transplant recipients and may significantly impact recipients’ long-term outcome and graft survival. Objective: This study aimed to evaluate the benefit of prophylaxis with acyclovir on post-transplant CMV infection prevention in a population of renal transplant recipients in Lagos, Nigeria. Subjects and Methods: The study was a cross-sectional design involving renal transplant recipients attending post-transplant follow-up clinics in Lagos, Nigeria between October 2004 and July 2005. Data on the use of CMV prophylaxis were obtained from the hospital case records of the study subjects. Enzyme-Linked Immunosorbent Assay (ELISA) was employed to detect CMV IgM antibodies for the diagnosis of post-transplant CMV infection and Microsoft Excel and EPI-Info 2002 statistical software were used for data entry and analysis. Results: Forty (40) renal transplant recipients were studied, 32 recipients were males and 8 were females with M:F ratio of 4:1. The mean age of the recipients was 39 ± 11.6 years old. The recipients’ post-transplant duration ranged from 2 to 80 months (Mean 17.6 ± 18.6 months). Fifteen (37.5%) of the transplant recipients received acyclovir prophylaxis for six months, one recipient (2.5%) received ganciclovir prophylaxis for three weeks while 24 recipients (60%) received no prophylactic therapy. There was no significant difference in the prevalence of seropositive CMV-IgM between transplant recipients who used CMV prophylaxis and those who did not (Fisher exact p = 0.45). Conclusion: Prophylaxis with acyclovir for six months showed no significant benefit on post-transplant CMV infection prevention in renal transplant recipients.

Awareness of Cytomegalovirus Infection among a Population of Nigerian Kidney Transplant Recipients

Background: Cytomegalovirus (CMV) is the most important infection in kidney transplant recipients and has significant impact on long term recipient and graft survival. Objective: The aim of this study is to assess the level of awareness of CMV infection among a population of kidney transplant recipients in Lagos, Nigeria. Subjects and Methods: The assessment of the level of awareness of CMV infection among kidney transplant recipients attending post-transplant follow-up clinics in Lagos, Nigeria was done by means of a structured pre-tested self-administered questionnaire from October 2004 to July 2005. Results: A total of 40 kidney transplant recipients were studied. Thirty-two recipients were males and eight were females with M:F ratio of 4:1. The mean age of the recipients was 39 ± 11.6 years old. The recipients’ post-transplant duration ranged from 2 to 80 months (Mean 17.6 ± 18.6 months). Only four (10%) of kidney transplant recipients studied had ever heard of CMV infection and only one recipient (2.5%) was aware that CMV infection could affect a transplanted kidney, and that CMV infection could be transmitted from the donor kidney graft to the recipient. One recipient (2.5%) was aware that blood transfusion could be a mode of transmission of CMV infection. None of the recipients was aware that CMV infection could be sexually transmitted. All the four recipients who were aware of CMV infection obtained the information from their doctors. Conclusion: Despite its significant impact on kidney transplant recipient and graft survival, the level of awareness of CMV infection and its relevance to kidney transplantation was very low among kidney transplant recipients. Transplant units in the study environment should include information and education about CMV infection and its impact on the transplant recipient and graft survival in their counseling programme for transplant recipients.

Invasive aspergillosis in liver transplant recipients, an infectious complication with low incidence but significant mortality

BACKGROUND Infections,including invasive fungal infections(IFIs),are among the leading causes of mortality in liver transplant recipients during the first year posttransplantation.AIM To investigate the epidemiology,clinical manifestations,risk factors,treatment outcomes,and mortality rate of post-liver transplantation invasive aspergillosis(IA).METHODS In this case-control study,22 patients with IA were identified by reviewing the archived and electronic medical records of 850 patients who received liver transplants at the Imam Khomeini Hospital complex in Tehran,Iran,between 2014 and 2019.The control group comprised 38 patients without IA infection matched for age and sex.The information obtained included the baseline characteristics of liver transplant patients,operative reports,post-transplantation characteristics of both groups and information about the fungal infection of the patient group.RESULTS The prevalence rate of IA among liver transplant recipients at Imam Khomeini Hospital was 2.7%.The risk factors of IA among studied patients included high serum creatinine levels before and post-transplant,renal replacement therapy,antithymocyte globulin induction therapy,post-transplant bile leakage,posttransplant hepatic artery thrombosis,repeated surgery within 30 d after the transplant,bacterial pneumonia before the aspergillosis diagnosis,receiving systemic antibiotics before the aspergillus infection,cytomegalovirus infection,and duration of post-transplant hospitalization in the intensive care unit.The most prevalent form of infection was invasive pulmonary aspergillosis,and the most common chest computed tomography scan findings were nodules,pleural effusion,and the halo sign.In the case group,prophylactic antifungal therapy was administered more frequently than in the control group.The antifungal therapy response rate at 12 wk was 63.7%.The 3-and 12-mo mortality rates of the patients with IA were 36.4%and 45.4%,respectively(compared with the mortality rate of the control group in 12 mo,which was zero).CONCLUSION In this study,the prevalence of IA among liver transplant recipients was relatively low.However,it was one of the leading causes of mortality following liver transplantation.Targeted antifungal therapy may be a factor in the low incidence of infections at our facility.Identifying the risk factors of IFIs,maintaining an elevated level of clinical suspicion,and initiating early antifungal treatment may significantly improve the prognosis and reduce the mortality rate of liver transplant recipients.

Valganciclovir for pre-emptive therapy of cytomegalovirus viraemia after hematopoietic stem cell transplantation： a prospective multi-center trial

Background Despite its widespread use in the management of HIV-related cytomegalovirus （CMV） infection, there have been surprisingly few reports of the use of valganciclovir （VGC） in the post-allotransplant setting.So far, no multi-center, non-crossover trial data have been available with the use of this drug as the primary pre-emptive.The present study evaluated the efficacy and safety of VGC for preemptive therapy of CMV infection after allogeneic hematopoietic stem cell transplantation （HSCT）.Methods From January to April 2007, VGC was adopted in eleven centers in China's Mainland for pre-emptive therapy of CMV infection in consecutive patients undergoing allogeneic HSCT.Allogeneic HSCT recipients were followed weekly via CMV pp65 antigenemia assay or real-time quantitative polymerase chain reaction （PCR） for detection of CMV-DNA.Patients with a positive assay were treated with VGC, 900 mg P.O.twice a day for 14 days followed by 900 mg P.O.once a day for 14 days after a negative result or the CMV-DNA load was lower.Results A total of 54 patients （15 siblings, 28 mismatched related donors, 11 unrelated donors） had a positive assay treated with oral VGC.The seroconversion rate was 89% （48/54） as confirmed by a negative assay; six patients failed oral VGC.No significant toxicity was encountered.No case of CMV disease was diagnosed in the responding patients with a median follow-up of 5.3 months after the drug administration.Conclusion Pre-emptive therapy of CMV viraemia with oral VGC is safe and effective in allogeneic HSCT.

Clinical application of real time-polymerase chain reaction in determining cytomegalovirus viral DNA load in renal transplant recipients

Background Cytomegalovirus （CMV） remains a significant clinical problem among immunosuppressed renal transplant patients. Quantitative PCR assays have become the most common methods in the determination of CMV infections in transplant patients. This study was to determine the relationship between CMV infection and the acute rejection of the transplanted kidney. Methods Plasma samples from 77 renal transplant patients that were pre-transplant negative for CMV infection were tested using reaD-time quantitative PCR and CMV gene-specific primers. The detected viral loads were retrospectively compared with the acute rejection rate and the chronic or mild rejection rates of the renal transplant. Results CMV-DNA was detected in 29 of 77 recipients, yielding a positive rate of detection of 37.7% for this procedure. Twelve of the 21 recipients （57.1%） who suffered acute rejection had positive CMV-DNA. Among the 56 recipients suffered from chronic or mild rejection, 17 （30.4%） had positive CMV-DNA plasma. Moreover, of the 29 recipients who had detectable CMV-DNA after transplant, 12 （41.4%） suffered from acute rejection; of the 48 recipients with undetectable CMV-DNA, only nine （18.8%） developed acute rejection. Post-transplant patients with acute rejection had a higher rate （57.1% vs. 30.4%, P=0.03） of post-transplant CMV infection than those with chronic or mild rejection. Conclusion CMV infection is a risk factor of acute renal transplant rejection and CMV infection should be prevented and treated in renal transplant recipients.

Human cytomegalovirus protects multiple myeloma cell line KM3 cells from apoptosis induced by growth factor withdrawal

Background There is a higher rate of cytomegalovirus (CMV) reactivation in patients with multiple myeloma after an autologous stem cell transplantation,but no attention has been given thus far to a possible pathogenetic interplay between CMV and multiple myeloma. CMV can infect many kinds of cells,and CMV infection has been shown to inhibit apoptotic responses in several cell systems. In this study the authors investigated the alterations in apoptosis in the multiple myeloma cell line KM3 after infection with CMV and proposed a possible mechanism.Methods KM3 cells were infected with 100,10,or 1 TCID50 of CMV and then cultured in serum-free RPMI 1640. An RT-PCR-based assay was used to detect mRNA expression of CMV-IE,glyceraldehyde-3-phosphate dehydrogenase (GAPDH),and IL-6 in CMV-infected and mock-infected cells. Flow cytometry was used to detect apoptotic cells. CMV particles and apoptotic cells were also examined with an electron microscope. Results CMV-infected KM3 cells clearly expressed immediate early (IE) antigen mRNA when compared to uninfected cells,and there were fewer apoptotic cells among cells treated with 100 or 10 TCID50 of CMV after culturing in serum-free RPMI 1640. CMV particles were observable in infected cells under an electron microscope. Expression of IL-6 mRNA increased after infection.Conclusion CMV can infect the multiple myeloma cell line KM3,inhibit the apoptotic response in these cells after apoptosis induction in serum-free culture,and increase the expression of IL-6 mRNA.

Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.