Management of cytomegalovirus infection after liver transplantation

Cytomegalovirus(CMV)infection is one of the primary causes of morbidity and mortality following liver transplantation(LT).Based on current worldwide guidelines,the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive treatment.CMV-IgG serology is the established technique for pretransplant screening of both donors and recipients.The clinical presentation of CMV infection and disease exhibits variability,prompting clinicians to consistently consider this possibility,partic-ularly within the first year post-transplantation or subsequent to heightened immunosuppression.At annual symposia to discuss CMV prevention and how treatment outcomes can be improved,evidence on the incorporation of immune functional tests into clinical practice is presented,and the results of studies with new antiviral treatments are evaluated.Although there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation,a consensus reflected in the guidelines has not been formed.Determining the most appro-priate strategy at the individual level appears to be the key to enhancing out-comes.Although prevention strategies reduce the risk of CMV disease,the disease can still occur in up to 50%of high-risk patients.A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant recipients.The objective of this study was to establish a compre-hensive framework for the management of CMV in patients who have had LT.

Cytomegalovirus infection in non-immunocompromised critically ill patients:A management perspective

Critically ill patients are a vulnerable group at high risk of developing secondary infections.High disease severity,prolonged intensive care unit(ICU)stay,sepsis,and multiple drugs with immunosuppressive activity make these patients prone to immuneparesis and increase the risk of various opportunistic infections,including cytomegalovirus(CMV).CMV seroconversion has been reported in up to 33%of ICU patients,but its impact on patient outcomes remains a matter of debate.Even though there are guidelines regarding the management of CMV infection in immunosuppressive patients with human immunodeficiency virus/acquired immuno deficiency syndrome,the need for treatment and therapeutic approaches in immunocompetent critically ill patients is still ambiguous.Even the diagnosis of CMV infection may be challenging in such patients due to non-specific symptoms and multiorgan involvement.Hence,a better understanding of the symptomatology,diagnostics,and treatment options may aid intensive care physicians in ensuring accurate diagnoses and instituting therapeutic interventions.

Pulmonary cytomegalovirus infection:A case report and systematic review

BACKGROUND Cytomegalovirus(CMV)is a common virus that can cause the first infection in childhood or adolescence and reactivate later in life due to immunosuppression.CMV pneumonia is a rare illness in immunocompetent patients but is one of the most significant opportunistic infections in immunocompromised patients.AIM To report a case and review published cases of pulmonary CMV infection in both immunocompromised and immunocompetent patients.METHODS We conducted a systematic search on the MEDLINE(PubMed)database,without date or language restrictions,to identify relevant studies using Medical Subject Headings and Health Science Descriptors.We manually searched the reference lists of the included studies.Simple descriptive analysis was used to summarize the results.RESULTS Our search identified 445 references,and after screening,43 studies reporting 45 cases were included in the final analysis,with 29(64%)patients being immunocompromised and 16(36%)being immunocompetent.Fever(82%)and dyspnea(75%)were the most common clinical findings.Thoracic computed tomography showed bilateral ground-glass opacities,a relevant differential diagnosis for severe acute respiratory syndrome coronavirus 2 infection.The majority of patients(85%)received antiviral therapy,and 89%of patients recovered,while 9%of patients died.CONCLUSION CMV pneumonia should be considered as a differential diagnosis for coronavirus disease 2019 pneumonia,especially in immunocompromised patients.Clinicians should be aware of the clinical presentation,management,and outcomes of CMV pneumonia to guide appropriate treatment decisions.

Destructive effects on endothelial cells of grafts in cytomegalovirus DNA-positive patients after keratoplasty

AIM:To investigate corneal graft survival rate and endothelial cell density(ECD)loss after keratoplasty in cytomegalovirus(CMV)positive patients.METHODS:This was a retrospective cohort study.We analyzed the clinical data of patients who underwent viral DNA detection in aqueous humor/corneal tissue collected during keratoplasty from March 2015 to December 2018 at the Peking University Third Hospital,Beijing,China.To further evaluate the effect of CMV on graft survival rate and ECD loss,patients were divided into three groups:1)CMV DNA positive(CMV+)group;2)viral DNA negative(virus-)group,comprising virus-group eyes pairwise matched to eyes in the CMV+group according to ocular comorbidities;3)control group,comprising virus-group eyes without ocular comorbidities.The follow-up indicators including graft survival rate,ECD,ECD loss,and central corneal thickness(CCT),were analyzed by Tukey honestly significant difference(HSD)test.RESULTS:Each group included 29 cases.The graft survival rate in CMV+group were lowest among the three groups(P=0.000).No significant difference in donor graft ECD was found among three groups(P=0.54).ECD in the CMV+group was lower than the virus-group at 12(P=0.009),and 24mo(P=0.002)after keratoplasties.Furthermore,ECD loss was higher in the CMV+group than in the virus-group in the middle stage(6-12mo)postkeratoplasty(P=0.017),and significantly higher in the early stage(0-6mo)in the virus-group than in the control group(P=0.000).CONCLUSION:CMV reduces the graft survival rate and exerts persistent detrimental effects on the ECD after keratoplasty.The graft ECD loss associate with CMV infection mainly occurrs in the middle stage(6-12mo postoperatively),while ocular comorbidities mainly affects ECD in the early stage(0-6mo postoperatively).

Coexisting cytomegalovirus colitis in an immunocompetent patient with Clostridioides difficile colitis:A case report

BACKGROUND Clostridioides difficile(C.difficile)colitis is one of the most common infections in hospitalized patients,characterized by fever and diarrhea.It usually improves after appropriate antibiotic treatment;if not,comorbidities should be considered.Cytomegalovirus(CMV)colitis is a possible co-existing diagnosis in patients with C.difficile infection with poor treatment response.However,compared with immunocompromised patients,CMV colitis in immunocompetent patients is not well studied.CASE SUMMARY We present an unusual case of co-existing CMV colitis in an immunocompetent patient with C.difficile infection.An 80-year-old female patient was referred to the infectious disease department due to diarrhea,abdominal discomfort,and fever for 1 wk during her hospitalization for surgery.C.difficile toxin B polymerase chain reaction on stool samples was positive.After C.difficile infection was diagnosed,oral vancomycin treatment was administered.Her symptoms including diarrhea,fever and abdominal discomfort improved for ten days.Unfortunately,the symptoms worsened again with bloody diarrhea and fever.Therefore,a sigmoidoscopy was performed for evaluation,showing a longitudinal ulcer on the sigmoid colon.Endoscopic biopsy confirmed CMV colitis,and the clinical symptoms improved after using ganciclovir.CONCLUSION Co-existing CMV colitis should be considered in patients with aggravated C.difficile infection on appropriate treatment,even in immunocompetent hosts.

Cytomegalovirus infection in liver transplant recipients

Objective: To explore cytomegalovirus （CMV） infec-tion in recipients of liver transplantation （LT）.Methods: 30 recipients of LT were screened for theappearance of CMV infection by using ELISA to testanti-CMV-Ab from serum samples and using im-munohistochemistry method to test CMV antigen ex-pression and nested-PCR to amplify CMV-DNA fromblood samples.Results: Four of 243 samples taken from 30 recipientscame out positive of anti-CMV IgC; and anti-CMVIgM with a positive rate of 100% and 1.6% respec-tively. 85 samples resulted in CMV antigen expression（35.0%） with the average antigen index being 4.2±3.1/5×10;WBC. Besides, 99 samples were found tobe positive by nested-PCR with a positive rate of40.7%. 61 samples were found to be simultaneously pos-itive in test of CMV antigen and DNA, with a rate of25.1%.Conclusions: Infection of CMV is common in recipi-ents of LT. Simultaneous screening of anti-CMV-Ab, CMV-Ag and CMV-DNA after liver transplanta-tion is very important for early diagnosis of CMV in-fection.

Long-term follow-up of ulcerative colitis patients treated on the basis of their cytomegalovirus antigen status

AIM:To clarify the impact of cytomegalovirus(CMV)activation and antiviral therapy based on CMV antigen status on the long-term clinical course of ulcerative colitis(UC)patients.METHODS:UC patients with flare-up were divided into CMV-positive and-negative groups according to the CMV antigenemia assay.The main treatment strategy provided for the patients in the CMV-positive group comprised a dose reduction of corticosteroids and administration of ganciclovir.RESULTS:The median number of days to initial remission was significantly greater for the patients in the CMV-positive group(21 d vs 16 d,P=0.009).However,the relapse rate after remission and colectomy rate during more than 30 mo of observation did not differ between the two groups.Multivariate analysis revealed that administration of ganciclovir was the only independent factor for avoiding colectomy in patients of the CMV-positive group.CONCLUSION:CMV antigen status did not significantly affect the long-term prognosis in UC patients under treatment with appropriate antiviral therapy.

Fulminant gastrointestinal graft-versus-host disease concomitant with cytomegalovirus infection:Case report and literature review

Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.

Association of cytomegalovirus infection with human leukocyte antigen genotypes in recipients after allogeneic liver transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is the important cause affecting the survival rate and function of the transplanted organ after transplantation. The occurrence of CMV infection after liver transplantation (LT) is associated with many factors. Lots of studies suggest that genetic mutation between hosts and CMV may play a role in the occurrence and development of CMV infection. CMV exists in an incubative state, affect or destroy the expression of human leukocyte antigen (HLA) molecules in the host cell surface, and interfere antigen's submission. This mechanism is the key of CMV to avoid immune defense mechanism of the host. To detect HLA and CMV antibody (CMV-Ab), CMV antigen (CMV-Ag) of transplantation recipients, we evaluated the association of CMV infection and the particular HLA genotypes in recipients after LT. METHODS: 277 blood samples were collected from 39 LT recipients. CMV antibody and antigen were detected by ELISA or immunohistochemical methods. The HLA types of the recipients were determined by PCR. To analyze the association of HLA alleles and the occurrence of CMV antigenemia in the patients, relative risk degree (RR) was used as the parameter for the Chi-square test. RESULTS: The LT recipients were serum CMV IgG positive (100%), but none of them was CMV IgM positive (0%). Thirty-three LT recipients (84.6%) were CMV antigenic positive with 1-50 positive leukocytes per 50000 leukocytes in extent and 7.2±4.2 positive leukocytes per 50000 leukocytes on average. Thirteen patients developed CMV pneumonia, with CMV antigenic positive (100%) and 17.7±5.5 positive leukocytes per 50000 leukocytes on average. Some HIA alleles were associated with the occurrence and extent of CMV antigenemia. HLA-A2 was the higher frequency allele for patients with antigenemia (P<0.05), and 7 patients carrying HLA-DR11 allele developed antigenemia (P<0.05). In the lower antigenemia group, HLA-A11 was higher in frequency than others (P<0.05). Besides, none of the patients carrying HLA-B16 allele developed clinical symptoms of CMV infection (P<0.05). CONCLUSIONS: The variability of HLA alleles might modulate immune response to CMV infection. HLA examination before transplantation should be made for prevention and treatment of CMV infection aider operation.

Novel approach for the diagnosis of occult cytomegalovirus cholangitis after pediatric liver transplantation:A case report

BACKGROUND Cytomegalovirus(CMV)infection is a common infection in liver transplant recipients,which is related to chronic rejection and biliary complications.It is often diagnosed based on serum CMV-DNA or CMV pp65.To our knowledge,this is the first report of the successful treatment of occult CMV cholangitis in a pediatric liver transplantation(LT)recipient.CASE SUMMARY A 7-mo-old baby girl received LT due to biliary atresia and cholestasis cirrhosis.At 1 mo following LT,the patient suffered from aggravated jaundice with no apparent cause.As imaging results showed intrahepatic and extrahepatic bile duct dilatation,the patient was diagnosed with biliary complications and percutaneous cholangiography and biliary drainage was performed.However,there was little biliary drainage and her liver function deteriorated.CMV-DNA was isolated from the bile with the surprising outcome that 3×106 copies/mL were present,whereas the CMV-DNA in serum was negative.Following antiviral therapy with ganciclovir,she gradually recovered and bilirubin decreased to normal levels.During the 4-year follow-up period,her liver function remained normal.CONCLUSION Bile CMV sampling can be used for the diagnosis of occult CMV infection,especially in patients with negative serum CMV-DNA and CMV pp65.Testing for CMV in the biliary tract may serve as a novel approach for the diagnosis of cholestasis post-LT.Timely diagnosis and treatment will decrease the risk of graft loss.

Endoscopic diagnosis of cytomegalovirus gastritis after allogeneic hematopoietic stem cell transplantation

AIM:To clarify the endoscopic and clinical findings of cytomegalovirus(CMV) gastritis after allogeneic hematopoietic stem cell transplantation(allo-SCT).METHODS:Between 1999 and 2005,523 patients underwent allo-SCT at our hospital,and 115 of these patients with gastrointestinal symptoms underwent esophagogastroduodenoscopy.RESULTS:CMV gastritis was diagnosed pathologically in seven patients(1.3%) with the other 108 patients serving as controls.Six of the seven patients developed positive CMV antigenemia,and five complained of abdominal pain.Development of abdominal pain preceded CMV antigenemia in four of the f ive patients.Endoscopic examination showed oozing(n=2),erosion(n=6),and redness(n=5) in the seven patients with CMV gastritis,while the control patients showed oozing(n=3),erosion(n=24),and redness(n=100).Erosion and oozing were more frequently documented in patients with CMV gastritis compared with the controls,and the differences were statistically significant(P=0.0012 and 0.029,respectively).CMV inclusion bodies were documented in 12 of 14 biopsy specimens obtained from erosive lesions,while they were identif ied in 4 of 15 biopsy specimens obtained from lesions other than erosions(P=0.0025).CONCLUSION:This study suggests that erosion and oozing,as well as abdominal pain,are useful indicators in the diagnosis of CMV gastritis following allo-SCT.

Cytomegalovirus infection after liver transplantation: Current concepts and challenges

Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R-serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specif ic CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R-liver transplant recipients.Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the effi cacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

Cytomegalovirus and ulcerative colitis:Place of antiviraltherapy

The link between cytomegalovirus(CMV) infection and inflammatory bowel diseases remains an important subject of debate. CMV infection is frequent in ulcerative colitis(UC) and has been shown to be potentially harmful. CMV reactivation needs to be diagnosed using methods that include in situ detection of viral markers by immunohistochemistry or by nucleic acid amplification techniques. Determination of the density of infection using quantitative tools(numbers of infected cells or copies of the genome) is particularly important. Although CMV reactivation can be considered as an innocent bystander in active flareups of refractory UC, an increasing number of studies suggest a deleterious role of CMV in this situation. The presence of colonic CMV infection is possibly linked to a decreased response to steroids and other immunosuppressive agents. Some treatments, notably steroids and cyclosporine A, have been shown to favor CMV reactivation, which seems not to be the case for therapies using anti-tumor necrosis factor drugs. According to these findings, in flare-ups of refractory UC, it is now recommended to look for the presence of CMV reactivation by using quantitative tools in colonic biopsies and to treat them with ganciclovir in cases of high viral load or severe disease.

Natural history of cytomegalovirus infection in a series of patients diagnosed with moderate-severe ulcerative colitis

AIM： To evaluate the natural history of human cytomegalovirus （HCMV） infection in a series of 28 ulcerative colitis patients in whom the search for HCMV was positive. METHODS： A series of 85 patients with moderate-se- vere ulcerative colitis flare-up were evaluated for a HCMV search by performing a haematoxylin and eosin stain, immunohistochemical assay and nested polymerase chain reaction on rectal biopsies. Among 85 screened patients （19 of whom were steroid resistant/dependant）, 28 were positive for HCMV; after remission the patients were followed up clinically and histologically. RESULTS： Among the 22 patients with complete follow- up, in 8 （36%） patients HCMV-DNA persisted in the in- testinal specimens. Among the HCMV positive patients, 4 （50%） experienced at least one moderate-severeflare-up of colitis without evidence of peripheral HCMV. Among the 14 HCHV negative patients, 3 with pouches developed pouchiUs and 5 out of 11 （45%） experienced a colitis flare-up. CONCLUSION： Our preliminary results suggest that HCHV may remain in the colon afber an acute coltis flare- up despite remission; it seems that the virus is not responsible for the disease relapse.

Cytomegalovirus infection in severe ulcerative colitis patients undergoing continuous intravenous cyclosporine treatment in Japan

AIM： TO investigate active cytomegalovirus （CMV） infection following the cydosporine A （CyA） treatment of steroid-refractory ulcerative colitis （UC）. METHODS： Twenty-three patients with severe UC not responding to steroid therapy （male 14, and female 9） enrolled at Nagoya University Hospital from 1999 to 2005. They received continuous intravenous infusion of CyA （average 4 mg/kg per day） for 1 mo. Serum and colonic biopsy samples were collected before CyA treatment and 4 d, 10 d, 20 d, and 30 d after treatment. Patients were evaluated for CMV by using serology （IgM antibody by ELISA）, quantitative real-time PCR for CMV DNA, and histopathological assessment of hematoxylin and eosin （HE）-stained colonic biopsies. CMV infection was indicated by positive results in any test. RESULTS： No patients had active CMV infection before CyA treatment. Eighteen of 23 UC patients treated with CyA were infected with active CMV （IgM antibody in 16/23 patients, 69.6%; CMV DNA in 18/23 patients, 78.2%; and inclusion bodies in 4/23 patients, 17.3%）. There was no difference in the active CMV-infection rate between males and females. Active CMV infection was observed after approximately 8 d of CyA treatment, leading to an exacerbation of colitis. Fifteen of these 18 patients with active CMV infection （83.3%） required surgical treatment because of severe deteriorating colitis. Treatment with ganciclovir rendered surgery avoidable in three patients. CONCLUSION： Our results suggest that active CMV infection in severe UC patients treated with CyA is associated with poor outcome. Further, ganciclovir is useful for treatment of CMV-associated UC after immunosuppressive therapy.

Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection

AIM:To identify specific colonoscopic findings in patients with ulcerative colitis (UC) complicated by cyto-megalovirus (CMV) infection.METHODS: Among UC patients who were hospitalized due to exacerbation of symptoms, colonoscopic findings were compared between 15 CMV-positive patients and 58 CMV-negative patients. CMV infection was determined by blood test for CMV antigenemia. Five aspects of mucosal changes were analyzed (loss of vascular pattern, erythema, mucosal edema, easy bleeding, and mucinous exudates) as well as five aspects of ulcerative change (wide mucosal defect, punched-out ulceration, longitudinal ulceration, irregular ulceration, and cobble-stone-like appearance). Sensitivity, specificity, positive predictive value, and negative predictive value of each finding for CMV positivity were determined.RESULTS: The sensitivity of irregular ulceration for positive CMV was 100%. The specificity of wide mucosal defect was 95%. Punched-out ulceration and lon-gitudinal ulceration exhibited relatively high sensitivity and specificity (more than 70% for each).CONCLUSION:Specific colonoscopic findings in patients with UC complicated by CMV infection were identified. These findings may facilitate the early diagnosis of CMV infection in UC patients.

Eosinophilic gastroenteritis with cytomegalovirus infection in an immunocompetent child

A 3-year-old boy developed transient protein-losing gastroenteropathy associated with cytomegalovirus (CMV) infection. Both IgG and IgM antibodies to CMV were positive in a serologic blood test. Upper gastrointestinal endoscopy showed multiple erosions throughout the body of the stomach, without enlarged gastric folds. Histological examination of the biopsy specimens indicated eosinophilic gastroenteritis and CMV infection. The patient had complete resolution without specific therapy for CMV in four weeks. An allergic reaction as well as CMV infection played important roles in the pathogenesis of this case.

Management of cytomegalovirus infection and disease in liver transplant recipients

Cytomegalovirus(CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferredstrategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors(D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/Rliver transplant recipients, and such occurrence of lateonset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach(antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ(including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation.

IL28B polymorphism and cytomegalovirus predict response to treatment in Egyptian HCV type 4 patients

AIM:To test whether the status of positive cytomegalovirus(CMV) DNA detection adds to the predictive value of IL28B and to further categorize C/T allele carriers.METHODS:This study included 166 chronic hepatitis C(CHC) patients who received combined interferon and ribavirin therapy for 48 wk,84 spontaneous hepatitis C virus(HCV) resolvers who were positive for IgG anti-HCV antibody and negative for HCV RNA,and 100 healthy subjects who were negative for both HCV antibodies and RNA as controls.Genomic DNA from peripheral blood was used for IL28B rs.12979860 single nucleotide polymorphism(SNP) and CMV DNA detection.A 139 bp fragment containing IL28B SNP was amplified in all subjects by polymerase chain reaction using a specifically designed primer.Then the IL28B rs.12979860 SNP was detected by restriction fragment length polymorphism(RFLP) genotyping.The presence of CMV DNA was tested by amplification of the gB1 gene using nested polymerase chain reaction.The role of CMV and IL28B rs.12979860 SNP genotypes in determining the response rate to combined interferon therapy and clinical status of patients were statistically analyzed.RESULTS:Current data showed that 67% of patients carrying the IL28B 12979860 C/C allele had a sustained viral response(SVR) while the genotypes C/T and TT were associated with lower SVR rates,50% and 48%,respectively.SVR rates for the C/C allele were lower than other HCV genotypes and/or other populations.Genotype CC was associated with the response to interferon(P = 0.025).Genotype C/C was reduced from 48% in controls to 14% in CHC patients suggesting its protective role against progression to chronicity.The majority of spontaneously cleared subjects(86%) were C/C,confirming its protective role.The C/T allele was present in 71% of CHC patients compared with 38% of controls,so the use of IL28B SNP genotyping only in these patients may be of little value as a predictor of response.CMV reactivation occurred in 40% of CHC patients.Co-infection with CMV seriously diminished the response to interferon(IFN) therapy,with SVR rates in C/C genotypes 87.5% in CMV-negative patients and 12.5% in CMV-positive patients(P < 0.0001).SVR rates among C/T carriers were reduced to < 50% in patients with positive CMV DNA while the non-response rate doubled.These data indicate that a supplemental assay for CMV viremia adds to the prognostic value of IL28B genotyping.CONCLUSION:The results suggest that both genetic(i.e.,spontaneous) and therapeutic(IFN-based therapy) arms are complementary in the battle against HCV.CMV DNA testing may be of value to better predict the response to IFN,particularly in IL28B C/T carriers.

Cytomegalovirus frequency in neonatal intrahepatic cholestasis determined by serology, histology, immunohistochemistry and PCR

AIM: To determine cytomegalovirus (CMV) frequency in neonatal intrahepatic cholestasis by serology, histological revision (searching for cytomegalic cells), immunohistochemistry, and polymerase chain reaction (PCR), and to verify the relationships among these methods.METHODS: The study comprised 101 non-consecutive infants submitted for hepatic biopsy between March 1982 and December 2005. Serological results were obtained from the patient's f iles and the other methods were performed on paraffin-embedded liver samples from hepatic biopsies. The following statistical measures were calculated: frequency, sensibility, specif ic positive predictive value, negative predictive value, and accuracy.RESULTS: The frequencies of positive results were as follows: serology, 7/64 (11%); histological revision, 0/84; immunohistochemistry, 1/44 (2%), and PCR, 6/77 (8%). Only one patient had positive immunohistochemical fi ndings and a positive PCR. The following statistical measures were calculated between PCR and serology: sensitivity, 33.3%; specificity, 88.89%; positive predictive value, 28.57%; negative predictive value, 90.91%; and accuracy, 82.35%. CONCLUSION: The frequency of positive CMV varied among the tests. Serology presented the highest positive frequency. When compared to PCR, the sensitivity and positive predictive value of serology were low.