Acute Cytomegalovirus Research Articles

ПРОЦЕССЫ ПЕРОКСИДАЦИИ ЛИПИДОВ В ЭНДОТЕЛИИ АРТЕРИИ ПУПОВИНЫ ПРИ ЦИТОМЕГАЛОВИРУСНОЙ ИНФЕКЦИИ

The purpose of the work is to study the processes of peroxidation of lipids and their influence on the structure of the endothelium of the umbilical artery of newborns from mothers who had experienced exacerbation of cytomegalovirus (CMV) infection in the third trimester of pregnancy. For the object of the study there were taken 45 umbilical cord samples during childbirth from women who had acute CMV infection in the third trimester of pregnancy (main group), and 25 umbilical cord samples from healthy women (control group). Clinical diagnosis of primary CMV infection was established by the presence of IgM antibodies to CMV and low-avid IgG in the peripheral blood (avidity index <50%), as well as CMV DNA detected by polymerase chain reaction in blood or urine; exacerbation of chronic CMV infection by the presence of IgM to CMV, high-avid IgG (avidity index >65%), and CMV DNA in scrapes taken from buccal epithelium. Lipid peroxides in the endothelium of the umbilical artery were detected by the Winkler-Schulze method. Morphological examination of the umbilical cord was performed by histochemical methods. The results of histochemical studies indicate that the exacerbation of CMV infection in the third trimester of pregnancy is associated with oxidative stress that causes the depletion of the protective systems and oxidant potential, which leads to the development of significant oxidative destruction of the endothelium of the umbilical cord artery of newborns. The revealed morphohistochemical changes in umbilical cord tissues in CMV infection can affect the functional state of this organ and be a morphological substrate for the appearance of its dysfunction, mainly the basis for the violation of fetoplacental blood circulation causing the development of hypoxia.

A Case of Acute Hepatitis With Co—Infections: Co—Existent Hepatitis E With a Positive Serology for Double Mono

Epstein—Barr virus (EBV), Cytomegalovirus (CMV) and Hepatitis E virus (HEV) are all known to cause mild and usually self—limiting acute viral hepatitis. Acute hepatitis caused by simultaneous presence of two viruses has been reported in literature. However, patients with positive serology for three acute viral infections causing acute hepatitis is very rare. A 23—year—old Caucasian female with an unremarkable past medical history presented with one—week duration of nausea, vomiting, generalized abdominal pain, fever and one day duration of scleral icterus and jaundice. The patient had stable vital signs but elevated liver enzymes on admission with AST 385 IU/L, ALT 290 IU/L, Alkaline phosphatase 461 IU/L, Total bilirubin 9 mg/dL and Direct bilirubin of 5.1 mg/dL. White blood cell (WBC) count was 13500/uL. Work up was unremarkable for acute hepatitis A, B & C viruses, Influenza A & B and infectious mono—spot test along with a negative pregnancy test. When Ultrasound and Computed tomography scan of the abdomen was unrevealing a magnetic resonance cholangiopancreatography was obtained and was unremarkable. Anti—mitochondrial antibody, anti—smooth muscle antibody, anti—nuclear antibody, Alpha—1 antitrypsin level and ceruloplasmin level were all un—remarkable. Infectious disease was consulted when the patient became febrile to 102.0 F despite negative work up. Serologic work up for acute EBV, CMV and HEV infections turned out to be positive; with positive PCR for EBV (Table. 1). The patient was subsequently managed conservatively per infectious disease recommendations and improved. She was discharged on her fourth hospital day with a 6 week follow up showing normalization of liver enzymes. The above patient was diagnosed with Infectious mononucleosis with associated acute hepatitis due to EBV infection. Positive CMV serology was thought to be false positive as the patient's CMV PCR titers were low. HEV PCR wasn't obtained but given the significantly elevated bilirubin in combination with positive serology, it was thought to be a true infection. The patient improved only with conservative management. This lead to two important conclusions: (1) If the patient has positive serology concerning for co—infection of EBV, CMV and/or HEV; it should be confirmed via PCR and (2) if the patient truly is co—infected supportive treatment is one management option in immunocompetent patients.3047.tif Figure 1: No Caption available.

OPTIMIZATION OF DIAGNOSIS OF CYTOMEGALOVIRUS INFECTION IN YOUNG CHILDREN

The results of a laboratory examination of 520 children aged 1—3 years are presented. The examination was conducted to determine the DNA of cytomegalovirus in children with acute cytomegalovirus infection in various biological media by polymerase chain reaction. The differences in the virus shedding into the blood, saliva, and urine are established: the median of the viral load for saliva is 4.9 lg copies of DNA/ml, the blood 3.4 lg copies of DNA/ml, urine — 3.85 lg copies of DNA/ml. The cut of extreme values of the viral load are determined with the help of mathematical modeling which determine the clinical probability of developing acute CMV infection which allows for more accurate and timely assignment of etiotropic therapy.

Etiology and Clinical Characteristics of Acute Cytomegalovirus Hepatitis in Children at the National Children’s Hospital

Aim: study of clinical and investigation characteristics of acute CMV hepatitis in children at the NationalChildren’s Hospital.Subjects and Methods study: Prospective descriptive study on 42 patients were diagnosed acuteCMVhepatitis at the National Children’s Hospital from 10/2015 to 9/2016Result: In 57 cases were identified acute viral hepatitis, the prevalence of CMV hepatitis is 73% (42 cases).Prominent clinical symptoms of patients with CMV hepatitis were jaundice, yellow eyes (86%), hepatomegaly(64%), spleenomegaly (24%), itchy rash (12%), ascites (7%). Most of cases had viral load in the blood over5000 copies/ml (92%).

A Multicenter Case-control Study of the Effect of Acute Rejection and Cytomegalovirus Infection on Pneumocystis Pneumonia in Solid Organ Transplant Recipients.

Pneumocystis pneumonia (PCP) is associated with morbidity and mortality in solid organ transplant (SOT) recipients. In this case-control study, we determined the association between posttransplant PCP and 3 variables: cytomegalovirus (CMV) infection, allograft rejection, and prophylaxis. Eight transplant centers participated. For each case (SOT recipient with PCP), 3-5 controls (SOT recipients without PCP) were included. Controls were matched to the cases based on transplant center, type of allograft, and date of transplantation (±6 months). We enrolled 53 cases and 209 controls. Transplant types included kidney (n = 198), heart (n = 30), liver (n = 15), kidney-pancreas (n = 14), and lung (n = 5). PCP occurred beyond 12 months after transplantation in 43 (81.1%) cases. Thirty-four cases (64.1%) required admission to the intensive care unit, and 28 (52.8%) had mechanical ventilation. Allograft failure occurred in 20 (37.7%) cases, and 14 (26.9%) died. No patient developed PCP prophylaxis breakthrough. The proportion of female sex (P = .009), kidney dysfunction (P = .001), cardiac diseases (P = .005), diabetes mellitus (P = .03), allograft rejection (P = .001), CMV infection (P = .001), and severe lymphopenia (P = .001) were significantly higher in cases. In the logistic regression model, CMV infection (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 2.0-10.5]) and allograft rejection (aOR, 3.0 [95% CI, 1.5-6.1]) significantly increased the likelihood of PCP. PCP was mostly a late-onset disease occurring after complete course of prophylaxis, particularly among patients with CMV infection or allograft rejection. PCP is associated with significant allograft loss. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PCP.

Everolimus Failure to Counteract the Cytotoxic Response Mediated by CD8+ T and NK Cells in Heart-Transplant Patients

The negative effects of immunosuppression after heart transplantation (HT) are hard to avoid, but they can be partially overcome using new drugs such as the everolimus (EVL) mTOR (mammalian target of rapamycin) inhibitor. Initial studies have shown that EVL administration in combination with low-doses of calcineurin inhibitors and corticosteroids is effective in reducing the acute rejection and cytomegalovirus infection, two of the main causes of the development of cardiac allograft vasculopathy (CAV), and induce the expansion of regulatory T cells (Tregs). However, the impact of EVL introduction after HT on the in vivo immune response remains poorly understood. Here, we analyzed the changes in the immune phenotype on peripheral blood samples of 56 HT recipients who were treated with mycophenolate mofetil (MMF) or switched from MMF to EVL, and low-dose tacrolimus. We studied two cohorts; a “late cohort” of recipients of more than 1 year post-HT, who were converted from MMF to EVL (EVL group, n=20) following clinical criteria or maintained on MMF (MMF group, n=20) and an “early cohort” (n=16), who were switched from MMF to EVL at 3 months post-HT. Blood samples were taken at a single time one year post-EVL initiation and at different post-transplant times (before EVL initiation 1, 3 and 9 months after EVL conversion) in the early cohort. Immune phenotype was analyzed by flow cytometry and DNA methylation profiles in immune genes by pyrosequencing. Our results showed that EVL conversion from MMF induced the expansion of cytotoxic NK (CD56dim CD16+) and effector-memory (CD45RA- CCR7-) CD8+ T populations, showing significantly higher levels of expression of cytotoxic molecules (granzyme, perforin and IFN-γ) and greater degranulation ability under activation. Treatment with EVL modifies the NK cell receptors repertoire increasing the activation state and cytolytic activity of these cells. These changes are already evident at 1 month after EVL initiation and gradually increase during the first year post-transplant. Moreover, only one month after EVL initiation, HT patients showed a significant expansion of Tregs and decrease of B cells. We observed that these phenotypic alterations were associated with changes in the DNA methylation patterns of key immune genes (IFNG, PRF, FASL and PD1). Thus, quantification of the methylation levels in these genes could help to predict the alterations in the immune phenotype and its functionality after EVL conversion. In short, we observed that both early and late EVL conversion from MMF induces changes in the immune system which could condition the post-transplant immune response. The consequences of EVL initiation after HT can be considered as a double-sided coin; on the one hand induces the Tregs expansion and reduces the B cells number contributing to the immune tolerance, but at the same time failure to blockage the cytolytic ability mediated by CD8+ T and NK cells. According to that, EVL conversion as a general strategy after HT must be taken with caution.

Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection.

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues.

Single-Center Experience Using Marginal Liver Grafts in Korea

BackgroundLiver transplantation (LT) is an established therapeutic modality for patients with end-stage liver disease. The use of marginal donors has become more common worldwide due to the sharp increase in recipients, with a consequent shortage of suitable organs. We analyzed our single-center experience over the last 8 years in LT to evaluate the outcomes of using so-called “marginal donors.” MethodsWe retrospectively analyzed the database of all LTs performed at our institution from 2009 to 2017. Only patients undergoing deceased-donor LTs were analyzed. Marginal grafts were defined as livers from donors >60 years of age, livers from donors with serum sodium levels >155 mEq, graft steatosis >30%, livers with cold ischemia time ≥12 hours, livers from donors who were hepatitis B or C virus positive, livers recovered from donation after cardiac death, and livers split between 2 recipients. Patients receiving marginal grafts (marginal group) were compared with patients receiving standard grafts (standard group). ResultsA total of 106 patients underwent deceased-donor LT. There were 55 patients in the standard group and 51 patients in the marginal group. There were no significant differences in terms of age, sex, Model for End-Stage Liver Disease score, underlying liver disease, presence of hepatocellular carcinoma, and hospital stay between the 2 groups. Although the incidence of acute cellular rejection, cytomegalovirus infection, and postoperative complications was similar between the 2 groups, the incidence of early allograft dysfunction was higher in the marginal group. With a median follow-up of 26 months, the 1-, 3-, and 5-year overall and graft (death-censored) survivals in the marginal group were 85.5%, 75%, and 69.2% and 85.9%, 83.6%, and 77.2%, respectively. Patient overall survival and graft survival (death-censored) were significantly lower in the marginal group (P = .023 and P = .048, respectively). On multivariate analysis, receiving a marginal graft (hazard ratio [HR], 4.862 [95% confidence interval (CI), 1.233–19.171]; P = .024) and occurrence of postoperative complications (HR, 4.547 [95% CI, 1.279–16.168]; P = .019) were significantly associated with worse patient overall survival. Also, when factors associated with marginal graft were analyzed separately, graft steatosis >30% was independently associated with survival (HR, 5.947 [95% CI, 1.481–23.886]; P = .012). ConclusionsPatients receiving marginal grafts showed lower but acceptable overall survival and graft survival. However, because graft steatosis >30% was independently associated with worse survival, caution must be exercised when using this type of marginal graft by weighing the risk and benefits.

Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: A meta-analysis

BackgroundData evaluating mTOR inhibitor use heart transplant (HT) patients comes from relatively small studies and controversy exists regarding their specific role. We performed a meta-analysis of randomized trials to evaluate the efficacy and safety of mTOR inhibitors in HT patients. MethodsWe performed a systematic literature search of Medline and Embase through July 2017 identifying studies evaluating mTOR inhibitors in HT patients reporting effects on coronary allograft vasculopathy (CAV), renal function, acute cellular rejection (ACR), cytomegalovirus (CMV) infection, and discontinuation due to adverse drug events (ADE). Data were pooled using a random-effects model producing a mean difference (MD; for continuous data) or odds ratio (OR; for dichotomous data) and 95% confidence interval (CI). Results14 trials reported at least one outcome of interest. Change in mean maximal intimal thickness was significantly reduced with mTOR (−0.04 [−0.07 to −0.02]) compared to calcineurin inhibitor/mycophenolate mofetil (CNI/MMF). Rates of CMV infection were also significantly reduced (0.26; [0.2 to 0.32]) with mTOR regimens compared to CNI/MMF therapy. ACR was more frequent with CNI-sparing regimens 6.46 [1.55 to 26.95]). eGFR was significantly improved with CNI-sparing therapies (mean difference 12.09 mL/min [2.43 to 21.74]), but was similar between CNI/mTOR versus CNI/MMF regimens (p > 0.05). Rates of discontinuation due to ADE were higher in mTOR-containing regimens (OR 2.15 [1.28 to 3.60], p = 0.01), while mortality rates were similar (OR 0.91 [0.61 to 1.37], p = 0.62). ConclusionsmTOR-containing regimens can attenuate CAV and CMV risk in HT recipients. A mTOR/MMF combination preserves renal function but increases the risk of ACR.

Improved Outcomes of Kidney Transplantation in Infants (Age < 2 years): A Single-Center Experience.

Infants (age, < 2 years) with end-stage renal disease (ESRD) have increased morbidity and mortality. We evaluated our long-term outcomes of kidney transplants (KTx) in infants. Between 1984 and 2014, 136 infants underwent KTx. We examined trends in survival rates and complications by era (1984-1993 [era 1], 1994-2003 [era 2], 2004-2014 [era 3]). Patients were 92.6% white and 70.6% males. Posttransplant (Tx) initial length of hospital stay declined 37% over the 30-year period (P <0.01). Ten-year death-censored graft survival improved from 60% (era 1) to 80% (era 2) (P = 0.04). The incidence of acute rejection, graft thrombosis, cytomegalovirus, and urine leaks did not significantly change across eras. Frequency of Epstein-Barr virus diagnosis (era 2 vs era 3, P < 0.01) increased. Post-Tx lymphoproliferative disorder incidence was increased in era 2 compared with eras 1 and 3 (P = 0.03). Infants deserve earlier consideration for KTx. Length of initial hospital stay and patient and graft survival rates after KTx have improved in infants since 1984.

The clinical laboratory characteristic of primary acute cytomegalovirus infection in non-immunocompromised adult patients

The purpose of study is the clinical laboratory characteristic of acquired acute cytomegalovirus infection in nonimmunocompromised adult patients. The sampling included 75 patients with acquired acute cytomegalovirus infection admitted to the specialized clinical infection hospital of the Minzdrav of the Krasnodar kraii. The verifcation of diagnosis was implemented using serological tests and polymerase chain reaction. It is demonstrated that males of younger age are most often infected with acute cytomegalovirus infection in the Krasnodar kraii. The disease takes its course in a generalized form. In clinical picture symptoms of intoxication (long-term temperature increasing, weakness), hepatomegaly with increasing of activity of hepatic enzymes, splenomegaly, monolymphocytosis prevail. In most of patients, manifestation of affection of upper respiratory tracts are observed and less frequently - community-acquired pneumonia. The alteration of immune status of patients in dynamics of disease was typical for acute faze of viral infection process with transition to a latent one. At the same time, certain percentage of patients preserved inhibition of neutrophil chain of immunity during re-convalescent period, hence developing menace of bacterial complications. The complex treatment with inclusion of etiotropic anti-viral pharmaceutical Gancyclovir with duration of 8,4±0,4 days resulted in normalization of fever, relief of organic affections and also disappearance of viral DNA from blood. The rate of wrong preliminary diagnoses (85.3%) at referral of patient to hospital testifes complicacy of clinical diagnostic of acute cytomegalovirus infection, conditioned by absence of pathognomonic symptoms under this disease. The last circumstance determines expediency of inclusion into algorithm of examination of patients with unidentifed genesis of fever, hepatosplenomegaly, lymphadenopathy, monolymphocytosis, increasing of activity of hepatic enzymes the analysis of antibodies to antigens of cytomegalovirus (IgM CMV, IgG CMV, avidity of IgG CMV) using enzyme-linked immunosorbent assay and also detection of DNA CMV in blood and urine using polymerase chain reaction technique. The alterations of immune status during re-convalescent period observed in one third of patients determine necessity of their dispensary observation.

Relevant pericardial effusion caused by cytomegalovirus infection in an immunocompetent patient: a case report

BackgroundCytomegalovirus infection is known to cause symptomatic disease in immunocompromised patients, while an infection in immunocompetent individuals normally causes few or no symptoms. We present the case of an immunocompetent adult patient with unexpected severe evolution.Case presentationAn otherwise healthy, 72-year-old Caucasian woman presented with complaints of progressive shoulder pain and dyspnoea on exertion. The blood test results showed elevated inflammation parameters and elevated hepatic transaminase levels. Radiologic examinations were carried out, and the computed tomography scan revealed a hepatomegaly and a chest X-ray showed evidence of a unilateral pleural effusion. A transthoracic echocardiography detected pericardial effusion with consecutive hemodynamic changes. Since it was considered that using ultrasound-guided pericardiocentesis could significantly increase the risk of liver injury due to hepatomegaly, a pericardial window was performed instead. Further investigation showed that our patient tested positive for an acute cytomegalovirus infection in the serologic tests. Laboratory findings included new evidence of immunoglobulin M seroconversion and high immunoglobulin G avidity, so we considered the possibility that a former cytomegalovirus infection may be coexisting with a new cytomegalovirus reinfection.ConclusionsIn immunocompetent individuals, a symptomatic cytomegalovirus primary infection or reinfection should be considered in patients presenting with pericardial effusion and serositis.

Eficacia y seguridad del uso de novo y precoz de tacrolimus de liberación prolongada en el trasplante cardiaco

Introduction and objectivesThe extended-release formulation of tacrolimus (ERT) allows once-daily dosage, thus simplifying the immunosuppressive regimen. This study aimed to describe the safety and efficacy of the de novo and early use of ERT in heart transplantation. MethodsThis was an observational, retrospective, multicenter study comparing the safety and efficacy of the de novo use of ERT (ERT group [n=94]), standard-release tacrolimus (SRT group [n=42]) and early conversion (EC) from SRT to ERT (EC group [n=44]). Extended-release tacrolimus was used between 2007 and 2012. One-year incidence rates of acute rejection, infection, and cytomegalovirus infection were analyzed. Safety parameters were also evaluated. ResultsThere were no significant between-group differences in the daily dose or trough levels of tacrolimus during the first year after transplantation. The rejection incidence rates were 1.05 (95%CI, 0.51-1.54), 1.39 (95%CI, 1.00-1.78), and 1.11 (95%CI, 0.58-1.65) episodes per patient-years in the SRT group, ERT group, and EC group, respectively (P=.48). The infection incidence rates were 0.75 (95%CI, 0.60-0.86), 0.62 (95%CI, 0.52-0.71), and 0.55 (95%CI, 0.40-0.68) in the SRT group, ERT group, and EC group, respectively (P=.46). Cytomegalovirus infection occurred in 23.8%, 20.2%, and 18.2% of the patients, respectively (P=.86). No significant between-group differences were found in laboratory tests or in allograft function. There was 1 death in the SRT group and 2 in the ERT group. ConclusionsBoth de novo and early use of ERT seem to have similar safety and efficacy profiles to conventional SRT-based immunosuppression.Full English text available from: www.revespcardiol.org/en

Intravascular Hemolysis as a Presenting Feature of Acute Cytomegalovirus Infection in an Immunocompetent Patient

Acute Cytomegalovirus (CMV) infection seldom presents with hemolytic anemia in an immunocompetent host. When hemolysis does occur, it is typically immune mediated and extravascular, but can be intravascular with the degree of anemia ranging from mild to severe. We report a case of a healthy 27-year-old woman who presented with jaundice and non-immune mediated intravascular hemolysis as an initial feature of acute CMV infection. Viral etiologies (including CMV) should be considered in the differential diagnosis of patients with Coombs negative intravascular hemolysis.

Efficacy and Safety of de Novo and Early Use of Extended-release Tacrolimus in Heart Transplantation

Introduction and objectivesThe extended-release formulation of tacrolimus (ERT) allows once-daily dosage, thus simplifying the immunosuppressive regimen. This study aimed to describe the safety and efficacy of the de novo and early use of ERT in heart transplantation. MethodsThis was an observational, retrospective, multicenter study comparing the safety and efficacy of the de novo use of ERT (ERT group [n=94]), standard-release tacrolimus (SRT group [n=42]) and early conversion (EC) from SRT to ERT (EC group [n=44]). Extended-release tacrolimus was used between 2007 and 2012. One-year incidence rates of acute rejection, infection, and cytomegalovirus infection were analyzed. Safety parameters were also evaluated. ResultsThere were no significant between-group differences in the daily dose or trough levels of tacrolimus during the first year after transplantation. The rejection incidence rates were 1.05 (95%CI, 0.51-1.54), 1.39 (95%CI, 1.00-1.78), and 1.11 (95%CI, 0.58-1.65) episodes per patient-years in the SRT group, ERT group, and EC group, respectively (P=.48). The infection incidence rates were 0.75 (95%CI, 0.60-0.86), 0.62 (95%CI, 0.52-0.71), and 0.55 (95%CI, 0.40-0.68) in the SRT group, ERT group, and EC group, respectively (P=.46). Cytomegalovirus infection occurred in 23.8%, 20.2%, and 18.2% of the patients, respectively (P=.86). No significant between-group differences were found in laboratory tests or in allograft function. There was 1 death in the SRT group and 2 in the ERT group. ConclusionsBoth de novo and early use of ERT seem to have similar safety and efficacy profiles to conventional SRT-based immunosuppression.

Hepatitis due to Epstein–Barr virus and cytomegalovirus: clinical features and outcomes

Objective: To determine the frequency of cytomegalovirus (CMV) and Epstein–Barr virus (EBV) hepatitis among those with acute CMV and EBV infection in a population based setting and to compare these two types of hepatitis and analyze the outcomes.Methods: A retrospective search was undertaken on all patients with IgM antibodies to CMV and EBV during the period of 2006–2015 in the virological database of the University Hospital of Iceland covering the metropolitan area of Reykjavík (population 202,255). Patients with available liver tests at the University Hospital and/or admitted to this institution were included and relevant clinical data obtained from medical records.Result: Overall, 190 patients had acute EBV infection during the study period and 118 patients were diagnosed with acute CMV. Overall, 82% of patients with acute EBV infection had hepatitis, males 43%, median age 17 years, 15% had jaundice and 26% hospitalized. Among those with acute CMV infection, 69% had elevated liver tests, 63% males, median age 33 years, 9% had jaundice and also 26% hospitalized. Overall, 17% of those with CMV hepatitis were immunosuppressed, 6% were pregnant and 4% developed Guillain–Barré syndrome following the infection.Conclusion: A high proportion of patients with acute CMV and EBV developed hepatitis and jaundice, most of those patients have good prognosis. Patients with CMV hepatitis were more often immunosuppressed, required hospitalization or were pregnant in comparison with patients with EBV hepatitis.

Abdominal Complications After Lung Transplantation in a Brazilian Single Center

Surgical and nonsurgical abdominal complications have been described after lung transplantation. However, there is limited data on this event in this population. The objective of this study was to analyze the incidence of abdominal complications in patients undergoing lung transplantation at the Heart Institute of the Faculty of Medicine, University of São Paulo (InCor-HCFMUSP) between the years 2003 and 2016. The main causes of abdominal complications were inflammatory acute abdomen (7 patients; 14%), obstructive acute abdomen (9 patients; 18%), gastroparesis (4 patients; 8%), distal intestinal obstruction syndrome (4 patients; 8%), perforated acute abdomen (7 patients; 14%), cytomegalovirus (CMV; 6 patients; 12%), and other reasons (12 patients; 26%). Separating these patients according to Clavien-Dindo classification, we had 21 patients (43%) with complications grade II, 4 patients (8%) with complications grade IIIa, 7 patients (14%) with grade IIIb complications, 7 patients (14%) with grade IV complications, and 10 patients (21%) with grade complications V. In conclusion, abdominal disorders are seriously increased after lung transplantation and correlate with a high mortality. Early abdominal surgical complication has worse prognosis.

Harnessing crossreactivity of cytomegalovirus-reactive γδ T cells for immunotherapy in childhood neuroblastoma: a preclinical study

BackgroundNeuroblastoma is the commonest cancer in infants. Survival in high-risk groups is low (40–50%). Newer treatments are needed to improve survival and morbidity. Cytomegalovirus (CMV) is a common viral infection, which increases γδ T cells. We investigated the use of CMV-reactive γδ T cells as a potential new immunotherapy. MethodsPeripheral blood mononuclear cells from 30 paediatric haemato-oncology patients with or without CMV infection were analysed by flow cytometry. γδ T cells were expanded, and then co-cultured with CMV targets or neuroblastoma cells. T-cell activation, cytokine secretion, killing activity, and mechanisms were determined by ELISA, MTT colorimetric assay, and blocking assays. Novel γδ T cell receptors (TCR) were identified by sequencing. FindingsIn paediatric haemato-oncology patients, acute CMV led to higher proportions of total γδ T cells (p=0·0002) with the dominant subtype Vδ1 (p=0·0035). CMV-reactive γδ T cells were of the effector memory phenotype and expanded to clinically significant numbers for adoptive transfer. When compared with γδ T cells from CMV-negative patients, CMV-reactive γδ T cells had statistically significantly higher interferon γ release (p<0·001) in co-cultures with CMV-infected fibroblasts and showed cytolytic activity against CMV-infected fibroblasts and neuroblastoma cells which was mediated by γδ TCR and the NKG2D receptor. Sequencing showed that the dominant γδ T-cell chains in CMV-infected patients were Vδ1 Vγ2. Within the TCRs, CDR3 sequences had minimal diversity, γ chains had wide variations, and we identified a novel subpopulation in some patients. InterpretationWe show that acute CMV infection in paediatric haemato-oncology patients leads to an increase in the Vδ1 Vγ2 subtype of γδ T cells. They can be expanded for adoptive transfer and are likely to retain killing ability post expansion. They recognise and kill CMV-infected targets and neuroblastoma cells via the γδ TCR and the NKG2D receptor. We have identified a novel TCR in a subpopulation of CMV-positive patients. FundingGreat Ormond Street Charity, National Institute for Health Research Biomedical Research Centre, Olivia Hodson Cancer Fund.

A Case of Multiple Venous Thromboses Associated with Acute Cytomegalovirus Infection

A previously healthy 44-year-old male presented with fever, abdominal pain, liver dysfunction and lymphadenopathy. He was diagnosed as having acute cytomegalovirus (CMV) infection with elevated CMV-IgG and IgM, and observed with supportive therapy. He was admitted to our hospital with prolonged fever lasting for a month. Enhanced CT revealed multiple thromboses in the right pulmonary artery and superior mesenteric vein. Follow-up CT after one week revealed new-onset thromboses in the left pulmonary artery and common iliac vein. Screening tests for thrombophilia were negative. His symptoms were improved with anticoagulant therapy with intravenous heparin, followed by oral warfarin. He was discharged on admission day 28 with good condition. Follow-up CT after 6 months revealed complete resolution of the thromboses. Anticoagulant therapy was stopped after 9 months, and he has been well without recurrence. Though vascular thrombosis is a rare complication, we must be alert to the signs and symptoms of thrombosis in patients with acute CMV infection.

Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+ T Cell Response by Preventing Type I IFN-Dependent Depletion of Dendritic Cells.

Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8+ T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8+ T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8+ T cell response to two immunodominant epitopes. The decreased response was due to type I IFN-dependent depletion of conventional dendritic cells and could be reproduced by specific depletion of dendritic cells from day 2 postinfection or by sterile induction of type I IFN. Increased virus replication and type I IFN specifically inhibited the response to two immunodominant epitopes that are known to be dependent on Ag cross-presented by DCs, but they did not inhibit the response to "inflationary" epitopes whose responses can be sustained by infected nonhematopoietic cells. Our results show that type I IFN can suppress CD8+ T cell responses to cross-presented Ag by depleting cross-presenting conventional dendritic cells.