Cytomegalovirus Hyperimmunoglobulin Research Articles

342.10: Evaluation of CMV Hyperimmunoglobulin Use in a large European non-interventional, multicenter study after heart and lung transplantation.

342.10: Evaluation of CMV Hyperimmunoglobulin Use in a large European non-interventional, multicenter study after heart and lung transplantation.

Role of Preemptive Cytomegalovirus Hyperimmunoglobulin in Cytomegalovirus Viremia Following Stem Cell Transplant: An Integrative Review.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in stem cell transplant (SCT) patients. Cytomegalovirus hyperimmunoglobulin (CMV-HIG) therapy has been described in the solid organ transplant setting. However, no review has focused on preemptive use of intravenous CMV immunoglobulins in the SCT setting. This review aims to consolidate findings regarding the preemptive use of CMV-HIG for CMV viremia in SCT patients. PubMed and Scopus were searched using specific search criteria for publications from 2011 to 2021. Search terms were: cytomegalovirus, CMV, immunoglobulins, immunoglobulin, IVIG, CMVIG, hematopoietic stem cell transplantation, and stem cell. Included studies discussed stem cell transplantation, immunoglobulins, and cytomegalovirus. 366 articles were identified from the search. Five articles met the inclusion and exclusion criteria. Preemptive CMV-HIG resulted in an overall response in 65% to 100% of patients with a clearance time of 14 to 21 days. Early use of CMV-HIG may shorten clearance time. No treatment-related mortality or serious adverse events were associated. CMV-HIG is an effective treatment option in SCT patients that is as safe as antivirals alone. Preemptive CMV-HIG with antivirals may provide the added advantage of reduced time to viremia clearance without adding renal injury. Larger, prospective studies are needed to evaluate CMV-HIG's impact on time to viremia clearance and the effectiveness of preemptive CMV-HIG use with antivirals.

Effectiveness of Prophylactic Human Cytomegalovirus Hyperimmunoglobulin in Preventing Cytomegalovirus Infection following Transplantation: A Systematic Review and Meta-Analysis.

Cytomegalovirus (CMV) is a common infection occurring in patients undergoing solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). CMV-specific hyperimmunoglobulin (CMVIG) has been used for the past four decades and is typically administered either prophylactically or pre-emptively. The present meta-analysis evaluated CMV infection rates in SOT patients who received prophylactic CMVIG. PubMed and the Cochrane Library were searched for studies published up to October 2021. The primary endpoint was CMV infection rate. Thirty-two SOT studies were identified (n = 1521 CMVIG-treated and n = 1196 controls). Prophylactic CMVIG treatment was often associated with a lower risk of CMV infection in transplant recipients. The average CMV infection rate was 35.8% (95% confidence interval [CI]: 33.4–38.2%) in patients treated prophylactically with CMVIG and 41.4% (95% CI: 38.6–44.2%) in the control group not receiving CMVIG (p = 0.003). Similar results were observed in analyses limited to publications evaluating currently available CMVIG products (Cytotect CP and Cytogam; p < 0.001). In combination with the established safety profile for CMVIG, these results suggest that prophylactic CMVIG treatment in patients undergoing solid organ transplantation may be beneficial, particularly in those at high risk of CMV infection or disease.

Serial Monitoring and Hyperimmunoglobulin versus Standard of Care to Prevent Congenital Cytomegalovirus Infection: A Phase III Randomized Trial

Introduction: Nonrandomized studies support the potential of cytomegalovirus hyperimmunoglobulin (CMV-HyperIg) in preventing maternofetal CMV transmission, but prospective interventional studies show equivocal results. We pre­sent a prospective phase-III international randomized open-label trial on the potential effect of CMV-HyperIg following serial monitoring of CMV serostatus. Methods: CMV-seronegative pregnant women (gestational age [GA] <14 weeks) were 1:1 randomized to monthly CMV-serostatus monitoring and CMV-HyperIg upon seroconversion (treatment), or routine prenatal care with CMV-serostatus testing at end of pregnancy (control). Ethical considerations required that control subjects with confirmed seroconversion be offered Cytotect®. The primary endpoint was the proportion of fetuses/newborns with congenital CMV infection. Secondary endpoints included neonatal CMV disease and safety during the 24-month follow-up. Results: The treatment arm counted 4,800 randomized subjects: 52 seroconverted (median GA 24 [11–35] weeks), of which 45 completed follow-up. The control arm counted 4,735 randomized subjects: 42 seroconverted, of which 34 completed follow-up (evaluable data for 28 newborns) and 8 subjects chose off-label Cytotect®. Congenital CMV rates were 13/28 newborns (46.4% [CI 27.51; 66.13]) vs. 16/45 newborns (35.6% [CI 21.87; 51.22]) in control and treated arms, respectively (p = 0.46). Newborn CMV disease was mostly mild and spontaneously resolving. There were no major safety concerns. The target sample was not reached within an acceptable time frame. Conclusions: Serial monitoring of CMV serostatus with CMV-HyperIg treatment was associated with a mild nonsignificant reduction in the vertical CMV transmission rate. Studies on the optimal preventive strategy are hampered by epidemiological and ethical challenges and should focus on GA-dependent transmission rates and accurate dating of infection.

Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection.

Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of 'direct' anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT.

EFFECTIVE HYPERIMMUNOGLOBULIN TREATMENT IN CMV-MYOCARDITIS

Over a period of 26 years we treated 37 consecutive patients with a CMV-PCR positive, histologically validated myocarditis with either CMV hyperimmunoglobulin (CMVhIg)in addition to heart failure therapy or with heart failure therapy alone. 19 pts received 2ml/kg i.v. for 3 and 1ml/kg for 2

Impact of Immunoglobulin Therapy in Intestinal Transplant Recipients With Posttransplantation Hypogammaglobulinemia

BackgroundSevere hypogammaglobulinemia (HGG) (IgG <400 mg/dL) following intestinal transplantation is common. Although IgG replacement therapy is commonly used, clinical outcomes associated with increasing IgG levels to >400 mg/dL are not well described. MethodsKaplan–Meier analysis was performed to estimate survival, the log-rank test to compare survival distributions between groups, and the Fisher exact test to determine the association between HGG and rejection. ResultsA total of 23 intestinal transplant (IT) recipients with a median age of 2.3 years (range, 0.7–41 years) at the time of HGG diagnosis were included. The types of transplants were liver–small bowel (73.9%), liver–small bowel–kidney (8.7%), and small bowel only (17.4%). The 3-year survival after the diagnosis of HGG was 50.2% (95% confidence interval [CI] = 28.2%–68.7%). There was no difference in survival (P = .67) when patients were dichotomized based upon IgG level at last follow-up (IgG ≥400 mg/dL, n = 14; and IgG <400 mg/dL, n = 9). There was no also evidence of an association between survival and: total dose (P = .58), frequency (P = .11), and number of IgG doses administered (P = .8). There was no difference in survival between patients receiving (n = 12) or not receiving (n = 11) cytomegalovirus hyperimmunoglobulin (P = .10). ConclusionsImproved survival rates were not found in our IT recipients with severe HGG with immunoglobulin therapy to IgG levels of ≥400 mg/dL, even when cytomegalovirus hyperimmunoglobulin was administered.

Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation.

Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation.

Does increasing immunoglobulin levels impact survival in solid organ transplant recipients with hypogammaglobulinemia?

Severe hypogammaglobulinemia (IgG<400mg/dL) has adverse impact on mortality during the first year post-transplantation. The aim of the study was to determine whether increasing IgG levels to ≥400mg/dL improved outcomes. Kaplan-Meier analyses were performed to estimate survival, log-rank test to compare survival distributions between groups, and Fisher's exact test to determine the association between hypogammaglobulinemia and rejection or graft loss. Thirty-seven solid organ transplant (SOT) recipients were included. Hypogammaglobulinemia was diagnosed at median of 5.6months (range: 0-291.8months) post-transplantation. Types of transplants: liver-small bowel (17); liver-small bowel-kidney (2); liver (5); small bowel (4); liver-kidney (1); kidney/kidney-pancreas (3); heart (3); heart-kidney (1); and heart-lung (1). The three-yr survival after the diagnosis of hypogammaglobulinemia was 49.5% (95% CI: 32.2-64.6%). Patients were dichotomized based upon IgG level at last follow-up: IgG≥400mg/dL (23 patients) and IgG<400mg/dL (14 patients). There was no evidence of a difference in survival (p=0.44), rejection rate (p=0.44), and graft loss censored for death (p=0.99) at oneyr between these two groups. There was no difference in survival between patients receiving or not immunoglobulin (p=0.99) or cytomegalovirus hyperimmunoglobulin (p=0.14). Severe hypogammaglobulinemia after SOT is associated with high mortality rates, but increasing IgG levels to ≥400mg/dL did not seem to translate in better patient or graft survival in this cohort.

426: Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease

426: Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease

Hyperimmunoglobulin for Prevention of Congenital Cytomegalovirus Disease

Primary cytomegalovirus (CMV) infection during the first half of pregnancy is responsible for the majority of symptomatic congenital infections. Between one-third and one-half of fetuses become infected, and up to one-half of infected fetuses will have neurologic or sensorineural sequelae at birth or later in life. Following favorable results obtained in animal experiments, observational studies have shown beneficial effects after administration of high-titer CMV hyperimmunoglobulin to pregnant women with fetal infection or disease subsequent to primary CMV infection. The mechanisms of action of hyperimmunoglobulin are multiple and not yet fully understood. However, they could reside in 2 major properties: (1) antiviral activities due to high-avidity neutralizing antibodies and (2) immunomodulating activities mostly including downregulation of cytokine-mediated cellular immune responses. A decreased viral pathogenicity occurs as an immediate consequence, whereas reduced placental inflammation and restored function are the long-term effects.

Cytomegalovirus infection and CMV-hyper immunoglobulin therapy

Cytomegalovirus infection and CMV-hyper immunoglobulin therapy

CMV Hyperimmunoglobulin Improves Outcome in Congenital Infection

CMV Hyperimmunoglobulin Improves Outcome in Congenital Infection

CMV Infection and Pregnancy

Cytomegalovirus (CMV) occurs in 0.2 % to 2.2 % of all live births and is the most common cause of intrauterine infection and the leading infectious cause of sensorineural hearing loss and mental retardation. This article reviews literature that relate to the pathogenesis, diagnosis, and treatment of this disease for pregnant women and their fetus. Primary maternal CMV infection during pregnancy has a much higher rate of mother-to-fetus transmission and causes symptoms at birth and long-term disability than nonprimary infection. In addition, some research has shown that children with congenital CMV infection following first-trimester maternal infection are more likely to have severe sequelae. The prenatal diagnosis of fetal CMV infection includes serological testing (IgM detection and IgG avidity assay), amniocentesis, and ultrasound examination. The combination of the presence of CMV IgM antibodies and low CMV IgG avidity, along with maternal or fetal symptoms is used for the diagnosis of a primary maternal infection. Amniocentesis should be complemented until approximately 20-21 weeks of gestation to increase the sensitivity. Because ultrasound abnormalities are only found in less than 25 % of infected fetuses, ultrasound is as a relatively poor predictor of symptomatic congenital infection. CMV hyperimmunoglobulin also may be considered when the pregnant women are confirmed as primary CMV infection with low IgG avidity and amniotic fluid is found to contain CMV or CMV DNA. There is no consensus on the benefit of prenatal administration of ganciclovir into the umbilical vein.

Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis

The aim of this study was to investigate the current prenatal "off-label use" of cytomegalovirus hyperimmunoglobulin (CMV-HIG) in the prevention and treatment of congenital CMV (cCMV) infection, including the long-term outcome of the children. This retrospective observational study comprised mothers and their children, born between January 1, 2006, and October 30, 2010. Prenatal CMV-HIG was administered after diagnosis of primary CMV infection of the mother. Clinical and virological data were collected from maternal and pediatric medical and laboratory reports. Follow-up was 12-36 months after birth. Forty-two women and 43 children met the study criteria. In total, 40 mothers and six unborn infants received 115 doses of CMV-HIG. The treatment group (TG; CMV-DNA polymerase chain reaction-positive amniotic fluid) included four mothers; the multinomial group (MG; CMV-positive mother and unknown CMV status of fetus) included 38 mothers (39 infants). For the four unborn infants in TG, CMV-HIG was administered either intraumbilically or into the amniotic fluid; three of the four mothers received intravenous CMV-HIG. Three children in TG remained CMV-positive and were asymptomatic at birth and during follow-up. One infant in TG had symptomatic cCMV infection in utero, at birth, and during follow-up. In MG, 37 of 38 women received intravenous CMV-HIG and two of 39 infants received CMV-HIG in utero. In total, 9 (23.1%) of 39 children in MG were positive for cCMV (including a terminated pregnancy). All eight instances of cCMV infection at birth in MG were asymptomatic at birth and during follow-up. The fetus from the terminated pregnancy showed no sonographic symptoms of cCMV infection. No severe side effect occurred in 115 CMV-HIG applications. CMV-HIG was well tolerated. Compared with published untreated mother-child pairs, we observed a trend toward a smaller risk for intrauterine CMV transmission following CMV-HIG application. Signs of prenatal cCMV disease were not reversed after CMV-HIG.

CMV Infection in Pregnancy

Abstract Cytomegalovirus (CMV) is a common and serious congenital infection affecting between 1 to 4% of newborns. Congenital infections can occur after both primary and recurrent maternal infections and are the major cause of childhood deafness, visual impairment, mental retardation and motor spastic or convulsive syndromes. Ultrasound findings including IUGR, ventriculomegaly, brain and hepatic and bowel calcifications, polyhydramnios, hydrops fetalis and pleural effusions are helpful and can aid in the prenatal diagnosis and followup of congenital CMV infection. CMV hyperimmunoglobulin is safe, and may be an effective treatment to minimize the morbidity and mortality of fetal CMV disease. There is ongoing research into the development of an effective vaccine for the prevention of CMV infection during pregnancy. Objectives Understand why CMV is an important cause of congenital injections Understand the role of ultrasound in the diagnosis of intrauterine CMV infections Understand the possible treatment options for a fetus infected with CMV

Cytomegalovirus hyperimmunoglobulin: mechanisms in allo‐immune response in vitro

Cytomegalovirus hyperimmunoglobulin (CMVIg) containing drugs are routinely administered in cardiac transplantation for prophylaxis against CMV disease. Yet little is known about their influence on transplant relevant immune functions. The aim of this study was to evaluate the effect of CMVIg on cellular immunity in in vitro experiments and to define their role in tolerance inducing mechanisms. CMVIg reduces proliferation in mixed lymphocyte reactions and anti-CD3 blastogenesis assays and is related to decreased production of immune modulating cytokines interleukin (IL)-2, interferonr (IFNgamma), IL-10. This antiproliferative effect is associated with a cell-cycle arrest in the G0/G1 phase and induction of apoptosis in CD8+ and natural killer cells. Co-incubation with CMVIg causes down-regulation of cell bound immunoglobulin and FcgammaRIII surface expression on natural killer cells and leads to attenuation of antibody dependent cellular cytotoxicity effector functions. We conclude that CMVIg induces immunological features on leukocytes in vitro that are known to be related to tolerance induction. Our observations extend the current concept of CMVIg as passive CMV prophylaxis to a therapeutic drug compound capable of reducing allogeneic immune response.

Emergence of drug‐resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes

Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir-resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug-resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis. The medical records of all CMV D+/R- kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug-resistant CMV were reviewed. During a four-yr-study period, a total of 225 CMV D+/R- transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty-five (29%) of the 225 patients developed delayed-onset primary CMV disease, including nine (14%) suspected to have drug-resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue-invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug-associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow-up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug-resistant CMV. Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug-resistant CMV is not uncommon in CMV D+/R- solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug-resistant CMV on the successful outcome of organ transplantation.

Intrauterine therapy with cytomegalovirus hyperimmunoglobulin for a fetus congenitally infected with cytomegalovirus

Reported herein is a case of hydrops fetalis in which the cord blood expressed cytomegalovirus (CMV) antigen. Fetal ascites was removed from an infected fetus with hydrops in utero and 2.5 g CMV hyperimmunoglobulin was administered into the fetal abdominal cavity at 28 weeks gestation. After immunoglobulin administration, fetal ascites vanished, preload index of the inferior vena cava decreased and platelet count of the infant increased. However, despite intrauterine therapy and intensive neonatal care, the infant died soon after birth. The expression of CMV antigen in the nucleus of polymorphonuclear leukocytes in fetal cord blood indicated that the fetal hydrops was caused by CMV infection. When symptomatic CMV infection of a fetus is suspected from serological and ultrasound findings, further examinations should be performed for the diagnosis. Intrauterine immunoglobulin therapy could be one of the therapeutic options for the affected fetus.

376: Anti-proliferative properties of CMV hyperimmunoglobulin are related to activation induced cell death in vitro: Possible role in tolerance induction

ANTI-PROLIFERATIVE PROPERTIES OF CMV HYPERIMMUNOGLOBULIN ARE RELATED TO ACTIVATION INDUCED CELL DEATH IN VITRO: POSSIBLE ROLE IN TOLERANCE INDUCTION K. Hoetzenecker, S. Hacker, W. Hoetzenecker, K. Sadeghi, A. Pollreisz, A. Mangold, B. Moser, M. Grimm, F. Muehlbacher, W. Klepetko, E. Wolner, H.J. Ankersmit, Department of Surgery, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Medical University Tubingen, Tubingen, Germany; Department of Surgery, Columbia University, New York