Hyperimmune Globulin Therapy Research Articles

Biweekly Versus Monthly Hyperimmune Globulin Therapy for Primary Cytomegalovirus Infection in Pregnancy.

Primary cytomegalovirus (CMV) infection during pregnancy is associated with an increased risk of congenital CMV (cCMV). Hyperimmune globulin (HIG) therapy has been proposed as a potential prophylaxis to reduce maternal-fetal transmission. Data on whether the administration of HIG every 2 weeks offers benefits over HIG administration every 4 weeks are lacking. This was a retrospective analysis including pregnant women with primary CMV infection diagnosed in the first or early second trimester between 2010 and 2022 treated with HIG every 4 weeks (300 IE HIG per kg) or every 2 weeks (200 IE HIG per kg), respectively. In total, 36 women (4 weeks: n = 26; 2 weeks: n = 10) and 39 newborns (4 weeks: n = 29; 2 weeks: n = 10) were included. The median gestational age at the first HIG administration was 13.1 weeks. There was no significant difference in the cCMV rates between the women who received HIG every 4 versus every 2 weeks (n = 8/24 [33.3%] vs. 3/10 [30.0%]; p = 0.850). An abnormal fetal ultrasound was present in three fetuses and fetal magnetic resonance imaging (MRI) anomalies in four fetuses were related to cCMV infection, with no significant difference in the frequency between the two groups. A larger study will be needed to determine whether HIG administration every 2 instead of every 4 weeks improves the maternal-fetal transmission rates.

Hyperimmune Globulins for the Management of Infectious Diseases

This review is focused on the use of hyperimmune globulin therapy to treat some infectious diseases of viral or bacterial origin. Despite the introduction of antibiotics and vaccines, plasma immunoglobulin therapy from whole blood donation can still play a key role. These treatments provide passive transfer of high-titer antibodies that either reduces the risk or the severity of the infection and offer immediate but short-term protection against specific diseases. Antibody preparations derived from immunized human donors are commonly used for the prophylaxis and treatment of rabies, hepatitis A and B viruses, varicella-zoster virus, and pneumonia caused by respiratory syncytial virus, Clostridium tetani, Clostridium botulinum. The use of hyperimmune globulin therapy is a promising challenge, especially for the treatment of emerging viral infections for which there are no specific therapies or licensed vaccines.

Prevention of Congenital Cytomegalovirus Infection: Review and Case Series of Valaciclovir versus Hyperimmune Globulin Therapy.

Cytomegalovirus (CMV) is the most common cause of congenital infections in developed countries because is capable of infecting the fetus after both primary and recurrent maternal infection, and because the virus may be spread for years through infected children. Moreover, CMV is the most serious congenital infection associated with severe neurological and sensorineural sequelae, which can occur at birth or develop later on. Hygienic measures can prevent CMV transmission, which mainly involve contact with children under 3 years of age and attending a nursery or daycare. In animal and human pregnancies, many observational and controlled studies have shown that CMV-specific hyperimmune globulin (HIG) is safe and can significantly decrease maternal-fetal transmission of CMV infection and, mostly, the occurrence of CMV disease. Recently, valaciclovir at the dosage of 8 g/day was also reported to be capable of decreasing the rates of congenital infection and disease. However, comparing the results of our two recent case series, the infants born to women treated with HIG showed significantly lower rates of CMV DNA positivity in urine (9.7% vs. 75.0%; p < 0.0001) and abnormalities after follow-up (0.0% vs. 41.7%; p < 0.0001). The implementation of CMV screening would enable primary prevention via hygiene counseling, improve the understanding and awareness of congenital CMV infection, and increase the knowledge of the potential efficacy of preventive or therapeutic HIG or antiviral administration.

The Association between Prenatal Nicotine Exposure and Offspring's Hearing Impairment.

The objective of this study is to evaluate whether there is an association between in-utero exposure to nicotine and subsequent hearing dysfunction. Secondary analysis of a multicenter randomized trial to prevent congenital cytomegalovirus (CMV) infection among gravidas with primary CMV infection was conducted. Monthly intravenous immunoglobulin hyperimmune globulin therapy did not influence the rate of congenital CMV. Dyads with missing urine, fetal or neonatal demise, infants diagnosed with a major congenital anomaly, congenital CMV infection, or with evidence of middle ear dysfunction were excluded. The primary outcome was neonatal hearing impairment in one or more ears defined as abnormal distortion product otoacoustic emissions (DPOAEs; 1 to 8 kHz) that were measured within 42 days of birth. DPOAEs were interpreted using optimized frequency-specific level criteria. Cotinine was measured via enzyme-linked immunosorbent assay kits in maternal urine collected at enrollment and in the third trimester (mean gestational age 16.0 and 36.7 weeks, respectively). Blinded personnel ran samples in duplicates. Maternal urine cotinine >5 ng/mL at either time point was defined as in-utero exposure to nicotine. Multivariable logistic regression included variables associated with the primary outcome and with the exposure (p < 0.05) in univariate analysis. Of 399 enrolled patients in the original trial, 150 were included in this analysis, of whom 46 (31%) were exposed to nicotine. The primary outcome occurred in 18 (12%) newborns and was higher in nicotine-exposed infants compared with those nonexposed (15.2 vs. 10.6%, odds ratio [OR] 1.52, 95% confidence interval [CI] 0.55-4.20), but the difference was not significantly different (adjusted odds ratio [aOR] = 1.0, 95% CI 0.30-3.31). This association was similar when exposure was stratified as heavy (>100 ng/mL, aOR 0.72, 95% CI 0.15-3.51) or mild (5-100 ng/mL, aOR 1.28, 95% CI 0.33-4.95). There was no association between nicotine exposure and frequency-specific DPOAE amplitude. In a cohort of parturients with primary CMV infection, nicotine exposure was not associated with offspring hearing dysfunction assessed with DPOAEs. · Nicotine exposure was quantified from maternal urine.. · Nicotine exposure was identified in 30% of the cohort.. · Exposure was not associated with offspring hearing dysfunction..

Hyperimmune globulin in pregnancy for the prevention of congenital cytomegalovirus disease

ABSTRACTIntroduction: Cytomegalovirus (CMV) is the most common and serious cause of congenital infections in developed countries since it is capable of infecting the fetus after both primary and recurrent maternal infection, and can be spread for years by infected children.Areas covered: Animal and human pregnancy studies about the prevention of congenital CMV infection and disease by CMV-specific hyperimmune globulin (HIG). Commercial HIG is manufactured from the plasma of selected donors with high anti-CMV antibody avidity and titers.Expert commentary: Currently available experimental and clinical studies and case reports support the possible effectiveness and safety of HIG infusions in pregnancy for the prevention of congenital CMV disease. The knowledge about the potential efficacy of preventive or therapeutic HIG administration should be enlarged by multi-center randomized studies, which may be favored by the implementation of CMV screening. Meanwhile, if ultrasound examinations show signs of fetal injury, or CMV is detected in the amniotic fluid, the patients should be advised about the possible option of HIG therapy.

Congenital Cytomegalovirus.

Congenital cytomegalovirus (CMV) is the leading viral intrauterine infection in the United States. It causes more developmental delays and long-term sequelae than Down syndrome (trisomy 21), neural tube defects, or fetal alcohol syndrome combined. Yet, this virus, a member of the herpes virus family, is not well known to the public and its prevention is typically not discussed in obstetric offices. Although many infants with congenital CMV are asymptomatic at birth, a significant proportion still may develop sequelae. Symptomatic infants face potentially devastating consequences. Pharmacologic treatment is reserved for those with severe organ or central nervous system involvement. Treatment of infants with congenital CMV can be complex and requires extensive outpatient follow-up. To educate nurses and nurse practitioners regarding the risks, signs, treatment, and care related to congenital CMV. PubMed was searched to obtain English language publications from 2005 to 2015 for studies examining the current knowledge base of congenital cytomegalovirus, sequelae, and subsequent treatment using key terms "cytomegalovirus" combined with "congenital." A total of 18 articles were retained for analysis. Overall, the greatest risk reduction strategy for CMV transmission is education of pregnant women. In the neonate at risk for congenital CMV, early identification, antiviral treatment, and care coordination are pivotal to maximizing outcomes. Increasing understanding of congenital CMV, modes of transmission, signs of infection, and intervention strategies as well as its impact on development are essential to maximizing outcomes. The need for research exists in the area of valganciclovir's impact on sensorineural hearing loss as well as potential vaccines to protect against CMV transmission. Research is also being conducted in the area of passive immunity via administration of CMV-specific hyperimmune globulin therapy to pregnant women diagnosed with a primary CMV infection.

Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review.

Human cytomegalovirus is the leading non-genetic cause of congenital malformation in developed countries. Congenital CMV may result in fetal and neonatal death or development of serious clinical sequelae. In this review, we identified evidence-based interventions for prevention of congenital CMV at the primary level (prevention of maternal infection), secondary level (risk reduction of fetal infection and disease) and tertiary level (risk reduction of infected neonates being affected by CMV). A systematic review of existing literature revealed 24 eligible studies that met the inclusion criteria. Prevention of maternal infection using hygiene and behavioural interventions reduced maternal seroconversion rates during pregnancy. However, evidence suggested maternal adherence to education on preventative behaviours was a limiting factor. Treatment of maternal CMV infection with hyperimmune globulin (HIG) showed some evidence for efficacy in prevention of fetal infection and fetal/neonatal morbidity with a reasonable safety profile. However, more robust clinical evidence is required before HIG therapy can be routinely recommended. Limited evidence also existed for the safety and efficacy of established CMV antivirals (valaciclovir, ganciclovir and valganciclovir) to treat neonatal consequences of CMV infection, but toxicity and lack of randomised clinical trial data remain major issues. In the absence of a licensed CMV vaccine or robust clinical evidence for anti-CMV therapeutics, patient education and behavioural interventions that emphasise adherence remain the best preventative strategies for congenital CMV. There is a strong need for further data on the use of HIG and other antivirals in pregnancy, as well as the development of less toxic, novel, antiviral agents.

Passive Immunization During Pregnancy for Congenital Cytomegalovirus Infection

Purpose of the Study. To investigate the effectiveness of cytomegalovirus (CMV)-specific hyperimmune globulin for primary CMV infection during pregnancy as a preventive therapy for fetal CMV infection. Study Population. One hundred fifty-seven pregnant women from 8 Italian cities with a primary CMV infection diagnosed via serologic testing. Methods. Women were placed in 1 of 2 groups. The therapy group comprised women who underwent amniocentesis and whose amniotic fluid contained either CMV detected by culture or CMV DNA detected by polymerase chain reaction. The group was offered intravenous CMV-specific hyperimmune globulin at a dose of 200 U per kg of maternal weight. Additional intravenous, intraumbilical-cord, or intra-amniotic doses were administered if evidence of persistent fetal involvement was present on ultrasound. Women with CMV-positive amniotic fluid who declined to receive hyperimmune-globulin infusions were followed as a comparison group. Those in the prevention group, consisting of women with a recent primary infection before 21 weeks’ gestation or who declined amniocentesis, were offered monthly hyperimmune globulin (100 U/kg intravenously). Pregnant women who declined monthly administration of hyperimmune globulin were followed as a comparison group. Results. In the therapy group, 31 women received hyperimmune globulin, only 1 (3%) of whom gave birth to an infant with symptomatic CMV disease, compared with 7 (50%) of 14 women who did not receive hyperimmune globulin. Thus, hyperimmune-globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio: 0.02; 95% confidence interval: −∞ to 0.15; P &amp;lt; .001). In the prevention group, 37 women received hyperimmune globulin, 6 (16%) of whom had infants with congenital CMV infection, compared with 19 (40%) of 47 women who did not receive hyperimmune globulin. Thus, hyperimmune-globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio: 0.32; 95% confidence interval: 0.10 to 0.94; P = .04). No adverse effects resulted from CMV-specific hyperimmune globulin administration. Conclusions. Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may be appropriate. Reviewer Comments. The risk of congenital CMV infection is high after primary maternal CMV infection. Although the majority of congenitally acquired CMV infections are asymptomatic, symptomatic infections result in significant morbidity and possible mortality. The implementation of CMV-specific hyperimmune globulin may reduce or prevent the devastating effects of symptomatic congenital CMV.

Passive Immunization during Pregnancy for Congenital Cytomegalovirus Infection

Currently, there is no effective intervention for a primary cytomegalovirus (CMV) infection during pregnancy. We studied pregnant women with a primary CMV infection. The therapy group comprised women whose amniotic fluid contained either CMV or CMV DNA and who were offered intravenous CMV hyperimmune globulin at a dose of 200 U per kilogram of maternal weight. A prevention group, consisting of women with a recent primary infection before 21 weeks' gestation or who declined amniocentesis, was offered monthly hyperimmune globulin (100 U per kilogram intravenously). In the therapy group, 31 women received hyperimmune globulin, only 1 (3 percent) of whom gave birth to an infant with CMV disease (symptomatic at birth and handicapped at two or more years of age), as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio, 0.02; 95 percent confidence interval, -infinity to 0.15; P<0.001). In the prevention group, 37 women received hyperimmune globulin, 6 (16 percent) of whom had infants with congenital CMV infection, as compared with 19 of 47 women (40 percent) who did not receive hyperimmune globulin. Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio, 0.32; 95 percent confidence interval, 0.10 to 0.94; P=0.04). Hyperimmune globulin therapy significantly (P<0.001) increased CMV-specific IgG concentrations and avidity and decreased natural killer cells and HLA-DR+ cells and had no adverse effects. Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate.

Posttransplant lymphoproliferative disorder in pediatric renal transplantation.

Of 84 renal transplants performed in our center since 1986, six recipients (7.1%) developed posttransplant lymphoproliferative disorder (PTLD). All received quadruple immunosuppression with Minnesota anti-lymphoblastic globulin or anti-thymocyte globulin, methylprednisolone, cyclosporine, and azathioprine or mycophenolate mofetil. Five were seronegative for Epstein-Barr virus (EBV) when they received their renal transplant. All patients received prophylactic acyclovir treatment postrenal transplant and none developed a cytomegalovirus (CMV) infection. All patients were positive for EBV by serology and polymerase chain reaction at the time of diagnosis of PTLD. Clinical features at presentation included fever (6/6), adenopathy (4/6), hypertrophied adenoids (4/6), liver involvement (2/6), and allograft involvement (2/6), 2-78 months (4/6<6 months) postrenal transplant. Histopathology of PTLD tissue revealed T cell rich/ Hodgkin disease-like B cell PTLD in one patient, polymorphic PTLD in four, and monomorphic (large B cell lymphoma) PTLD in one. Immunophenotyping of the PTLD biopsy specimen revealed predominant T cells in three, mixed B and T cells in two patients, and B cell in one. No aneuploid populations were identified by flow cytometric DNA ploidy assay. DNA from the PTLD tissue revealed weak to moderate IgH gene rearrangement in four of six patients but no T cell receptor beta-chain or c-myc gene rearrangement on Southern blot analysis. The child with monomorphic (large B cell lymphoma) PTLD was clonal with lambda light chain restriction on immunophenotyping. Treatment consisted of reduced immunosuppression and ganciclovir/ acyclovir in all patients. CMV hyperimmune globulin was used as an adjunctive therapy in two patients. Chemotherapy was needed in only one patient. A single rejection episode occurred in two children following reduction in immunosuppression, which reversed following intravenous methylprednisolone therapy. PTLD resolved in all patients and at present all patients are alive with functional grafts 2-54 months post diagnosis. Our experience suggests that reduced immunosuppression and anti-viral treatment is adequate in most cases of PTLD, but chemotherapy and hyperimmune globulin therapy may be beneficial in cases resistant to first-line therapy. Since all but one of our patients were EBV seronegative at the time of transplant, vigilance is especially important for early detection of PTLD in this group of the pediatric renal transplant population.

Guidance of ganciclovir therapy with pp65 antigenemia in cytomegalovirus-free recipients of livers from seropositive donors.

Guidance of ganciclovir therapy with pp65 antigenemia in cytomegalovirus-free recipients of livers from seropositive donors.

Hyperimmune Globulin Therapy of Clinical Cytomegalovirus Infection in Renal Allograft Recipients

Intravenous cytomegalovirus (CMV) hyperimmune globulin therapy was used in 24 episodes of proven CMV disease in 22 renal allograft recipients. All patients had fever up to 39-40 degrees C for at least 3 days. Many patients had thrombocytopenia, leukopenia, and/or elevation of serum transaminase levels. Five had pneumonitis. The diagnosis of CMV infection was confirmed by isolation of virus from urine or bronchoalveolar lavage fluid using a rapid culture method based on the demonstration of CMV early nuclear protein in cell culture monolayers and/or by the demonstration of CMV specific IgM antibodies. The hyperimmune globulin was given until fever disappeared. The infusions were well tolerated and no side effects were recorded. A clinical response defined as normalization of body temperature, occurred in 23/24 cases. One patient with septic fever and a fatal outcome had a superinfection with tuberculosis. Two other fatal complications were caused by invasive pulmonary aspergillosis and by multiple penetrating duodenal ulcers. Two reversible acute rejections and one recurrence of the original renal disease were recorded. 19/22 patients are alive, 18 with normal renal function. We conclude that hyperimmune globulin therapy is well tolerated and may help to control sever CMV infections in renal transplant recipients.