Hyperimmune Globulin Research Articles

Novel therapies for Helicobacter pylori infection.

Increasing antibiotic resistance has begun to impair our ability to cure Helicobacter pylori infection. To evaluate orally administered novel therapies for the treatment of H. pylori infection. Healthy H. pylori infected volunteers received: (a) hyperimmune bovine colostral immune globulins, (b) an oligosaccharide containing an H. pylori adhesion target, Neu5Aca2-3Galb1-4Glc-(3'-sialyllactose), or (c) recombinant human lactoferrin. Outcome was assessed by urea breath test or histological assessment of the number of H. pylori present. None of the novel therapies appeared effective and no adverse events occurred. Although in vitro data appeared promising, in vivo results were disappointing. Higher doses, longer duration of therapy, adjunctive acid suppression, or a combination could possibly yield better results.

Cytomegalovirus infection in Kidney Transplant Patients: Clinical Manifestations and Diagnosis

Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after solid organ transplantation. CMV infection after kidney transplantation was confirmed in 19 (54.3%) out of 35 patients. 16 of these (84.2%) developed CMV disease. CMV infection was diagnosed based on a fourfold or greater increase of anti-CMV IgG antibody titre, detection of CMV-IgM antibodies and/or virus isolation. Primary infection was observed in 3 patients, reactivation in 9 and an undefined type of infection in 7. In most patients (63%), infection was diagnosed in the first 2 months, and in 3 patients, after 3, 5 and 9 years following kidney transplantation. The most frequent symptoms of CMV disease were fever (58%), pneumonitis (26.3%) and enterocolitis (15.8%). In 53% of the patients, CMV infection co-occurred with other pathogens such as Candida albicans. Cryptococcus neoformans, bacteria or viruses (HBV, HCV, HSV). Treatment with polyvalent globulin (Sandoglobin) or hyperimmune globulin (Cytotect), in combination with ganciclovir in 7 patients, resulted in a regression of CMV disease.

Cytomegalovirus Viremia in Lung Transplant Recipients Receiving Ganciclovir and Immune Globulin

Cytomegalovirus (CMV) disease is an important cause of organ transplant-related morbidity and mortality. During the last 5 years at our institution, prophylactic ganciclovir and hyperimmune globulin have been routinely administered to lung transplant recipients whenever the donor or the recipient was CMV antibody-positive. We sought to assess the efficacy of prophylaxis on viremia, CMV disease, and bronchiolitis obliterans syndrome (BOS). A retrospective chart review of 61 consecutive lung transplants performed between recipients between January 1993 and August 1995 was performed. Fifty-six patients who survived at least 1 month were analyzed. Patients were considered at risk for CMV disease whenever pretransplant donor or recipient serology was positive. Fourteen of the 39 patients at risk (36%) had viremia while on prophylaxis. The rate of CMV disease was 13% during the first 6 months following transplantation. A donor whose CMV serology was positive appeared to increase the risk of BOS in a Cox regression model (relative risk=2.4; 95% confidence interval=0.86-6.74; p=0.0957). Neither age, CMV infection (viremia or a positive specimen from BAL), recipient's serology at the time of transplantation, or CMV disease was associated with BOS. None of these variables was associated with mortality on Cox regression analysis or univariate analysis. Administration of combination ganciclovir and hyperimmune globulin prophylactic therapy to lung transplant recipients at risk for CMV infection and disease is associated with a relatively low incidence of disease, which appears only after prophylaxis treatment with ganciclovir is completed. Ganciclovir prophylaxis does not prevent CMV viremia; however, viremia while on prophylaxis is not predictive of disease.

Bronchiolitis: Etiology and management

Bronchiolitis is one of the most common causes of hospitalization in the first year of life. Viruses, particularly respiratory syncytial virus, are the principal causitive agents, although bacterial superinfection may occur in certain populations. Various therapeutic options, many of which are effective in asthma of older children, have been investigated for treatment of bronchiolitis in infancy. This report provides a critical review of available data on the etiology and treatment of bronchiolitis and wheezy bronchitis. Supplemental oxygen administration remains the mainstay of therapy for bronchiolitis. Available data suggest that certain infants may respond positively to inhaled β- or α-adrenergic agents, but these drugs have no effect on the rate of hospitalization or duration of illness. Corticosteroids, ipratropium, interferon, vitamin A, and respiratory syncytial virus hyperimmune globulin also seem to be ineffective. Whereas ribavirin may have minor beneficial effects, the cost of the drug precludes its use in virtually all circumstances.

HIV hyperimmune globulin or intravenous immune globulin inhibits response to an HIV vaccine.

The murine model was developed to assess the effects of maternally transferred HIV hyperimmune globulin or human intravenous immune globulin on the immunization of the offspring at 18-21 days of age with rgp 120SF2-complete Freund's adjuvant. Either HIV hyperimmune globulin or intravenous immune globulin was administered intraperitoneally to post-partum BALB/c mice and was transferred via milk to the offspring. Both HIV hyperimmune globulin and intravenous immune globulin inhibited the offspring anti-rgp 120SF2 IgG response to the vaccine. The HIV hyperimmune globulin inhibition persisted for 28 days after immunization while the intravenous immune globulin inhibition was still present at 63 days after immunization. In addition, the intravenous immune globulin had a more generalized immunosuppressive effect, inhibiting the IgG response to both rpg 120SF2 and an additional protein antigen, hen egg-white lysozyme. Effects of maternal or exogenously administered pre-existing antibody, including control antibodies (intravenous immune globulin), on the newborn response to HIV and other vaccines must be carefully evaluated when vaccine studies proceed in newborns.

Respiratory syncytial virus immunoglobulin and monoclonal antibodies in the prevention and treatment of respiratory syncytial virus infection

Respiratory syncytial virus (RSV) infection is particularly severe in infants with bronchopulmonary dysplasia (BPD) and in premature infants without BPD. Attempts to develop a vaccine against RSV have been unsuccessful. Passive immunoprophylaxis of premature infants with or without BPD using a hyperimmune human globulin against RSV (RSVIg) decreases the severity of RSV infection such that the rate of hospitalization following infection is reduced by 40%. The severity of illness among hospitalized infants is also reduced. To avoid the difficulties associated with intravenous infusion of immunoglobulins, monoclonal IgG antibodies against the fusion protein of RSV have been developed. In one trial, the antibodies were ineffective, although subsequent trials using higher doses of the antibody show more promising results. Studies of IgA monoclonal antibodies directed against RSV, which are administered in the form of nose drops, are also in progress. None of these preparations appear to be effective in the treatment of established RSV infection. Each of the preparations appeared to be safe, with one exception. Infants with cyanotic heart disease who received RSVIg had an increased risk of surgical complications, perhaps related to increases in serum viscosity as a result of receiving the hyperimmunoglobulin monthly in doses of 750 mg/kg. While definitive cost/benefit analyses are pending, RSVIg may be useful in infants and children with BPD who have current or recent oxygen requirements, as well as in certain premature infants without BPD. Recommendations on the use of RSVIg are provided.

Antiviral Immunotherapy

Unselected intramuscular (IM) and intravenous (IV) immunoglobulins, as well as virus-specific hyperimmune globulins, occupy important roles as immunotherapy for viral infections. Standard IM immunoglobulins may be utilised in selected, susceptible patients for the prevention of hepatitis A and measles. Hyperimmune globulins to varicella zoster virus (VZV), hepatitis B virus and rabies have established indications for use as post-exposure prophylaxis. Cytomegalovirus (CMV) hyperimmune globulin has an indication for the prevention of primary CMV-associated disease in kidney transplantation and has been shown to decrease severe CMV-associated disease in liver transplantation. More recently, respiratory syncytial virus (RSV) hyperimmune globulin has been developed and is being utilised to prevent RSV disease in high risk infants and children during months of maximum risk for RSV infection. Unselected IV immunoglobulins (IVIg) have proven beneficial in preventing CMV-associated disease and graft-versus-host-disease in allogeneic bone marrow transplant recipients. In addition, IVIg plus ganciclovir is effective therapy for established CMV disease in both bone marrow and solid organ transplantation. IVIg for chronic anaemia associated with parvovirus B19 infection is gaining acceptance, as is the use of IVIg and intraventricular immunoglobulin for chronic meningoencephalitis associated with agammaglobulinaemia. Immunotherapy for the prevention or treatment of several other viral infections has been explored, but without clear conclusions. The use of human immunodeficiency virus (HIV) hyperimmune globulins in HIV-infected patients has yielded inconsistent results and the role of such therapy in the era of highly active antiretroviral therapy is uncertain. Oral immunoglobulins appear successful for rotaviral infections, but their exact use requires further clarification. Other immunotherapeutic modalities, such as monoclonal antibodies against CMV, RSV and HIV, have been developed but these agents have not undergone extensive clinical evaluation.

Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation.

"Escape" variants of hepatitis B virus (HBV) can cause infection despite previous immunization. These viruses show alterations of the immunogenic major hydrophilic loop of the HBV small surface protein (s-protein). We studied whether HBV "escape" variants were selected in patients with graft infection after liver transplantation for HBV-related diseases who received passive immunoprophylaxis with high-dose polyclonal hepatitis B hyperimmune globulin (HBIG). For that, pre- and posttransplantation sera of 34 patients were analyzed for the occurence of HBV S-gene variants. In addition, binding of in vitro-translated variant s-proteins to HBIG was studied. Variants with exchanges of amino acid (aa) 144 (s144) in HBV genotype A and 145 in genotype D (s145) were found to emerge, persist, and predominate during HBIG, and thus fulfilled criteria of "escape" variants selected. In addition to already-known variants sG145R/K/E, we could demonstrate that newly described variants sX144G and sG145A were antigenically altered and showed impaired recognition by polyclonal HBIG in vitro. Diminished recognition of variant s-proteins correlated with the failure of HBIG to prevent infection of the liver graft with antigenically altered variant HBV Patients infected with "escape" variants s144 or s145 showed a worse clinical outcome compared with the other patients on high-dose, long-term HBIG prophylaxis (44% vs. 23% graft failure caused by HBV infection). Our results suggest that antigenically altered HBV variants s144 and s145 can be selected by HBIG and can influence clinical outcome after liver transplantation.

İmmünoglobulinler ve Klinik Uygulamadaki Yerleri

In this paper current knowledge about and clinical uses of immunoglobulins has been reviewed Basic information has been summarized and the development of immunoglobulin production and some milestones in the history of treatment with these products has also been provided The usage of the different preparations of immunoglobulins which aim replacement prophylaxis or immunomodulation has been tabulated Key words: Immunoglobulins Gamma Globulin Hyperimmune Globulin Intravenous Immunoglobulin

O-antigen seroepidemiology of Klebsiella clinical isolates and implications for immunoprophylaxis of Klebsiella infections.

To provide a database for the development of an O-antigen-polysaccharide-containing vaccine against Klebsiella spp., we examined the O-antigen seroepidemiology of 378 Klebsiella clinical isolates collected prospectively in two university centers. Strains were typed by competitive enzyme-linked immunosorbent assay with rabbit antisera specific for serogroups O1 to O12 and monoclonal antibodies (MAbs) specific for serogroups O1, O2ab, O2ac, and the genus-specific core antigen. The numbers of isolates (percentages) of individual O serogroups were as follows: 148 (39.2) for serogroup O1, 40 (10.6) for serogroup O2ab, 4 (1.1) for serogroup O2ac, 89 (23.6) for serogroup O3, 2 (0.5) for serogroup O4, 32 (8.5) for serogroup O5, none for serogroups O7, O9, and O12, and 21 (5.6) for serogroup O11. Forty-two (11.1) of the strains were non-O-typeable. O-serogroup distributions were virtually identical between isolates from invasive infections and those from noninvasive infections or colonizations. A vaccine containing the O-specific polysaccharides of serogroups O1, O2ab, O3, and O5 would cover 82% of clinically occurring O-antigen specificities. Three hundred thirty-eight of 378 isolates (89.4%) reacted with the genus-specific MAb V/9-5, which recognizes an epitope of the outer core region of Klebsiella lipopolysaccharide. Antibodies directed against this epitope may represent a further alternative for O-antigen-targeted immunoprophylaxis of Klebsiella infections. These data support further experimental investigations on the protective potential of O-antigen-based vaccines and/or hyperimmune globulins in Klebsiella infection.

Respiratory Syncytial Virus Immune Globulin

Resistance to respiratory syncytial virus (RSV) in the lungs is primarily mediated by serum antibodies from the immunoglobulin G (IgG) isotype. Infants usually exhibit resistance to serious RSV infection of the lower respiratory tract (LRT) during the first 1 to 2 months of life through acquisition of protective transplacental IgG antibody titres (1 : 200 to 1 : 300). This transfer of maternal antibodies is incomplete in preterm infants, leaving them more vulnerable to RSV disease in early life. Animal data suggest that a high RSV serum neutralising antibody titre (~1 : 350) is required for pulmonary resistance to RSV infection hence, the development of a RSV hyperimmune globulin for passive immunoprophylaxis. Initial results from several well controlled prophylaxis and treatment trials ofRSV immune globulin in high-risk preterm infants are encouraging. A significant protective effect was demonstrated when parameters of morbidity, such as duration of hospitalisation, intensive care unit stay and mechanical ventilation, and the incidence and severity of RSV LRT infection, were assessed. Mortality data, however, are not yet conclusive. Results from treatment trials are less convincing. This is probably due to the biphasic pathogenesis of RSV LRT infection which is characterised by an early asymptomatic phase, when viral shedding is high, and a late symptomatic phase, when viral shedding is low or absent. Therefore, any treatment strategy that aims to attenuate the virulence and replication of the extracellular virus should be started well before the onset of widespread inflammation of the bronchiolar epithelium. Immunoprophylaxis of RSV infections with RSV immune globulin has proved to be effective, in terms of reducing morbidity, and well tolerated in infants with a history of bronchopulmonary dysplasia due to prematurity or prematurity alone. For

Respiratory Syncytial Virus Immune Globulin

Respiratory syncytial virus (RSV) immune globulin is a purified human hyperimmune globulin that provides passive immunity against complicated RSV disease in select groups of infants and young children. According to microneutralisation assay results, its RSV-neutralising antibody concentration was significantly greater than that of nonspecific immune globulin, thereby suggesting the potential for more reliable protection against RSV infection. In 2 randomised double-blind trials, prophylaxis with RSV immune globulin significantly reduced (vs no immune globulin) the incidence and severity of RSV disease in infants and young children with bronchopulmonary dysplasia, prematurity or bronchopulmonary dysplasia due to prematurity, or congenital heart disease (in 1 study). Treatment with RSV immune globulin did not significantly reduce the duration of hospitalisation and intensive care in children hospitalised with RSV infection in 2 randomised double-blind trials; however, a trend towards a significant treatment benefit was apparent in children with severe disease in 1 of these studies.

Sexual Transmission of the Hepatitis C Virus and Efficacy of Prophylaxis With Intramuscular Immune Serum Globulin

To estimate the risk of sexual transmission of hepatitis C and to assess the value of prophylaxis with periodic intramuscular immune serum globulin administration. Of 1102 steady heterosexual partners of patients with antibodies to the hepatitis C virus (HCV), 899 were enrolled in a single-blind, randomized, controlled trial. All the partners tested negative for antibodies to HCV and had normal baseline serum aminotransferase concentrations. The partners were assigned to receive 4 mL of 16% polyvalent immune serum globulin prepared from unscreened donors every 2 months (n = 450) or a placebo (n = 449). Tests for HCV infection were performed every 4 months. Eight hundred eighty-four partners completed the study. Seven partners became infected with HCV: 6 in the control group (incidence density, 12.00 per 1000 person-years; 95% confidence interval, 3.0 21.61) and 1 in the immune serum globulin group (incidence density, 1.98 per 1000 person-years; 95% confidence interval, 0-5.86). The risk of infection was significantly higher for partners in the control group (P = .03): for each year approximately 1% of the partners became infected. Sequence homology studies strongly suggest the sexual transmission of HCV. All immune serum globulin lots used had high enzyme-linked immunosorbent assay titers of neutralizing antibodies to HCV envelope glycoproteins and high neutralization titers in the neutralization of binding assay. Hepatitis C can be sexually transmitted. Immune serum globulin prepared from unscreened donors significantly reduced the risk. The treatment was safe and well tolerated. Because only immune serum globulin from unscreened donors (and not from those screened for HCV) contain anti-HCV neutralizing antibodies, hyperimmune anti-HCV immune serum globulin should be prepared from blood testing positive for antibodies to HCV, which is currently discarded.

Synergistic neutralization of a chimeric SIV/HIV type 1 virus with combinations of human anti-HIV type 1 envelope monoclonal antibodies or hyperimmune globulins.

A panel of 14 human IgG monoclonal antibodies (MAbs) specific for envelope antigens of the human immunodeficiency virus type 1 (HIV-1), 2 high-titer human anti-HIV-1 immunoglobulin (HIVIG) preparations, and 15 combinations of MAbs or MAb/HIVIG were tested for their ability to neutralize infection of cultured human T cells (MT-2) with a chimeric simian immunodeficiency virus (SHIV-vpu+), which expressed HIV-1 IIIB envelope antigens. Eleven MAbs and both HIVIGs were neutralizing. When used alone, the anti-CD4-binding site MAb b12, the anti-gp41 MAb 2F5, and the anti-gp120 MAb 2G12 were the most potent. When combination regimens involving two MAbs targeting different epitopes were tested, synergy was seen in all paired MAbs, except for one combination that revealed additive effects. The lowest effective antibody concentration for 50% viral neutralization (EC50) and EC90 were achieved with combinations of MAbs b12, 2F5, 2G12, and the anti-V3 MAb 694/98D. Depending on the combination regimen, the concentration of MAbs required to reach 90% virus neutralization was reduced approximately 2- to 25-fold as compared to the dose requirement of individual MAbs to produce the same effect. Synergy of the combination regimens implies that combinations of antibodies may have a role in passive immunoprophylaxis against HIV-1. The ability of SHIV to replicate in rhesus macaques will allow us to test such approaches in vivo.

Prevention of respiratory syncytial virus infection in high risk infants: consensus opinion on the role of immunoprophylaxis with respiratory syncytial virus hyperimmune globulin.

MEISSNER, H. CODY MD; WELLIVER, ROBERT C. MD; CHARTRAND, STEPHEN A. MD; FULTON, DAVID R. MD; RODRIGUEZ, WILLIAM J. A. MD, PHD; GROOTHUIS, JESSIE R. MD Author Information

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation.

To provide an overview of the role of cytomegalovirus (CMV) in the bone marrow transplant (BMT) population and update the current methods of prevention and treatment of CMV infection and disease, with emphasis on CMV interstitial pneumonia (CMV-IP). The current medical literature, including abstracts presented at recent national and international meetings, is reviewed. References were identified by searching the MEDLINE database from January 1988 through June 1994. The reference lists of the published studies and reviews obtained from the initial literature search were reviewed as well. Data regarding the epidemiology of CMV, the risk factor associated with CMV infection and disease, as well as data on the prevention and the treatment of CMV infection and disease in the BMT population are cited. Specific attention was focused on randomized, placebo-controlled studies pertaining to the prevention of CMV infection and disease in CMV-immunoglobulin G positive recipients undergoing allogeneic BMT. Information from nonrandomized, placebo-controlled studies was included in the absence of stronger data. Information contributing to CMV in the BMT population was reviewed. Data supporting and disputing specific preventive and treatment modalities are presented. The incidence of CMV seropositivity in the general population is high and while BMT becomes a widely accepted treatment modality, CMV reactivation and subsequent disease, especially CMV-IP, becomes a significant prognostic factor of morbidity and mortality. Even though antiviral agents such as ganciclovir and foscarnet can inhibit the viral replication in vivo, they have not been able to treat CMV-IP effectively. It has been suggested that CMV-IP is an immunopathologic process that can cause irreversible damage, hence, the low efficacy of antiviral therapy and the associated high mortality. Immunomodulating agents such as intravenous immune globulin and cytomegalovirus hyperimmune globulin can increase the efficacy of antivirals in the treatment of CMV-IP. This further supports the postulated immunopathologic process of this disease. The lack of understanding of the pathophysiology of the disease compromised the efforts of treatment and led to the development of preventive interventions with antiviral and immunomodulatory regimens that resulted in a significantly lower incidence of infection and disease. As a result of current data, the Eastern Cooperative Oncology Group has published guidelines for the prevention and treatment of CMV infection and disease. The prognosis of CMV disease in the BMT recipients has improved as a result of a wide variety of modifications in the management of BMT recipients. These include an increased understanding of the risk factors associated with CMV infection, routine screening for CMV replication and excretion, and more effective prophylactic regimens. Still, more than half of the patients who develop pneumonia will die, indicating that more studies are needed to increase the understanding of the pathophysiology and refine the preventive and therapeutic regimens against CMV.

Severe tick-borne encephalitis following passive immunization

We report on a 5-year-old girl with an unusually severe course of tick-borne encephalitis following passive immunization with specific hyperimmune globulin after a tick bite in an endemic area. Serial investigations of the CSF revealed intrathecal production of specific antibodies paralleled by increasing numbers of B-cells after initial T-cell pleocytosis. Focal central lesions were evident on MRI.ConclusionThe severity of the presented case questions the benefit of passive immunization and rather justifies consideration of vaccine recommendation to residents and travellers to areas endemic for tick-borne encephalitis virus.

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.

Definitions of cytomegalovirus disease after heart transplantation: antigenemia as a marker for antiviral therapy.

In this prospective study, cytomegalovirus (CMV) antigenemia was defined as the marker for initiation and episodes of antigenemia as the indicator for the duration of antiviral therapy (CMV hyperimmune globulin and ganciclovir). The CMV antigenemia assay and CMV-specific IgM and IgG antibody tests were used to monitor CMV infection in 22 heart transplant recipients who, between October 1992 and July 1994, were followed up for 6 months. A total of 178 out of 627 antigenemia assays tested positive. The highest number of positive cells was greater after primary infection than after either reactivation (43.3 vs 0.3; P < 0.01) or reinfection (43.3 vs 9.3; P = NS). Sixty episodes of antigenemia were observed. More episodes of antigenemia were seen after primary infection than after either reactivation (4.6 vs 0.2; P < 0.01) or reinfection (4.6 vs 2.2; P = NS). The detection of antigenemia indicated the initiation of antiviral therapy within 24 h after the blood sample was harvested. Therapy was stopped immediately after a subsequent negative result became available. Our experience indicates that antigenemia directed antiviral therapy prevents CMV disease after primary and secondary infection in heart transplant recipients.

Definitions of cytomegalovirus disease after heart transplantation: Antigenemia as a marker for antiviral therapy

Abstract In this prospective study, cytomegalovirus (CMV) antigenemia was defined as the marker for initiation and episodes of antigenemia as the indicator for the duration of antiviral therapy (CMV hy-perimmune globulin and ganciclovir). The CMV antigenemia assay and CMV-specific IgM and IgG antibody tests were used to monitor CMV infection in 22 heart transplant recipients who, between October 1992 and July 1994, were followed up for 6 months. A total of 178 out of 627 antigenemia assays tested positive. The highest number of positive cells was greater after primary infection than after either reactivation (43.3 vs 0.3; P < 0.01) or reinfection (43.3 vs 9.3; P = NS). Sixty episodes of antigenemia were observed. More episodes of antigenemia were seen after primary infection than after either reactivation (4.6 vs 0.2; P< 0.01) or reinfection (4.6 vs 2.2; P = NS). The detection of antigenemia indicated the initiation of antiviral therapy within 24 h after the blood sample was harvested. Therapy was stopped immediately after a subsequent negative result became available. Our experience indicates that antigenemia directed antiviral therapy prevents CMV disease after primary and secondary infection in heart transplant recipients.