Gamma-globulin Preparations Research Articles

Role of Pediatric Departments in Community Hospitals in Countermeasures against Measles Epidemics at Olympic Games Sites.

In preparation for the 2021 Tokyo Olympic/Paralympic Games, the Japanese government assessed the risks of infectious disease outbreaks and identified necessary preparations. This present study reviewed efforts made during a previous measles epidemic and describes the roles of hospitals. This descriptive study investigated the records of 198 children with measles. All children were treated at a general hospital during the period from January 1997 through February 1998. We also examined the actions of pediatricians during and after a measles outbreak in the community. Of the 198 children, 145 (73%) were hospitalized. The measles vaccination rate in the previous year was approximately 75%. Of the patients examined, 53% were younger than 2 years of age; mean age was 2.75 years. Pneumonia and gastroenteritis accounted for 46% and 30% of the complications, respectively. Issues requiring attention included the number of hospital beds located in a negative pressure room or private room with a window, the need for gamma globulin preparations with high measles antibody titers, the necessity of increasing vaccination opportunities, and extension of physician working hours. Visitors from other countries could cause measles outbreaks in Japan. Measures that might mitigate an outbreak were maintenance of high vaccination rates, ready availability of information on the location of negative pressure hospital rooms, knowledge of the status of the measle outbreak, and flexible medical staffing. There is a risk of measles outbreaks among infants and among those who do not have a measles antibody titer.

Overview of antibody-mediated immunity to S. pneumoniae: pneumococcal infections, pneumococcal immunity assessment, and recommendations for IG product evaluation.

Streptococcus pneumoniae (S. pneumoniae) strains colonize the nasopharynx and can cause mucosal infections in the upper airway and middle ear, pneumonias, and invasive infections like bacteremia, sepsis, and meningitis. Over 90 serotypes, defined by the structure of their capsular polysaccharides, are known. Twenty-three of these serotypes cause most infections and several of these serotypes can develop antibiotic resistance. Susceptibility factors that increase the susceptibility to S. pneumoniae mucosal and invasive infections include all forms of primary and secondary antibody deficiencies. Many patients affected by one of these deficiencies benefit from the regular administration of human gamma globulin (IgG) preparations. Donors of plasma units used to prepare human IgG have varying concentrations of IgG antibodies against relevant S. pneumoniae serotypes. These antibodies are developed in response to colonization and common subclinical infections and by routine vaccination with S. pneumoniae polysaccharide vaccines. The presence of an adequate concentration of these protective antibodies against all prevalent serotypes needs to be determined to assure the effectiveness of human IgG. All presently available methods to assess IgG antibodies against S. pneumoniae capsular polysaccharides have advantages and pitfalls that are analyzed in this review. In vitro testing does not provide a complete or necessarily accurate measurement of the effectiveness of antibodies in vivo. For regulatory purposes, caution needs to be used in the interpretation of currently available assays that measure pneumococcal antibody levels. Monitoring S. pneumoniae infections in patients treated with IgG and tracing information about IgG lots used to treat these patients should be encouraged.

Design, optimization and validation of a flow cytometry assay for quantitation of Igg-anti-D (rho) in the industrial process control of the anti rho-gamma globulin production

One of the main causes of the hemolytic disease of the newborn is due to the generation of anti-D antibodies, in response to a continuous antigenic challenge in pregnant mothers who do not possess the D antigen in their red blood cells. In order to prevent complications, the monitoring of anti-D antibody levels in pregnant women is carried out and the sensitization is prevented by prophylaxis with anti-D immunoglobulin (IgG anti-D). To date, the monitoring and titration of anti-D in plasma and finished products (IgG anti-D) is carried out continuous flow analysis with a Technicon Autoanalyzer, Radio Immuno Assay (RIA) and Enzymo Immuno Assay (EIA). In our laboratory, for the quantification of anti-D antibodies of the Gamma-Rho UNC and the products of the elaboration process, a house made technique of flow cytometry was developed as an alternative test to the reference method of the European Pharmacopoeia. Polyclonal anti-Rho antibodies and an anti FITC (fluorescein isothiocyanate) -labeled human IgG were used to measure the concentration of anti-D antibodies in a commercial preparation of gammaglobulin, semi-processed and human plasma. The method was developed using the 1st international WHO standard for anti-D IgG (69/419). At the concentration of red cells used in the method (5 x 104 cells/ul) there is no interference by auto agglutination. The obtained dose response curve (MFI vs. Log C) was linear in the adopted work range, presenting a correlation coefficient of 0.99. The specificity and recovery tests were satisfactory, the negative controls showed insignificant levels of fluorescence and did not present a serious interference in the determination. Knowing that the levels of anti-D sites antigen by red blood cell, vary according to the phenotype, our results show that the globules with phenotypes R1R1 present the best performance for this test, and can be replaced if necessary by R1R2 cells. The method was validated following the criteria of the group of Experts N°6B of the NIBSC and the European Pharmacopoeia who have standardized a similar procedure to be applied in the assessment of anti-D. Flow Cytometry allowed to obtain accurate, precise, sensitive and specific determinations at different concentrations of anti-D (100-0.9 ug/ ml) and in different biological matrices such as finished product, pre-filled concentrate product and fraction II of Cohn's method. The advantages found in the application of this method, in addition to the relatively low cost, include a strong fluorescence signal that does not require amplification, the use of highly diluted samples that minimize the risk of agglutination by IgM-Anti D or polymers. It is a simple, fast and reliable method to determine the serum levels of anti-D or quantify the concentration in an immunoglobulin solution.

The history and evolution of immunoglobulin products and their clinical indications

The history of providing antibodies to treat diseases began in the 19th century with the discovery of tetanus and diphtheria toxins and the demonstration that immunity to tetanus and diphtheria infections could be transferred by immune sera. Characterization of the mediators of this immunity resulted in the discovery that antibodies are proteins that can be isolated and used to protect against infectious diseases. Development of a method to isolate antibodies from human plasma that could be safely injected into people initiated the development of human gamma globulin preparations to provide antibodies to patients with inherited antibody deficiencies. To overcome the limitations imposed by intramuscular injection of gamma globulin, intravenous gamma globulin preparations were developed that began to be used in a wide variety of clinical conditions. Thus the original clinical indication for infection prevention was expanded to several other indications that employ large doses to suppress inflammatory and autoimmune disorders. The most recent development in immunoglobulin therapy is the production of concentrated immune globulins for subcutaneous injection. Home infusions of subcutaneous immunoglobulin are increasingly used to treat immunodeficient patients and are being studied for other clinical applications.

Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis.

Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis.

肺炎球菌感染を併発したインフルエンザ肺炎に，脳梁膨大部病変を伴う脳症を合併した 1 成人例

A 35-year-old male patient had a fever, cough, and other symptoms since the end of December 2010. The patient then developed a high fever and decreased SpO2, suggesting possible pneumonia. The patient was admitted to our hospital on the 6th day of illness. Chest computed tomography revealed multiple infiltrative shadows and ground-glass opacities distributed in a patchy pattern in the bilateral lungs. An atypical pneumonia was suspected, and we initiated antibiotic treatment with minocycline. However, the patient developed consciousness disturbance in the afternoon of the 7th day of illness. The high fever persisted, suggesting the patient's poor response to minocycline treatment, which was then replaced with ciprofloxacin and imipenem/cilastatin on the 8th day of illness. Streptococcus pneumoniae was detected in the blood culture bottles submitted at the time of admission. A head magnetic resonance imaging performed on that day showed a high intensity area in the splenium of the corpus callosum, leading to a diagnosis of encephalopathy. Methylprednisolone pulse therapy and gamma globulin treatment were initiated. The patient then recovered consciousness gradually with improvement of inflammatory responses and imaging findings. Subsequently, an influenza virus (H1N1) antibody level was found to have increased from less than 10 times to 640 times. Thus, it was determined that the patient's pneumonia and encephalopathy were attributable to the influenza A (H1N1) pdm09 virus during the flu season and Streptcoccal infection. Combination therapy, such as steroid pulse treatment, appropriate antibiotics and gamma globulin preparation was effective for both the flu-induced mixed pneumonia and encephalopathy in this patient.

The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions.

The life situations of 25 patients with hypogammaglobulinaemia were studied before and after the initiation of subcutaneous replacement therapy by using medical records, data registers and questionnaires (a study and a disease-specific questionnaire, the Sickness Impact Profile and the General Health Rating Index). Before treatment, the patients perceived more dysfunctions with regard to ambulation, mobility, emotional behaviour, social interaction, sleep and rest, household management, work and recreation or pastime activities compared with a Swedish reference group (P = 0.0001). A significant increase in the perceived frequency of infections was also seen in untreated patients compared with a group of healthy individuals (P = 0.0001). After 18 months of weekly subcutaneous infusions of an intramuscular gammaglobulin preparation (100 mg/kg), the patients reported a significantly increased, health-related function and improved self-rated health. A significantly higher pre-infusion IgG level was also found.

Comparison of the neutralizing and ELISA antibody titres to measles virus in human sera and in gamma globulin preparations

Measles virus infection as well as measles vaccination induces a long-lasting immune protection. Specific antibodies have been proven to be associated with this immune protection, since measles immunity can be transferred by immune globulin application (passive immunisation). The neutralisation test (NT) is regarded as the gold standard method for measles immunity because it measures functional neutralising antibody, while with the ELISA, which is often based on cell culture grown native virus antigens, predominantly antibodies to the nucleoprotein antigen were detected. To compare the results of NT and ELISA 199 individual sera and 364 gamma globulin samples, which were made from plasma pools, were tested. Qualitative results showed that the sensitivity of the ELISA was 141/144 (97.9%) and specificity was 48/55 (87.3%) when compared to the NT and focused to the patient samples. For the gamma globulin samples the sensitivity and specificity was 100%. As expected no measles NT negative plasma pool samples were found. The present study showed that with increasing NT-titre, the ELISA-values also rise. False negative ELISA results were obtained in 1.5% of patient sera, mainly containing low levels of neutralising antibody. In both antibody tests seropositive specimens revealed a quite good to moderate correlation. Taken together, the measles IgG ELISA is adequately for immunity testing and identifying of seronegative individuals for vaccination.

Antibodies raised in animals against the Streptococcus agalactiae proteins c alpha and R4 and normal human serum antibodies target distinct epitopes.

The targets for normal human serum antibodies that react with proteins c(alpha) and R4 isolated from group B streptococci (GBS; Streptococcus agalactiae) have been studied and compared with the targets for murine monoclonal and rabbit polyclonal antibodies raised against these proteins. The proteins were extracted by trypsin digestion and purified by precipitations and gel filtration and testing was based on enzyme immunoassays. The immune antibodies showed specificity for the corresponding protein, targeted that protein in Western blotting and recognized their targets after heat treatment (100 degrees C) of the proteins. Human antibodies in a commercial gammaglobulin preparation targeted a site(s) common to c(alpha) and R4. This target failed to bind the antibodies in Western blotting and was destroyed by heating. c(alpha)- and R4-reactive antibodies in sera from healthy pregnant women recognized the common, heat-labile determinant(s), but contained little or no antibodies against the heat-stable c(alpha)- or R4-specific determinants. These results are consistent with the notions that (i) the normal human antibodies and the immunization-induced animal antibodies targeted different sites on the c(alpha) and R4 proteins and that (ii) the natural human antibodies targeted conformational epitopes and the immune antibodies targeted linear epitopes. These findings are important for further clarification of GBS immunology and immunoprotection in humans.

A history of immune globulin therapy, from the Harvard crash program to monoclonal antibodies.

Processes for the large-scale fractionation of human plasma using cold ethanol were initially developed by Edwin Cohn and his colleagues at Harvard to provide albumin as a treatment for shock in World War II. Procedures for further purification of gamma globulins and other proteins precipitating at lower concentrations of ethanol were then developed by Oncley et al. Gamma globulin rapidly replaced convalescent and animal sera for the prevention and treatment of infectious diseases such as measles, hepatitis, and polio, then came into widespread use as replacement therapy in the primary immune deficiencies, which emerged in the antibiotic era of the early 1950s. Although it took 40 years to develop preparations of gamma globulin that could be safely given intravenously, the eventual accomplishment of that goal has led to better treatment of antibody deficiency syndromes and also the wide use of high-dose intravenous immunoglobulin in autoimmune and inflammatory diseases. Those uses continue to expand even as monoclonal antibodies are being introduced for specific infectious diseases in high-risk populations.

New therapies in systemic lupus erythematosus.

A new understanding of the pathogenesis of autoimmunity, the mechanisms of action of older drugs, the advent of target-specific biological therapies and pharmacogenomics has created multiple treatment options for the patient with systemic lupus erythematosus. These include topical therapies, more selective non-steroidal anti-inflammatory agents, hormonal interventions and a new generation of immune suppressives. Currently available strategies also include the use of intravenous gamma globulin, apheresis, stem-cell transplantation and antileprosy preparations alone or in combination with immune suppressives. A handful of biologicals have been studied in clinical trials. After two decades without new options for lupus patients practitioners now have a full menu of improved therapeutic options.

Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy.

Patients with IgA deficiency often demonstrate circulating antibodies against IgA, which have been suggested to be associated with transfusion reactions. Sera from three patients with common variable immunodeficiency (CVID) and one with a selective IgA deficiency with anti-IgA antibodies receiving subcutaneous gammaglobulin replacement therapy were analysed for serum levels of IgG, IgA and anti-IgA before and during a treatment period of 4-7 years. Treatment with gammaglobulin preparations containing significant amounts of IgA (< 5 mg/ml) resulted in a decrease or disappearance of the anti-IgA antibodies. Analysis of serum fractions, however, revealed anti-IgA activity in the complex-containing fractions. In vitro experiments gave similar results with a shift of anti-IgA activity from the monomeric to the complex-containing fractions (that could not be detected in whole serum). When the patients were subsequently switched to treatment with a preparation containing less IgA (< 80 microg/ml) or made an interruption in the treatment schedule, the anti-IgA antibodies reappeared. Importantly, however, one of the patients lost his anti-IgA activity during a 3-month period on the preparation containing the higher IgA levels, and these antibodies did not reappear after switching to the low IgA-containing preparation. After 5 years on this preparation, anti-IgA can still not be detected, suggesting induction of unresponsiveness.

Passive immunity against human pathogens using bovine antibodies.

The control and treatment of infectious diseases is increasingly complicated by the development of antibiotic-resistant organisms, the emergence and rapid dissemination of new pathogens, and the growing incidence of opportunistic infections. Identification and commercialization of new anti-microbial agents has always been a time-consuming and expensive process, and development of new strategies to control disease are therefore clearly warranted. The immune system has evolved to help combat various types of infections. As most pathogens enter through mucosal surfaces, the local immune defence may be of particular importance and evolutionary pressure has led to the development of a specialized immunoglobulin class in secretions—IgA. Patients with primary immunodeficiencies involving IgA are known to be highly susceptible to respiratory and gastrointestinal (GI) tract infections (for review see [1]), supporting the notion of a crucial role for antibodies in the mucosal defence. Infection-prone IgA-deficient patients are currently treated with human IgG given systemically [2]. However, a proportion of these patients still suffer from mucosal infections which necessitates development of additional forms of therapy, and human IgG in high doses has previously in fact been given orally, without adverse effects, to healthy volunteers [3] and to patients suffering from a variety of GI infections (for references see [4]). However, from a theoretical point of view human IgG is expected to be less effective than human IgA due to its comparatively low proteolytic stability, and it may also, due to its interaction with complement and phagocytosing cells, provoke an inflammatory reaction. Human breast milk, which contains secretory IgA, is known to protect against diarrhoea in infants. Oral administration of purified human immunoglobulin has previously also been suggested to exhibit a prophylactic effect against development of necrotizing enterocolitis in prematurely born children [5] and a therapeutic effect in Campylobacter jejuni [6] and Clostridium difficile [7] induced diarrhoea in immunodeficient patients as well as chronic diarrhoea of unknown aetiology in normal infants [8]. However, the titre against most human pathogens is rather low in the IgA-containing gammaglobulin preparations, and vaccination of volunteers for preparation of hyperimmune products is not feasible. Furthermore, there is always a risk of transmission of infectious agents when using human plasma as a starting material and since the cost for these preparations is high, alternative sources of antibodies must be sought. The common dairy cow may be one such alternative, as bovine antibodies are actively transported from plasma to milk in cows and are present in high concentrations in colostrum. The antibodies protect the calves from GI infections during the neonatal period and are of major importance for their survival. Bovine immunoglobulin preparations against rotavirus and Escherichia coli have previously been shown to be effective as prophylaxis against infections and have been commercially available for use in farm animals for decades. During the past few years, bovine immunoglobulin preparations have also been shown to protect against natural infection or challenge with a variety of different microorganisms in man. The effect of therapeutically administered bovine antibodies has not been as well documented, but successful intervention has been demonstrated in Helicobacter pylori, rotavirus and cryptosporidial infections (for references see [4,9]). Interaction between bovine antibodies and the human immune system is limited [10] and the preparation can be given without risk of serious adverse events. The titre of antibodies against many human pathogens is low in colostrum from non-immunized animals [4], and although a therapeutic effect has been suggested by oral administration of high doses of non-specific bovine immunoglobulins to patients with chronic diarrhoea [11–14], it is likely that a future product will have to be derived from immunized animals [10]. In this review, we will summarize published data on the use of bovine immunoglobulin-containing preparations for prophylaxis and therapy against selected mucosal infections in man and suggest directions for its future use.

Humoral immune response to proteins of human cytomegalovirus latency-associated transcripts

Latent human cytomegalovirus (CMV) infection of hematopoietic progenitor cells is associated with the presence of latency-associated transcripts that may express 6 proteins larger than 44 amino acids in size (open reading frame [ORF] 55, ORF45, ORF94, ORF59, ORF154, ORF152/UL124). The serologic response to these proteins was evaluated in healthy seropositive individuals as well as in individuals undergoing active CMV infection. Individual recombinant GST-fusion proteins, prepared from bacteria, were found by enzyme-linked immunosorbent assay to be recognized by between 8% and 44% long-term healthy seropositive individuals, with ORF94 and ORF55 being the most broadly and significantly recognized. Although nearly all of serum samples (85%) recognized at least 1 of these proteins, none reacted with all 6. Patterns of antibody prevalence to these proteins in long-term seropositive individuals were similar to many antigens expressed during productive replication (IE1, ppUL57, ppUL83/pp65), but none were broadly detected by a majority of individuals, a characteristic of only a few productive-phase antigens, including ppUL44/ICP36 and ppUL32/pp150. Consistent with prevalence in long-term seropositive individuals, commercial preparations of pooled human gamma globulin were also found to recognize latency-associated proteins. Serologic reactivity to latency-associated proteins was slow to develop following primary infection, in a pattern distinct from any of the characterized replication-phase proteins tested here, and was boosted late after secondary infection or reactivation in solid-organ transplant recipients without showing a correlation with viremia or disease. These results provide evidence that proteins expressed from the latent region during natural infection exhibit immunogenicity comparable with most other characterized viral antigens, although the narrow response to individual latency-associated proteins likely precludes their use in serologic assays to investigate clinical correlates or outcome in transplant recipients. Biol Blood Marrow Transplant 2000;6(2):100-8.

Receptor-Mediated Maternofetal Transfer of ImmunoglobulinsInhibition of Transport of Anti-HIV-1 Immunoglobulin by Generic Immunoglobulins in the in vitro Perfused Placenta

Objectives: The passage of immunoglobulin G (IgG) across the placenta is thought to involve Fc’ receptors on the syncytiotrophoblast. To confirm the receptor dependency of this process we have studied the changes in the tissue content and transfer kinetics of immunoglobulins and hyperimmune serum to HIV (HIVIG) during in vitro dual placental perfusion. Methods: Isolated lobules of term placentae from normal pregnancies were perfused in a model of maternal and fetal circulation. The perfused tissue was compared to fresh tissue samples from the same placenta for the content of IgG, IgG subclasses, IgM, cytokeratin, human placental lactogen and SP1 antigen by immunohistochemistry and by protein elution. Results: The immunoglobulin staining faded by an average of 40% during the 1st hour of perfusion. In contrast, staining for cytokeratin, human placental lactogen and SP1 remained unchanged. During a 4-hour recycling of endogenous immunoglobulins in the maternal circulation, IgG and HIVIG crossed to the fetal side in a steady rate. The transport of HIVIG could be inhibited by preperfusion with an intravenous gammaglobulin preparation (IVIG). Discussion: The transfer of IgG across the placenta occurs in a steady state rate consistent with a receptor-mediated mechanism. Furthermore, inhibition of HIVIG maternofetal transfer by IVIG further establishes the receptor-mediated transfer of immunoglobulins through the placenta.

静注用γ-グロブリン製剤中のベロ毒素中和抗体の検討

Intravenously administered immune globulin therapy has been reported to be an effective treatment for serious patients with verotoxin-producing Escherichia coli infections while an efficacy for VT2 are under discussion. We therefore examined in vitro commercially available immune globulin preparations for the presence of anti-VT neutralizing antibodies in expectation of protecting a patient from serious complications as HUS. We examined 47 lots of gamma-globulin prepared by 5 pharmaceutical companies in Japan. Of them 29 lots were prepared from imported blood and 18 lots were from Japanese donors' blood. They were prepared in each company following their own manufactures' process. Neutralizing activity for VT1 and VT2 were determined by means of cytotoxicity using ACHN (renal adenocarcinoma, human) cells. All lots of gamma-globulin preparations from imported blood completely neutralized 125 pg/ml VT1 at the concentration of 12.5 mg/ml, and no significant difference was found in the manufactures' process. On the other hand gamma-globulin preparations from Japanese donors' blood neutralized VT1 five times less than the former. None of all preparations neutralized VT2. Gammaglobulin preparations were produced from pooled human plasma. To know the difference of neutralizing activities in the source, we examined randomly selected 239 human plasma samples of which 51 were from Japanese donors' blood and 188 were from imported blood. Prevalences of neutralizing activity of VT1 in imported plasma and domestic plasma were 10.6% and 2.0%, respectively. The prevalence of neutralizing antibody in these plasma samples reflects the different neutralizing activity of VT1 in gamma-globulin preparations prepared from imported blood and Japanese donors' blood. From these results, by selecting the lot of gamma-globulin preparations or the material of plasma with highly neutralizing activity, intravenously administered immune globulin therapy may be effective for VT1. The lack of VT2-neutralizing activity in any gamma-globulin preparation promotes us to develop humanized anti-VT2-monoclonal antibody for the prevention of HUS in high risk children.

Preventive effect of IgG from EBV-seropositive donors on the development of human lympho-proliferative disease in SCID mice.

The effect of weekly treatments with various gammaglobulin preparations on the development of human B-cell tumors was studied in severe combined immunodeficient (SCID) mice. SCID mice were injected i.p. with human peripheral blood mononuclear cells (PBMCs) from an Epstein-Barr virus (EBV)-seropositive healthy blood donor. Repopulated SCID mice were divided into 7 treatment groups receiving either PBS, 2 commercial gammaglobulin preparations, purified IgG prepared from pooled plasma from EBV-seronegative or -seropositive blood donors, a rabbit anti-serum against EBV envelope glycoprotein gp340 or interferon (IFN)-alpha. All treatments started 1 day after injection of PBMC and continued for 8 weeks. In the PBS-treated control group, 85% of mice developed tumors in the abdominal cavity, mostly with liver metastasis within 150 days. Tumor formation was prevented by treatment with the 2 commercial gammaglobulin preparations as well as by purified IgG from EBV-seropositive donors. In contrast, purified IgG from EBV-seronegative donors, rabbit anti-gp340 anti-serum or IFN-alpha had no effect. Our results indicate that the effect of gammaglobulin is due to the presence of specific antibodies against EBV antigens. Further experiments showed that both the time of onset and the duration of treatment, as well as the dose of Ig, are important factors for prevention of tumor formation. Studies aiming at identification of target antigens for antibodies which prevent lymphoma development may be clinically relevant for prevention and possibly treatment of lympho-proliferative disease in severely immuno-compromised patients.

Intravenous Gamma-Globulin Therapy

Initially used as replacement therapy in patients with hypogammaglob-ulinemia, intravenous gamma-globulin (IVIg) preparations are increasingly being used as treatment for various autoimmune disorders. Although expensive, IVIg has become first-line or adjunctive therapy in the treatment of disorders as diverse as autoimmune or post-transfusion thrombocytopenia, autoimmune hemolytic anemia, Kawasaki's disease, inflammatory myositis, myasthenia gravis, pediatric acquired immune deficiency syndrome, bone marrow transplantation, and inflammatory de-myelinating polyneuropathy. IVIg remains the first line of therapy in patients with humoral immunodeficiency syndromes. Clinical studies support the selective use of this therapy in the above disorders; it has also been tried as therapy in many other diseases, with varied results. IVIg therapy has received Food and Drug Administration approval for use as maintenance treatment of patients with primary humoral immunodeficiencies and as therapy for acute or chronic autoimmune thrombocytopenic purpura.

Variability in parvovirus B19 IgG levels in intravenous immunoglobulin samples

Parvovirus B19 infection is an important cause of chronic anemia in patients infected with human immunodeficiency virus (HIV). Chronic infection is related to impaired humoral immunity (Kurtzman et al. 1987) and can be treated successfully with intravenous gamma globulin infusion (Kurtzman et al. 1989a). Treatment failures have been described clinically and, assuming that parvovirus viremia is the cause of the anemia, then failure may be attributable to failure to clear the virus or to subsequent relapse. Early treatment failures could be the result of immunoglobulin preparations that contain insufficient antiparvovirus activity. Gamma globulin preparations are manufactured using pooled serum. Marked variability in the levels of antibody to various infectious agents, such as cytomegalovirus (Roy and Grundy 1992) and hepatitis B virus (Hoofnagle et al. 1975), in these preparations have been reported. We analyzed the antibody concentration to human parvovirus B19 in a number of gamma globulin preparations in an attempt to define the range of B19 IgG antibody levels.

Prevention of fetal death in the antiphospholipid antibody syndrome.

The first treatment of pregnant women with antiphospholipid antibody syndrome (APLS) employed high doses of corticosteroids, plus low dose aspirin, with the goal of suppressing production of the autoantibody. Corticosteroids (usually prednisone), even when much lower doses are used, and even when tapered after midpregnancy, have been associated with significant maternal and obstetric risks and side effects: the most important are osteomalacia and preterm delivery (often precipitated by premature rupture of the membranes). Since the publication of a randomized trial demonstrating equivalent live birth rates of about 75% whether heparin or prednisone was used for treatment (plus low dose aspirin), the use of adjusted doses of heparin, together with low dose aspirin, has replaced prednisone for treatment of pregnant women; although prednisone may still be needed to treat manifestations of associated autoimmune disorders. A recent randomized trial has shown that the addition of heparin to aspirin is probably superior to treatment with aspirin alone. To achieve prophylactic levels of plasma heparin equivalent to those measured in patients who are not pregnant and are treated with the usual dose of standard heparin of 5000 IU every 12 h, the heparin dose required for treatment of pregnant women is usually higher. For that reason, heparin doses should be adjusted using the nadir APTT, or better plasma heparin measured by a factor Xa inhibition assay at the 2 h post-injection peak. Although low molecular weight heparin has been shown to be useful in prevention of fetal resorption in a mouse model, and appears to be equally safe for treatment of pregnant women, we still have no published data to show therapeutic equivalency, with respect to treatment of APLS-complicated pregnancy, to standard heparin preparations, and none that demonstrate any lower risk for the complication of most concern when heparin is given to pregnant women-osteopenia. Similarly, intravenous infusion of gamma globulins (IVG) appears on the basis of case reports to be effective additional treatment in cases where standard therapy has failed. Gamma globulin preparations contain anti-idiotypic antibodies that have been shown to bind to patient antiphospholipid antibodies. The place for the addition of IVG to standard therapy has not been defined, but clinically significant and corticosteroid-resistant thrombocytopenia complicating antiphospholipid antibody syndrome might be one indication for primary treatment with IVG +/- low dose aspirin. Overall, live birth rates in most treatment studies are in the range of 70-80%. The reported birth rate information, however, cannot be compared between studies. None of the studies reported have used tools such as logistic regression analysis to allow for such significant predictors of live birth as the number of prior miscarriages, maternal age, medical history, or a history of fetal death (loss of a viable and chromosomally normal fetus after the 10th gestational week).