Role of gamma globulin

The introduction of preparations of immune serum globulin that are safe for intravenous use (IVIG) has made possible safe and effective prophylactic treatment for patients with a variety of humoral immunodeficiencies. These include not only primary agammaglobulinemia and common variable hypogammaglobulinemia but also the antibody deficiencies that accompany chronic lymphocytic leukemia (CLL) and multiple myeloma, as well as the hypogamma-globulinemia found in very low birth weight newborns who have not received adequate transplacental IgG from their mothers. In contrast, trials to date have not shown efficacy of IVIG in preventing sepsis in burn patients. The ease of administration and efficacy of IVIG in preventing respiratory symptoms in hypogammaglobulinemic patients has suggested that many other patients presenting with sinusitis and asthma, recurrent bronchitis, and other chronic chest symptoms might also benefit from IVIG and that they should be worked up for IgG subclass or specific antibody deficiencies. Side effects of IVIG administration are generally minor and may be prevented by slow administration and/or pretreatment with aspirin or Benadryl. The only contraindication to IVIG treatment is anaphylactic sensitivity to IgA, which is extremely rare. IVIG is thus an effective and safe form of prophylaxis that can reduce the incidence of pneumonia and other respiratory infections in patients with antibody deficiency as a predisposing factor.     

Therapeutic uses of gamma globulin

Dr. Gold: In one of our conferences on therapy held in 1941 the topic of discussion was the use of human convalescent serum against infectious diseases. The object was to confer passive immunity for prophylaxis or for treatment in infectious diseases by the administration of antibodies obtained from humans. Human convalescent serum proved to be effective in prophylaxis against measles, in the prevention and cure of scarlet fever and there was some indication that it might be of value in mumps and whooping cough. There were serious obstacles in the way of the general development of this kind of therapy. The doses were large, the cost was high and human convalescent serum was available in only limited amounts and through special sources, as in the case of the Manhattan Convalescent Serum Laboratory which was affiliated with the Department of Health of New York City.This conference on the uses of gamma globulin is, in a sense, an extension of that subject in line with the developments which have taken place in the past few years. Dr. Edwin J. Cohn and his collaborators at Harvard Medical School devised a method for the large scale fractionation of plasma. It has been found that the protein fraction, termed “gamma globulin” in the form in which it was isolated, contains the major portion of the antibodies against infectious diseases. The solution of antibodies obtained from human plasma or serum has now become an article of commerce and is readily available at fairly reasonable cost. It is provided by several manufacturers in 2 cc. vials under the name of “immune serum globulin (human).” It represents an approximately 16 per cent solution of gamma globulin containing the antibodies present in normal pooled plasma but in a concentration about twenty-five times that of the original plasma. In the short period of time since the isolation of this material, its utility has been explored in a number of diseases: measles, scarlet fever, mumps, whooping cough, German measles, chicken pox, infantile diarrhea, poliomyelitis, serum hepatitis, infectious hepatitis and influenza. Thus far it has proved most effective in the prophylaxis of measles and infectious hepatitis. There is some indication that it may prevent homologous serum hepatitis and that large doses may act in a manner similar to convalescent serum in the prophylaxis or treatment of scarlet fever.The subject is still in the experimental stage. Evidence now exists indicating that some specific diseases in which gamma globulin prepared from normal pooled serum is not effective may respond to gamma globulin obtained from the plasma of patients convalescing from the disease. Thus, while the so-called “immune serum globulin (human)” has not been found effective in mumps, large doses of gamma globulin prepared from the plasma of convalescent patients have proved effective in preventing mumps orchitis, and gamma globulin prepared from the plasma of hyperimmunized donors has been found useful in the treatment and prevention of whooping cough.The use of gamma globulin in measles was discussed in some detail. The material now available is apparently without value after the disease is established and its use is restricted to prophylaxis. When the material is given at any time between the first and eighth day after exposure, it will either prevent measles or reduce measles to a very mild disease (modified measles) depending upon the size of the dose. The view was expressed that modification of measles is desirable in most cases since this apparently allows the patient to develop full immunity while passing through a very mild form of the disease, and that the prevention of the disease is desirable in only special cases as in very young infants and under other conditions in which an active measles would give rise to special hazards either to the individual or to contacts.The discussion also covered some of the details of administration and raised questions concerning the mode of action of gamma globulin. The current material is suitable only for intramuscular injection and is toxic by intravenous injection. The dose for complete prevention of measles is 0.2 cc. per Kg. and only about one-fourth of that, namely, 0.05 cc. per Kg. for the modification of measles. Local and systemic reactions occur in about 1 per cent of the cases and are usually mild. An interesting point concerning the mechanism of action was raised, namely, whether the results obtained with gamma globulin are due solely to the addition of antibodies to the patient's blood. There is some indication that the amount of antibodies so added may be too small to account for the protective effects and that some factor other than added antibodies may be, at least in part, responsible for the therapeutic results.     

Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease

The objective of this study was to evaluate the efficacy of intravenous gamma globulin (IVGG) therapy on the prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD), with reference to the literature on meta-analyses in randomized controlled studies. Studies from 1984 to the end of 2000 obtained from the National Library of Medicine or from the bibliographies of these articles were used in the analysis. The total number of patients with KD covered in 17 articles was 4020. All the articles were examined for the number of doses per day, the duration of administration, and the total number of IVGG doses. The number of patients in each group was counted, and the incidence of CALs was evaluated at 30 or 60 days after onset. The results of these searches were further analyzed by meta-analytical methods. The administration of IVGG significantly decreased the incidence of CALs in a dose-dependent manner: At 30 days after onset the incidence of CALs was 29.4% without IVGG but 21.6% with a total dosage of IVGG < 1000mg/kg, 10.8% with a total dosage of 1000–2000mg/kg, and 10.2% with a total dosage of 2000mg/kg. Compared with the incidence of CALs without IVGG, the odds ratio (OR) was 0.662 [95% confidence interval (CI) 0.519–0.815)] at <1000mg/kg, 0.292 (95% CI 0.222–0.371) with 1000–2000mg/kg, and 0.274 (95% CI 0.207–0.349) with 2000mg/kg. At 60 days, the values had decreased to 17.3%, 13.8% [OR 0.767 (95% CI 0.585–1.005)], 5.8% [OR 0.296 (95% CI 0.200–0.436)], and 4.9% [OR 0.244 (95% CI 0.170–0.349)], respectively. The meta-analyses also indicated that high doses of IVGG (2000mg/kg per day) given in a single dose prevented CALs more effectively than the same dosages divided into five daily doses in the patients with KD: The incidence of CALs at 30 days after disease onset was 2.4% with a single dose versus 12.9% with divided doses. Compared with divided doses, the OR with a single dose was 0.164 (95% CI 0.064–0.393) and 2.8% versus 6.1% at 60 days [OR 0.450 (95% CI 0.206–0.956)]. We clearly confirmed that higher doses of IVGG (2000mg/kg per day) administered in a single infusion were more effective for preventing CALs, as evaluated during both the subacute and convalescent phases of KD.     

Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease

Abstract

The objective of this study was to evaluate the efficacy of intravenous gamma globulin (IVGG) therapy on the prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD), with reference to the literature on meta-analyses in randomized controlled studies. Studies from 1984 to the end of 2000 obtained from the National Library of Medicine or from the bibliographies of these articles were used in the analysis. The total number of patients with KD covered in 17 articles was 4020. All the articles were examined for the number of doses per day, the duration of administration, and the total number of IVGG doses. The number of patients in each group was counted, and the incidence of CALs was evaluated at 30 or 60 days after onset. The results of these searches were further analyzed by meta-analytical methods. The administration of IVGG significantly decreased the incidence of CALs in a dose-dependent manner: At 30 days after onset the incidence of CALs was 29.4% without IVGG but 21.6% with a total dosage of IVGG < 1000?mg/kg, 10.8% with a total dosage of 1000–2000?mg/kg, and 10.2% with a total dosage of ≥2000?mg/kg. Compared with the incidence of CALs without IVGG, the odds ratio (OR) was 0.662 [95% confidence interval (CI) 0.519–0.815)] at <1000?mg/kg, 0.292 (95% CI 0.222–0.371) with 1000–2000?mg/kg, and 0.274 (95% CI 0.207–0.349) with ≥2000?mg/kg. At 60 days, the values had decreased to 17.3%, 13.8% [OR 0.767 (95% CI 0.585–1.005)], 5.8% [OR 0.296 (95% CI 0.200–0.436)], and 4.9% [OR 0.244 (95% CI 0.170–0.349)], respectively. The meta-analyses also indicated that high doses of IVGG (≥2000?mg/kg per day) given in a single dose prevented CALs more effectively than the same dosages divided into five daily doses in the patients with KD: The incidence of CALs at 30 days after disease onset was 2.4% with a single dose versus 12.9% with divided doses. Compared with divided doses, the OR with a single dose was 0.164 (95% CI 0.064–0.393) and 2.8% versus 6.1% at 60 days [OR 0.450 (95% CI 0.206–0.956)]. We clearly confirmed that higher doses of IVGG (≥2000?mg/kg per day) administered in a single infusion were more effective for preventing CALs, as evaluated during both the subacute and convalescent phases of KD.     

Methodological studies on the hemolytic anti-bovine gamma globulin plaque technic

Sheep red blood cells (SRBC) coated with specific bovine antibodies are suitable to detect anti-bovine gammaglobulin (BGG)-antibody-forming cells with the hemolytic plaque technique. The number of the definable anti-BGG-plaque-forming cells is dependent on the antibody density per SRBC. The developed plaques are specific for BGG. They are to inhibit with BGG only not with other proteins. The cellular kinetics of the anti-BGG response is to follow up in the spleen and poplitea lymph nodes of the immunized mice with this modification of the hemolytic plaque technique. The results are discussed.     

Tourist hepatitis and gamma globulin prophylaxis.

Millions of tourists from Northern Europe visit the Mediterranean basin each year. Some of them provide themselves with gamma globulin prophylaxis against hepatitis A before departure. In Sweden about 50% of these travellers receive prophylaxis which means that about half a million Swedish tourists are injected with gamma globulin each year. The risk of contracting hepatitis A in South or East Europe without prophylaxis seems to be around 1/3000 travellers according to calculations presented in this report. With gamma globulin prophylaxis the risk seems almost negligible.     

Sulfhydryl-dependent thermal aggregation of human gamma globulin

Hyaluronic acid (4 mg/ml) augmented elevenfold the copper-catalyzed (7 _βxM) thermal (63°C, 2 hours) aggregation of human gamma globulin (2 mg/ ml) in 0.075 M phosphate buffer, pH 7.4. Almost no augmentation of aggregation occurred with hyaluron-idase-treated hyaluronate. Hyaluronate-augmented copper-catalyzed thermal aggregation was inhibited by L-histidine, gold thiomalate, N-ethylmaleimide, p-chlo-romercuribenzoic acid, and ethylenediaminetetraacetic acid. Together with previous reports of a decreased blood histidine concentration in rheumatoid arthritis, these studies provide a possible explanation for the affinity of this disease for joints.     

In vivo behaviour of gamma globulin preparations

Metabolic properties of standard gamma globulin (St-GG) and of several gamma globulin (GG) preparations for intravenous use were analyzed in radioactive tracer studies. The in vivo behaviour of St-GG was investigated in 16 probands and found to be comparable to that of normal IgG. The kinetics of the resorption of St-GG from intramuscular deposits, its elimination from the intravascular compartment and from the body were studied in 2 probands. Metabolic properties of GG preparations for intravenous use were compared with those of St-GG in 3-4 probands after simultaneous injection of 125I- and 131I-labelled tracer doses. Important differences in the half-times of intravascular survival, in the rates of catabolism and in the distribution in the body were noticed for most of the preparations for intravenous use except for an improved acid-treated (pH 4) GG, the in vivo behaviour of which was similar to that of St-GG.