Use of Intravenous Immunoglobulins for Prophylaxis or Treatment of Infectious Diseases

By the advent of the era of antimicrobial drugs, passive immunization with pathogen-specific animal (usually horse, cow, or rabbit) sera for the prophylaxis or treatment of certain bacterial infections, bacterial toxin-mediated diseases such as tetanus, or serious viral infections such as rabies had become very sophisticated (13, 39, 43). Antimicrobial chemotherapy made it no longer necessary to expose patients to the serious risks posed by injection of animal sera for the treatment of pneumonia and sepsis. It is paradoxical that 60 years later, antimicrobial resistance of some bacterial and viral pathogens, new iatrogenic diseases arising from aggressive therapies for cancer or organ failure, and improved understanding of the pathogenesis and immunology of viral and bacterial infections have brought renewed interest in passive immunization for the prevention and treatment of certain infectious diseases. Nearly 50 years have passed since Ogden C. Bruton’s report of an 8-year-old boy with recurrent Streptococcus pneumoniae bacteremia whose plasma contained little gamma globulin (immunoglobulin G [IgG]). Bruton treated the boy’s agammaglobulinemia with regular intramuscular (i.m.) injections of human-plasma-derived IgG. The treatment resulted in increased serum IgG levels and an impressive reduction in the number of serious bacterial infections he experienced (6). At the time of Bruton’s report, few appreciated the implications of his seminal observations. Near the end of World War II, Edwin Cohn’s pooled human plasma “fraction 2” was injected intramuscularly to control outbreaks of red measles and infectious hepatitis in U.S. soldiers (7, 34, 53). Soon after, fractionated IgG became generally available for i.m. use. At that time, human IgG treatment was recommended to modify disease expression of measles and hepatitis A, but other indications for its clinical use were not fully defined. As IgG could be safely given only by the i.m. route, doses were limited to about 100 to 150 mg/kg of body weight/month. Larger doses were too painful. In the decades following Bruton’s report, the development of simple and reliable IgG assays permitted the identification of additional hypogammaglobulinemic patients. Also identified were preterm neonates, some other normal infants with transient low IgG levels in the first year of life, older infants, and occasional children and adults with congenital or acquired hypogammaglobulinemia (51). In the past 25 years, patients with lymphoid malignancies or those who were immune suppressed for organ transplantation or undergoing therapy for cancer were found to commonly experience serious infections. Might these patients also benefit from immune augmentation with IgG? When empiric parenteral immunoglobulins were given to these patients, it remained uncertain whether they experienced significantly fewer serious infections. An assumption underlying IgG formulations was that plasma pooled from large numbers of donors ensured that IgG lots contained comparable levels of antigen-specific antibodies. Despite this assumption, we and others demonstrated substantial lot-to-lot differences in neutralizing (NT) antibody levels for respiratory syncytial virus (RSV) and for specific opsonic antibodies to group B streptococci (GBS) (16, 18). Manufacturers were not required to quantify specific antibody content in their preparations. Hence, practitioners could not be confident of the quantities of pathogen-specific antibodies present in any given production lot of IgG.