INTRODUCTION

Intravenous gamma globulin preparations were originally developed for the treatment of antibody deficiency states.  However, it rapidly became apparent that these could be used to treat a variety of autoimmune diseases and as adjunct treatment for specific patients at high risk for potentially fatal infections.  Furthermore, it appears that they have important immunomodulating activities that provide insights into the mechanisms of immune regulation.

Preparations suitable for intravenous administration were introduced into clinical medicine approximately 10 years ago.  According to a recent issue of the Medical Letter (34:116, 1992), there are seven commercial preparations; there are little therapeutic differences between these.  IV-IgG is prepared from plasma pools obtained from between 3,000 to 50,000 donors. 

Because of these large donor pools, these preparations contain a wide spectrum of antibodies.  All IV-IgG products must contain adequate levels of antibodies against tetanus, measles, and polio, but antibody titers to common pathogens have been found to vary widely, not only from one product to another but also from one lot to the next.  In most cases, these preparations contain relatively normal concentrations of different IgG subclasses and varying amount of IgA.  None of the available forms contain IgM antibodies.  The IgA in the infusions can cause serious allergic reactions in individuals lacking this immunoglobulin isotype.

indications

A.     Humoral Immune Deficiencies 

IV-IgG is routinely used for the treatment of patients with antibody deficiency syndromes.  These patients frequently present with recurrent infections, primarily involving the upper and lower respiratory tracts.  Typically, the infecting organisms are the encapsulated pyogenic bacteria (S. pneumoniae and H. influenza).   

IV-IgG has substantially decreased both mortality and morbidity in those patients with primary hypogammaglobulinemia disorders, such as common variable hypogammaglobulinemia.  Recent studies suggest IV-IgG may also be useful in selected patients with either isolated IgG subclass deficiencies or in individuals with impaired responses to specific antigens.  In a cooperative study, IV-IgG has been also shown to be of value in selected patients with recurrent infections an severe hypogammaglobulinemia due to chronic lymphocytic leukemia (CLL).  IV-IgG does not afford any value to individuals with recurrent or chronic viral respiratory infections.

B.  Immune Mediated Diseases

The second major use of IV-IgG is in the treatment of patients with immune-induced thrombocytopenia (ITP).  In children, acute severe thrombocytopenia is generally a self-limited disorder; >80 percent completely recover within a few weeks, often irrespective of therapy.  However, severely affected patients are at risk of severe and potentially fatal hemorrhage.  In most instances, IV-IgG infusion can rapidly reverse the thrombocytopenia and has now become the treatment of choice for those children who require therapy. 

Adults, in contrast to children, rarely have a self-limited form of ITP.  In most instances, the disorder is chronic, often with spontaneous or drug-induced remissions and exacerbations.  IV-IgG has been used to acutely increase the platelet count; approximately two thirds of the treated patients will achieve a platelet count of > 100,000/mm³.  However, the beneficial effects are typically transient.  As such, IV-IgG is usually employed only as a temporizing measure in the management of selected adults whose thrombocytopenia is rapidly reversing.  Rarely, it may be used to maintain adequate platelet counts in patients resistant to other therapeutic modalities. 

IV-IgG has also been used in a variety of other hematologic disorders including immune neutropenia, autoimmune hemolytic anemia due to IgG autoantibodies, pure red cell aplasia, and in acquired Factor VIII inhibitors.  It is believed that the therapeutic effects in immune cytopenias may be due to the blockade of Fc receptors by IgG; with Factor VIII inhibitors and per other disorders, it may act by providing anti-idiotypic antibodies. 

One of the most controversial uses of IV-IgG is in preventing the destruction of transfused platelets in individuals who are alloimmunized.  It is generally agreed that IV-IgG is ineffective in preventing the destruction of random donor platelet transfusions.  Some investigators claim IV-IgG may have modest effects with HLA matched products, but this has not been proven in controlled studies. 

Another beneficial effect of IV-IgG is in the treatment of Kawasaki disease.  In combination with aspirin, there is a decrease in coronary artery aneurysm formation and other manifestations of this disease.  In other studies, IV-IgG has been shown to reduce the incidence of cytomegalovirus interstitial pneumonia in patients undergoing allogeneic bone marrow transplant.  IV-IgG appears to be as effective as plasma exchange in patients with Guillain-Barre syndrome.  It may also be useful in other neurologic diseases such as myasthenia gravis.

 

C.  Other Disorders

IV-IgG has also been used in a number of other disorders; however, its effectiveness to date cannot be fully assessed.  It may be of benefit in children with HIV infections, in very low birth weight infants, and in selected high-risk surgical patients.

DOSAGE

The dose of IV-IgG depends on the disorder being treated.  For severe hypogammaglobulinemia, the customary dose is 200 mg/kg.  Higher doses have been advocated in selected patients, particularly those with chronic sinusitis who do not show satisfactory responses to the lower dose.  Based on the half-life of IgG, which averages about 21 to 25 days in normal adults and somewhat longer in those who are immuno-deficient, infusions should be administered every 3 to 6 weeks.  For the symptomatic hypogammaglobulinemia associated with chronic lymphocytic leukemia, the recommended dose is 400  mg/kg.  In the treatment of ITP, the suggested dose of IV-IgG is 2 gms/kg given over one to five days.  The recommended dose is IV-IgG for Kawasaki disease is 400 mg/kg.  IV-IgG is expensive; a single treatment can cost up to $10,000.

 

SIDE EFFECTS

Common side effects from administration of IV-IgG include headache, back, or abdominal pain, nausea, vomiting, chills, fever, and myalgias.  Slowing the rate of infusion or pretreatment with corticosteroids and/or antipyretic drugs, such as acetaminophen, may moderate or prevent these symptoms.  A very rare but potentially one of the most serious problems is anaphylactic reactions occurring in patients with IgA deficiencies.  Transmission of HIV, hepatitis B and hepatitis C has not been reported with any of the preparations used in the United States and, with the multiple effective donor screening procedures and viral inactivation steps that are used in the manufacturing of IV-IgG, infection with these organisms does not appear possible.

Copies of the Transfusion Medicine Update can be obtained by contacting Deborah Small at (412) 209-7320 or
by e-mail:  dsmall@itxm.org.