Editorial QJM Intravenous immunoglobulin therapy

Since the serendipidious discovery that infusions of intravenous immunoglobulin (IVIg) caused the platelet count to rise in a child with both thrombocytopenia and primary antibody deficiency, there has been an enormous increase in the indications for use of this therapy in a wide range of diseases whose pathogenesis is proven or suspected autoimmunity. The challenge for physicians, particularly clinical immunologists, is to ensure that the efficacy of IVIg in a given disease is proven, preferably by a placebocontrolled randomized clinical trial. The use of polyclonal immunoglobulin must be both appropriate in relation to other therapies, and safe with regard to viral transmission and infusion-related reactions. An additional concern is that the indiscriminant use of any blood product will result in reduced availability of valuable resource such as IVIg which provides essential replacement therapy for the lifelong disease of primary antibody deficiency. The risk benefit of any new treatment must balance safety against proven efficacy. Polyclonal immunoglobulins for intravenous use are purified from a plasma pool comprising 6000 to 10 000 donations. Pools of this size provide polyclonal antibodies against a wide range of pathogens, but more recently it has been shown that a pool of between 100 and 1000 donors is also required to provide the range of regulatory immunoglobulins needed in some autoimmune diseases. These large pools increase the risk of viral transmission. Screening procedures for all individual donor units for antibodies to HIV and more recently to hepatitis C, in addition to antigen testing for hepatitis B, are routine. However this antibody screening is not foolproof if donors are in the 'window period' of viraemia between exposure and antibody production. With regard to HIV, manufacturers are required to show that each process of extraction used inactivates HIV. Furthermore, careful follow-up of cohorts of IVIg recipients have not detected a case of HIV transmission through immunoglobulin. There have however been several outbreaks of hepatitis C in immunoglobulin recipients. The most recent outbreak in 1994 was associated with the removal, from the final immunoglobulin preparation, of antibodies against hepatitis C as a result of the introduction of screening of donor units for these antibodies. Whilst such screening has significantly decreased the incidence of hepatitis C transmission by blood transfusion, it may have increased the risk of hepatitis C transmission in immunoglobulin. As a result manufacturers are now required to prove that lipid-envelope-coated viruses (by using surrogate viruses for HCV) are destroyed or inactivated in the manufacturing process; such steps include low-pH treatment, solvent detergent or pasteurization. Infusion-related reactions are uncommon in patients receiving replacement doses of intravenous immunoglobulin at doses around 0.4 g/kg body weight/month. However, with the increased doses (2 g/kg body weight over 2-5 days) used for immunomodulation, there are more serious adverse reactions related to an infusion. Acute meningism is a wellrecognized complication, particularly in patients with abnormalities in cerebral vasculature or previous cerebral pathology. There are a few reports of acute tubular necrosis, usually in patients with pre-existing renal disease; a transient rise in serum creatinine frequently follows an infusion of immunomodulatory dose of intravenous immunoglobulin, but without sequelae. Intravascular haemolysis has been reported in a few patients due to the presence of IgG antibodies to blood group haemaglutinnin A or rhesus D antigen in the immunoglobulin. Since this is extremely rare and unpredictable, we have now adopted a policy of checking for haemolysis preand 24 h into an immunomodulatory dose of intravenous immunoglobulin. Diseases in which high doses of intravenous immunoglobulin are used for immunomodulation range from Kawasaki disease (where the immunopathogenesis is unclear) to idiopathic thrombocytopenic purpura (where the role of the autoantibodies to platelet antigens is more defined). Diseases may be divided into those in which the role of intravenous immunoglobulin is proven, those in which open studies have prompted placebo-controlled trials which are not yet complete, and rare diseases in which immunoglobulin has been shown to be useful,