Current Allergy and Clinical Immunology - March 2008

INTRAVENOUS IMMUNOGLOBULINEA Goddard, MSc, MB ChB, PhD, MMed (Paed)School of Child and Adolescent Health, University ofCape Town and Red Cross Children's Hospital,Rondebosch, Cape Town, South AfricaABSTRACTThere has been a rapid expansion of the use of intravenousimmunoglobulin (IVIG) for an ever-growingnumber of conditions. IVIG is used at a ‘replacementdose’ (400-600 mg/kg/month) in antibody deficiencies.In contrast it is used at a high dose (2 g/kg/month) as an ‘immunomodulatory’ agent in anincreasing number of immune and inflammatory disorders.The limitations for IVIG are the cost of thepreparation and the need for intravenous infusions.Due to the cost, shortages and growing use of IVIGthere have been attempts to develop evidencebasedguidelines for the use of IVIG in a wide varietyof haematological, autoimmune and neurologicalconditions. This commentary provides the recommendationsand recent publication regarding theuse of IVIG in various conditions. Although IVIG is asafe treatment option when compared with otherimmunosuppressive agents there needs to be anunderstanding of the potential adverse reactionsand their management. It is important for the physicianto carefully assess and monitor patients on IVIGso that treatment can be optimised.INTRODUCTIONIntravenous immunoglobulin (IVIG) replacement therapyhas greatly reduced the morbidity due to bacterialinfections associated with major forms of antibody deficiency.IVIG has a few proven indications and manypotential ones. There has been a rapid expansion in theuse of IVIG. It has had a major impact in the treatmentof conditions in the fields of neurology, haematology,rheumatology and dermatology. In a recent study inCanada the leading indications for IVIG use were idiopathicthrombocytopenic purpura (17.3%), primaryimmune deficiency conditions (14.9%) and chronicdemyelinating polyneuropathy (11.8%). The leadingprescribing specialists were neurologists (32.2%) andhaematologists (26.1%). 1 It is safe and does not havethe side-effects of steroids or other immunosuppressiveagents.BACKGROUNDImmunoglobulin replacement has been standard therapyfor patients with primary immune deficiency diseasessince its use by Bruton in 1952. 2 For many years,these preparations could only be given intramuscularly.Administration of intramuscular immune serum globulinresulted in a decrease in the incidence of infectionsof patients with agammaglobulinaemia. However injectionswere painful, the IgG was absorbed slowly and itCorrespondence: Dr EA Goddard, Red Cross Children's Hospital,Klipfontein Rd, Rondebosch, 7701. Tel 021- 658-5111, fax 021-689-1287, e-mail liz.goddard@uct.ac.zawas difficult to maintain IgG levels above 2 g/l.Intravenous administration of immune serum globulincaused shock-like episodes, chills and hyperpyrexia.Although attempts were made to modify immuneserum globulin for intravenous use, intramuscular useremained the sole form of replacement therapy until1981 (29 years later) when intravenous preparationsbecame commercially available. This reduced the painof administration and allowed larger volumes to beinfused. Over 25 IVIG preparations are available worldwidewhich have been approved by various regulatorybodies. 3 All are tolerated and effective. The variousIVIG products differ in a number of ways includingimmunoglobulin and IgG subclass distribution, antibodycontent, approved maximum infusion rate and sideeffects.The characteristics of the various productsmay result in differences in efficacy and safety whichmay have a significant impact on the choice of productfor some patients.PRODUCTIONAn ideal IVIG preparation would contain structurally andfunctionally intact immunoglobulin molecules with anormal biological half-life and a normal proportion ofIgG subclasses. The preparation should contain highlevels of antibody or antibodies relevant to its proposeduse. There should be no contamination and vasomotorpeptides, endotoxin or infectious agents.Nearly all IVIG preparations are isolated from pooledhuman plasma (1 000 to 10 000 donors) by the Cohnalcohol fractionation method which results in five plasmafractions. The Cohn fraction II contains the bulk ofthe antibodies and is appropriate for intramuscular andsubcutaneous use. This fraction is further purified forthe production of IVIG. The WHO has established thefollowing production criteria for IVIG (1982): 41. Each lot should be derived from plasma pooled fromat least 1 000 donors.2. It should contain at least 90% intact IgG with thesubclasses present in ratios similar to normal pooledplasma.3. IgG molecules should maintain biological activitysuch as complement fixation.4. It should be free from contaminants of prekallikreinactivator kinins, plasma proteases and preservatives.5. It should be free from infectious agents.As for all blood products donors are screened forhepatitis B surface antigen, HIV -p24 antigen, and antibodiesto syphilis, HIV-1, HIV-2 and hepatitis C.Commercial lots are produced from plasma pooledfrom 1 000 to 10 000 donors so contain a broad spectrumof antibodies. Differences in the manufacturingprocesses of different IVIG preparations affect opsonicactivity, Fc-receptor function and complement fixation.Thus different IVIG preparations should not be consideredas a generic productMECHANISM OF ACTION OF IVIGIVIG acts via a variety of mechanisms in different diseasestates and these have been reviewed in detail byBallow 5 and Jolles et al. 6 The mechanisms of action of26 Current Allergy & Clinical Immunology, March 2008 Vol 21, No. 1