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Newsletter Edition no. 26 Intravenous immunoglobulins: Mode of action and Guidelines for use Dr. MC Ferreira M.Med.(Haematology), PG Dip (Transfusion Medicine) Haematologist 1. Mechanism of immuno-modulation High doses of immunoglobulin have both anti-inflammatory effects as well as immuno-suppressive effects and possibly exert their effects through the following mechanisms 1-2 : 1. It inhibits antibody formation probably through negative feedback and a reduction of B-cells after infusion of IVIg. 2. It directly binds the auto-antibodies through antiidiotype antibodies. Anti-idiotypical antibodies in the IVIg preparation may account for the efficacy of action seen in patients with acquired Haemophilia A. Auto-antibody concentrations may also decrease after administration of IVIg because of overall increase in catabolism of IgG. This happens because the Fc receptors on phagocytes (protection for IgG against catabolism) are saturated. The more IVIg is given, the higher the rate of catabolism. 3. It non-specifically blocks the Fc-receptors on phagocytes and inhibits the uptake of antibodycoated cells from the circulation in the spleen and liver. Antibody-mediated cellular toxicity is thus limited. In immune thrombocytopenic purpura (ITP) this is probably the dominant mechanism of action with possibly also ligation of Fc-receptor inhibition. A similar effect is obtained through use of anti-D in Rhpositive patients with ITP where the antibodycoated red cells “block” the phagocytic system in the spleen. Anti-Fas antibodies in IVIg bind with Fasligands and blocks apoptosis which is central in certain necrotising conditions. This is probably one of many undetermined antibodies present in a “soup” from different donors' plasma. 4. It decreases inflammatory cytokine release or action through down-regulation of the immune activation. This has been eloquently shown in Kawasaki disease where administration of IVIg, with binding to Fc-receptors on macrophages resulted in down-regulation of interleukin-1 release. 5. Antibodies have effects on microbes and toxins. It may bind to antigens on microbes leading to opsonification and activation of complement subsequently enabling lysis of bacteria. It can neutralize certain toxins known to act as superantigens (which can directly stimulate Tlymphocytes) leading to the release of proinflammatory cytokines which may compound the inflammatory reaction (e.g. in toxic shock syndromes). 6. It inhibits complement-mediated tissue injury through direct activation of complement, relaying the downstream complement activation pathway away from target cell membranes. This is probably part of the mechanism in dermatomyositis. 7. In immune neutropenia it is unclear whether IVIg is effective because it may induce neutrophils to enter the bloodstream or whether it is effective and prolongs neutrophil survival. Immune modulation is most probably a combination of different aspects described above. The effect IVIg may have on complement activation, macrophages or through “neutralising“ antibody is most likely not enough to explain the rapid clinical responses seen, but a combination may be more likely to explain the effectiveness. 2. Guidelines for the use of IVIg 3 Dosage 2g/kg, the dose interval is undetermined. Primary immunodeficiency syndromes or partial humoral immuno-deficiency Kawasaki syndrome It is indicated for the replacement of antibodies and increase of the level of circulating antibodies in a patient with primary immunodeficiency syndromes or partial humoral immunodeficiency. It is indicated to prevent coronary artery aneurysms in patients with this disease. Dosage 0.4-0.6g/kg administered every 3-4 weeks A trough level is drawn before administration; the baseline level is at least 500mg/dl. Trough levels may be determined every 3-6 months. B-cell chronic lymphocytic leukaemia It is indicated for the prevention of bacterial infection in patients with hypogammaglobulinaemia, recurrent bacterial infections or both in this patient group. Dosage 0.4g/kg administered once monthly Immune thrombocytopenic purpura IVIg is indicated to rapidly raise the platelet count, prevent or control bleeding, or optimize patients with ITP prior to surgery Dosage 0.4g/kg/d for 5 days. Dosage 1-2g/kg as a single dose in conjunction with aspirin. Haemolytic disease of the newborn It is indicated in patients who are haemolysing due to the presence of maternal antibodies. The aim is to prevent or reduce the need for exchange and / or top-up transfusion in these neonates. Dosage 1-2g/kg as a single dose. It may be repeated once if volume overload is not problematic. Note The only indications Polygam 4 (the product available in South Africa) is registered for, are: 1. R e p l a c e m e n t t h e r a p y i n p r i m a r y a n t i b o d y immunodeficiency syndromes 2. Adjunctive therapy in the prevention of infections in secondary antibody deficiency states 0.4mg/kg may be used as a single maintenance dose when required. 3. Immuno-modulation in: a. Immune thrombocytopenic purpura b. Kawasaki disease. Bone marrow transplantation References: It is indicated in patients 20 years of age or older to prevent sepsis or other infection, interstitial pneumonitis (infectious or other) and acute graft-vs.-host disease in the first 100 days after bone marrow transplantation. 1 Stiehm ER. Appropriate Therapeutic use of Immunoglobulin. Transfusion Medicine Reviews. 1996. 10(3):203-221. 2 Wiles CM, Brown P, Chapel H et al. Intravenous immunoglobulin in neurological disease: a specialist Dosage High-dose therapy is suggested, probably 2g/kg intermittently. review. Journal of Neurology, Neurosurgery and Psychiatry. 2002. 72:440-448. 3 Orange JS, Hossny EM, Weiler CR et al. Use of intravenous immunoglobulin in human disease: A review of evidence Reduction of serious bacterial infection in children with HIV by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, (This is a valid indication according to the FDA. It is definitely not widely practiced in South Africa possibly due to the cost of the product.) The use is advocated to limit serious bacterial infectious episodes, limit hospitalization and increase infection-free periods. Asthma and Immunology. Journal of Allergy and Clinical Immunology. 2006. 117:S525-53. 4 NBI. Polygam. Package insert. 1993.