424.11: A 5-Dose IVIG Protocol Decreases the Risk of Reinfection in Solid Organ Transplant Patients With Secondary Antibody Immunodeficiency: Results of a Multicenter Randomized Clinical Trial

Introduction: Infection is a leading cause of morbidity and health spending after solid organ transplantation (SOT). Secondary antibody deficiency (SAD), defined as IgG hypogammaglobulinemia, is frequently observed after SOT. In single center, multicenter and metanalysis, IgG hypogammaglobulinemia has been demostrated as a risk factor of severe infection in all SOT. Reinfection is more common among patients with SAD after SOT. Intravenous immunoglobulins (IVIG) are used for replacement therapy in primary and secondary immunodeficiencies. In primary immunodeficiency the protocols are well established. However, in SAD, the doses, number of doses and, above all, the time of therapy are not well defined. In a multicenter randomized clinical trial we evaluated the safety and efficacy of a 5-dose IVIG protocol to decrease the rate of reinfection in SOT with severe infections and SAD. Materials and Methods: Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and SAD (IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (visit 1, V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients performed at the coordinating center in Madrid (Gregorio Marañon Hospital). Results: The primary outcome measure (rate of reinfection) was lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Reconstitution of IgG between V1 and V7 was higher in IVIG group as compared with non IVIG group (361±223 vs 255±275 mg/dL, p=0.038). Higher levels of specific IgG anti-cytomegalovirus, IgG anticlostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in IVIG-recipients as compared with patients that were treated with antimicrobial therapy alone. A significant increase of specific antibodies between V1 and V7 was only observed in IVIG group. A significant decrease of serum BAFF levels was demostrated in IVIG group. 16 SAE were reported in 13 patients (6/21 IVIG treated patients (28.57%) and 7/18 non-IVIG patients (38.88%), p=0.496). None of SAE was considered to be related with study drug. Conclusions: We have demonstrated that IVIG is associated with lower rate of reinfection in SOT with severe infection and SAD. Reconstitution of specific antibodies and immunemodulation of serum BAFF was only observed in IVIG-treated patients. We believe that this way of administering IVIG can be validated in future clinical trials with a larger number of patients.