Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions Danielli C. Bichuetti-Silva ⁎, Fernanda P. Furlan, Fernanda A. Nobre, Camila T.M. Pereira, Tessa R.T. Gonçalves, Mariana Gouveia-Pereira, Rafael Rota, Lusinete Tavares, Juliana T.L. Mazzucchelli, Beatriz T. Costa-Carvalho ⁎ Division of Allergy Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo (UNIFESP-EPM), Rua dos Otonis 725, São Paulo, SP 04025–002, Brazil abstract article info Article history: Received 18 June 2014 Received in revised form 1 September 2014 Accepted 10 September 2014 Available online xxxx Keywords: Intravenous immunoglobulin Antibody Infusion-related Adverse reactions Primary immunodeficiency Intravenous immunoglobulin (IVIG) is increasingly recommended for many diseases apart from primary immu- nodeficiency diseases (PID). Although effective and safe, adverse reactions may occur. We conducted a 2-year prospective observational study in 117 patients with PID who received regular IVIG replacement therapy at a me- dian dose of 600 mg/kg every 3 to 4 weeks to examine IVIG's adverse effects; 1765 infusions were performed (mean = 15/patient) in 75 males and 42 females (aged 3 months to 77 years) in 3 groups: ≤9 years (34.2%), 10–19 years (26.5%), and ≥20 years (39.3%). Fifty patients had common variable immunodeficiency (CVID), 11 had X-linked agammaglobulinemia (XLA), and 55 had other immune system disorders. The drugs adminis- tered were Octagam® (49.1%), Tegeline® (17.3%), Imunoglobulin® (18.6%), Flebogama® (12.9%), Vigam® (1.2%), and Kiovig® (0.4%). Immediate infusion-related adverse reactions occurred in the cases of 38 out 1765 in- fusions (2.15%, IC95% 1.53%–2.94%), which were classified as mild (81.6%), moderate (10.5%), or severe (7.9%). Time until reaction ranged from 10 to 240 min (mean = 85.7, median = 60). Reaction rates were similar across age groups. The most common reactions were malaise, headache, and abdominal pain. Reported severe events were tightness of the throat and seizure. All symptoms improved with temporary or complete IVIG interruption and symptomatic medications. Sixteen of 38 reactions to infusions occurred in the presence of an acute infection (p = 0.09). Tegeline® represented a greater reaction risk factor than Octagam® (p b 0.001). These results indi- cate that IVIG infusion can be considered a safe procedure. Low reaction incidence and few severe immediate infusion-related adverse reactions were observed. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Intravenous immunoglobulin (IVIG) has become increasingly im- portant as a replacement therapy in primary and acquired immunodefi- ciencies, and as an immunomodulatory therapy in autoimmune and auto-inflammatory diseases and transplantation [1, 2]. The mechanisms through which IVIG produces effects in these distinct disorders are not fully understood, but multiple potential immunomodulatory functions have been described, and IVIG has been accepted as more than a passive replacement therapy [1]. IVIG is a blood derivative consisting primarily of intact IgG molecules from pooled plasma of human donors [3]. Despite the introduction of manufacturing steps that enhance purity, minimize damage to IgG molecules, decrease the frequency of adverse reactions, and result in a higher concentration of liquid IVIG, some adverse reactions associated with its regular administration still occur [4, 5]. Studies evaluating adverse reactions to IVIG have revealed incidence rates varying from 1% to as high as 81% of patients or infusions, but mostly between 30 and 40% of infusions [6–13]. These reactions can be mild, moderate, or severe, and immediate or delayed. Adverse reac- tions may be due to the antigenicity of IgG itself, large-molecular- weight IgG aggregates, presence of an antibody to a circulating microbi- al or self-antigens, or complement activation or direct release of cyto- kines from mononuclear cells. IVIG formulations may contain low- molecular-weight kinins or kallikreins, as well as procoagulant factors that were not removed during fractionation. The presence of these fac- tors varies considerably from brand to brand, and even from batch to batch of the same brand [14]. Other risk factors associated with infu- sions and patient characteristics have been well documented, such as a prior history of infusion reaction, first infusion, large dose, rapid dose, no pre-infusion or post-infusion hydration, fever/infection at the time of infusion, autoimmunity, older age, immobility, hypertension, high lipid levels, diabetes, smoking, prior/current thrombosis, estrogen use, and change of IVIG brand [5, 14–16]. International Immunopharmacology xxx (2014) xxx–xxx ⁎ Corresponding authors at: Rua dos Otonis 725, São Paulo, SP 04025–002, Brazil. Tel.: +55 11 55791590; fax: +55 11 50840285. E-mail addresses: daniellibichuete@gmail.com (D.C. Bichuetti-Silva), nandafurlan@hotmail.com (F.P. Furlan), aimeenobre@yahoo.com.br (F.A. Nobre), milatmp@hotmail.com (C.T.M. Pereira), tessarachel@gmail.com (T.R.T. Gonçalves), ma_rianinha@yahoo.com.br (M. Gouveia-Pereira), rota72@hotmail.com (R. Rota), lusinete_tavares@gmail.com (L. Tavares), juliana.mazzuccheli@gmail.com (J.T.L. Mazzucchelli), beacarvalho@terra.com.br (B.T. Costa-Carvalho). INTIMP-03406; No of Pages 5 http://dx.doi.org/10.1016/j.intimp.2014.09.015 1567-5769/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Please cite this article as: Bichuetti-Silva DC, et al, Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/j.intimp.2014.09.015