On the Dark Side of Therapies with Immunoglobulin Concentrates: The Adverse Events

Abstract

Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.

Antibody replacement therapy in primary antibody deficiencies and iatrogenic hypogammaglobulinemia

“…Less frequent, but more severe adverse effects include anaphylactic reactions, acute renal tubular necrosis, aseptic meningitis and thromboembolic events. These are more likely to occur with the use of higher immunoglobulin doses [61,62]. SCIG therapy is commonly associated with local swelling and redness, but systemic reactions are rarer than with IVIG [61,62].…”

“…These are more likely to occur with the use of higher immunoglobulin doses [61,62]. SCIG therapy is commonly associated with local swelling and redness, but systemic reactions are rarer than with IVIG [61,62]. When adverse events occur, (temporarily) switching from one mode of administration to another may be helpful.…”

Effect of intravenous immunoglobulin administration on erythrocyte and leucocyte parameters

“…In general, IVIG administrations are well tolerated with mild and transient common adverse reactions, such as headache and flu‐like symptoms. In certain cases, anaphylactic symptoms, aseptic meningitis, thrombosis, renal failure, transfusion‐related acute lung injury and haematological toxicities have been reported . A well‐documented, but under‐recognized serious complication is IVIG‐associated haemolysis, defined as a haemolytic episode occurring within 10 days of IVIG administration and characterized by a fall of ≥10 g/L in haemoglobin (Hb) levels, a positive direct antiglobulin test (DAT) and at least two of the following criteria: reticulocytosis, elevated levels of lactate dehydrogenase (LDH) or unconjugated bilirubin in serum, low haptoglobin, haemoglobinaemia, haemoglobinuria and the presence of spherocytosis in the absence of other possible causes of anaemia .…”

Hemolysis related to intravenous immunoglobulins is dependent on the presence of anti‐blood group A and B antibodies and individual susceptibility

“…In addition, hemolysis occurs more frequently in patients who receive a high dose of IVIG, for example, 2 g/kg body weight (bw) IVIG. IVIG preparations produced using chromatography have a higher concentration of anti‐A and anti‐B isoagglutinins compared with preparations produced by Cohn‐like ethanol fractionation, and with these preparations, a higher incidence of hemolysis has been reported …”

“…Most available IVIG preparations, including Privigen (CSL Behring), a 10% l ‐proline stabilized IVIG, have been shown to contain isoagglutinins and have been associated with hemolysis, including severe hemolysis in rare cases . In a previous study of Privigen in patients with primary immune thrombocytopenia (ITP), none of the 57 patients studied developed severe hemolysis …”