Intravenous immunoglobulins in pediatrics: immediate and delayed adverse events

Intravenous administration of immunoglobulins in pediatrics is used for an increasing number of indications. First of all, primary and secondary immunodeficiencies, but also and more and more frequently, inflammatory and autoimmune diseases such as Kawasaki disease, idiopathic thrombocytopenic purpura, Guillain-Barrè syndrome, autoimmune encephalopathies, myasthenia, polymyositis and epilepsy. The off-label use of intravenous immunoglobulins has been progressively extending to the neonatal period after their use in a case of hemolytic anemia due to Rh incompatibility was first described in 1987.¹
Recently, the SARS-CoV-2 pandemic has brought out an additional indication: multisystem inflammatory syndrome of the child, known by the acronym MIS-C (or PIMS-TS). This is a nosological entity very similar to Kawasaki disease, typical of the pediatric age, which occurs in rare cases a few weeks after infection with SARS-CoV-2 and that, similarly to what happens in Kawasaki disease, sees in the administration of intravenous immunoglobulins at high doses (2 g/kg) one of the cornerstones of treatment.²
While the rationale for the use of immunoglobulins (intravenous or subcutaneous) in immunodeficiencies is well encoded, their mechanism of action in autoimmune or inflammatory diseases is likely multifactorial and differs depending on the dose and pathology for which they are used: direct binding to autoantibodies, saturation of immunoglobulin receptors on macrophages, opsonization and prevention of immune complex attack on cell membranes, modulatory action on cell-mediated immunity, immunosuppressive or anti-infective effect.³
Intravenous immunoglobulin formulations are a concentrate of antibodies-primarily IgG, but also IgA and traces of other immunoglobulins from a pool of 1,000 to 100,000 healthy donors, along with cytokines, soluble receptors, and other plasma proteins.⁴ Their administration, in children as well as in adults, is considered safe overall, but not free from possible problems; in pediatric case series, adverse events have been reported in a percentage between 1% and 40%, with a frequency of 23.5% limited to neurological diseases and 37.5% during the first administration of intravenous immunoglobulins.⁵
Adverse events may be immediate or delayed.⁶

Immediate adverse events

Immediate adverse events occur within 30 to 60 minutes after the start of infusion, affect approximately 10% of pediatric patients, and manifest as mild (headache, nausea, fever, chills, and asthenia) or more severe (vomiting, chest pain, intense headache, seizures) symptoms, whereas anaphylactic reactions are extremely rare.^7,8
Immediate adverse events are likely attributable to the presence of excipients and stabilizers in intravenous immunoglobulin preparations, formation of immunoglobulin aggregates causing complement activation or antigen-antibody reactions, or too rapid infusion. Their incidence can be significantly reduced, especially if there is a history of previous adverse events from intravenous immunoglobulins, by slowing the infusion rate, attending to the patient’s hydration, or premedicating the patient with acetaminophen, antihistamines, and corticosteroids.^5,9

Delayed adverse events

Delayed reactions may occur in up to 40% of treated pediatric patients (and 21% of infusions), including headache (the most frequent symptom and one that can occur as both an immediate and late adverse event), myalgias, abdominalgia, and asthenia.⁷
Cases of aseptic meningitis within 96 hours of infusion are also reported.⁸ In a group of 145 children with immunodeficiency who had received a total of 1,214 infusions, adverse events occurred in 44.8% of patients and 14.2% of infusions (10.6% immediate and 10.2% late); the risk was greater in the presence of previous adverse events on IV immunoglobulin, concomitant infections, family or personal history of atopy, age less than 10 years, and during the first administration of IV immunoglobulin (see Table).

Table. Immediate and delayed reactions to intravenous immunoglobulins (n = 1,214 infusions, modified from ref 10)

Changing the preparation of intravenous immunoglobulins in subsequent infusions may also promote the occurrence of adverse events in 15-20% of patients, whereas the concentration of intravenous immunoglobulins (5% or 10%) of the product does not seem relevant.¹⁰
Finally, a recurring theme in the literature is the safety profile of intravenous immunoglobulin preparations containing traces of IgA in patients with IgA deficiency. In 30% of these patients, in fact, it is possible to find anti-IgA IgE or IgG theoretically responsible for even serious adverse events.¹¹ In practice, the risk of anaphylaxis, even if present, appears very rare and practically non-existent before adolescence. Thus, there is no reason to investigate patients preemptively to identify an IgA defect, nor to deny intravenous immunoglobulin infusion to those who may be affected.⁹ Once again, caution in infusion rate, hydration, and possible premedication are the most effective measures to take.