Reduction of Adverse Events and Re-Presentation to Medical Care After Intravenous Immunoglobulin Treatment in Children With Immune Thrombocytopenia With a Scheduled Post-Infusion Medication Strategy

Immune thrombocytopenia (ITP) is the most common acquired immune cytopenia in childhood, affecting 4-6 in 100,000 children. The pathophysiology of ITP is highly complex and incompletely understood. Accepted mechanisms include immune dysregulation caused by an often unidentified trigger leading to the formation of anti-platelet antibodies and antibody-mediated reticuloendothelial clearance. Cell-mediated platelet destruction and disruption of T cell homeostasis are also well described. ITP is also characterized by impaired platelet production due to antibody effect in the bone marrow and subsequent megakaryocyte ultrastructural abnormalities.

Children with ITP generally present with a sudden onset of symptoms. Bleeding tendency is variable, but the vast majority of children will experience cutaneous bleeding symptoms including bruising and petechiae. More extensive bleeding ranging from extensive oral bleeding, gastrointestinal bleeding, menorrhagia, or other significant bleeding necessitating urgent medical intervention develops in up to 20% of patients.8 Intracranial hemorrhage (ICH), the most feared and devastating complication of ITP, occurs in approximately 0.5% of pediatric patients. Bleeding phenotype is unable to be reliably predicted at diagnosis. In children who present with mucosal or more significant bleeding, treatment is indicated to achieve rapid hemostasis by increase in platelet count. Intravenous immunoglobulin (IVIG) is a commonly utilized first line agent to reduce bleeding symptoms and improve the platelet count to a hemostatic range within 24-48 hours of administration. The mechanism of action of IVIG in ITP is currently incompletely understood and likely involves multiple immunomodulatory mechanisms. Previous data has suggested IVIG leads to a rise in platelet count via blockade of Fc receptors on phagocytic cells within the reticuloendothelial system. Another hypothesis suggests IVIG upregulates the expression of the inhibitory IgG Fc receptor 2B encoded by FCGR2B gene, thus leading to decreased cell mediated destruction and decreased anti-platelet antibody production.14 Following IVIG administration, an improvement in clinical bleeding and an associated rise in platelet count is seen in approximately 75% of children with ITP

IVIG is a polyclonal antibody preparation developed from pooled donor plasma from 15,000 to 60,000 donors depending on the preparation utilized. The safety and efficacy of IVIG in patients with ITP has been demonstrated in multiple clinical trials, and IVIG is considered a first line therapy for the treatment of children with ITP. Overall, IVIG is well tolerated across patients with a spectrum of diseases. The majority of reported adverse events are mild, transient, and infusion related. The most commonly reported immediate adverse events include headache, fever, nausea/vomiting, malaise, back pain, flushing, and chills. In comparison to other patient populations who receive IVIG, patients with ITP carry the unique risk for intracranial hemorrhage due to profound thrombocytopenia. Mild side effects such as headache and nausea/vomiting can easily be attributed to recent IVIG administration in non-thrombocytopenic populations. However, these symptoms overlap with the heralding symptoms of an intracranial hemorrhage which, due to high morbidity and mortality, must not go undiagnosed in patients with ITP. To decrease the percentage of patients experiencing these immediate, infusion associated symptoms, patients with ITP at most pediatric centers are routinely pre-medicated with a single dose of acetaminophen and diphenhydramine prior to IVIG infusion.21 However, post-infusion medication regimens differ amongst providers and pediatric centers and frequently utilized acetaminophen and diphenhydramine as these symptoms arise.

Peak IgG concentration following IVIG administration occurs in the cerebrospinal fluid (CSF) between 24-48 hours after infusion. The common events of headache, nausea, and vomiting often peak during this time, when most patients have already been discharged from medical care. Headache and associated nausea/vomiting are particularly worrisome in patients with ITP given the risk for ICH and overlap of symptoms at presentation. Aseptic meningitis, a rare and serious adverse event following IVIG infusion, presents with headache, nausea/vomiting, nuchal rigidity, and fever. The development of aseptic meningitis is hypothesized to be dose dependent and has been noted to cluster within patients who suffer from migraines.

At Texas Children's Hospital, most children prescribed IVIG receive Gamunex-C, which has a reported incidence of headache in 30-50% of patients. At the onset of symptoms, patients typically remain severely thrombocytopenic and at highest risk of ICH. Many of these patients will develop symptoms severe enough to necessitate return to medical care, additional laboratory studies, and computed tomography (CT) of the head to rule out ICH. Texas Children's Hematology Center data reveals 28% of the 473 IVIG infusions administered to patients for ITP between 2010 and 2016 resulted in the report of headache or nausea/vomiting. Seventy-seven percent (103/133) of these infusions resulted in the patient developing symptoms sufficiently severe to cause re-evaluation by a medical provider. Subsequent urgent visits often come at significant expense. Of the 133 infusions resulting in the report of headache and/or nausea/vomiting, 45% (60/133) required additional lab work and 27% (36/133) required imaging via CT to rule out ICH ( please see Figure 1 in the full protocol). These 36 patients who required urgent head CTs represent 7.6% of all IVIG infusions administered for ITP between 2010 and 2016 (American Society of Hematology Conference Abstract 2018; further cohort data analysis in process).