Post IVIG Medication in Children With Immune Thrombocytopenia
Post IVIG Medication in Children With Immune Thrombocytopenia
This study is a single hospital system, single-arm year-long pilot to evaluate the
 feasibility of enrolling children with ITP who are receiving IVIG for treatment of disease to
 a scheduled post-infusion medication for 72 hours following IVIG infusion.

 This year-long feasibility pilot will test the (1) feasibility of enrollment and the
 willingness of families to participate in a scheduled medication regimen and (2) adherence of
 patients and families to the scheduled medication regimen. Clinical outcomes, as defined by
 rates of headache or nausea/vomiting or other adverse event following IVIG, return to medical
 care, and need for further laboratory or imaging studies, will be collected. These rates will
 be compared to retrospective, historical data from Texas Children's Hematology Center from
 2010 to 2019. However, due to the rate at which these events occur following IVIG, this
 feasibility pilot is not fully powered to detect differences in clinical outcomes.
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).

 The etiology of these neurologic IVIG-associated adverse events is not well understood. It is
 currently hypothesized that central nervous system (CNS) symptoms ranging from headache to
 aseptic meningitis following IVIG administration may represent a spectrum of symptoms
 secondary to IgG-mediated meningeal inflammation. This hypothesis is based off cerebrospinal
 fluid (CSF) analysis in patients who developed aseptic meningitis following IVIG. CSF
 demonstrated the presence of allogeneic IgG as well as pleocytosis with neutrophil
 predominance. As the pathophysiology underlying the development of these adverse events is
 currently not fully understood, it is reasonable to trial the safe pediatric medications that
 are already employed in premedication regimens. It is for this reason the investigators
 propose the use of acetaminophen and diphenhydramine for the post-IVIG infusion medication
 regimen.

 Currently, no evidence-based guideline exists for the administration of prophylactic
 medications following IVIG infusions as these specific IVIG side effects are of less concern
 in non-thrombocytopenic patients. The 2011 American Society of Hematology ITP Clinical
 Practice Guidelines found insufficient evidence to recommend or oppose routine premedication
 prior to IVIG. The newly released 2019 Guidelines note that headache can be particularly
 problematic, however they do not recommend a specific avoidance strategy. While providers
 often pre-medicate, post-infusion medication practices are entirely physician dependent and
 frequently involve the use of acetaminophen and diphenhydramine as symptoms arise. The
 investigators hypothesize that an alternative approach to post-infusion practices may alter
 IVIG-related symptomatology, particularly those symptoms most alarming in a patient with
 thrombocytopenia and at risk for ICH. Scheduled post-infusion medication with acetaminophen
 and diphenhydramine may decrease the rate of worrisome symptoms in patients with ITP and
 subsequently decrease the need to return to medical care where additional laboratory and
 imaging studies are often performed to further assess for ICH. The ability of routine
 post-infusion medication to decrease the rate of adverse events and subsequent return to
 medical care has yet to be studied in patients with ITP.

 It is unknown whether families of children with ITP are willing to enroll in a clinical trial
 to evaluate the effects and potential benefits of scheduled post-infusion. Additionally, it
 is unknown to what degree adherence to scheduled post-infusion medication can be achieved. In
 order to determine if enrollment and adherence can be achieved, the investigators plan to
 conduct a year-long feasibility study in patients in whom IVIG is indicated for treatment of
 bleeding symptoms and/or risk associated with ITP (Figure 2). The results of this feasibility
 study will assess the ability to successfully conduct future comparative randomized control
 trials (RCTs). This single-arm feasibility study with comparison to Texas Children's
 Hematology Center historical data will also provide preliminary clinical data regarding rates
 of return to medical care and additional medical interventions. Further RCTs will be critical
 to determine if the number of patients who must return to care and undergo further testing
 can be decreased with a scheduled post-infusion medication regimen. These data will inform
 future clinical practice guidelines.
Inclusion Criteria:

 -  Diagnosis of ITP confirmed by hematology team.

 -  Patient receiving IVIG for a clinical indication as determined by primary
 hematologist. IVIG can be administered in the inpatient, outpatient, and emergency
 room settings.

 -  Age 0 to 18 years

 Exclusion Criteria:

 -  Patients with a history of anaphylaxis to IVIG infusion.

 -  Patients receiving IVIG for indications other than ITP.

 -  Patients who require additional platelet direct therapies including corticosteroids,
 anti-D immunoglobulin, rituximab, or thrombopoietin receptor agonists.

 -  Other cause of thrombocytopenia (congenital thrombocytopenias, drug induced
 thrombocytopenia, bone marrow failure, liver disease, etc.) apparent by history and
 physical examination, and/or laboratory tests.

 -  Inability to tolerate oral medications

 -  Other medical or social factors at discretion of treating physician such as ability to
 follow-up, etc.