Changing trends in IVIG use in pediatric patients: A retrospective review of practices in a network of major USA pediatric hospitals

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Highlights

  • IVIG usage in pediatric inpatients has increased during the 2007–2014 period.

  • Most of IVIG prescriptions were off-label.

  • Kawasaki disease, ITP, GBS, and treatment of patients undergoing antineoplastic chemotherapy were top IVIG conditions.

  • The most significant increase was observed in the IVIG usage for the treatment of unspecified neutropenia and septicemia.

Abstract

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014.

IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain–Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy.

IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.

Introduction

Polyclonal immunoglobulin (IG) preparation as replacement therapy for patients with immune deficiency was first used in 1952 when an eight-year-old boy with agammaglobulinemia was treated for recurrent infections and sepsis by subcutaneous injections of “immune human serum globulin” [1]. The monthly immunoglobulin injections led to no sepsis occurrences for 14 months after treatment. The routine prophylactic treatment of patients with primary immune deficiencies (PID) by intravenous immunoglobulins (IVIG) started in the 1980s.

At present, IVIG preparations are made by pooling plasma collected from thousands of healthy donors. Immunoglobulin G (IgG) represents about 90% of all immunoglobulins present in a commercial IVIG preparation [2]. These preparations contain a broad range of opsonizing and neutralizing antibodies specific to a variety of bacterial and viral antigens [3]. IVIG is the treatment of choice for patients with humoral immune deficiencies but also can be used as an immunomodulatory or anti-inflammatory drug for the treatment of autoimmune disorders and systemic inflammatory diseases [3,4]. During 2007–2014, IVIG was approved by the FDA for use in six conditions: mucocutaneous lymph node syndrome (Kawasaki disease, KD), immune thrombocytopenic purpura (ITP), primary immunodeficiency (PID), secondary immunodeficiency (chronic lymphocytic leukemia, CLL), pediatric HIV infection, and prevention of graft versus host disease or infection in bone marrow transplant (BMT) patients ≥20 years of age [5]. IVIG was also used off-label to treat a wide variety of neurologic, dermatologic, rheumatologic, hematologic, and infectious diseases. The evidence supporting these uses vary [5]. For some indications, the evidence is reasonably convincing and based on a meta-analysis of randomized clinical trials or at least one randomized clinical trial or trial without randomization, while the recommendation for other indications is based on expert opinion [5,6]. For example, the use of IVIG is probably or may be beneficial for the treatment of juvenile idiopathic arthritis, dermatomyositis, Lambert-Eaton Myasthenic syndrome, prevention of neonatal sepsis, primary immune defects with normal IgG, and unlikely to be beneficial demyelinating neuropathy associated with monoclonal IgM, and isolated IgE or IgA deficiency.

IVIG treatments may result in several adverse events, which may occur in 2–25% of patients [2,7]. IVIG related adverse events include pyrexia, malaise, headache, backache, nausea, raised blood creatinine levels, leucopenia/neutropenia/pancytopenia, acute renal failure, coronary and cerebral thrombosis, aseptic meningitis and in rare cases, anaphylactic shock in patients with agammaglobulinemia or IgA-deficient patients [8].

IVIG treatment becomes critical for pediatric patients, especially those with PID when diagnosed very early in their lives. IVIG therapy is beneficial for the treatment of pediatric patients with ITP, Kawasaki disease (KD), chronic inflammatory demyelinating polyradiculopathy (CIDP), acute inflammatory polyneuropathy (Guillain Barré syndrome, GBS) and hemolytic disease of the newborn due to ABO and Rh incompatibility [2,9]. IVIG treatment was successfully used for the treatment of acute disseminated encephalomyelitis and post-streptococcal neurodegenerative disorders in pediatric patients [10]. Advantages and disadvantages of the IVIG usage in pediatric patients with primary and secondary immune deficiencies, neurologic, infectious and other diseases were reviewed by the Work Group of the American Academy of Allergy, Asthma and Immunology based on the existing evidences in 2017 [5]. The work Group have found that IVIG treatment of primary immune deficiencies will benefit pediatric patients by reducing rate of infections. Interestingly, the group recommended the IVIG treatment of ITP in only pediatric patients with increased risk of bleeding or patients with refractory chronic disease. IVIG treatment is definitively benefit pediatric patients with KD [5], although the large percentage of African-American pediatric patients with KD were refractory to IVIG treatments [11]. More recent studies indicated that KD treatment with infliximab or steroids reduces need of additional therapies compared to IVIG treatment [12]. Recent systematic review of the literature suggest that IVIG treatment of children with acute myocarditis did not improve survival rate and cannot be routinely recommended for treatment of acute myocarditis in children [13]. Another study reviewed thirteen studies with 1534 cases of acute myocarditis in children and adults and came to the conclusion that IVIG treatments increases survival of patients with acute myocarditis and supports recovery of left ventricular function [14].

To our knowledge, there are no studies summarizing frequency and trends of IVIG use among pediatric inpatients. Our study analyses a retrospective data obtained from an administrative database of pediatric patients receiving IVIG following hospitalization to the pediatric hospitals during the 2007–2014 period. Data were collected from 47 U.S.-based pediatric hospitals participating in the Pediatric Hospital Information System (PHIS). PHIS is an administrative database maintained by the Children's Hospital Association (CHA) (Lenexa, KS). The PHIS data contains hospital and patient demographic data, admission characteristics (e.g., Length of Stay, Disposition, ICD9 coding, etc.) and detailed billing data. The data is reviewed by the CHA and participating hospitals to ensure data quality.

Our analysis indicates that IVIG was more often than not prescribed to pediatric patients for off-label indications. However, KD and ITP, two FDA-approved indications, were the top indications for which IVIG was prescribed during this period. The IVIG use significantly increased for indications like encephalitis and encephalomyelitis with immune pathogenesis, unspecified neutropenia, and septicemia, while the use for other indications (e.g., Erythema multiforme and fever) has decreased. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications.

Section snippets

Methods

This retrospective study analyzed IVIG used by 47 US-based children's hospitals between January 1, 2007, and September 31, 2014.

Demographic characteristics of pediatric patients treated with IVIG during hospitalization to the US-based pediatric hospitals

We identified 72,852 admissions in which IVIG was administered to 53,648 unique patients. Demographic characteristics of patients admitted to the 47 pediatric hospitals and treated with IVIG are summarized in Table 1. About 55% of patients receiving IVIG treatments were males. Majority of IVIG treated patients were White, non-Hispanic (50%), followed by Black, non-Hispanic group (15%) and White, Hispanic (13%). The median age at the admission was four years. Seventy percent of patients with

Discussion

Data analysis of the IVIG usage by patients hospitalized to the major US-based pediatric hospitals has revealed that the absolute number and mean rate of IVIG admissions per 100,000 admissions have increased from January 1, 2007, to September 30, 2014. This was due to a growing number of IVIG admissions and an increase in the number of indications for which IVIG was prescribed. During the 2007–2014 period, IVIG has been prescribed to pediatric patients diagnosed with 2343 distinct indications.

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