Administration Of Intravenous Immune Globulin Research Articles

Relationship between Body Composition and Serum Immunoglobulin Concentrations after Administration of Intravenous Immune Globulin–Preclinical and Clinical Evidence

The purpose of this study was to investigate the effect of obesity on immunoglobulin G (IgG) pharmacokinetics in a rat model of obesity, and to collect clinical evidence for an association between the body composition and intravenous immune globulin (IVIG) pharmacokinetic parameters in humans. In a preclinical study, pharmacokinetics of human IgG was evaluated after intravenous (IV) and subcutaneous (SC) delivery to obese and lean rats (n = 6 in each group). Serial serum samples were analyzed using an ELISA. The animal body composition was assessed using computer tomography. Patients with primary immunodeficiency currently managed with IVIG, and at a steady state, were enrolled in the clinical study (n = 8). Serum immune globulin (Ig) concentrations were measured at baseline and immediately after the administration of two consecutive treatments, with an additional measurement at two weeks after the first administration. In addition to the patient demographic and clinical characteristics, body composition was measured using bioelectrical impedance analysis. The pharmacokinetics of human IgG was significantly different between the obese and lean rats after both the IV and SC administration of 0.5 g/kg. Furthermore, a significant difference in endogenous rat IgG was observed between the two strains. In the human study, total serum IgG and subtype (IgG1, IgG2, IgG3, IgG4) half-life negatively correlated with the body mass index and fat mass. The mean change in the total serum IgG concentration was significantly correlated to body mass index and fat mass. The results of the studies corroborated one another. In the animal study, most pharmacokinetic parameters of human IgG following IV and SC administration were significantly affected by obesity and changes in the body composition. In the clinical study, the mean serum IgG change after the IVIG administration strongly correlated to the BMI and body fat mass. Future studies are needed to establish the outcomes achieved with more frequent dosing in obese individuals with primary immunodeficiency.

Live Immunization Practices for Chronically Transfused Pediatric Patients

Introduction: Children with hemoglobinopathies often require chronic transfusion as a part of their care. The Canadian Immunization Guide, the National Advisory Committee on Immunizations, and the Centre for Disease Control recommend avoidance of live vaccination for a period following blood product transfusion. The literature indicates that human derived blood products contain significant amounts of antibodies to infectious agents that are prevalent in the general population, due to natural disease or vaccination of the donor, such as the measles virus and varicella zoster virus. The recommended time interval between packed red blood cell (PRBC) transfusion and live vaccination was extrapolated from a study which assessed vaccine responses after administration of Intravenous immune globulin. If practitioners adhere to guidelines, many chronically transfused pediatric patients would not be eligible to receive live vaccinations due to concerns of non-response to the vaccine. Thecomposition of blood products has changed over time and current immunization recommendations may not reflect the blood products being utilized today. Specifically, the amount of residual plasma in PRBCs has been reduced substantially, reducing passive antibody concentration and likely reducing interference in the immune response. To our knowledge, the immune response to live vaccines has not been formally studied in pediatric patients who undergo chronic transfusion with PRBCs. We aimed to determine the current live immunization practices of health care providers (HCPs) caring for chronically transfused pediatric patients.Hypothesis: Is there heterogeneity in the live immunization practices of North American Pediatric HCPs who care for chronically transfused children?Methods: The study was approved by the University of Alberta Research Ethics Board. A cross-sectional online survey was circulated to North American hematology HCPs. The survey was peer-reviewed by 7 practitioners prior to distribution for content and face validity with 3 versions before final approval and distribution. The survey was distributed via the Canadian Hemoglobinopathy Association (CanHaem,186 members) and the American Society of Pediatric Hematology/ Oncology (ASPHO, 1991 members) listservs. Responses were collated from June 2017-July 2017 in a REDcap database. Data was analyzed using descriptive statistics.Results: There were 60 respondents total. 60% of HCPs were from the U.S.A., and 70% cared for 1-19 patients meeting study criteria. The majority had 1-10 patients who travelled to measles endemic countries annually, and 33% of HCPs reported there had been a local outbreak of Measles, Mumps, Rubella or Varicella (MMRV) within the past year. Despite this, 50% were unaware of the MMRV immune-status of their patients. Eighty-seven percent of HCPs continued to administer live vaccinations as per the routine immunization schedule. Less than 10% had a protocol for the care of chronically transfused patients, and <25% complete pre-and-post vaccination serologies to assess immune-status in the transfused population. Respondents reported various follow-up strategies, including education of patients (40%), documentation of potential susceptibility to MMRV (15%), and education of the HCP's administering live vaccines (20%). Only 24/55 (44%) of respondents were aware of the recommendation to avoid live vaccinations in transfused patients, and 44% of respondents did not have a follow-up strategy for chronically transfused patients regarding immune-status.Conclusion: Live immunization practices for chronically transfused pediatric patients vary across North America. Many HCPs are unaware of the recommendations around avoidance of live immunizations post transfusion. Most respondents immunize their chronically transfused pediatric patients as per the routine schedule, but the immune-status post-vaccination is often unknown. Given changes to the processing of blood products over the last several decades, further research is needed in this area. Determination of pre-and-post-immunization serologies may help to establish the response of chronically transfused patients to live vaccinations, and allow for the development of evidence-based guidelines for live-immunization of this vulnerable patient population. DisclosuresBruce:Bristol-Meyers-Squibb - consultant 2016-2017: Consultancy; ovartis consult and ad board 2015-2016: Consultancy; Apopharma 2015: Consultancy.

Intravenous Immune Globulin (IVIG) for Treatment of Autoimmune Heparin-Induced Thrombocytopenia: A Systematic Review.

To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported. PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin. Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included. Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post-nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 109/L) within 5 days of initial IVIG dosing. aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight. Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.

Cytomegalovirus Induced Thrombocytopenia with No Platelets in an Immunocompetent Young Male

Introduction Immune thrombocytopenic purpura (ITP) is a common cause of acquired thrombocytopenia in an otherwise asymptomatic adult. It is generally believed to be caused by auto- antibodies against platelet antigens that destroy platelets peripherally and autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production. Cytomegalovirus (CMV) is a known cause of cause of morbidity and mortality in patients with immunosuppressed states, whereas in immunocompetent patients, it commonly manifest as asymptomatic or mononucleosis like syndrome. We are presenting a case of CMV induced thrombocytopenia with severe epistaxis and platelet count of 0 x10 9 in an otherwise healthy immunocompetent male who failed to improve after standard treatments with high dose steroids and intra venous immune globulin (IVIG). Case Description A 36-year-old Caucasian male without any past medical history presented to emergency room (ER) with flu like symptoms for five days associated with subjective fevers, anorexia, nausea, cough and weight loss of 15 lb. in two weeks. He also reported possible tick bite while working in the yard two days prior to admission. No dizziness, vomiting, diarrhea or any bleeding were reported. Denied any smoking, alcohol use or any illicit drug use. No significant family history was reported. On evaluation he was afebrile, normotensive with normal heart rate and respiratory rate. Physical examination was unremarkable. Initial laboratory data revealed hemoglobin of 11.2, platelet count 4 x109, white cell count of 13,100 with 4.5% atypical lymphocytes, aspartate aminotransferase of 41, alanine aminotransferase of 49, and creatinine of 1.4. He tested positive for Influenza A, CMV Immune globulin (Ig)M and IgG antibody. Serological tests for tick panel including anaplasma, babesia, Lyme disease and ehrlichia were negative. Epstein-Barr virus (EBV) antibody, parvo virus antibody, hepatitis screen, HIV screen, auto antibodies including anti-nuclear antibody and anti-double stranded DNA were negative. Coombs test was negative. Further work up includes ADAMTS13 activity was normal. No laboratory evidence of ADAMTS13 deficiency. After excluding all other causes, diagnosis of ITP was made. He was started on Tamiflu for Influenza A and high dose intra venous (IV) methyl prednisone for ITP. After platelet transfusion and two days of IV steroids platelet count improved 43 x 109 and he was discharged home with prolonged prednisone taper. Five days later, he presented to ER with severe epistaxis. Laboratory data revealed platelet count of 0 x109. Serum CMV-DNA was determined by PCR showed viral load of 8,790 copies/ml. Ultrasound abdomen showed mild splenomegaly. He received three doses of IVIG (1g/kg). Platelet count failed to improve after administration of IVIG. Bone marrow biopsy revealed hyper cellular marrow with trilineage hematopoiesis with no increase in CD 34 blasts. Per infectious disease and hematology recommendations, he was started on valganciclovir (900 mg PO BID). One month later, platelet count improved to 150 x 109 and CMV viral load dropped to 413 with subsequent resolution of patient's symptoms. Discussion Secondary ITP is an acquired thrombocytopenia caused by autoantibodies against platelets. Many patients with ITP are asymptomatic. For those who do have symptoms, initial presentations of ITP are petechiae, purpura and epistaxis, with a more severe progression to intracranial hemorrhage or gastrointestinal bleeding leading to a fatal outcome, if treatment is not started on a promptly manner. CMV induced thrombocytopenia in immunocompetent adults seems to be rare. we are presenting a case of CMV induced ITP which failed to improve after standard treatment with high dose steroids and IVIG but responded to anti-viral therapy with valganciclovir. In conclusion, it may be worthwhile to test for CMV infection in patients presenting with ITP. Further research is needed in order to establish treatment guidelines for CMV induced ITP in immunocompetent adults. Disclosures No relevant conflicts of interest to declare.

Serologic problems associated with administration of intravenous immune globulin (IVIg)

Intravenous immune globulin (IVIg) is manufactured from large pools of donor plasma and contains a high diversity of antibodies, primarily IgG. For this reason, IVIg is routinely used as antibody replacement therapy for patients having primary immunodeficiencies. In 1981, IVIg was also found to be a strong immunomodulator of various inflammatory and autoimmune conditions. This observation has led to the exponential increase in the use of IVIg throughout the world, with the United States and Canada being the biggest users of IVIg. Although relatively rare, adverse events, such as hemolytic anemia and thrombosis, can complicate the administration of IVIg. More frequently, the administration of IVIg can cause serologic challenges for the transfusion service including ABO discrepancies, positive direct antiglobulin tests, positive antibody detection tests, and incompatible crossmatches. This article will review each of the potential transfusion service challenges associated with IVIg administration.

Evaluation and identification of protocols for safe and efficacious institutional administration of intravenous immune globulin in hypogammaglobulinemia associated with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.

250 Background: Hematologic malignancies effect both humoral and cell-mediated immunity. We hypothesize that for patients with Chronic Lymphocytic Leukemia (CLL), Non-Hodgkins Lymphoma (NHL), and Multiple Myeloma (MM) outcomes improve with adherence to National Comprehensive Cancer Network (NCCN) guidelines for intravenous immunoglobulin (IVIG).Our objective is to understand resource allocation and implementation of IVIG in outpatient and inpatient settings. We identified a cohort of patients with hypogammaglobulinemia for assessing incidence of sepsis, outcomes, and resource use. We initiated this project by undertaking a large descriptive study of current IVIG use. Methods: A retrospective Institutional Review Board (IRB) approved data capture was conducted covering 2016-2018. Inclusion criteria involved those on an active chemotherapy plan, age &gt; 18 years and diagnosis of CLL, NHL, or MM. IgA deficiency, anaphylaxis to IVIG, planned chemotherapy, inherited immunodeficiency, and thymic deficiency were excluded. We considered patients to be suitable for IVIG if IgG was &lt; 500 mg/dL for CLL and MM and &lt; 400 mg/dL in NHL. Outcomes, number of admissions, sepsis, ICU care, infectious etiology, and monthly IgG levels were examined. Results: A preliminary i2b2 data capture identified a cohort of 563 patients that yielded 12% with bacteremia, 21% with sepsis, and 23% with pneumonia of which 87% were admitted. 28% received IVIG during the 2-year period. Of the 563, 77% were hospitalized and 21% required ICU care. 54% of ICU patients received inpatient IVIG. All influenza and parainfluenza cases were inpatient. Final data analysis will yield greater detail in comparing inpatient to outpatient IVIG use. Conclusions: Large academic institutions appear to have significant variability in use of IVIG in patients with lymphopenia and hematologic malignancies. With this data, we plan to assess for patient-level outcomes based on adherence to NCCN guidelines as a way to enhance Physician Quality Reporting System (PQRS) standards by prioritizing outpatient use of IVIG.

A Randomized, Double-Blinded, Placebo Controlled Study of IVIG Vs. IVIG with High Dose Methylprednisolone in Rapidly Augmenting Platelet Counts in Childhood ITP

The combination of intravenous (IV) methylprednisolone (IVMP) and IV immune globulin (IVIG) is often used in children with immune thrombocytopenia (ITP) to rapidly increase platelet counts (PCs) to a safe hemostatic level. However, there are no controlled data to support the use of combination therapy over IVIG alone in children with severe thrombocytopenia [PC <20 x109/L] and/or life-threatening bleeding.We conducted a randomized, double-blinded, placebo controlled, multicenter, prospective study to evaluate 2 regimens: IVMP (Solu-Medrol®, UpJohn) 30 mg/kg (max. 1 gram) over 1 hour (h) followed by IVIG 1 g/kg (Gammunex 10%, Bayer) given at a rapid infusion rate (over a maximum of 3 h), vs IV placebo over 1 h followed by IVIG 1 g/kg in children with primary ITP. The goal was to evaluate the rapidity of the PC increment and associated adverse events with both regimens.Eligible patients were children [ages: 1 to 17 years (y)] with acute (defined at the time of study initiation as <6 months (mo.) since diagnosis) or chronic primary ITP (>6 mo.), with PCs <20x109/L in whom it was decided to treat with IVIG. Exclusion criteria included: previous splenectomy, life/organ threatening hemorrhage, renal disease, diabetes, hypertension, sepsis, fever >38.5°C, disseminated intravascular coagulation, pregnancy or a previous documented lack of response to IVIG.Baseline studies included: a complete blood count (CBC), a reticulocyte count, Coombs test and renal and liver function tests. CBCs were repeated at the end of the IVIG infusion, at 8±1h, 24±2h, 72±4h, day 7±2 day (d) and day 21±3d following the start of the placebo/IVMP.The primary outcome measure was the PC increment over the first 24 h following the administration of therapy; the main secondary outcome measures were the attainment of a PC of ≥20x109/L and ≥50x109/L at times + 8, +24 and +72h.Sample size was estimated based on the assumption that patients treated with placebo + IVIG would attain a mean PC at +24h of 30x109/L vs. 50x109/L for those treated with IVMP + IVIG. For 80% power to show a difference in PC of 20x109/L (at +24h)with an a of 0.025 (two-sided) and a b of 0.2, 32 patients were required.Patients were stratified by block randomization according to type of ITP (acute vs. chronic) and according to center. The trial was registered in ClinicalTrials.gov. (NCT00376077).Thirty two patients were enrolled (ages: median 8 y; min. 1.2 y; max: 17.5 y; 22 male: 10 female; 16 acute: 16 chronic; 11 were blood type O; 14 blood type A and 7 blood type B). Fourteen patients were randomized to IVMP+IVIG while 18 were randomized to placebo+IVIG. Randomization was not equal as 1 patient was randomized and then immediately declined to participate and another patient was incorrectly assigned; both were assigned to the placebo group. PCs for the 2 groups of patients at the different time points are shown in table 1. The difference in PC was statistically significant at the 24 hr time point (p<0.0001). At this time the proportion of patients achieving a PC of ≥50x109/L was 77% in the IVMP+IVIG vs 50% in the placebo+IVIG.No patient experienced a severe bleed or an unexpected severe adverse event during the study. There was a statistically significant drop in mean Hb post-treatment among all patients (baseline 133.3 (13.6) g/L to 121.6 (14.2) g/L at time +8h) but there was no difference between O and non-O blood type patients or between treatment groups.This study showed that PCs increased rapidly following administration of IVIG with or without IVMP such that by 8h post initiation of therapy 55% (17/31) of all patients had achieved a PC ≥20x109/L. The mean PC was significantly different between the groups at time +24h. Our findings provide level 1 evidence to support the use of combination therapy (IVMP+IVIG) in life threatening situations where it is deemed to important to attain as rapidly as possible a hemostatic platelet count. [Display omitted] DisclosuresBlanchette:Shire: Consultancy, Other: Member of a Data Safety Monitoring Board, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL-Behring: Research Funding; Octapharna: Other: Member of a Data Safety Monitoring Board; Biogen Idec: Research Funding; Bayer Healthcare: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

Aseptic meningitis following therapy with immune globulins: a combination of product features and patient characteristics?

Aseptic meningitis (AM) represents a recognized side effect of immune globulin (IG) therapy and may warrant additional diagnostic procedures and therapy with anti-infective drugs until a definite diagnosis can be established. Although, to date, only small case series have been published, the objective of the current study was to investigate a large case series of patients with AM. The pharmacovigilance safety database of a 10% liquid IG (Gammagard Liquid) was queried for all reports of AM. Patient demographics, treatment-specific data, and product-specific data were determined. The proportional reporting rates of AM were compared according to the route of administration (intravenous vs. subcutaneous) and molecular size distribution of IG lot (dimer content ≥ 8 vs. < 8%). In total, 144 AM episodes were reported in 136 distinct patients. Females were affected by AM nearly four times more than males. AM was not limited to patients who received high-dose IG therapies but was observed in those who received low-dose regimens in percentages comparable to the estimated usage patterns of IG. Lots that had high dimer values were associated with AM significantly more often than lots that had low dimer values (p < 0.001), and subcutaneous IG administration was associated with lower rates of AM compared with intravenous IG administration (p = 0.055). In contrast to previously published data, AM was observed in both low-dose and high-dose regimens without favoring high IG doses, and females were affected nearly four times more often than males. Immunoglobulin G dimers may play a role in the etiology of AM, and subcutaneous administration may be associated with a lower rate of AM compared with intravenous administration.

Retrospective Analysis of Clinical Response in Children with Severe Immune Thrombocytopenia Undergoing Treatment with Intravenous Immune Globulin

Background:Childhood immune thrombocytopenia (ITP) is a common bleeding disorder characterized by an isolated thrombocytopenia resulting from unknown causes, commonly presenting between 1 to 10 years of age. Nearly one child in 20,000 will experience ITP each year in the United States. The American Society of Hematology recommends that children with platelet counts of <20,000/μL and significant mucous membrane bleeding, or with platelet counts of <10,000/μL and minor purpura, should receive treatment with intravenous immune globulin (IVIg), IV RhIG, or corticosteroids.Objective:The objectives of this retrospective analysis was to determine if pediatric patients with severe ITP are responding to IVIg treatment with or without concomitant corticosteroids and if different IVIg products have any difference in response. We evaluated mean platelet counts at initial presentation and following IVIg therapy. The endpoints of this study were rate, degree, and rapidity of the platelet count response, cost of treatment, adverse effects and comparison of these with different IVIg products.Methods:This study was a single center, retrospective analysis of patients undergoing IVIg treatment for severe ITP. After institutional IRB approval, subjects were identified through Intermountain's Enterprise Data Warehouse. Subjects were pediatric patients aged ≤18 years of age with immune thrombocytopenia that received treatment with IVIg from January 2009 through April 2015. Patients were eligible for inclusion if they had an initial platelet level of <20,000/mm3 drawn within 48 hours prior to starting IVIg therapy and at least one platelet level within seven days following IVIg administration. Patients were excluded if they received a platelet transfusion prior to IVIg therapy. Platelet increase was assessed by analyzing the mean difference in platelet increase between initial values preceding IVIg administration compared to the highest drawn platelet level within a 7 day period post-IVIg therapy. Three different IVIg products were used which included Gammagard, Gammagard S/D and Gamunex. Response was defined as a platelet rise to at least 20,000/mm3. Cost-effectiveness was also evaluated.Results:At Primary Children's Hospital between January 2009 and April 2015, approximately 150 patients were diagnosed with ITP, the majority of whom were either observed without treatment or received corticosteroid therapy. Forty six patients were identified as having severe ITP requiring IVIg therapy, of which 72% were males. Median age of ITP patients receiving IVIg was 8 years. Twelve patients were excluded, as eight patients received platelet transfusions, three patients had initial platelet levels above 20,000/mm3, and one patient did not have a documented follow-up platelet level. This left 34 eligible patients for data analysis. Twelve patients (35%) received both IVIg and steroids. Twenty two patients (65%) had an appropriate platelet response within the 7 day period. The mean platelet increase was 76,000/mm3 in patients who received IVIg. Mean platelet increase of 88,000/mm3 was observed in patients receiving only IVIg therapy, compared to 53,000/mm3 in patients receiving both IVIg and corticosteroids. Seventy-six percent of patients received Gammagard with an average platelet response of 88,000/mm3, of which 69% responded by day 7. Twelve percent of patients received Gamunex with an average platelet response of 89,000/mm3, of which 75% responded by day 7. Twelve percent of patients received Gammagard S/D with an average platelet response of 10,000/mm3, of which 25% responded by day 7. Average IVIg cost per patient was $2,736 with a mean expense of $36 per 1000/mm3 increase in platelet counts.Conclusion: Similar to other published reports, patients with severe ITP responded well to IVIg therapy. Patients who failed to respond to initial steroid treatment experienced a platelet response with concomitant corticosteroid and IVIg therapy. Though the numbers are small, our study suggests for the first time that IVIg product with >98% IgG levels (i.e. Gammagard, Gamunex) have better response rates than Gammagard S/D which has 90% IgG level. Further analysis needs to be completed evaluating duration of therapeutic effect from IVIg. This information will be used to help detect a clinically meaningful response to IVIg therapy directed at increasing platelet counts and preventing ITP complications. DisclosuresNo relevant conflicts of interest to declare.

Do immune complexes play a role in hemolytic sequelae of intravenous immune globulin?

Intravenous immune globulin (IVIG) was developed initially as an immunoglobulin replacement therapy for primary humoral immunodeficiency, but is now widely used in the treatment of autoinflammatory and autoimmune pathologies. In a small number of patients, hemolytic sequelae have been observed after IVIG administration. The lack of a simple one-to-one correlation between measurable hemagglutinins and hemolysis has led to complicated hypotheses involving coincident necessary variables (e.g., a two-hit hypothesis) and also to the positing of causal factors other than hemagglutinins. One such hypothesis is that immune complexes (ICs) contained within IVIG lead to hemolysis. IVIG-mediated hemolysis was addressed at a recent meeting sponsored by the Food and Drug Administration; the Plasma Protein Therapeutics Association; and the National Heart, Lung, and Blood Institute. The primary literature was reviewed at this meeting followed by detailed discussion. Participants concluded that there is both a theoretical basis by which ICs could contribute to hemolysis after IVIG administration and some published data in support of such a possibility. However, the reported data contain substantial caveats, and the existing evidence does not rise to a level sufficient to either confirm or reject a role for ICs. More detailed and focused human studies will be required to further assess the potential role of ICs in IVIG induced hemolysis. This paper summarizes the relevant literature and expands upon the conclusions of this workshop.

The "Platelet Boilermaker" Is an Option for Quickly Raising Platelet Counts in IVIG Refractory ITP

Most patients with immune thrombocytopenia (ITP) respond to first line therapy. Rarely there are patients who remain with very low platelet counts despite administration of intravenous immune globulin (IVIG). A protocol at our institution (colloquially known as the "platelet boilermaker") for these refractory patients is to give 1 gram/kg of IVIG continuously over 24 hours concurrent with one unit of plateletpheresis product given over 6 hours repeated times 4. We examined the charts of 10 patients in the past 6 years who have received combined therapy. 70% were male; all were refractory to steroids and IVIG. Results are in table: Abstract 5023. TableAgeGenderDiseaseBleedingPlts PreDay +1Day+2Day+3Results65MEvansGIB1110510Stopped bleeding59MITP, CLLBruising3656No response34FITPPregnancy2583175150Delivered81FITPEpistaxis15384167Splenectomy day +123FITPEpistaxis552165Splenectomy day +164MDITPEpistaxis, ruising252427Stopped bleeding89MITPEpistaxis4655046Splenectomy day +157MITPBruising9586946Splenectomy day +128MITPICH14133325326No extension78MITPGIB27354498Splenectomy day +1Plt = platelet count x 109/LDITP = drug induced ITP, ICH - intracranial hemorrhage. GIB - gastrointestinal bleeding9/10 patients had at least a transient rise in platelets greater than 30x109/L - 5 patients underwent emergent splenectomy with no bleeding complications. The patient with ICH had no extension and while the other patients who responded had cessation of bleeding. In summary for patients with IVIG refractory ITP who either have bleeding or need urgent splenectomy combined continuous platelets/IVIG is a therapeutic option. DisclosuresOff Label Use: profilnine - warfarin reversal rVIIa - warfarin reversal.

Dermatomyositis: A Rare but Deadly Cause of Dysphagia

Background: Dermatomyositis is part of a subgroup of inflammatory myopathies that includes polymyositis and inclusion-body myositis. Dermatomyositis is distinguished by its clinical features including pathognomonic rash with associated proximal muscle weakness. Dysphagia is a common but potentially life-threatening of dermatomyositis and can be present in up to 60% of cases. We report two cases of patients who developed moderate to severe dysphagia secondary to dermatomyositis treated with intravenous immune globulin (IVIG). Case Series: Patients with known dermatomyositis presented with acute oropharyngeal dysphagia. The first patient was a 28-year-old female who presented 2 weeks after being diagnosed with dermatomyositis with worsening oropharyngeal dysphagia. The second patient was an 80-year-old male with a 3-month history of dermatomyositis who presented with a 1-month history of progressively worsening oropharyngeal dysphagia. Both patients were ruled out for an acute upper pharyngeal obstruction with imaging of the neck and ENT evaluation. They each received highdose systemic corticosteroid and methotrexate but were refractory to treatment. This prompted the use of intravenous immune globulin (IVIG) for each. One patient had complete resolution of dysphagia 1 week after administration of IVIG and the other patient continued to have dysphagia ultimately requiring PEG tube placement. Discussion: Dermatomyositis is a complement-mediated intramuscular microangiopathy that affects skin and muscle. The complement membranolytic attack complex deposits into the capillaries which leads to skeletal muscle ischemia and muscle fiber necrosis. This process can affect the upper third of esophagus resulting in dysphagia which is associated with a 1-year mortality rate of 31%. Patients who cannot protect their airway are at increased risk of developing aspiration pneumonia which is the leading cause of death among this group. The mechanism of IVIG, though not entirely understood, works by blocking the Fc receptors on the vascular wall thus preventing and competing with the membrane attack complex deposits from entering endomysial capillaries. Although various studies have used a combination of therapies that include prednisone, methotrexate, azathioprine, cyclophophamide, or cyclosporine, many patients become resistant to all therapies. IVIG is then used with varying results. Conclusion: We present two cases of dermatomyositis complicated by dysphagia that was promptly treated with IVIG. Response to IVIG is variable which is consistent with previous studies. However, once dysphagia occurs, treatment options are limited and thus IVIG therapy should be instituted.

Incidence of Hypogammaglobulinemia in Patients Receiving Rituximab and the Use of Intravenous Immunoglobulin for Recurrent Infections

Rituximab targets normal B cells and tumor B cells. We used a unique data-mining tool to identify patients with lymphoma who were treated with rituximab and who had serial pre and post rituximab immunoglobulin concentrations evaluated. After treatment, 39% (69/179) of patients had low levels of immunoglobulin G. Recurrent sinopulmonary infections were seen in 6.6% (14/211). Intravenous immune globulin appeared to reduce the frequency of infection. Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG). Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded. Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients. In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

Serum adipokine profiles in Kawasaki disease

Adipokines are cytokines derived from adipose tissue. Recently it has been established that adipokines are closely linked to the pathophysiology of not only metabolic diseases, such as diabetes mellitus, obesity, and atherosclerosis, but also to inflammation and immune diseases. In this study we measured serum levels of adipokines in patients with acute Kawasaki disease to investigate the role of adipokines in the pathophysiology of Kawasaki disease. Serum resistin, high-molecular-weight (HMW) adiponectin, leptin, and visfatin levels were measured by enzyme-linked immunosorbent assay in a total of 117 subjects: 56 patients with acute Kawasaki disease, 30 healthy children, and 31 patients with acute infectious diseases. Serum resistin levels in patients with Kawasaki disease were significantly higher than those of healthy children and patients with acute infectious diseases. In contrast, mean serum HMW adiponectin, leptin, and visfatin levels in patients with Kawasaki disease exhibited no statistically significant differences compared with those in healthy children and patients with infectious diseases. Serum resistin levels decreased significantly after administration of intravenous immune globulin. Serum resistin levels on admission were significantly higher in nonresponders compared with responders to intravenous immune globulin therapy. A multivariate model revealed that C-reactive protein was a factor that was significantly related to elevated serum resistin level in patients with Kawasaki disease. In patients with Kawasaki disease, serum resistin levels were elevated, but decreased to nearly normal after intravenous administration of immune globulin. In contrast, serum HMW adiponectin, leptin, and visfatin levels showed no statistically significant changes. These findings suggest that resistin plays an important role, while other adipokines do not play a major role, in the pathogenesis of Kawasaki disease.

Acute Hepatitis B Infection Causing Guillain-Barré Syndrome (GBS): A Rare Case: 2011 ACG Presidential Poster

Purpose: We report a rare case of Guillain-Barré syndrome (GBS) in acute hepatitis B infection. We emphasize on the awareness of this association since an early diagnosis and a timely initiation of treatment determines the neurological recovery. A 42-year-old Vietnamese female presented with a two week history of nausea, vomiting, abdominal pain, and jaundice. No clear risk factor for acute hepatitis infection was identified. Physical examination revealed icteric sclera, right upper quadrant abdominal tenderness, and jaundice. She had no neurological deficits. Laboratory data showed total serum bilirubin was 14.4, direct bilirubin 10.8, AST 850, ALT 1817, alkaline phosphatase 211, and an INR of 1.2. HBsAg, IgM anti-HBc antibody, and HBV DNA were positive. She was diagnosed with acute hepatitis B infection. On hospital day four, she developed rapidly worsening bilateral upper and lower extremity weakness. She progressed to flaccid paralysis of all extremity, and deep tendon reflexes were absent. She required intubation due to respiratory failure. The diagnosis of GBS was strongly suspected. Lumbar puncture with cerebrospinal fluid (CSF) analysis showed normal WBC of 1 and elevated total protein of 71, representing albuminocytologic dissociation as seen in GBS. Electromyography (EMG) and nerve conduction studies (NCS) confirmed the diagnosis of GBS. Treatment with intravenous immune globulin (IVIG) was started within three days after onset of neurological symptoms. She was extubated after one week of mechanical ventilation and transferred to an acute rehabilitation center. After 6 weeks, she was discharged to home with a full neurological recovery. Viral hepatitis has been implicated in acute immune-mediated polyneuropathies classified under the eponym Guillain-Barré syndrome (GBS) and accounts for ˜ 1% GBS cases. We found less than 20 reported cases of GBS complicating acute hepatitis B infections to date. Proposed mechanisms by which HBV causes GBS include molecular mimicry between HBV DNA and myelin basic protein with host immunity attacking both, HBsAg-mediated immune complex vasculitis, and direct damage by HBV. The two available treatments are IVIG and plasma exchange (PE). IVIG is as effective as PE, and no difference in measures of recovery was seen when comparing PE followed by IVIG with either treatment alone. Plasma exchange is shown to be most effective when started with in seven days of symptom onset. Acute hepatitis B infection is rarely associated with GBS. Since early diagnosis and timely administration of IVIG or plasma exchange predicts the degree of neurological recovery, gastroenterologists should be aware of this association.

Serum adipokine profiles in Kawasaki disease

Adipokines are cytokines derived from adipose tissue. Recently it has been established that adipokines are closely linked to the pathophysiology of not only metabolic diseases, such as diabetes mellitus, obesity, and atherosclerosis, but also to inflammation and immune diseases. In this study we measured serum levels of adipokines in patients with acute Kawasaki disease to investigate the role of adipokines in the pathophysiology of Kawasaki disease. Serum resistin, high-molecular-weight (HMW) adiponectin, leptin, and visfatin levels were measured by enzyme-linked immunosorbent assay in a total of 117 subjects: 56 patients with acute Kawasaki disease, 30 healthy children, and 31 patients with acute infectious diseases. Serum resistin levels in patients with Kawasaki disease were significantly higher than those of healthy children and patients with acute infectious diseases. In contrast, mean serum HMW adiponectin, leptin, and visfatin levels in patients with Kawasaki disease exhibited no statistically significant differences compared with those in healthy children and patients with infectious diseases. Serum resistin levels decreased significantly after administration of intravenous immune globulin. Serum resistin levels on admission were significantly higher in nonresponders compared with responders to intravenous immune globulin therapy. A multivariate model revealed that C-reactive protein was a factor that was significantly related to elevated serum resistin level in patients with Kawasaki disease. In patients with Kawasaki disease, serum resistin levels were elevated, but decreased to nearly normal after intravenous administration of immune globulin. In contrast, serum HMW adiponectin, leptin, and visfatin levels showed no statistically significant changes. These findings suggest that resistin plays an important role, while other adipokines do not play a major role, in the pathogenesis of Kawasaki disease.

Humoral rejection after pediatric heart transplantation: a case report

Humoral rejection was observed 2 years after heart transplantation in a 10-year-old African American girl with sickle cell disease. Hemodynamic compromise developed, and the patient started treatment with extracorporeal membrane oxygenation within 24 hours of admission. With cellular rejection initially believed to be the cause, administration of thymoglobulin and high-dose steroids was initiated. Human leukocyte antigen antibody analysis revealed high titers of donor-specific class I and II antibodies. Aggressive treatment for antibody-mediated rejection was started with plasmapheresis and administration of intravenous immune globulin and rituximab. The patient displayed clinical signs of infection and was treated with antimicrobial, antiviral, and antifungal agents. Computed tomography of the chest suggested asperigillous infection. The patient underwent a left upper lobectomy. The patient recovered and has done well, now 4 years after having received the heart transplant. Antibody-mediated rejection should be considered early in heart transplant patients presenting with hemodynamic compromise and may respond to aggressive antibody and B cell-directed therapy. Vigilance for secondary infections, especially during treatment for rejection, is crucial.

Humoral Rejection after Pediatric Heart Transplantation: A Case Report

Humoral rejection was observed 2 years after heart transplantation in a 10-year-old African American girl with sickle cell disease. Hemodynamic compromise developed, and the patient started treatment with extracorporeal membrane oxygenation within 24 hours of admission. With cellular rejection initially believed to be the cause, administration of thymoglobulin and high-dose steroids was initiated. Human leukocyte antigen antibody analysis revealed high titers of donor-specific class I and II antibodies. Aggressive treatment for antibody-mediated rejection was started with plasmapheresis and administration of intravenous immune globulin and rituximab. The patient displayed clinical signs of infection and was treated with antimicrobial, antiviral, and antifungal agents. Computed tomography of the chest suggested asperigillous infection. The patient underwent a left upper lobectomy. The patient recovered and has done well, now 4 years after having received the heart transplant. Antibody-mediated rejection should be considered early in heart transplant patients presenting with hemodynamic compromise and may respond to aggressive antibody and B cell-directed therapy. Vigilance for secondary infections, especially during treatment for rejection, is crucial.

Use of intravenous immune globulin in the ICU: a retrospective review of prescribing practices and patient outcomes

Intravenous immune globulin (IVIG) is a pooled human blood product. Much of IVIG use in Canada is prescribed for 'unlabelled' or 'off-label' indications. Due to costs, risk of use and limited supply, knowledge about the use of IVIG is important. We collected data regarding the usage of IVIG and outcomes of patients receiving IVIG in the intensive care units (ICUs) of two community and three academic hospitals. We reviewed the charts of adult patients who received IVIG in the five ICUs over a 5-year period. Data collection included demographics, severity of illness, indication for and dose of IVIG, mortality and adverse effects. On the basis of a classification developed by Canadian Blood Services, the indications for IVIG were then classified as 'appropriate' or 'inappropriate'. One hundred and forty-five patients received IVIG in the ICU. In all, 19% of IVIG prescriptions were for 'appropriate' indications and 7% were 'inappropriate'. The remaining 74% were prescribed for indications with some evidence to support their use. Three indications accounted for 50% of all IVIG prescribed: Guillain-Barre syndrome (GBS), necrotising fasciitis (NF) and toxic epidermal necrolysis (TEN). Both the community and academic centres prescribed IVIG for similar indications. Adverse effects associated with IVIG administration included deep vein thrombosis/pulmonary embolism, fever and renal failure, although direct causation related to IVIG could not be established. The overall mortality rate was 55%. IVIG is used relatively infrequently in the critical care setting. The most common indications were GBS, TEN and NF. Mortality was high. There was no difference between community and academic ICUs.

TRANSFUSION PRACTICE: sHLA‐I contaminating molecules as novel mechanism of ex vivo/in vitro transcriptional and posttranscriptional modulation of transforming growth factor‐β1 in CD8+ T lymphocytes and neutrophils after intravenous immunoglobulin treatment

BACKGROUND: Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF‐β expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA‐I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF‐β1 modulation.STUDY DESIGN AND METHODS: Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF‐β1 in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed.RESULTS: Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF‐β1 mRNA and intracellular TGF‐β1 molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA‐I and/or soluble Fas ligand (sFasL) abolished TGF‐β1 modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes “contamination,” did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA‐I molecules enhanced TGF‐β1 mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation.CONCLUSION: On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF‐β1 might be related to the immunomodulatory activities of sHLA‐I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.