Research

Pharmacokinetics, Safety, and Tolerability of Subcutaneous Immune Globulin Injection (Human), 10 % Caprylate/Chromatography Purified (GAMUNEX®-C) in Pediatric Patients with Primary Immunodeficiency Disease.

J Clin Immunol. 2016 Jun 25;

Authors: Heimall J, Chen J, Church JA, Griffin R, Melamed I, Kleiner GI

Abstract
PURPOSE: This phase 4, multicenter, open-labeled, single-sequence, crossover study in pediatric patients (ages 2 to 16) with primary immunodeficiency disease (PID) evaluated the pharmacokinetics, safety, and tolerability for subcutaneously (SC) administered 10 % caprylate/chromatography purified human immune globulin injection (IGIV-C, GAMUNEX®) compared with intravenously (IV) administered IGIV-C.
METHODS: This study included a screening phase, run-in phase (where required), IV treatment phase, SC treatment phase, and end of study/early termination visit. Eligible patients receiving a stable dose of IGIV-C entered into the IV phase to receive two IV infusions of IGIV-C (200-600 mg/kg per infusion) every 3-4 weeks. The weekly SC dose of IGIV-C was calculated using a conversion factor of 1.37 times the prior IV dose.
RESULTS: Twelve subjects between the ages of 2 and 16 years participated in the clinical study with the median age being 11 years old. The adjusted weekly mean AUC0-τ,IV was 216,873.7 h*mg/dL for the IV phase versus a mean AUC0-τ,SC of 230,830.0 h*mg/dL for the SC phase. The mean (range) C trough was 997.2 (784-1320) mg/dL in the IV phase and 1325.0 (1077-1690) mg/dL in the SC phase. During the SC phase, 100.0 % of the patients (n = 11) experienced treatment-emergent adverse events (TEAEs) that were local infusion reactions and 9 patients (81.8 %) had TEAEs that were non-infusion site reactions. The majority of TEAEs were mild or moderate in severity.
CONCLUSION: In pediatric patients with PID, SC-administered IGIV-C provides comparable overall serum exposure to total IgG to that produced by IV-administered IGIV-C. We have concluded that weekly SC administration of 10 % IGIV-C based on a dose conversion factor of 1.37 is safe and well-tolerated in pediatric patients with PID.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01465958. https://clinicaltrials.gov/ct2/show/NCT01465958?term=NCT01465958.&rank=1.

PMID: 27342758 [PubMed – as supplied by publisher]

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NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation.

J Clin Immunol. 2016 Jun 23;

Authors: Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, Pickl W, Förster-Waldl E, Boztug K

Abstract
PURPOSE: NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID).
METHODS AND RESULTS: We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity.
CONCLUSIONS: Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.

PMID: 27338827 [PubMed – as supplied by publisher]

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Does the route of immunoglobin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort “Visages”.

Orphanet J Rare Dis. 2016;11(1):83

Authors: Bienvenu B, Cozon G, Hoarau C, Pasquet M, Cherin P, Clerson P, Hachulla E, Crave JC, Delain JC, Jaussaud R

Abstract
BACKGROUND: IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients’ satisfaction regarding IgRT and quality of life (QoL) in real-life conditions.
METHODS: The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire.
RESULTS: The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT.
CONCLUSION: PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient’s expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.

PMID: 27334100 [PubMed – in process]

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Efficacy, Safety, and Pharmacokinetics of a New 10 % Liquid Intravenous Immunoglobulin Containing High Titer Neutralizing Antibody to RSV and Other Respiratory Viruses in Subjects with Primary Immunodeficiency Disease.

J Clin Immunol. 2016 Jun 20;

Authors: Wasserman RL, Lumry W, Harris J, Levy R, Stein M, Forbes L, Cunningham-Rundles C, Melamed I, Kobayashi AL, Du W, Kobayashi R

Abstract
PURPOSE: Immune globulins for IgG supplementation have been produced for over 35 years with essentially no differentiating features regarding their specific antibody composition. Furthermore, the compositions of plasma donor pools used for IG manufacturing are not standardized. While all immune globulin products meet the specifications set by the US FDA for antibodies to pathogens like measles and polio, they have variable levels of antibodies to other important viruses and infectious pathogens, particularly respiratory syncytial virus (RSV).
METHODS: An IVIG was developed that satisfies the requirements for treating patients with primary immune deficiency disease (PIDD) and also has standardized elevated levels of RSV neutralizing antibodies (RI-002). Plasma donors who have naturally occurring high circulating levels of neutralizing anti-RSV antibody were selected as the source for manufacturing IVIG to treat patients with PIDD to prevent serious bacterial infections. While the introduction of the monoclonal antibody Palivizumab has had a dramatic impact in diminishing the burden of RSV disease in the pediatric population, it does not meet the standards for replacing the deficient immune compartments of patients with PIDD.
RESULTS: Fifty-nine patients with PIDD at 9 different sites across the US were enrolled in this study and received regular infusions of RI-002 over the course of 1 year.
CONCLUSIONS: There were zero serious bacterial infections, thus meeting the primary endpoint for this trial. The secondary endpoints including days missed from work due to infection, unscheduled visits to the physician, and days of hospitalization due to infection compared favorably to published reports of other IVIG products.

PMID: 27324887 [PubMed – as supplied by publisher]

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Unintended Immunological Consequences of Biologic Therapy.

Curr Allergy Asthma Rep. 2016 Jun;16(6):46

Authors: Henrickson SE, Ruffner MA, Kwan M

Abstract
Recent advances in the understanding of immune dysregulation in autoimmune diseases have enabled the development of new monoclonal antibody-based drugs called biologics. Biologics have been used to target aberrant immune responses in many diseases, but patients with rheumatologic and other autoimmune diseases have benefited the most and improvements in outcomes have been significant. The use of biologics is not without hazard, however, as these agents block immune pathways adapted to protect the host. This has been borne out by increased rates of infections as well as induction of new autoimmune and hematologic adverse effects. As new drugs for the treatment of autoimmune conditions are entering the pipeline, it is incumbent on the practicing immunologist to understand the mechanism of these biologics and the implications of clinical use.

PMID: 27324478 [PubMed – in process]

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Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches.

Biochim Biophys Acta. 2016 Jun 14;

Authors: Li J, Wei Z, Li YR, Maggadottir SM, Chang X, Desai A, Hakonarson H

Abstract
BACKGROUND: Common variable immunodeficiency disorder (CVID) is the most frequently encountered symptomatic primary immunodeficiency, characterized by highly heterogeneous immunological features and clinical presentations. As better targeted therapies are importantly needed for CVID, improved understanding of the genetic and epigenetic basis for the development of CVID presents the most promising venue for improvement.
SCOPE OF REVIEW: Several genomic and epigenomic studies of CVID have recently been carried out on cohorts of sporadic cases of CVID. Using high-throughput array and sequencing technologies, these studies identified several loci associated with the disease. Here, we review the omics approaches used in these studies and resulting discoveries. We also discuss how these findings lead to improved understanding of the molecular basis of CVID and possible future directions to pursue.
MAJOR CONCLUSIONS: High-throughput omic approaches have been productive in genetic and epigenetic studies of CVID, leading to the identifications of several significantly associated loci of different variant types, as well as genes and pathways elucidating the shared genetic basis of CVID and autoimmunity. Complex polygenic model of inheritance together with interplay between genetic components and environmental factors may account for the etiology of CVID and various associated comorbidities.
GENERAL SIGNIFICANCE: The genetic and epigenetic basis of CVID when further translated through functional studies will allow for improved understanding of the CVID etiology and will provide new insights into the development of potential new therapeutic approaches for this devastating condition. This article is part of a Special Issue entitled “System Genetics” Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.

PMID: 27316315 [PubMed – as supplied by publisher]

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Thirty-Day Hospital Revisit Rates and Factors Associated With Revisits in Patients Undergoing Septorhinoplasty.

JAMA Facial Plast Surg. 2016 Jun 16;

Authors: Spataro E, Branham GH, Kallogjeri D, Piccirillo JF, Desai SC

Abstract
Importance: Estimates of the 30-day hospital revisit rate following septorhinoplasty and the risk factors associated with revisits are unknown in the current literature. Surgical 30-day readmission rates are important to establish, as they are increasingly used as a quality care metric and can incur future financial penalties from third-party payers and government agencies.
Objective: To determine the rate of 30-day hospital revisits following septorhinoplasty and the risk factors associated with revisits.
Design, Setting, and Participants: A retrospective cohort analysis was conducted of 175 842 patients undergoing septorhinoplasty between January 1, 2005, and December 31, 2009, using data from the Healthcare Cost and Utilization Project state inpatient database, state ambulatory surgery database, and state emergency department database from California, Florida, and New York. Information on revisits for these patients was collected from the 3 databases between January 1, 2005, and December 31, 2012. Data analysis was conducted from September 1, 2014, to May 1, 2015.
Main Outcomes and Measures: Hospital revisits within 30 days after an index septorhinoplasty and the primary diagnosis at the time of the revisit were the main outcome measures. The revisit rate was calculated within subgroups of patients based on different demographic and clinical characteristics. A multivariable model was then used to determine independent risk factors for the occurrence of a hospital revisit within 30 days of the septorhinoplasty procedure.
Results: In total, 11 456 of 175 842 patients (6.5%) who underwent septorhinoplasty procedures revisited the hospital within 30 days of the procedure. Most of these revisits (6353 [55.5%]) were to the emergency department. The most common primary diagnosis was bleeding or epistaxis, occurring in 2150 patients (1.2%). Multivariable logistic regression showed that patients aged 41 to 65 years (adjusted odds ratio [aOR], 1.09; 99% CI, 1.02-1.16) or older than 65 years (aOR, 1.23; 99% CI, 1.06-1.43) had an increased revisit rate, as did black patients (aOR, 1.39; 99% CI, 1.16-1.66); those with Medicare (aOR, 1.55; 99% CI, 1.32-1.81) and Medicaid (aOR, 1.63; 99% CI, 1.33-2.01); those with diagnoses of autoimmune disorders or immunodeficiency (aOR, 2.69; 99% CI, 1.20-6.03), coagulopathy (aOR, 2.06; 99% CI, 1.33-3.20), anxiety (aOR, 1.79; 99% CI, 1.55-2.07), and alcohol use (aOR, 1.70; 99% CI, 1.35-2.14); and those who had a conchal cartilage graft (aOR, 2.01; 99% CI, 1.29-3.14).
Conclusions and Relevance: The study results suggest that patients with more medical comorbidities and lower socioeconomic status most commonly returned to the emergency department for surgical complications, such as bleeding or epistaxis, in the 30-day period after the procedure. These data provide valuable preoperative counseling information for patients and physicians. In addition, this study provides data to third-party payers or government agencies in which postprocedure readmissions in the 30-day period are used as a quality care metric affecting reimbursements and financial penalties.
Level of Evidence: 3.

PMID: 27311117 [PubMed – as supplied by publisher]

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[HOW TO APPROACH A PATIENT WITH SUSPECTED IMMUNODEFICIENCY].

Harefuah. 2016 Mar;155(3):170-6, 195

Authors: Toker O, Aggmon-Levin N, Somech R

Abstract
Our immune system protects us from various pathogens, autoimmune processes and malignancy. Primary immunodeficiency disorders are rare, however in contrast to the conventional perception, primary immunodeficiency diseases are more common than expected and may occur at any age. An insult to the immune system, primary or secondary, may lead to an increased incidence of infectious diseases, autoimmune diseases and malignancies. Primary care physicians, frequently encounter children and adults who suffer from recurrent infections, emphasizing the need for a structured approach for the evaluation of patients with suspected immunodeficiency. The growing knowledge of the fundamental mechanisms and function of the immune system together with recent developments in the field of clinical immunodeficiency enables us to use advanced diagnostic tools for the early diagnosis and treatment of these patients. In this review, we summarize the main aspects and updates of primary and secondary immune deficiency diseases, outline the “red flags” of immunodeficiency states and offer a stepwise workup approach for primary physicians and clinical immunology specialists. Some of the immunodeficiency “red flags” include recurrent infections, invasive infections, atypical pathogens, partial response to antibiotic treatment and frequent use of antibiotics, failure to thrive, chronic diarrhea and fungal infections, unexplained skin rash and a family history.

PMID: 27305752 [PubMed – in process]

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