Yonsei University

Mid-term outcomes of the Pulsta transcatheter pulmonary valve for the native right ventricular outflow tract.

The aim of this study is to present the mid-term outcomes of Pulsta valve. The Pulsta valve is a Self-expandable knitted nitinol-wire stent mounted with a treated tri-leaflet α-Gal-free porcine pericardial valve for percutaneous pulmonary valve implantation (PPVI) in patients with native right ventricular outflow tract (RVOT) lesions. A multi-center clinical trial using Pulsta valve® was designed for patients with severe pulmonary regurgitation (PR) in the native RVOT in multiple centers in South Korea and 25 patients were enrolled. Before PPVI, severe PR (mean PR fraction: 45.5 ± 6.9%) and enlarged RV volume (mean indexed RV end-diastolic volume; 169.7 ± 13.0 ml/m ) was present. The mean age was 21.6 ± 6.6 years old. All patients were successfully implanted with 26, 28, or 32 mm diameter of Pulsta valve loaded on the 18 or 20 French delivery catheters. At 6 months follow up, indexed RV end-diastolic volume was decreased to 126.9 ± 16.9 ml/m . At mean 33.1 ± 14.3 months follow-up, the mean value of mean pressure gradient in Pulsta valve was 6.5 ± 3.0 mmhg without significant PR. There was no serious device-related adverse event. A multi-center clinical trial was completed successfully with planned Pulsta valve implantation and demonstrated good mid-term effectiveness without device-related serious adverse events.

Nationwide pharmacovigilance data for cetuximab-induced anaphylaxis and predictive model validation using prospective specific IgE detection.

Cetuximab (chimeric monoclonal antibody to human epidermal growth factor receptor) is used to treat colorectal and head and neck cancers. Due to cross-reactivity with galactose-α-1,3-galactose (alpha-gal), it can induce hypersensitivity even at first administration. We aimed to determine the incidence and clinical manifestation of cetuximab-induced anaphylaxis, and to establish a means of predicting its incidence in patients ahead of treatment. Nationwide and single-center pharmacovigilance data from 2010 to 2017 were collected from the Korea Institute of Drug Safety-Korea Adverse Event Reporting System and Severance Regional Pharmacovigilance Center. Patients scheduled for cetuximab administration were enrolled prospectively. A skin prick test was carried out and serum IgE specific to cetuximab and cross-reactive allergens were measured. Reactions were monitored after cetuximab infusion. Over 8 years, there were 23 reports of anaphylaxis nationwide. In a single-center study, incidence of cetuximab-induced anaphylaxis was 1.1%. Most anaphylaxis occurred at first injection (93.3%), even under pretreatment with anti-allergic drugs. Four of 64 patients (6.3%) experienced severe anaphylaxis. The median cetuximab-specific IgE titer was 6.9 kU/L in patients experiencing anaphylaxis and 0 kU/L in those who did not (P < 0.001). The results of alpha-gal, beef sIgE, and cetuximab skin prick testing were similar to those of cetuximab sIgE. Patients who did not experience hypersensitivity were negative in all 4 allergy tests. Its positive and negative predictive values were 100%. Specific IgE detection of cetuximab or alpha-gal can accurately predict cetuximab-induced anaphylaxis prior to first administration.

Clinical Features and Culprit Food Allergens of Korean Adult Food Allergy Patients: A Cross-Sectional Single-Institute Study.

To investigate the causative allergens and clinical characteristics of Korean adult patients with food allergy (FA). This retrospective, cross-sectional single-institutional study enrolled Korean adult patients (n = 812) suspected of having FA. For diagnosis, causality assessment history taking, ImmunoCAP specific immunoglobulin E measurement and/or skin prick test were performed. Among 812 patients, 415 were diagnosed as having FA. The most common causative allergen was fruit, with a diagnosis of pollen food allergy syndrome (PFAS: 155, 37.3%), followed by crustaceans (111, 26.7%), wheat (63, 15.1%), fruits in patients without PFAS(43, 10.3%), buckwheat (31, 7.4%), peanut (31, 7.4%), walnut (25, 6.0%), red meat due to reaction to galactose-α-1,3-galactose (α-Gal) (8, 1.9%), and silkworm pupa (13, 3.1%). Allergy to egg, milk, fish, or shellfish was rare in Korean adults. One-third of patients with FA exhibited multiple FAs (238/415, 57.3%); the average number of causative allergens was 2.39. About 129 patients (31.0%) were diagnosed as having anaphylaxis; in these patients, wheat was the most frequent causative food. Twenty patients were further diagnosed with food-dependent exercise-induced anaphylaxis (FDEIA); all were due to wheat. In particular, crustaceans, wheat, PFAS, buckwheat, and red meat (α-Gal) were also frequent causes of anaphylaxis. Wheat, fruits with or without PFAS, and crustaceans are important and frequent causative allergens in Korean adult FA; these allergens differ from those found in childhood FA. It is notable that non-classic allergies, such as PFAS, FDEIA, and α-Gal allergy, are the important causes of anaphylaxis in Korean adult FA.

Validation of PROTIA™ Allergy-Q 64 Atopy® as a Specific IgE Measurement Assay for 10 Major Allergen Components.

Component-resolved diagnostics (CRD) is expected to provide additional diagnostic information in allergic patients. PROTIA™ Allergy-Q 64 Atopy®, a recently developed CRD-based multiplex specific immunoglobulin E (sIgE) assay, can quantitatively measure sIgE to major allergen components. The sIgE detection by PROTIA™ Allergy-Q 64 Atopy® and ImmunoCAP® assays was compared using the sera of 125 Korean allergic patients. Group 1 and 2 allergens of house dust mites (HDMs; (Der f) 1 and Der f 2 in PROTIA™ Allergy-Q 64 Atopy®, (Der p) 1 and Der p 2 in ImmunoCAP®), Bet v 1, Fel d 1, Que a 1, ω-5 gliadin, α-lactalbumin, β-lactoglobulin, casein and α-Gal were measured by both assays. Comparing the results from the 2 assays, the agreement rate for all the 10 allergens was > 88% (group 1 HDM allergen, 100%; group 2 HDM allergen, 94.6%; Bet v 1, 97.4%; Fel d 1, 90.5%; Que a 1, 89.2%; α-lactalbumin, 96%; β-lactoglobulin, 88%; casein, 88%; ω-5 gliadin, 96%; α-Gal, 100%). Correlation analysis indicated that, all the 10 allergen sIgEs showed more than moderate positive correlation (Pearson correlation coefficients > 0.640). Additionally, intra-class comparison showed more than high correlation for all the 10 allergens (Spearman's rank correlation coefficients > 0.743). PROTIA™ Allergy-Q 64 Atopy® is reliable and comparable to the ImmunoCAP® assay for component-resolved diagnosis.

Accurate assessment of alpha-gal syndrome using cetuximab and bovine thyroglobulin-specific IgE.

IgE against galactose-α-1,3-galactose (α-Gal) causes alpha-gal syndrome. Bovine thyroglobulin (BTG) and cetuximab share this epitope. We aimed to determine the utility of specific IgE (sIgE) against cetuximab as compared to BTG for diagnosing alpha-gal syndrome. Twelve patients with alpha-gal syndrome, 11 patients with immediate beef or pork allergy, 18 asymptomatic individuals with meat sensitization, and 10 non-atopic subjects were enrolled. We checked the levels of sIgE against BTG and cetuximab using the streptavidin CAP assay. Additionally, IgE reactivity to BTG and cetuximab was assessed by immunoblotting. All alpha-gal syndrome patients had a high concentration of sIgE against BTG, and cetuximab. In contrast to alpha-gal syndrome, patients with immediate allergic reactions to meat consumption and those with asymptomatic sensitization had significantly lower concentration of BTG and cetuximab sIgE, and a high prevalence of sIgE against bovine or porcine serum albumin. Although the concentration of sIgE against alpha-gal was lower in individuals with asymptomatic sensitization, IgE immunoblotting showed the presence of sIgE against α-Gal in this group. Differentiation of alpha-gal syndrome from patients with immediate allergy to meat consumption or asymptomatic sensitization requires quantification of cetuximab- or BTG-induced sIgE via detection of IgE for α-gal.

Clinical characteristics of adverse events associated with therapeutic monoclonal antibodies in Korea.

The use of monoclonal antibodies (mAbs) is increasing in various clinical fields. Although mAb safety must be demonstrated prior to approval, targeted pharmacovigilance is essential for the recognition and assessment of adverse reactions. The purpose of this study was to identify the major clinical features of adverse reactions to mAbs in Korea. Spontaneous reports of adverse reactions attributed to 18 mAbs from January 2005 to December 2014 were extracted from the Korea Adverse Event Reporting System. We analyzed these reports for information relating to patient characteristics and the types of adverse reactions. In total, 11 492 adverse reactions were reported in 7569 patients. Almost 19% of total study population showed suspected hypersensitivity reactions. Leukocyte abnormalities were reported frequently (10.0%), as well as infections (9.5%), drug eruptions (7.5%), and pruritus (5.0%). Furthermore, 3716 of the adverse reactions in 2538 patients were classified as serious; these included severe infections (18.2%), neutropenia (12.1%), visual dysfunctions (6.6%), and anaphylaxis (4.8%). The mAbs with the highest number of adverse reaction reports were rituximab (27.6%), adalimumab (17.5%), cetuximab (11.9%), and infliximab (10.7%). Hypersensitivity reactions were observed more frequently than expected, although no previously unrecognized reactions were observed. Adverse reactions occurred more frequently in children and in elderly patients. Close monitoring of adverse reactions to therapeutic mAbs is therefore warranted because these can potentially cause serious medical conditions or death. Copyright © 2016 John Wiley & Sons, Ltd.

IgE reactivity to carbohydrate moieties of glycoproteins in wheat allergy.

Carbohydrate moieties of different glycoproteins, such as cross-reactive carbohydrate determinants (CCDs) and galactose α-1,3-galactose, can induce IgE reactivity with varied clinical significance. In this study, the possible participation of glycan from wheat gliadin, with respect to its IgE-binding capacity, was investigated in children with food allergies to wheat. Total IgE and wheat-specific IgE quantification, documentation of history, and/or oral food challenge (OFC) were performed for 52 children. Subjects with positive wheat-specific IgE were characterized as the symptomatic group, never-exposed group, or asymptomatic group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and glycan detection in gliadin were performed. IgE binding to gliadin and deglycosylated gliadin was measured by immunoblotting and ELISA. Gliadin-specific IgE was detected and correlated with wheat-specific IgE in the symptomatic, never-exposed, and asymptomatic groups. The glycan range overlapped significantly with the gliadin range. Deglycosylation of gliadin reduced the allergenicity of gliadin. In gliadin, the allergenicity of the glycan portion was greater in the symptomatic group than in the never-exposed and asymptomatic groups. We conclude that N-glycan in gliadin might exhibit allergenicity as a possible carbohydrate epitope in wheat allergy in children.

Synthesis of nucleotide sugars and α-galacto-oligosaccharides by recombinant Escherichia coli cells with trehalose substrate.

Useful nucleoside diphosphate (NDP)-sugars and α-galacto-oligosaccharides were synthesized by recombinant Escherichia coli whole cells and compared to those produced by enzyme-coupling. Production yields of NDP-glucoses (Glcs) by whole cells harboring trehalose synthase (TS) were 60% for ADP-Glc, 82% for GDP-Glc, and 27% for UDP-Glc, based on NDP used. Yield of UDP-galactose (Gal) by the whole-cell harboring a UDP-Gal 4-epimerase (pGALE) was 26% of the quantity of UDP-Glc. α-Galacto-oligosaccharides, α-Gal epitope (Galα-3Galβ-4Glu) and globotriose (Galα-4Galβ-4Glu), were produced by the combination of three recombinant whole cells harboring TS, pGALE, and α-galactosyltransferase, with production yields of 48% and 54%, based on UDP, respectively. Production yields of NDP-sugars and α-galacto-oligosaccharides by recombinant whole-cell reactions were approximately 1.5 times greater than those of enzyme-coupled reactions. These results suggest that a recombinant whole-cell system using cells harboring TS with trehalose as a substrate may be used as an alternative and practical method for the production of NDP-sugars and α-galacto-oligosaccharides.

Coupling reactions of trehalose synthase from Pyrococcus horikoshii: cost-effective synthesis and anti-adhesive activity of α-galactosyl oligosaccharides using a one-pot three-enzyme system with trehalose.

A new sugar nucleotide cycling (SNC) process was established in a one-pot three enzyme-coupled reaction using disaccharide trehalose. Trehalose synthase from Pyrococcus horikoshii could be applied to the SNC process for the synthesis of functional α-galactosyl oligosaccharides, α-galactose (Gal) epitopes and globotriose, using the effective regeneration of UDP-Gal. The α-Gal epitopes and globotriose were found to attach to the cell-surface of enteropathogenic Escherichia coli O127 (EPEC) which were bound to human Caco-2 cells. These α-galactosyl oligosaccharides were able to prohibit the attachment of EPEC, which could have resulted in colonization and disease. The α-Gal epitope III with a lactulose acceptor showed the most inhibitory activity of anti-adhesion. The results suggest that the α-galactosyl oligosaccharides may be alternative anti-adhesion molecules that overcome antibiotic resistance.

Delayed mammalian meat-induced anaphylaxis confirmed by skin test to cetuximab.