Publications by authors named "Zsolt Szépfalusi"

65 Publications

Lessons from low seroprevalence of SARS-CoV-2 antibodies in schoolchildren: A cross-sectional study.

Pediatr Allergy Immunol 2021 Jan 29. Epub 2021 Jan 29.

Department of Pediatrics and Adolescent Medicine, Klinik Ottakring, Vienna, Austria.

Background: Children are discussed as hidden SARS-CoV-2 virus reservoir because of predominantly mild or even asymptomatic course of disease. The objective of this cross-sectional study in May-July 2020 was to assess the prevalence of SARS-CoV-2 antibodies and virus RNA in schoolchildren, consistent with previous infection by contact tracing.

Methods: School authorities approached parents for voluntary participation. Interested families were contacted by the study team. A nasal and oropharyngeal swab, a blood sample, and a questionnaire were employed. Primary endpoint was the frequency of SARS-CoV-2 real-time PCR (RT-PCR) and antibody-positive children. Antibody positivity was assessed by a highly sensitive first-line ELISA, and a neutralization assay and two other immunoassays as confirmatory assays.

Results: Of 2069 children (median age 13 years, IQR 10-15), 2 cases (0.1%) tested positive for SARS-CoV-2 RNA and 26 cases (1.3%) tested positive for specific antibodies. SARS-CoV-2-specific antibodies exhibited detectable virus-neutralizing activity in 92% (24 of 26 samples). Seropositivity was associated with a history of mild clinical symptoms in 14 children (53.8%), while 12 children (46.2%) remained asymptomatic. Among 13 seropositive children being tested concomitantly with their siblings, only one pair of siblings was seropositive. Contact tracing revealed adult family members and school teachers as potential index cases.

Conclusion: In schoolchildren, the infection rate with SARS-CoV-2 is low and associated with a mild or asymptomatic course of disease. Virus spreading seemed to occur more likely in intergenerational contacts than among siblings in the same household. The presence of neutralizing SARS-CoV-2 antibodies in children may reflect protective adaptive immunity.
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http://dx.doi.org/10.1111/pai.13459DOI Listing
January 2021

Hypopyon sign as an unusual complication of varicella infection in a girl with atopic dermatitis.

Wien Med Wochenschr 2021 Mar 10;171(3-4):61-64. Epub 2020 Dec 10.

Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Varicella-zoster virus (VZV) infection, also known as chickenpox, is a common childhood affliction. Generalized small itchy single-standing vesicles on erythematous skin are typical. Both cutaneous and systemic complications of the VZV infection may commonly occur. A three-year-old girl with a previous history of mild atopic dermatitis presented in our Pediatric Dermatology Clinic in poor general condition, with a skin rash predominantly consisting of generalized large blisters with hypopyon sign and erosions. On a closer look, scattered erythematous papules and vesicles were also visible. A positive Tzanck smear from an intact pinhead-sized vesicle and VZV PCR confirmed the clinical diagnosis of chickenpox. Cultures from hypopyon material revealed Staphylococcus aureus superinfection. We report an exceptional, not-yet described complication of chickenpox with hypopyon-forming superinfection in an atopic child. In addition, our case nicely underscores the necessity of early VZV vaccination, which has been available and recommended now for more than 10 years in pediatric vaccination programs to avoid severe complications.
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http://dx.doi.org/10.1007/s10354-020-00790-xDOI Listing
March 2021

Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: The Markers of Nut Allergy Study.

Allergy 2020 Dec 9. Epub 2020 Dec 9.

Translational Medicine, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.

Background: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed.

Objective: To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergies.

Methods: The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5-17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization from Canadian (n = 150) and Austrian (n = 50) tertiary pediatric centers. BAT using %CD63 basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001-1000 ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparison to extract and marker allergen-specific IgE.

Results: A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) in a sub-analysis in sensitized patients undergoing OFC.

Conclusions: Basophil activation test can predict allergic clinical status to peanut and tree nuts in multi-nut-sensitized children and may reduce the need for high-risk OFCs in patients.
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http://dx.doi.org/10.1111/all.14695DOI Listing
December 2020

Peanut induced anaphylaxis in children and adolescents: Data from the European Anaphylaxis Registry.

Allergy 2020 Dec 3. Epub 2020 Dec 3.

Division of Allergy and Immunology, Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents.

Methods: Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre.

Results: 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004).

Conclusions: The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.
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http://dx.doi.org/10.1111/all.14683DOI Listing
December 2020

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI).

Authors:
Ludger Klimek Oliver Pfaar Margitta Worm Thomas Eiwegger Jan Hagemann Markus Ollert Eva Untersmayr Karin Hoffmann-Sommergruber Alessandra Vultaggio Ioana Agache Sevim Bavbek Apostolos Bossios Ingrid Casper Susan Chan Alexia Chatzipetrou Christian Vogelberg Davide Firinu Paula Kauppi Antonios Kolios Akash Kothari Andrea Matucci Oscar Palomares Zsolt Szépfalusi Wolfgang Pohl Wolfram Hötzenecker Alexander R Rosenkranz Karl-Christian Bergmann Thomas Bieber Roland Buhl Jeroen Buters Ulf Darsow Thomas Keil Jörg Kleine-Tebbe Susanne Lau Marcus Maurer Hans Merk Ralph Mösges Joachim Saloga Petra Staubach Uta Jappe Klaus F Rabe Uta Rabe Claus Vogelmeier Tilo Biedermann Kirsten Jung Wolfgang Schlenter Johannes Ring Adam Chaker Wolfgang Wehrmann Sven Becker Laura Freudelsperger Norbert Mülleneisen Katja Nemat Wolfgang Czech Holger Wrede Randolf Brehler Thomas Fuchs Peter-Valentin Tomazic Werner Aberer Antje-Henriette Fink-Wagner Fritz Horak Stefan Wöhrl Verena Niederberger-Leppin Isabella Pali-Schöll Wolfgang Pohl Regina Roller-Wirnsberger Otto Spranger Rudolf Valenta Mübecell Akdis Paolo M Matricardi François Spertini Nicolai Khaltaev Jean-Pierre Michel Larent Nicod Peter Schmid-Grendelmeier Marco Idzko Eckard Hamelmann Thilo Jakob Thomas Werfel Martin Wagenmann Christian Taube Erika Jensen-Jarolim Stephanie Korn Francois Hentges Jürgen Schwarze Liam O Mahony Edward F Knol Stefano Del Giacco Tomás Chivato Pérez Jean Bousquet Anna Bedbrook Torsten Zuberbier Cezmi Akdis Marek Jutel

Allergol Select 2020 7;4:53-68. Epub 2020 Sep 7.

European Academy of Allergy and Clinical Immunology (EAACI).

Background: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2.

Materials And Methods: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic.

Results: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future.

Conclusion: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.
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http://dx.doi.org/10.5414/ALX02166EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480069PMC
September 2020

Modeling the conversion between specific IgE test platforms for nut allergens in children and adolescents.

Allergy 2021 Mar 16;76(3):831-841. Epub 2020 Aug 16.

Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.

Background: Multiplex tests allow for measurement of allergen-specific IgE responses to multiple extracts and molecular allergens and have several advantages for large cohort studies. Due to significant methodological differences, test systems are difficult to integrate in meta-analyses/systematic reviews since there is a lack of datasets with direct comparison. We aimed to create models for statistical integration of allergen-specific IgE to peanut/tree nut allergens from three IgE test platforms.

Methods: Plasma from Canadian and Austrian children/adolescents with peanut/tree nut sensitization and a cohort of sensitized, high-risk, pre-school asthmatics (total n = 166) were measured with three R&D multiplex IgE test platforms: Allergy Explorer version 1 (ALEX) (Macro Array Dx), MeDALL-chip (Mechanisms of Development of Allergy) (Thermo Fisher), and EUROLINE (EUROIMMUN). Skin prick test (n = 51) and ImmunoCAP (Thermo Fisher) (n = 62) results for extracts were available in a subset. Regression models (Multivariate Adaptive Regression Splines, local polynomial regression) were applied if >30% of samples were positive to the allergen. Intra-test correlations between PR-10 and nsLTP allergens were assessed.

Results: Using two regression methods, we demonstrated the ability to model allergen-specific relationships with acceptable measures of fit (r  = 94%-56%) for peanut and tree nut sIgE testing at the extract and molecular-level, in order from highest to lowest: Ara h 2, Ara h 6, Jug r 1, Ana o 3, Ara h 1, Jug r 2, and Cor a 9.

Conclusion: Our models support the notion that quantitative conversion is possible between sIgE multiplex platforms for extracts and molecular allergens and may provide options to aggregate data for future meta-analysis.
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http://dx.doi.org/10.1111/all.14529DOI Listing
March 2021

Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemie: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H.

Allergo J 2020 24;29(4):14-27. Epub 2020 Jun 24.

Zentrum für Rhinologie & Allergologie, An den Quellen 10, 65183 Wiesbaden, Germany.

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http://dx.doi.org/10.1007/s15007-020-2553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289636PMC
June 2020

Subsequent MRI of pediatric patients after an adverse reaction to Gadolinium-based contrast agents.

PLoS One 2020 3;15(4):e0230781. Epub 2020 Apr 3.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance imaging (MRI) scans often must be used repeatedly in pediatric oncologic patients. Although GBCAs are usually well tolerated, severe and life-threatening allergic reactions might occur, which can result in overly cautions adherence to special precautions in patients.

Purpose: To evaluate the management of the reported GBCA-associated adverse reactions in subsequent contrast-enhanced MRIs in pediatric patients, distinguishing non-allergic and allergic reactions.

Materials And Methods: In this retrospective, cross-sectional study, consecutive pediatric neurooncological patients who underwent GBCA-enhanced MRI at our university hospital, between 2007 and 2016, were eligible. The patients' history was evaluated with regard to any adverse events after GBCA administration. In a subset of patients with reported adverse reactions, the institutional premedication regime or an allergy work-up in clinical practice were performed, using either skin-prick tests or intravenous provocation tests in a double-blind procedure.

Results: Included were 8156 contrast-enhanced MRI scans in 2109 patients. Nineteen acute adverse events (19/8156; 0.23%) in 17 patients (17/2109; 0.81%) were reported. Despite a premedication regime in 14 patients, three patients (3/14; 21.4%) reported a breakthrough reaction. None of the 12 patients who underwent skin-prick tests or intravenous provocation tests showed allergic reactions. At least one well-tolerated GBCA was identified in almost every tested patient.

Conclusion: A fast-track allergy work-up can help to distinguish non-allergic and allergic reactions and to identify a well-tolerated GBCA, thus avoiding unnecessary premedication for subsequent GBCA administrations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122741PMC
July 2020

Biologicals in atopic disease in pregnancy: An EAACI position paper.

Allergy 2021 01;76(1):71-89

Division of Immunology and Allergy, Food Allergy and Anaphylaxis Program, The Hospital for Sick Children, Toronto, ON, Canada.

Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scarce and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, preconception counseling and healthcare provider education are crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy.
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http://dx.doi.org/10.1111/all.14282DOI Listing
January 2021

Transfer and loss of allergen-specific responses via stem cell transplantation: A prospective observational study.

Allergy 2020 09 23;75(9):2243-2253. Epub 2020 Jun 23.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Currently, no estimates can be made on the impact of hematopoietic stem cell transplantation on allergy transfer or cure of the disease. By using component-resolved diagnosis, we prospectively investigated 50 donor-recipient pairs undergoing allogeneic stem cell transplantation. This allowed calculating the rate of transfer or maintenance of allergen-specific responses in the context of stem cell transplantation.

Methods: Allergen-specific IgE and IgG to 156 allergens was measured pretransplantation in 50 donors and recipients and at 6, 12 and 24 months in recipients post-transplantation by allergen microarray. Based on a mixed effects model, we determined risks of transfer of allergen-specific IgE or IgG responses 24 months post-transplantation.

Results: After undergoing stem cell transplantation, 94% of allergen-specific IgE responses were lost. Two years post-transplantation, recipients' allergen-specific IgE was significantly linked to the pretransplantation donor or recipient status. The estimated risk to transfer and maintain individual IgE responses to allergens by stem cell transplantation was 1.7% and 2.3%, respectively. Allergen-specific IgG, which served as a surrogate marker of maintaining protective IgG responses, was highly associated with the donor's (31.6%) or the recipient's (28%) pretransplantation response.

Conclusion: Hematopoietic stem cell transplantation profoundly reduces allergen-specific IgE responses but also comes with a considerable risk to transfer allergen-specific immune responses. These findings facilitate clinical decision-making regarding allergic diseases in the context of hematopoietic stem cell transplantation. In addition, it provides prospective data to estimate the risk of transmitting allergen-specific responses via hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1111/all.14278DOI Listing
September 2020

Toward personalization of asthma treatment according to trigger factors.

J Allergy Clin Immunol 2020 06 18;145(6):1529-1534. Epub 2020 Feb 18.

Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, Sechenov First Moscow State Medical University, Moscow, Russia; NRC Institute of Immunology FMBA of Russia, Moscow, Russia; Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Karl Landsteiner University, Krems, Austria. Electronic address:

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.02.001DOI Listing
June 2020

Soluble FcεRI, IgE, and tryptase as potential biomarkers of rapid desensitizations for platin IgE sensitized cancer patients.

J Allergy Clin Immunol Pract 2020 06 4;8(6):2085-2088.e10. Epub 2020 Feb 4.

Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

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http://dx.doi.org/10.1016/j.jaip.2020.01.047DOI Listing
June 2020

An optimized, robust and reproducible protocol to generate well-differentiated primary nasal epithelial models from extremely premature infants.

Sci Rep 2019 12 27;9(1):20069. Epub 2019 Dec 27.

Division of Neonatology, Pediatric Intensive Care & Neuropediatrics, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

Extremely premature infants are prone to severe respiratory infections, and the mechanisms underlying this exceptional susceptibility are largely unknown. Nasal epithelial cells (NEC) represent the first-line of defense and adult-derived ALI cell culture models show promising results in mimicking in vivo physiology. Therefore, the aim of this study was to develop a robust and reliable protocol for generating well-differentiated cell culture models from NECs of extremely premature infants. Nasal brushing was performed in 13 extremely premature infants at term corrected age and in 11 healthy adult controls to obtain NECs for differentiation at air-liquid interface (ALI). Differentiation was verified using imaging and functional analysis. Successful isolation and differentiation was achieved for 5 (38.5%) preterm and 5 (45.5%) adult samples. Preterm and adult ALI-cultures both showed well-differentiated morphology and ciliary function, however, preterm cultures required significantly longer cultivation times for acquiring full differentiation (44 ± 3.92 vs. 23 ± 1.83 days; p < 0.0001). Moreover, we observed that recent respiratory support may impair successful NECs isolation. Herewithin, we describe a safe, reliable and reproducible method to generate well-differentiated ALI-models from NECs of extremely premature infants. These models provide a valuable foundation for further studies regarding immunological and inflammatory responses and respiratory disorders in extremely premature infants.
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http://dx.doi.org/10.1038/s41598-019-56737-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934534PMC
December 2019

ICER report for peanut OIT comes up short.

Ann Allergy Asthma Immunol 2019 11 9;123(5):430-432. Epub 2019 Sep 9.

Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA; Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2019.09.001DOI Listing
November 2019

PD-L1 and PD1 expression in post-transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter- and intra-individual descriptive study covering the whole spectrum of PTLD categories.

Cancer Med 2019 08 3;8(10):4656-4668. Epub 2019 Jul 3.

Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Vienna, Austria.

Therapy of children with post-transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD-L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD-L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD-L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra-individual assessment of PD-L1/PD1 expression. We observed lower PD-L1 and higher PD1 expression in non-destructive lesions, and higher PD-L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B-cell lymphomas (DLBCL, n = 10/21). The amount of PD-L1- and PD1-positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD-L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non-destructive early lesions. PD-L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune- and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD-L1 and PD1 in all PTLD categories.
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http://dx.doi.org/10.1002/cam4.2394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712474PMC
August 2019

Only α-Gal bound to lipids, but not to proteins, is transported across enterocytes as an IgE-reactive molecule that can induce effector cell activation.

Allergy 2019 10 16;74(10):1956-1968. Epub 2019 Jul 16.

Molecular Biotechnology Section, University of Applied Sciences, Vienna, Austria.

Background: The oligosaccharide galactose-α-1,3-galactose (α-Gal), present in mammalian proteins and lipids, causes an unusual delayed allergic reaction 3 to 6 hours after ingestion of mammalian meat in individuals with IgE antibodies against α-Gal. To better understand the delayed onset of allergic symptoms and investigate whether protein-bound or lipid-bound α-Gal causes these symptoms, we analyzed the capacity of α-Gal conjugated proteins and lipids to cross a monolayer of intestinal cells.

Methods: Extracts of proteins and lipids from beef were prepared, subjected to in vitro digestions, and added to Caco-2 cells grown on permeable supports. The presence of α-Gal in the basolateral medium was investigated by immunoblotting, thin-layer chromatography with immunostaining and ELISA, and its allergenic activity was analyzed in a basophil activation test.

Results: After addition of beef proteins to the apical side of Caco-2 cells, α-Gal containing peptides were not detected in the basolateral medium. Those peptides that crossed the Caco-2 monolayer did not activate basophils from an α-Gal allergic patient. Instead, when Caco-2 cells were incubated with lipids extracted from beef, α-Gal was detected in the basolateral medium. Furthermore, these α-Gal lipids were able to activate the basophils of an α-Gal allergic patient in a dose-dependent manner.

Conclusion: Only α-Gal bound to lipids, but not to proteins, is able to cross the intestinal monolayer and trigger an allergic reaction. This suggests that the slower digestion and absorption of lipids might be responsible for the unusual delayed allergic reactions in α-Gal allergic patients and identifies glycolipids as potential allergenic molecules.
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http://dx.doi.org/10.1111/all.13873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852507PMC
October 2019

Real-life safety of 5-grass pollen tablet in 5-to-9-year-old children with allergic rhinoconjunctivitis.

Ann Allergy Asthma Immunol 2019 07 19;123(1):70-80. Epub 2019 Apr 19.

Pediatric Pneumology and Allergology unit, Necker-Enfants Malades Hospital, Paris, France; Université Paris Descartes, Paris, France.

Background: Although 5-grass pollen sublingual immunotherapy has a good safety profile in controlled clinical trials, additional safety information among pediatric patients in a real-world setting would be useful.

Objective: To further document the safety of 5-grass tablet among children aged 5 to 9 years with allergic rhinoconjunctivitis (ARC).

Methods: This multicenter, observational study included allergy immunotherapy-naïve 5- to 9-year-old children with grass pollen-induced ARC prescribed with 5-grass tablet daily (3-day dose escalation to 300 index of reactivity [IR]). Patients were followed up daily for safety and tolerability over the first 30 treatment days. Adverse events (AEs) and adverse drug reactions (ADRs) were analyzed descriptively.

Results: Three hundred seven children (mean age, 7.1 years) were enrolled. Fifty-eight percent were confirmed as polysensitized, and 36% had mild-to-moderate asthma. Of 307 patients, 233 (76%) reported AEs, and 173/307 (56%) reported ADRs, most frequently mild application-site reactions (throat irritation, oral pruritus, oral paresthesia). Sixteen of 307 (5.2%) patients withdrew because of ADRs. In 143 of 173 (83%) patients, ADRs first occurred within 1 week of starting treatment. More than half of the ADRs lasted less than 2 days, and ADRs resolved spontaneously in 161 of 173 (93%) patients. Recurrences of ADRs were reported in 45 of 173 (26%) patients and were also mainly application-site reactions. No notable differences were found in ADRs related to whether patients had asthma at inclusion. Neither epinephrine use nor admission to intensive care unit was reported.

Conclusion: The safety profile of 5-grass tablet in pediatric ARC patients aged 5 to 9 years was consistent with safety findings in older patients, most ADRs being at the application site and mild to moderate. ClinicalTrials.gov identifier: NCT02295969; EUPAS registration number: 8104.
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http://dx.doi.org/10.1016/j.anai.2019.04.011DOI Listing
July 2019

Evidence for a Role of TGF-β-Activated Kinase 1 and MAP3K7 Binding Protein 3 in Peanut-Specific T-Cell Responses.

Int Arch Allergy Immunol 2019;179(1):10-16. Epub 2019 Mar 20.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria,

Peanut allergy is considered to be the most common cause for food-induced anaphylaxis. Currently, no approved treatment is available. Avoidance is the only measure to prevent anaphylactic reactions to peanuts. T-helper cells are of special importance for the sensitization process and the maintenance of allergic inflammation. Identifying markers of allergen-specific T-cell responses may help to develop novel treatment approaches. Therefore, we aimed to define new T-cell target genes in Ara h 2-specific T cells and to investigate the possibility of using them as biomarkers of peanut allergy in peripheral blood mononuclear cells (PBMCs). We performed whole mRNA array analysis (whole human genome oligo microarray) of in vitro expanded Ara h 2-specific T cells (CFSElowCD3+CD4+) from 5 peanut-allergic (PA) and 5 non-peanut-sensitized individuals. Expression of selected genes as a result of a two-step bioinformatic approach was confirmed in a second cohort by quantitative PCR. TGF-β- activated kinase 1 and MAP3K7 binding protein 3 (TAB3), calcium/calmodulin-dependent protein kinase type IV (CAMK4) and HemK methyltransferase family member 1 (HEMK1) were significantly upregulated in Ara h 2-specific T cells of PA patients. In addition, the expression of these genes was also assessed in unstimulated PBMCs from a cohort (n = 43) of PA, atopic non-PA, and nonatopic controls. Interestingly, in unstimulated PBMCs, TAB3 expression was significantly downregulated in PA patients compared to atopic non-PA individuals. Thus, TAB3 may play a significant role at the level of T-cell activation and may also be a candidate biomarker for PA.
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http://dx.doi.org/10.1159/000496438DOI Listing
May 2019

Preventive sublingual immunotherapy with House Dust Mite extract modulates epitope diversity in pre-school children.

Allergy 2019 04 1;74(4):780-787. Epub 2019 Jan 1.

Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: The preventive effect of allergen immunotherapy (AIT) on allergy and asthma development is currently assessed using primary and secondary AIT approaches. Knowledge of the immunological effects of these interventions is limited and the impact on epitope diversity remains to be defined.

Methods: We used high-density peptide arrays that included all known Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f) allergens and the whole proteome of Der f to study changes in House Dust Mite (HDM) linear peptide recognition during a 2-year preventive double-blind placebo-controlled sublingual HDM AIT pilot study in 2-5-year-old children with sensitization to HDM but without symptoms.

Results: Preventive AIT-treated patients showed significantly higher IgG epitope diversity to HDM allergens compared to placebo-treated individuals at 24 months of treatment (P < 0.05), while no increase in IgE diversity was seen. At 24 months of treatment, IgG4 diversity for HDM allergens was significantly higher in the pAIT-treated patients compared to placebo group (P < 0.05). Potentially beneficial changes in epitope recognition throughout the treatment are also seen in peptides derived from Der f proteome.

Conclusion: These data suggest a beneficial immunomodulation of preventive sublingual immunotherapy at a molecular level by favoring a broader blocking repertoire and inhibiting epitope spreading.
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http://dx.doi.org/10.1111/all.13658DOI Listing
April 2019

The influence of retransplantation on survival for pediatric lung transplant recipients.

J Thorac Cardiovasc Surg 2018 11 6;156(5):2025-2034.e2. Epub 2018 Jun 6.

Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Objectives: We reviewed our 25-year experience in pediatric lung transplantation with the aim to identify trends and influencing factors over time.

Methods: We reviewed our prospectively maintained database and analyzed all patients younger than age 18 years who underwent primary lung transplantation at Medical University of Vienna between 1990 and 2015.

Results: Eighty-six consecutive patients were enrolled with a mean age of 12.9 ± 4.1 years at primary transplantation. The most frequent indication for primary transplantation was cystic fibrosis (64.0). Bilateral double-lung transplantation was performed in 84 patients (97.7%), including lobar transplantation in 35 patients (40.7%). sixty-eight patients (79.1%) underwent transplant on venoarterial extracorporeal membrane oxygenation and 7 patients (8.1%) utilized cardiopulmonary bypass. The 30-day and in-hospital mortality was 8.1% and 17.4%, respectively, and 1-, 5-, and 10-year overall survival (OS) was 79.0%, 67.5%, and 57.1%, respectively. A significant improvement of OS was observed during the second treatment period after 2003 with a 1-, 5-, and 10-year OS of 86.0%, 73.9%, and 73.9%, respectively (P < .01). Seventeen retransplantations were performed in 14 patients. Twelve patients (85.7%) underwent 15 late elective retransplantations for chronic lung allograft dysfunction resulting in a 1- and 5-year OS of 91.7% and 80.2%, respectively. In contrast, 2 patients (14.3%) who underwent acute retransplantation for primary graft failure died during the postoperative period.

Conclusions: Our outcomes for pediatric lung transplantation have improved over the past 25 years and have become comparable to those for adult transplantation. Elective re-transplantations for pediatric patients were performed successfully, and strongly influenced improved long-term OS.
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http://dx.doi.org/10.1016/j.jtcvs.2018.05.080DOI Listing
November 2018

Non-celiac gluten/wheat sensitivity (NCGS)-a currently undefined disorder without validated diagnostic criteria and of unknown prevalence: Position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (DGAKI).

Allergo J Int 2018 28;27(5):147-151. Epub 2018 May 28.

10Department of Dermatology, Venereology and Allergology, Allergy Center Charité (ACC), Charité University Hospital, Berlin, Germany.

Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.
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http://dx.doi.org/10.1007/s40629-018-0070-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153714PMC
May 2018

An algorithm for the classification of mRNA patterns in eosinophilic esophagitis: Integration of machine learning.

J Allergy Clin Immunol 2018 04 19;141(4):1354-1364.e9. Epub 2017 Dec 19.

Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass. Electronic address:

Background: Diagnostic evaluation of eosinophilic esophagitis (EoE) remains difficult, particularly the assessment of the patient's allergic status.

Objective: This study sought to establish an automated medical algorithm to assist in the evaluation of EoE.

Methods: Machine learning techniques were used to establish a diagnostic probability score for EoE, p(EoE), based on esophageal mRNA transcript patterns from biopsies of patients with EoE, gastroesophageal reflux disease and controls. Dimensionality reduction in the training set established weighted factors, which were confirmed by immunohistochemistry. Following weighted factor analysis, p(EoE) was determined by random forest classification. Accuracy was tested in an external test set, and predictive power was assessed with equivocal patients. Esophageal IgE production was quantified with epsilon germ line (IGHE) transcripts and correlated with serum IgE and the T2-type mRNA profile to establish an IGHE score for tissue allergy.

Results: In the primary analysis, a 3-class statistical model generated a p(EoE) score based on common characteristics of the inflammatory EoE profile. A p(EoE) ≥ 25 successfully identified EoE with high accuracy (sensitivity: 90.9%, specificity: 93.2%, area under the curve: 0.985) and improved diagnosis of equivocal cases by 84.6%. The p(EoE) changed in response to therapy. A secondary analysis loop in EoE patients defined an IGHE score of ≥37.5 for a patient subpopulation with increased esophageal allergic inflammation.

Conclusions: The development of intelligent data analysis from a machine learning perspective provides exciting opportunities to improve diagnostic precision and improve patient care in EoE. The p(EoE) and the IGHE score are steps toward the development of decision trees to define EoE subpopulations and, consequently, will facilitate individualized therapy.
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http://dx.doi.org/10.1016/j.jaci.2017.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425755PMC
April 2018

Acute Respiratory Distress in a Child with H3N2 Infection.

Klin Padiatr 2018 01 11;230(1):50-52. Epub 2017 Sep 11.

Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Vienna, Austria.

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http://dx.doi.org/10.1055/s-0043-117961DOI Listing
January 2018

Bilateral Infiltrative Dacryoadenitis and Granulomatous Pneumonia in an 11-Year-Old Boy: A Case Report.

Klin Padiatr 2017 03 25;229(2):96-99. Epub 2017 Apr 25.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1055/s-0043-100381DOI Listing
March 2017

Early detection of lung function decrements in children and adolescents with cystic fibrosis using new reference values.

Wien Klin Wochenschr 2017 Aug 9;129(15-16):533-539. Epub 2017 Mar 9.

Department of Pediatrics and Adolescent Medicine, Wilhelminenspital Vienna, Montleartstrasse 37, 1160, Vienna, Austria.

Interpretation of lung function values in children with cystic fibrosis (CF) depends on the applied reference values. We hypothesize that differences between the new global lung function initiative (GLI) values and the formerly used Zapletal et al. values produce significantly different clinical results. We analyzed 3719 lung function measurements of 108 children and adolescents (n = 54 male; aged 6-18 years) with CF treated between September 1991 and July 2009. Data were analyzed in milliliters (ml) and % predicted (pred.) and interpreted using Zapletal and GLI reference values. Applying GLI compared to Zapletal resulted in significantly lower mean forced expiratory volume in 1s (FEV1)% pred.

Values: Zapletal 86.6% (SD 20.6), GLI 79.9% (SD 20.3) and 32% (n = 497/1543) were misclassified as normal when using Zapletal. Despite showing no overall differences in FEV1 and forced vital capacity (FVC) between concomitant Pseudomonas detection (PA+) in n = 938 and Pseudomonas negative (PA-) (n = 2781) using either reference PA+ resulted in lower FEV1 and FVC values with increasing age; however, measurement of small airway obstruction with forced expiratory flow at 75% of FVC (FEF75) values - available for Zapletal -showed significant differences. Reassurance regarding lung function when using old reference values may occur with potential clinical significance. Discrepancies in lung function interpretation underline the importance of using uniform and best available reference values.
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http://dx.doi.org/10.1007/s00508-017-1184-0DOI Listing
August 2017

A distinct microbiota composition is associated with protection from food allergy in an oral mouse immunization model.

Clin Immunol 2016 Dec 24;173:10-18. Epub 2016 Oct 24.

Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

In our mouse model, gastric acid-suppression is associated with antigen-specific IgE and anaphylaxis development. We repeatedly observed non-responder animals protected from food allergy. Here, we aimed to analyse reasons for this protection. Ten out of 64 mice, subjected to oral ovalbumin (OVA) immunizations under gastric acid-suppression, were non-responders without OVA-specific IgE or IgG1 elevation, indicating protection from allergy. In these non-responders, allergen challenges confirmed reduced antigen uptake and lack of anaphylactic symptoms, while in allergic mice high levels of mouse mast-cell protease-1 and a body temperature reduction, indicative for anaphylaxis, were determined. Upon OVA stimulation, significantly lower IL-4, IL-5, IL-10 and IL-13 levels were detected in non-responders, while IL-22 was significantly higher. Comparison of fecal microbiota revealed differences of bacterial communities on single bacterial Operational-Taxonomic-Unit level between the groups, indicating protection from food allergy being associated with a distinct microbiota composition in a non-responding phenotype in this mouse model.
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http://dx.doi.org/10.1016/j.clim.2016.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464391PMC
December 2016

Linear epitope mapping of peanut allergens demonstrates individualized and persistent antibody-binding patterns.

J Allergy Clin Immunol 2016 12 15;138(6):1728-1730. Epub 2016 Jul 15.

Department of Micro- and Nanotechnology, Technical University of Denmark, Kgs Lyngby, Denmark.

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http://dx.doi.org/10.1016/j.jaci.2016.06.019DOI Listing
December 2016