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1. A degranulation assay using Vγ9Vδ2 T cells for the rapid diagnosis of familial hemophagocytic syndromes

Author

Olivia Jorisch-Mühlebach, Dina Pitts, Raphaela Tinner, Hong Ying Teh, Conrad Roelli, Seraina Prader, Stefano Vavassori, and Jana Pachlopnik Schmid

Subjects
NK cell, K562, Vγ9Vδ2 T cell, gd T cell, HMBPP, degranulation assay, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune disorder characterized by uncontrolled lymphocyte and macrophage activation and a subsequent cytokine storm. The timely initiation of immunosuppressive treatment is crucial for survival.MethodsHere, we harnessed Vγ9Vδ2 T cell degranulation to develop a novel functional assay for the diagnosis of HLH. We compared the novel assay with the conventional natural killer (NK) cell stimulation method in terms of efficiency, specificity, and reliability. Our analysis involved 213 samples from 182 individuals, including 23 samples from 12 patients with degranulation deficiency (10 individuals with UNC13D deficiency, 1 with STXBP2 deficiency, and 1 with RAB27A deficiency).ResultsWhile both tests exhibited 100% sensitivity, the Vγ9Vδ2 T cell degranulation assay showed a superior specificity of 86.2% (n=70) compared to the NK cell degranulation assay, which achieved 78.9% specificity (n=213). The Vγ9Vδ2 T cell degranulation assay offered simpler technical requirements and reduced labor intensity, leading to decreased susceptibility to errors with faster processing times.DiscussionThis efficiency stemmed from the sole requirement of dissolving (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) powder, contrasting with the intricate maintenance of K562 cells necessary for the NK cell degranulation assay. With its diminished susceptibility to errors, we anticipate that the assay will require fewer repetitions of analysis, rendering it particularly well-suited for testing infants.ConclusionThe Vγ9Vδ2 T cell degranulation assay is a user-friendly, efficient diagnostic tool for HLH. It offers greater specificity, reliability, and practicality than established methods. We believe that our present findings will facilitate the prompt, accurate diagnosis of HLH and thus enable rapid treatment and better patient outcomes.

Published
2024
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2. Cardiac assessment and inflammatory markers in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) treated with methylprednisolone versus intravenous immunoglobulins: 6-month follow-up outcomes of the randomised controlled Swissped RECOVERY trialResearch in context

Author

Maya C. Andre, Carlos Sanchez, Sabrina Bressieux-Degueldre, Marie-Helene Perez, Daniela Wütz, Geraldine Blanchard-Rohner, Serge Grazioli, Nina Schöbi, Johannes Trück, Tatjana Welzel, Andrew Atkinson, Luregn J. Schlapbach, Julia Bielicki, Henrik Koehler, Spyridoula Gysi, Indra Janz, Andreas Bieri, Birgit Donner, Jürg Hammer, Ulrich Heininger, Clemens von Kalckreuth, Malte Kohns, Nicole Mettauer, Alexandra Meyer, Diana Reppucci, Chloé Schlaeppi, Daniel Trachsel, Nina Vaezipour, Andreas Woerner, Andreas Zutter, Federica Vanoni, Lisa Kottanattu, Calogero Mazzara, Alessia Severi Conti, Christoph Aebi, Philipp Agyeman, Andrea Duppenthaler, Martin Glöckler, Sabine Pallivathukal, Thomas Riedel, Petra Zimmermann, Hong-Phuc Cudré-Cung, Mladen Pavlovic, Alice Bordessoule, Anne-Laure Martin, Angelo Polito, Noemie Wagner, Marie Rohr, Arnaud L'Huillier, Vivianne Amiet, Thomas Ferry, David Longchamp, Julia Natterer, Rebecca Oppenheim, Michael Hofer, Michael Buettcher, Katharina Wechselberger, Alex Donas, Sara Germann, Michaela Lütolf Erni, Daniela Kaiser, Katharina Schwendener Scholl, Hans Peter Kuen, Katja Hrup, Janine Stritt, Douggl G.N. Bailey, Tanja Wachinger, Ingrid Beck, André Birkenmaier, Bjarte Rogdo, Philip Lorenz, Ivo Iglowstein, Konstanze Zöhrer, Martin Flade, Seraina Prader, Jana Pachlopnik Schmid, Michelle Seiler, Patrick Meyer Sauteur, Barbara Brotschi, Kathrin Weber, Elizabeth Whittaker, and Saul N. Faust

Subjects
Children, Immunoglobulins, PIMS-TS, Methylprednisolone, RCT, Coronary artery aneurysm, Medicine (General), R5-920
Abstract

Summary: Background: Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome–Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. Methods: This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). Findings: Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2–12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI) −0.05 to 1.0; p = 0.39). Interpretation: Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. Funding: NOMIS, Vontobel, and Gaydoul Foundation.

Published
2024
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3. Case report: ETS1 gene deletion associated with a low number of recent thymic emigrants in three patients with Jacobsen syndrome

Author

Tina Trachsel, Seraina Prader, Katharina Steindl, and Jana Pachlopnik Schmid

Subjects
Jacobsen syndrome, genetic disorder, ETS1, immunodeficiency, recent thymic emigrants, Immunologic diseases. Allergy, RC581-607
Abstract

Jacobsen syndrome is a rare genetic disorder associated with a terminal deletion in chromosome 11. The clinical presentation is variable. Although immunodeficiency has been described in patients with Jacobsen syndrome, a clear genotype-phenotype correlation has not yet been established. Here, we report on the immunologic phenotypes of four patients with Jacobsen syndrome. All four patients showed one or more atypical immunologic features. One patient suffered from recurrent viral infections, two patients had experienced a severe bacterial infection and one had received antibiotic prophylaxis since early childhood. One patient had experienced severe, transient immune dysregulation. Hypogammaglobulinemia and low B cell counts were found in two patients, while the number of recent thymic emigrants (CD31+CD45RA+ CD4 cells) was abnormally low in three. When considering the six immune-related genes located within the affected part of chromosome 11 (ETS1, TIRAP, FLI1, NFRKB, THYN1, and SNX19), only the ETS1 gene was found be deleted in the three patients with low numbers of recent thymic emigrants and non-switched memory B cells. Our findings support the hypothesis whereby Jacobsen syndrome is associated with a combined immunodeficiency with variable presentation. Further investigations of potential genotype-phenotype correlations are warranted and might help to personalize patient management in individuals lacking immune-related genes. In addition, we recommend immunologic follow-up for all patients with Jacobsen syndrome, as immune abnormalities may develop over time.

Published
2022
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4. X-Linked Lymphoproliferative Disease Mimicking Multisystem Inflammatory Syndrome in Children—A Case Report

Author

Seraina Prader, Nicole Ritz, Frédéric Baleydier, Maya C. Andre, Noémie Stähli, Kevin Schmid, Hanna Schmid, Andreas Woerner, Tamara Diesch, Patrick M. Meyer Sauteur, Johannes Trück, Fabienne Gebistorf, Lennart Opitz, Michael P. Killian, Tommaso Marchetti, Stefano Vavassori, Géraldine Blanchard-Rohner, Valerie Mc Lin, Serge Grazioli, and Jana Pachlopnik Schmid

Subjects
case report, fatal, pediatric, XLP1, HLH, SARS-CoV-2, Pediatrics, RJ1-570
Abstract

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.

Published
2021
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5. Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC assay – management recommendations

Author

Johannes Trück, Seraina Prader, Giancarlo Natalucci, Cornelia Hagmann, Barbara Brotschi, Janet Kelly, Dirk Bassler, Katharina Steindl, Anita Rauch, Matthias Baumgartner, Ralph Fingerhut, Mathias Hauri-Hohl, Tayfun Güngör, Jana Pachlopnik Schmid, Christoph Berger, and Janine Reichenbach

Subjects
newborn screening, primary immunodeficiency, inborn errors of immunity, T cells, B cells, TREC, Medicine
Abstract

The recent introduction of newborn screening for severe primary T and B cell deficiencies in Switzerland allows rapid identification of patients with severe combined immunodeficiency (SCID). Outcomes for SCID are greatly improved by early diagnosis and treatment with allogeneic haematopoietic stem cell transplantation or, in selected cases, gene therapy. National centralised newborn screening is performed in Switzerland since January 2019 using a combined T cell receptor excision circles (TREC) / κ-deleting recombination excision circles (KREC) assay, also revealing infants with non-SCID severe T and B cell disorders, who are often diagnosed with a substantial delay. Here, we outline the screening procedure currently performed in Switzerland and give recommendations for diagnostic evaluations and precautionary measures against infection in children with abnormal screening test results.

Published
2020
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6. Ikaros family zinc finger 1 regulates dendritic cell development and function in humans

Author

Urszula Cytlak, Anastasia Resteu, Delfien Bogaert, Hye Sun Kuehn, Thomas Altmann, Andrew Gennery, Graham Jackson, Attila Kumanovics, Karl V. Voelkerding, Seraina Prader, Melissa Dullaers, Janine Reichenbach, Harry Hill, Filomeen Haerynck, Sergio D. Rosenzweig, Matthew Collin, and Venetia Bigley

Subjects
Science
Abstract

IKZF1 is a transcription factor known to regulate mammalian B-cell development. Here the authors show that IKZF1 is required for human pDC development and regulation of DC cytokine production in patients with IKZF1 haploinsufficiency, findings which are recapitulated in lenalidomide-induced IKZF1 deficiency.

Published
2018
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7. Persistent mammalian orthoreovirus, coxsackievirus and adenovirus co-infection in a child with a primary immunodeficiency detected by metagenomic sequencing: a case report

Author

Dagmara W. Lewandowska, Riccarda Capaul, Seraina Prader, Osvaldo Zagordi, Fabienne-Desirée Geissberger, Martin Kügler, Marcus Knorr, Christoph Berger, Tayfun Güngör, Janine Reichenbach, Cyril Shah, Jürg Böni, Andrea Zbinden, Alexandra Trkola, Jana Pachlopnik Schmid, and Michael Huber

Subjects
Orthoreovirus, Coxsackievirus, Adenovirus, Primary immunodeficiency, Metagenomic sequencing, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case. Case presentation The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted. Conclusion This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation.

Published
2018
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8. Lymphadenopathy driven by TCR-Vγ8Vδ1 T-cell expansion in FAS-related autoimmune lymphoproliferative syndrome

Author

Stefano Vavassori, Jacob D. Galson, Johannes Trück, Anke van den Berg, Rienk Y.J. Tamminga, Aude Magerus-Chatinet, Olivier Pellé, Ulrike Camenisch Gross, Ewerton Marques Maggio, Seraina Prader, Lennart Opitz, Ursina Nüesch, Andrea Mauracher, Benjamin Volkmer, Oliver Speer, Luzia Suda, Benno Röthlisberger, Dieter Robert Zimmermann, Rouven Müller, Arjan Diepstra, Lydia Visser, Eugenia Haralambieva, Bénédicte Neven, Frédéric Rieux-Laucat, and Jana Pachlopnik Schmid

Subjects
Specialties of internal medicine, RC581-951
Published
2017
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9. Life-Threatening Primary Varicella Zoster Virus Infection With Hemophagocytic Lymphohistiocytosis-Like Disease in GATA2 Haploinsufficiency Accompanied by Expansion of Double Negative T-Lymphocytes

Author

Seraina Prader, Matthias Felber, Benjamin Volkmer, Johannes Trück, Agnes Schwieger-Briel, Martin Theiler, Lisa Weibel, Sophie Hambleton, Katja Seipel, Stefano Vavassori, and Jana Pachlopnik Schmid

Subjects
varicella-zoster virus, hemophagocytic lymphohistiocytosis, GATA2 deficiency, primary immumunodeficiencies, NK cell abnormalities, TCRγδ T cells, Immunologic diseases. Allergy, RC581-607
Abstract

Two unrelated patients with GATA2-haploinsufficiency developed a hemophagocytic lymphohistiocytosis (HLH)-like disease during a varicella zoster virus (VZV) infection. High copy numbers of VZV were detected in the blood, and the patients were successfully treated with acyclovir and intravenous immunoglobulins. After treatment with corticosteroids for the HLH, both patients made a full recovery. Although the mechanisms leading to this disease constellation have yet to be characterized, we hypothesize that impairment of the immunoregulatory role of NK cells in GATA2-haploinsufficiency may have accentuated the patients' susceptibility to HLH. Expansion of a double negative T-lymphocytic population identified with CyTOF could be a further factor contributing to HLH in these patients. This is the first report of VZV-triggered HLH-like disease in a primary immunodeficiency and the third report of HLH in GATA2-haploinsufficiency. Since HLH was part of the presentation in one of our patients, GATA2-haploinsufficiency represents a potential differential diagnosis in patients presenting with the clinical features of HLH—especially in cases of persisting cytopenia after recovery from HLH.

Published
2018
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10. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Author

Maria Elena Maccari, Hassan Abolhassani, Asghar Aghamohammadi, Alessandro Aiuti, Olga Aleinikova, Catherine Bangs, Safa Baris, Federica Barzaghi, Helen Baxendale, Matthew Buckland, Siobhan O. Burns, Caterina Cancrini, Andrew Cant, Pascal Cathébras, Marina Cavazzana, Anita Chandra, Francesca Conti, Tanya Coulter, Lisa A. Devlin, J. David M. Edgar, Saul Faust, Alain Fischer, Marina Garcia Prat, Lennart Hammarström, Maximilian Heeg, Stephen Jolles, Elif Karakoc-Aydiner, Gerhard Kindle, Ayca Kiykim, Dinakantha Kumararatne, Bodo Grimbacher, Hilary Longhurst, Nizar Mahlaoui, Tomas Milota, Fernando Moreira, Despina Moshous, Anna Mukhina, Olaf Neth, Benedicte Neven, Alexandra Nieters, Peter Olbrich, Ahmet Ozen, Jana Pachlopnik Schmid, Capucine Picard, Seraina Prader, William Rae, Janine Reichenbach, Stephan Rusch, Sinisa Savic, Alessia Scarselli, Raphael Scheible, Anna Sediva, Svetlana O. Sharapova, Anna Shcherbina, Mary Slatter, Pere Soler-Palacin, Aurelie Stanislas, Felipe Suarez, Francesca Tucci, Annette Uhlmann, Joris van Montfrans, Klaus Warnatz, Anthony Peter Williams, Phil Wood, Sven Kracker, Alison Mary Condliffe, and Stephan Ehl

Subjects
activated phosphoinositide 3-kinase δ syndrome, PIK3CD, PIK3R1, registry, natural history, rapamycin, Immunologic diseases. Allergy, RC581-607
Abstract

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Published
2018
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11. Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial

Author

Tatjana Welzel, Andrew Atkinson, Nina Schöbi, Maya C Andre, Douggl G N Bailey, Geraldine Blanchard-Rohner, Michael Buettcher, Serge Grazioli, Henrik Koehler, Marie-Helene Perez, Johannes Trück, Federica Vanoni, Petra Zimmermann, Carlos Sanchez, Julia A Bielicki, Luregn J Schlapbach, Andreas Bieri, Spyridoula Gysi, Indra Janz, Birgit Donner, Jürg Hammer, Ulrich Heininger, Malte Kohns Vasconcelos, Nicole Mettauer, Alexandra Meyer, Diana Reppucci, Chloé Schlaeppi, Daniel Trachsel, Nina Vaezipour, Clemens von Kalckreuth, Andreas Woerner, Andreas Zutter, Lisa Kottanattu, Calogero Mazzara, Alessia Severi Conti, Christoph Aebi, Philipp K A Agyeman, Andrea Duppenthaler, Martin Glöckler, Sabine Pallivathukal, Thomas Riedel, Hong-Phuc Cudré-Cung, Mladen Pavlovic, Alice Bordessoule, Arnaud G L'Huillier, Anne-Laure Martin, Angelo Polito, Marie Rohr, Maria Isabel Rodriguez, Noemie Wagner, Vivianne Chanez, Sabrina Bressieux-Degueldre, Thomas Ferry, Michael Hofer, David Longchamp, Julia Natterer, Rebecca Oppenheim, Alex Donas, Sara Germann, Katja Hrup, Daniela Kaiser, Hans Peter Kuen, Michaela Lütolf Erni, Katharina Schwendener Scholl, Janine Stritt, Katharina Wechselberger, Ingrid Beck, André Birkenmaier, Martin Flade, Bjarte Rogdo, Ivo Iglowstein, Philip Lorenz, Tanja Wachinger, Konstanze Zöhrer, Barbara Brotschi, Patrick M Meyer Sauteur, Jana Pachlopnik Schmid, Seraina Prader, Michelle Seiler, Kathrin Weber, Daniela Wütz, Elizabeth Whittaker, and Saul N Faust

Subjects
Pediatrics, Perinatology and Child Health, Developmental and Educational Psychology
Published
2023

12. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Author

Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.

Subjects
0301 basic medicine, Male, Pediatrics, syndromic, Sex Factor, Disease, registry, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Primary Immunodeficiency Disease, inborn error of immunity, Immunology and Allergy, warning signs, Age Factor, Registries, Family history, presenting symptom, Child, Primary immunodeficiency, Granuloma, autoimmune, immune dysregulation, inflammatory, Adult, Autoimmune Diseases, Female, Humans, Infections, Lymphoproliferative Disorders, Middle Aged, Primary Immunodeficiency Diseases, Sex Factors, Age Factors, 10177 Dermatology Clinic, Infections/epidemiology, 3. Good health, Settore MED/02, Warning signs, Lymphoproliferative Disorder, 2723 Immunology and Allergy, Infection, Human, medicine.medical_specialty, Immunology, 610 Medicine & health, Malignancy, primary immunodeficiency, Autoimmune Disease, 03 medical and health sciences, Immunity, Autoimmune Diseases/epidemiology, medicine, 2403 Immunology, business.industry, warning sign, Common variable immunodeficiency, Granuloma/epidemiology, Immune dysregulation, medicine.disease, Primary Immunodeficiency Diseases/epidemiology, 030104 developmental biology, Lymphoproliferative Disorders/epidemiology, Cohort Studie, business, 030215 immunology
Abstract

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Published
2021

13. Wenn hinter einer Immunthrombozytopenie, einer vermeintlichen Sarkoidose, rezidivierendem Fieber oder einer Lymphadenopathie ein angeborener Immundefekt steckt

Author

Seraina Prader, Géraldine Blanchard Rohner, Daniel Drozdov, Tayfun Güngör, and Jana Pachlopnik Schmid

Abstract

Angeborene Immundefekte sind einerseits selten, anderseits zeigen sie eine sehr variable initiale Symptomatik und stellen deshalb eine diagnostische Herausforderung dar. Prinzipiell können bei angeborenen Immundefekten drei Hauptprobleme auftreten: Beeinträchtigung der Infektabwehr, erhöhtes Malignomrisiko und Immundysregulation (z.B. Autoimmunerkrankungen und autoinflammatorische Syndrome).

Published
2022

14. Lorsque derrière une thrombocytopénie, une sarcoïdose présumée, une fièvre récidivante ou une lymphadénopathie se cache un déficit immunitaire congénital

Author

Seraina Prader, Géraldine Blanchard Rohner, Daniel Drozdov, Tayfun Güngör, and Jana Pachlopnik Schmid

Subjects
General Earth and Planetary Sciences, General Environmental Science
Abstract

Les déficits immunitaires congénitaux sont d’une part rares, d’autre part la symptomatologie initiale est très variable, leur diagnostic représente donc un défi. En principe un déficit immunitaire congénital peut se manifester par trois problèmes principaux: une perturbation de la défense immunitaire, un risque élevé de tumeurs malignes et une dysrégulation immunitaire (p.ex. maladies auto-immunes et syndromes auto-inflammatoires).

Published
2022

15. Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Author

Pere Soler-Palacín, Larysa Kostyuchenko, Peter Bader, Catharina Schuetz, Shereen M. Reda, Ruth Pia Duecker, Bodo Grimbacher, Sharhzad Bakhtiar, Nizar Mahlaoui, Ralf Schubert, Dagmar Graf, Juan Luis Santos Pérez, E.V. Deripapa, Necil Kutukculer, Claudio Pignata, Seraina Prader, Isabelle Meyts, Maria Kanariou, Markus G. Seidel, Sandra Woelke, Peter Ciznar, Aileen Buecker, Stephan Ehl, Koen J. van Aerde, E. Graham Davies, Carlos Rodríguez-Gallego, Sabine Huenecke, Fabian Hauck, Gerhard Kindle, Hermann Kreyenberg, John David M Edgar, Tim Niehues, Hans-Juergen Laws, Helena Donath, Kai Lehmberg, Barbara Pietrucha, Mary Slatter, Renate Krueger, Elizabeth M. McDermott, Nermeen Galal, Michiel van der Flier, Claire Bethune, Horst von Bernuth, Peter D. Arkwright, Laura Hora Marques, Ismail Reisli, Stefan Zielen, Ulrich Baumann, Luis Ignacio Gonzalez Granado, Sara Sebnem Kilic, Sabine M El-Helou, Alessandro Plebani, Svetlana O. Sharapova, Institut Català de la Salut, [Zielen S, Duecker RP, Woelke S, Donath H, Buecker A] Division of Allergology, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, Frankfurt, Germany. [Bakhtiar S] Division for Stem Cell Transplantation, Immunology and Intensive Care Unit, Department for Children and Adolescents, Goethe University, Frankfurt, Germany. [Soler-Palacín P] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Male, Lymphocyte, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Atàxia de Friedreich - Prognosi, Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebellar Diseases::Cerebellar Ataxia::Spinocerebellar Ataxias::Ataxia Telangiectasia [DISEASES], Ataxia-telangiectasia, Liver disease, T-Lymphocyte Subsets, Immunology and Allergy, Repertoire, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], IgG Deficiency, Child, Immunodeficiency, B-Lymphocytes, Middle Aged, Immunoglobulina A, medicine.anatomical_structure, Phenotype, Child, Preschool, T-Cell Subsets, Cohort, Deficiency, Original Article, Female, IgA deficiency, Receptor, Adult, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebelosas::ataxia cerebelosa::ataxias espinocerebelosas::ataxia telangiectasia [ENFERMEDADES], Adolescent, Immunology, Generation, Immunoglobulins, Infections, Ataxia Telangiectasia, Young Adult, Immunity, Other subheadings::Other subheadings::/immunology [Other subheadings], Lymphopenia, medicine, Humans, Lymphocyte Count, ddc:610, Mortality, Surrogate endpoint, business.industry, Infant, medicine.disease, Immunoglobulin A, Oxidative Stress, Respiratory failure, Immunoglobulin M, Immunoglobulin G, Atm, business
Abstract

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naive CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ss repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978), Projekt DEAL; German Federal Ministry of Education and Research (BMBF) [01GM0896, 01GM1111B, 01GM1517C, 01EO1303, 01ZZ1801B]; EU [HEALTHF2-2008-201549]; Novartis; GlaxoSmithKline; LFB; UCB UK; Plasma Protein Therapeutics Association (PPTA),; Care-for-Rare Foundation; PROimmune e.V; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [39087428]; UK National Institute of Health Research; Great Ormond Street Hospital Biomedical Research Centre, Open Access funding enabled and organized by Projekt DEAL. The ESID Registry was supported by the German Federal Ministry of Education and Research (BMBF 01GM0896, 01GM1111B, 01GM1517C, 01EO1303 and 01ZZ1801B) EU grant no. HEALTHF2-2008-201549 (EURO-PADnet), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, and UCB UK, the Plasma Protein Therapeutics Association (PPTA), the Care-for-Rare Foundation, PROimmune e.V, LFB, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence StrategyEXC 2155 RESIST-Project ID 39087428. EGD is supported by the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre.

Published
2021

16. Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency

Author

Christian Staufner, Dominic Lenz, Michael Huber, Ulrich Baumann, Lennart Opitz, Neveen A. Soliman, Raif S. Geha, Hundeep Kaur, Christian Klemann, Verena Klämbt, Sebastian Hiller, Matias Wagner, Jana Pachlopnik Schmid, Janet Chou, Andreas Klein-Franke, Danil Koovely, Chris Fraser, Karsten Häffner, Tommaso Marchetti, Michael T. Gabbett, Heike Olbrich, Christina Kessler, Matthias Griese, Tayfun Güngör, Michael F. Buckley, Veronika Haunerdinger, Craig D. Platt, George Elakis, Sabrina Weeks, Martin Schwemmle, Stefano Vavassori, Friedhelm Hildebrandt, Seraina Prader, Guido F. Laube, Megan Elkins, Laura Faletti, Abduarahman Almutairi, Patrick Frosk, Charlotte Gimpel, Luise A. Schuch, Maria Elena Maccari, Xianfei Gao, Pascal Joset, Stephan Ehl, Maria Forstner, Raimund Kottke, Tamar S. Rubin, Tony Roscioli, Simone Reu-Hofer, Raquel Planas, Thomas Kaiser, Achim Weber, Steffen Hartleif, Sandra von Hardenberg, Ying Zhu, Ekkehard Sturm, Barbara Brotschi, Julia Hoefele, Solange Moll, and Heymut Omran

Subjects
Male, 0301 basic medicine, Primary Immunodeficiency Diseases, Immunology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigens, Neoplasm, Interferon, Exome Sequencing, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, 610 Medicine & health, Immunodeficiency, Inflammation, business.industry, RIG-I, Interferon-stimulated gene, Infant, MDA5, medicine.disease, 030104 developmental biology, Virus Diseases, Child, Preschool, 030220 oncology & carcinogenesis, TLR3, Female, business, medicine.drug
Abstract

BACKGROUND Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. OBJECTIVE We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. METHODS Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. CONCLUSION ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Published
2021

17. Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients

Author

Olga Vougiouka, Seraina Prader, Francesca Minoia, Erbil Unsal, Susan Shenoi, Gianluigi Ardissino, Mikhail Kostik, Valentina Muratore, Angelo Ravelli, Toshiyuki Kitoh, Sebastiaan J. Vastert, Randy Q. Cron, Despoina Maritsi, Ozgur Kasapcopur, Ralf Trauzeddel, Jessica Tibaldi, Marija Jelušić, Concetta Micalizzi, Elif Çomak, Elena Tsitsami, Alessia Arduini, Guido F. Laube, Antonio Mastrangelo, Claudia Bracaglia, Jana Pachlopnik Schmid, Giovanni Filocamo, Romina Gallizzi, University of Zurich, and Minoia, Francesca

Subjects
musculoskeletal diseases, medicine.medical_specialty, Thrombotic microangiopathy, Adolescent, Thrombotic thrombocytopenic purpura, 610 Medicine & health, typical hemolytic uremic syndrome, hemophagocytic lymphohistiocytosis, hemophagocytic syndromes, macrophage activation syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, Antibodies, Monoclonal, Humanized, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Mixed connective tissue disease, 030225 pediatrics, Internal medicine, hemic and lymphatic diseases, Atypical hemolytic uremic syndrome, medicine, Humans, 2735 Pediatrics, Perinatology and Child Health, 030212 general & internal medicine, Child, Glucocorticoids, Juvenile dermatomyositis, Retrospective Studies, atypical hemolytic uremic syndrome, Plasma Exchange, business.industry, Thrombotic Microangiopathies, Macrophage Activation Syndrome, Undifferentiated connective tissue disease, Eculizumab, medicine.disease, Arthritis, Juvenile, 10036 Medical Clinic, Macrophage activation syndrome, Antirheumatic Agents, Child, Preschool, Pediatrics, Perinatology and Child Health, business, Biomarkers, medicine.drug
Abstract

Objective To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). Study design International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. Results Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. Conclusions The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

Published
2020

18. Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC assay - management recommendations

Author

Seraina Prader, Barbara Brotschi, Johannes Trück, Janine Reichenbach, Dirk Bassler, Mathias Hauri-Hohl, Cornelia Hagmann, Katharina Steindl, Ralph Fingerhut, Janet Kelly, Tayfun Güngör, Matthias R. Baumgartner, Christoph Berger, Giancarlo Natalucci, Jana Pachlopnik Schmid, Anita Rauch, University of Zurich, and Trück, Johannes

Subjects
Pediatrics, medicine.medical_specialty, inborn errors of immunity, 10039 Institute of Medical Genetics, Genetic enhancement, T-Lymphocytes, T cells, 610 Medicine & health, 2700 General Medicine, primary immunodeficiency, Neonatal Screening, medicine, Humans, TREC, B cell, Severe combined immunodeficiency, Newborn screening, B cells, B-Lymphocytes, business.industry, T-cell receptor excision circles, newborn screening, Infant, Newborn, General Medicine, medicine.disease, 10027 Clinic for Neonatology, Transplantation, agammaglobulinaemia, Haematopoiesis, medicine.anatomical_structure, 10036 Medical Clinic, Primary immunodeficiency, Severe Combined Immunodeficiency, KREC, business, Switzerland
Abstract

The recent introduction of newborn screening for severe primary T and B cell deficiencies in Switzerland allows rapid identification of patients with severe combined immunodeficiency (SCID). Outcomes for SCID are greatly improved by early diagnosis and treatment with allogeneic haematopoietic stem cell transplantation or, in selected cases, gene therapy. National centralised newborn screening is performed in Switzerland since January 2019 using a combined T cell receptor excision circles (TREC) / κ-deleting recombination excision circles (KREC) assay, also revealing infants with non-SCID severe T and B cell disorders, who are often diagnosed with a substantial delay. Here, we outline the screening procedure currently performed in Switzerland and give recommendations for diagnostic evaluations and precautionary measures against infection in children with abnormal screening test results.

Published
2020

19. Persistent mammalian orthoreovirus, coxsackievirus and adenovirus co-infection in a child with a primary immunodeficiency detected by metagenomic sequencing: a case report

Author

Jürg Böni, Cyril Shah, Christoph Berger, Seraina Prader, Riccarda Capaul, Dagmara W. Lewandowska, Andrea Zbinden, Osvaldo Zagordi, Jana Pachlopnik Schmid, Alexandra Trkola, Michael Huber, Tayfun Güngör, Martin Kügler, Fabienne-Desirée Geissberger, Janine Reichenbach, Marcus Knorr, University of Zurich, and Huber, Michael

Subjects
Diarrhea, 0301 basic medicine, 10028 Institute of Medical Virology, medicine.medical_specialty, Adenoviridae Infections, Orthoreovirus, Mammalian, 030106 microbiology, Coxsackievirus Infections, Case Report, 610 Medicine & health, Biology, Coxsackievirus, medicine.disease_cause, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Medical microbiology, Enterovirus Infections, medicine, Humans, Adenovirus, lcsh:RC109-216, Typing, Child, Orthoreovirus, Enterovirus, Primary immunodeficiency, Coinfection, Transmission (medicine), Immunologic Deficiency Syndromes, 2725 Infectious Diseases, medicine.disease, biology.organism_classification, Virology, Reoviridae Infections, Chronic infection, 030104 developmental biology, Infectious Diseases, 10036 Medical Clinic, 570 Life sciences, biology, Female, Metagenomics, Metagenomic sequencing
Abstract

Background We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case. Case presentation The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted. Conclusion This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation. Electronic supplementary material The online version of this article (10.1186/s12879-018-2946-7) contains supplementary material, which is available to authorized users.

Published
2018

20. Erythropoiesis defect observed in STAT3 GOF patients with severe anemia

Author

Raffaele Renella, Johannes Trück, Stephan Ehl, Sofia Tantou, Jana Pachlopnik Schmid, Adam Klocperk, Eugenia Haralambieva, Janine Woytschak, Seraina Prader, Maria Kanariou, Dieter R. Zimmermann, Kosmas Kotsonis, Audrey van Drogen, Lennart Opitz, Julia J.M. Eekels, Onur Boyman, Matthias Felber, Andrea A. Mauracher, Maximillian Heeg, Eva Adank, Silke Schroeder, Stefano Vavassori, Anna Sediva, Markus Schmugge, Alessandra Bosch, and Aikaterini Stergiou

Subjects
0301 basic medicine, STAT3 Transcription Factor, Lineage (genetic), Erythrocytes, Immunology, Inflammation, beta-Globins, medicine.disease_cause, Iron Chelating Agents, Severity of Illness Index, Autoimmunity, 03 medical and health sciences, STAT3 GOF, 0302 clinical medicine, Immunity, hemic and lymphatic diseases, Exome Sequencing, medicine, Receptors, Erythropoietin, STAT5 Transcription Factor, Immunology and Allergy, Humans, Erythropoiesis, STAT3, Child, Erythropoietin, Cells, Cultured, Germ-Line Mutation, Cell Proliferation, biology, Cell Differentiation, medicine.disease, Hedgehog signaling pathway, Asthma, 030104 developmental biology, Gene Expression Regulation, biology.protein, Anemia, Hemolytic, Autoimmune, medicine.symptom, 030215 immunology, Signal Transduction
Abstract

STAT3 mediates inflammation and modulates immunity. We found that in addition to its role in autoimmunity, over-activated STAT3 interferes in early erythro-myeloid precursor development and reduces commitment towards the erythroid lineage by interfering with the erythropoietin-STAT5 signalling pathway.

Published
2019

21. Beat Richner MD

Author

Seraina Prader

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Cardiology, medicine, MEDLINE, Beat (acoustics), Cardiology and Cardiovascular Medicine, business
Published
2019

22. Modern management of phagocyte defects

Author

Ulrich Siler, Seraina Prader, Lorenza Lisa Serena Lanini, Janine Reichenbach, University of Zurich, and Reichenbach, Janine

Subjects
0301 basic medicine, Neutropenia, Phagocyte, Neutrophils, Primary Immunodeficiency Diseases, Genetic enhancement, Immunology, 610 Medicine & health, Disease, Granulomatous Disease, Chronic, 03 medical and health sciences, 0302 clinical medicine, Chronic granulomatous disease, Immune system, Phagocytosis, Granulocyte Colony-Stimulating Factor, medicine, Animals, Congenital Bone Marrow Failure Syndromes, Humans, Immunology and Allergy, 2735 Pediatrics, Perinatology and Child Health, Congenital Neutropenia, Respiratory Burst, Myelopoiesis, 2403 Immunology, business.industry, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, High-Throughput Nucleotide Sequencing, Cell Differentiation, Antibiotic Prophylaxis, medicine.disease, Immunity, Innate, Respiratory burst, 030104 developmental biology, medicine.anatomical_structure, 10036 Medical Clinic, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, 2723 Immunology and Allergy, Warts, business
Abstract

Phagocytic neutrophil granulocytes are among the first immune cells active at sites of infection, forming an important first-line defense against invading microorganisms. Congenital immune defects concerning these phagocytes may be due to reduced neutrophil numbers or function. Management of affected patients depends on the type and severity of disease. Here, we provide an overview of causes and treatment of diseases associated with congenital neutropenia, as well as defects of the phagocytic respiratory burst.

Published
2016

23. Lymphadenopathy driven by TCR-Vγ8Vδ1 T-cell expansion in FAS-related autoimmune lymphoproliferative syndrome

Author

Lydia Visser, Eugenia Haralambieva, Jana Pachlopnik Schmid, Benno Röthlisberger, Seraina Prader, Benedicte Neven, Ursina Nüesch, Anke van den Berg, Ulrike Camenisch Gross, Ewerton Marques Maggio, Dieter R. Zimmermann, Benjamin Volkmer, Stefano Vavassori, Luzia Suda, Arjan Diepstra, Andrea A. Mauracher, Lennart Opitz, Frédéric Rieux-Laucat, Olivier Pellé, Rouven Müller, Oliver Speer, Johannes Trück, Aude Magerus-Chatinet, Rienk Y. J. Tamminga, Jacob D. Galson, Stem Cell Aging Leukemia and Lymphoma (SALL), Translational Immunology Groningen (TRIGR), University of Zurich, and Vavassori, Stefano

Subjects
0301 basic medicine, GENES, SCLEROSIS PATIENTS, T cell, CYTOMEGALOVIRUS, 2720 Hematology, 610 Medicine & health, ORGANIZATION, PERIPHERAL-BLOOD, FAMILIES, 03 medical and health sciences, REPERTOIRE, PYRIMETHAMINE, 10049 Institute of Pathology and Molecular Pathology, Journal Article, Medicine, In patient, business.industry, MUTATIONS, T-cell receptor, Hematology, medicine.disease, Peripheral blood, APOPTOSIS, 030104 developmental biology, medicine.anatomical_structure, Methylprednisolone, 10036 Medical Clinic, Apoptosis, Autoimmune lymphoproliferative syndrome, 10032 Clinic for Oncology and Hematology, Immunology, business, medicine.drug
Abstract

Key Points FAS-dependent apoptosis in Vδ1 T cells makes the latter possible culprits for the lymphadenopathy observed in patients with FAS mutations. Rapamycin and methylprednisolone resistance should prompt clinicians to look for Vδ1 T cell proliferation in ALPS-FAS patients.

Published
2017

24. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS

Author

Asbjørg Stray-Pedersen, Jeana S. Bush, William K. Dolen, Julie E. Niemela, Harry R. Hill, Monica G. Lawrence, Nancy H. Augustine, Charlotte Cunningham-Rundles, Sarah T. South, Katherine R. Calvo, Keith R. Pierce, Jordan K. Abbott, Aurélie Cobat, Erwin W. Gelfand, Betty B. Wray, Sundar Ganesan, Attila Kumánovics, Sergio D. Rosenzweig, Jordan S. Orange, Yuval Itan, Patrick Maffucci, Hanne Sørmo Sorte, Mary Ellen Conley, Karl V. Voelkerding, Janine Reichenbach, Hye Sun Kuehn, Thomas B. Martins, Thomas A. Fleisher, Jean-Laurent Casanova, Bertrand Boisson, Seraina Prader, University of Zurich, and Conley, Mary Ellen

Subjects
0301 basic medicine, Proband, Adult, Male, Heterozygote, Adolescent, 610 Medicine & health, 2700 General Medicine, medicine.disease_cause, Article, Hypogammaglobulinemia, 03 medical and health sciences, Ikaros Transcription Factor, Antigens, CD, Bone Marrow, medicine, Humans, Exome, Lymphocyte Count, Child, Gene, Genetics, Mutation, B-Lymphocytes, business.industry, Common variable immunodeficiency, Bone Marrow Examination, General Medicine, Sequence Analysis, DNA, medicine.disease, Pedigree, 030104 developmental biology, Common Variable Immunodeficiency, 10036 Medical Clinic, Child, Preschool, Immunoglobulin G, Female, business, Chromosomes, Human, Pair 7, Comparative genomic hybridization
Abstract

Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Published
2016
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