Publications by authors named "Tim Niehues"

105 Publications

Analysis of chromosomal aberrations and γH2A.X foci to identify radiation-sensitive ataxia-telangiectasia patients.

Mutat Res 2021 Jan-Feb;861-862:503301. Epub 2020 Dec 10.

Department of Effects and Risks of Ionising and Non-Ionising Radiation, Federal Office for Radiation Protection, Ingolstädter Landstraße 1, 85764, Oberschleißheim, Germany.

Ataxia-telangiectasia (AT) is a rare inherited recessive disorder which is caused by a mutated Ataxia-telangiectasia mutated (ATM) gene. Hallmarks include chromosomal instability, cancer predisposition and increased sensitivity to ionizing radiation. The ATM protein plays an important role in signaling of DNA double-strand breaks (DSB), thereby phosphorylating the histone H2A.X. Non-functional ATM protein leads to defects in DNA damage response, unresolved DSBs and genomic instability. The aim of this study was to evaluate chromosomal aberrations and γH2A.X foci as potential radiation sensitivity biomarkers in AT patients. For this purpose, lymphocytes of 8 AT patients and 10 healthy controls were irradiated and induced DNA damage and DNA repair capacity were detected by the accumulation of γH2A.X foci. The results were heterogeneous among AT patients. Evaluation revealed 2 AT patients with similar γH2A.X foci numbers as controls after 1 h while 3 patients showed a lower induction. In regard to DNA repair, 3 of 5 AT patients showed poor damage repair. Therefore, DNA damage induction and DNA repair as detected by H2A.X phosphorylation revealed individual differences, seems to depend on the underlying individual mutation and thus appears not well suited as a biomarker for radiation sensitivity. In addition, chromosomal aberrations were analyzed by mFISH. An increased frequency of spontaneous chromosomal breakage was characteristic for AT cells. After irradiation, significantly increased rates for non-exchange aberrations, translocations, complex aberrations and dicentric chromosomes were observed in AT patients compared to controls. The results of this study suggested, that complex aberrations and dicentric chromosomes might be a reliable biomarker for radiation sensitivity in AT patients, while non-exchange aberrations and translocations identified both, spontaneous and radiation-induced chromosomal instability.
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http://dx.doi.org/10.1016/j.mrgentox.2020.503301DOI Listing
December 2020

[Methodological Standard for the Development of Quality Indicators within Clinical Practice Guidelines - Results of a structured consensus process].

Z Evid Fortbild Qual Gesundhwes 2021 Feb 20;160:21-33. Epub 2021 Jan 20.

Zentrum für Evidenzbasierte Gesundheitsversorgung (ZEGV), Universitätsklinikum und Medizinische Fakultät Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Deutschland.

Background: Recommendations of evidence- and formally consensus-based clinical practice guidelines (CPGs) represent a valuable source of quality indicators (QIs). Nevertheless, a standardized methodological procedure for developing QIs in the context of CPGs does not yet exist in Germany for all CPGs. For this reason, a methodological standard for the guideline-based development of QIs (QI Standard) was developed based on a structured consensus process involving multiple key stakeholders.

Methods: The proposed content of the QI Standard was derived from evidence, drawing upon results of reviews and qualitative studies, and considered German manuals for guideline-based QI development of two guideline programs. A multi-perspective consensus panel, broadly representing key stakeholders from the German healthcare system with expertise in CPGs and/or quality management, was nominated to vote on recommendations for guideline-based development of QIs. The iterative, structured consensus process included a two-stage online survey based on the Delphi method ("preliminary voting") and a moderated final stakeholder conference where all those recommendations were definitely included in the QI Standard that received approval of more than 75 % (consensus criterion) of the consensus panel.

Results: Based on the agreed QI Standard, the QI development process starts with a criteria-based selection of "potential" QIs which - in case of adoption - are published in CPGs as "preliminary" QIs and can achieve the status "final" after successful testing. The QI Standard is composed of a total of 30 recommendations, which are allocated to six areas: A) preparatory work steps for the guideline-based recommendation of QIs, B) QI development group and cooperation with the CPG group, C) development of potential QIs, D) critical appraisal of potential QIs, E) formal adoption and publication as well as F) piloting/testing of preliminary QIs and conversion into final QIs.

Discussion: Before the QI Standard can be recommended for implementation in future CPGs, it should have been successfully tested in selected German CPG projects. In addition to methodological requirements for the QI development, it must be ensured that guideline groups have adequate resources for the implementation of the QI Standard.

Conclusion: By using the QI Standard, scientifically sound and healthcare-relevant QIs can be expected.
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http://dx.doi.org/10.1016/j.zefq.2020.11.008DOI Listing
February 2021

Retained primary teeth in STAT3 hyper-IgE syndrome: early intervention in childhood is essential.

Orphanet J Rare Dis 2020 09 10;15(1):244. Epub 2020 Sep 10.

Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and HelmholtzZentrum München, Munich/Augsburg, Germany.

Background: STAT3 hyper-IgE syndrome (STAT3-HIES) is a rare primary immunodeficiency that clinically overlaps with atopic dermatitis. In addition to eczema, elevated serum-IgE, and recurrent infections, STAT3-HIES patients suffer from characteristic facies, midline defects, and retained primary teeth. To optimize dental management we assessed the development of dentition and the long-term outcomes of dental treatment in 13 molecularly defined STAT3-HIES patients using questionnaires, radiographs, and dental investigations.

Results: Primary tooth eruption was unremarkable in all STAT3-HIES patients evaluated. Primary tooth exfoliation and permanent tooth eruption was delayed in 83% of patients due to unresorbed tooth roots. A complex orthodontic treatment was needed for one patient receiving delayed extraction of primary molars and canines. Permanent teeth erupted spontaneously in all patients receiving primary teeth extraction of retained primary teeth during average physiologic exfoliation time.

Conclusions: The association of STAT3-HIES with retained primary teeth is important knowledge for dentists and physicians as timely extraction of retained primary teeth prevents dental complications. To enable spontaneous eruption of permanent teeth in children with STAT3-HIES, we recommend extracting retained primary incisors when the patient is not older than 9 years of age and retained primary canines and molars when the patient is not older than 13 years of age, after having confirmed the presence of the permanent successor teeth by radiograph.
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http://dx.doi.org/10.1186/s13023-020-01516-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488068PMC
September 2020

Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline.

Eur J Immunol 2020 10 9;50(10):1432-1446. Epub 2020 Sep 9.

Department of Immunology, Labor Berlin Charité - Vivantes GmbH, Berlin, Germany.

This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4-, and LRBA-deficiency).
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http://dx.doi.org/10.1002/eji.202048713DOI Listing
October 2020

COVID-19 in a Child with Pre-Existing Immunodeficiency, Cardiomyopathy, and Chronic Pulmonary Disease.

Klin Padiatr 2020 09 6;232(5):275-278. Epub 2020 Aug 6.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Centre for Child and Adolescent Health, University Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Düsseldorf.

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http://dx.doi.org/10.1055/a-1210-2639DOI Listing
September 2020

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency.

Blood 2020 Dec;136(23):2638-2655

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
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http://dx.doi.org/10.1182/blood.2020006738DOI Listing
December 2020

Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie.

J Clin Immunol 2020 07 26;40(5):708-717. Epub 2020 May 26.

Department of Paediatrics, Helios Klinikum Krefeld, Krefeld, Germany.

Purpose: Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany.

Methods: The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID).

Results: Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening.

Conclusions: SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
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http://dx.doi.org/10.1007/s10875-020-00782-xDOI Listing
July 2020

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol 2020 Oct 9;146(4):901-911. Epub 2020 Apr 9.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS (Centre for Integrative Biological Signalling Studies), University of Freiburg, Freiburg, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany; Institute of Immunology and Transplantation, Royal Free Hospital and University College London, London, United Kingdom; DZIF (German Center for Infection Research) Satellite Center Freiburg, Freiburg, Germany; Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.

Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
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http://dx.doi.org/10.1016/j.jaci.2019.11.051DOI Listing
October 2020

[Coronavirus disease in children-initial data from Wuhan].

Monatsschr Kinderheilkd 2020 Mar 24:1-2. Epub 2020 Mar 24.

2Zentrum für Kinder- und Jugendmedizin, Helios Klinikum Krefeld, Lutherplatz 40, 47805 Krefeld, Deutschland.

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http://dx.doi.org/10.1007/s00112-020-00907-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095346PMC
March 2020

Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.

Eur J Immunol 2020 07 20;50(7):1078-1080. Epub 2020 Apr 20.

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.

AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.
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http://dx.doi.org/10.1002/eji.201948504DOI Listing
July 2020

Lost in Transition: A Risk Factor for Mortality in Youth Living With HIV.

Pediatr Infect Dis J 2020 02;39(2):e14-e16

Zentrum für Kinder- und Jugendmedizin, Helios Klinikum Krefeld, Lehrkrankenhaus der RWTH Aachen, Krefeld, Germany.

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http://dx.doi.org/10.1097/INF.0000000000002540DOI Listing
February 2020

Tuberculosis disease in children and adolescents on therapy with anti-tumor necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study.

Clin Infect Dis 2019 Dec 4. Epub 2019 Dec 4.

Department of Paediatrics, University of Melbourne, Parkville, Australia.

Background: In adults, anti-tumor-necrosis-factor (TNF)-α therapy is associated with progression of latent tuberculosis infection (LTBI) to tuberculosis (TB) disease. The existing paediatric data are very limited.

Methods: Retrospective multi-centre study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy.

Results: Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified; Crohn´s disease (n=8;42%) and juvenile idiopathic arthritis (n=6;32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-gamma release assay) was performed in 15 patients before commencing anti-TNF-α therapy, but only identified one LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR:7.1-20.3) months. All cases presented with severe disease, predominately miliary TB (n=14;78%). One case was diagnosed post-mortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR:46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae.

Conclusions: The data indicate that LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease, and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low TB prevalence settings.
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http://dx.doi.org/10.1093/cid/ciz1138DOI Listing
December 2019

The Efficacy and Evidence-Based Use of Biologics in Children and Adolescents: Using Monoclonal Antibodies and Fusion Proteins as Treatments.

Dtsch Arztebl Int 2019 10;116(42):703-710

Department of Pediatrics and Adolescent Medicine, HELIOS Klinikum Krefeld.

Background: Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety and efficacy in the treatment of the most common chronic inflammatory diseases.

Methods: We systematically searched PubMed, AWMF.org, and other databases for high-quality trials (i.e., randomized controlled trials with clinical primary endpoints) and guidelines published at any time up to 10 December 2018 that dealt with mAb and FP that are approved for pediatric use. The search term was "monoclonal anti- body/fusion protein [e. g. adalimumab] AND children."

Results: The 620 hits included 25 high-quality trials (20 of them manufacturer- sponsored) on 9 mAb/FP (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept), as well as 6 guidelines (3 each of levels S3 and S2k) on the treatment of bronchial asthma, psoriasis, juvenile idopathic arthritis, and chronic inflammatory bowel diseases. For none of these conditions are mAb and FP the drugs of first choice. Adverse drug effects are rare but sometimes severe (infection, immune dysregulation, tumors).

Conclusion: The retrieved trials have deficiencies that make it difficult to reliably evaluate the efficacy, safety, and utility of mAb/FP for children and adolescents with chronic inflammatory diseases. mAb/FP nonetheless represent a treatment option to be considered in case conventional immune-modulating drugs are ineffective. Researcher-initiated, high-quality trials and manufacturer-independent, systematic long-term evaluations of adverse effects (e.g., tumors) are sorely needed.
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http://dx.doi.org/10.3238/arztebl.2019.0703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891884PMC
October 2019

The German National Registry of Primary Immunodeficiencies (2012-2017).

Authors:
Sabine M El-Helou Anika-Kerstin Biegner Sebastian Bode Stephan R Ehl Maximilian Heeg Maria E Maccari Henrike Ritterbusch Carsten Speckmann Stephan Rusch Raphael Scheible Klaus Warnatz Faranaz Atschekzei Renata Beider Diana Ernst Stev Gerschmann Alexandra Jablonka Gudrun Mielke Reinhold E Schmidt Gesine Schürmann Georgios Sogkas Ulrich H Baumann Christian Klemann Dorothee Viemann Horst von Bernuth Renate Krüger Leif G Hanitsch Carmen M Scheibenbogen Kirsten Wittke Michael H Albert Anna Eichinger Fabian Hauck Christoph Klein Anita Rack-Hoch Franz M Sollinger Anne Avila Michael Borte Stephan Borte Maria Fasshauer Anja Hauenherm Nils Kellner Anna H Müller Anett Ülzen Peter Bader Shahrzad Bakhtiar Jae-Yun Lee Ursula Heß Ralf Schubert Sandra Wölke Stefan Zielen Sujal Ghosh Hans-Juergen Laws Jennifer Neubert Prasad T Oommen Manfred Hönig Ansgar Schulz Sandra Steinmann Klaus Schwarz Gregor Dückers Beate Lamers Vanessa Langemeyer Tim Niehues Sonu Shai Dagmar Graf Carmen Müglich Marc T Schmalzing Eva C Schwaneck Hans-Peter Tony Johannes Dirks Gabriele Haase Johannes G Liese Henner Morbach Dirk Foell Antje Hellige Helmut Wittkowski Katja Masjosthusmann Michael Mohr Linda Geberzahn Christian M Hedrich Christiane Müller Angela Rösen-Wolff Joachim Roesler Antje Zimmermann Uta Behrends Nikolaus Rieber Uwe Schauer Rupert Handgretinger Ursula Holzer Jörg Henes Lothar Kanz Christoph Boesecke Jürgen K Rockstroh Carolynne Schwarze-Zander Jan-Christian Wasmuth Dagmar Dilloo Brigitte Hülsmann Stefan Schönberger Stefan Schreiber Rainald Zeuner Tobias Ankermann Philipp von Bismarck Hans-Iko Huppertz Petra Kaiser-Labusch Johann Greil Donate Jakoby Andreas E Kulozik Markus Metzler Nora Naumann-Bartsch Bettina Sobik Norbert Graf Sabine Heine Robin Kobbe Kai Lehmberg Ingo Müller Friedrich Herrmann Gerd Horneff Ariane Klein Joachim Peitz Nadine Schmidt Stefan Bielack Ute Groß-Wieltsch Carl F Classen Jessica Klasen Peter Deutz Dirk Kamitz Lisa Lassay Klaus Tenbrock Norbert Wagner Benedikt Bernbeck Bastian Brummel Eusebia Lara-Villacanas Esther Münstermann Dominik T Schneider Nadine Tietsch Marco Westkemper Michael Weiß Christof Kramm Ingrid Kühnle Silke Kullmann Hermann Girschick Christof Specker Elisabeth Vinnemeier-Laubenthal Henriette Haenicke Claudia Schulz Lothar Schweigerer Thomas G Müller Martina Stiefel Bernd H Belohradsky Veronika Soetedjo Gerhard Kindle Bodo Grimbacher

Front Immunol 2019 19;10:1272. Epub 2019 Jul 19.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
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http://dx.doi.org/10.3389/fimmu.2019.01272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659583PMC
October 2020

Lung disease in STAT3 hyper-IgE syndrome requires intense therapy.

Allergy 2019 09 4;74(9):1691-1702. Epub 2019 Apr 4.

Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.

Background: Pulmonary complications are responsible for high morbidity and mortality rates in patients with the rare immunodeficiency disorder STAT3 hyper-IgE syndrome (STAT3-HIES). The aim of this study was to expand knowledge about lung disease in STAT3-HIES.

Methods: The course of pulmonary disease, radiological and histopathological interrelations, therapeutic management, and the outcome of 14 STAT3-HIES patients were assessed.

Results: The patients' quality of life was compromised most by pulmonary disease. All 14 patients showed first signs of lung disease at a median onset of 1.5 years of age. Lung function revealed a mixed obstructive-restrictive impairment with reduced FEV1 and FVC in 75% of the patients. The severity of lung function impairment was associated with Aspergillus fumigatus infection and prior lung surgery. Severe lung tissue damage, with reduced numbers of ATP-binding cassette sub-family A member 3 (ABCA3) positive type II pneumocytes, was observed in the histological assessment of two deceased patients. Imaging studies of all patients above 6 years of age showed severe airway and parenchyma destruction. Lung surgeries frequently led to complications, including fistula formation. Long-term antifungal and antibacterial treatment proved to be beneficial, as were inhalation therapy, chest physiotherapy, and exercise. Regular immunoglobulin replacement therapy tended to stabilize lung function.

Conclusions: Due to its severity, pulmonary disease in STAT3-HIES patients requires strict monitoring and intensive therapy.
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http://dx.doi.org/10.1111/all.13753DOI Listing
September 2019

Increased proportions of γδ T lymphocytes in atypical SCID associate with disease manifestations.

Clin Immunol 2019 04 15;201:30-34. Epub 2019 Feb 15.

Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Severe combined immunodeficiencies (SCID) comprise a group of genetic diseases characterized by abrogated development of T lymphocytes. In some case reports of atypical SCID patients elevated proportions of γδ T lymphocytes have been reported. However, it is unknown whether these γδ T cells modulate or reflect the patient's clinical phenotype. We investigated the frequency of elevated γδ T cell proportions and associations with clinical disease manifestations in a cohort of 76 atypical SCID patients. Increased proportions of γδ T lymphocytes were present in approximately 60% of these patients. Furthermore, we identified positive correlations between elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias. We discuss that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune cytopenias. We advocate that atypical SCID patients should be screened for elevated proportions of γδ T lymphocytes, CMV infection and autoimmune cytopenias.
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http://dx.doi.org/10.1016/j.clim.2018.11.006DOI Listing
April 2019

A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency.

J Allergy Clin Immunol 2019 06 13;143(6):2296-2299. Epub 2019 Feb 13.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory AMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677392PMC
June 2019

Erratum zu: Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (II) Impfen bei 1. Primären Immundefekterkrankungen und 2. HIV-Infektion.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Mar;62(3):378

Ständige Impfkommission am Robert Koch-Institut Berlin, Berlin, Deutschland.

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http://dx.doi.org/10.1007/s00103-019-02897-yDOI Listing
March 2019

Erratum zu: Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (II) Impfen bei 1. Primären Immundefekterkrankungen und 2. HIV-Infektion.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2018 10;61(10):1307-1308

Ständige Impfkommission am Robert Koch-Institut Berlin, Berlin, Deutschland.

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http://dx.doi.org/10.1007/s00103-018-2807-yDOI Listing
October 2018

Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.

J Allergy Clin Immunol 2018 12 4;142(6):1932-1946. Epub 2018 May 4.

Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, United Kingdom. Electronic address:

Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects.

Objective: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers.

Methods: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers.

Results: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression.

Conclusions: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.
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http://dx.doi.org/10.1016/j.jaci.2018.02.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215742PMC
December 2018

Familial Mediterranean fever in children and adolescents: factors for colchicine dosage and predicting parameters for dose increase.

Rheumatology (Oxford) 2017 09;56(9):1597-1606

Pediatric Pneumology and Immunology, Charité University Medicine Berlin.

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future.

Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA.

Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease.

Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.
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http://dx.doi.org/10.1093/rheumatology/kex222DOI Listing
September 2017

Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen(I) Grundlagenpapier.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017 Jun;60(6):674-684

3Ständige Impfkommission (STIKO), Robert Koch-Institut, Berlin, Deutschland.

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http://dx.doi.org/10.1007/s00103-017-2555-4DOI Listing
June 2017

Favourable Outcome in Two Pregnancies in a Patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency.

JIMD Rep 2017 21;37:1-5. Epub 2017 Feb 21.

Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

In patients with 3-hydroxy-3-methylglutaryl(HMG)-CoA lyase deficiency (OMIM 246450), five pregnancies have been described worldwide, which were either terminated or resulted in severe metabolic sequelae during pregnancy or delivery. Here, we report on a patient with HMG-CoA lyase deficiency, who underwent two uncomplicated pregnancies. The 19-year-old patient was admitted because of recurrent vomiting and nausea. Diagnostics revealed pregnancy at week 8 of gestation. Metabolic analyses revealed normal lactate and blood glucose levels and normal acid-base status. Urine organic acid analysis showed an elevated excretion of 3-CH-glutaric acid, 2,3-CH-glutaconic acid, and 3-CH-3-OH-glutaric acid. Oral treatment with carnitine and glucose wes administered intravenously during the period of nausea and vomiting. After clinical recovery, a diet with 0.89 g/kg of protein/d and 38 kcal/kg body weight/d was given. Meals were taken every 3 h. Additionally, 70 g of starch was given at midnight to maintain normoglycemia at night time. Peripartum, a complete parenteral nutrition, was delivered through a central venous catheter. The patient delivered a healthy male infant by Caesarean section at week 38 of gestation (Apgar 9/10/10) and remained metabolically stable throughout the peripartum period. Postpartum nutrition was gradually changed from parenteral to oral diet. Two years later, the patient became pregnant again and presented with hyperemesis gravidarum. With metabolic monitoring and treatment as before no decompensation occurred. At week 38 of gestation, she delivered a healthy female infant by elective Caesarian section (Apgar 9/10/10). This case report describes the metabolic and obstetric management of two pregnancies in a patient with HMG-CoA lyase deficiency with favorable outcome without metabolic complications.
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http://dx.doi.org/10.1007/8904_2017_7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740040PMC
February 2017

Human RAD52 - a novel player in DNA repair in cancer and immunodeficiency.

Haematologica 2017 02 15;102(2):e69-e72. Epub 2016 Dec 15.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.

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http://dx.doi.org/10.3324/haematol.2016.155838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286958PMC
February 2017

A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis.

J Allergy Clin Immunol 2017 Apr 19;139(4):1302-1310.e4. Epub 2016 Sep 19.

Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background: Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions.

Objectives: We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.

Methods: In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.

Results: A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of "atypical" SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution.

Conclusions: The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
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http://dx.doi.org/10.1016/j.jaci.2016.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311415PMC
April 2017

Immunisation practices in centres caring for children with perinatally acquired HIV: A call for harmonisation.

Vaccine 2016 11 7;34(46):5587-5594. Epub 2016 Oct 7.

Department of Pediatrics, Unit of Immune and Infectious Diseases, Children's Hospital "Bambino Gesu", Rome, Italy; Research Unit in Congenital and Perinatal Infections, Academic Department of Pediatrics, Division of Immune and Infectious Diseases, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy. Electronic address:

Background: Current national immunisation schedules differ between countries in terms of vaccine formulation, timing of vaccinations and immunisation programme funding and co-ordination. As a result, some HIV infected paediatric population may be left susceptible to vaccine preventable infections. Vaccines used in healthy population should be subjected to high quality ethical research and be explicitly validated for use in children with special vaccination needs such as those infected with HIV. This survey was completed to assess current vaccination practices and attitudes toward vaccination among pediatricians who care for vertically HIV infected children.

Methods: An online questionnaire was completed by 46 experts in paediatric HIV-infection from the Paediatric European Network for Treatment of AIDS (PENTA). Data were collected between November 2013 and March 2014.

Results: 46units looking after 2465 patients completed the questionnaire. The majority of units (67%) reported that common childhood immunisation were administered by the family doctor or local health services rather than in the HIV specialist centre. Vaccination histories were mostly incomplete and difficult to obtain for 40% of the studied population. Concerns were reported regarding the use of live attenuated vaccines, such as varicella and rotavirus, and these were less frequently recommended (61% and 28% of the units respectively). Monitoring of vaccine responses was employed in a minority of centres (41%). A range of different assays were used resulting in diverse units of measurement and proposed correlates of protection.

Conclusion: Vaccination practices for perinatally HIV-infected children vary a great deal between countries. Efforts should be made to improve communication and documentation of vaccinations in healthcare settings and to harmonise recommendations relating to additional vaccines for HIV infected children and the use of laboratory assays to guide immunisation. This will ultimately improve coverage and vaccine induced immunity in this vulnerable patient group.
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http://dx.doi.org/10.1016/j.vaccine.2016.09.035DOI Listing
November 2016

Outcome and Trends in Treatment of Systemic Juvenile Idiopathic Arthritis in the German National Pediatric Rheumatologic Database, 2000-2013.

Arthritis Rheumatol 2016 12;68(12):3023-3034

German Rheumatism Research Centre Berlin and Charité University Hospital Berlin, Berlin, Germany.

Objective: To investigate the clinical presentation and medical treatment of patients with systemic juvenile idiopathic arthritis (JIA) during the first year of illness. Our study focused on 3-year outcomes in a subsample of patients who were followed up longitudinally.

Methods: From 2000 to 2013, 597 patients with systemic JIA and a disease duration of ≤12 months were recorded in the National Pediatric Rheumatologic Database. Among those patients, 3-year outcome data were available for 133. These data included the clinical Juvenile Arthritis Disease Activity Score in 10 joints (JADAS-10) and the physician's global assessment score (on a numerical rating scale), as well as assessment of joint involvement, growth retardation, and patient-reported outcomes.

Results: The median clinical JADAS-10 declined significantly, from 7 in 2000 to 2 in 2013, while the proportion of patients with inactive disease increased from 19% in 2000 to 41% in 2013. The rate of treatment with systemic glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) remained stable from 2000 to 2013. By 2013, the proportion of patients with systemic JIA who were treated with biologic DMARDs had increased to 20%. At 3-year follow-up, 72% of patients with systemic JIA had inactive disease, and 77% had no functional limitations. Growth retardation was associated with persistently high disease activity and continuing treatment with systemic glucocorticoids. At the 3-year follow-up, one-third of patients were still being treated with systemic glucocorticoids.

Conclusion: The proportion of patients with inactive disease has increased over the past decade. Possible explanations may include improved access to specialized care, additional treatment options, and earlier or faster step-up treatment. However, challenges in the management of systemic JIA remain, as ∼30% of patients continue to present with ongoing active disease.
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http://dx.doi.org/10.1002/art.39796DOI Listing
December 2016