Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations - 19/05/21

Doi : 10.1016/j.jaci.2021.04.015

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

^a Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^b Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^c Rare Disease and Pediatric Research Centers, Hospital for Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and HUS Helsinki, University Hospital, Helsinki, Finland
^d Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
^e French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
^f DZIF – German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
^g CIBSS – Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany
^h RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
ⁱ St James’s Hospital, Dublin, Ireland
^j Trinity College Dublin, Dublin, Ireland
^k Institute of Immunity and Transplantation, University College London, United Kingdom
^l Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom

^∗Corresponding author: Stephan Ehl, MD, Institute for Immunodeficiency, University Medical Center, Breisacher Strasse 115, 79106 Freiburg, Germany.Institute for ImmunodeficiencyUniversity Medical CenterBreisacher Strasse 115Freiburg79106Germany

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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.

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Key words : Primary immunodeficiency, inborn error of immunity, presenting symptom, immune dysregulation, autoimmune, inflammatory, syndromic, warning signs, registry

Abbreviations used : ALPS, AT, CVID, DGS, ESID, HIES, IEI, IUIS, PID, SCID, WAS

Plan

Methods

Patients

Initial presenting manifestations

Data analysis

Results

Infection is the most frequent initial presenting manifestation of IEI

Symptoms of immune dysregulation are important initial manifestations of IEI and are relevant in IEI subgroups primarily presenting with infections

Syndromic features are frequent initial signs of IEI before or at presentation with other clinical manifestations

Infection is an important initial presenting symptom in diseases of immune dysregulation

Malignancies can be the initial presenting symptom of various IEI

Age at initial presenting manifestation

Differences between countries

Discussion

	The European Society for Immunodeficiencies Registry was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF] grant nos. 01GM0896, 01GM1111B, 01GM1517C, 01EO1303, and 01ZZ1801B), the European Union (grant no. HEALTH-F2-2008-201549 [EURO-PADnet]), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, UCB UK, and Pharming, the Plasma Protein Therapeutics Association, the Care-for-Rare Foundation, PROimmune e.V., ERN RITA, and the European Society for Immunodeficiencies (www.ESID.org).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
	Data sharing: Deidentified patient data collected for this study are available to others with publication of this article according to the European Society for Immunodeficiencies Registry data access and publication rules (Data-access-and-Publication-rules-Research-Proposal-Form).