TY - JOUR
T1 - Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children
AU - Tulling, Adam J.
AU - Holierhoek, Marloes G.
AU - Jansen-Hoogendijk, Anja M.
AU - Hoste, Levi
AU - Haerynck, Filomeen
AU - Tavernier, Simon J.
AU - Oostenbrink, Rianne
AU - Buysse, Corinne M.P.
AU - Bannier, Michiel A.G.E.
AU - Bekhof, Jolita
AU - Breukels, Mijke
AU - Hammer, Sanne C.
AU - Jacobs, Monique A.M.
AU - Kamps, Arvid W.A.
AU - van der Linden, Jan W.
AU - Lebon, Ankie
AU - Oudshoorn, Johanna H.
AU - Tramper-Stranders, Gerdien A.
AU - Vastert, Sebastiaan J.
AU - Wieringa, Jantien W.
AU - Terheggen-Lagro, Suzanne W.J.
AU - Wildenbeest, Joanne G.
AU - von Asmuth, Erik G.J.
AU - van den Akker, Erik B.
AU - van Gijn, Marielle E.
AU - Lugthart, Gertjan
AU - Buddingh, Emilie P.
N1 - Funding Information:
The authors like to thank Estefan\u00EDa Laney (Trialbureau Willem-Alexander Children's Hospital) for practical support and Dennis Hendriksen and Bart Charbon (Department of Genetics; University Medical Center Groningen) for technical support of the variant interpretation pipeline. The following people have assisted in study set-up and patient recruitment in the COPP study: Leontien B. van der Aa (Zaans Medical Center); Koen J. van Aerde, Ronald Petru, Kim Stol, Saskia N. de Wildt (Radboud University Medical Center); Wineke Armbrust, Elizabeth G. Legger (University Medical Center Groningen); Bettina Auffarth-Smedema (Ommelander Hospital); Ingeborg Y. Bart (Canisius-Wilhelmina Hospital); Cherise Beek, Kevin H. van \u2018t Kruys, Gideon O. Olivieira (Academic Hospital Paramaribo); Gitanjali I. Bechan (Alrijne Hospital); J. Merlijn van den Berg, Mariken Gruppen, Simone Hashimoto, Martijn van der Kuip (Emma Children's Hospital); Venje H. Boonstra (BovenIJ Hospital); Caroline L. H. Brackel (Tergooi Medical Center); Danielle M.C. Brinkman, Petra C.E. Hissink Muller, Rian Schopmeijer, David Slotboom, Anne B. Verbeek (Willem-Alexander Children's Hospital); Patricia C.J.L. Bruijning-Verhagen (Julius Center for Health Sciences and Primary Care); Stephanie C. de Crom, Christiaan van Woerden (Bravis Hospital); Margot R. Ernst-Kruis (Meander Medical Center); Pieter L.A. Fraaij, Naomi Ketharanathan, Marielle W.H. Pijnenburg, Miriam G. Mooij (Sophia Children's Hospital); Helma B. van Gameren-Oosterom (Groene Hart Hospital); Joyce Goris (ZorgSaam Hospital); Michael Groeneweg, Xandra W. van den Tweel (Maasstad Hospital); Marlies A. van Houten (Spaarne Gasthuis); Lindy Janssen, Shirley Lo-A-Njoe, Meindert E. Manshande (Cura\u00E7ao Medical Center); Carien J. Miedema (Catharina Hospital); Mirjam van Veen, Esther J.E. Peeters, Denise Rook (Juliana Children's Hospital); Charlie C. Obihara (Elisabeth-TweeStedenziekenhuis); Lonneke van Onzenoort-Bokken (M\u00E1xima Medical Center); Kim Schilleman (Admiraal de Ruyter Hospital); Annette M.M. Vernooij-van Langen (St Jansdal Hospital); Wim J.E. Tissing (Prinses M\u00E1xima Center for Pediatric Oncology); Han Hendriks (Zuyderland Medical Center); Jenneke Homan-van der Veen (Deventer Hospital); Manouk van der Steen (University Medical Center Maastricht); Yolande E.M. Thomasse (Dijklander Hospital). The following people have assisted in study set-up and patient recruitment in the GHENT study: Petra Schelstraete, Jef Willems, Kristof Vandekerckhove, Joke Dehoorne, Julie Willekens, Heidi Schaballie, Sabine Van Daele, Laure Dierickx, Sara David, Evelyn Dhont, Ann Verrijckt, Annick de Jaeger, Emma Beel (Ghent University Hospital); Inge Matthijs, Aur\u00E9lie Minne, Karin Decaestecker (AZ Delta Campus Rumbeke); Jijo John (AZ Delta Campus Menen); Thomas EM Crijnen, Muriel Koninckx, Joery Verbruggen, Goele Nys, Samira Akhnikh (ZNA Queen Paola Children's Hospital); Els LIM Duval (AZ Sint-Jan Brugge-Oostende campus Serruys); Tine Van Ackere (Jan Ypermanziekenhuis); Astrid Verbist, Charlotte Daeze, Caroline Becue, Justine De Paepe (AZ Sint-Lucas); Jo Keepers (AZ Alma); Bruno Bruylants (O.L.V. Hospital); Sabine Kuypers (AZ Zeno); Siel Daelemans, Jutte van der Werff ten Bosch, Gerlant van Berlaer (University Hospital Brussel); Alexandra Dreesman (Centre Hospitalo Universitaire Saint-Pierre); Benoit Florkin (CHR Citadelle); Catherine Heijmans, Jean Papadopoulos (Centre Hospitalier de Jolimont). Study coordination and sample processing in Ghent was facilitated by Karlien Claes and Veronique Debacker, respectively. The graphical abstract was created with BioRender.com.
Funding Information:
This study was funded by the #wakeuptocorona crowdfund initiative of the Bontius Stichting and the Leiden University Fund, and by ZonMw (10430072110007, 10430102110009). The Vlaamse Instituut voor Biotechnologie (VIB) Tech Watch Fund and the VIB Grand Challenges Program provided funding for the Olink analysis.
Publisher Copyright:
© 2024
PY - 2024/7/1
Y1 - 2024/7/1
N2 - Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.
AB - Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.
KW - COVID-19
KW - HLH
KW - Immune dysregulation
KW - MIS-C
KW - SARS-CoV-2
U2 - 10.1016/j.clim.2024.110252
DO - 10.1016/j.clim.2024.110252
M3 - Article
SN - 1521-6616
VL - 264
JO - Clinical Immunology
JF - Clinical Immunology
M1 - 110252
ER -