Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Adam J. Tulling; Marloes G. Holierhoek; Anja M. Jansen-Hoogendijk; Levi Hoste; Filomeen Haerynck; Simon J. Tavernier; Rianne Oostenbrink; Corinne M.P. Buysse; Michiel A.G.E. Bannier; Jolita Bekhof; Mijke Breukels; Sanne C. Hammer; Monique A.M. Jacobs; Arvid W.A. Kamps; Jan W. van der Linden; Ankie Lebon; Johanna H. Oudshoorn; Gerdien A. Tramper-Stranders; Sebastiaan J. Vastert; Jantien W. Wieringa; Suzanne W.J. Terheggen-Lagro; Joanne G. Wildenbeest; Erik G.J. von Asmuth; Erik B. van den Akker; Marielle E. van Gijn; Gertjan Lugthart; Emilie P. Buddingh

doi:10.1016/j.clim.2024.110252

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Adam J. Tulling, Marloes G. Holierhoek, Anja M. Jansen-Hoogendijk, Levi Hoste, Filomeen Haerynck, Simon J. Tavernier, Rianne Oostenbrink, Corinne M.P. Buysse, Michiel A.G.E. Bannier, Jolita Bekhof, Mijke Breukels, Sanne C. Hammer, Monique A.M. Jacobs, Arvid W.A. Kamps, Jan W. van der Linden, Ankie Lebon, Johanna H. Oudshoorn, Gerdien A. Tramper-Stranders, Sebastiaan J. Vastert, Jantien W. WieringaSuzanne W.J. Terheggen-Lagro, Joanne G. Wildenbeest, Erik G.J. von Asmuth, Erik B. van den Akker, Marielle E. van Gijn, Gertjan Lugthart, Emilie P. Buddingh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	110252
Journal	Clinical Immunology
Volume	264
DOIs	https://doi.org/10.1016/j.clim.2024.110252
Publication status	Published - 1 Jul 2024

Keywords

COVID-19
HLH
Immune dysregulation
MIS-C
SARS-CoV-2

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10.1016/j.clim.2024.110252Licence: CC BY

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Tulling, A. J., Holierhoek, M. G., Jansen-Hoogendijk, A. M., Hoste, L., Haerynck, F., Tavernier, S. J., Oostenbrink, R., Buysse, C. M. P., Bannier, M. A. G. E., Bekhof, J., Breukels, M., Hammer, S. C., Jacobs, M. A. M., Kamps, A. W. A., van der Linden, J. W., Lebon, A., Oudshoorn, J. H., Tramper-Stranders, G. A., Vastert, S. J., ... Buddingh, E. P. (2024). Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children. Clinical Immunology, 264, Article 110252. https://doi.org/10.1016/j.clim.2024.110252

@article{d60faa2adec84e84b388923134d88fae,

title = "Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children",

abstract = "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.",

keywords = "COVID-19, HLH, Immune dysregulation, MIS-C, SARS-CoV-2",

author = "Tulling, {Adam J.} and Holierhoek, {Marloes G.} and Jansen-Hoogendijk, {Anja M.} and Levi Hoste and Filomeen Haerynck and Tavernier, {Simon J.} and Rianne Oostenbrink and Buysse, {Corinne M.P.} and Bannier, {Michiel A.G.E.} and Jolita Bekhof and Mijke Breukels and Hammer, {Sanne C.} and Jacobs, {Monique A.M.} and Kamps, {Arvid W.A.} and {van der Linden}, {Jan W.} and Ankie Lebon and Oudshoorn, {Johanna H.} and Tramper-Stranders, {Gerdien A.} and Vastert, {Sebastiaan J.} and Wieringa, {Jantien W.} and Terheggen-Lagro, {Suzanne W.J.} and Wildenbeest, {Joanne G.} and {von Asmuth}, {Erik G.J.} and {van den Akker}, {Erik B.} and {van Gijn}, {Marielle E.} and Gertjan Lugthart and Buddingh, {Emilie P.}",

note = "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: {\textcopyright} 2024",

year = "2024",

month = jul,

day = "1",

doi = "10.1016/j.clim.2024.110252",

language = "English",

volume = "264",

journal = "Clinical Immunology",

issn = "1521-6616",

publisher = "Academic Press Inc.",

}

Tulling, AJ, Holierhoek, MG, Jansen-Hoogendijk, AM, Hoste, L, Haerynck, F, Tavernier, SJ, Oostenbrink, R, Buysse, CMP, Bannier, MAGE, Bekhof, J, Breukels, M, Hammer, SC, Jacobs, MAM, Kamps, AWA, van der Linden, JW, Lebon, A, Oudshoorn, JH, Tramper-Stranders, GA, Vastert, SJ, Wieringa, JW, Terheggen-Lagro, SWJ, Wildenbeest, JG, von Asmuth, EGJ, van den Akker, EB, van Gijn, ME, Lugthart, G & Buddingh, EP 2024, 'Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children', Clinical Immunology, vol. 264, 110252. https://doi.org/10.1016/j.clim.2024.110252

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 -

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Abstract

Keywords

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