Detectable A Disintegrin and Metalloproteinase With Thrombospondin Motifs-1 in Serum Is Associated With Adverse Outcome in Pediatric Sepsis

Navin P Boeddha; Gertjan J Driessen; Nienke N Hagedoorn; Daniela S Kohlfuerst; Clive J Hoggart; Angelique L van Rijswijk; Ebru Ekinci; Debby Priem; Luregn J Schlapbach; Jethro A Herberg; Ronald de Groot; Suzanne T Anderson; Colin G Fink; Enitan D Carrol; Michiel van der Flier; Federico Martinón-Torres; Michael Levin; Frank W Leebeek; Werner Zenz; Moniek P M de Maat; Jan A Hazelzet; Marieke Emonts; Willem A Dik

doi:10.1097/CCE.0000000000000569

Detectable A Disintegrin and Metalloproteinase With Thrombospondin Motifs-1 in Serum Is Associated With Adverse Outcome in Pediatric Sepsis

Crit Care Explor. 2021 Nov 8;3(11):e0569. doi: 10.1097/CCE.0000000000000569. eCollection 2021 Nov.

Authors

Navin P Boeddha^{1

2}, Gertjan J Driessen³, Nienke N Hagedoorn², Daniela S Kohlfuerst⁴, Clive J Hoggart^{5

6}, Angelique L van Rijswijk⁷, Ebru Ekinci², Debby Priem⁸, Luregn J Schlapbach^{9

10

11}, Jethro A Herberg⁵, Ronald de Groot^{12

13

14}, Suzanne T Anderson¹⁵, Colin G Fink¹⁶, Enitan D Carrol¹⁷, Michiel van der Flier^{18

19}, Federico Martinón-Torres^{20

21}, Michael Levin⁵, Frank W Leebeek⁸, Werner Zenz⁴, Moniek P M de Maat⁸, Jan A Hazelzet²², Marieke Emonts^{23

24

25}, Willem A Dik⁷

Affiliations

¹ Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.
² Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Department of Paediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
⁴ Department of General Paediatrics, Medical University of Graz, Graz, Austria.
⁵ Section of Pediatrics, Imperial College London, London, United Kingdom.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY.
⁷ Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁸ Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁹ Child Health Research Center, The University of Queensland, Brisbane, QLD, Australia.
¹⁰ Queensland Children`s Hospital, Brisbane, QLD, Australia.
¹¹ Pediatric and Neonatal Intensive Care Unit, University Children's Hospital Zurich, Zurich, Switzerland.
¹² Radboudumc Technology Center Clinical Studies, Radboudumc, Nijmegen, The Netherlands.
¹³ Section of Pediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
¹⁴ Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, The Netherlands.
¹⁵ MRC Unit The Gambia at the LSHTM, Banjul, The Gambia.
¹⁶ Micropathology Ltd, University of Warwick Science Park, Venture Centre, Coventry, United Kingdom.
¹⁷ Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.
¹⁸ Paediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, The Netherlands.
¹⁹ Paediatric Infectious Diseases and Immunology, Radboudumc, Nijmegen, The Netherlands.
²⁰ Translational Pediatrics and Infectious Diseases Section, Pediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
²¹ Genetics-Vaccines-Infectious Diseases and Pediatrics research group GENVIP, Health Research Institute of Santiago IDIS/SERGAS, Santiago de Compostela, Spain.
²² Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
²³ Paediatric Infectious Diseases and Immunology Department, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
²⁴ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
²⁵ NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, United Kingdom.

Abstract

Importance: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking.

Objectives: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome.

Design: Data from two prospective cohort studies.

Setting and participants: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission).

Main outcomes and measures: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay.

Results: In cohort 1 (n = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; p = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; p = 0.04). In cohort 2 (n = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; p = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; p = 0.003), which was mostly attributable to patients with Neisseria meningitidis.

Conclusions and relevance: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with death, particularly in meningococcal sepsis. Future studies should confirm the prognostic value of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 and should study pathophysiologic mechanisms.

Keywords: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein; bacterial infections; biomarkers; inflammation; mortality; sepsis.