Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections: A Prospective Multicenter Study

Nienke N. Hagedoorn, Navin P. Boeddha, European Union Childhood Life-threatening Infectious Disease (EUCLIDS) Consortium, Daniela S. Kohlfuerst, Suzanne Anderson, Enitan D. Carrol, Paul Agapow, Michiel van der Flier, Jan Hazelzet, Jethro Herberg, Taco Kuijpers, Michael Levin, Federico Martinon-Torres, Angelique van Rijswijk, Luregn J. Schlapbach, Clementien Vermont, Werner Zenz, Willem A. Dik, Gertjan Driessen, Marieke Emonts

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OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens (Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci (n = 83), pneumococci (n = 64), S. aureus (n = 50), and GAS (n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score). Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens (p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.

Bibliographical note

Funding Information:
Drs. Hagedoorn’s and Zenz’s institutions received funding from the European Union (EU). Dr. Boeddha received funding from GlaxoSmithKline. Drs. Kohlfuerst’s, Hazelzet’s, and Emonts’ institutions received funding from EU Project European Union Childhood Life-threatening Infectious Disease study (EUCLIDS). Dr. Kohlfuerst received support for article research from EU Project EUCLIDS. Drs. Carrol, van der Flier, and Herberg received support for article research from EU Horizon 2020. Dr. Hazelzet’s institution received funding from Erasmus Medical Centre. Dr. Zenz received support for article research from the EU. Dr. Driessen’s institution received funding from Merck and the Elizabeth von Freyburg Foundation. Dr. Emonts’ institution received funding from the EU, FP7, EU H2020 Personalized Risk assessment in Febrile illness to Optimize Real-life Management across the European Union (PERFORM), and EU H2020 Diagnosis and Management of Febrile Illness using RNA Personalised Molecular Signature Diagnosis (DIAMONDS). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Funding Information:
Supported, in part, from the European Union’s Seventh Framework program under number 279185 (European Union Project European Union Childhood Life-threatening Infectious Disease study).

Publisher Copyright:
© 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.


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