. 2023 Jun 2:12:e48183.

doi: 10.2196/48183.

Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT)

Katrijn Daenen^{1

2}, Jilske A Huijben¹, Anders Boyd^{3

4

5}, Lieuwe D J Bos^{6

7}, Sara C M Stoof¹, Hugo van Willigen⁸, Diederik A M P J Gommers¹, Hazra S Moeniralam⁹, Corstiaan A den Uil¹⁰, Nicole P Juffermans^{11

12}, Merijn Kant^{13

14}, Abraham J Valkenburg¹⁵, Janesh Pillay^{16

17}, David M P van Meenen^{6

18}, Frederique Paulus^{6

19}, Marcus J Schultz^{6

7}, Virgil A S H Dalm^{20

21}, Eric C M van Gorp^{2

22}, Janke Schinkel⁸, Henrik Endeman¹; PRoVENT- and PRoAcT-COVID Collaborative Group²³

Collaborators, Affiliations

Collaborators

PRoVENT- and PRoAcT-COVID Collaborative Group:
S Ahuja, J P van Akkeren, A G Algera, C K Algoe, R B van Amstel, P van de Berg, D C Bergmans, D I van den Bersselaar, F A Bertens, A J Bindels, J S Breel, C L Bruna, M M de Boer, S den Boer, L S Boers, M Bogerd, L D Bos, M Botta, O L Baur, H de Bruin, L A Buiteman-Kruizinga, O Cremer, R M Determann, W Dieperink, J v Dijk, D A Dongelmans, M J de Graaff, M S Galekaldridge, L A Hagens, J J Haringman, S T van der Heide, P L van der Heiden, L L Hoeijmakers, L Hol, M W Hollmann, J Horn, R van der Horst, E L Ie, D Ivanov, N P Juffermans, E Kho, E S de Klerk, A W Koopman, M Koopmans, S Kucukcelebi, M A Kuiper, D W de Lange, I Martin-Loeches, G Mazzinari, D M van Meenen, N van Mourik, S G Nijbroek, E A Oostdijk, F Paulus, C J Pennartz, J Pillay, I M Purmer, T C Rettig, O Roca, J P Roozeman, M J Schultz, A Serpa Neto, C Sivakorn, G S Shrestha, M E Sleeswijk, P E Spronk, A C Strang, W Stilma, P Swart, A Tri, A M Tsonas, C M A Valk, A P Vlaar, L I Veldhuis, W H van der Ven, P van Velzen, P van Vliet, P van der Voort, L van Welie, B van Wijk, T Winters, W Y Wong, A R van Zanten, E Aydeniz, M Bevers, W Coene, M Delmte, V Di Leo, T P Dormans, L M Elting, A A Esmeijer, M Gama de Abreu, A R Girbes, D M Go, R L Goossen, H J Hansen, L E van Ingen, L J Kuipers, E Koornstra, A Lokhorst, I Martin–Loeches, S Myatra, M Offermans, T Pisters, A Prins, P van Oosten, A S Rezaee, T C D Rettig, N M Rosenberg, N Schavemaker, A A Sciascera, G Shrestha, P R Tuinman, M Verboom, F L van der Ven, E J Verhoef, T D Vermeulen, J J Voorham, P H van der Voort, M van der Woude, Weiner, N Yaali, J M Zandvliet, T Z van Zijl, S A Zonneveld

Affiliations

¹ Department of Intensive Care, Erasmus University Medical Center, Rotterdam, Netherlands.
² Department of Viroscience, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, Netherlands.
⁴ HIV Monitoring Foundation, Amsterdam, Netherlands.
⁵ Infectious Diseases, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, Netherlands.
⁶ Department of Intensive Care, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
⁷ Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
⁸ Department of Medical Microbiology & Infection Prevention, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, Netherlands.
⁹ Department of Internal Medicine and Intensive Care, St Antonius Hospital, Nieuwegein, Netherlands.
¹⁰ Department of Intensive Care, Maasstad Ziekenhuis, Rotterdam, Netherlands.
¹¹ Department of Intensive Care, Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, Netherlands.
¹² Laboratory of Translational Intensive Care, Erasmus University Medical Center, Rotterdam, Netherlands.
¹³ Department of Pulmonology, Amphia Hospital, Breda, Netherlands.
¹⁴ Department of Intensive Care, Amphia Hospital, Breda, Netherlands.
¹⁵ Department of Anesthesiology and Intensive Care, Isala Clinics, Zwolle, Netherlands.
¹⁶ Department of Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
¹⁷ Department of Pathology and Medical Biology, Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
¹⁸ Department of Anesthesiology, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
¹⁹ Center of Expertise Urban Vitality, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, Netherlands.
²⁰ Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands.
²¹ Division of Allergy & Clinical Immunology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
²² Department of Internal Medicine, Erasmus University Medical Center, Erasmus, Netherlands.
²³ See Acknowledgements, .

PMID: 37266993
PMCID: PMC10276318
DOI: 10.2196/48183

Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT)

Katrijn Daenen et al. JMIR Res Protoc. 2023.

. 2023 Jun 2:12:e48183.

doi: 10.2196/48183.

Authors

Collaborators

PRoVENT- and PRoAcT-COVID Collaborative Group:
S Ahuja, J P van Akkeren, A G Algera, C K Algoe, R B van Amstel, P van de Berg, D C Bergmans, D I van den Bersselaar, F A Bertens, A J Bindels, J S Breel, C L Bruna, M M de Boer, S den Boer, L S Boers, M Bogerd, L D Bos, M Botta, O L Baur, H de Bruin, L A Buiteman-Kruizinga, O Cremer, R M Determann, W Dieperink, J v Dijk, D A Dongelmans, M J de Graaff, M S Galekaldridge, L A Hagens, J J Haringman, S T van der Heide, P L van der Heiden, L L Hoeijmakers, L Hol, M W Hollmann, J Horn, R van der Horst, E L Ie, D Ivanov, N P Juffermans, E Kho, E S de Klerk, A W Koopman, M Koopmans, S Kucukcelebi, M A Kuiper, D W de Lange, I Martin-Loeches, G Mazzinari, D M van Meenen, N van Mourik, S G Nijbroek, E A Oostdijk, F Paulus, C J Pennartz, J Pillay, I M Purmer, T C Rettig, O Roca, J P Roozeman, M J Schultz, A Serpa Neto, C Sivakorn, G S Shrestha, M E Sleeswijk, P E Spronk, A C Strang, W Stilma, P Swart, A Tri, A M Tsonas, C M A Valk, A P Vlaar, L I Veldhuis, W H van der Ven, P van Velzen, P van Vliet, P van der Voort, L van Welie, B van Wijk, T Winters, W Y Wong, A R van Zanten, E Aydeniz, M Bevers, W Coene, M Delmte, V Di Leo, T P Dormans, L M Elting, A A Esmeijer, M Gama de Abreu, A R Girbes, D M Go, R L Goossen, H J Hansen, L E van Ingen, L J Kuipers, E Koornstra, A Lokhorst, I Martin–Loeches, S Myatra, M Offermans, T Pisters, A Prins, P van Oosten, A S Rezaee, T C D Rettig, N M Rosenberg, N Schavemaker, A A Sciascera, G Shrestha, P R Tuinman, M Verboom, F L van der Ven, E J Verhoef, T D Vermeulen, J J Voorham, P H van der Voort, M van der Woude, Weiner, N Yaali, J M Zandvliet, T Z van Zijl, S A Zonneveld

Affiliations

¹ Department of Intensive Care, Erasmus University Medical Center, Rotterdam, Netherlands.
² Department of Viroscience, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, Netherlands.
⁴ HIV Monitoring Foundation, Amsterdam, Netherlands.
⁵ Infectious Diseases, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, Netherlands.
⁶ Department of Intensive Care, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
⁷ Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
⁸ Department of Medical Microbiology & Infection Prevention, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, Netherlands.
⁹ Department of Internal Medicine and Intensive Care, St Antonius Hospital, Nieuwegein, Netherlands.
¹⁰ Department of Intensive Care, Maasstad Ziekenhuis, Rotterdam, Netherlands.
¹¹ Department of Intensive Care, Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, Netherlands.
¹² Laboratory of Translational Intensive Care, Erasmus University Medical Center, Rotterdam, Netherlands.
¹³ Department of Pulmonology, Amphia Hospital, Breda, Netherlands.
¹⁴ Department of Intensive Care, Amphia Hospital, Breda, Netherlands.
¹⁵ Department of Anesthesiology and Intensive Care, Isala Clinics, Zwolle, Netherlands.
¹⁶ Department of Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
¹⁷ Department of Pathology and Medical Biology, Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
¹⁸ Department of Anesthesiology, Amsterdam University Medical Centers, location Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
¹⁹ Center of Expertise Urban Vitality, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, Netherlands.
²⁰ Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands.
²¹ Division of Allergy & Clinical Immunology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
²² Department of Internal Medicine, Erasmus University Medical Center, Erasmus, Netherlands.
²³ See Acknowledgements, .

PMID: 37266993
PMCID: PMC10276318
DOI: 10.2196/48183

Abstract

Background: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19.

Objective: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19.

Methods: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand.

Results: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024.

Conclusions: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment.

Trial registration: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359.

International registered report identifier (irrid): DERR1-10.2196/48183.

Keywords: COVID-19; corticosteroid; infectious diseases; virology.

©Katrijn Daenen, Jilske A Huijben, Anders Boyd, Lieuwe D J Bos, Sara C M Stoof, Hugo van Willigen, Diederik A M P J Gommers, Hazra S Moeniralam, Corstiaan A den Uil, Nicole P Juffermans, Merijn Kant, Abraham J Valkenburg, Janesh Pillay, David M P van Meenen, Frederique Paulus, Marcus J Schultz, Virgil A S H Dalm, Eric C M van Gorp, Janke Schinkel, Henrik Endeman, PRoVENT- and PRoAcT-COVID Collaborative Group. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 02.06.2023.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: None declared.

Figures

**Figure 1**
Integration of work packages in the Steroids in Hospitalized Patients with COVID-19 in The Netherlands (SELECT) study. On the y-axis, the viral and host inflammatory response are depicted. On the x-axis, the admission to the ward or intensive care unit (ICU) is shown, and below that, the World Health Organization (WHO) clinical progression scale is displayed as a measure of supplemental oxygen therapy. steroids: corticosteroids; HDS: high-dose corticosteroids; WP: work package.

**Figure 2**
Participating hospitals of the Steroids in Hospitalized Patients with COVID-19 in The Netherlands (SELECT) study. UMC: University Medical Center. MC: Medical Center; OLVG: Onze Lieve Vrouwe Gasthuis.

**Figure 3**
Patient inclusion. World Health Organization (WHO) classification: 0=uninfected, 1=asymptomatic; viral RNA detected, 2=symptomatic; independent, 3=symptomatic; assistance needed, 4=hospitalized; oxygen by mask or nasal prongs, 5=hospitalized; oxygen by mask or nasal prongs, 6=hospitalized; oxygen by noninvasive ventilation or high flow, 7=intubation and mechanical ventilation partial pressure of oxygen in arterial blood–fraction of inspiratory oxygen concentration (PaO2/FiO2) ratio of ≥150, 8=mechanical ventilation PaO2/FiO2 ratio of <150 or vasopressors, 9=mechanical ventilation PaO2/FiO2 ratio of <150 and vasopressors, dialysis or extracorporeal membrane oxygenation, 10=dead. PCR: polymerase chain reaction; WP: work package.

See this image and copyright information in PMC

References

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Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT)

Collaborators

Affiliations

Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT)

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

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