COVIP study group (see appendix 1 covip@med.uni-duesseldorf.de)

Utrecht University Repository

Steroid use in elderly critically ill COVID-19 patientsTo the Editor:More than a year after the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)pandemic, treating patients with coronavirus disease 2019 (COVID-19) remains a challenge. In contrast tothe rapid development of effective vaccines against SARS-CoV-2, the development of specific andeffective therapeutics against COVID-19 remains largely unresolved.In addition to standard intensive care, including oxygen therapy and organ support when required, the useof systemic corticosteroids was found to have a positive effect in randomised trials. However, dataregarding treatment of elderly COVID-19 patients are scarce.Importantly, treatment with corticosteroids has well documented deleterious effects [1]: While theimmunosuppressive effect in patients with COVID-19 is presumably responsible for the desired therapeuticeffect, it may also render the patients more prone to secondary bacterial infections and potentially decreaseviral clearance [2]. Corticosteroid therapy is also associated with hyperglycaemia, has catabolic effects andis associated with neuropathy. This could potentially affect the risk–benefit balance, especially invulnerable patient groups, such as elderly, frail patients.The aim of this secondary analysis was to investigate the effects of corticosteroid therapy in aninternational observational prospective study of critically ill elderly patients with COVID-19.The COVIP study (“Corona Virus disease (COVID19) in Very Elderly Intensive care Patients (VIPs)”;NCT04321265) included patients aged 70 years or older with proven COVID-19 and admitted to anintensive care unit (ICU) [3]. 30-day mortality was defined as the primary endpoint. The study wasconducted by the Very old Intensive care Patient (VIP) network [4] across 207 ICUs in 35 countries. Datawere collected through an electronic case report form. A prospective study design was chosen to achievehigh-quality data. Informed consent was taken if not waived by the local ethical committee.Two multi-level logistic regression models were utilised: the first model used the hospital unit as randomeffect and the steroid use as fixed effect; the second model was a multi-variable model adjusting for “TheSequential Organ Failure Assessment” (SOFA) score and frailty as assessed by the Clinical Frailty Scale.Sensitivity analyses complemented the analysis.In total, 3082 patients were included in the COVIP study; 2115 patients received corticosteroids, and 967patients received none. Median age was 75 (interquartile range (IQR) 72–79) years in both groups. With amedian SOFA score of 5 (IQR 3–8), there was no difference between the two groups.30-day mortality was 53% in the group treated with corticosteroids and 42% in the no-corticosteroid group(p<0.001).The univariate 30-day mortality rates were higher in patients receiving corticosteroids (53 versus 42%;aOR 1.16, 95%CI 1.28–2.02; p<0.001). This association of corticosteroid use was even more pronouncedafter 3 months (69% versus 49%; p<0.001; figure 1a). In addition, we found that corticosteroids remainedassociated with increased odds of 30-day mortality after multivariable adjustment (aOR 1.60, 95% CI1.26–2.04; <0.001). Further sensitivity analyses consistently confirmed the finding in subgroups stratifyingCopyright ©The authors 2021.This version is distributed underthe terms of the CreativeCommons AttributionNon-Commercial Licence 4.0.For commercial reproductionrights and permissions contactpermissions@ersnet.orgReceived: 6 April 2021Accepted: 2 June 2021Shareable abstract (@ERSpublications)This secondary analysis of the COVIP study shows a higher 30-day mortality in critically ill elderlyCOVID-19 patients who received steroids as part of their treatment @cjungMD https://bit.ly/3xdyEurCite this article as: Jung C, Wernly B, Fjølner J, et al. Steroid use in elderly critically ill COVID-19patients. Eur Respir J 2021; 58: 2100979 [DOI: 10.1183/13993003.00979-2021].https://doi.org/10.1183/13993003.00979-2021 Eur Respir J 2021; 58: 2100979EUROPEAN RESPIRATORY JOURNALRESEARCH LETTERC. JUNG ET AL.for age (<80/⩾80 years), frailty (fit/vulnerable/frail), mechanical ventilation (yes/no), noninvasiveventilation (yes/no), sex (female/male), symptom onset (⩽7 days/>7 days), and vasopressor therapy (yes/no)(figure 1b). Furthermore, in sensitivity analyses evaluating patients in the first surge (March–May, aOR1.38, 95% CI 1.05–1.82; p=0.02; n=1448) and the second surge (September–December, aOR 2.09, 95% CI1.04–4.21; p=0.04; n=1414) the finding was sustained.In this prospective study of more than 3000 critically ill COVID-19 patients aged 70 years and older, wehave found an independent association of steroid use with increased mortality.These results question the routine use of corticosteroid treatment in elderly COVID-19 patients. While theimmunosuppressive effect of steroids is undisputed and desirable in the context of severe COVID-19treatment, the adverse effects of steroid treatment in elderly patients may outweigh the potential benefits.This is the largest prospective analysis of critically ill elderly patients in relation to corticosteroid use totreat severe COVID-19 disease. Corticosteroid therapy has been established as standard of care in all ICUpatients. However, even landmark randomised controlled trials do not support this with evidence in elderlypatients. The RECOVERY study [5] showed no effect of corticosteroids in their subgroup of patients>70 years. Of note, only 169 patients in this group were on mechanical ventilation. The CoDEX studyfound no effect on mortality after 28 days, but no data was supplied specifically looking at patients above70 years old [6]. Thus, both studies included far fewer patients than our current analysis. It is important tonote that our data does not question the corticosteroid strategy in younger COVID-19 patients. It justemphasises that the decision to use corticosteroids needs to be individually tailored, first and foremostaccording to age, but also with regards to comorbidities and other factors [7].Our analysis has limitations: First, this is a secondary analysis of a prospective study. Second, our study isnot randomised and, despite multivariable adjustment, it is likely that unknown confounding factors mayhave contributed to our findings. Third, we have no detailed information about dosage and duration ofcorticosteroid treatment.In conclusion, in this prospective observational study we found a higher 30-day mortality in critically illelderly COVID-19 patients who received steroids as part of their treatment.0 201.00a)b)log-rank p<0.0010.75Subgroup Odds ratio (95% CI)1.58 (1.25–1.99)1.86 (1.12–3.07)1.59 (1.24–2.05)1.23 (0.83–1.81)1.74 (1.33–2.29)1.56 (1.24–1.97)1.45 (1.01–2.10)1.66 (1.32–2.09)1.61 (1.18–2.20)1.68 (1.22–2.33)1.35 (0.95–1.92)1.82 (1.40–2.36)1.67 (1.09–2.57)1.42 (0.81–2.50)1.47 (0.82–2.65)Age <80 yearsAge 80–90 yearsFit (CFS 0–3)Vulnerable (CFS 4)Frail (CFS ≥5)No mechanical ventilationMechanical ventilationNo NIVNIVFemaleMaleSymptom onset ≤7 daysSymptom onset >7 daysNo vasopressorVasopressorSurvival probability0.500.25095% CI 95% CINo corticosteroids Corticosteroids40Time (days)60 80 0.3 0.5 1Favours steroids Favours no steroids2 3 4FIGURE 1 a) Plot of the Kaplan–Meier estimator illustrating survival probability up to 90 days after admission to the intensive care unit for patientswith and without corticosteroid treatment. Log-rank-test: p<0.001. b) Sensitivity analyses stratifying 30-day mortality in subgroups forpatient-specific characteristics and management strategies using multi-level logistic regression models. We depicted adjusted odds ratios from themodel with the hospital unit as random effect and steroid use as fixed effect. CFS: Clinical Frailty Scale; NIV: noninvasive ventilation.https://doi.org/10.1183/13993003.00979-2021 2EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | C. JUNG ET AL.Christian Jung 1, Bernhard Wernly2, Jesper Fjølner3, Raphael Romano Bruno1, David Dudzinski4,Antonio Artigas5, Bernardo Bollen Pinto6, Joerg C. Schefold7, Georg Wolff1, Malte Kelm 1,Michael Beil8, Sviri Sigal8, Peter Vernon van Heerden9, Wojciech Szczeklik10,Miroslaw Czuczwar 11, Muhammed Elhadi12, Michael Joannidis13, Sandra Oeyen14,Tilemachos Zafeiridis15, Brian Marsh16, Finn H. Andersen17,18, Rui Moreno 19, Maurizio Cecconi 20,Susannah Leaver21, Ariane Boumendil22,23, Dylan W. De Lange24, Bertrand Guidet22,23,Hans Flaatten25,26 and the COVIP study group1Medical Faculty, Dept of Cardiology, Pulmonology and Vascular Medicine, Heinrich-Heine-UniversityDuesseldorf, Duesseldorf, Germany. 2Dept of Anaesthesiology, Perioperative Medicine and IntensiveCare Medicine, Paracelsus Medical University, Salzburg, Austria. 3Dept of Intensive Care, AarhusUniversity Hospital, Aarhus, Denmark. 4Cardiac Intensive Care Unit, Massachusetts General Hospital,Boston, MA, USA. 5Dept of Intensive Care Medicine, CIBER Enfermedades Respiratorias, CorporacionSanitaria Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain. 6Dept ofAcute Medicine, Geneva University Hospitals, Geneva, Switzerland. 7Dept of Intensive Care Medicine,Inselspital, Universitätsspital, University of Bern, Bern, Switzerland. 8Dept of Medical Intensive Care,Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.9Dept of Anesthesia, Intensive Care and Pain Medicine, Hadassah Medical Center and Faculty ofMedicine, Hebrew University of Jerusalem, Jerusalem, Israel. 10Center for Intensive Care andPerioperative Medicine, Jagiellonian University Medical College, Krakow, Poland. 112nd Dept ofAnesthesiology and Intensive Care, Medical University of Lublin, Lublin, Poland. 12Faculty of Medicine,University of Tripoli, Tripoli, Libya. 13Division of Intensive Care and Emergency Medicine, Dept ofInternal Medicine, Medical University Innsbruck, Innsbruck, Austria. 14Dept of Intensive Care 1K12IC,Ghent University Hospital, Ghent, Belgium. 15Intensive Care Unit General Hospital of Larissa, Larissa,Greece. 16Mater Misericordiae University Hospital, Dublin, Ireland. 17Dept Of Anaesthesia and IntensiveCare, Ålesund Hospital, Ålesund, Norway. 18Dept of Circulation and Medical Imaging, NorwegianUniversity of Science and Technology, Trondheim, Norway. 19Unidade de Cuidados IntensivosNeurocríticos e Trauma, Hospital de São José, Centro Hospitalar Universitário de Lisboa Central,Faculdade de Ciências Médicas de Lisboa, Nova Médical School, Lisbon, Portugal. 20Dept ofAnaesthesia IRCCS, Instituto Clínico Humanitas, Humanitas University, Milan, Italy. 21General IntensiveCare, St George’s University Hospitals NHS Foundation Trust, London, UK. 22Sorbonne Universités,UPMC Univ Paris 06, INSERM, UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique,Equipe: épidémiologie hospitalière qualité et organisation des soins, Paris, France. 23AssistancePublique - Hôpitaux de Paris, Hôpital Saint-Antoine, Service de réanimation médicale, Paris, France.24Dept of Intensive Care Medicine, University Medical Center, University Utrecht, Utrecht, TheNetherlands. 25Dept of Clinical Medicine, University of Bergen, Bergen, Norway. 26Dept of Anaesthesiaand Intensive Care, Haukeland University Hospital, Bergen, Norway.Corresponding author: Christian Jung (christian.jung@med.uni-duesseldorf.de)This study is registered at Clinicaltrials.gov as NCT04321265.Conflict of interest: C. Jung has nothing to disclose. B. Wernly has nothing to disclose. J. Fjølner has nothing todisclose. R.R. Bruno has nothing to disclose. D. Dudzinski has nothing to disclose. A. Artigas reports grants fromGrifols and Fisher&Paykel, personal fees for advisory board work from Grifols, Novartis and Lilly Foundation,outside the submitted work. B. Bollen Pinto has nothing to disclose. J.C. Schefold has nothing to disclose. G. Wolffhas nothing to disclose. M. Kelm has nothing to disclose. M. Beil has nothing to disclose. S. Sigal has nothing todisclose. P.V. van Heerden has nothing to disclose. W. Szczeklik has nothing to disclose. M. Czuczwar has nothingto disclose. M. Elhadi has nothing to disclose. M. Joannidis has nothing to disclose. S. Oeyen has nothing todisclose. T. Zafeiridis has nothing to disclose. B. Marsh has nothing to disclose. F.H. Andersen has nothing todisclose. R. Moreno has nothing to disclose. M. Cecconi has nothing to disclose. S. Leaver has nothing to disclose.A. Boumendil has nothing to disclose. D.W. De Lange has nothing to disclose. B. Guidet has nothing to disclose.H. Flaatten has nothing to disclose.Support statement: This work was supported by the European Commission, APHP and Health Region West(Norway). Funding information for this article has been deposited with the Crossref Funder Registry.References1 Waterer GW, Rello J. Steroids and COVID-19: we need a precision approach, not one size fits all. Infect Dis Ther2020; 9: 701–705.https://doi.org/10.1183/13993003.00979-2021 3EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | C. JUNG ET AL.2 Britt RC, Devine A, Swallen KC, et al. Corticosteroid use in the intensive care unit: at what cost? Arch Surg2006; 141: 145–149.3 Jung C, Flaatten H, Fjolner J, et al. The impact of frailty on survival in elderly intensive care patients withCOVID-19: the COVIP study. Crit Care 2021; 25: 149.4 Guidet B, de Lange DW, Boumendil A, et al. The contribution of frailty, cognition, activity of daily life andcomorbidities on outcome in acutely admitted patients over 80 years in European ICUs: the VIP2 study.Intensive Care Med 2020; 46: 57–69.5 Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med2021; 384: 693–704.6 Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free inpatients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomizedclinical trial. JAMA 2020; 324: 1307–1316.7 Gogali A, Kyriakopoulos C, Kostikas K. Corticosteroids in COVID-19: one size does not fit all. Eur Respir J 2021;57: 2100224.https://doi.org/10.1183/13993003.00979-2021 4EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | C. JUNG ET AL.

Steroid use in elderly critically ill COVID-19 patients

https://dspace.library.uu.nl/bitstream/1874/443117/1/2100979.full.pdf

Steroid use in elderly critically ill COVID-19 patients

Abstract

Similar works

Full text

Available Versions

Utrecht University Repository