Amar, B

Boisson, T

Challan-Belval, T

Chroboczek, T

Dechaene, V

Hubac, J

Lacoste, M

Lassale, C

Leduc, D

Masse, C

Megessier, S

Touhiri-Maximin, L

Wackenheim, C

English

UCL Discovery

Accepted Manuscript © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. Title: Corticosteroids in patients with COVID-19: what about the control group?  Authors: Tomasz Chroboczek1, Marie Lacoste1, Chloe Wackenheim1, Thibaut Challan-Belval1, Benjamin Amar2, Thomas Boisson2, Jason Hubac2, Dominique Leduc1, Colleen Masse1, Victor Dechaene1, Laetitia Touhiri-Maximin1, Sandrine Megessier1, Camille Lassale3,4. Affiliations:  1 Service de maladies infectieuses et tropicales, Centre Hospitalier Alpes Léman, 558 route de Findrol, 74130 Contamine sur Arve, France 2 Service de médecine Interne, Centre Hospitalier Alpes Léman, 558 route de Findrol, 74130 Contamines sur Arve, France 3 Hospital del Mar Medical Research Institute (IMIM), Carrer Dr Aiguader, 88, 08003 Barcelona, Spain 4 Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom Corresponding author: Tomasz Chroboczek ORCID ID : https://orcid.org/0000-0001-8449-085X Mail: tchroboczek@gmail.com Tel: (0033) 0450823057 / Fax : (0033) 0450823029  Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020Accepted Manuscript  Dear Editor. Effect of corticosteroids in COVID-19 still needs to be examined [1-3]. In their article, Fadel et al. compared two groups of patients hospitalized with COVID-19, with over half of them receiving corticotherapy in both groups (68.2%, vs 56.8% p=0.094), but different median time between hospitalization and therapy initiation (2 days, IQR 1-3, vs 5 days , IQR 3-7). Negative evolution of the disease occurred less often in the early group (34.9 vs 54.3%, p=0.005). They conclude that corticotherapy may improve the evolution of COVID-19 [4]. To reach this conclusion, comparison of treated and untreated patients should have been made. In our hospital, we investigated retrospectively all cases of confirmed COVID-19 requiring more than 3L of oxygen, in adult patients hospitalized between 10 March and 9 April, 2020. The outcome of interest was oro-tracheal intubation, and we aimed to study the effect of corticotherapy. The study received approval from our Ethics Committee, the patients were informed, and the study was declared to the National Comity for Informatics and Liberties. The independent contribution of the patient’s characteristics to the risk of intubation was analyzed by logistic regression (Table). In order to compute the average treatment effect (ATE) of corticotherapy on intubation, we calculated a propensity score (PS) of exposure to corticosteroids using a logistic regression model, including: age, sex, Charlson index>1, BMI>25 kg/m2, hypertension, time from initiation of symptoms to hospitalization>7 days, CRP>150 mg/L, oxygen>3L, treatment with hydroxychloroquine, and azithromycin. These variables include potential confounders (related to treatment and outcome) and prognosis of the outcome [5]. We used PS matching, matching 1:1 to the nearest neighbor with a caliper of 0.25, to estimate the ATE on intubation of a treatment in a population where all individuals have the same probability of receiving the treatment. As sensitivity analysis, we used inverse probability weighting with the PS.  Out of 70 ases, 35 (50%) required mechanical ventilation, due to respiratory failure. Corticotherapy affected the risk of intubation with a risk difference (ATE) of -47.1% (95%CI -71.8 to -22.5). Using inverse probability weighting, the ATE was similar: -47.5% (95%CI -70.0% to -25.0%). Among the 49 patients that did not receive corticosteroids, 32, i.e. 65%, were intubated. Based on these results, systematic corticotherapy may have resulted in 65% - 47.1% =17.9%, i.e. 12 intubations overall. That would have lifted the pressure on the limited number of beds at the ICU unit. Fadel et al. found that the effect of corticosteroid varies according to the timing of their administration. In our study, mean duration of symptoms before hospitalization was 7.6 ± 4 days, and mean duration before Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020Accepted Manuscript  corticosteroid initiation was 13.0 ± 4.2 days. In our opinion, it is the delay after symptom’s onset that presents a practical interest. This information is rarely found in other comparative studies [4, 6-9].  Further studies are urgently needed, in order to determine not only the effect and the best timing of corticosteroids in COVID-19, but also the best protocol of administration in the best target population.      Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020Accepted Manuscript  Contribution: All authors have seen and approved the manuscript, and contributed significantly to the work.   Acknowledgments  Authors are grateful to Juliusz Chroboczek for his help with proof-reading. An early version of the text in pdf version has been sent on the preprint server MedRxiv.org.  Conflict of interest and funding sources  No financial support was received, and none of the authors has a conflict of interest concerning this report. Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020Accepted Manuscript  References 1. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395(10223): 473-5. 2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395(10229): 1033-4. 3. Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Clin Infect Dis 2020. https://doi.org/10.1093/cid/ciaa478  4. Fadel R, Morrison Austin R, Vahia A, et al. Early Short Course Corticosteroids in Hospitalized Patients with COVID-19. Clinical Infectious Diseases 2020. https://doi.org/10.1101/2020.05.04.20074609  5. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable selection for propensity score models. Am J Epidemiol 2006; 163(12): 1149-56. 6. Zha L, Li S, Pan L, et al. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Med J Aust 2020. https://doi.org/10.5694/mja2.50577  7. Wang Y, Jiang W, He Q, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv 2020: 2020.03.06.20032342. 8. Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther 2020; 5(1): 57. 9. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020. https://doi.org/10.1001/jamainternmed.2020.0994   Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020Accepted Manuscript  Table 1: Multivariable odds ratios of intubation associated with patients characteristics, n=70  Odds Ratio (95% CI) p Age 1.12 (0.98 to 1.29) 0.105 Sex  0.18 (0.01 to 4.71) 0.303 Charlson index > 1 9.52 (0.55 to 164.42) 0.121 BMIa ≥ 25 kg/m-2 1.34 (0.06 to 29.28) 0.852 High blood pressure 4.18 (0.44 to 39.81) 0.213 Duration before hospitalization > 7d 0.36 (0.032 to 4.17) 0.416   Oxygen dose at entrance > 3 l/mn 54.69 (2 to 1497.49) 0.018 Highest CRPb > 150 mg/L   73.47 (2.37 to 2277.84) 0.014   Azythromycine 0.36 (0.02 to 5.19) 0.451 Hydroxychloroquine 99.36 (1.67 to 5907.55) 0.027 Corticosteroids < 0.001 (3.24e-06 to 0.09) 0.004 aBMI: Body Mass Index; CRPb: C-Reactive Protein Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa768/5858270 by guest on 18 June 2020

Corticosteroids in Patients With COVID-19: What About the Control Group?

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Corticosteroids in Patients With COVID-19: What About the Control Group?

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