# Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study

Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet

<figure><img src="image_1.png" /></figure>

## To cite this version:

Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet. Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study. PLoS ONE, 2023, 18 (3), pp.e0283165. 10.1371/journal.pone.0283165. inserm-04546906

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RESEARCH ARTICLE

# Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study

<figure><img src="image_1.png" /></figure>

Matthieu Peretti<sup>1</sup>, Stanislas Rebaudet<sup>2,3</sup>, Laurent Chiche<sup>2*</sup>, Hervé Pegliasco<sup>4</sup>, Emilie Coquet<sup>1</sup>

1 Service de Pharmacie, Hôpital Européen, Marseille, France, 2 Service d'Infectiologie et de Médecine Interne, Hôpital Européen, Marseille, France, 3 UMR1252 SESSTIM, Aix-Marseille Univ, Inserm, IRD, ISSPAM, Marseille, France, 4 Service de Pneumologie, Hôpital Européen, Marseille, France

* l.chiche@hopital-european.fr

<figure><img src="image_2.png" /></figure>

OPEN ACCESS

**Citation:** Peretti M, Rebaudet S, Chiche L, Pegliasco H, Coquet E (2023) Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study. PLoS ONE 18(3): e0283165. https://doi.org/10.1371/journal.pone.0283165

**Editor:** Robert Jeenchen Chen, Stanford University School of Medicine, UNITED STATES

**Received:** July 7, 2022

**Accepted:** February 21, 2023

**Published:** March 17, 2023

**Peer Review History:** PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0283165

**Copyright:** © 2023 Peretti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

**Data Availability Statement:** According to the European Data Protection Regulation (General Data

## Abstract

### Objectives

To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic.

### Methods

This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves.

### Results

A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials.
RESEARCH ARTICLE

# Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study

<figure><img src="image_2.png" /></figure>

Matthieu Peretti<sup>1</sup>, Stanislas Rebaudet<sup>2,3</sup>, Laurent Chiche<sup>2*</sup>, Hervé Pegliasco<sup>4</sup>, Emilie Coquet<sup>1</sup>

1 Service de Pharmacie, Hôpital Européen, Marseille, France, 2 Service d'Infectiologie et de Médecine Interne, Hôpital Européen, Marseille, France, 3 UMR1252 SESSTIM, Aix-Marseille Univ, Inserm, IRD, ISSPAM, Marseille, France, 4 Service de Pneumologie, Hôpital Européen, Marseille, France

* l.chiche@hopital-european.fr

<figure><img src="image_3.png" /></figure>

## OPEN ACCESS

**Citation:** Peretti M, Rebaudet S, Chiche L, Pegliasco H, Coquet E (2023) Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study. PLoS ONE 18(3): e0283165. https://doi.org/10.1371/journal.pone.0283165

**Editor:** Robert Jeenchen Chen, Stanford University School of Medicine, UNITED STATES

**Received:** July 7, 2022

**Accepted:** February 21, 2023

**Published:** March 17, 2023

**Peer Review History:** PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0283165

**Copyright:** © 2023 Peretti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

**Data Availability Statement:** According to the European Data Protection Regulation (General Data

## Abstract

### Objectives

To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic.

### Methods

This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves.

### Results

A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials.
Protection Regulation, GDPR), data including
individual patient characteristics which support the
findings of the present study could not be
deposited in any integrated repository. However,
the full pseudo-anonymised database is available
upon reasonable request to Miss Cecile Berthelier
(Clinical Research Department) at c.
berthelier@hopital-europeen.fr and Miss Margaux
Garreau (Ethic Committee) at m.garreau@hopital-
europeen.fr.

**Funding:** The author(s) received no specific
funding for this work.

**Competing interests:** The authors have declared
that no competing interests exist.

Conclusions

The effective dissemination of evidence-based and concerted recommendations seems to
have allowed an optimized management of COVID-19 drug therapies in the context of this
emerging infection with rapidly evolving therapeutic questions.

Introduction

In 2020, the SARS-CoV-2 pandemic was a unique health event that caused the health care system to be overwhelmed in several French regions [1]. The initial "shock" was followed by a rapid reorganization of the management of patients suffering from a new pathology, COVID-19, for which the medical teams had very little data, particularly in terms of medication. The Hôpital Européen Marseille (HEM) is a 610-bed private non-profit hospital located in the heart of Marseille's impoverished districts and having, in particular, emergency, infectious diseases, pneumology and intensive care wards (ICU). From February 2020 onwards, HEM was committed by the regional public health authorities in the response to the COVID-19 pandemic, and played a major role in the care of COVID-19 patients in the Marseille area. At the peak of the first epidemic wave (April 1, 2020), HEM was taking care of up to 75 hospitalized patients, thanks to the involvement of a large part of the establishment's medical community.

As early as March 16, a COVID multidisciplinary consultation meeting (RCP) was set up,
bringing together infectiologists, respirologists, internists, ICU physicians, cardiologists, radi-
ologists, biologists, immunologists, epidemiologists and pharmacists. RCP objectives were: (1)
to ensure a permanent monitoring of the published literature and guidelines concerning the
management of COVID patients; (2) to share observations or difficulties from the field (lack of
staff, drugs in short supply...); (3) to propose a regular update of local management recom-
mendations; and (4) to organize daily medical discussions of specific COVID patients, not
only to homogenize and rationalize rapidly evolving practices, but also to reassure clinicians in
a context of off-label prescriptions. Digital tools (WhatsApp group, hospital COVID-19 thera-
peutic guide on smartphone, webinars) facilitated the real-time dissemination of updated rec-
ommendations, as well as advice requests from clinicians and feedback. Pharmacists also had a
role in informing about the availability of certain off-label treatments and monitoring the
stock status of life-saving drugs.

In order to evaluate the impact of local therapeutic recommendation updates made by the
COVID RCP in this context of great initial uncertainty, the objective of the present study was
to describe the drug prescriptions for COVID-19 at HEM during the first two waves of the
epidemic.

**Methods**

The main aim of the COVID multidisciplinary consultation meeting (RCP) at Hôpital Européen Marseille (HEM) was to develop evidence-based, rapid, living guidelines intended to support our clinicians in their decisions about management of severe COVID infection. A living review of the peer-reviewed and grey literature (including preprints articles) was conducted at regular intervals (daily to weekly) and discussed by a panel of experts from various area including infectious diseases specialists, experts in public health as well as other front-line clinicians, specializing in immunology, medical microbiology, critical care, pneumology, internal medicine, hepatology, nephrology, neurology, gastroenterology, and pharmacists. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach
Protection Regulation, GDPR), data including
individual patient characteristics which support the
findings of the present study could not be
deposited in any integrated repository. However,
the full pseudo-anonymised database is available
upon reasonable request to Miss Cecile Berthelier
(Clinical Research Department) at c.

berthelier@hopital-europeen.fr and Miss Margaux
Garreau (Ethic Committee) at m.garreau@hopital-
europeen.fr.

**Funding:** The author(s) received no specific
funding for this work.

**Competing interests:** The authors have declared
that no competing interests exist.

Conclusions

The effective dissemination of evidence-based and concerted recommendations seems to
have allowed an optimized management of COVID-19 drug therapies in the context of this
emerging infection with rapidly evolving therapeutic questions.

Introduction

In 2020, the SARS-CoV-2 pandemic was a unique health event that caused the health care system to be overwhelmed in several French regions [1]. The initial "shock" was followed by a rapid reorganization of the management of patients suffering from a new pathology, COVID-19, for which the medical teams had very little data, particularly in terms of medication. The Hôpital Européen Marseille (HEM) is a 610-bed private non-profit hospital located in the heart of Marseille's impoverished districts and having, in particular, emergency, infectious diseases, pneumology and intensive care wards (ICU). From February 2020 onwards, HEM was committed by the regional public health authorities in the response to the COVID-19 pandemic, and played a major role in the care of COVID-19 patients in the Marseille area. At the peak of the first epidemic wave (April 1, 2020), HEM was taking care of up to 75 hospitalized patients, thanks to the involvement of a large part of the establishment's medical community.

As early as March 16, a COVID multidisciplinary consultation meeting (RCP) was set up,
bringing together infectiologists, respirologists, internists, ICU physicians, cardiologists, radi-
ologists, biologists, immunologists, epidemiologists and pharmacists. RCP objectives were: (1)
to ensure a permanent monitoring of the published literature and guidelines concerning the
management of COVID patients; (2) to share observations or difficulties from the field (lack of
staff, drugs in short supply...); (3) to propose a regular update of local management recom-
mendations; and (4) to organize daily medical discussions of specific COVID patients, not
only to homogenize and rationalize rapidly evolving practices, but also to reassure clinicians in
a context of off-label prescriptions. Digital tools (WhatsApp group, hospital COVID-19 thera-
peutic guide on smartphone, webinars) facilitated the real-time dissemination of updated rec-
ommendations, as well as advice requests from clinicians and feedback. Pharmacists also had a
role in informing about the availability of certain off-label treatments and monitoring the
stock status of life-saving drugs.

In order to evaluate the impact of local therapeutic recommendation updates made by the
COVID RCP in this context of great initial uncertainty, the objective of the present study was
to describe the drug prescriptions for COVID-19 at HEM during the first two waves of the
epidemic.

**Methods**

The main aim of the COVID multidisciplinary consultation meeting (RCP) at Hôpital Européen Marseille (HEM) was to develop evidence-based, rapid, living guidelines intended to support our clinicians in their decisions about management of severe COVID infection. A living review of the peer-reviewed and grey literature (including preprints articles) was conducted at regular intervals (daily to weekly) and discussed by a panel of experts from various area including infectious diseases specialists, experts in public health as well as other front-line clinicians, specializing in immunology, medical microbiology, critical care, pneumology, internal medicine, hepatology, nephrology, neurology, gastroenterology, and pharmacists. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach
was used to assess the certainty of evidence and make recommendations [2]. For all recommen-
dations, the expert panellists reached consensus. Guidelines from various medical societies were
considered as potential external validation but never awaited for our internal recommendations.
The regular reviewing process was followed by a rapid recommendation development checklist
made immediately available to our clinicians via a web-based COVID-19 therapeutic guide on
smartphone and WhatsApp groups. The RCP fostered inclusion of patients into ongoing
cohorts and trials as much and as early as possible: French COVID Cohort (ClinicalTrials.gov
Identifier: NCT04262921); HYCOVID (Hydroxychloroquine Versus Placebo in COVID-19
Patients at Risk for Severe Disease–NCT04325893) [3]; FORCE (Avdoralimab an Anti-C5aR
Antibody, in Patients With COVID-19 Severe Pneumonia–NCT04371367) [4]; ANACONDA
(Anakinra for COVID-19 Respiratory Symptoms–NCT04364009) [5].

In order to evaluate the impact of local therapeutic recommendation updates made by the
COVID RCP, we retrospectively included all patients hospitalized for COVID-19 between
February 1, 2020 and January 21, 2021. We extracted specific anti-COVID-19 therapies (ST)
from computerized patient record, including those administered in clinical trials in which the
hospital participated, as well as patients’ demographic characteristics, comorbidities (including
BMI, modified Charlson index [6]), and outcome (ICU admission, death). The evolution of ST
prescriptions during the study period was described and put into perspective with the updates
of local recommendations. We performed a comparative analysis between patients who did
(ST+) or did not (ST-) receive specific anti-COVID-19 therapies, excluding anticoagulation,
and between patients of the first (W1, from 2/24/2020 to 7/27/2020), and second (W2, from 7/
28/2020 to 1/21/2021) epidemic waves in France. The Chi-square and the Student’s t tests were
used for categorical and quantitative variables, respectively, and computed using RStudio
v1.2.5033 for Windows.

This retrospective observational study analysed data from the hospital’s pharmaceutical file.
The study did not involve humans, but only reused routine patient records. Data access com-
plied with French relevant data protection and privacy regulations. The study thus required
neither information nor non-opposition of the included individuals and was approved by the
institutional and ethical review board of the Hôpital Européen Marseille (n°2022-01-01).

Results

During the first two waves, HEM teams managed a total of 607 COVID-19 hospitalized patients, including 197 patients during W1 and 410 during W2 (Fig 1). In patients characteristics and outcomes are summarized in Table 1. Their mean age was 65 years-old, and they presented frequent comorbidities: hypertension (43%), diabetes (33%) and obesity (28%). In patients mean age and comorbidities were similar between W1 and W2 (Table 1).

In total, 93% of hospitalized patients received ST (i.e. at least one specific anti-COVID-19 therapy) (Fig 1): anticoagulants (90%), including low molecular weight heparin (n = 468, 86%), unfractionated heparin (n = 52, 10%), direct oral anticoagulants (n = 45, 8%) and vitamin K antagonists (n = 8, 1.5%); glucocorticoids (39%), mainly during W2 (49% vs 17%, P<0.001); and azithromycin (30%) (Table 1). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during W1. Remdesivir was never administered in HEM (Table 1). Hydroxychloroquine and lopinavir-ritonavir were administered to 7 and 17 patients, respectively, and only in March-April 2020 (Fig 1). Prescription of azithromycin was frequent during W1 (71% of patients), then it markedly dropped during W2 (10%). A total of 22 inpatients were enrolled into clinical trials testing hydroxychloroquine (NCT04325893) [3] or Avdoralimab (NCT04371367) [4]. The monthly evolution of ST prescriptions followed the recommendations of the COVID RCP (Fig 1).
was used to assess the certainty of evidence and make recommendations [2]. For all recommen-
dations, the expert panellists reached consensus. Guidelines from various medical societies were
considered as potential external validation but never awaited for our internal recommendations.
The regular reviewing process was followed by a rapid recommendation development checklist
made immediately available to our clinicians via a web-based COVID-19 therapeutic guide on
smartphone and WhatsApp groups. The RCP fostered inclusion of patients into ongoing
cohorts and trials as much and as early as possible: French COVID Cohort (ClinicalTrials.gov
Identifier: NCT04262921); HYCOVID (Hydroxychloroquine Versus Placebo in COVID-19
Patients at Risk for Severe Disease–NCT04325893) [3]; FORCE (Avdoralimab an Anti-C5aR
Antibody, in Patients With COVID-19 Severe Pneumonia–NCT04371367) [4]; ANACONDA
(Anakinra for COVID-19 Respiratory Symptoms–NCT04364009) [5].

In order to evaluate the impact of local therapeutic recommendation updates made by the
COVID RCP, we retrospectively included all patients hospitalized for COVID-19 between
February 1, 2020 and January 21, 2021. We extracted specific anti-COVID-19 therapies (ST)
from computerized patient record, including those administered in clinical trials in which the
hospital participated, as well as patients’ demographic characteristics, comorbidities (including
BMI, modified Charlson index [6]), and outcome (ICU admission, death). The evolution of ST
prescriptions during the study period was described and put into perspective with the updates
of local recommendations. We performed a comparative analysis between patients who did
(ST+) or did not (ST-) receive specific anti-COVID-19 therapies, excluding anticoagulation,
and between patients of the first (W1, from 2/24/2020 to 7/27/2020), and second (W2, from 7/
28/2020 to 1/21/2021) epidemic waves in France. The Chi-square and the Student’s t tests were
used for categorical and quantitative variables, respectively, and computed using RStudio
v1.2.5033 for Windows.

This retrospective observational study analysed data from the hospital’s pharmaceutical file.
The study did not involve humans, but only reused routine patient records. Data access com-
plied with French relevant data protection and privacy regulations. The study thus required
neither information nor non-opposition of the included individuals and was approved by the
institutional and ethical review board of the Hôpital Européen Marseille (n°2022-01-01).

**Results**

During the first two waves, HEM teams managed a total of 607 COVID-19 hospitalized patients, including 197 patients during W1 and 410 during W2 (Fig 1). In patients characteristics and outcomes are summarized in Table 1. Their mean age was 65 years-old, and they presented frequent comorbidities: hypertension (43%), diabetes (33%) and obesity (28%). In patients mean age and comorbidities were similar between W1 and W2 (Table 1).

In total, 93% of hospitalized patients received ST (i.e. at least one specific anti-COVID-19 therapy) (Fig 1): anticoagulants (90%), including low molecular weight heparin (n = 468, 86%), unfractionated heparin (n = 52, 10%), direct oral anticoagulants (n = 45, 8%) and vitamin K antagonists (n = 8, 1.5%); glucocorticoids (39%), mainly during W2 (49% vs 17%, P<0.001); and azithromycin (30%) (Table 1). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during W1. Remdesivir was never administered in HEM (Table 1). Hydroxychloroquine and lopinavir-ritonavir were administered to 7 and 17 patients, respectively, and only in March-April 2020 (Fig 1). Prescription of azithromycin was frequent during W1 (71% of patients), then it markedly dropped during W2 (10%). A total of 22 inpatients were enrolled into clinical trials testing hydroxychloroquine (NCT04325893) [3] or Avdoralimab (NCT04371367) [4]. The monthly evolution of ST prescriptions followed the recommendations of the COVID RCP (Fig 1).
<figure><img src="image_3.png" /><figcaption>**Fig 1.** Monthly trends in prescriptions of specific anti-COVID-19 therapies (excluding clinical trials*) in hospitalized patients, and main recommendations of the COVID RCP (numbered arrows) during the first two waves (W1 and W2). Arrow n°1: HCSP and ISTH [7, 8] official recommendations, and critical analysis of the first publications concerning the lopinavir-ritonavir [9] combination, hydroxychloroquine (HCQ)-azithromycin (AZT) [10] combination and remdesivir [11] by the COVID multidisciplinary consultation meeting (RCP) of the hospital. Arrow n°2: First randomized trial involving hydroxychloroquine [12] and alerts from pharmacovigilance centres (HCQ ± AZT, lopinavir-ritonavir). Arrow n°3: first randomized trial of dexamethasone [13]. Arrow n°4: randomized trial on azithromycin [14]. *Clinical trials: HYCOVID (NCT04325893, n = 1) [3] and FORCE (NCT04371367, n = 21) [4] evaluating hydroxychloroquine and avdoralimab, respectively.</figcaption></figure>

https://doi.org/10.1371/journal.pone.0283165.g001

Patients with comorbidities were more likely to receive a ST (excluding anticoagulation) against COVID-19 (S1 Table): BMI was significantly higher (28.0 vs 26.7, P-value = 0.015), high blood pressure was significantly more frequent (46% vs 37%, P-value = 0.031), and diabetes tended to be more frequent (37% vs 29%, P-value = 0.050) in the ST+ group than in the ST-group.

Non-specific treatments were prescribed to numerous patients: 440 patients (72%) received antipyretics (including paracetamol); 33 (5%) patients received non-steroid anti-inflammatory drugs such as ibuprofen and ketoprofen; 250 patients (41%) received oral antidiabetic treatment or insulin therapy; 360 patients (59%) received anti-hypertensive treatment; and 413 patients (68%) received either antidiabetic or anti-hypertensive treatment.

The overall average length of hospital stay was 13.3 days. A total of 134 inpatients (22%) were admitted to the ICU, and the overall mortality rate was 15% (Table 1). The proportion of patients admitted to the ICU and the mortality rate were similar during W1 and W2 (Table 1). The length of hospital stay was longer in the ST+ group than in the ST- group (16.8 vs 7.9 days, P-value<0.001). Finally, the proportion of patients admitted to the ICU was higher in the ST+ group than in the ST- group (32% vs 6%, P-value < 0.001) (S1 Table).

Discussion

Hydroxychloroquine, azithromycin and lopinavir-ritonavir were the most used repurposed drugs in different centres around the world for treatment of COVID-19 patients in 2020 [15].
<figure><img src="image_4.png" /><figcaption>**Fig 1.** Monthly trends in prescriptions of specific anti-COVID-19 therapies (excluding clinical trials*) in hospitalized patients, and main recommendations of the COVID RCP (numbered arrows) during the first two waves (W1 and W2). Arrow n°1: HCSP and ISTH [7, 8] official recommendations, and critical analysis of the first publications concerning the lopinavir-ritonavir [9] combination, hydroxychloroquine (HCQ)-azithromycin (AZT) [10] combination and remdesivir [11] by the COVID multidisciplinary consultation meeting (RCP) of the hospital. Arrow n°2: First randomized trial involving hydroxychloroquine [12] and alerts from pharmacovigilance centres (HCQ ± AZT, lopinavir-ritonavir). Arrow n°3: first randomized trial of dexamethasone [13]. Arrow n°4: randomized trial on azithromycin [14]. *Clinical trials: HYCOVID (NCT04325893, n = 1) [3] and FORCE (NCT04371367, n = 21) [4] evaluating hydroxychloroquine and avdoralimab, respectively.</figcaption></figure>

https://doi.org/10.1371/journal.pone.0283165.g001

Patients with comorbidities were more likely to receive a ST (excluding anticoagulation) against COVID-19 (S1 Table): BMI was significantly higher (28.0 vs 26.7, P-value = 0.015), high blood pressure was significantly more frequent (46% vs 37%, P-value = 0.031), and diabetes tended to be more frequent (37% vs 29%, P-value = 0.050) in the ST+ group than in the ST-group.

Non-specific treatments were prescribed to numerous patients: 440 patients (72%) received antipyretics (including paracetamol); 33 (5%) patients received non-steroid anti-inflammatory drugs such as ibuprofen and ketoprofen; 250 patients (41%) received oral antidiabetic treatment or insulin therapy; 360 patients (59%) received anti-hypertensive treatment; and 413 patients (68%) received either antidiabetic or anti-hypertensive treatment.

The overall average length of hospital stay was 13.3 days. A total of 134 inpatients (22%) were admitted to the ICU, and the overall mortality rate was 15% (Table 1). The proportion of patients admitted to the ICU and the mortality rate were similar during W1 and W2 (Table 1). The length of hospital stay was longer in the ST+ group than in the ST- group (16.8 vs 7.9 days, P-value<0.001). Finally, the proportion of patients admitted to the ICU was higher in the ST+ group than in the ST- group (32% vs 6%, P-value < 0.001) (S1 Table).

Discussion

Hydroxychloroquine, azithromycin and lopinavir-ritonavir were the most used repurposed drugs in different centres around the world for treatment of COVID-19 patients in 2020 [15].
<table><caption>Table 1. Characteristics and outcome of patients hospitalized with COVID-19, and specific therapies administered during the first (V1) and second (V2) epidemic waves.</caption><thead><tr><th></th><th>Global</th><th>First epidemic wave (W1)</th><th>Second epidemic wave (W2)</th><th>W1 vs W2 (P-value)<sup>§</sup></th></tr></thead><tbody><tr><td>Number of patients hospitalized for COVID-19</td><td>607</td><td>197</td><td>410</td><td></td></tr><tr><td>Patients' characteristics (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>sex ratio (M/F)</td><td>1.7</td><td>1.9</td><td>1.6</td><td>0.417</td></tr><tr><td>mean age ± SD (years)</td><td>64.8 ± 16.2</td><td>64.2 ± 16.2</td><td>65.1 ± 16.2</td><td>0.507</td></tr><tr><td>mean BMI ± SD (kg/m2) (n = 529)</td><td>28.1 ± 13.3</td><td>27.2 ± 5.2</td><td>28.5 ± 15.6</td><td>0.342</td></tr><tr><td>mean modified Charlson index ± SD</td><td>1.3 ± 2.2</td><td>1.3 ± 2.3</td><td>1.3 ± 2.2</td><td>0.751</td></tr><tr><td>obesity (%) (n = 531)</td><td>148 (28%)</td><td>49 (30%)</td><td>99 (27%)</td><td>0.515</td></tr><tr><td>diabetes (%)</td><td>203 (33%)</td><td>67 (34%)</td><td>136 (33%)</td><td>0.910</td></tr><tr><td>high blood pressure (%)</td><td>259 (43%)</td><td>82 (42%)</td><td>177 (43%)</td><td>0.785</td></tr><tr><td>Patients' outcome (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>ICU admission (%)</td><td>134 (22%)</td><td>48 (24%)</td><td>86 (21%)</td><td>0.402</td></tr><tr><td>average length of stay ± SD (days)</td><td>13.3 ± 16</td><td>13.8 ± 15.5</td><td>13.1 ± 16.2</td><td>0.585</td></tr><tr><td>mortality rate (%)</td><td>92 (15%)</td><td>31 (16%)</td><td>61 (15%)</td><td>0.877</td></tr><tr><td>mean age at death ± SD (years) (n = 92)</td><td>71.5 ± 16.3</td><td>71.2 ± 15.2</td><td>71.7 ± 16.8</td><td>0.903</td></tr><tr><td>Specific anti-COVID-19 therapies (ST) (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>At least 1 ST (including anticoagulant)</td><td>561 (93%)</td><td>182 (92%)</td><td>379 (92%)</td><td>1</td></tr><tr><td>At least 1 ST (exclusion of anticoagulant)</td><td>372 (63%)</td><td>154 (78%)</td><td>218 (53%)</td><td>&lt;0.001</td></tr><tr><td>anticoagulants (%)</td><td>547 (90%)</td><td>174 (88%)</td><td>373 (91%)</td><td>0.379</td></tr><tr><td>azithromycin (%)</td><td>183 (30%)</td><td>140 (71%)</td><td>43 (10%)</td><td>&lt;0.001</td></tr><tr><td>corticosteroids (%)</td><td>235 (39%)</td><td>34 (17%)</td><td>201 (49%)</td><td>&lt;0.001</td></tr><tr><td>others (%):</td><td>46 (9%)</td><td>23 (12%)</td><td>23 (6%)</td><td>0.001</td></tr><tr><td>lopinavir/ritonavir</td><td>17</td><td>17</td><td>0</td><td></td></tr><tr><td>hydroxychloroquine</td><td>7</td><td>7</td><td>0</td><td></td></tr><tr><td>remdesivir</td><td>0</td><td>0</td><td>0</td><td></td></tr><tr><td>tocilizimab</td><td>2</td><td>2</td><td>0</td><td></td></tr><tr><td>anakinra</td><td>2</td><td>1</td><td>1</td><td></td></tr><tr><td>convalescent plasma therapy</td><td>1</td><td>0</td><td>1</td><td></td></tr><tr><td>clinical trials*</td><td>22</td><td>1</td><td>21</td><td></td></tr></tbody></table>

SD, standard deviation; BMI, body mass index

In comparison, in our centre, hydroxychloroquine and lopinavir-ritonavir were administered to a very small group of patients and only at the very start of the pandemic, while azithromycin prescription dramatically dropped after the first pandemic wave. Remdesivir was never prescribed to our COVID-19 inpatients during our study period because: this specific drug was not available in our hospital at the beginning the pandemic; it was not judged clinically meaningful according to our implementation process based on the continuous critical reviewing of the available medical literature; and the French drug authorities (*Haute Autorité de Santé*) eventually considered in September 2020 that remdesivir did not bring any improvement in medical benefit in the cure of inpatients with moderate illness, and brought an insufficient medical benefit for those with severe or critical illness [16]. Of note, anti-COVID-19 vaccines and monoclonal antibodies were not available in France during our study period.

The effective dissemination of evidence-based and concerted recommendations during daily multidisciplinary meetings and through digital tools seems to have allowed an optimized

<footnote>* HYCOVID (NCT04325893, hydroxychloroquine, n = 1) [3] et FORCE (NCT04371367, avdoralimab, n = 21) [4]</footnote>

<footnote>§ Chi-square was used for categorical variables and the Student's t test was used for quantitative variables</footnote>
<table><caption>Table 1. Characteristics and outcome of patients hospitalized with COVID-19, and specific therapies administered during the first (V1) and second (V2) epidemic waves.</caption><thead><tr><th></th><th>Global</th><th>First epidemic wave (W1)</th><th>Second epidemic wave (W2)</th><th>W1 vs W2 (P-value)<sup>§</sup></th></tr></thead><tbody><tr><td>Number of patients hospitalized for COVID-19</td><td>607</td><td>197</td><td>410</td><td></td></tr><tr><td>Patients' characteristics (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>sex ratio (M/F)</td><td>1.7</td><td>1.9</td><td>1.6</td><td>0.417</td></tr><tr><td>mean age ± SD (years)</td><td>64.8 ± 16.2</td><td>64.2 ± 16.2</td><td>65.1 ± 16.2</td><td>0.507</td></tr><tr><td>mean BMI ± SD (kg/m2) (n = 529)</td><td>28.1 ± 13.3</td><td>27.2 ± 5.2</td><td>28.5 ± 15.6</td><td>0.342</td></tr><tr><td>mean modified Charlson index ± SD</td><td>1.3 ± 2.2</td><td>1.3 ± 2.3</td><td>1.3 ± 2.2</td><td>0.751</td></tr><tr><td>obesity (%) (n = 531)</td><td>148 (28%)</td><td>49 (30%)</td><td>99 (27%)</td><td>0.515</td></tr><tr><td>diabetes (%)</td><td>203 (33%)</td><td>67 (34%)</td><td>136 (33%)</td><td>0.910</td></tr><tr><td>high blood pressure (%)</td><td>259 (43%)</td><td>82 (42%)</td><td>177 (43%)</td><td>0.785</td></tr><tr><td>Patients' outcome (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>ICU admission (%)</td><td>134 (22%)</td><td>48 (24%)</td><td>86 (21%)</td><td>0.402</td></tr><tr><td>average length of stay ± SD (days)</td><td>13.3 ± 16</td><td>13.8 ± 15.5</td><td>13.1 ± 16.2</td><td>0.585</td></tr><tr><td>mortality rate (%)</td><td>92 (15%)</td><td>31 (16%)</td><td>61 (15%)</td><td>0.877</td></tr><tr><td>mean age at death ± SD (years) (n = 92)</td><td>71.5 ± 16.3</td><td>71.2 ± 15.2</td><td>71.7 ± 16.8</td><td>0.903</td></tr><tr><td>Specific anti-COVID-19 therapies (ST) (n = 607)</td><td></td><td></td><td></td><td></td></tr><tr><td>At least 1 ST (including anticoagulant)</td><td>561 (93%)</td><td>182 (92%)</td><td>379 (92%)</td><td>1</td></tr><tr><td>At least 1 ST (exclusion of anticoagulant)</td><td>372 (63%)</td><td>154 (78%)</td><td>218 (53%)</td><td>&lt;0.001</td></tr><tr><td>anticoagulants (%)</td><td>547 (90%)</td><td>174 (88%)</td><td>373 (91%)</td><td>0.379</td></tr><tr><td>azithromycin (%)</td><td>183 (30%)</td><td>140 (71%)</td><td>43 (10%)</td><td>&lt;0.001</td></tr><tr><td>corticosteroids (%)</td><td>235 (39%)</td><td>34 (17%)</td><td>201 (49%)</td><td>&lt;0.001</td></tr><tr><td>others (%):</td><td>46 (9%)</td><td>23 (12%)</td><td>23 (6%)</td><td>0.001</td></tr><tr><td>lopinavir/ritonavir</td><td>17</td><td>17</td><td>0</td><td></td></tr><tr><td>hydroxychloroquine</td><td>7</td><td>7</td><td>0</td><td></td></tr><tr><td>remdesivir</td><td>0</td><td>0</td><td>0</td><td></td></tr><tr><td>tocilizimab</td><td>2</td><td>2</td><td>0</td><td></td></tr><tr><td>anakinra</td><td>2</td><td>1</td><td>1</td><td></td></tr><tr><td>convalescent plasma therapy</td><td>1</td><td>0</td><td>1</td><td></td></tr><tr><td>clinical trials*</td><td>22</td><td>1</td><td>21</td><td></td></tr></tbody></table>

SD, standard deviation; BMI, body mass index

In comparison, in our centre, hydroxychloroquine and lopinavir-ritonavir were administered to a very small group of patients and only at the very start of the pandemic, while azithromycin prescription dramatically dropped after the first pandemic wave. Remdesivir was never prescribed to our COVID-19 inpatients during our study period because: this specific drug was not available in our hospital at the beginning the pandemic; it was not judged clinically meaningful according to our implementation process based on the continuous critical reviewing of the available medical literature; and the French drug authorities (Haute Autorité de Santé) eventually considered in September 2020 that remdesivir did not bring any improvement in medical benefit in the cure of inpatients with moderate illness, and brought an insufficient medical benefit for those with severe or critical illness [16]. Of note, anti-COVID-19 vaccines and monoclonal antibodies were not available in France during our study period.

The effective dissemination of evidence-based and concerted recommendations during daily multidisciplinary meetings and through digital tools seems to have allowed an optimized

<footnote>* HYCOVID (NCT04325893, hydroxychloroquine, n = 1) [3] et FORCE (NCT04371367, avdoralimab, n = 21) [4]</footnote>

<footnote>§ Chi-square was used for categorical variables and the Student's t test was used for quantitative variables</footnote>
management of COVID-19 drug therapies in the context of this emerging infection with rap-
idly evolving therapeutic questions. This approach made it possible to initiate exceptional off-
label therapies whose interest was then confirmed by clinical trials, and on the contrary to
avoid and/or limit uncontrolled prescriptions of therapies secondarily considered ineffective
or even deleterious [3, 17], while reassuring hospitalists in the particular context of Marseille,
France.

Limitations of the study include the lack of dosage of administered treatments as well as the impossibility to distinguish patients' usual medications against previous comorbidities from those introduced as a consequence of the COVID-19 infection.

The implementation of updated recommendations was eased by immediate diffusion via web application/WhatsApp to front-line clinicians, and daily multidisciplinary discussion in every concerned departments. These new and agile modalities of drug stewardship have been widely used during the following epidemic waves in our hospital, for new anti-COVID therapies such as tocilizumab, convalescent plasma therapy, or monoclonal antibodies. They should, due to their capacity to secure prescriptions, be perpetuated as a new standard of care beyond the pandemic episode.

**Supporting information**

S1 Table. Characteristics and outcomes of patients with (ST+) or without (ST-) anti-
COVID-19 specific therapies (excluding anticoagulant) during the first (W1) and second
(W2) epidemic waves.

(DOCX)

Author Contributions

**Conceptualization:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Data curation:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche.

**Formal analysis:** Matthieu Peretti, Stanislas Rebaudet.

**Supervision:** Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Validation:** Stanislas Rebaudet, Laurent Chiche.

**Visualization:** Matthieu Peretti.

**Writing – original draft:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Writing – review & editing:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Emilie Coquet.

**References**

1. Gaudart J, Landier J, Huiart L, Legendre E, Lehot L, Bendiane MK, et al. Factors associated with the spatial heterogeneity of the first wave of COVID-19 in France: a nationwide geo-epidemiological study. Lancet Public Health. 2021 Apr; 6(4):e222-e231. https://doi.org/10.1016/S2468-2667(21)00006-2 PMID: 33556327

2. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol. 2011 Apr; 64(4):407–15. https://doi.org/10.1016/j.jclinepi.2010.07.017 PMID: 21247734
management of COVID-19 drug therapies in the context of this emerging infection with rap-
idly evolving therapeutic questions. This approach made it possible to initiate exceptional off-
label therapies whose interest was then confirmed by clinical trials, and on the contrary to
avoid and/or limit uncontrolled prescriptions of therapies secondarily considered ineffective
or even deleterious [3, 17], while reassuring hospitalists in the particular context of Marseille,
France.

Limitations of the study include the lack of dosage of administered treatments as well as the impossibility to distinguish patients’ usual medications against previous comorbidities from those introduced as a consequence of the COVID-19 infection.

The implementation of updated recommendations was eased by immediate diffusion via web application/WhatsApp to front-line clinicians, and daily multidisciplinary discussion in every concerned departments. These new and agile modalities of drug stewardship have been widely used during the following epidemic waves in our hospital, for new anti-COVID therapies such as tocilizumab, convalescent plasma therapy, or monoclonal antibodies. They should, due to their capacity to secure prescriptions, be perpetuated as a new standard of care beyond the pandemic episode.

**Supporting information**

S1 Table. Characteristics and outcomes of patients with (ST+) or without (ST-) anti-
COVID-19 specific therapies (excluding anticoagulant) during the first (W1) and second
(W2) epidemic waves.

(DOCX)

Author Contributions

**Conceptualization:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Data curation:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche.

**Formal analysis:** Matthieu Peretti, Stanislas Rebaudet.

**Supervision:** Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Validation:** Stanislas Rebaudet, Laurent Chiche.

**Visualization:** Matthieu Peretti.

**Writing – original draft:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Hervé Pegliasco, Emilie Coquet.

**Writing – review & editing:** Matthieu Peretti, Stanislas Rebaudet, Laurent Chiche, Emilie Coquet.

References

1. Gaudart J, Landier J, Huiart L, Legendre E, Lehot L, Bendiane MK, et al. Factors associated with the spatial heterogeneity of the first wave of COVID-19 in France: a nationwide geo-epidemiological study. Lancet Public Health. 2021 Apr; 6(4):e222-e231. https://doi.org/10.1016/S2468-2667(21)00006-2 PMID: 33556327

2. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol. 2011 Apr; 64(4):407–15. https://doi.org/10.1016/j.jclinepi.2010.07.017 PMID: 21247734
3. Dubée V, Roy PM, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, et al., Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021 Aug; 27(8):1124-1130. https://doi.org/10.1016/j.cmi.2021.03.005 PMID: 33813110

4. Carvelli J, Meziani F, Dellamonica J, Cordier PY, Allardet-Servent J, Fraisse M, et al., Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE]). Crit Care Med. 2022 Dec 1; 50(12):1788-1798. https://doi.org/10.1097/CCM.0000000000005683 PMID: 36218354

5. Audemard-Verger A, Le Gouge A, Pestre V, Courjon J, Langlois V, Vareil MO, et al. Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial. PLoS One. 2022 Aug 4; 17(8):e0269065. https://doi.org/10.1371/journal.pone.0269065 PMID: 35925914

6. Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011 Mar 15; 173(6):676-82. https://doi.org/10.1093/aje/kwq433 PMID: 21330339

7. HCSP. Coronavirus SARS-CoV-2: recommandations thérapeutiques [Internet]. Rapport de l'HCSP. Paris: Haut Conseil de la Santé Publique; 2020 mars [cité 3 oct 2021]. Disponible sur: https://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=785

8. Hachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25; 18(5):1023-6. https://doi.org/10.1111/jth.14810 PMID: 32338827

9. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7; 382(19):1787-99. https://doi.org/10.1056/NEJMoa2001282 PMID: 32187464

10. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimycrob Agents. 2020 Jul; 56(1):105949. https://doi.org/10.1016/j.ijantimicag.2020.105949 PMID: 32205204

11. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 Nov 5; 383 (19):1827-1837.

12. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020 May 14; 369: m1849. https://doi.org/10.1136/bmj.m1849 PMID: 32409561

13. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 feb 25; 384(8):693-704. https://doi.org/10.1056/NEJMoa2021436 PMID: 32678530

14. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 Feb 13; 397 (10274):605-12 https://doi.org/10.1016/S0140-6736(21)00149-5 PMID: 33545096

15. Prats-Uribe A, Sena AG, Lai LYH, Ahmed WU, Alghoul H, Alser O, et al. Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study. BMJ. 2021 May 11; 373:n1038. https://doi.org/10.1136/bmj.n1038 PMID: 33975825

16. VEKLURY (remdesivir) [Internet]. Haute Autorité de Santé. [cité 1 déc 2022]. Disponible sur: https://www.has-sante.fr/jcms/p_3201793/fr/veklury-remdesivir

17. Bosquet A, Affo C, Plaisance L, Poenou G, Mortier E, Mahé I. Outside any therapeutic trial prescription of hydroxychloroquine for hospitalized patients with covid-19 during the first wave of the pandemic: A national inquiry of prescription patterns among French hospitalists. PLoS One. 2022 Jan 21; 17(1): e0261843. https://doi.org/10.1371/journal.pone.0261843 PMID: 35061735
3. Dubée V, Roy PM, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, et al., Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021 Aug; 27(8):1124-1130. https://doi.org/10.1016/j.cmi.2021.03.005 PMID: 33813110

4. Carvelli J, Meziani F, Dellamonica J, Cordier PY, Allardet-Servent J, Fraisse M, et al., Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE]). Crit Care Med. 2022 Dec 1; 50(12):1788-1798. https://doi.org/10.1097/CCM.0000000000005683 PMID: 36218354

5. Audemard-Verger A, Le Gouge A, Pestre V, Courjon J, Langlois V, Vareil MO, et al. Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial. PLoS One. 2022 Aug 4; 17(8):e0269065. https://doi.org/10.1371/journal.pone.0269065 PMID: 35925914

6. Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011 Mar 15; 173(6):676-82. https://doi.org/10.1093/aje/kwq433 PMID: 21330339

7. HCSP. Coronavirus SARS-CoV-2: recommandations thérapeutiques [Internet]. Rapport de l'HCSP. Paris: Haut Conseil de la Santé Publique; 2020 mars [cité 3 oct 2021]. Disponible sur: https://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=785

8. Hachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020 Mar 25; 18(5):1023-6. https://doi.org/10.1111/jth.14810 PMID: 32338827

9. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7; 382(19):1787-99. https://doi.org/10.1056/NEJMoa2001282 PMID: 32187464

10. Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimycrob Agents. 2020 Jul; 56(1):105949. https://doi.org/10.1016/j.ijantimicag.2020.105949 PMID: 32205204

11. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 Nov 5; 383 (19):1827-1837.

12. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020 May 14; 369: m1849. https://doi.org/10.1136/bmj.m1849 PMID: 32409561

13. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 feb 25; 384(8):693-704. https://doi.org/10.1056/NEJMoa2021436 PMID: 32678530

14. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 Feb 13; 397 (10274):605-12 https://doi.org/10.1016/S0140-6736(21)00149-5 PMID: 33545096

15. Prats-Uribe A, Sena AG, Lai LYH, Ahmed WU, Alghoul H, Alser O, et al. Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study. BMJ. 2021 May 11; 373:n1038. https://doi.org/10.1136/bmj.n1038 PMID: 33975825

16. VEKLURY (remdesivir) [Internet]. Haute Autorité de Santé. [cité 1 déc 2022]. Disponible sur: https://www.has-sante.fr/jcms/p_3201793/fr/veklury-remdesivir

17. Bosquet A, Affo C, Plaisance L, Poenou G, Mortier E, Mahé I. Outside any therapeutic trial prescription of hydroxychloroquine for hospitalized patients with covid-19 during the first wave of the pandemic: A national inquiry of prescription patterns among French hospitalists. PLoS One. 2022 Jan 21; 17(1): e0261843. https://doi.org/10.1371/journal.pone.0261843 PMID: 35061735