Pathway of Suspected-COVID-19 Patients From French Emergency Departments During The First Outbreak : A Prospective Controlled Cohort Study

marion DOUPLAT (  marion.douplat@chu-lyon.fr ) Hospices Civils de Lyon Antoine GAVOILLE Hospices Civils de Lyon Fabien SUBTIL Hospices Civils de Lyon Julie HAESEBAERT Hospices Civils de Lyon Laurent JACQUIN Hospices Civils de Lyon Guillaume DURAND Hôpital de Villefranche JeanChristophe LEGA Hospices Civils de Lyon Thomas PERPOINT Hospices Civils de Lyon Véronique POTINET Hospices Civils de Lyon Alain SIGAL Hospices Civils de Lyon Julien BERTHILLER Hospices Civils de Lyon Nathalie PERRETON Hospices Civils de Lyon Karim TAZAROURTE Hospices Civils de Lyon

ED in patient triage was crucial in order to contain and isolate the suspected COVID-19 cases. The need of a dynamic in the patient ow processing has been highlighted [8] and several hospital emergency management plans have been proposed including before-admission triage center [9][10][11]. Several studies have focused on the outcomes of patients during the COVID-19 pandemic but a few have investigated the management of COVID-19 cases from the perspective of EDs [12][13][14]. However, the need to understand how to manage these patients in EDs is a necessity to avoid the overcrowding, to guarantee the safety of the healthcare workers, to anticipate the future need for beds and staff members, and to be able to continue caring for non-COVID-19 patients [12,15].
As the number of COVID-19 cases is rapidly increasing in France at the beginning of March, 2020 we have set up the COVID-ER cohort study. It aimed to provide an exhaustive description over time of the pathway and outcome of patients admitted in French EDs for COVID-19 suspicion from March to May, 2020. The characteristics associated with COVID-19 diagnosis con rmation and prognosis, including ICU admission and all-cause mortality, were described.

Study design and setting
A multicenter prospective observational cohort study was conducted between the March 6 and May 10, 2020 in 4 French EDs comprising 3 universities (Edouard Herriot, Lyon Sud and Croix Rousse Hospital) and 1 general hospital (Villefranche Hospital) around Lyon. The Lyon urban area is the second largest in France and counts 1.6 millions of people. The three university EDs are in urban hospitals and count more than 40,000 annual ED visits for two of them and 80,000 for the third. The ED of the general hospital is suburban and counts 50,000 annual ED visits. This study complied with the Declaration of Helsinski, was approved by both the Institutional Ethics Committee of Hospices Civils of Lyon (N°20-47) and the National Committee for Data Protection (n° 20-090), as requested by the French law. The present manuscript met the STROBE statement [16]. According to French legislation, no written consent was required but only an oral consent approved by the Ethics Committee of Hospices Civils of Lyon (N°20-47) and the National Committee for Data Protection (n° 20-090). All patients were informed that their data were being collected as part of the COVID-ER study via a written information notice and they could object to the collect of their information.

Selection of Participants
All adult patients (≥18 years) presenting to the ED for COVID-19 suspicion (with symptoms evocative of severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection) and requiring hospitalization were included. These symptoms and the criteria of hospitalization are detailed in Supplementary material 1 (S1). Were excluded the COVID-19-suspected patients who did not require hospitalization because there were sent back home without testing due to the limited availability of PCR tests in France at the time of the study.
Patients were tested for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) of respiratory samples. The RT-PCR assays were performed using the RdRp IP2-IP4 primers and probes of the Institut Pasteur protocol, which is used in France for SARS-CoV-2 detection. This protocol, detecting two targets in the RdRp gene, was adapted on the Panther Fusion® (Hologic) molecular system for high throughput diagnostic. A con rmed case of COVID-19 was de ned as a test positive for the detection of SARS-CoV-2. In case of multiple sampling during hospitalization, the nal virological diagnostic was classi ed as positive if one of the samples was tested positive.

Data Collection and Processing
All data were collected from electronic medical records and were for each included patient: demographic  The vital status was collected in EDs and during hospitalization for the whole cohort. We also collected patient management and pathway: destination from EDs (intensive care units (ICU) conventional hospitalization), secondary admission from conventional hospitalization to ICU, ventilator support, decision of withholding or withdrawing life-sustaining treatments, re-hospitalization within 30 days after discharge.

Primary Data Analysis
Continuous variables were expressed as mean ± standard-deviation (SD), or median [interquartile range, IQR] for duration, and categorical variables as count (percentage). Comparisons of outcomes between the COVID-19 positive and COVID-19 negative groups were performed using logistic regression for binary outcomes, and using linear regression with logarithmic transformation for delays. Multivariate analyses were performed: the effect of the COVID-19 status on the outcomes was adjusted for age, sex, number of comorbidities, and loss of autonomy. Unless speci ed otherwise, p-values reported correspond to the ones of multivariate analyses. The sample sizes and percentages over the study period were described using smoothed curved obtained using a LOESS algorithm. The changes in the percentage of death between age categories was compared between the COVID-19 positive and COVID-19 negative groups using a logistic regression model, testing the interaction between the age and group. P-values were considered signi cant below 0.05. Analyses were performed using R, version 3.6.1. (R Core Team (2019), Vienna, Austria, https://www.R-project.org/).

Results
From March 6, 2020 to May 10, 2020, 20,341 patients were admitted in the participating EDs, 7,199 (35.4%) were hospitalized, 2,789 of whom were suspected of SARS-CoV-2 infection. A total of 103 patients were not included in the study due to missing RT-PCR test. Among the 7,199 admitted patients, 2,686 (37.3%) were tested and 760/2,686 (28.3%) tests were positive. The ow chart is detailed on Figure   1.  Table   1).

Outcomes of patients
The proportion of patients admitted in ICU directly from ED was signi cantly higher among COVID-19 positive patients (86, 11.3%) compared to COVID- 19 Table 2).
Changes in terms of care over the study period among COVID-19 positive patients The number of COVID-19 positive patients rapidly increased over the course of March, 2020 with a peak number reached on March 27, 2020 (Fig 3). The number of patients admitted to the ICU decreased since the beginning of the study. The death rate was stable over the study period. However, before April 15, 2020 patients requiring ICU and intubation were more likely to die whereas after April 15, 2020 patients who did not go into ICU were more likely to die (Fig 4). The number of decisions of withholding or withdrawing life-sustaining treatments was stable over time. The age of COVID-19 positive patients admitted to EDs was stable during the study period. The age of the deceased COVID-19 positive patients increased during the second period of the study (supplemental material S2 and S3).

Patient outcomes according to age
No COVID-19 positive patients over 90 was concerned by hospitalisation of less than 48 hours, but about 19.2% (39) of COVID-19 negative patients over 90 were. The ICU admission concerned mostly COVID-19 positive patients under 80. The proportion of death was higher in higher-aged groups, this proportion was even higher among COVID-19 positive patients (33.6% of death for patients over 80) compared to COVID-19 negative patients (11.9% of death for patients over 80; p=0.014; Fig 5).

Discussion
This study highlights the pathway and the outcomes of suspected COVID-19 patients during the rst outbreak from EDs. The present study emphasized that the management and the outcomes of suspected COVID-19 patients were different depending on their COVID-19 status. COVID-19 positive patients required more resource in terms of ICU admission, rehabilitation admission, ventilator support, and stayed longer in the hospital than COVID-19 negative patients. Mortality was also higher among COVID-19 positive patients, this difference was even greater among patients over 80. The results presented herein also suggested that the pro le of patients admitted to the EDs, and who die, differed over the study period.
Before April 15 th , COVID-19 positive patients were younger and were more likely to be admitted to ICU, whereas after April 15 th , they were older, more likely to die in general wards, and were concerned by more decisions of withholding and withdrawing life-sustaining treatments.
The characteristics of the COVID-19 positive patients of the present study broadly re ect the ones reported in other studies, especially in terms of symptoms and co-morbidities (2,3,(17)(18)(19). The rate of obesity was low, about two times lower than in the United States of America (USA)). These trends are consistent with the prevalence of obesity in the general population in France and the United States (20). (2), USA (7), and Italy (18), but a similar median age compared to UK patients (19). These differences may be explained by the different recruitment methods that were used. Herein, ambulatory patients, who are most often younger, were not included, but all hospitalized patients (corresponding to older patients who are more vulnerable and frail) were included.

COVID-19 positive patients had a higher median age than patients in China
The proportion of COVID-19 positive patients admitted to ICU was higher previous studies conducted in USA (New York) (12,18) and UK (19). Several factors may explain these differences. First, the availability of ICU beds is different between countries. At the time of the study, the study ICUs were not overloaded but still reached maximum capacities despite a 30% increase in the number of beds during the rst COVID-19 outbreak. Second, secondary ICU admissions were included herein in the follow-up and were more numerous than primary admissions, whereas they were not always considered in the previously mentioned studies. They correspond to patients who have worsened secondarily within an average of 1 to 2 days. This point has already been emphasized by Singer et al. who have insisted on the need to take secondary ICU admissions into account in order to better estimate ICU capacities. Indeed, they demonstrated that for every 100 persons under investigation who are admitted to the hospital, 9 will require immediate ICU and another 12 will require ICU or invasive mechanical ventilation within 2 to 3 days (12). Finally, the use of mechanical ventilation for COVID-19 positive patients was similar to other studies (18,19) whereas the rate of nasal high-ow nasal oxygen therapy and non-invasive ventilation were higher in our study, suggesting that practices differ across countries (22).
The mortality rated observed herein was lowered compared the one reported in the UK population (19), but not different from the one reported in the US (18,21) or in Italy (17). This could be due to differences in healthcare systems between the UK and Europe and in the proportion of ICU beds to hospital beds, as it has been suggested (19). In addition, patient comorbidities and drug exposure (included glucocorticoids) may differ between cohorts. We showed herein that COVID-19 positive patients over 80 bene ted from very few ICU admissions and mechanical ventilation and died more often than the COVID-19 negative patients. This observation has been supported by other studies (12;19). An interesting point is the fact that, during the second period of the study, patients who died were not admitted into ICU and were older, suggesting the presence of clusters in retirement homes at this time of the outbreak. Retirement homes were also affected in the US as a similar proportion of patients coming from retirement homes has been reported (12).
The decisions of withholding and withdrawing life-sustaining treatments during the COVID-19 pandemic have been rarely studied because of the di culty to collect data regarding the a priori decided level of care (19). In the present study, a high prevalence of these decisions concerning COVID-19 positive patients was reported. However, there was no difference in the amount of these decisions prior to death between COVID-19 positive and negative patients. In our opinion, this can be explained by the fact that the COVID-19 health crisis led healthcare teams to anticipate the potential aggravation of patients. Indeed, it has been previously shown that there was little anticipation regarding end-of-life decisions in the EDs and that the management such decisions should be improved (23)(24). The decision-making process of these decisions is especially di cult in the context of emergency medicine because of lack of time, absence of anticipation in chronic diseases, and restrictions of access to families in EDs due to the pandemic. Therefore, the healthcare teams face several challenges with these decisions for which the consequences are not well assessed (25).
Understanding what happened during this rst outbreak in the EDs is crucial to anticipate other health crises. Emergency departments are on the front line in this type of crises and must also manage potential COVID-19 patients that contribute to the health care burden and ED overcrowding. In Australia, despite the low rate of COVID-19 positive cases, an increasing number of ED patients are likely to require isolation because the testing criteria are broadened (26). The same statement has been reported in the ED sin New York where more than two thirds of all the admissions were patients suspected of COVID-19 (12). In our opinion, this rst outbreak helped us to better quantify to the need for ICU beds and to underline the importance of exible organizations to quickly adapt conventional and ICU capacities to the incoming ow of COVID-19 positive patients.
The present cohort was composed of a large sample of patients admitted in ED for COVID-19 suspicion, during the rst COVID-19 outbreak in France, over a period that included the totality of the rst containment in France. The region of Lyon was one of the most impacted during the rst outbreak, after the Great East region and the region of Paris, which provided an interesting viewpoint regarding the management of the COVID-19 pandemic in EDs. Nevertheless, this study has several limitations. First, we included a majority of university hospitals, which had a greater capacity of ICU beds and which certainly has in uenced the ICU admission rate. Second, the study was conducted only during the rst outbreak and over a reduced period. Since then, practices have changed: the test criteria are broader, corticosteroids (mainly dexamethasone) have been introduced systematically for the most critical patients, and there is an increase in physician expertise. Finally, despite the use of multivariable model, we cannot excluded residual confounders.

Conclusion
In conclusion, COVID-19 positive patients require more resources in ICU beds and their management is different compared to COVID-19 negative patients. These differences must be considered in order to adapt the necessary resources. Understanding the pro le of patients and their pathway in the EDs during the rst outbreak of COVID-19 is essential in order to improve hospital practices and anticipate the next waves.

Declarations
Ethics approval and consent to participate: The study was approved by the ethic committee of the University Hospital of Lyon on April 17, 2020 (N°20-47).
Consent for publication: During the study period, patients were informed that their data were being collected as part of the COVID ER study via a written information notice. They could object to the collection of their information in accordance with current French legislation.
Availability of data and materials: The datasets used and/or analyzed in the present study are available upon reasonable request to the corresponding author. Data transfer must be approved by the Comission nationale de l'informatique et libertés (CNIL: French commission on data privacy).
Competing interests: The author(s) declare no potential con ict of interest with respect to the research, authorship, and/or publication of this manuscript.
Funding: The Hospices Civils of Lyon made research staff available for data collection during the study period.
Authors' contributions: MD conceived the study and designed the study. JB and NP supervised the conduct of the study and data collection, undertook recruitment of participating centers and patients, and managed the data, including quality control. FS and AG provided statistical advice on study design and analyzed the data. MD drafted the manuscript, and all authors contributed substantially to its revision. MD takes responsibility for the manuscript as a whole.   Number of patients admitted in EDs, suspected COVID-19 and con rmed COVID-19 by day admission.

Figure 4
Comparative evolutions of ICU transfers (primary and secondary) and deaths depending on the day of ED admissions among COVID-19 positive patients (proportion (LOESS curve) and effective, with the average over the whole period represented by the black horizontal line)