MD Lionel Piroth

Jonathan Cottenet

MD Anne-Sophie Sophie Mariet

MD Philippe Bonniaud

MD Mathieu Blot

Pascale Tubert-Bitter

MD Catherine Quantin
email: catherine.quantin@chu-dijon.fr

Catherine Pr

Quantin

Jonathan Cottenet Msc

PhD Pascale Tubert- Bitter

Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study

Keywords: Covid-19, influenza, comparative study, morbidity, Mortality, administrative data, hospital, SARS-CoV-2, severity, France, age group

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

In December 2019, a new disease now known as COVID-19 (Coronavirus Disease- [START_REF]L'état de santé de la population en France[END_REF], caused by the new SARS-CoV-2 coronavirus, emerged as a major world threat. Considering its ability to spread and the relatively low case fatality rates initially reported in China, SARS-CoV2 was thought to be more similar to influenza than SARS-CoV-1 [START_REF] Petersen | Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics[END_REF]. The preventive measures for this new infection were thus based on a comparison with the influenza virus since the viruses have similar modes of transmission and cause respiratory disease. It was anticipated that COVID-19 patients could also benefit from the clinical knowledge and care management of influenza.

On July 10 th , 2020, more than 12 million cases of COVID-19 and 554,000 COVID-19-related deaths had been identified worldwide. In France, it had already caused more than 30,000 deaths, nearly 20,000 of which were in hospital. At this point, COVID-19 had developed into a pandemic associated with substantial morbidity and mortality, putting significant strain on hospitals and the health system in general.

The case fatality rate in COVID-19 appears to be higher than in seasonal influenza, even though both mainly affect frail older adults. This may be due to a difference in underlying comorbidities, the pathogenicity of the virus, population immunity, and host response to infection. For example, there are available vaccines and treatments for influenza but not for COVID-19. Moreover, the massive strain that was put on hospitals within a short period of time led to limitations in available care for the frailest patients.

Few studies have directly compared the respective burdens of the two epidemics [2] [START_REF] Verity | Estimates of the severity of coronavirus disease 2019: a model-based analysis[END_REF]. Nevertheless, underscoring the risk factors for hospitalization and comprehensively assessing their respective mortality risk factors and rates seems of the utmost importance. Such data could be used to identify risk factors and specific at-risk populations, strengthen and focus specific preventive measures in these populations, and help define the future needs of health care facilities.

The aim of the present study was thus to compare, using French nationwide data, the population hospitalized for COVID-19 and the population hospitalized for influenza during the 2018-2019 season, and to assess the differences in terms of risk factors, clinical characteristics and outcomes.

Methods

Study design and participants

A retrospective cohort study was conducted using the national Programme de Médicalisation des Systèmes d'Information (PMSI) database, which is designed to include discharge summaries for all inpatients admitted to public and private hospitals in France. Inspired by the American DRG (diagnosis-related groups) model, the gathering of national administrative health data was established in France in 1991 and extended to all French healthcare facilities in 1997. This coding system was initially designed to analyse hospital activity and to contribute to the development of strategic healthcare plans. Since 2008, each hospital's budget depends on the medical activity described in a specific computer program that compiles discharge abstracts for all admissions. The information in these abstracts is anonymous and covers both medical and administrative data. Diagnoses identified during the hospital stay are coded according to the 10th edition of the International Classification of Diseases (ICD10), and procedures performed during the hospitalisation are coded according to the French Common Classification of Medical Procedures. Each facility produces its own standardised anonymous data set, and these are compiled to create a national data set. The fact that these national data are used for the allocation of hospital budgets encourages improvement in data quality in terms of coherence, accuracy and exhaustiveness. For the COVID-19 cohort, all patients hospitalized for COVID-19 from March 1 st , 2020, to April 30 th , 2020, were included, regardless of their age. Patients were followed up until the end of their hospital stay, even if that date was after April. Hospital stays for COVID-19 were identified by the primary diagnoses (PD), related diagnoses (RD) or associated diagnoses (AD) by the ICD-10 codes U0710, U0711, U0712, U0714 or U0715. For the influenza cohort, all patients hospitalized during the 2018-2019 influenza outbreak period (admitted from December 1 st , 2018, to February 28 th , 2019), and identified by ICD-10 codes J09, J10 or J11 (as PD, RD or AD) were included, whatever their age.

In France

Statistical analysis

The following variables were extracted for each inpatient stay: age, sex, transfer to an intensive care unit (ICU), and hospital death. We also included all diagnoses (PD, RD and AD, ICD-10 codes) recorded in the discharge abstracts for the included hospital stays (COVID-19 and influenza) in order to analyse comorbidities (hypertension, diabetes, dementia, HIV, heart failure, chronic respiratory and kidney diseases, cirrhosis, peripheral vascular disease, overweight, dyslipidemia, deficiency anemia, pulmonary bacterial infection, immunocompromised status) and complications (acute respiratory and kidney diseases, stroke, myocardial infarction, atrial fibrillation, venous thrombosis including pulmonary embolism). Deficiency anemia included iron anemia and other causes of deficiency anemia. Immunocompromised patients were those with agranulocytosis, immunodeficiency, medullar aplasia and cancer treated by chemotherapy. We also identified ventilation procedures. The Charlson comorbidity index [START_REF] Charlson | A new method of classifying prognostic comorbidity in longitudinal studies: development and validation[END_REF] and the Elixhauser comorbidity score [5] were retrieved. We also used the social deprivation index (taking into account the socio-economic environment of the patient) [START_REF]Ecological association between a deprivation index and mortality in France over the period 1997 -2001[END_REF]. In theory, this index ranges from -6•4 for the least deprived areas to 21•2 for the most deprived areas. Thus, the higher the score, the more disadvantaged the municipality. We divided this index into 4 quartiles, with the lowest quartile representing the least deprived group.

Nine age classes were assessed: younger than 18, 18-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90 and >90. For patients younger than 18, four subclasses were created: 0-1, 1-5, 6-10 and 11-17. All identified medical conditions were accounted for in relation to the patient. If a patient had at least once one condition during one of the stays for COVID-19 or for influenza, then the patient is considered to have had the condition. Qualitative variables are provided as frequencies (percentages), and quantitative variables are provided as means ± standard deviation (SD) and medians [interquartile range (Q1-Q3)].

The different variables studied in the cohort of patients hospitalized for COVID-19 were compared using the Chi-2 test or the Fisher's exact test (for qualitative variables) and Student's t test or Mann-Whitney test (for quantitative variables) when applicable to the variables of the influenza population to see if some populations are more represented among COVID-19 cases. These comparisons were made for all patients and then by age group.

In order to account for a possible age difference between the two populations, we also stratified the results by age. Furthermore, we estimated an age-standardized mortality ratio by calculating a mortality ratio between the observed number of hospital deaths in the COVID-19 population and the number of deaths that would be expected with the same influenza age-specific case fatality rates.

Considering the potential heterogeneity of patients admitted to hospital in the three stages of the epidemic, we performed a sensitivity analysis restricted to Stage 3 of the epidemic (March 14th onwards).

The statistical significance threshold was set at < 0.05. All analyses were performed using SAS (SAS Institute Inc, Version 9.4, Cary, NC).

Role of the funding source:

The project was funded by the French National Research Agency. The corresponding author had full access to all of the data and the final responsibility to submit for publication. All authors had access to all the data reported in the study. The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. CQ and JC had access to the raw data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Nearly twice as many patients were hospitalized for COVID-19 than for seasonal influenza (89,350 over two months vs 45,819 over three months, respectively). The baseline characteristics of these patients are presented in Table 1. Patients hospitalized for COVID-19 were more often male. The age distribution also differed, with a median age of 68 for COVID-19 and 71 for influenza, while the proportions in extreme ages (below 18 and above 80) were higher for influenza. There were differences in the distribution of the social deprivation score, but there was no distinct trend since the 2 extremes (the best and the worst) were both more frequently observed in the COVID-19 group. The deprivation score was significantly lower among COVID patients older than 40 years, including in the oldest age groups. Conversely, it was significantly higher in COVID-19 patients between 18 and 40 years.

The Charlson comorbidity index was slightly higher in the influenza group than in the COVID-19 group, but statistical significance was not reached with the Elixhauser comorbidity score. More specifically, COVID-19 patients were more often obese or overweight, diabetic, hypertensive, and dyslipidemic, whereas the influenza patients suffered more often from chronic heart failure, peripheral vascular disease, chronic respiratory disease, cirrhosis, and deficiency anemia. By contrast, people living with HIV were not over-or under-represented in the COVID-19 group. However, there were fewer immunocompromised patients in the COVID-19 group than in the influenza group. Pulmonary bacterial coinfection was diagnosed in 6,286 (7•0%) COVID-19 patients and in 3,142 (6•9%) patients with influenza (p=0•26). The results are presented by age class in supplementary Table 1

(pages 1-3).

Regarding the clinical evolution following admission (Table 2), hospitalized COVID-19 patients were more likely to develop respiratory distress, pulmonary embolism and septic shock, but less likely to develop myocardial infarction and atrial fibrillation. For strokes, we found that only hemorrhagic strokes were more frequent among COVID-19 patients. COVID-19 patients were more likely to need intensive care, and the median length of stay in the ICU for COVID-19 was twice as long (15 for COVID-19 vs 8 days for influenza, p<0.01). A quarter of COVID-19 patients remained in the ICU for more than 3 weeks. COVID-19 patients required more invasive mechanical ventilation (9•7% vs 4•0%, p<0•01). When admitted in ICU, COVID-19 patients requested also more frequently mechanical ventilation that influenza patients. Finally, the in-hospital case fatality rate was higher in patients hospitalized for COVID-19 (16•9% vs 5•8%, p<0•01), with a relative risk of death of 2•9 [2•8-3•0]. We found a standardized mortality ratio of 2•82. This means that the number of observed deaths was 2•82 times higher than what would be expected if the COVID-19 population had the same probability of dying as the influenza population. The case fatality rate was also higher in COVID-19 patients admitted to the ICU, whether they were mechanically ventilated or not. After stratifying patients according to the main comorbidities, the in-hospital mortality for COVID-19 patients was roughly three times higher than that of patients with influenza, whatever the comorbidity (supplementary Table 2), and roughly two times higher in those with pulmonary bacterial coinfection (case fatality rate of 25•4% for COVID-19 vs 13•9% for influenza).

After stratification on age (Figure 1, supplementary Table 3 and supplementary Figure 1, pages 5 and 6), the rates of hospitalization in the ICU in the COVID-19 group were significantly higher for patients younger than 18 years and those 61 to 80 years. On the contrary, this rate tended to be lower in particular for patients older than 80 years. However, in patients older than 50 years and younger than 18 years, the case fatality rates were consistently higher in the COVID-19 group.

We identified 1,227 children hospitalized for COVID-19 and 8,942 children hospitalized for influenza (Figure 2, supplementary Table 4 and supplementary Figure 2, pages 7 and 8). The need for intensive care was highest in COVID-19 patients younger than 5 years (14/613 for COVID-19, 2•3% vs 65/6,973 for influenza, 0•9%), but the case fatality rate in this group was not higher than for influenza (3, 0•5% vs 13, 0•2%). However, the case fatality rate was tenfold higher for COVID-19 in children aged 11-17 with COVID-19 than in patients in the same age group with influenza (5/458, 1•1% vs 1/804, 0•1%). The 11-17-year-old children hospitalized for COVID-19 were more likely to be obese (2•0% vs 0•5%, p<0•01) or overweight (2•6% vs 1•1%, p<0•01) than those hospitalized for influenza. By contrast, they were less likely to be diabetic (1•5% vs 4•1%, p<0•01) or to have chronic pulmonary disease (0•7% vs 2•1%, p<0•01).

Our sensitivity analysis, which was restricted to Stage 3 of the epidemic (March 14th onwards), provided similar results (supplementary Tables 5, 6, 7 and 8, pages 9 -13).

Discussion

In this nationwide survey comparing the COVID-19 epidemic to seasonal influenza, the most striking result is that nearly twice as many patients were admitted to hospital for COVID-19 over a two-month period than for seasonal influenza over a 3-month period. There is a small possibility that certain patients hospitalized in 2020 were misclassified as COVID-19 when they actually had influenza. However, this risk should be limited because the period studied in 2020 was at the end of the influenza epidemic in France and because the results of sensitivity analysis limited to Stage 3 of the epidemic were similar to those of the main analysis. The observed difference in admissions is likely underestimated considering that the COVID-19 epidemic peaked in the first week of April, and since universal lockdown measures were already in place in France by March 17 th , contributing to a reduction in the rate of transmissions and thus of hospitalization in the following weeks [START_REF] Roux | COVID-19: One-month impact of the French lockdown on the epidemic burden[END_REF]. On the other hand, influenza vaccination coverage against seasonal influenza in France was 29.7% for those under 65 and 51•0% for those over 65 in 2018-2019 according to the National Public Health Agency. The influenza vaccine thus likely contributed modestly to lower rates of hospitalization for seasonal influenza and the associated case fatality rate [START_REF]Equipes de surveillance de la grippe. Influenza activity in France, season 2018-2019[END_REF], which suggests that this ratio could be higher in other settings or periods, or if the residual population immunity acquired from previous seasonal influenzas (which cannot be assessed) is lower than usual.

Our second key finding is that the in-hospital case fatality rate associated with COVID-19 was nearly three times higher than for seasonal influenza, with an age standardized mortality ratio of 2•82. In addition, COVID-19 patients were twice as likely to be put under invasive mechanical ventilation, and COVID-19 patients hospitalized in the ICU stayed nearly twice as long as those with influenza. It is worth noting that the 2018-2019 period had the highest case fatality rate for seasonal influenza in France within the past 5 years (12,300 deaths including 8,100 directly attributable to influenza) [START_REF]Equipes de surveillance de la grippe. Influenza activity in France, season 2018-2019[END_REF]. This indicates that the excess mortality observed for COVID-19 was not the result of an influenza season that was less severe than usual. Another potential explanation for the higher case fatality rate is that the sudden influx of patients over a short period of time created medical structural constraints, and care teams were led to prioritize patients based on clinical status and prognosis. This hypothesis is supported by the lower rate of transfer to ICU in patients older than 80 years with COVID-19, which strongly contrasts with the higher case fatality rate in these same patients. Considering France's national health insurance system and the lack of association with the social deprivation score as a whole, it seems likely that the drop in intensive care transfers is related to poorer prognoses rather than to socio-economic considerations. Nevertheless, it cannot be excluded that social deprivation may be a significant risk factor in younger adults since the deprivation score was significantly higher in patients aged 18 to 40 years.

The higher in-hospital case fatality rates observed in particular in younger COVID-19 patients also suggests that COVID-19 is intrinsically more severe than influenza. Even though children seemed to have a lower risk of being hospitalized for COVID-19 (as shown here by the very low rate of hospitalization for COVID-19 compared with seasonal influenza in patients younger than 18), the in-hospital death rate in these children was more than 4 times higher than it was for children with influenza. This contrasts sharply with recent reports stating that the clinical manifestations of COVID-19 are very often mild in children [START_REF] Sinha | COVID-19 infection in children[END_REF] [10] [START_REF] Götzinger | COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study[END_REF]. The clinical manifestations of COVID-19 appear to be milder than those of influenza in children under 5 years [START_REF] Li | Comparison of hospitalized patients with pneumonia caused by COVID-19 and influenza A in children under 5 years[END_REF], and did not seem more severe than other CoV or influenza infections in children under one year [START_REF] Vanhems | For the Pneumonia Study GABRIEL members. Comparison of the Clinical Features of SARS-CoV-2, Other Coronavirus and Influenza Infections in Infants Less Than 1-Year-Old n[END_REF]. If excess in-hospital mortality in our study seemed to be avoided by an increased use of intensive care support for children younger than 5 years, the comparatively higher rate of mortality associated with COVID-19 in children 11 to 17 years old indicates that there is a need to be particularly vigilant in young people with overweight or obesity. The increase in the case fatality rate might be partly linked to pediatric inflammatory multisystem syndrome (PIMS, also Kawasaki-like syndrome). Indeed, an unexpectedly high incidence of this syndrome has been observed recently, including in teenagers with COVID-19 [START_REF] Davies | Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study[END_REF] [START_REF] Feldstein | Multisystem Inflammatory Syndrome in U.S. Children and Adolescents[END_REF], but it remains rare and does not likely explain the increased risk of mortality. In addition, even though this syndrome may sometimes lead to death, no association with overweight has been reported so far.

The third main finding is that severity may be linked to the comorbidities associated with each viral disease. The median age of patients hospitalized for COVID-19 in France was within the range reported in other large international studies [2] [START_REF] Docherty | Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study[END_REF]. The overall comorbidity scores tended to be lower in COVID-19 patients than in patients with seasonal influenza, and the patients admitted with COVID-19 were more typically male with fewer comorbidities, as previously observed [2]. Whereas diabetes and overweight seem to be particular risk factors for COVID-19 hospitalization [2] [16] [17] [START_REF] Petrilli | Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study[END_REF], major comorbidities such as heart failure, chronic respiratory disease and cirrhosis, albeit frequently associated with COVID-19 [2] [START_REF] Docherty | Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study[END_REF] [17] [START_REF] Petrilli | Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study[END_REF], were more often observed in the seasonal influenza group. The higher short-term impact of these three conditions when compared with diabetes and obesity [START_REF]L'état de santé de la population en France[END_REF] is another argument in favour of an intrinsic increased severity of SARS-CoV2. Thus, though the differences in comorbidities might explain the difference in disease severity, these underlying conditions may also be due to an exaggerated immune response in COVID-19, or to the exacerbation of comorbidities in influenza infection. Another point of interest is that people living with HIV in our study did not seem to be more affected by COVID-19 than seasonal influenza. This supports the hypotheses that i) virologically controlled HIV populations do not have a considerably higher risk of developing severe COVID-19 (as sometimes observed in countries with low antiretroviral rates [START_REF]HIV raises the risk of death from COVID-19 in South Africa's Western Cape. AidsmapCom n.d[END_REF]), and, ii) on the contrary, people with HIV should not be considered at a lower risk because of a potential preventive effect of antiretroviral therapy [START_REF] Vizcarra | Description of COVID-19 in HIV-infected individuals: a single-centre, prospective cohort[END_REF].

Fourth, regarding the outcomes of hospitalized patients, respiratory complications were more frequent in COVID-19 than in seasonal influenza. Similar to other studies, we found that bacterial superinfections were infrequent in COVID-19 [16] [22], conversely to what has been reported for influenza epidemics [START_REF] Bengoechea | SARS-CoV-2, bacterial co-infections, and AMR: the deadly trio in COVID-19?[END_REF]. It therefore seems that SARS-CoV2 has a superior potential for respiratory pathogenicity, potentially by inducing an upregulation of a small number of inflammatory mediators (including IL-6) [START_REF] Mudd | Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease[END_REF], and that respiratory complications are mainly responsible for the excess mortality observed in COVID-19. As previously reported, COVID-19 patients have a higher risk of pulmonary embolism [START_REF] Fauvel | Pulmonary embolism in COVID-19 patients: a French multicentre cohort study[END_REF]. A higher risk of haemorrhagic strokes (but not ischemic strokes, as more often observed [START_REF] Merkler | Risk of Ischemic Stroke in Patients With Coronavirus Disease 2019 (COVID-19) vs Patients With Influenza[END_REF] [27]) has also been described, not only because of specific COVID-19-induced cerebral vasculitis, but also because of the high doses of anticoagulants used to prevent or reduce the risk of thromboembolism. And, more surprisingly, we found that COVID-19 patients, who are often considered to have higher cardiac risks (including for acute coronary syndrome, myocarditis, arrhythmias, and cardiogenic shock) [START_REF] Kevin | COVID-19 and Cardiovascular Disease[END_REF], actually had lower cardiac risk than seasonal influenza patients. Patients with influenza were more likely to have chronic heart failure at baseline, but the question of whether the incidence and the impact of seasonal-influenzarelated myocarditis is underestimated requires further investigation [START_REF] Datta | Detection of influenza myocarditis using national healthcare safety network surveillance definitions accounting for fever in older adults[END_REF].

Although this study includes data collected on a national level from more than 100,000 hospitalized patients of all ages, we recognize that there are several limitations. First of all, the comparison between COVID-19 and seasonal influenza may seem difficult given possible testing biases and differences between viruses. It is likely that more patients were being tested for COVID -19 than influenza during the 2018-19 season, but we included in our study only hospitalized patients. Tests systematically carried out in an ambulatory care setting for COVID -19 should have a limited influence on the number of patients hospitalized, particularly in intensive care units. However, testing practices for influenza are likely to be highly variable across hospitals, whereas practices for COVID-19 may be more standardized (eg. all hospitalized patients require testing). The comparison between COVID-19 and seasonal influenza may also be not direct since the study periods are roughly one year apart. It also cannot be ascertained that the 2018-2019 seasonal influenza is representative of all seasonal influenzas, even though it was the most severe season in the past 5 years in France. It is also possible that some COVID-19 patients were suffering from influenza at the same time, but such a possibility seems unlikely since influenza diagnostic procedures were accessible throughout the study period, and moreover because the 2019-2020 influenza epidemic was ending at the start of the COVID-19 epidemic. In addition, we found no differences between the sensitivity analyses restricted to Stage 3 of the COVID-19 epidemic and the main analyses. In the Stage 3 period (March 14th onward), it is very unlikely that COVID-19 patients were suffering from influenza. . The characteristics of patients who died from COVID-19 in places outside of the hospital setting, in a nursing home for example, could be different than the 15,104 deaths identified in our study. Another limitation concerns a potential for misclassification-related or under-detection-related bias, especially for comorbidities since they were only identified during the stays for COVID-19 or for influenza. Even so, this misclassification bias is likely to be non-differential for the majority of the comorbidities. We cannot always distinguish between acute and chronic conditions, for example in heart failure where the same code is used for chronic heart failure and for cardiac decompensation. Moreover, the PMSI inpatient database for COVID-19, with accelerated transmission of COVID-19-related patient data, was only recently developed on the request of the government (following the decree of April 21), and these data are still pending consolidation. This is, in particular, the consequence of the strain on our health care system and its mobilization to care for the sick, and the willingness to act quickly. Information relative to do-not-resuscitate orders was not available in our database, nor was ethnicity data since its collection is not authorised in France. We were also lacking detailed data for some potentially relevant findings such as the higher frequency of septic shock in COVID-19 patients or the underlying reasons for mortality in teenagers. We acknowledge that, despite the collection of nationwide data, the conclusions about ICU support and deaths in children are based on small numbers (e.g. in children under 5 years, 3 deaths were associated with COVID-19 and 13 with influenza). Whether genetic characteristics could be associated with severity could not be assessed in these cases [START_REF] Zhang | Severe COVID-19 in the young and healthy: monogenic inborn errors of immunity?[END_REF]. Finally, we did not have to deal with incomplete data. For some variables, information is not completed in the discharge abstract when there is no impact on patient care during hospitalisation. It is often the case for daycare hospitalisations but this situation does not apply for the considered hospitalisations.

In conclusion, despite the initial speculation, there are significant differences between patients with COVID-19 and seasonal influenza requiring hospitalization. SARS-CoV2 appears to have a higher potential for respiratory pathogenicity, leading to more respiratory complications in patients with fewer comorbidities, and it is associated with a higher risk of mortality, particularly in teenagers, but any conclusions for this age group need to be taken with caution considering the small number of deaths. These findings were confirmed even after we took into account the constraints linked to the sudden influx of patients during the epidemic. In future, the possibility of overlapping influenza and COVID-19 epidemics will certainly also increase the complexity of patient management. At a time when no treatment has proven effective for the COVID-19 clinical course, this study highlights -yet again -the importance of all measures of physical prevention and the need for a specific vaccine and treatment for SARS-CoV2.

Contributors

PB, LP, CQ, PTB were involved in the conception and design of the study. CQ was the coordinator of the study. JC, ASM, CQ were responsible for the data collection, LP, CQ and PTB wrote the first draft. JC was in charge of the analysis. JC and CQ accessed and verified the data. PB, LP, CQ, PTB, ASM, JC, MB were involved in the interpretation, critically reviewed the first draft, and approved the final version.

Declaration interests

For Lionel Piroth, since 2017, travel grants from Janssen-Cilag, MSD, Pfizer, and Gilead.

For Philippe Bonniaud: Roche (board/advice/travel for ERS conference), Boehringer (board/advice/congress fees), Novartis (board/advice/conference), TEVA (board/advice), Chiesi (travel for ERS), AstraZeneca (board/advice), Stallergene (CFA conference fees). All other authors declare no competing interests.

  , Stage 1 of the COVID-19 epidemic was declared on February 23, Stage 2 was declared on February 29, and Stage 3 on March 14, 2020. The peak of the epidemic occurred during the second week of April, 2020. While during Stage 1 and 2 all patients with COVID-19 were hospitalized regardless of clinical presentation, only those in serious clinical condition were admitted to hospital during Stage 3. A PMSI database was developed for COVID-19, and hospitals were asked to perform accelerated data transmission for COVID-19 patients from March 2020 onwards on the request of the government, according to the decree dated April 21, 2020.

  This study was approved by the Comité Ethique et Scientifique pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé (CESREES, Ethics and Scientific Committee for Research, Studies and Evaluation in Health, June 9 2020) and the Institut des Données de Santé (INDS, French Institute of Health Data, registration number 1611357, June 15, 2020) and authorized by the Commission Nationale de l'Informatique et des Libertés (CNIL, French Data Protection Authority, registration number DR-2020-250, July 3, 2020).

Figure 1 :

 1 Figure 1: Intensive case support and case fatality rates of patients hospitalized in France for COVID-19 (from March 1 st , 2020, to April 30 th , 2020) or seasonal influenza (from December 1st, 2018, to February 28th, 2019), according to their age at admission

Acknowledgements

The project was funded by the French National Research Agency. The authors thank Suzanne Rankin for reviewing the English and Gwenaëlle Periard for her help with the layout and management of this article.

The project was funded by the French National Research Agency

Data sharing:

The PMSI database was transmitted by the national agency for the management of hospitalization data. The use of these data by our department was approved by the National Committee for data protection. We are not allowed to transmit these data. PMSI data are available for researchers who meet the criteria for access to these French confidential data (this access is submitted to the approval of the National Committee for data protection) from the national agency for the management of hospitalization (ATIH -Agence technique de l'information sur l'hospitalisation).

Address:

Agence technique de l'information sur l'hospitalisation 117 boulevard Marius Vivier Merle 69329 Lyon Cedex 03


Alexandre Addad

T Barras

R Hadjersi

Sabine Chegroune

Rabah Szunerits

M A Boukherroub

Amin

Madjid Ifires

Ahmed Addad

Alexandre Barras

Toufik Hadjersi

Redouane Chegroune

Sabine Szunerits

Rabah Boukherroub
email: rabah.boukherroub@univ-lille.fr

Mohammed A Amin

Cathodic pre-polarization studies on the carbon felt/KOH interface: An efficient metal-free electrocatalyst for hydrogen generation

Keywords: Electrocatalysis, Hydrogen evolution reaction, Carbon felt, Cathodic activation, Alkaline electrolytes

diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

In recent years, there has been a continuous shift towards the development of clean and renewable energy sources to limit the dependence on fossil fuels, but also to minimize the impact on the environment [START_REF] Dincer | A review on clean energy solutions for better sustainability[END_REF]. In this context, tremendous efforts have been put on the search for highly efficient fuel cells, new metal-air batteries, and more effective production approaches of energy carriers such as hydrogen (H2) [START_REF] Dincer | A review on clean energy solutions for better sustainability[END_REF][START_REF] Peng | Catalyst engineering for electrochemical energy conversion from water to water: Water electrolysis and the hydrogen fuel cell[END_REF]. All these technologies require development of high-performance, cost-effective, and earth abundant heterogeneous electrocatalysts [START_REF] Peng | Catalyst engineering for electrochemical energy conversion from water to water: Water electrolysis and the hydrogen fuel cell[END_REF]. H2, as a promising and valuable energy source, has received increasing attention in the last decade with a plenty of studies focused on the catalyst preparation, hydrogen precursors and cell design [START_REF] Peng | Catalyst engineering for electrochemical energy conversion from water to water: Water electrolysis and the hydrogen fuel cell[END_REF]. Water electrolysis, i.e., hydrogen evolution reaction (HER), was recognized as an interesting strategy to fulfill the needs in the development of renewable and energy conversion devices. HER is a two-electron electrocatalytic process that produces H2 as a final product from H + in acidic media or H2O from basic media, as underlined in Table 1 [START_REF] Lasia | Handbook of Fuel Cells[END_REF]:

Table 1.
Water electrolysis in acid and alkaline media.

Electrolyte

Water electrolysis Acidic solution Cathode: 2H + + 2e -→ H2 Anode: H2O → 2H + + ½O2 + 2e -

Alkaline solution

Cathode: 2H2O + 2e -→ H2 + 2OH - Anode: 2OH -→ H2O + ½O2 + 2e -

The rate determining step in HER can be inferred from the Tafel analysis [START_REF] Shinagawa | Insight on Tafel slopes from a microkinetic analysis of aqueous electrocatalysis for energy conversion[END_REF].

Platinum (Pt) and its composites are the most performing catalysts for HER in acidic media, owing to their low onset potential, high exchange current densities and a Tafel slope of about 30 dec -1 [START_REF] Shinagawa | Insight on Tafel slopes from a microkinetic analysis of aqueous electrocatalysis for energy conversion[END_REF]. In contrast, the reaction in alkaline media is hindered by the strong Pt-H binding energy, and Pt poisoning susceptibility by underpotential deposition in the presence of trace metal ions in the electrolyte solution. Therefore, the reaction rate is decreased by more than one order of magnitude, recording higher Tafel slope values (50-150 dec -1 ).

Additionally, the high price of Pt and its low abundance favored a search for alternative catalysts with a performance comparable to that of Pt in acidic media and surpassing it in alkaline condition.

Therefore, the last decade has witnessed a huge load of research investigations on the development of metal-free electrocatalysts for overall water splitting [START_REF] Hu | Carbon-based metal-free electrocatalysis for energy conversion, energy storage, and environmental protection[END_REF][START_REF] Wang | Carbon-based electrocatalysts for sustainable energy applications[END_REF]. In this context, carbon-based materials, commonly used as catalyst supports, represent an outstanding class of electrodes for HER in acidic and alkaline media, owing to their high stability, high abundance, good electronic conductivity, and low cost. These multiple benefits have boosted their utilization in many electrochemical processes for sustainable energy applications [START_REF] Hu | Carbon-based metal-free electrocatalysis for energy conversion, energy storage, and environmental protection[END_REF][START_REF] Wang | Carbon-based electrocatalysts for sustainable energy applications[END_REF].

Among these carbon materials, carbon nanotubes, graphene and biomass-derived carbon are the most investigated electrode materials [START_REF] Hu | Carbon-based metal-free electrocatalysis for energy conversion, energy storage, and environmental protection[END_REF][START_REF] Wang | Carbon-based electrocatalysts for sustainable energy applications[END_REF]. Despite the interest of the carbon-based electrodes in electrolysis, the as-prepared materials are commonly less efficient for HER.

Thus, many strategies have been designed to improve their electrocatalytic performance.

These include heteroatom doping (mono-and multi-atom), surface functionalization, structural defect engineering, etc. [START_REF] Hu | Carbon-based metal-free electrocatalysis for energy conversion, energy storage, and environmental protection[END_REF][START_REF] Wang | Carbon-based electrocatalysts for sustainable energy applications[END_REF][START_REF] Liu | Carbon-based metal-free catalysts[END_REF][START_REF] Zhang | Activity origins in nanocarbons for the electrocatalytic hydrogen evolution reaction[END_REF][START_REF] Shang | Recent advances of nonprecious and bifunctional electrocatalysts for overall water splitting[END_REF][START_REF] Zhou | A review of advanced metal-free carbon catalysts for oxygen reduction reactions towards the selective generation of hydrogen peroxide[END_REF][START_REF] Bhatt | Advancement of platinum (Pt)-free (non-Pt precious metals) and/or metal-free (non-precious-metals) electrocatalysts in energy applications: A review and perspectives[END_REF].

Another elegant approach to improve the catalytic performance of carbon-based electrodes for advancing the field of metal-free HER is the cathodic activation. This method not only offers the advantage of being environmentally-friendly, it also takes place in the same electrochemical cell used for HER measurements, limiting additional costs. Despite these benefits, cathodic activation of carbon-based materials is scarce in the literature. Early study by Prosini et al. revealed that cathodic polarization of CNTs substrate allowed to improve its electrocatalytic activity for HER [START_REF] Prosini | Electrochemical studies of hydrogen evolution, storage and oxidation on carbon nanotube electrodes[END_REF]. Das et al. demonstrated that cycling single-wall carbon nanotubes (SWNT) film in H2SO4 at 50 mV/s (+0.2 to -0.7 V vs. NHE), followed by a long soak time allowed to achieve a high performance for HER. The activation process was believed to be due to H2SO4 intercalation within the nanotubes [START_REF] Das | Extraordinary hydrogen evolution and oxidation reaction activity from carbon nanotubes and gaphitic carbons[END_REF]. Cui and coworkers found that a two-step activation process of multi-walled carbon nanotubes (MWCNTs), consisting of 4 h oxidation in HNO3 at 120°C, followed by cathodic activation at -2 V vs. saturated calomel electrode (SCE) for 4 h in H2SO4, enhanced considerably the electrocatalytic properties for HER of the substrate [START_REF] Cui | Activated carbon nanotubes: a highlyactive metal-free electrocatalyst for hydrogen evolution reaction[END_REF]. Cathodic activation of mesoporous bacteriumderived carbon electrocatalysts (-2 V vs. SCE for 4 h) in 0.1 M H2SO4 improved their HER performance, delivering a Tafel slope of 58.4 mV dec -1 , an onset overpotential of 76 mV, and an exchange current density of 1.72 10 -2 mA cm -2 [START_REF] Wei | A highperformance metal-free hydrogen evolution reaction electrocatalyst from bacterium derived carbon[END_REF]. The enhanced HER activity was ascribed to surface oxidation during the cathodic process, introducing oxygen containing groups which could act as proton acceptors/relays to facilitate H2 evolution. Some of us have found that a cathodic cycling at -2 V in 0.5 M H2SO4 of Au-Pd NPs/rGO electrode led to enhanced HER activity. Even though this phenomenon was highly reproducible, its origin was not very clear [START_REF] Darabdhara | Reduced graphene oxide nanosheets decorated with Au, Pd and Au-Pd bimetallic nanoparticles as highly efficient catalysts for electrochemical hydrogen generation[END_REF].

Unlike carbon nanotubes and graphene, carbon felt (CF) has been mostly investigated as a carbon support for different metal and metal oxide nanoparticles for HER [START_REF] Demir | Fabrication of Mo-modified carbon felt as candidate substrate for electrolysis: Optimization of pH, current and metal amount[END_REF][START_REF] Demir | Preparation, characterization and hydrogen production performance of MoPd deposited carbon felt/Mo electrodes[END_REF][START_REF] Koca | NiGa modified carbon-felt cathode for hydrogen production[END_REF][START_REF] Dmitriev | Electrodeposition of α-Ni/β-Co composite coatings on the carbon felt: Structural features and electrochemical performance[END_REF][START_REF] Yoon | Cobalt phosphide nanoarrays with crystallineamorphous hybrid phase for hydrogen production in universal-pH[END_REF], owing to its open and free-standing structure, high stability in corrosive media and low cost [START_REF] Mitov | Novel nanostructured electrocatalysts for hydrogen evolution reaction in neutral and weak acidic solutions[END_REF][START_REF] Döner | Effect of C-felt supported Ni, Co and NiCo catalysts to produce hydrogen[END_REF].

Even though CF exhibits unique benefits as a support, its catalytic activity is not recognized to be sufficient to drive effectively various electrochemical processes [START_REF] Mitov | Novel nanostructured electrocatalysts for hydrogen evolution reaction in neutral and weak acidic solutions[END_REF][START_REF] Döner | Effect of C-felt supported Ni, Co and NiCo catalysts to produce hydrogen[END_REF]. Therefore, its activation might represent an appealing mean to explore all the benefits of this material and realize metal-free electrocatalysis.

In this study, we report for the first time the electrochemical activation of CF in 1.0 M KOH aqueous solution with the aim to improve its catalytic performance. A systematic investigation of the influence of various operating pre-polarization parameters such as applied cathodic potential and polarization time was carried out to find the better conditions. Under optimized conditions, the CF cathodically polarized at -4.0 V vs. RHE for 12 h achieved a high exchange current density of 0.1 mA cm -2 and a Tafel slope value as low as 90 mV dec -1 .

Additionally, it required an overpotential of 180 mV vs. RHE to deliver 10 mA cm -2 .

Interestingly, the CF experienced enhanced activation during a continuous cycling stability test. Based on XPS analysis, it is hypothesized that cathodic activation induces surface oxidation. The generation of oxygen functional groups could serve as catalytic sites for protons adsorption and their effective reduction to H2.

Experimental section

Electrochemical measurements

Electrochemical measurements were performed in a standard 200 mL three-electrode cell comprising Hg/HgO, NaOH (0.1 M) (Princeton Applied Research) and a graphite rod (Sigma-Aldrich, 99.999%) reference and auxiliary electrodes using an Autolab (PGSTAT30/FRA system, Ecochemie, The Netherlands) potentiostat. enhances with increasing the polarization potential time, tpp. The cathodic current also increases as the pre-polarization potential is made more negative (from -2.0 to -4.0 V vs. RHE), Figure 3(a). This effect suggests that the electrocatalytic properties of the cathode (catalyst) surface induced by the evolution of hydrogen are modified: the initial surface has inferior catalytic performance, and the reduction process of water molecules is extremely slow. However, after cathodic activation, the reduction of water molecules, and hence the HER kinetics, at the cathode surface is prompted. The catalyst is, therefore, activated upon cathodic pre-treatment. In the near-surface area, it is plausibly related to hydrogen incorporation into the CF lattice. A similar effect has been previously reported in our laboratory for hydrogen evolution on various nanostructured materials [START_REF] Mostafa | Cathodic activation of synthesized highly nanoparticles for efficient electrochemical 2 functionalized ZrO -defective monoclinic hydroxyl production of hydrogen in alkaline media[END_REF][START_REF] Mezni | Cathodically activated Au/TiO by a new facile solvothermal method: An efficient electrocatalystwith Pt-likeactivity for hydrogen generation[END_REF][START_REF] Darabdhara | Au-Ni alloy nanoparticles supported on reduced grapheneoxide as highly efficient electrocatalysts for hydrogen evolution and oxygen reduction reactions[END_REF][START_REF] Amin | Cathodic activation of titanium-supported gold nanoparticles: An efficient and stable electrocatalyst for the hydrogen evolution reaction[END_REF].

The various electrochemical parameters, describing the kinetics of the HER, associated with such polarization measurements are depicted in the Table 2. Table 2. Electrochemical HER kinetic parameters recorded for CF under various cathodic pre-treatment conditions. Measurements were performed at room temperature in deaerated KOH solution (1.0 M) at 5.0 mV s -1 . Double layer capacitance (Cdl) and electrochemical active surface area (EASA) values were determined from the non-Faradaic capacitive current associated with double-layer charging from the cyclic voltammetry measurements conducted at various scan rates (20-120 mV s -1 ). Another important electrochemical parameter commonly employed for the comparison and assessment of the activities and performance of catalysts towards the HER is the overpotential the catalyst must acquire to deliver 10 mA cm -2 , η10 [START_REF] Mccrory | Benchmarking heterogeneous electrocatalystsfor the oxygen evolution reaction[END_REF].

Like EHER, reduced η10 values refer to enhanced catalytic activity. The value of η10 was found to decrease following exactly the same sequence exhibited by EHER. It follows from Table 2 that, at a constant applied potential (-2.0 V vs. RHE), the value of η10 decreases, corresponding to efficient hydrogen generation at lower overpotentials (i.e., enhanced catalytic activity), as tpp becomes longer. Also, at a given tpp (12 h), the value of η10 diminished as Ec was made more negative. These findings demonstrated the benefits of the cathodic polarization pre-treatment processes on the CF catalytic efficiency for the HER.

On the one hand, there is no definite variation or trend in the Tafel slopes (b), and hence in the jo values estimated from the Tafel extrapolation method, for the CF samples cathodicallyactivated at -2.0 V vs. RHE for various tpp values. On the other hand, at a constant tpp value of 12h, there was an apparent decrease in the b values from 175 to 90 mV dec -1 , corresponding to increased jo values from 2.95 × 10 -2 to 9.7 × 10 -2 mA cm -2 , upon increasing the applied cathodic potential (Ec) from -2.0 to -4.0 V vs. RHE. As lower Tafel slopes usually refer to profusion in the availability of active sites on the catalyst surface, this apparent decrease in b denotes prompted HER kinetics [START_REF] Shinagawa | Insight on Tafel slopes from a microkinetic analysis of aqueous electrocatalysis for energy conversion[END_REF]. The lowest b value (90 mV dec -1 ) and the highest jo value (9.7 × 10 -2 mA cm -2 ) were recorded for the CF samples cathodically-activated at -4.0 V vs.

RHE for 12 h thus, highlighting its effective HER catalytic activity.

Comparing the b values estimated here (Table 2) with the theoretical ones listed below in the Eqs. (1-3), which illustrates the path of the HER in alkaline electrolytes on a particular catalyst [START_REF] Mahmood | Electrocatalysts for hydrogen evolution in alkaline electrolytes: Mechanisms, challenges, and prospective solutions[END_REF], will enable us to understand the HER key mechanism under these conditions.

H2O + e -→ Hads + HO - (Volmer step)

2.34RT αF ≅ 120 mV/dec

The Volmer step is followed by either the desorption Heyrovsky step:

H2O + e -+ Hads→ H2 + HO - (Heyrovsky)

2.34RT 2F ≅ 40 mV/dec or a combination of adsorbed species to form molecular H2:

Hads + Hads → H2ads (Tafel step)

2.34RT 1 α F ≅ 30 mV/dec

The b values estimated for the two CF samples cathodically-activated for 12 h at -2.5 and -3.0 V vs. RHE (110 and 126 mV dec -1 ), which are close to the standard b value of 120 mV dec -1 , suggest the Volmer step, Eq. ( 1), as the main step controlling the HER.

The HER kinetics of the other activated CF samples are limited by the ineffectual number of catalytically active sites on which Hads species form [START_REF] Shinagawa | Insight on Tafel slopes from a microkinetic analysis of aqueous electrocatalysis for energy conversion[END_REF][START_REF] Mahmood | Electrocatalysts for hydrogen evolution in alkaline electrolytes: Mechanisms, challenges, and prospective solutions[END_REF], indicated by their high b values (175-332 mV dec -1 ). On the other hand, the decreased b value (90 mV dec -1 ) of the CF sample exposed to 12 h of cathodic activation at a high potential of -4.0 V vs. RHE catalyst infers that the number of active sites available on the catalyst surface has increased, resulting in enhanced HER kinetics [START_REF] Darabdhara | Reduced graphene oxide nanosheets decorated with Au, Pd and Au-Pd bimetallic nanoparticles as highly efficient catalysts for electrochemical hydrogen generation[END_REF][START_REF] Mostafa | Cathodic activation of synthesized highly nanoparticles for efficient electrochemical 2 functionalized ZrO -defective monoclinic hydroxyl production of hydrogen in alkaline media[END_REF][START_REF] Mezni | Cathodically activated Au/TiO by a new facile solvothermal method: An efficient electrocatalystwith Pt-likeactivity for hydrogen generation[END_REF][START_REF] Darabdhara | Au-Ni alloy nanoparticles supported on reduced grapheneoxide as highly efficient electrocatalysts for hydrogen evolution and oxygen reduction reactions[END_REF][START_REF] Amin | Cathodic activation of titanium-supported gold nanoparticles: An efficient and stable electrocatalyst for the hydrogen evolution reaction[END_REF].

Long-term stability tests

Various electrochemical techniques performed under severe cathodic conditions were applied to the CF/KOH interface to evaluate the CF catalyst's sustainability.

These techniques include continued potential cycling (up to 10,000 cycles) and chronoamperometry (current against time at a given potential). -3). This activation enhances as the cathodic potentials goes to the more negative values, as hydrogen evolves abundantly at the higher cathodic potentials.

The catalyst was also subjected to a prolonged chronoamperomery (current vs. time at a constant cathodic potential), Figure 5, and chronopotentiometry (potential vs. time at a given cathodic current), Figure 6, tests for 24 h to further assess its stability and durability.

Time / h

attaining its minimum value (-0.4 A cm -2 ) at t~14 h. This minimum current value (-0.4

A cm -2 ) is still lower (more negative) than that of the instantaneous current (-0.08 A cm -2 ), meaning that the catalyst is partly deactivated. The catalyst's partial deactivation at this stage is most probably due to blocking of some active sites by the accumulation of H2 bubbles. The cathodic current then rises again (catalyst reactivation) with almost the same slope to -0.46 A cm -2 , forming a broad hump with a small height.

The current oscillations are characteristics of a continued competition between two processes, namely the release and accumulation of H2 bubbles [START_REF] Darabdhara | Au-Ni alloy nanoparticles supported on reduced grapheneoxide as highly efficient electrocatalysts for hydrogen evolution and oxygen reduction reactions[END_REF][START_REF] Xie | th additional active edge sites for enhanced ultrathin nanosheets wi 2 Defect-rich MoS electrocatalytic hydrogen evolution[END_REF]. The aggregation of bubbles during H2 piling up is anticipated to separate the catalyst's active sites in the electrolyte from the electroactive species, hindering the transfer of charge and thus, decreases the current (catalyst deactivation). The current is then strengthened by the liberation of gas (catalyst reactivation), leaving the active sites free for a new H2O molecule reduction process [START_REF] Darabdhara | Au-Ni alloy nanoparticles supported on reduced grapheneoxide as highly efficient electrocatalysts for hydrogen evolution and oxygen reduction reactions[END_REF][START_REF] Xie | th additional active edge sites for enhanced ultrathin nanosheets wi 2 Defect-rich MoS electrocatalytic hydrogen evolution[END_REF]. The accumulation/release process of H2 bubbles is replicated in a very short time (Inset in Figure 5), resulting in the manifestation of current noise. In spite of the continuous competition between the liberation of H2 bubbles and accumulation processes, the net result is an increase in the cathodic current throughout the run, denoting catalyst activation during the operation.

During the long-term electrolysis test at high cathodic overpotential, where hydrogen is profusely released, hydrogen is postulated to integrate into the catalyst's crystal lattice, creating new catalytically active sites for water molecules' reduction [START_REF] Darabdhara | Au-Ni alloy nanoparticles supported on reduced grapheneoxide as highly efficient electrocatalysts for hydrogen evolution and oxygen reduction reactions[END_REF][START_REF] Xie | th additional active edge sites for enhanced ultrathin nanosheets wi 2 Defect-rich MoS electrocatalytic hydrogen evolution[END_REF]. Hydrogen incorporation into the catalyst's structure is turned into a marked increase in the catalyst's electrochemical active surface area (EASA). This is manifested from the catalyst surface's electrochemical double-layer capacitance (Cdl), calculated from the non-Faradaic capacitive current, associated with double-layer charging from the cyclic voltammograms [START_REF] Benck | Amorphous molybdenum sulfide catalysts for electrochemical hydrogen production: insights into the origin of their catalytic activity[END_REF][START_REF] Trasatti | Real surface area measurements in electrochemistry[END_REF]. CV measurements were performed (2) tpp = 0.5h @ Ec = -2.0 V vs. RHE; (3) tpp = 2.0h @ Ec = -2.0 V vs. RHE; (4) tpp = 4.0h @ Ec = -2.0 V vs. RHE; (5) tpp = 12h @ Ec = -2.0 V vs RHE; (6) tpp = 12h @ Ec = -2.5 V vs. RHE; [START_REF] Liu | Carbon-based metal-free catalysts[END_REF] increased from 4.75 mF cm -2 for the nonactivated CF sample to 6.7, 11.61, 18.99, and 28.68 mF cm -2 for the CF samples after 0.5, 2, 4, and 12 h of cathodic activation at -2.0 and -4.0 V vs. RHE, respectively. At a given tpp (12 h), the value of Cdl is further increased as the applied cathodic potential was more negative. It increased from 28.68 mF cm -2 at Ec = -2.0 V vs. RHE to 37.66, 44.43, and 48.52 mF cm -2 at Ec values of -2.5, -3.0, and -4.0 V vs. RHE, respectively. These findings confirmed the beneficial impact of the cathodic activation process, since electrocatalysts with higher Cdl values possess plenty of attainable active surface sites [START_REF] Zhou | Efficient hydrogen evolution by ternary molybdenum sulfoselenide particles on self-standing porous nickel diselenide foam[END_REF][34][35]. This, in turn, expedites efficacious charge transfer, leading to high catalytic performance. EIS measurements (Supporting Information, Figures S9, with a suitable equivalent circuit depicted in Figure S10) supported the enhanced charge transfer upon cathodic activation. Equation ( 4) is used to calculate the value of EASA before and after cathodic activation, considering 40 μF cm -2 as the average specific capacitance (Cs) value for a typical flat electrode (1.0 cm 2 ) [36]:

EASA = Cdl / Cs (4)
Based on Eq. ( 4), the highest EASA value (1213.00 cm 2 ) was determined for the CF sample after exposure to 12 h of cathodic pre-polarization at -4.0 V vs. RHE. This value is 10 times greater than that of the untreated CF sample (118.75 cm 2 ).

The obvious increase in the Cdl values upon cathodic activation indicates some contribution from the highly active surface area of the cathodically activated CF catalysts, as evidenced from the EASA values (Table 2). However, there is also a significant improvement in the cathodic current density among the studied cathodically activated CF samples (revisit Figures 2 and3). This suggests that the cathodically activated CF samples' superior HER catalytic performance cannot be solely attributed to the change of active surface area, but also to the structural changes that occurred at the atomic level, as a result of the process of cathodic activation.

To gain further insight into the high intrinsic catalytic activity of the cathodically activated CF samples, the number of active sites n were determined using Eq. ( 5) [37]:

n = Q/2F ( 5
)
where Q is the catalyst's voltammetry charge determined from the CV measurements, Figure 6. The number 2 refers to the number of electrons consumed during the HER reaction, and F is the Faraday's constant (96485 C/mol). Table S1 (Supporting Information) depicts the values of Q and n recorded for the cathodically-activated CF samples in a comparison with the inactivated (as-received) one. Results revealed that, at a constant applied potential (Ec = -2.0 V vs. RHE), the value of n increases with increasing tpp, and further increases at a given tpp (12 h) as Ec was held at more cathodic values.

To determine the per-site turnover frequencies (TOFs, s -1 ), the formula depicted in Eq. ( 6) is used.

TOF = |I| / 2Fn ( 6
)
where I is the current value (A cm -2 ) measured at a specific overpotential. Merging Eqs. [START_REF] Peng | Catalyst engineering for electrochemical energy conversion from water to water: Water electrolysis and the hydrogen fuel cell[END_REF] and (3) yields Eq. ( 7):

TOF = | I | / Q (7)
It is therefore possible, based on Eq. ( 7), to turn the current densities obtained from LSV measurements into TOF values, Figures S11 and S12 (Supporting Information).

It is inferred from Figures S11 and S12 that, for any investigated catalyst, the TOF value increases as the voltage applied to the CF/KOH interface is made more cathodic, where H2 gas is excessively released. At any applied voltage, particularly at high negative values, the value of TOF is found to enhance with tpp. At a given tpp (12 h), significant increase in TOF is observed when the CF sample is subjected to cathodic activation under high negative Ec values. These results add additional evidence for the remarkable catalytic role of the various cathodic pre-polarization processes applied to the CF/OH -interface in catalyzing the alkaline HER.

In order to further compare the HER electrocatalytic performance, the investigated cathodically-activated CF catalysts' Faradaic efficiency (FE%) is calculated. Detailed calculations are shown in Section S1.4 (Supporting Information), and Table 3 collects the data obtained, namely the estimated and measured volumes of H2 produced through the applied electrolysis process. Results show that the value of FE% increases with increasing tpp at a constant cathodic potential (Ec = -2.0 V vs. RHE), and further increased at a given tpp (12 h) as Ec was kept at more cathodic values. The CF sample cathodically-activated at Ec = -4.0

V for 12 h is also reported here as the most active catalyst for the HER among the other activated samples tested, as it recorded the largest amount of H2 (32.66 μmol h -1 ) measured by GC with an FE% value of 98.78%. These results highlight the outstanding HER catalytic activity of the CF catalyst cathodically-activated at -4.0 V vs. RHE for 12 h, which is analogous to the catalytic performance of the most efficacious metal-free electrocatalysts for HER published in the literature (Supporting Information, Table S2).

Characterization of the CF samples before and after cathodic activation

To gain some insights on the impact of the cathodic activation, the morphology of the CF samples before and after polarization at -2 V for 12 h in 1.0 M KOH was assessed using scanning electron microscopy (SEM). Figure 7a displays the SEM image of non-treated CF sample consisting of carbon fibers (~2 µm in diameter) arranged in form of bundles with an average size of 10 μm. The magnification SEM image revealed smooth fiber walls with a few protrusions (Fig. 7b). After cathodic activation, there was no obvious change in the surface morphology, although a significant number of small humps is apparent at high magnification (Fig. 7d). These humps could explain the increased electrochemical surface area recorded after cathodic polarization and thus improved electrocatalytic performance for HER. From these observations, one could infer that the electrochemical activation did not affect the bulk of the fibers and any change that occurred during this process was limited to the CF surface.

The results are in accordance with the high corrosion stability of the CF in different media [START_REF] Mitov | Novel nanostructured electrocatalysts for hydrogen evolution reaction in neutral and weak acidic solutions[END_REF]. Energy dispersive X-ray (EDX) analysis of the CF samples was further conducted to examine the chemical changes that took place during the cathodic activation in 1.0 M KOH (Table S3). The results revealed a small increase of the oxygen content from 0.30 to 0.48 at.% after cathodic activation, which is in accordance with a surface-confined process. Indeed, b)

(c) (a) (b) (d)
EDX provides chemical information of the bulk material, while the electrochemical activation process is believed to occur essentially on the CF surface.

EDX mapping showed homogeneous distribution of carbon and oxygen throughout the CF surface before and after cathodic polarization at -2 V for 12 h in 1.0 M KOH (Figure S13).

The chemical composition of the CF samples was further probed through X-ray photoelectron spectroscopy (XPS) analysis to gain more insight on chemical changes that have occurred on the CF surface upon electrochemical activation. Figure S14 depicts the XPS survey spectra of the CF samples before and after cathodic activation. Both spectra contain only carbon and oxygen, in full agreement with their chemical composition. It is worth to notice that the amount of oxygen increased from 6.17 to 9.66 at.% after cathodic activation, implying, as expected, an oxidation of the surface (Table S4). The result is in full accordance with EDS analysis. Raman spectroscopy is valuable tool for the characterization of carbon-based materials. (tpp = 24h @ -2.0 V vs. RHE).

Conclusion

The results gathered in the present study demonstrated that the electrocatalytic properties of carbon felt (CF) can be improved through a simple cathodic activation process in KOH (1.0 M) aqueous solution. Under optimized operating conditions, i.e. applied voltage and polarization time, the catalytic performance for the hydrogen evolution reaction (HER) was drastically enhanced. Under metal-free conditions, the cathodically activated CF recorded a current density of 10 mA cm -2 at an overpotential of 180 mV vs. RHE and a long-term stability. This performance was achieved under experimental conditions that did not require huge investment as the activation process was conducted in the same electrochemical cell and electrolyte solution used for HER measurements. Under our experimental conditions, X-ray photoelectron spectroscopy analysis revealed surface oxidation. The formation of oxygencontaining groups on the CF surface are believed to enhance water adsorption and act as active sites for hydrogen generation. Taken together the findings in this study hold promise for the development of metal-free electrodes that can operate in alkaline media with a performance that could challenge the most commonly used noble-metal free catalysts.

Figure 1

 1 Figure1shows the cathodic polarization curves recorded for as-received CF in 1.0 M KOH

Figure 1 .

 1 Figure 1. Cathodic polarization plots acquired for the as-received CF sample in deaerated 1.0 M KOH aqueous solution using different potential sweep rates (5-100 mV s -1 ) at room temperature: (1) 5.0 mV s -1 ; (2) 25 mV s -1 ; (3) 50 mV s -1 ; (4) 100 mV s -1 .

Figure 2 .

 2 Figure 2. (a) Linear cathodic polarization curves acquired for the as-received CF sample after holding it at a cathodic potential of -2.0 V vs. RHE for various duration periods (0.5-12 h). (b) Fitting the experimental polarization data with Tafel equation. Measurements were performed in deaerated 1.0 M KOH solution at 5.0 mV s -1 at room temperature. (1) 0.0 h; (2) 0.5 h; (3) 2 h; (4) 4 h; (5) 12 h.

Figure 3 .

 3 Figure 3. (a) Linear cathodic polarization curves acquired for the as-received CF sample after holding it at various cathodic potentials for 12 h. (b) Fitting the experimental polarization data with Tafel equation. Measurements were performed in deaerated 1.0 M KOH solution at 5.0 mV s -1 at room temperature: (1) -2.0 V, (2) -2.5 V, (3) -3.0 V, (4) -4.0 V vs. RHE.

Figure 4 . 4 . 2 - 2 E

 4422 Figure 4. Long-term stability test of the CF sample (as-received) performed under repetitive cycling (10,000 cycles). Measurements were performed in deaerated 1.0 M KOH aqueous solution at 25 o C.

Figure 5 .

 5 Figure 5. Chronoamperometry plot of bare carbon felt polarized at -2 V vs. RHE in 1.0 M KOH.

Figure 6 .

 6 Figure 6. Cyclic voltammograms of as-received CF samples, before (curve 1) and after cathodic pre-polarization conditions (curves 2-8), recorded in a non-Faradaic region of the voltammogram for determining the catalyst's electrochemically-active surface area.Measurements were performed in deaerated KOH solution (1.0 M) at 100 mV s -1 at room temperature. (1) as-received (inactivated) CF; cathodically activated CF samples:(2) tpp = 0.5h @ Ec = -2.0 V vs. RHE; (3) tpp = 2.0h @ Ec = -2.0 V vs. RHE; (4) tpp = 4.0h @ Ec = -2.0 V vs. RHE; (5) tpp = 12h @ Ec = -2.0 V vs RHE; (6) tpp = 12h @ Ec = -2.5 V vs. RHE; (7) tpp = 12h @ Ec = -3.0 V vs. RHE; (8) tpp = 12h @ Ec = -4.0 V vs.RHE.

  Figure 6. Cyclic voltammograms of as-received CF samples, before (curve 1) and after cathodic pre-polarization conditions (curves 2-8), recorded in a non-Faradaic region of the voltammogram for determining the catalyst's electrochemically-active surface area.Measurements were performed in deaerated KOH solution (1.0 M) at 100 mV s -1 at room temperature. (1) as-received (inactivated) CF; cathodically activated CF samples:(2) tpp = 0.5h @ Ec = -2.0 V vs. RHE; (3) tpp = 2.0h @ Ec = -2.0 V vs. RHE; (4) tpp = 4.0h @ Ec = -2.0 V vs. RHE; (5) tpp = 12h @ Ec = -2.0 V vs RHE; (6) tpp = 12h @ Ec = -2.5 V vs. RHE; (7) tpp = 12h @ Ec = -3.0 V vs. RHE; (8) tpp = 12h @ Ec = -4.0 V vs.RHE.

Figure 7 .

 7 Figure 7. SEM images at different magnifications of carbon felt samples before (a, b), and after cathodic activation (c, d).

Figure 8 .

 8 Figure 8. Core level XPS spectra of the C1s of CF before (a) and after (b) cathodic activation(tpp = 24h @ -2.0 V vs RHE).

Figure 9 Figure 9 .

 99 Figure 9 displays the Raman spectra of the CF before and after cathodic activation in KOH (1.0 M) for 12 h. Both spectra comprise two main bands at around 1354 and 1580 cm -1

in Section S1 (Supporting Information). 3. Results and discussion 3.1. Electrochemical measurements

	(CV) technique and CA measurements performed at a cathodic overpotential of -2.0 V vs.
	RHE for 24 h. CA technique was also applied to estimate the cathodically-activated CF
	catalysts' HER Faradaic efficiency (FE%) values.
	The cathodically-activated CF electrocatalysts' Faradaic efficiency (FE%) values toward
	the HER were determined by measuring the volume of H2, (VH2)measured, evolved through a
	controlled galvanostatic electrolysis, conducted in KOH (1.0 M) for 1.0 h at room
	temperature, by a gas chromatograph (GC). The (FE%) value was then calculated from the
	ratio (VH2)measured / (VH2)calculated, where (VH2)calculated denotes the anticipated volume of H2
	theoretically calculated during that electrolysis. The employed electrochemical techniques and
	The reference electrode was immersed in a FE% calculation are fully described 3.2.1. Effect of cathodic pre-treatment on the HER catalytic activity
	Luggin capillary (Princeton Applied Research) filled with 2 M potassium nitrate (KNO3,
	Sigma Aldrich) solution. This capillary acts as the salt bridge to minimize the junction
	potentials, and inhibit contamination of the test solution with traces of mercury from the
	reference electrode. The working electrode (WE), namely the CF sample, was first activated
	through chronoamperometry, CA, (current vs. time at a fixed cathodic potential)
	measurements conducted under various conditions of cathodic pre-treatment processes,
	namely applied cathodic voltage and pre-polarization time.
	Linear sweep voltammetry (LSV) and electrochemical impedance spectroscopy (EIS)
	techniques were then employed to assess the HER catalytic activity of the cathodically-
	activated CF samples. The long-term stability and durability tests were carried out using
	continuously repeated potential cycling (up to 10000 cycles) employing cyclic voltammetry

  HER catalytic activity of the CF samples was, therefore, significantly improved upon cathodic activation. The cathodically-activated CF samples' HER catalytic performance has increased to different extents, depending on the cathodic prepolarization conditions applied to the CF/KOH interface. For instance, the EHER value decreased from -810 mV vs. RHE for the nonactivated CF sample to -800, -610, -530, and -386 mV vs. RHE for the CF samples cathodically-activated by holding the CF sample at -2.0 V vs. RHE for tpp values of 0.5, 2.0, 4.0, and 12 h, respectively. The EHER value was further reduced from -386 mV for the CF sample cathodically activated

	The
	Cathodic pre-	Cathodic	-EHER /	-b /	jo /	η10 /	Cdl /	EASA
	polarization	pre-	mV vs.	mV dec -1	mA cm -2	mV	mF cm -2	/ cm 2
	conditions applied to	treatment	RHE
	the CF/OH -interface	parameters
		tpp = 0.0 h	810	290	5.6 × 10 -3	890	4.75	118.75
	Effect of pre-	tpp = 0.5 h	800	253	4.9 × 10 -3	870	6.70	167.5
	polarization time (tpp): holding the	tpp = 2.0 h	610	332	6.3 × 10 -2	725	11.61	290.25
	electrode at -2.0 V vs RHE for various	tpp = 4.0 h	530	320	8.9 × 10 -2	640	18.99	474.75
	tpp values
		tpp = 12 h	386	175	2.95 × 10 -	440	28.68	717.0
					2
		Ec = -2.5 V	260	126	3.55 × 10 -	295	37.66	941.5
	Effect of cathodic	vs. RHE			2
	potential (Ec): the
	electrode is held for	Ec = -3.0 V	205	110	5.0 × 10 -2	240	44.43	1110.8
	12 h at various Ec	vs. RHE
	values
		Ec = -4.0 V	157	90	9.7 × 10 -2	182	48.52	1213.0
		vs. RHE

These HER kinetic parameters are extracted through fitting the experimental polarization data, Figures 2(a) and 3(a), to the Tafel equation yielding the Tafel plots depicted in Figures 2(b) and 3(b). It is obvious, from the results of the Table

2

, that the various cathodic pre-polarization conditions applied to the CF/KOH interface have a significant catalytic impact on the HER kinetics on CF. The nonactivated CF sample (tpp = 0.0 and Ec = -2.0 V vs. RHE) exhibited inferior catalytic activity with a highly negative onset potential (EHER) value of -810 mV vs. RHE. The EHER values markedly drifted towards the less negative (active) direction, Table

2

, when the CF sample was exposed to various cathodic polarization pre-treatment conditions (cathodic activation).

for tpp = 12 h at -2.0 V vs. RHE to -260, -205, and -157 mV vs. RHE for the samples cathodically-activated upon holding the CF sample at -2.5, -3.0, and -4.0 V vs. RHE for the same pre-polarization duration period, respectively.

Table 3 .

 3 Mean value (standard deviation) of VH2 (measured and calculated) after 1 h of a controlled galvanostatic electrolysis (CGE) * , along with the Faradaic Efficiency values, ε(%), for the investigated catalysts.

	Cathodic pre-	Cathodic	H2 measured	Calculated H2 based on	FE(%)
	polarization conditions applied to the CF/OH -interface	pre-treatment parameters	by GC (H2 / μmol h -1 )	the charge passed during electrolysis
				Charge	H2 / μmol
				passed / C	h -1
		tpp = 0.0 h	12.72(0.15)	3.02(0.04)	15.65(0.2) 81.3(1.05)
	Effect of pre-polarization time (tpp):	tpp = 0.5 h	15.14(0.18)	3.4(0.048) 17.62(0.33) 85.9(1.12)
	holding the electrode at -2.0 V vs. RHE for	tpp = 2.0 h	18.02(0.25)	3.88(0.05) 20.11(0.38) 89.6(1.2)
	various tpp values	tpp = 4.0 h	21.98(0.30)	4.6(0.07)	23.84(0.42) 92.2(1.3)
		tpp = 12 h	26.80(0.40)	5.4(0.10)	27.98(0.55) 95.8(1.2)
		Ec = -2.5 V	28.84(0.45)	5.77(0.11)	29.90(0.6) 96.44(1.4)
	Effect of cathodic	vs. RHE
	potential (Ec): the
	electrode is held for 12	Ec = -3.0 V	30.03(0.50)	5.96(0.11) 30.89(0.62) 97.2(1.35)
	h at various Ec values	vs. RHE
		Ec = -4.0 V	32.66(0.53)	6.38(0.12) 33.06(0.65) 98.78(1.5)
		vs. RHE
	* CGE: the catalyst is held at a current density of -10 mA cm -2 for 1 h in 1.0 M KOH solution
	at 25 o C.

Acknowledgements

The authors gratefully acknowledge financial support from the Centre National de la Recherche Scientifique (CNRS), the University of Lille, and the Hauts-de-France region. The authors are also thankful to the Taif University Researchers Supporting Project number (TURSP-2020/03), Taif University, Taif, Saudi Arabia.

for each cathodically-activated CF sample, see Figure 6 as a representative example.

The rest of the CV data are shown in Figures S1-S8 (Supporting Information), and the calculated values of Cdl and EASA are also reported in Table 2.

Conflict of interest

No conflict of interest to declare.

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