Psy.D Raffaella Calati
email: raffaella.calati@gmail.com

MD Emilie Olié

MD Déborah Dassa

MD Carla Gramaglia

MD Sébastien Guillaume

MD Fabio Madeddu

MD Philippe Courtet

EUTHANASIA AND ASSISTED SUICIDE IN PSYCHIATRIC PATIENTS: A SYSTEMATIC REVIEW OF THE LITERATURE

Keywords: euthanasia, assisted suicide, end-of-life care, psychiatric disorders, depression

The number of psychiatric patients requesting Euthanasia or Assisted Suicide (EAS) continues to increase. The aims of this systematic review were to: 1) describe the available data related to psychiatric patients having received or requesting EAS (pEAS) for each country in which is allowed; 2) and describe the ethically salient points that arise. PubMed, PsycINFO, and Scopus databases were used to identify articles published up to September 2020. Among the retrieved publications, only studies on pEAS cases (pEAS-C), pEAS requests, or physician reports/attitude towards pEAS reporting some quantitative data on patients having received or requesting pEAS were retained. Among the 24 selected studies, thirteen (54%) were about pEAS in the Netherlands, four (17%) in Belgium, and seven (29%) in Switzerland. Results were different across different countries. In the Netherlands, pEAS-C were mostly women (70-77%) and often had at least two psychiatric disorders (56-97%). Mood disorders were mainly represented (55-70%) together with personality disorders (52-54%). History of suicide attempts was present in 34-52%. Moreover, 37-62% of them had at least one comorbid medical condition. In Belgium pEAS-C were mostly women (75%), but the majority (71%) had a single diagnosis, mood disorder. In Switzerland available data were less detailed. As pEAS-C seem to be very similar to 'traditional suicides', pEAS procedures should be carefully revised to establish specific criteria of access and guidelines of evaluation of the request. A deeper focus on unbearable suffering, decision capacity and possibilities of improvements is warrented as well as the involvement of mental health professionals.

Highlights

Features of psychiatric patients having received Euthanasia or Assisted Suicide (pEAS) were different across different countries In the Netherlands the percentage of pEAS cases increased from 0% to 1.1% (from 0 to 68) in [2009][2010][2011][2012][2013][2014][2015][2016][2017][2018][2019] In Belgium the percentage of pEAS cases increased from 0% to 2.2% (from 0 to 40) in 2002-2013 Mood disorders were mainly represented Cases of pEAS seem to be very similar to 'traditional suicides'

Introduction

Euthanasia or Assisted Suicide (EAS) (see Box 1 for acronyms mainly used in this manuscript and Box 2 for useful definitions) can be legally practiced in the Netherlands, Belgium, Luxembourg, Switzerland, Colombia, and Canada, as well as in nine states and the district of Columbia within the United States [START_REF] Emanuel | Attitudes and Practices of Euthanasia and Physician-Assisted Suicide in the United States, Canada, and Europe[END_REF], and Australian state of Victoria. In the Netherlands, Belgium, Luxembourg, and Switzerland, EAS is not restricted to patients at the end of life stage. For instance, in the Benelux countries, "unbearable suffering" due to a medical (somatic or mental) condition that "can not be alleviated" and in the absence of reasonable alternatives is among eligibility requirements for receiving EAS. The number of patients who request EAS is progressively increasing in countries where this procedure is allowed [START_REF] Emanuel | Attitudes and Practices of Euthanasia and Physician-Assisted Suicide in the United States, Canada, and Europe[END_REF] and legalising it can have this consequence [START_REF] Moller | The ongoing discussion on termination of life on request. A review from a German/European perspective[END_REF]. The same is happening concerning psychiatric patients requesting/receiving EAS. A Duch survey among physicians (n = 1456) found that 2% of all requests were from psychiatric patients [START_REF] Van Der Heide | Tweede evaluatie Wet toetsing levensbeëindiging op verzoek en hulp bij zelfdoding ZonMw[END_REF]. In fact, psychological/mental pain can become intolerable, like or even more than physical pain, and it has overlapping neuroanatomical substrates with physical pain [START_REF] Eisenberger | The pain of social disconnection: examining the shared neural underpinnings of physical and social pain[END_REF]. EAS on the grounds of unbearable mental suffering caused by a psychiatric disorder (psychiatric EAS, or pEAS hereafter) remains a limited practice; however, its increasing frequency raises ethical and legal concerns [START_REF] Lopez-Castroman | About the practice of psychiatric euthanasia: a commentary[END_REF]Olie and Courtet, 2016a, b), particularly because of the absence of specific or additional eligibility criteria for psychiatric patients. Indeed, the eligibility requirement of unbearable mental suffering is a condition also commonly experienced by psychiatric patients at suicidal risk [START_REF] Ducasse | Psychological pain in suicidality: a meta-analysis[END_REF]. To date, only a previous review focused on the legal status of EAS and the available data on attitudes and practices was published [START_REF] Emanuel | Attitudes and Practices of Euthanasia and Physician-Assisted Suicide in the United States, Canada, and Europe[END_REF]. To the best of our knowledge, no previous systematic review focused on pEAS.

Aims of the Study

This is the first systematic review with the primary aim to identify and describe the available data related to patients having received or requesting pEAS for each country in which is allowed. We will firstly report results separately for each country since pEAS is regulated by different laws in each one. Our secondary aim, covered in the discussion, is to examine main themes of the included studies and describe the ethically salient points that arise from the empirical literature on this topic. To this aim we reviewed articles concerning all known cases of pEAS (pEAS-C) and pEAS requests (pEAS-R) worldwide.

Methods

This systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement [START_REF] Moher | Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement[END_REF]. A literature search (articles published until September 30th, 2020) was independently performed by RC and EO using PubMed, PsycINFO, and Scopus databases with the search terms (euthanasia[title] OR "assisted suicid*"[title] OR "assisted dying"[title] OR "physician assistance in dying" [title]) AND (psych* OR mental) with appropriate filters (abstract, humans, English). We used EndNote software (EndNote X9, Thomson Reuters, USA) to identify the duplicates among the three databases. The reference lists of the identified studies and reviews were also checked to find additional relevant articles.

In Belgium, a previous study analyzed all pEAS cases reported to the Federal Control and Evaluation Committee on Euthanasia (FCEC) [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF]. As no analogous study exists for the Netherlands, the summary reports of all EAS cases identified by the Dutch Regional Euthanasia Review Committees (DRERC, Regionale Toetsingscommissies Euthanasie; https://www.euthanasiecommissie.nl), and the End-of-Life Clinic (now Expertisecentrum Euthanasie) annual reports (http://www.levenseindekliniek.nl/informatie/) were analyzed. Studies were included if: 1) they focused on pEAS-C and/or pEAS-R; 2) they reported some quantitative data on patients having received or requesting pEAS; 3) they were written in English language. All study designs were included. In the case of surveys on physicians' practice towards EAS, only studies considering (also) psychiatric patients were included. Studies were excluded if: 1) they only considered terminally ill patients or patients with a chronic medical condition who could also have a psychiatric comorbidity; 2) they focused on patients with dementia (for reviews on suicide and EAS in dementia see [START_REF] Diehl-Schmid | Suicide and assisted dying in dementia: what we know and what we need to know. A narrative literature review[END_REF][START_REF] Draper | Suicidal behavior and assisted suicide in dementia[END_REF][START_REF] Tomlinson | Assisted dying in dementia: a systematic review of the international literature on the attitudes of health professionals, patients, carers and the public, and the factors associated with these[END_REF]); 3) they did not report quantitative data but they focused on opinions concerning pEAS; 4) they were case series of extremely small sample size (n<5) (e.g., [START_REF] Benrimoh | Euthanasia requests in a Canadian psychiatric emergency room: A case series: Part 1 of the McGill University euthanasia in psychiatry case series[END_REF][START_REF] Perreault | Euthanasia requests in a Canadian psychiatric outpatient clinic: A case series part 2 of the McGill University euthanasia in psychiatry case series[END_REF]); 5) they were commentaries, letters to the Editor, reviews (see Figure 1 for the study flowchart). From each included article, RC and DD independently extracted: country of the study, analysed period, sample, male gender, age, ethnicity, medical conditions, psychiatric conditions, main results, and results on psychiatric patients (when different from main results) (Table 1). RC and DD independently evaluated the strength of reporting with the Quality Assessment Tool for Case Series Studies (National Institutes of Health, 2014), the checklist for reporting survey research [START_REF] Bennett | Reporting guidelines for survey research: an analysis of published guidance and reporting practices[END_REF], the COnsolidated criteria for REporting Qualitative research (COREQ) checklist [START_REF] Tong | Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups[END_REF], and the checklist for reporting observational longitudinal studies [START_REF] Tooth | Quality of reporting of observational longitudinal research[END_REF]. In the following description, when studies included overlapping samples of patients, we followed these steps: we mentioned all the studies at the beginning of the related paragraph, we described the more comprehensive study/studies in the text of the results, we included and described each study in the descriptive table (Table 1). In the following text we will use the term "pEAS" when we specifically refer to EAS granted or requested for psychiatric reasons and "EAS" when we refer to EAS in general, not only granted or requested for psychiatric reasons but for every reason.

Results

History and current law

For a description of the history of legislation and current law of states and countries where EAS is allowed see Box 3.

Description of main studies

At the end of the selection process (Figure 1), 24 articles were retained (Table 1): thirteen (54%) were about pEAS in the Netherlands, four (17%) in Belgium, and seven (29%) in Switzerland. Four main study designs were represented: 1) pEAS case series (n=13; 54%); 2) surveys on physicians' practice of/attitudes towards pEAS (n=6; 25%); 3) qualitative studies (n=4; 17%); and 4) longitudinal study (n=1; 4%). Among the included studies, some described pEAS-C, some pEAS-R, some referred to pEAS request withdrawal, and some described not granted pEAS requests. In the following paragraphs we will present a narrative synthesis of the studies, distinguishing these 4 types when possible.

Netherlands Prevalence of pEAS

Analysis of the annual reports by the DRERC (from 2002 to 2019) and the End-of-Life Clinic (from 2012 to 2017) indicated that the number of pEAS-C is progressively increasing in the Netherlands, although still limited (Figure 2 and 3). According to DRERC, the percentage of pEAS-C increased from 0% to 1.07% (from 0 to 68) in ten years (2009-2019) (Figure 2), while according to the Endof-Life Clinic the percentage of pEAS-C increased from 6.8% to 8.7% (from 9 to 65) in 4 years (2013-2017) (Figure 3).

Characteristics associated with pEAS

The first studies were performed years before the promulgation of the formal legislation (2002). From a first article concerning the most important reasons for discussing 120 reported cases in the Assembly of Prosecutors General (1991)(1992)(1993)(1994)(1995), "primarily mental suffering" was already reported for 6 patients (5%), although no further detailes were specified/were available [START_REF] Van Der Wal | Evaluation of the notification procedure for physician-assisted death in the Netherlands[END_REF]. Characteristics of patients were available from: a) the data of the annual reports published by the DRERC (pEAS-C); b) the data of the End-of-Life Clinic (a single study including pEAS-C, pEAS-R, pEAS request withdrawal, and not granted pEAS requests); c) surveys on physicians (both pEAS-C and pEAS-R). We referred to the DRERC data for the description of pEAS-C and to surveys of physicians for pEAS-R because of the limited numbers of pEAS-C reported in the physicians' surveys.

DRERC -pEAS-C

The characteristics of patients who received pEAS were available from the data of the annual reports published by the DRERC and were analysed in some studies, such as [START_REF] Doernberg | Capacity Evaluations of Psychiatric Patients Requesting Assisted Death in the Netherlands[END_REF][START_REF] Kim | Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014[END_REF][START_REF] Miller | Euthanasia and physician-assisted suicide not meeting due care criteria in the Netherlands: a qualitative review of review committee judgements[END_REF][START_REF] Nicolini | Euthanasia and assisted suicide of persons with psychiatric disorders: the challenge of personality disorders[END_REF][START_REF] Tuffrey-Wijne | Euthanasia and assisted suicide for people with an intellectual disability and/or autism spectrum disorder: an examination of nine relevant euthanasia cases in the Netherlands (2012-2016)[END_REF][START_REF] Van Veen | Euthanasia of Dutch Patients with Psychiatric Disorders between 2015 and 2017[END_REF]. Three studies in particular analysed pEAS-C: 66 patients who received pEAS in the period 2011-2014 [START_REF] Kim | Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014[END_REF]; 35 new cases who received pEAS in the period [START_REF] Draper | Suicidal behavior and assisted suicide in dementia[END_REF][START_REF] Lopez-Castroman | About the practice of psychiatric euthanasia: a commentary[END_REF][START_REF] Van Veen | Euthanasia of Dutch Patients with Psychiatric Disorders between 2015 and 2017[END_REF]; 74 cases who received pEAS for personality and related disorders in the period 2011-2017 [START_REF] Nicolini | Euthanasia and assisted suicide of persons with psychiatric disorders: the challenge of personality disorders[END_REF] (hence, this sample partially overlaps with the previous ones). The main pEAS-C features of these patients can be summarized as following: they were mostly women (70-77%) and often had at least two psychiatric disorders (56-97%); mood disorders were mainly represented (55-70%) together with personality disorders (52-54%); history of suicide attempts was present in 34-52%; 37-62% of them had at least one comorbid medical condition.

End-of-Life Clinic (Expertisecentrum Euthanasie)

The End-of-Life Clinic is a mobile euthanasia clinic that provides EAS to patients whose requests have been rejected by their physicians, but fulfil the legal criteria for EAS. Analysis of the EAS application forms received by the End-of-Life Clinic during its first year of operation (2012-2013) (n=645) showed that psychiatric (n=53) or psychological conditions (n=121) were self-reported by 174 applicants (27%) [START_REF] Snijdewind | A Study of the First Year of the End-of-Life Clinic for Physician-Assisted Dying in the Netherlands[END_REF]. Among these patients with psychiatric/psychological conditions, EAS (and not pEAS for the reason we will explain in the next paragraph) was granted to 8.2% individuals. Moreover, among all the subjects who withdrew their requests, 36.8% had psychiatric/psychological conditions, so the rate of withdrawal was high. Among them, EAS requests were not granted in 43.6% and 15.4% died before decision. One limitation of this study is that "psychiatric" and "psychological" conditions were inferred from the patients' and families' initial self-reported application form/registration to the End-of-Life Clinic. Such conditions were not further specified or validated by medical records or by a physician's evaluation of the patients. Moreover, psychiatric/psychological conditions were not indicated as the main cause of EAS request but can be comorbid with medical condition(s), so we cannot consider these patients under the label "pEAS". This may be also the reason (or one of the reasons) why numbers reported in Figure 3 are different.

Physicians' surveys

The characteristics of patients who requested pEAS were available through some surveys on physicians' practice of/attitudes towards pEAS, including psychiatrists (Evenblij et al., 2019a;[START_REF] Groenewoud | Psychiatric consultation with regard to requests for euthanasia or physician-assisted suicide[END_REF][START_REF] Groenewoud | Physician-assisted death in psychiatric practice in the Netherlands[END_REF], general practitioners (GPs) (Jansen-van der [START_REF] Jansen-Van Der Weide | Granted, undecided, withdrawn, and refused requests for euthanasia and physician-assisted suicide[END_REF], and physicians who certified deaths (Evenblij et al., 2019b). In the surveys of psychiatrists, not surprisingly the reported numbers of pEAS-R were higher compared to GPs. A first analysis of the data from a survey of Dutch psychiatrists (552 respondents out of 673) indicated that among patients who requested pEAS in the previous two years (n=201, 63% women), the most frequent diagnoses were mood disorder (51%) and personality disorder (64%), or both (48% of patients) [START_REF] Groenewoud | Physician-assisted death in psychiatric practice in the Netherlands[END_REF]. Among these patients, 64% refused the remaining psychiatric treatment options. In a second study, a further sample of 500 Dutch psychiatrists was considered (Evenblij et al., 2019a). Of the 207 responding psychiatrists, 54% had received at least one pEAS-R and 4% had performed pEAS at least once. Interestingly, Evenblij et al. investigated patients whose pEAS request was denied (Evenblij et al., 2019a): after the request was not granted, the majority of the patients were still alive (69%); they died by suicide (16%); they died of natural causes (3%); they died as a result of EAS performed by the End-of-Life Clinic (3%); they stopped eating and drinking (1.6%). Surveys of GPs and physicians who certified deaths give us the picture of the phenomenon from another perspective. In fact, the considered samples did not include only psychiatric patients. Analysis of the results of a questionnaire sent to GPs who were asked to describe the most recent EAS requests they had received (n=1,681 requests) (Jansen-van der [START_REF] Jansen-Van Der Weide | Granted, undecided, withdrawn, and refused requests for euthanasia and physician-assisted suicide[END_REF] showed that depression (7%) and to be tired of living (17%) were among the reasons for requesting (p)EAS. Moreover, among the 144 patients who withdrew their EAS application, 10% initially requested EAS because of their depression and 22% because they were tired of living. However, in this study depression was listed among the reasons for requesting EAS but it is not clear whether this condition was comorbid and how it has been diagnosed. Hence, also in this case, we cannot consider these patients without doubts under the label "pEAS". Finally, among the 150 patients whose request was refused, 18% were depressed and 37% tired of living. In a national mortality follow-back study, questionnaires were sent to physicians (n=9,351, response 78%) who certified deaths of patients who died between August and December 2015 (Evenblij et al., 2019b). Out of the 5,361 deceased patients, 183 (3.4%) had a psychiatric disorder; of them, 11.4% requested pEAS and 4.8% received pEAS. The presence of a psychiatric disorder was associated with a lower likelihood of having a EAS request being carried out, even in the case of comorbid severe and life-limiting somatic illness.

Belgium Prevalence of pEAS

All the pEAS-C reported to the FCEC in the period 2002-2013 were summarized [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF] (for this reason we did not perform an independent review of the FCEC biannual reports, like the one we did for the Dutch DRERC reports, even if an update would be needed). The percentage of pEAS-C increased from 0% to 2.2% (from 0 to 40) in eleven years (2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013).

A study examining the first 10 years after legislation (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)) (all euthanasia cases: n=8,752) [START_REF] Dierickx | Euthanasia in Belgium: trends in reported cases between 2003 and 2013[END_REF] reported that the average psychiatric disorders annual change was +0.3%. Physical and psychological suffering increased during years (average annual change: +1.8%), while physical suffering only and psychological suffering only decreased (average annual change: -1.5% and -0.3% respectively). This could correspond to the increase of more complex conditions, including psychiatric disorders and 'tiredness of life', and to the recognition that medical conditions are highly associated with psychological distress.

Characteristics associated with pEAS FCEC -pEAS-C

The characteristics of patients who received pEAS were available from the data of the Belgium FCEC and were reported in some studies, such as [START_REF] Dierickx | Euthanasia in Belgium: trends in reported cases between 2003 and 2013[END_REF][START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF][START_REF] Smets | Legal euthanasia in Belgium: characteristics of all reported euthanasia cases[END_REF]. Among the pEAS-C reported to the FCEC in the period 2002-2013, 117 cases (88 women, 75%) were identified [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF]: 71% had only a mood disorder, 10% a mood disorder with another psychiatric disorder, and 19% had other psychiatric disorders. Patients with only mood disorders were generally older than 60 years of age (65%), whereas the others were generally younger than 60. Most patients (74%) reported only psychological suffering while 26% reported both psychological and physical suffering. Interestingly, Dierickx et al. did not include patients with physical diseases. pEAS-R An analysis of 100 consecutively referred pEAS-R (Thienpont et al., 2015a) showed that 77 of these patients were women, with an average age at intake of 46±16 years for men and 47±12 years for women. Ninety patients had more than one psychiatric diagnosis, and the most frequent psychiatric diagnoses were depression (n=58) and personality disorder (n=50); however, there was an unusually high number of autism spectrum disorder cases. All 100 were considered competent to request pEAS, and were deemed by the authors to be suffering unbearably and irremediably. At the end of the evaluation, 48 of the pEAS-R were accepted and 35 patients underwent pEAS. Eleven out of these 48 patients decided to postpone or cancel the pEAS. In this last group, eight said that "knowing they had the option to proceed with euthanasia gave them sufficient peace of mind to continue their lives". Thirty-eight people withdrew their requests during the evaluation process. After a follow up period of 1-4 years, 57 of the original 100 patients were still alive, with 9 cases "still in process" and 48 "on hold" because "they were managing with regular, occasional or no therapy". However, this can be also correlated to the high rate of pEAS that were not granted.

Switzerland Prevalence of pEAS

Switzerland has no central register for EAS-C. The Swiss Federal Statistical Office started to document EAS deaths only since 2011. In a recent analysis of death records , among 3,666 EAS-C, patients with mental illness only were 61 (2.1%) while patients with mental and somatic disorders were 46 (1.6%) [START_REF] Bartsch | Assisted Suicide in Switzerland[END_REF].

Characteristics associated with pEAS

In the study by Bartsch et al., concerning the mentioned 61 patients with mental illness only and the 46 patients with mental and somatic disorders, data on specific psychiatric diagnoses were not reported [START_REF] Bartsch | Assisted Suicide in Switzerland[END_REF]. However, considering all the 3,666 cases, psychiatric diagnoseshence with possible psychiatric comorbidities -were present in 13.1% of cases, and in this case specific diagnoses were mentioned, in particular, depression (8.8%), other/not further specified (5.8%), psychosis (0.4%) and bipolar disorder (0.3%). Several Swiss "Right-to-Die" organizations provide EAS, among them EXIT and Dignitas. Some studies reported EAS-C specifically performed by EXIT [START_REF] Bosshard | 748 cases of suicide assisted by a Swiss right-to-die organisation[END_REF][START_REF] Fischer | Reasons why people in Switzerland seek assisted suicide: the view of patients and physicians[END_REF][START_REF] Fischer | Suicide assisted by two Swiss right-to-die organisations[END_REF][START_REF] Frei | Assisted suicide as conducted by a "Right-to-Die"-society in Switzerland: a descriptive analysis of 43 consecutive cases[END_REF]. The suicide tourism phenomenon has been also studied. All EAS-C of non-Swiss residents between 2008 and 2012 were reviewed [START_REF] Gauthier | Suicide tourism: a pilot study on the Swiss phenomenon[END_REF] and compared with those of two previous studies [START_REF] Bosshard | 748 cases of suicide assisted by a Swiss right-to-die organisation[END_REF][START_REF] Fischer | Suicide assisted by two Swiss right-to-die organisations[END_REF]. This analysis suggests that the number of pEAS concerning foreigners with mental disorders (including dementia) is increasing: 9 cases (2.7%) in the period 1990-2000 [START_REF] Bosshard | 748 cases of suicide assisted by a Swiss right-to-die organisation[END_REF], 12 cases (2.9%) in the period 2001[START_REF] Groenewoud | Psychiatric consultation with regard to requests for euthanasia or physician-assisted suicide[END_REF][START_REF] Fischer | Suicide assisted by two Swiss right-to-die organisations[END_REF], and 21 cases (3.4%) in the period 2008-2012 [START_REF] Gauthier | Suicide tourism: a pilot study on the Swiss phenomenon[END_REF]. Interestingly, assisted and unassisted suicides were compared in terms of socio-demographic factors [START_REF] Steck | Assisted and unassisted suicide in men and women: longitudinal study of the Swiss population[END_REF]. While the unassisted suicide rate was higher in men than women, no difference was found for assisted suicides. Higher education was positively associated with assisted suicide and negatively with unassisted suicide; living alone, not having children and absence of religious affiliation were factors associated with both assisted and unassisted suicide [START_REF] Steck | Assisted and unassisted suicide in men and women: longitudinal study of the Swiss population[END_REF].

Strength of reporting

Assessment of the strength of reporting for the selected studies, according to the study design, indicated that all case series studies had good/fair ratings, with the exception of one with poor reporting because of the partial description of the sample [START_REF] Bartsch | Assisted Suicide in Switzerland[END_REF] (Table 2). The question about consecutive cases (investigating if patients received/requested pEAS in the order in which they were identified) was considered not applicable in the majority of the studies because all the published cases/requests that met the criteria might not have been consecutive. We indicated "Yes" only for the two studies explicitedly reporting the term "consecutive" for cases [START_REF] Frei | Assisted suicide as conducted by a "Right-to-Die"-society in Switzerland: a descriptive analysis of 43 consecutive cases[END_REF]Thienpont et al., 2015a). All the surveys on physicians' practice and attitudes did not report evidence of reliability/validity and details on the development of the administered research tool (Table 3). In most of the qualitative studies [START_REF] Doernberg | Capacity Evaluations of Psychiatric Patients Requesting Assisted Death in the Netherlands[END_REF][START_REF] Kim | Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014[END_REF][START_REF] Miller | Euthanasia and physician-assisted suicide not meeting due care criteria in the Netherlands: a qualitative review of review committee judgements[END_REF] data collection could not be evaluated because studies were performed using already available data (Table 4). The only longitudinal study is shown in Table 5. It should be underlined that some of the included studies did not report details concerning psychiatric diagnoses. These are the studies for which the psychiatric diagnosis as a reason for EAS was stated in other terms: primarily mental suffering (van der [START_REF] Van Der Wal | Evaluation of the notification procedure for physician-assisted death in the Netherlands[END_REF]; psychiatric history [START_REF] Frei | Assisted suicide as conducted by a "Right-to-Die"-society in Switzerland: a descriptive analysis of 43 consecutive cases[END_REF]; psychiatric or psychological conditions [START_REF] Snijdewind | A Study of the First Year of the End-of-Life Clinic for Physician-Assisted Dying in the Netherlands[END_REF]. Moreover, for example, as already underlined, in the study by Jansen-van der Weide et al., depression was listed among the reasons for requesting EAS but it is not clear whether this condition was comorbid and how it has been diagnosed (Jansen-van der [START_REF] Jansen-Van Der Weide | Granted, undecided, withdrawn, and refused requests for euthanasia and physician-assisted suicide[END_REF]. For other studies it was difficult to determine whether the psychiatric disorder was the reason for requesting pEAS or was comorbid to another condition (e.g., [START_REF] Smets | Legal euthanasia in Belgium: characteristics of all reported euthanasia cases[END_REF][START_REF] Snijdewind | A Study of the First Year of the End-of-Life Clinic for Physician-Assisted Dying in the Netherlands[END_REF]).

Discussion

Discussion of main results

Our aims were to: 1) review the scientific literature focused on EAS in psychiatric patients (pEAS) in order to identify and describe for the first time the available data related to pEAS for each country in which the practice is allowed; 2) and describe the ethically salient points that arise from the empirical literature on this topic.

Prevalence of pEAS

As previously reported, (p)EAS is progressively increasing in countries where it is allowed [START_REF] Emanuel | Attitudes and Practices of Euthanasia and Physician-Assisted Suicide in the United States, Canada, and Europe[END_REF]. In the Netherlands, the percentage of pEAS-C increased from 0% to 1.07% in the period 2009-2019 according to DRERC data, and from 6.8% to 8.7% in the period 2013-2017 according to the End-of-Life Clinic. Rates are different because the End-of-Life Clinic provides EAS to patients whose requests have been rejected by their physicians, so total numbers are lower (e.g., 747 total EAS cases at the End-of-Life Clinic in 2017 versus 6,585 at DRERC in the same year). In Belgium, pEAS-C increased from 0% to 2.2% in the period 2002-2013. In this case total numbers are lower compared to the Netherlands (around 1,800 cases of EAS in 2013) but an update is needed. Concerning Switzerland it was possible an estimate of the rate of pEAS (2.1%) considering death records of the period 1985-2014 (n=3,666).

Characteristics associated with pEAS

Concerning pEAS-C, both the Netherlands and Belgium patients who received pEAS were mostly women (70-77%). However, in the Netherlands they often had at least two psychiatric disorders (56-97%), while in Belgium the majority (71%) had a single diagnosis. In both countries mood disorders were the main diagnosis (55-71%) while personality disorders were frequent in the Netherlands (52-54%) (and in requestors of pEAS in Belgium) but not in the data from Belgium FCEC database (4%). In the Netherlands a high rate of patients (37-62%) had at least one comorbid medical condition. Interestingly, in the study by [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF] (Belgium) patients were selected to be without somatic condition but still 26% of them reported both psychological and physical suffering. However, it should be underscored that data from Belgium derive from a single study, while those from the Netherlands from three studies, making them more likely to be representative. Further, the Belgian paper was based on summary data from the FCEC rather than from more detailed case files as in the Dutch studies. Concerning pEAS-R, results were similar across different countries, with a majority of women (63-77%), mood disorders (51-58%), personality disorders (50-64%) and medical comorbidity (22-23%). However, in one case series from Belgium there was a high rate of autism spectrum disorder (Thienpont et al., 2015b). A comparison can be traced between pEAS-C/pEAS-R and 'traditional' suicide. Women were preponderant in both pEAS-C and pEAS-R [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF][START_REF] Groenewoud | Physician-assisted death in psychiatric practice in the Netherlands[END_REF]Kim et al., 2016;[START_REF] Nicolini | Euthanasia and assisted suicide of persons with psychiatric disorders: the challenge of personality disorders[END_REF]Thienpont et al., 2015a;[START_REF] Van Veen | Euthanasia of Dutch Patients with Psychiatric Disorders between 2015 and 2017[END_REF]. This ratio corresponds to the sex ratio among suicide attempters and is the opposite of the sex ratio in suicide deaths [START_REF] Bachmann | Epidemiology of Suicide and the Psychiatric Perspective[END_REF][START_REF] Canetto | The gender paradox in suicide[END_REF][START_REF] Fox | Examining the role of sex in self-injurious thoughts and behaviors[END_REF] often attributed to men's use of more fatal means. Thus, the ratio of women to men among pEAS-C is what one would find if a random sample of suicide attempters were given reliably lethal means of suicide. Hence, we can hypothesize that pEAS provides a highly lethal means for women, who are relatively protected against suicide. In fact, in the study comparing assisted and unassisted suicide in Switzerland, the rate of unassisted suicides was higher in men than women while the rate of assisted suicides was similar in both sexes [START_REF] Steck | Assisted and unassisted suicide in men and women: longitudinal study of the Swiss population[END_REF]. This is not the only hypothesis to explain the higher rate of women. Another one is related to different social expectations and norms in relation to traditional masculinity [START_REF] Moller-Leimkuhler | The gender gap in suicide and premature death or: why are men so vulnerable?[END_REF], that may not be associated with representations related to EAS. Another hypothesis can be related to the preponderance of women having a diagnosis of depression [START_REF] Hyde | Gender Differences in Depression: Biological, Affective, Cognitive, and Sociocultural Factors[END_REF], one of the main diagnoses in pEAS. Individuals who obtained or requested pEAS are remarkably similar to individuals who die by 'traditional' suicide. In fact psychopathology, particularly mood and personality disorders, and concurrent physical illnesses are among the factors affecting suicide risk [START_REF] Turecki | Suicide and suicidal behaviour[END_REF]. Moreover, according to Dierickx et al., psychological suffering was the main motivation of EAS-C, in 72% of cases or more [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF]. In the same direction we know that higher psychological pain levels are associated with suicidal ideation and attempts [START_REF] Ducasse | Psychological pain in suicidality: a meta-analysis[END_REF]. More in general, the analysis of the included studies indicates that -not surprisingly -psychiatric patients who obtained or requested pEAS had frequently a particularly severe symptomatology, with a high rate of psychiatric and physical comorbidities. It is well known that comorbidities are particularly frequent in suicide attempters, especially in re-attempt [START_REF] Blasco-Fontecilla | Patterns of Comorbidity of Suicide Attempters: An Update[END_REF]. Moreover, the role of physical pain in suicidal thoughts and behaviors has been reported [START_REF] Calati | Framing the impact of physical pain on suicide attempts. A reply to Stubbs[END_REF][START_REF] Calati | Association between lifetime headache and history of suicide attempts in the elderly[END_REF][START_REF] Calati | The impact of physical pain on suicidal thoughts and behaviors: Meta-analyses[END_REF]. Approximately 1 in 4 patients reported the presence of physical pain, together with psychological pain, despite the absence of reported physical illnesses [START_REF] Dierickx | Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases[END_REF]. As patients who obtained or requested pEAS seem to have clinical features that overlap with those of unassisted suicides, the current risk could be to convert "traditional" suicides into pEAS or to increase suicide mortality by giving access to lethal methods to suicidal patients. People dying from medical illnesses who receive EAS tend to be empowered people who value self-determination and control. Psychiatric patients in the acute phase of their illness which could lead to suicidal risk may not have these characteristics (American Association of Suicidology, 2017).

Some relevant aspects in mental health Unbearable and irremediable suffering

In the analysed countries (Netherlands, Belgium, and Switzerland) EAS is not restricted to patients at the end of life stage but is allowed in presence of "unbearable suffering" and in the absence of reasonable alternatives. The concept of unbearable suffering [START_REF] Dees | Unbearable suffering of patients with a request for euthanasia or physician-assisted suicide: an integrative review[END_REF], and the distinction between unbearable physical suffering and unbearable mental suffering are not clear. The presence of intense mental suffering in patients with a psychiatric/psychological condition could limit their capacity to foresee feasible alternatives and could induce the wish to die. It is a paradox that unbearable psychological suffering is a target for suicide prevention in daily practice and also a required criterion for EAS: in fact unbearable mental suffering may limit the individual capacity of self-determination and control, making it impossible for patients to be eligible for EAS (for data on the moderating effect of decision-making in the relationship between psychological/physical pain and depression see [START_REF] Alacreu-Crespo | Decision-Making Skills Moderate the Relationship between Psychological and Physical Pain with Suicidal Behavior in Depressed Patients[END_REF]). Furthermore, a patient may experience her/his unbearable suffering as irremediable, but in fact some correlates of suffering, for example economic or resource access issues, could change over time [START_REF] Verhofstadt | When unbearable suffering incites psychiatric patients to request euthanasia: qualitative study[END_REF]. The issue of irremediable/irreversible suffering should be considered also in relation to the high percentage of patients who no longer wish to die and/or withdraw their pEAS request, indicating the possible transient nature of unberable mental suffering and its complexity [START_REF] Caceda | Differential Processing of Physical and Psychological Pain during Acute Suicidality[END_REF]. Suicidal acts should be considered as the expression of an attempt to escape from psychological suffering. It is possible to find similarities between reasons to request pEAS and taking overdoses of drugs [START_REF] Bancroft | The reasons people give for taking overdoses[END_REF]: among 128 subjects interviewed after their recovery from a suicide attempt (overdose), 42% were "escaping from the situation", 52% wanted to obtain "relief from a terrible state of mind", 33% were "seeking help", and 19% were "trying to influence someone". Hence, pEAS may also be a solution to cope with suffering for some patients, while for others pEAS might represent loss of hope, and demoralization. Someone may argue that, while the perception of unbearable suffering is patient-related, whether the patient's medical condition is incurable and whether or not the suffering can be alleviated should be informed by the involved physician's knowledge and perception-related [START_REF] Bernat | Medical futility: definition, determination, and disputes in critical care[END_REF]. However, psychiatrists/clinical psychologists may not always be involved in the pEAS evaluation process.

Medical futility

Irremediable suffering in pEAS is not predictable. Similarly, the prognosis of psychiatric disorders and efficacy of treatment is not predictable. In psychiatry, the issue of medical futility (i.e., uncertain available data on improvements with a specific therapy [START_REF] Bernat | Medical futility: definition, determination, and disputes in critical care[END_REF]) is particularly difficult to determine. Patients' treatment refusal in the context of an uncertain prognosis (e.g., treatment-resistant depression) should be considered in the context of pEAS evaluation. Most of pEAS patients plausibly suffered from a treatment-resistant mood disorder. However, there is still no consensus on the definition of resistance, and it is generally considered only as the absence of a pharmacological response (i.e., a depressive disorder not responding to one antidepressant or two or more antidepressants from different pharmacological classes at adequate dose and duration [START_REF] Berlim | What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials[END_REF]). A study focused on cognitive behavioural therapy (CBT) in addition to usual care has shown CBT to be an effective treatment for primary care patients with treatment-resistant depression [START_REF] Wiles | Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial[END_REF].

Psychological understanding

During the pEAS decision process, it is important to identify the forces that can affect decisionmaking and that could be under-recognized not only by GPs but also by psychiatrists: transference and counter-transference [START_REF] Hicks | Physician-assisted suicide: a review of the literature concerning practical and clinical implications for UK doctors[END_REF]. In some suicidal patients, the request to die can represent a request for a reason to live, for reassurance of their value, or a paradoxical attempt to regain control over their lives. Clinicians' counter-transference reactions could represent an over-identification with the patient and/or, similarly to patients, indicate a low tolerance for situations that are impossible to control [START_REF] Nicolini | Euthanasia and assisted suicide of persons with psychiatric disorders: the challenge of personality disorders[END_REF]. Despite its importance, the assessment of the influence of transference and counter-transference was not frequent (24% of patients in the article that addressed this issue) [START_REF] Groenewoud | Psychiatric consultation with regard to requests for euthanasia or physician-assisted suicide[END_REF], even if it is highly recommended.

Decision-making

Patients requesting pEAS should have intact decision capacity. Even if psychopathology does not automatically mean the patient lacks mental capacity, it is highly likely to influence his/her decision-making or increase the risk of incapacity. Four criteria for medical decision-making capacity are widely accepted: the ability to understand the relevant information, the ability to appreciate the disorder and the medical consequences of the situation, the ability to reason about treatment choices and the ability to communicate a choice [START_REF] Appelbaum | Assessing patients' capacities to consent to treatment[END_REF]. Some critics have even suggested that a request for assisted suicide is itself suggestive or even indicative of a lack of decision-making capacity. Related cognitive impairments raise the question of ability to decide for ending life, and may also alter the stability of such choices. Psychiatric patients seeking pEAS may reverse their decision with time, usually in the direction of initial acceptance to later rejection of pEAS. Inconsistent decisions regarding pEAS are more frequent in depressed patients [START_REF] Blank | Instability of attitudes about euthanasia and physician assisted suicide in depressed older hospitalized patients[END_REF]. Patients having a history of suicide attempt have impaired decision-making even after accounting for psychiatric comorbidity [START_REF] Richard-Devantoy | A meta-analysis of neuropsychological markers of vulnerability to suicidal behavior in mood disorders[END_REF]. This susceptibility trait persists beyond the acute depressive state. Consequently, patients requesting pEAS may have limited ability to foresee alternatives and long-term perspectives to select adequate choices. Altered decision making relies on prefrontal dysfunction. Suicidal patients are very often ambivalent about wish to live and wish to die. In fact, after requesting pEAS, some psychiatric patients withdrew their requests or were on hold. Contrary to what might be expected, physicians do not use, and the review committees do not require, a high threshold of decision-making capacity for requesting [START_REF] Doernberg | Capacity Evaluations of Psychiatric Patients Requesting Assisted Death in the Netherlands[END_REF][START_REF] Tuffrey-Wijne | Euthanasia and assisted suicide for people with an intellectual disability and/or autism spectrum disorder: an examination of nine relevant euthanasia cases in the Netherlands (2012-2016)[END_REF]. As patients receiving pEAS have conditions known to raise the risk of decisional incapacity, this issue deserves further consideration in policy debates on pEAS (Olie and Courtet, 2016a, b).

The pEAS option as a trigger of change

The high percentage of patients still alive after a not granted pEAS request (69%) and the high rate of pEAS requests withdrawals (37%) can be seen not only as a consequence of the fact that death desire is transient in nature. Another interpretation of these data is that the sole act of requesting (p)EAS (as well as the approval of the request) could trigger a process of change. According to some authors, the EAS evaluation process can be therapeutic and help patients to regain perspective. Thus, some advocate a "two-track approach" during which a recovery-oriented treatment ("recovery track") should continue in parallel with the pEAS evaluation procedure ("euthanasia track") [START_REF] Jones | Euthanasia and Assisted Suicide[END_REF][START_REF] Vandenberghe | Physician-Assisted Suicide and Psychiatric Illness[END_REF][START_REF] Verhofstadt | When unbearable suffering incites psychiatric patients to request euthanasia: qualitative study[END_REF]. Some have in the past used paradox in therapy [START_REF] Bateson | Steps to an Ecology of Mind: Collected Essays in Anthropology, Psychiatry, Evolution, and Epistemology[END_REF]. However, in this light, we may consider the ethical problems related to the proposition of pEAS to patients only for its paradox effect and without considering it as a real option but only a paradoxical one. Furthermore, it should be noted that if an evaluation for pEAS has a therapeutic effect in alleviating suffering, this means that the patient's suffering is not irremediable.

Strengths and limitations

This is the first systematic review focused on pEAS and the first attempt to describe the available patients' features related to pEAS-C and pEAS-R for each country in which the practice is allowed. As this is a rapidly evolving topic, the related current laws and the available documentation are rapidly changing. However, the amount of information in English in international websites of relevance is limited; the number of studies on this topic is still scant; the studies are extremely heterogeneous, considering both pEAS-C and pEAS-R, with different study designs, and different types of patients. So standard procedures to report the data and open data repositories in English language would be of great help in this field. A major problem is the partial overlap among the studies' samples (e.g., in different studies the same patients were included). Furthermore, some of the included studies did not report details concerning psychiatric diagnoses. Hence, this review is focused on psychiatric patients having received or requesting EAS (pEAS) but we were not able to include only pEAS-C and pEAS-R strictly considered (i.e. only patients for which the unique reason to request EAS is a formally diagnosed psychiatric disorder). Moreover, in general, there is a lack of clarity on how psychiatric diagnoses were obtained, probably with no standardized assessment, especially concerning personality disorder. Finally, there is the issue of comorbidity: in the present review we tried to focus on psychiatric problems as the main reason for EAS request but the rate of cases in which the decision is precipitated by the comorbidity of a psychiatric disorder and a primary somatic problem is much higher and it should be considered in the future.

Conclusion

Given that suicide prevention remains an important public health priority, there is a need to ensure that pEAS is not simply a (highly efficient) way of completing suicide. Currently, there is ample evidence that patients receiving/requesting pEAS are very similar to those who die by suicide. Individual physicians have tremendous leeway in evaluating, performing and reporting cases of pEAS, despite the known difficulties in applying the eligibility criteria. Thus, the current practice may not be optimal to ensure valid and reliable judgments in pEAS evaluations. Some clinicians with experience in pEAS evaluations have argued for a stricter legal framework for pEAS that includes a rigorous futility criterion, but not the patients' refusals of reasonable treatment options; a continued recovery-oriented care in parallel with pEAS evaluation; a sufficiently long and thorough evaluation by multiple assessors; and a prospective multi-expert panel to review pEAS requests, not merely a post-EAS review, with the involvement of mental health professionals; a deeper focus on unbearable suffering, decision capacity and possibilities of improvements. Such a system, combined with close monitoring and research, may be the best way to ensure that highly vulnerable patients' lives are not erroneously terminated. Recently, some new recommendations on pEAS in Flanders were analysed (Verhofstadt et al., 2019b): the need for at least two positive advices from at least two psychiatrists and the two-track approach, focusing simultaneously on the assessment of the patient's EAS request and on that person's continuation of the treatment, were included. However, it should be noted that if there is insufficient evidence base to make highly reliable judgments of irremediability, then adding more opinions into the mix is unlikely to improve the accuracy. Moreover, a specific instrument has been proposed to assess the nature and extent of suffering in psychiatric patients (Verhofstadt et al., 2019a). For future research, it would be important to: a) systematically determine which are common points and differences between pEAS-C/pEAS-R and suicide victims and suicide attempters; b) compare the increasing numbers of deaths by means of pEAS versus the numbers of deaths by means of suicide in those countries where EAS became legally practiced; c) consider a strict definition of pEAS (i.e. only patients for which the unique reason to request EAS is a formally diagnosed psychiatric disorder); d) consider cases of comorbidity between a primary somatic problem and psychiatric disorders e) include also studies published in languages other than English (e.g., Dutch) and gray literature.

Fuani Marino

We conclude this paper citing the words of an Italian writer, Fuani Marino, who attempted suicide as a consequence of a severe post partum depression and described her experience in a book some years later [START_REF] Marino | Svegliami a mezzanotte[END_REF]. In the selected paragraphs the paradoxical nature of pEAS is elegantly described. "I wonder if it would not be less traumatic for those who want to leave, but also for those who remain, to be able to benefit from an aid. Frankly, I think so. In fact, there is a profound despair, not only in the desire to die, but also in being obliged to find a way to do it. In having to gather your own strengths and alone, with your own hands, kill yourself. This is a moment of extreme fragility and total solitude, because the suicidal aspirant knows that no one will help him and that indeed they will try to divert him from what he thinks -and that in some cases is -the only solution". "Among these [cases of depressed patients requesting EAS], that of a twenty-four-year-old Belgian girl who, claiming to have always lived, since she was a child, with the deep desire to die, has obtained the opportunity to use euthanasia. I don't think it's a coincidence that once she was given permission, the girl then gave up. The depressed person who has a tendency to suicide experiences the prohibition to die by suicide, and the attempts to avoid it by family members and medical personnel, like a vexation. I think it is similar to what happens to people suffering from anorexia subjected to forced feeding". Table 1. Features of the included original studies on euthanasia or assisted dying in psychiatric patients (studies presented for each country are in chronological order).

ADHD: attention-deficit/hyperactivity disorder; COPD: chronic obstructive pulmonary disease; EAS: euthanasia or assisted dying; pEAS: euthanasia or assisted dying in psychiatric patients; GPs: general practitioners; HIV/AIDS: human immunodeficiency virus/acquired immune deficiency syndrome; OCD: obsessive-compulsive disorder; PTSD: post-traumatic stress disorder. The majority of the patients had at least two psychiatric disorders (56%)

Study

The most frequent diagnoses were depression (55%) and personality related problems (52%)

The majority of patients (58%) had at least one comorbid medical condition [START_REF] Miller | Euthanasia and physician-assisted suicide not meeting due care criteria in the Netherlands: a qualitative review of review committee judgements[END_REF] 2012

FiguresFigure 1 .

 1 Figures

Figure 2 .

 2 Figure 2. Euthanasia or Assisted Suicide (EAS) summaries identified by the Dutch Regional Euthanasia Review Committees (numbers on bars are numbers of cases with psychiatric disorders). Categories of conditions are the ones reported by DRERC.

Figure 3 .

 3 Figure 3. Euthanasia or Assisted Suicide (EAS) summaries of the End-of-Life Clinic (numbers on bars are numbers of cases with psychiatric disorders). Categories of conditions are the ones reported by the End-of-Life Clinic.

Figure

  Figure 1. PRISMA flow diagram.

Table 2 .

 2 Quality of reporting of the included case series studies (n=13) according to the Quality Assessment Tool for Case Series Studies (NA: not applicable).

		1	2	3	4	5	6	7	8	9	Quality Rating
											(Good, Fair, or
		Was the	Was the	Were the	Were the	Was the	Were the	Was the	Were the	Were the	Poor)
		study	study	cases	subjects	intervention	outcome	length of	statistical	results well-
		question	population	consecutive?	comparable?	clearly	measures	follow-up	methods	described?
		or	clearly and			described?	clearly	adequate?	well-
	Study	objective	fully				defined, valid,		described?
		clearly	described,				reliable, and
		stated?	including a				implemented
			case				consistently
			definition?				across all
							study
							participants?
	(Frei et al.,	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Fair
	2001)
	(Bosshard et	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Good
	al., 2003)
	(Fischer et al.,	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Good
	2008)
	(Fischer et al.,	Yes	Yes	NA	Yes	Yes	Yes	Yes	Yes	Yes	Good
	2009)
	(Smets et al.,	Yes	Yes	NA	Yes	Yes	Yes	Yes	No	Yes	Fair
	2010)

Table 3 .

 3 Quality of reporting of the included surveys (n=6) according to the checklist for reporting survey research described by Bennett et al. ( : item reported) (NA: not applicable).

	Study	Background						Methods	Sample selection	Research tool	Results	Response rates	Interpretation and discussion	Ethics and disclosure
	1	2	3	4	5	6	7	8	9	10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34	35	36	37	38
											Surveys of physicians' practice
	(van der Wal
	et al., 1996)
	(Groenewoud
	et al., 1997)
	(Groenewoud
	et al., 2004)
	(Jansen-van
	der Weide et
	al., 2005)
	(Evenblij et al., 2019b)														NA	NA
	(Evenblij et al., 2019a)														NA	NA

Table 4 .

 4 Quality of reporting of the included qualitative studies (n=4) according to the COnsolidated criteria for REporting Qualitative research (COREQ) Checklist ( : item reported; NA: not applicable).

		Domain 1: Research team and reflexivity					Domain 2: Study design							Domain 3: Analysis and findings
	Study	Personal Characteristics	Relationship with participants	Theoretical framework	Participant selection		Setting				Data collection			Data analysis		Reporting
		1	2	3	4	5	6	7	8	9	10 11 12	13	14	15	16	17	18	19	20	21	22	23	24 25 26	27	28	29 30 31 32
	(Doernberg et al., 2016)	NA					NA NA				NA		NA		NA NA NA NA NA NA NA			NA
	(Kim et al., 2016)	NA					NA NA				NA		NA		NA NA NA NA NA NA NA			NA
	(Miller and Kim, 2017)	NA					NA NA				NA		NA		NA NA NA NA NA NA NA			NA
	(Tuffrey-
	Wijne et al.,	NA					NA NA				NA		NA		NA NA NA NA NA NA NA		NA NA
	2018)

Table 5 .

 5 Quality of reporting of the included longitudinal study according to the checklist for reporting observational longitudinal studies dsecribed byTooth et al. ( : item reported; NA: not applicable).

	Study	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	20	21	22	23	24	25	26	27	28	29	30	31	32	33
	(Steck et al., 2016)												NA NA NA						NA NA NA					NA

October 2007-December 2011; follow-up at the end of December

Acknowledgments

We would like to thank: Prof. Scott Y. H. Kim, for his precious suggestions during the writing of this manuscript; Dr. Elisabetta Andermarcher, for her careful linguistic revision of the manuscript; William Mansi, for his help with the literature search. Dr. Raffaella Calati received a grant from FondaMental Foundation, Créteil, France (2015-2016). Dr. Emilie Olié received research grants from AstraZeneca, Servier, Institut UPSA de la Douleur and fees for presentations at congresses from Janssen, Lundbeck, Otsuka, Servier. Prof. Sébastien Guillaume has received honoraria, research or educational conference grants from Bristol-Myers Squibb, Otsuka, Servier, Lundbeck, AstraZeneca and Janssen. Prof. Philippe Courtet received research grants from Servier, and fees for presentations at congresses or participation in scientific boards from Janssen, Lundbeck, Otsuka, Servier.

Data availability statement Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Conflicts of interest None.

Contributors

Dr. Raffaella Calati performed the search, extracted data from the included studies, assessed their strength of reporting, and wrote the first version of the manuscript. Dr. Emilie Olié and Prof. Philippe Courtet proposed the topic. Dr. Olié contributed to the search of the studies. Dr. Déborah Dassa independently extracted data from the included studies and assessed their strength of reporting. Dr. Olié, Prof. Gramaglia, Prof. Guillaume, and


Antoine Devie
email: adevie@chu-reims.fr

Lukshe Kanagaratnam

Jeanne-Marie Perotin

Damien Jolly

Jean-Noël Ravey

Manel Djelouah

Christine Hoeffel

COVID-19: A qualitative chest CT model to identify severe form of the disease

Keywords: Severe acute respiratory syndrome coronavirus 2, Tomography, X-ray computed (CT), COVID-19, Risk factors, Severity of illness index Chronic obstructive pulmonary disease COVID-19: Coronavirus disease 2019 CT: Computed tomography EWS: Early warning score characteristic RT-PCR: Reverse transcriptase-polymerase chain reaction RUL: Right upper lobe SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2 SD: standard deviation

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

Introduction

By the end of 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan City, China, and rapidly spread worldwide [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF]. Although the majority of symptomatic patients have a mild form with fever, dry cough, dyspnea, myalgia and fatigue [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF], some patients can develop a severe form. The latter may present with rapid worsening, sometimes resulting in acute respiratory distress syndrome that may require mechanical ventilation or intensive care unit (ICU) monitoring, and even in death [START_REF] Guan | Clinical characteristics of Coronavirus Disease 2019 in China[END_REF]. Severe disease has been reported to occur in around 15% of the patients and mortality is around 2% of COVID-19 cases [START_REF] Wu | Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention[END_REF]. After a massive "first wave", which has been particularly contagious and deadly and put health systems under strain in the spring of 2020 [START_REF] Denys | Interventional oncology at the time of COVID-19 pandemic: problems and solutions[END_REF][START_REF] Soyer | Lessons learned from chest CT in COVID-19[END_REF][START_REF] Barral | COVID-19 pandemic: A stress test for interventional radiology[END_REF], a period of relative transitional lull appeared during the summer. In Europe, however, since September 2020, the number of new cases of COVID-19 has started to rise again. The need to early identify patients at risk of a severe form of COVID-19, for an early and appropriate management is rendered critical due to the large number of affected patients, the limited number of beds in health centers and the lack of specific of effective treatment to date.

The gold standard for establishing the diagnosis of SARS-CoV-2 infection is based on the biological analysis of respiratory secretions by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Computed tomography (CT) not only can help make the diagnosis of COVID-19 with greater sensitivity than RT-PCR test [START_REF] Ai | Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases[END_REF][8][START_REF] Hani | COVID-19 pneumonia: a review of typical CT findings and differential diagnosis[END_REF][START_REF] Kim | Diagnostic performance of CT and reverse Transcriptase Polymerase Chain Reaction for Coronavirus Disease 2019: a meta-analysis[END_REF][START_REF] Li | Radiology indispensable for tracking COVID-19[END_REF], but has also been used to suggest disease severity or outcome of the disease [START_REF] Feng | Early prediction of disease progression in COVID-19 pneumonia patients with chest CT and clinical characteristics[END_REF][START_REF] Yu | Nomogram to identify severe coronavirus disease 2019 (COVID-19) based on initial clinical and CT characteristics: a multi-center study[END_REF][START_REF] Liu | CT quantification of pneumonia lesions in early days predicts progression to severe illness in a cohort of COVID-19 patients[END_REF]. Indeed, some clinical, biological and radiological features are associated with the severity of the disease [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF]. Regarding CT, the most widely proposed CT tool to assess severity is a semi-quantitative CT score, aimed at reflecting the extent of the lung abnormalities related to the COVID-19 [START_REF] Pan | Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19)[END_REF][START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF]. However, the way to calculate these "total CT scores" vary throughout the literature, along with their thresholds used to optimize differentiation between non severe and severe disease, thus limiting their implementation in clinical practice [START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF][START_REF] Francone | Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis[END_REF][START_REF] Wang | Multicenter study of temporal changes and prognostic value of a CT visual severity score in hospitalized patients with COVID-19[END_REF][START_REF] Bernheim | Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection[END_REF][START_REF] Khosravi | Predictive value of initial CT scan for various adverse outcomes in patients with COVID-19 pneumonia[END_REF]. We hypothesized that a model based only on qualitative features should be more robust and less cumbersome to use, particularly in a context of increased clinical workload.

The purpose of this study was to investigate the clinical and CT features associated with severe COVID-19 patients, and to propose a model based on qualitative CT features able to rapidly identify these patients.

Materials and methods

Study population

In accordance with French law, this retrospective study on medical records was authorized by the "Commission Nationale de l'Informatique et des Libertés". The participants were informed of the possibility of using the information concerning them, for biomedical research purposes, and had a right of opposition. Among a cohort of 499 patients over 18 years of age hospitalized from February 25th to April 30th 2020 in Reims University Hospital for COVID-19, those with confirmation of the diagnosis of COVID-19 using RT-PCR assay of SARS-CoV-2 and with a chest CT examination performed after the onset of the symptoms were retrospectively included. Patients with missing clinical data (n = 1), patients with prior lobectomy (n = 2) and those for whom CT examination was not available (n = 3), not interpretable (n = 2) or performed more than 15 days after the onset of the symptoms (n = 22) were excluded. Figure 1 shows the flow chart of the study population. . Patients were assigned to two groups, including "non-severe cases" and "severe cases" according to the worst clinical situation during hospitalization, assessed at the end of hospitalizationThe "severe cases" patients were hospitalized patients who required noninvasive ventilation or humidified nasal high-flow oxygen system (Optiflow™) or invasive ventilation or extracorporeal membrane oxygenation =, as well as those who died prior to discharge. "Non-severe cases" patients corresponded to the other patients, regardless of the need for oxygen therapy.

The clinical parameters including age, sex, body mass index, New Early Warning Score 2 (NEWS2), hospital length of stay, time between the onset of the symptoms and the first CT examination (divided into two groups, 0 to 7 days and 8 to 15 days), admission or not into ICU during hospitalization stay, worst clinical situation during hospitalization, status (dead or alive) at day 28 after the onset of the symptoms, comorbidities (diabetes mellitus, cardiovascular disease, systemic hypertension, asthma and chronic obstructive pulmonary disease), symptoms and clinical signs, as well as laboratory findings, were collected and evaluated. We used an Early Warning Score (EWS) based on an adapted version of the NEWS2 score with age ≥ 65 (score 3 points) developed in by Liao et a.l [START_REF] Liao | Novel coronavirus infection during the 2019-2020 epidemic: preparing intensive care units-the experience in Sichuan Province, China[END_REF].

CT examinations and imaging evaluation

CT protocol

All patients underwent chest CT examinations covering from the apex to the lung base, in the supine position, using a 64-row helical CT scanner (GE Revolution EVO CT Scanner, GE Medical Systems). The scanning parameters were as follows: reconstruction matrix of 512 mm x 512 mm and 1.375:1 helical pitch. Lung window setting was with a window level of -600 Hounsfield units (HU) and window width of 1600 HU. One hundred and seven (107/158; 67.7%) CT examinations were acquired without intravenous administration of iodinated contrast material, with the following parameters: tube voltage, 120 kV; automatic tube current, mA 100 to 320 mA; and slice thickness, 1.25 mm with 1.25 mm increment. Fifty-one (51/158; 32.3%) CT examinations were acquired after intravenous administration of iodinated contrast material at a pulmonary arterial phase, with the following parameters: tube voltage, 100 kV; automatic tube current, mA 100 to 450 mA; slice thickness, 0.625 mm with 0.625 mm increment.

Image analysis

A radiologist, blinded to clinical data and laboratory findings reviewed all CT examinations (the first CT when the patients had multiple CT examinations), using a computerized structured report for COVID-19 available on the web platform ("Keydiag", Keymaging, Grenoble, France, https://keydiag.fr/login?returnUrl=%2Fnav%2Fdiagnose). This structured report is based on the guidelines for COVID-19, issued by the French Thoracic Imaging Society. It includes the following imaging features, defined according to the Fleischner Society Glossary of Terms for Thoracic Imaging [START_REF] Hansell | Fleischner Society: glossary of terms for thoracic imaging[END_REF], as follows: ground glass opacity (GGO) (nodular or area of GGO), consolidation (rounded or subpleural band or area of consolidation), crazy-paving pattern, axial distribution of the disease (presence of central involvement or not), sagittal distribution (inferior and/or posterior involvement), number of lobes affected, lobar distribution, degree of involvement of each lung lobe, overall extent of lung involvement measured as detailed below. Other abnormalities including intralobular reticulation, vascular enlargement (dilatation of pulmonary vessels around and within the lesions), air bronchogram sign within GGO or consolidation, bronchiectasis, traction bronchiectasis, halo sign, reversed halo sign, pleural thickening, intrathoracic lymph node enlargement (short-axis diameter ≥ 10 mm), pleural effusion and pericardial effusion, were noted. Presence of pulmonary embolism, pulmonary infarction and enlargement of the pulmonary trunk (diameter of main pulmonary artery > 29 mm) was reported too.

Each of the five lung lobes was assessed for degree of involvement and scored as "0" (0%), "1" (1%-9%), "2" (10%-24%), "3" (25%-49%), "4" (50%-74%) or "5" (75%-100%). A "total CT score" was established by summing up the degree of involvement of each lobe (quoted from 0 to 5) so as to obtain a score ranging from 0 to 25. Overall extent of lung involvement was also classified according to the French guidelines [START_REF] Jalaber | Chest CT in COVID-19 pneumonia: a review of current knowledge[END_REF] as follows: none (0%), minimal (1%-9%), moderate (10%-24%), extensive (25%-49%), severe (50%-74%) and critical (75%-100%), and was obtained in two ways: 1. visually and 2. using Keydiag software. The overall extent, assessed visually, was dichotomized into two groups: "none, minimal, moderate and extensive" overall extent (0-49%) and "severe and critical" extent (50-100%). The involvement of all five lobes was also reported. Area of GGO and area of consolidation were defined as non-nodular opacities, concerning multiple adjacent pulmonary lobules.

For the purpose of this study, we created a new qualitative imaging criterion reflecting the extent of the disease in a lobe. A visual involvement of more than half of a lobe was then called "large involvement".

Statistical analysis

Categorical variables were expressed as raw numbers, proportions and percentages. Continuous variables were expressed as means ± standard deviation (SD) or medians (interquartile ranges) and ranges. Differences between the non-severe group and the severe group were analyzed using Chi-square or Fisher's exact test for categorical variables and Student t-test or Wilcoxon-Mann-Whitney U-test for continuous variables. The calculation of the weighted kappa coefficient was performed to assess the agreement between the visual analysis and the analysis with Keydiag software [START_REF] Benchoufi | Interobserver agreement issues in radiology[END_REF]. NEWS2 was analyzed both as a continuous variable (ranging from 0 to 15) and as a dichotomized variable: "0 to 6" and "7 to 15".

Multivariate logistic regression with backward selection, including variables with a P value < 0.05 by univariate analyses, was used to identify the independent risk factors associated with the development of severe COVID-19. Systematic adjustment was performed on age and on time between the first symptoms and the first CT examination. The most relevant clinically and radiologically qualitative variables were chosen in building the multivariable model. Goodness of fit of the final model was assessed using the Hosmer-Lemeshow test. Receiver operating characteristic (ROC) analysis was used to determine the clinical value of total CT scores in distinguishing the non-severe and severe forms, and find the corresponding cutoff value. Then, another multivariate model was built replacing the qualitative variable representing the degree of spatial extent by the total CT score as a categorical variable, using the determined cutoff. The discriminatory ability of the two multivariate models was evaluated by using the area under the ROC curve (AUC) and its 95% CI, and compared using the method of DeLong et al [START_REF] Delong | Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach[END_REF]. Differences in diagnostic performances between the total CT score and the NEWS2 as continuous variables were also analyzed by comparing the ROC curves. All analyses were performed by using SAS statistical software (version 9.4, SAS Institute, Cary) and R software program (version 3.6.1, R Foundation for Statistical Computing). The level of statistical significance was set at P < 0.05.

Results

Patient demographics and clinical manifestations

One hundred and fifty eight patients constituted the final population: 84 (84/158; 53.2%) men and 74 (74/158; 46.8%) women. Mean age was 68 ± 14 (SD) years (range: 24-96 years). Among the 158 patients, 100 (100/158; 63.3%) were non severe cases and 58 (58/158; 36.7%) were severe cases. Table 1 summarizes demographics and clinical baseline characteristics between non severe group and severe group. There was no significant age or sex difference between the two groups.

In the non-severe group, 67 (67/100; 67%) patients required oxygen therapy. In the severe group, according to the worst clinical situation during hospitalization, 14 (14/58; 24.1%) patients required non-invasive ventilation or humidified nasal high-flow oxygen system (Optiflow™), 11 (11/ Patients in the severe group had a significantly greater NEWS2 than those in the nonsevere group (9.3 ± 2.9 [range: 3-15] vs. 6.1 ± 3.4 [range: 0-15]; P < 0.001). Furthermore, a NEWS2 ≥ 7, corresponding to a "high clinical risk requiring urgent or emergency response" [START_REF] Khosravi | Predictive value of initial CT scan for various adverse outcomes in patients with COVID-19 pneumonia[END_REF], was also significantly more often found in the severe group (P < 0.001). There were no significant differences of symptoms and clinical signs between the two groups except for the respiratory rate that was significantly greater in the severe group (P < 0.001).

Laboratory findings

Chest CT findings

On CT, COVID-19-related abnormalities were present in 142/158 patients (89.9%) (Table 3). The most common CT findings in both groups included GGO (139/158; 88.0%), consolidation (116/158; 73.4%), intralobular reticulation (120/158; 76.0%), vascular enlargement (113/158; 71.5%), pleural thickening (107/158; 67.7%), crazy-paving pattern (96/158; 60.8%) and air bronchogram sign (93/158; 58.9%).

Central involvement of lung parenchyma by the disease, area of consolidation, air bronchogram sign, bronchiectasis, traction bronchiectasis and pleural effusion were significantly more often seen in the severe group (Table 3). So was "large involvement of at least one of the three following lobes including LUL, RUL and ML" (P < 0.001). Regarding the visual overall extent of lung involvement, an involvement ≥ 50% was also significantly more often seen in the severe group (P < 0.001).

Weighted kappa coefficient for correlation between visual analysis and Keydiag software to determine the overall extent of lung involvement was excellent (0.929; CI: 95%: 0.895-0.962).

Median total CT score was 11.5 (IQR, 6, 16; range: 0-24). Area under the curve (AUC)of ROC of the total CT score, taken as a categorical variable with a cutoff value of 15 and performed to identify patients at risk of severe form, was 0.672. With this cutoff value, sensitivity and specificity were 53.4% and 81.0%, respectively (Fig. 2). Thus, 19 (19/100; 19.0%) patients had a score ≥ 15 in the non-severe group vs. 31 (31/58; 53.5%) in the severe group. The total CT scores of severe patients were then significantly greater than those of the non-severe patients with this cutoff (P < 0.001).

Among the 51 (51/158; 32.3%) patients in whom pulmonary arterial phase contrastenhanced CT examination was available, only 3 (3/51; 5.9%) had CT signs of pulmonary embolism. There was only one pulmonary infarction, in the severe group. Among the 27 (27/158; 17.1%) patients who presented with a pleural effusion, none was of great abundance. At the end of the CT analysis, 29 (29/158; 18.4%) cases had a condition described as "compatible" with COVID-19 and 113 (113/158; 71.5%) as "very suggestive" or "typical". The AUC of the total CT score as a continuous variable was 0.713 (95% CI: 0.612-0.813) and the AUC of the NEWS2 was 0.768 (95% CI: 0.690-0.845). No significant difference in diagnostic performances between the total CT score and the NEWS2 as continuous variables was found (P = 0.327) (Fig. 3).

Multivariate analysis and models associated with a severe form of COVID-19

Table 4 shows the most relevant clinically and radiologically qualitative multivariate model in relationship to the severe form of COVID-19. The qualitative model included central involvement (OR = 2.760), pleural effusion (OR = 2.699) and large involvement of LUL or RUL or ML (OR = 2.473), and had an AUC of 0.722 (95% CI: 0.638-0.806). Table 5 shows the second multivariate model that was built replacing the qualitative variable "large involvement of at least RUL or LUL or ML", representing the degree of spatial extent, by the total CT score as a categorical variable using the cutoff of 15. This semi-quantitative model included central involvement (OR = 2.344), pleural effusion (OR = 2.754) and total CT score ≥15 (OR = 3.342), and had an AUC of 0.739 (95% CI: 0.656-0.823). No significant difference in diagnostic performances between these two models was found (P = 0.209) (Figure 4).

Discussion

We propose a new qualitative model allowing a simple and quick evaluation of first chest CT examination performed in patients with COVID-19, similarto identify patients at risk of developing a severe form of the disease. This model is based on the assessment of central involvement of lung parenchyma by the disease, of pleural effusion and of large involvement of at least one upper lobe or of the middle lobe.

Our qualitative model does not differ in terms of performances from a model integrating the most commonly used and previously validated total semi-quantitative CT score, based on the overall extent of the disease [START_REF] Pan | Time course of lung changes at chest CT during recovery from coronavirus disease 2019 (COVID-19)[END_REF]. Although the time needed to assess this total CT score has never been calculated, to our knowledge, it is highly likely that the time required to sum up the scores of each five lobes is higher than just rapidly checking three lobes for the presence of any large COVID-19 related abnormality. Of note, calculation of well-aerated lung in COVID-19 patients using automatic software has been reported as taking a median time of as much as 270 seconds, even though software-assisted calculations are meant to be quicker than human quantifications [START_REF] Colombi | Well-aerated lung on admitting chest CT to predict adverse outcome in COVID-19 Pneumonia[END_REF]. Moreover, the use of a total semiquantitative CT score seems difficult to translate to daily practice as the way to calculate the score widely vary throughout the different studies [START_REF] Feng | Early prediction of disease progression in COVID-19 pneumonia patients with chest CT and clinical characteristics[END_REF][START_REF] Yu | Nomogram to identify severe coronavirus disease 2019 (COVID-19) based on initial clinical and CT characteristics: a multi-center study[END_REF][START_REF] Wang | Multicenter study of temporal changes and prognostic value of a CT visual severity score in hospitalized patients with COVID-19[END_REF][START_REF] Bernheim | Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection[END_REF][START_REF] Zhao | Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study[END_REF]. Besides, the cutoffs used to differentiate non severe and severe forms of COVID-19 also vary, depending on the type of score used, the outcome of the study, the type and size of the population, the number of severe cases included [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF][START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF][START_REF] Francone | Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis[END_REF][START_REF] Khosravi | Predictive value of initial CT scan for various adverse outcomes in patients with COVID-19 pneumonia[END_REF][START_REF] Mahdjoub | Admission chest CT score predicts 5-day outcome in patients with COVID-19[END_REF].

In our study, the performances of the qualitative model and of the model with integration of the total semi-quantitative CT score, as well as the performances of the semiquantitative CT score on its own, were all lower than those reported in the literature. Notably, the area under the ROC curve for the total semi-quantitative CT score on its own was 0.672 using an optimal threshold of 15, whereas other authors have reported values of AUC in the range of 0.85-0.9 using a total CT score with the same range (0-25), albeit not with the same cutoffs [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF][START_REF] Mahdjoub | Admission chest CT score predicts 5-day outcome in patients with COVID-19[END_REF]. Differences in criteria at inclusion as well as in the clinical definition of severe forms may explain these discrepancies.

Area of consolidation, bronchiectasis and traction bronchiectasis were significantly more often found in the severe group of patients. In line with some other studies, air bronchogram sign [START_REF] Yu | Nomogram to identify severe coronavirus disease 2019 (COVID-19) based on initial clinical and CT characteristics: a multi-center study[END_REF][START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF] and pleural effusion [START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF] were also significantly more often found. Unlike in some other studies, pericardial effusion was not found as a criteria associated with a severe form, nor was lymph node enlargement, nor was crazy-paving pattern [START_REF] Yu | Nomogram to identify severe coronavirus disease 2019 (COVID-19) based on initial clinical and CT characteristics: a multi-center study[END_REF][START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF]. The most relevant CT features were all related to the extent of the disease. The total CT scores of the patients in the severe group were significantly higher than those of the non-severe group, which was consistent with most studies [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF][START_REF] Lyu | The performance of chest CT in evaluating the clinical severity of COVID-19 pneumonia: identifying critical cases based on CT characteristics[END_REF][START_REF] Francone | Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis[END_REF][START_REF] Mahdjoub | Admission chest CT score predicts 5-day outcome in patients with COVID-19[END_REF].

As far as clinical criteria are concerned, Early Warning Scores have been reported to be among the most accurate tools for predicting patient deterioration outside ICU [START_REF] Panday | Prognostic value of early warning scores in the emergency department and acute medical unit: a narrative review[END_REF] and have been designed to assess infected patients at their arrival to the emergency department. Some of the variants of the EWS, such as the one used in our study, which is an adapted version of the NEWS2, were suggested to evaluate physiological parameters in acute COVID-19 patients and thus to be able to early and rapidly identify patients requiring ICU admission [START_REF] Gidari | Predictive value of National Early Warning Score 2 (NEWS2) for intensive care unit admission in patients with SARS-CoV-2 infection[END_REF][START_REF] Kostakis | The performance of the National Early Warning Score and National Early Warning Score 2 in hospitalised patients infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[END_REF]. In our study, NEWS2 had performances similar to those of the total semi-quantitative CT score, thus emphasizing the value of this easy to perform and quick clinical tool in identifying patients at risk of a severe form of COVID-19. To our knowledge, so far, our study is the first to compare both EWS and CT in this context.

In line with other studies, in our study severe patients had higher neutrophil and lower lymphocyte counts, as well as higher C-reactive protein serum level [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF][START_REF] Francone | Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis[END_REF][START_REF] Wang | Multicenter study of temporal changes and prognostic value of a CT visual severity score in hospitalized patients with COVID-19[END_REF][START_REF] Khosravi | Predictive value of initial CT scan for various adverse outcomes in patients with COVID-19 pneumonia[END_REF]. Conversely, and unlike in other studies [START_REF] Durhan | Visual and software-based quantitative chest CT assessment of COVID-19: correlation with clinical findings[END_REF][START_REF] Wang | Multicenter study of temporal changes and prognostic value of a CT visual severity score in hospitalized patients with COVID-19[END_REF][START_REF] Zhang | Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China[END_REF], D-dimer level was not found to be significantly associated with severity. However, this result has to be considered in light of the low number of patients with pulmonary embolism in our study compared to what has been reported so far in some studies [START_REF] Grillet | Acute pulmonary embolism associated with COVID-19 pneumonia detected with pulmonary CT angiography[END_REF][START_REF] Léonard-Lorant | Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to D-dimer levels[END_REF][START_REF] Berre | Concomitant acute aortic thrombosis and pulmonary embolism complicating COVID-19 pneumonia[END_REF][START_REF] Cellina | Acute pulmonary embolism in a patient with COVID-19 pneumonia[END_REF].

Limits of our study include its retrospective nature. Patients thus underwent CT examinations based on clinical need and not based on a predesigned study protocol. This may have caused a selection bias of the more clinically ill patients. Moreover, patients may have received treatments before the CT examination with a potential impact on the extent and nature of the lesions. Another limit is the absence of inter-observer reproducibility. However, evaluation of the CT examinations was thorough and standardized through the use of a computerized standardized report illustrating each CT feature with a typical image. Lastly, the time between the onset of the symptoms and the CT examination was not standardized. Yet, we included patients whose CT examinations were performed within the first 15 days and the median time wound up being of seven days in both non severe and severe groups.

In conclusion, we suggest the use of a qualitative model associating three "easy to assess" qualitative CT features including central involvement of lung parenchyma by the disease, pleural effusion and large involvement of at least one upper lobe or of the middle lobe. Using this qualitative model may facilitate the assessment of the chest CT by the radiologist by avoiding the cumbersome calculation of the total semi-quantitative CT score. Our results need to be verified by further larger scale-studies with a more balanced data between the two groups.

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FIGURE LEGENDS

Fig. 1 .

 1 Fig. 1. Study flow chart. COVID-19: Coronavirus disease 2019; CT: Computed tomography; RT-PCR: Reverse transcriptase-polymerase chain reaction.

Fig. 2 .

 2 Fig.2. ROC analysis of the total CT score taken as a categorical variable with a cutoff value of 15: the area under the curve to identify patients at risk of a severe form of COVID-19 was 0.672 (95% CI: 0.597-0.748). The cutoff value of 15 yielded 53.4% sensitivity and 81.0% specificity. AUC = area under the curve; CI = confidence interval.

Fig. 3 .

 3 Fig. 3. ROC curves of the total CT score and the NEWS2 as continuous variables for diagnosing severe COVID-19 patients. No significant difference in diagnostic performances between the total CT score and the NEWS2 as continuous variables was found (P = 0.327).

Fig. 4 .

 4 Fig. 4. ROC curves of the qualitative and the semi-quantitative multivariate models for diagnosing severe COVID-19 patients. No significant difference in diagnostic performances between these two models was found (P = 0.209).

  58; 19.0%) invasive ventilation or extracorporeal membrane oxygenation and 33 (33/58; 56.9%) died prior to discharge. Forty-two (42/158; 26.6%) patients were admitted in ICU during their hospitalization and 33 (33/158; 20.9%) died within the 28 days after the first symptoms. Median time from the onset of the symptoms to the first CT examination was 7 days (IQR; 4, 10; range: 0-15 days); 86 (86/158; 54.4 %) patients underwent CT within the first 7 days after the onset of the symptoms and 72 (72/158; 45.6 %) between 8 and 15 days.

Table 2

 2 summarizes laboratory findings between non severe group and severe group. Patients in the severe group had a lower lymphocyte count and greater levels of serum inflammatory biomarkers.

Table 1 .

 1 Demographics and clinical baseline characteristics of non-severe group and severe group.

Table 2 .

 2 Laboratory findings between non-severe group and severe group.

Table 3 .

 3 CT features in non-severe group and severe group.

Table 4 .

 4 Qualitative multivariate model associated with a severe form of Covid-19.

Table 5 .

 5 Semi-quantitative multivariate model associated with a severe form of COVID-19. adjusted on age and on time delay between the first symptoms and the first CT examination AUC: 0.722 (95% CI, 0.638-0.806) RUL, right upper lobe; LUL, left upper lobe; ML, middle lobe; OR, odd ratio. adjusted on age and on time delay between the first symptoms and the first CT examination AUC: 0.739 (95% CI, 0.656-0.823) CT, computed tomography; OR = odd ratio.

	Variable*	OR	95% confidence interval
	Central involvement	2.760	1.239-6.148
	Pleural effusion	2.699	1.092-6.669
	Large involvement of at	2.473	1.103-5.546
	least RUL or LUL or ML

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Human rights

The authors declare that the work described has been carried out in accordance with the Declaration of Helsinki of the World Medical Association revised in 2013 for experiments involving humans.

Funding

This work did not receive any grant from funding agencies in the public, commercial, or notfor-profit sectors.

Informed consent and patient details

The authors declare that this report does not contain any personal information that could lead to the identification of the patients. The authors declare that they obtained a informed consent from the patients included in the article. The authors also confirm that the personal details of the patients have been removed.

Disclosure of interest

The authors declare that they have no competing interest.

Author contributions

All authors attest that they meet the current International Committee of Medical Journal Editors (ICMJE) criteria for Authorship.