<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04401241</url>
  </required_header>
  <id_info>
    <org_study_id>20-06</org_study_id>
    <nct_id>NCT04401241</nct_id>
  </id_info>
  <brief_title>How Routine Biomarkers and Blood Leucocytes Count Can Assist Diagnosis of COVID-19 in Emergency Department</brief_title>
  <acronym>MONACOVID</acronym>
  <official_title>Accuracy of Routine Biomarkers and Blood Leucocytes Count to Assist Diagnosis of COVID-19-related Pneumonia in Adult Patients Visiting the Emergency Department</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Princesse Grace</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Hospitalier Princesse Grace</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      December 2019 was the onset of an outbreak of an infection related to SARS-CoV-2, a new&#xD;
      coronavirus detected in January 2020 and responsible for a disorder termed COVID-19. Since&#xD;
      then, COVID-19 has spread worldwide and is responsible for an unprecedented pandemic with&#xD;
      major threat on global health and social and economic stability.&#xD;
&#xD;
      Covid-19 has a large spectrum of symptoms. Most patients experience mild or moderate flu-like&#xD;
      disorder with cough, fever, and shortness of breath. More severe presentations may occur;&#xD;
      patients sometimes develop an acute pneumonia that can lead to adult respiratory distress&#xD;
      syndrome. A considerable number of publications have been released for the last 10 weeks to&#xD;
      help physicians making diagnosis and treat patients. Chinese authors have extensively&#xD;
      proposed description of the disease. As signs and symptoms are poorly specific, diagnosis&#xD;
      mostly relies on detection of the virus by RT-PCR in the upper respiratory tract. Some&#xD;
      uncommon images and localization are highly specific and sensitive on chest CT-scan, which is&#xD;
      cornerstone for initial diagnosis. However, resources may lack during healthcare crisis and&#xD;
      results of these investigations may be delayed or unavailable developper. Special attention&#xD;
      should also be paid to usual laboratory analysis. Indeed, decreased lymphocytes and&#xD;
      eosinophilic counts are frequently described as well as increase in D-dimers levels.&#xD;
      Variation of C-reactive protein (CRP) and procalcitonin (PCT) have been reported. Coronavirus&#xD;
      may have cardiac tropism and changes in cardiac biomarkers concentration may occur.&#xD;
      Therefore, some data suggest that values of routine biomarkers and blood cell count may&#xD;
      assist physicians at bedside to support diagnosis of COVID-19.&#xD;
&#xD;
      To face the outbreak, organization of emergency departments (ED) was mandatory to separate&#xD;
      patients flows and avoid mixing patients with COVID-19 and others. Most patients visiting EDs&#xD;
      dedicated to initial COVID-19 management suffered of pneumonia-like symptoms. Despite initial&#xD;
      triage, patients had either COVID-19-related pneumonia either alternative diagnoses. We took&#xD;
      advantage of this to evaluate the ability of routine biomarkers and leucocytes count helping&#xD;
      identification of COVID-19 from alternative diagnoses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Methods Setting Investigator designed a single center, retrospective, observational study&#xD;
      conducted from February 2020 to April 2020 in the emergency department (ED) of Princesse&#xD;
      Grace Hospital center, a general hospital in Monaco. The study was monitored by the research&#xD;
      department of the Hospital Center. No specific funding was obtained for this study. The&#xD;
      institutional review board for the protection of human subjects approved the study protocol&#xD;
      and waved the need for written informed consent for inclusion.&#xD;
&#xD;
      Objectives The primary objective was to assess sensitivity of routine biomarkers and blood&#xD;
      cell count for diagnosis of COVID-19-related pneumonia in low and high probability groups for&#xD;
      level of certainty using the adjudication committee classification.&#xD;
&#xD;
      Secondary objectives were :&#xD;
&#xD;
        -  to compare values in the four different categories of level of certainty and between low&#xD;
           and high probability groups;&#xD;
&#xD;
        -  to assess performance of combined routine biomarkers and blood cell count for diagnosis&#xD;
           of COVID-19-related pneumonia;&#xD;
&#xD;
        -  to assess whether usual biomarkers and blood cell count were associated with diagnosis&#xD;
           of COVID-19-related pneumonia using sensitivity analyses in two predefinite subgroups&#xD;
           chosen a priori; Group 1 : when considering patients classified as having low&#xD;
           probability and high probability COVID-19-related pneumonia; Group 2 : when patients&#xD;
           with excluded COVID-19-related pneumonia and diagnosed extra-pulmonary infectious&#xD;
           disease were not taken into account, in the low probability COVID-19-related pneumonia&#xD;
           group.&#xD;
&#xD;
      Adjudication committee Based on data collected from baseline on standardized case report&#xD;
      forms, results of low dose chest CT-scan, of SARS-Cov-2 specific RT-PCR, and full access to&#xD;
      all available data including patients' discharge summary, an adjudication committee&#xD;
      consisting of three independent senior experts in infectious diseases, pneumology and&#xD;
      radiology retrospectively assigned the probability of COVID-19-related pneumonia diagnosis&#xD;
      using the 4-level Likert scale. For this study, the gold standard was the diagnosis assessed&#xD;
      by the adjudication committee. Alternative diagnoses were established for low probability&#xD;
      COVID-19-related pneumonia and classified as non-COVID pulmonary diseases and extra-pulmonary&#xD;
      infectious diseases and others.&#xD;
&#xD;
      A Likert scale allowed distribution of patients in four categories:&#xD;
&#xD;
        1. absence of COVID-19-related pneumonia hereafter referred to as excluded;&#xD;
&#xD;
        2. possible COVID-19-related pneumonia;&#xD;
&#xD;
        3. probable COVID-19-related pneumonia;&#xD;
&#xD;
        4. definite COVID-19-related pneumonia. After this first classification, patients were&#xD;
           distributed in two groups: low probability COVID-19-related pneumonia (excluded and&#xD;
           possible) and high probability COVID-19-related pneumonia (probable and definite).&#xD;
&#xD;
      Study population For the study purpose and to ensure quality of the final adjudication&#xD;
      committee diagnosis, investigator selected consecutive adults (18 years of age and above)&#xD;
      visiting the COVID-19-dedicated ED if they presented with clinically suspected&#xD;
      COVID-19-related pneumonia and had SARS-Cov-2 RT-PCR and/or low dose chest CT-scan.&#xD;
&#xD;
      Patient management and usual biomarkers and blood cell count Patients' management in the&#xD;
      COVID-19-dedicated ED was based on local protocoled practices based upon collegial&#xD;
      multidisciplinary decision if they presented with suspected COVID-19-related pneumonia.&#xD;
      Recorded baseline data consisted of demographic data (age, gender), coexisting illnesses,&#xD;
      treatments, symptoms, clinical findings and predetermined laboratory tests including:&#xD;
      SARS-Cov-2 specific RT-PCR obtained on nasopharyngeal swab; low-dose chest CT-scan; standard&#xD;
      blood analysis (complete blood count, hemostasis, metabolic panel, creatinine, blood urea&#xD;
      nitrogen, liver enzymes), D-dimers (Vidas, Biomérieux), procalcitonin, C-reactive protein&#xD;
      (CRP), high sensitive cardiac troponin T (cTnT-hs, Cobas, Roche diagnostics), NT-pro-brain&#xD;
      natriuretic peptide (NT-proBNP, Cobas, Roche diagnostics). For each individual, CRB65 and&#xD;
      Pneumonia Severity Index (PSI) were calculated.&#xD;
&#xD;
      Microbiological samples Naso-pharyngeal swabs were collected at admission and placed in a&#xD;
      Middle Virocult MWE (Sigma®) transport medium. Samples were kept at room temperature and sent&#xD;
      to the laboratory immediately after collection. For the presence of SARS-COV-2, swabs were&#xD;
      sent to French referent centers of virology (Nice, Marseille, Paris). Routine microbiological&#xD;
      examinations were also performed at the discretion of the emergency physicians and included :&#xD;
      presence of influenza A and B viruses and respiratory syncytial virus (RSV) A and B on&#xD;
      nasopharyngeal swabs, blood culture, urine antigens for Streptococcus pneumoniae and&#xD;
      Legionella pneumophila type I, serodiagnosis of Mycoplasma pneumoniae. These results were&#xD;
      available to the adjudication committee.&#xD;
&#xD;
      Low dose chest CT-scan data and COVID-19-related pneumonia diagnosis classification&#xD;
      Multidetector low dose thoracic CT-scan was performed for each individual patient and&#xD;
      interpretation was recorded using a standardized report form according to guidelines. The&#xD;
      level of COVID-19-related pneumonia probability according to low dose chest CT scan were&#xD;
      defined.&#xD;
&#xD;
      Statistical analysis Baseline and follow-up characteristics were described by means and&#xD;
      standard deviations (SD) or by median and interquartile range (IQR) for continuous variables&#xD;
      with normal or with skewed distribution, respectively, and by percentages for categorical&#xD;
      variables. Chi-square or Fisher exact tests were performed when appropriate for qualitative&#xD;
      variables. The Student or Mann-Whitney tests were used to compare baseline characteristics&#xD;
      and study outcomes between study groups for continuous variables with skewed distributions.&#xD;
&#xD;
      The distribution of values for usual biomarkers and blood cell count were determined in the&#xD;
      different populations of patients using boxplots. The performances of current laboratory data&#xD;
      in predicting definite COVID-19-related pneumonia were evaluated by sensitivity analysis&#xD;
      (definite vs excluded COVID-19-related pneumonia). CRP was evaluated at several cut-off&#xD;
      points of 20 mg/L, 30 mg/L, 50 mg/L, 70 mg/L, and 100 mg/L, values used in previous studies.&#xD;
      Several cut-off points for PCT were chosen at the level of 0.10 μg/L, and at the two levels&#xD;
      for suspected bacterial infection as stated by the manufacturer, i.e., 0.25 μg/L and 0.50&#xD;
      μg/L. Cut-offs for cTnT-hs were 0.014ng/mL and 50ng/mL. Cut-offs for D-dimers test were&#xD;
      500µg/ml and age-adjusted threshold. Sensitivities, specificities, positive predictive values&#xD;
      (PPVs), negative predictive values (NPVs), and likelihood ratio were calculated. Receiver&#xD;
      operating characteristic (ROC) curves were drawn, area under the curve AUC was computed and&#xD;
      optimal cut-off was identified by the maximization of the Youden's index, comparing&#xD;
      laboratory results values in patients with excluded COVID-19-related pneumonia and definite&#xD;
      COVID-19-related pneumonia. From these optimal cut-offs for laboratory results, sensitivity&#xD;
      analyses were performed combining cut-offs.&#xD;
&#xD;
      A multivariate logistic regression model was built to identify factors associated with having&#xD;
      definite COVID-19-related pneumonia as compared to having an excluded COVID-19-related&#xD;
      pneumonia diagnosis. Investigator excluded from the excluded CAP diagnosis group, patients&#xD;
      with an extra-pulmonary infectious disease. All variables with a p value of &lt; 0.25 in the&#xD;
      bivariate analysis were entered into a multivariate logistic regression with a backward&#xD;
      stepwise approach; the discrimination was evaluated by the C-index and its 95 % confidence&#xD;
      interval (95 % CI) and the calibration was evaluated by the Hosmer Lemeshow goodness-of-fit&#xD;
      test.&#xD;
&#xD;
      All tests were two-sided, and p-values below 0.05 were considered to denote statistical&#xD;
      significance. All statistical analyses were performed using SPSS statistical software version&#xD;
      21.0 (SPSS Inc., Chicago, IL, USA).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 1, 2020</start_date>
  <completion_date type="Actual">May 15, 2020</completion_date>
  <primary_completion_date type="Actual">May 1, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>routine biomarkers and blood cell count are discriminant to diagnose COVID-19</measure>
    <time_frame>2 months</time_frame>
    <description>assess sensitivity of routine biomarkers and blood cell count for diagnosis of COVID-19-related pneumonia in low and high probability groups for level of certainty using the adjudication committee classification</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and CRP</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding CRP.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and PCT</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding PCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and Ddimers</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding Ddimers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and NTproBNP</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding NTproBNP.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and cTnT-HS</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding cTnT-HS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Probability of COVID-19 and blood cell counts</measure>
    <time_frame>2 months</time_frame>
    <description>An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding blood cell counts.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>performance of combined routine biomarkers</measure>
    <time_frame>2 months</time_frame>
    <description>Assess performance of combined routine biomarkers and blood cell count for diagnosis of COVID-19-related pneumonia independent parameters that will significantly differ in a univariate analysis will be combined. Their characteristics will be reported (Se, Sp, PPV, NPV, Likelihood ratios). The above mentioned assessment will be held at the exclusion of others</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess usual biomarkers and blood cell count</measure>
    <time_frame>2 months</time_frame>
    <description>ii) to assess performance of combined routine biomarkers and blood cell count for diagnosis of COVID-19-associated pneumonia; assessment of characteritics for high probability and low probability patients : P value and AUC [95% CI] will be assessed comparing the 2 groups.&#xD;
iii) to assess whether usual biomarkers and blood cell count were associated with diagnosis of COVID-19-associated pneumonia using sensitivity analyses in predefinite subgroups chosen a priori; 1) when comparing definite versus excluded patients; 2) when comparing high vs. low probability patients, excluding bacterial infection (respiratory and extra-respiratory) in the low probability COVID-19-associated pneumonia group; 3) when comparing definite versus excluded probability patients, excluding bacterial infections (respiratory and extra-respiratory) in excluded patients. For each, P value and AUC [95% CI] will be assessed comparing the 2 groups</description>
  </secondary_outcome>
  <enrollment type="Actual">257</enrollment>
  <condition>Covid19</condition>
  <eligibility>
    <study_pop>
      <textblock>
        For the study purpose and to ensure quality of the final adjudication committee diagnosis,&#xD;
        we selected consecutive adults visiting the COVID19 dedicated ED if they presented with&#xD;
        clinically suspected COVID19-related pneumonia and had SARS-Cov-2 RT-PCR and/or low dose&#xD;
        chest CT-scan. Clinically suspected COVID-19-related pneumonia was based on physician's own&#xD;
        judgment and if they fulfilled the following criteria: new onset of features concordant&#xD;
        with viral infection (at least one among: sweat, chills, aches and pain, temperature ≥38°C&#xD;
        or &lt;36°C or perception of fever, loss of smell and/or taste) and symptoms of an acute lower&#xD;
        respiratory tract illness (at least one among: cough, sputum production, respiratory rate&#xD;
        ≥20 per minute, dyspnea, chest pain, altered breathing sounds at auscultation)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patient suspected of COVID19&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patient unsuspected of COVID19&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <location>
    <facility>
      <name>Centre Hospitalier Princesse Grace</name>
      <address>
        <city>Monaco</city>
        <state>MON</state>
        <zip>98000</zip>
        <country>Monaco</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Monaco</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 18, 2020</study_first_submitted>
  <study_first_submitted_qc>May 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>May 22, 2020</last_update_submitted>
  <last_update_submitted_qc>May 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Covid19, biomarkers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Emergencies</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04401241
org study id: 20-06
nct id: NCT04401241
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
December 2019 was the onset of an outbreak of an infection related to SARS-CoV-2, a new
      coronavirus detected in January 2020 and responsible for a disorder termed COVID-19. Since
      then, COVID-19 has spread worldwide and is responsible for an unprecedented pandemic with
      major threat on global health and social and economic stability.

      Covid-19 has a large spectrum of symptoms. Most patients experience mild or moderate flu-like
      disorder with cough, fever, and shortness of breath. More severe presentations may occur;
      patients sometimes develop an acute pneumonia that can lead to adult respiratory distress
      syndrome. A considerable number of publications have been released for the last 10 weeks to
      help physicians making diagnosis and treat patients. Chinese authors have extensively
      proposed description of the disease. As signs and symptoms are poorly specific, diagnosis
      mostly relies on detection of the virus by RT-PCR in the upper respiratory tract. Some
      uncommon images and localization are highly specific and sensitive on chest CT-scan, which is
      cornerstone for initial diagnosis. However, resources may lack during healthcare crisis and
      results of these investigations may be delayed or unavailable developper. Special attention
      should also be paid to usual laboratory analysis. Indeed, decreased lymphocytes and
      eosinophilic counts are frequently described as well as increase in D-dimers levels.
      Variation of C-reactive protein (CRP) and procalcitonin (PCT) have been reported. Coronavirus
      may have cardiac tropism and changes in cardiac biomarkers concentration may occur.
      Therefore, some data suggest that values of routine biomarkers and blood cell count may
      assist physicians at bedside to support diagnosis of COVID-19.

      To face the outbreak, organization of emergency departments (ED) was mandatory to separate
      patients flows and avoid mixing patients with COVID-19 and others. Most patients visiting EDs
      dedicated to initial COVID-19 management suffered of pneumonia-like symptoms. Despite initial
      triage, patients had either COVID-19-related pneumonia either alternative diagnoses. We took
      advantage of this to evaluate the ability of routine biomarkers and leucocytes count helping
      identification of COVID-19 from alternative diagnoses.
Methods Setting Investigator designed a single center, retrospective, observational study
      conducted from February 2020 to April 2020 in the emergency department (ED) of Princesse
      Grace Hospital center, a general hospital in Monaco. The study was monitored by the research
      department of the Hospital Center. No specific funding was obtained for this study. The
      institutional review board for the protection of human subjects approved the study protocol
      and waved the need for written informed consent for inclusion.

      Objectives The primary objective was to assess sensitivity of routine biomarkers and blood
      cell count for diagnosis of COVID-19-related pneumonia in low and high probability groups for
      level of certainty using the adjudication committee classification.

      Secondary objectives were :

        -  to compare values in the four different categories of level of certainty and between low
           and high probability groups;

        -  to assess performance of combined routine biomarkers and blood cell count for diagnosis
           of COVID-19-related pneumonia;

        -  to assess whether usual biomarkers and blood cell count were associated with diagnosis
           of COVID-19-related pneumonia using sensitivity analyses in two predefinite subgroups
           chosen a priori; Group 1 : when considering patients classified as having low
           probability and high probability COVID-19-related pneumonia; Group 2 : when patients
           with excluded COVID-19-related pneumonia and diagnosed extra-pulmonary infectious
           disease were not taken into account, in the low probability COVID-19-related pneumonia
           group.

      Adjudication committee Based on data collected from baseline on standardized case report
      forms, results of low dose chest CT-scan, of SARS-Cov-2 specific RT-PCR, and full access to
      all available data including patients' discharge summary, an adjudication committee
      consisting of three independent senior experts in infectious diseases, pneumology and
      radiology retrospectively assigned the probability of COVID-19-related pneumonia diagnosis
      using the 4-level Likert scale. For this study, the gold standard was the diagnosis assessed
      by the adjudication committee. Alternative diagnoses were established for low probability
      COVID-19-related pneumonia and classified as non-COVID pulmonary diseases and extra-pulmonary
      infectious diseases and others.

      A Likert scale allowed distribution of patients in four categories:

        1. absence of COVID-19-related pneumonia hereafter referred to as excluded;

        2. possible COVID-19-related pneumonia;

        3. probable COVID-19-related pneumonia;

        4. definite COVID-19-related pneumonia. After this first classification, patients were
           distributed in two groups: low probability COVID-19-related pneumonia (excluded and
           possible) and high probability COVID-19-related pneumonia (probable and definite).

      Study population For the study purpose and to ensure quality of the final adjudication
      committee diagnosis, investigator selected consecutive adults (18 years of age and above)
      visiting the COVID-19-dedicated ED if they presented with clinically suspected
      COVID-19-related pneumonia and had SARS-Cov-2 RT-PCR and/or low dose chest CT-scan.

      Patient management and usual biomarkers and blood cell count Patients' management in the
      COVID-19-dedicated ED was based on local protocoled practices based upon collegial
      multidisciplinary decision if they presented with suspected COVID-19-related pneumonia.
      Recorded baseline data consisted of demographic data (age, gender), coexisting illnesses,
      treatments, symptoms, clinical findings and predetermined laboratory tests including:
      SARS-Cov-2 specific RT-PCR obtained on nasopharyngeal swab; low-dose chest CT-scan; standard
      blood analysis (complete blood count, hemostasis, metabolic panel, creatinine, blood urea
      nitrogen, liver enzymes), D-dimers (Vidas, Biomérieux), procalcitonin, C-reactive protein
      (CRP), high sensitive cardiac troponin T (cTnT-hs, Cobas, Roche diagnostics), NT-pro-brain
      natriuretic peptide (NT-proBNP, Cobas, Roche diagnostics). For each individual, CRB65 and
      Pneumonia Severity Index (PSI) were calculated.

      Microbiological samples Naso-pharyngeal swabs were collected at admission and placed in a
      Middle Virocult MWE (Sigma®) transport medium. Samples were kept at room temperature and sent
      to the laboratory immediately after collection. For the presence of SARS-COV-2, swabs were
      sent to French referent centers of virology (Nice, Marseille, Paris). Routine microbiological
      examinations were also performed at the discretion of the emergency physicians and included :
      presence of influenza A and B viruses and respiratory syncytial virus (RSV) A and B on
      nasopharyngeal swabs, blood culture, urine antigens for Streptococcus pneumoniae and
      Legionella pneumophila type I, serodiagnosis of Mycoplasma pneumoniae. These results were
      available to the adjudication committee.

      Low dose chest CT-scan data and COVID-19-related pneumonia diagnosis classification
      Multidetector low dose thoracic CT-scan was performed for each individual patient and
      interpretation was recorded using a standardized report form according to guidelines. The
      level of COVID-19-related pneumonia probability according to low dose chest CT scan were
      defined.

      Statistical analysis Baseline and follow-up characteristics were described by means and
      standard deviations (SD) or by median and interquartile range (IQR) for continuous variables
      with normal or with skewed distribution, respectively, and by percentages for categorical
      variables. Chi-square or Fisher exact tests were performed when appropriate for qualitative
      variables. The Student or Mann-Whitney tests were used to compare baseline characteristics
      and study outcomes between study groups for continuous variables with skewed distributions.

      The distribution of values for usual biomarkers and blood cell count were determined in the
      different populations of patients using boxplots. The performances of current laboratory data
      in predicting definite COVID-19-related pneumonia were evaluated by sensitivity analysis
      (definite vs excluded COVID-19-related pneumonia). CRP was evaluated at several cut-off
      points of 20 mg/L, 30 mg/L, 50 mg/L, 70 mg/L, and 100 mg/L, values used in previous studies.
      Several cut-off points for PCT were chosen at the level of 0.10 μg/L, and at the two levels
      for suspected bacterial infection as stated by the manufacturer, i.e., 0.25 μg/L and 0.50
      μg/L. Cut-offs for cTnT-hs were 0.014ng/mL and 50ng/mL. Cut-offs for D-dimers test were
      500µg/ml and age-adjusted threshold. Sensitivities, specificities, positive predictive values
      (PPVs), negative predictive values (NPVs), and likelihood ratio were calculated. Receiver
      operating characteristic (ROC) curves were drawn, area under the curve AUC was computed and
      optimal cut-off was identified by the maximization of the Youden's index, comparing
      laboratory results values in patients with excluded COVID-19-related pneumonia and definite
      COVID-19-related pneumonia. From these optimal cut-offs for laboratory results, sensitivity
      analyses were performed combining cut-offs.

      A multivariate logistic regression model was built to identify factors associated with having
      definite COVID-19-related pneumonia as compared to having an excluded COVID-19-related
      pneumonia diagnosis. Investigator excluded from the excluded CAP diagnosis group, patients
      with an extra-pulmonary infectious disease. All variables with a p value of < 0.25 in the
      bivariate analysis were entered into a multivariate logistic regression with a backward
      stepwise approach; the discrimination was evaluated by the C-index and its 95 % confidence
      interval (95 % CI) and the calibration was evaluated by the Hosmer Lemeshow goodness-of-fit
      test.

      All tests were two-sided, and p-values below 0.05 were considered to denote statistical
      significance. All statistical analyses were performed using SPSS statistical software version
      21.0 (SPSS Inc., Chicago, IL, USA).
observational model: Other
time perspective: Retrospective
measure: routine biomarkers and blood cell count are discriminant to diagnose COVID-19
time frame: 2 months
description: assess sensitivity of routine biomarkers and blood cell count for diagnosis of COVID-19-related pneumonia in low and high probability groups for level of certainty using the adjudication committee classification
measure: Probability of COVID-19 and CRP
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding CRP.
measure: Probability of COVID-19 and PCT
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding PCT.
measure: Probability of COVID-19 and Ddimers
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding Ddimers.
measure: Probability of COVID-19 and NTproBNP
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding NTproBNP.
measure: Probability of COVID-19 and cTnT-HS
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding cTnT-HS.
measure: Probability of COVID-19 and blood cell counts
time frame: 2 months
description: An adjudication committee with full access to medical charts will classify patients in 4 categories for diagnosis of COVID-19 associated pneumonia : certain, probable, unlikely, and excluded. Patients will be distributed in 2 probability groups : high probability (certain + probable) and compared with low probability patients (unlikely + excluded). Se, Sp, PPV, NPV, Likelihood ratios will be assessed comparing the 2 groups regarding blood cell counts.
measure: performance of combined routine biomarkers
time frame: 2 months
description: Assess performance of combined routine biomarkers and blood cell count for diagnosis of COVID-19-related pneumonia independent parameters that will significantly differ in a univariate analysis will be combined. Their characteristics will be reported (Se, Sp, PPV, NPV, Likelihood ratios). The above mentioned assessment will be held at the exclusion of others
measure: Assess usual biomarkers and blood cell count
time frame: 2 months
description: ii) to assess performance of combined routine biomarkers and blood cell count for diagnosis of COVID-19-associated pneumonia; assessment of characteritics for high probability and low probability patients : P value and AUC [95% CI] will be assessed comparing the 2 groups.
iii) to assess whether usual biomarkers and blood cell count were associated with diagnosis of COVID-19-associated pneumonia using sensitivity analyses in predefinite subgroups chosen a priori; 1) when comparing definite versus excluded patients; 2) when comparing high vs. low probability patients, excluding bacterial infection (respiratory and extra-respiratory) in the low probability COVID-19-associated pneumonia group; 3) when comparing definite versus excluded probability patients, excluding bacterial infections (respiratory and extra-respiratory) in excluded patients. For each, P value and AUC [95% CI] will be assessed comparing the 2 groups
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
facility: 
country: Monaco
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Emergencies