<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/NCT04474067</url>
  </required_header>
  <id_info>
    <org_study_id>DM002</org_study_id>
    <nct_id>NCT04474067</nct_id>
  </id_info>
  <brief_title>COVID-19 - Cytokine Storm</brief_title>
  <official_title>A Multi-Center Study Evaluating Clinical Course in Patients With COVID-19 and Its Relationship to Cytokine Storm</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hadassah Medical Organization</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Barzilai Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Chaim Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hadassah Medical Organization</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>
      This is a multi-center study comparing clinical outcomes in patients with COVID-19 in&#xD;
      subjects hospitalized at Hadassah and other hospitals for PCR or serology confirmed COVID-19&#xD;
      and compare the outcomes to the presence of different degrees of a cytokine storm. The&#xD;
      patients will be subdivided into a mild, moderate, and severe course according to NEWS2.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Rationale&#xD;
&#xD;
      Over 100 patients were hospitalized at Hadassah in the recent 2 months with the diagnosis of&#xD;
      COVID-19.&#xD;
&#xD;
      We would like to summarize the clinical outcomes and their correlation to a cytokine storm at&#xD;
      Hadassah and additional hospitals and additional hospitals in Israel.&#xD;
&#xD;
      COVID-19, the name given to the clinical syndrome associated with the newly recognized virus&#xD;
      SARS-CoV-2 has become pandemic with a mortality estimated based on reports from China between&#xD;
      1-3% and complications among hospitalized patients leading to up to 15-25% admissions to the&#xD;
      ICU.&#xD;
&#xD;
      The clinical presentation includes both upper and lower respiratory tract infection, but&#xD;
      patients may also be asymptomatic.&#xD;
&#xD;
      A diagnostic PCR assay was rapidly developed in Hong Kong and Berlin that accurately detects&#xD;
      SARS-CoV-2 in samples from nose and throat swabs or sputum of hospitalized patients and is&#xD;
      used by public-health authorities around the world.&#xD;
&#xD;
      To avoid cross-reactivity with SARS-CoV or other coronaviruses, the test detects a region of&#xD;
      the gene encoding RNA-dependent RNA polymerase that is unique to SARS-CoV-2.&#xD;
&#xD;
      Not all patients need hospitalization but due to the high index of infection spread, all&#xD;
      detected patients are put in isolation to prevent transmission of the infection to others.&#xD;
&#xD;
      The development of vaccines is undoubtedly an important step and several MERS vaccines were&#xD;
      already in clinical trials when word of the new outbreak spread. However, developing and&#xD;
      testing the correct viral protein that will be effective (and probably not 100% protective)&#xD;
      will take some time.&#xD;
&#xD;
      In the meantime, anti-viral agents are tested including a combination of two human&#xD;
      immunodeficiency virus (HIV) antivirals. Lopinavir and ritonavir have been taking center&#xD;
      stage as potential therapies for COVID-19 and there are at least three registered randomized&#xD;
      clinical trial testing the lopinavir-ritonavir combination in Chinese patients infected with&#xD;
      SARS-CoV-2 (NCT04255017, NCT04252885 and NCT04251871) with the results of one being negative,&#xD;
      as published in the New England Journal of Medicine in March 2020. A handful of other HIV&#xD;
      antivirals are currently in clinical testing against SARS-CoV-2, including&#xD;
      darunavir-cobicistat. , donated by the US pharmaceutical company Johnson &amp; Johnson to the&#xD;
      Shanghai Public Health Clinical Center. Nucleoside analogs are being considered too and&#xD;
      Remdesivir was used to treat the first US patient infected with SARS-CoV-2, who recovered. It&#xD;
      is also in phase 3 trials in Wuhan patients infected with SARS-CoV-2, overseen by the&#xD;
      China-Japan Friendship Hospital in Beijing (NCT04252664 and NCT04257656). However, SARS-CoV-2&#xD;
      have its own proteases, including its main protease, Mpro, and HIV antivirals design are&#xD;
      tailored specifically to block the activity of HIV proteases to avoid off-target effects on&#xD;
      human cells, which makes them less likely to bind SARS-CoV-2 proteases as well. Chloroquine&#xD;
      was recently suggested as an additional anti-viral medication. In addition, even if&#xD;
      anti-viral therapy will be found to be efficacious against SARS-CoV-2, will this be the&#xD;
      treatment of choice in patients admitted to the ICU? Not necessarily.&#xD;
&#xD;
      The term &quot;cytokine storm&quot; calls up vivid images of an immune system gone awry and an&#xD;
      inflammatory response flaring out of control. The term has captured the attention of the&#xD;
      public and the scientific community alike and is increasingly being used in both the popular&#xD;
      media and the scientific literature. Indeed, a few publications have indicated an important&#xD;
      part of the complications in COVID-19 are related to a cytokine storm (Huang et al. Lancet&#xD;
      2020, Mehta et al. Lancet 2020).&#xD;
&#xD;
      Taken together, in patients with moderate to severe COVID-19, there may be an underlying&#xD;
      immunological mechanism of action that is a hyper-inflammatory pathway associated with&#xD;
      increased death.&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      A multi-center study comparing clinical outcomes in patients with COVID-19 in subjects&#xD;
      hospitalized at Hadassah and other hospitals for PCR or serology confirmed COVID-19 and&#xD;
      compare the outcomes to the presence of different degrees of a cytokine storm.&#xD;
&#xD;
      The patients will be subdivided into five severities of COVID-19 illness according to the new&#xD;
      NIH Patient Classification&#xD;
      (www.covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/):&#xD;
&#xD;
        -  Asymptomatic or Pre-symptomatic Infection: Individuals who test positive for SARS-CoV-2&#xD;
           by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or&#xD;
           antigen test, but have no symptoms.&#xD;
&#xD;
        -  Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19&#xD;
           (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of&#xD;
           breath, dyspnea, or abnormal chest imaging.&#xD;
&#xD;
        -  Moderate Illness: Individuals who have evidence of lower respiratory disease by clinical&#xD;
           assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.&#xD;
&#xD;
        -  Severe Illness: Individuals who have respiratory frequency &gt;30 breaths per minute, SpO2&#xD;
           &lt;94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction&#xD;
           of inspired oxygen (PaO2/FiO2) &lt;300 mmHg, or lung infiltrates &gt;50%&#xD;
&#xD;
        -  Critical Illness: Individuals who have respiratory failure, septic shock, and/or&#xD;
           multiple organ dysfunction.&#xD;
&#xD;
      The cytokine storm will be compared to cytokine storm in sepsis and in chimeric antigen&#xD;
      receptor (CAR)-T therapy, associated with Cytokine release Syndrome (CRS).&#xD;
&#xD;
      Handling of blood samples&#xD;
&#xD;
      Blood results will be taken from the Hospital clinical evaluation system (MAHAR). Blood&#xD;
      leftover samples obtained from Hadassah biological blood bank, or for serological&#xD;
      confirmation or IL6 level tests (as a rationale for injecting tocilizumab, or from any&#xD;
      routine blood examination, will be used for cytokines/chemokines/hematopoietic growth&#xD;
      factors/ Complement/ DNA methylation measurements.&#xD;
&#xD;
      In the case of hospitalized patients, a total amount of up to 10 ml of blood will be drawn.&#xD;
      Blood samples will be obtained and handled according to the institutional guidelines and&#xD;
      approvals.&#xD;
&#xD;
      Statistical Analysis&#xD;
&#xD;
      The data will be summarized by different clinical outcomes listing the mean, standard&#xD;
      deviation, minimum, median, maximum, and number of subjects for continuous data, or in tables&#xD;
      listing count and percentage for categorical and event data, as appropriate. Descriptive&#xD;
      analyses and, where appropriate, statistical testing will compare between each of the&#xD;
      subgroups.&#xD;
&#xD;
      All statistical analyses will be performed, and data appendixes will be created using the&#xD;
      SAS® system (SAS Institute, Cary, NC), Version 9.4, or higher.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">June 28, 2020</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">March 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Outcomes of Patients with COVID-19 using the National Early Warning Score 2 (NEWS2) system</measure>
    <time_frame>6 months</time_frame>
    <description>To compare the clinical outcomes of patients with COVID-19 to Sepsis and CAR-T-related cytokine storm.&#xD;
This will be done by assessment of acute-illness severity using the NEWS2 scoring system (Higher scores mean more severe illness)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Outcomes of Patients with COVID-19 using the new NIH Patient Classification of severity of illness</measure>
    <time_frame>6 months</time_frame>
    <description>To compare the clinical outcomes of patients with COVID-19 to Sepsis and CAR-T-related cytokine storm.&#xD;
This will be done by assessment of acute-illness severity using the new NIH Patient Classification to (1) Asymptomatic or Pre-symptomatic Infection; (2) Mild Illness; (3) Moderate Illness; (4) Severe Illness; (5) Critical Illness As detailed in the Study design section.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>6 months</time_frame>
    <description>Incidence rate of Mortality from any cause</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cytokine/Chemokine/Hematopoietic Growth Factors/ Complement and Other Immune Modulators in Patients with COVID-19</measure>
    <time_frame>6 months</time_frame>
    <description>To assess cytokine/chemokine/hematopoietic growth factors/ Complement and other immune modulators in patients with COVID-19 by measuring the serum concentrations of these factors in COVID-19 patients and compare those the levels of patients with sepsis and CAR T cytokine release syndrome.</description>
  </primary_outcome>
  <number_of_groups>7</number_of_groups>
  <enrollment type="Anticipated">300</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>• Asymptomatic or Pre-symptomatic Infection</arm_group_label>
    <description>Individuals who test positive for SARS-CoV-2 by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or antigen test, but have no symptoms.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mild COVID-19</arm_group_label>
    <description>Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal chest imaging.&#xD;
According to NIH classification</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate COVID-19</arm_group_label>
    <description>COVID-19 patients who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Severe COVID-19</arm_group_label>
    <description>COVID-19 patients who have respiratory frequency &gt;30 breaths per minute, SpO2 &lt;94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) &lt;300 mmHg, or lung infiltrates &gt;50%</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Critical COVID-19</arm_group_label>
    <description>COVID-19 patients who have respiratory failure, septic shock, and/or multiple organ dysfunction.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sepsis</arm_group_label>
    <description>A control group of patients with sepsis-related cytokine storm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CAR-T CRS</arm_group_label>
    <description>A control group of patients with cytokine release syndrome due to CAR-T therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No intervention</intervention_name>
    <description>This is an observational study, with no intervention.</description>
    <arm_group_label>CAR-T CRS</arm_group_label>
    <arm_group_label>Critical COVID-19</arm_group_label>
    <arm_group_label>Mild COVID-19</arm_group_label>
    <arm_group_label>Moderate COVID-19</arm_group_label>
    <arm_group_label>Sepsis</arm_group_label>
    <arm_group_label>Severe COVID-19</arm_group_label>
    <arm_group_label>• Asymptomatic or Pre-symptomatic Infection</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples obtained from patients with COVID-19, sepsis, or CAR T and cytokine storm&#xD;
      following a consent, for a total amount of up to 10 ml of blood. Also, Blood leftover samples&#xD;
      obtained from Hadassah biological blood bank, or from any routine blood examination, or a&#xD;
      total amount of up to 10 ml of blood from hospitalized COVID-19 patients is retained.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients that were hospitalized at Hadassah Medical Center and other hospitals in Israel,&#xD;
        with the diagnosis of COVID-19 (as specified in the inclusion criteria).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients, male or female of any age diagnosed with COVID-19, as defined below:&#xD;
&#xD;
          1. Laboratory confirmation of SARS-CoV-2 infection by reverse transcription-polymerase&#xD;
             chain reaction (RT-PCR) from any diagnostic sampling source.&#xD;
&#xD;
             OR&#xD;
&#xD;
          2. Serological evidence of SARS-CoV-2 infection&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Dror Mevorach, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hadassah Medical Organization</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dror Mevorach, MD</last_name>
    <phone>972-2- 6777317</phone>
    <email>mevorachd@hadassah.org.il</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hadassah Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <zip>91120</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dror Mevorach, MD</last_name>
      <phone>972-2- 6777317</phone>
      <email>mevorachd@hadassah.org.il</email>
    </contact>
    <investigator>
      <last_name>Dror Mevorach, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <reference>
    <citation>Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020 May;39(5):405-407. doi: 10.1016/j.healun.2020.03.012. Epub 2020 Mar 20. No abstract available.</citation>
    <PMID>32362390</PMID>
  </reference>
  <reference>
    <citation>Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:</citation>
    <PMID>31986264</PMID>
  </reference>
  <reference>
    <citation>Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.</citation>
    <PMID>32192578</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 16, 2020</study_first_posted>
  <last_update_submitted>December 20, 2020</last_update_submitted>
  <last_update_submitted_qc>December 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hadassah Medical Organization</investigator_affiliation>
    <investigator_full_name>Mevorach Dror</investigator_full_name>
    <investigator_title>Professor &amp; Head, Department of Internal Medicine B; Head, Rheumatology Research Center, Hadassah and the Hebrew University Medical School</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Cytokine Release Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04474067
org study id: DM002
nct id: NCT04474067
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a multi-center study comparing clinical outcomes in patients with COVID-19 in
      subjects hospitalized at Hadassah and other hospitals for PCR or serology confirmed COVID-19
      and compare the outcomes to the presence of different degrees of a cytokine storm. The
      patients will be subdivided into a mild, moderate, and severe course according to NEWS2.
Study Rationale

      Over 100 patients were hospitalized at Hadassah in the recent 2 months with the diagnosis of
      COVID-19.

      We would like to summarize the clinical outcomes and their correlation to a cytokine storm at
      Hadassah and additional hospitals and additional hospitals in Israel.

      COVID-19, the name given to the clinical syndrome associated with the newly recognized virus
      SARS-CoV-2 has become pandemic with a mortality estimated based on reports from China between
      1-3% and complications among hospitalized patients leading to up to 15-25% admissions to the
      ICU.

      The clinical presentation includes both upper and lower respiratory tract infection, but
      patients may also be asymptomatic.

      A diagnostic PCR assay was rapidly developed in Hong Kong and Berlin that accurately detects
      SARS-CoV-2 in samples from nose and throat swabs or sputum of hospitalized patients and is
      used by public-health authorities around the world.

      To avoid cross-reactivity with SARS-CoV or other coronaviruses, the test detects a region of
      the gene encoding RNA-dependent RNA polymerase that is unique to SARS-CoV-2.

      Not all patients need hospitalization but due to the high index of infection spread, all
      detected patients are put in isolation to prevent transmission of the infection to others.

      The development of vaccines is undoubtedly an important step and several MERS vaccines were
      already in clinical trials when word of the new outbreak spread. However, developing and
      testing the correct viral protein that will be effective (and probably not 100% protective)
      will take some time.

      In the meantime, anti-viral agents are tested including a combination of two human
      immunodeficiency virus (HIV) antivirals. Lopinavir and ritonavir have been taking center
      stage as potential therapies for COVID-19 and there are at least three registered randomized
      clinical trial testing the lopinavir-ritonavir combination in Chinese patients infected with
      SARS-CoV-2 (NCT04255017, NCT04252885 and NCT04251871) with the results of one being negative,
      as published in the New England Journal of Medicine in March 2020. A handful of other HIV
      antivirals are currently in clinical testing against SARS-CoV-2, including
      darunavir-cobicistat. , donated by the US pharmaceutical company Johnson & Johnson to the
      Shanghai Public Health Clinical Center. Nucleoside analogs are being considered too and
      Remdesivir was used to treat the first US patient infected with SARS-CoV-2, who recovered. It
      is also in phase 3 trials in Wuhan patients infected with SARS-CoV-2, overseen by the
      China-Japan Friendship Hospital in Beijing (NCT04252664 and NCT04257656). However, SARS-CoV-2
      have its own proteases, including its main protease, Mpro, and HIV antivirals design are
      tailored specifically to block the activity of HIV proteases to avoid off-target effects on
      human cells, which makes them less likely to bind SARS-CoV-2 proteases as well. Chloroquine
      was recently suggested as an additional anti-viral medication. In addition, even if
      anti-viral therapy will be found to be efficacious against SARS-CoV-2, will this be the
      treatment of choice in patients admitted to the ICU? Not necessarily.

      The term "cytokine storm" calls up vivid images of an immune system gone awry and an
      inflammatory response flaring out of control. The term has captured the attention of the
      public and the scientific community alike and is increasingly being used in both the popular
      media and the scientific literature. Indeed, a few publications have indicated an important
      part of the complications in COVID-19 are related to a cytokine storm (Huang et al. Lancet
      2020, Mehta et al. Lancet 2020).

      Taken together, in patients with moderate to severe COVID-19, there may be an underlying
      immunological mechanism of action that is a hyper-inflammatory pathway associated with
      increased death.

      Study Design

      A multi-center study comparing clinical outcomes in patients with COVID-19 in subjects
      hospitalized at Hadassah and other hospitals for PCR or serology confirmed COVID-19 and
      compare the outcomes to the presence of different degrees of a cytokine storm.

      The patients will be subdivided into five severities of COVID-19 illness according to the new
      NIH Patient Classification
      (www.covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/):

        -  Asymptomatic or Pre-symptomatic Infection: Individuals who test positive for SARS-CoV-2
           by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or
           antigen test, but have no symptoms.

        -  Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19
           (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of
           breath, dyspnea, or abnormal chest imaging.

        -  Moderate Illness: Individuals who have evidence of lower respiratory disease by clinical
           assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.

        -  Severe Illness: Individuals who have respiratory frequency >30 breaths per minute, SpO2
           <94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction
           of inspired oxygen (PaO2/FiO2) <300 mmHg, or lung infiltrates >50%

        -  Critical Illness: Individuals who have respiratory failure, septic shock, and/or
           multiple organ dysfunction.

      The cytokine storm will be compared to cytokine storm in sepsis and in chimeric antigen
      receptor (CAR)-T therapy, associated with Cytokine release Syndrome (CRS).

      Handling of blood samples

      Blood results will be taken from the Hospital clinical evaluation system (MAHAR). Blood
      leftover samples obtained from Hadassah biological blood bank, or for serological
      confirmation or IL6 level tests (as a rationale for injecting tocilizumab, or from any
      routine blood examination, will be used for cytokines/chemokines/hematopoietic growth
      factors/ Complement/ DNA methylation measurements.

      In the case of hospitalized patients, a total amount of up to 10 ml of blood will be drawn.
      Blood samples will be obtained and handled according to the institutional guidelines and
      approvals.

      Statistical Analysis

      The data will be summarized by different clinical outcomes listing the mean, standard
      deviation, minimum, median, maximum, and number of subjects for continuous data, or in tables
      listing count and percentage for categorical and event data, as appropriate. Descriptive
      analyses and, where appropriate, statistical testing will compare between each of the
      subgroups.

      All statistical analyses will be performed, and data appendixes will be created using the
      SAS® system (SAS Institute, Cary, NC), Version 9.4, or higher.
observational model: Case-Control
time perspective: Prospective
measure: Clinical Outcomes of Patients with COVID-19 using the National Early Warning Score 2 (NEWS2) system
time frame: 6 months
description: To compare the clinical outcomes of patients with COVID-19 to Sepsis and CAR-T-related cytokine storm.
This will be done by assessment of acute-illness severity using the NEWS2 scoring system (Higher scores mean more severe illness)
measure: Clinical Outcomes of Patients with COVID-19 using the new NIH Patient Classification of severity of illness
time frame: 6 months
description: To compare the clinical outcomes of patients with COVID-19 to Sepsis and CAR-T-related cytokine storm.
This will be done by assessment of acute-illness severity using the new NIH Patient Classification to (1) Asymptomatic or Pre-symptomatic Infection; (2) Mild Illness; (3) Moderate Illness; (4) Severe Illness; (5) Critical Illness As detailed in the Study design section.
measure: Mortality
time frame: 6 months
description: Incidence rate of Mortality from any cause
measure: Cytokine/Chemokine/Hematopoietic Growth Factors/ Complement and Other Immune Modulators in Patients with COVID-19
time frame: 6 months
description: To assess cytokine/chemokine/hematopoietic growth factors/ Complement and other immune modulators in patients with COVID-19 by measuring the serum concentrations of these factors in COVID-19 patients and compare those the levels of patients with sepsis and CAR T cytokine release syndrome.
arm group label: • Asymptomatic or Pre-symptomatic Infection
description: Individuals who test positive for SARS-CoV-2 by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction) or antigen test, but have no symptoms.
arm group label: Mild COVID-19
description: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal chest imaging.
According to NIH classification
arm group label: Moderate COVID-19
description: COVID-19 patients who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) ≥94% on room air at sea level.
arm group label: Severe COVID-19
description: COVID-19 patients who have respiratory frequency >30 breaths per minute, SpO2 <94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mmHg, or lung infiltrates >50%
arm group label: Critical COVID-19
description: COVID-19 patients who have respiratory failure, septic shock, and/or multiple organ dysfunction.
arm group label: Sepsis
description: A control group of patients with sepsis-related cytokine storm
arm group label: CAR-T CRS
description: A control group of patients with cytokine release syndrome due to CAR-T therapy
intervention type: Other
intervention name: No intervention
description: This is an observational study, with no intervention.
arm group label: CAR-T CRS
arm group label: Critical COVID-19
arm group label: Mild COVID-19
arm group label: Moderate COVID-19
arm group label: Sepsis
arm group label: Severe COVID-19
arm group label: • Asymptomatic or Pre-symptomatic Infection
Blood samples obtained from patients with COVID-19, sepsis, or CAR T and cytokine storm
      following a consent, for a total amount of up to 10 ml of blood. Also, Blood leftover samples
      obtained from Hadassah biological blood bank, or from any routine blood examination, or a
      total amount of up to 10 ml of blood from hospitalized COVID-19 patients is retained.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
last name: Dror Mevorach, MD
role: Principal Investigator
affiliation: Hadassah Medical Organization
last name: Dror Mevorach, MD
phone: 972-2- 6777317
email: mevorachd@hadassah.org.il
facility: 
status: Recruiting
contact: 
investigator: 
country: Israel
citation: Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020 May;39(5):405-407. doi: 10.1016/j.healun.2020.03.012. Epub 2020 Mar 20. No abstract available.
PMID: 32362390
citation: Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
PMID: 31986264
citation: Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
PMID: 32192578
responsible party type: Principal Investigator
investigator affiliation: Hadassah Medical Organization
investigator full name: Mevorach Dror
investigator title: Professor & Head, Department of Internal Medicine B; Head, Rheumatology Research Center, Hadassah and the Hebrew University Medical School
mesh term: COVID-19
mesh term: Cytokine Release Syndrome
sharing ipd: Undecided