COVID-19 - Cytokine Storm

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multi-Center Study Evaluating Clinical Course in Patients With COVID-19 and Its Relationship to Cytokine Storm

Conditions
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COVID-19

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients, male or female of any age diagnosed with COVID-19, as defined below: Laboratory confirmation of SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-PCR) from any diagnostic sampling source. OR Serological evidence of SARS-CoV-2 infection Exclusion Criteria: None

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| • Asymptomatic or Pre-symptomatic Infection<br>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. | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| Mild COVID-19<br>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 | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| Moderate COVID-19<br>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. | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| Severe COVID-19<br>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% | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| Critical COVID-19<br>COVID-19 patients who have respiratory failure, septic shock, and/or multiple organ dysfunction. | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| Sepsis<br>A control group of patients with sepsis-related cytokine storm | Other: No intervention<br>* This is an observational study, with no intervention.<br>|
| CAR-T CRS<br>A control group of patients with cytokine release syndrome due to CAR-T therapy | Other: No intervention<br>* This is an observational study, with no intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Outcomes of Patients with COVID-19 using the National Early Warning Score 2 (NEWS2) system | 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) | 6 months | 
| Clinical Outcomes of Patients with COVID-19 using the new NIH Patient Classification of severity of illness | 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. | 6 months | 
| Mortality | Incidence rate of Mortality from any cause | 6 months | 
| Cytokine/Chemokine/Hematopoietic Growth Factors/ Complement and Other Immune Modulators in Patients with COVID-19 | 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. | 6 months |