NGS Diagnostic in COVID-19 Hosts - Genetic Cause Relating to the Course of Disease Progression

Study Overview
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Brief Summary
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In this study (i) the host genome to identify susceptibility regions of infection, inflammation, and host defense, (ii) host response to Severe Acute Respiratory Syndrome-Corona-Virus-2 (SARS-CoV-2) infection, and (iii) viral sequence composition to define viral sequences which may be correlated with disease severity in addition to the metagenome of the throat swab will be analysed .

Detailed Description
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This study aims to recruit adult persons with diagnostically confirmed Corona-Virus- Disease-19 (COVID-19) infection and with different disease manifestation who are included into diagnostic or therapeutic care at the University Hospital Tübingen (UKT). The COVID-19 Next-Generation-Sequencing (NGS) study aims to cover as many patients in Germany as possible. It is expected to include in Phase 1 (pilot study): 250 patients with different disease manifestation (extreme phenotypes) and individual risk factors by whole genome analysis Phase 2 (verification study): 1.000 clinically well-defined patients to ensure a broader range of overlapping phenotypes, to verify data from the pilot study. Phase 3 (confirmation study): > 10.000 patients to increase the power (anticipated).

Official Title
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NGS Diagnostic in COVID-19 Hosts - Genetic Cause Relating to the Course of Disease Progression

Conditions
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COVID-19

Intervention / Treatment
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* Genetic: Whole Genome Analysis
* Genetic: T-cell receptor (TCR) repertoire
* Genetic: SARS-CoV-2 viral composition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COVID-19 infection confirmed COVID-19 disease manifestation Age > 18 years Exclusion Criteria: Missing informed consent of the patient/ legal guardian/ relatives

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Host Genome Analysis<br>For 150 patients from the extreme phenotypes - complementary to Whole Genome Analysis of each patient also Whole Transcriptome will performed Analysis; DNA methylation analysis using EPIC arrays will be performed in the pilot study (phase 1). Identically, in phase 2 starting from month 4, will be generated WGS, Whole transcriptome sequencing (WTS), and methylation data of the 500 patients. Epigenetic changes are likely to occur upon Corona infection. Subsequently, genome and epigenome data with RNA expression pattern will be correlated. | Genetic: Whole Genome Analysis<br>* Whole Genome Analysis with whole transcriptome analysis and deoxyribonucleic acid (DNA) methylation analysis using Methylation beadchip (EPIC) arrays<br>|
| Other: Host Response to SARS-CoV-2 Infection<br>Focus on longitudinal analysis of TCR repertoire of CD4+ and CD8+ T cells from blood samples (PBMCs) from clinically characterized patients (n = 24). The bulk- T-cell receptor (TCR) sequencing will be performed at different time points during the course of disease progression and recovery. | Genetic: T-cell receptor (TCR) repertoire<br>* Longitudinal analysis of TCR repertoire of Cluster of Differentiation 4+ (CD4+) and CD8+ T cells from blood samples (Peripheral Blood Mononuclear Cells, PBMCs) from clinically characterized patients<br>|
| Other: Viral Sequence Composition<br>The Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) viral composition is determined by Next Generation sequencing (different protocols for enrichment are available, and are currently being tested to successfully analyse the virus from different isolates). It is known that SARS-CoV-2 sequence is changing at least one position every second passing from person to person. Numerous variants have been described deriving from 3 different ancestral viruses (named A, B, and C) reflecting different distributions in East Asia, Europeans and Americans. At it is anticipated that other (super)infections may add to the severity of the infection and disease course, the entire metagenome of the throat is being sequenced and analyzed as well. | Genetic: SARS-CoV-2 viral composition<br>* Determined by Next Generation sequencing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral evolution | The change in the genetic makeup of a virus population (measured in numbers) as the viruses mutate and multiply over time at different time points | Day 1, Day 3-5, Day 7-9, 48 hours after recovery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune response | CD4+ and CD8+ T cells from blood (per µl) at different time points measured | Day 1, Day 3-5, Day 7-9, 48 hours after recovery | 
| Disease severity | Clinical classification according to severity: Light and uncomplicated (mild symptoms) Moderate (mild pneumonia) Severe pneumonia Critical (Acute Respiratory Distress Syndrome (ARDS), sepsis, septic shock) Evaluated at several time points | Day 1, Day 3-5, Day 7-9, 48 hours after recovery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, Next-Generation-Sequencing, Whole Genome Analysis, MultiOmics, Extreme phenotypes