Microbiota in COVID-19 Patients for Future Therapeutic and Preventive Approaches

NCT04410263 | Unknown

• 1 other identifier: 2020-00646
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

In light of the rapidly emerging pandemic of SARS-CoV-2 infections, the global population and health care systems are facing unprecedented challenges through the combination of transmission and the potential for severe disease. Acute respiratory distress syndrome (ARDS) has been found with unusual clinical features dominated by substantial alveolar fluid load. It is unknown whether this is primarily caused by endothelial dysfunction leading to capillary leakage or direct virus induced damage. This knowledge gap is significant because the initial balance between fluid management and circulatory support appear to be decisive. On progression of the disease, bacterial superinfection facilitated by inflammation and virus related damage, has been identified as the main factor for patient outcome, but the role of the host versus the environment microbiome remains unclear. The overarching aim of the present research proposal is to improve therapeutic strategies in critically ill patients with ARDS due to SARS-CoV-2 infection by advancing the pathophysiological understanding of this novel disease. This research thus focuses on inflammation, microcirculatory dysfunction and superinfection, aiming to elucidate risk factors (RF) for the development of severe ARDS in SARS-CoV-2 infected patients and contribute to the rationale for therapeutic strategies. The hypotheses are that (I) the primary damage to the lung in SARS-CoV-2 ARDS is mediated through an exaggerated pro-inflammatory response causing primary endothelial dysfunction, and subsequently acting two-fold on the degradation of the lung parenchyma - through the primary cytokine response, and through recruitment of the inflammatory-monocyte-lymphocyte-neutrophil axis. The pronounced inflammation and primary damage to the lung disrupts the pulmonary microbiome, leading secondarily to pulmonary superinfections. (II) Pulmonary bacterial superinfections are a significant cause of morbidity and mortality in COVID-19 patients. Pathogen colonization main Risk Factor for lower respiratory tract infections. To establish colonization, pathogens have to interact with the local microbiota (a.k.a. microbiome) and certain microbiome profiles will be more resistant to pathogen invasion. Finally, (III) Handheld devices used in clinical routine are a potential reservoir and carrier of both, SARS-CoV-2, as well as bacteria causing nosocomial pneumonia.

Conditions

Corona Virus Infection; ARDS; Coinfection

Keywords

COVID 19; SARS Cov2; Coinfection

Outcome Measures

Primary Outcomes (3)

• Change of pro-inflammatory response over the ICU stay as a causative for primary endothelial dysfunction

  Daily recorded Vitals and Inflammatory Response will be analyzed by means of multivariable mixed effect models analysis and generalized linear models, with corrections for time and randomness. To account for the different units of measure we will standardize all values to an absolute measure by means of the z-score. The following variables will be considered: Respiratory values, Vital signs, Haemodynamic monitoring, Microcirculation, Inflammatory values, Hematology: T-cells CD3, 4 and 6 Chemistry: Inflammatory Cytokines and Biomarkers:CRP, PCT, MR-ProADM, IFN-1, IFN-γ, TNF-α/β, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, MIG, RANTES, MCP-1, IP-10, PD1, PD-L1 Lipid-pannel3: LDL, HDL, Cholesterol, Triglyceride Other: HLA DR/DQ TBS, Swabs, sublingual nonnvasive microscopy

  Admission, on day 0, day 1, day 2 , day 3, day 5, every 5 days up to 1 year

• Time-to-event "pulmonary bacterial superinfection or death"

  COX proportional hazards model and generalized mixed effect models assessing the effect of positive bacterial infection on mortality. Correction for time and randomness (multiple sampling). Super infection will be defined as a positive bacterial/ fungal sample (Bood cultures, BAL, TBS, Swabs, Urine)

  Through study completion, an average of 30 days

• Positive bacteria and/ or SARS-CoV-2 cultures on handheld devices used in clinical routine and correlation to the adherence to disinfection protocols

  Mobile devices will be swabed for bacterial and viral contamination, simultaneously adherence of the user to disinfection protocols will be assessed.

  Through study completion, an average of 30 days

Secondary Outcomes (1)

• Life Quality after COVID-19 Infection

  follow up 30 + 90 days and 1 year after discharge

Study Arms (1)

COVID-positive ICU patients

The collective of COVID-positive patients on the ICU

Diagnostic Test: Sampling (EDTA blood, pharyngeal and nose swabs, bronchoalveolar lavage ,urine)

Interventions

Sampling (EDTA blood, pharyngeal and nose swabs, bronchoalveolar lavage ,urine) DIAGNOSTIC_TEST

Most data and part of the biological material required for addressing the research questions in this project are generated in the treatment of the patients. The following data and samples are collected specifically for this project according to the study schedule (i.e. extra sampling or additional questioning): * blood samples (day 0= 40 ml EDTA, day 2= 20 ml EDTA, day 3= 30 ml EDTA, day 5=10 ml EDTA, every 5 days = 20 ml EDTA) * Swabs (oral +/- nasal +/- nasopharyngeal) * Sublingual microscopy

Also known as: Sublingual microscopy

COVID-positive ICU patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

COVID 19 patients admitted to the intensive care unit of the University Hospital Zurich

You may qualify if:

• SARS-CoV-2 infection confirmed according to WHO guidelines
• Hospitalization in intensive care unit for severe ARDS
• Confirmation of an independent doctor to safeguard the interests of the patient

You may not qualify if:

• Visible opposition to participate in the research project, expressed either verbally or through behavior

Sponsors & Collaborators

• University of Zurich: lead

Study Sites (1)

University Hospital Zurich

Zurich, Canton of Zurich, 8091, Switzerland

RECRUITING

Related Publications (2)

• Strickler NS, Hofmaenner DA, Schuepbach RA, Scheier TC, Buehler PK, Takala J, Brugger SD, Frey PM. Use of carbon dioxide production to detect bacterial superinfections in mechanically ventilated patients with acute respiratory distress syndrome: an exploratory prospective cohort study. BMJ Open Respir Res. 2025 Aug 28;12(1):e002760. doi: 10.1136/bmjresp-2024-002760.

  PMID: 40876958 DERIVED

• Busnadiego I, Abela IA, Frey PM, Hofmaenner DA, Scheier TC, Schuepbach RA, Buehler PK, Brugger SD, Hale BG. Critically ill COVID-19 patients with neutralizing autoantibodies against type I interferons have increased risk of herpesvirus disease. PLoS Biol. 2022 Jul 5;20(7):e3001709. doi: 10.1371/journal.pbio.3001709. eCollection 2022 Jul.

  PMID: 35788562 DERIVED

MeSH Terms

Conditions

Coronavirus Infections; Coinfection; COVID-19

Condition Hierarchy (Ancestors)

Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Silvio Brugger, SB

  USZ

  PRINCIPAL INVESTIGATOR

• Philipp K Buehler, PB

  USZ

  STUDY CHAIR

Central Study Contacts

Philipp K Buehler, PB

CONTACT

+41 43 253 13 40; philipp.buehler@usz.ch

Silvio Brugger, SB

CONTACT

+41 43 25 39896; silvio.brugger@usz.ch

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2020
• First Posted: June 1, 2020
• Study Start: April 9, 2020
• Primary Completion: December 30, 2023
• Study Completion: December 31, 2023
• Last Updated: June 1, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)