Pathological Findings of Fatal COVID-19 (HISTOCOVID)

Pathological Findings in Critically-ill Patients Who Died From SARS-CoV-2 Related Acute Respiratory Distress Syndrome

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new coronavirus discovered in December 2019 in Wuhan, China and currently responsible of a worldwide outbreak and the death of more than 55,000 patients in France. The more severe form of COVID-19 disease induces a pneumonia with profound hypoxemia which may require invasive mechanical ventilation. It is estimated that 5% of COVID-19 patients are admitted to the Intensive Care Unit (ICU) for management. Hospital mortality in patients who develop severe acute respiratory distress syndrome (ARDS) ranges between 40% and 60%. The investigators purpose to investigate the pathological findings of COVID-19 patients who died from ARDS in the ICU by doing post-mortem lung biopsies

Study Overview

• Status: Completed
• Conditions: Covid19; Respiratory Distress Syndrome; SARS-CoV-2; Intensive Care Units; Pathology
• Intervention / Treatment: Other: 2 post-mortem transcutaneous lung biopsies (1 anterior ; 1 posterior) using anatomical landmarks

Detailed Description

Forty-four French ICUs participate to this study with the aim to perform 200 lung biopsies in 100 patients over a 12-month period. This cohort will be the largest pathological database of COVID-19 patients who developed ARDS. In accordance with the French law, this study has been approved and registered by the French Agency of Biomedicine and the French Ministry of Education and Research (#PFS 20-016). Two transcutaneous lung biopsies per patient will be performed using a 14G needle and anatomical landmarks (1 anterior biopsy and 1 posterior biopsy). All biopsies will be referred to the Department of Pathology of Nantes university hospital and analysed by a group of pathologists specialized in lung tissue. The primary objective is to describe and characterize the lesions of the lung induced by the SARS-CoV-2 infection. The secondary objectives are to correlate the pathological findings with the patients' demographics, the treatments administered during the ICU stay, the ventilator settings, to document the percentage of co-infections and their types, compare the radiographic findings (Chest X-ray and CT-scan of the chest) with the pathological findings, to compare the pathological findings of early deaths (<1week after ICU admission) versus late deaths (>1 week). These pathological findings will undoubtedly help to better understand the pathophysiology of SARS-CoV-2 pneumonia and pave the way to the development of new therapeutic strategies

• Study Type: Observational
• Enrollment (Actual): 170

Contacts and Locations

• Study Contact: Name: CANET Emmanuel; Phone Number: 02-40-08-31-61; Email: emmanuel.canet@chu-nantes.fr
• Study Contact Backup: Name: MORIN Jean; Email: jean.morin@chu-nantes.fr

Study Locations

• France
  • Amiens, France
    • CH Amiens
  • Angers, France
    • Angers University Hospital
  • Angoulême, France
    • CH Angoulême
  • Annecy, France
    • CH Annecy
  • Antony, France
    • Hôpital Privé d'Antony
  • Argenteuil, France
    • CH Argenteuil
  • Belfort, France
    • CH Belfort
  • Bordeaux, France
    • CHU Bordeaux
  • Bry-sur-Marne, France
    • Hopital Sainte Camille
  • Cahors, France
    • CH Cahors
  • Cergy-Pontoise, France
    • CH Cergy Pontoise
  • Cholet, France
    • Ch Cholet
  • Clermont-Ferrand, France
    • CHU Clermont-Ferrand
  • Compiègne, France
    • CH Compiègne-Noyon
  • La Roche-sur-Yon, France
    • CHD Vendée
  • Lyon, France
    • Hopital Lyon Sud
  • Marseillette, France
    • Marseille Hopital Nord APHM
  • Melun, France
    • CH Melun
  • Montélimar, France
    • CH Montélimar
  • Nantes, France, 44000
    • Nantes University Hospital
  • Nice, France
    • CHU Nice
  • Orléans, France
    • CHR Orléans
  • Paris, France
    • CH Ambroise Paré APHP
  • Paris, France
    • GHEF Marne La Vallée
  • Paris, France
    • Hopital Antoine Béclère APHP
  • Paris, France
    • Hôpital Cochin APHP
  • Paris, France
    • Hopital Georges Pompidou APHP
  • Paris, France
    • Hopital La Pitié Salpetrière APHP
  • Paris, France
    • Hopital Louis Mourier APHP
  • Paris, France
    • Hopital Necker APHP
  • Paris, France
    • Hopital Saint-Antoine APHP
  • Paris, France
    • Hôpital Saint-Louis APHP
  • Poissy, France
    • CH Poissy
  • Quincy-sous-Sénart, France
    • Hôpital Privé Claude Galien
  • Reims, France
    • CH Reims
  • Rennes, France
    • CHU Rennes
  • Saint-Brieuc, France
    • CH Saint-Brieuc
  • Saint-Étienne, France
    • CHU Saint-Etienne
  • Suresnes, France
    • Hopital Foch
  • Tours, France
    • CHRU Tours
  • Troyes, France
    • CH Troyes
  • Vannes, France
    • CH Vannes
  • Versailles, France
    • CH Versailles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients deceased in the ICU from a Covid-19 during the study period

Description

Inclusion Criteria:

• Adult patients (Age≥18 years-old)
• Hospitalized in Intensive Care Unit (ICU)
• Dead in the ICU from documented Covid-19 (clinical and radiological signs of pneumonia with a positive SARS-Cov-2 PCR from the upper or lower respiratory tract)
• Not registered in the national register of refusal of the French Biomedicine Agency
• According to French law, there was no requirement for signed consent, but the patient's next of kin were informed about the study before enrolment and were given a letter of information about the study.

Exclusion Criteria:

• Covid-19 not documented by a positive SARS-Cov-2 PCR
• Patient with a positive SARS-Cov-2 PCR but without any signs of pneumonia during the ICU stay (no clinical and no radiological signs of pneumonia)
• Patient registered in the "national register of refusal" of the French Biomedicine Agency
• Refusal expressed by the patient's next of kin to participate to the study

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Critically-ill adult patients who died in the Intensive Care Unit from a documented COVID-19

Other: 2 post-mortem transcutaneous lung biopsies (1 anterior ; 1 posterior) using anatomical landmarks; All specimens are fixed with 4% neutral formaldehyde and embedded in paraffin wax in the department of pathology of each participating centre. Afterwards, all samples are sent for analysis to the department of pathology of Nantes university hospital. All biopsies are independently analysed by a group of pathologists who are experts in lung tissue and blinded to clinical information. All biopsies will be analysed using a predetermined semi-quantitative histological scoring grid. The pathologists are asked to assess the degree of: edema, cell necrosis, hyaline membrane formation, proliferation of alveolar type 2 cells, fibrosis, capillary congestion, alveolar edema, neutrophilic infiltration, and microscopic thrombosis. Finally, the following patterns are recorded: exudative diffuse alveolar damage (DAD), proliferative DAD, fibrosis, intra-alveolar haemorrhage, lymphocytic pneumonia, organizing pneumonia, acute fibrinous organizing pneumonia (AFOP), thrombotic microangiopathy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of the pathological findings of a large cohort of patients who died from COVID-19 in the ICU	Detailed description and analysis of the primary lesions of the lungs in patients who died in the ICU from Covid-19.	Two post-mortem lung biopsies performed immediately after death.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison between early (<1 week after ICU admission) and late (≥1 week) deaths	Comparison of pathological findings according to the time between ICU admission and death.	Two post-mortem lung biopsies performed immediately after death.
Analysis of the influence of ARDS severity and length on pathological findings	Comparison of pathological findings according to the length of acute respiratory syndrome.	Two post-mortem lung biopsies performed immediately after death.
Analysis of the influence of ARDS severity and length on pathological findings	Comparison of pathological findings according to the duration of acute respiratory syndrome.	Two post-mortem lung biopsies performed immediately after death.
Analysis of the influence of pharmacological treatments (steroids) on pathological findings	Comparison of pathological findings between patients who received steroids and those who did not.	Two post-mortem lung biopsies performed immediately after death.
Analysis of the correlation between radiological findings and pathological findings	Comparison between radiological description of the CT of the lungs and the radiological findings.	Two post-mortem lung biopsies performed immediately after death.
Association between the primary cause of death and pathological findings	Analysis of the pathological findings according to the primary cause of death (hypoxia, shock, hypoxia and shock, cardiac arrest, other).	Two post-mortem lung biopsies performed immediately after death.
Analysis of the correlation between the ventilator settings and pathological findings	Analysis of the correlation between the ventilator settings (tidal volume, PEEP, driving pressure, plateau pressure, static compliance, volume or pressure mode) and pathological findings.	Two post-mortem lung biopsies performed immediately after death.
Co-infections	Description of the co-infection (bacterial or fungal infections) documented by pathological findings	Two post-mortem lung biopsies performed immediately after death.

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: National Research Agency, France

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2020
• Primary Completion (Actual): March 3, 2021
• Study Completion (Actual): March 3, 2021

Study Registration Dates

• First Submitted: December 15, 2020
• First Submitted That Met QC Criteria: December 17, 2020
• First Posted (Actual): December 19, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Pneumonia; Acute Respiratory Distress Syndrome; Histopathology; Intensive care units
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; COVID-19; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn
• Other Study ID Numbers: MR_HISTOCOVID

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No