The teams of the cardiac and thoracic surgery departments (Prof. Pascal Leprince, Dr Guillaume Lebreton), and intensive medicine-intensive care (Prof. Alain Combes) of the Pitié-Salpêtrière hospital AP-HP, Sorbonne University and the Inserm, reported the results of the ECMO in the care of patients with extremely serious respiratory damage caused by Covid-19, and the regional organization set up by the Ile-de- France to deal with the pandemic. This work is the subject of a publication on April 19, 2021, in the Lancet Respiratory .

In extremely serious respiratory disorders (ARDS) escaping conventional resuscitation techniques, ECMO (extracorporeal membrane oxygenation) can be used to ensure oxygenation of the blood while awaiting healing of the lungs.

At the start of the Covid-19 pandemic, it was not certain that ECMO could be used for the care of patients with extremely serious respiratory damage caused by Covid-19. Very quickly, in Ile-de-France, a group of experts met to reflect on the place that ECMO could have in this indication, but also on the organization to be put in place to be able to cope with this indication. crisis. Regional regulation has been put in place by ARS Ile-de-France, in conjunction with all stakeholders, to centralize indications and pool resources. A regional doctrine has been developed and published in this direction.

In this multicenter cohort study, the authors present an analysis of all adult patients with laboratory-confirmed Covid-19 infection and severe ARDS requiring ECMO, who were admitted to 17 care units intensive in Ile-de-France between March 8 and June 3, 2020.

During the first wave, six ECMO mobile teams were formed and 17 resuscitations with ECMO experience were identified. 302 patients were thus able to be assisted by ECMO throughout the region, whether or not they were taken care of in intensive care units equipped with ECMO thanks to the mobile teams (mobile circulatory assistance units). These UMACs ensured the establishment of the ECMO then the transfer (55% of patients) of the patient to a specialized intensive care unit.

The analysis of the results at 90 days shows a survival of 46% for these most serious patients with a predictable survival without ECMO almost zero. The age of the patients, the duration of mechanical ventilation before ECMO, renal impairment and the volume of ECMO of the centers appeared to be prognostic factors. The results of cannulation of the patient by a mobile team and then transfer to ECMO in a specialized intensive care unit were not significantly different from those of patients cannulated in a center with ECMO, which validates the concept of a mobile unit. circulatory assistance (UMAC).

Regional regulation, pooling of resources and centralization of indications made it possible to effectively cope with the first wave of Covid-19 by assisting patients requiring ECMO in the Ile-de-France region, regardless of their hospital of origin. After this experience, this organizational model was extended for the following waves.

SARS-CoV-2 coronavirus attached to human respiratory epithelial cell cilia.  © Manuel Rosa- Calatrava, Inserm; Olivier Terrier, CNRS; Andrés Pizzorno, Signia Therapeutics; Elisabeth Errazuriz-Cerda UCBL1 CIQLE. VirPath (International Research Center for Infectious Diseases U1111 Inserm – JRU 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.

How long can COVID-19 symptoms persist after hospitalization for SARS-CoV-2 infection? Scientists continue to have many questions about this emerging virus and the long-term impacts of the disease it causes. The teams studying the problem of so-called “long COVID” include the investigators of the French COVID cohort, sponsored by Inserm. In a new study published in the journal CMI, these researchers from Inserm, the Paris hospitals group AP-HP and Université de Paris show that a significant proportion of patients who were hospitalized and followed up as part of French COVID continue to have symptoms three and six months after infection.

Is it possible to have COVID-19 symptoms several months after being infected with SARS-CoV-2? The question of “long COVID” continues to interest the scientific and medical community and is at the center of a number of research projects, notably those conducted by the French COVID investigators.

Launched at the end of January 2020, French COVID is a French cohort study sponsored by Inserm. It is based on the follow-up of a large group of patients having developed a clinical form of the disease that required hospitalization, either in a medical department or in intensive care. As at March 17, 2021, a total of 4,310 patients had been enrolled in this cohort, the largest French cohort to date of patients hospitalized with SARS-CoV-2 infection.

For each participant, clinical, virological, immunological, genetic, serological and transcriptomic data are collected in order to better characterize the disease. The objective is to build up knowledge on COVID-19, especially its most severe forms, in order to improve management in cases where hospitalization is required. The aim is also to better understand the short and long-term outcomes of patients by looking at the potential persistence of symptoms in the months following diagnosis.

Impact of long COVID

In their new study, the team describes the frequency and nature of symptoms persisting in 1,137 patients from the French COVID cohort, assessed at follow-up visits three and six months after they were hospitalized for COVID-19.

This research suggests that 60% of patients are still affected by at least one symptom six months after infection and one quarter by three or more symptoms.

A correlation between the initial severity of the disease and the persistence of symptoms over the long term also appears to be emerging. Indeed, the persistence of three or more symptoms six months after infection is more common in those whose COVID-19 disease required a stay in ICU compared with those hospitalized in a medical department, and in the most symptomatic patients on the day of hospital admission. The researchers also observe differences according to sex: while men are at greater risk of severe forms, women appear to be at greater risk of persistent symptoms over time.

Finally, the study underlines that these forms of “long COVID” sometimes also have wider economic and social consequences. For example, among patients reporting symptoms at six months who were working when they became infected, one-third did not return to work.

In order to better understand the consequences of the virus on the body and the long-term impact of the disease, and above all to provide better patient care, continuing this follow-up beyond six months on an even larger population could be of great interest.

“The mechanisms that cause symptoms to persist after the body has rid itself of the virus remain unclear. We will continue to follow up the patients included in French COVID up to 18 months after infection, by also proposing tests to evaluate the neurocognitive functions,” emphasizes the cohort’s coordinator, Jade Ghosn, who is an associate professor-hospital practitioner at Université de Paris and a professor in the Department of Infectious and Tropical Diseases at Bichat Claude-Bernard Hospital AP-HP.

Scanning electron microscopy image showing changes in the olfactory epithelium following SARS-CoV-2 infection. The ciliated cells towards the edges of the photograph are normal. In the center, loss of cilia 2 days post-infection is discernible. Viral particles are budding off the surface of infected cells that have lost their cilia. © Perception and Memory Unit – Institut Pasteur

Loss of smell, or anosmia, is one of the earliest and most commonly reported symptoms of COVID-19. But the mechanisms involved had yet to be clarified. Scientists from the Institut Pasteur, the CNRS, Inserm, Université de Paris and the Paris Public Hospital Network (AP-HP) determined the mechanisms involved in the loss of smell in patients infected with SARS-CoV-2 at different stages of the disease. They discovered that SARS-CoV-2 infects sensory neurons and causes persistent epithelial and olfactory nervous system inflammation. Furthermore, in some patients with persistent clinical signs, anosmia is associated with prolonged epithelial and olfactory nervous system inflammation and lasting presence of the virus in the olfactory epithelium. These findings were published in the journal Science Translational Medicine on May 3, 2021.

Although COVID-19 caused by the SARS-CoV-2 virus is principally a respiratory disease, many patients present with non-respiratory symptoms. These include a sudden loss of smell in individuals infected with SARS-CoV-2, which has been reported throughout the world since the beginning of the pandemic. Until recently, there has been uncertainty as to whether the virus plays a direct role in anosmia. According to one hypothesis generally accepted until now, it was assumed that a transient edema of the olfactory clefts inhibited airflow transporting odor molecules to the olfactory neurons (the familiar sensation of a blocked nose experienced during a common cold).

In a recent study, scientists from the Institut Pasteur, the CNRS, Inserm, Université de Paris, and the Paris Public Hospital Network (AP-HP) shed light on the mechanisms involved in COVID-19-related anosmia. The study was conducted with COVID-19 patients and supplemented with tests on an animal model. This study unexpectedly demonstrates that nasopharyngeal swabs may test negative by standard RT-qPCR even if the virus is still present at the back of the nasal cavities, in the olfactory epithelium. In light of this discovery, SARS-CoV-2 diagnosis by nasal brushing may be envisaged in addition to nasopharyngeal swabbing for the PCR test in patients experiencing loss of smell.

This work also sheds light on the mechanism of COVID-19-related smell loss by revealing a series of chronological steps:

1) Cilia carried by sensory neurons are lost post-viral infection. These cilia enable the sensory neurons to receive odor molecules;
2) Virus present in sensory neurons;
3) Disruption of the olfactory epithelium (sensory organ) integrity linked to apoptosis (i.e. cell death). The epithelium is organized into regular lamellae, which are destructured by coronavirus infection;
4) Virus dissemination to the olfactory bulb, which is the first cerebral relay station in the olfactory system;
5) Inflammation and viral RNA present in several regions of the brain.

Diagram representing the various steps occurring in the sensory system and contributing to COVID-19-related anosmia.

This study demonstrates that loss of smell is also caused by deterioration of the sensory organ at the back of the nasal cavities. “We observed that SARS-CoV-2 infects not only the sensory neurons, but also the olfactory nerve and the olfactory nerve centers in the brain,” comments Pierre-Marie Lledo, CNRS scientist, head of the Perception and Memory Unit (Institut Pasteur/CNRS), and co-author of the study.

“Another key finding from this study emerged from an observation of animal models, which revealed that once the virus enters the olfactory bulb, it spreads to other nerve structures, where it induces a major inflammatory response,” explains Hervé Bourhy, head of the Lyssavirus Epidemiology and Neuropathology Unit at the Institut Pasteur and co-author of the study. Infection of the olfactory neurons may therefore provide a gateway to the brain and explain why some patients develop various psychological clinical signs (anxiety disorders, depression) or those of a neurological nature (cognitive decline, susceptibility to developing a neurodegenerative disease), for which further studies are necessary.

Marc Lecuit, head of the Biology of Infection Unit (Institut Pasteur, Inserm, Université de Paris, AP-HP) and co-author of the study concludes: “According to our results, loss of smell in COVID-19 may persists for several months in some patients and this persistence of clinical signs may be attributed to the persistence of the virus and inflammation in the olfactory mucosa.” These observations should be used to adapt the diagnosis and management of long-term COVID-19 signs.

In summary, this study has led to the following 4 key findings:

• The virus can be detected by nasal brushing in instances where it is not detected by swabs;
• SARS-CoV-2 may persist in the olfactory epithelium for several months;
• SARS-CoV-2 infects sensory neurons and prompts immune cell recruitment in the sensory organ;
• SARS-CoV-2 may cause persistent inflammation of the olfactory epithelium and the olfactory nervous system.