A European clinical trial to evaluate four experimental treatments for COVID-19 starts today. Coordinated by Inserm as part of the Reacting consortium, this trial will include at least 800 French patients with severe forms of COVID-19.

A clinical trial, called Discovery and coordinated by Inserm as part of the Reacting consortium, starts today in France to test four experimental treatments against COVID-19. This is a European project, the French part of which is financed by the Ministries of Higher Education, Research and Innovation (MESRI) and Health and Solidarity (MSS). The European part is supported at least by COMBACTE, PREPARE and RECOVER. It is led by Florence Ader, infectiologist in the Infectious and Tropical Diseases Department of the Croix-Rousse Hospital of Lyon University Hospital and researcher at the CIRI International Research Centre in Infectiology (Inserm/CNRS / Claude Bernard University Lyon 1).

The objective is to evaluate the efficacy and safety of four experimental therapeutic strategies which, in light of latest scientific information, might be effective against COVID-19.

“We analysed data from the scientific literature on SARS and MERS coronaviruses and the first publications on SARS-COV2 from China in order to come up with a list of antiviral molecules to be tested: remdesivir, lopinavir and ritonavir in combination, the latter being administered with or without interferon beta and hydroxychloroquine. The list of these potential drugs is also based on the subset of experimental treatments classified as top priorities by the World Health Organization (WHO).

The great strength of this trial is its “adaptive” nature. This means that ineffective experimental treatments can very quickly be dropped and replaced by other molecules that emerge from research efforts. We will therefore be able to make changes in real time, in line with the most recent scientific data, in order to find the best treatment for our patients,” explains Florence Ader.

It is planned to include 3200 European patients from Belgium, France, Germany Luxembourg, the Netherlands, Spain, Sweden, and the United Kingdom. In France, at least 800 hospitalized COVID-19 patients will be recruited in conventional medicine departments or in intensive care. “Five French hospitals will initially participate (Paris – Hôpital Bichat-AP-HP, Lille, Nantes, Strasbourg, Lyon) and then we will open other centres to reach at least 20 participating establishments. Our strategy of opening centres will follow the epidemiological situation of the epidemic with a priority for opening new sites in hospitals under high pressure”. Recruitment  starts today.

“This trial is designed to be pragmatic and adaptive. Its aim is to analyze the efficacy and safety of treatment options for patients within a limited time frame. It is a resolutely proactive approach to develop tools against the disease,” she concludes.

This trial will also complement the data that will be collected as part of another international clinical trial that will soon begin under the auspices of the World Health Organization, called Solidarity.  

For more information:

The DISCOVERY trial includes five treatment modalities:

• standard of care
• standard of care plus remdesivir
• standard of care plus lopinavir and ritonavir,
• standard of care plus lopinavir, ritonavir and interferon beta
• standard of care plus hydroxy-chloroquine.

Allocation of patients to the various treatment modalities will be randomized, i.e. by random draw, but patients and physicians will know which treatment is used (this is called an open trial). The analysis of treatment efficacy and safety will be evaluated 15 days after inclusion of each patient.

Tampon use is thought to currently concern around 60 to 80% of women in France. Credits: Josefin on Unsplash

Each year, some twenty cases of Staphylococcal toxic shock syndrome linked to tampon use are reported in France. Characterized by various symptoms, such as high fever and skin rash, it can lead to multiple-organ failure and death in the most extreme cases. Although its incidence remains rare, research teams from the International Center for Research in Infectious Diseases (Inserm/CNRS/ENS de Lyon/Université Claude Bernard Lyon 1) and the National Reference Center for Staphylococci (Hospices civils de Lyon/ Université Claude Bernard Lyon 1) have identified several risk factors, notably showing that wearing tampons for more than six hours or overnight is linked to an increased risk of toxic shock syndrome. This study was published in eClinicalMedicine on March 10, 2020.

Staphylococcal toxic shock syndrome associated with tampon use generated a lot of attention in the 1980s. Affecting almost 10 in 100,000 young women in the USA each year back then, its incidence has since fallen considerably thanks to the use of tampons made from cellulose fibers or cotton. Nevertheless, several cases are still being reported each year, on both sides of the Atlantic and primarily in adolescents. For the researchers it was therefore essential to identify the risk factors that increase the likelihood of developing this syndrome, especially since tampon use is thought to currently concern 60 to 80% of women in France.

Toxic shock syndrome is linked to the presence of Staphylococcus aureus in the vaginal microbiota of certain women, a bacteria which can produce the toxin TSST-1. However, the presence of this bacteria does not in itself explain toxic shock. The woman also needs to be using intravaginal protection (tampon, menstrual cup…) and she needs to lack the antibodies that are capable of fighting TSST-1. The fact that certain women fulfil these three risk criteria but do not develop complications suggests that the issue is not tampon use, but rather misuse.

In a study published in eClinicalMedicine, researchers from Inserm, CNRS, ENS, Université Claude Bernard Lyon 1 and Hospices Civils de Lyon, within the teams of the International Center for Research in Infectious Diseases and National Reference Center for Staphylococci, sought to identify the characteristics of tampon use that are linked to an increased risk of toxic shock syndrome.

Duration of wear

The study took the form of a questionnaire, completed by 55 tampon users who had toxic shock syndrome between 2011 and 2017, and by 126 control women who had never had it. The median age of the participants was 17, which reflects the fact that it primarily affects young women. The questions concerned the length of time for which they wear tampons, their reading of the package leaflet enclosed with the tampons, and the education they had received on the subject.

The researchers have shown that the risk of toxic shock syndrome doubles when tampons are worn for longer than six hours, and triples when worn overnight (whereby the duration of use can be up to eight hours or longer). In addition, not reading the instructions supplied with the tampons, or not respecting them, is also linked to an increased risk of toxic shock.

“In the USA, the FDA recommends not exceeding eight hours of use, which is generally also stated on the tampon packs sold in France. Our study is the first to challenge this duration. In addition, we also wish to draw attention to the need to improve the education of adolescents. It is often their mothers who educate them on this, and although they are quite capable of explaining how to use tampons, they are not always properly informed about the risk of toxic shock and how to prevent it”, emphasizes study leader, Gérard Lina.

While menstrual toxic shock syndrome mainly affects adolescents, with a peak at around 15 years of age, the authors of the study call for inclusion of the subject in school sex education lessons and for greater involvement of the healthcare professionals of these young patients, in order to get the prevention messages across.

Cytomegalovirus (CMV) infection in a human being. In red and green, the natural killer (NK) cells try to make their way to the infected cell. Inserm/Jabrane-Ferrat, Nabila

In previous years, various studies have established a link between psychological stress and reduced immune defenses, but the mechanisms involved remained poorly elucidated. Sophie Ugolini, Inserm Research Director at the Center of Immunology Marseille-Luminy, and her colleagues at CNRS and Aix-Marseille Université have recently shown that such a link is to a large extent mediated by a type of receptor that binds to stress hormones: the β2-adrenergic receptor. Their findings have been published in Journal of Experimental Medicine.

For several years now, the scientific community has been interested in the effects of psychological stress on health. Studies have shown that when infection strikes, stress is linked to reduced immune defense system efficacy. With her team, Sophie Ugolini, Inserm Research Director at the Center of Immunology Marseille-Luminy (Inserm/CNRS/Aix-Marseille Université), has sought to explain the biological mechanisms behind this phenomenon. The researchers focused on receptors expressed on the surface of many of the body’s cells (including the immune cells) and which are specific to the stress hormones adrenaline and noradrenaline – the β2-adrenergic receptors.

To study their role, the team first reproduced a situation of chronic stress in mice by administering for seven days a molecule which, like the stress hormones, stimulates the β2-adrenergic receptors. They then exposed the animals to a virus from the herpes family, cytomegalovirus MCMV. The mortality rate of the “stressed” mice having received the molecule proved to be much higher than that of the untreated mice (90% versus 50%).

The researchers then evaluated the animals’ resistance to infection in the absence of these receptors. This involved taking mice that are genetically modified to be devoid of β2-adrenergic receptors and exposing them to cytomegalovirus. In these animals, the stress hormones could no longer bind to β2 receptors and as a consequence could no longer act. They presented much greater resistance to the viral infection (90% survival versus only 50% for the control mice). These initial findings therefore suggest that stimulation of the β2-adrenergic receptors by the stress hormones is responsible for the weakening of the immune system in situations of psychological stress.

Towards new therapeutic avenues

In order to better understand the mechanisms involved, the team also analyzed the immune response of the mice devoid of β2-adrenergic receptors. They observed an increased production of inflammatory cytokines – molecules produced by the immune cells which promote the elimination of viruses.

The researchers discovered that the β2-adrenergic receptors most particularly inhibit the response of certain immune cells, known as natural killer (NK) cells. Stimulated by the stress hormones, the β2-adrenergic receptors prevent the NK cells from producing a particular type of cytokine required in order to eliminate viruses.

“We have confirmed in an experimental setting that the stress hormones that bind to the β2-adrenergic receptors reduce immune response, which involves a decrease in the production of certain inflammatory cytokines required to eliminate viruses”, specifies Ugolini. According to the researcher, this study could open up new therapeutic avenues. “By targeting the β2-adrenergic receptor, it would in some disease settings be conceivable to deactivate the immune brakes triggered by states of stress”, she concludes.

Recent studies have shown that Mycobacterium ulcerans infection causes the aggregation of immune cells (B cells) around the infected areas. Using fluorescent staining, a mouse spleen section shows B cells (in blue) and two sub-populations of T cells (in green and red). Credits: CIML/INSERM/CNRS/Mailfert, Sébastien/Chasson, Lionel

Buruli ulcer is the world’s third most common tropical mycobacterial disease after tuberculosis and leprosy. Caused by Mycobacterium ulcerans, it leads to the destruction of skin tissue and the development of large ulcers which can affect entire limbs right down to the bone. Researchers from Inserm, Université de Nantes, Université d’Angers and CNRS at the Nantes-Angers Oncology and Immunology Research Center (CRCINA) studied the rare cases of spontaneous healing from this disease in order to better understand its mechanisms. In addition to publishing their findings in the journal Science Advances, the team has filed a patent, opening up avenues for the deployment of hitherto inexistent diagnostic tools.

Buruli ulcer is a disease caused by Mycobacterium ulcerans (M.ulcerans), whose mode of transmission to humans is still not known. This bacterium produces a toxin called mycolactone which destroys skin cells and prevents the immune system from mounting an effective response, leading to the propagation of disease-characteristic ulcers on the limbs. Incapacitating and stigmatizing, Buruli ulcer affects children and adolescents most particularly. This little-known this disease is especially prevalent in West and Central Africa and has a very poor diagnostic and therapeutic arsenal. The World Health Organization (WHO) has classified it as a neglected tropical disease. Antibiotic treatment is effective if the disease is diagnosed quickly, although this is not yet possible in the majority of cases.

As part of a study published in Science Advances[1], a team led by Inserm researcher Estelle Marion at Nantes-Angers Oncology and Immunology Research Center (Inserm/Université de Nantes/Université d’Angers/CNRS) used mice to investigate the phenomenon of spontaneous healing that is observed in around 5% of infected patients.

Until now, research into Buruli ulcer focused on whole-body immune response. However, recent skin tissue studies have revealed that Mycobacterium ulcerans infection causes the aggregation of immune cells (B cells) around the infected areas. With this in mind, the researchers decided to focus on local immune response, at the site infected by the bacterium.

B cells produce a family of antibodies known as immunoglobulins (Ig). The major subgroups are IgA – found mainly in the mucous membranes and epidermis, IgM – present on the surface of the lymphocytes and for which a high count is synonymous with an ongoing infection, and IgG – the most numerous, which circulate primarily in the blood and eliminate foreign bodies encountered there.

Towards a diagnostic avenue

The researchers worked with two types of mice – one with the ability to spontaneously heal from Mycobacterium ulcerans infection, the other without. They began by studying immune reaction during infection, including during the spontaneous healing process, by analyzing skin samples from the area close to the infected site.

In both types of mouse, the level of cutaneous immunoglobulins increases during infection, but not to the same extent. In those unable to heal, IgM predominate, whereas in those able to heal, IgG predominate.

The researchers showed that these IgG bind to the toxin mycolactone. They went on to discover that only the mice that heal produce a very particular sub-type of IgG, IgG2a – capable of neutralizing the action of mycolactone. Finally, the researchers discovered the presence of the latter in the tissues of patients infected with M. ulcerans.

 “This study suggests for the first time that the body could efficiently respond to Mycobacterium ulcerans infection thanks to the production of antibodies that are capable of recognizing and neutralizing the toxin secreted by the mycobacterium. Although therapeutic avenues are still a long way off, this research offers new diagnostic ones”, concludes Inserm researcher Estelle Marion, who led this study.

According to the priorities issued by WHO, the team is envisaging the development of a quick and simple diagnostic test strip, based on the detection of antibodies recognizing mycolactone, thereby indicating M. ulcerans infection.

[1] This research was funded by Fondation Raoul Follereau, the French National Research Agency, the Pays de la Loire region, Université d’Angers, and Inserm (ATIP – Avenir Program).

Section of lungs infected with influenza virus with a major inflammation which results in a marked infiltration of neutrophil polynuclear cells, dark cells. © Inserm/Si-Tahar, Mustapha

Researchers from the CNRS, INSERM, the Institut Pasteur de Lille, INRAE (France) and from Brazilian (Belo Horizonte), Scottish (Glasgow) and Danish (Copenhagen) laboratories have shown for the first time in mice that perturbation of the gut microbiota caused by the influenza virus favours secondary bacterial superinfection. Published in Cell Reports on March 3, 2020, these results open up new prospects for the prevention and treatment of bacterial pneumonia, a major cause of death in elderly or vulnerable people infected with the influenza virus.

Influenza and its complications continue to be a significant public health concern as well as a major social and economic burden. Vaccination campaigns, together with the discovery of new antiviral therapies, provide preventive and therapeutic solutions. However, impairment of defence mechanisms against secondary bacterial infections, which considerably worsen the clinical picture of people with influenza, remains a major problem.

Specializing in the field of pulmonary immunity, a team led by François Trottein, a CNRS researcher at the Lille Centre for Infection and Immunity (CNRS/INSERM/Institut Pasteur de Lille/University of Lille/CHU Lille), focused on the gut microbiota, well known for their key role in many physiological processes, including immune defence mechanisms. Scientists have shown that, in mice, influenza temporarily alters the composition and metabolic activity of the gut microbiota, probably due to reduced food consumption during illness. During influenza, the production of short-chain fatty acids by the bacteria of the microbiota is also diminished. The team has now shown that these fatty acids remotely favour the bactericidal activity of macrophages present in the lungs.  Perturbation of the intestinal microbiota by influenza thus compromises lung defences, particularly against Streptococcus pneumoniae, the leading cause of bacterial pneumonia in humans.

The researchers also showed that this sensitivity to bacterial superinfection can be corrected by treatment with acetate, one of the main short-chain fatty acids produced by the microbiota. Their work could have practical applications for the well-being of infected patients, who would be better protected against influenza-related complications.  This work was made in collaboration with scientists from the Micalis Institute (INRAE/AgroParistech/Université Saclay), the Lille Inflammation Research International Center (INSERM/Université de Lille/CHU Lille), the Laboratory of Design and Application of Bioactive Molecules (CNRS/University of Strasbourg), the Molecular Virology and Immunology Unit (INRAE) and GenoScreen (Lille), the Universidade Federal de Minas Gerais (Belo Horizonte, Brazil), the Institute of Molecular, Cell and Systems Biology (Glasgow, Scotland) and the Department of Pharmacology (University of Copenhagen, Denmark). This discovery represents a major breakthrough in the understanding of the mechanisms behind bacterial superinfections in influenza patients. It could lead to the development of new nutritional and/or therapeutic strategies to better control bacterial infections.