Health Coronavirus: what science still ignores at the time of...

Coronavirus: what science still ignores at the time of deconfinement, By Hervé Morin, Sandrine Cabut, David Larousserie, Pascale Santi, Paul Benkimoun, Nathaniel Herzberg and Chloé Hecketsweiler Le Monde

The period of deconfinement begins in France, while a certain number of uncertainties remain on the behavior of the new coronavirus and our capacity to stop the epidemic outside a very constrained framework of reduction of the interindividual contacts, factors of contamination . For four months, the scientific machine has been running at full speed to understand the specifics of this pandemic, but it is far from having unraveled all its secrets. At a time when we are about to lower our guard against SARS-CoV-2, a review of outstanding scientific questions.

Who were the containment contaminates?

According to figures from the Directorate General for Health, 8,674 new positive tests for SARS-CoV-2 were officially registered between 1er and on May 9, in France. Despite the barrier gestures, despite the social distancing, despite the confinement, there would still be, in reality, 3,000 to 4,000 new infections each day, according to epidemiologist Daniel Lévy-Bruhl, head of the respiratory infections unit of Public Health France (SPF). “It’s significantly less than a month ago, but it’s still a lot, recalls Anne-Claude Crémieux, professor of infectious diseases at Saint-Louis hospital in Paris. So we will deconfinate with chains of contamination still active and very rough knowledge of what’s going on. We do not have an inventory of all nursing homes, or in all hospitals, and we do not know the conditions of infection of new infected, while this period should have allowed us to properly analyze all these points. There has been no real public health strategy to achieve deconfinement. “

The finding is severe. It is true that the infectious disease specialist has been alerting for a month already, through press releases from the Academy of Medicine, of which she is a member, or through press interviews. “When we saw that after three weeks of confinement the infection levels remained very high, we demanded a change in strategy. “ Like breaking family chains in particular by developing patient care in medical hotels. Various international studies have shown, it is true, the role of home contamination. As of February, the first Chinese studies carried out on the clusters of more than three cases concluded that 80% were familial. Another study, carried out in Hong Kong on 318 patient groups, found the same result. Far behind were transportation.

Other investigations have followed the chains of contamination. In Shenzhen, the rate of secondary attacks, in other words the proportion of people in contact with a first patient and who thus find themselves contaminated, is 11% in the family, according to a study published on April 27 in Tea Lancet Infectious Diseases. In Taiwan, it is lower, close to 5%. “But outside the family, it’s 1%”, insists Anne-Claude Crémieux, on the basis of an article published in the review JAMA Internal Medicine. The infectious disease professor further advances the observation made in Wuhan when, after multiple distancing measures, with patients kept at home, the R0 – that is to say the number of people infected by an infected individual – remained at 1.32. “They decided to isolate the patients in requisitioned hotels: the R0 fell to 0.32. “

Families, therefore. But also hospitals and accommodation facilities for dependent elderly people (Ehpad). Didier Guillemot, director of unit at the Institut Pasteur and professor of medicine at the Assistance Publique-Hôpitaux de Paris (AP-HP), has just launched a large study to try to determine the extent and origin of the contamination of hospital staff. “How did they get infected?” In contact with patients, their families, elsewhere in the city? “, he wonders. And who did they in turn infect? The issue is essential as the role of the hospital in the global epidemic dynamics seems ambiguous. “When we hospitalize the most contagious patients, do we lower this dynamic, because we are thus controlling potential vectors, or does the hospital play the role of an amplifier? “ Professor Guillemot intends to provide an answer. “But not before early July”, he warns.

It was also not until July that Professor Philippe Vanhems, of the Hospices Civils de Lyon, hoped to have the first results of a study of the same type on the Ehpad in the region, which should make it possible to characterize the grouping of cases, according to the situation of patients, caregivers, organization of resources, the external environment … A lightning pace for research, but which will only offer lessons two months after deconfinement.

“We have some empirical observations, explains Renaud Piarroux, head of the parasitology service at Pitié-Salpêtrière Hospital in Paris, and promoter of the Covisan network, these mobile teams recently set up in the Paris region, responsible for locating patients and tracing their contacts. We see a lot of families in large crowds. Residents of homes. Some contaminations at work, also: police, hospital or nursing home staff, odd jobs But it remains very impressionistic. The truth is that to my knowledge there has been no specific study. First, people were told to stay at home as long as they could so as not to clutter the system. So we withdrew all information. Now we’re going to see them, but we were asked not to overwhelm them with questions, just the minimum, enough to find their contacts, isolate them, break the chains of contamination. We never gave ourselves the means to know. “

What is the weight of the asymptomatic?

What do we know about the proportion of asymptomatics and their role in the spread of the epidemic? According to Daniel Lévy-Bruhl, they would represent between 20% and 50% (of the total contaminated), with a lot of uncertainty: “For France, we will have a more precise idea when the results of seroepidemiological surveys [permettant de mesurer la présence d’anticorps dans le sang] will be available. They will tell us how many people have been infected, which we will compare with the estimated number of cases. But this will remain an approximate calculation. “ The viral load of asymptomatic people is probably not much different from that of symptomatic people, he believes. “But transmissibility is probably linked to the clinical expression of the disease: if you cough, if you sneeze, you have a much higher transmission potential than someone who has no symptoms. “

“The proportion of asymptomatic carriers is still poorly known, evaluated around 20% or more, with all the caution that this figure requires”, advanced the Covid-19 Scientific Council in an opinion of April 20. In fact, studies carried out in different countries find very variable results. Between 1.2% and 57% of individuals tested positive are asymptomatic, and between 23% and 78% of people asymptomatic at the time of the test develop symptoms in the following days (we speak of presymptomatic people), according to a Quebec report of the National Institute of Excellence in Health and Social Services.Article reserved for our subscribers

“The percentage of asymptomatics depends on many factors: the circulation of the virus in the population studied and its profile, the test technique, but also what is retained as symptoms suggestive of Covid”, lists Professor Xavier Duval, of the clinical investigation center of Bichat Hospital (AP-HP, Paris). With his team, he is studying a prospective cohort of subjects who have had proven contact with a Covid + person, identified during a survey of contact tracing at the start of the epidemic (including the Contamines-Montjoie cluster in Haute-Savoie), or during the follow-up of infected caregivers. The study nearly completed the inclusion of the 300 participants planned. “Our first estimates, under our experimental conditions and on the basis of preliminary results, show that after close, unprotected, often unique contact with a Covid + individual, one in five people would become infected. And only 20% of them would remain completely asymptomatic as a result of this infection “, summarizes Professor Duval, specifying that any symptom, even banal (headaches …), is taken into account, and that this prospective collection allows great sensitivity.

This French research has also shown that some individuals excrete the virus before even showing any symptoms, if they declare it. The weight of asymptomatic or presymptomatic subjects in the transmission of SARS-CoV-2 is even important: they are responsible for almost half of the cases of contamination (44%), according to a Chinese study published on April 15 in the journal Nature Medicine, involving a hundred patients.

Are children poor transmitters?

Children appear to be as prone to SARS-CoV-2 infection as adults. However, in South Korea or Iceland, the under-10s would be less affected (6.7%) than the over-10s (14%). The analysis presented by the team of Professor Christian Drosten (La Charité Hospital, Berlin) indicates that very young patients infected with SARS-CoV-2 do not have a significantly different viral load than that of adults.

Globally, the number of children with Covid-19 represents between 1% and 5% of all cases. They have fewer severe forms and present mainly asymptomatic or mild forms. In France, between 1er March and April 24, those under 18 accounted for 0.16% of hospitalized cases and 0.04% of hospital deaths, according to SPF.

Little is known about the importance of children in the transmission of the virus. Transmission is dependent on symptoms and their severity, as shown by Lei Luo’s Chinese study (Center for Disease Control and Prevention, Guangzhou-Canton) on transmission to close contacts. Contrary to what was said at the beginning of the epidemic, by analogy with other viruses like the flu, children would transmit the disease less. “In several series, the majority (almost 90%) of infected children were infected through intra-family exposure to a suspected or confirmed case in an adult”, underlines SPF. A recent study from Australian health services found that in fifteen primary and secondary schools from New South Wales, 18 people (nine students and nine staff) tested positive for coronavirus. In their entourage of 735 students and 128 staff members, only two children seem to have contracted the virus.

On the adolescent side, however, transmission in the school environment seems to be stronger than in the family, as indicated by an antibody detection study against SARS-CoV-2, conducted by a team led by Arnaud Fontanet (Institut Pasteur) in Crépy-en-Valois (Oise), around a high school where two cases had been detected in early February, one of the first epidemic foci in France. It highlighted among high school students a frequency of the presence of antibodies (38%) approaching that of their teachers (43%) or administrative staff (59%) – sign of a significant circulation of the virus in the ‘establishment – but significantly higher than in their family environment (10% of parents and 11% of siblings). Other ongoing studies aim to better assess the risk. At this stage of knowledge, “It is currently very difficult to assess the circulation of the virus”, explained an SPF document in early May. Therefore, “The appreciation of the role of children during” deconfinement “is very uncertain”, noted the establishment.

As for why children and adolescents develop less serious forms, several hypotheses are raised. According to pediatrician Robert Cohen, “There are several examples of more serious infectious diseases in adults than in children, chickenpox, measles, mumps … where we see that the child better controls his immune response.” One of the gateways to the virus, the ACE2 cell receptor, which allows it to enter respiratory cells, is said to be virtually absent in children. The genetic track is also explored.

An unknown woman remains in cases of children and adolescents hospitalized in France and in other countries for rare inflammatory syndromes, with cardiac damage in some cases close to Kawasaki syndrome. Forty cases in France are under investigation for these attacks “Probably linked to a symptomatic infection or not with SARS-CoV-2”, specified SPF on May 4. New York State Governor Andrew Cuomo announced on Saturday May 9 the death of three “Young New Yorkers” of this inflammatory disease. Seventy-three cases have been reported in the United States.

Epidemic models evaluating the impact on the capacities of the resuscitation services of Ile-de-France of different scenarios of reopening of schools preceded the decision, announced Thursday May 7 by the Prime Minister, to hire from 11 may be a gradual exit from containment. The Inserm-Sorbonne University of Vittoria Colizza and Pierre-Yves Boëlle team thus predicted that a resumption for only nursery and primary school children on May 11 would only mobilize 72% of hospital capacity in two configurations: maintaining the closure of other establishments until the summer holidays or a reopening to 25% of middle and high schools, with a gradual increase in the following weeks. Conversely, a resumption of all students, from kindergarten to high school, on May 11, would have exposed to a second epidemic wave, similar to the first. An event which, according to the models, could be avoided by limiting the workforce for all classes to 50%.

Can we recognize the “super propagators”?

The installation of the epidemic made one forget that behind the averages there are strong individual variations. The R0 parameter, which indicates how many people can be infected with a virus carrier, is a key epidemiological element for understanding and monitoring the epidemic: above 1, the disease develops; below, it stops. But this parameter is an average and does not prevent people from being able to contaminate more, or on the contrary less than what this average R0 indicates.

Thus it is very likely that old chains of contamination have stopped by themselves, when we were not yet talking about an epidemic, since the R0 of the contaminated was less than 1. “It also means that the first case detected may not be the one responsible for the epidemic”, recalls Samuel Alizon, researcher at the National Center for Scientific Research (CNRS) in the laboratory of infectious diseases and vectors: ecology, genetics, evolution and control of Montpellier.

In Minneapolis in 1992, one person was responsible for 35% of the tuberculosis cases.

Conversely, it is known that epidemics are characterized by “super propagator” profiles whose number of contaminations far exceeds the average of R0 and which cause outbreaks. In a 2010 article fromInternational Journal of Infectious Diseases taking stock of knowledge on this phenomenon, the biologist Richard Stein (Princeton University) even recalls a kind of rule: a small percentage, for example 20%, causes the majority of infections, for example 80%. In Minneapolis in 1992, one person was responsible for 35% of the tuberculosis cases. These events can therefore have an effect on the evolution of the epidemic, making it more explosive. They are all the more unpredictable as specialists ignore whether they are linked to the virus (a particular virulence), to the host (its genetic profile, its immune state), to a co-infection with this new virus, to the environment (a gathering, ventilation systems). The threat of post-containment is potentially there. Hence the precaution to continue to limit gatherings.

Will summer kill the virus?

Examples of other respiratory infections show a seasonal pattern of these illnesses, with a decrease in summer due to temperature, but mainly humidity. In 2010, American epidemiologist Marc Lipsitch (Harvard) noted this favorable correlation for seasonal flu. “But that is often not true for new viruses. We remember that in 2009 summer had not stopped influenza A, but that it had continued to circulate quietly before re-emerging in late October, earlier than the seasonal flu “, recalls Pierre-Yves Boëlle, epidemiologist at Sorbonne University. Will SARS-CoV-2 behave the same way ? Initial hope was born that the “tropical” countries seemed to be little affected, but that did not last and the coronavirus spread to Brazil or other countries in the southern hemisphere.

On April 28, a team from Beijing University took stock in Science of the Total Environment by analyzing data from over 160 countries. Temperature and humidity do have an effect. One more degree reduces the number of daily cases from 1.5% to 4.6%. One percent more humidity lowers that number from 0.5% to 1.2%. But, warn the researchers, if “The epidemic could be partially suppressed by increases in temperature and humidity, (…) active measures must be taken to control the sources of infections and block transmissions in order to avoid future outbreaks “.

In one preprint posted on April 7 on Medrxiv.org, their Princeton colleagues even estimate, through simulations, that the number of cases could increase this summer in the absence of control measures. Finally, still in prepublication, a Brazilian team on April 27 reviewed 17 articles on the subject and concluded that there is weak evidence that the weather could stop the epidemic.

Are there solid therapeutic avenues?

No specific treatment has yet proven successful with Covid-19, the management being essentially that of symptoms and complications (oxygen therapy, ventilatory assistance, prevention of pulmonary embolism, etc.). The numerous clinical studies launched worldwide since the start of the epidemic have not yet shown the proven efficacy of the drugs tested. These are “repositioned” treatments – none have yet been developed specifically to combat SARS-CoV-2.

Many approaches are being studied: antivirals, modulators of immunity, antibodies present in the plasma of convalescents, traditional Chinese pharmacopoeia … Every day, several studies now appear in scientific journals or in prepublication, that is to say without having yet been examined and validated by experts. This scientific production must be approached with caution, since few clinical studies meet the highest standardsa treatment compared to others or to a placebo, administered to several groups of patients randomized, and without patients and doctors having knowledge of the drug delivered.Article reserved for our subscribers

May 8, The Lancet However, published a study approaching these criteria, showing an increased effectiveness of a treatment combining interferon beta-1b, lopinavir-ritonavir and ribavirin. “This is the first study showing an undisputable antiviral effect, notes pharmacologist Mathieu Molimard (University of Bordeaux). There seems to be a reduction in the length of hospital stay This needs to be confirmed by a phase 3 study. ”

The AP-HP had reported interesting results with tocilizumab in severe forms, but this premature announcement, outside of scientific publication, resulted in the resignation of the scientific council which supervised this ongoing clinical trial.

In the United States, the National Institute of Allergy and Infectious Diseases (or Niaid, for National Institute of Allergy and Infectious Diseases) also reported encouraging results (reduction in length of hospital stay) for remdesivir given early, but had to admit that mortality remained unchanged – as shown by a Chinese study published in The Lancet.

Finally, concerning the treatment recommended by Didier Raoult (Mediterranean Infections hospital-university institute), combining hydroxychloroquine and azithromycin, no quality study has yet confirmed its therapeutic value – pharmacovigilance alerts warning against potential undesirable effects , of cardiac order in particular.

What is the correct safety distance?

Six feet, that is to say 1.83 m; 1.50 m or 1 meter? The recommendations for physical distance between two people vary by country. US and UK authorities recommend six feet, Italy 2 meters. It is 1.50 m in countries like Germany, Belgium and the Netherlands. France is among those who have aligned themselves with the recommendations of the World Health Organization (WHO): at least 1 meter.

Whatever the threshold, the objective is to reduce the risk of contamination of the new coronavirus, which is mainly transmitted from person to person. According to the United States Center for Disease Control (CDC), this transmission occurs primarily through “Respiratory droplets produced when an infected person coughs, sneezes or talks”, “These can land in the mouth or nose of people nearby or be inhaled in the lungs”. For the record, contamination can also be done through the hands or stool. There are also indirect transmissions from infected surfaces and possibly aerosols, as several studies have suggested.

In an opinion validated on April 24, the High Public Health Committee (HCSP) considers that “The distance of at least 1 meter promoted in France for years corresponds to a minimum safety distance, closely dependent on biological, climatic and behavioral characteristics”. The HCSP notes that “This distance has been regularly questioned for other respiratory diseases in the past”.

“As a general rule and when the site allows, a free space of 4 m2 around a person is recommended “The High Committee for Public Health

In fact, the question is not simple: if the vast majority of droplets spreading the virus disperse within a radius of 1 or 2 meters, there is no certainty of not finding any viral particle beyond this distance, it’s just the probability that decreases. The work of a researcher from the Massachusetts Institute of Technology (Cambridge) has thus shown that, under certain conditions, droplets containing pathogens emitted during coughs or postilions can be propelled in a cloud up to about 8 meters (JAMA, March 26).

“As a general rule and when the site allows, a free space of 4 m2 around a person is recommended “, says the HCSP. It is also prudent to distance yourself during sports activities with sustained ventilation, because “Droplet emissions are particularly high and at risk of transmission”, explains the HCSP. When jogging or cycling, the minimum distance to be observed is 10 meters, warns the sports ministry.

How many people did containment save (and endanger)?

Containment would have prevented nearly 62,000 deaths in France, a reduction from 67% to 96%, according to models carried out by a team from the School of Advanced Studies in Public Health (EHESP), not yet published. . According to the same study, confinement would also have reduced hospitalizations in France by 87.8% (- 587,730 people), by 90.8% in intensive care admissions (- 140,320), avoiding saturation of the hospital system. But this analysis has been criticized by Eric Le Bourg (CNRS), Quentin de Larochelambert and Jean-François Toussaint (Irmes) who question several parameters, notably the confidence interval. These mathematical models are subject to discussion. There is no doubt, however, that confinement saved many people. But some fear the collateral effects of this measure to protect the population.

Since the start of confinement, consultations with medical specialists have dropped by 51%

Hospitals have in fact had to increase the capacity of resuscitation beds and deprogram surgical operations. Since the start of confinement, consultations with medical specialists have decreased by 51%, according to figures communicated on May 7 by the Ministry of Health and health authorities, and by 25% among general practitioners, from April 13 to 26. 2020, compared to the same period in 2019.

A decrease in the number of emergency visits and hospitalizations for cardio and neurovascular pathologies likely to represent life-threatening emergencies was also noted at the start of confinement, which raises fears of delays in treatment.

In cancer, a study by Alvina Lai and colleagues (University College London), published on ResearchGate in pre-publication form, showed that there would be an additional 6,270 deaths among cancer patients in one year from now. England and 33,890 additional deaths among cancer patients in the United States for the same period. Another study by a team from the Institute Cancer Research (London), published in preprint, points out that a delay of six months per patient would lead to the death of 10,555 people. “These estimates seem fairly close to reality, although it will be difficult to measure it precisely”, says Professor Jean-Yves Blay, President of the National Federation of Cancer Control Centers (CLCC, Unicancer).

“Delays in diagnosis lead to an excess mortality of 10% to 25% per month of delay, with differences according to the types of cancer and their location”, specifies the oncologist. Since the start of the epidemic, “First appointment consultations have dropped by 50% in our eighteen centers”, says Jean-Yves Blay, who says he is concerned, fearing advanced stages of the disease.

While the CLCCs that treat only cancers have generally not postponed their tumor surgeries, outside of specific regional contexts, other hospitals have had more difficulties and have had to postpone these interventions. The tense situation in healthcare establishments, the closure of several departments (radiology, scanner, etc.) and the hierarchy of care lead to “Diagnostic delays putting many lives at risk”, recently alerted the League against cancer in a statement.

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