This transmission electron microscope image shows SARS-CoV-2, isolated from a patient in the U.S., emerging from the surface of cells cultivated in a laboratory. © National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH. Public domain.

Several months after infection with SARS-CoV-2, some patients still have symptoms: a phenomenon commonly referred to as “long COVID”. In new research, teams from Inserm and Université Paris Cité[1], in collaboration with the University of Minho in Braga (Portugal), have shown that this could be explained biologically by abnormalities of the immune system associated with the persistence of the virus in the mucous membranes. These findings, published in Nature Communication, could in the longer term pave the way for a diagnostic tool for long COVID.

Despite the fact that various studies consider long COVID to affect between 10 and 30% of people infected with SARS-CoV-2, its diagnosis and treatment remain difficult. The team of Inserm researcher Jérôme Estaquier, in collaboration with that of Ricardo Silvestre at University of Minho in Portugal, is conducting research to explain this phenomenon from the biological point of view.

At the present time, few biological criteria, apart from the persistence of symptoms beyond three months after the acute infection, enable its diagnosis. Once a patient is not fully recovered after this period, they are considered to have long COVID. Without a more reliable means of diagnosis, it is difficult to offer the appropriate care.

In order to better understand long COVID and find diagnostic markers, the researchers studied the immune systems of 164 people six months after they were infected.  They analysed the blood samples of 127 people, half of whom with long COVID (fatigue, shortness of breath, cough, muscle or chest pain, anxiety, etc.) and those of 37 controls who had not been infected.

The researchers focused on certain immune cells, namely the T cells (including CD8 cells) involved in eliminating the virus, and the SARS-CoV-2 antibodies. In addition, they had blood samples that were taken during the acute phase of the disease for 72 of these patients, enabling them to retrospectively compare the level of inflammation at the early stage in those who went on to develop long COVID or not.

Several immune markers identified

The researchers identified a number of blood markers present six months after infection in 70-80% of the subjects with long COVID, while those same markers were rare in the subjects who had not developed it.

In particular, the teams showed that a CD8 cell subtype expressing the inflammatory protein granzyme A is present in excess, whereas another CD8 subtype, this time expressing integrin b7, is present in small quantities. Yet it is the latter subpopulation that is essential for controlling viruses in the mucous membranes. In addition, virus-specific IgA antibodies are also present in excess whereas they should be rapidly eliminated if the virus is absent. These observations suggest the persistence of the virus in the body and especially in the mucous membranes.

The researchers hypothesise that SARS-CoV-2 could make itself at home in the intestinal mucosa as it is more “permissive” in immune terms than the rest of the body, insofar as the virus has to tolerate the bacterial flora. Other viruses, such as HIV, also use this escape strategy. Initially present in the lung mucosa, SARS-Cov-2 could therefore descend to the intestine and persist there without the immune system being able to eliminate it completely.

In the final stage of the study, when evaluating the initial level of inflammation during the acute phase, the scientists observed an association between an inflammatory response characterized particularly by very high levels of interferon IP-10 or interleukin IL-6 and the risk of going on to develop long COVID.

“This confirms clinical observations that the initial severity of COVID is associated with a higher risk of developing long COVID,” specify the researchers. “One hypothesis is that people with more exacerbated early immunodeficiency develop more severe initial forms of COVID-19 and fail to effectively eliminate the virus that passes into the intestinal mucosa, where it settles for a long time. The immune system kind of ends up tolerating it at the cost of persistent symptoms of varying intensity and nature,” explains Estaquier.

The objective is now to validate these findings in new cohorts to determine whether some of these markers could be used as a diagnostic tool.

“If measuring IgA some time after the acute phase and potentially CD8 b7 cells was able to diagnose long COVID, doctors could make an objective diagnosis. Then we could think about therapeutic targets based on this research,” concludes Estaquier.

[1]This research in France was supported by the Fondation pour la Recherche Médicale, the French National Research Agency (ANR), and ANRS | Emerging Infectious Diseases.

During the first wave of COVID-19, participants from the Constances cohort completed two questionnaires to determine the presence of symptoms during the previous 15 days. Credits: Adobe Stock

Several months after infection with SARS-CoV-2, some patients are still having symptoms – a phenomenon known as “long COVID” or “post-COVID-19 condition”. Still poorly understood, scientists are now attentively studying long COVID in order to improve knowledge and offer patients the best possible treatment. Researchers from Inserm, Université Paris-Saclay and Sorbonne Université at the Pierre-Louis Institute of Epidemiology and Public Health, in collaboration with ANRS | Emerging Infectious Diseases, have used data from around 26,000 Constances cohort volunteers to identify the persistent symptoms most commonly reported by SARS-CoV-2 patients compared with the rest of the population. These are mainly loss of taste or smell, difficulty breathing and fatigue and are particularly seen in patients who experienced typical COVID symptoms at the time of infection. Their findings have been published in The Lancet Regional Health – Europe.

Many people report symptoms that persist for several months after infection with SARS-CoV-2. Still poorly understood, “long COVID” is currently the subject of rigorous research in order to better define its prevalence in the general population and decipher its underlying pathophysiological mechanisms.

The persistent symptoms most commonly described in the scientific literature include dyspnea (difficulty breathing), asthenia (fatigue), joint and muscle pain, cognitive complaints, digestive complaints, and anosmia/dysgeusia (loss of smell and taste).

Apart from anosmia/dysgeusia, these clinical manifestations are not specific to COVID-19 and may, for example, be related to other infections occurring during the same period or to more restricted access to health care during the pandemic.

In order to better understand and treat long COVID, it is therefore essential for scientists to determine which persistent symptoms are more specifically associated with SARS-CoV-2 infection than with other conditions.

A general population study

A new study published in The Lancet Regional Health has examined this issue. One of the aspects that makes this research original is that it was carried out in a general population cohort.

General population cohorts differ from cohorts constructed from samples of COVID patients (who, by definition, are all “symptomatic”, often with severe clinical forms or hospitalized), which are not representative of everyone with the infection.

General population cohorts therefore make it possible to understand public health problems through the creation of comparison groups, for example focusing on the severity of symptoms at the time of infection.

Another novel aspect is that the participants all underwent a serological test to screen for a history of SARS-CoV-2 infection. This differentiates this study from the majority of its counterparts, which focus on those having performed a PCR test and who have presented symptoms.

For example, this study compared the persistence of symptoms seven to eight months after the first wave of the pandemic in four groups of participants[1] distributed according to the symptoms they had during that first wave and their serological status (whether or not they had been infected with SARS-CoV-2). 

Long-term symptoms according to serological status

A total of 25,910 participants from the Constances cohort (see box) completed two questionnaires during the first wave of COVID-19 to determine the presence of symptoms during the fifteen days prior. They then underwent a serological test, between May and November 2020, to identify those who had been exposed to the virus.

Finally, between December 2020 and February 2021, they completed a third questionnaire, which looked at symptoms having persisted or persisting for at least two months. This questionnaire included the list of symptoms focused on during the first waves of questionnaires, as well as new symptoms presented by people with long COVID (problems with concentration and attention, chest pains, etc.).

The researchers compared the individuals having presented symptoms suggestive of acute respiratory infection based on the results of their serological test. They observed that symptomatic individuals seropositive for SARS-CoV-2 had more persistent anosmia/dysgeusia, dyspnea and fatigue than those who were seronegative. The frequency of the other symptoms was equivalent.

Links between symptoms at the time of infection and persistent symptoms

The researchers then explored the link between infection, acute symptoms, and persistent symptoms. The results of their statistical analyses show that SARS-CoV-2 mainly affects the persistence of symptoms if it induces certain symptoms during the acute phase of the infection.

“Our findings confirm the importance of the clinical expression of the initial infectious episode in the risk of developing persistent symptoms. They can help guide public policies by providing more accurate data on the type of persistent COVID-19 symptoms and encourage the development of strategies for more effective treatment. Promoting preventive therapies and approaches, such as vaccination, that reduce symptoms in the acute phase of the disease could also have a beneficial effect on long COVID,” the study authors noted.

These findings reflect the complexity of the mechanisms that can explain the persistent symptoms, emphasizing that these symptoms may be related to the virus, to the initial clinical presentation of the infection, and to other non-specific causes.

They also suggest the importance of conducting studies on post-infectious conditions, regardless of the micro-organism in question.

Further research is under way to understand the mechanisms behind long COVID and to quantify the extent to which these persistent symptoms can be attributed to SARS-CoV-2 infection

[1] The members of the first group of participants all had a positive COVID-19 serological test and had reported symptoms during the first wave. Those of the second group had a positive test but no symptoms. Those of the third group had a negative test and symptoms, while those of the fourth group were asymptomatic during the first wave and with a negative test.

Scientists are considering new strategies to continue to promote vaccination among the populations that remain hesitant © Mat Napo on Unsplash

Although the majority of its population is fully vaccinated, the virus continues to actively circulate in France. As health restrictions are being lifted, fears of a resurgence of the epidemic and of the emergence of new more contagious variants are leading scientists to consider new strategies to continue to promote vaccination among populations that remain hesitant. A new modeling study by researchers from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health shows that a “reactive” vaccination strategy targeting homes, schools and workplaces where cases are detected could have beneficial effects, reducing the number of COVID-19 cases in certain epidemic situations. The findings of this research have been published in Nature Communications.

Mass COVID-19 vaccination campaigns in many countries have greatly reduced the pandemic. However, the vaccination rate is now stalling in Europe and the USA due to logistical constraints and the vaccine hesitancy of part of the population.

In March 2022, 79% of French people were fully vaccinated with a two-dose regimen and 53% had received the third (booster) dose. While these figures are high, efforts to counter the epidemic must be maintained: against a background of ever-intense viral circulation and the lifting of health restrictions, a resurgence of the epidemic remains possible – and with it the appearance of more contagious variants.

In such a context, and to improve efficacy, many scientists therefore believe that other vaccine strategies promoting accessibility and acceptability should be tested.

Researchers from Inserm and Sorbonne Université were therefore interested in a “reactive” vaccination strategy, which involves vaccinating homes, schools and workplaces where cases have been detected. This approach is already used in other epidemics, for example against outbreaks of meningitis. In COVID-19, it has occasionally been used on the ground in France, for example in Strasbourg at the Haute Ecole des Arts du Rhine (HEAR), following the discovery of a cluster of the delta variant.

The research team wished to evaluate the effects of this reactive approach on viral circulation and the number of cases of COVID-19 in different epidemic scenarios. In order to build their model, the scientists used National Institute of Statistics and Economic Studies (INSEE) data to model a typical population with the sociodemographic characteristics, social contacts, and professional situations of a population the size of an average French city.

Several parameters were also incorporated into the model, such as disease characteristics, vaccination coverage, vaccine efficacy, restrictions on contact in workplaces or in the community, travel, and the implementation of contact tracing strategies.

The scientists were then able to study the impact of a reactive vaccination strategy on several scenarios of epidemic dynamics. They show that in the majority of the scenarios, with the same number of vaccine doses, a reactive strategy is more effective than other vaccination strategies in reducing the number of COVID-19 cases.

For example, in a context where vaccination coverage is approximately 45% and viral circulation is high, the reduction in the number of cases over a two-month period increases from 10 to 16% when comparing a mass vaccination program with a program in which reactive vaccination is set up in parallel to mass vaccination.

The findings suggest that this strategy is especially effective when vaccination coverage is low and when combined with robust contact tracing measures.

When vaccination coverage is high, a reactive strategy is less useful, as most of those in contact with an infected person are already vaccinated. Nevertheless, such an approach would still have the benefit of reaching people who are not vaccinated and convincing them more easily of the utility of the vaccine. Indeed, exposure to the virus increases one’s perception of the risks and tends to make vaccination more acceptable.

“The model we built enables reactive vaccination to be considered as an effective strategy for increasing vaccination coverage and reducing the number of cases in some epidemic scenarios, especially when combined with other measures such as effective contact tracing. This is a tool that can also be reused and adapted in France should another variant emerge and where the efficacy of a reactive strategy needs to be tested in order to administer any boosters. This modeling may also be of interest to other countries with sociodemographic characteristics similar to France, but lower vaccination coverage,” explains Chiara Poletto, Inserm researcher and last author of the study.