A simple blood test predicts your chances of surviving Covid-19<

Variation in red blood cell size, a commonly sought indicator in standard blood tests, is strongly correlated with the risk of dying from the coronavirus, independent of other mortality factors. A mechanism still unexplained but which would allow patients at risk to be treated more quickly.

[IN VIDEO] Diagnosis of COVID19: an update on testsLately, there has been a lot of talk about diagnostic tests for COVID19. How do they work? What is their respective usefulness and reliability? Details.

Why some Covid-19 patients are hit harder than others remains unclear. We know, for example, that obese people, men or the elderly are more at risk of developing serious forms of the disease.

Researchers recently found that genetic abnormalities cause 15% of severe Covid-19 cases. Other biological markers such as interferons (see below) have been identified as an index to predict disease severity. Nevertheless, predicting in advance whether a particular patient is likely to develop complications or die remains highly hypothetical.

The variation in the size of red blood cells says a lot about the state of health. © Lucas Barioulet, AFP

The size of red blood cells, a convincing index

Researchers from Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) announce that they have found a simple and quick way to predict the risk of death from Covid-19 using a standard examination. “We wanted to find a way to identify as early and as easily as possible the Covid-19 patients who present the most risk, that is to say those likely to become seriously ill […] and whose The condition is likely to worsen rapidly,” says John Higgings, professor of biology at HMS and lead author of the study published in the journal JAMA Network Open.

Did you know ?

Red Blood Cell Volume Deviation Index (RBDI) or Coefficient of Variation of Red Blood Cell Volume (CVGR) indicates the percentage change in the size of red blood cells. The more the blood contains red blood cells of varying size (large and small), the higher the value of the IDVE (its normal value is between 11.5% and 14.5%). In general, a high IDVE suggests iron deficiency anemia, vitamin B12 deficiency or bone marrow damage (myelodysplastic syndrome).

2.8 more likely to die from Covid-19

The researchers analyzed blood samples from 1,641 patients admitted to Boston hospitals and infected with the SARS-CoV-2 coronavirus for relevant biomarkers. They then noticed an amazing correlation. "We were surprised to find that a standard test that quantifies variation in red blood cell size -- called the RBC Volume Deviation Index (RBDI) -- was strongly correlated with patient mortality, and that the correlation persisted. when we controlled for other identified risk factors such as the patient's age and certain pre-existing diseases,” confirms Jonathan Carlson, co-author of the study.

Patients with an IVDE greater than 14.5% on admission are thus 2.8 times more likely to die from Covid-19 than the others (31 against 11%). A particularly striking index in young patients, a priori less at risk. The study also shows that an increase in IVDE during hospitalization is a sign of worsening of the disease.

A change in blood composition

The mechanism of IDVE alteration remains obscure. Previous studies have shown that Covid-19 causes a change in the composition of the blood in some patients with, in particular, an overproduction of blood platelets leading to hypercoagulation. The study also does not specify if the elevated IDVE was pre-existing in the patients or if it is the virus that causes this increase.

The advantage of using this marker is that it is a commonly performed examination during standard blood tests, requiring no special equipment or extensive investigations. The IDVE could thus represent an effective tool for determining the patients most in need of clinical care.

A track to predict the serious forms of Covid-19?

Article by Julien Hernandez published on 07/21/2020

A recent report reveals a similar marker in severe forms of Covid-19: abnormal activity of certain proteins from the cytokine family, called interferons. However, it is still too early to speak of causality. Details in this article.

A recent report by teams from the National Institute of Science and Medical Research (Inserm), the University of Paris and the Institut Pasteur suggests that an abnormal activity of certain proteins, interferons (IFN) type I, could be a predictive marker to anticipate the evolution of Covid-19 to a severe form and treat accordingly. However, these results are preliminary and further investigation is needed.

In this study, the scientists noticed, in their cohort of fifty patients, that IFN1 levels were lower in cases that worsened markedly after the installation of mechanical ventilation. Before discussing this observation at greater length, knowing what it is worth, whether it is new, and what it implies, let us return briefly to IFNs.

A bit of immune history

It was two scientists, Alick Isaacs and Jean Lindenmann who discovered interferons in 1957. Pierre Marschall, doctor in immunology, tells us a little more about this discovery. “Sometime before this discovery, it had been reported that treating cells with a dead or live virus could prevent the same cells from being infected with another virus later. The phenomenon has been named viral interference. Isaacs and Lindenmann were working with a chicken membrane rich in blood vessels (the chorioallantoic membrane), the mammalian equivalent of the placenta. In the experiment of their discovery, they put this membrane in the presence of an inactivated influenza virus. They succeeded in detecting a hitherto unknown compound produced by the cells of the membrane. They recovered the liquid medium where these new compounds had diffused and added a new membrane and a live influenza virus, ready to infect cells. But now, in the presence of these new molecules, the virus could not effectively infect the cells and multiply there. Their conclusion was therefore that, thanks to the intact virus, the membrane of the initial experiment had produced a compound which interfered with the cycle of the virus. Hence the name: interferon! »

We have therefore known the NFIs for more than half a century. Nevertheless, have we pierced all their secrets? “Far from it,” says Pierre Marschall. He continues: “The study of IFNs continues today. They are still the subject of clinical trials for certain pathologies, but basic research is still working on them to better understand how they are regulated and the mechanisms on which they act”.

We are far from having pierced all the secrets of interferons. © Sebastian Kaulitziki, Fotolia

What is an interferon?

As we have just seen, an IFN is a compound which makes it possible to induce an interference. But by whom is it produced exactly? And does it only serve to interfere between our cells and viruses? “IFNs could be compared to molecular SMS. They can be sent by different cells in our body, including our immune cells. Their major role is to allow the cells to communicate with each other or with itself, to inform of a danger”, explains Pierre Marschall.

It must therefore be understood that IFN is not the compound which interferes but which allows the interferences. Indeed, it is he who will send an alert message. “When our cells detect a danger, such as a virus, they produce IFNs which warn their neighbors that something is wrong. A defense system is set up and gives rise to the interference mechanism described by Isaacs and Lindenmann in 1957. But that's not all. IFNs also play a complex role in regulating the immune system. They are essential for maintaining a careful balance between an effective response to eliminate the danger and a sufficiently moderate response not to cause too much damage to the body”, explains Pierre Marschall.

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How does this complex machinery work?

It all looks extremely simple. However, the functioning of our immunity is far from being. But, let's try a metaphor to see more clearly. Imagine that our body is a military base and that the people there are our cells. If it is attacked, it will be able to detect signals to identify who is its aggressor (a terrorist group, renegades, the army of another state, etc.). Well, our cells know how to do the same thing. “Our cells are equipped with detectors for microbes, called 'pattern detection receptors' (PRRs). The sense of pattern, here, is an element which makes it possible to determine that we are dealing with a microbe”, specifies Pierre Marschall.

Let's imagine that a manipulative assailant tries to attack our military base. He's going to put on a similar uniform so others will think he's on our side. And to increase his striking power, he will try to rally other soldiers to his cause to bring down the base. The strategy is formidable. But the military base is not fooled. It will detect abnormal actions on the part of the assailant. From then on, it will set up a defense system, in doubt, to prevent mutiny. In the case of our body, the assailant is the virus. “Within our cells, our DNA is strictly confined to the nucleus. There are therefore PRRs present outside the nucleus and which are activated if they detect DNA: it is possibly a virus which is trying to infect the cell by injecting DNA into it. Once the cell has detected, through various mechanisms, that it is being attacked by a virus, it will then begin to produce IFNs,” emphasizes Pierre Marschall.

But, within an army, even in a sub-unit, all the agents do not have the same role. The same is true for IFN alarms. “There are three families of IFN: type I, type II and type III. They are classified, as can be seen, according to the receptor (alpha and beta for type I, gamma for type II and lambda for type III) on which they will act on the surface of the cells. And yes, immunologists and Greek, it's a long love story...", confides Pierre Marschall.

When an attack occurs, the primary goal is to warn everyone. From then on, an agent from your sub-unit will be responsible for warning neighboring units, and so on until everyone is aware that an attack is in progress. The secretion of IFN by our cells is somewhat the same thing. This is called positive feedback, as Pierre Marschall explains to us: “Cells constantly have the material they need to quickly produce a first wave of IFN when a virus attacks. This first wave, which arrives in a few hours, will act on the producer cells themselves and further increase the production of IFN type I and II. This means that, during an infection, our cells are able to quickly produce this alarm signal. And they do it loud enough to alert everyone around them. So here are the cells warned: a microbe is coming...”.

The cells are warned: a microbe is coming... © imaginima, iStock.com

Our agents will then deploy primary defenses to prevent the mutiny from gaining momentum while waiting for reinforcements from the general base. Limit contact between officers who have been brainwashed by the assailant and officers who are still safe and reason with hesitant officers. As well as our cells: "the cells will therefore implement strategies that prevent the replication of the virus: limit the transcription of DNA into RNA, limit the translation of RNA into proteins and destroy the RNA present and try to limit the assembly of viruses already replicating in the cell”, develops Pierre Marschall.

And the warning signal sounded loud enough for the general base to be warned. This is where the cavalry lands with several objectives: identify, kill and, if necessary, facilitate the arrival of other units. "IFNs will at the same time activate our immune cells, including monocytes, which can turn into macrophages and "gobble" viruses before digesting them [kill the enemy, editor's note] but also generate an inflammatory micro-environment to attract more immune cells [to facilitate the arrival of reinforcements, note]. These monocytes can also differentiate into dendritic cells. They are the sentinels of immunity. They capture the pathogen, cut it up and show the pieces (the anti-gene) to other immune cells so that they can better recognize this microbe and fight it [identify, note]. This is the start of an adaptive immune response”, summarizes Pierre Marshall.

But, the alarm was also heard by the secret base of the secret agents, in the basement of our military base. By the time they get ready and go to the front, their arrival is therefore a little later. Their objectives are clear: to control the invader but also to kill the corrupt agents for whom nothing is more possible in order to prevent them from corrupting other agents in turn. And these secret agents also have a special communication channel to send weapons to their allies and thereby make them more resilient and able to fight. In a more scientific language it gives this: “The IFN2 receptor (which can also be dendritic cells) is mainly produced by an immune cell called “natural killer lymphocyte” (NK, according to the English abbreviation). NKs are part of the innate immune response and their specialty is to explode cells infected by viruses by forcing them to commit suicide or by sending a cytotoxic "bomb" in their face. They are activated and attracted by IFN1. They therefore arrive later in the course of the infection. In addition to their active and direct role in controlling viral infection, NKs increase cell resistance to viruses through IFN2 which can facilitate the arrival of new immune cells by dilating blood vessels, make the environment more difficult for viruses to live in by asking macrophages to produce toxic products that will destroy microbes. Finally, NK cells potentiate the antiviral adaptive immune response, in particular by acting on dendritic cells”, indicates Pierre Marshall.

Unfortunately, our system is not flawless. If the particular alarm triggered that maximizes the effectiveness of the response lasts too long, it can lead to a cessation of the response. This secondary effect is very useful so that the units do not take too much unnecessary damage to the military base. But it can also be fatal if the attackers have not been completely neutralized. “IFN1s can also inhibit immune cell function. In fact, they promote the anti-viral response initially, but their chronic production will lead to the inhibition of this same response. Immune cells will then be less attracted to the site of infection and those that are already there will be more likely to die because chronic stimulation by IFNs will increase the expression of death receptors, or even simply inhibit the immune response. by producing anti-inflammatory molecular messengers. This paradoxical effect of IFN1 can be beneficial: a rapid and intense response allows control of the infection, while guiding the response of the immune system so that it is as effective as possible. In the longer term, by blocking the immune response, they can limit the damage caused by inflammation to the surrounding tissue. The problem being that if the pathogen is not effectively "cleaned up" before this inhibition phase arrives, it risks rebounding and the infectious cycle starting to rise again”, concludes Pierre Marshall.

In mice, a rapid and significant production of interferon results in a moderate pathology while a slow and chronic production leads to a severe form of the disease. © Park, Annsea, and Akiko Iwasaki. "Type I and Type III Interferons–Induction, Signaling, Evasion, and Application to Combat COVID-19", Cell Host & Microbe (2020)

Interferons and coronaviruses

There have already been studies done (1, 2, 3, 4, 5) regarding IFNs and coronaviruses before the one that motivated the writing of this article. We know, for example, that for SARS-CoV-1 or MERS, in mice, a rapid and large increase in IFN1 is associated with a controlled viral load and less severe disease. Conversely, when this proves to be slow and becomes chronic, the viral load increases before the necessary interferon peak and the disease becomes severe. Injections of interferons in the animal model make it possible to protect the mouse against the severe development of the disease. These results are consistent with those obtained by the authors of the study, recently published in Science. Also, a body of evidence exists regarding children secreting less IFN and the severity of disease caused by syncytial virus.

However, it is still too early to speak of causality. The study has limitations clearly assumed by the authors themselves, such as the small number of patients and the poorly developed design of the study, the results of which were obtained through biological analyzes (for the level of IFN) and by a severity classification made at the time of admission. “This severity may have changed over time, and that is why the authors were able to observe this association between the level of IFN1 at the time of admission and the severity of the course of the disease. However, the biological analyzes were carried out only once. A longitudinal study would consist of monitoring the level of interferons in patients, this would make it possible to know the details of the kinetics of interferons in patients with good or bad evolution and to have a better understanding of the quality of IFNs in as prognostic markers", explains Pierre Marshall.

There have been many studies that have looked at the roles of interferons in coronavirus infections. © Antonio Rodríguez, Adobe Stock

One of the authors of the study, Professor Benjamin Terrier, confirms that "it is very important in science, in general, that the results obtained by a team can be confirmed by other groups, and other approaches experimental. Data on human cell lines and in animals have found completely comparable results on the defect in the production of IFN1 during Covid-19, and another French group practicing an assay of interferon alpha a also highlighted this defect in the production of interferon alpha in severe patients. At the same time, research teams, in particular at the Imagine Institute with whom we have collaborated, are working on the mechanisms that could explain this IFN defect, the main hypotheses being either a defect induced by SARS-CoV-2, or a particular genetic background of infected people”.

With regard to SARS-CoV-2, the results on dexamethasone from the British Recovery study also add to the body of evidence we were talking about. “The results of the RECOVERY trial confirm the importance in severe forms of reducing the inflammatory storm, in this trial by means of a corticosteroid, dexamethasone. Other molecules blocking this inflammatory storm have been evaluated with encouraging preliminary results. However, the effectiveness of these treatments is not perfect, hence the importance of better understanding the mechanisms explaining immune dysfunctions, in order to propose even more appropriate and effective strategies,” says Professor Terrier.

Also, studies are underway to confirm or invalidate the predictive capacity of the IFN1 assay in the context of Covid-19 and their usefulness in treating patients. According to Professor Terrier “studies will be carried out on samples from patients who were kept during the Covid-19 epidemic, with in particular IFN1 assays. He continues: as far as clinical trials are concerned, some have started or are about to start in the world or in France. A trial of aerosolized interferon alpha has been conducted in China and a trial starting in the United States will evaluate another type of IFN important in defense against viruses, namely lambda IFN. In France, the DISCOVERY trial studied lopinavir/ritonavir in combination with IFN beta, without a clear signal of efficacy. If a new wave of epidemic were to occur in France, we should, within the framework of the CORIMUNO trial platform, evaluate the combination of IFN alpha with an anti-inflammatory”.

For the moment, we must therefore be cautious about the ability of this IFN1 level to be a good predictive marker of the worsening of the disease, even if the lead is considered very serious and could prove to be a real asset. to care for the sick.

Plausible explanation and clinical practice

These results, although limited, have a robustness by the previous observations carried out and the explanatory mechanisms at work that we know. Indeed, coronaviruses that affect humans know how to defend themselves and escape the effects of IFNs. “When they replicate their RNA genome in our cells, they do so in a sort of little bubble to hide from the PRRs that detect viral RNAs. The RNAs produced by our cells have special modifications that allow them to be distinguished from viral RNAs, but studies have shown that the coronavirus causing SARS can make the same modifications to its own genome to trick our cells into believing that it is a ARN who has every reason to be here, and that everything is fine (6, 7). SARS-CoV-2 has proteins that look very similar to those that make these changes, so we can assume that this mechanism is conserved in the virus that causes Covid-19. »

And, even when the virus is unmasked, it still has more than one trick up its sleeve to inhibit the production of IFN or the consequences of their production. “Regarding SARS-CoV-2, its genome differs from the two other coronaviruses mentioned above in several points and recent studies (in pre-print) suggest that this allows SARS-CoV-2 to better suppress interferons in vitro. but paradoxically makes it more sensitive to these molecules, still in vitro. »

In vitro, SARS-CoV-2 would be able to suppress interferons easily but would also be more sensitive to their actions. © tilialucida, Fotolia

Let's remember what we saw above: the more the IFN peak comes before the viral load peak, the more effective it is. If it arrives later than this peak, it may be useless, even deleterious. "In vitro studies have shown that during infections with SARS-CoV, the IFN peak is delayed and comes after a peak of other immune mediators, which are very inflammatory but less effective than IFNs in combating viral infections (8, 9). SARS-CoV-2 could follow a similar strategy by trying to time-shift the IFN response in order to replicate as much as possible. As soon as the viral load increases dramatically, the immune system may try to control it as best it can. But in the absence of the appropriate response, he risks getting carried away and the significant viral multiplication, associated with this famous immune runaway which will cause the cytokine storm of which we speak so much, will prove to be deleterious for the patient.

Are all these more or less known and identified mechanisms useful for making IFNs a therapy of choice? The idea is not new, it is found to treat hepatitis B and C and in certain forms of cancer. They have also already been tested against SARS-CoV-1 and MERS-CoV. The results turned out to be mixed. According to Pierre Marshall, this lack of clear conclusion can be explained by several points: a relatively small number of patients in the studies, mainly retrospective studies where comorbidities were not necessarily informed, the use of drugs in combinatorial strategies (for example, with corticosteroids or other antivirals such as ribavirin) and above all, significant variability between the time when the interferons were administered in relation to the onset of the pathology. However, clinical trials are still ongoing for MERS-CoV. At present, several dozen clinical trials including IFNs have been registered in the context of the treatment of Covid-19, with in particular the Discovery trial piloted by Inserm.

References :

(1) Frieman MB, Chen J., Morrison TE, Whitmore A., Funkhouser W., Ward JM, ... & Baric, RS (2010). SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog, 6(4), e1000849.

(2) Mahlakoiv T., Ritz D., Mordstein M., DeDiego ML, Enjuanes L., Müller MA, ... & Staeheli, P. (2012). Combined action of type I and type III interferon restricts initial replication of severe acute respiratory syndrome coronavirus in the lung but fails to inhibit systemic virus spread. Journal of general virology, 93(12), 2601-2605.

(3) Channappanavar R., Fehr AR, Vijay R., Mack M., Zhao J., Meyerholz DK & Perlman S. (2016). Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell host & microbe, 19(2), 181-193.

(4) Zhao J., Li K., Wohlford-Lenane C., Agnihothram SS, Fett C., Zhao J., ... & McCray PB (2014). Rapid generation of a mouse model for Middle East respiratory syndrome. Proceedings of the National Academy of Sciences, 111(13), 4970-4975.

(5) Channappanavar R., Fehr AR, Zheng J., Wohlford-Lenane C., Abrahante JE, Mack M., ... & Perlman S. (2019). IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. The Journal of clinical investigation, 129(9).

(6) Chen Y., Cai H., Xiang N., Tien P., Ahola T., & Guo D. (2009). Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proceedings of the National Academy of Sciences, 106(9), 3484-3489.

(7) Daffis S., Szretter KJ, Schriewer J., Li J., Youn S., Errett J., ... & Thiel V. (2010). 2′-O methylation of the viral mRNA cap escapes host restriction by IFIT family members. Nature, 468(7322), 452-456.

(8) Yoshikawa T, Hill TE, Yoshikawa N, Popov VL, Galindo CL, Garner HR, & Peters CJ (2010). Dynamic innate immune responses of human bronchial epithelial cells to severe acute respiratory syndrome-associated coronavirus infection. PloS one, 5(1), e8729.

(9) Menachery VD, Eisfeld AJ, Schäfer A., ​​Josset L., Sims AC, Proll S., ... & Chang J. (2014). Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. MBio, 5(3).

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