Conversation with Frédéric Altare: obesity, a very aggravating factor of Covid-19

Conversation with Frédéric Altare: obesity, a very aggravating factor of Covid-19

UBeing overweight greatly increases the risk of developing a severe form of Covid-19. Frédéric Altare, Director of the Department of Immunology at the Nantes-Angers Cancer and Immunology Research Center, provides The Conversation with an overview of the relationship between obesity and the SARS-CoV-2 coronavirus.

The Conversation: Is it true that overweight people have a higher risk than others of developing a severe form of Covid-19?

Frédéric Altare: Yes. Significant overweight is the main comorbidity associated with severe forms of Covid-19, which require admission to intensive care. It can be estimated that in some places up to 80% of them are linked to obesity.

However, this percentage varies from one region to another, because the prevalence of obesity is not the same throughout the territory. In regions where the population is less prone to it, other comorbidities (such as cardiovascular disease, high blood pressure and diabetes in particular) can sometimes be more represented than obesity in intensive care units. However, if we take a national average, obesity certainly represents more than half of the proportion of people admitted to intensive care.

This association between overweight and severe forms was already known for other respiratory infections. such as influenza A (H1N1). In the case of Covid-19, some believe that the differences in mortality between China and Italy could be explained in particular by the higher prevalence of obesity among our neighbors. The fact that obesity creates a bias favorable to the worsening of the disease is also confirmed by the outbreak of the epidemic observed in the United States, where nearly 36% of the population is severely obese.

TC: Who are the people most at risk?

FA: People who end up in intensive care are especially those who have passed the milestone of morbid obesity. Overweight is assessed using the famous "body mass index", or BMI, which is the ratio of weight to height squared. It is considered that a person with a BMI over 25 begins to be slightly overweight. From 30, we speak of proven overweight with the onset of obesity, at 35 we begin to speak of severe obesity, and from 40 we enter what is called "morbid" obesity. Morbid, because the people concerned are considered to be at risk of developing pathologies, mainly cardiovascular and atherosclerosis, but also type 2 diabetes, liver damage, certain forms of cancer, etc.

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TC: How can we explain that obesity leads to such pathologies? What is its impact on infection with the SARS-CoV-2 coronavirus?

FA: We now know that all these pathologies are the direct result of inflammation.

It all starts with fat. This is made up of cells that specialize in metabolizing fat, called adipocytes. They are able to “machine” the lipids provided by food in order to use them, or to store them to later serve as “energy source” for the cell. They are used in particular to manufacture lipid compounds used to build and regenerate the membrane of cells. When the amount of fat supplied by the diet is normal, this metabolism (called oxidative metabolism) works well. Fat cells store lipids and multiply.

The problem arises when the proportion of fat supplied by the diet increases too much and the adipocytes are overwhelmed. To deal with the over-accumulation of lipids, they set up a chain of secondary processing, called non-oxidative metabolism. Problem: this alternative metabolism also processes dietary lipids, but instead of producing constituents that can be used for cell membranes, it produces other compounds, in particular ceramides. These are very little stored by the adipocytes, which release them to the outside.

However, ceramides promote inflammation: when cells of the immune system come into contact with them, they consider them to be danger signals. They start to activate, and in turn produce many compounds that promote inflammation, intended to attract other immune cells, which in turn will go on alert and increase inflammation, etc.

TC: Which immune cells are involved?

FA: These are mainly macrophages. These members of the "white blood cells" (or leukocytes, immune cells produced by the bone marrow) infiltrate the tissues and patrol in search of unwanted hosts that they ingest, before warning other immune cells. Attracted by the metabolic by-products released by fat cells, macrophages can represent up to 40% of all cells in fatty tissue. The more important the latter, the more macrophages will be numerous. If the number of macrophages is therefore logically higher in overweight people, these cells are nevertheless also present, in smaller quantities, in the fatty tissue of "lean" individuals. So we all have a little inflammation in our body fat.

When the situation is normal, this inflammation is kept under control. Indeed, there are two kinds of macrophages, those of type M1, which are rather proinflammatory, and those of type M2, rather anti-inflammatory. In lean individuals, type M2 macrophages predominate and slow down the induction of inflammation due to fat. They are helped in this by other immune cells, the “regulatory” lymphocytes. These "firefighters" have the role of extinguishing the inflammation or the immune response, so that it does not last after an infection, for example.

In obese individuals, it was found not only that these regulatory lymphocytes were few in number or even absent, but also that M2 macrophages were replaced by M1 macrophages, which were much more stimulated by ceramides. However, M1 macrophages produce many molecules that promote inflammation, such as cytokines IL-1 or IL-6, chemical messengers.

TC: What happens in the event of an infection with the SARS-CoV-2 coronavirus?

FA: When the coronavirus infects us, our immune system reacts by producing antibodies in 7 to 10 days. The problem is, while some of these antibodies are neutralizing and prevent the virus from entering our cells, others are facilitators. Not only do these not block the virus from entering cells, but more importantly, like all antibodies, they activate macrophages and other immune cells, which promotes inflammation.

This reaction is believed to eventually kill the virus. But this is not what happens in severe forms of Covid-19: the inflammation is carried away, and a real cytokine storm is triggered, which will ultimately destroy the organs. In particular the lungs, initially, but also other organs such as the kidneys or the heart.

In the case of obese people, the occurrence of this cytokine storm is all the more likely when the level of inflammation is already high from baseline. In cases of severe obesity, there are indeed between 2 and 5 million inflammatory cells per gram of adipose tissue, which is almost more than in lymphoid organs, whose job is to generate this type of cells. It's like if people with severe obesity have a second immune system in their fat tissue! When inflammation is triggered in these people, its punching power is therefore major ...

TC: So it is this inflammatory storm that is dangerous for the patient?

FA: Absolutely. The affected patients would probably eventually recover from the virus, over a longer or shorter time, depending on their immune response.
Remember that this is what happens for the majority of patients infected with the coronavirus. Young people, for example, develop very few severe forms, unlike older people, whose immune systems are less effective as they age. They cannot control the virus, which multiplies and activates an inflammatory response that ends up being out of control.

In them, as in obese people and other patients who develop severe forms, it is not the virus that destroys the lungs: it only activates cells which are already there and which, by their activation, destroy the lungs. lung tissue.

It starts at the vascular level: the cells that make up the walls of the vessels that pass through the lungs stiffen, become fibrotic, under the action of inflammation. The tissue necroses, holes are formed in the lungs, blood vessels, destroyed, can no longer carry oxygen ...

TC: Is there any protection for lower BMI?

FA: No, being skinny does not protect in an inversely proportional way. If the risk really manifests itself from the moment we enter the “morbid obesity” category, being below in terms of BMI is not a protective factor. Someone who has a very low BMI could even, on the contrary, present other risks, linked to potential undernutrition for example ...

In addition, "skinny" people may have problems with unknown comorbidities, such as certain underlying cardiovascular pathologies. Their arteries can, for example, be clogged with atheroma plaques, if their diet is too destabilized towards lipids. Normally, excessively high cholesterol levels in the blood vessels, including the vessels of the respiratory tract, may go unnoticed. However, in the event of infection with SARS-CoV-2, the consequences can be serious. This situation may concern athletes or young people who are reluctant to carry out analyzes of this kind.

TC: How long does it take to develop a severe form?

FA: The critical zone is between 7 and 10 days, that is to say the duration of production of the antibodies. Vulnerable people can develop a bearable pathology at first (fever with just a little cough, some minor breathing problems…), which seems to reach a plateau after a week.

This is when some patients will switch: if the immune system has allowed the virus to multiply to the point of triggering sufficient pre-inflammation to create a cytokine storm, within a few hours the person's condition deteriorates. An x-ray of the lungs reveals large white masses: it is not the virus, but the inflammatory mass.

TC: What are the control strategies?

FA: In intensive care, on a daily basis, it is less a question of fighting the virus, for which there is not yet really very effective antivirals, than of fighting inflammation and avoiding the inflammatory storm, or stop it if it is already there.

In particular, inhibitors of the cytokines IL-1 and IL-6, which are the two main mediators of inflammation, are used for this. These treatments are already conventionally used in rheumatology or in autoimmune pathologies. They have already been tested, we know how they work, we know the doses ... They do not work too badly to fight against Covid-19: thanks to them we are able to recover the sick. We can for example cite tocilizumab, an anti-IL6 for which there is an ongoing trial in Italy.

The problem with anti-inflammatory drugs is that they can inhibit part of the body's anti-infective response. A patient's inflammation is reduced to save their organs, but at the same time they are prevented from effectively fighting the virus. It is therefore necessary to juggle a razor's edge with these anti-inflammatory drugs, which makes the care of Covid-19 patients so delicate.

Concerning antivirals, avenues are being studied, but for the moment these are mainly “first-line” strategies: in an emergency we are trying to reuse drugs that were not designed to fight against virus, hoping some have a little effect. It's about saving time. Decreasing the amount of coronavirus, or reducing its lifespan by 3 days in the body, means leaving the inflammation much less time to set in, which can prevent people from going into intensive care. Patients are admitted there when at least one of their organs is failing.

TC: What decides the fate of a patient in intensive care?

FA: This is his condition: if several organs are affected, we will be able to reduce the inflammation, but the damage has already been done, and it does not say that the organs will hold. The issue of sequelae is particularly important. In patients who have recovered and left intensive care, lesions have been observed in various organs. Mainly in the lungs, obviously, but also in the kidneys for example. Their body has indeed undergone, for sometimes several weeks, a significant inflammatory state whose long-term consequences remain to be determined.

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These after-effects could result in problems of more or less loss of respiratory capacity, of kidneys filtering less well ... It's a bit like when a building has burned down: once the fire is out, it remains to be seen in what state is the structure… For the moment the urgency is to save people's lives, but then we will have to follow them.

TC: The usual recommendations, losing weight, exercising, monitoring your cholesterol are therefore particularly important at this time ...

FA: Yes, because any decrease in fat mass will help decrease the rate of residual inflammation. And any less inflammation is another chance to better resist the coronavirus, which itself triggers inflammation.

So the less fat you have, the better. Playing sports, changing your diet to limit lipid storage can help stop making these famous ceramide-type reagents, which are harmful and activate inflammation. We need fat to live, we can obviously eat it, but we must avoid overloading.

In recent years, another interesting lead has emerged: work has revealed that the microbiota of obese people was very different from that of non-obese people. Some bacteria, in particular, were absent. Our own research has shown that some of these bacteria, which are "missing" in obese people, are usually responsible for the emergence of regulatory lymphocytes, those firefighters that extinguish inflammation.

Are these bacteria absent because a diet that is too lipidic is not suitable for them? Or rather because this excessively rich diet promotes other bacteria? We don't know yet. But it is likely that their absence explains why regulatory lymphocytes are less numerous or even absent from the adipose tissue of obese people. This would explain why the inflammation flares without control in them. Not only do the ceramides activate it, but moreover the cells supposed to limit it are not there… It is the double penalty.

It is too early for these observations to translate into treatment, but they encourage advice to take care of your microbiota, in particular by ensuring a balanced diet and limiting your alcohol consumption.The Conversation

Frederic Altare, Inserm Research Director, Director of the Department of Immunology at the Nantes-Angers Cancer and Immunology Research Center (CRCINA), Inserm

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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