Why does coronavirus kill some people and save others?

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Six months after the start of a pandemic that has killed more than 400,000 people worldwide, scientists are still trying to understand the highly variable nature of Covid-19, the disease caused by the virus.

Among their areas of research: are distinct strains of the coronavirus more dangerous? Does a patient’s blood type affect the severity of the disease? Do other genetic factors play a role? Are some people partially protected from covid-19 because they have recently been exposed to other coronaviruses?

Much of the research remains tentative or ambiguous, and at the moment scientists cannot do much better than saying that covid-19 is more likely to be worse for older adults – often described as having over 60 years – and for those suffering from chronic diseases such as hypertension, diabetes, lung disease and heart disease.

This describes tens of millions of people in the United States alone. Nor is this a big explanation: the link between chronic disease and the severity of covid-19 is more in the correlation category than causation. The “why” of the question is unclear.

The question of variability in the disease “is the most critical question about Covid,” said Edward Behrens, head of the rheumatology division at Children’s’s Hospital in Philadelphia.

“Why do some people get sick?” Why do some people have no problem? ” he said.

Social and demographic factors, including gender, race, ethnicity, income and access to quality health care, play a major role in how and who suffers the most from this pandemic . The ultimate goal of many researchers is to develop a personalized risk score – so that someone who has covid-19, or who remains vulnerable to the disease, has an idea of ​​how to navigate the pandemic.

Blood markers

A potential breakthrough was highlighted by the director of the National Institutes of Health Francis Collins on his blog: scientists have developed an artificial intelligence tool that has sorted the blood of Covid-19 patients and found 22 proteins that appear regularly among critically ill patients.

At this point, such a blood marker only tells doctors what they can already see with their own eyes – a very sick patient. But if such a blood test and analysis could be deployed at the onset of the disease, it could help doctors decide which patients are most vulnerable.

Blood group research is also intriguing. European scientists published a study online this month – not yet peer-reviewed – that found close links between two-way genome variations and respiratory failure in Covid-19 patients in Italy and in Spain.

One, the ABO gene, determines the type of blood. The researchers found that patients who had type A blood had a 50% higher risk of needing oxygen or a ventilator. Type O blood appears to have a partial protective effect.

The reason why this gene is important remains unknown, according to co-author Andre Franke, professor of molecular medicine at the University of Kiel in Germany. The genetic variant can lead to risk by being associated with inflammation.

Another possibility is that type A blood is associated with small blood clots that characterize some severe cases of covid-19. And “there may be other things cooking in this region” of the genome, said Franke.

Consumer genetics giants Ancestry.com and 23andMe are getting involved. 23andMe recently released preliminary results showing that people with type O blood are 9-18% less likely to test positive for covid-19 than people with other types of blood. Society is still studying the links between blood type and the severity of the disease.

More than 750,000 of the company’s customers responded to an online survey of their experiences with covid-19, and 2,000 of them said they had been hospitalized for the disease. The company is now recruiting 10,000 non-clients who have been hospitalized with covid-19.

“It would be great if there was a single gene that we could understand to confer different levels of risk for covid-19,” said Adam Auton, senior scientist at 23andMe. “In reality, tens, even hundreds, even thousands of genes all contribute very little to the risk of disease.”

Jean-Laurent Casanova, head of the St. Giles Laboratory for Human Genetics of Infectious Diseases at Rockefeller University, co-leads an international team looking for “outlier” genomes – patients under 50 who had no known pre-existing conditions, but who were hospitalized with fatal cases of covid-19. They are looking for unusual genetic variants that these patients have in common.

Casanova and colleagues previously discovered genetic mutations that increase a person’s susceptibility to infectious diseases, such as severe pneumonia caused by the flu.

“There are very many infectious diseases for which genetic variation has been shown to be causal,” said Casanova. “So when the summons happened, if I may say so, it is as usual. “

How the virus infects you – and how much

Many articles have explored whether different strains of the virus are more transmissible or fatal. A strain has become dominant in much of Europe and the United States. This strain has a genetic mutation affecting what is called the peak protein – the structure that allows the virus to bind to receptor cells in humans.

So far, there has been no consensus that this or any other mutation is clinically significant. Collins, the director of NIH, says of the different strains, “I think they all act the same. “

Another possibility frequently discussed by researchers is that the mode of transmission is essential for understanding the severity of the disease. Many scientists argue that, contrary to what the World Health Organization and the Centers for Disease Control and Prevention have repeatedly stated, the virus sometimes spreads through tiny aerosol particles, not just through large respiratory droplets.

This leads some scientists to believe that the transmission of aerosols could allow the virus to penetrate deep into the lungs and trigger a more serious infection.

The body has an “innate immune system” that includes physical barriers to any invading virus. But tiny particles can go with the air flow and potentially reach the deepest regions of the lungs, said Raymond Tellier, microbiologist at the McGill University Health Center.

For Tellier, this is a sign that this virus must spread in part through aerosols.

“How else would the virus get down into the lower respiratory tract where cells can become infected?” ” he asks.

The amount of virus initially transmitted from one person to another could play a role in determining the course of the disease: more viruses, sicker patients. Albert Ko, an infectious disease epidemiologist at the Yale School of Public Health, said, “If I spit a lot of virus at you and you are one foot away, you will get a higher inoculum than if you are six feet away. ”

Idiosyncrasies of the immune system

Even with all the attention paid to the virus and its mutations and potential dosages, the most critical factor is the infected person – “the host”. Not everyone hosts the virus in the same way. The human immune system is “a complicated tangle of pathways and partners,” as Collins says.

It is conceivable, said Collins, that some people have a better prepared immune system for this new invader due to previous exposure to genetically related coronaviruses. It’s still very speculative.

The immune system can not only be protective, it can also go haywire and worsen disease catastrophically. If the immune system is an army that attacks infections, molecules called cytokines are the messengers that tell the troops what to do to repel the invader. Too few cytokines, and the defense will be too weak, allowing the infection to progress. Too many, and the commands become a cacophony that causes an erratic and reactive immune response – a storm of cytokines.

“The military is going crazy and somehow doing more damage than it would expect,” said Behrens, of the Children’s Hospital in Philadelphia.

“You start making too many cytokines at the same time. Now your immune cells are confused. They are trying to do everything at the same time, “he said. “Now it’s no longer the virus that kills you, it’s the immune system that kills you. “

Some children infected with coronavirus have a severe, sometimes fatal, Kawasaki-like syndrome. It affects several organs – “the gut, the heart, the skin, the eyes,” said Behrens – and his team’s research suggests that it is a cytokine storm. Behrens hopes the team study of children with covid-19 will also help to understand why some adults get so sick.

It is essential to quickly identify a cytokine storm, which can be detected in blood tests. In March, CHOP developed a rapid diagnostic test, which provides patient results in one day. But there is still a lot to learn.

“What is their particular storm? Where are they in the process? What medicine should we take off the shelf? Behrens said. “This type of personalized precision medicine is the Holy Grail for it all. “

Obesity

In the UK, health officials have released two different risk measures. One developed by the National Health Service examines age, gender and very granular medical factors such as suffering from pre-existing conditions such as high blood pressure or diabetes.

People at low risk are encouraged to take social distance when the economy reopens. Those most at risk are asked to “protect themselves”, which means staying indoors as much as possible and avoiding contact with others.

Jennifer Lighter, a hospital epidemiologist at NYU Langone, has found obesity the # 1 risk factor in her hospital system for those under 60 years of age. Patients with a body mass index between 30 and 34 – obese according to CDC definitions – were twice as likely to be admitted to the ICU than patients with a BMI below 30 years of age. Those with a BMI of 35 and over were three times more likely to die than those with a healthy BMI.

“As we open the nation, one idea is to consider opening up to at-risk groups,” said Lighter.

Broadly speaking, the risk of a bad result is pretty clear. It is better to be young and healthy if the coronavirus visits.

Among the 238 sailors aboard the aircraft carrier USS Theodore Roosevelt who tested positive for the virus after an epidemic on the ship, only two had to be hospitalized, according to a new CDC study. One in five reported no symptoms.

The elderly suffer from immunosenescence. Their immune system becomes “deregulated”. Casanova describes this as “the inevitable downward slope of life from around 18 or 19 years of age.”

The median age of those who died in northern Italy ravaged by the virus was 81 years.

“The difference between catching lust and dying is so blatant as you get older, it’s important to recognize this,” said Carl Heneghan, director of the Center for Evidence-Based Medicine at the University of Oxford. In the UK, there have been “virtually no excessive deaths” for people under the age of 45 since the start of the pandemic, he said.

Another wrinkle is that people with little history of viral infections tend to have more severe reactions when they are infected later in life.

“You have to try to stay healthy, get in shape,” said Heneghan. “If you have diabetes, you need to lose weight and moderate it. If you do all of these things, your risk of dying is low or very low. “

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