Six months into a pandemic that has killed more than 400,000 people globally, scientists are still trying to understand the wildly variable nature of covid-19, the disease caused by the virus.
Among their lines of inquiry: Are distinct strains of the coronavirus more dangerous? Does a patient’s blood type affect the severity of the illness? Do other genetic factors play a role? Are some people partially protected from covid-19 because they’ve had recent exposure to other coronaviruses?
Much of the research remains provisional or ambiguous, and for now scientists can’t do much better than say that covid-19 is more likely to be worse for older people — often described as over the age of 60 — and for those with chronic conditions such as hypertension, diabetes, lung disease and heart disease.
That describes tens of millions of people in the United States alone. It also isn’t much of an explanation: The link between chronic disease and the severity of covid-19 is more in the category of correlation than causation. The “why” of the matter remains unclear.
The issue of disease variability “is the most critical question about covid,” said Edward Behrens, chief of the rheumatology division at Children’s Hospital of Philadelphia.
“Why do some people get sick? Why do some people have no problem at all?” he said.
Social and demographic factors, including sex, race, ethnicity, income and access to quality health care, play major roles in how this pandemic affects people and who suffers the most. The ultimate goal of many researchers is to develop a personalized risk score — so that a person who has covid-19, or remains vulnerable to catching the disease, would have some idea of how to navigate the pandemic.
Blood markers
One potential breakthrough was highlighted by National Institutes of Health Director Francis Collins on his blog: Scientists developed an artificial intelligence tool that sorted the blood of covid-19 patients and found 22 proteins that consistently appear among the patients who are severely ill.
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 rolled out early in the course of the disease, it could help doctors decide which patients are most vulnerable.
Blood-type research is also intriguing. This month, European scientists posted online a study — not yet peer-reviewed — that found strong links between variations on two places in the genome and respiratory failure in covid-19 patients in Italy and Spain.
One, the ABO gene, determines blood type. The researchers found that patients who had Type A blood had a 50 percent higher risk of needing oxygen or a ventilator. Type O blood seemed to have a partial protective effect.
Why that gene matters remains unknown, according to co-author Andre Franke, a professor of molecular medicine at the University of Kiel in Germany. The genetic variant may cause the risk by being associated with inflammation.
Another possibility is that Type A blood is associated with small blood clots that characterize some severe covid-19 cases. And “there may be other things cooking in that region” of the genome, Franke said.
The consumer genetics giants Ancestry.com and 23andMe are getting involved. 23andMe recently released preliminary findings showing that people with Type O blood are 9 to 18 percent less likely to test positive for covid-19 than people with other blood types. The company is still exploring links between blood type and disease severity.
More than 750,000 of the company’s customers have completed a web-based survey about their experiences with covid-19, and 2,000 of them said they’d been hospitalized from the disease. The company is now recruiting 10,000 non-customers who have been hospitalized with covid-19.
“It would be very nice if there was a single gene that we could understand as conferring different levels of risk for covid-19,” said Adam Auton, 23andMe’s principal scientist. “In reality, dozens or hundreds or even thousands of genes are all making very small contributions toward disease risk.”
Jean-Laurent Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University, is co-leading an international team searching the genomes of “outliers” — patients younger than 50 who had no known preexisting conditions, but were hospitalized with life-threatening cases of covid-19. They’re looking for unusual gene variants that these patients have in common.
Casanova and his colleagues have previously found genetic mutations that increase a person’s susceptibility to infectious diseases, such as severe pneumonia caused by influenza.
“There are many, many infectious diseases for which genetic variations have been shown to be causal,” Casanova said. “So when covid occurred, if I may say, it’s business as usual.”
How the virus infects you — and how much
Numerous papers have explored whether different strains of the virus are more transmissible or lethal. One strain has become dominant in much of Europe and the United States. That strain has a genetic mutation affecting what is called the spike protein — the structure that lets the virus bind to receptor cells in humans.
So far, there is no consensus that this or other mutations are significant from a clinical standpoint. Collins, the NIH director, says of the different strains, “I think they’re all acting the same.”
Another possibility frequently discussed by researchers is that the mode of transmission is key to 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 simply through large respiratory droplets.
That leads some scientists to think the aerosol transmission could enable the virus to penetrate deep into the lungs and trigger a more severe infection.
The body has an “innate immune system” that includes physical obstacles for any invading viruses. But tiny particles can go with the air flow and potentially reach the deepest regions of the lungs, said Raymond Tellier, a microbiologist at McGill University Health Center.
For Tellier, that’s a sign that this virus must be spreading in part through aerosols.
“How else would the virus go down the lower respiratory tract where the cells can be infected?” he asks.
The amount of virus initially transmitted from one person to another could play a role in determining the course of illness: more virus, sicker patients. Albert Ko, an infectious-disease epidemiologist at the Yale School of Public Health, said, “If I spew out a lot of virus at you and you’re one foot away, you’re going to get a higher inoculum than if you’re six feet away.”
Immune system idiosyncrasies
Even with all the focus on the virus, and its potential mutations and dosages, the most critical factor is the person getting infected — the “host.” Not everyone hosts the virus the same way. The human immune system is “a complicated tangle of pathways and partners,” as Collins puts it.
It’s conceivable, Collins said, that some people have immune systems that are better primed for this new invader because of previous exposure to genetically related coronaviruses. That’s still highly conjectural.
The immune system not only can be protective, it can also go haywire and make an illness catastrophically worse. If the immune system is an army that attacks infections, molecules called cytokines are the messengers that tell the troops what to do to beat back 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 overreactive immune response — a cytokine storm.
“The army goes crazy and just sort of does more damage than they would intend to do,” said Behrens, of Children’s Hospital of Philadelphia.
“You start making too many cytokines all at the same time. Now your immune cells are confused. They’re trying to do everything all at once,” he said. “Now it’s no longer the virus that’s killing you, it’s the immune system that’s killing you.”
Some children infected with the coronavirus have a severe, sometimes fatal Kawasaki-like syndrome. It affects multiple organs — “the gut, the heart, the skin, the eyes,” Behrens said — and research by his team suggests it is a cytokine storm. Behrens hopes the team’s study of children with covid-19 will also shed light on why some adults get so sick.
Quickly identifying a storm of cytokines, which can be detected in blood tests, is key, he said. In March, CHOP developed a rapid diagnostic test, which delivers patients’ results in a day. But there’s much more to learn.
“What is their particular storm? Where in the process are they? Which drug should we pull off the shelf?” Behrens said. “That kind of personalized precision medicine is the holy grail for all this.”
Obesity
In the United Kingdom, health officials have released two different measures of risk. One developed by the National Health Service looks at age, gender and very granular medical factors such as whether you have preexisting conditions such as high blood pressure or diabetes.
Those at low risk are asked to social distance as the economy reopens. Those at higher risk are asked to “shield,” which means staying inside as much as possible and avoiding contact with others.
Jennifer Lighter, a hospital epidemiologist at NYU Langone, found that obesity was the No. 1 risk factor in her hospital system among those younger than 60. Patients with a body mass index between 30 and 34 — obese under CDC definitions — were two times as likely to be admitted to the ICU than patients with a BMI under 30. Those with a BMI of 35 and over were three times more likely to die than those with a healthy BMI.
“As we are opening up the nation, one idea is to consider opening up by risk groups,” Lighter said.
In the broadest sense, the risk of a bad outcome is pretty clear. It’s better to be young and healthy if the coronavirus pays a visit.
Among the 238 sailors aboard the aircraft carrier USS Theodore Roosevelt who tested positive for the virus after an outbreak on the ship, only two required hospitalization, according to a new study from the CDC. One out of 5 reported no symptoms at all.
Older people suffer from immunosenescence. Their immune systems become “dysregulated.” Casanova describes this as “the inevitable descending slope of life from about the age of 18 or 19.”
The median age of people who died in virus-ravaged northern Italy was 81.
“The difference between catching covid and dying is so stark the older you get, it’s important to recognize that,” said Carl Heneghan, director of the Center for Evidence-Based Medicine at Oxford University. In the U.K., there’s been “virtually no excess death” for people under age 45 since the pandemic began, he said.
Another wrinkle: People who have little history of viral infections tend to have more severe reactions when they get infected later in life.
“You have to try and stay healthy, get fit,” Heneghan said. “If you’ve got diabetes, you’ve got to lose weight and moderate that. If you do all those things, your risk of dying is small, or very small.”
