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Published On April 14, 2020

BASIC RESEARCH

Why Do Young, Healthy People Die from COVID-19?

They represent a small minority of victims. But their illness could hold valuable lessons about how COVID-19 works—and how to stop it.

In late March, a 16-year-old girl died of coronavirus in Paris. Her name was Julie, and she had no history of medical problems. Her illness started with just a cough, which she treated with over-the-counter medications. A short while later, she developed shortness of breath and was eventually taken to one of the best hospitals in the city. Within a couple of days, Julie took a turn for the worse and had to be placed on a ventilator. She never recovered.

The stories of a handful of patients like Julie—young and otherwise healthy people who succumb to COVID-19—have surfaced during the past month. A 25-year-old pharmacy technician with no underlying medical conditions died of coronavirus in a La Quinta, California home. A healthy young Chinese physician named Dr. Xia Sisi, just 29, died after a seeming recovery in February. In late March, a 13-year-old boy named Ismail with no health problems died of the virus in London. He was the youngest identified victim of the disease in the U.K.

What is most notable about these cases, medically, is that they are statistical outliers. By and large, youth is protective. Through mid-March, data from the Centers for Disease Control and Prevention showed that no one under the age of 19 had died from COVID-19 in the United States—documented cases since have been rare. For those aged 20 to 54, the death rate was less than 1%. An uneventful medical history also seems protective. Nearly all COVID-19 patients who have died in the United States (94%), and the vast majority of those admitted to intensive care (78%) had at least one underlying health condition, such as hypertension, diabetes, pulmonary disease or obesity, according to CDC data from March 31.

So why do a few of the young and healthy succumb when their peers do not? The question is far from academic. The study of medical outliers—people whose bodies respond in unusual ways to disease—can provide critical clues to the mechanisms at work. For just this reason, research on the young and healthy has become the focus of several COVID-19 teams around the globe.

One project is the COVID Human Genetic Effort. Led by Jean-Laurent Casanova at Rockefeller University in New York City and Helen Su at the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID), the effort relies on a global network of researchers that includes scientists from the Karolinska Institute in Sweden, the Imperial College London and Columbia University in New York City. By early April, the group had enrolled 100 patients under 50 who had no underlying medical conditions, but had been admitted to the ICU for COVID-19. So far the group has sequenced the genetic data for 30 of them.

The hypothesis driving the project is that the particular susceptibility of these patients is genetic: they have heritable, single-gene mutations that influence their immune systems. Such distinctive errors have been found in many other cases of young people—children, adolescents and even young adults—who are healthy but suddenly succumb to a life-threatening infection. Casanova laid out this single-gene immunity argument, using data from the previous two decades, in a widely circulated paper published in 2015.

Each disease he researched was, for the most part, associated with a different genetic mutation. “We’ve discovered hundreds of errors of inborn immunity underlying a variety of infections—bacterial, viral, fungal,” Casanova says. “This includes diseases such as severe influenza or pneumonitis, which are very similar to what we’re seeing now.” But some of the implicated genes overlapped. For example, mutations in genes that code for toll-like receptors—surface proteins on immune system cells—are associated with a special susceptibility to the herpes simplex virus encephalitis and influenza, says Casanova. Although he remains optimistic that researchers will find similar errors in some COVID-19 patients, he notes that it could take weeks or years—or the connection might not be there at all.

In previous pandemics, including HIV/AIDS, research on outlier cases has yielded valuable clues. Immunologist Philip Murphy of the NIAID worked on HIV genetics, and in 1996 his lab was one of several that simultaneously identified a key mutation in a human cell surface protein called CCR5 by looking at people who had been heavily exposed to HIV but had not developed the illness. CCR5, it turns out, serves as a dock, or entry point, for HIV to enter immune cells. Having the mutation makes people highly resistant to HIV and has become a major target of HIV prevention and therapy. Outliers are “more likely to give you a simple answer that might lead you to a more expansive understanding of risk,” says Murphy. 

A parallel to CCR5 exists in COVID-19. The cell surface protein called ACE2 is found throughout the body but is especially concentrated in parts of the lungs and small intestine. This is where the SARS-CoV-2 virus, which causes COVID-19, attaches itself when a person is first infected. Some researchers suspect ACE2 may play an important role in who is susceptible to severe infection and may dictate age differences in who gets sickest. Children’s lung cells, for instance, may manufacture less ACE2 than the lungs of older people. This could make it tougher for the virus to bind to cells and spread in the young.

But others argue that having less ACE2 could result in less protection, not more, since the protein is designed in part to defend against viruses that infect human airways. It is furthermore unclear whether the young have fewer ACE2 receptors, since rodent studies show that ACE2 levels decrease with age.

Enzymes that help the virus attach to ACE2 may also play a role in the resilience of young people, says Alessandra Renieri, professor of medical genetics at University of Siena in Italy and director of medical genetics at the General Hospital of Siena. So far her research suggests that people who have more of these enzymes may be more susceptible to the virus, Renieri says, and in young people these enzymes tend to be less active. Variants in the genes that code for such enzymes might moderate COVID-19 susceptibility.

As more genetic studies look for clues about COVID-19, immune system genes are a logical place to focus. Not only do certain immune cells respond to immediate infection with COVID-19, they also play into later complications of the disease. A so-called cytokine storm, considered a factor in the rapid deterioration of some patients who die from COVID-19, occurs when the immune system overreacts to the invading virus and ends up overstimulating the cells that are meant to protect the body from infection.

In Denmark, a project called CHILD-COVID, a partnership between Rigshospitalet (one of the country’s largest hospitals), the National Hospital’s Children’s Clinic and the country’s other children’s wards, aims to use data from young patients to map the “signaling molecules” that a person’s immune system creates when they are infected. The project’s scientists are trying to understand why most children are fine while a tiny minority get very sick from COVID-19. The leader of that project, Kjeld Schmiegelow, in the department of pediatrics and adolescent medicine at Rigshospitalet, has found anecdotally that children with cancer have not been as susceptible to COVID-19. He has proposed that this may be the result of an already inhibited immune system in children with cancer, resulting in less severe inflammatory reactions.

Still other researchers point to evidence that many children have already been exposed to the four milder coronaviruses that infect humans in schools and on playgrounds, and so may have developed antibodies that are versatile enough to fight off COVID-19. None of these theories quite explains why young adults as opposed to children might also be generally protected against the virus, however, nor why some of the young and healthy are susceptible to it. But they do suggest some possible places to begin to look.

Young people who get sick aren’t the only outliers. Geneticist Manuel Rivas at Stanford University is also trying to identify genes underlying immune responses to SARS-CoV-2. But he is more interested in outliers at the other extreme: people who are highly resistant to the virus despite repeated exposure, such as health care workers on the front lines. He cites the HIV research on CCR5 by Murphy and others, including Stephen O'Brien, formerly chief of the National Cancer Institute's laboratory of Genomic Diversity, as a precedent and “one of the most beautiful study designs I've seen for this.”

Understanding these outliers—how some people control the virus or why others are uniquely vulnerable to it—could advance treatment and vaccine research by helping map how COVID-19 works in the body. If it were possible to identify which young, otherwise healthy patients might be at risk for severe or deadly COVID-19, it might also be easier to protect them. A genetic marker would be useful, although its widespread use would be limited by costs.

But such a marker could also be invaluable for a more limited application. People who are young and healthy may be asked to consider taking an important role on the horizon: being participants in so-called “human challenge” trials. In this model, robust volunteers are inoculated with a promising vaccine candidate and then infected with the virus. If the vaccine successfully protects them, it can be rolled out to more vulnerable people.

Because of the risk of serious illness and death from COVID-19, a trial that intentionally gives patients a disease would be considered a last resort. Late last month, a trio of researchers proposed using a human challenge to fight COVID-19 in The Journal of Infectious Diseases. The authors, including Marc Lipsitch, professor of epidemiology and director of the Center for Communicable Disease Dynamics of Harvard T.H. Chan School of Public Health, recognize that such trials might still put some volunteers in a dangerous spot. They are hoping for help in making the process as safe as possible. “Any approach that could remove those at high risk of bad outcomes from the trial would be valuable,” Lipsitch says. Knowing exactly how young people respond to the disease—and why some succumb while others don’t—could help move forward a vaccine to protect the rest of the world.

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