Authored by Kaleigh Rogers, via Five Thirty Eight

Most young people who get Covid-19 get pretty nasty flu-like symptoms but fight off the infection on their own with bed rest and over-the-counter pain medication. Some, though, have a severe, even deadly, case.

Why is it that someone who seems healthy and has no underlying conditions could be killed by this virus when so many of their peers pull through just fine?

Let's break down what we know and what research is needed to answer this Covid-19 mystery.

What we know

Our understanding of why some people get mild infections while others wind up hospitalized or killed by Covid-19 is still limited. In the U.S., 34 percent of confirmed Covid-19 cases are in patients under the age of 45, according to Centers for Disease Control and Prevention data from mid-March. Of patients known to be hospitalized, about 20 percent were under 45, and of those known to be admitted to the ICU, 12 percent were under 45. The CDC also reports that the case fatality rate is less than 1 percent for people age 20-54.

But there isn't much we know about why some young people are getting extremely sick and others aren't. We know that age is a risk factor — the case fatality rate for Covid-19 climbs steeply for patients over 60. This is true for a lot of infections and generally has to do with diminishing immune systems and underlying health conditions.

But that doesn't help us figure out what's going on with these cases where young people get sick and it quickly turns serious. It's not as simple as pointing to underlying conditions. Many conditions, such as asthma, haven't been definitively confirmed as risk factors, though many doctors suspect they are.

"We have guesses, but we don't know," said Dr. David Smith, the head of the Division of Infectious Diseases and Global Public Health at the University of California San Diego. "It's going to take some time to figure that out."

What we don't know (and how we figure it out)

Sure, there's plenty scientists don't know, but that's what hypotheses are for. Researchers have already begun studies to uncover which factors contribute to a severe or deadly case.

Some are looking into genetic differences. Our genes can affect the way our immune system responds to an infection, which could explain why some people fare worse than others. "The possibilities, unfortunately, are endless," said Dr. Jean-Laurent Casanova, an investigator at the Howard Hughes Medical Institute and physician at Rockefeller University Hospital. "Between the first encounter with the virus and death, you can imagine that there are lots and lots of steps. At any of these steps, a defective immunity in any of the cells encountered by the virus can be responsible for severe disease and therefore death."

Casanova is leading a global study to try to identify what, if any, genetic mutations may cause otherwise healthy young people to have a more severe or deadly infection. The study will look for any shared genetic mutations among otherwise healthy patients under 50 who tested positive for Covid-19 and were admitted to an ICU. From there, they can investigate those mutations further to determine whether they cause a susceptibility to severe Covid-19.

Another factor being investigated is the infectious dose, or the amount of virus a patient was exposed to when they first became ill. Could it affect how sick someone becomes, regardless of their age or health? This can be determined through epidemiological studies, where researchers compare groups of patients to learn more about how they first became infected and whether higher levels of viral exposure correspond to sicker patients. For example, Smith explained that researchers could track households where at least one member got Covid-19 and measure how much virus the patient is shedding, then observe how other members of the household fare. It can also be studied using animals in a lab to see how immune responses change at different levels of exposure.

There's also a chance that whether or not you have already been exposed to Covid-19 can determine how severe your infection is. With the dengue virus, for example, the first time someone is exposed to the virus, they often have only a mild infection, but if they encounter it a second time, it can become deadly. Researchers believe this is due to the antibodies the body creates after first exposure, which start to diminish over time. If they drop to a low enough level, they're not able to fight off the virus, but instead they inadvertently assist the virus in infecting cells. It's called antibody-dependent enhancement, and researchers are investigating whether past exposure to this or a similar coronavirus could worsen the symptoms of Covid-19.

Other researchers are looking at whether the microbiome — the menagerie of bacteria, viruses and fungi that live in and on the human body — could be playing a role. Microbiomes differ from person to person and some microbes have been known to help or hinder an individual's ability to fight off infection.

All of these possibilities will require studies that use control groups to determine whether these variables are actually causing a more severe reaction or if their presence is just a coincidence. It might be true that a high proportion of Covid-19 patients drink coffee, for example, but that doesn't necessarily mean drinking coffee puts you at a higher risk of Covid-19. (And, god, can you imagine if it did?) The only way to know for sure is by running a trial and comparing a group with one set of factors to a group without those factors to see if there's a consistent difference between them.

In the midst of an ongoing crisis, one way to ethically do this (without purposely giving people a potentially deadly infection) is through a case control study, which looks retroactively at infections that have already played out.

"So you have a case and a control and they look the same, except one progressed and one didn't," Smith, of UCSD, said. "Then you sort of work your way backwards and say, ‘What is really different between these two groups?' And you need lots of people [in the study] to get that figured out."

Another option is called a cohort study, where a sample of the population is enrolled and then followed over time to see who gets sick and how sick they get. Those who got seriously ill can then be compared to those who didn't get sick or had less severe infections to see what differences stand out.

Luckily, many of the studies needed to determine why some young people get severe infections are already underway, and we could see preliminary results in a matter of months. But it may take years to fully understand why Covid-19 affects people differently.

Special Report: Fighting The New Coronavirus