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Like many other respiratory conditions, COVID-19—the disease caused by SARS-CoV-2—can vary widely among patients. The vast majority of confirmed cases are considered mild, involving mostly cold-like symptoms to mild pneumonia, according to the latest and largest set of data on the new coronavirus outbreak released February 17 by the Chinese Center for Disease Control and Prevention.

Fourteen percent of confirmed cases have been “severe,” involving serious pneumonia and shortness of breath. Another 5 percent of patients confirmed to have the disease developed respiratory failure, septic shock, and/or multi-organ failure—what the agency calls “critical cases” potentially resulting in death. Roughly 2.3 percent of confirmed cases did result in death.

Scientists are working to understand why some people suffer more from the virus than others. It is also unclear why the new coronavirus—like its cousins SARS and MERS—appears to be more deadly than other coronaviruses that regularly circulate among people each winter and typically cause cold symptoms. “I think it’s going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others,” says Angela Rasmussen, a virologist at Columbia University’s Mailman School of Public Health.

In the meantime, the latest data from China and research on other coronaviruses provide some hints.

Elderly and sick people are most susceptible to severe forms of COVID-19

The latest data from China stem from an analysis of nearly 45,000 confirmed cases, and on the whole suggest that the people most likely to develop severe forms of COVID-19 are those with pre-existing illnesses and the elderly.

While less than 1 percent of people who were otherwise healthy died from the disease, the fatality rate for people with cardiovascular disease was 10.5 percent. That figure was 7.3 percent for diabetes patients and around 6 percent for those with chronic respiratory disease, hypertension, or cancer.

While overall, 2.3 percent of known cases proved fatal—which many experts say is likely an overestimate of the mortality rate, given that many mild cases might go undiagnosed—patients 80 years or older were most at risk, with 14.8 percent of them dying. Deaths occurred in every age group except in children under the age of nine, and, generally speaking, “we see relatively few cases among children,” World Health Organization Director General Tedros Adhanom Ghebreyesus said last week.

This pattern of increasing severity with age differs from that of some other viral outbreaks, notably the 1918 flu pandemic, for which mortality was high in young children and in people between 20 and 40 years of age. However, it’s broadly consistent with records of the SARS and MERS coronavirus outbreaks, notes Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill. “If you’re over fifty or sixty and you have some other health issues and if you’re unlucky enough to be exposed to this virus, it could be very bad,” she says.

I think it’s going to take a really, really long time to understand the mechanistic, biological basis of why some people get sicker than others. —Angela Rasmussen, Columbia University

Scientists don’t know what exactly happens in older age groups. But based on research on other respiratory viruses, experts theorize that whether a coronavirus infection takes a turn for the worse depends on a person’s immune response. “The virus matters, but the host response matters at least as much, and probably more,” says Stanley Perlman, a virologist and pediatric infectious disease specialist at the University of Iowa.

Once SARS-CoV-2 gets inside the human respiratory tract, it’s thought to infect and multiply in cells lining the airway, causing damage that kicks the immune system into action. In most people, it should trigger a wave of local inflammation, recruiting immune cells in the vicinity to eradicate the pathogen. The immune response then recedes, and patients recover.

For reasons that aren’t entirely clear, some people—especially the elderly and sick—may have dysfunctional immune systems that fail to keep the response to particular pathogens in check. This could cause an uncontrolled immune response, triggering an overproduction of immune cells and their signaling molecules and leading to a cytokine storm often associated with a flood of immune cells into the lung. “That’s when you end up with a lot of these really severe inflammatory disease conditions like pneumonia, shortness of breath, inflammation of the airway, and so forth,” says Rasmussen.

Local inflammation can turn into widespread inflammation of the lungs, which then has ripple effects across all organs of the body. This could also happen if the virus replicates faster than the immune system can respond, so that it then has to play catch-up to contain the pathogen—a situation that could also cause the immune defense to spiral out of control. “With mice, we know that in some cases, particularly for SARS and MERS coronaviruses, virus replication is very rapid and in some cases overwhelming” to the immune system, says Perlman.

It’s harder to explain why young, healthy people also sometimes die from the disease—for instance, Li Wenliang, a 34-year-old doctor who first sounded the alarm about the virus. He died a few weeks after contracting the pathogen.

Genetic and environmental risk factors might help explain the severity of infections. Though it’s clear that genetic factors can strongly determine the outcome of viral infections in mice—as some of Rasmussen’s work has shown for Ebola, for instance—researchers haven’t yet been able to tease out specific genes or variants in mice, let alone in people, that are responsible for varying degrees of illness. Environmental factors, such as smoking or air quality, may also play a role in disease severity, Rasmussen adds.

A lot of research has gone into understanding what causes respiratory failure that results from systemic inflammation of the lungs—also called acute respiratory distress syndrome (ARDS)—that can occur from coronaviruses and other infections. Yet researchers still don’t know how it occurs exactly, let alone how to treat it, Gralinksi notes. “It’s still a really poorly understood issue.”

Men might be more affected by COVID-19 than women

An intriguing finding in the new data released last week is that although similar numbers of men and women have contracted SARS-CoV-2, more men are dying from the disease. The death rate for males was 2.8 percent and 1.7 percent for women. Rasmussen is quick to caution that although the data encompass nearly 45,000 patients, “that’s still not that many people to determine if there’s really a gender bias—you’d have to look at this in a much larger population of patients in a number of different countries,” she says.

That said, if there is a bias, it would be consistent with what epidemiologists have observed during the SARS and MERS outbreaks. In the 2003 SARS outbreak in Hong Kong, for instance, nearly 22 percent of infected men died, compared to around 13 percent of women. In an analysis of MERS infections between 2017 and 2018, around 32 percent of men died, and nearly 26 percent of women. The difference could have something to do with the fact that the gene for the ACE-2 receptor, which is used by both SARS-CoV-2 and the SARS virus to enter host cells, is found on the X chromosome, she speculates. If it’s a particular variant of the protein that makes people more susceptible to the virus, then females could compensate for that one bad variant because they’d have two copies of the X chromosome, whereas men would be stuck with only one copy. Or, “it could be that men are more likely to be smokers and so their lungs are already a bit compromised. There’s definitely more to be teased out there,” Gralinski says.

Some of Perlman’s research, which demonstrated that the sex disparity also holds true in SARS-infected mice, points to the hormone estrogen as possibly having protective effects: Removing the ovaries of infected female mice or blocking the estrogen receptor made the animals more likely to die compared to infected control mice. The effects are probably more pronounced in mice than in people, Perlman tells The New York Times.

Does an infection make people immune to the virus?

Whether patients develop antibodies after SARS-CoV-2 infection that will protect them against future infections is still a mystery. Surveys of SARS patients around five or 10 years after their recovery suggest that the coronavirus antibodies don’t persist for very long, Gralinski says. “They found either very low levels or no antibodies that were able to recognize SARS proteins.”

However, for the new coronavirus, “we would expect some immunity, at least in the short term,” she says.

Why different coronaviruses vary in severity

There are seven coronaviruses known to infect people. Four of them—229E, NL63, OC43, and HKU1—typically cause a cold and only rarely result in death. The other three—MERS-CoV, SARS-CoV, and the new SARS-CoV-2—have varying degrees of lethality. In the 2003 SARS outbreak, 10 percent of infected people died. Between 2012 and 2019, MERS killed 23 percent of infected people. Although the case fatality rate of COVID-19 is lower, the virus has already killed more people than the other two outbreaks combined, which some have attributed to the pathogen’s fast transmission.

The cold-causing coronaviruses, as well as many other viruses that cause common colds, are typically restricted to the upper respiratory tract, that is, the nose and sinuses. Both SARS-CoV and SARS-CoV-2, however, are capable of invading deep into the lungs, something that is associated with more severe disease.

One possible reason for this is that the virus binds to the ACE-2 receptor on human cells in order to gain entry. This receptor is present in ciliated epithelial cells in the upper and lower airway, as well as in type II pneumocytes, which reside in the alveoli in the lower airway and produce lung-lubricating proteins. “The type II pneumocytes are . . . important for lung function, so this is part of why the lower respiratory disease can be so severe,” notes Gralinksi.

The new coronavirus also appears to use the ACE-2 receptor, which may help partially explain why, like SARS, it is more deadly than the other four coronaviruses. Those pathogens use different receptors, except for NL63, which also uses the ACE-2 receptor but binds to it with less affinity, says Gralinski. (MERS is thought to use an entirely different receptor, which is also present in the lower airways.)

Sustained interest required

To understand these questions fully will take time, research, and consistent funding for long-term studies. Coronavirus funding has been criticized for following a boom-and-bust cycle; viral spillovers from animals to people cause an initial surge of interest that tends to wane until the next outbreak occurs, Rasmussen warns.

“I’m hopeful that in this case it will be really apparent to everybody in the world that we need to be funding this type of basic science, fundamental science, to understand these mechanisms of disease,” she says. “Otherwise, we’re going to be in the same situation when the next outbreak happens—whether it’s a coronavirus or something else.”

Katarina Zimmer is a New York–based freelance journalist. Find her on Twitter @katarinazimmer.