You might have a sniffle and be done. You might run a fever with a cough and unshakable fatigue for five days—or 10. Or you might end up in a hospital, gasping air into congested lungs, an immunological storm raging in your body. And you might not make it through COVID-19 alive.

What determines if someone gets desperately ill from the disease that is ripping its way across the planet? You are likely familiar with the broad categories of people who face greater risk: older individuals, men, those who have certain chronic conditions, and—notably in the U.S. and England—people of color. But researchers are looking deeper into these groups to determine the underlying roots, both biological and social, for their vulnerability. Investigators are relating age-related risk to the ways that the immune system changes over the years, for example, and examining male-female differences in immune responses. Some scientists are probing for genetic variations that might raise susceptibility. Others are highlighting the social, environmental and economic factors that elevate risk, including racism.

For a given individual, the elements of risk stack up like the layers of a Russian nesting doll. The innermost core includes genes, biological sex and age. Cellular and hormonal factors that accompany these characteristics affect vulnerability to infectious microbes, including SARS-CoV-2, the coronavirus causing the pandemic. The second layer consists of diseases and chronic conditions acquired over time, many of which make it easier for the virus to enter cells or harder for the body to fight it effectively. The outermost layer reflects the accumulated nicks and gouges of external circumstance: housing and work conditions, poor access to health care, nutritional status, and exposure to toxins and pollution. For people of color, these social and economic aspects include the cumulative stresses of systemic racism and discrimination.

These layers are not independent. With aging, for example, comes more chronic disease and, too frequently, a decline in living conditions such as housing, social support and food security. Nor are all the contributing risk factors known for an infection that emerged little more than eight months ago. Still, by applying existing science to emerging data about the features that make up these layers, researchers say, one can begin to make sense of COVID-19’s dramatic range of severity.

How Age Impacts Immunity

Age is probably the single biggest determinant of how sick someone gets from the coronavirus. In China, where the pandemic began, the average person with a confirmed infection had a 2.3 percent chance of dying. But for people between 70 and 79, it was 8 percent, and for those older than 80, it was 14.8 percent. In New York City, nearly half of confirmed deaths were among the elderly, aged 75 and older, and another quarter were among those aged 65 to 74. An analysis of 17 million people in England, published in Nature in July, concluded that patients older than 80 were at least 20 times more likely to die of the infection than those in their 50s.

“Age was our biggest predictor of outcome,” says Mangala Narasimhan, regional director of critical care at Northwell Health, the largest health care provider in the New York City area, and a co-author of a report in JAMA on the characteristics of 5,700 hospitalized COVID-19 patients. The dense concentration of elderly people in nursing homes, where infections can spread quickly and prevention is often inadequate, is clearly one reason for this correlation. But biology is another factor, particularly the aging of the immune system.

As the decades roll by, the human body becomes less effective at fighting infections. This decline is one reason why roughly 90 percent of U.S. deaths from influenza are among people aged 65 and older and why vaccines are less protective in the elderly. Basically, our defensive cells become thinned out in number and variety. And like old warriors, they become more geared toward fighting yesterday’s battles with familiar enemies than tackling something new, such as the latest flu strain or the novel coronavirus.

[A visual guide shows what scientists have learned about the workings of SARS-CoV-2 and how it causes devastating disease.]

With age, B cells, which make antibodies, and T cells, some of which directly kill infected cells and some of which alert the B cells, are no longer produced in large quantities in the bone marrow and thymus gland, respectively. Eventually, production nearly grinds to a halt. “It goes from a fire hose at eight years old to a leaky, dripping faucet when you are 80,” explains immunologist Kenneth Dorshkind, a professor of pathology and laboratory medicine at the University of California, Los Angeles. Older adults maintain populations of these essential immune cells in the lymph nodes and spleen, but “they develop defects with age, so they don’t function as well,” he says.

For example, as people age, both the stem and arms of the Y-shaped antibody molecule become less flexible. This limits the body’s ability to modify them to match an unfamiliar invader. As a result, antibodies may not lock on as effectively. T cells, meanwhile, lose a lot of the variety of receptors that allow them to respond to diverse pathogens, and they may lack the vigor to rapidly multiply in response to infection, says Jörg Goronzy, an immunologist who studies T cell aging at Stanford University. “Healthy old people have lost at least 75 percent of their T cell receptor repertoire,” he estimates. “At one point, we may lack the receptors that have an optimal fit” for the invading microbe.

Older people are also far more prone to chronic diseases that involve low-grade inflammation, which seems to further compromise the immune system. Goronzy says it is unclear whether a geriatric immune system resorts to more inflammation to protect the body or whether the inflammation comes first and impairs defenses. He suspects it is a combination of the two. Both he and Dorshkind predict that if a coronavirus vaccine becomes available, it will probably be less protective for aged people. As with the flu shot, an extra strong dose or some kind of booster may be needed.

Why Men Fare Worse

Sex also contributes to COVID-19 severity: men are roughly twice as likely to die of the infection as women, although the gender gap varies somewhat from place to place. In Italy, for example, 70 percent of those who died by this spring were men; in the U.S, the figure was 59 percent. Whether men are also more likely to acquire the infection is unclear because of biases and country-by-country discrepancies in who gets tested for the virus. But globally, “the death rate data is more robust and consistent,” says molecular biologist Sabra Klein, co-director of the Johns Hopkins Center for Women’s Health, Sex and Gender Research.

Klein sees three plausible biological factors in women’s relative survival. First, the female immune system is simply stronger at just about every level, partly because female estrogen hormones tend to amp up the immune system, whereas male androgen hormones tend to dial it back. (A hypervigilant system is a double-edged sword for women, who pay a price by having a greater risk of autoimmune diseases.)

“When the female immune system sees a virus, we tend to mount a much more rapid response, and the magnitude is often greater,” Klein says. This advantage, which includes antibody response, has been shown with other infections and reactions to vaccines and in mouse models of the earlier SARS coronavirus, which also killed more men than women. Women may have evolved a stronger immune system to allow for antibodies, intercell signals called cytokines and other defense mechanisms to be passed to their babies in utero and through breast milk.

A second factor in the sex gap, Klein says, is that “as they start to hit their 50s and 60s, men have more of the underlying conditions—heart disease, hypertension, diabetes”—that worsen coronavirus outcomes. Women tend to develop these ailments somewhat later, which could help explain why the discrepancy between male and female mortality in the U.S. appears largest in the 45-to-64 age range.

A third possible contributor is differences between genes on the female X and male Y sex chromosomes. “It turns out that there are over 60 genes associated with immune function on the X chromosome,” Klein says. Some are involved in the production of interferons, key modulators of the body’s response to viruses. “My group and others have shown that females show greater expression of some of these genes than do males,” Klein adds, “and this can have functional significance.”

Behavior may also factor into the higher male death rate. In many cultures, men are more likely to smoke—a habit linked to a worse prognosis. Women, in contrast, are inclined toward more protective conduct. They were about 50 percent more likely than men to wear a face mask, wash their hands and avoid public transit during earlier respiratory disease epidemics such as bird flu and SARS, according to a 2016 meta-analysis by Kelly Moran and Sara Del Valle, both at Los Alamos National Laboratory. Such gender differences in attitude and behavior have continued in the current pandemic, according to a survey conducted in March and April by the National Bureau of Economic Research. Responses from 21,649 people in eight developed nations indicated that women are more likely to take COVID-19 seriously and agree to comply with public safety measures.

Genetic Vulnerability

Other genes besides those on the sex chromosomes might influence vulnerability to COVID-19. Andrea Ganna and Mark Daly, both at the University of Helsinki’s Institute of Molecular Medicine Finland, have organized a global consortium called the COVID-19 Host Genetics Initiative to search for genetic variations that might put people at a higher or lower risk of becoming seriously ill. (Most variants affect the genes in subtle ways without interfering with their main functions.) Some of the more intriguing findings so far come from a study of 1,980 patients in Italy and Spain that was published in the New England Journal of Medicine. The researchers identified a cluster of variants on chromosome 3 that are associated with severe illness and respiratory failure in COVID-19 patients. A few of the genes encode key immune system molecules called cytokines. An additional one codes for a protein that interacts with the molecular doorway that the virus uses to enter cells: a surface enzyme called angiotensin-converting enzyme 2, or ACE2.

More tentatively, the investigators found that genes on chromosome 9 that determine blood type could be linked to risk, putting people with type A blood in slightly greater danger of severe illness. “The jury is still out” on that finding, Ganna says, because a larger analysis did not confirm it. “But the signal on chromosome 3 is real and has been replicated robustly. It is associated with COVID severity.”

[How DNA changes tied to immune reactions, a viral doorway and possibly blood type could influence COVID-19 severity.]

A second genetics initiative, led by Jean-Laurent Casanova of the Rockefeller University and Helen Su of the National Institute of Allergy and Infectious Diseases, is searching for genes that might help account for two types of pandemic outliers. The first group is made up of young, otherwise healthy individuals who develop severe COVID-19, or, as Casanova puts it, “the guy who runs a marathon in 2019 and then he is in the ICU, intubated.” The second group comprises people who remain uninfected despite extreme exposure, such as the virus-negative spouse of an ill patient. “We will test the hypothesis that some of them carry single-gene variations that make them naturally resistant to the entry of the virus,” Casanova says. Such a gene, if it exists, would be analogous to one discovered in 1996 called CCR5 delta 32, which confers resistance to HIV.

The identification of genes providing immunity or raising vulnerability, even if their effects are small, could offer useful clues for developing drugs for COVID-19, Ganna and Casanova say.

How Underlying Disorders Raise Risks

From the earliest days of the pandemic, it has been clear that patients with certain chronic diseases are especially endangered by SARS-CoV-2. The JAMA report on 5,700 patients who were hospitalized for COVID-19 in and around New York City found that 94 percent had at least one chronic condition and 88 percent had more than one.

In mid-June, the U.S. Centers for Disease Control and Prevention published an analysis of 287,320 confirmed cases for which accompanying conditions were reported. It showed that the most common ones were cardiovascular disease (in 32 percent of patients), diabetes (30 percent) and chronic lung disease (18 percent). People with COVID-19 who had chronic ailments such as these were six times as likely to be hospitalized and 12 times as likely to die as those who did not have them.

The high-risk conditions share a couple of things. First, most are associated with chronic low-grade inflammation, which compromises immune system function. Although the precise mechanisms by which inflammation does so are unclear, there are several leading suspects. One of them, at least in people who are significantly overweight, is the activity of fat cells, which churn out a variety of inflammatory substances such as interleukin-6. “People with excess fat tissue may have a dysregulated immune response and not be able to counterbalance a severe infection,” says Erin D. Michos, a cardiologist and epidemiologist at the Johns Hopkins University School of Medicine.

Diabetes, hypertension, cardiovascular disease and obesity have something else in common, Narasimhan observes: “All have upregulation of ACE2.” Heightened expression of the protein in these conditions may possibly give the virus more entry points throughout the body. Doctors already know that SARS-CoV-2 breezes into a host via the respiratory tract and attacks the lungs. But additional evidence suggests that it may move into other ACE2-rich tissues such as the heart and kidneys. When it hits those organs, the damage—whether from the virus itself or the body’s battle to contain it—can include blood clots and strokes, kidney injury, heart attacks, heart failure and arrhythmias.

Michos says that preexisting chronic conditions endanger COVID-19 patients in multiple ways. At the most elemental level, people with these ailments have less “cardiopulmonary reserve” to call on when the body is fighting a massive respiratory infection. Lack of oxygen from overwhelmed lungs forces the heart to work so hard that it can fail—especially if its capacity is already limited by narrowed arteries or heart disease. “It’s like a tremendous stress test,” Michos says. Another route to danger are the now infamous immune-system freak-outs known as cytokine storms, which can further damage organs that are already fragile.

The Hazards of Inequality and Racism

Beyond the inner layers, a wide range of external stressors also shape vulnerability to a virus such as SARS-CoV-2. As the pandemic has torn through the population of the U.S., it has taken an uneven toll. The CDC’s mid-June analysis looked at 599,636 U.S. cases where race and ethnicity were reported. It found that 33 percent occurred in people of Latinx origin and 22 percent in Black people, even though these groups form, respectively, just 18 percent and 13 percent of the U.S. population. Some Native American groups, such as the Navajo, are also being hit tremendously hard. Mortality is disproportionate as well: Overall, Black Americans are dying at more than twice the rate of white people. In some states, their deaths occur at four or five times that rate.

Many factors contribute to this excessive toll, but they stem from the biased attitudes and actions of American society, not from Black American biology, says epidemiologist and family physician Camara Phyllis Jones of the Morehouse School of Medicine. “Race doesn’t put you at higher risk. Racism puts you at higher risk,” says Jones, who is a past president of the American Public Health Association. “Racism puts you at higher risk through the two mechanisms of being more infected because we are more exposed and less protected, and then, once infected, we are more likely to have a very severe course and die.”

[Physician Camara Phyllis Jones explains the multiple ways that racial injustice and racism increase Black people’s vulnerability to the virus.]

The higher risk of catching the virus comes both on the job and at home. An analysis conducted for Bloomberg found, for example, that only 19.7 percent of Black workers were in a position to work remotely during lockdowns, as opposed to 29.9 percent of white workers. A larger proportion of the jobs held by people of color are essential but low-paid ones. These are positions such as home health aide, grocery store worker, meatpacker, delivery worker and hospital orderly—roles that require constant contact with the public or crowded conditions with co-workers, both of which lead to high exposure to the coronavirus. The jobs do not come with the protections, such as telecommuting, afforded to those in higher-paid positions. For such workers, Jones says, “the personal protective equipment has been very slow in coming.”

On top of that, she says, many people of color live in high-density, lower-income neighborhoods. “You’re in a one-bedroom apartment with five people living there, and one is your grandmother,” Jones relates. “You can’t safely isolate, so people are more exposed by family members who are frontline workers that have gone out and then bring the infection home.” In addition, compared with white Americans, a higher proportion of minority group members are held in prisons and sleep in homeless shelters, where infections spread quickly.

When people of color get the coronavirus, they are more at risk of becoming severely ill because they shoulder a greater burden of the chronic illnesses that can make COVID-19 more deadly. Black Americans, for example, suffer a 40 percent higher rate of hypertension and a 60 percent higher rate of diabetes than white Americans. Native Americans, meanwhile, are twice as likely to have diabetes as white Americans. Structural inequities—such as neighborhoods that lack high-quality food options, the absence of safe places and leisure time to exercise, and poor air quality—contribute to these elevated levels of illness, noted Sherita Hill Golden, an endocrinologist at Johns Hopkins Medicine, at a May seminar on racial disparities and COVID-19.

Poorer access to medical care and discrimination within the health care system add to these burdens. As the pandemic got worse in early spring, many people of color had a hard time getting tested for COVID-19. “Testing sites were often located in more affluent neighborhoods,” Jones says. “Or there was drive-through testing. And what if you don’t have a car?”

Golden points out that fear of immigration authorities and concerns about the Trump administration’s new public charge rule—which makes it difficult for people who use Medicaid to gain legal immigration status—might be leading undocumented individuals to “avoid using [health] services they might otherwise have used.”

Epidemiologists who study health inequities have found that lifelong stressors related to racial and ethnic discrimination take a direct toll on health. Ongoing elevated levels of stress hormones, such as cortisol and catecholamines, are thought to mediate this wear and tear and aggravate tissue damage. As a result, Black Americans tend to develop hypertension, glaucoma and some other aging-associated disorders earlier than white people do. The phenomenon has been termed “weathering” by Arline Geronimus, a professor of public health at the University of Michigan. Her research indicates that this premature aging cannot be explained by poverty and posits that it is the direct result of race-based injustice and bias.

[The stress of racism, which accompanies the growing gap between poor and rich, inflicts biological harm through several pathways.]

As these and other COVID-19 risk factors become clearer, physicians and scientists say, health authorities need to shift resources and intensify protections for communities, groups and individuals who are most vulnerable. That effort has begun to happen in nursing homes, for example— though only after tremendous losses of life. Diagnostic testing for the virus is one such resource. “We know that there are communities at higher risk, and we need to be doing more testing there,” Jones says. And that means examining people without symptoms who are able to spread the virus without knowing they are infected. “If we restrict ourselves to only testing people who are symptomatic,” she warns, “we will just be documenting the course of the pandemic, but we will lose the opportunity to change the course of the pandemic.”

On an individual level, people need to take stock of every layer of their own vulnerability, from the biological to the societal, and do what they can to mitigate hazards through pandemic-specific practices such as social distancing, mask wearing and avoiding crowds. (It is also important to try to maintain healthy habits, such as a good diet and regular exercise, although current circumstance can make doing so difficult.) At the same time, it is wise to remember that risk-group analyses reflect averages. An individual might have no obvious risk factors and still wind up desperately sick or dead. “The only job of this virus is to replicate itself,” Jones points out. “It will make its way through all the susceptibles that it can find.”

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