Why COVID-19 kills some people and spares others. Here's what scientists are finding.

The SARS-CoV-2 virus invades human cells by attaching to ACE2 receptors on the surfaces of those cells.

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The novel coronavirus causing COVID-19 seems to hit some people harder than others, with some people experiencing only mild symptoms and others being hospitalized and requiring ventilation. Though scientists at first thought age was the dominant factor, with young people avoiding the worst outcomes, new research has revealed a suite of features impacting disease severity. These influences could explain why some perfectly healthy 20-year-old with the disease is in dire straits, while an older 70-year-old dodges the need for critical interventions.

Underlying health conditions are thought to be an important factor influencing disease severity. Indeed, a study of more than 1.3 million COVID-19 cases in the United States, published June 15 in the journal Morbidity and Mortality Weekly Report, found that rates of hospitalizations were six times higher and rates of death were 12 times higher among COVID-19 patients with underlying conditions, compared with patients without underlying conditions. The most commonly reported underlying conditions were heart disease, diabetes and chronic lung disease.

About 8 out of 10 deaths associated with COVID-19 in the U.S. have occurred in adults ages 65 and older, according to the U.S. Centers for Disease Control and Prevention (CDC). The risk of dying from the infection, and the likelihood of requiring hospitalization or intensive medical care, increases significantly with age. For instance, adults ages 65-84 make up an estimated 4-11% of COVID-19 deaths in the U.S, while adults ages 85 and above make up 10-27%.

That fits with what researchers have seen with other infections and diabetes. For instance, flu and pneumonia are more common and more serious in older individuals with type 2 diabetes, scientists reported online April 9 in the journal Diabetes Research and Clinical Practice. In a literature search of relevant studies looking at the link between COVID-19 and diabetes, the authors of that paper found a few possible mechanisms to explain why a person with diabetes might fare worse when infected with COVID-19. These mechanisms include: "Chronic inflammation, increased coagulation activity, immune response impairment and potential direct pancreatic damage by SARS-CoV-2."

No research has looked at this particular virus and immune response in patients with diabetes; however, in a study published in 2018 in the Journal of Diabetes Research, scientists found through a review of past research that patients with obesity or diabetes showed immune systems that were out of whack, with an impairment of white blood cells called Natural Killer (NK) cells and B cells, both of which help the body fight off infections. The research also showed that these patients had an increase in the production of inflammatory molecules called cytokines. When the immune system secretes too many cytokines,a so-called "cytokine storm" can erupt and damage the body's organs. Some research has suggested that cytokine storms may be responsible for causing serious complications in people with COVID-19, Live Science previously reported. Overall, type 2 diabetes has been linked with impairment of the very system in the body that helps to fight off infections like COVID-19 and could explain why a person with diabetes is at high risk for a severe infection.

People with type 1 diabetes (T1D) are also at elevated risk of adverse outcomes, a small study published in Diabetes Care suggests. The study, coordinated by T1D Exchange — a nonprofit research organization focused on therapies for those with type 1 diabetes — found that of 64 people with either COVID-19 or COVID-19-like symptoms, two died. Nearly 4 in 10 people had to be treated in a hospital. And nearly a third experienced diabetic ketoacidosis — a potentially deadly condition in which the body experiences a shortage of insulin and blood sugar levels rise dangerously high. The average patient was about 21 years old, suggesting that risks could be potentially higher for older age groups.

The first reported coronavirus death in the U.S., for instance, occurred when the virus somehow damaged a woman's heart muscle, eventually causing it to burst, Live Science reported. The 57-year-old maintained good health and exercised regularly before becoming infected, and she reportedly had a healthy heart of "normal size and weight." A study of COVID-19 patients in Wuhan, China, found that more than 1 in 5 patients developed heart damage — some of the sampled patients had existing heart conditions, and some did not.

In one scenario, by attacking the lungs directly, the virus might deplete the body's supply of oxygen to the point that the heart must work harder to pump oxygenated blood through the body. The virus might also attack the heart directly, as cardiac tissue contains angiotensin-converting enzyme 2 (ACE2) — a molecule that the virus plugs into to infect cells. In some individuals, COVID-19 can also kickstart an overblown immune response known as a cytokine storm, wherein the body becomes severely inflamed and the heart could suffer damage as a result.

People who smoke cigarettes may be prone to severe COVID-19 infections, meaning they face a heightened risk of developing pneumonia, suffering organ damage and requiring breathing support. A study of more than 1,000 patients in China, published in the New England Journal of Medicine, illustrates this trend: 12.3% of current smokers included in the study were admitted to an ICU, were placed on a ventilator or died, as compared with 4.7% of nonsmokers.

Cigarette smoke might render the body vulnerable to the coronavirus in several ways, according to a recent Live Science report. At baseline, smokers may be vulnerable to catching viral infections because smoke exposure dampens the immune system over time, damages tissues of the respiratory tract and triggers chronic inflammation. Smoking is also associated with a multitude of medical conditions, such as emphysema and atherosclerosis, which could exacerbate the symptoms of COVID-19.

Many of the receptors appear on so-called goblet and club cells, which secrete a mucus-like fluid to protect respiratory tissues from pathogens, debris and toxins. It's well-established that these cells grow in number the longer a person smokes, but scientists don't know whether the subsequent boost in ACE2 receptors directly translates to worse COVID-19 symptoms. What's more, it's unknown whether high ACE2 levels are relatively unique to smokers, or common among people with chronic lung conditions.

"This has important and practical implications" in a country like the U.S. where nearly 40% of adults are obese, the authors wrote in the study, which was accepted into the journal Clinical Infectious Diseases but not yet peer-reviewed or published. Similarly, another preliminary study that hasn't yet been peer-reviewed found that the two biggest risk factors for being hospitalized from the coronavirus are age and obesity. This study, published in medRxiv looked at data from thousands of COVID-19 patients in New York City, but studies from other cities around the world found similar results, as reported by The New York Times.

A preliminary study from Shenzhen, China, which also hasn't been peer-reviewed, found that obese COVID-19 patients were more than twice as likely to develop severe pneumonia as compared with patients who were normal weight, according to the report published as a preprint online in the journal The Lancet Infectious Diseases. Those who were overweight, but not obese, had an 86% higher risk of developing severe pneumonia than did people of "normal" weight, the authors reported. Another study, accepted into the journal Obesity and peer-reviewed, found that nearly half of 124 COVID-19 patients admitted to an intensive care unit in Lille, France, were obese.

It's not clear why obesity is linked to more hospitalizations and more severe COVID-19 disease, but there are several possibilities, the authors wrote in the study. Obesity is generally thought of as a risk factor for severe infection. For example, those who are obese had longer and more severe disease during the swine flu epidemic, the authors wrote. Obese patients might also have reduced lung capacity or increased inflammation in the body. A greater number of inflammatory molecules circulating in the body might cause harmful immune responses and lead to severe disease.

Jiao Zhao, of The Southern University of Science and Technology, Shenzhen, and colleagues looked at blood types of 2,173 patients with COVID-19 in three hospitals in Wuhan, China, as well as blood types of more than 23,000 non-COVID-19 individuals in Wuhan and Shenzhen. They found that individuals with blood types in the A group (A-positive, A-negative and AB-positive, AB-negative) were at a higher risk of contracting the disease compared with non-A-group types. People with O blood types (O-negative and O-positive) had a lower risk of getting the infection compared with non-O blood types, the scientists wrote in the preprint database medRxiv on March 27; the study has yet to be reviewed by peers in the field.

In a more recent study of blood type and COVID-19, published online April 11 to medRxiv, scientists looked at 1,559 people tested for SARS-CoV-2 at New York Presbyterian hospital; of those, 682 tested positive. Individuals with A blood types (A-positive and A-negative) were 33% more likely to test positive than other blood types and both O-negative and O-positive blood types were less likely to test positive than other blood groups. (There's a 95% chance that the increase in risk ranges from 7% to 67% more likely.) Though only 68 individuals with an AB blood type were included, the results showed this group was also less likely than others to test positive for COVID-19.

The researchers considered associations between blood type and risk factors for COVID-19, including age, sex, whether a person was overweight, other underlying health conditions such as diabetes mellitus, hypertension, pulmonary diseases and cardiovascular diseases. Some of these factors are linked to blood type, they found, with a link between diabetes and B and A-negative blood types, between overweight status and O-positive blood groups, for instance, among others. When they accounted for these links, the researchers still found an association between blood type and COVID-19 susceptibility. When the researchers pooled their data with the research by Zhao and colleagues out of China, they found similar results as well as a significant drop in positive COVID-19 cases among blood type B individuals.

Why blood type might increase or decrease a person's risk of getting SARS-CoV-2 is not known. A person's blood type indicates what kind of certain antigens cover the surfaces of their blood cells; These antigens produce certain antibodies to help fight off a pathogen. Past research has suggested that at least in the SARS coronavirus (SARS-CoV), anti-A antibodies helped to inhibit the virus; that could be the same mechanism with SARS-CoV-2, helping blood group O individuals to keep out the virus, according to Zhao's team.

For instance, a study published April 17 in the Journal of Virology suggests that specific combinations of human leukocyte antigen (HLA) genes, which train immune cells to recognize germs, may be protective against SARS-CoV-2, while other combinations leave the body open to attack. HLAs represent just one cog in our immune system machinery, though, so their relative influence over COVID-19 infection remains unclear. Additionally, the Journal of Virology study only used computer models to simulate HLA activity against the coronavirus; clinical and genetic data from COVID-19 patients would be needed to flesh out the role of HLAs in real-life immune responses.

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Why COVID-19 kills some people and spares others. Here's what scientists are finding.

Age

Diabetes

Heart disease and hypertension

Smoking

Obesity

Blood type

Genetic factors