COVID-19: Why is it mild for some, deadly for others?

April 17, 2020

Among the confounding aspects of the novel coronavirus is the wide range of disease severity patients experience. While a minority of COVID-19 patients require hospitalization, the effects of infection for these people are dramatic and in some cases life threatening.

Why do some people get severe and life-threatening COVID-19, while others suffer no symptoms or just mild ones?

Older vs. Younger

Age is one risk factor. Compared to younger patients, middle-aged and older ones are far more likely to suffer symptoms, to be hospitalized, and to die. One recent analysis of Chinese data estimated the chance of death in confirmed COVID-19 cases at more than 13 percent for patients 80 and older, compared to about 0.15 percent for patients in their 30s, and virtually zero percent for patients under 20. A study of early U.S. cases by the Centers for Disease Control and Prevention (CDC) had similar findings.

Partly this may be explained by the fact that older immune systems tend to be less efficient at clearing viral infections. However, that’s probably not the full story. “People in their 40s, 50s, and 60s generally aren’t hit by other viral infections, such as flu, the way they’re hit by COVID-19,” said Dr. Fred Pelzman, associate professor of clinical medicine at Weill Cornell Medicine and associate attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.

Severe COVID-19 is driven not just by viral damage to cells but by a reactive “storm” of inflammation that harms the lungs and other organs. There may be changes in different parts of the immune system from aging that make the middle-aged more vulnerable to this storm than younger patients, even if they are healthy and have no underlying medical conditions. There may also be lifestyle factors, such as a greater likelihood of encountering the virus in social and work settings that middle-aged people frequent, that contribute to their vulnerability, Dr. Pelzman said.

Children can get COVID-19 infections, but are largely spared severe illness. Again, the reason isn’t clear. One suggestion from studies of other viruses, including the related coronavirus that caused the 2002-04 SARS epidemic, is that children and younger animals may be much less likely to develop an inflammatory storm when infected.

Men vs. Women

Men and women appear to get COVID-19 at roughly equal rates, but in most countries men are much more likely to die of it. In Italy and Ireland, for example, males account for about 70 percent of COVID-19 deaths.

There is no shortage of hypotheses for this difference. One is that there are sex differences in the immune response—studies of influenza, for example, have found that older men tend to have worse outcomes than older women. Men also are more likely to drink alcohol, which weakens the immune system and increases susceptibility to pneumonia. Men are much more likely to smoke tobacco, which weakens immunity and overall lung function, primes the lungs and other vital organs for greater inflammation, and leads to greater susceptibility to respiratory infections and pneumonia. Chinese clinicians treating COVID-19 cases early this year found that a history of cigarette smoking was a very strong risk factor in predicting worse disease outcomes.

Even so, the studies needed to determine the factors underlying men’s extra vulnerability just haven’t been done yet, Dr. Pelzman emphasized.

Underlying Medical Conditions

Patients who develop serious or fatal COVID-19 are disproportionately likely to have at least one major underlying health condition, such as diabetes, hypertension, obesity, cardiovascular disease, asthma, kidney disease, or chronic obstructive pulmonary disorder.

In some cases, the possible explanations for these links are obvious. Diabetes and obesity are associated with a weaker resistance to infections; a letter from Weill Cornell Medicine physicians published on April 17 in NEJM suggested that obesity, particularly in men, was associated with treatment requiring mechanical ventilation. Asthma and chronic obstructive pulmonary disorder involve reduced lung function, and a greater susceptibility to lung inflammation; moreover, patients with these disorders often use corticosteroid immune-suppressing drugs, which reduce immunity to respiratory infections. In general, any serious underlying medical condition can make a vital organ less able to withstand the biological stresses caused by an infection and resulting inflammation.

Some researchers have suggested that common treatments for high blood pressure and diabetes may worsen COVID-19 risk, based on the fact that these drugs can boost the levels of ACE2, a cell-surface enzyme that the COVID-19 coronavirus uses to get into cells. However, there is no clinical evidence that these drugs worsen risk, and doctors generally have not advised patients to stop taking them.

Many people take non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for chronic conditions such as arthritis. These drugs are known to stress the kidneys when taken long-term and may even cause chronic kidney disease. That is potentially a problem in the context of COVID-19 because the infection often attacks the kidneys. Some intensive care specialists have observed unexpectedly severe cases of COVID-19 in people with histories of long-term NSAID use, Dr. Pelzman said.

Having an unusually weakened immune system, for example due to cancer treatments, organ transplants, or other conditions requiring patients to take immune-suppressing drugs, is another factor that may greatly increase the susceptibility to serious COVID-19 infection – and make people more contagious during infection. Doctors have been advising those with suppressed immune systems to be extra careful to avoid potential exposure to the virus, for example by staying home, and washing hands frequently..

Race

There is emerging evidence that African Americans are disproportionately likely to develop severe COVID-19. Currently in Louisiana, for example, this group accounts for about 70 percent of COVID-19 deaths, although they make up only a third of the state population. Similar discrepancies are found in many other states. It is simply too early to know what accounts for this apparent vulnerability, but possible factors include African Americans’ relatively high rates of medical conditions already linked to severe COVID-19, including hypertension, kidney disease, obesity, and diabetes. Socioeconomic factors, such as poverty, access to healthcare and health insurance may also play a role.

Immune system “gaps”

Some people who seem perfectly healthy and are not considered immune-deficient may nevertheless have inherited immune system features that leave them more vulnerable than average to certain viral infections. This may be due to random genetic variation as well as ethnic background—in principle, populations with less historical exposure to coronaviruses could be more vulnerable to COVID-19. Research linking immune system gene variants to COVID-19 susceptibility is just beginning, however.

Viral dose

Doctors have long known that the amount, or “dose,” of exposure to an infectious agent can be an important determinant of disease severity. Researchers now are looking at this as a factor that possibly explains why some otherwise healthy people are hit so hard by COVID-19.

“Catching a low dose from someone who was mildly symptomatic on the subway may involve a lower risk of severe illness, compared to catching a high dose from a very sick and highly contagious patient,” Dr. Pelzman said.

Viral strain

SARS-CoV-2, which causes COVID-19, is a single-stranded RNA virus that has the ability to mutate quickly. Over time, and as it spreads around the world, it will develop genetically distinct strains. Some of these strains may spread more easily, or cause more severe disease. However, to date there is no evidence that the SARS-CoV-2 viruses circulating now are clinically very different from each other or that their minor genetic differences explain the range of symptom severity patients are experiencing.

Unknowns

Ultimately, researchers will need time to analyze the coronavirus that causes COVID-19 and evaluate the characteristics of patients who become infected in order to tease out the complex factors that explain why some people get mortally sick while others get only a brief fever and cough – or no symptoms at all.