Why Some People Get Sicker Than Others

Source: James Hamblin, The Atlantic, 4/21/2020

COVID-19 is proving to be a disease of the immune system. This could, in theory, be controlled.

The COVID-19 crash comes suddenly. In early March, the 37-year-old writer F. T. Kola began to feel mildly ill, with a fever and body aches. To be safe, she isolated herself at home in San Francisco. Life continued apace for a week, until one day she tried to load her dishwasher and felt strangely exhausted.

Her doctor recommended that she go to Stanford University’s drive-through coronavirus testing site. “I remember waiting in my car, and the doctors in their intense [protective equipment] coming towards me like a scene out of Contagion,” she told me when we spoke for The Atlantic’s podcast Social Distance. “I felt like I was a biohazard—and I was.” The doctors stuck a long swab into the back of her nose and sent her home to await results.

Lying in bed that night, she began to shake, overtaken by the most intense chills of her life. “My teeth were chattering so hard that I was really afraid they would break,” she said. Then she started to hallucinate. “I thought I was holding a very big spoon for some reason, and I kept thinking, Where am I going to put my spoon down?

An ambulance raced her to the hospital, where she spent three days in the ICU, before being moved to a newly created coronavirus-only ward. Sometimes she barely felt sick at all, and other times she felt on the verge of death. But after two weeks in the hospital, she walked out. Now, as the death toll from the coronavirus has climbed to more than 150,000 people globally, Kola has flashes of guilt and disbelief: “Why did my lungs make it through this? Why did I go home? Why am I okay now?”

COVID-19 is, in many ways, proving to be a disease of uncertainty. According to a new study from Italy, some 43 percent of people with the virus have no symptoms. Among those who do develop symptoms, it is common to feel sick in uncomfortable but familiar ways—congestion, fever, aches, and general malaise. Many people start to feel a little bit better. Then, for many, comes a dramatic tipping point. “Some people really fall off the cliff, and we don’t have good predictors of who it’s going to happen to,” Stephen Thomas, the chair of infectious diseases at Upstate University Hospital, told me. Those people will become short of breath, their heart racing and mind detached from reality. They experience organ failure and spend weeks in the ICU, if they survive at all.

Meanwhile, many others simply keep feeling better and eventually totally recover. Kola’s friend Karan Mahajan, an author based in Providence, Rhode Island, contracted the virus at almost the same time she did. In stark contrast to Kola, he said, “My case ended up feeling like a mild flu that lasted for two weeks. And then it faded after that.”

“There’s a big difference in how people handle this virus,” says Robert Murphy, a professor of medicine and the director of the Center for Global Communicable Diseases at Northwestern University. “It’s very unusual. None of this variability really fits with any other diseases we’re used to dealing with.”

This degree of uncertainty has less to do with the virus itself than how our bodies respond to it. As Murphy puts it, when doctors see this sort of variation in disease severity, “that’s not the virus; that’s the host.” Since the beginning of the pandemic, people around the world have heard the message that older and chronically ill people are most likely to die from COVID-19. But that is far from a complete picture of who is at risk of life-threatening disease. Understanding exactly how and why some people get so sick while others feel almost nothing will be the key to treatment.

Hope has been put in drugs that attempt to slow the replication of the virus—those currently in clinical trials like remdesivirivermectin, and hydroxychloroquine. But with the flu and most other viral diseases, antiviral medications are often effective only early in the disease. Once the virus has spread widely within our body, our own immune system becomes the thing that more urgently threatens to kill us. That response cannot be fully controlled. But it can be modulated and improved.


One of the common, perplexing experiences of COVID-19 is the loss of smell—and, then, taste. “Eating pizza was like eating cardboard,” Mahajan told me. Any common cold that causes congestion can alter these sensations to some degree. But a near-total breakdown of taste and smell is happening with coronavirus infections even in the absence of other symptoms.

Jonathan Aviv, an ear, nose, and throat doctor based in New York, told me he has seen a surge in young people coming to him with a sudden inability to taste. He’s unsure what to tell them about what’s going on. “The non-scary scenario is that the inflammatory effect of the infection is temporarily altering the function of the olfactory nerve,” he said. “The scarier possibility is that the virus is attacking the nerve itself.” Viruses that attack nerves can cause long-term impairment, and could affect other parts of the nervous system. The coronavirus has already been reported to precipitate inflammation in the brain that leads to permanent damage.

Though SARS-CoV-2 (the new coronavirus) isn’t reported to invade the brain and spine directly, its predecessor SARS-CoV seems to have that capacity. If nerve cells are spared by the new virus, they would be among the few that are. When the coronavirus attaches to cells, it hooks on and breaks through, then starts to replicate. It does so especially well in the cells of the nasopharynx and down into the lungs, but is also known to act on the cells of the liver, bowels, and heart. The virus spreads around the body for days or weeks in a sort of stealth mode, taking over host cells while evading the immune response. It can take a week or two for the body to fully recognize the extent to which it has been overwhelmed. At this point, its reaction is often not calm and measured. The immune system goes into a hyperreactive state, pulling all available alarms to mobilize the body’s defense mechanisms. This is when people suddenly crash.

Bootsie Plunkett, a 61-year-old retiree in New Jersey with diabetes and lupus, described it to me as suffocating. We met in February, taping a TV show, and she was her typically ebullient self. A few weeks later, she developed a fever. It lasted for about two weeks, as did the body aches. She stayed at home with what she presumed was COVID-19. Then, as if out of nowhere, she was gasping for air. Her husband raced her to the hospital, and she began to slump over in the front seat. When they made it to the hospital, her blood-oxygen level was just 79 percent, well below the point when people typically require aggressive breathing support.

Such a quick decline—especially in the later stages of an infectious disease—seems to result from the immune response suddenly kicking into overdrive. The condition tends to be dire. Half of the patients with COVID-19 who end up in the intensive-care unit at New York–Presbyterian Hospital stay for 20 days, according to Pamela Sutton-Wallace, the regional chief operating officer. (In normal times, the national average is 3.3 days). Many of these patients arrive at the hospital in near-critical condition, with their blood tests showing soaring levels of inflammatory markers. One that seems to be especially predictive of a person’s fate is a protein known as D-dimer. Doctors in Wuhan, China, where the coronavirus outbreak was first reported, have found that a fourfold increase in D-dimer is a strong predictor of mortality, suggesting in a recent paper that the test “could be an early and helpful marker” of who is entering the dangerous phases.

These and other markers are often signs of a highly fatal immune-system process known as a cytokine storm, explains Randy Cron, the director of rheumatology at Children’s of Alabama, in Birmingham. A cytokine is a short-lived signaling molecule that the body can release to activate inflammation in an attempt to contain and eradicate a virus. In a cytokine storm, the immune system floods the body with these molecules, essentially sounding a fire alarm that continues even after the firefighters and ambulances have arrived.

At this point, the priority for doctors shifts from hoping that a person’s immune system can fight off the virus to trying to tamp down the immune response so it doesn’t kill the person or cause permanent organ damage. As Cron puts it, “If you see a cytokine storm, you have to treat it.” But treating any infection by impeding the immune system is always treacherous. It is never ideal to let up on a virus that can directly kill our cells. The challenge is striking a balance where neither the cytokine storm nor the infection runs rampant.

Cron and other researchers believe such a balance is possible. Cytokine storms are not unique to COVID-19. The same basic process happens in response to other viruses, such as dengue and Ebola, as well as influenza and other coronaviruses. It is life-threatening and difficult to treat, but not beyond the potential for mitigation.

At Johns Hopkins University, the biomedical engineer Joshua Vogelstein and his colleagues have been trying to identify patterns among people who have survived cytokine storms and people who haven’t. One correlation the team noticed was that people taking the drug tamsulosin (sold as Flomax, to treat urinary retention) seemed to fare well. Vogelstein is unsure why. Cytokine storms do trigger the release of hormones such as dopamine and adrenaline, which tamsulosin can partially block. The team is launching a clinical trial to see if the approach is of any help.

One of the more promising approaches is blocking cytokines themselves—once they’ve already been released into the blood. A popular target is one type of cytokine known as interleukin-6 (IL-6), which is known to peak at the height of respiratory failure. Benjamin Lebwohl, director of research at Columbia University’s Celiac Disease Center, says that people with immune conditions like celiac and inflammatory bowel disease may be at higher risk of severe cases of COVID-19. But he’s hopeful that medications that inhibit IL-6 or other cytokines could pare back the unhelpful responses while leaving others intact. Other researchers have seen promising preliminary results, and clinical trials are ongoing.

If interleukin inhibitors end up playing a significant role in treating very sick people, though, we would run out. These medicines (which go by names such as tocilizumab and ruxolitinib, reading like a good draw in Scrabble) fall into a class known as “biologics.” They are traditionally used in rare cases and tend to be very expensive, sometimes costing people with immune conditions about $18,000 a year. Based on price and the short supply, Cron says, “my guess is we’re going to rely on corticosteroids at the end of the day. Because it’s what we have.”

That is a controversial opinion. Corticosteroids (colloquially known as “steroids,” though they are of the adrenal rather than reproductive sort), can act as an emergency brake on the immune system. Their broad, sweeping action means that steroids involve more side effects than targeting one specific cytokine. Typically, a person on steroids has a higher risk of contracting another dangerous infection, and early evidence on the utility of steroids in treating COVID-19, in studies from the outbreak in China, was mixed. But some doctors are now using them to good effect. Last week, the Infectious Diseases Society of America issued guidelines on steroids, recommending them in the context of a clinical trial when the disease reaches the level of acute respiratory distress. They may have helped Plunkett, the 61-year-old from New Jersey. After three days on corticosteroids, she left the ICU—without ever being intubated.

Deciding on the precise method of modulating the immune response—the exact drug, dose, and timing—is ideally informed by carefully monitoring patients before they are critically ill. People at risk of a storm could be monitored closely throughout their illness, and offered treatment immediately when signs begin to show. That could mean detecting the markers in a person’s blood before the process sends her into hallucinations—before her oxygen level fell at all.

In typical circumstances in the United States and other industrialized nations, patients would be urged to go to the hospital sooner rather than later. But right now, to avoid catastrophic strain on an already overburdened health-care system, people are told to avoid the hospital until they feel short of breath. For those who do become critically ill and arrive at the ER in respiratory failure, health-care workers are then behind the ball. Given those circumstances, the daily basics of maintaining overall health and the best possible immune response become especially important.

The official line from the White House Coronavirus Task Force has been that “high-risk” people are older and those with chronic medical conditions, such as obesity and diabetes. But that has proven to be a limited approximation of who will bear the burden of this disease most severely. Last week, the Centers for Disease Control and Prevention released its first official report on who has been hospitalized for COVID-19. It found that Latinos and African Americans have died at significantly higher rates than white Americans. In Chicago, more than half of the people who have tested positive, and nearly 60 percent of those who have died, were African American. They make up less than one-third of the city’s population. Similar patterns are playing out across the country: Rates of death and severe disease are several times higher among racial minorities and people of low socioeconomic status.

These disparities are beginning to be acknowledged at high levels, but often as though they are just another one of the mysteries of the coronavirus. At a White House briefing last week, Vice President Mike Pence said his team was looking into “the unique impact that we’re seeing reported on African Americans from the coronavirus.” Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, has noted that “we are not going to solve the issues of health disparities this month or next month. This is something we should commit ourselves for years to do.”

While America’s deepest health disparities absolutely would require generations  to undo, the country still could address many gaps right now. Variation in immune responses between people is due to much more than age or chronic disease. The immune system is a function of the communities that brought us up and the environments with which we interact every day. Its foundation is laid by genetics and early-life exposure to the world around us—from the food we eat to the air we breathe. Its response varies on the basis of income, housing, jobs, and access to health care.

The people who get the most severely sick from COVID-19 will sometimes be unpredictable, but in many cases, they will not. They will be the same people who get sick from most every other cause. Cytokines like IL-6 can be elevated by a single night of bad sleep. Over the course of a lifetime, the effects of daily and hourly stressors accumulate. Ultimately, people who are unable to take time off of work when sick—or who don’t have a comfortable and quiet home, or who lack access to good food and clean air—are likely to bear the burden of severe disease.

Much is yet unknown about specific cytokines and their roles in disease. But the likelihood of disease in general is not so mysterious. Often, it’s a matter of what societies choose to tolerate. America has empty hotels while people sleep in parking lots. We are destroying food while people go hungry. We are allowing individuals to endure the physiological stresses of financial catastrophe while bailing out corporations. With the coronavirus, we do not have vulnerable populations so much as we have vulnerabilities as a population. Our immune system is not strong.


JAMES HAMBLIN, M.D., is a staff writer at The Atlantic. He is also a lecturer at Yale School of Public Health and author of the forthcoming book Clean.

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