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发帖数: 4796 | 1 HEALTH
Why Some People Get Sicker Than Others
COVID-19 is proving to be a disease of the immune system. This could, in
theory, be controlled.
Editors Note: The Atlantic is making vital coverage of the coronavirus
available to all readers. Find the collection here.
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 I spoke with her 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?”
[Read: Why the coronavirus has been so successful]
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.
[Read: Why does the president keep pushing a malaria drug]
Hope has been put in drugs that attempt to slow the replication of the virus
—those currently in clinical trials like remdesivir, ivermectin, 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.
[Read: My whole household has COVID-19]
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 Lebwhol, 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.
[Read: The best hopes for a coronavirus drug]
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.
[Read: What the racial data show]
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.
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Sign up for The Atlantic Daily | k*****k
发帖数: 1 | 2 免疫系统超级复杂，需要大量T细胞，B细胞协调工作
很多人免疫失调都不知道，协调失败当然死的快 | w***x
发帖数: 1763 | | m******r
发帖数: 1033 | 4 一句话总结 ‘The
challenge is striking a balance where neither the cytokine storm nor the
infection runs rampant.’
就是你的免疫系统，太强也不行，太弱也不行。 |
|
