By Meredith
Wadman, Jennifer
Couzin-Frankel,
Jocelyn
Kaiser, Catherine
Matacic
Apr.
17, 2020 , 6:45 PM
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GEORGE WASHINGTON HOSPITAL AND SURGICAL THEATER
The coronavirus wreaked extensive damage (yellow) on the lungs of a 59-year-old
man who died at George Washington University Hospital, as seen in a 3D model
based on computerized tomography scans.
Science’s
COVID-19 reporting is supported by the Pulitzer Center.
On rounds in a 20-bed intensive care unit (ICU) one recent day, physician Joshua
Denson assessed two patients with seizures, many with respiratory failure and
others whose kidneys were on a dangerous downhill slide. Days earlier, his
rounds had been interrupted as his team tried, and failed, to resuscitate a
young woman whose heart had stopped. All shared one thing, says Denson, a
pulmonary and critical care physician at the Tulane University School of
Medicine. “They are all COVID positive.”
As the number of confirmed cases of COVID-19 surges past 2.2 million globally
and deaths surpass 150,000, clinicians and pathologists are struggling to
understand the damage wrought by the coronavirus as it tears through the body.
They are realizing that although the lungs are ground zero, its reach can extend
to many organs including the heart and blood vessels, kidneys, gut, and brain.
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“[The disease] can attack almost anything in the body with devastating
consequences,” says cardiologist Harlan Krumholz of Yale University and Yale-New
Haven Hospital, who is leading multiple efforts to gather clinical data on
COVID-19. “Its ferocity is breathtaking and humbling.”
Understanding the rampage could help the doctors on the front lines treat the
fraction of infected people who become desperately and sometimes mysteriously
ill. Does a dangerous, newly observed tendency to blood clotting transform some
mild cases into life-threatening emergencies? Is an overzealous immune response
behind the worst cases, suggesting treatment with immune-suppressing drugs could
help? What explains the startlingly low blood oxygen that some physicians are
reporting in patients who nonetheless are not gasping for breath? “Taking a
systems approach may be beneficial as we start thinking about therapies,” says
Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of
Pennsylvania (HUP).
Related story
·
For survivors of severe COVID-19, beating the virus is just the beginning
What follows is a snapshot of the fast-evolving understanding of how the virus
attacks cells around the body, especially in the roughly 5% of patients who
become critically ill. Despite the more than 1000 papers now spilling into
journals and onto preprint servers every week, a clear picture is elusive, as
the virus acts like no microbe humanity has ever seen. Without larger,
prospective controlled studies that are only now being launched, scientists must
pull information from small studies and case reports, often published at warp
speed and not yet peer reviewed. “We need to keep a very open mind as this
phenomenon goes forward,” says Nancy Reau, a liver transplant physician who has
been treating COVID-19 patients at Rush University Medical Center. “We are still
learning.”
The infection begins
When an infected person expels virus-laden droplets and someone else inhales
them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It
finds a welcome home in the lining of the nose, according to a preprint from
scientists at the Wellcome Sanger Institute and elsewhere. They found that cells
there are rich in a cell-surface receptor called angiotensin-converting enzyme 2
(ACE2). Throughout the body, the presence of ACE2, which normally helps regulate
blood pressure, marks tissues vulnerable to infection, because the virus
requires that receptor to enter a cell. Once inside, the virus hijacks the
cell’s machinery, making myriad copies of itself and invading new cells.
As the virus multiplies, an infected person may shed copious amounts of it,
especially during the first week or so. Symptoms may be absent at this point. Or
the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell
and taste, or head and body aches.
If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the
virus then marches down the windpipe to attack the lungs, where it can turn
deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny
air sacs called alveoli, each lined by a single layer of cells that are also
rich in ACE2 receptors.
Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels
that lie beside the air sacs; the oxygen is then carried to the rest of the
body. But as the immune system wars with the invader, the battle itself disrupts
this healthy oxygen transfer. Front-line white blood cells release inflammatory
molecules called chemokines, which in turn summon more immune cells that target
and kill virus-infected cells, leaving a stew of fluid and dead
cells—pus—behind. This is the underlying pathology of pneumonia, with its
corresponding symptoms: coughing; fever; and rapid, shallow respiration. Some
COVID-19 patients recover, sometimes with no more support than oxygen breathed
in through nasal prongs.
But others deteriorate, often quite suddenly, developing a condition called
acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet
and they struggle ever harder to breathe. On x-rays and computerized tomography
scans, their lungs are riddled with white opacities where black space—air—should
be. Commonly, these patients end up on ventilators. Many die. Autopsies show
their alveoli became stuffed with fluid, white blood cells, mucus, and the
detritus of destroyed lung cells (see graphic).
An invader’s impact
In serious cases, SARS-CoV-2 lands in the lungs and can do deep damage there.
But the virus, or the body’s response to it, can injure many other organs.
Scientists are just beginning to probe the scope and nature of that harm.
8256734WindpipeBile ductBronchiiImmune cellsCapillaryBlood vesselEndothelial
cellACE2SARS-CoV-2SARS-CoV-2ClotMucus12 LiverUp to half of hospitalized patients
have enzyme levels that signal a struggling liver. An immune system in overdrive
and drugs given to fight the virus may be causing the damage.7 NoseSome patients
lose their sense of smell. Scientists speculate that the virus may move up the
nose’s nerve endings and damage cells.6 EyesConjunctivitis, inflammation of the
membrane that lines the front of the eye and inner eyelid, is more common in the
sickest patients.3 KidneysKidney damage is common in severe cases and
makes death more likely. The virus may attack the kidneys directly, or kidney
failure may be part of whole-body events like plummeting blood pressure.4
IntestinesPatient reports and biopsy data suggest the virus can infect the lower
gastrointestinal tract, which is rich in ACE2 receptors. Some 20% or more of
patients have diarrhea.1 LungsA cross section shows immune cells crowding
an inflamed alveolus, whose walls break down during attack by the
virus, diminishing oxygen uptake. Patients cough, fevers rise, and it takes more
and more effort to breathe.8 Heart and blood vesselsThe virus (green) enters
cells, likely including those lining blood vessels, by binding to ACE2 receptors
on the cell surface. Infection can also promote blood clots, heart attacks, and
cardiac inflammation.5 BrainSome COVID-19 patients have strokes,
seizures, mental confusion, and brain inflammation. Doctors are trying to
understand which are directly caused by the virus.
V. ALTOUNIAN/SCIENCE
Some clinicians suspect the driving force in many gravely ill patients’ downhill
trajectories is a disastrous overreaction of the immune system known as a
“cytokine storm,” which other viral infections are known to trigger. Cytokines
are chemical signaling molecules that guide a healthy immune response; but in a
cytokine storm, levels of certain cytokines soar far beyond what’s needed, and
immune cells start to attack healthy tissues. Blood vessels leak, blood pressure
drops, clots form, and catastrophic organ failure can ensue.
Some studies have shown elevated levels of these inflammation-inducing cytokines
in the blood of hospitalized COVID-19 patients. “The real morbidity and
mortality of this disease is probably driven by this out of proportion
inflammatory response to the virus,” says Jamie Garfield, a pulmonologist who
cares for COVID-19 patients at Temple University Hospital.
But others aren’t convinced. “There seems to have been a quick move to associate
COVID-19 with these hyperinflammatory states. I haven’t really seen convincing
data that that is the case,” says Joseph Levitt, a pulmonary critical care
physician at the Stanford University School of Medicine.
He’s also worried that efforts to dampen a cytokine response could backfire.
Several drugs targeting specific cytokines are in clinical trials in COVID-19
patients. But Levitt fears those drugs may suppress the immune response that the
body needs to fight off the virus. “There’s a real risk that we allow more viral
replication,” Levitt says.
Meanwhile, other scientists are zeroing in on an entirely different organ system
that they say is driving some patients’ rapid deterioration: the heart and blood
vessels.
Striking the heart
In Brescia, Italy, a 53-year-old woman walked into the emergency room of her
local hospital with all the classic symptoms of a heart attack, including
telltale signs in her electrocardiogram and high levels of a blood marker
suggesting damaged cardiac muscles. Further tests showed cardiac swelling and
scarring, and a left ventricle—normally the powerhouse chamber of the heart—so
weak that it could only pump one-third its normal amount of blood. But when
doctors injected dye in the coronary arteries, looking for the blockage that
signifies a heart attack, they found none. Another test revealed why: The woman
had COVID-19.
How the virus attacks the heart and blood vessels is a mystery, but dozens of
preprints and papers attest that such damage is common. A 25 March paper in JAMA
Cardiology documented heart damage in nearly 20% of patients out of 416
hospitalized for COVID-19 in Wuhan, China. In another Wuhan study, 44% of 138
hospitalized patients had arrhythmias.
The disruption seems to extend to the blood itself. Among 184 COVID-19 patients
in a Dutch ICU, 38% had blood that clotted abnormally, and almost one-third
already had clots, according to a 10 April paper in Thrombosis Research.
Blood clots can break apart and land in the lungs, blocking vital arteries—a
condition known as pulmonary embolism, which has reportedly killed COVID-19
patients. Clots from arteries can also lodge in the brain, causing stroke. Many
patients have “dramatically” high levels of D-dimer, a byproduct of blood clots,
says Behnood Bikdeli, a cardiovascular medicine fellow at Columbia University
Medical Center.
“The more we look, the more likely it becomes that blood clots are a major
player in the disease severity and mortality from COVID-19,” Bikdeli says.
Infection may also lead to blood vessel constriction. Reports are emerging of
ischemia in the fingers and toes—a reduction in blood flow that can lead to
swollen, painful digits and tissue death.
The more we look, the more likely it becomes that blood clots are a major player
in the disease severity and mortality from COVID-19.
Behnood Bikdeli, Columbia University Irving Medical Center
In the lungs, blood vessel constriction might help explain anecdotal reports of
a perplexing phenomenon seen in pneumonia caused by COVID-19: Some patients have
extremely low blood-oxygen levels and yet are not gasping for breath. It’s
possible that at some stages of disease, the virus alters the delicate balance
of hormones that help regulate blood pressure and constricts blood vessels going
to the lungs. So oxygen uptake is impeded by constricted blood vessels, rather
than by clogged alveoli. “One theory is that the virus affects the vascular
biology and that’s why we see these really low oxygen levels,” Levitt says.
If COVID-19 targets blood vessels, that could also help explain why patients
with pre-existing damage to those vessels, for example from diabetes and high
blood pressure, face higher risk of serious disease. Recent Centers for Disease
Control and Prevention (CDC) data on hospitalized patients in 14 U.S. states
found that about one-third had chronic lung disease—but nearly as many had
diabetes, and fully half had pre-existing high blood pressure.
Mangalmurti says she has been “shocked by the fact that we don’t have a huge
number of asthmatics” or patients with other respiratory diseases in HUP’s ICU.
“It’s very striking to us that risk factors seem to be vascular: diabetes,
obesity, age, hypertension.”
Scientists are struggling to understand exactly what causes the cardiovascular
damage. The virus may directly attack the lining of the heart and blood vessels,
which, like the nose and alveoli, are rich in ACE2 receptors. Or perhaps lack of
oxygen, due to the chaos in the lungs, damages blood vessels. Or a cytokine
storm could ravage the heart as it does other organs.
“We’re still at the beginning,” Krumholz says. “We really don’t understand who
is vulnerable, why some people are affected so severely, why it comes on so
rapidly … and why it is so hard [for some] to recover.”
Multiple battlefields
The worldwide fears of ventilator shortages for failing lungs have received
plenty of attention. Not so a scramble for another type of equipment: dialysis
machines. “If these folks are not dying of lung failure, they’re dying of renal
failure,” says neurologist Jennifer Frontera of New York University’s Langone
Medical Center, which has treated thousands of COVID-19 patients. Her hospital
is developing a dialysis protocol with different machines to support additional
patients. The need for dialysis may be because the kidneys, abundantly endowed
with ACE2 receptors, present another viral target.
According to one preprint, 27% of 85 hospitalized patients in Wuhan had kidney
failure. Another reported that 59% of nearly 200 hospitalized COVID-19 patients
in and near Wuhan had protein and blood in their urine, suggesting kidney
damage. Those with acute kidney injury (AKI), were more than five times as
likely to die as COVID-19 patients without it, the same Chinese preprint
reported.
Medical staff work to help a COVID-19 patient in an intensive care unit in
Italy.
ANTONIO MASIELLO/GETTY IMAGES
“The lung is the primary battle zone. But a fraction of the virus possibly
attacks the kidney. And as on the real battlefield, if two places are being
attacked at the same time, each place gets worse,” says Hongbo Jia, a
neuroscientist at the Chinese Academy of Sciences’s Suzhou Institute of
Biomedical Engineering and Technology and a co-author of that study.
Viral particles were identified in electron micrographs of kidneys from
autopsies in one study, suggesting a direct viral attack. But kidney injury may
also be collateral damage. Ventilators boost the risk of kidney damage, as do
antiviral drugs including remdesivir, which is being deployed experimentally in
COVID-19 patients. Cytokine storms also can dramatically reduce blood flow to
the kidney, causing often-fatal damage. And pre-existing diseases like diabetes
can boost the risk of AKI. “There is a whole bucket of people who already have
some chronic kidney disease who are at higher risk for acute kidney injury,”
says Suzanne Watnick, chief medical officer at Northwest Kidney Centers.
Buffeting the brain
Another striking set of symptoms in COVID-19 patients centers on the brain and
central nervous system. Frontera says neurologists are needed to assess 5% to
10% of coronavirus patients at her hospital. But she says that “is probably a
gross underestimate” of the number whose brains are struggling, especially
because many are sedated and on ventilators.
Frontera has seen patients with the brain inflammation encephalitis, with
seizures, and with a “sympathetic storm,” an immune response that’s the brain’s
version of a cytokine storm. Some people with COVID-19 briefly lose
consciousness. Others have strokes. Many report losing their sense of smell. And
Frontera and others wonder whether in some cases, infection depresses the brain
stem reflex that senses oxygen starvation. This is another explanation for
anecdotal observations that some patients aren’t gasping for air, despite
dangerously low blood oxygen levels.
ACE2 receptors are present in the neural cortex and brain stem, says Robert
Stevens, an intensive care physician at Johns Hopkins Medicine. But it’s not
known under what circumstances the virus penetrates the brain and interacts with
these receptors. That said, the coronavirus behind the 2003 severe acute
respiratory syndrome (SARS) epidemic—a close cousin of today’s culprit—could
infiltrate neurons and sometimes caused encephalitis. On 3 April, a case study
in the International Journal of Infectious Diseases, from a team in
Japan, reported traces of new coronavirus in the cerebrospinal fluid of a
COVID-19 patient who developed meningitis and encephalitis, suggesting it, too,
can penetrate the central nervous system.
A 58-year-old woman with COVID-19 developed encephalitis, resulting in tissue
damage in the brain (arrows).
N. POYIADJI ET AL., RADIOLOGY, (2020) DOI.ORG/10.1148/RADIOL.2020201187
But other factors could be damaging the brain. For example, a cytokine storm
could cause brain swelling, and the blood’s exaggerated tendency to clot could
trigger strokes. The challenge now is to shift from conjecture to confidence, at
a time when staff are focused on saving lives, and even neurologic assessments
like inducing the gag reflex or transporting patients for brain scans risk
spreading the virus.
Last month, Sherry Chou, a neurologist at the University of Pittsburgh Medical
Center, began to organize a worldwide consortium that now includes 50 centers to
draw neurological data from care patients already receive. The early goals are
simple: Identify the prevalence of neurologic complications in hospitalized
patients and document how they fare. Longer term, Chou and her colleagues hope
to gather scans, lab tests, and other data to better understand the virus’
impact on the nervous system, including the brain.
Chou speculates about a possible invasion route: through the nose, then upward
and through the olfactory bulb—explaining reports of a loss of smell—which
connects to the brain. “It’s a nice sounding theory,” she says. “We really have
to go and prove that.”
Most neurological symptoms “are reported from colleague to colleague by word of
mouth,” Chou adds. “I don’t think anybody, and certainly not me, can say we’re
experts.”
Reaching the gut
In early March, a 71-year-old Michigan woman returned from a Nile River cruise
with bloody diarrhea, vomiting, and abdominal pain. Initially doctors suspected
she had a common stomach bug, such as Salmonella. But after she developed
a cough, doctors took a nasal swab and found her positive for the novel
coronavirus. A stool sample positive for viral RNA, as well as signs of colon
injury seen in an endoscopy, pointed to a gastrointestinal (GI) infection with
the coronavirus, according to a paper posted online on in The American
Journal of Gastroenterology (AJG).
Her case adds to a growing body of evidence suggesting the new coronavirus, like
its cousin SARS, can infect the lining of the lower digestive tract, where the
crucial ACE2 receptors are abundant. Viral RNA has been found in as many as 53%
of sampled patients’ stool samples. And in a paper in press at Gastroenterology,
a Chinese team reported finding the virus’ protein shell in gastric, duodenal,
and rectal cells in biopsies from a COVID-19 patient. “I think it probably does
replicate in the gastrointestinal tract,” says Mary Estes, a virologist at
Baylor College of Medicine.
Related
·
Antibiotic treatment for COVID-19 complications could fuel resistant bacteria
·
·
See all of our coverage of the coronavirus outbreak
Recent reports suggest up to half of patients, averaging about 20% across
studies, experience diarrhea, says Brennan Spiegel of Cedars-Sinai Medical
Center in Los Angeles, co–editor-in-chief of AJG. GI symptoms aren’t on
CDC’s list of COVID-19 symptoms, which could cause some COVID-19 cases to go
undetected, Spiegel and others say. “If you mainly have fever and diarrhea, you
won’t be tested for COVID,” says Douglas Corley of Kaiser Permanente, Northern
California, co-editor of Gastroenterology.
The presence of virus in the GI tract raises the unsettling possibility that it
could be passed on through feces. But it’s not yet clear whether stool contains
live, infectious virus, not just RNA and proteins. To date, “We have no
evidence” that fecal transmission is important, says coronavirus expert Stanley
Perlman of the University of Iowa. CDC says that based on experiences with SARS
and with the virus that causes Middle East respiratory syndrome, another
dangerous cousin of the new coronavirus, the risk from fecal transmission is
probably low.
The intestines are not the end of the disease’s march through the body. For
example, up to one-third of hospitalized patients develop conjunctivitis—pink,
watery eyes—although it’s not clear that the virus directly invades the eye.
Other reports suggest liver damage: More than half of COVID-19 patients
hospitalized in two Chinese centers had elevated levels of enzymes indicating
injury to the liver or bile ducts, according to two preprints. But several
experts told Science that direct viral invasion isn’t likely the culprit.
They say other events in a failing body, like drugs or an immune system in
overdrive, are more likely driving the liver damage.
This map of the devastation that COVID-19 can inflict on the body is still just
a sketch. It will take years of painstaking research to sharpen the picture of
its reach, and the cascade of cardiovascular and immune effects it might set in
motion. As science races ahead, from probing tissues under microscopes to
testing drugs on patients, the hope is for treatments more wily than the virus
that has stopped the world in its tracks.
Posted in:
·
Biology
·
Coronavirus
doi:10.1126/science.abc3208
Meredith Wadman
·
Twitter
Jennifer Couzin-Frankel
Staff
Writer
·
Email Jennifer
Jocelyn Kaiser
Jocelyn is
a staff writer for Science magazine.
·
Email Jocelyn
Catherine Matacic
Catherine
Matacic is an associate online editor, specializing in linguistics and the
social sciences.
·
Twitter
March 29, 2020
Dear Sierra Club Members, Volunteers and Friends,
In accordance with the Sierra Club policy due to the
spread of the Coronavirus/COVID-19 all
NJ Chapter Outings are cancelled
indefinitely.
Based on National’s decision that there's just
no evidence to support easing restrictions
or letting up our safety precautions.
Wishing everyone good health and well-being through
these extraordinary times. We look forward to seeing you on future Outings
when we can resume offering them.
We encourage you to enjoy the local outdoors on your
own: this should be a perfect time for individuals to get into the woods with
clippers for trail maintenance, ears tuned for evening frog symphonies, eyes
right for spring buds.
Please check that your local park is open before
going there, and please maintain a 6-foot distance from everyone as recommended
by the CDC.
Stay well,
Ellen Blumenkrantz
Outings Chair
Sierra Club New Jersey Chapter
March 13, 2020
How the Sierra Club Is Responding
to the COVID-19 Pandemic
By Michael
Brune
As we all begin to deal with a global pandemic, I want to let you know how the
Sierra Club is adapting and responding, so we can keep doing the important work
of protecting our natural environment and fighting for a just, clean energy
future.
First, we’re prioritizing the health of our volunteers, activists, staff, and
entire community. The COVID-19 pandemic is a social and economic justice issue,
as well as a health crisis. Protecting our community is our number one priority,
and we recognize that we have a social responsibility to be good actors in
keeping others safe, too.
Here are some specific steps we’re taking:
-
We are
requiring all nonessential staff and volunteers to work from home between
now and April 12th;
-
-
We are
suspending all Sierra Club planned events of any size for the next month,
including all volunteer and staff in-person meetings; and,
-
-
We are drawing down Outings across the organization, and more specific
guidance and planning will be issued next week.
While we may not be able to meet up in public, we are continuing to build a
strong community of changemakers online. Please keep following us on Facebook, Twitter,
or Instagram for
your daily dose of inspiration, reliable information, and activism. You can also join
our Resist Facebook group to connect with other activists
creating a community of positive social interaction focused on protecting the
environment. You can also subscribe
to our Daily
Ray of Hope for uplifting and inspirational pictures and quotes.
I
also want to acknowledge that this crisis is impacting all of us in different
ways. Many of us are processing feelings of fear, isolation, confusion, anger,
and sadness around this pandemic, and how it is being handled by a reckless
administration that puts vulnerable communities last. In the past few weeks,
I’ve been angered by accounts of racism and harm experienced by those
identifying as Asian, Asian-American, and Pacific Islander. I encourage you to
put yourself in other people’s shoes and engage with sensitivity and care.
This crisis shows how deeply we depend on one another to act for a greater
common good. While social distancing may be necessary at this time, it is also
increasingly necessary for us to come together to work through this crisis.
While some will try to use this time to demagogue and sow distrust and fear, we
need to overcome that by creating real community and trust and listening to
experts and science.
In this frightening, uncertain moment, we must take care of ourselves and our
beloved communities -- so we are able to keep up the fight for the places and
people we care about most deeply.
