June 1, 2020 / BIOON / — in a 20-bed intensive care unit (ICU) recently, Joshua Denson, a pulmonary and intensive care physician at tulane university school of medicine, evaluated two patients with epilepsy, many with respiratory failure, and others with dangerous kidney slides.
A few days ago, his rounds were interrupted when his team tried and failed to save a young woman whose heart had stopped beating.
All of these people have one thing in common, Denson says.
“They are all covid-19 positive.”
With more than six million confirmed cases of covid-19 and more than 360,000 deaths worldwide, clinicians and pathologists are working to understand the damage caused to humans by novel coronavirussars-cov-2.
They realized that although the lungs were ground zero, their effects could extend to many organs, including the heart and blood vessels, the kidneys, the intestines and the brain.
“[the disease] can attack almost anything in the body with devastating results,” says Harlan Krumholz, a cardiologist at Yale university school of medicine’s new haven hospital.
Its ferocity was shocking and suffocating.”
Krumholz is leading efforts to collect clinical data on covid-19.
Understanding this rampant condition could help doctors on the front lines treat those who are desperately and sometimes mysteriously ill.
Could a dangerous, newly observed tendency to clot turn some mild cases into life-threatening emergencies?
Does the excessive immune response that leads to severe cases mean that treatment with immunosuppressive drugs may be helpful?
What causes some doctors to report patients with alarmingly low oxygen levels but no asthma?
“When we start thinking about treatments, it may be helpful to take a systematic approach,” says Nilam Mangalmurti, a pulmonary icu physician at the university of Pennsylvania hospital in the United States.
Here’s an understanding of how the virus attacks cells throughout the body at a rapid rate, especially in about 5 percent of severely ill patients.
Although more than 1,000 papers are published each week in journals and on preprint servers, we still don’t have a clear understanding because the virus ACTS like a pathogen that humans have never seen before.
Without the larger prospective controlled studies that are only now beginning, scientists would have to get information from small studies and case reports, which are often published with astonishing speed and without peer review.
“We need to keep a very open mind as this phenomenon evolves,” says Nancy Reau, a liver transplant physician who treats covid-19 patients at rush university medical center in the United States.
We’re still learning.”
Infection began
The sars-cov-2 virus enters the nose and throat when an infected person expels virus-bearing droplets and others inhale them.
The virus has found a welcome home in the lining of the nasal cavity, according to a paper published on a preprint server by scientists at the wellcome trust sanger institute and elsewhere.
They found that the cells there were rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2).
Throughout the body, ACE2’s presence — which often helps regulate blood pressure — means that tissues are susceptible to infection, because the virus needs this receptor to get into cells.
Once inside the cell, the virus hijacks the molecular machinery in the cell, making countless copies of itself and invading the new cell.
As the virus multiplies, infected people can shed large amounts of the virus, especially in the first week or so.
You may not have any symptoms.
Or new victims of the virus may experience fever, dry cough, sore throat, loss of smell and taste, and head and body pain.
If the immune system fails to fight off sars-cov-2 at this initial stage, the virus travels down the windpipe and attacks the lungs, where it can become lethal.
The thinner, more distant branches of the respiratory tree are small air sacs called alveoli, each containing a layer of ACE2 receptor rich cells.
Normally, oxygen passes through the alveoli into the capillaries, the small blood vessels next to the air sacs, which carry it to the rest of the body.
But when the immune system engages an invader, the battle itself can disrupt this healthy delivery of oxygen.
Frontline white blood cells release inflammatory molecules called chemokines, which in turn call on more immune cells to target and kill infected cells, leaving behind a mixture of fluid and dead cells called pus.
This is the basic pathology of pneumonia, with its associated symptoms: cough, fever, and rapid, shallow breathing.
Some patients with covid-19 can recover, sometimes simply by inhaling oxygen through the nasal cannulas.
But some patients get worse, often suddenly, and develop a condition called acute respiratory distress syndrome (ARDS).
Their blood oxygen levels plummet and breathing becomes more difficult.
During X-ray and computed tomography (CT) scans, their lungs were filled with white shadows that should have been black.
Often, these patients end up on a ventilator.
Many people died.
Autopsy results showed that their alveoli were stuffed with fluid, white blood cells, mucus and the remnants of damaged lung cells.
The influence of intruders
In severe cases, sars-cov-2 can land in the lungs and cause profound damage.
But the virus, or the body’s response to it, can harm many other organs.
Scientists are just beginning to explore the scope and nature of the damage.
For the brain, some patients with covid-19 have strokes, seizures, confusion and encephalitis, and doctors are trying to understand which symptoms are directly caused by the virus.
To the eye, conjunctivitis sees the patient with the most serious disease more.
With the nose, some patients lose their sense of smell.
The scientists speculate that the virus may move up the nerve endings in the nose, damaging cells.
In the lungs, a cross section shows immune cells packed with inflamed alveoli, or air sacs, whose walls can break under the virus’s attack, reducing the absorption of oxygen.
The sufferer may cough, have a fever, and have difficulty breathing.
In the case of the heart and blood vessels, the virus enters cells (possibly including those located in the lining of blood vessels) by binding to ACE2 receptors on the cell surface.
The infection can also promote blood clots, heart attacks and heart inflammation.
In the liver, enzyme levels in up to half of hospitalized patients indicate liver dysfunction.
The overdrive of the immune system, combined with antiviral drugs, may be to blame for liver damage.
In severe cases, kidney damage is common and makes death more likely.
The virus may attack the kidneys directly, or kidney failure may be part of a systemic event, such as a drop in blood pressure.
In the gut, patient reports and biopsy data suggest that the virus infects the lower digestive tract, which is rich in ACE2 receptors.
More than 20 percent of patients have diarrhea.
Some clinicians suspect that the deterioration of many critically ill patients is driven by a catastrophic overreaction of the immune system, known as cytokine storms, triggered by other viral infections.
Cytokines are chemical signaling molecules that guide a healthy immune response, but during a cytokine storm, levels of certain cytokines soar far beyond what is needed, and immune cells begin to attack healthy tissue.
Blood vessels leak, blood pressure drops, blood clots form, and catastrophic organ failure can ensue.
Some studies have shown elevated levels of these inflammation-induced cytokines in the blood of hospitalized covid-19 patients.
“The true morbidity and mortality of the disease may be due to an excessive inflammatory response to the virus,” said Jamie Garfield, a pulmonologist who CARES for covid-19 patients at temple university hospital in the United States.
But others are not convinced.
Joseph Levitt, a pulmonary intensive care physician at Stanford university school of medicine in the United States, said, “it seems that someone has been quick to associate covid-19 with these highly inflammatory states.
I have yet to see convincing data that this is the case.”
He also worries that efforts to suppress the cytokine response could backfire.
Several drugs that target specific cytokines are being tested in patients with covid-19.
But Levitt worries that the drugs may suppress the body’s immune response to the virus.
“We are at risk of allowing more virus replication,” Levitt said.
At the same time, other scientists are targeting an entirely different organ system – the heart and blood vessels – that they say is responsible for the rapid deterioration of some patients.
Touches the heart
In brescia, Italy, a 53-year-old woman walked into the emergency room of a local hospital with all the hallmarks of a heart attack on her electrocardiogram, including the tell-all signs of a heart attack. High levels of a marker in her blood indicate damage to her heart muscle.
Further tests revealed swelling and scarring in the heart, and the left ventricle – usually the heart’s power room – was so fragile that it could only pump out a third of its normal blood volume.
But when doctors injected dye into coronary arteries, looking for blockages that signal a heart attack, they found none.
Another test showed why: this woman had covid-19.
How the virus attacks the heart and blood vessels is a mystery, but dozens of preprinted articles and papers have shown that such damage is common.
A paper published March 25 in the journal JAMA Cardiology records that of 416 patients hospitalized with covid-19 in wuhan, China, nearly 20% developed heart injuries.
In another study conducted in wuhan, 44 percent of 36 hospitalized ICU patients developed arrhythmias.
The damage to the heart also seems to extend to the blood itself.
Among 184 covid-19 patients in an intensive care unit in the Netherlands, 38 percent had abnormal blood clots, and nearly a third had blood clots, according to an April 10 paper published in the journal runners Research.
Blood clots can rupture and stay in the lungs, blocking vital arteries, a condition known as pulmonary embolism, which has been reported to kill covid-19 patients.
Blood clots in arteries can also build up in the brain, leading to strokes.
Behnood Bikdeli, a cardiovascular medicine researcher at Columbia University medical center in the United States, said many patients had “significantly” high levels of d-dimer, a byproduct of blood clots.
“The more we look, the more likely we are to conclude that blood clots play an important role in the severity and mortality of covid-19,” Bikdeli said.
Infections can also cause blood vessels to constrict.
Ischemia of the fingers and toes – a loss of blood flow – has been reported to cause swelling, pain and tissue death in the fingers.
In the lungs, vasoconstriction may help explain a puzzling phenomenon in pneumonia caused by covid-19: some patients have extremely low blood oxygen levels but no wheezing.
It is possible that at some stage of the disease, the virus alters the delicate balance of hormones that help regulate blood pressure, causing the blood vessels leading to the lungs to constrict.
Thus, oxygen uptake is blocked by constricted blood vessels, not by alveolar blockages.
“One theory is that the virus affects vascular biology, and that’s why we’re seeing these very low levels of blood oxygen,” Levitt said.
If sars-cov-2 targets blood vessels, it may also help explain why patients with pre-existing vascular damage, such as those with diabetes and hypertension, are at higher risk for serious disease.
A recent analysis by the centers for disease control and prevention (CDC) of inpatient data from 14 states found that about a third of people have chronic lung disease – almost as many have diabetes, and half have pre-existing high blood pressure.
Mangalmurti said she was “shocked” that the intensive care unit at the university of Pennsylvania hospital did not have a large number of patients with asthma or other respiratory problems.
“We were very surprised that the risk factors seemed to be related to blood vessels: diabetes, obesity, age and high blood pressure.”
Scientists are trying to understand what causes cardiovascular damage.
Like the nose and alveoli, the virus may directly attack the lining of the heart and blood vessels, which are rich in ACE2 receptors.
Or it could be a lack of oxygen caused by a lung disorder that destroys blood vessels.
Or cytokine storms can damage the heart as well as other organs.
“We’re still in the early stages,” Krumholz said.
We really don’t understand who the susceptible group is, why some people are so affected, why it comes so quickly…
And why it’s so difficult [for some people] to recover.”
Multiple battlefield
Worldwide, concerns about a shortage of ventilators for patients with lung failure have drawn widespread attention.
The scramble for another device, the dialyzer, is different.
“If these people were dying not of lung failure, but of kidney failure,” says Jennifer Frontera, a neurologist at New York university langone medical center.
Her hospital has treated thousands of covid-19 patients and is developing a dialysis program that USES different machines to support more patients.
Dialysis may be required because the kidney, which is rich in ACE2 receptors, is another viral target.
Of the 85 hospitalized patients in wuhan, 27 percent developed kidney failure, according to a preprint article.
Another report said that of nearly 200 hospitalized covid-19 patients in China’s hubei and sichuan provinces, 59 percent had protein in their urine and 44 percent had blood in their urine.
This is indicative of kidney damage.
As reported in this preprint article, covid-19 patients with acute kidney injury (AKI) are more than five times more likely to die than covid-19 patients without acute kidney injury.
‘the lungs are the main combat area,’ says Hongbo Jia, a neuroscientist at the Chinese academy of sciences’ suzhou institute of biomedical engineering and technology.
However, a small number of viruses may attack the kidneys.
“Just like in a real battlefield, if two places are attacked at the same time, each place gets worse.”
In one study, sars-cov-2 virus particles were found in electron micrographs of the kidney from an autopsy, suggesting that the virus directly attacked the kidney.
However, kidney damage can also be collateral damage.
Respiratory opportunities increase the risk of kidney damage, as do antiviral compounds including redesivir, which is currently being used experimentally in patients with covid-19.
Cytokine storms also dramatically reduce blood flow to the kidneys, causing often fatal damage.
Pre-existing conditions such as diabetes also increase the risk of kidney damage.
“There are a lot of people who already have chronic kidney disease, and they are at higher risk for acute kidney injury,” said Suzanne Watnick, chief medical officer at northwestern kidney center.
Impact on the brain
Another striking set of symptoms in covid-19 patients centers on the brain and central nervous system.
Frontera says neurologists at her hospital need to assess 5 to 10 percent of patients with coronavirus.
But she says this may significantly underestimate the number of people with brain problems, especially since many are on sedatives and ventilators.
Frontera seen encephalitis, epilepsy and “sympathetic storm (sympathetic storm) – an overreaction of the sympathetic nervous system, causing symptoms epilepsy samples, after traumatic brain injury is the most common”.
Some people with covid-19 may lose consciousness briefly.
Others had strokes.
Many patients report losing their sense of smell.
Frontera and others wondered whether viral infections, in some cases, inhibit the brainstem reflex that senses lack of oxygen.
This is another explanation for patients who are not panting despite dangerously low blood oxygen levels.
ACE2 receptors are found in the neural cortex and brain stem, says Robert Stevens, an intensive-care physician at Johns Hopkins university school of medicine.
But it is not known under what circumstances sars-cov-2 may enter the brain and interact with these receptors.
The coronavirus sars-cov, which caused the severe acute respiratory syndrome (SARS) epidemic in 2003 — and is closely related to sars-cov-2 — can invade neurons, sometimes causing encephalitis.
In a case study published April 3 in the International Journal of Infectious Diseases, a team in Japan reported that traces of the novel coronavirus were found in the cerebrospinal fluid of a covid-19 patient with meningitis and encephalitis, suggesting that it can also invade the central nervous system.
But other factors may also be causing brain damage.
For example, cytokine storms can cause brain swelling, and the tendency of blood to overclot can lead to strokes.
The challenge now is to move from guesswork to confidence as workers focus on saving lives, and risk spreading the virus when inducing an vomiting reflex or transporting patients for brain scans to assess the nervous system.
Last month, Sherry Chou, a neurologist at the university of Pittsburgh medical center, began assembling a global consortium of 50 centers to gather neurological data from patients who have received care.
The early goal was simple: determine the prevalence of neurological complications in hospitalized patients and document their condition.
In the long run, Chou and her colleagues hope to collect scans, lab tests and other data to better understand the virus’s effects on the nervous system, including the brain.
Chou speculated on a possible route of invasion: through the nose, then up, through the olfactory bulb — which explains reports of patients losing their sense of smell — and to the brain.
“It’s a theory that sounds good,” she said.
We have to prove it.”
Chou added that most neurological symptoms “are reported through word of mouth among colleagues.
I don’t think anyone can say we are experts, nor can I.
Arrived in the intestinal tract
In early march, a 71-year-old Michigan woman returned from a Nile river cruise with bloody diarrhea, vomiting and abdominal pain.
At first, doctors suspected she had a common stomach infection, like salmonella.
But after she developed a cough, doctors took a nasal swab and found she was novel coronavirus positive.
According to a paper published online in the American Journal of Gastroenterology, her stool sample was positive for viral RNA and she saw signs of colon damage on an endoscopy, suggesting a novel coronavirus infection in the gastrointestinal tract.
As in her case, there is growing evidence that novel coronavirussars-cov-2, like sars-cov, can infect the lining of the lower digestive tract rich in ACE2 receptors.
Viral RNA was found in stool samples from as many as 53% of patients.
And in a paper published in the journal Gastroenterology, a Chinese team reports finding viral protein capsids in stomach, duodenal and rectal cells in biopsy samples from a covid-19 patient.
“I think it’s very likely that it does replicate in the gastrointestinal tract,” said Mary Estes, a virologist at baylor college of medicine in the United States.
Recent reports suggest that in an average of about 20 percent of studies, as many as half of patients experience diarrhea, says Brennan Spiegel of cedars-sinai medical center in the United States.
Spiegel and others say that gastrointestinal symptoms are not on the U.S. CDC’s list of covid-19 symptoms, which could lead to some cases of covid-19 going undetected.
“If your primary symptoms are fever and diarrhea, you’re not going to get a covid-test,” says Douglas Corley of Kaiser bear healthcare in the United States.
The presence of the virus in the gastrointestinal tract raises the disturbing possibility that it could be transmitted through faeces.
But it is not clear whether the feces contained the full, infectious sars-cov-2 virus, or just viral RNA and proteins.
So far, “we have no evidence” that fecal transmission is important, explains Stanley Perlman, a coronavirus expert at the university of Iowa.
Based on experience with sars-cov and the Middle East respiratory syndrome (MERS) coronavirus, another coronavirus closely associated with sars-cov-2, the risk of fecal transmission is likely to be low, the CDC said.
The gut is not the end of the disease’s spread through the body.
For example, as many as a third of hospitalized patients develop conjunctivitis, though it is not clear whether the virus directly enters the eye.
Other reports suggest liver damage.
More than half of covid-19 patients hospitalized at two Chinese centers had elevated enzyme levels, indicating damage to their livers or bile ducts.
But several experts told the journal Science that a direct virus attack is unlikely to be the culprit.
Other events in a failing body, such as drugs or the immune system going into overdrive, are more likely to cause liver damage, they say.
This map of the damage caused to the body by covid-19 is only a sketch at this time.
It will take years of painstaking research to get a clearer picture of the extent of its effects and the range of cardiovascular and immune effects it could trigger.
As science continues to advance rapidly, from detecting tissues under microscopes to testing drugs on patients, the hope is that more ingenious treatments than the virus will be found to put the world back on track.
