How does coronavirus kill? Clinicians trace fierce outbursts across the body, from brain to toe | Science

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The coronavirus caused extensive (yellow) damage to the lungs of a 59-year-old man who died at George Washington University Hospital, as shown in a 3D model based on computerized CT scans.

George Washington Hospital and Surgical Theater

By Meredith Wadman, Jennifer Couzin-Frankel, Jocelyn Kaiser, Catherine Matacic

Sciences COVID-19 reports are supported by the Pulitzer Center.

One day, during visits to a 20-bed intensive care unit (ICU), doctor Joshua Denson assessed two patients with seizures, several with respiratory failure and others with kidneys on a dangerous descent. A few days earlier, his rounds had been interrupted when his team tried, and failed, to resuscitate a young woman whose heart had stopped. They all shared one thing, said Denson, a pulmonary and intensive care doctor at Tulane University School of Medicine. “They are all positive for COVID. “

As the number of confirmed cases of COVID-19 exceeds 2.2 million worldwide and the deaths exceed 150,000, clinicians and pathologists find it difficult to understand the damage caused by the coronavirus as it occurs. rips through the body. They realize that, although the lungs are on zero ground, their reach can extend to many organs, including the heart and blood vessels, kidneys, intestines, and brain.

” [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 collect clinical data on COVID -19. “His ferocity is breathtaking and humiliating. “

Understanding the outburst could help primary care physicians to treat the fraction of infected people who become desperately and sometimes mysteriously ill. Does a dangerous and recently observed tendency to clot blood turn some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting that treatment with immunosuppressive drugs might help? What explains the surprisingly low blood oxygen level that some doctors report in patients who are not yet short of breath? “Taking a systems approach can be beneficial as we start to think about therapies,” said Nilam Mangalmurti, a pulmonary intensivist at the University of Pennsylvania Hospital (HUP).

The following is a snapshot of the rapidly evolving understanding of how the virus attacks cells in the body, particularly in approximately 5% of patients who fall seriously ill. Despite the fact that more than 1,000 articles are now leaking to magazines and pre-print servers every week, a clear picture is difficult to achieve, as the virus acts like no microbe has ever been seen by humans. Without larger prospective controlled studies that are only being launched now, scientists must draw information from small studies and case reports, often published at high speed and not yet peer reviewed. “We have to keep a very open mind as this phenomenon progresses,” says Nancy Reau, a liver transplant who treated COVID-19 patients at Rush University Medical Center. “We are still learning. “

Infection begins

When an infected person expels virus-laden droplets and someone else inhales them, the new coronavirus, called SARS-CoV-2, enters the nose and throat. He finds a welcome home in the lining of the nose, according to a preprint from scientists at the Wellcome Sanger Institute and elsewhere. They discovered that cells there are rich in a cell surface receptor called the angiotensin 2 converting enzyme (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissue that is vulnerable to infection because the virus requires this receptor to enter a cell. Once inside, the virus hijacks the machinery of the cell, creating a myriad of copies of itself and invading new cells.

As the virus multiplies, an infected person can lose large amounts, especially during the first week or so. Symptoms may be absent at this stage. Or the new victim of the virus may develop fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system does not repel SARS-CoV-2 during this initial phase, the virus then descends the windpipe to attack the lungs, where it can become fatal. The thinner and more distant branches of the respiratory tree of the lungs end in tiny air sacs called alveoli, each lined with a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen passes through the alveoli in the capillaries, tiny blood vessels that are found next to the air sacs; the oxygen is then transported to the rest of the body. But while the immune system fights with the invader, the battle itself disrupts this healthy transfer of oxygen. First-line white blood cells release inflammatory molecules called chemokines, which in turn invoke more immune cells that target and kill virus-infected cells, leaving a stew of dead, liquid cells – pus – behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: cough; fever; and rapid and shallow breathing. Some COVID-19 patients recover, sometimes without more support than the oxygen blown in through the nasal teeth.

Others, however, deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). The oxygen levels in their blood drop and they have trouble breathing. On the x-rays and CT scans, their lungs are riddled with white cloudiness where the black space – the air – should be (see graph). Typically, these patients end up on respirators. Many die. Autopsies show that their alveoli have filled with fluid, white blood cells, mucus and detritus from destroyed lung cells.

The impact of an invader

In severe cases, SARS-CoV-2 lands in the lungs and can damage it deeply. But the virus, or the body’s response to it, can injure many other organs. Scientists are just beginning to probe the extent and nature of this harm.

8 2 5 6 7 3 4 Trachea Bile duct Bronchii

Immune cells Capillary Some blood ship Endothelial cells ACE2 SARS-CoV-2 SARS-CoV-2 Clot Mucus 1 2 LiverUp to half of people hospitalized patients have enzyme levels that signal a liver in trouble. An immune system overdrive and medications given to fight the virus can cause the damage. 7 noseSome patients lose their senses smell. Scientists speculate that the virus can move the nerve endings of the nose and damage the cells. 6 eyesConjunctivitis, inflammation of the membrane that lines the front of the eye and inside eyelid, is more common in the sickest patients. 3 kidneysKidney damage is common in severe cases and made death more likely. The virus can attack the kidneys directly, or kidney failure can be part of the whole body events like the fall arterial pressure. 4 intestinesPatient reports and biopsy data suggest the virus can infect the the lower gastrointestinal tract, which is rich in ACE2 receptors. Around 20% or more patients have diarrhea. 1 lungsA cross section shows immune cells clutter up a inflamed socket, of which the walls break during virus attack, decreased oxygen uptake. Patients cough, fevers go up, and it takes more and more effort to breathe. 8 Heart and blood vesselsThe virus (green) enters the cells, probably including those who line the blood ships, by binding to ACE2 receptors on the surface of cells. The infection can also promote blood clots, heart attacks and heart attacks inflammation. 5 BrainSome COVID-19 patients having blows, convulsions, mental and brain confusion inflammation. The doctors are try to figure out which one are directly caused by the virus.

V. ALTOUNIEN /SCIENCE

Some clinicians suspect that the driving force behind the descent trajectory of many critically ill patients is an overwhelming and disastrous immune system reaction known as the “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, the levels of some cytokines rise far beyond what is needed, and immune cells begin to attack healthy tissue. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can result.

Some studies have shown elevated levels of these cytokines inducing inflammation in the blood of COVID-19 hospital patients. “The actual morbidity and mortality from this disease is likely due to this disproportionate inflammatory response to the virus,” said Jamie Garfield, a pulmonologist who treats COVID-19 patients at Temple University Hospital.

But others are not convinced. “There seems to have been a rapid movement to associate COVID-19 with these hyperinflammatory conditions. I haven’t really seen any convincing evidence that this is the case, “said Joseph Levitt, a physician in pulmonary intensive care at Stanford University School of Medicine.

He is also concerned that efforts to attenuate the cytokine response will backfire. Several drugs targeting specific cytokines are in clinical trials in COVID-19 patients. But Levitt is concerned that these drugs may suppress the immune response the body needs to fight the virus. “There is a real risk that we will allow greater viral replication,” says Levitt.

Meanwhile, other scientists are focusing on an entirely different organ system, which they say leads to rapid deterioration in some patients: the heart and blood vessels.

Hit the heart

In Brescia, Italy, a 53-year-old woman entered the emergency room of her local hospital with all the classic symptoms of a heart attack, including telltale signs in her EKG and high levels of a marker blood suggesting damaged heart muscles. Other tests have shown swelling of the heart and scarring, and a left ventricle – normally the central chamber of the heart – so weak that it could only pump a third of its normal amount of blood. But when doctors injected dye into the coronary arteries, looking for the blockage that meant 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 prepublications and documents attest to the fact that such damage is common. An article from March 25 JAMA Cardiology documented heart damage in almost 20% of 416 patients hospitalized for COVID-19 in Wuhan, China. In another Wuhan study, 44% of the 138 hospital patients suffered from arrhythmias.

The disturbance seems to extend to the blood itself. Among 184 COVID-19 patients in a Dutch intensive care unit, 38% had abnormally clotted blood, and almost a third already had clots, according to an article in April 10 in Thrombosis research. Blood clots can separate and land in the lungs, blocking the vital arteries – a condition known as pulmonary embolism, which has reportedly killed patients with COVID-19. Clots in the arteries can also get lodged in the brain, causing a stroke. Many patients have “dramatically” high levels of D-dimer, a byproduct of blood clots, says Behnood Bikdeli, a cardiovascular fellow at Columbia University Medical Center.

“The more we look, the more likely it is that blood clots are a major player in the severity and mortality of COVID-19 disease,” says Bikdeli.

The infection can also cause constriction of blood vessels. Ischemia is reported in the fingers and toes – a reduction in blood flow which can lead to swollen and painful figures and tissue death.

The more we look, the more likely it is that blood clots are a major player in the severity and mortality of COVID-19 disease.

Behnood Bikdeli, Columbia University Irving Medical Center

In the lungs, constricted blood vessels may help explain the anecdotal reports of a confusing phenomenon seen in pneumonia caused by COVID-19: Some patients have extremely low blood oxygen levels and yet are not at breathless. It is possible that at certain stages of the disease, the virus can alter the delicate balance of hormones that help regulate blood pressure and restrict the blood vessels going to the lungs. The absorption of oxygen is therefore hindered by narrowed blood vessels, rather than by clogged alveoli. “One theory is that the virus affects vascular biology and that’s why we see these really low oxygen levels,” says Levitt.

If COVID-19 targets blood vessels, it may also help explain why patients with pre-existing damage to these vessels, such as diabetes and high blood pressure, are at higher risk for serious disease. Recent data from the Centers for Disease Control and Prevention (CDC) on hospital patients in 14 US states found that about one-third of patients had chronic lung disease, but almost as many had diabetes and half of them had pre-existing high blood pressure.

Mangalmurti says she was “shocked that we don’t have a lot of asthmatics” or patients with other respiratory illnesses in the HUP ICU. “It is very striking to us that the risk factors seem to be vascular: diabetes, obesity, age, hypertension. “

Scientists have a hard time understanding exactly what causes cardiovascular damage. The virus can directly attack the lining of the heart and blood vessels, which, like the nose and alveoli, are rich in ACE2 receptors. Or maybe the lack of oxygen, due to the chaos in the lungs, damages the blood vessels. Or a storm of cytokines could ravage the heart like it does for other organs.

“We are still at the beginning,” says Krumholz. “We really don’t understand who is vulnerable, why some people are so badly affected, why it happens so quickly … and why it is so difficult [for some] to recover. “

Several battlefields

Global concerns over a shortage of ventilators for failed lungs have received much attention. Not if a rush for another type of equipment: dialysis machines. “If these people don’t die of lung failure, they die of kidney failure,” said neurologist Jennifer Frontera of the Langone Medical Center at New York University, who has treated thousands of COVID-19 patients. His hospital is developing a dialysis protocol with different machines to care for other patients. The need for dialysis may be due to the fact that the kidneys, abundantly endowed with ACE2 receptors, present another viral target.

According to a prepublication, 27% of the 85 patients hospitalized in Wuhan suffered from kidney failure. Another said that 59% of the nearly 200 patients hospitalized at COVID-19 in and around Wuhan had protein and blood in the urine, suggesting kidney damage. Those with acute renal failure (AKI), were more than five times more likely to die than COVID-19 patients without it, reported the same Chinese prepublication.

Medical staff work to assist a COVID-19 patient in an intensive care unit in Italy.

Antonio Masiello / Getty Images

“The lung is the main battle area. But a fraction of the virus may be attacking the kidney. And like on the real battlefield, if two places are attacked at the same time, each place gets worse, “said Hongbo Jia, neuroscientist at the Suzhou Institute of Biomedical Engineering and Technology at the Chinese Academy of Sciences and author of this. study.

Viral particles were identified on electron micrographs of kidneys from autopsies in one study, suggesting a direct viral attack. But kidney damage can also be collateral damage. Ventilators increase the risk of kidney damage, as do antiviral drugs, including remdesivir, which is experimentally deployed in COVID-19 patients. Cytokine storms can also dramatically reduce blood flow to the kidney, causing often fatal damage. And preexisting illnesses like diabetes can increase the risk of AKI. “There is a whole group of people who already have chronic kidney disease and who are at higher risk for acute kidney injury,” said Suzanne Watnick, chief physician of the Northwest Kidney Centers.

Shake the brain

Another striking set of symptoms in COVID-19 patients focuses on the brain and central nervous system. Frontera says neurologists are needed to assess 5% to 10% of patients with coronavirus in his hospital. But she says that “is probably a gross underestimation” of the number of people with brain problems, particularly because many are sedated and ventilated.

Frontera has seen patients with cerebral inflammatory encephalitis, seizures and a “sympathetic storm”, an immune response that is the brain version of a cytokine storm. Some people with COVID-19 briefly pass out. Others have been beaten. Many claim to have lost their sense of smell. And Frontera and others wonder if, in some cases, the infection depresses the brainstem reflex that detects oxygen starvation. This is another explanation for anecdotal observations that some patients are not short of breath, despite dangerously low blood oxygen levels.

ACE2 receptors are found in the neural cortex and the brainstem, says Robert Stevens, an intensive care physician at Johns Hopkins Medicine. But it is not known under what circumstances the virus enters the brain and interacts with these receptors. That said, the coronavirus that caused the 2003 Severe Acute Respiratory Syndrome (SARS) epidemic – a close relative of today’s culprit – could infiltrate neurons and sometimes cause encephalitis. On April 3, a case study in the International Journal of Infectious Diseases, a team in Japan, reported traces of new coronavirus in the cerebrospinal fluid of a COVID-19 patient who developed meningitis and encephalitis, suggesting that it may also penetrate the central nervous system.

A 58-year-old woman with COVID-19 developed encephalitis, causing tissue damage in the brain (arrows).

N. Poyiadji et al., Radiology, (2020) doi.org/10.1148/radiol.2020201187

But other factors could damage the brain. For example, a storm of cytokines could cause the brain to swell and the exaggerated tendency for blood to clot could trigger strokes. The challenge now is to move from guesswork to trust, at a time when staff are focused on saving lives, and even neurological assessments like inducing the gag reflex or transporting patients for brain tests may spread the virus.

Last month, Sherry Chou, neurologist at the University of Pittsburgh Medical Center, began organizing a global consortium that now includes 50 centers to collect neurological data on the care that patients are already receiving. The first objectives are simple: identify the prevalence of neurological complications in hospitalized patients and document their evolution. In the longer term, Chou and his colleagues hope to collect analyzes, laboratory tests and other data to better understand the impact of the virus on the nervous system, including the brain.

Cabbage speculates on a possible path of invasion: through the nose, then upwards and through the olfactory bulb – explaining the reports of a loss of odor – which connects to the brain. “It’s a beautiful theory that sounds,” she says. “We really have to go and prove it. “

Most neurological symptoms “are reported from colleague to colleague by word of mouth,” adds Chou. “I don’t think anyone, and certainly not me, can say that we are experts. “

Reach the gut

In early March, a 71-year-old Michigan woman returned from a Nile cruise with bloody diarrhea, vomiting and abdominal pain. Doctors initially suspected that she had a common stomach bug, such as Salmonella. But after developing a cough, the doctors took a nasal swab and found it positive for the new coronavirus. A stool sample positive for viral RNA, as well as signs of colon damage seen during an endoscopy, revealed a gastrointestinal (GI) infection with the coronavirus, according to an article published online at The American Journal of Gastroenterology ((AJG).

His case is added to a growing body of evidence suggesting that the new coronavirus, like its cousin SARS, can infect the lining of the lower digestive tract, where crucial ACE2 receptors are abundant. Viral RNA was found in as much as 53% of the stool samples of the sampled patients. And in an article in press at Gastroenterology, a Chinese team reported finding the protein envelope of the virus in gastric, duodenal and rectal cells in biopsies from a COVID-19 patient. “I think it probably reproduces in the gastrointestinal tract,” says Mary Estes, virologist at Baylor College of Medicine.

According to Brennan Spiegel of the Cedars-Sinai Medical Center in Los Angeles, co-editor of AJG. Gastrointestinal symptoms are not on the CDC’s COVID-19 symptom list, which could cause some COVID-19 cases to go undetected, according to Spiegel and others. “If you mainly have fever and diarrhea, you will not be tested for COVID,” says Douglas Corley of Kaiser Permanente, Northern California, co-editor of Gastroenterology.

The presence of viruses in the gastrointestinal tract increases the disturbing possibility that it could be transmitted through the feces. But it is not yet clear whether the stool contains live infectious viruses, not just RNA and proteins. To date, “we have no evidence” that fecal transmission is significant, says coronavirus expert Stanley Perlman of the University of Iowa. The CDC says that based on experiences with SARS and the virus that causes Middle East respiratory syndrome, another dangerous cousin of the new coronavirus, the risk of fecal transmission is likely to be low.

The intestines are not the end of the disease in the body. For example, up to a third of hospital patients develop conjunctivitis – pink, watery eyes – although it is unclear whether the virus directly invades the eye. Other reports suggest liver damage: more than half of COVID-19 patients hospitalized in two Chinese centers had high levels of enzymes indicating damage to the liver or bile ducts, according to two pre-prints. But several experts said Science this direct viral invasion is probably not the culprit. They say that other events in a failing body, such as drugs or an over-boosted immune system, are more likely to cause liver damage.

This map of the devastation COVID-19 can inflict on the body is still just a sketch. It will take years of painstaking research to refine the picture of its litter and the cascade of cardiovascular and immune effects it could trigger. As science progresses, from surveying tissue under microscopes to testing drugs on patients, the hope is to find smarter treatments than the virus that stopped the world in its tracks.

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