How does coronavirus kill?
US, WASHINGTON (ORDO NEWS) — Having recently made a round-trip of patients in the intensive care unit with 20 beds, doctor Joshua Denson evaluated the condition of two patients with convulsive seizures, several with pulmonary insufficiency and several more who had kidneys in a dangerous condition. A few days earlier, he was forced to interrupt his rounds in order to, together with his colleagues, try to reanimate a young woman whose heart stopped. According to Denson, a pulmonologist and resuscitator at the medical faculty of Tulane University, all these patients had one thing in common – they became infected with COVID-19.
The number of confirmed cases of COVID-19 infection worldwide exceeded 2.2 million, and the number of deaths exceeded 150,000. Under these conditions, attending physicians and laboratory diagnostics specialists are eager to understand what damage the coronavirus does to the body when it enters it. They understand that the lungs should be considered the epicenter, but the virus affects a wide variety of organs, including the heart, blood vessels, kidneys, intestines, and brain.
“This disease can affect almost everything in the body, with disastrous consequences,” says cardiologist Harlan Krumholz of the New Haven Hospital, who also works at Yale University and oversees the large-scale clinical data collection work on COVID-19. “The severity of this disease is striking and shocking.”
If doctors understand the causes and course of the disease, they will be able to help those few infected patients whose illness is extremely difficult, and sometimes mysterious. Could the recent tendency to form blood clots lead to an aggravation of a mild form of the disease, making it life threatening? Or maybe the cause of the worst cases is an excessive immune response, indicating that suppressive immunity drugs will help here? How to explain the strikingly low levels of oxygen in the blood noted by some doctors in patients who, nevertheless, do not suffocate? “When we think about treatment, we need a systematic approach,” says pulmonologist and resuscitator Nilam Mangalmurti, who works at the University of Pennsylvania Hospital.
The following is a brief description of the rapidly expanding understanding of how the virus attacks cells throughout the body, especially in 5% of seriously ill patients. Although more than 1,000 works on coronavirus appear in scientific journals and websites every week, there is no clear picture because this virus behaves quite differently from other microbes. Large-scale studies with a look in perspective begin only now, and in these conditions, scientists are forced to draw information from smaller-scale studies, as well as from case histories and from clinical case reports, which are often published with distortions and without prior review by colleagues. “We need to think openly about how this phenomenon will develop. We’re just learning, ”says transplant surgeon Nancy Reau,
Infection begins
When an infected person transfers the virus by droplet to another person who inhales it, SARS-CoV-2 enters the nasopharynx. He finds a warm welcome in the nasal mucosa, as scientists from the Sanger Institute and other research institutions tell in a draft of their work. They found that the cells there had many receptors called ACE2 (angiotensin converting enzyme 2). ACE2, which usually helps regulate blood pressure, is present in tissues that are vulnerable to infection because the virus needs such a receptor to enter the cell. Once inside, the virus takes control of cellular mechanisms, reproducing with their help numerous copies of itself and penetrating new cells.
As the coronavirus multiplies, the infected person spreads it in large quantities, especially in the first week after infection. Symptoms may not be present at this time. Or the new victim of the virus develops a high fever, a dry cough, a sore throat, he loses his sense of smell and taste, he has a headache and aches in the body.
If at this initial stage the immune system does not defeat SARS-CoV-2, the virus descends into the trachea and infects the lungs. There he can become a source of mortal danger. The thinner and more distant branches of the respiratory pulmonary tree end in tiny air sacs called alveoli. Each pulmonary alveolus has a cover of one layer of cells, which also have many ACE2 receptors.
Usually, oxygen passes through the pulmonary alveoli into the capillaries, tiny blood vessels located behind the air sacs. According to them, oxygen is distributed throughout the body. But when the immune system fights with the invader, this battle alone prevents the normal supply of oxygen to the body. White blood cells on the front edge of the white blood cells secrete inflammatory chemokine molecules, which in turn attract immune cells to the site of inflammation, and they kill the virus-infected cells, leaving behind pus (this is a mixture of liquid and dead cells). This is the main pathology of pneumonia with the corresponding symptoms, such as coughing, fever and fast, shallow breathing. Some patients with COVID-19 recover by receiving only minor assistance in the form of oxygen inhaled through nasal cannulas.
In others, the condition worsens, sometimes completely unexpectedly. They have a syndrome of acute respiratory failure. The oxygen content in the blood drops sharply, and it becomes increasingly difficult for such patients to breathe. X-ray images and tomography show that their lungs are penetrated by white opacities where there should be black space, that is, air. Typically, such patients are placed on a ventilator. Many are dying. An autopsy shows that their pulmonary alveoli are filled with fluid, white blood cells, mucus, and the remains of destroyed lung cells.
Some doctors suspect that the cause of this deterioration in many seriously ill patients is the catastrophic overreaction of the immune system, known as hypercytokinemia (cytokine storm). It also occurs with other viral infections. Cytokines are chemical signaling molecules that control a healthy immune response. But with a cytokine storm, the content of some cytokines far exceeds the required level, and immune cells begin to attack healthy tissues. Blood vessels begin to leak, blood pressure drops, blood clots form, and as a result, the vital organs of the human body can fail.
Some studies show that blood levels in hospitalized patients with COVID-19 have elevated levels of these inflammatory-causing cytokines. “In fact, the morbidity and mortality from this disease is most likely caused by a disproportionate inflammatory response to the virus,” says pulmonologist Jamie Garfield, who treats patients with COVID-19 at Temple University Hospital.
But it does not convince others. “It seems like many quickly decided to associate COVID-19 with this hyper-inflammatory condition. But I don’t see any convincing evidence to support such a connection, ”said Joseph Levitt, a pulmonologist and resuscitator at Stanford University School of Medicine.
He is worried that attempts to weaken the cytokine reaction may be counterproductive. Currently, patients with COVID-19 are undergoing clinical trials of drugs aimed at specific cytokines. However, Levitt has concerns that these drugs may suppress the immune response that the body needs to fight the virus. “There is a very real danger that we will allow additional replication of the virus,” he says.
Meanwhile, some scientists pay attention to completely different organs, which, according to them, contribute to the rapid deterioration of the condition in a number of patients. This is the heart and blood vessels.
Heart beat
In Brescia, Italy, a 53-year-old woman was taken to the intensive care unit of a local hospital with classic heart attack symptoms. An ECG and a high blood level of substances indicating myocardial damage indicated a heart attack. Further tests revealed an enlargement of the heart and damage to it. And the left ventricle, which is usually the main generator of the heart, was so weak that it pumped blood three times less than normal. But when the doctors injected the dye into the coronary arteries to find a blockage point indicating a heart attack, they found nothing. Another analysis was performed, and the reason became clear: the woman had COVID-19.
How the virus attacks the heart and blood vessels remains a mystery; but many scientists and doctors in their reports show that this happens often. On March 25, an article was published in the journal JAMA Cardiology, indicating that almost 20% of the 416 patients treated in Wuhan with COVID-19 showed signs of myocardial damage. Another study said that 44% of 138 hospitalized patients had arrhythmia.
It seems that the damage extends to the blood. Among the 184 COVID-19 patients in the Netherlands who were put in intensive care, 38% had abnormal blood clotting, and almost one in three already had blood clots, as described in a paper published on April 10 in the publication “Thrombosis Research”. These blood clots can disintegrate and settle in the lungs, blocking vital arteries. This condition is called pulmonary embolism, and it kills patients with COVID-19. Blood clots from arteries can also enter the brain, causing a stroke. According to Behnood Bikdeli, a specialist in cardiovascular diseases at the Columbia University Medical Center, many patients have significantly increased levels of D-dimer, a marker of thrombosis.
“The more we study this issue, the clearer it becomes that blood clots significantly affect the severity of the disease and mortality from COVID-19,” says Bikdeli.
Infection can also lead to a narrowing of blood vessels. There are reports of ischemia of finger tissue. This is the result of a reduction in blood flow, which can lead to painful swelling of the fingers and tissue death.
Narrowing of blood vessels in the lungs can explain some cases of the mysterious phenomenon of pneumonia caused by COVID-19. Some patients have extremely low levels of oxygen in the blood, and yet they do not suffocate. It is possible that at some stages of the disease, the virus changes the precarious balance of hormones that help regulate blood pressure, and narrows the blood vessels that go into the lungs. Thus, not clogged pulmonary alveoli, but narrowed blood vessels interfere with oxygen absorption. “According to one theory, the virus affects vascular biology, and therefore we observe such a low oxygen content,” says Levitt.
If COVID-19 affects blood vessels, this can also explain why patients with damaged vessels from other diseases (say, diabetics and hypertensives) have a higher risk of getting sick seriously. Recent data from the Centers for Disease Control and Prevention for hospitalized patients in 14 US states indicate that about a third have chronic lung disease, one third have diabetes, and half have hypertension.
According to Mangalmurti, she was “shocked by the fact that we have few asthmatics” and patients with other respiratory diseases in intensive care units. “We are surprised that the risk factors relate to the vessels: diabetes, obesity, age, hypertension.”
Scientists still can not understand what exactly causes damage to the heart and blood vessels. Perhaps the virus directly attacks the heart and blood vessels, which, like the nose and alveoli, have many ACE2 receptors on the surface. Or maybe the vessels are damaged due to lack of oxygen caused by chaos in the lungs. Or a cytokine storm damages the heart in the same way as other organs.
“We are at the very beginning,” says Krumholtz. “We don’t really understand who is vulnerable, why some people suffer so badly, why the disease comes so quickly … and why [some] it is so hard to recover from it.”
War on many fronts
Now all the attention in the world is focused on the lack of mechanical ventilation devices that help lungs that cannot cope with their task. But few people talk about the shortage of dialysis machines. “If these people don’t die from pulmonary insufficiency, they die from kidney failure,” says neurologist Jennifer Frontera of the New York University Medical Center, which has to treat thousands of patients with COVID-19. Her center is developing a dialysis protocol with different machines to help more patients. The need for dialysis is due to the fact that the kidneys, which have a large number of ACE2 receptors, are another target for the virus.
According to preliminary data from one study, 27% of the 85 patients hospitalized in Wuhan suffered from kidney failure. According to other sources, 59% of the nearly 200 patients hospitalized with COVID-19 in Wuhan and its environs contained protein and blood. And this suggests that they had out of order kidneys. Patients with acute renal failure COVID-19 died five times more often than those who did not have this disease.
Lungs are the main battlefield. But some viruses attack the kidneys. “Like in a real battle, if the offensive starts in two places at the same time, it will be harder for the defenders in each of them,” says neuroscientist Hongbo Jia, who works in Suzhou at the Institute of Biomedical Engineering and Technology of the Chinese Academy of Sciences and co-authored this. research.
On electron microscope photographs of the kidneys at the autopsy of the dead, viral particles were detected, indicating a direct viral attack. Ventilation devices increase the risk of kidney damage, as do antiviral drugs, including remdesivir, which is given to patients with COVID-19 as part of the experiment. Hypercytokinemia can also significantly reduce blood flow to the kidneys, causing damage that often becomes fatal. And pre-existing diseases such as diabetes increase the risk of acute renal failure. “There are many people with chronic kidney disease who are at higher risk for acute renal failure,” says Suzanne Watnick, chief physician at the Northwest Center for Renal Disease.
Brain damage
And COVID-19 affects the brain and central nervous system. According to Frontera, neurologists in her hospital have to examine 5-10% of those infected with coronavirus. However, she notes that “this is probably a serious underestimation” of the number of those who have suffered brain damage, especially due to the fact that many are connected to the ventilator and take a sedative.
Frontera met patients with brain inflammation, encephalitis, convulsive seizures, as well as a “sympathetic storm,” as the cerebral version of the cytokine storm is called. Some patients with COVID-19 lose consciousness for a short time. Some have strokes. Many report a loss of smell. Frontera and some other experts believe that in some cases the infection suppresses the reflex of the brain stem, which feels oxygen starvation. This is another explanation of why some patients do not suffocate, although they have dangerously low blood oxygen levels.
ACE2 receptors are present in the cerebral cortex and in its trunk, says Robert Stevens, a physician in the intensive care unit at Johns Hopkins University School of Medicine. But it is not known under what circumstances the virus enters the brain and comes into contact with these receptors. It should be said that coronavirus, which caused an epidemic of severe acute respiratory syndrome (SARS) in 2003 (it is a close relative of the current coronavirus), penetrated into nerve cells and sometimes caused encephalitis. On April 3, a team from Japan published research data in the International Journal of Infectious Diseases, reporting traces of a new coronavirus in the cerebrospinal fluid of a patient with COVID-19 who developed meningitis and encephalitis. This also suggests that the virus enters the central nervous system.
But there are other factors that damage the brain. For example, a cytokine storm can cause cerebral edema, and increased blood clotting can cause a stroke. Now it’s time to move from assumptions to confidence, because doctors are busy saving people, and even neurological evaluations of the causes of the gag reflex or transporting patients to scan the brain can create a risk of the virus spreading.
Last month, a neurologist at the University of Pittsburgh Medical Center, Sherry Chou, set about creating a global consortium that today brings together 50 centers. He collects neurological data on patients being treated. The initial tasks are quite simple: to identify neurological complications in hospitalized patients and see what results they have. In the future, Chow and his colleagues hope to collect MRI data, laboratory tests and other information that will help to better understand the effect of the virus on the nervous system, including the brain.
Chow makes assumptions about a possible route of penetration: through the nose, then up and through the olfactory bulb (this explains the loss of smell), which connects to the brain. “That sounds great in theory,” she says, “but we need to prove it.”
Mostly, colleagues “verbally communicate each other with neurological symptoms,” Chow adds. “But I think that no one can now call himself an expert in this matter. I definitely can’t, ”she emphasizes.
Reaching the intestines
In early March, a 71-year-old Michigan resident returned from a River Nile cruise with bloody diarrhea, vomiting, and pain in her abdomen. At first, doctors suspected that she had ordinary Escherichia coli like Salmonella. But when the woman had a cough, they took a swab from her nose and found out that she had contracted a new coronavirus. Fecal analysis showed viral RNA, and endoscopy showed signs of colon damage. All this indicated a gastrointestinal infection with coronavirus, as reported on the website of the American Journal of Gastroenterology.
This case formed the general treasury of evidence indicating that the new coronavirus, like its relative SARS, can infect the lower part of the gastrointestinal tract, where ACE2 receptors are abundant. Viral RNA was detected in fecal analyzes of 53% of patients. A Chinese team of scientists in their work reported that they found the envelope of protein proteins in biopsy materials of patients with COVID-19, such as cells of the stomach, duodenum and rectum. “I think it can replicate in the gastrointestinal tract,” says virologist at Baylor College of Medicine Mary Estes.
Recent evidence suggests that up to half of patients suffer from diarrhea, says Brennan Spiegel, who works at the Cedars Sinai Medical Center in Los Angeles and is editor in chief of the American Journal of Gastroenterology. Gastrointestinal symptoms are not included in the list of symptoms of COVID-19, compiled by this center, which is why some cases of diseases could go unnoticed. “If you have only fever and diarrhea, you won’t be tested for COVID,” says Douglas Corley of the Kaiser Permanente Medical Center in Northern California. He is also the editor of the American Journal of Gastroenterology.
The presence of the virus in the gastrointestinal tract suggests that it can be transmitted through feces. But while it is not clear what is contained in the feces: a living and contagious virus, or just RNA and proteins. Today, we have no evidence that transmission with fecal matter is important, says coronavirus expert Stanley Perlman from Iowa State University. The Center for Disease Control and Prevention reports that, based on the experience of combating SARS and the Middle East respiratory syndrome virus, which is another dangerous relative of the new coronavirus, the risk of transmission of infection with fecal matter is probably very low.
The intestine is not the final destination for the advancement of the disease in the human body. For example, a third of hospitalized patients develop conjunctivitis (reddened, watery eyes), although it is unclear whether the virus directly enters the eyes. There are reports that the virus infects the liver. More than half of COVID-19 patients hospitalized in two Chinese centers had elevated liver enzymes, indicating damage to the liver or biliary tract. However, a number of experts told Sines magazine that direct viral introduction is unlikely to be the cause. In their opinion, the cause of liver damage could be more likely drugs or overexcitation of the immune system.
All these stories about the devastating effects of COVID-19 on the body are nothing more than a rough draft. It will take a year of intense research before we can make an objective picture. Meanwhile, this effect can trigger a cascade of immune and cardiovascular effects. While science is hastily engaged in searches, examining tissues under a microscope and testing drugs on patients, we can only hope that the drugs created will turn out to be more cunning and powerful than the virus that has stalled the whole world.
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