What the Coronavirus Does Inside the Body
SARS-CoV-2 does much more damage to the human body than initially assumed. It can attack any number of organs and even penetrates the brain. But why do some people experience worse symptoms than others?
By Philip Bethge
The heart and its blood vessels can experience significant damage. / K H Fung/ SciencePhotoLibrary
The pathogen has already done a fair bit of damage. It has only been five days since the patient began exhibiting typical COVID-19 symptoms, but already, menacing shadows can be seen in the CT scans of the lungs.
"It's like frosted glass," is how Christian Strassburg, a professor of internal medicine at the Bonn University Hospital, describes the changes made visible by the scan. "The lung tissue is saturated with fluid." Secretions and dead cells are gumming up the walls of the pulmonary alveoli "like Jell-O," he says.
"It is extremely difficult for oxygen to permeate a layer like that to get from the lung into the bloodstream," the professor explains. It is a phenomenon he has been seeing frequently in recent weeks and it is caused by the novel coronavirus, SARS-CoV-2. The number of confirmed COVID-19 patients worldwide is now well over 4.2 million and the number of deaths is approaching 300,000. Meanwhile, doctors and biologists are doing all they can to gain a better understanding of the pathogen behind the pandemic.
SARS-CoV-2 behaves differently than almost any other virus that humans have faced before, and even now, several months into the pandemic, there is disagreement as to what percent of COVID-19 patients experience severe symptoms. Estimates tend to come in at around 5 percent of all infections. And in those cases, the virus unfolds unfathomable destructive power.
The epicenter of such infections is almost always the lungs. But as medical professionals now realize, the virus can also affect other organs and tissues - including the heart, the brain, the kidneys and the bowels. In the worst case, the body begins attacking itself. When the immune system spins out of control like that, doctors call it a "cytokine storm," and when patients die as a result, multiple organ failure tends to be the cause.
Over 100 vaccine candidates are currently being developed worldwide to combat SARS-CoV-2, but in the worst-case scenario, it could take years before a vaccine is available. Until it is, the virus will still be with us. Even if the pandemic does weaken a bit, experts believe a second wave is just around the corner.
Early talk of COVID-19 as being mostly a mild illness has been proven to be "dangerously false," Richard Horton, editor-in-chief of the medical journal The Lancet, has written. At the bedside, he says, it is "a story of terrible suffering, distress and utter bewilderment."
U.S. cardiologist Harlan Krumholz described the ferocity of COVID-19 in the magazine Science as "breathtaking and humbling." The disease, he continued, "can attack almost anything in the body with devastating consequences."
The best way to learn more about SARS-CoV-2 is to start small. Coronaviruses are a mere 160 nanometers in size. In order to multiply, the tiny pathogens are reliant on the cells belonging to a different organism.
The novel coronavirus likely comes from bat viruses, and it is thought that, even before it made the jump to humans, it developed the mechanism allowing it to bind with human cells. Some bat viruses are able to bind to a receptor called ACE2. This molecule can be found on the surface of human cells and helps regulate blood pressure. But it also functions as a kind of doorway to the interstices of the cell, and viruses that have the key can get inside.
Researchers believe that bats carry around 3,200 different coronaviruses. Chance, time and opportunity fueled the creations of the SARS-CoV-2 virus, which ultimately managed to jump to humans.
The Attack
But how exactly does the virus find its way into the human body? Internal medicine professor Strassburg is quite familiar with the process. At the Bonn University Hospital, he is currently in charge of between 10 and 20 COVID-19 patients. On one day recently, eight of them were intubated, having become so ill that they were forced to rely on ventilators. "Luckily, that is the minority," Strassburg says. "Most of those infected by the virus get away with only mild symptoms."
Early on, virologists thought that the novel coronavirus would spread only slowly, in part due to the similarities between SARS-CoV-2 and the SARS coronavirus that appeared in China in 2002. From November 2002 and July 2003, almost 800 people died of the disease, the full name of which is Severe Acute Respiratory Syndrome.
But then, the epidemic disappeared. It was a stroke of luck for humanity: That pathogen appears to have been more deadly than SARS-CoV-2, but it focused its attentions on the lungs. The virus multiplied deep within the body, making it less contagious. Furthermore, it was easy to identify and isolate those who had fallen ill from the virus.
Experts initially hoped that the same would hold true of SARS-CoV-2, but they were mistaken. The novel coronavirus doesn't just attack the lungs. Throat swabs from patients revealed early on that the pathogen first goes after the mucous membrane in the upper respiratory tract.
That is advantageous for the virus. The distance from one throat to another throat is much shorter than the distance from one person's lung to another.
"That means that those carrying the virus are highly contagious," says Strassburg. A huge number of the viruses are found in the nasal cavity and pharynx, "even in people who aren't yet experiencing symptoms," he adds, "which is why the pathogen was able to circle the globe so quickly."
There are three stages in the attack on the human body. Initially, the coronavirus binds with club-shaped protein complexes on the ACE2 receptors of human cells. That opens up the host cell and allows genetic material from the pathogen to enter. The virus then converts the cell into a virus factory. Huge numbers of viruses thus produced then leave the host cell and attack other cells.
The SARS-CoV-2 Virus focuses its attack on the lungs. The delicate alveoli are most at risk.
George Washington University Hospital/ ddp images/Ferrari Press
The resulting viral load is enormous, particularly in the first week following infection. And initially, there are hardly any symptoms. Often, there is merely a dry cough, says Strassburg, with the body's temperature hardly rising at all.
"Even patients who are more severely affected generally have a temperature below 38 degrees Celsius (100.4 degrees Fahrenheit)." That is a significant difference to the flu: "For influenza, a sudden rise in temperature is typical, along with a distinctive feeling of being sick. But that's not the case here."
In this initial phase of the illness, much depends on the patient's immune system. Immune cells attack the invaders, but because the body isn't yet familiar with the virus, the weapons at their disposal are relatively basic.
A battle of attrition ensues, one that determines whether the patient will quickly recover or whether the disease will get the upper hand. Will the immune system stop the attack in the upper respiratory tract? Or will the pathogen be able to find its way into the lungs? The answers to those questions determine whether the illness becomes life threatening or not.
Researchers are still trying to figure out why the virus is able to reach the lungs of some patients but is stopped short in others. One of the factors appears to be the number of pathogens that attack the body at the beginning. More than anything, though, patients with underlying medical conditions seem to have the most to fear from SARS-CoV-2. According to estimates, about a quarter of the population in Central Europe has such an underlying condition.
Those at risk include people suffering from obesity, diabetes and high blood pressure. And smokers: "Their mucous membranes and lung ventilation are already impaired," says Strassburg. Tiny hair-like projections known as cilia, which normally help keep pathogens and mucous out of the lungs and respiratory tract, no longer function appropriately.
In such cases, there are hardly any hurdles for the virus on the way to the lungs. Gravity is sufficient for the tiny pathogens to reach their target. Once the virus advances into the smaller, branch-like bronchioles, it meets a particularly vulnerable layer of cells, the membranes of which are also covered with ACE2 receptors. Directly in the pulmonary alveoli, the tiny sacs where oxygen is transferred into the bloodstream, SARS-CoV-2 finds perfect conditions.
The Defensive Battle
To depict the precise damage the virus does in the lungs, thoracic surgeon Keith Mortman of George Washington University Hospital in Washington, D.C., turned to computer modelling. The 3-D imagery from the clinic shows the lungs of a man in his late 50s. Yellow-tinged deposits can be seen in many areas within the organ.
"The damage we are seeing is not isolated to any one part of the lung," says Mortman. Initially, he says, the patient experienced a fever and a cough, before then developing serious breathing difficulties. He was intubated and attached to a ventilator, but when that proved insufficient, he was hooked up to a so-called ECMO machine.
The machine infuses blood with oxygen outside of the body before pumping it back inside. The hope is that the procedure will give the lungs the time they need to recover.
Doctors now have a deeper understanding of how SARS-CoV-2 damages lung tissue. White blood cells discover the virus and attract other immune cells to the site, which attack the infected lung cells and kill them. They leave behind cell detritus, which clog up the alveoli. If the body isn't able to gain control over the reaction to the infection, acute lung failure looms.
But other organs can also be damaged as a result of the infection. The more SARS-CoV-2 patients are treated around the world, the clearer it has become just how comprehensive the attack staged by the virus is.
According to data from China, around 20 percent of patients requiring hospitalization suffer damage to the heart. It remains unclear whether the virus goes after heart muscle cells directly or if damage to the coronary blood vessels is to blame. The blood clotting function is also disrupted, leading to clumps that could result in heart attacks, lung embolisms and strokes.
The kidneys of some hospitalized patients also come under attack, as evidenced by blood or protein in urine samples. As a result, dialysis machines have had to join ventilators in ICUs devoted to treating COVID-19 patients.
Doctors have likewise observed brain inflammation and seizures in some patients. The virus apparently advances all the way into the brain stem, where important control centers are located, such as the one responsible for breathing. The virus likely gets to the brain via the mucous membrane inside the nose and the olfactory nerve. This could also be the reason that many patients temporarily lose their sense of smell.
SARS-CoV-2 can also attack the digestive tract, with patients complaining of bloody diarrhea, nausea and abdominal pain.
Doctors have also reported a possible link between COVID-19 and a rare blood vessel syndrome in children called Kawasaki Disease. In Britain, the disease has even killed a few children who became infected with SARS-CoV-2. The disease involves the inflammation of blood vessels throughout the body and can damage the heart.
Doctors now believe that SARS-CoV-2 attacks tissue and organs virtually everywhere in the body. And the disease can also apparently leave behind long-term damage. Chinese researchers have examined the blood of patients and found that even after the infection has passed, certain blood values remain abnormal for an extended period. Despite the virus no longer being present in the body, for example, their livers still don't exhibit normal functionality.
The virus can make it all the way into the brain, triggering seizures and inflammation.
K H FUNG / SCIENCE PHOTO LIBRARY
The lungs, too, likely suffer lasting damage in severe cases. "When inflammation does not subside with time, then it becomes essentially scarring in the lungs, creating long-term damage," says Mortman, the doctor from George Washington University Hospital.
It is still too early for a comprehensive understanding of the long-term consequences of COVID-19. But doctors are familiar with cytokine storms and acute lung failure from other severe infections. Some of the survivors of the first SARS epidemic, for example, experienced limited lung functionality for up to 15 years after the illness.
Life or Death?
But why do some people emerge virtually unscathed from this multifaceted attack while others do not? Thus far, researchers do not have an answer to this question. There are indications that the virus - similar to the pathogen that causes AIDS – is able to attack certain white blood cells, thus damaging precisely that line of defense that is supposed to stop the infection.
Are some patients more susceptible than others to that phenomenon for genetic reasons? The biotechnology company 23andMe intends to comb through the DNA of its 10 million customers in the search for sequences that could be predictive of their susceptibility to severe COVID-19.
Until the question is answered for sure, however, most patients can continue to rely on hope. After all, most people do not experience severe symptoms from the disease. "Among patients without underlying conditions, even severe cases have an 80 percent survival rate," estimates Christian Strassburg, the internal medicine specialist. Still, it is by no means time to let down our guard, he says, particularly now that restrictions on public life are increasingly being lifted. "The danger remains extremely high that a large number of patients will soon have to be treated in hospitals."
That will heap even more pressure on doctors and nurses. The condition of some patients, after all, can worsen dramatically within just a few days.
Should death be the ultimate result, it is often not the virus itself that causes it, but the immune system of the infected patient, which can disastrously overreact and attack the body.
In such instances, huge numbers of so-called cytokines are released. These chemical signaling molecules produced by the body trigger a cascade of biochemical reactions that affect the immune system. The development of a fever accelerates the metabolism and helps kill the virus. Blood vessel walls are made more permeable, allowing easier access for immune cells, such as phagocytes, to attack the virus. The heartrate speeds up.
"The reaction is actually quite sensible," says Strassburg. But in cases of severe infection, the immune system can overreact and trigger a cytokine storm.
"The result is a reaction that looks like a massive blood infection, but isn't one," says Strassburg. It can lead, however, to multiple organ failure. "If the immune system overreaction to the pathogen continues for too long or is too severe, it will kill the body."
Vast destruction is the result, as pathologists can attest. Johannes Friedmann is a professor at Lüdenscheid Hospital just south of Dortmund and has examined the bodies of several patients who succumbed to COVID-19. In the alveoli of these patients, he has found epithelial cells in the lung that have been "scaled off" in addition to protein "deposits" in the blood resulting from blood vessels that have become permeable. He has also discovered cells with multiple or enlarged nuclei, a phenomenon that is typical of viral illnesses.
The walls of the vast majority of the alveoli in the lungs are "widened to many times their normal thickness," Friemann says, adding that the lungs of many COVID-19 casualties are "insufficiently inflated." That impedes oxygen transfer.
Friemann's findings have been consistent with those of medical professionals in Hamburg, the United States, Switzerland and elsewhere: Most of those who died were sick before they came into contact with SARS-CoV-2. Friemann has found cases of liver cirrhosis, severe arterial sclerosis and extremely high blood pressure.
Did these patients die of SARS-CoV-2 or from other maladies? "You can't live with such a lung, so I would point to the virus as being the cause of death," says Friemann. "Many of these people would still be alive without the infection."
Indeed, a recent calculation by British epidemiologists casts significant doubt on claims that most COVID-19 victims would have died soon anyway. They found that female victims of the disease lose an average of 11 years of life. For men, the number was 13 years.
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