The Great Invader: How COVID-19 Attacks Every Organ

Neha Pathak, MD

April 23, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

UPDATED October 16, 2020 // Editor's note: This article was updated with new research about COVID and how it affects the body.

We have underestimated and misunderstood COVID-19 since it first appeared.

And as we learn more, it's clear that COVID-19 can be more than just a respiratory disease. It's joined the ranks of other "great imitators" — diseases that can look like almost any condition.

It can be a gastrointestinal disease causing only diarrhea and abdominal pain. It can cause symptoms that may be confused with a cold or the flu. It can cause pinkeye, a runny nose, loss of taste and smell, muscle aches, severe fatigue, diarrhea, loss of appetite, nausea and vomiting, whole-body rashes, and areas of swelling and redness in just a few spots.

In a more severe disease, doctors have also reported people having heart rhythm problems, heart failure, kidney damage, confusion, headaches, seizures, brain inflammation, Guillain-Barre syndrome, and fainting spells, along with new sugar control problems, blood clots throughout the body, and severe immune system responses. It's not just a fever and coughing, leading to shortness of breath, like everyone thought at first.

Some people may have lingering effects for months afterward.

Some people can have no symptoms at all.

This makes it incredibly difficult to diagnose and even harder to treat.

"This is a disease progression we have never seen for any infection that I can think of, and I've been doing this for a couple of decades," says Joseph Vinetz, MD, an infectious disease specialist at Yale School of Medicine.

How It Invades

When viral particles land in our eyes, nose, or mouth, "spike proteins" on the virus connect with a specific receptor, known as ACE2, on the surface of our cells, allowing entry. ACE2 receptors make a great target because they are found in organs throughout our bodies. Once the virus enters, it turns the cell into a factory, making millions and millions of copies of itself — which can then be breathed or coughed out to infect others.

A lot of what we know about the infectious capability of SARS-CoV-2, the virus that causes COVID-19, closely parallels what we learned about the coronavirus that causes SARS. What makes COVID-19 uniquely dangerous is that unlike SARS, this virus is much more effective at binding to ACE2 receptors, both in the upper respiratory tract and lower down, in the lungs — making it as easy to transmit as a cold and as damaging to the lungs as SARS.

We have also learned from SARS that in order to evade early detection, a coronavirus can use multiple tools to prevent the infected cells from calling out for help. The virus can snip off distress-signal proteins that cells make when they are under attack. It also destroys antiviral commands inside the infected cell. This gives the virus much more time to make copies of itself and infect surrounding areas before it is identified as an invader. This may be part of the reason why the virus spreads before immune responses, like fever, begin.

Direct Attack

Many with mild or no symptoms are able to fend off the virus before it gets worse. These people may have symptoms only in the upper airway, at the site where they were first infected. But when someone's body can't destroy the virus at its entry point, viral particles march deeper into the body. The virus seems to take a few paths from there, either setting up camp in the lungs, fighting its way into the digestive tract, or doing some combination of both.

"There's clearly a respiratory syndrome, and that's why people end up in the hospital. Some people get a gastrointestinal illness with diarrhea, maybe some abdominal pain, which may or may not be associated with a respiratory illness," says Vinetz.

Once the virus is deeply embedded in the body, it begins to cause more severe disease. This is where direct attack on other organs that have ACE2 receptors can occur, including heart muscle, kidneys, blood vessels, the liver, and potentially the central nervous system (CNS). This may be one reason for the vast array of symptoms COVID-19 can cause. It's still not clear exactly how the virus gets around inside the body. Scientists are still trying to figure out if the virus travels to different organs through blood or through cells that line blood vessels.

"It's highly unlikely that any other organs can be affected through direct invasion without severe disease," Vinetz adds.

The brain and nerves may also fall prey to direct attack. Kenneth Tyler, MD, chair of the Department of Neurology at the University of Colorado School of Medicine, cautions that direct CNS attack is still being worked out. There are many routes a virus could take to invade the CNS. One somewhat disputed view is that the loss of smell could indicate that the nerve responsible for smell is infected and can carry the virus into the CNS, including the brain. "This can be shown to occur in experimental models with non-human coronaviruses and is a potential route of invasion for some other viruses. However, there is no evidence to date establishing that this actually occurs with SARS-CoV-2."

Findings, including those from autopsy and biopsy reports, show that viral particles can be found not only in the nasal passages and throat, but also in tears, stool, semen, the kidneys, liver, pancreas, GI tract, and heart. One case report found evidence of viral particles in the fluid around the brain in a patient with meningitis.

Collateral Damage That Kills

Severe damage to the lungs can cause acute respiratory distress syndrome (ARDS) and may be one trigger that activates and overstimulates the immune system through a barrage of signaling chemicals, including those known as cytokines.

The flood of these chemicals can set off what is referred to as a "cytokine storm." This is a complex interplay of chemicals that can cause blood pressure to drop, attract more killer immune and inflammatory cells, and lead to even more injury within the lungs, heart, kidneys, and brain. Some researchers say cytokine storms may be the cause of sudden decompensation, leading to critical illness in COVID-19 patients.

There may be another deadly culprit. Many doctors have discovered that abnormal clotting, known as thrombosis, may also play a major role in lethal COVID-19. Doctors are seeing clots everywhere: large-vessel clots, including deep vein thrombosis (DVT) in the legs and pulmonary emboli (PE) in the lungs; clots in arteries, causing strokes; and small clots in tiny blood vessels in organs throughout the body. Early autopsy results are also showing widely scattered clots in multiple organs.

Adam Cuker, MD, a hematologist at the Hospital of the University of Pennsylvania who specializes in clotting disorders, says these clots are happening at high rates even when patients are on blood thinners for clot prevention. In one study from the Netherlands, 31% of patients hospitalized with COVID-19 got clots while on blood thinners.

Cuker says that "new studies validate what we have all been seeing with our eyes, which is that 'boy, it seems that these patients are clotting a lot.' ... And it could be that the rate of thrombotic events are even higher than we truly recognize." Though the reason for the clotting is still not clear, it seems to be playing a much larger role in death than previously understood.

Beyond the collateral damage from cytokine storms and clotting, other things like loss of ACE2 receptors from direct viral attack, low blood pressure that comes from a severe illness, low oxygen levels, ventilator use, and drug treatments themselves can all harm organs throughout the body, including the heart, kidneys, liver, brain, nerves, and other organs.

There have also been serious complications in a small number of previously healthy children who have experienced severe shock, similar to Kawasaki disease or toxic-shock syndrome. This syndrome, now called multisystem inflammatory syndrome in children (MIS-C), involves fevers and damage to multiple organs. Researchers are still trying to understand the exact cause, but they've found that children with MIS-C are negative for the virus but positive for antibodies. For these children, the trigger may be some sort of immune response after the infection has been cleared.

Double-Edged Sword

Even though researchers are learning more each day about the virus and how and where it attacks the body, treatment geared toward these targets also pose significant problems. Many drugs come with a risk of destroying the delicate balance that allows the body to help fight the disease or to manage inflammation.

The ACE2 receptor that the virus uses to enter cells is a key player in lowering inflammation and reducing blood pressure. Targeting or blocking this receptor as a treatment strategy to prevent viral entry into cells may actually worsen blood pressure, increase the risk of heart failure and kidney injury, and increase inflammation that may worsen lung injury.

Drugs that target the immune response to lower the risk of a cytokine storm may also tamp down the immune response, making it hard to kill off the virus over the long run.

Using medicines to prevent clotting may end up causing severe bleeding. Cuker points out that "we don't have a good read on bleeding ... we have limited evidence about the clotting risk ... we have zero evidence on bleeding risk in these patients, and it's a real priority to understand this risk, especially because one of our strategies to treat the clotting is stepping up intensity the of anticoagulation."

Timing is likely to be key in treatment strategies. For example, patients may need a drug to boost the immune system early on in the disease, and then one to tamp it down if the disease progresses and cytokine markers begin to rise.

Just the Tip of the Iceberg

Cuker says that what we know about clotting and almost everything else when it comes to COVID-19 "is just the tip of the iceberg."

Sanober Amin, MD, PhD, a dermatologist in Texas, agrees.

She posted images on social media that show the wide variety of skin findings she has been seeing and hearing about. Her post received a massive response. Amin says that "dermatologists from around the world, from Turkey to France to Canada to the US, are sharing information about rashes that they've observed in people with COVID-19."

Some rashes seem to be consistent with what's called a viral exanthema, which is a term for a general rash that can happen with almost any virus. But, Amin says, "some skin findings are more consistent with superficial clotting in blood vessels close to the skin."

This is what some have called "COVID toes," similar to pernio. Dermatologists are seeing more cases of these small clots in toes and fingers, especially in children.

Researchers still need to work out which symptoms may be caused by the virus and which may just be unrelated early findings.

The Long Haulers

One open question is what the long-term effects may be for survivors. What does life look like after being on a ventilator or suddenly needing dialysis? Will we see decreases in heart, lung, and kidney function that are long-lasting and permanent, or will patients eventually recover? We are learning that for some people who fight past their initial bout with COVID-19, months later, life is still not the same. They have survived the infection, but have not fully recovered. These people are being called "long-haulers." From minor complaints to severe functional decline, long-haulers are experiencing a vast array of aftereffects.

Given the wide range of damage caused by COVID-19 and long hospitalizations for many who recover, it's not surprising that regaining function can take time. Those with severe disease may have experienced lung damage, heart attacks, arrhythmias, strokes, and blood clots. Others may have had inflammation of the brain, confusion, delirium, and new onset diabetes or sugar control problems.

Doctors are studying survivors to learn more about the long-term effects of COVID-19. Early findings show lung scarring on scans even 3 months after infection. Based on studies of SARS survivors, some never fully recovered lung function more than 15 years after infection. Many other organs that take a hit are also slow to recover, including the heart and kidneys.

Some people whose condition was not serious enough to require hospitalization are also describing persistent symptoms of chest discomfort, shortness of breath, "brain fog," headaches, and severe exhaustion and fatigue. Similar to the aftermath of SARS, some people are experiencing a condition very similar to chronic fatigue syndrome, also known as myalgic encephalomyelitis, a condition involving severe fatigue after activity that doesn't improve with rest.

Heart and lung damage has been found on tests even in people who never experienced any COVID symptoms at all. Concerns about heart damage, including inflammation of the heart muscle, are so serious that the American Academy of Pediatrics recommends that youth athletes who suffered from multiple days of fevers and concerning symptoms like shortness of breath should not return to playing sports until they are fully evaluated by their doctor, even after symptoms have gone away.

A recent study found that "long COVID" may actually be up to four different syndromes, depending on the patient.

In order to prepare for other potential long-term effects, scientists are looking at patients that recovered from SARS. Mental health concerns like depression, anxiety, and post-traumatic stress disorder (PTSD) are among the persistent conditions that people have experienced after recovery. These have been identified in many after COVID-19 as well.

It will take time to tease apart what long-term effects are due to organ damage from direct attack by the virus, the overactive immune response and widespread blood clotting, or side effects from treatment and prolonged hospitalization. Recently, long-term nerve damage has been identified as a possibly permanent side effect, likely from treatment with prone positioning while on a ventilator.

One concerning finding is that while many of those who die from COVID-19 are older with other medical conditions, one survey of long-haulers in New York City found that the most were women, with an average age of 44 who were generally healthy before their bout with COVID-19. How long various effects will last, who is most at risk and whether or not full recovery is possible remains to be seen.

Unanswered Questions

For now, much of the information we have about the symptoms of COVID-19 come from hospitalized patients who are very sick by the time they seek care.

We still don't know the full extent of what mild and moderate versions of the disease look like and what exactly the disease does to people who have symptoms but aren't quite sick enough to be hospitalized, or those who have no symptoms at all.

We also don't know how people will clear infections. If the new coronavirus ends up being an acute infection, like other coronaviruses, most recovered people should develop at least a short-term immunity. It's also possible that the virus may persist as a latent infection, like chickenpox, lying dormant in the body, only to re-emerge periodically as shingles, or become a chronic infection, like hepatitis B, living within the body for a sustained period of time, causing long-term damage.

"It's definitely going to be an acute infection ... there's no way it's going to be latent or chronic, no way ... I think so ... we'll see," Vinetz says.

Sources

medRxiv: "COVID-19 Antibody Seroprevalence in Santa Clara County, California."

Joseph Vinetz, MD, professor, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT.

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Brain, Behavior, and Immunity: "Nervous system involvement after infection with COVID-19 and other coronaviruses"

The Lancet: "Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence?"

medRxiv: "Pulmonary and Cardiac Pathology in COVID-19: The First Autopsy Series from New Orleans."

Kenneth Tyler, MD, chair, Department of Neurology, University of Colorado School of Medicine; faculty, American Academy of Neurology, Boulder, CO.

International Journal of Infectious Diseases: "A first case of meningitis/encephalitis associated with Sars-Cornoavirus-2."

Adam Cuker, MD, associate professor of medicine, Hospital of the University of Pennsylvania.

bioRxiv: "SARS-CoV-2 invades host cells via a novel route: CD147-spike protein."

Sanober Amin, MD, PhD, dermatologist, Grapevine, TX.

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