As more cases are being reported globally there are more cases of unusual damage being reported ranging from hundreds of tiny blood clots to strokes in young people as well as mysterious inflammatory responses such as full body rashes in children and red lesions that are unofficially being called COVID toe.
While these symptoms are strange and they may seem scary they have all been seen in viral medicine before the advent of COVID-19, and to some degree they are to be expected. Each human is unique, as such a disease that is striking millions of people will yield some oddities, and that is what is happening now.
It appears as if this virus starts off as a respiratory disease when it invades the nose, throat, and lungs to begin replicating to cause flu-like symptoms that can progress to pneumonia and even punch holes in the lung. For many this is the worst of the virus, but unfortunately for others the immune system goes haywire in overdrive to release cytokine proteins to fight off the infection. This storm of cytokines can leak into the bloodstream and fill the body where the immune cells will start killing off anything they encounter and creating massive inflammation that weakens the blood vessels, causing fluid to seep into the lung air sacs triggering respiratory failure, and the storm can also damage the liver or kidneys resulting in multi-organ failure.
Heart infections: The virus can go beyond the lungs, moving to wreak havoc in the heart with 1 in 5 patients experiencing some form of cardiac injury according to recent studies. Respiratory virus can interfere with the balance of supply and demand; when a virus attacks the lungs they become less efficient at supplying oxygen to the bloodstream. Infections can also inflame arteries causing them to narrow and supply less blood to the organs, which includes the heart, triggering the heart to work harder to compensate and this can lead to cardiovascular distress.
One of the more unusual and yet to be explained symptoms that is appearing in young and otherwise healthy individuals is myocarditis. This is a relatively rare condition in which inflammation weakens the heart muscle. Reports are suggesting that this virus may be embedding itself directly into the heart through receptor proteins called ACE-2 that this SARS-CoV-2 virus uses as the doorway of favorite choice to attack the lungs.
“No one convincingly has shown with a biopsy that there’s actually viral particles inside the heart muscle cells,” says Robert Bonow, a professor of cardiology at the Northwestern University Feinberg School of Medicine and past president of the American Heart Association. He goes on to note that these signs of myocarditis could also be brought on by a cytokine storm that’s inflaming the rest of the body. However, viruses such as chickenpox and HIV have been known to directly infect heart muscle, and research suggests that the coronavirus can invade the blood vessel lining.
There are increasing questions of whether COVID-19 should also be classed as a cardiovascular disease as emerging evidence suggests the heart plays a significant role in this disease. “It’s led to lots of questions about how we treat patients these days,” Bonow says. “When a 75-year-old man comes in with chest pain, is it a heart attack or COVID?”
Blood Clotting: For many patients this virus is causing a lot of clotting in an unusual number of ways. Over 160 years ago three reasons abnormal blood clots can occur were detailed by Rudolf Virchow. When the inner lining of blood vessels become injured; when the blood flow becomes stagnant; and when vessels become cluttered with platelets or other circulating proteins that repair wounds.
“I think we have evidence that all three of those are playing a role in COVID,” says Adam Cuker, an associate professor of medicine at the Hospital of the University of Pennsylvania who specializes in clotting disorders.
Cytokine storms can also exacerbate inflammatory conditions that clog arteries, which is why pre-existing cardiovascular disease correlates with severe COVID-19 infection. Still the medical community is puzzled by the blood clotting caused by this infection that is manifesting in some fairly abnormal ways including hundreds of microclots that form in the bloodstream, collect in the lungs, and clog dialysis machines.
Some hospitals and ICUs are seeing 3 times as many clots in those with COVID-19 than they see in those without this disease. It is not clear why these clots are so tiny and are filling organs by the hundreds, it may be due to a part of the immune systems’ complement pathway which involves normally inactive proteins that circulate in the blood; inappropriate activation of this pathway in other diseases can manifest as tiny clots.
“All of these systems may be playing a role, and we need to understand that,” says Adam Cuker, an associate professor of medicine at the Hospital of the University of Pennsylvania who specializes in clotting disorders, who is helping to develop guidelines on how to treat COVID-related clotting for the American Society of Hematology.
Strokes: The increased clotting may help to explain why young patients without any cardiac risk factors are experiencing strokes. The majority of the reported strokes have been ischemic which arise from a clot plugging one of the vessels supplying blood to the brain. Some involve hemorrhagic stroke which occurs when a weakened blood vessel ruptures and bleeds into the brain compressing the surrounding brain tissues. How common strokes and clotting are among the infected patients is not clear because most of the observations are confined to the ICU, meaning that the record is missing from discharged patients who later developed a COVID-19 related clot, or in those whose infections had mild or no symptoms before the clot.
“Is this just a small number of cases getting a lot of attention, or is this actually a more common problem that rises to the level of a public health issue?” Cuker asks.
“Almost all the [neurological] things we’re seeing now with COVID-19 are things you might have predicted would have happened,” says Kenneth Tyler, chairman of the department of neurology at the University of Colorado School of Medicine and a fellow of the American Academy of Neurology.
Brain Inflammation: COVID-19 patients have also been linked to suffering from encephalitis, as well as the much rarer Guillain Barre in which the immune system attacks the nerves. In milder cases encephalitis can cause flu-like symptoms and in more severe cases it can cause seizures, paralysis and confusion.
This virus is not novel in this regard as many different viruses including the original SARS can cause encephalitis when they invade the nervous system where they can then injure and inflame the brain either by directly killing cells or by triggering the immune system to do it via a cytokine storm. The problem is, with this virus, the cause is still not known.
Guillain Barre disorder has only been observed in a handful of COVID-19 patients. The exact mechanism to GB is not known, but it appears to be associated with the body’s acquired immune system which responds to a pathogen by developing specific antibodies to fight infection. These antibodies can take weeks to develop, and they are typically protective, but occasionally they too can go haywire to attack the nerves and their coating in a storm.
Skin: One of the more recent discoveries and most inexplicable signs of COVID-19 is a broad range of inflammatory symptoms that appears to be manifesting on the skin in rashes, painful red lesions, and a collection of symptoms in children that are being labeled Kawasaki like conditions.
“It’s like reading a dermatology textbook, because it really spans the full gamut,” says Kanade Shinkai, a professor of dermatology at the University of California, San Francisco.
Viruses can trigger rashes in 2 ways; by spreading across the body to deposit itself directly on the skin, or by activating the immune system to produce rashes in nonspecific patterns all over the skin both as part of a normal response to the infection or as an overreaction associated with a cytokine storm.
Viral rashes typically occur in 2% of patients with other common viruses, COVID-19 rashes take on many different patterns making it hard to tell if any are unique to SARS-CoV-2. This situation is so mystifying that some experts are questioning whether these rashes may just be a coincidence.
“Some people have even argued that what we’re seeing is rashes during the time of COVID-19, but not necessarily rashes associated with COVID-19,” Shinkai says. “That’s a big mystery and a big scientific question that still needs to be answered.”
Dermatologists are seeing an increase in patients presenting with painful red or purple lesions on their toes and fingers which may be caused by micro clots or inflammation in the blood vessels. Most have tested positive for COVID-19 but this symptom is also present in those who have tested negative for both the virus and the antibodies generated in response, according to Shinkai.
Scientists are baffled by the diseases in children that have been grouped as Kawasaki like syndrome, while the cause remains unknown symptoms include full body rashes, swelling, bloodshot eyes, diarrhea, and abdominal pain; this typically resolves in its own without long term consequences but it can cause severe heart complications.
Recent emerging reports are identifying COVID-19 positive children sharing all or some of the symptoms of Kawasaki disease, and physicians are just beginning to describe the connections. Two forms have been identified; one centers on viral sepsis, and the other emerges in the weeks after infection/exposure with some of the more classic Kawasaki symptoms including changes in the shape of the heart’s arteries. This condition is very rare, only being observed in clusters of European and North American children.
More studies are needed that comprehensively describe these skin manifestations to better understand them. Finding the answers will depend on more comprehensive patient descriptions, and better access to testing and clinical trials, says Michael Agus, chief of medical critical care at Boston Children’s Hospital.
While the medical community is working hard to find the answers, we should all stay focused on maintaining the standard practices to protect ourselves from this virus which includes careful distancing, meticulous hand washing, and wearing masks. “That’s going to be the answer,” Agus says, “whether this turns into one syndrome or four syndromes.”
