Written by: David Clark, PhD, chair of the Coalition for Hemophilia B

NOTE: This article is not intended as medical advice. Readers should seek the advice of their own physician. Because information regarding COVID-19 (novel coronavirus) is ever changing, readers are also asked to check for frequent updates on our website.

First, I want to add a little more to the previous post about the course of COVID-19 infections. These clinical symptoms and timings are just the typical ones seen in the majority of patients. There are still many patients who don’t fit that description. Remember that this is an unusual virus, and it hits some people in unusual ways. Some people have no symptoms at all or very mild symptoms. Others might be much more severe than indicated. We don’t know why yet. The accompanying New York Times article discussed some of that in more detail, and I suggest you read it.

NEW SYMPTOMS 

Until now, the U.S. Centers for Disease Control and Prevention (CDC) had only listed three possible symptoms for COVID-19: fever, cough, and shortness of breath. The CDC has now released six additional symptoms. The complete list is:

• Fever

• Cough

• Shortness of breath

• Chills

• Repeated shaking with chills

• Muscle pain

• Headache

• Sore throat

• Loss of taste or smell

In addition, the World Health Organization (WHO) includes fatigue, nasal congestion, and diarrhea as symptoms. Both the CDC and WHO also warn that people should seek medical help if they experience sudden confusion, cannot be aroused, or if their lips or face turn a bluish color.

Not every COVID-19 patient will have all of these symptoms; some may have none and some may have other, less common symptoms. Note that in all cases, the earlier you are diagnosed, the more likely you will respond to treatment. Here are a couple of the less common symptoms.

COVID Toe

One of the things that doctors have noticed in some patients is being called “COVID toe.” This is a reddish/purplish color and/or blistering of the toes, heels, and/or soles of the feet similar to chilblains. Its cause is unknown, but doctors are speculating that, like chilblains, it is a result of inflammation of the endothelial cells that line the insides of the small blood vessels in the feet. In chilblains, the endothelial cells are damaged by cold; in COVID-19, they are probably damaged by the virus. There is some evidence that the coronavirus can infect endothelial cells. Some patients have COVID toe along with other COVID-19 symptoms. Others seem to only develop COVID toe and nothing else, which might indicate that they have a very mild infection. We don’t know much about it yet, but if you develop this symptom, call your doctor.

There is some evidence that the coronavirus can infect endothelial cells that line the insides of the small blood vessels.

Rare Childhood Reactions.

Most children who are infected have relatively mild cases, but doctors are starting to see small numbers of children with unusual symptoms, as first observed in the United Kingdom. A few children are coming in with abdominal pain, other gastrointestinal symptoms, and cardiac (heart) inflammation and are testing positive for COVID-19. They also can develop a reddish-purplish rash, which is like COVID toe (see above) all over the body. These children are critically ill with a multisystem inflammatory state that requires intensive care in the hospital. Some of the symptoms resemble Kawasaki disease, a rare childhood illness that causes endothelial cells to become inflamed (like COVID toe). While this is still very uncommon and parents should not panic, they should be aware that these reactions can happen. If your child has any of these symptoms, please call a doctor right away.

Relapse? Recurrence? Reinfection? 

A number of patients have relapsed after they seemed to have recovered. We do not know what this is about yet. It could be that these patients never fully recovered. It could be that the virus hides somewhere in the body and can be reactivated. It could be that they had little residual immunity and were re-infected. It could also be continuing inflammation, as I’ll discuss below.

One thing we have seen is that the recurrence is sometimes much more severe. One of the strangest things we have seen is that healthy young people who seem to have recovered will suddenly be hit with another severe outbreak after they have felt fine for a few days or even weeks. These relapses are sometimes quickly fatal, so if you feel that you are relapsing, call your doctor right away.
“Unusual,” “Strange,” “Some,” and “Sometimes” I use these words a lot lately because we really do not know what’s going on yet. If you have any kind of unusual symptoms, call your doctor.

INFLAMMATION 

When you have the flu and you feel fever, chills, aches, pains, or sweating, those symptoms are not caused by the flu virus. They are caused by your immune system’s reaction to the infection. This is inflammation—a part of the immune system’s arsenal of tricks to fight off an infection. Immune system cells embedded in the tissues being attacked (infected) get activated and send out signals to the rest of the immune system that the tissue needs help. The signals are small molecules called cytokines that are released into the bloodstream. 

White blood cells, part of the immune system, follow the cytokines backward to find the tissue that needs help. Specific kinds of white blood cells gobble up viruses and infected or damaged cells and start the healing process. This is a quick brute-force defense that also often damages unaffected cells as much as the viruses or bacteria trying to cause an infection. Its purpose is to try to clear away the infection by physically destroying the tissue around the site of infection. This gives other parts of the immune system time to rev up and start making antibodies. 

Inflammation is a sledgehammer that destroys everything around it in order to destroy the infection. Antibodies are tweezers that just pick out the cause of the problem. 

There are many different kinds of cytokines that have different jobs in this process. Say that you had an early treatment for hepatitis C that included interferon. Interferon is a cytokine. That’s why it made you feel so lousy—it was turning on this inflammatory response. Certain cytokines are called interleukins.

The inflammatory response is supposed to turn itself off once the infection is removed. The cytokines degrade quickly in the bloodstream, so once the immune cells at the site of infection stop cranking them out, everything should die down and go back to normal. In some people, that doesn’t happen, but we don’t know why. This is called chronic inflammation. We have learned over the last decade or so that a number of human diseases appear to be caused or made worse by a chronic inflammatory response. These include conditions like asthma, celiac disease, lupus, rheumatoid arthritis, and many others. 

From the beginning, the role of inflammation in COVID-19 has been questioned. Pneumonia and ARDS (acute respiratory distress syndrome) are inflammatory diseases of the lungs, which are involved in many of the most severe COVID cases. Doctors wonder whether it is actually the body’s inflammatory response that is harming people as much as or more than the virus itself. The inflammatory system might not be getting turned off, or there might be something else, caused by the virus, that keeps stimulating the response.

You might have heard the term “cytokine storm.” The media loves these kinds of vivid descriptors. This means that the bloodstream is full of cytokines, the signals to turn on inflammation. This could be because the immune system is overreacting and cranking out many more cytokines than necessary, or it could be because there are so many sites of infection, each sending out its own set of cytokines, that the bloodstream is overloaded with them. 

Remember that the white blood cells follow the stream of cytokines backward toward the site of infection. They do that by following the concentration of cytokines as it increases back to where the concentration is highest, near the site of infection. That’s fine if there are only a limited number of infection sites. However, if there are thousands of infection sites spread all over the body, the bloodstream will be full of cytokines, and the white blood cells won’t know where to go. They will think they are at the site of infection and just take out their sledgehammers and go to work, whether it is on healthy tissue or infected tissue.

Severe and fatal cases of COVID-19 probably involve both the viral infection and the inflammation that follows it.

Cytokine storms result from a number of kinds of infections. They are common with the flu as well as with many coronavirus diseases including SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), the common cold, and now COVID-19. Interestingly, they are also a feature of multiple sclerosis. They also appear to be unique to humans, which is one reason animal studies are not as useful here. This was discovered after a 2006 study in the United Kingdom. Six patients were given a drug that was supposed to actually calm the immune system for treatment of multiple sclerosis, leukemia, and arthritis. The drug had been tested extensively in mice and monkeys and seemed safe. However, within 90 minutes of being given the drug, all six patients developed raging cytokine storms, resulting in multiple organ failure that almost killed them. 

In summary, severe and fatal cases of COVID-19 probably involve both the viral infection and the inflammation that follows it. Treatment will probably involve both an anti-viral medication and a drug to control inflammation. Researchers are still trying to tease out the details of what is actually happening—stay tuned.

Remember that all of this is still a developing story. Some of the above has been proven and some is just speculation based on what has been seen so far. It changes every day. As I said previously, if you have any kind of weird symptoms, please call your doctor. Today’s weird symptom might lead to tomorrow’s breakthrough. Be safe and well.