CLEVELAND — Roughly a third of adults who get COVID-19 report having had what is considered long COVID. And months after the initial infection, a staggering number of those who haven’t recovered – up to 80% – have some trouble carrying out their daily activities.
A Brookings report from August said a conservative estimate was that 16 million people were suffering from long COVID-19 at that time. The CDC says it may be as high as 19 million adults.
But whether 16 million or 19 million, one thing is clear: there’s a lot of them. Here in Cleveland and across the country, scientists and doctors are trying to figure out what’s wrong and how to help them.
The symptoms that fall under the long COVID umbrella include everything from a persistent loss of taste and smell to fatigue so disabling that the affected person is unable to return to work or daily life. In between, there are reports of brain fog, headaches, chronic gastrointestinal issues, increased incidence of diabetes, blood clots, heart arrythmias and intolerance to exercise.
To the untrained eye, the list of symptoms is dizzying and appears specific to each individual patient.
However, behind the scenes, and thus far largely out of media fanfare, researchers and clinicians have doggedly made strides in not only classifying and defining what long COVID is, but also in identifying the underlying mechanism of the disorder and how they might treat it.
One of the largest centers of research is right here in our own back yard at University Hospitals Case Medical Center and MetroHealth System.
The economic impact from the sheer volume of American workers who could be permanently disabled is troubling. In fact, it was of such concern that in December 2020 Congress gave more than $1 billion to the National Institutes of Health to fund research on the prevention and treatment of long COVID.
University Hospitals and MetroHeath System jointly was the recipient of one of the 15 grants the NIH subsequently awarded to research institutions around the country in early 2021, and currently counts itself as the largest in terms of the number of research subjects.
To date, they have enrolled over 800 patients, and they hope to add 300 to 400 more, said Dr. Grace McComsey, an infectious disease specialist who heads up the project at UH.
The goal, said McComsey, is to uncover so-called biomarkers of COVID disease – any sort of measurable biological change – that could identify, and ultimately separate out patients who had an acute COVID infection and continued to experience COVID symptoms months after they no longer tested positive.
McComsey said that over the last year they and the other researchers around the country have collected samples of blood, saliva, urine or stool, and cataloged the progression of symptoms from patients with and without COVID.
Eerily similar to HIV
McComsey, who has spent the last two decades studying HIV, said that the data they have found so far paints a picture that is eerily familiar.
“Now I just look at it, and I’m like gosh, it’s like a déjà vu,” McComsey said.
If the idea that the behavior of the SARS-CoV-2 virus might have any similarities to HIV is news to you, you aren’t alone. But McComsey said that for the HIV researchers who have made the crossover to studying this new coronavirus, the similarities that emerged were unmistakable.
To be clear, McComsey isn’t suggesting that the viruses themselves are similar. Coronaviruses are not retroviruses like HIV, nor are they sexually transmitted like HIV. But it’s the way they make the people they infect sick that caught her attention. It hides in the body and continues to wreak havoc in the various organ system by driving inflammation and disrupting the immune response.
“HIV patients don’t die from the virus itself. They die from immune activation – from the high levels of inflammation that causes cancer, heart disease, liver and kidney disease,” she said.
“The only reason we cannot cure HIV is because the virus hides where the HIV drugs can’t go in. So it continues to fuel this high inflammation. That’s why somebody like me who has been studying HIV for the last 20 years found that COVID is extremely similar to HIV. It’s a virus that produces a lot of inflammation. We see a lot of conditions that are known to stem from inflammation, and now we have some evidence that it persists in different organs.”
McComsey is referring to various published research papers that suggest the SARS-Cov-2 may linger in various organ tissues long after nasal swabs and blood tests come back negative.
An early pre-print autopsy study from the NIH has found the virus throughout the body – in a wide range of tissues including muscle, fat, gut, and brain tissue of patients who died with COVID, and in some cases in those who were asymptomatic, or had mild infections and died many months later. This proving, the authors say, that SARS-Cov-2 is capable of persisting in the body for many months after infection.
Another study further suggests that the SARS-Cov2 virus may have stolen yet another page from the HIV playbook, hijacking ancient and normally dormant human DNA sequences to reverse engineer its viral RNA and insert itself into the genomes of our cells.
Although, the paper was originally met with a firestorm of criticism and fearmongering about the possibility that their results open up the possibility that RNA-based COVID sequences in vaccines might somehow integrate themselves into our DNA (the authors immediately squashed this idea), some scientists do not find their theory so implausible, McComsey among them.
“It is a big possibility. I would say it is very possible, even likely,” she said.
Untangling long COVID-19 – initial findings
The NIH funded study McComsey directs is called RECOVER – an acronym that stands for Researching COVID to Enhance Recovery – and has uncovered some important pieces of information.
* First, it found that people with long COVID-19 are primarily women, around 75% of McComsey’s nearly 900 subjects are women, and not by choice. “We don’t go looking for them,” she said. “These are the people who are calling us.”
* Second, researchers have found that although one’s risk of developing long COVID increases with the severity of the initial infection, people can and do develop long COVID even after infections that were asymptomatic or considered mild.
* Third, vaccination dramatically reduces a person’s chances of developing long COVID. A fully vaccinated individual is five times less likely to continue to have any symptoms or ill-effects three months after their initial infection compared to someone who has not been vaccinated. And that, said McComsey, makes a strong case for continued vaccination. “I’m not afraid of getting acute COVID,” she said. “I’m worried about Long COVID.”
* And finally, researchers have discovered that patients with long COVID generally have symptoms that fall into three categories or phenotypes: fatigue, neurocognitive symptoms such as brain fog or headaches, and cardiovascular symptoms such as shortness of breath, heart arrythmias, exercise intolerance, and blood clots. Patients may have more than one type, and some also have symptoms like constipation, diarrhea, or loss of taste and smell that don’t seem to fit neatly into one of the three groups.
One explanation for the different groups of symptoms is the lingering presence of the virus in specific tissues, where it presumably continues to reignite an inflammatory response.
For example, someone who has headaches or brain fog may have a virus that resides in their brain tissue, whereas someone with cardiovascular symptoms may have virus present in the heart, lungs or vasculature. And a chronically heightened immune response and widespread inflammation throughout the entire body may partially explain why so many – more than 50% of Long COVID sufferers—-experience the devastating fatigue.
According to McComsey, the research on biomarkers which is still ongoing, may yet help to tease these subtypes apart.
She said anyone who currently has COVID-19 or has been infected within the last 30 days is invited to join the study. They want to track the changes in these biomarkers along with symptoms from the time of infection until symptoms resolve and beyond, and they still need several hundred subjects. She also said it doesn’t matter if you have had COVID before, because one of the things they hope to learn is whether the chances of developing Long COVID increase with each subsequent exposure.
Coming up with a treatment
Meanwhile, she said that in the next few months they plan to begin the second phase of their research – testing treatments.
These treatments may take many forms, including anti-inflammatory medications, but the initial clinical trials will likely be anti-viral drugs targeted specifically against SARS-Cov-2. The idea is that if the symptoms of long COVID-19 are the result of the virus hiding in various body tissues, then the obvious course of action is to root it out and destroy it.
Of course, that may be easier said than done, especially if any of that rooting is required in the brain.
Although several types of viruses can easily infect the brain, thanks to something called the blood-brain-barrier, anti-viral drugs have a much harder time penetrating the brain from the bloodstream. This problem has been the bane of HIV clinical research for decades.
Progress with the research, but no guarantees
McComsey stressed that although they have made significant progress, there is still quite a long way to go, and there are no guarantees.
For example, it’s possible that the SARS-CoV-2 virus does organ damage, activates other dormant viruses in the body, or that it causes permanent and irreversible changes to the balance of the immune system that lead to chronic bouts of inflammatory disorders even in the absence of virus.
“Unfortunately, it could be that antivirals may only attenuate it – or not do anything,” she said. That is why the study is looking at anti-inflammatory drugs as well.
She said that she knows that for those who are suffering without answers or treatments, the wait can be very difficult.
Many patients can feel abandoned when their physicians can’t do anything for them and are wondering why it takes so long. Doctors want to get it right, McComsey said, and unfortunately that takes time.
Meanwhile, she hopes that at least by knowing an effort is being made toward a treatment, they begin to feel heard.
“People who enroll in the study always say that one of the stressors is that their physician thought that they were exaggerating the symptoms,” McComsey said. “I think now most people know that this is real,” she said. “It’s very real.”
