There are, fundamentally, two ways to prevent an illness from causing harm: Prevent it or cure it. Right now the only way to prevent Long Covid, the constellation of sometimes-disabling symptoms that plague millions long after their acute COVID-19 infection has faded, is to keep from getting COVID-19 in the first place. But as I pointed out here a few weeks ago, the US—and indeed most of the world – has pretty much given up trying to prevent the spread of SARS-CoV-2, the virus responsible.
So how about a cure? If we’re not going to prevent COVID-19 and Long Covid, are we anywhere near a cure?
The short answer is no, but scientists’ understanding of the illness is steadily growing and the federal Long Covid research effort is finally starting to put more focus on developing treatments.
The scientific community now churns out new research papers on Long Covid at a pretty steady clip, and much of the news remains disturbing. One recent study, for example, found that having been hospitalized for COVID-19 leads to increased risk of heart attack or stroke even 1,000 days after the hospitalization. Over time, “there’s no sign of attenuation of that risk,” Cleveland Clinic researcher Dr. Stanley Hazen told CNN.
Another recent report, from researchers at Oxford and Cambridge in Great Britain, found signs of brain stem abnormalities in post-COVID patients. This could be important, as the brain stem is a key control center for automatic functions like breathing. As one of the researchers explained, “The fact that we see abnormalities in the parts of the brain associated with breathing strongly suggests that long-lasting symptoms are an effect of inflammation in the brainstem following COVID-19 infection.”
THE PICTURE AT THE CELLULAR LEVEL
But looking at these individual studies is a bit like looking at one piece of a 500-piece jigsaw puzzle: It may show an interesting detail but can’t describe the overall picture. Happily, a review published in early October in the journal Cell lays out the most comprehensive picture thus far of what researchers know about Long Covid and what that may mean for treatment. The article, authored by UC San Francisco researchers Michael J. Peluso and Steven G. Deeks, is way too long and scientifically dense for me to give any more than a brief sketch here, but it’s worth reading for anyone who wants to take a deep dive into the subject.
Peluso and Deeks take the mass of accumulated knowledge and put into an intelligible structure, roughly like this:
A) Biological mechanisms, i.e. effects of SARS-CoV-2 at the biochemical level and on particular types of cells, including evidence that the viruspersists in certain tissues even after initial symptoms have faded
B) Physiologic models of Long Covid, or the resulting dysfunction of tissues and organs that result
C) The symptoms that follow from these dysfunctions
D) Possible therapeutic targets suggested by these sequences.
The problem, though, is that my little explanation above vastly understates the complexity of these relationships, most of which are at best partly understood. In reality, the many pieces of A) above overlap, intersect and seem to occur in different combinations in different people, making the downstream sequence of events really hard to sort out.
But those upstream, cellular-level impacts are beginning to come into focus, even if a lot of details remain to be understood. For example, in addition to the respiratory tract, SARS-CoV-2 can infect gastrointestinal cells called enterocytes. Many other types of cells have the ACE2 receptor that the virus attaches to, including cells in the blood vessels, heart and kidneys, though doubt remains about whether these cells get directly infected. There is now substantial evidence that the virus persists after acute infection in many individuals—seemingly in fairly small amounts, but possibly enough to cause mayhem.
SARS-CoV-2 clearly can produce a chronic state of inflammation long after initial symptoms are gone – a phenomenon that may be related to that small amount of persistent virus setting off alarm bells in the immune system. As Peluso and Deeks explain, “Multiple studies have also begun to link specific markers of inflammation and immune dysfunction with Long Covid.” These include chronic activation of a particular type of immune cells, called CD8+ T cells, and signs of what are picturesquely termed “exhausted T-cells.” Some of these immune system effects have been tracked for as long as two and a half years after the initial infection. Signs of neuroinflammation in several brain regions have also been noted, seemingly connected to blood markers signifying dysfunction in blood vessels.
A few Long Covid patients show signs of an autoimmune response, in which the immune system attacks healthy cells, but studies attempting to connect these responses to Long Covid symptoms have produced inconsistent results. The issue remains a work in progress.
Meanwhile, the impact of COVID-19 on blood clotting is becoming clearer. Acute infection clearly raises the risk of dangerous blood clots, apparently due to the virus’s interaction with a key clotting substance called fibrinogen. That impact seems to continue in many patients. Peluso and Deeks write, “Multiple lines of investigation are emerging that implicate clotting as a mechanism for LongCovid,” including studies identifying “microclots” as a potentially significant issue, suggesting that “an imbalance between clot generation and degradation may be central to the syndrome.”
A new study in the journal Nature, published after the Peluso/Deeks review, reinforces that view, highlighting the connection between fibrinogen, clotting, inflammation, and loss of nerve cells in Long Covid, with the authors urging that this be considered as a target for treatment.
And those issues are just the start. Deeks and Peluso also lay out the evidence for several other mechanisms that seem to be at work, including COVID-19 reactivating latent viral infections like Epstein-Barr virus, disruption of beneficial bacteria in the intestinal tract, and disruption to the functioning of critical cellular structures called mitochondria. It’s now well beyond doubt that this viruscan damage the body in multiple, often unseen ways, some of which can last for years. Put another way, COVID-19 is absolutely, definitively not “just a cold.”
FROM CELLS TO SYSTEMS AND SYMPTOMS
While we have an improving if still incomplete picture of the sorts of long-term, cellular-level dysfunction SARS-CoV-2 causes, how that dysfunction leads to the symptoms people with Long Covid experience remains harder to sort out. The picture is complicated by the fact that these cellular and biochemical issues occur in different combinations in different people and may interact with each other in complex ways.
Some symptoms are clearly caused by direct damage to tissues, damage that often can’t be reversed – including damage to the pancreas leading to diabetes, as well as damage to the nervous system. But that doesn’t explain everything, and there are plenty of ways that the various biochemical and cellular-level disruptions could, either by themselves or in combination with others, trigger a wide variety of symptoms. Those microclots, for example, can lead to all sorts of problems, including damage to nerve cells, and could be implicated in a number of symptoms. But so could other things, such as chronic inflammation, which can also mess with nerves and other tissues.
Damage to nerve cells pretty clearly plays a role in some significant Long Covid symptoms, such as Postural Orthostatic Tachycardia Syndrome, or POTS, characterized by a racing heart, lightheadedness, tremor, nausea and blurred vision when going from a sitting position to standing up. But the exact pathways from the mayhem caused by the virus within cells to the pain and disability Long Covid patients experience remain largely speculative. Peluso and Deeks lay out many other possible pathways for which there is some evidence, and several of them may well operate at once, at least in some patients. If this sounds complicated, it is.
Still, researchers have figured out enough bits and pieces that, when combined with reasonable conjectures about the parts still to be clarified, many scientists see pathways to possible treatments. That, as you can imagine, rates a high priority within the patient community. Too often patients, even when lucky enough to find a medical provider with a reasonable level of knowledge and who doesn’t dismiss Long Covid as being imaginary or psychosomatic (and yes, some medical providers still erroneously feel that way), are frustrated to find there’s little available that can help them. Some symptoms can be managed and at least made more bearable, but no one yet has a good answer for what to do about POTS or brain fog, for example.
One of the factors complicating the search for an understanding of the disease process and how to stop or reverse it has the been lack of a clear, agreed-upon definition of Long Covid – a complex illness that can manifest is many different ways. As a result, studies – including many of those mentioned above – have used different definitions and, as a result, studied patients who weren’t directly comparable to those in other studies, making comparisons between studies challenging. Patient advocates have criticized some definitions in use as being too narrow and not reflecting real-world patient experiences.
That may at last be changing. Lisa McCorkell, co-founder of the Patient-Led Research Collaborative, points to an updated definition recently published by the National Academies of Sciences, Engineering, and Medicine —regarded by many as being clearer and more inclusive than other attempts—as being a major step in the right direction.
TIME FOR A MOONSHOT
As they lay out the mechanisms apparently involved in Long Covid symptoms, Peluso and Deeks suggest multiple potential treatment approaches that deserve study, expressing some frustration at the slow pace of progress but also seeing signs of change: “Numerous therapeutic targets have been identified,” they write. “Nevertheless, the rollout of Long Covid clinical trials has been painfully slow. This is now beginning to change, with well-powered, randomized clinical trials now being reported. Patients and clinicians are still frustrated, however, particularly given the massive successes in vaccines and therapeutics for acute COVID.”
The federal government has put significant funding into a Long Covid research effort called RECOVER, spearheaded by the National Institutes of Health, but not everyone thinks the money has been well spent. As a June article in Medscape explains, “More than $1.5 billion in US federal funding has been earmarked to study long COVID, but the National Institutes of Health (NIH) has faced criticism from patients and scientists alike for its slow progress and emphasis on observational studies instead of research that could unravel the biological roots of long COVID. Among the clinical trials announced by the NIH’s RECOVER initiative, only a handful involve studying pharmaceutical treatments.”
That message does seem to have finally gotten through. A recently-launched offshoot of RECOVER, called RECOVER-TLC (the TLC stands for Treating Long Covid) will focus specifically on treatment trials, and seems to be making a real effort to involve the patients and clinicians on the front lines of Long Covid in setting priorities. “I am optimistic about RECOVER-TLC,” McCorkell says. “They hosted a workshop [in September] that demonstrated they’re listening to the criticisms of RECOVER and want to do better, including by having meaningful patient engagement and by learning from other infection-associated chronic conditions.”
Even if RECOVER-TLC overcomes many of the shortcomings of earlier efforts, it will need serious funding over the long haul to adequately address a problem as gnarly and complicated as Long Covid. Hannah Davis, another Patient-Led Research Collaborative cofounder, points to the Long Covid Moonshot Act (S.4964), introduced in the US Senate in August by Sen. Bernie Sanders and five cosponsors, with a parallel bill recently introduced in the House of Representatives by Representatives Ilhan Omar and Ayana Pressley, that has been celebrated by health activists. “The Moonshot,” Davis explains, “calls for not only $1 billion per year in research funding for 10 years, but also for surveillance, public education, medical education, outcome assessments, etc. This is a rare opportunity, and we need this to pass—Long Covid is going to affect literally every family in the next few years, and this kind of funding is the only way we’re going to be able to find a cure.”
