No Golden Pills: Long Covid Clinical Research Faces Long Climb

Three years since the very peak of the COVID-19 pandemic, appreciation for the virus as an overall health risk is waning. A nationally representative survey from the Kaiser Family Foundation (KFF) last month showed that just 1 in 5 US adults had received the updated COVID-19 vaccine recommended by the Centers for Disease Control and Prevention (CDC) for persons ≥6 months old and made available beginning in September. Another 51% of surveyed adults responded that they were at least not likely to get the vaccine.¹

That trend correlates with KFF survey data showing more adults who received a previous COVID-19 vaccine are likely to not get the new recommended shot (31%) than those who are (27%). More than half (52%) of vaccinated adults without the new dose stated they are not worried about getting COVID-19; another 54% are not worried about increasing COVID-19 cases and hospitalizations during the winter season.

To clinicians like Marc Sala, MD, co-director of the Northwestern Medicine Comprehensive COVID Center, this is very unideal timing for everyone to get laxed on COVID-19 precaution. That said, the lay population are not the only party guilty of dismissing the continued threat of COVID-19—and if anything, he sees his peers setting a poor precedent for them.

Sala was first interviewed by HCPLive about his team’s work at the Northwestern COVID Center for a feature article published this March; at the time, Sala discussed the logistical challenges of adequately diagnosing, treating and rehabilitating patients with the mysterious post-COVID-19 condition (PCC), or “long Covid”—a chronic effect of acute infection that presents in any of 200 symptoms in patients of all ages and backgrounds.²

In a conversation with HCPLive that returned to the subject 9 months later, the most notable update that Sala had on his and his peers’ work is that the field is diminishing. He’s watched care centers and clinics dedicated to post-acute COVID-19 treatment shutter in the last year, as his peers in critical care and pulmonary move on from the fight.

“There's almost this rapid onset amnesia of what we've been going through,” Sala told HCPLive this month. “And instead, you see a lot of people getting back to business as usual and closing their multidisciplinary centers.”

COVID-19 is no longer a national priority, so expresses much of the population, its caregivers—and even its government, as the Biden administration reallocated funds toward testing and treatment access at the conclusion of the public health emergency earlier in May. New hospital admissions due to COVID-19 were 33% lower in this last week than just 1 year prior, according to CDC data.³ The virus is now endemic, and to many Americans, out of sight and out of mind.

All the while, though, clinicians like Sala and investigators around the globe continue to work toward helping patients affected by long Covid achieve the same mindset post-pandemic. Though substantial progress in research was made this year, it may not be anytime soon that the chronic effects of the virus are out of sight, out of mind.

“The last six months have bred more literature that's had more insight and inspired me more than the entire thing from the beginning,” Sala said. “I mean, these things have taken time to define and to research, and one of the issues early on was that there were so many symptoms that fell under the suspicions of what was the virus doing that we've only recently started to form more sustainable patterns on this. And I think the best is yet to come in terms of not just understanding this virus, but viral host impact in the future.”

The Scope and Scale

Research published throughout 2023 has helped to better characterize the epidemiology of long Covid. From the UK-based REACT trial program alone, there is now a clear understanding that women and those with ≥1 comorbidity are significantly more likely to experience COVID-related symptoms for ≥12 or ≥52 weeks post-infection than the general population.⁴ The UK analysis additionally observed disparities in long Covid prevalence and duration based on waves of circulating variants; Donald Alcendor, PhD, took away from the data that vaccine-induced immunity has played a greater role in mitigating long Covid than anything else imaginable. While reported rates of chronic symptoms in post-acute patients has decreased this year, so has the rate of vaccine uptake. Alcendor, associate professor of cancer biology at Meharry Medical College, and adjunct associate professor of pathology, microbiology and immunology at Vanderbilt University School of Medicine, told HCPLive that the reported approximate 17% uptake of the CDC-recommended shot since September should be considered a failure to keep advantage against the virus.

“What we see on the vaccine line…is that older people willing to vaccinate, and we see people 40 and younger not willing to vaccinate,” Alcendor said. “We start to see a jump in vaccination when we get to around 50. These are folks that clearly understand—they've had friends and family die of COVID or had been hospitalized. Many of them have had long Covid, some of them for a long time. But I'm concerned about the headwinds when it comes to vaccine hesitancy and people just having fatigue from having so many different COVID vaccines.”

The central issue is that younger populations are far from immune to long Covid, regardless of their previous vaccinations. Approximately 1 in 10 patients with long Covid symptoms are 2 – 11 years old, Alcendor said, and the most affected subpopulations appear to be females in their mid-to-late 30s and 40s. Alcendor noted data suggesting a positive correlation between increased rates of COVID-19 vaccine doses and reduced risk of long Covid incidence—from approximately 25% with 1 dose, to approximately 75% with ≥3 doses. Only now, the highest-risk population is waning on updated boosters.

“Every time you're infected with COVID, you have the risk of developing long COVID,” Alcendor said. “And that should be an incentive to be vaccinated.”

Beyond prophylaxis, there’s little evidence supporting any singular therapy for patients with the heterogenous and multifactorial disease. Alcendor emphasized nirmatrelvir tablets (PAXLOVID), when taken within 5 days of acute COVID-19 symptoms presenting, may help reduce risk of long Covid by transitive law alone. But even uptake of the antiviral drug has been slow among higher-risk individuals—especially following the reduced federal funding for doses at the end of the public health emergency in May.

The best opportunity to curb long Covid is to prevent it altogether, Alcendor explained—whether though vaccination, public health precautions, timely antiviral therapy, or any combination of the lot. After that, the pharmacologic prospects get murky.

“I believe that a one-hit intervention to knock out long COVID with a Golden Pill is beyond reach,” Alcendor said. “I think what you're looking at is long COVID being very complicated and the treatments becoming individualized and specific for specific patients that are suffering from the different abnormalities associated with long Covid.”

Gaps in Treatment

The patient phenotype at Sala’s COVID center has fluctuated over the last few years. “It’s ebbed and flowed not just in numbers, but in terms of symptoms, such that now if you ask me how many patients I saw for alower lung illness or end-stage lung disease, it's very minimal in terms of that not being the problem that we see,” Sala explained. “It hasn't been largely since probably Omicron in general.”

Today, many patients with long Covid who seek care are presenting with exercise intolerance, general fatigue, and “brain fog”—a combination of cardiopulmonary and cognitive symptoms that, combined with frequent cases of chest pain, do not indicate a single “golden pill” as Alcendor would describe. Instead, Sala and his colleagues are turning to means of simple respiratory relief and rehabilitation to address the poor quality of life.

“I think a lot of patients at this point are able to respond to inhalers for bringing down inflammation in their lungs, so your (budesonide/formoterol) to the world has been very helpful for people with chronic cough,” Sala said. “After COVID exercise intolerance, we found that a lot of people have a variety of pulmonary rehab regiments are able to get them back into reconditioning with that.”

A breakthrough in treating the poor cardiopulmonary condition of patients—particularly those with once much greater tolerance for physical exertion—remains dependent on science evolving to understand the symptom better. For Sala, the “holy grail” of long Covid treatment would be better interpret and adequately treat the neurocognitive symptoms: why are so many patients impacted by brain fog and fatigue, and can a therapy resolve it?

“Not only is it hard to pin down at the bedside in terms of, how do you work that up?” Sala said. “But then at the end of the day, how do you help someone who has this really profound fatigue, and sometimes it really is quite disabling for them?”

Similarly to Alcendor, Sala has been encouraged in discoveries this year that help to better characterize long Covid. He noted recent research that indicated a significant difference in cortisol levels among patients who have and have not recovered from long Covid symptoms.

“Cortisol is our is our main driver of metabolism in a lot of ways,” Sala said. “So you can imagine people who have feelings of energy deficit, that would be possibly an important pathway to evaluate for them. And that opens a lot of doors and questions—but at least it's something, right?”

Alcendor additionally noted European-based research showing an outpatient treatment regimen including metformin was associated with a 10-fold greater risk reduction of progression to long Covid among patients who tested positive with COVID-19 versus placebo.⁵ For whatever it's worth, investigators are observing possible interplay—and avenues of treatment—with metabolic drugs for the virus.

“But you can see in this study, that they have to give that in the first 5 days of symptoms,” Alcendor noted. “It tells you that an early intervention may be important in terms of diverting risk for developing long COVID. But again, who's going to catch COVID in the first 5 days of symptoms? These are patients that have to be monitored carefully for that to happen.”

Sala added that recent research elucidated signs of reactivated viruses in certain patients with long Covid—latent cases of Epstein-Barr or herpes viruses that could implicate some of the worse chronic cases being observed. “And then, in that same vein, there's been ongoing papers describing evidence of circulating signs of ongoing viral COVID itself in people,” he added. “The intestines seem to be a likely source for starting some kind of residual SARS-CoV-2. And that's particularly interesting, because there are at least you can imagine an antiviral strategy, which is one of the hot topics and about giving people a lot of PAXLOVID for a while.”

Sala coupled those findings with data published in Cell suggesting a mechanism in which disrupted gut microbiome correlates with vagus nerve disruption in mouse models—which, if replicated in human models, would fit the various manifestations of long Covid under 1 umbrella.

“And that would encompass everything from chest pain, to irregular heart rates, to fluctuations in blood pressure, to your neurocognitive symptoms of fatigue and everything else,” Sala explained. “So, it'd be a very unifying mechanism for things if it pans out that way in people.”

What’s critical, of course, is for scientists to progress these discoveries toward applied clinical care, where Sala and colleagues are operating with reliable but rudimentary tools—and patients are often navigating without a diagnosis nor clear guidance of care. Through monitoring online forums like Reddit and in his own experience in the intensive care unit (ICU), Sala has observed trends in tried (and failed) long Covid therapies.

“We had a very long period of time where patients and sometimes providers alike swore by an anti-histamine approach to things, and others swore that physical rehabilitation was going to set people back and such,” he described. “One of the things that scared me as an ICU doctor that was going on, probably about a year ago, was people were putting themselves on a variety of orally available thrombolytics. We would have people who weren't getting checked to see what the consequences were on their measure of thinning of their blood. And that was a little frightening to me, because that was based on a hypothesis of diffuse blood clotting as being the cause to all of these symptoms uniformly.”

All the same, it’s hard to blame patients with a mysterious, life-debilitating condition taking risky measures to resolve their symptoms. Their frustration with the vacant treatment pipeline is shared with experts at every level.

“Well first, let me acknowledge that we're all frustrated by this,” FDA commissioner Robert Califf, MD, told HCPLive in an interview this month. “There are millions of people with a post-viral syndrome—in this case, post-COVID syndrome—but there are also other viruses that leave very similar populations affected. And I have to say we don't understand it well.”

“And, you know, I have a phrase, 'I got a spot on my desk,' which pertains to a lot of things in my work,” Califf continued. “But there's a spot on my desk for applications related to long COVID and products that will work. And, of course, by law, our job is to judge the safety and effectiveness, the risk-benefit balance. To do that, we have to have product and clinical trials that have the data. So that's the phase we're in right now. NIH is proceeding with both epidemiologic and clinical trials, and hopefully we'll get some good news from that.”

Setting a Precedent

The trial program which Califf referred to—and Sala and Alcendor additionally highlighted as a promising prospect—is the ongoing Researching COVID to Enhance Recovery (RECOVER) program under the National Institutes of Health (NIH). A globally-representative cohort of patients with long Covid, the RECOVER program uses more than 60 million electronic health records (EHRs) while enrolling up to 20,000 adults, pregnant people and children to comprise a vast data pool of patient demographics, clinical presentation, real-world trial data and evidenced avenues toward treatment development.⁶

“RECOVER data includes more than 40 pathobiology studies on more than 50 types of tissues, and studies of autopsies and tissue pathology,” the program’s site states. “We are using the findings from each of these study types and from patient experiences to inform 5 integrated platform clinical trials. The clinical trials will identify possible treatments to help with long COVID symptoms.”

RECOVER investigators are conducting research across 5 fronts to help better define and treat long Covid:

1. Autopsies and tissue pathology, to help interpret the pathophysiology and mechanisms of long Covid.
2. Clinical trials, each assessing interventions for long Covid as they relate to addressing symptoms including autonomic dysfunction, cognitive dysfunction, exercise intolerance and fatigue, sleep disturbance, and viral persistence.
3. Real-world data from EHRs to interpret population-based prevalence and burden of long Covid, as well as potential preventive or curative strategies.
4. Longitudinal observational cohort analysis interpreting the duration and long-term effects of long Covid.
5. Pathobiology studies to understand the nature of long Covid and its functional and structural changes to patients.

Alcendor shared his own experience working with the NIH-backed program coordinators, having helped to recruit key patient populations including minority women and pregnant people to participate in the ongoing assessments—a component of RECOVER that which he emphasized the importance of prioritizing.

“They have many sites in different places throughout the United States, and they are trying to get access to everybody—by ethnicity, gender, race, and so forth,” Alcendor said. “They've also included something that I think is very important: pregnant women and their children as well. For the longest time in clinical trials, pregnant women have been excluded based on the risk to the developing fetus. However, what we know from COVID is that pregnant women were at high risk of developing severe disease and dying due to COVID. And again, it's based on that condition, because they're carrying a semi-allogeneic fetus and nature gives them a condition that increases their cardiopulmonary load to carry the baby—it puts them at greater risk for respiratory tract infections. In the old days, it was influenza that was the killer of pregnant women. And now COVID has joined that group of respiratory infections that are bad for pregnant women.”

Alcendor believes long-awaited breakthroughs in understanding and treating long Covid will come from comprehensive analyses such as RECOVER. So as long as the disease presents variably and with little predictability, not 1 biomarker nor time-dependent treatment will address it; investigators must confidently identify numerous markers and risk factors across a representative population.

“This has taken doctors back,” he said. “You're looking at a little clinic in Mississippi that has 500 long Covid patients, and 1 doctor to serve so many people in a small clinic. You're looking at those very good clinical trials out there in Michigan, that for somebody in Mississippi to get to be a part of becomes a daunting task and a challenge just based on logistics. The clinical trials need to be inclusive of all people; there should be equity to access clinical trials, because whatever comes out of this to treat long COVID, you want to make sure that this is available and can be functional in multiple populations.”

An exact physician who would benefit significantly from this robust analysis, Sala does anticipate breakthroughs from programs like RECOVER—though he stressed precaution to the investigators in analyzing such a diverse patient population. He noted the RECOVER Vital trial, in which 15-day and 25-day doses of PAXLOVID will be compared to control ritonavir 100 mg plus plus nirmatrelvir matching placebo for the treatment of long Covid,⁷ may not distinguish the “one size fits all” treatment strategy that may would hope for.

“When you don't necessarily separate people out who, for example, spent some time in the ICU and have pulmonary fibrosis and lower oxygen, from that person who's just young and can't get back to his normal gym routine—if you group those sorts of people together, historically what happens is you get a negative trial, because you dilute the entire thing so much with different types of folks,” he explained. “One of the fears that we have is that when doing these trials is that if you don't make distinctions—which they are trying to do—about the different clusters of folks with different mechanisms of disease, that you're going to give them all the same medication, and at the end of the day, you just get a negative trial and you're none the better.”

Sala said negative clinical trial results are a frequent issue in critical care research. But from his perspective in managing long Covid on the frontlines, he hopes RECOVER and similar precedent-setting trials help to establish strategies against the 3 most challenging symptoms he observes: brain fog, shortness of breath, and fatigue.

“Someone who has chronic cough who calls me after COVID, I can give them a timeframe for what I can expect for that and my remedies for it,” he said. “These other 3, though...people and doctors struggled to fix these.”

Alcendor suggested clinical research should consider the pattern of care patients with long Covid will likely experience: many patients will first be assessed and potentially treated by primary care physicians before being referred to specialists for advanced testing and more symptom-specific care. Early dosing with PAXLOVID or another antiviral may work, but it may not be a practical solution.

“The idea is that they really have to do a ‘seek, find and treat’ approach,” he explained. “When you're thinking about interventions, you want to have your intervention at an early stage, because long Covid seems to not be something you can come in and interrupt with an intervention. The idea is finding out who is likely to develop long Covid, and that will include biomarkers, and of course, functional tests.”

It seems as if the fight against long Covid is fated to resemble that of the original SARS-CoV-2 pandemic response: burdened frontline caregivers and exhaustive investigators—aided by unprecedented networks of data-sharing and pharmaceutical industry and regulatory agency support—work to forge new advances in medicine to curb a public health crisis. And just like the pandemic, the afflicted patients and their physicians are left to wonder, “Does anyone even realize this is still happening?”

“Outside of RECOVER, you see a tapering enthusiasm for some of this. But as the climate warms and other issues occur, we need to know more about the viral impact on things. And I think this is our opportunity, right?” Salas said. “I'm not sure if it's just this other balance of people just wanting to get back to their lives. I don't know what that is.”

References

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5. ^{Bramante CT, Buse JB, Liebovitz DM, et al. Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial [published correction appears in Lancet Infect Dis. 2023 Sep 1;:]. Lancet Infect Dis. 2023;23(10):1119-1129. doi:10.1016/S1473-3099(23)00299-2}
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