Erica Hayes, 40, hasn't felt healthy since November 2020 when she first fell ill with COVID.
Hayes is too sick to work, so she's spent much of the last four years sitting on her beige couch, often curled up under an electric blanket.
"My blood flow now sucks, so my hands and my feet are freezing. Even if I'm sweating my toes are cold," says Hayes, who lives in Western Pennsylvania. She misses feeling well enough to play with her 9-year-old son, or attend her 17-year-old son's baseball games.
Along with claiming the lives of 1.2 million Americans, the COVID pandemic has been described as a mass disabling event. Hayes is one of millions of Americans who suffer from long COVID. Depending on the patient, the condition can rob someone of energy, scramble the autonomic nervous system, or fog their memory, among many other symptoms.
Estimates of prevalence range considerably, depending on how researchers define long COVID in a given study, but the Centers for Disease Control and Prevention puts it at 17 million adults.
Despite long COVID's vast reach, the federal government's investment in researching the disease — to the tune of $1.15 billion to date — has so far failed to bring any new treatments to market. This disappoints and angers the patient community.
"It's unconscionable that more than four years since this began, we still don't have one FDA- approved drug," says Meighan Stone, executive director of Long COVID Campaign, a patient-led advocacy organization. Stone was among several people with long COVID who spoke at a workshop hosted by the National Institutions of Health in September where patients, clinicians and researchers discussed their priorities and frustrations around the agency's approach to long COVID research.
Some researchers are also critical of the agency's research initiative, called RECOVER, or Researching COVID to Enhance Recovery. Without clinical trials, physicians specializing in treating long COVID must rely on hunches to guide their clinical decisions, says Dr. Ziyad Al-Aly, the chief of research and development at the VA St Louis Healthcare System.
"What [RECOVER] lacks, really, is clarity of vision and clarity of purpose," says Al-Aly, saying he agrees that the NIH has had enough time and money to produce more meaningful progress.
Now the NIH is starting to determine how to allocate another $515 million of funding for long COVID research, which it says will have a significant focus on clinical trials. At the end of October, RECOVER issued a request for clinical trial ideas that look at potential therapies, including medications, saying its goal is, "to work rapidly, collaboratively, and transparently to advance treatments for Long COVID."
This turn suggests the NIH has begun to respond to patients and has stirred cautious optimism among those who say that the agency's approach to long COVID has lacked urgency in the search for effective treatments.
"The patient community has been really clear for years that we want to see trials that test real interventions that patients can't access without a doctor's prescription," says Stone. "So we don't want to see clinical trials for over-the-counter supplements … exercise therapy or cognitive behavioral therapy."
NPR contacted the NIH several times to ask about plans for this new chapter of RECOVER. The agency did not make anyone available for an interview, nor would it answer written questions via email.
Good science 'takes time'
In December 2020, Congress appropriated $1.15 billion for the NIH to launch RECOVER, raising hopes in the long COVID patient community.
Then-NIH director Dr. Francis Collins explained that RECOVER's goal was to better understand long COVID as a disease and that clinical trials of potential treatments would come later.
According to RECOVER's website, it has funded eight clinical trials to test the safety and effectiveness of an experimental treatment or intervention. Just one of those trials has published results.
On the other hand, RECOVER has supported more than 200 observational studies, such as research on how long COVID affects pulmonary function, or which symptoms are most common. And the initiative has funded more than 40 pathobiology studies, which focus on the basic cellular and molecular mechanisms of long COVID.
RECOVER's website says this research has led to crucial insights on the risk factors for developing long COVID, and understanding how the disease interacts with pre-existing conditions.
It notes that observational studies are important in helping scientists to design and launch evidence-based clinical trials.
Good science takes time, says Dr. Leora Horwitz, the co-principal investigator for the RECOVER-Adult Observational Cohort at New York University. And, long COVID is an "exceedingly complicated" illness that appears to affect nearly every organ system, said Horwitz through email.
This makes it more difficult to study than many other diseases. Because long COVID harms the body in so many different ways, with widely variable symptoms, it's harder to identify precise targets for treatment.
"Simply trying treatments because they are available without any evidence about whether or why they may be effective reduces the likelihood of successful trials and may put patients at risk of harm," Horwitz says.
NYU received nearly $470 million of RECOVER funds in 2021, which the institution is using to spearhead the collection of data and biospecimens from up to 40,000 patients. Horwitz says nearly 30,000 are enrolled so far.
This vast repository, says Horwitz, supports ongoing observational research, allowing scientists to understand what is happening biologically to people who don't recover after an initial infection — and that will help decide which clinical trials for treatments are worth undertaking.
Dashed hopes or incremental progress?
The consensus from patient advocacy groups is that RECOVER should have done more to prioritize clinical trials from the outset. Patients also say RECOVER leadership ignored their priorities and experiences when determining which studies to fund.
RECOVER has scored some gains, says JD Davids, co-director of Long COVID Justice. This includes findings on differences in long COVID between adults and kids. But Davids says the NIH shouldn't have named the initiative "RECOVER," since it wasn't designed as a streamlined effort to develop treatments.
"The name's a little cruel and misleading," he says.
RECOVER's initial allocation of $1.15 billion probably wasn't enough to develop a new medication to treat long COVID, says Dr. Ezekiel J. Emanuel, the co-director of the University of Pennsylvania's Healthcare Transformation Institute.
But the results of preliminary clinical trials could have spurred pharmaceutical companies to fund more studies on drug development, as well as testing how existing drugs influence a patient's immune response.
Emanuel is one of the authors of a March 2022 COVID roadmap report. He notes that RECOVER's lack of focus on new treatments was a problem. "Only 15% of the budget is for clinical studies. That is a failure in itself — a failure of having the right priorities," he told NPR via email.
And though the NYU biobank has been impactful, there needs to be more focus on how existing drugs influence immune response.
Emanuel says some clinical trials that RECOVER has funded are "ridiculous," because they've focused on symptom amelioration, for example, to study the benefits of over-the-counter medication to improve sleep. Other studies looked at non-pharmacological interventions, such as exercise and "brain training" to help with cognitive fog.
People with long COVID say this type of clinical research contributes to the gaslighting they experience from doctors, who sometimes blame a patient's symptoms on anxiety or depression, rather than acknowledging long COVID as a real illness with a physiological basis.
"I'm just disgusted," says long COVID patient Hayes. "You wouldn't tell somebody with diabetes to breathe through it."
Chimére L. Sweeney, the director and founder of the Black Long COVID Experience, says she's even taken breaks from seeking treatment after getting fed up with being told that her symptoms were due to her diet or mental health.
"You're at the whim of somebody who may not even understand the spectrum of long COVID," Sweeney says.
Insurance battles over experimental treatments
Since there are still no FDA-approved long COVID treatments, anything a physician prescribes is classified as either experimental — for unproven treatments — or an off-label use of a drug approved for other conditions. This means patients can struggle to get insurance to cover prescriptions.
Dr. Michael Brode — the medical director of UT Health Austin's Post-COVID-19 Program — says he writes many appeal letters. And some people pay for their own treatment.
For example, intravenous immunoglobulin therapy, low-dose naltrexone and hyperbaric oxygen are all promising treatments, he says.
For hyperbaric oxygen, two small randomized controlled studies show improvements for the chronic fatigue and brain fog that often plagues long COVID patients. The theory is that higher oxygen concentration and increased air pressure can help heal tissues that were damaged during a COVID infection.
However, the out-of-pocket cost for a series of sessions in a hyperbaric chamber can run as much as $8,000, Brode says.
"Am I going to look a patient in the eye and say, 'You need to spend that money for an unproven treatment?'" he says. "I don't want to hype up a treatment that is still experimental. But I also don't want to hide it."
There's a host of pharmaceuticals that have promising off-label uses for long COVID, says microbiologist Amy Proal, president and chief scientific officer of the Massachusetts-based PolyBio Research Foundation. For instance, she's collaborating on a clinical study that repurposes two HIV drugs to treat long COVID.
Proal says research on treatments can move forward based on what's already understood about the disease. For instance, she says that scientists have evidence — partly due to RECOVER research — that some patients continue to harbor small amounts of viral material after a COVID infection. She has not received RECOVER funds but is researching antivirals.
But to vet a range of possible treatments for the millions suffering now — and to develop new drugs specifically targeting long COVID — clinical trials are needed. And that requires money.
RECOVER's deadline to submit long COVID research proposals is Feb. 1.
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