The U.S. has had the most covid cases in the world. Why isn’t it doing more to study long covid?

The U.S. seems determined to put covid in the rearview mirror. Across the country, mask mandates and social-distancing rules have fallen, and hotels and airlines are bracing for a booming summer of travel.

But for millions of Americans with long covid — whose debilitating symptoms can include exhaustion, brain fog and shortness of breath — a return to normal remains out of reach. Experts say that help, in the form of new treatments or even just a better understanding of the condition, can’t come soon enough. But many are worried that one of these patients’ best chances to find some of these crucial answers is slipping out of reach.

The National Institutes of Health, which received more than $1 billion to study long covid, is struggling to enroll participants in its flagship clinical trial, named RECOVER, and frustrating patient advocates. The study, originally planned to enroll 40,000 people, had recruited only 2,600 as of early May. And while the virus has hit people of color and low-income communities disproportionately hard, the way the trial has been run so far fails to meet the needs of these populations.

Long covid patients also take issue with the decision by the NIH to focus the study’s initial phase on describing the condition rather than developing the treatments that people with long covid desperately need.

“I had high hopes for what it could mean for people with long covid,” said Lisa McCorkell, a patient since spring 2020 and leading member of the Patient-Led Research Collaborative, a group of long covid patients that studies their condition. “That kind of investment in a research study is pretty unprecedented and was a sign that our government was taking this seriously.”

The trial’s leadership has taken steps to address patient advocates’ concerns in recent months, including a meeting last week with McCorkell and others. And advocates say they are eager to work with the NIH on resolving issues with recruiting, patient engagement and connections with other post-viral illnesses. Still, patients and outside scientists are worried that RECOVER won’t provide meaningful answers — even as millions more people are likely to get long covid in coming surges.

The stakes are high: In March, the Government Accountability Office estimated that between 7.7 and 23 million people in the U.S. have long covid, and cases continue to rise as the virus spreads. Scientists don’t yet understand what factors predispose a person to developing the condition, which is also known as Post-Acute Sequelae of SARS-CoV-2, or PASC. Nor do they agree on the constellation of symptoms that can signal the illness, or how a coronavirus infection may lead to such a broad array of medical complications.

But what is clear is that millions of people are suffering, some to the point of total disability. Last year, the Department of Health and Human Services issued guidance listing long covid as a condition covered by the Americans with Disabilities Act. The Brookings Institution estimated in January that about 1.6 million Americans could have left full-time work due to long covid, accounting for 15 percent of the country’s unfilled jobs at that time.

“If we don’t address [long covid] now and find a solution, then we’re going to be dealing with this for the rest of people’s lives,” said Karyn Bishof, founder of the COVID-19 Longhauler Advocacy Project.

Turning around the battleship

Congress approved $1.15 billion in December 2020 for the NIH to study questions plaguing long covid patients and find potential treatments, amid mounting concern about the prevalence of the condition and the long-term prospects for people who develop it. The agency formally announced its RECOVER initiative in February 2021 and invited researchers to apply to participate.

In September, the NIH awarded $470 million to New York University Langone Health as the core leader of clinical science research for RECOVER. The agency and NYU have selected additional study sites on a rolling basis; once a site has joined the trial, it can begin recruiting patients and characterizing their long covid symptoms.

Though the NIH is a massive agency, with a budget that this year tops $45 billion, the long covid study is among the largest the agency has ever organized.

Eric Topol, a prolific covid commentator and director of the Scripps Translational Research Institute, said the U.S. has failed to perform “large, impactful, randomized” clinical trials for decades. That’s due in part to the fractured U.S. health system, difficulties researchers face in securing large grants and permissions to run clinical trials and the reliance on large pharmaceutical companies to study their own products.

During the pandemic, most U.S.-funded covid trials have maxed out at 2,000 to 3,000 patients, Topol added. That can result in findings that are not statistically significant and inconsistent results among trials trying answer the same or similar questions. Scientists have criticized covid research for overly relying on low numbers of patients.

The underlying problem is that large federal agencies and academic centers are “like battleships,” Topol said. They “can’t really make turns and adapt to new opportunities.”

By contrast, European researchers are better equipped to conduct “mega-trials” in which more than 10,000 patients are assembled to study a disease’s symptoms or potential treatments in a standardized fashion. A major U.K.-funded covid trial, called RECOVERY, enrolled more than 40,000 people and made crucial discoveries. Among them: that the inexpensive steroid dexamethasone sharply reduces deaths in the sickest patients and that the much-touted anti-malarial drug hydroxychloroquine does not produce a measurable benefit in hospitalized covid patients.

The U.K.’s long covid initiative, which is similar in scale to the U.S. RECOVER trial, has already begun to report results from its “characterizing the disease” phase and is moving to evaluate treatments, said Amitava Banerjee, a health informatics professor at University College London and lead researcher on the U.K. study.

The U.K. study faces its own challenges, such as obtaining funding and public support from a government that has declared “covid is over.” Still, the U.K.’s national health system has allowed this trial to quickly recruit patients and standardize research practices at sites across the country, while also providing researchers like Banerjee with better estimates of long covid prevalence from the get-go.

“Having the centralized approach means we know about places like [rural health clinics], can access their data and plan accordingly,” Banerjee said.

Finding volunteers

The NIH study is being carried out by a network of about 75 study sites, as of mid-April — each generally a university or major medical center. At each site, doctors, nurses and other medical personnel recruit and examine patients.

Overseeing the entire effort is a network of committees composed of a mix of NIH and academic scientists, as well as patient representatives. These committees meet regularly to make decisions for the study, such as which tests participants should undergo and how to ensure the study’s findings are applicable to other post-viral illnesses.

Outside the committee structure, crucial decisions about the trials have been left up to individual researchers at each study site — including how to recruit participants.

Some RECOVER sites are reaching out to people in their existing networks. This method prioritizes patients who are already receiving care at local long covid clinics, participated in previous clinical trials or were hospitalized at the sites. But the majority of long covid patients were never hospitalized, and many also face a variety of intersecting barriers to healthcare.

Others, like Stanford Medicine, are casting a broader net. Upi Singh, a lead researcher for this location, said the site is recruiting patients who test positive at Stanford-run covid testing centers and is doing outreach on social media. “Over 50 percent of our participants are those who are underrepresented in medicine,” Singh said.

Covid has hit people of color and low-income communities harder than those with more socioeconomic privilege. As a result, many long covid patients and advocates suspect that the demographics of this prolonged condition are likely similar. But the long covid patients who are believed by their doctors, who garner media attention, who serve on RECOVER committees — they’re more likely to be white and financially better-off, said Netia McCray, a Black STEM entrepreneur and long covid patient who has enrolled in the trial.

About 2,600 patients have joined the adult study as of May 3, according to NYU; the goal is 17,700 total. A parallel study of children with long covid, aiming to enroll 10,000 pairs of patients and their caregivers, is just starting now at seven sites. (The NIH has already revised these enrollment goals downward from its initial target of recruiting 40,000 people among both trials.)

Leora Horwitz, a leading researcher for RECOVER’s “clinical science core” at NYU, said that the study’s cohort so far includes 17 percent Black patients (compared with a target of 16 percent); 11 percent Hispanic patients (target of 27 percent); and 6.5 percent in a lumped-together category of Asian, Native American or Alaska Native, and Native Hawaiian or Pacific Islander patients (target of 4 percent). The basis of these targets is unclear, as no U.S. institution has any comprehensive, demographic information on long covid patients.

In a statement, Horwitz said the lag in Hispanic enrollment was due to delays in translating clinical trial documents — including the questionnaire for potential participants — into Spanish. She noted that all study and recruitment documents are now available in Spanish, Chinese and Arabic, and are reviewed by a “dedicated health literacy team” to ensure patients can easily read them.

But such translation efforts pale in comparison to the active outreach that’s needed, McCray said. RECOVER sites should reach out directly to healthcare providers and community organizations that work with underserved groups, she said, and should tailor their outreach to avoid mentioning long covid, a term that many potential patients still don’t know.

“Science communication is key,” McCray said. “And we know science communication has not been the strong suit of a lot of government, state and national organizations at this time.” This has extended to some long covid clinics, she said, which are waiting for patients to come to them rather than reaching out to people — particularly essential workers and those in low-income communities — who may not know that their enhanced exhaustion or brain fog is actually long covid.

McCray suggested that RECOVER sites follow the example of a phone survey conducted in the U.K., which asked people direct questions about their symptoms, such as “Are you extremely tired?” rather than asking, “Do you have long covid?” Such surveys have enabled the U.K. to compile more accurate estimates of how many people in the country have long covid than what’s available in the U.S.

Cutting through red tape

Despite RECOVER’s flaws, patient advocates and researchers haven’t given up hope. “We want to be partners on this, we want to see this study succeed more than anyone,” said McCorkell, of the Patient-Led Research Collaborative.

In late November, the group posted an open letter to RECOVER’s leadership, outlining the patients’ concerns with the study so far. Nearly 50 other long covid support groups and research organizations signed on, along with hundreds of individuals. In response to this criticism, the NIH and NYU arranged for a meeting with patient leaders, which took place last week.

McCorkell said that the meeting made it clear that the NIH and RECOVER leadership understand that improving patient engagement is key to the study’s success. “We agreed to work together to strengthen trust, improve representation of patients, and ensure greater accountability and transparency,” she said in an emailed statement.

Meaningful patient engagement is critical for ensuring that long covid research actually meets the needs of patients, said J.D. Davids, an advocate who served as a patient representative for an AIDS clinical trial group in the 1990s. Many scientists agree: When studying a novel condition like long covid, researchers should “turn to the true expert, which is the person with the condition,” said David Putrino, leader of a lab at Mount Sinai that focuses on health innovations and was one of the first in the country to begin studying long covid, adding that this type of coordination is crucial.

For other researchers who’ve worked with the NIH, the gap in time between the open letter and the resulting meeting is a classic example from a large agency not used to moving quickly. “What the NIH does very well, better than most national research organizations around the world, is supporting research that slowly develops small innovations in scientific knowledge,” Putrino said. The agency normally supports series of stepwise trials, climbing from one tiny aspect of research into a condition or treatment to the next.

This method is good for “long-term innovations that take 20 years,” Putrino said, but not for “disruptive innovation.” Treatments for long covid fall into the latter category: higher-risk, higher-reward science that may be viewed as a waste of government funding if it doesn’t pay off.

Even when riskier trials are funded, U.S. researchers also face miles of red tape, much more than their peers in other countries. Testing new pharmaceutical products — which could be key for long covid treatment — is especially difficult, Putrino said. He would love to study whether Paxlovid, an antiviral treatment for acute covid, may help with long covid. But “I physically don’t have the bandwidth to fill out the hundreds of pages of documents” and jump over other bureaucratic hurdles that such a trial would require, Putrino said.

In the meantime, members of Congress have also taken notice of the long covid trial’s struggles. Democratic Sens. Sheldon Whitehouse (R.I.) and Ed Markey (Mass.) wrote to the acting director of the NIH in mid-April expressing concern about the slow pace of the RECOVER study and the agency’s decision to delay research into studies of potential treatments. “While research on the underlying science of long COVID is critical to enhancing our understanding of the condition, trials and research on treatments may help provide relief to individuals experiencing the effects of long COVID today,” the pair wrote. Markey also joined a group of lawmakers, led by Rep. Ayanna Pressley (D-Mass.), in introducing legislation that would expand access to long covid treatment.

The White House itself has drawn attention recently to long covid research, with an early April memorandum establishing a task force that will work across federal agencies to address the condition. Biden also asked the HHS to build on RECOVER with a “National Research Action Plan” on long covid.

This memo was a step in the right direction, said Ziyad Al-Aly, a leading researcher at the Veterans Affairs healthcare system in St. Louis who has contributed to major long covid studies. But he criticized the federal government for its lack of urgency in studying and treating long covid. “The cost of this delay is really, people are suffering,” he said.

Scientists like Al-Aly and Putrino who study long covid outside of RECOVER, along with patient advocates, noted that the scientists working on the trial ultimately share the same goals as they do: understanding the condition and working toward meaningful treatments for the millions of Americans suffering from long-term symptoms. But there are a lot of improvements that could bring the study and its critics into closer alignment.

They say it’s not too late to diversify recruiting efforts at the RECOVER study sites. This could involve partnerships with community health organizations, direct contact with people who recently tested positive and more media outreach to spread awareness about long covid. Social media ads and television commercials could quickly get the word out to thousands of people, Topol said.

More transparency and accountability on the delays from the NIH and RECOVER researchers would be helpful, too. “They really need to look back at the past year, do an analysis and figure out, how can they learn from their mistakes?” Al-Aly said.

In late April, the NIH called for scientists to propose clinical trials on potential long covid treatments — finally bringing recovery into RECOVER. But other studies, run in countries like the U.K. with more centralized healthcare systems or even run by long covid patients themselves, may produce meaningful treatments well before the NIH initiative does.

Thanks to Lillian Barkley for copy editing this article.