How to End the Futile Blame Game Over Failed Long COVID Research 

Wheelchairs are posed in front of the German Reichstag building in Berlin to protest a lack of progress on Long COVID.

The health outlook for Long COVID sufferers is no better today than it was when the condition was first recognized in early 2020. This has been attributed in large measure to the disappointing results of clinical research, particularly when compared to the magnitude of the problem. 

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Now with hundreds of published results emerging from federally conducted or sponsored research, outraged experts and patient advocates say that there is little to show for it. The critique is that the pace of the work is slow and opaque, and that little has emerged that directly impacts prevention or patient care. The biomedical community has been under steady attack for lack of progress in prevention and treatment underlying a failure to help patients.

There is a lot at stake in getting the U.S.’s Long COVID research strategy right. With a national prevalence of the disease in the range of 5% to 15%, an estimated 10 to 35 million working-age adults have Long COVID, and it may be keeping as many as 4 million people out of work. There is a desperate need for effective treatments to mitigate their devastating frustration, suffering, functional impairment, and disability.

But what if the medical research community spends years and hundreds more millions of dollars digging a dry hole? The answer is not to dig deeper but to dig elsewhere with a more promising outlook and sharper tools.

A national health catastrophe

This national health catastrophe was foreseen early in the Long COVID pandemic. With a firm belief in the value of scientific innovation in mitigating harm, the federal government in late 2020 responded with a $1.15 billion investment in Long COVID research. Several agencies including the National Institutes of Health, the Centers for Disease Control and Prevention, and the Veterans Administration embarked on an ambitious program to delve into its mysteries.

The promise of harnessing the power of research was further raised in August 2022, when the White House unveiled the National Research Plan on Long COVID. In the public mind, this heavily promoted commitment had similarities to previous high-profile government disease research campaigns such as the “war on cancer” and Operation Warp Speed.

With these raised expectations now mostly dashed, there has been much finger-pointing among researchers, patients and advocates, experts and the media. Blame has been laid in several areas of the research domain: an unproductive focus on how the disease develops rather than on directly helping patients, duplicative descriptive studies on symptoms and trajectory which contribute little new knowledge, too many observational studies and not enough clinical trials to discover new therapies, the undertaking of large-scale multi-institutional research that buckles under the weight of bureaucracy, and straying into studies of alternative cures or even potentially harmful remedies. Government inattention and underfunding have also been deemed to play a significant role.

Unsurprisingly, the recommended fix for this predicament from many in the Long COVID ecosystem is to call for increased government investment and for channeling it into more productive biomedical research. 

Although intuitively unimpeachable, what if this logic is simply wrong?

Before reaching the conclusion that more and better biomedical research is needed, we must address why over three years of research has failed to move the needle. Lessons from the past should influence this calculus, as well as serve as a guide for future return-on-investment and likelihood of success.

A new theory to explain Long COVID

We suggest a unifying hypothesis that explains the striking lack of progress in understanding Long COVID through a traditional biomedical and public health lens. Our recent editorial in STAT posits that Long COVID is a new name for an old syndrome. It is virtually indistinguishable from the condition long known in the medical lexicon as post-infectious syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—in colloquial terms known simply as “chronic fatigue syndrome.” Logic and reason dictate that acute SARS-CoV-2 infection causes Long COVID. Or, more accurately, acute COVID-19 triggers ME/CFS in the same way many other infectious agents trigger ME/CFS. 

The implications of this hypothesis should be addressed head-on. Blind faith in the critical role and payout of future biomedical research may be misplaced and set-up society and the research community itself for further disappointment.

Read More: Long COVID Recovery Remains Rare

It is true that ME/CFS is still not well-understood and its research has been chronically underfunded. However there are decades of relevant clinical and research experience that should be productively and rapidly applied to Long COVID. The established track-record of ME/CFS research exploring cause and pathogenesis has been singularly unproductive. By analogy, the current research directed at finding diagnostic and mechanistic clues to Long COVID is a resource-intensive, lengthy uncharted process. In the ME/CFS paradigm it will produce further leads for more biomedical research, but with a low ultimate likelihood of helping patients.

Why is this research unlikely to be productive? Because either there is nothing to find, or currently available tools are insufficient to detect and validate mechanisms behind the myriad of symptoms. This should not be viewed as a failure of science. Negative observations—the absence of a link between cause-and-effect—cannot be proven, no matter how intensively probed. Yes, we can always pursue those mechanistic studies more rigorously and smartly. But at what point does the public sector decide that doing so has reached a point of diminishing returns? This is where we appear to be heading with ME/CFS/Long COVID.

Does this mean that Long COVID is not “real?” This is a false binary divide when viewed through a biomedical lens. Through a post-infectious disease historical lens it’s absolutely real and needs to be addressed as such. This includes platforms for comprehensive care, multi-disciplinary expertise and professional empathy through well-described (but frequently inaccessible) symptom management and functional rehabilitation pathways.

Challenging an existing paradigm

Scientifically and humanistically this may not be a welcome construct. It challenges the foundation and belief in the power of scientific knowledge and techniques. It grates against the standards of the biomedical paradigm. However, this hypothesis is not only consistent with the current lack of research progress, but ominously predicts more of the same lack of meaningful impact, controversy, finger-pointing and patient disillusionment going forward.

Research still has a vital role in the new ME/CFS/Long COVID paradigm. But it should be a different kind of research. The kind that no longer focuses on biomarkers and mechanisms. These are sure to provide “promising” but false leads and divert resources. Focus should be on health services research and on measures that directly impact the welfare of Long COVID sufferers: prevention, improved prognosis, access to empathetic care and quality of life issues. This includes investigation into symptom management, the effectiveness of comprehensive care delivery models, and social science research on actionable solutions applicable to at-risk subgroups (e.g., women, obstetrics and pediatric patients, people of color, underserved populations). Patients and advocacy groups should be closely involved in every stage of study design and execution, as they will have the major stake in living with the findings and are the ultimate determinants of success.

Now with the benefit of hindsight and a new paradigm that fits most observed clinical characteristics of Long COVID, we can envision a more productive and less friction-filled forward path for research. Meeting the shared objectives of the research and patient communities will require a further willingness to build bridges of cooperation, pragmatism and foresight. Given the magnitude of the challenges and the complexity of the Long COVID ecosystem, the central organizing forum for research policy and strategy should be an agency of the U.S. government, with the mandate and resources commensurate to the task. The recently formed Health and Human Services Office of Long Covid Research and Practice should be tasked with this important planning and coordination responsibility.

With Long COVID research now reaching a mature stage, there is a realistic hope that patient and biomedical communities can collaboratively reset the national research agenda to mutual benefit under the umbrella of a new paradigm and sponsor.

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Contributor: Steven Phillips and Michelle Williams