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Long Covid

Trial By Error: Long COVID, the Long COVID Alliance, and ME International

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By David Tuller, DrPH

The advent of Long COVID has brought an enormous amount of attention to the illness or cluster of illnesses collectively known these days as ME/CFS. That attention is not always positive, as we saw recently with a Wall Street Journal opinion piece that dismissed both ME/CFS and Long COVID as forms of mental illness. The trainee-psychiatrist who penned that piece of crap even referred to PACE as representing the “prevailing view” of the medical profession.

Many other articles have explored the overlaps between Long COVID and ME/CFS in more thoughtful ways. A major problem, of course, is that both categories grapple with definitional issues. What has been dubbed Long COVID has been officially named “post-acute sequelae of COVID-19” (PASC), which at least recognizes that the term covers a diversity of symptoms and conditions. With ME and ME/CFS, various currently used definitions—the 2003 Canadian Consensus Criteria for ME/CFS, the 2011 International Consensus Criteria for ME, and the US Centers for Disease Control and Prevention’s 2015 definition for what it called “systemic exertion intolerance disease”–identify different albeit overlapping populations. That can create difficulties in implementing studies and interpreting the findings.

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Trial By Error: Biopsychosocial Brigades Seek Traction with Long Covid

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By David Tuller, DrPH

Last week, two major articles on long Covid appeared in well-known US publications—one in the Atlantic, the other in Vox. Like the New York Times Magazine article that ran in January, these stories addressed with nuance the complex and unclear relationship between the varieties of long Covid and the group of entities collectively known these days as ME/CFS. They did not presume patients in either category were suffering from psychogenic symptoms.

Today, The New York Times ran an opinion piece from two women who helped spark the patient-directed long Covid movement. In their piece, Fiona Lowenstein and Hannah Davis made these pertinent observations about some of the inadequacies of the societal response to long Covid:

“We’ve seen this before with myalgic encephalomyelitis, also known as chronic fatigue syndrome. Because ME/CFS, as it is also called, is difficult to diagnose, many patients have gone uncounted, and research into treatments and cures remains underfunded compared to other illnesses. As a result, clinicians tend to be undereducated and patients are less likely to receive adequate care and government support. There’s a risk of repeating this cycle with people with long Covid.”

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The UK is still arguing over graded exercise therapy…

In the UK, much of the discourse has been different, so reading stuff from both sides of the Atlantic can be disorienting. Of course “exercise”–in the sense of “movement”–is being discussed and debated. It is a standard component of rehabilitative strategies, and variations of “exercise” for the range of long Covid presentations are being explored—although no one has a real clue about what’s going on for many or most of these patients. .

What I haven’t noticed in the US is this specific obsession with and controversy over graded exercise therapy (GET). This intervention, at least as designed for ME/CFS, attributes the perpetuation of the symptoms to deconditioning rather than any ongoing organic illness.

Aren’t we all bored with this already? Hasn’t the PACE trial testing this approach to ME/CFS been debunked? Why am I discussing this again? Because the biopsychosocial ideological brigades appear to have mounted a spirited campaign against the forces undermining their former hegemony in this field of medicine. Even Professor Peter White, the Queen Mary University of London psychiatrist and one of the lead PACE investigators, has reemerged from retirement to engage the naysayers. Professor White is one of three co-authors of a letter this week in The Guardian touting the benefits of GET for ME/CFS. For real!

The letter contained this doozy of a statement with no hint of irony or shame: “We know that graded exercise therapy is an effective treatment for chronic fatigue syndrome (or ME), a clearly related condition.”

It is hard to know how to respond to such a statement from Professor White. In the PACE trial, he and his colleagues reported GET to be “effective” only after rampant outcome-swapping. Re-analyses of the PACE data based on the investigators’ original outcome measures yielded either null results or very marginal benefits that wore off by long-term follow-up. It apparently needs to be repeated without cease that a study in which participants could be counted as “recovered” even if they got worse and in which 13 % of participants met an outcome threshold at baseline does not meet the minimal requirements for publication in any journal.

The Guardian letter is part of what seems to be a backlash emerging from some disgruntled folks against the UK’s National Institute for Health and Care Excellence, the agency that issues clinical guidelines for medical conditions. In November, NICE issued a draft for a new guidance that was three years in development. The draft categorically rejected GET or any interventions focused on increased activity and premised on the notion of deconditioning as a causative factor. It also rejected cognitive behavior therapy as a curative treatment, although it allowed for that and other approaches framed as supportive care.

An evidence review conducted for NICE as part of the guidance development process rated the quality of all the findings in support of GET and CBT as either “low” or “very low.” They applied a widely used system for this process called GRADE (for Grading of Recommendations Assessment, Development, and Evaluation). Since then, various luminaries in the biopsychosocial and evidence-based-medicine fields have assailed this negative assessment of the research base in statements posted on BMJ.com.

One group argued in an editorial that NICE’s findings were off because standard randomized controlled trials and GRADE are not the best way to assess complex interventions like those tested in PACE. One problem with that argument was that one of the editorial’s two co-authors had previously praised PACE as an excellent test of the interventions. (That was before PACE was publicly discredited. Oops!)

In a response, a second group defended the integrity of GRADE and assailed the authors of the editorial for not appreciating it. They argued that GRADE itself was fine but that the NICE team engaged in a “disastrous application” of the methodology. That these experts can’t agree among themselves about the reasons for their disapproval suggests they are flailing about for counter-arguments to the NICE draft that might stick—so far, without apparent success.

Those waging this debate over ME/CFS actually seem to be arguing about long Covid. The biopsychosocial brigadiers have been losing the argument over ME/CFS, given the questionable body of research they have produced and continue to cite. The NICE draft demonstrated that the tide was shifting in the other direction. With long Covid, they seem to be making much the same arguments over again—and simultaneously trying to un-write the last few years of critical debunking of the PACE approach. As the letter to The Guardian suggests with its call for a trial of GET for long Covid, they hope their efforts to reframe that narrative will help them gain footing and funding in a world awash with patients experiencing persistent and disabling symptoms after a viral illness.

Studies of all sorts of treatments for long Covid are of course warranted. However, the investigators responsible for much of the body of biopsychosocial ME/CFS research do not appear competent enough or knowledgeable enough about legitimate methodology and appropriate ethics to be entrusted with such an important mission.

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Is CBT different than the Lightning Process?

As a final point, I’m having trouble at this point understanding the distinction between the the PACE approach and the Lightning Process (LP). There is certainly a lot of cross-over among the investigators and experts. Professor Esther Crawley, Bristol University’s methodologically and ethically challenged pediatrician and grant rainmaker, conducted the methodologically and ethically disastrous trial of the LP for kids with ME/CFS. Professor Trudie Chalder, a CBT expert at King’s College London and a lead PACE investigator, has also been involved in LP research.

In a statement supportive of Professor Crawley’s LP trial, Professor Michael Sharpe, a psychiatrist at Oxford and another lead PACE investigator, drew favorable parallels between cognitive behavior therapy (CBT) and the LP. In Norway, proponents of CBT for ME/CFS are among those pushing for a new study of the LP. And Professor Paul Garner, an infectious disease expert at the Liverpool School of Tropical Medicine, has advised those with long Covid not to listen to sick ME/CFS patients and has directed them instead to Recovery Norway, a site full of LP testimonials. (Professor Garner was a co-signer with Professor White of the Guardian letter.)

As far as I can tell, the operating concept behind the PACE treatment approach and the LP are the same: Positive thoughts are good, negative thoughts are bad. Positive thoughts will heal you, negative thoughts will keep you sick. Being more active will also help.

That’s it. That’s the theory.

Trial By Error: National Institutes of Health Director Francis Collins on Plans for Long COVID Research

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By David Tuller, DrPH

The US government seems to be taking Long COVID seriously. In December, Congress allocated $1.15 billion over four years for research into the issue. This week, Francis Collins, director of the National Institutes of Health, announced the agency’s plans for that funding. (I’ve posted his announcement in full below.) In a post last month he highlighted the plight of the long-haulers and praised the most extensive report yet on their situation. That well-received research report was spearheaded and produced by a patient-led team from the Body Politic COVID-19 Support Group, an online community.

The relationship between what is generally being called ME/CFS and what is generally being called Long COVID is unclear. A number of high-profile news articles–including ones published by The New York Times, The Guardian, and Kaiser Health News–have noted the apparent overlaps in symptoms and in possible or hypothesized causes. These articles have taken at face value the notion that ME/CFS patients are suffering from a serious disease and have not presumed that psychotherapy and exercise are the optimal approaches to treatment.

Both ME/CFS and long COVID are complex phenomena–as is evident from confusion and disagreement over the appropriate nomenclature. ME/CFS is an unsatisfactory hybrid term used to refer to a range of described clinical entities. Long COVID is a convenient and easy-to-understand term but it conveys nothing about the condition’s expansive range of presentations. That variety is better expressed through the scientific name it has been given: Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In other words, there are lots of different sequelae–not just one entity called Long COVID.

Ramped up funding for research into Long COVID could be beneficial for ME/CFS patients. My sense is that many of the latter are hopeful that these investigations could reveal biological mechanisms and pharmaceutical treatments that could be relevent for them as well–especially given apparent similarities in symptoms like post-exertional malaise and cognitive impairment. (I never expected to see the phrase “brain fog” in news headlines all around the world.)

At the same time, there is cause to be wary. This pandemic is now early in its second year, so so-called Long COVID is still a relatively short phenomenon–especially when compared to the decades of illness experienced by many with ME/CFS. Reports of persistent symptoms are known to be common after many viral infections. It is also known that these cases self-resolve most of the time–even if it can take a year or more in some cases.

If it is asserted prematurely or simplistically that Long COVID and ME/CFS are somehow the same, what happens if most of these legions of Long COVID patients get better in the next few months or over the next year? It could easily be presumed that the “multi-disciplinary rehabilitation”–or any number of helpful or non-helpful interventions–led to improvements, even if the recoveries would have happened in any event. In such a scenario, that advice could be presumed to be applicable to ME/CFS patients. Before declarative statements can be made, we need to see a lot more data.

In the meantime, it’s great that NIH has found more than $1 billion to investigate Long COVID. It certainly suggests that more money could have been found ten or twenty years ago to study ME/CFS than the pittance that has historically been allocated. While the amount has increased significantly in recent years, two or three times a pittance is still a relative pittance. (Jennie Spotila provides regular analyses of NIH funding at Occupy M.E., her blog)

Below is the announcement from NIH Director Francis Collins:

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NIH launches new initiative to study “Long COVID”

I write to announce a major new NIH initiative to identify the causes and ultimately the means of prevention and treatment of individuals who have been sickened by COVID-19, but don’t recover fully over a period of a few weeks. Large numbers of patients who have been infected with SARS-CoV-2 continue to experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. Often referred to as “Long COVID”, these symptoms, which can include fatigue, shortness of breath, “brain fog”, sleep disorders, fevers, gastrointestinal symptoms, anxiety, and depression, can persist for months and can range from mild to incapacitating. In some cases, new symptoms arise well after the time of infection or evolve over time. In December, NIH held a workshop to summarize what is known about these patients who do not fully recover and identify key gaps in our knowledge about the effects of COVID-19 after the initial stages of infection. In January, I shared the results from the largest global study of these emerging symptoms. While still being defined, these effects can be collectively referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). We do not know yet the magnitude of the problem, but given the number of individuals of all ages who have been or will be infected with SARS-CoV-2, the coronavirus that causes COVID-19, the public health impact could be profound.

In December, Congress provided $1.15 billion in funding over four years for NIH to support research into the prolonged health consequences of SARS-CoV-2 infection. A diverse team of experts from across the agency has worked diligently over the past few weeks to identify the most pressing research questions and the areas of greatest opportunity to address this emerging public health priority. Today we issued the first in a series of Research Opportunity Announcements (ROAs) for the newly formed NIH PASC Initiative. Through this initiative, we aim to learn more about how SARS-CoV-2 may lead to such widespread and lasting symptoms, and to develop ways to treat or prevent these conditions. We believe that the insight we gain from this research will also enhance our knowledge of the basic biology of how humans recover from infection, and improve our understanding of other chronic post-viral syndromes and autoimmune diseases, as well as other diseases with similar symptoms.

Some of the initial underlying questions that this initiative hopes to answer are:

  • What does the spectrum of recovery from SARS-CoV-2 infection look like across the population?
  • How many people continue to have symptoms of COVID-19, or even develop new symptoms, after acute SARS-CoV-2 infection?
  • What is the underlying biological cause of these prolonged symptoms?
  • What makes some people vulnerable to this but not others?
  • Does SARS-CoV-2 infection trigger changes in the body that increase the risk of other conditions, such as chronic heart or brain disorders?

These initial research opportunities will support a combination of ongoing and new research studies and the creation of core resources. We anticipate subsequent calls for other kinds of research, in particular opportunities focused on clinical trials to test strategies for treating long-term symptoms and promoting recovery from infection.

Research Studies: A SARS-CoV-2 Recovery Cohort—the central program of this initiative—will leverage ongoing COVID-19 studies, long-term cohort studies established well before the pandemic began, and new studies of people with Long COVID. These studies aim to characterize the long-term effects of infection in a diverse set of people and the trajectory of symptoms over time. The initiative will support a multidisciplinary consortium of investigators who collaborate and coordinate across studies. The initiative also will support two complementary studies: 1) large data studies from resources such as electronic health records and health systems databases that will be critical to understand how many people are affected and what factors contribute to recovery; 2) studies of biological specimens to understand injury to the brain and other organs.

Core Resources: A clinical science core, data resource core, and biorepository core will provide overall consortium coordination, clinical expertise in post-acute COVID symptoms, and facilitate the use of standardized data and biological specimens collected from the consortium studies by consented volunteers.

Our hearts go out to individuals and families who have not only gone through the difficult experience of acute COVID-19, but now find themselves still struggling with lingering and debilitating symptoms. Throughout this pandemic, we have witnessed the resilience of our patient, medical, and scientific communities as they have come together in extraordinary ways. NIH deeply appreciates the contributions of patients who have not fully recovered from SARS-CoV-2 infection and who have offered their experiences and insights to lead us to this point, including those with other post-viral infections. Through the PASC Initiative, we now ask the patient, medical, and scientific communities to come together to help us understand the long-term effects of SARS-CoV-2 infection, and how we may be able to prevent and treat these effects moving forward.

Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health