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By David Tuller, DrPH

In late December, the International Journal of Clinical and Health Psychology published an article called “Prevalence and treatment of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and co-morbid severe health anxiety.” This paper, from investigators at the University of Bath and Oxford University, actually included two separate studies documenting the purported relationship between a construct called “health anxiety” and CFS/ME, as the investigators currently refer to the illness in question.

The first study described in the paper is a cross-sectional survey of health anxiety and symptoms in CFS/ME patients. (An acknowledged limitation of cross-sectional data is that they document associations only and do not provide evidence of causation.) The second study described in the paper involves the delivery of a specialized treatment—a cognitive behavior therapy approach that addresses health anxiety, called CBT-HA—to ten patients.

As far as I can tell, the animating hypothesis is more or less the same as that behind the PACE trial, except in this case the psychological entity that is presumed to inhibit patients from engaging in activity is called “health anxiety” rather than something called “fear avoidance.” Health anxiety seems to be essentially a friendlier, less derogatory name for hypochondriasis. Here is how the investigators describe the basis for their intervention:

“CBT-HA is based on the notion that ambiguous health-related stimuli are subject to interpretation which hence informs behavioural responses such as hypervigilance to physiological sensations, avoidance, bodily monitoring and reassurance seeking in order to prevent realisation of health concerns. However, these strategies often increase distress.

This all sounds pretty much like the notions embodied in the PACE approach. Am I missing something? Is there a substantive difference here?

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What Is Health Anxiety?

For the new study, health anxiety was measured according to a 14-item instrument published in 2002. On the scale, higher total scores represent greater overall health anxiety. For each question, each consecutive answer receives a higher score. Here are two examples of the included questions:

a) I do not worry about my health.
b) I occasionally worry about my health.
c) I spend much of my time worrying about my health.
d) I spend most of my time worrying about my health.

a) As a rule I am not aware of bodily sensations or changes.
b) Sometimes I am aware of bodily sensations or changes.
c) I am often aware of bodily sensations or changes.
d) I am constantly aware of bodily sensations or changes.

These questions might make sense for assessing health anxiety in some contexts. But anyone with CFS/ME will likely spend more time worrying about their health and more time being aware of their bodily sensations than those who are well. That would rate them higher on the health anxiety scale. Yet all it means is they have understandable concerns and anxieties about their health, given their serious medical condition.

In both the health anxiety and fear avoidance formulations, the choice to avoid engagement in activity is posited as leading to negative health outcomes. Here is how it is explained in the current paper:

“We suggest that due to largely unexplained physical sensations, lack of effective reassurance from medical practitioners (due to the condition being poorly understood) and the complex anxiety provoking and problematic nature of managing fatigue, some patients with CFS/ME may be prone to employing strategies to prevent worsening of symptoms such as restricting and/or avoidance of physical activity, paying attention to ‘warning signs’ or excessively resting as part of a health anxiety cycle, subsequently resulting in lower levels of physical functioning and fatigue on exertion.”

And here’s an explanation of the therapeutic intervention:

“In CBT-HA, cognitions related to health concerns (e.g., I will collapse) trigger behavioural responses designed to prevent the feared outcome. However, these (safety seeking) behaviours (SSB) serve to prevent disconfirmation of the feared outcome, thus reinforcing the behaviour through operant mechanisms…

The CBT-HA formulation draws out the unintended consequences of the SSB (e.g., anxiety/frustration, intensified pain/deconditioning) and how these further reinforce fear of ‘collapse’, for example. This creates a vicious self-reinforcing cycle of distress which is maintained by SSB originally employed to reduce the likelihood of physical collapse or other feared outcome.”

This statement is like a reprise of the paradigm developed throughout the 1990s, complete with the purported “vicious self-reinforcing cycle,” that resulted in the PACE trial. The description does seem to include some other terminology, such as “SSB.” Perhaps that’s an effort to present the hypothesis as an intellectual or conceptual advance demanding exploration and its own funding stream.

Let’s be clear: This paper reads not like an intellectual or conceptual advance but like a copycat version of the PACE approach, which has already failed to live up to its claims. In recognition of that failure, more than 100+ international experts signed Virology Blog’s open letter to The Lancet about the PACE study’s “unacceptable methodological lapses” and the US Centers for Disease Control and Prevention dropped the PACE-inspired recommendations.

To be fair, the investigators of this study note that the intervention is not based on the assumption that health anxiety explains all the symptoms of the illness. They also acknowledge that stigmatization of patients and related factors could themselves increase health anxiety. But these cautionary statements play a secondary role to suggestions that symptoms of the illness are amplified and exacerbated by health anxiety and that health anxiety should therefore be a specific target of intervention.

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The Theoretical Framework for CBT-HA

The impression that CBT-HA is simply the PACE CBT strategy in lipstick and a tutu is reinforced by a review of the theoretical framework of the intervention, as outlined in a 2017 paper. In that paper, two Bath University investigators described how a single patient successfully completed the CBT-HA therapy course and showed improvement on self-reported measures. That triumph paved the way for the case series described in the recent publication.

In 2017, here’s how the investigators explained their thinking:

1. Cognitive beliefs relating to CFS and CFS symptoms inform behavioural strategies that maintain CFS. Targeted cognitive restructuring (and associated behavioural experiments) will lead to a reduction in the 100% conviction that specific behaviours (i.e., SSB) are necessary to prevent a worsening of CFS, and that a worsening will lead to collapse.

2. Symptoms of CFS (specifically fatigue and pain) are maintained by behavioural strategies that are designed to prevent worsening of (CFS) symptoms. Extinction of specific strategies identified in the formulation will lead to an improvement in the primary physical symptoms of fatigue (Chalder Fatigue Scale) and pain (VAS).

3. The health-focused anxiety serves to exacerbate the CFS symptoms and vice versa; therefore, addressing both within an integrated approach will lead to reductions in both CFS symptoms (Chalder Fatigue Scale) and health anxiety (health anxiety inventory) as well as improvements in functioning (SF-36) and self-efficacy (self-efficacy scale).

Let’s be clear. This is a hypothesis. As with PACE’s similar claims, there is no credible evidence that “health-focused anxiety serves to exacerbate” the course of the illness. The investigators apparently believe that their new paper provides that credible evidence. It does not. Interestingly, they do not mention or cite PACE. Nor do they mention that the PACE results were either null or explainable by placebo effects when assessed by the methods promised in the protocol. (I was a co-author of the PACE-debunking paper.)

(At this point, I suppose it makes sense for other investigators, even former supporters of the PACE trial, to avoid all mention of it. PACE is indefensible as a piece of science. It will forever be the study in which participants could get worse on key outcome measures and still be found to have achieved “recovery.” It has been put to its best use at Berkeley, where my colleagues have assigned it in epidemiology seminars as a case study of awful research.)

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The Unsurprising Study Results

But I digress. Here is how the investigators describe the results of the paper’s first study–the cross-sectional analysis:

“Findings from study one indicate that health anxiety in CFS/ME is common and significantly associated with symptom severity. Participants with high health anxiety were more fatigued, anxious and depressed, demonstrating lower levels of physical functioning than those without.”

This makes sense. If patients are experiencing severe symptoms that are questioned by doctors, family and friends, they could certainly experience high levels of anxiety about their health. In the absence of evidence beyond hypothetical speculations and anecdotal observations, it is unwarranted to believe these data indicate that “health-focused anxiety serves to exacerbate the CFS symptoms.” Many smart observers would view the data and assume that any causal relationships are likely to run in the opposite direction.

The second study involved offering patients the 12-session CBT-HA intervention, delivered by the lead investigator, and testing them on various self-reported measures at the start and finish of treatment. Of 10 who began the program, two dropped out—a 20% rate of loss-to-follow-up. Those who remained reported various improvements on questionnaires.

It should not be surprising that patients who spent many hours one-on-one with a sympathetic therapist reported on questionnaires that they felt better and were less anxious. That is especially so if they were assured that the intervention they received could improve their health and make them feel better, as occurred as part of the CBT delivered in PACE and related trials.

Moreover, the final assessments were made at the time of the last session–the point at which participants were most likely to be maximally biased in favor of the intervention. It is common that reported positive effects in such studies wear off after weeks or months, when the impact of any bias is likely to have dwindled. With such a tiny sample and in the absence of a comparison group, such findings tell us very little if anything about actual treatment effects, if any.

Unblinded research relying on self-reported findings can be quite successful at altering questionnaire-response behavior, especially in the context of a positive therapeutic relationship. These kinds of subjective reports are essentially artifacts of the study design more than signs of any genuine improvement. This point is highlighted by the tendency of any apparent therapeutic benefits to wear off in follow-up studies as well as by the consistent failure of objective outcomes, such as number of steps taken as measured by actimeters, to support the self-reported findings.

In advocating for a randomized controlled trial, the investigators assert that it “would generate further evidence to support the utility of CBT-HA in CFS/ME.” This is an odd statement. The purpose of a clinical trial is to examine whether something does or does not happen, not to prove what is already known to be true. In this case, the investigators have virtually promised that a full trial would provide “further evidence to support the utility” of their custom-tailored intervention. That categorical declaration suggests the kind of allegiance to a pre-determined outcome that can seriously undermine the objectivity and integrity of scientific research.

From DukeNUS Medical School, Vincent speaks with Ashley, Sheemei, Eng Eong and Dahai about their careers and their research on flaviviruses and sensing of viral RNA.

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By David Tuller, DrPH

I’m always highlighting dodgy research from the CBT/GET ideological brigades. These studies are fun to tear apart (metaphorically and sometimes literally), but it’s also nice to be able to recommend some decent research. Below are a few recent papers that I have found to be of interest. All of them were published by the journal Work.

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Daniel Griffin provides a clinical update on COVID-19, then we review SARS-CoV-2 infections in non-humans, vesicular stomatitis in Kansas horses, and answer listener questions.

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By David Tuller, DrPH

Earlier today, I sent the following letter to Dr David Perez, a neurologist and psychiatrist at Massachusetts General Hospital in Boston. Dr Perez, an expert on functional neurological disorders, wrote a commentary for Lancet Psychiatry that accompanied the publication of the results for CODES, a major study of cognitive behavior therapy as a treatment for dissociative seizures.

My critique of the commentary is here. My previous posts on CODES are here and here

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By David Tuller, DrPH

By all accounts, the recently published CODES trial was the most authoritative study to date of whether cognitive behavior therapy (CBT) was an effective treatment for so-called dissociative seizures–a point confirmed in a commentary accompanying the paper in Lancet Psychiatry. Unfortunately, the CODES investigators and the commentary author seem to interpret the null results for the primary outcome as a call to find other assessment measures—not as a reason to seriously question the therapeutic intervention and its theoretical foundation.

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Most of the 172 SARS-CoV-2 vaccines in development will be administered by intramuscular injection, a traditional route for many effective vaccines. In my opinion the use of needles for immunization will one day be replaced by microneedle patches, which can not only be self-administered but have a variety of other advantages compared with injection.

A microneedle patch is fabricated with a plastic containing the vaccine antigen. When applied to the skin with a band-aid, the needles pass through the dead upper layers of skin and into the underlying dermis and epidermis. The latter is rich in antigen presenting and accessory cells of the immune system, an environment that favors potent and durable adaptive immunity. The needles dissolve in the skin, releasing antigen. The release of antigen is a small area increases vaccine concentration while reducing the dose used compared with injection. Afterwards the patch, which is no longer sharp, is discarded in normal trash.

Immunization via microneedle patch does not require a trained health care worker, an obvious advantage which saves money and allows deployment in resource challenged areas. Furthermore, incorporation of antigen into the plastic matrix appears to confer thermal stability, eliminating the need for a cold chain.

A variety of microneedle based vaccine candidates for viruses, bacteria, and protozoan parasites have been formulated and tested in experimental animals and in humans. The latest is a vaccine candidate for SARS-CoV-2; the results demonstrate that this platform is suitable for use in rapidly developing vaccines against emerging pathogens.

Within 3 weeks of publication of the genome sequence of SARS-CoV-2, the gene for the spike glycoprotein was synthesized and inserted into mammalian cells in culture. The recombinant spike protein was purified and microneedle patches were fabricated using molds filled with carboxymethyl cellulose mixed with antigen.

Microneedle patches were applied to the skin of mice and sera were collected at different times afterwards. High levels of virus-specific IgG was detected by week 2. Sterilization of the patches by gamma-irradiation did not compromise immunogenicity.

The next step is to determine whether the antibodies induced by microneedle patch immunization can neutralize SARS-CoV-2 infectivity. If they do, with the proper preclinical data this vaccine candidate can proceed to human clinical trials. Given the many advantages of microneedle patches compared with needle-based immunization, I am hopeful that they will be one of the vaccines that are approved and used to prevent COVID-19. Such use would validate microneedle patches as a vaccine platform and enable their use for future emerging viruses.

Of course, kids (and their parents) will love microneedle patches – they don’t hurt!

Vincent, Rich, and Brianne discuss a study estimating the fraction of symptoms and severe disease after SARS- CoV-2 infection, cellular immune responses without seroconversion during interfamilial infections, and answer listener email.

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Jessie, Allie and Tyler join Nels and Vincent to describe their work on deep mutational scanning of the SARS-CoV-2 receptor binding domain.

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By David Tuller, DrPH

UK Funding for Major Genetics ME Study

Two of the UK’s largest public funding agencies announced this week that they would provide £3.2 million (around $4 million at current rates) for a study that will analyze genetic material from as many as 20,000 people to search for underlying causes of myalgic encephalomyelitis. The Medical Research Council and the National Institute for Health Research are providing, respectively, £1.8 million and £1.4 million to support the project, called DecodeME.

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