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An Uncommissioned Editorial

Andrew Lloyd produced one of the most seminal series of studies in ME/CFS history. The Dubbo studies established that a wide variety of pathogens trigger ME/CFS in about ten percent of those infected. Stronger symptoms and high cytokine levels early in the illness appeared to set the stage for ME/CFS. Lloyd’s formula caught on and other researchers have since copied his powerful model of investigating ME/CFS as it occurs in real time.

andrew lloyd

Andrew Lloyd – ME/CFS researchers and op-ed writer

The Dubbo studies established Lloyd as an important thinker and researcher in ME/CFS.

Andrew Lloyd is also known as a great debunker. I remember him standing up at the Symposium on Viruses, fearlessly thrashing – with many of the researchers present –  study after study for their shortcomings.

He’s still thrashing away. In a recent op-ed “The Long Wait for a Breakthrough in Chronic Fatigue Syndrome” commissioned by the British Medical Journal, Lloyd hailed cognitive behavioral therapy and graded exercise therapy for the advances they’ve presented while largely dismissing other avenues of study.

He stated

“Over decades, research into the pathophysiology has failed to find convincing evidence of either persistent infection or immunological, endocrine, or metabolic change”

It’s true that “convincing” evidence; i.e. well replicated evidence is lacking for many factors but not for every factor. Certainly not for natural killer cell dysfunction. Lloyd’s dismissal of that finding must have been a jaw-dropper for his colleagues in Australia and elsewhere who are busy trying to figure out what’s going on there.

Even Lloyd’s former funder, the CDC, which stayed away from natural killer cells for decades, no longer questions the veracity of the NK cell findings in ME/CFS. The CDC, in fact, has attempted to get at the cause of the NK cell dysfunction and has talked of producing a more readily available test.

Exhaustive Array of Treatment Trials Fails in ME/CFS

Lloyd asserted that the treatment aspect of ME/CFS is, with two exceptions, equally bleak.

““Similarly, an exhaustive array of randomised controlled trials seeking curative outcomes from antiviral, immunological, hormonal, antidepressant, and many other therapies have failed to show any benefit over placebo, or failed the replication test.”

The Oxford Dictionaries definition of exhaustive is “examining, including, or considering all elements or aspects; fully comprehensive”. This is the first time I’ve ever seen that adjective applied to treatment trials in ME/CFS.

A search for randomized, controlled clinical trials for ME/CFS for the past five years was exhausting (through @ 1800 Pubmed citations) but it hardly uncovered an “exhaustive array”of treatment trials.

ME/CFS clinical trials

The search for randomized clinical trials in ME/CFS suggested an exhaustive array of clinical trials had hardly been undertaken in ME/CFS

Eleven trials were found over five years, six of which had positive effects. They included a  negative Clonidine trial, a positive yoga trial, a negative Vitamin D3 trial examining vascular health , a positive Coq10 trial , a positive qigong trial, a lukewarmly positive acupuncture trial,  a positive Rituximab trial,  a somewhat positive valganciclovir trial, a positive lisdexamfetamine trial, a positive Ampligen trial.

Other positive non-randomized, controlled trials included antivirals, B-12 and folate, and a positive sodium oxybate trial. Over the same period of time dozens of CBT/GET trials and analyses of CBT/GET trials were done.

Contrary to Lloyds assertions most of the trials, in fact, had positive results – probably as positive as the results in the CBT/GET trials.  Their major problem didn’t appear to be their efficacy, but in getting replicated – something that only appears to occur regularly with government supported CBT/GET trials.

Eleven trials over five years hardly constitutes an “exhaustive” search for treatments. What might an exhaustive search  look like? The eighty plus randomized trials (and analyses of randomized trials) that took place in multiple sclerosis over the past year. 

Lloyd failed to note that the small sizes and study design problems permeate so many of the poorly funded ME/CFS trials, that the recent AHRQ report  rejected over 90% of them. Nor did he note the enormous discrepancy in resources provided to CBT/GET trials relative to others. Size matters in clinical trials and CBT/GET trials tend to be larger than other trials. The same effect that fails to achieve significance in a smaller trial, may very well do so in a larger trial. The playing field between CBT/GET and other treatments is simply not level.

Four Areas of Significant Progress

Lloyd asserted that convincing progress has not been made in immune, metabolic, endocrine or infectious disease research or in most treatment areas. Next he provides some cheer, though:  he reports that significant progress has been made in four areas.

  1.  It’s now clear that pathogens can trigger ME/CFS
  2. Brain imagining studies implicate the brain as the center of pathophysiology in ME/CFS
  3. Mood disorders and sleep disorders provide the basis for treatments
  4. Cognitive behavioral therapy (CBT) and  graded exercise therapy (GET) help patients manage their symptoms.

With point four we get to the central theme of the editorial. The op-ed, it turns out, was not about the next breakthrough at all. Lloyd spends little time discussing potential breakthroughs in ME/CFS. The op-ed is intended to bolster CBT and GET’s reception in ME/CFS. That is what the BMJ apparently asked Lloyd to deliver and that’s what he spends the most time on.  Lloyd states

“there is solid evidence from multiple controlled studies that patients can gain control of symptoms and functional improvement through multidisciplinary interventions incorporating graded exercise therapy and cognitive behavioural therapy. These interventions have clearly positive outcomes in systematic reviews and meta-analyses”

But is the evidence really so solid – so “convincing”? Lloyd has dismissed much of the progress the field has made because of the lack of “convincing” evidence, but is he applying the same rigorous standards to CBT and GET?

He reported that the Cochrane report on GET in ME/CFS concluded “patients with CFS [chronic fatigue syndrome] may generally benefit and feel less fatigued”. The same Cochrane report, however, also stated GET did not affect “physical functioning, depression, anxiety or sleep” and they were not able to draw any conclusions regarding it’s ability to reduce pain,  increase overall health or reduce the use of health service resources.

caution regarding CBT and GET

Several distinguished reports suggested Lloyd overstated the efficacy of both GET and CBT

The 2009 Cochrane Report on CBT was much less sanguine than Lloyd regarding the positive effects of CBT in ME/CFS.  CBT did increase the percentage of patients showing clinical improvement relative to those who received standard clinical care by about 50%. Even with that 50% gain, though, the majority of patients (60%) still showed no significant clinical improvement at all. 

Even the 40% improvement rate was something of a chimera. Follow up studies suggested that people who remained on the CBT regimen did continue to have lower fatigue levels, but so many people stopped CBT that in the end the study found no difference in fatigue levels between those who’d participated in CBT and those receiving usual care.

That begs three questions:

(1) If your fatigue was really substantially improved by a treatment would you stop it?

(2) What use is a treatment, really, if it only it works when you’re part of a treatment trial?

(3) Why does the most virulent opposition to these practices occur in the countries that are saturated with them?  Shouldn’t we expect satisfied patients in these countries to be leading the charge for CBT/GET?

The AHRQ reports provide another “gold-standard” of analysis.  The recent AHRQ report Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome hardly provided a strong endorsement of either CBT or GET.

Contrast the “solid evidence” and “clearly positive” outcomes Lloyd  asserts CBT has in ME/CFS, with the “moderate” confidence the AHRQ had that CBT is able to reduce fatigue and provide “global improvement”. Or the low confidence they had, that CBT is able to improve/enhance quality of life, or any kind of important functional measure (overall functioning,  increase working hours, or reduce work impairment.)

As Lloyd was citing one report stating there was little evidence of harm in GET the  AHRQ report was acknowledging the dangers associated with poorly managed exercise and GET programs. They noted that harms were not well reported in GET studies and that several factors, including high degree of harms in one trial, high dropout rates in another, and higher withdrawal rates whenever the arms of trials included exercise, indicated they could be significant.

The AHRQ also reported that several studies find that exercise worsens symptoms, and that an ME Association survey reported that GET had higher rates of symptom exacerbation than other treatments.

Nor did Lloyd note the confounding factors that the Oxford definition – commonly used in both types of studies – may introduce. The AHRQ report warned that studies containing the Oxford definition, “in particular”, might not contain any ME/CFS patients. The IOM report simply recommended that the Oxford definition be consigned to the dustbin of history.

Consider that nowhere are CBT/GET presented as producing other than moderate benefits in a few areas. Then consider how easily those moderate benefits might disappear if more rigorous cohorts were used, or if smaller trials were done.

Lloyd’s clearly positive outcomes and strong evidence seem to be an overreach when other citations are referenced.

 

Poor Fitness

Lloyd does present an enlightened viewpoint of why GET may be helpful.  Instead of placing the “blame” on overly worried patients he suggests that nervous system sensitisation that takes place during exercise is placing patients in pain causing them to avoid exercise or to go for broke and suffer the consequences in a crash-burn pattern. He also adds the important note that GET programs should be personalized.

Lloyd sticks his head in the sand, though, when he states “..there is little evidence for loss of aerobic fitness in patients with chronic fatigue syndrome, and limited evidence for improved physical performance after successful graded exercise therapy.”

Lloyd, then, accounts for the rather disturbing  fact for GET proponents that there’s no evidence indicating that it improves physical functioning by asserting there simply is no problem with physical functioning; i.e., the aerobic pathways are functioning fine in ME/CFS.

By doing so he negates several studies showing declines in energy production during a two-day exercise testing regime as well as other studies documenting problems with energy production pathways in ME/CFS.  I don’t think anyone believes the aerobic energy production situation in ME/CFS is resolved (the studies tend to be small), but the evidence is trending strongly in one direction – and Lloyd is trending in another.

Lloyd called the emergence of  two therapies that do not increase functioning in a disorder with very rates of functional impairment-  significant progress.

Lloyd called the emergence of two therapies that do not increase functioning – in a disorder with very high rates of functional impairment- significant progress.

Lloyd, thankfully, notes that criteria for recovery in the Pace trial were skewed and that its estimates for recovery (25%) were overly generous. Even mentioning the word recovery, however, in this ceiling afflicted, functionally impaired (no valid assessments of functioning) trial with its geriatric results on the walk test is problematic.

In the end Lloyd counts as significant progress two therapies neither of which have “convincingly” been shown to increase functionality at all in an illness that is significantly more functionally impairing than congestive heart failure, type II diabetes mellitus,  acute myocardial infarction, multiple sclerosis, and depression. This in an illness that Bill Reeves of the CDC stated is also as functionally impairing as people with AIDS, breast cancer and chronic obstructive pulmonary disease”.

This is not to say that CBT and a properly managed (preferably heart-rate based) GET prgram cannot be helpful. I believe they can be.  Nobody knows how to manage a significant chronic illness and if CBT or other practices can help people manage  their illnesses better and improve their health somewhat, I’m all for that. Dr. Klimas, for instance, employs heart-rate based exercise programs to good effect.

These programs have their place in ME/CFS and FM and other illnesses. But should we, in year 2015, be celebrating the fact that we have CBT/GET or should we be emphasizing the fact that since they appeared some twenty years ago nothing else has come along? CBT, by the way, appears to produce about the same benefits in multiple sclerosis – modest decreases in fatigue – that it does in ME/CFS.

Lloyd’s bar for progress – the recognition that mood disorders and sleep issues are present in ME/CFS– and that CBT/GET helps –is incredibly low.  He could have made the same case ten years ago.

The big surprise regarding Lloyd in this op-ed is not that he’s controversial – he’s always been controversial – but that his op-ed lacks so much rigor. The researcher who with some joy in his heart loved to poke holes in other researchers findings, is not being rigorous himself. He’s become more of an advocate rather than a trusted resource.

He’s the wrong man for the job, anyway.

It’s understandable for Peter White to publicly support CBT and GET: his work depends on CBT/GET funding, but why is Andrew Lloyd doing that? It’s clear why BMJ would want him; he’s a respected researcher with no CBT work in his past. He’s not tooting his own horn. So why is he doing it? Why did he feel the already CBT/GET saturated Brits needed an op-ed  asserting the primacy of CBT/GET? I have no idea.

Business As Usual Vs Urgency

Contrast the warm and fuzzy light Lloyd casts the state of ME/CFS with the urgent appeals for funding by two large federally funded reports – produced, one might add, mostly by outsiders. Here’s Lloyd touting the “modest increments” of progress made in ME/CFS.

“As is often the case in medical research, progress is predominantly made in modest increments not breakthroughs”

Here’s what the federal reports have to say about the state of ME/CFS.

“Remarkably little research funding has been made available to study the cause of ME/CFS, mechanisms associated with the development and progression of the disease, or effective treatment, especially given the number of people affected.” Institute of Medicine

“Unfortunately, ME/CFS is an area where the research and medical community has frustrated its constituents, by failing to assess and treat the disease and by allowing patients to be stigmatized….Over the last 20 years, minimal progress has been made to improve the state of the science for patients with ME/CFS. Innovative biomedical research is urgently needed to identify risk and therapeutic targets, and for translation efforts.” NIH Pathways to Prevention Report

A Call For Stasis

Two faces of ME/CFS - the  IOM/P2P reports and Lloyd's warm and fuzzy account in the BMJ: which better reflects your reality?

Two faces of ME/CFS – the IOM/P2P reports and Lloyd’s warm and fuzzy account in the BMJ: which better reflects your reality?

Marx said religion is the opiate for the masses. I propose that op-ed’s like Lloyd’s are opiates for those who believe ME/CFS doesn’t need any more funding. Why would a disease whose treatment options for ME/CFS have been “exhaustively” explored need more funding? Why would patients who can manage their own symptoms (make them disappear?) need more help? Why would you give increased funding to a disorder whose advocates define “progress”  like Lloyd does?

The op-ed, whether Lloyd intends it or not, is more a call for stasis – for business as usual –  when just the opposite is needed.  I  don’t think it does ME/CFS or Lloyd himself any good. I imagine it just became a bit more difficult for some funders to sign a check with Lloyd’s name on it. And for what? To repackage mostly old news about CBT/GET, depression and sleep and call them significant progress? This is the wrong blog at the wrong time.

Lloyd begins the piece talking about the “decline and fall” of XMRV but I see a different arc.  I see a man  who was on the cutting edge of ME/CFS  research in the mid 2,000’s  ten years later asserting that  mood disorders, sleep problems and CBT/GET constitute real progress in this disorder. It’s hard to see that.

The big mystery for me is not that this op-ed got written, but that Andrew Lloyd wrote it.

The big question for me is what the heck  has happened to Andrew Lloyd?

What ME/CFS and what I would argue, is that what Andrew Lloyd really needs is more funding.  I believe Lloyd should have gotten much more funding after the Dubbo studies, and I hope he gets more funding in the future. I also hope he stays away from op-eds. If he writes another one, though, I hope it’s one that argues for the possible breakthroughs that more funding could achieve, and how those breakthroughs might translate into treatments.

That would be an editorial worth writing and reading.

Inquiry of the Day on the Health Rising Forums: Tell us if you’ve tried CBT/GET and if you have how it went for you.

 

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