Paul Has Measles is a children's book about viruses and vaccines available in English (download link) Spanish (download link) French (download link) and German (download link).

By David Tuller, DrPH

The recent Reuters article about the illness, or cluster of illnesses, variously called CFS, ME, CFS/ME and ME/CFS was problematic for many reasons. One of them was the information included from the US Centers for Disease Control and Prevention. In explaining why the CDC dropped its longstanding recommendations for cognitive behavior therapy and graded exercise therapy, Dr Elizabeth Unger, chief of the chronic viral diseases branch, repeated the tired trope that the agency believed people had “misinterpreted” what it meant.

It is long past time for the CDC to drop this unconvincing claim. As a public health agency, it has a responsibility to acknowledge when it has made mistakes, as it has in this case, rather than advancing absurd arguments to cover its tracks.

Let’s review the history. Prior to the summer of 2017, the CDC removed its continuing medical education module on the illness, which included references to PACE. Although the agency left recommendations for CBT and GET in place on the website, it positioned them as generic management strategies. This was clearly nonsense–a face-saving way of not admitting error. For one thing, the agency does not routinely recommend CBT and GET as generic management strategies for other chronic illnesses. For another, the CME module had linked the treatment recommendations directly to PACE; only after the module was removed were CBT and GET deemed to be generic management strategies.

When the CDC removed the recommendations themselves two years ago, it did so quietly. The change became public after I noticed it mentioned on an advocacy forum and then questioned the agency. At that point, I received a statement explaining that the recommendations had been removed because people had expressed “confusion” about what the agency meant by CBT and GET. Apparently Dr Unger conveyed a similar message to Kate Kelland, the Reuters reporter.

Note to Dr Unger: No one who knows anything about this field misinterpreted what the CDC meant in recommending CBT and GET as treatments. By pushing this untenable argument, you make yourself and the agency look ridiculous. Please just acknowledge that the CDC got it wrong in endorsing PACE and the CBT/GET paradigm in the first place.

As clearly explained in the 2011 PACE paper in The Lancet and other publications, the two treatments were based on the unproven theory that patients’ persistent symptoms were perpetuated by deconditioning. This deconditioning was itself, per the theory, caused by sedentary behavior arising from unhelpful beliefs about having a physical illness that could be exacerbated by excess activity. The goal of the treatments was to reverse these unhelpful beliefs and the attendant deconditioning through a mix of psychological and behavioral strategies.

Yet PACE was an open label trial that relied on subjective outcomes—a study design that generates an unknown amount of bias. The trial also used a broad definition for the illness that has been shown to identify many people who don’t actually have it. Moreover, the study’s reported success on the subjective measures was possible only because of dramatic changes to the methods of assessing these outcomes. Finally, in PACE, the objective outcomes all failed to match the subjective reports—a failure downplayed by the investigators and their enablers.

The CDC has adopted the new definition of the disease presented in a 2015 report from the US Institute of Medicine, now the National Academy of Medicine. The 2015 report found that the illness is associated with neurological, immunological and energy metabolism impairments that cannot be attributed to the effects of deconditioning. According to the new definition, the cardinal symptom is not fatigue per se but “exertion intolerance”—the tendency to suffer relapses after minimal activity, often called “post-exertional malaise.”

And if exertion intolerance is the cardinal symptom, then a program of steadily increasing exercise like GET would clearly be contra-indicated. So would the form of CBT used in PACE, which was designed to alleviate patients of the supposedly unhelpful beliefs about their illness that purportedly kept them from engaging in activity.

For years, the CDC—the country’s lead public health agency–placed its faith in PACE. Yet the study was riddled with methodological anomalies that first-year epidemiology students can spot. In PACE, for example, participants could be “recovered” or “within normal range” on key outcome thresholds at baseline, before any treatment at all—a feature that should have disqualified any trial from getting published. These problems were immediately evident to patients. Why did the CDC fail to notice?

The CDC has evaded answering this question by pretending that readers “misinterpreted” its advice rather than admitting that agency officials themselves screwed up big time. And the CDC’s refusal to provide an honest accounting—to state that it removed the CBT and GET recommendations because the science it had previously cited could not in fact be defended—is disturbing. This abdication of responsibility allows biased and misguided reporters like Kelland to suggest, without evidence beyond the speculations of PACE defenders, that the agency acted under pressure and intimidation from science-illiterate patients.

The CDC’s statements and actions matter because other medical institutions and public health agencies follow its cues. As soon as the agency removed the CBT and GET recommendations in 2017, it should have launched a serious outreach effort to alert medical providers of the change. That it did not helps explain why major centers like the Mayo Clinic have continued to push ME/CFS patients toward psychotherapy and exercise-based treatments despite the lack of quality evidence to support their use. (The CDC has recently updated its website material for medical professionals, but it has still done far too little to counter the potential damage from its past recommendations.)

Given the history, I suppose it is not surprising that the CDC and Dr Unger continue to disappoint in this domain. But it is nonetheless very, very dispiriting. Even after all this time, they appear unable to act in ways deserving of their leadership roles.

The TWiVstars reveal the diversity of herpes simplex virus type 2 in a neonatal population, and parallel adaptation of rabbits in three countries to myxoma virus.

Click arrow to play
Download TWiV 540 (66 MB .mp3, 109 min)
Subscribe (free): iTunesGoogle PodcastsRSSemail

Become a patron of TWiV!

Rabbits around the waterholeWhen viruses are introduced into a new population, selection pressures can lead to evolution of both pathogen and host. The pathogen must adapt to a new host, while the latter can become resistant to infection, leading to an arms race. An archetypal example of such host-pathogen evolution is illustrated by the attempt to control rabbit populations in Australia by the release of a pathogenic virus. Recent work illuminates the changes that occurred as the rabbits became resistant to infection.

European rabbits were introduced into Australia for sport in 1859, and lacking natural predators, the animals reproduced to huge numbers (image credit). After other control measures failed, myxoma virus was released in the 1950s in an attempt to rid the continent of the animals. The virus is spread by mosquito vectors, and European rabbits are killed rapidly – infection is 90 to 99% fatal.

In the first year, the virus was efficient in killing rabbits, with a 99.8% mortality rate. However, by the second year, the mortality dropped dramatically to 25%. In subsequent years, the rate of killing was lower than the reproductive rate of the rabbits, and hopes for 100% eradication were dashed. Epidemiological analysis of this artificial epidemic provided important information about the evolution of viruses and their hosts.

As expected, the infection spread rapidly during spring and summer, when mosquitoes are abundant, but slowly in winter. Given the large numbers of rabbits and virus particles, and the almost 100% lethal nature of the infection, attenuating mutations were selected quickly; within 3 years, less-virulent viruses appeared, and some infected rabbits were able to survive over the winter. The host-virus interaction observed was that predicted for an evolving host, coming to an equilibrium with the pathogen. A balance is struck: some infected rabbits die, but many survive.

For 69 years this story of rabbits and viruses has fascinated researchers. Recently a study was undertaken to understand how the rabbits changed after myxoma virus infection. The coding region from the genome of modern rabbits from Australia as well as France and the UK (where myxoma virus had also been released) were determined and compared with animals from museums that had been stored before the virus release.

The first examination of the data revealed that more rabbit alleles changed in frequencies across the three countries than would be expected by chance. The vast majority of these SNPs (single nucleotide polymorphisms) were already present in museum samples. This observation explains why rabbit resistance to myxoma virus arose so rapidly: the mutations were already in the population 800 years ago!

Initially 193 SNPs were identified in 98 genes and 7 intergenic regions that changed in their frequency from museum to modern rabbits. Of these, 20 SNPs were specific to the population of one of the three countries, and 20 were selected in parallel. The population specific changes were likely a consequence of differences in ecology, the genetic background of the rabbit, or simply independent paths of evolution with the virus.

Some of the rabbit alleles with an increased frequency are within one of the interferon (IFN) genes, which encodes a protein of the first line of defense against viruses. The proteins carrying these changes were more effective at inhibiting the replication of an attenuated strain of myxoma virus. It is possible that virulent myxoma virus selected for increased potency of this particular IFN.

Another SNP occurred in the rabbit gene encoding VPS4, which is not antiviral but is required for viral replication. The change might in some way alter VPS4 so that it is less able to support viral replication. SNPs were also found in the gene encoding a protein needed for proteasome function. The proteasome is needed for myxomavirus replication and it is possible that changes in the gene have suppressed this function.

It is informative that only 1% of the selected alleles have become fixed in the modern rabbit populations. The implication is that resistance to myxomavirus infection involves multiple genes which vary in frequency across the genome. Consequently virus reproduction is reduced, but not eliminated. This situation would favor the emergence of more virulent viruses, which was observed after the initial decline in viral virulence. As might be expected, these viruses have become highly immunosuppressive – to counter the effects of changes in the host immune system described in this study.

By David Tuller, DrPH

This morning I sent the following e-mail to Kate Kelland, the Reuters reporter who wrote last week’s story about horrible patients and horrible me, and about how all this horribleness is affecting Professor Michael Sharpe. I cc’d Professor Racaniello and the two Reuters editors listed on the story.

**********

Hi, Kate–

Congratulations on last week’s piece. It was late August when we met in New York, so I was wondering when it would appear. While I will be responding at greater length in the near future, I wanted to raise two issues of immediate concern.

[continue reading…]

By David Tuller, DrPH

Matthew Hotopf is a professor of general medicine psychiatry at King’s College London. He served as a peer-reviewer for a study by Bristol University investigators that was published in BMJ Open in 2011. The study involved whether school absences could be used to identify cases of diagnosed CFS/ME (as the study called the illness).

[continue reading…]

The TWiV hosts present two potentially seminal papers, on long-distance chemoattraction of a host by a chlorovirus, and replication of a nanovirus across multiple cells in a plant.

Click arrow to play
Download TWiV 539 (62 MB .mp3, 102 min)
Subscribe (free): iTunesGoogle PodcastsRSSemail

Become a patron of TWiV!

Show notes at microbe.tv/twiv

The London Patient

HIV binding CD4 and ccrby Gertrud U. Rey

Timothy Ray Brown, also known as the Berlin patient (reviewed in a previous post), was the only person ever to be cured of HIV/AIDS. Until last week.

[continue reading…]

By David Tuller, DrPH

Update:

When I posted earlier today, I also meant to update what was happening with the exercise review. On March 8, Cochrane announced, through a notice appended to the review, that the authors would submit another revision in May. (Cochrane has already rejected a previous revision submitted last fall.) That is also the month when Dr Tovey leaves his position as Cochrane’s as editor-in-chiefl it is unclear what that coincidence portends, if anything. Presumably the final decision on the exercise review will rest with Dr Tovey’s successor.

Here is the notice appended to the review:

‘Cochrane’s editors and the review author team have jointly agreed that there will be a further period up to the end of May 2019, in which time the author team will amend the review to address changes aimed at improving the quality of reporting of the review and ensuring that the conclusions are fully defensible and valid to inform health care decision making. The changes will also address concerns raised in feedback since the Robert Courtney complaint. The amendment will not include a full update, but a decision about this will made subsequently.’ [continue reading…]

By David Tuller, DrPH

Over the years, I’ve slammed U.S. medical and health care institutions that have championed the GET/CBT treatment paradigm for the illness or cluster of illnesses variously known as ME, CFS, ME/CFS or CFS/ME. I have done this both before and after the U.S. Centers for Disease Control and Prevention removed its own recommendations for the two therapies in the summer of 2017.

[continue reading…]

TWiV travels to the University of Iowa to speak with Wendy Maury and Stanley Perlman about their research on Ebolavirus entry and coronavirus pathogenesis.

Click arrow to play
Download TWiV 538 (37 MB .mp3, 62 min)
Subscribe (free): iTunesGoogle PodcastsRSSemail

Become a patron of TWiV!

Show notes at microbe.tv/twiv