By David Tuller, DrPH

On Friday, I had an e-mail exchange with Sir Andrew Dillon, chief executive of the NICE Guidance Executive. The other seven Guidance Executive members are various directors within the NICE hierarchy, including the communications director. This group will make the final decision about whether to accept the provisional decision of a NICE surveillance review team to leave as is CG53, the guidance for CFS/ME released in 2007. (I have written about the NICE review process on CG53 here, here and here.)

That ten-year-old CFS/ME guidance recommends treatment with graded exercise therapy and cognitive behavior therapy. NICE reaffirmed the guidance after the 2011 publication of the first PACE results, which were taken as evidence that these treatments were effective. As part of the current review process, NICE provided stakeholders with a two-week window last month to submit comments about the provisional decision not to change CG53. Not surprisingly, this recommendation has alarmed many patients and advocates.

I didn’t expect to get answers to my questions from the Guidance Executive, but I felt an obligation to pose them anyway, given the importance of the issues. In fact, Sir Andrew responded to my e-mail within an hour. He explained that no comments would be forthcoming while the Guidance Executive was reviewing the situation. I have posted his response below my initial e-mail.

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Sir Andrew Dillon
Chief Executive
National Institute for Health and Care Excellence
 
Dear Sir Andrew:
 
I am a journalist and public health researcher at the University of California, Berkeley. I have reported on the current review of CG53, the NICE guidance for CFS/ME, for the science site Virology Blog, which is hosted by Professor Vincent Racaniello, a microbiologist at Columbia University. I have previously reported for Virology Blog on the PACE trial and other issues related to graded exercise therapy and cognitive behavior therapy. Earlier this year, I co-authored a commentary about the serious problems with PACE for the Sunday opinion section of The New York Times. 
 
In my role as a journalist covering this issue, I have some questions for you and the other members of the NICE Guidance Executive about the decision-making process concerning the provisional recommendation to make no changes to CG53: 
 
1) For many years, the U.S. Centers for Disease Control recommended GET and CBT as treatments, citing PACE. In late June or early July, the agency removed all references to these therapies from its main pages on the illness. Does the Guidance Executive plan to consult with American public health officials about what prompted this major “dis-endorsement” of these two therapies that NICE continues to promote? 

2) In 2015, both the U.S. National Institutes of Health and the Institute of Medicine (now the National Academy of Medicine) released reports on the illness (they call it ME/CFS). These reports both concluded that it is a serious organic disease involving pathophysiological processes and not a psychological or psychiatric disorder—a determination that would have significant impact on treatment options. Does the Guidance Executive plan to consider these two reports and consult with any of the members of the panels that wrote them?
  
3) Other fields of medicine have abandoned the use of the trial design favored in this entire body of research, including PACE: open-label studies with subjective outcomes. That’s because other fields of medicine recognize that the combination of those two features in one study inherently produces bias. Does the Guidance Executive share these concerns about results from open-label studies with subjective outcomes, or does it believe that such studies can produce reliable and unbiased evidence suitable for clinical decision-making?  
 
4) In PACE and other studies from this field, objective measures have largely failed to support the subjective results that have generated claims of “recovery” or significant clinical improvement. Does this pattern of sharp contradiction between objective and subjective results raise questions for the Guidance Executive about whether patients are objectively getting better?
 
5) In the 2011 Lancet paper, 13 % of the PACE participants had already met one of the study’s outcome thresholds at trial entry—that is, although assessed as “disabled” enough in physical function to qualify for the study, they were also found to be “within normal range” for physical function, before any treatment at all. In the 2013 Psychological Medicine paper, the same 13 % were already “recovered” for physical function at baseline, before any treatment at all—that is, they were simultaneously “disabled” for physical function and “recovered” for physical function. These facts were not included in the published papers but emerged later through a patient’s freedom-of-information request. Does the Guidance Executive have confidence in the reported results of a study in which a significant minority of participants have already met a key outcome threshold at baseline? If so, can the Guidance Executive point to other studies in the clinical trial literature in which a significant number of participants have already met a key outcome threshold at baseline? Does the Guidance Executive believe that the published PACE papers should have mentioned the fact that a signifiant minority of participants had already met a key outcome threshold at baseline? 
 
6) In February 2016, forty-two leading scientists and clinicians signed an open letter to The Lancet in which they outlined the methodological lapses of the PACE trial, stated unequivocally that “such flaws have no place in published research,” and demanded an independent investigation. In March 2017, more than 100 experts signed an open letter to Psychological Medicine, asking the journal to retract immediately its core finding that GET and CBT helped patients “recover.” Does the Guidance Executive plan to review these open letters and consult with any of the signatories–from Columbia, University College London, Harvard, Stanford, Berkeley, etc.—about their reasons for publicly dismissing the PACE findings as invalid? 
 
7) Both GET and CBT, as described in PACE and other studies from this field of research, involve telling participants that the treatments can reverse the illness and return them to a state of health. Is the Guidance Executive concerned that telling study participants repeatedly about the effectiveness of the treatments could bias their responses, augmenting any bias already inherent in open-label studies with subjective outcomes? 
 
8) Some defenders of PACE note that CBT is also recommended for patients with cancer and other chronic diseases. But the approach advocated in PACE and related studies is not the kind of CBT focused on helping patients adapt to the reality of their illness. Rather, this form of CBT is specifically designed to alleviate patients of their purportedly “unhelpful” beliefs of having an ongoing medical disease that can be exacerbated by activity and exercise. Is the Guidance Executive aware of this critical distinction between CBT as normally administered in the case of other chronic illnesses and the adapted form of CBT investigated in PACE and other studies in this field? 
 
9) The PACE trial used the Oxford criteria to identify participants. This case definition requires only six months of unexplained fatigue, so its use could result in the selection of participants with depression or other unidentified fatiguing illnesses. Some of these other illnesses might resolve spontaneously or respond to behavioral and psychological interventions like GET and CBT. In fact, the NIH report noted that using the broad Oxford case definition could “impair progress and cause harm,” and recommended that it be “retired.” Is the Guidance Executive concerned that populations derived using the Oxford criteria might contain many participants experiencing prolonged fatigue for a range of reasons unrelated to the illness being investigated? Is the Guidance Executive concerned that such heterogeneity in study samples could lead to erroneous findings about treatments?
 
10) The U.S. Agency for Healthcare Research and Quality found evidence to support GET and CBT for ME/CFS in its review of multiple studies. However, when the agency subsequently removed Oxford criteria studies from this analysis, it found no evidence that GET provided any benefits and almost no evidence that CBT provided benefits. Is the Guidance Executive considering this AHRQ re-analysis in its decision-making? Does the Guidance Executive plan to consult with officials at the agency to discuss why they conducted this re-analysis and how it subsequently led them to downgrade their assessments of the therapies? 
 
11) The surveillance review team cites Cochrane reviews of GET and CBT to support the recommendation to leave the 2007 guidance as is. Many of the trials included in these Cochrane reviews rely on a broad case definition like the Oxford criteria. Is the Guidance Executive comfortable relying on Cochrane reviews for confirmation of controversial findings when the reviews themselves include the studies that feature the methodological problems being questioned? Will the Guidance Executive consider asking Cochrane to follow the lead of American public health officials and conduct a re-analysis of its GET and CBT reviews with Oxford criteria studies removed from the sample? 
 
12) In the PACE trial protocol, the investigators promised to follow the Declaration of Helsinki, which requires researchers to tell prospective participants about “any possible conflicts of interest.” The three main PACE investigators have had longstanding relationships with insurance companies, advising them to offer GET and CBT to claimants diagnosed with the illness. Yet the investigators did not tell prospective PACE participants about these extensive consulting and financial links with insurance companies or include the information in consent forms. Is the Guidance Executive concerned that this clear violation of the investigators’ protocol promise to disclose “any possible conflicts of interest” to prospective participants means that they did not obtain properly “informed” consent? Does the Guidance Executive believe it should base clinical guidelines on studies that have not obtained properly “informed” consent? 
 
13) More than 15,000 people signed the ME Association’s online petition outlining their concerns with the 2007 guidance and their objection to the provisional decision to leave it unchanged. Is it unusual for that many people to sign a petition protesting a NICE guidance? 
 
14) Surveys of patients who have undergone GET have routinely found that more patients report harms from the intervention than benefits. In making its decision, does the Guidance Executive plan to consider these reports based on the clinical experiences of patients receiving GET in the real world? 
 
15) The conduct and findings of the PACE trial have become a worldwide controversy. The study has been presented as a paragon of bad science at conferences of epidemiologists and statisticians and in graduate-level seminars. Leading scientists and clinicians have publicly denounced the trial’s perplexing irregularities. The CDC has removed references to PACE and has dropped the associated treatment recommendations. In making its decision about the 2007 guidance, does the Guidance Executive plan to consider that large segments of the scientific and public health worlds have already rejected the evidence base for GET and CBT as interventions for CFS/ME, ME/CFS, or whatever the disease entity is called? Given the public health stakes involved, will the Guidance Executive consider commissioning a more extensive, authoritative, independent and unbiased review of the evidence–and perhaps even a review in which the reviewers read the actual studies on which they are basing their recommendations, and not just the study abstracts?   
 
I have other questions, but will leave it at that for now. I would be delighted should you and/or other members of the Guidance Executive choose to respond.
 
Kind regards–David
 
David Tuller, DrPH
Senior fellow in public health and journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley

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Sir Andrew’s réponse to me:

Dear Dr Tuller,

Thank you for your enquiry.

It looks like you are aware that we have recently concluded a public consultation about our provisional decision on the review of this clinical guideline. We are in the process of reviewing the results of that consultation and will make our final decision in due course. We will make that decision public, together with any other statements we think will be helpful to contextualise it. Until then, we don’t intend to respond to enquiries about the provisional decision. It may be that our final decision, when placed in the public domain, will help you with some of your questions, but if not, we will endeavour to answer them as best we can at that time.

Yours sincerely,

Andrew Dillon
Chief Executive
National Institute for Health and Care Excellence
10 Spring Gardens | London | SW1A 2BU | United Kingdom

Sharon Isern and Scott Michael return to TWiV for a Zika virus update, including their work on viral evolution and spread, and whether pre-existing immunity to dengue virus enhances pathogenesis.

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The short answer to the question posed in the title of this blog is: we don’t know.

Why would we even consider that a prior dengue virus infection would increase the severity of a Zika virus infection? The first time you are infected with dengue virus, you are likely to have a mild disease involving fever and joint pain, from which you recover and develop immunity to the virus. However, there are four serotypes dengue virus, and infection with one serotype does not provide protection against infection with the other three. If you are later infected with a different dengue virus serotype, you may even experience more severe dengue disease involving hemorrhagic fever and shock syndrome.

The exacerbation of dengue virus disease has been documented in people. Upon infection with a different serotype, antibodies are produced against the previous dengue virus encountered. These antibodies bind the new dengue virus but cannot block infection. Dengue virus then enters and replicates in cells that it does not normally infect, such as macrophages. Entry occurs when Fc receptors on the cell surface bind antibody that is attached to virus particles (illustrated). The result is higher levels of virus replication and more severe disease. This phenomenon is called antibody-dependent enhancement, or ADE.

When Zika virus emerged in epidemic form, it was associated with microcephaly and Guillain-Barré syndrome, diseases that had not been previously known to be caused by infection with this virus. As Zika virus and dengue virus are closely related, because ADE was known to occur with dengue virus, and both viruses often co-circulated, it was proposed that antibodies to dengue virus might exacerbate Zika virus disease.

It has been clearly shown by several groups that antibodes to dengue virus can enhance Zika virus infection of cells in culture. Specifically, adding dengue virus antibodies to Zika virus allows it to infect cells that bear receptors for antibodies – called Fc receptors. Without Fc receptors, the Zika virus plus dengue antibodies cannot infect these cells. ADE in cultured cells has been reported by a number of groups; the first was discussed here when it appeared on bioRxiv.

The important question is whether antibodies to dengue virus enhance Zika virus disease in animals, and there the results are mixed. In one experiment, mice were injected with serum from people who had recovered from dengue virus infection, followed by challenge with Zika virus. These sera, which cause ADE of Zika virus in cultured cells, led to increased fever, viral loads, and death of mice.

These finding were not replicated in two independent studies conducted in rhesus macaques (paper one, paper two). In these experiments, the macaques were first infected with dengue virus, and shown to mount an antibody response to that virus. Over one year later the animals were infected with Zika virus (the long time interval was used because in humans dengue ADE is observed mainly with second infections 12 months or more after a primary infection). Both groups concluded that prior dengue virus immunity did not lead to more severe Zika virus disease.

Which animals are giving us the right answer, mice or monkeys? It should be noted that the mouse study utilized an immunodeficient strain lacking a key component of innate immunity. As the authors of paper one concluded, it’s probably not a good idea to use immune deficient mice to understand the pathogenesis of Zika virus infection of people.

When it comes to viral pathogenesis, we know that mice lie; but we also realize that monkeys exaggerate. Therefore we should be cautious in concluding from the studies on nonhuman primates that dengue virus antibodies do not enhance Zika virus pathogenesis.

The answer to the question of whether dengue antibodies cause Zika virus ADE will no doubt come from carefully designed epidemiological studies to determine if Zika virus pathogenesis differs depending on whether the host has been previously infected with dengue virus. Such studies have not yet been done*.

You might wonder about the significance of dengue virus antibodies enhancing infection of cells in culture with Zika virus. An answer is provided by the authors of paper one:

In vitro ADE assays using laboratory cell lines are notoriously promiscuoius and demonstrate no correlation with disease risk. For example, DENV-immune sera will enhance even the homotypic serotype responsible for a past infection in the serum is diluted to sub-neutralizing concentrations.

The conundrum of whether ADE is a contributor to Zika virus pathogeneis is an example of putting the cart before the horse. For dengue virus, we obtained clear evidence of ADE in people before experiments were done in animals. For Zika virus, we don’t have the epidemiological evidence in humans, and therefore interpreting the animals results are problematic.

*Update 8/12/17: A study has been published on Zika viremia and cytokine levels in patients previously infected with dengue virus. The authors find no evidence of ADE in patients with acute Zika virus infection who had previously been exposed to dengue virus. However the study might not have been sufficiently powered to detect ADE.

By David Tuller, DrPH

On November 17, 2015, a few weeks after publication of my 15,000-word investigation of the PACE trial, I posted a blog about a talk Peter White gave to Swiss Re employees on the findings from his bogus study. Professor White, of course, was the lead PACE investigator and also served–and apparently still serves–as “chief medical officer” for the insurance company.

Swiss Re has released information about its 2017 “insurance medicine summit,” to be held this coming November. Not surprisingly, Professor White is on the schedule. Although he has retired from his academic position, he apparently continues his work promoting his egregious research to insurers. His talk is called “Burn out, vital exhaustion and chronic fatigue syndrome: Old wine in new bottles?” Presumably he will once more be discussing the false PACE trial results and perhaps the campaign of “harassment” that he claims angry patients have waged against him.

It cannot be repeated often enough that the tribunal decision from last summer, which ordered the release of the raw trial data, dismissed the claims of harassment as baseless. The tribunal found that the only credible evidence of such behavior was that Professor Trudie Chalder was once heckled during a lecture. However, the tribunal’s scathing decision hasn’t prevented these dishonest researchers from continuing their disinformation campaign against the patient community.

Given Professor White’s ongoing role with the Swiss Re, I decided to repost the 2015 blog below. Shortly after I initially posted the blog, the insurance company removed from its website the article touting Professor White’s presentation. Therefore, in this version, I am linking instead to a screen-shot of the “disappeared” page. (Thanks, Anil van der Zee!)

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Trial by Error, Continued: PACE Team’s Work for Insurance Companies Is “Not Related” to PACE. Really?

By David Tuller, DrPH

In my initial story on Virology Blog, I charged the PACE investigators with violating the Declaration of Helsinki, developed in the 1950s by the World Medical Association to protect human research subjects. The declaration mandates that scientists disclose “institutional affiliations” and “any possible conflicts of interest” to prospective trial participants as part of the process of obtaining informed consent.

The investigators promised in their protocol to adhere to this foundational human rights document, among other ethical codes. Despite this promise, they did not tell prospective participants about their financial and consulting links with insurance companies, including those in the disability sector. That ethical breach raises serious concerns about whether the “informed consent” they obtained from all 641 of their trial participants was truly “informed,” and therefore legitimate.

The PACE investigators do not agree that the lack of disclosure is an ethical breach. In their response to my Virology Blog story, they did not even mention the Declaration of Helsinki or explain why they violated it in seeking informed consent. Instead, they defended their actions by noting that they had disclosed their financial and consulting links in the published articles, and had informed participants about who funded the research–responses that did not address the central concern.

“I find their statement that they disclosed to The Lancet but not to potential subjects bemusing,” said Jon Merz, a professor of medical ethics at the University of Pennsylvania. “The issue is coming clean to all who would rely on their objectivity and fairness in conducting their science. Disclosure is the least we require of scientists, as it puts those who should be able to trust them on notice that they may be serving two masters.”

In their Virology Blog response, the PACE team also stated that no insurance companies were involved in the research, that only three of the 19 investigators “have done consultancy work at various times for insurance companies,” and that this work “was not related to the research.” The first statement was true, but direct involvement in a study is of course only one possible form of conflict of interest. The second statement was false. According to the PACE team’s conflict of interest disclosures in The Lancet, the actual number of researchers with insurance industry ties was four—along with the three principal investigators, physiotherapist Jessica Bavington acknowledged such links.

But here, I’ll focus on the third claim–that their consulting work “was not related to the research.” In particular, I’ll examine an online article posted by Swiss Re, a large reinsurance company. The article describes a “web-based discussion group” held with Peter White, the lead PACE investigator, and reveals some of the claims-assessing recommendations arising from that presentation. White included consulting work with Swiss Re in his Lancet disclosure.

The Lancet published the PACE results in February, 2011; the undated Swiss Re article was published sometime within the following year or so. The headline: “Managing claims for chronic fatigue the active way.” (Note that this headline uses “chronic fatigue” rather than “chronic fatigue syndrome,” although chronic fatigue is a symptom common to many illnesses and is quite distinct from the disease known as chronic fatigue syndrome. Understanding the difference between the two would likely be helpful in making decisions about insurance claims.)

The Swiss Re article noted that the illness “can be an emotive subject” and then focused on the implications of the PACE study for assessing insurance claims. It started with a summary account of the findings from the study, reporting that the “active rehabilitation” arms of cognitive behavioral therapy and graded exercise therapy “resulted in greater reduction of patients’ fatigue and larger improvement in physical functioning” than either adaptive pacing therapy or specialist medical care, the baseline condition. (The three intervention arms also received specialist medical care.)

The trial’s “key message,” declared the article, was that “pushing the limits in a therapeutic setting using well described treatment modalities is more effective in alleviating fatigue and dysfunction than staying within the limits imposed by the illness traditionally advocated by ‘pacing.’”

Added the article: “If a CFS patient does not gradually increase their activity, supported by an appropriate therapist, then their recovery will be slower. This seems a simple message but it is an important one as many believe that ‘pacing’ is the most beneficial treatment.”

This understanding of the PACE research—presumably based on information from Peter White’s web-based discussion—was wrong. Pacing is not and has never been a “treatment.” It is also not one of the “four most commonly used therapies,” as the newsletter article declared, since it has never been a “therapy” either. It is a self-help method practiced by many patients seeking the best way to manage their limited energy reserves.

The PACE investigators did not test pacing. Instead, the intervention they dubbed “adaptive pacing therapy” was an operationalized version of “pacing” developed specifically for the study. Many patients objected to the trial’s form of pacing as overly prescriptive, demanding and unlike the version they practiced on their own. Transforming an intuitive, self-directed approach into a “treatment” administered by a “therapist” was not a true test of whether the self-help approach is effective, they argued–with significant justification. Yet the Swiss Re article presented “adaptive pacing therapy” as if it were identical to “pacing.”

The Swiss Re article did not mention that the reported improvements from “active rehabilitation” were based on subjective outcomes and were not supported by the study’s objective data. Nor did it report any of the major flaws of the PACE study or offer any reasons to doubt the integrity of the findings.

The article next asked, “What can insurers and reinsurers do to assist the recovery and return to work of CFS claimants?” It then described the conclusions to be drawn from the discussion with White about the PACE trial—the “key takeaways for claims management.”

First, Swiss Re advised its employees, question the diagnosis, because “misdiagnosis is not uncommon.”

The second point was this: “It is likely that input will be required to change a claimant’s beliefs about his or her condition and the effectiveness of active rehabilitation…Funding for these CFS treatments is not expensive (in the UK, around £2,000) so insurers may well want to consider funding this for the right claimants.”

Translation: Patients who believe they have a medical disease are wrong, and they need to be persuaded that they are wrong and that they can get better with therapy. Insurers can avoid large payouts by covering the minimal costs of these treatments for patients vulnerable to such persuasion, given the right “input.”

Finally, the article warned that private therapists might not provide the kinds of “input” required to convince patients they were wrong. Instead of appropriately “active” approaches like cognitive behavior therapy and graded exercise therapy, these therapists might instead pursue treatments that could reinforce claimants’ misguided beliefs about being seriously ill, the article suggested.

“Check that private practitioners are delivering active rehabilitation therapies, such as those described in this article, as opposed to sick role adaptation,” the Swiss RE article advised. (The PACE investigators, drawing on the concept known as “the sick role” in medical sociology, have long expressed concern that advocacy groups enabled patients’ condition by bolstering their conviction that they suffered from a “medical disease,” as Michael Sharpe, another key PACE investigator, noted in a 2002 UNUMProvident report. This conviction encouraged patients to demand social benefits and health care resources rather than focus on improving through therapy, Sharpe wrote.)

Lastly, the Swiss Re article addressed “a final point specific to claims assessment.” A diagnosis of chronic fatigue syndrome, stated the article, provided an opportunity in some cases to apply a mental health exclusion, depending upon the wording of the policy. In contrast, a diagnosis of myalgic encephalomyelitis did not.

The World Health Organization’s International Classification for Diseases, or ICD, which clinicians and insurance companies use for coding purposes, categorizes myalgic encephalomyelitis as a neurological disorder that is synonymous with the terms “post-viral fatigue syndrome” and “chronic fatigue syndrome.” But the Swiss Re article stated that, according to the ICD, “chronic fatigue syndrome” can also “alternatively be defined as neurasthenia which is in the mental health chapter.”

The PACE investigators have repeatedly advanced this questionable idea. In the ICD’s mental health section, neurasthenia is defined as “a mental disorder characterized by chronic fatigue and concomitant physiologic symptoms,” but there is no mention of “chronic fatigue syndrome” as a discrete entity. The PACE investigators (and Swiss Re newsletter writers) believe that the neurasthenia entry encompasses the illness known as “chronic fatigue syndrome,” not just the common symptom of “chronic fatigue.”

This interpretation, however, appears to be at odds with an ICD rule that illnesses cannot be listed in two separate places—a rule confirmed in an e-mail from a WHO official to an advocate who had questioned the PACE investigators’ argument. “It is not permitted for the same condition to be classified to more than one rubric as this would mean that the individual categories and subcategories were no longer mutually exclusive,” wrote the official to Margaret Weston, the pseudonym for a longtime clinical manager in the U.K. National Health Service.

Presumably, after White disseminated the good news about the PACE results at the web-based discussion, Swiss Re’s claims managers felt better equipped to help ME/CFS claimants. And presumably that help included coverage for cognitive behavior therapy and graded exercise therapy so that claimants could receive the critical “input” they needed in order to recognize and accept that they didn’t have a medical disease after all.

In sum, contrary to the investigators’ argument in their response to Virology Blog, the PACE research and findings appear to be very much “related to” insurance industry consulting work. The claim that these relationships did not represent “possible conflicts of interest” and “institutional affiliations” requiring disclosure under the Declaration of Helsinki cannot be taken seriously.

Update 11/17/15 12:22 PM: I should have mentioned in the story that, in the PACE trial, participants in the cognitive behavior therapy and graded exercise therapy arms were no more likely to have increased their hours of employment than those in the other arms. In other words, there was no evidence for the claims presented in the Swiss Re article, based on Peter White’s presentation, that these treatments were any more effective in getting people back to work.

The PACE investigators published this employment data in a 2012 paper in PLoS One. It is unclear whether Peter White already knew these results at the time of his Swiss Re presentation on the PACE results.

Update 11/18/15 6:54 AM: I also forgot to mention in the story that the three principal PACE investigators did not respond to an e-mail seeking comment about their insurance industry work. Lancet editor Richard Horton also did not respond to an e-mail seeking comment.

From the Vector-Borne Viruses Symposium in Hamilton, Montana, Dickson and Vincent speak with Diane Griffin about her career and her work on understanding viral infections of the central nervous system.

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By David Tuller, DrPH

This week, the Journal of Health Psychology published a special issue containing a raft of commentaries on the PACE trial. Most of them slammed the study for its many, many unacceptable flaws. Not surprisingly, Sir Simon Wessely’s lackeys at the Science Media Centre immediately posted three comments from “experts” lauding the trial and criticizing the JHP commentaries. I thought it might be helpful to deconstruct these rather pathetic efforts at defending the indefensible.

I’ve posted all three statements below, followed by my comments. I decided to keep them relatively brief, although I could have gone on much longer.

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Prof. Malcolm Macleod, Professor of Neurology and Translational Neuroscience, University of Edinburgh, said:

“The PACE trial, while not perfect, provides far and away the best evidence for the effectiveness of any intervention for chronic fatigue; and certainly is more robust than any of the other research cited. Reading the criticisms, I was struck by how little actual meat there is in them; and wondered where some of the authors came from. In fact, one of them lists as an institution a research centre (Soerabaja Research Center) which only seems to exist as an affiliation on papers he wrote criticising the PACE trial.

“So I don’t think there is really a story here, apart from a group of authors, some of doubtful provenance, kicking up dust about a study which has a few minor wrinkles (as all do) but still provides information reliable enough to shape practice. If you substitute ‘CFS’ for ‘autism’ and ‘PACE trial’ for ‘vaccination’ you see a familiar pattern…”

Professor Macleod’s comments reflect a lack of understanding of both the illness itself and the fatal flaws of the PACE study. In his first sentence, he refers to “chronic fatigue.” As I and others have noted about 7 million times, “chronic fatigue” is a symptom of a great many illnesses; “chronic fatigue syndrome,” or “myalgic encephalomyelitis,” or ME/CFS or CFS/ME, or “systemic exertion intolerance disease,” is a specific disease entity.

Although there is still no universally accepted case definition, calling it “chronic fatigue” is a clear indication that Professor Macleod does not have a firm grasp on what he is talking about. The same could be said for the Science Media Centre’s failure to correct this phrasing. If they can’t even properly cite the illness in question, how can anything they claim about it be viewed as authoritative?

Professor Macleod does not engage in any substantive discussion about the criticisms outlined in the JHP commentaries. Instead, like other PACE defenders, he chooses to insult the authors. He notes that he “wondered where some of the authors came from” and suggests that some are of “doubtful provenance,” whatever that means. If he is still wondering who the commentary authors are, I can clue him in: They include experts from University College London, Northwestern University, DePaul University, the University of Hertfordshire, Victoria University of Wellington in New Zealand, UC Berkeley (that’s me), and the ME Association. Others are from patients and independent scholars who have proven themselves time and again to be expert researchers with more integrity and honesty than the entire cabal of PACE defenders.

Professor Macleod also states this about the rampant outcome-switching in PACE: “The main think (sic) is whether it was done without knowledge of the outcomes already accumulated in the trial and before data lock – which is what was done here.” This further demonstrates that he does not understand what happened in PACE. There are, in some cases, legitimate reasons to change outcome assessment methods in clinical trials. However, simply deciding mid-trial that you like other outcome methods better is not a legitimate reason—especially when every single change allows the researchers to report more impressive results.

Moreover, in an open label trial with subjective outcomes like PACE, investigators should have a pretty good idea which way things are trending before seeing the actual results. It is specious to assume that the PACE investigators were “without knowledge of the outcomes already accumulated”—they could have easily known things were not going well and relaxed all their outcome measures as a result.

Furthermore, while they obtained oversight committee approval for changing the primary outcome in the 2011 Lancet paper, they apparently received no approval for their overhaul of the definition of “recovery”—at least, no such approval is cited in the 2013 Psychological Medicine paper. And two of the four “recovery” criteria—the physical function and fatigue outcomes—were from post-hoc analyses, so they were obviously not generated before “data lock.” Professor Macleod does not mention this issue; like the PACE authors themselves, he would prefer to ignore the embarrassing fact that 13% of participants were already “recovered” for physical function at baseline.

Finally, it is rich that he brings up the analogy of anti-vaccination campaigners. Given that it was The Lancet that dramatically spurred that movement with its publication of the now-discredited 1998 Andrew Wakefield paper linking autism to vaccines, Professor Macleod’s statement just makes him appear clueless about The Lancet’s egregious behavior in both cases. I hope someone lets him know, sooner rather than later, that he has made a fool of himself.

Lancet editor Richard Horton vigorously defended the Wakefield study for years, just as he has defended PACE. And just as The Lancet finally retracted that paper, it will ultimately have to retract PACE as well.

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Dr Neha Issar-Brown, Programme Manager, Population and Systems Medicine at the Medical Research Council (co-funders, along with the National Institute for Health Research, of the PACE trial), said: 

“The Medical Research Council funded and supported the PACE trial after subjecting the research proposal to a robust peer-review process involving experts in the field, as is the case with all our funding decisions.  This included ensuring adherence to standardised trials methodology and design principles. The researchers’ findings were then peer-reviewed before publication in journals. All research evolves by continually re-evaluating existing evidence and looking for new knowledge and we would always welcome high-quality research applications to better understand the underlying disease mechanisms, causes, prevention and treatments for this extremely debilitating condition.”

This statement from the Medical Research Council is not in fact a defense of PACE or a response to any of the criticisms. It is simply a statement of the MRC’s role and an explanation of the process of publication. Yet it is simply false that the PACE trial was conducted according to “standardised trial methodology and design principles,” as the commentaries make abundantly clear. Repeating this claim without engaging critics does not alter the facts.

Moreover, the published studies are so full of flaws that it is absurd to cite the fact that they were peer-reviewed as evidence of their validity and reliability. Any study in which participants could meet outcome thresholds at baseline—and that includes both the 2011 and 2013 papers—should obviously never have passed peer review. What we know about The Lancet publication, in particular, is that the paper went through “endless rounds of peer review,” per editor Horton’s words, yet was simultaneously fast-tracked to publication. Despite my many efforts to extract an explanation from Dr. Horton, he has never bothered to explain how many “endless rounds of peer review” it is possible to complete during a fast-track peer review process.

**********

A spokesperson for University of Oxford said:

“Oxford University considers Professor Sharpe and his colleagues to be highly reputable scientists whose sole aim has been to improve quality of life for patients with ME/CFS. While scientific research should always be open to challenge and debate, this does not justify the unwarranted attacks on professionalism and personal integrity which the PACE trial team have been subjected to.”

Finally, this statement from Oxford’s unnamed “spokesman” is just a jumble of public relations nonsense. It is always suspicious when an institution declines to put a name to a statement—it often means no individual is willing to take responsibility for what is being said. In the case of this utterly vacuous statement, it makes sense that smart communications professionals would not want to have it attributed to them.

Let’s take this paragraph in particular: “The allegation that criteria for patient improvement and recovery were changed to increase the reported benefit of some treatments is completely unfounded. As the study authors have repeatedly made clear, the criteria were changed on expert advice and with oversight committee approvals before any of the outcome data was analysed.”

The claim that the PACE investigators obtained “oversight committee approvals” for the wholesale redefinition of “recovery” is a lie. They did not obtain any committee approvals for this; at least, that’s the only conclusion that can be drawn from the fact that no such approvals were mentioned in the Psychological Medicine paper. It is perplexing to see an official statement from Oxford—presumably vetted by Professor Sharpe and the SMC (or perhaps not)—contain such a blatantly false claim.

Moreover, it is silly to argue that boosting outcomes was not the aim of the PACE investigators. Obviously, it was. The PACE investigators themselves have argued repeatedly that they relaxed outcome measures, particularly for “recovery,” because they decided mid-trial that the original measures were too stringent. So they clearly knew that the changes they made would improve the reported findings. In that sense, it doesn’t really matter whether they examined the data beforehand; if you make it easier to meet outcome measures by lowering your standards, then you obviously know you will achieve better results.

So this Oxford statement is laughable. If these are the best defenses the Science Media Centre can concoct at this stage of the controversy, then PACE is really in big, big trouble.

By David Tuller, DrPH

The National Institute for Health and Care Excellence, the U.K. organization that develops clinical guidelines for medical conditions, has rejected my freedom-of-information request for the names of the experts involved in the reassessment of the guidance for the illness it calls CFS/ME. This isn’t surprising, since the agency also recently rejected similar requests from the Countess of Mar and the ME Association. However, NICE’s response to the FOI request, which I received on Friday, contains some useful information and clarifies the decision-making process. I have included the NICE response below, but here are some key observations.

The 2007 guidance, called CG53, endorsed cognitive behavior therapy and graded exercise therapy as the treatments of choice. According to the FOI response, the surveillance team that drew up the recently published “consultation document,” which recommends no change in this guidance, includes four NICE staffers: a technical analyst, a technical adviser, a clinical adviser and an associate director. In developing their proposal, they consulted with seven “topic experts”–three psychiatrists, two neurologists, a pediatrician and a patient representative. The surveillance team’s provisional decision to leave the guidance as is triggered this month’s two-week period for receiving comments from stakeholders. The final call will now be made by a group of eight top NICE employees, collectively called the “guidance executive.” Among the eight are Sir Andrew Dillon, NICE’s chief executive; Mark Baker, director of the Centre for Clinical Practice; and communications director Jane Gizbert.

According to the FOI response, four of the topic experts consulted were members of the committee that developed the guidance in 2007. That list included Professor Esther Crawley of Bristol University, who could presumably be the pediatrician among the topic experts. (For those who have not followed this saga closely, Professor Crawley falsely accused me of libeling her in two high-profile lectures this year—her inaugural address at her own institution and a talk to the British Renal Society. Despite my multiple efforts to extract an explanation from her, she has failed to provide any documentation for this ridiculous allegation.)

It is inappropriate and unsatisfactory that psychiatrists were the largest group represented among the topic experts. Apparently NICE still fails to recognize that the disease in question is most emphatically not a psychiatric or psychological disorder; the agency apparently accepts without question the specious perspective of the cabal of U.K. psychiatrists, psychologists and others who have hijacked the debate for the last three decades. The 2015 reports from the U.S. National Institutes of Health and the Institute of Medicine (now the National Academy of Medicine) authoritatively documented that ME/CFS, as American government agencies now generally call the illness, is an actual organic disease and not a figment of patients’ fevered imaginations.

The PACE/CBT/GET counter-narrative—that deconditioning alone accounts for the perpetuation of the symptoms, and that patients harbor “unhelpful beliefs” about having a medical condition—is not grounded in legitimate scientific research. Despite the desperate attempts by the PACE investigators to defend their pet theoretical framework, it is now clear to the international scientific community that the study’s reported findings in The Lancet (2011) and Psychological Medicine (2013) were wildly inflated—the result of rampant outcome-switching and other egregious methodological lapses.

In addition to PACE and other Oxford criteria studies, the NICE document cites the Cochrane reviews of CBT and GET in support of its conclusion. First of all, Cochrane includes the illness it calls CFS in its mental health disorders section, which immediately raises questions about the organization’s biased perspective. Moreover, given the inclusion of PACE and other studies using overly broad case definitions in the Cochrane analyses, the NICE consultation document is seriously misguided to cite these reviews as reliable evidence. After all, the Cochrane analyses cannot be legitimate and accurate when the studies they include are not. (I plan to take on Cochrane in an upcoming post.)

Both CBT and GET involve telling patients that these approaches will help them get better—an obvious method of biasing the results, especially given that the study was not blinded. The treatments appear to provide modest boosts in subjective measures but no long-term benefits over other treatment or management approaches. Neither PACE nor other studies from this group of researchers have documented objective improvements to match these subjective results; indeed, objective measures have consistently failed to support the claims of improvement and recovery. The significance of these salient facts appears lost on the NICE surveillance review team, which apparently suffers from the same “dysfunctional cognitions” as the PACE investigators about the efficacy of their strategy.

In normal circumstances, it might be appropriate to include committee members who worked on previous guidance as topic experts in the review process. But these are not normal circumstances. With this illness, relying on these committee members is a bad move. It stands to reason that those who developed the utterly inadequate and potentially dangerous 2007 guidance would be unwilling to challenge their own past perspective that GET and CBT are effective. This is especially true given that the PACE authors and other adherents of the biopsychosocial approach have consistently demonstrated their unwillingness to accept any criticism that challenges their viewpoint. They refuse to acknowledge, for example, that any study in which participants can meet outcome thresholds at baseline, before any treatment at all, has no place in the scientific literature, as many dozens of well-known experts have made clear in open letters to The Lancet and Psychological Medicine.

In Professor Crawley’s case, her research on the prevalence of the illness among children consistently conflates the symptom of “chronic fatigue” with “chronic fatigue syndrome.” This conflation serves to dramatically inflate the numbers of those purported to be afflicted. Her work, such as her proposal for the FITNET-NHS study of online CBT for kids, also misrepresents the NICE guidance that she herself was involved in developing, in ways that appear to render post-exertional malaise as an optional symptom rather than a required one. When called to account for these distortions, she chooses to insult her critics rather than provide satisfactory explanations of her flawed methodological choices. It is therefore highly troubling that the NICE consultation document cites FITNET-NHS as important new research that will inform future guidance.

The NICE response to my FOI request indicates that the agency reached out to the topic experts seeking their opinions on being identified. Three of them expressed concerns about having their names made public; a fourth could not be reached. The response does not indicate the answer, if any, from the remaining three; perhaps they didn’t object at all. Nevertheless, based on the responses from the three who objected, NICE has decided to keep all the names secret.

According to the NICE response, here’s why the three topic experts objected: “Reasons given include their experience, and that of other experts in the field, of being connected with this topic area. These included concerns about personal harassment, previous abuse and threats they have been subjected to when involved in work on this topic.”

It needs to be stated clearly that the PACE authors have routinely wielded this overhyped claim as a way of discrediting critics. However, the tribunal decision last summer that ordered Queen Mary University of London to release the raw trial data dismissed the claims as unfounded. The tribunal decision noted pointedly that the only reliable evidence presented to the court about such behavior involved an incident in which Professor Trudie Chalder, one of the three main PACE investigators, was heckled at a lecture. Professor Chalder herself acknowledged in her testimony at the tribunal that none of the investigators had received death threats, despite their habit of hyperventilating about the issue of abuse from patients. As has been previously documented, the wave of news stories about these purported death threats was a public relations stunt organized by the Science Media Centre.

So have some CBT/GET investigators received offensive e-mails or other communications that have upset them? I have no reason to doubt it. Perhaps some of these messages have even contained what could be construed as threats. But Professor Crawley and her colleagues have routinely deflected attention from the defects of their research by wrapping themselves in martyrdom, complaining vociferously that even the filing of freedom-of-information requests constitutes harassment—a preposterous argument, given that patients have a legal right to seek key information about publicly funded trials. And these researchers also frame accurate criticism as vexatious and illegitimate. That’s what Professor Crawley did earlier this year when she accused me of “libelous blogging” in a slide shown during her two speeches.

So despite its claims of valuing an open and transparent process, NICE is allowing the topic experts involved—including four whose names are already public as part of the 2007 guidance committee–to cloak themselves in anonymity. That is not acceptable. Given the enormous importance of this reassessment of CG53 and the huge public interest in understanding how the decisions are being made, NICE should reconsider this rejection of my request.

I am appealing to the agency to overturn its initial decision. Following the agency’s expected rejection of my appeal, I will then appeal to the Information Commissioner’s Office. Whatever the ultimate outcome of my request, the FOI response suggests that it is critical that the members of the guidance executive recognize that a pro forma ratification of the 2007 guidance will be a public relations disaster. More than 15,000 people signed the ME Association petition protesting the NICE provisional decision; that’s a lot of very, very unhappy patients. With PACE now exposed as a dishonest and even fraudulent piece of research, the ground in the debate has shifted. It is no longer time for business as usual.

**********

Here is the substantive part of the NICE response to my FOI request:

Thank you for your request for information under the Freedom of Information Act (FOIA), received at this office on 07 July 2017. You requested the following information about the review of the CFS/ME guideline (CG53):
 
1.       The number of people on the expert panel who will review input from stakeholders
2.       The number, if any, of these people who are the same as those who were on the panel that developed the 2007 guidelines
3.       The names of the people on the expert panel reviewing the CFS/ME guidelines, those currently serving and those who have served in the past year.
 
Background

There is no expert panel which reviews input from stakeholders in our review process. You can read more about how we check that published guidelines are current and accurate in our guidelines manual.
 
For this review we followed the process for the 4 and 8 year checks. It includes extensive searches to identify any new primary and secondary studies, including any economic studies. The focus is on the scope of the published guideline, but any additional areas or changes in practice that are identified are also considered if they fall within the referral of the published guideline. A literature search is conducted across a range of sources. These may vary from topic to topic. They are selected according to their relevance to the topic and are based on those used in the published guideline.
 
Topic experts and members of the original guideline committee are asked for their opinion, in their personal capacity, on the relevance of the published guideline, recent developments in the topic area and their knowledge of any new important evidence since publication of the guideline. Guideline committees are responsible for the recommendations made and we publish the membership of them. We do not routinely publish the identities of topic experts because while they may express an opinion they are not part of the decision making body. 
 
NICE’s surveillance review team summarises the relevant evidence and highlights any studies that may have an important impact on our recommendations. The main themes of new, relevant evidence across the guideline are also summarised, along with any other identified information (such as changes in licensing indications for a medicine or updated national policy). The surveillance team is made up of NICE employees – a Technical Analyst, Technical Adviser, Clinical Adviser and Associate Director.
 
The information identified as part of the surveillance review forms the basis of a review proposal for NICE’s Guidance Executive. In this case the review proposal was a public consultation document. When the information summarised in the review indicates that a ‘no update’ decision should be considered there is a 2‑week consultation with stakeholders who are registered for the published guideline.
 
The final decision about whether an update is need is based on a balanced assessment of new relevant evidence published since guideline publication, the views of the topic experts, feedback during consultation and other sources of information on the continued relevance of the guideline. The findings of the check on the need for an update are discussed with topic experts. All proposals go through an internal validation process (including sign‑off by the Associate Director and Director) before submission to NICE’s Guidance Executive. It is Guidance Executive that takes the decision to update the guideline or not.
 
Response to your request under the FOIA

Given the background above, in responding to your request, I have assumed that by ‘expert panel’ you mean the topic experts who were asked for their opinion on the relevance of the published guideline.
 
1.       The number of people on the expert panel who will review input from stakeholders.
Seven topic experts were asked for their opinion on the relevance of the published guideline.
 
2.       The number, if any, of these people who are the same as those who were on the panel that developed the 2007 guidelines.
Four of these people were also members of the original guideline committee.
 
3.       The names of the people on the expert panel reviewing the CFS/ME guidelines, those currently serving and those who have served in the past year.
We hold the names of the topic experts who were asked for their opinion on the relevance of the published guideline. For your information the topic experts are from the following fields: neurology (2), psychiatry (3), paediatrics (1), patient representative (1). However, we consider that the names are exempt from disclosure under 2 sections of the FOIA. We explain these exemptions and why we have applied them below.
 
Section 40 – personal information

Section 40 provides an exemption from the right to know where the information requested is personal data protected by the Data Protection Act. Personal data is data that relates to a living individual who can be identified from that data. The names of these individuals is clearly personal data.
 
Under section 40(2) we are withholding the names of the topic experts because we consider that to release it would contravene the principles of the Data Protection Act. In reaching this decision we considered whether disclosure would be fair to the individuals concerned, the consequences of disclosure, the reasonable expectations of the individuals and any legitimate public interest in disclosing the information.
 
NICE does not routinely publish the names of topic experts who contribute to the review process therefore the individuals had no expectation that this information would be made public. We wrote to the topic experts to ask them if they had any objections to their identities being disclosed to the public, and if so, what those objections were. Three of them were strongly opposed to their identities being made public in this context and one could not be contacted within the time available.
 
Reasons given include their experience, and that of other experts in the field, of being connected with this topic area. These included concerns about personal harassment, previous abuse and threats they have been subjected to when involved in work on this topic. We were sent a link to a news story from the Guardian describing threats and abuse directed at researchers and professionals in this field.
 
NICE is also concerned that disclosing the identities of the topic experts would have a significant impact on our ability to get experts to contribute to our work on this topic in the future. This point was supported by Mr Justice Simon in the judicial review that followed the publication of the original guideline. While Mr Simon was referring to guideline committee members in his judgement we consider that the impact would be the same if the identities of the topic experts asked for their opinion in the review process were made public.
 
When individuals are members of a guideline development group (also known as a guideline committee) their identities are publicly available on our website because the membership, as a whole, is responsible for the recommendations made. As described above, in the review process, the topic experts are asked for their opinion but the review decision is taken by NICE’s Guidance Executive whose membership is publicly available on our website.
 
As 3 of the topic experts expressed concerns over their identities being made public and 1 could not be contacted we consider that it would not be fair to make the remaining names public as this could have the effect of unreasonably focusing activity on these individuals. 
 
We recognise the public interest in ensuring public authorities remain transparent, accountable and open to scrutiny. We also recognise that disclosure would enable individuals to understand decisions made by public authorities in more detail, however on balance we do not consider the public interest in disclosure overrides the interest in maintaining these individuals’ privacy.
 
We therefore conclude it would not be fair to disclose the information under section 40(2) of the FOIA.
 
Section 38 – health and safety

Section 38 states that information is exempt from disclosure if its disclosure would, or would be likely to
(a)    endanger the physical or mental health of any individual, or
(b)   endanger the safety of any individual
 
The topic experts, and other experts in the same field, have specifically referenced threats and harassment they have been subject to in the past, as described above.
 
We have also considered if some of this information is already in the public domain because of the individuals previous work in this or other fields. As 4 of the topic experts were also on the guideline committee, their interest in this field is already in the public domain. However, in the context of the review, consultation and the campaigning activity around NICE’s proposal, we consider that releasing the information at this time would create a direct link between the experts and the review proposal and would raise their profile. Therefore disclosure at this time is likely to increase the risk that these individuals would be targeted and that this could lead to additional harm.
 
Mr Justice Simon also referenced unfounded allegations made against guideline committee members and his judgement stated that ‘unfounded as they were, the allegations were damaging to those against whom they were made; and were such as may cause health professionals to hesitate before they involve themselves in this area of medicine. A perception that this is an area of medicine where contrary views are not to be voiced, and where scientific enquiry is to be limited, is damaging to science and harmful to patients.’
 
Given the volume and nature of the correspondence (enquiries, petitions, letters, activity on message boards, Freedom of Information requests) we have received to date we are concerned that the experts may be targeted individually by any campaign and that such activity would impact on experts’ wellbeing and on their and others’ willingness to contribute to the work of NICE in the future, especially when they are not part of the decision making body.
 
We can’t be certain that the release of the withheld information would put the individuals at risk but we consider that there is sufficient evidence to conclude that they would be singled out for harassment, intimidation and possibly threats of violence. 
 
This exemption is subject to the public interest test. We accept that there is significant public interest in being accountable and transparent for the decisions we take and for individuals under understand how we make our decisions. However, NICE also has a duty to protect the physical and mental wellbeing of the individuals concerned.
 
In this case the makeup of the decision making body, Guidance Executive, is already in the public domain. The review proposal is also publicly available and contains comprehensive discussion of the evidence including the feedback from the topic experts.
 
NICE operates openly and transparently. All of our guidance development processes are published in detail on the website. We believe the process and information on which the proposal is based is publicly available and subject to consultation. We consider that those with an interest in this guideline have sufficient information to be able to understand both the process and consideration of the evidence.
 
Given the concerns raised by the individuals and other evidence of previous incidents of experts in this field being targeted for harassment, including threats of violence, in the past we conclude that the public interest in disclosing the information does not outweigh the interest in maintaining the exemption in light of the likely risks to the health and safety of the individuals.
 
We therefore conclude it would not be fair to disclose the information under section 38 of the FOIA.

Lynda Coughlan joins the weekly virtual bus companions for a discussion of a host defense peptide from frogs that destroys influenza virus, and mouse models for acute and chronic hepacivirus infection.

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Frogs don’t get flu (as far as I know) but their skin contains a peptide that inhibits the replication of influenza virus (link to paper).

Frog skin contains host defense peptides (HDPs), part of the innate immune defenses of many species. They were first found in amphibians by Michael Zasloff, who, as part of his research, performed surgery on frogs and then returned them to an aquarium – which was not sterile. He wondered why the frogs always healed without signs of infection, which lead him to discover the antimicrobial peptides, called magainins, in frog skin. HDPs had been first discovered years earlier in the silk moth.

Amphibian HDPs are active against bacteria, fungi, viruses, and protozoa. To discover HDPs that inhibit influenza virus, 32 HDPs from skin secretions of the Indian frog Hydrophylax bahuvistara were screened by mixing them with virus followed by a plaque assay. One peptide was found to potently inhibit influenza virus replication without cell toxicity. It was called urumin, after the whip sword known as urumi.

Urumin inhibits infectivity of influenza H1N1 viruses far better than H3N2 viruses. The reason is that the peptide targets the viral H1 hemagglutinin, one of two glycoproteins in the viral envelope. Furthermore, the peptide appears to interact with the conserved stalk region of the HA glycoprotein, and not with the globular head.

Currently two different antiviral drugs, oseltamivir and relenza, are used to control influenza virus infection. Viruses resistant to these drugs were still inhibited by urumin, indicating that should urumin ever be licensed, it would be useful in the event that oseltamivir and relenza resistant viruses became more common.

Examination of urumin treated virus particles by electron microscopy revealed that they are disrupted by the peptide. How urumin breaks influenza virus particles is not known. However, the HDP nisin destroys bacteria by first binding to a bacterial membrane component, then moving into the membrane. After binding to HA, urumin might in a simlar way disrupt the membrane of influenza virus particles.

Urumin also reduced disease, death, and the amount of virus in the lung in mice intranasally infected with influenza virus.

These observations suggest that urumin is worthy of additional study as an influenza virus inhibitor. HDPs are attractive antimicrobial compounds because resistance to their mechanisms of action is lower than for other types of inhibitors. However, enthusiasm for urumin is dampened because, despite extensive study, no HDP has yet been approved by the US Food and Drug Administration for use in humans. The obstacles to therapeutic success of HDPs have not been identified.