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By David Tuller, DrPH

Leonard Jason, a professor of psychology at DePaul University in Chicago, is a recognized expert in research on the prevalence of and case definitions for the illness (or cluster of illnesses) variously referred to as myalgic encephalomyelitis, chronic fatigue syndrome, ME/CFS, CFS/ME and other names. I posted an interview with him on case definition a couple of years ago.

Professor Jason recently co-led a study called “The prevalence of pediatric myalgic encephalomyelitis/chronic fatigue syndrome in a community-based sample.” The study–the most rigorous of its kind–was published last month by the journal Child & Youth Care Forum. I asked him why he thought the study was needed. Here’s what he said:

I did the study because most prior pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination.

The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample. The results are clear cut–using physicians or health care workers to identify youth with ME/CFS will result in under-diagnosis of this illness. In other words, many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness, and ultimately to find ways to treat those with this illness, most of which have not been diagonosed.

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Simon McGrath, who covers scientific issues on his invaluable blog, ME/CFS Research Review, has written about this new study. I am reposting his excellent blog below, with his permission:

Leonard Jason research finds that many young people have ME/CFS (by Simon McGrath)

How do you find out how common an illness is when it is hard to diagnose, most doctors know little about it and many of them dismiss it as trivial? ME/CFS just is such an illness. Asking doctors to report the number of people they have diagnosed is likely to miss many real cases and studies using this method concluded that ME/CFS is rare. A better approach, used by a new study, is to screen large numbers of people in the community to find those that might have the illness, then give those people a thorough medical workup to establish who actually has it.

Professor Leonard Jason and Dr Ben Katz led the new study and they estimated that 0.75% of young people aged 5 to 17 have ME/CFS, roughly one in every 130. The estimate isn’t exact, and the study authors say the figure could be as low as 0.54% and as high as 0.96%. Even using the low estimate would mean 290,000 in the US have the illness, along with 55,000 in the UK. Which suggests that ME/CFS is far from rare and is ruining a lot of young lives.

The 0.75% estimate is significantly higher than most generally-accepted estimates for adults. The CDC estimated 0.24% of adults had ME/CFS and Jason estimated 0.42%, both using a community screening approach similar to that used in the new study. ME/CFS affects a lot of adults but it appears to be an even more common problem for children. “The most important thing for children is to be accepted by their peers and if you don’t have the energy to socialize and do things with them and develop those friendships, that is a real obstacle,” Professor Jason told the Chicago Tribune

Worryingly, the study also found that only 1 in 20 of the young people they diagnosed with ME/CFS already had a diagnosis. Though perhaps this is not so surprising, given that other studies in the US have found that only 10% to 15% of adults who have ME/CFS actually have a diagnosis.

ME/CFS is more common in older and non-white under 18s

This study collected data from 10,000 young people with diverse ethnic backgrounds and was able to estimate how common ME/CFS is in people with different ethnicity. It found that the illness was significantly more common among African American (1.1% prevalence) and Hispanic (1.3%) young people than among whites (0.63%).

ME/CFS also becomes increasingly common as children move into adolescence, as the graph below shows.

Graph of prevalence by age (0.15% age 5-9 to 1.25% age 15-17)
Percentage of each age group with ME/CFS

The authors suggested the changes with age could be due to the hormonal and psychological changes of adolescence. It could, they say, also be due to children being exposed to more environmental and biological factors as they get older. One factor in the increase is likely to be glandular fever (infectious mononucleosis), which leads to ME/CFS for about one person in ten. Glandular fever becomes more common in adolescence because the virus that triggers it is spread by kissing.

How the study worked

The study had two phases. In the community screening phase, the study used trained volunteers to call 137,000 telephone numbers in greater Chicago. These calls identified 23,000 households with children between the ages of five and 17. Just under a quarter of these households, 5,600 (24%), agreed to take part in the screening questionnaire, which collected information on 10,000 children.

The screen of 10,000 children identified 295 who might have ME/CFS, because they had fatigue or school/learning/memory problems, significantly reduced ability to function, and particular symptoms. They also didn’t have any illnesses such as multiple sclerosis that would rule out a diagnosis of ME/CFS.

A telephone screen identified possible cases of ME/CFS. These were invited to a clinic for expert medical assessment, and diagnosis where appropriate.

In the second, diagnostic phase, researchers invited all 295 children and teenagers to attend a clinic in Chicago for a full medical evaluation. This involved questionnaires screening for psychological problems, measuring ME/CFS symptoms and assessing fatigue, as well as blood tests and a physical examination by Dr Ben Katz, one of the leading US children’s physicians specializing in ME/CFS.

A team of physicians made the final decision about who had ME/CFS after reviewing each patient’s information. To get a diagnosis, every patient also had to meet three case definitions (for the geeks: IOM, Fukuda and Canadian consensus criteria).

The researchers assessed 165 and concluded that 42 of them had ME/CFS. Only two of the 42 already had a diagnosis of the illness. The 42 cases computes to an ME/CFS prevalence of 0.75%.

Low response to telephone survey introduces uncertainty

A limitation of the study, mentioned by the authors in their paper, is the low response rate to the telephone screen. This is a general trend: people are increasingly unwilling to take part in telephone surveys. It is possible that the relatively small proportion of people who did take part are not a representative sample, and if that were the case it would affect the accuracy of the prevalence estimate.

The calculation of 0.75% prevalence assumes that those who do respond to studies like this are much the same as the ones who don’t. That assumption might not hold true when most people don’t respond. As the authors say in their paper, this has become a real problem for telephone surveys, including their own.

Back in the 1990s, Jason ran an adult prevalence study with a similar design. Two-thirds of the households they contacted not only answered the phone but went on to complete the screening questionnaire. In this new study, of the minority who answered the phone (and who had children the right age) only a quarter were willing to complete the screening questionnaire.

Jason and colleagues pointed out that the young people they diagnosed had family incomes significantly higher than average for Chicago. Rather than a higher family income makes a child more likely to develop ME/CFS, the authors believe that such families might be more willing to participate in the study or to be more able to take the time to attend the clinic for the assessment.

There could, some patients suggest, be a similar but bigger problem where families who have a child with fatigue are more willing to take part in the screening phone call than families who don’t. This would place a disproportionate number of fatigued people in the study, which would produce a prevalence figure for ME/CFS that is too high. But we don’t know if this has happened to a significant extent.

A strong study design

Despite the problems of the low response rate, this NIH funded research uses a strong design and is the best study yet on prevalence in young people.

In fact, the findings of the new study are backed up by an earlier study run by Professor Esther Crawley. Her team used a slightly different approach, screening all children who had missed more than 20% of school in a six week period, and found a prevalence of 1%. Even allowing for differences in method between the two studies, the results are pretty similar. [Virology Blog: Of course, this is the study in which Professor Crawley interviewed many dozens of minors and their family members without ethical review, based on the false claim that the study constituted “service evaluation” and was therefore exempt from such oversight.]

The relatively high rate of ME/CFS in young people found by the study equates to hundreds of thousands of people living with the illness. The vast majority of them probably have no diagnosis. ME/CFS is a serious condition, is the biggest cause of long-term school absence and takes a huge toll on young lives. We know next to nothing about the causes of ME/CFS and there are no effective treatments. Only serious levels of investment in research can put this right.

By David Tuller, DrPH

I have been trying to find out why Mahana Therapeutics, a San Francisco-based start-up, has chosen to disseminate misleading information about a web-based cognitive behavior therapy program for people with irritable bowel syndrome. Because Mahana’s co-founder and CEO, Rob Paull, has not responded to my letters, I have contacted some of those listed as science advisors on the company’s website.

Earlier this month, I sent one such letter to Dr Mel Heyman, a pediatric gastroenterologist at University of California, San Francisco–one of Berkeley’s sister UC campuses. I received an automatic e-mail response that Dr Heyman was out of the office for a period of time. Last week, after his stated return date, I sent another letter:

Dear Dr Heyman–

I know you have been away and undoubtedly have many matters to attend to. I wanted to re-send the message I sent a couple of weeks ago about Mahana Therapeutics, given your role as one of the company’s gastroenterology advisor.

As I have noted in multiple posts on the science site Virology Blog, the changes in symptom severity reported for Mahana’s web-based cognitive behavior therapy program for irritable bowel syndrome cannot reasonably be described as “substantial,” “durable,” “dramatic,” and “potentially game-changing.” Yet that is how Mahana has described them in a press release and on its website.

I have so far received no response from my multiple attempts to reach the company itself, which is why I am reaching out to you and others serving as scientific advisors. I look forward to hearing from you. (I have once again cc’d Vincent Racaniello, a Columbia professor of microbiology and host of Virology Blog.)

Thanks much!

Best–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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BerkeleyWellness.com is a popular consumer health website whose content is vetted and approved by experts from the university. Last year, the site posted my interview with Dr Steve Olson, the Kaiser Permanente doctor who spearheaded the medical organization’s efforts to switch gears on its approach to the illness (or cluster of illnesses) variously referred to as myalgic encephalomyelitis, chronic fatigue syndrome, ME/CFS, and CFS/ME, among other terms. It also featured my interview with journalist Maya Dusenberry, the author of Doing Harm: The Truth About How Bad Medicine and Lazy Science Leave Women Dismissed, Misdiagnosed, and Sick.

Last week, BerkeleyWellness.com published a short article about the UK study at the root of the inflated claims that CBT is an effective treatment for IBS symptoms. The piece was blunt about the limitations of the findings. Here is the text:

Irritable bowel syndrome (IBS) is a common gastrointestinal condition characterized by cramping, bloating, gas, and diarrhea or constipation. It likely has multiple causes, and many patients continue to suffer despite taking medication. Cognitive behavioral therapy (CBT) has sometimes been recommended as a treatment based on the notion that it can help patients reduce stress, change their eating patterns, and modify how they think about the illness. But now the largest study to date of CBT for IBS has shown that it has little impact in reducing symptom severity.

The UK study, conducted by investigators at King’s College London and the University of Southampton, included 558 people with unresolved IBS. Participants were randomly assigned to receive telephone-delivered CBT, web-based CBT, or no intervention. All three groups continued to receive their usual medical treatment. The study did not test in-person CBT. The 12-month and 24-month results were published in 2019 in, respectively, the journals Gut and Lancet Gastroenterology & Hepatology.

At 12 months, those in both CBT groups reported a statistically significant reduction on the standard scale for assessing IBS symptoms. However, the average benefit for telephone-delivered CBT over treatment-as-usual was only slightly above the threshold considered clinically significant. At 24 months, the average benefit in this group was no longer clinically significant.

For the web-based group, the average benefit at 12 months was already below the critical threshold for clinical significance. At 24 months, the average benefit was neither clinically significant nor statistically significant.

Both groups reported modest benefits in other domains, such as social adjustment and depression—not surprising after a course of CBT. Given the weak results for reductions in symptom severity, however, these reported improvements likely have little or nothing to do with treating the illness itself.

Moreover, this was an unblinded trial relying solely on self-reported rather than objective outcomes. Since this kind of study design is likely to generate an unknown amount of bias, any positive findings should be taken with caution.

The TWiV team returns this week to SARS-CoV-2019 coverage to review the latest epi curves, the fatality rate, furin cleavage site and receptor binding domain in the spike glycoprotein, related CoV recovered from pangolins, evidence that the virus did not escape from a laboratory, and many more questions sent in by listeners.

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coronavirus SpikeA coronavirus related to SARS-CoV-2 has been isolated from Malayan pangolins illegally imported into Guangdong province. It is not the precursor of SARS-CoV-2, but comparison of viral genome sequences provides further evidence that the virus currently infecting humans was not produced in a laboratory.

There are two important sequences in the viral spike glycoprotein (pictured) that are important for tracing the origin of SARS-CoV-2: a furin cleavage site (discussed last week) and the receptor binding domain (RBD).

The results of experiments in cells in culture have shown that the SARS-CoV-2 spike glycoprotein binds the cell receptor ACE2. Six amino acids in the RBD are critical for binding to this receptor. Five of these six amino acids differ in the RBD of SARS-CoV-2 compared with sequence from the bat virus RaTG13, the most closely related virus. The SARS-CoV-2 spike glycoprotein binds ACE2 with high affinity, an outcome not predicted by computational analysis of the RBD sequence. If someone were to engineer an RBD into a bat SARS-like CoV to allow efficient infection of human cells, they would not use the amino acid sequence in the SARS-CoV-2 spike. Rather the specific sequence was likely selected during replication in cells with human-like ACE2.

As discussed previously, the furin cleavage site in the SARS-CoV-2 spike is not present in the bat virus RaTG13. Its acquisition could allow enhanced infection of human cells. In addition to the furin cleavage site, an extra proline is also present, a change predicted to lead to the addition of O-linked glycans in the vicinity. If someone were to engineer the furin cleavage site into the spike, it is not likely that the extra proline would have been included. Furthermore, the addition of such glycans typically occurs under immune selection.

The genome sequences of CoVs recently isolated from pangolins are not close enough to SARS-CoV-2 to have been its immediate progenitor. However, the RBD of these pangolin CoVs are identical to that of SARS-CoV-2 at 6 of 6 of the key amino acids discussed above. This observation indicates that passage of CoV in a host with human-like ACE2 could select for a RBD with high-affinity binding. Such passage could also select for insertion of the furin cleavage site, which is not present in pangolin CoVs. Once a virus with the appropriate RBD and furin cleavage site arose in an animal – a bat or intermediate host – it would then replicate once introduced into humans.

Another possibility is that viruses with the correct RBD have been repeatedly jumping into humans, but efficient human to human transmission was not established until the acquisition of the furin cleavage site. Such is the scenario with MERS-CoV, which has jumped multiple times from camels to humans, but each chain of infection is short and soon ends. The virus has never become established in humans because the required mutations have not entered the viral genome. Serological surveys specific for SARS-CoV-2 might test this hypothesis for its emergence.

Could laboratory passage of a bat SARS-like virus lead to isolation and accidental emergence of SARS-CoV-2? This scenario would require starting with a virus that is very close to the current isolates. Passage in cell culture might have selected for the RBD amino acid changes to enable high affinity ACE2 binding. However this virus would have had to be very similar to SARS-CoV-2, and no such isolate is known to be present in any laboratory. Selection of viruses with a furin cleavage site would likely have taken extensive passaging in cells. Finally, it is unlikely that the O-linked glycan addition site would have emerged without immune pressure, which is absent in cell cultures.

Proving or disproving any of these hypotheses for the emergence of SARS-CoV-2 might never be possible. Nevertheless, isolation of SARS-like viruses from a variety of animals might help to clarify the steps to emergence in humans. For MERS-CoV, a priority should be to prevent human infections, perhaps by immunizing camels, to avoid the emergence of another epidemic CoV with sustained transmission in humans.

By David Tuller, DrPH

When I was in Australia two years ago–wow, can’t believe it’s been that long!–I spent some time with Dr Mark Guthridge, an associate professor of biomedical science at Deakin University in Melbourne. Several years ago, after a bout of mononucleosis/glandular fever, he developed myalgic encephalomyelitis, which in Australia even patients and specialist doctors generally call chronic fatigue syndrome. (Actually, many or most actually say “chronic fatigue”–I kept trying to nudge people to at least use the word “syndrome,” but it was a pretty hopeless endeavor.)

[continue reading…]

By David Tuller, DrPH

Last week, I wrote to Rob Paull, the co-founder and CEO of Mahana Therapeutics, regarding the company’s misleading claims about the web-based cognitive behavior therapy program for irritable bowel syndrome it recently licensed from King’s College London. I have also written to Professor Rona Moss-Morris, the co-lead investigator of ACTIB, the study that road-tested the program, as well as three of Mahana’s prominent gastroenterology advisors.

[continue reading…]

coronavirus SpikeThe spike glycoprotein of the newly emerged SARS-CoV-2 contains a potential cleavage site for furin proteases. This observation has implications for the zoonotic origin of the virus and its epidemic spread in China.

The membrane of coronaviruses harbors a trimeric transmembrane spike (S) glycoprotein (pictured) which is essential for entry of virus particles into the cell. The S protein contains two functional domains: a receptor binding domain, and a second domain which contains sequences that mediate fusion of the viral and cell membranes. The S glycoprotein must be cleaved by cell proteases to enable exposure of the fusion sequences and hence is needed for cell entry.

[continue reading…]

By David Tuller, DrPH

Venture capitalist Robert Paull is listed on the Mahana Therapeutics website as the company’s co-founder and CEO. I have no idea how he got involved with this group of UK researchers and King’s College London. Given my own experiences, I would certainly have advised him against getting in bed with them, had he asked me–which he didn’t.

As it is, Mr Paull’s company has now licensed a product that generates minimal and transient reported benefits in reducing symptom severity in irritable bowel syndrome–yet is promoting the product based on its purported success in long-term reduction of symptom severity. I pointed out this dilemma in the letter I sent Mr Paull earlier today.

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Dear Mr Paull–

[continue reading…]

By David Tuller, DrPH

I’ll soon post a blog on why I’m spending so much time on this IBS issue when I’m supposed to be focused on ME (or CFS, ME/CFS, CFS/ME, or whatever term is being used to refer to this illness or cluster of related illnesses). In the meantime, here’s a copy of the letter I sent this morning to two more of Mahana Therapeutics gastroenterology advisors, after the one I sent to a UCSF guy last week. (I received an auto-response, which informed me that the doctor was currently out of town.)

This time I wrote to Dr Peter Lu and Dr Carlo di Lorenzo. Both are well-regarded gastroenterologists at Nationwide Children’s Hospital in Columbus, Ohio.  Mahana has more than a dozen gastroenterology and psychology advisors. I guess that means it is likely I will send additional letters while I continue to wait for answers.

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Subject line: Mahana Therapeutics unwarranted claims about web-based CBT for IBS

Dear Dr Lu and Dr Di Lorenzo–

[continue reading…]

By David Tuller, DrPH

Ten days ago, I sent a letter to Professor Rona Moss-Morris of King’s College London, seeking information about the licensing deal involving her web-based program of cognitive behavior therapy to treat irritable bowel syndrome. Since I have not heard back, this morning I made a second attempt to reach out to her and obtain some answers to my questions.

In both letters, I have made it clear that I would be happy to post any response she should send me on Virology Blog–at full length and without editorial interruption from me. I feel now I have done my due diligence in soliciting her input. I doubt I will reach out to her a third time–although I do not categorically exclude the possibility, depending on developments. (The subject line for my latest e-mail: “reaching out a second time about IBS, CBT and Mahana Therapeutics”)

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Dear Professor Moss-Morris— [continue reading…]