Paul Has Measles is a free children's book about viruses and vaccines available in 16 languages (link). Paul Stays Home is a free children's book about COVID-19 (link).

By David Tuller, DrPH

As post-covid syndrome has emerged as a major public health concern, so has the likelihood that members of the biopsychosocial ideological brigades will roll out their typical interventions for the “long-haulers”–patients suffering from profound exhaustion and other symptoms for many weeks and months after getting infected with the coronavirus. The situation has created an unforeseen dilemma for UK’s National Institute of Health and Care Excellence, which is currently in the process of revising its misguided 2007 guidance for what it then called chronic fatigue syndrome/myalgic encephalomyelitis and now calls ME/CFS.

The panel that created the 2007 document was dominated by cognitive behavior therapy and graded exercise therapy proponents, so those interventions ended up as core treatment recommendations. Three years ago, NICE conducted a perfunctory review and decided that the guidance did not need updating. An onslaught of negative public comment followed, along with the revelation (on Virology Blog, via a freedom of information request) that the expert review panel was remarkably free of diverse voices. NICE reversed itself and launched a full-scale revision process.

The new ME/CFS guidance was supposed to be issued later this year but the pandemic has understandably disrupted the schedule. It is now scheduled to be released next April. The stakes are high, and not just for the patient community. Careers have been built on touting the benefits of these interventions, despite the failures of trials like PACE and FINE and others of their ilk. If the new NICE guidance rejects this approach, it could have a huge negative impact on their reputations and their ability to obtain further funding to pursue wrong-headed ideas.

Before, no one besides patients and their advocates paid much attention to the anti-scientific nature of the claims being made by the PACE authors and their colleagues. But in recent years, international support for the CBT/GET paradigm has cratered, based on recognition of serious methodological and ethical lapses in major research–although support remains strong in the august halls of psychiatry and psychology departments at King’s College London, Oxford, Bristol and Bath. To the 100+ signers of the 2018 open letter to The Lancet requesting an independent investigation of the PACE trial, it is clear that some of these investigators–professorships notwithstanding–either don’t mind violating basic principles of scientific research or don’t understand these principles in the first place.

The biopsychosocial approach to ME/CFS is grounded in the unproven theory that patients are plagued by unhelpful beliefs about having an organic illness and could recover by increasing their activity to counteract the presumed deconditioning. But deconditioning is not the cause of ME/CFS symptoms. Since patients suffer severe relapses after minimal exertion, strategies designed to promote increased activity are in fact contra-indicated. In multiple surveys, more patients have reported being harmed than helped by graded exercise therapy.

When NICE decided to revise its outdated guidance, many people—including me—urged the organization to withdraw the current guidance, or at least to warn readers about possible harms from the recommended treatments. NICE declined. It is likely that well-meaning clinicians around the world are still prescribing CBT and GET to their ME/CFS patients, and will do so until the guidance changes.

Bouts of extreme fatigue seem to be a major symptom of post-covid syndrome. That means many people seeking treatment information from NICE–patients, clinicians, policy-makers–are likely to consult the soon-defunct 13-year-old CFS/ME guidance. If some or many post-covid syndrome patients respond to over-exertion the way ME/CFS patients do, then pushing them to exercise could easily make them worse.

Given this possibility, members of the NICE guidance revision panel pressed the organization on the issue. A post on the ME Association site describes that the effort was spearheaded by its medical director, Dr Charles Shepherd, and Dr William Weir, an infectious disease expert, who collaborated on a letter to NICE. Both men are. members of the NICE revision panel. Other panel members added their names. According to the MEA:

The letter pointed out that recommendations in the current (2007) NICE guideline regarding the use of GET in ME/CFS could cause serious harm if applied to people who are failing to recover from COVID-19 and who are experiencing Post-Covid Syndrome and other complications.

The letter also pointed out that there is a need for guidance from NICE about the use of Pacing as a sensible and safe alternative to Graded Exercise Therapy in respect of Post-Covid Syndrome.

Last Friday, NICE issued the following statement about “graded exercise in the context of COVID-19.” The statement clarified that the 2007 guidance is only for those diagnosed with ME/CFS and not meant for people with post-covid syndome:

 “NICE is aware of concerns about graded exercise therapy (GET) for people who are recovering from COVID-19. NICE’s guideline on ME/CFS (CG53) was published in 2007, many years before the current pandemic and it should not be assumed that the recommendations apply to people with fatigue following COVID19. The recommendations on graded exercise therapy in CG53 only apply to people with a diagnosis of ME/CFS as part of specialist care, and CG53 is clear that this should be part of an individualised, person-centred programme of care, with GET only recommended for people with mild to moderate symptoms.

As the guideline is currently being updated, it is possible that these recommendations may change. The evidence for and against graded exercise therapy is one of the important issues the guideline committee is considering. NICE plans to consult on the updated guidance in November 2020.

NHS England has recently published guidance on After-care needs of inpatients recovering from COVID-19 that includes advice on fatigue.

This NICE statement does not mean that the biopsychosocial campaigners will refrain from applying what they think they know to post-covid syndrome patients. On the contrary. They have sought to colonize what one might call the “fatigue space” in some of its many manifestations–cancer-related, MS-related, HIV-related, and so on. Post-covid fatigue could represent fertile new ground to plow with their failed biopsychosocial template.

Daniel Griffin provides a clinical update on COVID-19, then Viviana Simon joins to review serological assays developed at Mt. Sinai for SARS-CoV-2 infection, tracking the outbreak in NYC, and listener questions.

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Intro music is by Ronald Jenkees

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coronavirus Spike

Don’t believe the headlines that SARS-CoV-2 is becoming more transmissible! Virologists are making conclusions that are not justified by the data.

SARS-CoV-2 virus isolates from many parts of the world have a single amino acid change in the spike protein, D614G. This observation in itself doesn’t mean very much. It could be that the change arose early in the outbreak and as this virus spread to other areas it was maintained because it has no fitness cost. We call this behavior ‘founder effect’. Whether the change has been selected for – what we would call ‘positive selection’, as claimed by many virologists, needs to be proven by experiments that have not been done.

The D614G change appears to make the virus more infectious in cells in culture. However, there are limitations to the conclusions that may be drawn from these data. First, cells that have been used are irrelevant to human transmission, such as a kidney cell line (VERO) from Vervet monkeys. I would like to see data from cultures of human respiratory epithelial cells, including airway-liquid cultures and lung organoids. Second, SARS-CoV-2 was not used for these experiments, but pseudotyped viruses – recombinant retroviruses or vesicular stomatitis virus with the SARS-CoV-2 spike glycoprotein gene inserted. The reason for this approach is that working with SARS-CoV-2 requires a BSL-3 laboratory which is not easy to come by. Nevertheless, even if all these issues were addressed, do we really think that results in cell culture tell us anything about human to human transmission? Seriously, virology colleagues? A monolayer of cells in culture in no way compares with the architecturally complex respiratory epithelium with mucus, antibodies, innate and adaptive responses.

I don’t mention using an animal model to assess SARS-CoV-2 transmission potential because there are no good models (yet) for animal to animal transmission of the virus.

I can think of experiments that could be done to determine if viruses with D614G behave differently in humans, but they have not been done. One approach would be to determine if the change leads to higher shedding of infectious virus from the upper tract. One study reported higher levels of viral RNA in the upper tract of patients infected with 614G compared with patients infected with 614D. This observation is meaningless, because everyone knows that nucleic acids detected by PCR does not always mean that infectious virus is present. Increased RNA might be a consequence of a change in the viral RNA polymerase caused by another mutation that accompanies the spike change. What needs to be done is to measure the levels of INFECTIOUS VIRUS shed from the upper respiratory tract of humans infected with either variant. Even then I would argue that the results cannot be interpreted, because we do not know how much of an increase in virus shedding would lead to an increase in transmission. Would twofold more virus be enough? Fivefold? Tenfold? A thousand fold? Anyone who says they know is wrong.

We know that the dispersion factor, k, of SARS-CoV-2 is 0.1, which means that about 10% of cases lead to 80% of spread. Which virus are these individuals transmitting, 614D or 614G? The results would contribute to an understanding of the role of this amino acid change in transmission.

It’s unfortunate that during a serious outbreak, rigorous science appears to be relegated to the back seat. You might remember during the 2015 Ebolavirus outbreak in West Africa, a viruses with a single amino acid change in the spike protein arose early and predominated. This change made the virus more infectious in cells in culture in the laboratory, but was never shown to have any effect on human transmission. In a nonhuman primate model, the change actually reduced virulence of the virus. Whether the predominance of virus isolates with the amino acid change was a founder effect or positive selection was never determined.

An important consideration is to identify the selection pressure for SARS-CoV-2 viruses with increased transmission. By the time the virus was detected in China late in 2019, it was already very good at transmitting among humans. I fail to see what selection pressure would lead to the emergence of such a variant.

The D614 change does not appear to change the virulence of SARS-CoV-2, nor its ability to be neutralized by antibodies. Let’s toss all the above arguments aside and assume that D614G increases human transmission. What should we do? Wear face masks, avoid large gatherings of people, embrace physical distancing. All of which are already being done – or are they?

In this episode, approval of an Ad5 vectored SARS-CoV-2 vaccine for the military in China, description and clinical trials of a Novavax vaccine joining Operation Warp Speed, prevalence of SARS-CoV-2 in Spain, shedding and transmissibility of the virus, and listener email.

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From Georgia State University, Vincent speaks with Chris, Andrew, Priya, and Richard about their careers and their work on Ebolaviruses, rotavirus, and antiviral drug development.

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By David Tuller, DrPH

Note: The DecodeME team held a Facebook Q-and-A this week. If you want more information about the study, you can watch the video here.

Two major UK government funding agencies recently announced grants totalling £3.2 million to support a major genetics study of ME. Whatever the long-term findings of DecodeME, spearheaded by the CFS/ME Research Collaborative and the CureME Biobank at the London School of Hygiene and Tropical Medicine, the immediate results were impressive—the kind of fair and thoughtful news coverage that has been sparse in this domain of science, especially in the UK. In particular, The Times (the UK version, that is; to a New Yorker, there is only the other Times) published a package of six stories over two days–June 23-24–that took the issue and the illness seriously.

[continue reading…]

Daniel Griffin provides a clinical update on COVID-19, then we review SARS-CoV-2 shedding in children, how to resume school safely, the need for widespread testing and wearing face masks, and much more, including listener email.

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By David Tuller, DrPH

I have written two more letters and have posted them below.

The first letter is a nudge to BMJ’s research integrity department, which missed a deadline this week for providing me with an update on the status of that music therapy study from Norway. You know, the one that started off as a fully powered trial but failed on multiple metrics and ended up being published as a feasibility study seeking data to support the need for a fully powered trial, as I recently documented. I sent the letter this morning.

[continue reading…]

by Gertrud U. Rey

It is well established that children experience less severe disease after infection with SARS-CoV-2. However, to what extent infected children contribute to transmission of the virus is less clear. This topic is of great interest as we prepare for the start of a new school year. 

Are children less susceptible to infection with SARS-CoV-2 or are they just less likely to develop clinical symptoms? Do infected children produce as much virus as infected adults? How likely are asymptomatically infected children to transmit the virus to others? The answers to these questions are inconsistent and confusing, for at least a couple of reasons. At this time it is difficult to directly measure these variables because most schools have been closed for the better part of the pandemic and children have been isolated from others. Also, children are often missed as index (first identified) cases in groups of related cases because they are more likely to be asymptomatic. To assess transmission from children to adults, many scientists have turned to statistical models. 

The authors of one such published statistical study applied data from China, Japan, Italy, Singapore, South Korea, and Canada to three different variants of a mathematical model to analyze age-dependent effects on transmission of SARS-CoV-2. A first variant of the model assumed that susceptibility to infection varies by age – with susceptibility being the probability of infection on contact with an infected person; a second variant assumed that the likelihood of developing clinical symptoms varies by age; and a third variant assumed that neither susceptibility nor clinical disease depend on age. The authors conclude that people under the age of 20 are half as susceptible to infection as those over 20, and that interventions aimed at children have at most a 20% impact on reducing SARS-CoV-2 transmission.

Another modeling study (a preprint, not yet peer-reviewed) out of Israel suggests that children are slightly less than half as susceptible to infection as adults, while their infectivity is 85% relative to that of adults. Infectivity is the probability that an individual can become infected within a certain time frame when making contact with another, identically susceptible individual. The authors conclude that children are less likely to become infected with SARS-CoV-2 than adults and that the chances of infection increase with age. 

preprint out of France suggests that while high school students are as likely as adults to transmit the virus to others, children aged 6-11 are much less likely to do so. The authors show that three separate introductions of virus into three different elementary schools resulted in no further transmission of virus to other students or staff; consistent with results from Australia, Ireland, and a different French study.

However, these findings do not align with results from inquiries assessing viral load in children. After analyzing 3,303 COVID-19 patient sputum samples using two different PCR systems, German virologist Christian Drosten determined that children under the age of 19 produce virtually the same average levels of viral RNA as adults. Drosten argues that studies showing lower viral RNA levels in children relative to adults are subject to sampling bias because children are less likely to have symptoms and are therefore unlikely to be tested early in infection when virus levels in the nasopharynx are high. Instead, children are usually tested as contacts of index cases in symptom-triggered household studies, meaning that samples from children are obtained later in infection when virus levels in the nasopharynx are reduced. One way of validating this argument would be by analyzing children’s stool samples.    

Consistent with this suggestion, a recent report in Emerging Infectious Diseases suggests that both mildly symptomatic and asymptomatic children have high levels of viral RNA in the nose and saliva early during infection, but that these levels decline drastically within 1-2 weeks. In contrast, viral RNA levels in the feces remain high for more than three weeks after onset of symptoms. 

The data on transmission of SARS-CoV-2 from school-aged children to adults are limited because most schools have been closed since March. However, many child care centers in the US have remained open throughout the pandemic to care for the children of frontline workers and there have been no recorded coronavirus outbreaks directly linked to these facilities. Similar reports from Iceland, where extensive testing and contact tracing were implemented early during the pandemic, reveal only two documented cases of child-to-parent transmission, even though elementary schools and day care centers remained operational. 

School closures are a key intervention during epidemics of respiratory infections, and decisions surrounding the re-opening of schools this fall are fraught with uncertainty. While asymptomatically infected children are less likely to spread virus by coughing, and children have a smaller exhaled air volume than adults, they do engage in closer social contact with each other and are more physically active than adults. They are also more likely to put things in their mouths and share items. On the other hand, lengthy school closures have a negative impact on academic achievement and tend to increase educational inequalities because children of lesser means have less parental support and reduced access to resources for home learning. Only time will tell how school openings will affect the course of the pandemic. In the meantime, weekly testing of all students, followed by contact tracing and isolation of infected students and their contacts would be advisable.

TWiV reviews a new H1N1 swine influenza virus from China with pandemic potential, Ad5 vectored SARS-CoV-2 oral vaccine candidate, Operation Warp Speed vaccine candidates, FDA guidance on vaccine approval, and answer listener email.

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