By David Tuller, DrPH

In the days before coronavirus was everything, I was writing about a major study of cognitive behavior therapy for irritable bowel syndrome. The study tested telephone-delivered cognitive behavior therapy, web-based CBT against treatment-as-usual for IBS symptom severity and other more generic domains.

Although the pre-COVID era feels like ancient history already, my last post on the IBS study was on February 24th–not much more than a month ago. On March 9th–the day I was supposed to be arriving in Bristol to attend the CFS/ME Research Collaborative conference–I received a response from King’s College London to a freedom of information request I’d sent. I wanted some details about a licensing deal for the web-based CBT program that the university had signed with a San Francisco-based start-up, Mahana Therapeutics.

In the study, the web-based program showed no clinically significant benefits over treatment-as-usual in reducing symptom severity. Yet Mahana Therapeutics has hyped the symptom severity findings and hailed the reported results as “dramatic” and “potentially game-changing.” These claims are ridiculous. They are not supported by the study data.

Not surprisingly, King’s College London cited commercial reasons to reject my request for more information about this questionable deal. I have pasted the letter in below.

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Dear David,

Request for information under the Freedom of Information Act 2000 (“the Act”)

Further to your recent request for information held by King’s College London, I am writing to confirm that the requested information is held by the university.

Your request

We received your information request on 27th January 2020 and have treated it as a request for information made under section 1(1) of the Act.

You requested the following information:

1. The amount Mahana Therapeutics has paid to license the intervention and for how long.

2. The proportion of the money paid by Mahana Therapeutics that will be received by the researchers.

3. How much the National Health Service will have to pay for each patient who receives the intervention.

4. A copy of the agreement with personal information removed.

Our response

1.-4. The university has withheld the information under the following exemption: Section 43. The University would like to draw attention to the timing of this request being pivotal to the use of S43(2). The University recognises that, with the passing of time, the sensitivity of the information withheld under these exemptions is likely to decrease and allow the University to revaluate its response:

Section 43(2)

Section 43(2) provides for information to be exempt from disclosure where disclosure under this Act would, or would be likely to, prejudice the commercial interests of any person. The University holds that, due to the highly competitive nature of securing licensing agreements and the recent nature of this agreement, the information contained in the agreement and its related costings, are still commercially sensitive.

Universities are required to operate in a highly competitive market with other HEPs and, if disclosed, details about deal structure, development plan and Mahana’s commercial intentions would be likely to damage the university’s future prospects of securing such funding.

Therefore, although the University recognises the inherent public interest in accountability through the transparency of the licensing process, the effect in this case would be likely to prejudice the university’s commercial interests. There is significant public interest in the university being able to maintain sources of income other than public funding. The public interest then favours the withholding of this information at the present time.

This completes the university’s response to your information request.

[The rest is about my right to appeal to the Information Commissioner’s Office.]

by Rich Condit

Rich Condit is a virologist and emeritus Professor, University of Florida, Gainesville and a host on This Week in Virology.

Modeling done by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington suggests that if stringent social distancing measures are kept in place, the “first wave” of covid-19 disease in the US may subside by mid-June, with a total accumulation of ~93,000 deaths.  The IHME states that: “By end the of the first wave of the epidemic, an estimated 97% of the population of the United States will still be susceptible to the disease, so avoiding reintroduction of COVID-19 through mass screening, contact tracing, and quarantine will be essential to avoid a second wave.

I find it more than a little unnerving that after a grueling “first wave” of disease, a mere 3% of the population may be infected and thus be (at least relatively) immune to re-infection.  I seriously doubt if after the first wave the virus will be “gone”, rather just beaten back but nevertheless broadly if thinly distributed throughout the population and poised for a comeback when social distancing restrictions are lifted.  If at that time, 97% of the population remains uninfected, then we are destined for a very significant second wave of infection.

But is that 3% infection ratio accurate, and if not, what is the real number?  To understand this, we need to understand the difference between case fatality rate (CFR) and infection fatality rate (IFR).  CFR is the ratio of the number of deaths divided by the number of confirmed (preferably by nucleic acid testing) cases of disease.  IFR is the ratio of deaths divided by the number of actual infections with SARS-CoV-2.  Because nucleic acid  testing is limited and currently available primarily to people with significant indications of and risk factors for covid-19 disease, and because a large number of infections with SARS-CoV-2 result in mild or even asymptomatic disease, the IFR is likely to be significantly lower than the CFR.  The Centre for Evidence-Based Medicine (CEBM) at the University of Oxford currently estimates the CFR globally at 0.51%, with all the caveats pertaining thereto.  CEBM estimates the IFR at 0.1% to 0.26%, with even more caveats pertaining thereto.

Crunching some numbers, if IHME estimates 3% of the US population (~330M) resistant to the disease after the first wave, that implies 9.9M infections.  The IHME prediction of ~93,000 deaths implies an IFR of 0.9%, close to the commonly estimated 1% CFR globally.  Note that IHME is really only projecting deaths based on real data, and therefore should not be faulted for choosing a conservative estimate of infection rate (~1%), especially given that the IFR is, at this point in time, a particularly slippery number.  However, if, just for argument’s sake, the IFR is really as low as 0.1%, then it follows that after the first wave of disease, as much as 30% of the US population will have been infected and thus resistant to reinfection.  It seems to me that this would give the virus considerably less fertile ground to grow on and significantly dampen the impact of a second wave.

This is not just an intellectual exercise.  Understanding the true infection fatality rate has major consequences for planning control measures following our first encounter with SARS-CoV-2.

We can and should obtain a direct measure of the SARS-CoV-2 IFR to help plan for the future of the pandemic.  Simple and relatively inexpensive kits have become available which test for antibodies to SARS-CoV-2 in a drop of blood in a few minutes.  These kits adapt existing technology developed for other pathogens to SARS-CoV-2.  The kits allow for “point-of-care” testing, that is, they can be used anywhere and results are obtained in real time, and they require only minimal instruction for use. (An example of how such a kit works can be found here.  The FDA has given Emergency Use Authorization to Cellex, Inc. for use of their kit.  Dozens of other companies and laboratories are developing similar tests.)  The kits test for both IgM and IgG antibodies specific for SARS-CoV-2 in the blood.  IgM is the first antibody to appear after an infection, usually within about one to two weeks.  Within about three weeks IgM disappears and is gradually replaced with IgG.  Therefore, the kit can determine whether a test subject has ever been infected with SARS-CoV-2, and if so, whether that infection was recent.

If I were king, I would distribute SARS-CoV-2 test kits free of charge to pharmacies nation-wide, and consider setting up testing stations at commonly frequented locations such as schools, sporting events, polling stations, and yes, even bars.  I would also establish a centralized, web based database for collecting and collating the test results. The data collected could be used to determine exactly the IFR in the US, along with a geographic distribution and possibly other demographic information.

We were asleep at the switch for the first wave.  Let’s wake up and catch the second wave.

http://covid19.healthdata.org/

https://www.cebm.net/covid-19/global-covid-19-case-fatality-rates/

https://www.newscientist.com/article/2239497-why-we-still-dont-know-what-the-death-rate-is-for-covid-19/

Immunologist Jon Yewdell joins Vincent and Rich to discuss immune responses in the context of infection with SARS-CoV-2.

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TWiV covers trials of hydroxychloroquine and convalescent plasma therapy for COVID-19, and answers listener questions on blood tests for antibodies, cross-protection among coronaviruses, acquiring infection from food or the gas pump, face masks containing copper, and much more.

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By David Tuller, DrPH

My sweet friend Anil van der Zee lives in Amsterdam–more accurately, he lives on his bed in an apartment somewhere in Amsterdam. Like too many, he’s had a lot of experience at self-isolating.

Below is part of the blog he posted a few days ago.

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The Distant Corona Connection

Adjusting.
We are in a crisis! A pandemic! The coronavirus is spreading. It’s frightening. Will I be infected? My friends? And most importantly how will it affect us? The uncertainty of the unknown is probably the most unsettling of the whole situation. As we are dealing with a new virus there aren’t any effective treatments or cures. The only treatment the medical world has to offer at this point are ways to try to ease the potentially devastating symptoms and support the immune system as much as possible in the hopes that the patient will get the best chance of recovery. Sadly we now know that not everyone will. [continue reading…]

by Gertrud U. Rey

The prevalence of SARS-CoV-2, the virus that causes COVID-19, is steadily increasing around the world. Yet despite this unsettling fact, one statistic continues to hold true: most infected children experience mild symptoms, respond well to treatment, recover more quickly than adults, and have a better prognosis.

An initial report from China showed that only 965 out of 44,672 confirmed COVID-19 patients were under the age of  19. A letter to the editor of the New England Journal of Medicine reported only six cases of COVID-19 out of 366 hospitalized children. Only one of these children required admission to the intensive care unit, and all six patients recovered after an average of 8 days. According to the largest study of COVID-19 in children to date, more than 90% of children with laboratory-confirmed COVID-19 had asymptomatic, mild, or moderate disease. A comprehensive review of COVID-19 in children published on March 23 shows that even in Italy, the country with the highest number of COVID-19-related deaths so far, only 1.2% of patients were children, and none of these children died.

What is the reason for this low morbidity and mortality in children? Although the answer isn’t clear, there are a few possible explanations. Children are thought to have fewer underlying disorders and healthier respiratory tracts because of less exposure to cigarette smoke and air pollution. There is speculation that the non-specific, innate immune response that occurs upon an initial encounter with a pathogen is stronger in children. This type of immune response seems to be delayed in the elderly, and in an effort to “catch up,” may result in excessive inflammation, thereby ultimately causing more severe damage.

Another possible explanation is tied to angiotensin-converting enzyme 2 (ACE2), the host cell surface protein that serves as a receptor for SARS-CoV-2 entry into cells. ACE2 is prevalent on lung, kidney, intestinal, and arterial cells, where it normally controls blood pressure by regulating the volume of fluids in the body. ACE2 is also an important regulator of the immune response, especially in the context of inflammation. Some suggest that ACE2 is less mature in young children and thus may not function properly as a receptor for SARS-CoV-2. Furthermore, it is more abundant on cells of the lower respiratory tract, which is typically the site of severe COVID-19 disease. Consistent with this observation, data indicate that children experience more SARS-CoV-2 infections in the upper respiratory tract than the lower respiratory tract.

It has also been suggested that ACE2 is expressed more abundantly on senescent cells, which have stopped dividing and exist predominantly in the elderly. Considering that senescent cells are still metabolically active and contain all the factors necessary for virus replication, this hypothesis seems plausible.

It is also possible that early childhood vaccines provide some protective immunity against SARS-CoV-2. For example, a study from 2008 shows that the measles vaccine elicits neutralizing (virus-inactivating) antibodies against SARS-CoV, the virus responsible for the 2003 coronavirus epidemic. Immunity derived from childhood vaccines typically wanes with age, thereby possibly increasing the risk of severe COVID-19 in the elderly.

As is typical of newly emerging pathogens, many characteristics of the diseases they cause are largely unknown. As such, the exact reasons for why COVID-19 is less severe in children remain ambiguous. Hopefully the answer will become clearer as more data emerge over the next few months.

By David Tuller, DrPH

I am slowly adjusting to the new realities and what they mean for life and work for at least the next couple of months; this lockdown or “sheltering-at-home” or whatever is likely to continue through most of May, if not longer. This is a marathon, not a sprint.

Being largely homebound is not my normal existence. Yet after several years on this project, I have come to a much deeper understanding of how this is, for many people, a necessary and unavoidable method of managing their illness. And I’m sure many such people are experiencing a range of reactions as the rest of the world struggles to come to terms with this state of existence.

[continue reading…]

Daniel Griffin MD joins TWiV from a hospital parking lot to provide updates on COVID-19 diagnostics, clinical picture, and therapeutics, and then the TWiV team continues coverage of the coronavirus pandemic caused by SARS-CoV-2.

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By David Tuller, DrPH

It’s a frightening time for everyone. As we know, people with underlying medical conditions are at greater risk from coronavirus. At the same time, many of these individuals long ago adopted some of the strategies everyone is now being asked to adopt. Certainly people with ME–or with what is referred to as CFS, CFS/ME, or ME/CFS–often have lots of practice sheltering at home and not socializing with other people.

[continue reading…]