COVID-19 medical discussion

Anastasis · June 30, 2020

10 minutes ago, Post Oak said:

Sure that should be the "goal".

Not gonna happen though

School looking like football season imo.

Anastasis · June 30, 2020

Some info from Italy on asymptomatic cases....

https://www.nature.com/articles/s41586-020-2488-1?

Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’

On the 21st of February 2020 a resident of the municipality of Vo’, a small town near Padua, died of pneumonia due to SARS-CoV-2 infection1. This was the first COVID-19 death detected in Italy since the emergence of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province2. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days3. We collected information on the demography, clinical presentation, hospitalization, contact network and presence of SARS-CoV-2 infection in nasopharyngeal swabs for 85.9% and 71.5% of the population of Vo’ at two consecutive time points. On the first survey, which was conducted around the time the town lockdown started, we found a prevalence of infection of 2.6% (95% confidence interval (CI) 2.1-3.3%). On the second survey, which was conducted at the end of the lockdown, we found a prevalence of 1.2% (95% Confidence Interval (CI) 0.8-1.8%). Notably, 42.5% (95% CI 31.5-54.6%) of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic (i.e. did not have symptoms at the time of swab testing and did not develop symptoms afterwards). The mean serial interval was 7.2 days (95% CI 5.9-9.6). We found no statistically significant difference in the viral load of symptomatic versus asymptomatic infections (p-values 0.62 and 0.74 for E and RdRp genes, respectively, Exact Wilcoxon-Mann-Whitney test). This study sheds new light on the frequency of asymptomatic SARS-CoV-2 infection, their infectivity (as measured by the viral load) and provides new insights into its transmission dynamics and the efficacy of the implemented control measures.

Anastasis · July 1, 2020

Comprehensive vaccine update.

https://blogs.sciencemag.org/pipeline/archives/2020/06/29/coronavirus-vaccine-update-june-29

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Here’s the latest on the ones I’ve covered before and with new efforts added. There are now so many of these running that unless the program is especially noteworthy I’ll only touch on the ones that are in trials right now, or about to start soon. And I’m going to arrange them by vaccine class – the April 15 background post goes into some more detail on these, but I’ll start each group off with a short scientific summary. Neither the order in which these different mechanisms are presented nor the order in which companies are listed within them is meant to reflect any horserace handicapping on my part.

Viral Vectors:

This class uses some other infectious virus, but with its original genetic material removed. In its place goes genetic instructions to make coronavirus proteins, and when your infected cells do that, it will set off an immune response. Note that this is different than being infected with a “real” virus, whose instructions are (naturally enough) to produce more virus, which go off and infect more cells. No, in this case each viral particle that you’re injected with will be able to infect one cell, and that’s it. An advantage of this approach is that it should appear to your immune system like a pretty realistic viral attack, and set off a full range of responses. A disadvantage is that this technique (as far as I can tell) has only once been used in human therapy (the Ebola vaccine, see below – update: edited this section to reflect this) – a lot of people have been working on it over the years, but things have now accelerated. Another disadvantage is that (depending on which virus you pick as a vector) some of your patients may already have antibodies to that one. That can mean that your attempt to repurpose it might crash and burn as the carefully designed vector gets attacked by antibodies and eaten by immune cells before it can even do its work. It also means that booster shots would have an uphill battle, since the antibodies from that first dose will be waiting for the second one. Antibodies to the viral payload: good. Antibodies to the viral vector itself: not so much.

Oxford/AstraZeneca: ChAdOx1-nCov19/AZD122: This is one of the frontrunning candidates in human trials (the WHO agrees), and it’s recently started dosing in South Africa and Brazil as well as the ongoing trials in the UK, etc. We’re going to be seeing a lot of that jump-around-the world pattern, tracking the places that have significant outbreaks in order to get the best statistics. That means that the organizations behind each candidate either have to have substantial resources themselves, or partner with those who do (pharma, the WHO, groups such as CEPI and the Gates Foundation, etc.) I don’t know when the next report of human data will be on this one, but it will be very closely watched indeed – see the May 18 post for the reaction to the last big data drop, which had some observers (not all) worried about the vaccine’s effectiveness. This one tries to get around the pre-existing antibody problem by using an adenovirus from chimpanzees (the “Ch” in the name).

CanSino/AMMS: their Ad5-nCov, we find out this morning, has been approved for use in the Chinese military “after clinical trials proved it was safe and showed some efficacy”. That’s probably how I would put it, too – the company reported on the Phase I data a few weeks ago, and one of the notable features was that about half the patients that they dosed, in all age cohorts, had pre-existing antibodies to the vector. That’s adenovirus-5, as the name implies, and it’s a pretty common human pathogen. This one was widely used earlier (back to the 1980s) in the viral-vector field (which encompasses both vaccines and gene therapy) and a great deal is known about its behavior in humans, but the existing immune response has been a problem every step of the way. Ad5 is also considered a good choice if you want your payloads delivered to the liver and not much of anywhere else – it tends to concentrate there, and it wouldn’t surprise me if a lot of the coronavirus protein production with the CanSino vaccine is taking place in that tissue. At any rate, an executive with the company has said that their Phase II results will be published very soon, while not missing a chance to take a shot at Moderna for not doing the same (see below), so it’s going to be very interesting to dig through those.

Johnson & Johnson (Janssen): J&J, on the other hand, is working with a different adenovirus platform, Ad26. That’s a much rarer strain, and very few people have pre-existing antibodies to it. They’ve been investing in this for years now, and the coronavirus epidemic has, as it has for so many other areas, accelerated things past anything that was contemplated before. This is the time to mention, though, that it’s not just the pre-existing response that can be a problem – if you raise too vigorous a response to the new viral vector you can cause trouble, too (and, as mentioned, perhaps wipe out the chances to ever use that particular vector for anything again). No big announcements since the company said that they were speeding up human trials to first dosing in July.

Gamaleya Research Institute: Those previous entries are a good lead-up to this one, because the Russian GRI vaccine is a mixture of Ad5 and Ad26 vectors. To be honest, I’m not sure of the thinking behind giving both, but it will be an interesting comparison with the Chinese and J&J efforts, for sure. This work made headlines not long ago when the head of the institute let it be known that he and other workers there had actually injected themselves with their own candidate vaccine (!) This was not, he said, an attempt to prove safety, but rather a means to protect the staff while they were working with the coronavirus itself. One would suspect that the Russian language, with its rich stockpile of phrases, would have a metaphor similar to the English “putting the cart before the horse”, wouldn’t it? At any rate, this one has gone into human dosing in Russia.

Reithera: This Rome-based company is taking a similar approach to the Oxford group, in that they have a gorilla-infecting coronavirus platform that should be immunologically novel in a human population. Data are scarce, although the company has said that they expect to go into human trials “this summer”, and some stories on them say July.

Altimmune: Here’s another adenovirus vector, but administered via a different route. They’re going intranasal, and thus hoping to bring in a mucosal immune response as well. Since this seems to be the same platform as their earlier Nasovax influenza vaccine program, I will assume that this is also an Ad5 vector. This one is still listed as “preclinical” on the company’s web site, with such studies taking place partly at the University of Alabama-Birmingham. It’s good to see another technique being applied here; we’re going to need all the shots on goal that we can get.

Merck/Iavi: Now here’s a non-adenovirus vector. Merck’s partnership with nonprofit Iavi is around vesicular stomatitis virus (VSV), which is what was successful in the development of the Ebola vaccine. In that case, the gene for the VSV glycoprotein was replaced by one for the Ebola protein, and I would assume that something similar will be done to swap in the coronavirus spike protein here. Merck is expected to use the same Vero cell line production for this that they used for making the Ebola vaccine and for their rotavirus vaccine. That last one isn’t a VSV vector, but rather a group of mixed bovine-human rotavirus strains – but for all of these you need cells to serve as factories to crank out viral particles for you. I have seen no projected date for first-in-human dosing for this one, though

Merck/Themis: In another non-adenovirus move, Merck had been collaborating with Themis on using attenuated measles virus as a therapeutic, platform, and about a month ago they announced that they were buying them outright. The attenuated measles vaccine (see below for attenuated viruses in general) has a very good safety record and has long been considered an attractive candidate for repurposing, and now we’re going to find out how that works rather before we thought we would. The plan is for this to go into patients sometime later this year.

Vaxart: Now, these folks I had not heard much until the other day, when they popped up with a surprise press release saying that their vaccine candidate had been selected as part of the government’s “Operation Warp Speed” for a challenge test in primates. They have a platform developing oral vaccines – an adenovirus vector delivered in a coated tablet to get past the stomach and into the small intestine. (There’s an immediately obvious difference this route and the injectables in ease of storage and administration, which might be quite advantageous). This “mucosal immunity” technique will be familiar to many via its use in the oral polio vaccine, and the differences between it and the immune response generated by injection are quite complex. Vaxart hopes to go into Phase I later this year, and it will be very interesting to see what happens in the primate study and in humans. This route could turn out to be noticeably better or noticeably worse than other the efforts in the category, or might even end up as an adjunct to another vaccination route. I’m very glad that we have a completely different approach being looked at. (Update: corrected and moved the category on this one; I’d initially thought they were using just recombinant proteins).

Genetic Vaccines:

These take DNA or RNA coding for coronavirus proteins and inject that directly into the bloodstream. “Directly” isn’t quite the right word, though – for these things to work, they have to be formulated and modified to survive destruction in the blood, to be taken up through cell membranes, and to be used for protein production once they’re inside. There have been extensive experiments in animal models over the years, but this is another category where no existing human vaccine uses the technology (yet!) Advantages include fast development and (possibly) ease of manufacture, depending on how exotic the final form turns out to be, and lack of an existing immune response to the vaccine itself (as seen with some of the viral vectors above). The big disadvantage is, well, once again no one has taken these things into humans yet. And another one is that some of these may need to be stored at not even the usual cold-chain conditions (which are enough of a logistical problem, thanks, particularly outside the industrialized countries) but even colder than that to keep them stable (for example) – an underappreciated problem, perhaps, that we’ll have to keep an eye on. Others have been shown to be stable without cold chain storage, so there’s clearly a wide variation.

Moderna: mRNA1273: this one, the leading mRNA vaccine candidate has been getting a lot of the coronavirus vaccine headlines, of course. They’re still heading for Phase III in July, and have signed up with Catalent (who are also working with J&J) for support in vaccine production, labeling, and distribution for that effort. This in addition to their own production work and the deal that they’ve already signed with Lonza in Europe. The company’s CEO said earlier this week that the best-case timeline had them with efficacy data before Thanksgiving, and yeah, I believe that would be the “everything goes flawlessly the first time through” situation. What we haven’t seen are many more details about how the vaccine has been performing so far. All we have is that small mid-May press release, and it’s been a while, hasn’t it? At some point, there’s going to be a dumptruck of data that will have to be released on this one, and until then we’re all just sort of tapping our collective feet.

Pfizer/BioNTech: Not much news here, but we definitely will be getting some. This effort started out with four different mRNA approaches, and there’s no word on if they’ve narrowed things down yet. Pfizer’s CEO Albert Bourla said recently that they’re sticking to a strict policy of not commenting on their vaccine results until they’re published in a journal. He also emphasized that they are not part of the government’s “Operation Warp Speed” effort, saying “We don’t take the money because we don’t need the money”, and believes that doing so would just slow down the company’s own efforts. They’re also planning for about 30,000 patients in their eventual Phase III trial, with about 100 sites (US and international). The number of drug companies that can organize (and pay for) something like that with cash-on-hand can be easily counted on your fingers, and Pfizer is certainly one of them. The company has also said that their best-cast timeline has a possible emergency use authorization in October (!), which will also require everything to ring the bells exactly on time. Not everyone believes that’s possible, but hey, we’ll find out pretty damn soon, won’t we?

Inovio: this DNA vaccine candidate (INO-4800) is getting messy. The company had sued their manufacturing partner, VGXI, claiming that they were in breach of contract and holding up Inovio’s program because they could not fulfill their targets for delivery. A judge has just ruled against Inovio’s request to force disclosure of VGXI’s proprietary manufacturing techniques. For my part, I was already out of sympathy with Inovio after their announced early on in the pandemic that they had produced a vaccine in about three hours, when what he was actually talking about – as people who know any molecular biology whatsoever realized instantly – was a candidate construct for a possible vaccine. That brought on shareholder lawsuits, as the shares were whacked back and forth like a tennis ball between enthusiastic dice-rolling long investors and you-gotta-be-kidding-me short-sellers. I should note that the company has a stock market following that is need of therapy all by itself. Anyway, at this stage, a serious vaccine player should be talking about where they’re going to round up all the glass vials, where the sterile production lines are, how they’re going to handle the logistics for tens of thousands of clinical trial doses, and so on. Not off hammering on their contractual partners in the Montgomery County Court of Common Pleas.

CureVac: hey, remember these guys? Back in March, there was a flare of a story about how the US had allegedly tried to buy up the company (or the rights to any mRNA vaccine they produced), with sourcing of the news to irate members of the German government. There hasn’t been anything quite that lively around them since, but they recently got a 300 million Euro investment from the German government (who now own 23% of the company). They have continued to state that they expect to go into Phase I human trials before the end of June, which means that they have about 28 hours to go (Central European Time), as I write this.

Imperial College: this is another mRNA candidate, but it’s a self-amplifying one, like one of the four Pfizer/BioNTech variations – these are the only two that I know of using this technique. The vaccine went into human volunteers just a few days ago. The way these things work is to deliver messenger RNA that codes not only for the antigen protein of interest, but for an RNA polymerase enzyme (there’s a useful one that’s been borrow from alphaviruses) that will turn around and make more copies of the mRNA itself. The idea is that you can then dose with much smaller amounts of material, since it’s going to go out and make more of itself anyway.

Sanofi/Translate: this one is still scheduled to go into human trials in December. Sanofi has recently expanded their collaboration with Translate in this area, but I haven’t been able to track down details on the vaccine itself. There are an awful lot of ways to deal with the problem mentioned in the intro to this section, though, and I would expect this to be a different run at them than the other mRNA players have taken. Given that we have no idea how these things are going to perform in human subjects, a diversity of opinion is no bad thing.

Genexine: this South Korean company’s DNA vaccine, GX-19, has started human dosing. These folks and Inovio seem to be the front-running DNA vaccine players for now; everyone else in this category is RNA. I would assume that none of this testing is going to be done in Korea itself, though, since COVID-19 levels are so low there (and good for them).

AMMS/Abogen/Walvax: this is the first mRNA coronavirus vaccine in China, and was recently approved for human trials there. An interesting feature is that it’s said to be stable at room temperature for up to a week – rather surprising for an mRNA construct, but something to keep an eye on.

Recombinant protein vaccines

Here we get to a technique that really is used for human vaccines. The previous two categories force your own cells to make viral antigen proteins, but here you’re making them industrially and just injecting them directly. The advantage can be that such protein production can be accomplished in many different ways and is already done on a large scale. That said, every new protein is a new project, with its own idiosyncrasies. A disadvantage is that this technique sometimes does not produce enough of a robust immune response by itself (at reasonable doses of protein, anyway), and needs added “adjuvants” as part of the vaccine formulation. These are substances that increase immunologic reaction – through mechanisms that honestly have not always been so well understood over the years (more here) and you’ll see these in the entries below.

Novavax: The company has been raising significant amounts of money as they push on with their recombinant vaccine (a Spike protein produced in an Sf9 insect cell system). Otherwise, there’s very little news – now everyone waits to see their Phase I results!

Clover Biopharmaceuticals: These folks are also teaming up with GSK to use their adjuvant, as well as testing their recombinant glycoprotein with another adjuvant from Dynavax. Dosing of these trial arms has already started; they were the second effort in the recombinant protein space to go into humans after Novavax.

Sanofi/GSK: This one, a recombinant version of the Spike protein along with GSK’s own adjuvant, has also had its timeline pushed up. Dosing was scheduled to start in December, but’s now slated for September, with rollout in mid-2021 if everything works. The GSK adjuvant is the one used in their shingles vaccine, and even before the pandemic the company had planned to make this the centerpiece of their vaccine programs. It’s a mixture of a bacterial lipid from a strain of Salmonella and an extract of the Chilean soapbark tree. “Saponin” compounds of that sort have long been known as adjuvants, but this one really seems to ring the bells. I certainly noticed a reaction when I got the shingles vaccine myself (particularly the second dose).

Zhifei Biological Products: Basically, all I know about this one is that it’s just been approved to go into human trials. There’s a lot of stuff going on in China – some of it (like CanSino’s) being well published, and some of it almost totally in the dark.

Queensland/CFL/GSK: Back at the end of April, the team at the University of Queensland announced preclinical results on antibody response to their vaccine candidate. They’re also looking at adjuvants from both GSK and Dynavax, and have partnered with several other companies for production and logistics so far. From what I can see, they’re recruiting patients now to start dosing next month. I’m not sure what the coronavirus situation is in Queensland itself, though – where will the majority of dosing be done?

Stabilitech: Here’s another small company working on oral vaccines, in this case with recombinant proteins (from what I can see). Their web site seem to claim to have formulations that have been through animal dosing, and says that they are ready to start human clinical trials “pending secured funding”. With all the money sloshing around in this area, I would have to assume that they have knocked on some doors, so we’ll see if this goes anywhere.

Attenuated Virus Vaccines:

This is another well-precedented vaccination technique. It involves producing a weakened form of the actual infectious virus, one that is not capable of causing damage but can still set off the immune system. There are several ways to do this, and it’s a bit of an art form involving taking the virus through a huge number of replications in living cells as you select for variants that are less and less harmful. An advantage is that such vaccines can be quite effective at raising a response – ideally, the immune system reacts exactly as it would to the real pathogen, except you avoid all the getting-sick part. A disadvantage is that part about it being an art form: balancing the lack of harm with immunogenicity is not something that can always be achieved. Some viruses have a wider window for this sort of thing than others, and it’s not easy (or possible, really) to know if this is a feasible pathway up front. That may well be one reason why (at the moment) I know of no candidate vaccines for this coronavirus that are using this method.

Inactivated Virus Vaccines:

This is also one that’s also been used in medical practice for many years, and it’s another inactivation step beyond the attenuated viruses. Heat or chemical agents are used to damage the virus to the point that it can no longer infect cells at all, but the plan is for there to be enough of the viral material left unaltered to still raise an immune response. Not the most high-tech approach, but it can definitely work. Many times, though, vaccines of this don’t provide enough of a response in a single shot, so you may be looking at a booster vaccine schedule. Interestingly, the Chinese groups seem to have this field to themselves; I’m not aware of any inactivated-virus vaccine for the pandemic that’s in serious development anywhere else.

SinoVac: When last heard from, the company had released positive Phase II data – well, some data. The full report on the trial is not out yet, but two weeks ago they issued a statement saying that over 90% of the participants had neutralizing antibodies at 14 days after dosing. That’s good news, but you’d want to see a lot more detail, such as actual antibody titers, and it hasn’t shown up yet (although SinoVac says it’s coming). Their Phase III trial will be starting shortly in Brazil – which given the epidemic situation there at the moment seems like (sadly) a good choice of venue. More on this one when more data show up.

SinoPharm/Wuhan Institute of Biological Products: This is the one that’s already being given to employees of Chinese state-owned companies who are traveling to high-risk areas overseas, so hey, why bother with clinical trial results? Well, anyway, the organization has announced that antibody titers were “high” in the initial trials, and the the seroconversion rates (at 28 days) were a flat 100%. One would like to see a full paper on these data, but I don’t know when (or if) that will ever show up; SinPharm seems to like to announce these things on Weibo and move on. The Phase III trials will take place in the United Arab Emirates, (and likely other locations as well?)

SinoPharm/Beijing Institute: This is the other SinoPharm vaccine, and just today the company has announced that it also passed safety trials and generated neutralizing antibodies. But this was another Weibo posting, so that’s all we have. I also have no clear idea about the differences between this one and the Wuhan-originated vaccine – all I know is that they’re both some form of inactivated coronavirus.

Institute of Medical Biology (China): Last week there was an announcement that this one had moved into Phase II testing, but we don’t know much more. There was a Phase I trial in May (China Daily link) with 200 people, whose results (as far as I can tell) have not been reported, either. Nor do we know anything about the method used to inactivate the virus in this candidate (just like the other two, actually).

Brisketexan · July 1, 2020

15 minutes ago, Anastasis said:

Comprehensive vaccine update.

https://blogs.sciencemag.org/pipeline/archives/2020/06/29/coronavirus-vaccine-update-june-29

Are there betting lines on any of those?

I'm kinda serious....

Bevo · July 1, 2020

11 minutes ago, Brisketexan said:

Are there betting lines on any of those?

I'm kinda serious....

I would most likely want the Sanofi/GSK recombinant. I would probably bet on Pfizer. I don't think I could be convinced to take a coronavirus vaccine developed in China.

triplehorn · July 2, 2020

Really a great interview on the use of Ivermectin in the DR:

President of Dominican Republic’s Largest Private Health Group Discusses the Success of Ivermectin as a Treatment for Early Stage COVID-19

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How did you learn about Ivermectin & How did it become a treatment in Dominican Republic?

Of course we know of Ivermectin for anti-parasite medicine but we first learned about the Monash University lab experiment and then a network formed in Latin America to begin studying how it could be used to help people who fell ill to SARS-CoV-2—e.g. COVID-19.

Has the national health authorities approved of Ivermectin?

No. They are following WHO and other funders’ guidance.

How have you been able to treat COVID-19 patients with ivermectin?

The hospitals have approved our protocol for use of an approved human anti-parasitic drug off label for the novel coronavirus.

Dominical Republic has over 32,000 cases of COVID-19 and 747 reported deaths. How come the authorities are not following Rescue Group’s lead?

A confluence of factors and forces, including the fact that A) they follow WHO, U.SA and other guidance (based on funding); and B) government health moves much slower than the private sector. We have more flexibility.

What is the treatment amounts?

Well we started with what is in the standard anti-parasite protocol of 100 to 200 micrograms per kilogram and have progressed that to 400 micrograms per kilogram of bodyweight. We also include it with Azithromycin.

How many patients have you treated and what has been the success rate?

Of the 1,300 patients we have treated (early state cases), over 99% have been cured within 8 to 10 days. It has been frankly amazing. It’s truly feels like a gift from above.

Have there been any adverse events/side effects?

Yes, but a very minimal number reported and it comes down to heart burn and mild diarrhea. But again, it is a small number of cases.

Interesting bit re currents in US medical practice and the weighty thumb of big pharma:

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Have doctors from the United States contacted you? If so, what is your sense as to how many doctors in America are using Ivermectin for COVID-19 patients?

Yes. Several doctors have contacted me and I have been in touch with the doctor in Broward County TSN interviewed. I don’t know how many doctors in America have embraced Ivermectin but it is a lot and that number is growing every day. It is kept sort of a secret in the United States.

On that note, why do you think that is?

Well, economics. The big drug companies cannot really profit off of a generic drug that is in use worldwide for treating parasites. Moreover, the priorities are wrong. A key along with a vaccine is to work to treat the disease early: stop it from progressing to a more severe state. It is a horrific death from COVID-19. We don’t really understand this disease fully yet. But we do know we lose our family members, and the death rate once the disease progresses to the severe to critical state is very high.

Treat early early early

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What is the benefit of treating people earlier with Ivermectin?

The results speak for themselves. Going from 21 days down to 10 days for average disease duration is incredible. Remember the remdesivir numbers (14 to 11 days) is hospitalization/severe cases. If you compare the results of Ivermectin and Remdesivir, well the latter really isn’t to treat a majority of the people who have a mild cases. After all, for Remdesivir it is for more progressed cases, involves an intravenous administration, etc.

Then lets talk about the health, economic and social benefit of cutting 10 days out of the sickness and reducing the amount of time a person is contagious with COVID-19. This has been a huge impact. A huge value to society. Look at what this pandemic has done to the global economy! Look at New York City—the greatest city with per capital perhaps the greatest doctors and health systems yet look at the amount of death and the impact. It is horrific; a tragedy.

When time and money are lacking for RCTs, on the indispensable life saving value of Observational Studies in the context of an established safety profile:

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What about those that say we must have critical trials results first before treatments?

Well it is very expensive to conduct clinical trials. In developed nations in the Caribbean, Central and South America, countries in Africa and some in Asia we must act now to stop the disease from progressing and spreading. We have an investigation we are in fact undertaking and there are other good studies in the works from Johns Hopkins University to Sheba Medical Center in Israel. But those will take some time. The network in Latin America and the Caribbean has acted on observational, off label data, and it is working. After all, over a trillion doses of Ivermectin are given annually for fighting parasites. It is an incredibly safe drug.

cont.

chitown bevo · July 3, 2020

Aggies leading the way with proper mask wearing

Edited July 3, 2020 by chitown bevo

Liquor and Poker · July 3, 2020

16 hours ago, triplehorn said:

Really a great interview on the use of Ivermectin in the DR:

President of Dominican Republic’s Largest Private Health Group Discusses the Success of Ivermectin as a Treatment for Early Stage COVID-19

I’m sorry- I hope ivermectin is in fact the great cure, especially given that my dogs had to switch to a much more expensive heartworm drug because it’s in short supply. But that interview reads like a chapter from “Secret Cures They Don’t Want You To Know About!” or whatever that book was called.

“99% cure rate” from early-stage infections is not meaningful to me given that the serious illness rate is pretty low, particularly among younger people, who are relatively over-represented in the DR.

Anastasis · July 3, 2020

On 7/1/2020 at 10:48 AM, Bevo said:

I would most likely want the Sanofi/GSK recombinant. I would probably bet on Pfizer. I don't think I could be convinced to take a coronavirus vaccine developed in China.

AZ/Oxford first to market IMO. MRNA delaying their trial. PFE just getting out the gate. Agree wrt SNY/GSK, but that won't get here until mid 2021.

triplehorn · July 4, 2020

On 7/3/2020 at 6:41 AM, Liquor and Poker said:

I’m sorry- I hope ivermectin is in fact the great cure, especially given that my dogs had to switch to a much more expensive heartworm drug because it’s in short supply. But that interview reads like a chapter from “Secret Cures They Don’t Want You To Know About!” or whatever that book was called.

“99% cure rate” from early-stage infections is not meaningful to me given that the serious illness rate is pretty low, particularly among younger people, who are relatively over-represented in the DR.

I really don't get your negative response to the interview. I didn't read it as him being an expert and a guiding light. It's what he reveals about forces affecting pragmatism and influencing process. Nothing earthshaking that we haven't known before, just more confirmation it's happening with negative consequences during a deadly pandemic causing death and disability.

The lack of coherent national communication and apolitical decision making in the US (no CR) has created a void that naturally is being filled by those intent on maximizing profit and/or sowing confusion. The US historically has been a primary leader in medical problem solving and response, but right now there's quite a role reversal happening. Private US physicians are reaching out across borders to learn if they can help their patients avoid hospitalization and they are clearly taking action. However as it relates to access to timely outpatient care for covid19, should they want it, a giant swath of Americans infected with covid19 are left on the outside looking in. Here, forget about early treatment options, the first 3 months in the US was about where the hell you could even get fucking tested.

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“99% cure rate” from early-stage infections is not meaningful to me given that the serious illness rate is pretty low, particularly among younger people, who are relatively over-represented in the DR."

The stated philosophy:

"First, we must do everything within our power to address this disease earlier in the process. That is why the development of anti-viral medications targeting COVID-19 are so important. Ivermectin happens to have an incredible inhibiting effect on COVID-19 and we were pragmatic. Dominican Republic is blessed with beauty everywhere, incredible people and a great potential for business but it is still a relatively poor country. We don’t have the time to wait. We must treat as many people as possible and reduce the number of severe to critical cases."

This is the key advantage to having safe and inexpensive generic medications available for off-label use (Iver is ~$0.12 per dose). Due to established safety with minimal or known potential side effects, you can give them without knowing what the exact future course of illness holds for each person. It can be limited to use in people with risk factors like age and medical co-morbidities, but ultimately it's an individual choice to gamble against briefly taking a safe med or becoming one of the unfortunate ones to experience disability or death.

When observed through the lens of US media coverage, what he says about Ivermectin in the context of comparing to Remdesivir is also revealing wrt the lack of coverage of what is known and being done with off-label medications, repeating and amplifying unsubstantiated negative stories, and the unwarranted boosting of remdesivir. The study that led to Gilead's billion dollar windfall in the US did not even find a significant mortality reducing effect, only that length of hospital stay was reduced by 4 days in people who survived. With Ivermectin, they are observing an early illness reducing effect from 21 days to 10 days duration which has a direct impact on overall virus transmission in a population. The transmission reducing effect would also be true for infected young healthy people who are potential super-spreaders.

Re several comments about Ivermectin used for heart worms in dogs and horses etc., realize it was first prescribed for people, not animals, to treat infectious disease, and has continued to be used in people on a very large scale. But that's also the case in like 99% of medications used in vet medicine for surgery, endocrine problems, infectious disease, and so on. A total red herring.

Anastasis · July 5, 2020

"Smell my pickle" may be a useful screening technique to add to fever checks.

https://www.statnews.com/2020/07/02/smell-tests-temperature-checks-covid19/

As experts have cast around for other screening tools, some have zeroed in on smell tests, which could be as simple asking people to identify a particular scent from a scratch-and-sniff card. Though not a universal symptom, loss of smell is one of the earliest signs of Covid-19 because of how the virus acts. Support cells in the olfactory epithelium, the tissue that lines the nasal cavities, are covered with the receptors that SARS-CoV-2 uses to enter cells. They become infected very early in the disease process, often before the body has mounted the immune response that causes fever.

“These support cells either secrete molecules that shut down the olfactory receptor neurons, or stop working and starve the neurons, or somehow fail to support the neurons,” said Danielle Reed, associate director of Monell Chemical Senses Center, a world leader in the science of taste and smell. As a result, “the [olfactory neurons] either stop working or die.”

In an analysis of 24 individual studies, with data from 8,438 test-confirmed Covid-19 patients from 13 countries, 41% reported that they had lost their sense of smell partly or completely, researchers reported in Mayo Clinic Proceedings. But in studies that used objective measurements of smell rather than simply asking patients, the incidence of anosmia was 2.3 times higher.

A Monell analysis of 47 studies finds that nearly 80% of Covid-19 patients have lost their sense of smell as determined by scratch-and sniff tests, Reed said. But only about 50% include that in self-reported symptoms. In other words, people don’t realize they have partly or even completely lost their sense of smell. That may be because they’re suffering other, more serious symptoms and so don’t notice this one, or because smell isn’t something they focus on.

Related:

Pharma giants to unveil major $1 billion venture to push novel antibiotics

In a recent study of 1,480 patients led by otolaryngologist Carol Yan of UC San Diego Health, someone with anosmia was “more than 10 times more likely to have Covid-19 than other causes of infection,” she said. Nasal inflammation from some 200 cold, flu, and other viruses can cause it, she said, but especially during the summer, when those infections are pretty rare, the chance that anosmia is the result of Covid-19 rises.

“Anosmia was quite specific to Covid-19,” she said.

Fever, in contrast, has many possible causes. Temperature checks will therefore flag more people as potentially infected with Covid-19 than smell tests will. The likelihood that anosmia indicates Covid-19, called a test’s positive predictive value, increases as the prevalence of Covid-19 increases, as it is in many areas of the U.S.

F250 · July 6, 2020

10 hours ago, Anastasis said:

"Smell my pickle" may be a useful screening technique to add to fever checks.

https://www.statnews.com/2020/07/02/smell-tests-temperature-checks-covid19/

I've been using that line for years.

"Hey baby, smell my pickle."

CHIEF · July 6, 2020

Here is a West Texas doctor that says he has had success with Budesonide. It is an anti-inflammatory corticosteroid he uses in nebulizers. Don't know much about any of that, but thoughts from our Docs would be nice to hear:

CHIEF

Captainant · July 6, 2020

28 minutes ago, CHIEF said:

Here is a West Texas doctor that says he has had success with Budesonide. It is an anti-inflammatory corticosteroid he uses in nebulizers. Don't know much about any of that, but thoughts from our Docs would be nice to hear:

CHIEF

Not a medical expert like any of our docs, but from some googling it looks like it's useful for treating acute respiratory symptoms, which could absolutely help to save lives in ICU. Seems to have many considerations and side effects to account for in prescribing though

Quote

Budesonide is used to prevent difficulty breathing, chest tightness, wheezing, and coughing caused by asthma. Budesonide powder for oral inhalation (Pulmicort Flexhaler) is used in adults and children 6 years of age and older. Budesonide suspension (liquid) for oral inhalation (Pulmicort Respules) is used in children 12 months to 8 years of age. Budesonide belongs to a class of medications called corticosteroids. It works by decreasing swelling and irritation in the airways to allow for easier breathing.

Liquor and Poker · July 6, 2020

On 7/4/2020 at 11:32 AM, triplehorn said:

I really don't get your negative response to the interview. I didn't read it as him being an expert and a guiding light. It's what he reveals about forces affecting pragmatism and influencing process. Nothing earthshaking that we haven't known before, just more confirmation it's happening with negative consequences during a deadly pandemic causing death and disability.

The lack of coherent national communication and apolitical decision making in the US (no CR) has created a void that naturally is being filled by those intent on maximizing profit and/or sowing confusion. The US historically has been a primary leader in medical problem solving and response, but right now there's quite a role reversal happening. Private US physicians are reaching out across borders to learn if they can help their patients avoid hospitalization and they are clearly taking action. However as it relates to access to timely outpatient care for covid19, should they want it, a giant swath of Americans infected with covid19 are left on the outside looking in. Here, forget about early treatment options, the first 3 months in the US was about where the hell you could even get fucking tested.

The stated philosophy:

"First, we must do everything within our power to address this disease earlier in the process. That is why the development of anti-viral medications targeting COVID-19 are so important. Ivermectin happens to have an incredible inhibiting effect on COVID-19 and we were pragmatic. Dominican Republic is blessed with beauty everywhere, incredible people and a great potential for business but it is still a relatively poor country. We don’t have the time to wait. We must treat as many people as possible and reduce the number of severe to critical cases."

This is the key advantage to having safe and inexpensive generic medications available for off-label use (Iver is ~$0.12 per dose). Due to established safety with minimal or known potential side effects, you can give them without knowing what the exact future course of illness holds for each person. It can be limited to use in people with risk factors like age and medical co-morbidities, but ultimately it's an individual choice to gamble against briefly taking a safe med or becoming one of the unfortunate ones to experience disability or death.

When observed through the lens of US media coverage, what he says about Ivermectin in the context of comparing to Remdesivir is also revealing wrt the lack of coverage of what is known and being done with off-label medications, repeating and amplifying unsubstantiated negative stories, and the unwarranted boosting of remdesivir. The study that led to Gilead's billion dollar windfall in the US did not even find a significant mortality reducing effect, only that length of hospital stay was reduced by 4 days in people who survived. With Ivermectin, they are observing an early illness reducing effect from 21 days to 10 days duration which has a direct impact on overall virus transmission in a population. The transmission reducing effect would also be true for infected young healthy people who are potential super-spreaders.

Re several comments about Ivermectin used for heart worms in dogs and horses etc., realize it was first prescribed for people, not animals, to treat infectious disease, and has continued to be used in people on a very large scale. But that's also the case in like 99% of medications used in vet medicine for surgery, endocrine problems, infectious disease, and so on. A total red herring.

I don’t disagree with much of that view on the state of things, but the article has more than a tinge of “I have the truth and it’s indisputable but they just won’t listen!” backed up by very little data other than anecdote.

orangeut · July 6, 2020

Edited July 6, 2020 by orangeut
another opinion

DDD Dad · July 6, 2020

28 minutes ago, orangeut said:

Oh, good. An opinion piece produced for Sinclair Media by conservative think-tank policy wonk who happens not to be an epidemiologist.

I'll give it a listen but color me skeptical.

ETA: Well this probably should go in the "non-political" general COVID thread. He really doesn't add anything to the medical discussion. It's all policy and statistical analysis.

Edited July 6, 2020 by DDD Dad

orangeut · July 7, 2020

Well maybe you should listen to it, it talks about schools starting and opinions he has about it which is pertaining to some of the above posts. I don't know anything about any Sinclair Media, I thought it was just interesting being from the Hoover Institute of Stanford University.

DDD Dad · July 7, 2020

Well maybe you should listen to it, it talks about schools starting and opinions he has about it which is pertaining to some of the above posts. I don't know anything about any Sinclair Media, I thought it was just interesting being from the Hoover Institute of Stanford University.

I did listen to it, and he has a point regarding schools. There is some belief but still far from a consensus that children (pre-puberty) don’t seem to be as contagious because the virus tends to manifest as inflammation rather than traditional cold/flu respiratory symptoms.

That said, the risk of schools being super spreader vectors to those in the children’s families and to the school staff is an issue that he seems to ignore or minimize.

But leaving aside this particular video, this guy has been anti-lockdown since day one.

Liquor and Poker · July 7, 2020

30 minutes ago, orangeut said:

Well maybe you should listen to it, it talks about schools starting and opinions he has about it which is pertaining to some of the above posts. I don't know anything about any Sinclair Media, I thought it was just interesting being from the Hoover Institute of Stanford University.

that guy is the go-to med pundit for the Daily Caller, Washington Times, Fox News, and National Review. His opinions are far from non-political. Just google him

GRHorn · July 7, 2020

Anecdotal note here, but the first doc I know in SA that was positive, caught it on a ski trip over spring break to Colorado. At one surgery center where they periodically check she just came back with no antibodies.

I haven’t really dug into immunology since med school days, but I have a hard time thinking that if she was exposed to Covid again today that she wouldn’t have a much milder course of illness. So how is that likely mediated? T cells, NK cells? Are the tests just missing different antibodies to the same virus?

When I combine that story with the study showing 5% seroprevalence in Spain, it really makes me question how many people have been exposed in Spain and elsewhere and how much immunity the community has.

DDD Dad · July 7, 2020

32 minutes ago, GRHorn said:

Anecdotal note here, but the first doc I know in SA that was positive, caught it on a ski trip over spring break to Colorado. At one surgery center where they periodically check she just came back with no antibodies.

I haven’t really dug into immunology since med school days, but I have a hard time thinking that if she was exposed to Covid again today that she wouldn’t have a much milder course of illness. So how is that likely mediated? T cells, NK cells? Are the tests just missing different antibodies to the same virus?

When I combine that story with the study showing 5% seroprevalence in Spain, it really makes me question how many people have been exposed in Spain and elsewhere and how much immunity the community has.

https://www.nytimes.com/2020/06/18/health/coronavirus-antibodies.html

Short answer is, no one knows yet. Some suspect that immunity may exist after antibodies disappear (through T cells, B cells, e.g.), but I haven't seen any formal studies published.

Anastasis · July 7, 2020

38 minutes ago, GRHorn said:

Anecdotal note here, but the first doc I know in SA that was positive, caught it on a ski trip over spring break to Colorado. At one surgery center where they periodically check she just came back with no antibodies.

I haven’t really dug into immunology since med school days, but I have a hard time thinking that if she was exposed to Covid again today that she wouldn’t have a much milder course of illness. So how is that likely mediated? T cells, NK cells? Are the tests just missing different antibodies to the same virus?

When I combine that story with the study showing 5% seroprevalence in Spain, it really makes me question how many people have been exposed in Spain and elsewhere and how much immunity the community has.

Article on Derek Lowe's blog about this today. His blog is regularly updated with timely information and is worth a follow.

More on T Cells, Antibody Levels, and Our Ignorance

By Derek Lowe 7 July, 2020

https://blogs.sciencemag.org/pipeline/archives/2020/07/07/more-on-t-cells-antibody-levels-and-our-ignorance

I wrote here about the reports of rather short antibody persistence in recovering coronavirus patients, and what’s been coming out in the two weeks since then has only made this issue more important. In that post, I was emphasizing that although we can measure antibody levels, we don’t know how well that correlates with exposure to the virus nor to later immunity from it, and that T cells are surely a big part of this picture that we don’t have much insight into.

This Twitter thread by Eric Topol is exactly what I mean, and this article that he references is an important read. Its schematic at right (see also here) will help make clear that antibody levels are only one aspect of the immune response to the infection – it’s an important one, but we’re making it look even more important than it is because it’s by far the easiest part of the process to measure. The T-cell response (much harder to get good data on) is known to be a key player in viral infections, and is also known to be highly variable, both between different types of pathogens and among individuals themselves. The latter variations are also beginning to be characterized among patients in the current pandemic. We have to get more data on it across a broader population of patients in order to make sense of what we’re seeing.

Many readers will have seen, for example, this new paper from The Lancet on a large study in Spain. Testing tens of thousands of people across the country continues to show that (on average) only about 5% of the population is seropositive (that is, has antibodies to the virus). There are a lot of interesting findings – such as rather large differences in those positive testing rates in different regions of the country, as well as the realization that at least one-third of the people who now test positive never showed any symptoms at all. But we are still not sure if this means that 95% of the Spanish population has never been exposed to the virus, because we don’t know how many people might have cleared it without raising enough of an antibody response to still be detectable. This paper does show that seroprevalence was about 90% in people 14 days after a positive PCR test, which indicates that most people do raise some sort of antibody response, but we don’t know how many of these people will still show such antibodies at later testing dates. Remember the paper discussed in that link in the first paragraph above, which found that 40% of asymptomatic patients went completely seronegative during their convalescence.

In other words, the Spanish survey may appear to show that 95% of the country has not yet been exposed to the coronavirus, but that’s almost certainly not true. The authors do mention that cellular immunity is important and not something that they were able to address, but the combination of that factor plus the apparent dropoff in antibody levels with time makes these large IgG surveys almost impossible to interpret. But note that if there are indeed many people who have been exposed but do not read out in such surveys, that we also have no idea how immune they are to further infection. At a minimum, you’d want to know antibody levels over time, T-cell response over time, and (importantly) what a protective profile looks like for both of those. We barely have insight into any of this: the large-scale data are just a snapshot of antibody levels, and that’s not enough.

We have similar data here in the US: several surveys of IgG antibodies show single-digit seroconversion. You could conclude that we have large numbers of people who have never been exposed – and indeed, the recent upswing in infections in many regions argues that there are plenty of such people out there. But we need to know more. We could have people who look vulnerable but aren’t – perhaps they show no antibodies, but still have a protective T-cell response. Or we could have people who look like they might be protected, but aren’t – perhaps they showed an antibody response many weeks ago that has now declined, and they don’t have protective levels of T-cells to back them up. Across the population, you can use the limited data we have and our limited understanding of it to argue for a uselessly broad range of outcomes. Things could be better than we thought, or worse, getting better or deteriorating in front of our eyes. We just don’t know, and we have to do better at figuring it out.

Liquor and Poker · July 7, 2020

2 minutes ago, Anastasis said:

Article on Derek Lowe's blog about this today. His blog is regularly updated with timely information and is worth a follow.

More on T Cells, Antibody Levels, and Our Ignorance

By Derek Lowe 7 July, 2020

https://blogs.sciencemag.org/pipeline/archives/2020/07/07/more-on-t-cells-antibody-levels-and-our-ignorance

So we don't know. Like everything else. The Scooby Doo COVID episode is getting old.

gmr548 · July 7, 2020

My mind went to Derek Lowe, the pitcher, and I was really getting a kick out of the idea of him having a medical blog.

TwiceHorn · July 8, 2020

So, physicians and healers. I am detecting, not for the first time, that hospitalizations greatly outnumber ICU "visits."

What is the progression here? People are hospitalized for? Respiratory distress mostly? High fever?

And then how are they treated? Oxygen? Pulmonary steroids? Blood thinners/anticoagulants?

It doesn't seem inevitable that they are put on a vent in ICU (I assume that ventilator pretty much means ICU).

What percentage of those hospitalized end up in ICU, and then dead?

Sawbonz · July 10, 2020

On 7/6/2020 at 2:51 PM, Captainant said:

Not a medical expert like any of our docs, but from some googling it looks like it's useful for treating acute respiratory symptoms, which could absolutely help to save lives in ICU. Seems to have many considerations and side effects to account for in prescribing though

This is the generic for pulmacort I believe. Millions of people with asthma, including infants and toddlers, use this daily either as an inhaler or nebulizer. Probably almost as safe as intranasal steroids many of which are now otc. I read an in vitro study of a related drug that showed inhibition of Covid-19 replication in lung cells.

Chronic asthmatics and COPDers have shown a paradoxically low incidence of COVID-19 infection and complications, and one explanation could be their daily use of inhaled steroids.

I know a couple of PCPs using a cocktail of oral dexamethasone and a broad spectrum antibiotic on their covid patients and have not had any require hospitalization. Small numbers treated early so who knows what their natural course would have been, but it makes sense to suppress the body’s inflammatory attack on the lungs and prevent bacterial superinfection

Apparently similar regimens are common in Asian countries from their previous SARS experiences, and their death rates have been extremely low. Probably multiple factors leading to that though

Anastasis · July 10, 2020

16 minutes ago, Sawbonz said:

Chronic asthmatics and COPDers have shown a paradoxically low incidence of COVID-19 infection and complications, and one explanation could be their daily use of inhaled steroids.

Have you seen any formal analysis of this? If so please link. That would be quite interesting.

Liquor and Poker · July 10, 2020

1 hour ago, Sawbonz said:

This is the generic for pulmacort I believe. Millions of people with asthma, including infants and toddlers, use this daily either as an inhaler or nebulizer. Probably almost as safe as intranasal steroids many of which are now otc. I read an in vitro study of a related drug that showed inhibition of Covid-19 replication in lung cells.

Chronic asthmatics and COPDers have shown a paradoxically low incidence of COVID-19 infection and complications, and one explanation could be their daily use of inhaled steroids.

I know a couple of PCPs using a cocktail of oral dexamethasone and a broad spectrum antibiotic on their covid patients and have not had any require hospitalization. Small numbers treated early so who knows what their natural course would have been, but it makes sense to suppress the body’s inflammatory attack on the lungs and prevent bacterial superinfection

Apparently similar regimens are common in Asian countries from their previous SARS experiences, and their death rates have been extremely low. Probably multiple factors leading to that though

So we have had wild and crazy swings on corticosteroids too. Early in the European wave corticosteroids were anything from ineffective to being blamed for killing people with COVID.

In the last 4 months I have seen credible (well, at least credible-looking and reported) data telling me to (1) immediately stop taking ARBs and ACEIs, or load up on them as soon as you get sick; (2) take some elderberry shit, or do everything I can to not even look at an elderberry (easy enough there); (3) start taking zinc now, or try not to take it at least until symptoms; (4) wean your asthmatics off corticosteroids and make sure hospitals don’t give them, or maybe everyone should be puffing away.

I’m not even counting the whole hydroxychloroquine thing.

You’d thing by now at least some of this shit would have sorted out.

Bevo · July 10, 2020

25 minutes ago, Liquor and Poker said:

So we have had wild and crazy swings on corticosteroids too. Early in the European wave corticosteroids were anything from ineffective to being blamed for killing people with COVID.

In the last 4 months I have seen credible (well, at least credible-looking and reported) data telling me to (1) immediately stop taking ARBs and ACEIs, or load up on them as soon as you get sick; (2) take some elderberry shit, or do everything I can to not even look at an elderberry (easy enough there); (3) start taking zinc now, or try not to take it at least until symptoms; (4) wean your asthmatics off corticosteroids and make sure hospitals don’t give them, or maybe everyone should be puffing away.

I’m not even counting the whole hydroxychloroquine thing.

You’d thing by now at least some of this shit would have sorted out.

Maybe, maybe not. Corticosteroids may still be a problem if given in high doses. With inhaled corticosteroids, very little enters the bloodstream and its actions remain mainly in the pulmonary tract. Oral and IV corticosteroids in general weaken your immune system and can make you more susceptible to viral and bacterial infections. On the other hand, oral and IV corticosteroids block the inflammatory response which is a major cause of mobidity and mortality in COVID patients. So, it is a complicated subject with no clear answers and the timeframe from January to now has been too short to get definitive answers.

Edited July 10, 2020 by Bevo

Sawbonz · July 10, 2020

5 hours ago, Anastasis said:

Have you seen any formal analysis of this? If so please link. That would be quite interesting.

Anecdotally noted by the investigators who are running this trial:

https://www.trialsitenews.com/oxford-queensland-university-of-technology-team-on-stoic-trial-can-inhalers-stop-covid-19-from-progressing/

GRHorn · July 14, 2020

Study review of some of the stuff related to pediatric transmission.

Spoiler

VII editorial: Part of the theme of today’s Daily Briefing revolves around the controversy how and when to reopen schools. One thing is clear, truly little is clear and there is no roadmap. The dilemma is how to minimize the spread of SARS-CoV-2 in schools while making sure students are prepared for the future. The UK’s Royal College of Pediatrics and Child Health has warned that leaving schools closed “risks scarring the life chances of a generation of young people.” The organization’s American counterpart, the American Academy of Pediatrics (AAP), has urged administrators to begin from “a goal of having students physically present in school.” Keeping schools closed for prolonged periods of time has serious implications for social, academic, and child development. For many students, school serves more than just a place for academics, but also serves as a place where they can receive reliable meals and health care as well as physical and mental development. As the article below (and comment) suggests most evidence to date suggests that even if children under 12 are infected at the same rates as the adults around them, they are less likely to spread it. The experience from abroad has indicated that measures such as social distancing, masking, increasing cleaning, daily screening, hand washing, installation of physical barriers, repurposing gyms and cafeteria to increase space, and using available outdoor space can make a difference. Students with underlying medical problems should be offered full distance learning. Superintendents must also consider the safety of their teachers some who may be older and/or have underlying medial conditions. Teachers should be given necessary appropriate equipment and physical barriers in their classroom and in other common areas. Since the pandemic is unpredictable, schools need to be flexible and have several alternative plans for the coming year: traditional classroom learning, full distance learning, and a hybrid of inclassroom learning and distance learning. School may need to have staggered schedules depending on the number of students and ability to maintain social distancing at school. Implementing appropriate measures, however, will be costly and districts will need both financial and technical support. Parents need schools too. They need school to help raise their children and many parents also need to work and depend on children being in school as a safe place for them while they are at work. I agree with IDSA/HIVMA(see below) that local officials should have the discretion to tailor actions based on local conditions on the ground. This should not be political-we should adopt reasonable measures so we can open schools as safely as possible so we can meet the educational and social needs of our children. As the AAP acknowledges, the best interventions can reduce risk, but not entirely eliminate risk. Also included the today’s COVID-19 Daily Briefing an article on hold long taste and smell return after SARS-CoV-2 infection, an article on risk of PPIs and SARS-CoV-2 infection, a study on the incidence of stillbirth and preterm delivery during the pandemic, and lastly the measurement of airborne particle exposure during simulated tracheal intubation using various proposed aerosol containment devices(e.g. intubation box) during the COVID-19 pandemic.

COVID-19 in Children and the Dynamics of Infection in Families, Journal of Pediatrics published online July 2020 Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute SARS-CoV-2 transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission. The aim of this work was to describe the clinical presentation of the first 40 pediatric cases of COVID-19 in Geneva and the dynamics of their familial clusters. From March 10 to April 10, 2020, all patients <16 years old with SARS-CoV-2 infection were identified by means of the Geneva University Hospital’s surveillance network. The network notifies the institution’s pediatric infectious diseases specialists about results of nasopharyngeal specimens tested for SARS-CoV-2 by PCR. Among a total of 4310 patients with SARS-CoV-2, 40 were <16 years old (0.9%). All but one was available for evaluation. 29 (74%) patients were previously healthy; the most frequently reported comorbidities were asthma (10%), diabetes (8%), obesity (5%), premature birth (5%), and hypertension (3%). Seven patients (18%) were hospitalized to the ward, for a median duration of 3 days (IQR: 2–4) No patient required ICU admission or SARS-CoV-2–specific therapies. The others 32 patients were managed as outpatients. All patients had a complete resolution of symptoms by day 7 after diagnosis. In 79% of households, ≥1 adult family member was suspected or confirmed for COVID-19 before symptom onset in the study child, confirming that children are infected mainly inside familial clusters. Surprisingly, in 33% of households, symptomatic household contacts (HHCs) tested negative despite belonging to a familial cluster with confirmed SARSCoV-2 cases, suggesting an underreporting of cases. In only 8% of households did a child develop symptoms before any other HHC, which is in line with previous data in which it is shown that children are index cases in <10% of SARS-CoV-2 familial clusters. Comment: The study sample may not represent the total number of pediatric SARS-CoV-2 cases during this time period since patients with milder or atypical presentation might not have sought medical attention. In addition, the recall of symptom onset among HHCs might be inaccurate, although this seems less likely because of the confinement measures and anxiety in the community. These findings are consistent with other recently published HHC investigations in China. Similarly, transmission of SARS-CoV-2 by children outside household settings seems uncommon, although information is limited. In a study from France, a 9-year-old boy with respiratory symptoms associated with picornavirus, influenza A, and SARS-CoV-2 coinfection was found to have exposed over 80 classmates at 3 schools; no secondary contacts became infected, despite numerous influenza infections within the schools, suggesting an environment conducive to respiratory virus transmission. (Clin Infect Dis published online April 11, 2020). In a publication from Australia, 9 students and 9 staff infected with SARS-CoV-2 across 15 schools had close contact with a total of 735 students and 128 staff. Only 2 secondary infections were identified, none in adult staff; 1 student in primary school was potentially infected by a staff member, and 1 student in high school was potentially infected via exposure to 2 infected schoolmates. (National Centre for Immunization Research and Surveillance; 2020) On the basis of these data, SARS-CoV-2 transmission in schools may be less important in community transmission than initially feared. This would be another manner by which SARS-CoV-2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy. Accumulating evidence and collective experience argue that children, particularly school-aged children, are far less important drivers of SARS-CoV-2 transmission than adults. This information should be considered in allowing schools to remain open, even during periods of COVID-19 spread.

Infectious Diseases Society of America(IDSA) and the HIV Medicine Association(HIVMA) Call for Evidence based Decisions on School Reopenings published July 10, 2020 highlights IDSA/HIVMA recognize the need to balance concerns surrounding the ongoing COVID-19 pandemic with community concerns, including the benefits of reliable nutrition, physical activity and social development that are provided by onsite education of our children. While data indicate that children are less likely to develop serious illness due to COVID-19 and to transmit the disease, instances in which children have fallen seriously ill — including with multi-system inflammatory syndrome in children (MIS-C) – and in which children have died, should raise concerns, given that much remains unknown about the dynamics of the new coronavirus. In addition, teachers, school administrators and other adults critical to school operation may be more vulnerable, due to age or conditions carrying higher risks to severe COVID-19 disease and death. Flexibility must be provided for students, teachers and staff with underlying health conditions that place them at risk for complications from COVID-19. Provisions for at-risk students should include distance learning only, and for their at-risk teachers, the option to provide only distance education. Policies for symptom screening of students and school staff, and responses in the event of student or staff member COVID-19 illness, must be in place prior to school reopening, with the understanding that those policies must be adapted to continued advances in our understanding of the virus. Recognizing that a substantial proportion of individuals who are asymptomatic may be capable of transmitting infection, adequate access to testing is also a concern. New funding for all school systems is essential, and it must be adequate to ensure safe conditions, including appropriate physical distancing, as well as sufficient quantities of masks and other personal protective equipment, hand sanitizer, and appropriate cleaning and disinfection of classrooms and surfaces in common areas, school buses and other community forms of transportation for students. In settings where remote learning remains necessary, funding is needed to support access to tablet or laptop computers and broadband in the home so that educational disruption is minimized. Sustained reductions in overall community transmission rates are critical to safe school reopening, and the use of face masks and appropriate distancing in all settings for all community members must remain paramount. No school should be forced to open in a situation that presents unacceptable risks.

texhorn · July 14, 2020

Some good news on the Moderna effort:

https://www.businesswire.com/news/home/20200714006042/en/Moderna-Announces-Publication-New-England-Journal-Medicine

Txzen · July 15, 2020

I'm hopeful as anyone else, mostly because mRNA vaccines may be the best approach from a scalability standpoint for a global pandemic. It's great to see there's a titer raised, but we don't yet know if it is effective (or protective). The adverse events with the 250ug injection mirror some of the moderate to severe reactions seen in previous trials with this approach in a cancer setting. Still a lot to understand with this system.

Txzen · July 15, 2020

Link to the above paper : https://pediatrics.aappublications.org/content/pediatrics/early/2020/07/08/peds.2020-1576.full.pdf?download=true

It's a study from Switzerland, looking at families and family transmission from March to April of this year, 'the clinical presentation of the first 40 pediatric cases of COVID-19 in our city'.

The positive read to the data is that ~80% of the time it appeared that the adults in the household appeared COVID positive first, and 'only' 8% of the time were the children positive. Note that in Switzerland schools closed in March and only just reopened in May (link). The potential conclusion here is that children are less likely to be the primary vector of transmission, I suppose. But if the schools were closed, does this really tell us much? And 'only' 8%, in a situation where perhaps the children are mostly sequestered, may underreport the risk (and they ackloedge as much in the paper).

A longer rebuttal to my argument here, with additional global examples which may suggest that the potential transmission from child to adult is rare : COVID-19 Transmission and Children: The Child Is Not to Blame

Anastasis · July 15, 2020

10 minutes ago, Txzen said:

Link to the above paper : https://pediatrics.aappublications.org/content/pediatrics/early/2020/07/08/peds.2020-1576.full.pdf?download=true

It's a study from Switzerland, looking at families and family transmission from March to April of this year, 'the clinical presentation of the first 40 pediatric cases of COVID-19 in our city'.

The positive read to the data is that ~80% of the time it appeared that the adults in the household appeared COVID positive first, and 'only' 8% of the time were the children positive. Note that in Switzerland schools closed in March and only just reopened in May (link). The potential conclusion here is that children are less likely to be the primary vector of transmission, I suppose. But if the schools were closed, does this really tell us much? And 'only' 8%, in a situation where perhaps the children are mostly sequestered, may underreport the risk (and they ackloedge as much in the paper).

A longer rebuttal to my argument here, with additional global examples which may suggest that the potential transmission from child to adult is rare : COVID-19 Transmission and Children: The Child Is Not to Blame

What about the reverse, positive child transmitting to parents. Only a small number of anecdotes, but I have seen a number of situtations where an entire family was testing and only one of the children were positive. Negative for everyone else. And children in both cases were asymptomatic.

Txzen · July 15, 2020

I think that's what the Swiss paper is arguing - children rarely infected the household. But honestly, we're dealing with such minuscule information at this stage, I think it's hard to understand all the permutations. Maybe Orange County will be the test case.

BradInATX · July 15, 2020

So if Moderna can only make 500mm doses in year 1, does that mean all of America and 200mm left for the rest of the world to fight over?

Edited July 15, 2020 by BradInATX

TwiceHorn · July 15, 2020

3 minutes ago, BradInATX said:

So if Moderna can only make 500mm doses in year 1, does that mean all of America and 200mm left for the rest of the world to fight over?

Well, if they file patents elsewhere in the world, they may be subject to compulsory licensing, which would authorize manufacture in that country whether Moderna consents or not.

Moderna would probably be wise, from a PR standpoint. to license out the "formula" and all the know-how to make it.

BradInATX · July 15, 2020

2 minutes ago, TwiceHorn said:

Well, if they file patents elsewhere in the world, they may be subject to compulsory licensing, which would authorize manufacture in that country whether Moderna consents or not.

Moderna would probably be wise, from a PR standpoint. to license out the "formula" and all the know-how to make it.

That was sort of my understanding of this vaccine in general too - that it would serve the company to license it for as rapid as possible deployment of 6 billion doses and just sit and shower in the money bukkake. But the few articles I've read about this one seem to say that Moderna has capacity for 500mm doses/year as if it's going to be limited to that. That's why I asked, not sure if poor journalism or if there's reason to believe Moderna wouldn't want to license it.

Sbbruin · July 15, 2020

7 minutes ago, BradInATX said:

So if Moderna can only make 500mm doses in year 1, does that mean all of America and 200mm left for the rest of the world to fight over?

It is going to be manufactured by numerous pharmaceutical cos. Anyone with the capacity. Pfizer is already helping with the manufacturing. They are talking about having 1 billion doses available by January.

Anastasis · July 16, 2020

MRNA has a plant lined up here and one in Spain for European distribution. Assume that they will do different things for third world and emerging markets.

Skipper · July 16, 2020

For those that have studied the vaccine trials a little more closely, I've read several trials to date required multiple doses. Do we think a 'final' vaccine with multiple doses is likely? Because I think we are already looking at a material portion of the population that would refuse a vaccine, and if you require multiple doses, it seems like the percentage opting out would be even larger.

Txzen · July 16, 2020

Well, nature has a way of dealing with those people.

For the mRNA based Moderna vaccine it seems likely to require multiple hits. Not sure it’s necessary for the attenuated AstraZeneca/Oxford one.

GRHorn · July 16, 2020

On 7/7/2020 at 8:51 PM, TwiceHorn said:

So, physicians and healers. I am detecting, not for the first time, that hospitalizations greatly outnumber ICU "visits."

What is the progression here? People are hospitalized for? Respiratory distress mostly? High fever?

And then how are they treated? Oxygen? Pulmonary steroids? Blood thinners/anticoagulants?

It doesn't seem inevitable that they are put on a vent in ICU (I assume that ventilator pretty much means ICU).

What percentage of those hospitalized end up in ICU, and then dead?

No one has really answered so I’ll give you what I’ve observed.

First of all, last week there was probably 4-5 patients sent home from the ER with a positive diagnosis for every one that was admitted. They are admitted for acute hypoxic respiratory failure. Low O2 sats, shortness of breath, usually tachypneic. Most do not progress to ICU. Just need O2 support for a day or two. They’re all getting oral steroids, anticoagulation prophylaxis with lovenox. Also getting the Vit C, zinc, axithromycin, rocephin combo. For any given day typically there’s twice as many floor patients vs icu. Evidently it’s pretty clear which patients are going to pitstop In the hospital for a day or two and go home, and which are gonna deteriorate.

I have one later today that follows a fairly typical pattern for the ones that do worse. Came to hospital after having cough for about 10 days at home. The last few days was short of breath with nausea and vomiting. Admitted to icu and started on above meds and high flow nasal bipap, similar to your cpap machine at home. Condition kind of waxed and waned a little. Consulted for remdesivir and convalescent plasma. He refused the plasma because he’s a Jehovah’s Witness. Committee approval required for remdesivir. On about hospital day 6 he gets a cold foot. Taken for emergent thrombectomy (removal of clot from artery). Had to be intubated for surgery and stayed that way after. Put on heavier anticoagulation. Foot now dead a couple days later. Gonna have amputation. Kidneys failing. He’s fucked.
71 year old. Diabetes, HTN.

Anastasis · July 17, 2020

Maybe we finally move on...

Early intervention, North America-based, HCQ RCT, writing on the wall for a while, finally hits the press.

https://www.acpjournals.org/doi/10.7326/M20-4207

Abstract

Background:

No effective oral therapy exists for early coronavirus disease 2019 (COVID-19).

Objective:

To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients.

Design:

Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668)

Setting:

Internet-based trial across the United States and Canada (40 states and 3 provinces).

Participants:

Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset.

Intervention:

Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo.

Measures: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.

Results:

Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, −0.27 points [95% CI, −0.61 to 0.07 points]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).

Limitations:

Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.

Conclusion:

Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.

Edited July 17, 2020 by Anastasis

Bruno Sardine · July 17, 2020

23 minutes ago, Anastasis said:

Maybe we finally move on...

Early intervention, North America-based, HCQ RCT, writing on the wall for a while, finally hits the press.

https://www.acpjournals.org/doi/10.7326/M20-4207

Abstract

Background:

No effective oral therapy exists for early coronavirus disease 2019 (COVID-19).

Objective:

To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients.

Design:

Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials.gov: NCT04308668)

Setting:

Internet-based trial across the United States and Canada (40 states and 3 provinces).

Participants:

Symptomatic, nonhospitalized adults with laboratory-confirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset.

Intervention:

Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo.

Measures: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days.

Results:

Of 491 patients randomly assigned to a group, 423 contributed primary end point data. Of these, 341 (81%) had laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or epidemiologically linked exposure to a person with laboratory-confirmed infection; 56% (236 of 423) were enrolled within 1 day of symptoms starting. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (difference in symptom severity: relative, 12%; absolute, −0.27 points [95% CI, −0.61 to 0.07 points]; P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine versus 22% (46 of 211) receiving placebo (P < 0.001). With placebo, 10 hospitalizations occurred (2 non–COVID-19–related), including 1 hospitalized death. With hydroxychloroquine, 4 hospitalizations occurred plus 1 nonhospitalized death (P = 0.29).

Limitations:

Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.

Conclusion:

Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.

Is that study better than this study?

https://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext

I ask because I really don't know. Yours is newer, for sure. Just noting that it's confusing when studies seem to contradict one another.

Edited July 17, 2020 by Bruno Sardine

Anastasis · July 17, 2020

1 minute ago, Bruno Sardine said:

Is that study better than this study?

https://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext

I ask because I really don't know.

Yes, the design is stronger. Prospective trial with random assignment and placebo control vs. retrospective observational study.

Anastasis · July 17, 2020

7 minutes ago, Bruno Sardine said:

Just noting that it's confusing when studies seem to contradict one another.

And I agree. There is so much noise right now, it's hard to detect the signal. HCQ pimpers aren't really helping the situation. Might as well be rubbing a quartz rock at this point.

Bruno Sardine · July 17, 2020

7 minutes ago, Anastasis said:

Yes, the design is stronger. Prospective trial with random assignment and placebo control vs. retrospective observational study.

Gracias.

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