Saturday, March 4, 2023

Leak Or Leap?


Promising treatments new and old, more and better data on vaccine effectiveness, the origin battle featuring the phony House investigation, international oddities, masks and other shields, the impending non-emergency, and varieties of bunk.


How interferon spurs the innate immune system to attack viruses

Molnupiravir: Evidence is starting to come in that the failed antiviral molnupiravir is actually, not just theoretically, breeding new variants. Here’s one study, and here’s another. Though in early 2022 it was being prescribed widely, more recently molnupiravir has been largely discarded in favor of Paxlovid and remdesivir. In Australia it was the most widely prescribed antiviral until December, when new guidelines recommended it only as a last resort. In Hong Kong it is still being used. UK authorities now recommend against it, but only because of its cost, the same reasonthey shamefully restrict the use of remdesivir. Following proof that molnupiravir does not work to prevent progression of COVID-19, Merck has been forced to report that it also does nothing to prevent the transmission of SARS-CoV-2 among household members. This drug should be scrapped.

Paxlovid in hospitalized patients: Paxlovid is effective in reducing severe outcomes in COVID-19 outpatients, but does it help people who are already gravely ill? A Chinese study of patients hospitalized in April-May 2022 leaves the question open. Among 132 patients randomized to Paxlovid, 5 died within 28 days, versus 8 among the 132 getting standard care alone, a superiority that was not statistically significant. Omicron so rarely kills that it would have taken a much much larger study to give a definitive answer. The researchers chose their sample sizes assuming that 30% of the hospitalized patients would die, whereas only 4.9% actually did.

Paxlovid in the Age of Omicron: In a study from the University of Colorado high-risk patients – mostly vaccinated and boosted – who received Paxlovid were less than half as likely to require hospitalization and just an eighth as likely to die as those who did not.

Interferon: A single subcutaneous injection of an immune booster, pegylated interferon lambda, has been reported to halve rates of a combination endpoint (hospitalization plus prolonged ER visits) in high-risk, mostly double-vaccinated Brazilian COVID-19 patients. There were hardly any side effects, because lambda is a Type 3 interferon, unlike the toxic drugs formerly used for hepatitis C. The senior author founded the manufacturing company and sits on its Board, the sort of thing that raises red flags. Jeremy Faust, who’s as skeptical an observer as I am but clearly a more careful reader, also noticed, buried in Supplementary Table 4 in the online Appendix, that when the researchers looked at all-cause rather than COVID-19-specific ER visits, hospitalizations, or death, the benefit completely disappeared. He says sensibly, “As a patient, I don’t really care whether I die of Covid or of something else. If a drug lowers my Covid death rate, but not my overall death rate, I sort of lose interest.” Also, the drug did nothing to shorten illness (remember, Paxlovid doesn’t either). And Faust thinks one injection will likely cost many thousands of dollars, if it ever hits the market at all. The NEJM has posted a superb oral discussion of interferon lambda, though I’m afraid it may go over the head of non-medical listeners. 

Convalescent plasma: Now that monoclonal antibody treatments have lost the race with COVID-19 variants, interest might rekindle in convalescent plasma, which has a similar mechanism but whose efficacy has always been unclear. A new meta-analysis, however, suggests that giving COVID-19 patients serum with high levels of anti-SARS-CoV-2 antibodies within 5 days of their falling ill cuts the risk of disease progression in half.

Snake oil: Republicans are more likely than Democrats to believe in quack COVID-19 cures such as hydroxychloroquine and ivermectin. Now we know one reason why – their doctors are too. In a new study, physicians who self-identified as conservative were 5 times more likely than liberal or moderate ones to prescribe hydroxychloroquine to a hypothetical patient with severe COVID-19. They were also just as likely as conservative laypeople to think vaccines were ineffective. In case you’re curious, the prize for biggest malprescriber goes to the infamous Stella Immanuel, of demon sex/alien DNA fame,who wrote 69,000 prescriptions for hydroxychloroquine and 32,000 for ivermectin in 2021 (but only 30,996 and 16,085 in 2022!). Enough to sprain anybody’s writing hand.

Ensitrelvir fumaric acid: This new antiviral, like Paxlovid an oral protease inhibitor, will now be tested on hospitalized COVID-19 patients in a trial sponsored by the US National Institutes of Health as part of ACTIV-3. Why not test it on outpatients instead, as in the main Japanese study? According to a press release, this drug proved its efficacy by shortening the duration of symptoms, though the difference between 167.9 and 192.2 hours seems clinically insignificant to me. Frankly, I’m much more optimistic about the new Chinese antiviral, VV116, a derivative of remdesivir.

Remdesivir: First used in hospitalized patients, this drug was found to be much more effective when given to outpatients during their first few days of illness. Now for the first time a study, or rather a large meta-analysis, has succeeded in showing that it does in fact reduce mortality in selected inpatients. The death rate fell by only 12%, though, and patients on ventilators actually did a bit worse on remdesivir. I’m not impressed.



One proposed approach for new and better vaccines

Covifenz: The Canadian company making this grown-on-tobacco COVID-19 vaccine has folded. I always suspected the whole story was something of a scam.

Next generation: Here’s a summary of some of the new directions researchers are going in order to get better and broader vaccines.

Booster compositionJeremy Faust thinks that future ones should be all Omicron instead of half-and-half. I’m not so sure, because of how well the old monovalent Wild strain boosters have continued protecting against severe disease. He also has written a balanced presentation of the bivalent debate that may have been outdated by the studies I report below…

Booster effectiveness: An FDA report says, on the positive side, that bivalent boosters are quite effective against XBB sublineages. On the negative side, that protection starts waning fast. In people over 65 the added protection against symptomatic COVID-19 at 2-4 weeks after the shot was 55% against BA.5 and 50% against XBB, but it fell at 2-3 months to 32% and 42% respectively. Protection against hospitalization was considerably better, starting at 73-83% and fading more slowly. A study from the University of North Carolina compared bivalent to monoclonal boosters in late 2022, and found the bivalent version much more effective in preventing severe COVID-19 or death: 61.8% vs. 24.9% overall. Followup was long enough to be able to see that the updated boosters’ effectiveness started to waneafter just a month, and that by 14 weeks it had dropped to under 30%. 

Booster frequency: A CDC expert panel has recommended that everybody, even the immunocompromised, get boosters only once a year. The final decision is still unclear. Given that their effectiveness plummets after just a few months, I’m skeptical. FDA advisers Eric Rubin, Jerry Weir, and Pamela McInnes, plus my most trusted experts Paul OffittEric Topol, and Jeremy Faust, all share my doubts

CoronaVac: Protection against hospitalization from this Chinese whole-virus vaccine was as long-lasting as from Pfizer’s vaccine. But we have always known that CoronaVac’s efficacy against infection and milder disease is weak.

Little kids: Results from the Phase 3 study of 3-dose Pfizer vaccination in babies and toddlers shows overall efficacy of 71.8% against symptomatic COVID-19. Unfortunately they had only 4 months’ follow-up, and even more unfortunately the efficacy was only 13.3% against BA.4, based on 3 cases. The researchers will continue to follow their subjects until at least June 2023, so we’ll have a chance to see how the protection evolves over time and against new variants.


Leak vs. leap

Debates over the pandemic's origin are definitely the hottest recent COVID-19 stories.

Newly unredacted emails show that prominent NIH scientists once seriously considered the possibility that a lab leak was behind the pandemic. Let me point out that those emails are from January-February 2020, even before a pandemic had been declared, when we knew next to nothing about COVID-19 or the SARS-CoV-2 virus that causes it, and two years before strong epidemiological and molecular evidence of a species leap was published in Science. One of the scientists who harbored those initial suspicions, Robert Garry, changed his tune just a month later and by late 2022 had become a prominent voice arguing for a natural origin of the virus, as was Kristian Anderson, who also featured in those emails.

As I’ve said in previous posts, I don’t care very passionately whether SARS-CoV-2 leaked or leapt. But given how many people do, I don’t think the addition of that subject to the mission of the House Coronavirus select subcommittee is a bad thing, even though the chief characters behind that shift, Jim Jordan and James Comer, are the last people to look to regarding anything scientific. See Washington Post columnist Philip Bump’s nice summary ofboth the politics and the science. The Coronavirus House Energy and Commerce Committee held a hearing on February 8th where their prime witness, the acting director of the National Institutes of Health, pushed back stronglyagainst the lab leak theory. Now the Coronavirus select subcommittee itself has begun issuing subpoenas, including to Anthony Fauci who is eager to testify

The subcommitte has now officially kicked off its investigation, and I was horrified though frankly not surprised to learn that it did so with a roundtable featuring three COVID-19 conspiracy theorists: Jay Bhattacharya and Martin Kulldorff, who wrote the notorious Great Barrington Declaration pushing a discredited herd immunity concept, and Marty Makary, who has been on Tucker Carson’s show spouting such absurdities as “We don’t even know if any healthy child has ever died of covid.” THE 3-MINUTE MAKARY VIDEO IS WORTH A WATCH!

In reality, as of February 2023, 1,460 children 1-17 had died of COVID-19 in the US, and at least 17,400 worldwide, and when it’s not deadly, pediatric COVID-19 is not always (though it usually) brief and benign. One study found that 25% of children who got COVID-19 with pre-Omicron variants had symptoms that lasted 4 weeks or more; and somethough not all researchers have found true long COVID to be just as common in children as in adults. 

Both the US Energy Department and the FBI have now declared in favor of the lab leak hypothesis, on the basis of secret new intelligence which may come from an obscure group of scientists known as the Z-division; I suggest checking out a nice summary of the controversy in the Washington Post. I continue to come down squarely on the side of natural transmission from animals to humans. The Chinese, who are best placed to know, have never cooperated fully with investigations. About the only new (though tangential) support I see to the lab leak theory is a recent reportfrom the Inspector General of the Health and Human Services Department concluding that the National Institutes of Health were sloppy in their oversight of the virus research they funded in Wuhan through Ecohealth Alliance.

I do care passionately about regulating research in such a way as to prevent new pandemics. On that front, two National Science Advisory Board Working Groups recently produced a draft report with detailed recommendations for preventing the kind of gain-of-function virus research that could lead to the most disastrous lab leaks. 


Which country is craziest?


The New York Times has shown graphically what happened after China dumped its COVID-19 restrictions, by tracing obituaries of members of the Chinese Academy of Engineering and the Chinese Academy of Sciences. Left: obituaries published in November 2022. Right: obituaries published in December.

The Times has also revisited the most notorious COVID-19 fatality, with new details about the death of Dr. Li Wenliang, the physician who tried in vain to blow the whistle on impending disaster. The article raises some doubts as to the adequacy of his treatment during his final days.


I’ve always thought the Swedes were sensible people, and that the herd immunity philosophy had been suggested but never really caught on. But according to one Swedish source the latest official advice in her country is to abandon all caution and tell people with respiratory symptoms to just go to work as normal. No tests, no self-isolation, just let it rip, infecting as many people as possible. But no – in reality this seems to be nonsense, because whereas the person who tweeted it out said the changed guideline took effect February 15th, the official government public health pageupdated on that precise date continues to say the exact opposite: “Stay home from work, school, preschool, and other activities if you feel ill and have symptoms that could be due to COVID-19.”


Joseph Ladapo and Ron DeSantis

Governor Ron DeSantis once more leads the pro-COVID pack, permanently banning vaccine and mask mandates in the state of Florida. His henchman Surgeon General Joseph Ladapo, seems to have recently come out with a “study” explaining why young men shouldn’t be vaccinated against COVID-19. I put study in quotes and say “seems to have” because the document is not only not peer-reviewed, it’s not even signed. A medical school faculty task force from the University of Florida, where Ladapo is earning $337,000 a year for unclear duties, have presented a detailed critiqueof this so-called research. The task force recommended the university investigate, but it has declined to do so. I guess black history isn’t the only subject whose study is banned in Florida. 



Brain MRIs of long COVID patients

study from the University of Michigan reports that patients who had been hospitalized for COVID-19 got worse, not better, over 6 months. For example 67.3% had heart and lung problems one month after discharge and 75.4% five months later, fatigue rose from 40.7% to 50.8%. This is odd, because all the other studies I’ve seen report long COVID symptoms resolving by 6 months in almost all cases. Perhaps the explanation is that all these patients started out so sick they had to be hospitalized.

small study looking at MRIs in patients with long COVID following mild illness reports that they have measurably less grey matter in their brains than norms taken from a large UK databank.

A publication from the Nurses’ Health Study, a huge prospective research project, reports that adherence to a healthy lifestyle prior to falling ill with COVID-19 cuts the risk of developing long COVID in half. I’m not convinced, based on cases I’ve treated and read about.

Chinese study of people who survived severe COVID-19 in January-March 2020 has reported that more than a third of them had respiratory symptoms and abnormal chest CAT scans of the lungs 2 years after being discharged from the hospital. This is not really surprising, and seems to me irrelevant to people catching COVID-19 today. Current variants are milder, and most people are vaccinated and/or previously infected, so many fewer patients get sick enough to require hospitalization.

In a small-scale study using peculiar methodology, reported only as an abstract from a medical conference, an anticoagulant-like drug called Sulodexide was said to improve a variety of symptoms in a subgroup of long COVID patients who were considered to have dysfunctional blood vessel linings. Low-dose naltrexone has been proposed as another candidate. I was mystified that the otherwise thorough review article where I found these two references failed to mention the only treatment that has been validated by a sham-controlled double-blind study, hyperbaric oxygen therapy. Also the NIH is finally sponsoring a trial of Paxlovid, which I’ve been hoping for since forever! 



Possible mechanisms for BCG against COVID-19

Natural immunity: A meta-analysis in The Lancet, similarly to the review I cited last time, found a BA.1 Omicron infection to give only 45.3% protection against a second bout with the same identical variant. This is again no surprise, we all know people who’ve had one Omicron infection after another.

BCG: Early in the pandemic, it seemed people living in countries where this tuberculosis vaccine was given may have been having lower rates of COVID-19, and it was hypothesized that the vaccine might be enhancing the immune system in a nonspecific way, as per the illustration above. Two small studies, one among diabetics and the other in older patients with comorbidities, gave some support to this concept. But in two larger trials with better methodology, one in the Netherlands and the other in South Africa, BCG flopped both for preventing infection and for reducing progression.

SHIELD”: A study that somehow got published in the top journal Nature reports that an inhaled powder designed to reinforce upper respiratory tract mucus protected monkeys from COVID-19 pneumonia – but only if they inhaled it shortly before being exposed to the SARS-CoV-2 virus. I can’t see any way this study could be relevant to protecting human beings from COVID-19.

FacemasksOne headline from the Washington Free Beacon, an ultraconservative rag funded by “vulture capitalist” and activist Paul Singer, reads “This Study Could Be 'Scientific Nail in the Coffin' for Masks.” Another, from moderate conservative New York Times columnist Bret Stephens, is “The Mask Mandates Did Nothing. Will any lessons be learned?” What they’re both talking about is a Cochrane Library review that was unable to document benefits for face masks against the spread of respiratory infections on the basis of controlled trials performed up until October 2022. Here’s how the authors themselves begin their conclusions: “The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions.” Almost all the studies were pre-2016 and involved not COVID-19 but influenza or flu-like illnesses. In response, Leana Wen correctly emphasizes that face masks can only decrease community levels of respiratory diseases if the vast majority of people in the community are wearing them, true of almost none of the studies under review. Incidentally, the review ran through October 2022, and the two best studies during the pandemic, both supportive of masking, were both published after that date. One found that kids had lower rates of COVID-19 in school districts that required face masks, and the other that KN95 masks are better than surgical masks at protecting healthcare workers, provided that community levels of SARS-CoV-2 are low enough that the workers aren’t being exposed elsewhere.


By any other name

An excellent op-ed by physician Eric Reinhart in the New York Times maintains that physicians’ widespread demoralization – one in 5 has imminent plans to leave practice – commonly described as “burnout,” shouldn’t be interpreted as a matter of individual psychology. The author argues, persuasively in my view, that the root cause is the awfulness of working within the chaos of the American healthcare non-system that, uniquely in the world, is based on maximizing profits rather than health.


New dangers

It seems that deer, that ubiquitous and charming American pest, may constitute a reservoir of old variants of SARS-CoV-2 that could come back to bite us.

And that the next big one could be an H5N1 bird flu, which risks being similar to the virus that killed more than 50 million people in 1918-19.

Then there’s the latest new variant, CH.1.1 ("Orthrus"), which is now causing more than 10% of cases in Europe but very few as yet in the US. In addition to being extraordinarily capable of escaping immunity related to vaccines and previous infections, it shares a mutation with the Delta variant, raising alarm in some circles that it might turn out to be more virulent than other Omicron subvariants.


States of emergency

A Johns Hopkins Coronavirus Resource Center map of global hotspots

Leana Wen, after having been the only pundit who leapt to agree with Joe Biden last September when he said the pandemic was over, has followed up with a column approving the impending end to the COVID-19 state of emergency. She does mention, and of course condemn, the fact that many million Medicaid recipients will be left high and dry without insurance.

A emergency-end twist I hadn’t known about is that laboratories will no longer be required to report COVID-19 test results to the CDC, so CDC statistics will become useless. Also, hospitals will no longer be able to be able to expand capacity if new surges happen.

Another nasty one: SNAP (Food Stamps) will cut its benefits and start kicking people off its rolls in March, even before the emergency ends. Its 42 million recipients will lose an average of $82 a month towards buying food, just when the price of groceries has been soaring. For a family of four that’s $328 less a month, and apparently elderly Americans receiving the minimum benefit could see their SNAP payments tumble from $281 to as little as $23 per month.

And yet another: The Johns Hopkins Coronavirus Resource Center is going to stop tracking COVID-19 statistics on March 10th. The best excuse they’ve come up with is “After three years of round-the-clock work building and maintaining a 24/7 global resource, we have reached the appropriate time to close this chapter of our response.” This shutdown could really be disastrous, since sources from the New York Times to Our World In Data depend on the JHCRC for authoritative data.

In my last post I listed 3 silver linings of the impending end to the pandemic emergency in the US, but two of them are losing their shine: 1) enhanced federal funding to Medicaid starts shrinking in April and will dry up entirely at the end of the year, so not so many people will get to stay on Medicaid just because of states dragging their heels. 2) Title 42 may in fact end, but Biden is by now nearly as tough on asylum seekers as Trump.

But there’s some good news – REALLY good news! Moderna has backpedaled on its outrageous plan to charge uninsured Americans $120 or so for each dose of its vaccine once the emergency ends. Now it says the vaccines will be free for people who are “uninsured or underinsured,” through a “patient assistance program.” Pfizer has promised to follow suit with a similar program, but is less clear on what it means by that.


Nuts and bolts, especially nuts

The notorious Project Veritas has moved on from trashing Planned Parenthood and CNN to producing what looks to me like a blatantly fake and in any case heavily edited video that within two days had been viewed 15 million times, showing “Jordan Trishton Walker,” identified as the head of Research and Development for Pfizer, chatting away in a bar about his company’s gain-of-function viral research. Pfizer’s actual head of R&D is on the left, the supposed one on the right. There is no evidence that the other guy even works for Pfizer, except for an crudely doctored CV and the word of the founder of Project Veritas, whose own Board recently gave him the boot. That was after internal arguments in which he accused his opponents of “fabricating stories” – talk about the pot calling the kettle black! I must say that Pfizer’s related press release seems a bit evasive.

An article by economist Mark Skidmore that somehow succeeded in getting published in a legitimate medical journal claims that the number of Americans who have been killed by COVID-19 vaccines could be as high as 278,000. Medical blogger Colin Bannon asks, “Is this the worst COVID research ever?” and does a brilliant job of ripping it to shreds. If it’s the worst, it’s had plenty of strong competition to overcome.

An utterly fictitious claim from a well-known conspiracy theorist says, “Thailand to BAN Pfizer After Thai Princess Falls Into a Coma Following Booster Jab.”

One blogger goes far beyond COVID-19 by saying viruses (all viruses, not just SARS-CoV-2) don’t exist. “The concept of a virus is illogical because viruses don't have any means of locomotion or any sensory organs. Thus, they can't protect themselves or hunt their prey,” and “The conception of the virus is just a money making scam.”