Pills good and not-so-good, boosters hot off the presses, mask debates, variant watch, long COVID, First Family snafus, pandemic upticks, collateral damage, disastrous summings-up, human challenge studies, Africa, and an array of nonsense.
|The chemical structure of VV116|
VV116: Several letters to the New England Journal of Medicine have raised serious issues with the study claiming this experimental Chinese drug, an oral form of remdesivir, works just as well as Paxlovid. Their critiques have considerably dampened my initial enthusiasm.
Paxlovid: Outcomes improve in vaccinated people over 50 years old, but what about younger folks? A new study, though with some methodological limitations, says it can benefit vaccinated adults under 50 with preexisting cancer or heart disease, but not those with asthma or chronic obstructive pulmonary disease.
Molnupiravir: Merck’s oral antiviral has unfortunately resurfaced. An observational study from the Cleveland Clinic, in the Omicron era, published in the pay-to-publish JAMA Network Open, claims that molnupiravir is as good as Paxlovid at preventing hospitalizations and deaths due to COVID-19. This contradicts the best previous research and literature reviews finding the drug so ineffective that Italy stopped using it and Merck withdrew its application for full EU approval in the face of deauthorization. We already knew it didn't combat Delta and didn’t reduce household transmission. Plus even more important issues: teratogenicity, possible mutagenicity, and especially the potential to prolong infection duration, induce mutations transmissible to other people, and breed new variants, leading some experts to demand its authorization be revoked world-wide. The Cleveland Clinic article doesn’t discuss the impact on its results of NIH recommendations that molnupiravir be used only when the more effective and less iffy drugs Paxlovid and remdesivir cannot be.
The FDA and the EU have given full approval to XBB.1.5 boosters from Moderna and Pfizer even though the latter has never been tested in people. Contrary to expectation, the CDC recommends them not only to the elderly and the medically fragile, but to all Americans older than 6 months. Medicare and Medicaid are supposed to provide vaccines gratis, but see the above picture from a Medicaid recipient who had an appointment at CVS. The federal government is paying three times as much per dose than they did a year ago – $81.61 for Moderna and $85.10 for Pfizer – and private insurers even more. Compare that with about $26 in Europe, on which the drug companies are presumably still making a profit. Those companies are supposed to provide doses gratis to uninsured Americans through a temporary Bridge Access Program. Articles in the Washington Post and the New York Times try to sort out the many glitches. The underlying problem is that in the US vaccines are now considered a commercial product rather than a public good.
The public largely boycotted last year’s bivalent boosters. Everyone over 60 or with chronic medical conditions should go for the new version, but despite FDA/CDC recommendations, I’m not convinced healthy young people need it. I advise choosing Moderna, which has been shown to induce antibodies in human beings. Pfizer tested its new vaccine only in mice, and Novavax, whose booster is still under review, only in monkeys – see slide 34 of the CDC presentation.
Updated boosters hit American pharmacies in mid-September, and in early October should reach Italy, where they are recommended for people over 60 or medically fragile but will be provided on request – free of charge of course – to anyone over six months old.
World Health Organization vaccine experts now recommend that some older and medically vulnerable people get COVID-19 boosters every six months. This makes sense for these high-risk populations, since it’s about how long protection lasts. I hope the US will take that advice rather than sticking with a one-size-fits-all, once-a-year-with-the-flu-shot policy.
An interesting study found that a vaccine mandate on a university campus lowered SARS-CoV-2 viral levels in the entire surrounding community.
For years people have been fantasizing about nasal spray vaccines. Some COVID-19 experts and immunologists think they’d be more effective, and they’re a stated goal of Project Next Gen. Dartmouth researchers may have recently come up with one, though clinical trials are still only in the planning stage.
And Ron DeSanctimonious is back on the warpath: “I will not stand by and let the FDA and CDC use healthy Floridians as guinea pigs for new booster shots that have not been proven to be safe or effective.” His sidekick Joseph Ladapo decreed that nobody under 65 should receive the new booster, whatever their health status, and that even the elderly discuss “potential concerns” with their doctor rather than just making appointments for the jab. Ladapo instead urges people to eat their veggies and take the sun – while spewing nonsense about high levels of spike protein from vaccines persisting in the body “for an indefinite period of time, which may carry health risks.” Some Florida Republicans go even farther, calling vaccines biological weapons! Florida, alas, currently leads the nation in COVID-19 hospitalizations. And Floridians’ uptake of the previous bivalent booster was particularly low, despite its having one of the nation’s highest proportions of elderly residents.
Prevention and protection
There is actually ample evidence of the efficacy of masking: studies in Maryland, Tennessee, Germany, Bangladesh, and Massachusetts, a review and meta-analysis in the BMJ, a comparison of countries with and without mask mandates, a case-control study by the CDC, and most impressively an international trial whose Canadian results are particularly convincing. Check out commentary by David Gorski, Zeynep Tufekci, and others on the flaws of the Cochrane study and the dubious history of its chief author, Tom Jefferson.
A CDC draft proposal equating surgical masks with N95 respirators and KN95 masks for protecting against COVID-19 has drawn justified backlash from healthcare workers and the public, and a letter of protest from several hundred experts in relevant fields.
Then there are the University of Liverpool researchers who claim to have found a new miracle facemask material, still at the “proof of concept stage.” B.S.?
Remember Regeneron, the company that made the first effective monoclonal antibody treatment? It’s begun working on an updated product for immunosuppressed individuals, as an alternative to vaccines.
I mentioned in my June post that a year-old preprint saying the gene HLA-B*15:01 might protect people from getting sick if they’re infected with SARS-CoV-2 had not yet been published, saying I suspected it hadn’t survived peer review. Now it’s been published, sort of, in Nature Open Access – which is equivalent to self-publishing.
There was concern that one Omicron subvariant, BA.2.86, had mutated so extensively that the XBB.1.5 booster wouldn’t touch it. I’d like to thank epidemiologist Ken Rosenberg for pointing me to a tweet by Ninaad Lasrado, whose lab at Harvard’s Beth Israel hospital has shown this worry to be misplaced. Six months after having XBB infections, patients had antibodies against BA.2.86 at levels if anything higher than those against variants such as EG.5. Swedish researchers have found similar results.
…there’s also a doubly encouraging preprint from Chinese researchers, showing both that BA.2.86 is less capable of escaping prior immunity than was predicted from its number of mutations, and also that it seems less capable of invading cells than XBB.1.5 or EG.5.
Complications of COVID-19
I was excited to hear there had been a conference in Santa Fe entirely devoted to long COVID. But the research, at least as described in the lay press, seems underwhelming. I was particularly disappointed in Resia Pretorius, mother of the theory that circulation-clogging microclots lie at the root of long COVID. Her first preliminary findings were published fully two years ago and she still hasn’t done a proper clinical trial, instead reporting before-and-after results, on 91 patients, of her usual antiplatelet/anticoagulant combo. Supposedly the number with cognitive complaints fell from 82 to 21, and the number with fatigue from 81 to 18. A before-and-after observational study without a control group is the weakest possible research methodology, and I am frankly scandalized that she would consider these results worthy even of a preprint. And note that nobody else has ever detected those microclots, which Pretorius claims to have seen in diseases from diabetes to lupus.
I’ve always suspected Pretorius was on to something, however, and a UK study provides some very indirect support. A high fibrinogen level during hospitalization for COVID-19 predicted both objective and subjective cognitive deficits 6 and 12 months later, and elevated D-dimer levels predicted subjective brain fog. Fibrinogen and D-dimer are related to both clotting and inflammation, so the researchers adjusted for an inflammatory marker, C-reactive protein, and the results held. I don’t see much there there.
On September 16th I searched a definitive database for treatment studies of long COVID, and wasn’t impressed. There’s a German phase 2 trial of “BC 007,” a heart disease drug billed as “neutralizing functional autoantibodies directed against G-protein coupled receptors.” Other researchers propose dietary supplements, saunas, a glutamate modulator, SSRI antidepressants, a muscle relaxant, mindfulness meditation, beta blockers, sympathetic nervous system blocks, and intravenous immunoglobulin, none of which look particularly promising. A study of autologous stem cells, a costly commercial product, might conceivably be interesting, but hasn’t even reached phase one.
COVID-19 increases the risk of dying if you have a heart attack, chronic lung disease, or a stroke. We can now add systemic fungal infections to that list. Not vaginal yeast or oral thrush, but aspergillosis and mucormycosis, infections that attack bodily organs and can be deadly. CDC data show that the mortality in patients hospitalized for such infections was 12.3% without COVID-19, 48.5% if the patient was co-infected with SARS-CoV-2.
The CDC’s latest update tells us that in 2022 6.9% of American adults (about 18 million) had had long COVID, and 3.4% (about 9 million) were currently affected. Women were much more susceptible and wealthier people somewhat less so.
Leana Wen wrote a column for the Washington Post whose basic point is that long COVID exists and is important. Great! But she claimed the diabetes drug metformin is known to reduce the risk of post-covid conditions. Not really. As I wrote about the preprint of a study of overweight and obese patients now published in The Lancet Infectious Diseases, metformin only really benefited individuals who were unvaccinated, whose risk of long COVID fell from 14.1% to 6.3%. People who had received even just a primary vaccine series saw their risk drop only from 7.2% to 6.1%, confirming that vaccination cuts the risk of long COVID in half. The message should not be “take metformin” but “get vaccinated.”
Wen followed up with another column arguing that the already overly lenient CDC guidelines be further liberalized. No, Leana, the CDC should not “treat covid like it does influenza and other viral illnesses,” at least not until we see “long influenza” and “long colds.”
When people get COVID-19 more than once, is each infection a new roll of the dice, or does long COVID become more – or less – likely with each new infection? One expert thinks that question remains open, but points out that reinfection makes pre-existing symptoms worse.
NYU researchers have shown that SARS-CoV-2 can directly infect coronary arteries, explaining at least in part why COVID-19 patients have an increased risk of heart attacks etc. during the following year. Valentina Puntmann, a German expert in long COVID, thinks that an immune response to persistent infection could contribute to its origins.
Another recurrent hypothesis is dysfunctional mitochondria. The brilliant Eric Topol is impressed by the latest study, but its findings seem to me more relevant to the severity of COVID-19 than to the persistence of symptoms.
An article in “Frontiers in Medicine,” China’s Ministry of Education journal, reviews similarities between long COVID and Chronic Fatigue Syndrome, notably proinflammatory cytokines, autoantibodies, and reactivation of latent herpesviruses. Yale researchers confirmed viral reactivation and additionally found low cortisol levels, high anti-SARS-CoV-2 antibody levels, and abnormalities in both T-cell and B-cell lymphocytes.
California researchers report that farmworkers, who are largely undocumented and have little access to healthcare, have shockingly high rates of long COVID.
One of the most significant COVID-19 sequelae may turn out to be new-onset hypertension, which developed in one in five hospitalized patients, bearing risk of stroke and heart attacks.
Abusing the bully pulpit
Waves and wavelets
|Ons Jabour, who became abruptly short of breath at the U.S. Open|
Italians are freaking out about resurgent COVID-19, with front-page headlines such as “COVID Autumn,” “The COVID Hawks are Back,” and “COVID frightens, from the US Open to Italy.” The number of confirmed weekly cases leapt from 3320 in mid-July to 38,775 on September 29th. Those statistics are more reliable than in the US, since testing in Italy remained fairly steady throughout the summer, whereas in the US nobody’s tracked those numbers for a year.
Italy is hospitalizing fewer COVID-19 patients per capita than the US, though the rate is soaring in both countries. The rolling average of daily Italian deaths rose fivefold between the end of July (2.4) and the first week in September (13.4). In the US, COVID-19 deaths merely doubled between early July and mid-September, possibly reflecting superior treatment of critically ill patients.
In late June Americans were “like, ‘COVID, what’s COVID?’”, but a Gallup poll says many are starting to worry again. Nobody’s tracking case numbers but they are surely rising, judging from hospitalization rates that have more than tripled since early July, cases among prominent Americans including the First Lady, persistently high wastewater levels, anecdotal reports of surging cases in schools in the D.C. area and elsewhere, and outbreaks at – for example – workplaces in Los Angeles and probably the U.S. Open tennis tournament in New York. Unfortunately even hospitals – hotbeds of respiratory infections – have largely dropped mask requirements. But the minisurge has been enough to make the Biden administration start distributing free antigen tests again.
Jeremy Faust points out that even those disturbing hospitalization figures are likely underestimates. US hospitals used to test all new admissions for COVID-19, but now only selected patients get tested, guaranteeing cases get missed. In Italy, public hospitals have similarly stopped universal screening, but when I was admitted to a private hospital six weeks ago with a broken hip I couldn’t go up to the ward without a negative swab.
I wrote last time about new post-Emergency surges in Australia and China. Now we can add Japan to the list, with hospitalizations rising tenfold over five months and straining hospital capacity, though they’ve fallen in the last few weeks.
You might be interested to know how American COVID-19 experts are handling masking, eating out, travel, etc.
|Matt Hancock testifying|
Matt Hancock, who was Boris Johnson’s Health Secretary, has blasted his own pandemic response as “completely wrong,” testifying at a public Covid inquiry that planning – believe it or not – was focused on “the provision of body bags and how to bury the dead, rather than stopping the virus taking hold.” When he tried to approach bereaved families to apologize, they turned their backs.
Some of the glaring defects in the American public health system have been outlined in the New England Journal of Medicine by two experts, and more weakly by ex-CDC Director Rochelle Walensky, who before stepping down faced idiotic grilling by a House committee. Walensky’s replacement, Mandy Cohen, sees her chief challenge as rebuilding trust in the agency.
Since the 1980s, longevity in the United States has lagged behind that of other advanced economies. Six years ago when I was completing my memoir, Dottoressa: An American Doctor In Rome, Italians lived five years longer than Americans. Now American researchers have extended similar statistics into the pandemic period and calculated what they call “missing Americans” – how many US deaths would have been averted if our death rate had equaled the average of 21 other wealthy nations: 622,534 excess deaths in 2019, and more than a million in both 2020 and 2021, half occurring in people under 65 and disproportionately in African-Americans and Native Americans. Though this important article is only marginally about COVID-19, I suggest checking it out, also an opinion piece at MedPage Today that explains why “Meaningful Healthcare Access Requires So Much More Than Insurance Coverage.”
Students’ test scores, on the contrary, plummeted during the pandemic and haven’t come back. A BMJ article makes a fairly convincing case against the school closings and distance learning that led untold millions of children to fall behind educationally. I have always thought elementary schools, at least, should have remained open. But more could have been done to protect teachers and staff, who were at higher risk for severe illness: improving ventilation, installing HEPA filters in classrooms, holding classes outdoors.
New diagnoses of six types of cancer plunged early in the pandemic, when people were avoiding all medical care. The dip only lasted a few months, but was deep enough that there were fewer new diagnoses overall in 2020 than in 2019, of major cancers eligible for screening (colorectal, breast, lung, and prostate).
But the opposite is true for sexually transmitted infections, which in New York City rose substantially between 2020 and 2021, especially among African-Americans, perhaps due to the “slutty summer” of 2021. Particularly worrisome: a nearly 30% surge in syphilis among women and the consequent increase in congenital syphilis.
Detection and transmission
In its first and perhaps only paper, the would-be momentous UK human challenge study has brought forth a mouse. Eighteen out of 34 young unvaccinated people who had wild-strain SARS-CoV-2 injected into their noses became infected and developed “mild-to-moderate” symptoms (defined rather vaguely in the Supplementary Appendix). Viral RNA could be detected in about a quarter of air, surface, and hand samples, and in 43% of swabs from face masks; the amount of virus emitted by individuals varied hugely, and was unrelated to symptom severity. The researchers conclude: the nose is the most important source of transmission, fomites do carry some risk, a few individuals may be superspreaders, and being sicker doesn’t make you more contagious. One medical podcaster was more impressed than I was.
In related news, Northwestern researchers have preprinted a study tracking the number of viral particles exhaled during natural breathing by several dozen COVID-19 patients over the course of their infections. Patients averaged 80 virus particles per minute, though a few spiked as high as 800, unrelated to vaccination status or SARS-CoV-2 variant, and falling sharply after eight days. Viral RNA was collected only in close proximity to the patient’s mouth, and subjects were specifically told not to talk, shout, or sing during air collection, so this study sheds no light on the still-unresolved question of whether COVID-19 is spread by long-distance airborne transmission. And since the dose needed to transmit infection, perhaps 300-800, is not known precisely, these results are hard to interpret.
Home antigen tests are even worse than we thought at detecting Omicron infections. A single test detected only 44% of all infections, and only 63% of infections with a viral load high enough to be contagious. The authors conclude that even daily tests can miss infectious cases. And the most serious error is testing too early.
The Africa exception
Africa has reported far fewer COVID-19 deaths per capita than Europe or the Americas, fewer even than Asia (which was dominated by zero-COVID China). This has been presumed due to a combination of youthful populations, low obesity rates, and inadequate testing. But a new review and meta-analysis suggests still another contributory factor: prior immunity. In 26 studies examining pre-pandemic data sets, 11.5% of blood samples showed antibodies against SARS-CoV-2 at a level that could give some resistance to infection. People from areas with more malaria had more antibodies. This makes sense to me. Malaria and other diseases endemic on the continent create high levels of gamma globulin, which is mostly a slew of antibodies. I have observed this phenomenon in many of my own African patients.
“Compounds that could stop covid and flu viruses infecting human cells have been discovered in sea spongesResearchers say “their discovery paves the way for new antivirals than can help treat the virus.” But hydroxychloroquine also blocks entry of SARS-CoV-2 into human cells is, but is utterly useless against COVID-19.
“According to new CDC data, the Covid vaccine could take 24 years off of your life” What will they think of next?
“Pfizer’s COVID Vaccine Causes VAIDS in Children, Study Proves,” that would be vaccine-induced AIDS, a non-existent condition. And the cited "study" says nothing of the sort.