Does it Fly Through the Air with the Greatest Of Ease?

Alexander Calder, the Flying Trapeze, 1925

Featuring metformin, masks, surfaces, aerosols, boosters, emergencies, politics, Raccoon dogs, long COVID, and malarky.

 

Treatment

Metformin: An August 2022 publication from the American COVID-OUT study showed no significant prevention of severe COVID-19 among overweight adults for fluvoxamine, metformin, or ivermectin, but hinted at a benefit for metformin. Now a preprint from the same group reports a substantial reduction with metformin, during the Omicron era, of the risk of long COVID. But metformin only really benefited people who were unvaccinated, whose risk fell from 14.1% to 6.3%. In people who had received even just a primary vaccine series, long COVID risk fell only from 7.2% to 6.1%, confirming aside from anything else that vaccination cuts the risk of long COVID in half. What shocked me most was that fully half the subjects were unvaccinated: the chief lesson should be not “take metformin” but “get vaccinated”! 

Ensitrelvir: Infectious disease guru Paul Sax is impressed by this antiviral’s potential to prevent long COVID. I’m not. The data were presented as exploratory analyses at a conference; we need at least a proper manuscript.

Vilobelimab (Gohibic): The FDA has emitted an Emergency Use Authorization for this monoclonal antibody in critically ill COVID-19 patients, despite a horrifying set of side effects, on the basis of a study showing it reduced mortality from 42% to 32%. It’s been a long time since we had new treatments for very sick COVID-19 patients, and this one is welcome.

Nitric oxide:  Thai researchers offered nitric oxide, in the form of Enovid nasal spray 4 times a day, to students whose roommates had COVID-19 and university staff with high-risk exposures. Of those who actually used the spray, 6.4% became infected with SARS-CoV-2, versus 25.6% of those who did not. Since these results were reported informally in May 2022 and have not yet led to a manuscript much less a publication, there’s likely no there there.

 

Vaccines

Repeat doses: Not a day passes without someone asking me whether they should get a second bivalent booster now, since boosters largely wear off by 6 months, or wait for the fall. I think yes if you’re over 65 or otherwise at risk, and if you have plans that might put you particularly at risk (foreign travel, a wedding), you should try to get it a week or two beforehand. The problem is that second bivalent boosters have not been authorized in either the US or Italy, though they have been in the UK and Canada with quite restrictive criteria. It now looks like the FDA will follow suitin May, for people who are over 65 or immunocompromised and had a bivalent booster at least 4 months earlier. One caveat: if you’re double-boosted and have had COVID-19 within the last 6-8 months, you might give the second bivalent a pass, because combined protection likely lasts a year. The World Health Organization recently issued similar guidelines, recommending further boosters after 6-12 months to “high-priority” individuals: elderly, immunocompromised, pregnant, or front-line healthcare workers.

Vascular complications: Some months some saw a slight hint of ischemic strokes in American older people following the bivalent booster. Further analyses more or less wiped out the initial concern, and now a French study gives additional evidence. Similarly, a British study reports that cardiac death increases after SARS-CoV-2 infection, but not after mRNA vaccines or boosters.

Immune imprinting: A careful retrospective cohort study out of Qatar, whose authors include Jeremy Faust, highlights the downsides of (monovalent) boosters. A 61.4% increase in effectiveness against Omicron infection nearly disappeared by 6 months, and during months 7-12 people who had had boosters were actually more likely to get infected than those who had had only the primary series, suggesting what has been called negative immune imprinting, where repeated exposures tire out the immune response. Pfizer boosters were confirmed as more effective than Moderna. But the authors acknowledge their data have important limitations, and the heightened protection against severe or fatal illness remained high over the full year-long followup period (76.6% in high-risk and 57.9% in low-risk individuals). Since we already knew that unboosted vaccination gives almost no protection against any Omicron variant, and that all SARS-CoV-2 vaccinations tend to lose most of their value against infection by 6 months, I see no reason this study should make anyone hesitate to get boosted.

Novel vaccines: After Trump’s $18-billion-dollar Operation Warp Speed comes Biden’s $5-billion-dollar Project Next Gen, aimed at updating vaccines with mucosal (nasal) versions, new bivalents, and possibly even the holy grail, pancoronavirus vaccines that could cover future variants.

Wow! Here’s one for you: the Idaho state legislature has gone beyond banning vaccine mandates to pass a bill banning mRNA vaccines altogether, making it a misdemeanor to administer them. Will Governor Brad Little sign it?

 

The state of COVID research

Expert observers have found COVID-19 research to be generally low quality, with researchers often overreaching their areas of expertise. This is not limited to politicized drugs such as hydroxychloroquine and ivermectin, and is especially true for observational studies; at least 6 apparently promising drugs flopped when they were properly studied in randomized controlled trials. Even in RCTs the results are all too often “fragile” rather than “robust,” i.e. if just a few patients had had a different outcome the results would no longer be statistically, or clinically, significant. Maybe some of the dross will start getting picked up earlier with new tools designed to weed out bogus research.

 

Bye bye pandemic, goodbye

Jeremy Faust has graphed the dwindling attention to COVID: 

But even if nobody cares much any more, COVID-19 is still killing nearly 300 Americans every day. And if you’re sick enough to be hospitalized, the risk of dying is 61% higher for Omicron than for influenza. I hear personally of new cases daily, among friends in the US or patients in Italy, often dragging on at length. The pandemic is not over, though the Biden administration has basically abandoned all leadership on COVID-19 by disbanding its COVID-19 team and fully privatizing testing and treatment. 

Slightly good news: 43 states estimate that they will need a year or more to go through all their Medicaid recipients to see whether they are still eligible. But the impact of the Emergency ending still promises to be tragic.

My joy at seeing that Moderna would be establishing a “patient assistance program” to get free vaccines to uninsured/underinsured people has already been tempered, in that similar existing programs have a reputation for making people jump through hoops to get access to the promised drugs. The online red tape is expected to be daunting, particularly for uninsured populations, who are likely to be less tech-savvy.

An ill-advised Op-Ed in the Washington Post suggests scrapping the 5-day self-isolation period for COVID-19 patients in favor of “stay home when sick,” arguing that’s how we handle other viral syndromes that can be contagious for 7-8 days. But for one thing fully 80% of COVID-19 patients are still contagious after 5 days, and many after 10. And, for another, colds don’t give you long COVID.

 

Leaks and leaps

Raccoon dog

On March 7^th an op-ed by a virologist and an infectious-disease epidemiology researcher made a clear case for why spillover from animals is by far the most plausible source for SARS-CoV-2, the COVID-19 virus.

And no sooner had that op-ed appeared than possibly the strongest evidence yet emerged in favor of a species leap: “Mining a trove of genetic data taken from swabs at the Huanan Seafood Wholesale Market in Wuhan in early 2020, virus experts said they found samples containing genetic material from both the coronavirus and illegally traded raccoon dogs. The finding, while hardly conclusive, pointed to an infected animal.” I.e., animals at the Huanan seafood market – specifically “raccoon dogs” bred for fur and meat – seem to have been carrying SARS-CoV-2. Those findings have already been published, and though not definitive they are both timely and suggestive, and have been put nicely in context by the New York Times and Nature. Clearly China has plenty of evidence it has never shared, and its safety protections in virus labs seem weak; it would be nice if they cooperated with investigations, as the WHO urges vigorously, and as they claim unconvincingly to have done all along.

 

Bleach your veggies?

Disinfecting packages in China

British researchers have reported that the presence of SARS-CoV-2 on surfaces increased the risk that household contacts of COVID-19 patients would get infected themselves. So should we go back to disinfecting our packages like in spring 2020, when we thought the virus spread mainly through contaminated surfaces? Nope! For one thing, the association between surface contamination and infection was small and barely reached statistical significance. For another, even just one dose of a COVID-19 vaccine had a huge protective effect, cutting risk by 75% (p = 0.015), overwhelming the 66% increased risk from virus on surfaces (p = 0.044). I think what these data say is get vaccinated and don’t fret about surfaces. 

 

Do masks work?

After all the fuss over the Cochrane review that was misinterpreted as saying masking is useless, now we learn from Zeynep Tufekci that the Cochrane project’s chief plans to publish a rebuttal, correcting both the Plain Language Summary and the scientific abstract. Tufekci explains why, and Leana Wen chimes in. The worst misinterpretation actually came from the review’s lead author, Tom Jefferson, who said in an interview that the review determined “there is just no evidence that [masks] make any difference.” Jefferson has a history of making terrible calls during the pandemic, including back in April 2020. When New York City had seen thousands of deaths and was setting up field hospitals in Central Park, he considered it just a prolonged flu season. And he kept pressing the fomite theory of COVID-19 transmission long after it was discredited.

I recommending the thorough explanation of the flaws in the Cochrane mask review from David Gorski at Science-Based Medicine. He slams Tom Jefferson, whom he’s followed since 2009, and also explains how the Cochrane people fetishize the randomized clinical trial. If RCTs were the only source of valid medical information, we’d have never known, for example, that cigarette smoking causes lung cancer. 

 

The politics of public health

CDC official Anne Schuchat with DJT

Curious how things were inside Trump’s Centers for Disease Control in the early months of the pandemic? We knew it was bad, but recent reporting from the Washington Post, the New York Times, and Politico shows that the corruption, bullying, and political interference with its scientific mission were worse than even I thought.

The United States has always had a relatively weak public health system, and now state lawmakers and conservative/libertarian lawsuits have been hobbling what systems have been functional up to now. At least 30 red states have passed laws limiting the ability of public health officials faced by future pandemics to enforce such standard control measures as vaccines, facemasks, quarantining the exposed, or closing businesses, schools, or churches that are epicenters for outbreaks. I find this terrifying.

 

Ladapo, redux

Allow me to re-introduce Joseph Ladapo, Ron DeSantis’s surgeon general. He belonged to the right-wing COVID-19-denier group “Frontline Doctors.” He advocated consistently against shutdowns, and a year and 600,000 American deaths later was still complaining about “overreaction to the virus.” He boasts of his affiliation with UCLA’s prestigious David Geffen School of Medicine, but that institution has expunged him from their website. His claims to have treated COVID-19 patients seem to be false. Now, in response to his recommending against COVID-19 vaccines for children and young men, he has received a scathing letter from the chiefs of the FDA and the CDC warning him that his misinterpretations of vaccine data are “incorrect, misleading and could be harmful to the American public.” 

 

Long COVID

The VA study suggesting that Paxlovid reduces the risk of long COVID, which I described as a preprint, has now been published. But as an editorialist points out, much of the protective effect could result from Paxlovid’s ability to prevent severe COVID-19, which carries a higher risk of long-lasting symptoms.

People generally assume that Omicron infections, being milder, would be much less likely to lead to long COVID. Now a giant retrospective study (5 million COVID-19 cases) sponsored by the Washington Post, Epic Systems, and the Kaiser Family Foundation seems to have found just that. There’s no manuscript yet, so all we have to depend on is an article in the Washington Post. That article says, first, that non-white ethnicity and poverty did not increase risk, probably because of methodology biased in favor of detecting cases among people with better access to health care. (Known risk factors include severe COVID-19, female gender, older age, obesity, chronic lung disease, chronic kidney disease, and smoking.)

But the key finding is supposedly that the rate of long COVID after Omicron is a quarter what it was for Delta and a seventh what it was for the Wuhan wild strain. Blogger mikethemadbiologist has pointed out some major limitations. First, the researchers problematically define long COVID as at least one symptom the patient did not have before having COVID-19. Symptom number and severity don’t count, though long COVID typically involves multiple organ systems. Furthermore, the symptom has to be brand-new, so that for instance an asthmatic whose cough and shortness of breath merely worsen wouldn’t qualify. Furthermore, the baseline symptom rate during the Omicron era looks suspiciously higher than during the other waves, possibly due to undiagnosed COVID-19 infections that had left patients slightly unwell. This artifactually makes any increase in symptoms less evident. If one instead assumes a similar baseline symptom rate before all infections, the long COVID rate after Delta is no longer quadruple the rate after Omicron but about twice as high, in line with other reports. A commenter points out that people with Omicron are more likely to have been vaccinated, thus more protected against long COVID. Data indicate that in the middle of the Omicron wave Americans were 12% more likely to have been vaccinated than at the end of the Delta wave, and 2.5 times more likely to have been boosted.

Another, better examination of variants and long COVID has been published in The Lancet. The researchers cleverly matched more than a million COVID-19 patients with people with other respiratory infections, on parameters including demographics, COVID-19 risk factors, and vaccination status. Most had had the Wuhan wild strain, but there were about 40,000 each with Alpha, Delta, and Omicron variants. Six months later, COVID-19 patients were significantly more likely than their matched controls to have developed muscle disease, anxiety, mood disorders, brain fog, dementia, epilepsy, psychosis, insomnia, Guillain-Barré syndrome, or stroke. There was particularly high excess risk (25%-plus) for brain fog, dementia, muscle disease, and psychosis. Mood disorders and stroke saw risk subside after a few months, but risk for cognitive problems, dementia, psychotic disorder, and seizures persisted for 2 years or more. Risks were largely similar at all ages, except that only children developed encephalitis or peripheral nerve disorders, children had no excess risk of depression or anxiety, and their brain fog resolved more quickly; and the elderly were more at risk for psychosis and dementia. Omicron patients were more likely than Delta patients to develop dementia or peripheral nerve problems, and less prone to mood disorder, brain fog, insomnia, or encephalitis; otherwise the two variants were similar.

Leana Wen wrote recently: “We might come to expect some frequency of post-covid symptoms, and the resulting disability, as a ‘new normal.’ In that case, health resources must shift from avoiding the coronavirus to reducing and treating its worst consequences – including long COVID.” Huh??? Long COVID still happens, vaccination and Paxlovid reduce risk only moderately, and we still have no decent treatments.

 

Special populations

Wall of Cook County jail

Immunocompromised youth: According to at least one large prospective study immunocompromised children and young people are, unlike adults, not at increased risk of severe or fatal COVID-19

Incarcerated people: COVID-19 mortality in prison was even worse than we thought, with total death rates of incarcerated people up 50% in 2020 as compared to 2019, and in 6 states more than doubling.

Men: Men are more likely to get infected with SARS-CoV-2 and if infected more likely to die. Most of us assumedthat was due to a combination of hormonal differences, women’s higher vaccination rates, and women’s greater caution with masking and distancing. But I missed an article from a year ago pointing out another very important factor: men are more likely to work in sectors such as transportation, factories, and meatpacking, and more likely to be incarcerated or homeless.

Pregnant women: The United States sees far more women die in childbirth than other industrialized nations, twice as many as France, with vast racial disparities, and the pandemic has only made things worse. Deaths among pregnant and recently-pregnant women rose sharply, especially if they were black or American Indian, by 29% between 2019 and 2020, and by 40% between 2020 and 2021. The huge increase in 2021 was caused largely by COVID-19 deaths, whereas in 2019-2020 it was more related to nonpregnancy causes such as drug overdoses, homicide, car accidents, and (among American Indian women) suicide. Inadequate prenatal and postnatal care during the pandemic surely contributed, and the Dobbs decision reversing Roe v. Wade will put the cherry on top, given that states that sharply limit abortion access already have 62% higher maternal mortality.

 

The COVID trapeze

Most experts believe that transmission of tiny aerosol particles at large distances is a – or even the – major way SARS-CoV-2 spreads from one person to another. I’ve honestly never been convinced of this theory, though I have chosen to act prudently as though it were true, including by installing a HEPA filter in my office. A systematic review article published in the BMJ last May only added to the uncertainty by saying the concept is based on low-quality research, mostly from very early in the pandemic. An editorialist called the evidence “tenuous,” but still came down in favor. 

Now we finally have a study that is based neither on circumstantial evidence from small local outbreaks, nor on theoretical models. Researchers directly measured the amount of viable, transmissible SARS-CoV-2 virus particles in tiny airborne droplets of cell culture medium, duplicating aerosolized droplets in exhaled air. The infectivity of the aerosol dropped by half in the first 5 seconds, and had fallen to 10% at the end of 20 minutes. This makes it unlikely that COVID-19 gets transmitted by tiny droplets traveling long distances. Another study using a different coronavirus found that if you construct your droplets with artificial saliva, they can stay airborne for 2 hours in dry air, but their measurements seem to be at only 40 cm, failing to document the long-distance transmission central to the airborne hypothesis.

 

Makary Malarky

Marty Makary

In an article published in Newsweek, Johns Hopkins surgeon and bestselling author Marty Makary opines that the real problem with COVID-19 research was Anthony Fauci’s NIH agency failing to distribute funds fast enough during the first year of the pandemic. Despite Makary’s lofty credentials and his laudable denunciations of the profit motive in American medicine, the errors in this particular article are so over the top that I feel moved to refute them in detail:

- Main gripe: “The average time from the funding opportunity announcement to the award notice date was 151 days.” But it was worse before the pandemic, as per the NIAID website: “For applications funded on the first try [most aren’t], it typically takes between 8 and 20 months after the due date to get an award.” 

- He claims the CDC kept saying COVID-19 was mainly spread by fomites and on surfaces until August 2021. Actually its website said the opposite in May 2020.

- “The NIH spent almost $1.2 billion on long COVID research, but virtually nothing on masks, natural immunity, COVID in children, or vaccine complications.” Vaccine complications, natural immunity, and masks have been studied up the wazoo. And thank heavens they’re researching long COVID!!!

- “We still don't have randomized trials for so many drug recommendations, including the new bivalent vaccine, COVID vaccine boosters in young people, the optimal vaccine dosing interval, and even the antiviral drug Paxlovid in vaccinated people.” There have been at least two good studies of Paxlovid in vaccinated people, and the evidence for the updated boosters is burgeoning, as per my last post. 

- He blasts the NIH for not studying dexamethasone as a treatment for COVID-19 inpatients. Why should they have? The British RECOVERY trial of dexamethasone began enrolling patients in March 2020, and its main results were published just 3 months later.

- He claims vitamin D does miracles against COVID-19, but the study he cites is bullshit research. It merely confirms that people who take supplements of vitamin D, who are more health-conscious, eat better diets, of higher SES, and less likely to be essential workers – less often get severe COVID-19. Randomized trials of vitamin D have proven the opposite.