Emergencies Come, Emergencies Go

 

Much more data about bivalent boosters, interesting long COVID news, a looming post-Emergency disaster, airplane panic, the Swedish model, deaths with vs. deaths from, and updates on both the pandemic and its conspiracy theories.

 

Treatment

China: Pfizer shipped millions of Paxlovid courses to mainland China in January, complementing those to be manufactured by Huahai Pharmaceutical. Patients might theoretically be able to obtain it cheap, but between slow-walked prescribing and price-gouging, many eligible patients die first. 

Fluvoxamine: For months I prescribed this antidepressant to high-risk COVID-19 patients, based on what seemed convincing research. Now, though, a trial giving fluvoxamine to 674 patients and placebo to 614 proves beyond the shadow of a doubt that it doesn’t reduce symptom duration or prevent severe outcomes. This is a relief of sorts, since so many patients couldn’t tolerate its side effects.

Molnupiravir: If you feel like taking a deep dive into the current status of this controversial antiviral I suggest the superb presentation – and the comments – at Paul Sax’s blog. 

Paxlovid: It’s now been shown to prevent severe disease in vaccinated older people in two studies, in Israel and the US.

 

Vaccines and testing

Price-gouging: Moderna and Pfizer-BioNTech will start charging Americans between $110 and $130 per dose of COVID-19 vaccine once the federal government stops providing them free, which should happen within months. Senators Sanders and Warren have righteously protested. On the low government price per dose, $19 to Pfizer and $22 to Moderna for the original vaccines and about 50% more for the bivalent boosters, both companies have made tens of billions of dollars and Moderna’s CEO has become a multibillionaire. Insurers will likely foot the bill, but the uninsured may wind up paying list price.

Myocarditis: A Harvard group that detected circulating SARS-CoV-2 spike protein in the blood of long COVID sufferers (see below) has also found it floating around in the blood of 14 out of 16 patients with post-vaccine myocarditis, versus none of 45 healthy, vaccinated, age-matched controls. I’m not sure what to make of this.

Evusheld: AstraZeneca’s monoclonal antibody cocktail, intended to prevent COVID-19 for months at a time in people too immunocompromised to mount an antibody response to vaccines, has had its Emergency Use Authorization revoked in the USA because more than 90% of new cases are now caused by resistant variants. Unfortunately, contrary to the FDA’s cheery “Paxlovid, Veklury (remdesivir) and Lagevrio (molnupiravir) . . . are expected to work against currently circulating variants,” Paxlovid is the only one likely to treat the currently dominant BQ.1.1 and especially XBB.1.5, “the most transmissible subvariant that has been detected yet.” With Evusheld helpless against those strains, the immunocompromised are left out on a limb.

Monovalents: They’re history. The FDA will no longer authorize products aimed only at the Wuhan wild strain of the SARS-CoV-2 virus, recommending updated bivalent vaccines for both primary series and boosters. Boosters will be given yearly in the fall, based on which variant was predicted in the spring, with those at high risk possibly advised to get two doses instead of one. Given how quickly protection fades, it might be better to offer vulnerable populations more frequent boosters. And given how frequently variants appear and disappear, a fixed timetable seems foolish. Better to give targetted boosters for new strains when surges are looming. 

Novavax: Spike protein vaccine makers haven’t thrown in the sponge but are, I’d say, behind the times. The New England Journal of Medicine has, strangely, published a research letter saying that 4 doses of Novavax can neutralize the BA.5 variant, despite BA.5 being long gone in the US and on its way out in Europe.

Waning: A review concludes that protection against symptomatic COVID-19 from both vaccination and previous infection fades over time, more quickly with vaccines (down 25-33% after 6 months) than with natural infection (only marginally at 12 months), and that a combination of both, “hybrid immunity,” may be longer-lasting. Unfortunately the studies it cites are almost all pre-Omicron. People who had COVID-19 from the original Wuhan virus almost never got it again, but by the BA.5 era, having had pre-Omicron disease lowered the risk of reinfection by only 36%. Even infection with BA.1 Omicron lowers symptomatic reinfection by only 72% to 76%. I’ve personally seen people with Omicron infections just 2 or 3 months apart. And later subvariants BQ.1, BQ.1.1, BF.7, XBB, and XBB.1 are even more likely to escape existing immunity. 

Kids: A thorough review and meta-analysis found a two-dose regimen of mRNA vaccines quite effective in children 5 to 11. It cut symptomatic infections by 47%, hospitalizations by 68%, and multisystem inflammatory syndrome by 95%. Most of the studies were performed in the Omicron period, when adults were on the contrary nearly unprotected without a booster. Mild side effects were common, but myocarditis after the second dose occurred in fewer than one in 500,000 children (compare one in 5000-8000 adolescent boys).

Antigen tests: A meta-analysis has concluded that rapid tests detect only 73% of symptomatic infections, a false-negative rate of more than one in four. A New York Times article makes useful suggestions on how to beat the odds.

Masking: World Health Organization guidelines have upgraded their masking recommendations, advising everybody at high risk for severe COVID-19 and anyone in “a crowded, enclosed, or poorly ventilated space,” to wear a mask. They also advocate for wider use of Paxlovid and, unfortunately, liberalize self-isolation guidelines.

 

Bivalent boosters, new data

In the lab:

One small American study reported higher neutralizing antibody levels against BA.2.75.2, BQ.1.1, and XBB with bivalent than monovalent boosters. But another one found no difference, with both doing poorly against BA.2.75 and BA.2.75.2. The only subjects with decent antibody levels against those recent strains were those who had had breakthrough BA.4-BA.5 infections after 3 or 4 monovalent doses. 

A large Harvard study that I cited some months back in preprint as showing superiority for bivalent boosters seems less positive in published form. 

A much larger study in an older population only adds more confusion. First because it examined not the Wuhan/BA.5 booster but a BA.1 bivalent vaccine that is not currently being used anywhere. Second because it yielded high levels of neutralizing antibodies against BA.1, which is long gone, moderate levels against BA.5, which is nearly gone, but low levels against BA.2.75, which is itself more susceptible to neutralization than the XBB.1.5, BQ.1.1 and BQ.1 subvariants that now cause more than 90% of new cases in the United States and 60% in Italy.

In the real world

Israel: A Lancet preprint says that elderly Israelis who received the bivalent Pfizer booster were 81% less likely to wind up hospitalized for COVID-19 than those who did not. That’s close to the 71% reduction reported in a similar population by the CDC. Three major caveats apply. First, no studies have compared monovalent to bivalent boosters head-to-head. Second, since the updated boosters have been available for only a few months, we have no idea of how long the added protection lasts. Third, only a minority of those eligible in either country went in for the updated booster, and they are likely the same kind of people who will wear masks and avoid crowds, making the vaccines falsely appear more effective.

Cleveland Clinic: Researchers report that the bivalent booster reduced employees’ risk of becoming infected with SARS-CoV-2 by only 30%, even though the local Omicron subvariants mostly matched the booster. The authors unfortunately didn’t distinguish between symptomatic and asymptomatic cases; if many infections were detected because of exposures rather than because of symptoms, that would lower the apparent effectiveness of the booster. Since protection against clinical COVID-19 is regularly found to be higher than protection against mere infection (and lower than protection against hospitalization), 30% against infection is compatible with the 50% or so against symptomatic COVID-19 reported by the CDC. And the above 3 caveats apply here as well.

North Carolina: University of North Carolina researchers have done the closest yet to a head-to-head study of old vs. new boosters, by comparing people boosted during the summer of 2022 using a monovalent booster with those who received a bivalent version in September-October. Protection against COVID-19 hospitalization 15-99 days after the dose was 25.2% for the monovalent booster and 58.7% for the updated version. Pretty impressive. But until mid-November the dominant strain in the US was BA.5, whose spike protein is targeted in those boosters, after which more immune-evasive subvariants took over.

United States: CDC data from December-January now indicate that the bivalent booster is just about as effectiveagainst symptomatic XBB.1.5 as it is against BA.5, and lasts at least 3 months. The added protection is unfortunately lower in older people (52% ages 18-49, 43% ages 50-64, 37% 65+),

Bottom line: 

More than 4 months after the updated boosters were introduced, it’s still not 100% sure they offer any advantage over another dose of the original vaccines, as Jeremy Faust and Paul Offit point out. Offit suggests boosters be given only to those most at risk for severe disease, rather than offering young healthy people short-lived, partial protection from strains that may disappear a few months later. 

 

Special risk factors

Air travel: A terrifying tweet from an apparently reliable sourse was titled, “Testing wastewater from planes found that almost all flights had passengers with COVID,” says that SARS-CoV-2 was found in 96% of flights. True… but a little sleuthing revealed that those were flights arriving in Kuala Lumpur! Malaysia apparently tests every plane that lands. The CDC may start similar testing in the United States, though I’ll bet they’ll only do it on flights from China instead of – as they should – on random samples of all flights.

Pregnancy: We’ve always known that COVID-19 late in pregnancy puts babies at risk, but we’ve now learned, from an analysis of studies involving more than 13,000 pregnant women, that COVID-19 during pregnancy can kill mothers as well, raising maternal mortality by a shocking factor of 7.

Chills: Why do respiratory infections of all kinds peak in the winter? The medical party line has always been that it’s because people are spending more time indoors, in company. Now an interesting study suggests there may be a physiological mechanism as well, with colder temperatures impairing the functioning of the innate immune system. I have to question the real-world importance of these findings given that the two countries that come closest to the US death toll, Brazil and India, are both tropical,. Thanks to my brother Daniel for the tip.

 

The next superspreader event?

At a moment when the US was running 500 confirmed COVID-19 deaths every day and the US House of Representatives was meeting and voting nonstop there was nary a mask in sight. I suspect if anyone caught the bug there we’ll never find out.

Speaking of the Republican takover of the House, they’ve drastically changed the mission of the existing coronavirus committee, intending to hype the lab leak hypothesis, blast pandemic restrictions, and blame Anthony Fauci for everything under the sun. This has already had real-world implications, discouraging scientists from working to prevent the next pandemic – though I confess that the research described at Boston University looks a little worrying even to me. Last fall ProPublica drew intense criticism for publishing a long article about an interim report on the origins of COVID-19 released by the Republican oversight staff of a Senate committee, promulgating a laboratory origin for the SARS-CoV-2 virus. 

 

Long COVID

Numbers: A December 2022 CDC survey found that 24 million Americans currently had long COVID, and that 14.4% of all adults have had it at some point during the pandemic, about 30% of everybody ever diagnosed with COVID-19. Montana and Wyoming were the worst-off states, at nearly 20%. Of those currently affected, 19 million said it gave them trouble carrying out their daily activities, including 6 million with “a lot” of trouble; as of last August 4 million still weren’t capable of working. Another study, of workman’s compensation claims in New York State, diagnosed long COVID if people were still under medical treatment or still out of work 60 days after COVID-19 they caught on the job, while admitting that these criteria probably miss many patients who are either “toughing it out” or don’t know they’re eligible for workman’s comp. Particularly interesting findings: the incidence of long COVID increased linearly with age rather than peaking in middle age; 71% of patients still qualified after 6 months; 18% were unable to work for a year or more; and a disproportionate number were essential workers. A Brooking Institution study suggests that at any given moment more than 3 million Americans are either working reduced hours or not working at all due to long COVID. The impact on our workforce is clearly severe. 

Spikes: In a pilot study, Harvard researchers detected SARS-CoV-2 spike protein circulating in the blood of two-thirds of patients with long COVID, even 12 months after their initial illness, and in none who had recovered fully. This suggests persistent viral reservoirs in the body in some long COVID patients, and a possible therapeutic role for antivirals such as Paxlovid and remdesivir.

Cytokines: Memorial Sloan-Kettering researchers support a different etiology by finding proinflammatory cytokines in the cerebrospinal fluid of cancer patients with substantial neurological symptoms that persist after hospital discharge. Their patients, who were immunocompromised because of cancer and had severe COVID-19, were not your run-of-the-mill long COVID patient. And the research was done in 2020, long before vaccines or therapies. This study does, however, faintly suggest that corticosteroids might benefit post-COVID-19 brain fog.

Mono: By age 25, more than than 90% of people have been exposed to the Epstein-Barr virus. Only a quarter of them had classic mononucleosis, with the rest mimicking the common cold. EBV is relevant both because mononucleosis can sometimes be followed by chronic fatigue syndrome and because EBV can reactivate when a person becomes sick or immunocompromised (EBNA IgG antibodies reappear). It’s been suspected that reactivated EBV may be involved in some cases of long COVID, and now we have some solid evidence. Researchers in San Francisco evaluated post-COVID symptoms and viral reactivation in 280 patients over 4 months. The 74% of patients with at least one long COVID symptom at 16 weeks and the 35% who had severe cases (more than 5 symptoms) were much more likely to have EBNA IgG antibodies than those who had recovered completely (45% and 47% vs. 28%). EBV reactivation was particularly associated with fatigue and brain fog. They also examined 2 other viruses: HIV (which was associated with cognitive difficulties), and reactivated cytomegalovirus (which was actually protective against long COVID, especially against brain fog).

Pacing: Chronic Fatigue Syndrome (“myalgic encephalomyelitis”) has been considered the closest relative of long COVID. Now UK researchers have performed a randomized trial of 3 proposed treatments for CFS: cognitive-behavioral therapy, graded exercise therapy, and adaptive pacing therapy, all provided by experienced clinicians over 12 months. Though many patients are convinced that adaptive pacing is the best approach, it was far outrun by the other 2, giving no benefit over standard medical care, whereas CBT and especially graded exercise yielded substantial improvements in fatigue and general physical function. I remain skeptical, after seeing pacing help individual long COVID patients, but maybe what this study really means is that long COVID isn’t as similar to CFS as we thought.

Recovery: An Israeli study reports that outpatients who developed long COVID pre-Omicron usually felt fine a year later. Leana Wen thinks this is reassuring. I don’t. 

 

The state of the pandemic

China: China officially reported exactly 37 COVID-19 deaths between December 7^th and January 8^th despite evidence – including from these satellite photos of a new parking lot outside a funeral home – that a surge was raging. On January 14^th they revised those figures upward, to 59,938. Then, going from one extreme to the other, the head of the Chinese CDC apparently said on January 21^st that 80% of all Chinese had had COVID-19 during the present surge. I don’t think that’s even medically possible, given the 3-day average incubation period.

United States: Is the winter COVID-19 surge fizzling out, as the Washington Post says? I’m not convinced. COVID-19 deaths do seem to have passed their peak in the EU, though not in the UK (ignore the phony zero death tolls) and certainly not in the US, where they’re holding steady or continuing to rise. I limited the above chart to recent months for clarity, but here’s a simplified all-time version. 

Admittedly recent deaths are much fewer than in earlier surges, but I agree with the WHO that the pandemic is not over yet.

Leana Wen recently wrote a Washington Post column titled “We are overcounting covid deaths and hospitalizations. That’s a problem.” In it she claimed that most of those hundreds of daily American COVID-19 deaths are “with” not “from,” swabs incidentally positive in patients hospitalized for other reasons. As often before, I find her position nonsense. It reminds me of how the Chinese – until January – considered a death to be related to COVID-19 only if the patient died in respiratory failure. “Incidental” positive swabs are particularly relevant in people who are seriously ill; someone hospitalized for a heart attack is much more likely to die if they’re infected with SARS-CoV-2. Jeremy Faust sees it exactly as I do, urging Dr. Wen to at least change her headline. Now even the CDC has chimed in, with its Chief Medical Officer writing a direct rebuttal to Wen titled bluntly, “We are not overcounting covid deaths in the United States.”

The COVID-19 emergency in the United States was first extended through February, then 9 days later scheduled to expire on May 11; the WHO says only that the pandemic is at a transition point. The consequences for Americans will be dire. Enhanced food stamp benefits will end on March 1^st, and starting April 1^st as many as 19 million people (or as “few” as 15 million) could be kicked off Medicaid, about 6 million of whom will have no other road to health insurance. Childhood nutrition will also deteriorate, with millions of schoolkids no longer eligible for free lunches at school. Not to speak of new bills for vaccines, tests, and treatments that will particularly devastate the uninsured while also harming the insured. I see 3 silver linings: 1) there are so many people currently on Medicaid that states may take many months to review all their cases; 2) Medicare coverage of telemedicine runs through 2024; 3) Title 42 should end.

 

The Swedish model

Fantasy: Headline: Sweden has the lowest excess mortality rate after the pandemic, despite refusing to lock down. “Proof”: this chart of data through June 2022. 

Reality: here's excess mortality through June 2022 from the authoritative Our World In Data:

Sweden’s excess mortality at that date was lower than the US, Italy, or the UK, but that’s not saying much. It was 63% higher than Norway’s, 3 times Denmark’s, and far far from New Zealand, which runs fewer deaths than expected even today. Incidentally, Sweden is currently running the highest daily average of COVID-19 deaths in Western Europe, 76% higher than the runner-up UK, and triple the US.

 

Recent pandemic madness

Ron Johnson, Juli Mazi

Senator Ron Johnson is still running on about vaccines doing no good and lots of harm. As Grudgie the Whale points out, “Lies like this are why Republicans died at like a 3 to 1 rate from COVID since the vaccines came out.” (True! The ratio is 2.5 to 1, due primarily to differences in vaccine uptake and masking behavior.) A fascinating study finds that the voting records of members of Congress correlate with COVID-19 death rates in their home districts – the more conservative, the worse the outcomes (taking into account race, income, health, and even vaccination rates).

Naturopathic “physician” Juli A. Mazi has been sentenced to 33 months in prison for selling fake vaccine cards. Her main defense – I kid you not – is that “as a Native American she is ‘immune to legal action.’”

Conspiracy theorist Stew Peters has released an antivaccine pseudodocumentary under the title of Died Suddenly, which was viewed 5 million times in 2 days. Science-Based Medicine calls it “A tsunami of antivax misinformation and conspiracy theories,” and a health law professor says it’s “so scientifically absurd it feels like satire.” Peters’s previous video claimed that the disease known as COVID-19 was caused by “snake venom secretly injected into the water supply by the Catholic Church and government agencies.”

Conservative media proclaim: “Pfizer’s COVID-19 Vaccine Linked to Blood Clotting: FDA” and “The FDA Drops BOMBSHELL over Pfizer Vaccine” The raw data in the FDA study they’re talking about did find small increases in several clotting problems among older people following Pfizer vaccination. But most of those associations disappeared after further evaluation, with only pulmonary embolism retaining a significant linkage. Since the authors did not adjust for preexisting conditions, even that limited finding is questionable. Then there were the headlines saying bivalent boosters caused strokes. That was unlikely from the start, and was ruled out by a deeper look at the data.

Yet another new antivax conspiracy theory holds that vaccines cause miscarriages and stillbirths, based on the true fact that both increased greatly in 2021-22. The reality is just the opposite: pregnant women who are vaccinated have a one-third lower rate of stillbirths and a one-fifth lower rate of miscarriages than those who are unvaccinated. Having COVID-19, on the contrary, increases the risk of miscarriage and doubles the risk of stillbirth. The spikes in both these bad pregnancy outcomes during the pandemic are due to disease, not to vaccination.