Tuesday, February 23, 2021

Beat That Bug!

Lots of encouraging treatment news, for once. Then onward to vaccines, of course, with a variant detour and a Godly coda.


Nip it in the bud

The Gout (James Gillray, 1799)

Colchicine: Used to treat gout since the time of the Pharaohs, this drug is claimed to reduce “hospitalizations by 25%, the need for mechanical ventilation by 50%, and deaths by 44%” in high-risk COVID-19 outpatients, as compared with placebo. A preprint of the manuscript reveals that the results are only just barely statistically significant, but it’s big news nonetheless – colchicine is the very first oral medication to show any benefit. My skeptometer reading is for once relatively low, because by now we’re used to finding novel targets for this ancient drug, from pericarditis to canker sores. And after 3500 years there will be no surprise side effects. I’ll prescribe colchicine for my next patient with COVID-19.

Oral or injected corticosteroids – beware: Since a patient told me the other day that friends with COVID-19 get stuffed with steroids by their Italian physicians, I thought I’d reiterate wht a bad idea this is. Dexamethasone and other steroids can be life-saving for patients on respirators, but when given early in the disease these drugs actually increasethe risk of both hospitalization and death.

Inhaled corticosteroids: Steroid asthma inhalers are another story altogether. Patients who start them early are less likely to go downhill and get well faster. according to the preprint of a new study. Ten out of 69 patients given a placebo inhaler eventually needed urgent care, as versus 1 out of 71 who received inhaled budesonide. Inhaled budesonide and similar steroids stay in the airways without being absorbed into the body, so they can’t have the negative effects I just described. My next COVID-19 patients will get this one too.

Bamlanivimab plus etesevimab (Lilly): This combination of monoclonal antibodies has scored a major triumph: a single intravenous infusion given early to high-risk outpatients, already known to decrease viral load, has now been shown to reduce the rate of hospitalization by a rip-roaring 70% compared to placebo. All 10 deaths were in the placebo group. The US Food and Drug Administration promptly approved it for emergency use; Germany has started using American antibody preparations without waiting for European Union authorization. Intravenous administration is still awkward and labor-intensive, though. If only there were a more convenient way of getting monoclonal antibodies into patients…

REGEN-COV (Regeneron): …but maybe there is. The Regeneron antibody cocktail has gotten a new boost from a Phase 3 trial as a preventative for household contacts of COVID-19 patients. Nobody who received the drug became ill, versus 8 in the placebo group. Even more exciting, the drug was given as a simple subcutaneous injection, which makes antibody treatment of outpatients feasible for the first time. If it were available in Italy, I’d give my next COVID-19 patient this one too.

Dimeric lipopeptide: Well glory be. Just when I had given up on these nose drops after November’s preprint, here they come again as a real publication. Unfortunately it’s still the same old data, those same old 6 ferrets… in the intervening 3 months somebody could have started human studies.

Convalescent plasma: The nice Argentine trial I mentioned a couple of months ago has now been properly publishedtoo. Antibody-loaded plasma given very early to elderly patients cut the risk of severe disease in half. This low-tech, inexpensive solution should get widely used in the developing world.

“COVID kits”: In Italy, outpatients are regularly prescribed azithromycin, corticosteroids, and vitamin D. Brazilian docs add ivermectin, hydroxychloroquine, and an anticoagulant …plus or minus a local special: rectally infused ozone, a venerable quack treatment described by the American Food and Drug Administration as “a toxic gas with no known useful medical application.” There’s no good evidence any of this stuff helps, though the NIH has softened upsome on ivermectin, shifting from a “recommend against” stance to “insufficient data to recommend either for or against.”


Zap it on the wards

Early COVID-19 pneumonia

Solidarity trial: The final results of the World Health Organization megatrial – 11,000 hospitalized patients, 30 countries – have now been published. But we already knew the main findings: hydroxychloroquine, lopinavir, and interferon beta-1a were useless, while remdesivir merely shortened hospitalization by a few days. It’s too bad remdesivir was started relatively late in illness; given earlier it might have worked better. 

Heparin: According to a press release, anticoagulating hospitalized COVID-19 patients improves outcomes. No news – they’ve been hospital routine for months.

Anakinra (Kineret): This cytokine blocker is the latest arthritis drug being repurposed against COVID-19. A poorly-done Italian study claimed it was life-saving.  In a better randomized trial among hospitalized French patients with moderate COVID-19 pneumonia, it did no good at all. The drug might conceivably be useful for sicker patients.

Vitamin D: An excellent Brazilian study has looked at vitamin D in hospitalized patients: it tanked. As I’ve explained in the past, we see low vitamin D levels in people who are frail and generally unhealthy, so they are correlated with all kinds of serious diseases including COVID-19. But correlation does not mean causation, and supplementation with this evergreen panacea fails over and over again in treating anything except flimsy bones. That Brazilian study came out just in the nick of time to ward off a crank article:

Mr. Cook bases his article on a preprint so transparently invalid that it was withdrawn within 48 hours. If you click on the link in his article what you find is:

Rescue missions

Advanced COVID-19 pneumonia (same patient as above)

Tocilizumab (Actemra): This drug has long since flunked out for treating mild-to-moderate COVID-19, but trials in severely ill patients run about half yes half no. The latest one, from the UK’s RECOVERY series, is putatively positive but bolsters my usual mantra: if this drug helps at all, it doesn’t help much. When added to dexamethasone in treating patients with low oxygen levels and severe whole-body inflammation, it did reduce 28-day mortality significantly. Only from 33% to 29%, though, and only because so many subjects were enrolled (that’s how statistics work). 

Allocetra and EXO-CD24: Two separate Israeli teams are claiming to have invented two separate, as yet untested, drugs that can each save the lives of critically ill COVID-19 patients. I’m not holding my breath.


Vaccine updates

Doses of AstraZeneca refused by Italian doctors

Sinopharm: This Chinese vaccine was rolled out long ago without any proper data, though we’ve had hints of good unpublished Phase 3 results. But I never mentioned their Phase 2 trials last August showing that it did induce antibodies. Unfortunately those trials only enrolled healthy adults ages 18-59...

AstraZeneca: This vaccine received (forgive me) a shot in the arm on February 10th when the World Health Organization recommended its use in all countries, at all ages, and with an 8 to 12-week gap between doses. But offered a choice between vaccines that protect you from COVID-19 at a 95% level (Moderna, Pfizer) and one that protects you at a 63% level (AstraZeneca) who would choose the latter? That’s why Germany and France are seeing a lot of no-shows for AstraZeneca appointments. And some Swedish regions have stopped giving it to health workers because of severe side effects.

Given the lack of data in people over 55, older people should get better-proven options where they are available – at least until data arrive from the American Phase 3 AstraZeneca trial. The infection rate in the US has now plummeted so far that those results, initially expected this month, won’t arrive until well into March.

OK, 63% is much better than nothing. AstraZeneca is also cheap, easy to transport, and storable in the fridge. If you’re under 55 and are offered this vaccine, I’d say you should grab it now rather than waiting months for something better to come your way. It may not be as good at preventing milder forms of COVID-19 (though “mild” can be pretty nasty) but, as President Biden’s illustrious advisory council points out, it will keep you from winding up hospitalized or dead. If the South African variant spreads more, or if new, better vaccines become widely available, I may change my tune.

Given its price and carefree logistics, AstraZeneca is the only realistic option at the moment for many developing countries, though Chinese and Russian vaccines may eventually prove stiff competition.

Pfizer: It seems the cold chain doesn’t have to be quite as subarctic as we thought. Pfizer now says its vaccine can be kept for two weeks at around -10º F. (-25º C.), which though colder than your home fridge matches many pharmacy freezers and is a lot easier to manage than -80º F (-70º C.).


Vaccine issues…

Volunteer drinking weakened typhoid in vaccine challenge trial

Unethically challenged? It had seemed those vaccine challenge trials threatened by UK researchers had been strangled in the womb. Now they've reappeared, though. It looks like the first volunteers will be having SARS-CoV-2 squirted up their noses in just a couple of weeks.

How dangerous are vaccinated people? They’re less likely to get sick, and much less likely to get die. But can they pass SARS-CoV-2 on to others? We already know that the RNA vaccines cut infections and therefore disease transmission by at least two-thirds, maybe even 89% according to recent Israeli data. We also know that AstraZeneca does not. But now comes more good news: the few Pfizer vaccinees who do become infected carry only 20-30% as many viral particles in their nose and throat as those who get infected before the vaccine has taken effect. If we multiply 33% by 20-30% we get a risk of disease transmission reduced to 6-10% (or even 2-3%, based on the Israeli study) of what it would have been without the vaccine. So clearly a person vaccinated with Pfizer or Moderna is very unlikely to make other people sick. Unfortunately the same can’t be said for people vaccinated with AstraZeneca.

Double down? Should we give people only one dose of vaccine, to cover the population faster? New research in Israel has been claimed to support that approach. But it doesn’t! The Israelis examined people 15-28 days after their first dose of Pfizer, when that dose had kicked in but the second one hadn't. They found that COVID-19 cases had alreadydropped by 85%. This is great, but it’s no news. Two months ago I gave you the FDA’s very similar 82% calculated from Pfizer’s own data. But we know nothing whatever about whether that one-dose protection lasts two weeks, two months, two years, or a lifetime. My guess back in December was that a 6-week rather than 3-week gap would likely be all right in a pinch, but longer could be risky. I'll stick with that for now. The media badly misconstrued the Israeli researchers’ own cautious conclusions: “Early reductions of COVID-19 rates provide support of delaying the second dose in countries facing vaccine shortages and scarce resources, so as to allow higher population coverage with a single dose. Longer follow-up to assess long-term effectiveness of a single dose is needed to inform a second dose delay policy.”

A letter to the New England Journal of Medicine along the same lines took an even more radical position, suggesting “deferring second doses until all priority group members are offered at least one dose." I think, and Pfizer researchers seem to agree, that such a prolonged gap between doses would be unjustified and unethical.

A single dose of the AstraZeneca vaccine, on the other hand, has been shown to maintain its efficacy for up to 12 weeks, in a self-selected low-risk group of volunteers. But beware of missing that 12-week cutoff – once you hit week 13 the vaccine’s protection goes up in smoke:


Perks of the jab

Now that millions of us have been fully vaccinated, we’re chomping at the bit to get back to a normal life. Can we? Opinions differ, but I’d say it’s OK to:

Skip quarantine after exposure to someone who’s tested positive (as per the CDC).

Go for routine medical and dental visits.

Socialize indoors, unmasked, with other vaccinated people.

Go into stores wearing a simple cloth mask instead of a surgical mask or a high-filtration respirator. 

Go back to college? US college students are all for obligatory vaccinations. They figure vaccination means throw away your mask and party. I’d hate to have to be the one to tell them otherwise. Of course their age group won’t be up for a long time.

Fly on Qantas. Letting vaccinated people fly freely is actually a pretty silly idea, since people vaccinated with AstraZeneca can easily infect others.

Travel to Cyprus, Poland, Romania, Georgia, or (starting in May) Iceland – but only if you’re a European Union resident. Non-EU tourists, vaccinated or not, are unlikely to be welcome in most of Europe for a while. Americans can vacation in Albania, Mexico, North Macedonia, or Tanzania without testing or quarantines, and in many other countries following local requirements.

Maybe socialize indoors with unvaccinated people, masked, distanced, windows open.

Maybe indoor restaurants, movie theaters, and concerts, masked and distanced. 


Crystal balls…

On the one hand we have scientists working on a single vaccine to protect permanently against all coronaviruses, not just SARS-CoV-2 but also any future bat-leapers or pagolin-hoppers. If this project does succeed, it will take years.

On the other hand we have Johnson & Johnson’s CEO saying we’re likely to need yearly COVID-19 boosters from here to eternity. I have a feeling he’s talking through his hat, perhaps with his eye on the bottom line.

Might deliberate mixing and matching be the future of COVID-19 vaccines? It would be great if people who’ve had one dose of AstraZeneca could get a better vaccine as their booster dose. The AstraZeneca/Sputnik V combo is already being tested, and AstraZeneca/Pfizer is next up.


Getting shots into arms

Young woman in granny garb sneaking into a Florida vaccine center

France: French authorities have acted fast on those studies about COVID-19 survivors I described last time, recommending COVID ex-patients have not two vaccine doses but just one, ideally 3- 6 months after their infection. They’re also rushing to contain the AstraZeneca-resistant South African variant, having high-risk individuals receive only Pfizer or Moderna in areas where that variant has been detected.

Italy: If the latest European Union schedule holds, we should be OK. Here’s Italy’s promised share of the doses (in millions – Italian commas are the equivalent of our decimal points):

Let me crunch those numbers for you. By the end of March: 12,003,500 doses of our best vaccines (Pfizer and Moderna) should have arrived, enough to vaccinate 6 million people.  During the second quarter 14,406,500 more, for another 7.2 million. Plus 7.3 million who’ll get the one-dose Johnson & Johnson vaccine and 3.6 million the two-dose Curevac – if it comes through – and you’re up to 24 million. By June Italy is also supposed to have received 26 million doses of AstraZeneca, another 13 million vaccinees, covering all 40 million adults if you exclude a few no-vaxxers and assume the country can ramp up its delivery capacity to 300,000 a day. That shouldn’t be hard, since Italy has countless empty spaces to repurpose as vaccine centers, and has enough unemployed and underemployed doctors to provide a vast army of vaccinators.

And the 20 million Italians younger than 18, especially adolescents? Awaiting Moderna’s, Pfizer’s, and AstraZeneca’s pediatric trials.

After a month of vaccine drought, a brief shower of doses arrived in Italy the week of February 8th, swelling into a virtual deluge – more than a million new doses – last week. But that included some of the less effective AstraZeneca, which isn’t polling well among Italian physicians or teachers assigned to it. In the UK people who turn down one vaccine keep their place in the priority line, we don’t know yet whether Italy will be as generous. 

Rome’s Lazio region has barely begun giving Pfizer to over-80-year-olds and AstraZeneca to essential workers, but it’s hoping to move on soon to vaccinating everybody 55 (or now, unfortunately, 65) and under with AstraZeneca. For that they’ll thankfully abandon their hopeless websites and call centers, but it may be a mess nonetheless. Italy was going to emulate the sensible British approach, having National Health Service doctors contact their patients in reverse age order, but yesterday’s newspaper says there may instead be a free-for-all. In any case the NHS docs will administer the shots themselves.




Map of COVID-19 variants in USA

Until now only the Brits were warning of their variant’s increased transmissibility. But now there’s some evidence from Denmark to back them up, saying it’s 36% more contagious (far, though, from Boris Johnson’s 70%). I find the Danes more credible, both because their country has done a marvelous job of controlling its epidemic and because they seem to have calculated real R(t) numbers from how many people get sick after one household member tests positive for SARS-CoV-2. If that’s true, then B.1.1.7 is definitely somewhat more contagious, though undeserving of its superspreader rap. UK authorities now also suggest the B.1.1.7 variant may be 30% deadlier, though this remains to be confirmed.

A much bigger deal is the spread of the South African B.1.531 variant. The Novavax and Johnson & Johnson vaccines are somewhat less effective against it, AstraZeneca is practically useless, and testtube studies suggest that Pfizer and Moderna may be a little less effective as well. Worse yet, B.1.531 can apparently reinfect COVID-19 survivors. These risks could spell big trouble for the many countries that intend to base their vaccination campaigns on AstraZeneca, notably the UK, where the variant is already spreading


Half empty or half full?

Nearly a third of Americans are putting up some resistance to COVID-19 vaccination. Sadly, that includes many nursing home staff, one of the few groups for whom vaccines really should be mandatory (and not just new hires).

Is one-third a glass half empty?

…or a glass half full? 


I’m a half full girl on this one. Looking at the trends over time, I think in the end practically everybody will choose to get vaccinated.

The decrease in vaccine hesitancy is worldwide, as per a survey at the end of January (look at the far right column): 



Physical distancing at the Torlonia Marbles exhibition

Rome’s museums are reopening. Weekdays only, reservations obligatory, strict masking, open windows, exemplary physical distancing. When we visited the marvelous Torlonia Marbles exhibition on the Campidoglio it looked like the above photo. 

However. On Saturday the 13th the Vatican Museums were allowed to open their doors, benefitting from who knows what papal dispensation. Visitors who expected a holy space to provide extra-careful mitigation measures found themselves, instead, packed in like sardines. Facebook and Tripadvisor were deluged with complaints, especially from tour guides infuriated at putting their clients’ lives at risk. No comment from Vatican authorities.

Mob scene in the Vatican museum

If Catholics aren’t shining at COVID-19 mitigation, neither are Jews, at least not the ultraorthodox Israeli kind. Even during a nasty third wave, they’re superspreading as eagerly as ever. Flaunting guidelines has given them 28% of the COVID-19 infections in Israel, with only 12.6% of the population.

Ultraorthodox funeral in Israel

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