Friday, June 26, 2020

Pack ‘Em In, Pass It On…

Trump's Tulsa rally: crowded on the floor, empty in the bleachers
Dottoressa special: you can sign up now for a virtual book event! The New York Italian Cultural Institute’s presentation of my memoir, Dottoressa: An American Doctor in Rome, a reading in conversation with Alexander Stille that had to be cancelled in March, is going to be held via Zoom on Wednesday, July 1s, at 2:00 pm Eastern time. Click here to register.

Treatment Update
Dexamethasone: On June 15th researchers for the British RECOVERY trial claimed in a press release that a cheap, familiar corticosteroid, dexamethasone, cut death rates in seriously ill COVID-19 patients by one-third. “Major breakthrough” “Fantastic” “Groundbreaking.” Your resident cynic’s first reaction, like other scientists', was to advise caution – in part because these results seemed to turn previous thinking on its head. A large study of patients with rheumatic diseases and COVID-19 had found that those who were taking corticosteroids were much more likely to needhospitalization. And just a month ago an important meta-analysis concluded that “Corticosteroid use was associated with delayed virus clearing… There was no significant reduction in deaths... Hospitalization duration was prolonged and use of mechanical ventilation increased.” As the head of one of the United States’ best intensive care units commented, “We have been burned before . . . with exciting results that when we have access to the data are not as convincing.” 
But we cynics were wrong this time, I think. Just a week later we were able to see those data in a preprint, and it does indeed look good. One excellent commentator explains how to make these results jibe with the many negative studies: the RECOVERY study found the sweet spot in terms of patient selection, dosage, and timing. In RECOVERY patients with milder disease, not in need of oxygen therapy, dexamethasone actually increased the risk of death. In patients who needed oxygen but could breathe on their own, the drug helped a little. In critically ill patients on a respirator, it helped a lot. After a little thought, these results make sense. In mild or early phases of this dastardly disease damage is caused by the virus actively multiplying in the body, and suppressing the immune system (as steroids do) will allow it to multiply faster. Late in the game it seems to be the body’s attempt to fight off the infection, the “cytokine storm” of an immune system in overdrive, that brings tissue destruction and death.
You should realize, though, that this study may not have a huge influence on the treatment of COVID-19 patients. Most intensivists already use corticosteroids as part of their last-ditch treatment of dying patientsOne poll found that 54% of institutions already do just what the British authors suggest, giving corticosteroids routinely to all COVID-19 patients who require oxygen. And probably many more give steroids selectively to patients on oxygen, or routinely to all patients on respirators. 
Hydroxychloroquine (Plaquenil): I thought it was going to finally be time to say Hasta La Vista hydroxychloroquine, now that the US Food and Drug Administration decertified it for COVID-19 treatment and both the National Institutes of Health and the World Health Organization cancelled their ongoing trials. …But no!!! You can’t kill the damn thing!!! Someone has brainwashed the reputable American Journal of Epidemiology into publishing a hydroxychloroquine promotional piece with the over-the-top title “Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis.” This execrable piece of writing, which cites the same phony and borderline-mendacious publications I have been blasting in these pages for months, would be flunked in an undergrad epidemiology course. The AJE doesn’t allow for online comments, but they will be receiving an avalanche of outraged Letters to the Editor, including one from me.

Remdesivir: Its star is slightly dimmer lately. In a trial among moderately ill COVID-19 patients, patients who received the drug for five days supposedly did marginally better than those who only received standard care (some improvement in 76% vs. 66%). Those who took it for ten days, however, did not (70%). As is all too common nowadays, all we have to go on is a press release from the manufacturer, Gilead, not a finished manuscript much less a publication. I join the rest of the scientific community in finding these results downright weird.
I can’t resist reprinting an entire paragraph from the Lown Report, in view of Gilead’s venal history of drug pricing:
ICER [the Institute for Clinical and Economic Review]  recently released a report with alternative prices for remdesivir, taking into account the uncertainty of its effectiveness in actually saving lives. They estimate that a dose of remdesivir could be priced up to $50,000 if the drug does save lives, but only $1,170 if it turns out the drug does not save lives. ICER also provides what is called a “cost recovery” pricing model, which estimates how much a drugmaker would need to charge to recoup their investment. For remdesivir, ICER found that it costs $10 to manufacture one 10-day course of the drug. Since remdesivir was already an existing drug, there were no additional research & development costs for Gilead to create it.
EIDD-2801: The earlier you start an antiviral drug, the better it works, so the holy grail is something you take on day one of COVID-19 and it nips the coronavirus in the bud. Remdesivir, however effective it might turn out to be, can’t work in the real world because it needs intravenous infusion. Could another antiviral, still known by the investigational moniker of EIDD-2801, do the trick? It’s similar to remdesivir but has the huge advantage of coming in pill form. The only problem is nobody’s ever tried it against the novel coronavirus. All we know is that it works in animals against some other coronaviruses, and that the manufacturer claims some volunteers have taken it without any dire side effects. They’ve just begun a small Phase 2 trial in COVID-19 patients. If it shows even a hint at lowering their viral load, two proper placebo-controlled Phase 3 trials will take off, one in outpatients and one in newly hospitalized patients. Fingers crossed but breath not held.
Tocilizumab (Actemra): This antibody against interleukin-6, which like dexamethasone targets cytokine storm and which had shown promise in early reports, was tried in Italian COVID-19 patients with early-stage pneumonia and flopped. Didn’t keep them out of the intensive care unit, didn’t prevent death. But the manufacturer is pushing on, thinking it might help sicker patients.
Ruxolitinib (Jakavi): This antiinflammatory drug is ordinarily used against obscure blood cancers. A pilot study in 41 severely ill Chinese patients has suggested it might possibly be useful in blocking cytokine storm. Not much to go on.
Colchicine: in a small Greek study among 105 hospitalized patients those receiving this ancient sui generisantiinflammatory drug – its approved uses are for gout, pericarditis, and familial Mediterranean fever – seemed to deteriorate more slowly than those receiving usual care. A hint of a possibility of a benefit.
Follow the money: The federal government has quietly eliminated one source of new funding for research into treatments for advanced COVID-19 lung disease or preventing COVID-19 in the first place. They had better things to do with our tax dollars, like sending stimulus checks to people whose reason for being unemployed was that they were dead.
Vaccines: I reported a few weeks ago that the Chinese CanSino vaccine had induced an active immune response in human beings. Their paper has now become the first such study to be published, in The Lancet; the volunteers developed not only ELISA antibodies and neutralising antibodies, but also a specific T-cell (cellular immunity) response. This is very encouraging, though there were lots of bothersome side effects.
Remember Coronavac, the other Chinese candidate, the one that worked so well in monkeys? The manufacturers now say in a press release that it’s passed Phase 2 with flying colors, inducing neutralizing antibodies in more than 90% of volunteers. No more details yet, but they’ll be moving on to Phase 3 trials, the ones testing whether those antibodies do anything in the real world. They’ll be performed in Brazil, whose poverty- and overcrowding-driven raging epidemic makes it, sadly, an ideal location – the more likely your human guinea pigs are to catch a disease, the faster you can find out whether a vaccine prevents it.
Meanwhile the Oxford group is charging ahead with its own candidate vaccine, starting their own Phase 3 trials in the UK, South Africa, the US, and Brazil. They are also now recruiting Italy and several other European countries to underwrite development research by AstraZeneca in exchange for promises of an advance supply of the vaccine. In Italy alone 60 million doses are supposed to be delivered as early as this fall for administration (free on the National Health Service) to health workers, the elderly, and others at high risk. If, that is, the vaccine makes it to the finish line and if it does well in Phase 3.
Natural immunity: You may have been worried to read this week about Chinese reports that antibodies to the novel coronavirus fade quickly over time, especially in people who had mild or no symptoms. Many figure this means vaccines are likely to fail. Not true. For one thing, even low levels of antibodies may help protect against reinfection. And for another, with COVID-19, as with many other viral diseases, a less known second arm of the immune system may be more important than antibodies. So-called “cellular immunity” works by producing targetted T-cell lymphocytes, that can attack the virus directly and/or stimulate the antibody-making apparatus to a rapid response. But fortunately vaccines can potentially elicit not only anti-coronavirus antibodies but just those kinds of targetted T cells – and the CanSino candidate COVID-19 vaccine, for one, does.
We still don’t know whether you can get COVID-19 twice. Beaumont Health’s study of COVID-19 antibodies among 38,000 hospital employees, which ought to be able to show whether prior infection is protective, is unfortunately still just gathering data. Some results ought to have been available by now…

God Bless the Coronavirus
The few people who share my obsession with the Centers for Disease Control’s now-you-see-them-now-you-don’t pandemic guidelines for places of worship will be pleased to know that they were released at last. Only to be altered 24 hours later – apparently on orders coming straight from the White House – to yet another version, altered to be full of such mealy-mouthed social distancing language as “Consider whether physical contact (e.g., shaking hands, hugging, or kissing) can be limited among members of the faith community,” and specifically cutting out warnings against group singing, despite deadly superspreader events that have struck congregations and church choirs
The publicity stunt that Mr. Trump pulled three weeks ago, evicting peaceful demonstrators with rubber bullets and tear gas so he could be photographed brandishing an upside down Bible in front of St. John’s Episcopal church, could be the last straw for all Christians except the hardest-dying evangelicals – and some of the latter are losing their enthusiasmand even leaning toward Biden. The Episcopal Bishop of Washington declared herself “outraged,” while the head of the entire denomination blasted Trump for “Us[ing] a church building and the Holy Bible for partisan political purposes.” 

Transmission update
As the pandemic proceeds we’re learning more about the way the novel coronavirus gets spread. There’s some good news: it’s less likely to be picked up from surfaces than was first thought. The CDC has revised the advice on its website to reflect this – please stop tormenting yourself over those packages and grocery bags. 
Also positive was a small but careful contact-tracing study in Taiwan, which found that none of the subjects who were swab-positive but never developed symptoms transmitted the coronavirus to other people. But we know that COVID-19 carriers can continue to be swab-positive for weeks, so we can’t be 100% sure there is no risk. 
The period when a COVID-19 patient is most contagious turns out to be the day they get sick and the couple of days before that. Fortunately patients stop being contagious within a week or so of developing symptoms, even if they remain severely ill. Being within close range of an infected individual for 10 or 15 minutes – maybe even less if they’re singing – can be enough to pick up the bug, so as usual the most important precaution is to keep your distance. 
And here’s the scary part: some people infected with the novel coronavirus seem to be particularly infectious, whether because they have more virus in their bodies or because they spew out more particles when they talk – and if you get close to them indoors they can be super-duper spreaders. A good example may be Mattia, the poor fellow who set off the disastrous Lombardy epidemic near-single-handedly. It’s now estimated that as few as 10% of patients may cause 80% of infections. Check out this terrific interactive portrayal of several superspreader events in a Spanish paper.

Crowded in, crowded out
The Centers for Disease Control spent weeks and weeks working out guidelines for how to act in the months or even years we’re going to be drumming our fingers on the table waiting for a great vaccine for COVID-19, or an A-1 cure. Worst case scenario? Indoor venues holding masses of people shoulder to shoulder without masks. Wannabe protagonist of worst-case scenario? Our bleach-drinking Commander In Chief, a/k/a Individual Number 1, who has chosen to personally host the very first mass indoor gatherings in the US of A since the coronavirus hit. Thank heavens the MAGA-ites are a bit less suicidal than their Duce, and left his first rally, in Tulsa, two-thirds empty. They were right to worry. At least two members of the advance team who attended the Tulsa rally have tested positive for the coronavirus, and another half-dozen tested positive but stayed home that day. And Tulsa County has reported record spikes in new cases twice in a row, 4 and 5 days after the rally – slightly surprising, since so few of the attendees were locals.
A striking and contrasting lesson in COVID-19 transmission comes from a natural experiment: the anti-racism protests following George Floyd’s murder. As feared, a few cases of COVID-19 have come to light among the tens of thousand demonstrators who were out on the streets, but the protective effect of outdoor air seem to have largely overcome the risks related to the crowding, the screaming, the teargas, and the paucity of face masks.

Testing and tracing
Want to find out whether that “flu” you had in March was actually COVID-19? In Italy now you can, on your own say-so but at your own risk. Walk into any of the dozen or more private labs in Rome that offer antibody testing, stick out your arm, hand over some cash, and the deed is done. 
A practical recommendation: find somewhere that uses the Abbott brand, supposedly 99.9% specific (yes, the same Abbott that makes a notoriously unreliable swab test). Other manufacturers claim 95% specificity, which sounds good but isn’t: in an area where fewer than 5% of people have been exposed to the virus, such as Rome and most everywhere else, more than half of their “yesses” will be false positives. In Rome, one place that offers the Abbott test is the Centro Diagnostico, near the Pyramid. No prescription required, just show up before 11 am with €25.
But let’s get back to “at your own risk.” Italy has decreed that anybody who has a blood test showing antibodies has to self-isolate until they’ve done a swab test for active disease and gotten negative results. This is madness, since by the time you have IgG antibodies against the coronavirus, the ones usually tested for, you are no longer contagious. But the madness varies by region. In some, such as the Marche, your General Practitioner is empowered to let you off the hookif you get tested additionally for the early, IgM type of antibody and they’re absent. But in other regions, such as Lazio, the GP has no leeway, and anyone with any type of antibody is stuck at home until they’re proven swab-negative which can take many days.
But there are still more complications. For one thing, all swab testing has to go through a doctor on the National Health Service and many, maybe even most of my own patients are foreigners, or are Italian United Nations employees who aren’t on the National Health Service. 
Furthermore, having a positive swab test is not equal to being contagious. People can remain swab-positive for weeks or even months after contracting COVID-19, but those late swabs are detecting fragments of virus, not infectious organisms – it is so unusual for COVID-19 to be transmitted late in the disease that the latest guidelines from the World Health Organization and the Centers for Disease Control allow patients to return to work without testing, 10 days after they first developed symptoms or 3 days after they feel OK.
Then there’s contact tracing, part two of the epidemic-buster’s mantra. The Immuni contact-tracing app has now been rolled out in Italy, the Corona-Warn-App in Germany, and StopCovid in France, but the only place people are signing up in any numbers is Germany. The UK has thrown in the sponge over technical glitches, and the apps have so many limitations, including in terms of both false alarms and false negatives, as to make them a poor substitute for boots-on-the-ground contact tracing. In the US, it’s a mess as usual. The apps haven’t taken off at all, and while determined Washington State health officers have proven that even here it’s possible to do real contact tracing, in New York so far that’s been a total flop.

Speak No Evil See No Evil
Donald Trump has now moved on from pointing out that doing fewer tests would mean detecting fewer cases, to “I said to my people, ‘Slow the testing down, please!’” (The doctors who would be “his people” deny hearing anything of the sort.) But he’s not the only President to use an ostrich strategy against COVID-19. Now President Bolsenaro of Brazil, whose country has passed 50,000 deaths and still climbing, hopes that keeping information about the epidemic secretwill magically make it go away. So, apparently, does Erdogan, the President of Turkey, who publically downs mulberry molasses as a prophylactic. Meanwhile Nicaragua has joined Tanzania and long-suffering Yemen in choosing the bury-them-under-cover-of-night method of hiding COVID-19 deaths.
The novel coronavirus continues to rampage across South America and the Indian subcontinent, where all attempts to keep the virus down run aground in the face of poverty, overcrowding, and inadequate health care resources. Today the hit parade of countries with the most active cases has South Africa in 10th place, then Frances, Mexico, Bangladesh, Peru, Pakistan, India, Russia, Brazil, with the gold star to the only country to have no excuses except stupidity: the United States of America.
P.S.  I’ve learned that various Stethoscope On Rome posts about COVID-19 have been cited in The Telegraph, plugged by Destination Books, and excerpted in The Salem News. And I can’t resist mentioning a new review of Dottoressa in the Times Literary Supplement.

No comments:

Post a Comment