Sunday, July 26, 2020

Varieties of Wishful Thinking

Treatment update
Inhaled interferon-beta (SNG001): Back in March my blog featured this old drug, reformulated to be inhaled rather than injected, as a possible treatment for COVID-19. Well now the first results of a clinical trial have been reported, and they may turn out to live up to the promise: in a double-blind British trial, according to the manufacturers, the risk of going from merely needing oxygen to needing mechanical ventilation was reduced by 79% and there was a hint that lives may have been saved. The trial was small – 101 patients – but at least, unlike too many COVID-19 studies, it was a properly-done, placebo-controlled piece of research. Probably larger trials will follow quickly, but I wouldn’t be surprised if some hospitals started improvising their own home-made inhalable form of this drug, and using it right now.
Remdesivir: The same RECOVERY trial that showed dexamethasone to save lives in COVID-19 was supposed to have an arm testing remdesivir. But it was cancelled – apparently because the manufacturer, Gilead, refused to make enough of the drug available to the researchers. One wonders: was Gilead afraid the results wouldn’t come out well and preferred not to take the risk? It’s unfortunate in any case, because this would have been the best-designed test of remdesivir yet.
A fishing expedition: The UK’s ACCORD program (Accelerating Covid-19 Research and Development) is doing preliminary clinical testing of a whole series of new drugs, hoping to fold any of them that show promise into RECOVERY: MEDI3506 (a cytokine antibody), zilucoplan (another immune-based antiinflammatory), bemcentinib (it’s been tried for cancer and Lou Gehrig’s disease), and acalabrutinib (used against blood cancers but potentially also antiinflammatory).
Hydroxychloroquine: Two more reports: a randomized trial in people with mild, early disease and a one in outpatientswith recent symptom onset which added a placebo control. Neither found any benefit from hydroxychloroquine, despite considerable side effects. Out of 674 randomized trials of drugs against COVID-19, 132 – nearly one in four – have involved chloroquine or hydroxychloroquine, despite there being no real evidence of efficacy for either. What a shame that so much effort has been wasted on testing these drugs, only to demonstrate time and time again that they do nothing. I think I will stop mentioning them.
TocilizumabYet another report of a retrospective drug trial. Yet another claim of efficacy (reducing the risk of death by 45%!). And yet another set of fatal flaws: the patients were not randomized, there was no placebo control, and the criteria for treatment shifted during the course of the trial. And – very important – the patients who received the drug were younger, healthier, and less sick than the ones who didn’t, so they were more likely to survive anyway. Useless. Tocilizumab had already performed badly in previous studies, and what this one chiefly added was that it increased the risk of bacterial infections. We don’t need more observational studies of this or anything else, as Anthony Fauci says, we need large, randomized, controlled trials.
Dexamethasone: The famous British trial showing this corticosteroid decreased mortality in patients sick enough to require respiratory support, but may have increased it in milder cases, has now been published in the New England Journal of Medicine.
FenofibrateIsraeli scientists are claiming this cholesterol-lowering drug “could eradicate COVID-19 from lungs in days.” If you believe that one, I have a great bridge in New York I could sell you cheap.
Vaccines: The Oxford study showing their candidate vaccine to be relatively safe and to induce neutralizing antibodies in 90% of volunteers has now been published in The Lancet. Also in the same issue were very similar results from the Chinese company CanSino, drawing a cautiously optimistic editorial.
Here’s a badge of honor for COVID-19 vaccine researchers in the US, Europe, and Canada: Russian hackers are already trying to steal their data. Maybe Chinese hackers too. In the meantime, the United States government is hedging its bets on which vaccines to invest in – not only Moderna’s (they’ve bought up 100,000,000 doses) but also British-Swedish AstraZeneca’s (the Oxford vaccine, 300,000,000 doses) and German Pfizer’s (another 100,000,000 doses). That’s half a billion doses total, one and a half for every man, woman, and child in the United States, which considering that 41% of Americans say they wouldn’t get vaccinated could be all we need, if – and it’s a big if – all three turn out to work. AstraZeneca has already begun Phase 3 trials, enrolling tens of thousands of high-risk real-world volunteers in the UK, South Africa, and Brazil, and similar studies from ModernaPfizer, and the Chinese CanSino group are set to launch literally within days.
The truly bad idea of vaccine challenge trials - where researchers deliberately expose volunteers to a disease they've been given a new vaccine against in order to prove that the vaccine works - continues to march forward. An open letter promoting them has attracted 100-plus “prominent scientist” signatories including no less than 15 Nobel laureates, and the vaccine scientists at Oxford apparently plan to actually do one. Shame on all of them. The 1DaySooner organization that wrote the open letter tries to normalize the approach at its website by cataloguing the times challenge trials were used successfully in the past. But the comparison is misleading: virtually all such trials in the modern era have been for diseases such as typhoid fever which we’re very good at treating, in case the volunteer gets sick despite the vaccine. The one exception was for dengue fever, which like COVID-19 is caused by an untreatable virus – but in that case the researchers did not expose people to dengue itself but to a weakened version of the virus. There is no weakened version of COVID-19 now, nor is anyone working on one as far as I know. And though the whole point of the exercise would be to push vaccine production forward in time, there are so many necessary preliminaries that any actual viral challenges can’t start up until around the end of the year in any case. By that time we should already have excellent field data for the vaccines that are being tested ethically in Brazil and other COVID-19 hotspots.

You can’t have one without the other
The terrifying surge in COVID-19 cases in the United States over the last few weeks to over 70,000 new diagnoses a day, due to Republican governors’ mad rush to reopen the economy, seemed pretty benign at first in terms of hospitalizations and deaths. This led to all kinds of wildly optimistic speculation: the increased diagnoses were an artifact of increased testing, the virus was getting less virulent, the new cases’ youth and vigor would keep them from getting very sick, etc. Now the honeymoon is over because, like love and marriage in the old song, COVID-19 and death go together like a horse and carriage. Hospitals in the worst-hit states began to be overwhelmed with desperately ill patients, many of whom are, inevitably, dying. Here’s the case of Florida, nicely illustrated. The Phase 2 reopening of bars and restaurants was followed after 2 weeks by a rise in cases, after 4 weeks by a rise in hospitalizations, and after 6 weeks by a surge – now becoming a flood – of deaths. You can see that the partial reclosing, forced on a reluctant governor by the spike in cases, is already decreasing the number of new diagnoses.
In that same state, things may get even further out of control because of critical shortages of such therapeutic tools as remdesivir and convalescent serum.

Six feet away or six feet under
A large American study measuring mobility using cellphone data confirms what we already knew: distancing works. And an international team has calculated that the combination of measures countries have taken to keep people out of each other’s immediate vicinity has probably averted half a billion cases of COVID-19 worldwide, and millions of deaths.
One mid-July county-by-county map from the National Geographic further drives home, if the Florida example wasn’t enough, what a little physical distancing can do: merely closing down a few nightclubs at the end of June turned Arizona and southern California from red (cases increasing) to blue (cases decreasing), while the South and much of the West kept getting worse. 

Spit and polish
For a while there’s been a dream around of rapid antigen tests for active COVID-19: spit in a tube, add a few drops of reagent, and know in minutes whether you got it or you don’t. Like a home pregnancy test, or the one I use in my office for strep throat. If people could self-test several times a week it could be a game changer. Well the dream is getting closer to reality now but, as so often, I have to say “don’t hold your breath.” Tests launched by BD and under development by researchers in ColoradoSouthampton, and various places in Asia still require specialized equipment and can’t be done at home; even the companies who are working frenetically on the problem admit they’re months or more away from solving it.

Herding cats
When I said something recently to a British friend about the Oxford group’s great vaccine and promising timeline, he said, “Susan, all Oxford researchers are in Boris Johnson’s pocket. Ignore anything they say.” I dismissed this as silly – until a few days later that same group came out with an absurdist revival of the herd immunity concept. They argue that what with all the coronaviruses we’ve all been exposed to in our lifetimes, 20% of the  UK population may already be immune to COVID-19, enough herd immunity to prevent a second wave of the pandemic. Both terms in this equation are nonsense: having had one coronavirus notoriously gives you no protection against another one – it doesn’t even protect you much against reinfection from the one you already had – and nobody except these guys think a herd will be protected until at least 60% of its members are immune. All the article’s fancy statistics are, I suspect, a way of pulling wool over eyes. In any case the UK would do well to put off thinking toward the second wave until after it’s managed to swim its way out from under the first one – with similar populations, the UK had 546 COVID-19 deaths in the past week to Italy’s 69, and more than 3 times as many new cases.
The whole vaccine enterprise, the herd immunity mirage, and everybody’s dreams for the future depend on the notion of lasting immunity to COVID-19. This has been brought into question lately with reports of patients who recover but then test positive again. Though most experts believe those patients are almost always experiencing prolonged single episodes, with false negative swabs intervening between true positive ones, there have been a very few convincing reports of individuals catching the damn thing twice. Does this make a vaccine impossible? I don’t think so. There are other diseases that you almost always but not quite always get only once – a common example is shingles (herpes zoster), which recurs in about 1% of patients.

The vanishing virologist, take 3
You will not remember, but back at the beginning of March I said Anthony Fauci was “pussyfooting around” by sucking up to Trump. Well now those chickens are coming home to roost in a remarkable way: Trump sicc’ed his advisors on the good doctor, getting on his case now not for being too alarmist – as usual – but for not being alarmist enough, i.e. for echoing (toeing?) the presidential line early on. For instance they lifted out of context a phrase from an interview back in February when Fauci said, “at this moment, there is no need to change anything that you’re doing on a day-by-day basis.” If Fauci’s approach boomerangs in a big way and gets him further sidelined, the boomerang is likely to make another spin and land back on the President’s head – at last call Fauci beat Trump 67% to 26% for public trust about the virus. As I’ve said before, firing him, while not easy, would be the gift that keeps giving – good for getting Trump out and good for finally freeing Fauci to say exactly what he thinks whenever he wants, without (as the Italians say) hairs on his tongue. Unfortunately on both counts, Trump now seems to be seeking to make nice with Fauci, though not enough to invite him back into those newly revived daily briefings.

Donkeys and elephants
Just in case anybody bristled when I said the recent surge in American COVID-19 cases was the fault of Republicans, I’ll hammer the point home with a cute, and highly eloquent, graph from ex-CDC’ers Bruce G. Weniger and Chin-Yih Ou:

Running out of steam?
While I was in quarantine in Rome a prominent Milanese intensive care physician named Alberto Zangrillo made a modest splash with claims that the coronavirus had become less virulent and “clinically no longer exists in Italy,” so we might just as well go back to life as normal. According to most experts that’s bullshit, offspring of the marriage between an Italian taste for grandstanding and right-wing political sympathies – Zangrillo is the personal physician of Silvio Berlusconi (his ally, infectious disease specialist Matteo Bassetti, shares those politics). Zangrillo is no newcomer to COVID-19 denial. Way way back, in February, he was already minimizing the threat on Facebook, predicting that “The so-called health emergency will soon be only a bad dream.” On the contrary, it turned into a true nightmare, causing the total number of deaths in his native city to double as compared to the year before.

Reading and 'riting and 'rithmetic, Taught to the tune of the hick'ry stick
One of the few issues that see me and Donald Trump on more or less the same side is reopening schools. As I’ve said before, kids under about 10 virtually never spread the virus, and the sole well-publicized instance of an outbreak supposedly caused by a child actually was the fault of the mother, who knew she was sick but nonetheless repeatedly exposed all her kid’s preschool classmates and teachers. High schools can space out their desks – which will usually preclude in-person full time classes for all – and their students are old enough to bear with wearing masks. The appalling outbreaks in Israeli high schools were due to thoughtless abandonment of both precautions.
Reopening colleges, on the other hand, is a recipe for disaster. As one opinion piece put it, “it’s clear higher education institutions stand about as much chance of enforcing masks and social distancing as alcohol consumption and abstinence.” It is rumored that college kids are already holding coronavirus “parties” where everybody chips in and the first to fall ill gets to take home the pot

Party girl
Speaking of which, when I was a kid in the ‘50s I attended a rubella (German measles) party. At the time there was no vaccine against the disease, so my parents brought me to visit a girl with the disease hoping I’d catch it myself. I don’t know whether they thought I did catch it, but when I was in med school I was tested for antibodies and didn’t have any, so I probably didn’t.
Whether or not it worked in my case, rubella parties were a reasonable strategy, because the disease was known to be very mild in kids, just a few days of rash and fever, whereas if a woman caught it when she was pregnant it could cause severe birth defects in the baby. But nobody would have ever been so foolish as to hold that kind of party for the regular kind of measles, which was often serious and occasionally deadly.
These crazy days, though, we have idiots deliberately exposing themselves to the potentially fatal illness known as COVID-19. The country where they’re supposedly holding “COVID parties” is my beloved, muddled homeland, natch, and the protagonists are young people who think they’re invulnerable, natch, and now at least one of them has died at the age of 30. Natch. More deaths as yet to come if this viral Russian roulette catches on, not to speak of lots of long-lasting or permanent damage to partiers’ hearts, their lungs, and whatever sits inside their skulls passing for brains.

What do these all have in common?
-       Eucalyptus necklaces
-       Asthma inhalers
-       Hennessy cognac
-       Stem cells
-       Mouthwash
-       Salt water gargles
-       Saunas
-       Chlorine dioxide bleach
-       Cocaine
-       Cannabis
-       Light machines
-       Cow urine
-       Sleep
-       Indian echinacea
-       Garlic
-       Remote prayer
-       Datura
-       Cow dung
-       Television screens
-       Anal violet oil
-       Mangoes
Three guesses, and the first two don’t count.