Sunday, March 29, 2020

Treating the dread corona: Myths and promise

Salvarsan, the original "magic bullet": an arsenic derivative to cure syphilis
Scientists all around the globe are scrambling to find a pharmacological fix for covid-19. There’s been so much confusion, and so much ballyhooing of false leads, that I felt I should dedicate a slightly wonkish and unusually serious blog post running through the candidate medications, with help from three authoritative and up-to-datesources.
Mostly hype 
1)    Chloroquine
Doctors are hoarding this ancient antimalarial and its cousin, hydroxychloroquine, for themselves and their families. Hydroxychloroquine is now in such short supply that patients who really need it, for autoimmune diseases such as lupus and Sjögren’s syndrome, can’t fill their prescriptions. And a few poor fools are killing themselves by self-dosing with fish bowl cleaner made from chloroquine phosphate.
They’re all convinced we have found the magic bullet. But how come? 
First of all, of course, there’s Donald Trump swearing “It’s going to be great,” while Anthony Fauci tries to hold him back. The National Review has slammed skeptical articles in the press as politically-motivated.
Second, hydroxychloroquine is already FDA-approved, so it can be given off-label immediately by any doctor for any disease, and it is known not to be horribly toxic.
Third, the drug does inhibit coronavirus in test tubes
Believe it or not, that’s all there is on the positive side. In research on actual covid-19 patients the results for hydroxychloroquine have been a wash. 
Studies in China were said to have found it effective, but for a long time the original research reports weren’t available. When Western physicians finally managed to see them a few days ago, the drug turned out to have worked no better than a placebo. 
The only other study* of hydroxychloroquine, in France, made a splash by claiming that 20 patients treated with hydroxychloroquine cleared the coronavirus in their noses faster than 16 patients who received standard treatment alone. 
There are serious problems with this study, even beyond the tiny number of patients. I would suggest you consider looking at the paper for yourselves. I did, and I noticed that their Results section was oddly missing any subsection reporting patients’ clinical status. But I didn’t understand why, until a more careful reader than myself noticed that the paper did in fact mention clinical results – hidden where you wouldn’t notice them, in a subsection entitled “Demographics.” The French researchers, it turns out, had started out giving hydroxychloroquine not to 20 but to 26 patients, and the patients who received the drug actually did worse than those receiving standard treatment: three of them needed to be transferred to the intensive care unit and a fourth died. (Two others dropped out voluntarily.)  No control patient had these outcomes. These damning results suggest that the researchers may have buried their clinical findings on purpose.
One expert has commented, “Researchers have tried this drug on virus after virus, and it never works out in humans.”
As Gertrude Stein said of her native Oakland, “There is no there there.”
2)    Existing antiviral drugs
a.     Lopinavir plus ritonavir: This two-drug combination used in HIV patients performed dismally among Chinese patients with mild-to-moderate disease. 
b.     Umifenovir: Used in Russia for the flu, it was tried in China for covid-19 but similarly flopped.
c.     Oseltamivir (Tamiflu): This widely-used influenza drug has been tried in China and is undergoing some “Why not?” clinical trials, but there is no reason to expect it to be effective.
d.     Baloxavir: A brand-new antiinfluenza drug similarly set to begin clinical trials in China soon but with little hope.
e.     Niclosamide: A deworming medicine that was found long ago to have some effect against the SARS virus in test tubes but never went on to clinical trials.
3)    Corticosteroids (dexamethasone, methylprednisolone….)
Steroids have been used for years as a kind of hail-Mary pass in patients with uncontrollable bacterial infection (septic shock), so it is reasonable to try them in end-stage covid-19. One Chinese study of methylprednisolone suggested a positive effect in desperately ill patients, but its methodology was weak, and the international expert consensus at the moment is that corticosteroids are more likely to do harm than good.
4)    Azithromycin (Z-Pak)
This anti-bacterial (not antiviral) antibiotic is sometimes used to counter bacterial superinfection in serious viral illness, and has been given to some covid-19 patients in combination with hydroxychloroquine. It is known to be safe, but there is no evidence it has any benefit, and some suggestion it may do harm.
5)    Other medications
A panoply of FDA-approved drugs are currently under study in covid-19 patients on theoretical grounds, with no evidence and little hope of a clinical effect: nitric oxide (an inhaled agent used for acute respiratory distress syndrome), vitamin C, sirolimus (another kind of imunosuppressant), and losartan (an anti-hypertensive drug that many experts fear may make covid-19 worse instead of better).
Where I’d put my money
1)    Remdesivir
This antiviral, effective against a variety of coronavirus diseases, is considered by many experts to be the most promising antiviral for covid-19 and is already undergoing numerous trials. It has been used in northern Italian hospitals for weeks, when they can obtain it, and one manufacturer, Gilead, is currently expanding its availability in the US for compassionate care.
2)    Favipiravir
A Japanese antiviral that reduced recovery time and improved chest x-ray abnormalities in two trials completed in Wuhan and Shenzhen involving a total of 340 patients. It is approved for general use in China and for compassionate use in Italy, and is now formally under study, but is not available in the United States.
3)    Convalescent serum
Most people who recover from infections develop antibodies that protect them from reinfection. Products derived from their blood – either whole blood, or the antibody-rich serum that remains when you remove the red blood cells, or a more refined immunoglobulin product – can be effective drugs. For decades, a century ago before we had antibiotics, they was the mainstay of treatment for infection, and are still potentially invaluable. Such products werethe only decent drug treatment for Ebola, and there is reason to hope not only that they might keep moderate covid-19 from deteriorating, but that small daily doses might protect people at very high risk, such as health care workers on the front lines, from becoming infected. The Chinese brought some covid-19 immune serum to Italy, but soon Italy – and eventually the US – will be able to produce their own, now that there is a large enough pool of patients in convalescence. Researchers, including notably a group at my alma mater, New York’s Mount Sinai Hospital, are working to develop blood tests that will be able to identify people who have antibodies against covid-19 and therefore could usefully donate blood for this purpose.
4)    Tocilizumab (Actemra)
This “biologic,” most often used for inflammatory diseases such as rheumatoid arthritis, is an antibody against the proinflammatory cytokine interleukin-6. It has no direct action against viruses, but might help tamp down an overactive inflammatory response in the lungs of patients with covid-19 pneumonia. Preliminary results among 20 Chinese patients suggested improvement over several days, following one or two doses. Unfortunately this drug may also have the potential to promote viral replication, and long-term complications include tuberculosis and other serious infections, so it is only appropriate to try in the sickest patients. A large study has been started by Roche, and sarilumab (a similar antibody) is also being examined.
5)    Interferon
Interferon alpha, beta, and gamma (Avonex and others), like tocilizumab, have complex effects on the immune system, and they may in addition suppress viral multiplication. They are usually prescribed for hepatitis C and multiple sclerosis, and have shown promise in non-covid-19 coronavirus disease. Interferon is quite toxic, however, and like tocilizumab risks making patients worse rather than better.
Injected interferon beta is undergoing clinical trials, but it is hoped that an inhaled formulation of the same drug, code named SNG001, might give similar benefits with fewer side effects. It has been found to improve the recovery of asthma and COPD (chronic obstructive pulmonary disease) patients with lung infections, and is due to begin testing in the United Kingdom in critically ill COVID-19 patients. 
Both antiviral drugs and convalescent serum seem to be more effective early in the course of disease, while the powerful, toxic antiinflammatory medications such as tocilizumab and inhaled beta-interferon are more appropriately used late in the disease, in severely ill patients on respirators, in the hope of warding off off total body shutdown.
The final solution
Our hope for social distancing and even anti-covid-19 medications is basically that they will get us into a holding pattern until an effective vaccine can knock out the pandemic entirely. Groups in a half-dozen countries have already developed candidate vaccines, and a few volunteers have received a first dose. 
Politics has been involved even here: President Trump really really wants the best vaccine to be produced on American soil, for Americans. He apparently tried to lure a German company, CureVac, to do its research and production, if it comes to that, in the United States, and to guarantee the US monopoly rights. The company’s lead investor has confirmed that some such approach was made, and the in the end it seems the German governmentintervened.
Most vaccine research, on the contrary, has been proceeding in the spirit of international cooperation, starting with the Chinese researchers who rapidly sequenced the virus and shared their results.

But it will probably not be before at least the fall of 2021 that we will have developed a vaccine, proven it effective, and administer it to enough people that herd immunity will protect the uninfected. So for now our best bet lies in sheltering at home and other social distancing measures. Fortunately, there’s double good news on that front. One I’ve mentioned before but it bears repeating: experts say that social distancing measures can be effective even if they are less than draconian and less than constant. And the other is that today, exactly three weeks after northern Italy was locked down, my adoptive country’s rates of death and use of ICU beds are falling convincingly at last (see graphs at end). 

*Interestingly, in the 24 hours since I posted this essay, the French hydroxychloroquine researchers have changed the text of their article, though it is still at the same url. Chiefly, they now specify that 6 patients were - for unexplained reasons -given azithromycin in addition to hydroxychloroquine, and report that those 6 patients cleared the coronavirus particularly well. This changes nothing in the real results of the study: 4 among the 26 patients given active drug and no patients in the control group wound up either in the intensive care unit or dead. Other scientists and a group of sharp psychiatrists have now pointed out these issues as well.

Thursday, March 26, 2020

Coronavirus: Quick fixes or slow Italian slogs

Early in the 1980s Italian cars had seatbelts but if you wanted you could just let them dangle. The cops once pulled me over for wearing one, apparently because for someone at the wheel of a sporty Rabbit convertible this was suspicious behavior. When seatbelts finally became obligatory, Neapolitans responded by printing up t-shirts with a broad black stripe from left shoulder to right waist, to make it look from a distant police car as though you were had one on. 
Now the same national ingenuity has been put to work for a nobler purpose. Ten days ago a hospital in the northern Italian city of Brescia, hard hit by covid-19, was running out of the valves that hook up patients to ventilators, and the supplier couldn’t keep up with the demand. Two young Italian guys who owned a 3D-printing company brought a valve home, took some measurements, and 24 hours later had printed 100 fully-functional replicas. Their latest trick is turning snorkeling masks into respirators…
Italy is otherwise short lately on quick fixes – and on la dolce vita. Under the gentle Californian social distancing rules, we can’t eat in a restaurant but we can order out anything from Burmese to Ethiopian. We can’t go to a gym but we can stroll around the neighborhood any time we want or drive up to Tilden Park for a hike. We can’t have a friend over to dinner but we can meet her in a green space and have a chat, though at two meters one may avoid intimate subjects. We drove way across town to score a bottle of olive oil good enough for adoptive Romans.
The Italian stay-at-home, on the other hand, is more like house arrest – you can’t walk out the front door without written justification, which is frequently checked. Most of our friends in the now truly naked city of Rome can’t even take a pleasure walk. That privilege is limited to dog-owners, and then only within 500 meters of home. Parks are closed, you can’t drive except for health or essential work purposes, and in-person meetups are a no-no at whatever distance. All my informants agree that Romans, defying their reputation as scofflaws, are being amazingly compliant with the restrictions, and from conviction, not just fear of the patrolling cops and drones. There are no spring-break parties on Italian beachs.
Desperate measures are being taken – Italian medical students, who usually get little hands-on training, are being brought to work on the wards, courageous physicians from southern Italy have gone to the covid-striken North to fight the virus, and doctors have come out of retirement to lend a hand. Twenty-four of the 33 physicians who have died of covid-19 were over 65, including an 87-year-old woman psychiatrist from Brescia. Thousands of physicians and nurses have fallen ill with the disease.
Rome now has five dedicated covid-19 hospitals or buildings, two of them comandeered private hospitals, with a total of over 1000 beds.
Italy had to practically abandon the test-and-track-contacts strategy after a month cohabitating with the coronavirus, for lack of test kits and of personal protective equipment for the testers. Only people sick enough to require hospitalization are now getting a definitive diagnosis. Widespread testing is strongly advocated by the World Health Organization, and has proved invaluable both in Korea and in Italy itself.
Some aid is coming in from China. Chinese provinces have already donated 30 ventilators, 400,000 masks, 60,000 test kits, and 5500 protective suits to Italy, the Bank of China donated 100,000 masks and 50 ventilators, and a combination of donations and purchases brought another 100 ventilators and 2,000,000 masks. Two batches of Chinese doctors and nurses arrived bearing both their own experience and bags of convalescent serum for treating patients. It was rumored two weeks ago that China was making another 1000 ventilators, 50,000 test kits, and many million masks available for Italy to purchase, but that seems to have come to naught.
Part of that Chinese know-how is an artificial intelligence program supposedly capable of diagnosing covid-19 with 98.5% accuracy in 10 seconds by analyzing CAT scan images of the lungs…
It turns out, by the way, that I was wrong in my last post about the 500,000 test kits supposedly shipped on military planes to the US: they weren’t Chinese but Italian (from the Copan company in Brescia), they weren’t test kits but just swabs (those long Q-tips they stick up your nose), and they are, remarkably, not in short supply.
Incidentally, I keep trying to track the million masks and 500,000 test kits Jack Ma promised to the US. A first shipment supposedly arrived over a week ago, but I’ve found no word of it since. 
But there is now truly good news coming out of Italy: the rigorous countrywide social distancing measures are bearing fruit. In parts of the North the situation in hospitals is still horrific, 662 Italians died yesterday from covid-19, and in Rome the epidemic still hasn’t hit its peak. After just two weeks of nation-wide lockdown, though, the number of patients in Italy’s intensive care units is already plateauing, and the number of deaths are falling day by day – today the total death toll went up by only 8.8%, compared with over 30% a day before the lockdown. My updated graphs are below, and a New York Times article has made the same mathematical point. Deaths should start trending downward about ten days from now, trailing the ICU curve by a week or so. Exactly as optimistic virologists predicted.

(It’s important to understand that covid-19 is a slow disease, so the effects of preventive measures take a long time to kick in. As a comparison, if influenza develops into pneumonia it takes only a few days. With covid-19 pneumonia develops gradually, over two or three weeks, and recovery is also much slower, so patients who need a respirator need it longer.)
I had hoped to be able to devote this piece to debunking putative covid-19 treatments, but after Donald Trump’s latest about-face I thought it was better to hammer home the Italian example instead. Just ten days ago, before I last posted, Trump embraced social distancing and those of us who believe in science started to breathe easy. Now he has back-tracked, floating on Sunday the prospect of getting back to business as usual, doubling down on Monday, declaring Tuesday that social distancing is a “cure worse than the disease,” and proposing that the country should be “opened up and raring to go” by Easter. 
The number of deaths in New York City has gone from 10 a week ago to 281 just now. Trump fiddles while his hometown burns – and proud of it. Just as he’s proud of having chosen Easter as a deadline not based on any scientific data but because “I just thought it was a beautiful time.
You don’t have to go as far as Italy to demonstrate the advantages of social distancing, by the way. The Imperial College study by Ferguson and his colleagues, the one that pushed Boris Johnson and – briefly – Donald Trump into advocating social distancing, thought “Stopping mass gatherings is predicted to have relatively little impact.” Unfortunately that may have been one of their few inaccurate guesses, judging from the counter-example of New Orleans. Its Mardi Gras was followed two weeks later by the very first case of covid-19 in Louisiana, and now, a month after Mardi Gras, there have been 1795 cases and 65 deaths. 
Experts agree that in the first growth phase of this pandemic, which the United States has barely entered, social distancing will take time to work – only now, after two months of draconian measures, is China cautiously daring to begin a return toward normality. Something like that time scale, however painful, will have to be applied here as well if we want to avoid going down the paths of China and Italy. A brillian new study shows that countrywide distancing measures are very effective in reducing covid-19 deaths even if they are not as draconian as China’s or even Italy’s. Fortunately city and state governments, the only ones to impose social distancing regulations thus far, can do so whatever the President says. But there is justifiable concern that the 60% of Americans who told Gallup pollsters last week they think Trump is handling the coronavirus crisis just fine will now feel freer to flaunt any guidelines put into place locally. 
The chance of a concerted national effort to contain the virus already lost three precious weeks between Feb 26, when Trump said “We’re going very substantially
down, not up
,” and March 17 when he “Felt it was a pandemic long before it was called a pandemic.” Now there may be no chance at all.
Bill Gates has already lost billions due to the shutdown of the economy. Here, contrary to his own financial interest, is his vicious paraphrase of the President’s new position: “Hey, keep going to restaurants, go buy new houses, ignore that pile of bodies over in the corner.” 
Or you may prefer The Onion’s version: “Trump Urges Loosening CDC Restrictions To Let Coronavirus Get To Work.”

Thursday, March 19, 2020

Diary of a coronavirus refugee: Schadenfreude and relief

Lockdown in Rome's Testaccio market (note 1-meter distancing strips) and San Francisco

Schadenfreude = the uniquely German concept of enjoying other people’s suffering. 
I had a great gush of it on Monday, watching Donald Trump eat humble pie through clenched teeth, if you’ll forgive the mixed metaphor. After weeks of “We have it very well under control” and “One day – it’s like a miracle – it will disappear,” the current occupant of the White House, the same guy who two years ago closed down the American pandemic preparedness taskforce, had been forced to admit that coronavirus is a real threat and to recite a litany of guidelines for controlling the epidemic. Never one to be outdone by the competition, Trump went the Centers for Disease Control one better: the previous day they had advised no gatherings of over 50 people, he said no more than 10. 
Friends have written to me about hearing a nurse in Hawaii say the coronavirus story was “all hype,” a gym mate who thought covid-19 was “just the flu”… According to recent Kaiser Family Foundation polls, an incredible 46% of the US population trust what the President tells them about the coronavirus, and 44% think he’s doing a good job at handling it. That poll was taken between March 11th and 15th, before Trump made his 180º policy swing. What are those gullible Trumpers going to think now? Hopefully they’ll flip in turn, start taking the pandemic seriously, and stop being such a threat to themselves and others.
I must say, though, that my Trumpward Schadenfreude was far outweighed by relief. If the CDC had been allowed at last to make some concrete recommendations, with Trump backing them – if denial is no longer the Administration’s party line – there is now, I think, a good chance the US will escape the worst-case scenario.
Everywhere in the US the social distancing message is sinking in. Here in the San Francisco Bay Area, my current place of refuge, they have now instituted a “shelter-in-place” ordinance on the Italian model. Its rules are somewhat less rigorous – unlike the Italians, we’re allowed to go out for a stroll if we want, and can use our cars if we want to go shopping or hiking outside our immediate neighborhood. And thus far it’s much less rigorous in practice, relying on voluntary compliance rather than on the police cars that roam the streets of Rome in search of errant pedestrians. Between March 11th and March 18th, Italian cops had stopped and checked 1,226,169 people for compliance with the covid-19 ordinance, and given out 51,892 fines. Nobody’s been sent to jail yet, but sentences could theoretically be for up to 12 years.
Where the US is still failing abysmally is in applying the most important antiepidemic tool according to the World Health Organization: “test, test, test.” Anyone with symptoms of possible infection should be tested, their contacts should be traced and tested in turn, and everyone with positive tests plus everyone in each of their households should be quarantined (it’s now clear that the disease can be transmitted even before symptoms develop). As of early this weekItaly had tested 148,657 people; the United States, with a population five times greater, has only tested 41,552, and in a fashion more haphazard than systematic.
Alvin and I have been watching a lot of CNN, whose sole subject by now is the coronavirus. We’ve been shocked by two things: First, the endless direct-to-consumer ads for powerful prescription drugs with potentially fatal side effects, a criminal practice nearly unique to the US. Second, the way coverage of the pandemic has been virtually limited to the US – if it weren’t for a feelgood clip or two of Italians singing on balconies, you’d never know there was coronavirus beyond our borders.
Buried along with any foreign news has been the extraordinary aid that China has been giving countries badly affected by the pandemic to help cope. The Chinese government has started sending Italy everything from coronavirus test kits to ventilators, as well as teams of physicians and nurses experienced in treating the disease. And did you know that Jack Ma, the wealthiest man in China, has promised to give the United States 500,000 coronavirus test kits and 1 million face masks? They left Shanghai this Monday, and may have continued on to the US the same day on military aircraft, for eventual distribution by the CDC. His generous donation, by itself, may make a substantial contribution to stemming the American epidemic. 
By the way, Joe Biden was mistaken when he said at Sunday’s debate that the US had refused kits from the World Health Organization.
The Italian lockdown seems to be starting to bear fruit. Admittedly today’s coronavirus news looked bad: Italy has now passed China in total number of deaths. But that death rate, awful though it looks, is starting to rise less rapidly day by day than it was ten days ago, and the growth in the number of covid-19 patients in intensive care has similarly been slowing down (see my charts at the bottom).
The growth in confirmed cases has been improving less strikingly, but you can’t count on those data because they are so dependent on the amount of testing that’s being done.
Let me go back for a moment to the last Democratic debate. Another of Biden’s bad moments was a misguided attack on Italy, when he pivoted from a question about coronavirus into making a dig at Bernie Sanders’ Medicare-for-all. “With all due respect to Medicare-for-all, you have a single-payer system in Italy. It doesn’t work there. It has nothing to do with Medicare-for-all.”
I’d guess Sanders hadn’t been prepped for that particular line of attack, because he didn’t respond, as he should have, that if there hadn’t been a National Health System in Italy things would have been much worse. Aside from the well-organized medical response per se, all Italians knew from the get-go that if they needed testing or treatment they wouldn’t pay a penny out of pocket, so nobody hesitated to seek medical services. And the Italian welfare state helped greatly: all regular wage earners too sick to work, caring for a sick family member, or laid off because of closings knew they would keep earning their salary, or a good chunk of it, for many months. 
Italian medicine is terribly underfunded and undersupplied (it has 1/3 as many ICU beds as the US, and spends 1/3 as much on health care), and I haven’t hesitated to point out its uneven quality. But in this crisis the system has really come through, to the extent that resources allow it. The response was well-coordinated, physicians stay efficiently informed of the rapidly shifting national guidelines, private hospitals are commandeered to meet public need, and medical staff are giving their all and beyond; as of today, 13 Italian doctors have died of covid-19.  

It should be said, though, that many Italians who depend on the gig economy or are independent contractors, something around 17% of the workforce, are being left in the lurch and will suffer economically. My musician husband and I both fall into that category. All of Alvin’s gigs have been cancelled for the foreseeable future, and as a physician in private practice I obviously earn nothing as long as I’m in the US, while incurring unchanged office expenses. Even if I were home in Rome I’d likely be scraping together only some 10% of my usual income by giving a few paid phone and Skype consultations. Thank heavens for his Social Security, and for my small Italian pension!