Wednesday, April 8, 2020

Drug Dreams, Italian Realities

Piazza Navona reverting to wilderness
Treatment Update 
I was going to put this section at the end, but so much has happened in the week since my last post that I will lead with it instead.
Convalescent serum – exciting news
Several preliminary steps have been whizzed through. A blood test capable of telling who’s had covid-19 has gone in a week from a hope to a reality. An antibody-rich preparation from recovered patients’ blood has proved effective in both China and northern Italy. The Food and Drug Administration has classified covid-19 convalescent serum as an investigational drug, allowing American hospitals to start administering it. Now not only are large studiesunderway, but the National COVID-19 Convalescent Plasma Project has set up a dedicated website to recruit potential donors. If you are in the United States and think you have had covid-19, even if you were never tested, or if you know someone in that situation, please go to the NCCPP website to get more information, and sign up. One blood donation treats one sick patient – you might save a life!
Antiviral drugs
Remdesivir: This new antiviral, widely available on a compassionate basis, might see the first results of clinical studies as early as next week from China and at the end of April from the United Kingdom. Fingers crossed. The patent-holder, Gilead Science, tried to get its monopoly extended by having remdesivir declared an “orphan drug,” causing such an outcry that it had to back off.
Favipiravir (Avigan): the report of one of the two published trials, which was in any case seriously flawed, has been abruptly withdrawn by the researchers. We’ll see what the better ongoing studies will show.
Lopinavir/ritonavir (Kaletra): A small trial had found no benefit, and now a second, larger one has proved just as disappointing. This medication is probably a dead end.
Leronlimab: An experimental drug with antiviral as well as antiinflammatory properties, which very recently began testing. It’s far too early to say much. 
Hydroxychloroquine (Plaquenil)
Trump went on Saturday from “It will be wonderful” to “I really think they should take it,” and two more reports now claim Plaquenil is good for treating covid-19. HOWEVER. One is a repeat performance from the French researchers whose study I panned last week, and the new one is methodologically even worse. The other, a Chinese study pre-published by its authors without going through any kind of review, is just as fishy: poorly written, peculiar methods, and unclear results. My doubts remain unallayed.
Between the strange new Plaquenil study, the older ones whose great results evaporated when the results were actually examined, and the mysterious favipiravir story, I have to admit I’m getting a bit skeptical of any covid-19 research that comes out of China.
Vaccines
A possible covid-19 vaccine coming out of Pittsburgh has now been tested in mice, and the mice produced antibodies. This is good. Volunteers in China, the United Kingdom, and Seattle have already received doses of three other vaccines, so we’ll soon know whether people will produce antibodies too. Even if they do, though, it doesn’t shorten the 12-18 month timeline before a useful vaccine may be available. Two weeks ago there were already 44candidate vaccines, being studied in 500 centers spread across a dozen countries.

Covid-19 in Italy: Facts and Flimflam
Origin stories
The wildfire spread of the pandemic in northern Italy is still not fully understood. One factor was likely the return of many Chinese immigrants from New Year’s celebrations in Wuhan. Not everybody, especially outside Italy, realizes that the virus’s choice of its first known victim was also particularly clever. Mattia (who was on a respirator for weeks but survived) was a previously-healthy man of 38, with absolutely no Chinese connections, who in the week before he fell ill had gone to work every day in a large building, run two races, played soccer, and partied at least three evenings. He went several times to his local Emergency Room, exposing myriad people, before he was admitted with pneumonia to a non-isolation ward, and spent several more days infecting patients and staff before a brilliant anesthesiologist broke protocol and tested him for the novel coronavirus.
The death rate “scandal”
China is known to have vastly underreported its covid-19 death toll. Ten days ago it came out in the Italian press, then the international press, that Italy did too. In hard-hit Bergamo and Brescia, in particular, a suspiciously low number of deaths were being attributed to covid-19 in proportion to the increase in overall death rate. Many deaths were being classified as influenza or pneumonia, without coronavirus testing. 
The reality is neither scandalous nor nefarious. True, at the peak of the epidemic, the health system was so overwhelmed and test kits so lacking that many elderly people with probable covid-19 were left at home to die undiagnosed. But just a week after Italy’s lockdown the epidemic began improving continuously and steadily, suggesting that underreporting of deaths likely happened only in limited areas and for limited periods without greatly impacting the overall statistics. Daily deaths are now down by at least a third, and every region of Italy now has ICU beds to spare – partly because the absolute number of very sick covid-19 patients has dropped, partly because the country succeeded in expanding those beds from 5324 to 9284. 
Now the New York Times writes that the same underreporting is happening in the United States: “Hospital officials, public health experts and medical examiners say that official tallies of Americans said to have died in the pandemic do not capture the overall number of virus-related deaths, leaving the public with a limited understanding of the outbreak’s true toll.” So it wasn’t the Italians being Italians, after all.
The sickest patients
I have been tracking the number of covid-19 patients in intensive care units at my Facebook page as a good way of following the pandemic, and the curves are looking great:

Unfortunately, no comparable figures are available for the United States. Diagnosed cases and death toll, yes, but not how many patients are hospitalized, in ICUs, or in home isolation – all data published daily in Italy. Yet another reason to be grateful to the Italian National Health Service. 
All I can tell from meagre data is that there are now at least 7200 covid-19 patients in ICUs in New York, California, and Louisiana. Since those three states have accounted for 51% of the deaths in the US, we can guess the total number of covid-19 patients in American ICUs at about 14,400 – more times as many as in Italy.
When I write about the pandemic I generally ignore data on diagnosed covid-19 cases, because they are so dependent on how many tests are being done, and on whom. But I’ll break that rule now for Italy, because for four weeks the criteria for coronavirus testing have been pretty stable: all people sick enough to need hospitalization, and only those people, are tested. So we can probably trust the steady drop during that period in the daily rate of increase in total Italian cases, from 23% on March 11th to 2% today.
Terrible rationing choices had to be made in the worst-hit hospitals in northern Italy at the peak of the epidemic. Right-wing American media outlets have been spinning them as “socialized medicine” running “death panels.” Ignorant, dangerous nonsense, as even those know-nothings will realize if and when American hospitals find themselves similarly overwhelmed.
Doctor patients
In Italy an outsized proportion of diagnosed covid-19 cases have been in health care workers – 11,252 cases as of Friday, 8% of the total. As of today 94 Italian physicians have died, most of them over 65 years old, many retirees who heroicially volunteered to man the front line; here is a heartbreaking if incomplete list of names, cities, specialties, and birthdates. Interestingly, the Spallanzani Hospital in Rome, which specializes in infectious diseases and has treated vast numbers of covid-19 patients, has reportedly had no cases among its own doctors and nurses. And in the United States, where the death toll is now up to three-quarters of the Italian total, only one physician has died from the disease. Why so much variation? In part, it’s due to varying degrees of training in the care of contagious patients. But in part it is surely related to the horrific conditions in northern Italy at the height of the epidemic. In Lombardy, where the vast majority of those doctors died, staff in some ICUs were intubating seven covid-19 patients a day and working 14-hour shifts for weeks on end, while family physicians with no protective equipment went door to door signing death certificates for patients who died at home. 
Life under lockdown
In Italy, ads for malpractice lawyers are burgeoning in the middle of the covid-19 epidemic. In the United States, Republicans are using the epidemic as an excuse for reducing access to abortions. To each country its con.
My Italian friends tell me the famous evening balcony songfests have mostly petered out . But it’s spring, and everybody with a personal or rooftop terrace is hanging out there – one friend wrote she’ll be  “walking, reading, eating a sandwich among the sheets hung out to dry – it’s like being in a movie by Scola.” 
Cuba sent 52 doctors and nurses to help out in the Northern Italian city of Cremona. The right-wing regional government welcomed them with open arms.
Pallets of medical supplies donated by the Chinese consumer electronics company Xiaomi arrived in Italy bearing labels that quoted the Roman stoic philosopher Seneca: “We are waves of the same sea, leaves of the same tree, flowers of the same garden.”
Yesterday a guy yelled at me in a California supermarket for not wearing a mask: “It’s the law!” (Actually it’s not, at least not yet.) That’s no surprise in Berkeley but it is in Italy where, a friend says, “Everybody’s turned into carabinieri.”
Carabinieri maybe, but generous ones. Signs are popping up all around Italy, on tables or baskets laden with pasta, milk, tomato sauce, olive oil, crackers…, labelled with variations on, “Chi ha metta, chi non ha prenda,” “If you have, contribute. If you don’t have, take.”

Fake news

I think I’ll end with a romp through the nonsense about covid-19 that has been flying around Italian social media. Some is international:
-       The coronavirus was created in a Wuhan laboratory by NATO to help elect Trump
-       The coronavirus was created in a Wuhan laboratory by China as a bioweapon
-       500 lions are roaming the streets of Moscow to keep people indoors
-       Swarms of helicopters fly over cities at night spraying disinfectant
-       Eat garlic, take vitamina C, and drink plenty of water and you’ll be immune
And some is home-grown:
-       The coronavirus was created by the Italian government, to save money by killing off old folks
-       The coronavirus was created by Bill Gates, so he could make billions off a vaccine
-       People living in Rome but officially resident elsewhere are to be expelled
-       Public servants earning over $60,000/year are to have their salaries slashed to $10,000
-       Pensions are to be cut by 50%

-       Only Italians have had covid-19, immigrants are immune

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.