Thursday, April 16, 2020

Tunnels and Lights

An Italian bookstore, newly reopened

Treatment updates: the big guns
Convalescent serum: Since I last wrote the recruitment of recovered American covid-19 patients has proceeded apace, blood banks now vying with hospitals to find donors. The Red Cross has set up a donor website in addition to the National COVID-19 Convalescent Plasma Project one that I linked to last week. Patients with confirmed diagnoses are already donating plasma at the New York Blood Center, and they soon will be in at least another nine statesIn Italy, the Tuscan blood bank has begun sending letters to recovered covid-19 patients inviting them to donate plasma, withLombardy and Veneto soon to follow suit and Lazio, Campania, Marche and Molise the next comers.
Remdesivir: Some good preliminary news: the manufacturer has reported outcomes for the first 61 covid-19 patients given this antiviral on compassionate grounds. Most promisingly, with remdesivir only 18% of the patients on ventilators died. Compare that with the experience in New York City hospitals without remdesivir – 80% of covid-19 patients placed on ventilators died. This report is NOT a controlled trial, but its results encourage such trials to go forward.
Hydroxychloroquine: Its reputation is based on a single dubious study in France, and that study’s plausibiility slides from bad to worse. The society whose journal published it has said officially the article “Does not meet the society’s accepted standard.” And the first author, Didier Raoult, turns out to be a shady character. He was once temporarily banned from publishing, after being caught out falsifying research results, and the rest of his bibliography is nearly as dubious. In an as yet unreviewed paper, a different French group studying covid-19 patients with pneumonia has now reported hydrochloroquine to be useless. 
If you want to follow covid-19 treatment research for yourself and can handle technical language, here’s a constantly updated page.
Minor contenders touted in the media
Nitric oxide: a trial of this inhalant is now underway at the University of Alabama.
Heparin: Desperately ill patients sometimes develop Disseminated Intravascular Coagulation, widespread blood clotting, treated with blood thinners such as heparin. In a Chinese study, covid-19 patients with DIC supposedly died much less (40% vs. 64%) if they were given heparin. But this was a retrospective study, not a clinical trial, and heparin is standard therapy in any case. No magic bullet.
Ivermectin: This drug for head lice and pinworms turns out to block the growth of SARS-CoV-2 virus in test tubes and may soon be tested in human beings. Its chief promoter looks like a charlatan; I wouldn’t hold my breath.
BCG: Dubious statistics suggest that covid-19 takes less root in countries where this tuberculosis vaccine is widely used (which include China). Studies are underway to see whether BCG might give a general boost to the immune system  and help fight off covid-19 – “the equivalent of a Hail Mary pass.” 
Viagra: A pilot study is on in China. Lots of luck.
Snake oil department
Ozone: A quack treatment with no known efficacy, considered by the American Food and Drug Administration to be “a toxic gas with no known useful medical application,” being pushed as a treatment for covid-19. 
Colloidal silver: The FDA has issued warning letters to its manufacturers for fraudulently claiming effectiveness against covid-19. 
There is no evidence that any supplement or foodstuff, from zinc to elderberry to CBD to sauerkraut, can help prevent or treat covid-19.
Vaccines
Of the scores of research teams racing to develop one, four have already moved beyond animal testing to trials on human volunteers. But the timetable is all over the map.
-       Most experts continue to think a vaccine should be ready to roll out in autumn 2021.
-       Others are afraid it will take years.
-       The research team in Oxford, England, thinks theirs may be set for widespread use as early as this September.
-       One virologist has hinted that a vaccine could be obtained even faster if researchers overcame their moral scruples and deliberately infected volunteers with coronavirus.
Be aware that even a functioning vaccine may not eliminate the pandemic. We hope the winning entry will act like the measles vaccine, which gives permanent 97% protection after two doses. But it might instead turn out to be like the yearly flu vaccine, which only reduces infections by 50% or so. What we already know about immunity to coronaviruses is discouraging. Some coronaviruses cause the common cold, and immunity after you’ve had a case lasts only a couple of years, even though natural infection is better than vaccines at goosing the immune system.

Italy update
Italians are flexible, resourceful, and sensible. One friend writes, “The natives are observing with great dedication the lockdown and distancing rules, and – as if in tandem with the Easter season – we haven't seen so much hand washing in the Bel Paese since Pontius Pilate strode the dusty streets of Rome on his disgraced return from Judea. This shocking discipline reminds me a bit of the overnight adherence to the no-smoking regime, years ago, which no one would have predicted.” But another correspondent emphasizes the negative: neighbors having a drink together on the roof, biddies distributing olive branches door to door on Palm Sunday.
Much of the economic impact of the Italian epidemic is cushioned by generous sick pay, unemployment benefits, and universal health care without co-pays or deductibles. An emergency decree forbids layoffs, slashes rents, pays baby-sitters, etc. Self-employed workers are supposed to receive bonuses totalling $2500 over three months, supplemented by contributions from some professional societies. (My composer husband will get neither, because he receives an Italian pension – €124 ($136) a month!) But the millions who work off the books in Italy’s vast underground economy aren’t eligible for unemployment benefits or bonus payments, so the shutdown of the economy will cause real suffering. Two weeks ago a few people rolled their full shopping carts up to the checkout line in a Sicilian supermarket and refused to pay, and more serious unrest was widely anticipated. It never materialized.

Italy is shaking off covid-19, with the number of people in intensive care units now decreasing steadily:


New cases continue to be diagnosed, however, and there are still 500+ deaths every day, mostly in the ravaged North – likely new infections inside nursing homes, within patients’ families, and in factories that exploit legal loopholes to keep their workers crammed in. 
One Rome high-rise inhabited by 600 Eritrean squatters houses 18 definite and 33 suspected cases of covid-19. The authorities, instead of doing mass testing and moving people out as necessary to enable social distancing, have sent the army to keep the whole building under quarantine. They did, however, distribute milk, pasta, tomatoes…and chocolate Easter eggs.
Some Italian cities are now offering “drive in” covid-19 testing for people with relatively mild symptoms. In Rome, you start the process with a phone call to 06 3306.2738, 06 3306.4748, 06 3306.2847, or 06 3306.2707.
As of April 15th, 121 Italian physicians have died of covid-19.

Glimmers
Italy has taken initial baby steps toward reopening the economy, allowing a bizarre list of productive activities: dry cleaners, forestry, computer factories, and stores selling books, stationery, or baby clothes. But several regions where the fires of covid-19 are still burning, such as Lombardy, have declined the invitation.
Donald Trump and his buddies are chafing at the bit to do the same and more. The militia sorts are openly defying stay-at-home orders, some ministers held in-person Easter services… Is it time yet? And if and when, how?
In the United States it’s clearly too early, whether your chosen authority is Anthony Fauci or The Onion. Lacking consistent federal guidance, our shutdowns have been patchwork, in dribs and drabs. Every state experiences a different epidemic according to whether and how much it’s closed up shop, how well people are complying, and who is being tested. While California enters the downslope of the first-wave curve, New York still loses more than 700 people to covid-19 every day, and the death rate rises sharply in New Jersey, Georgia, Connecticut, and Michigan. How could guidelines be countrywide? I won’t go into details, just state a few principles:
First of all, when the number of active cases is low enough, we can finally do as we should have when the first cases appeared: test all suspected cases, isolate those who test positive, track down and test everybody who’s had contact with them, and quarantine the positives among those contacts. Germany was the only Western country to do this, under the exemplary leadership of Angela Merkel, and they have had 3800 deaths as compared with more than 13,000 in other European countries with comparable populations. 
Second, we need explicit criteria for determining restrictions. The Imperial College study that got social distancing going in both the US and the UK famously modelled the benefits of various mitigation strategies. But it also, less famously, modelled an ideal strategy over time, using the number of covid-19 patients in intensive care units as the indicator of when restrictions should stop and start:
A conservative model of an on-again off-again coronavirus lockdown

Based on an “on” trigger for the United Kingdom of 100 ICU cases in a week and an “off” trigger of 50 cases, and assuming testing, isolation, and quarantining, they calculated that while we wait for a vaccine, social distancing could be lifted a third of the time.
Now that we’ve gotten used to social distancing, though, I think we can accept some degree of it as the norm for the duration. With moderate social distancing, we should be able to lead a relatively normal life most of the time, as long as criteria are established and rigorously followed. Forget about packed baseball stadiums and sold-out Broadway shows, but there could be picnics, restaurants with proper table spacing, sports events and movie theatres with six feet between spectators, church services, dinner parties… Dinner parties!!! I can imagine drive-in stands where people can get swabbed for active infection, obtain their results in five minutes, and if negative be given a certificate good for a week’s freedom of movement. 
In addition to PCR swab tests for active disease, blood testing for antibodies against the coronavirus should play an important role. People with antibodies will probably be shown to be immune, at least temporarily, so they could work, socialize, and attend events with impunity. Some are hoping that mass blood testing will show that enough people are already immune to protect the rest by “herd immunity.” This is unlikely, since protection only seems to kick in when more than 90% of the population are immune, but we can hope.

Privilege and covid-19
Coronavirus is not an equal opportunity bug, with poor and minority populations suffering the most. This has been shown on a neighborhood level in New York, on a county level in Michigan, and on a statewide level both there – African-Americans make up 14% of the population but 40 percent of the dead – and in Louisiana, where the corresponding percentages are 33% and 70%. Many of the poorest states also have governors who resist stay-at-home orders, including South Dakota, where at least 350 workers at a single meat processing plant – largely immigrantsspeaking more than 80 languages – have tested positive for the coronavirus. 
As Charles Blow points out, African-Americans and impoverished populations are more likely to have underlying conditions and limited access to health care, more likely to be doing “essential” manual or service jobs without the luxury of working or sheltering at home, and more likely to share crowded living quarters; social conditions are at least as important a risk factor for severe covid-19 infection as medical conditions. 
The underprivileged, who rarely have adequate unemployment compensation, sick pay, or healthcare insurance, will also suffer more from the economic effects of a shutdown. Their children need those free school lunches, and often can’t attend virtual classes for lack of internet access. 
But the greatest tragedy due to socioeconomic discrepancies may be at the world level. When covid-19 hits the global South in force, the impact could be devastating. In the developed world the novel coronavirus seems to be more or less as contagious and deadly as the influenza virus that a century ago infected one-third of the people on the planet and killed 20 to 50 million. That pandemic hit at a moment when populations had been weakened by wartime suffering, and when there were no intensive care units, no ventilators, no oxygen therapy, no antivirals, not even antibiotics. 
This suggests that covid-19 is intrinsically much deadlier than the 1918-19 flu. In areas of Africa, South America, and Asia with few modern hospitals and high rates of chronic disease and malnourishment, it may well cause a holocaust.Statistics from many of those countries are unreliable, but the upswing may be starting now – India, despite fighting back early and hard, went from 1000 cases on March 29th to 12,000 on April 14th
For diseases with no pharmacological cure, such as covid-19 and Ebola, supportive care in modern ICUs is crucial. The death rate for Ebola was 74% in Africa, 18.5% in the US and Europe.
As the New York Times points out in an editorial entitled “The Global Coronavirus Crisis Is Poised to Get Much, Much Worse,” South Sudan – population 12 million – possesses exactly three ventilators. Already local quacks are touting useless nostrums: Benin’s Valentin Agon, whose apivirine has “successfully treated dozens of Covid-19 patients,” South Africa’s Kim Joachim Mvuselelo Cools, who peddles Magic of the Healers Juice. (American hucksters plug the likes of Superblue toothpaste.) While the economic devastation of anti-pandemic shutdowns in impoverished nations could kill more people than the virus.

Cutting through the crap
The Los Angeles Times was the first to circulate the claim that the novel coronavirus may have been around in California as early as the fall of 2019. There is no evidence this is true.
It has also been suggested that the way the coronavirus starves the body of oxygen is not by attacking the lungs but by binding directly to hemoblogin in the blood. This is, as Rachel Maddow might say, bullpucky.
I wouldn’t have thought anyone doubted the dangers of the pandemic any more, but wild theories still circulate that deaths from other causes are being falsely attributed to the coronavirus, it’s more common to die “with” the virus than “from” the virus, and so forth.
The respected journalist Fareed Zakaria has spread a version of this on CNN and in the Washington Post, suggesting that the reason fewer people than expected have died so far in the US is because the virus is not really very dangerous. His source is the contrarian epidemiologist Dr. John Ioannidis, who has written, and I quote, “If we had not known about a new virus out there, and had not checked individuals with PCR tests, the number of total deaths due to ‘influenza-like illness’ would not seem unusual this year.” 
This is utter nonsense. Here are the numbers of total deaths in northern Italy as compared with past years – not from “influenza-like illness” but from all causes. More than twice as many people than expected died, overall, during the pandemic.
Death rates from all causes in selected northern Italian cities: 2020 vs. predicted

It has been debated whether American covid-19 deaths have been overcounted or undercounted. But in New York Cityhundreds, perhaps thousands, of coronavirus victims who died at home alone didn’t make it into the official statistics, with a true death toll perhaps 70% higher than official reports. There’s no need to quibble over details – just look at this graph of total deaths in New York City since the year 2000. 



A horrendous spike, 2730 more deaths than expected, reflects the September 2001 terrorist attack. And an even more horrendous spike, 5330 more than expected, occurs between March 4th and April 4th of this year, with covid-19 the only possible reason. 


Zakaria and Ioannidis are right that many people infected with the novel coronavirus have few or no symptoms, and that the mortality rate of the coronavirus is therefore lower than it appears from diagnosed cases. So what? The reason covid-19 failed to decimate the US population is not that it is mild, but that prescient local politicians were relatively quick to enact stay-home orders, following the effective Italian model.
Forgive me for saying that those prescient politicians do not include Governor Andrew Cuomo of New York, despite his excellent leadership later on. My husband and I had been supposed to go to New York on March 13th, but we cancelled at the last minute, figuring the city would be too dangerous: once the coronavirus hit it would spread like wildfire, since the city’s iconic subway system would be a petri dish. Friends wrote that they tried to pick less crowded cars, hold the poles in the crook of their elbow, etc., but the virus seemed destined to win, as in fact it did, killing at least 10,899 people. 
Then, on March 16th, seven counties in and around San Francisco made the radical move of telling people to shelter in place. A lightbulb should have gone on instantly inside the head of Governor Cuomo and Mayor De Blasio, but it didn’t. If New York had issued a stay-at-home order on March 17th instead of waiting until March 22rd, hundreds if not thousands of lives would have been saved.

Personal notes from my gilded cage in Berkeley
You know how when you have laryngitis you hear a singer and can’t fathom how they’re doing it? Or when you have a sprained ankle and marvel at a passing jogger? I might have thought watching movies would be like that, night after stay-at-home night. But no, those scenes of crowded dance floors and hot kisses look perfectly normal. What did touch that nerve of unreality was reading an oldish New Yorker, writers all obsessed with unthinkables – art openings, restaurants, political rallies, trips to Europe – blessedly unaware that the world was about to, or could ever, grind to a halt.
A light now flickers at the end of my own refugee tunnel. Alitalia has kept up daily nonstop flights from New York to Rome, but they are nightmares. I’ve heard of people being abandoned in transit at JFK for days on end. I’ve read about repatriation flights taking off from New York and Madrid with every seat occupied. Other planes sat on runways for hours with hundreds of passengers packed cheek to jowl. Following scandalized interrogations in the Italian Parliament, Alitalia now claims it will start inflight social distancing… but even better, they’re promising a brand new nonstop flight from San Francisco to Rome. It will be inaugurated on June 1st, and my husband and I will be on it. 

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