The Long Haul

 

For many weeks I’ve been wanting to discuss “long COVID” and bring you up to date on the Italian situation. Needing more space to cover vital vaccine news and updated CDC guidelines, I decided to sacrifice most of this post’s treatment section.

Treatment news

Convalescent plasma: A few posts back I wrote that high-dose convalescent plasma had been shown to work for COVID-19. Now an English study has made headlines saying it doesn’t. There’s really no contradiction: the new, negative trial was in hospitalized patients, while the positive trial was in outpatients. But now we have yet another trial, which randomized high-risk patients who showed up at an Emergency Room after a few days of symptoms; they did no better on plasma than on placebo. So we’re left as uncertain as ever.

Ivermectin: The first decent trial of this controversial treatment has now been published, and sadly it’s a wash. Researchers in Colombia gave 5 days of ivermectin or placebo pills to 476 patients who were either at home with mild COVID-19 or hospitalized with moderate disease. Ivermectin did not get them well faster or keep them from going downhill. The US Food and Drug Administration has returned to its previous advice, warning physicians against using this drug.

EXO-CD24: I said of this new Israeli nasal spray aimed at fighting cytokine storm in critically ill COVID-19 patients that I wasn’t expecting miracles. But somebody is: Jair Bolsenaro! He’s importing tons of it to use in Brazil, even though the researchers themselves say, “It’s not possible to judge whether it works at this point.”

Aspirin: Two retrospective studies are reporting that people who took aspirin in the days before being hospitalized for COVID-19 are less likely to need intubation or die. This kind of claim has been made for many other drugs, and I’ll stay skeptical until we hear from the randomized trial ongoing in the UK. But aspirin’s innocuous enough that based on these studies I might add it to my short stack of medications for future COVID-19 patients.

 

Vaccine news

A suspected rare side effect of AstraZeneca

AstraZeneca: These weeks have been quite a roller-coaster for AstraZeneca’s vaccine. First it took a hit when many European countries blocked it following the deaths of several vaccinees from blood clots on or disseminated intravascular coagulation. The pros and cons of this choice were nicely laid out in a Science article.

Next an upswing when most countries took it back, after clearance by the European Medicines Agency following a quick investigation and some risk/benefit calculations. Some German and Norwegian scientists, though, are convinced the link to blood clots is real and is caused by anti-platelet antibodies. 

(For comparison: In 1955, 51 American children were paralyzed and 5 died after getting shots from a faulty batch of polio vaccine; the oral vaccine later gave paralytic polio to 10-12 kids every year. Tetanus and smallpox vaccines have each killed a few dozen out of many billions. Yellow fever vaccine: 35 deaths among 500 million doses. Measles vaccine: no deaths reported.)

This Monday, just as the blood clot kerfuffle was calming down, really big news hit: interim results from the long-awaited American Phase 3 trial. AstraZeneca announced, in a press release remarkably skimpy on data, that the vaccine was 79-80% effective in preventing clinical COVID-19, and 100% in preventing severe disease, equally at all ages. Their inexpensive, easy-to-store vaccine had come up roses. 

But within 24 hours the roller-coaster hurtled downhill again, with today’s astonishing headline: 

Here's what I understand. The National Institute of Allergy and Infectious Diseases thinks AstraZeneca may have fudged its results by choosing to report them as of February 17^th, when it actually has later (and potentially worse) follow-up data that it chose not to include. This is doubly astounding. First, because a rebuke of that sort from the National Institutes of Health is apparently unprecedented. Second, because after messing up all their previous research AstraZeneca knew that everything about this trial would be gone through with a fine-tooth comb and nonetheless perhaps decided to cherry-pick their data.

For the moment I’ll take the results in the press release at face value. But how can we make them jibe with the lower 63% overall efficacy in earlier Phase 3 trials, and with the studies in Scotland and England that found the vaccine considerably less effective in the old than in the young? Here’s the Levenstein hypothesis: volunteers in the US trial received their second doses 4 weeks after the first one, not 12 weeks as in current UK and European protocols. Perhaps that earlier booster is superior after all, especially in elderly people with weaker immune systems.

AstraZeneca says it will assemble full data “in the coming weeks” for publication and for an application to the US Food and Drug Administration. I’m looking forward to that, especially after the doubts raised by the National Institute of Allergy and Infectious Diseases. And I’m looking forward to AstraZeneca coming through for the European Union in the second quarter of 2021 after undersupplying us by 60% or 70% in the first quarter. Pretty unlikely, though, if the company itself foresees providing fewer than half the doses they contracted for.

Pfizer: New results from the UK vaccination campaign confirm that it’s wrong to hold the second Pfizer dose until 12 weeks after the first. Among older people who were given a second dose on time, the vaccine was 90% effective. If the second dose was postponed, only 60%. I don’t understand why Pfizer has continued to supply vaccine to the UK when it’s being so misused.

I’ve mentioned a preprint saying that sera from people who’d had the Pfizer vaccine did a good job of neutralizing all 3 major variants. Now it’s been properly published and gives even stronger evidence than before. Israeli data suggest not only that Pfizer works as well against the English B.1.1.7 variant as against the Wuhan original, but also that it prevents 94% of asymptomatic infections, better than anybody thought. (Though it’s, predictably, not quite so effective among frail nursing home residents.)

Moderna, on the other hand, is relatively ineffective against the South African B.1.351 variant, though it’s making progress on fixes. Johnson & Johnson and Novavax are less effective too, while AstraZeneca is a complete dud.

 

Sputnik, the satellite

Sputnik V: The European Union has begun a “rolling review.” Some expect the vaccine to be approved in May, though Gamaleya hasn’t yet put in an application. Doses arriving in June may be a bit late.

Italy is so vaccine-starved that I started softening up on Sputnik. But I got a bit concerned when the excellent Enrico Bucci, a Temple University biologist and biostatistician, said new data cast doubt on Russian claims of efficacy, as many scientists already suspected. In the Argentinian study he was referring to, vaccinees developed anti-spike antibodies at a 1:1600 level, much lower than the 1:6400 in Gamaleya’s published Phase 3 article. Numbers that don’t match feed my skepticism. I think the European Medicines Agency has been wise to wait to authorize Sputnik until we see whether the vaccine’s real world effectiveness matches its claimed efficacy.

There’s also some concern that Sputnik V might increase vulnerability to AIDS – the unfortunate effect of a candidate HIV vaccine produced using a similar technology. And HIV is rampant in some of Sputnik’s target markets.

Johnson & Johnson: I continue to worry that vaccine hesitancy will rise in marginalized (read black and brown) communities if they are prioritized for this somewhat less effective vaccine. Johnson & Johnson may be particularly well-suited to people who’ll have a hard time getting a second jab on schedule, such as the homeless and migrant farmworkers following the crops. I still think prime targets should be young people, at low risk for severe disease themselves but likely to pass the virus on to their elders. In any case I strongly believe that people should be allowed to choose their own vaccine.

Novavax: Exciting new Phase 3 trial results, announced thus far only in a press release. Efficacy against COVID-19 from the original Wuhan strain of virus was 96.4%, as good as Moderna and Pfizer. Against the English B.1.1.7 strain, 86.3%, and (as we already knew) only about 50% against the worrisome South African B.1.351. I hope for quick approval.

COVAX, Côte d'Ivoire

COVAX, Cambodia

COVAX: The World Health Organization program to vaccinate the developing world has kicked off, sending 20 million doses the first week to 20 countries from Ghana to Cambodia, then 14 million to another 31. But with Italy spearheading the European Union’s “keep it at home” policy by refusing to send a batch of AstraZeneca to Australia, and with doses lacking everywhere, COVAX is likely to remain merely symbolic for months, until AstraZeneca ramps up production. India, a major vaccine producer, wants to make COVID-19 vaccines for the developing world but has been stonewalled by all the Western companies.

Testing: People ask: “Should one be tested for (a) covid and/or (b) antibodies before receiving the vaccine? How much in advance?” Nope, no need to do any tests before, or after. 

Kids: All the big vaccine makers are busy doing studies in children, Moderna (and soon Johnson & Johnson) even in babies. They hope authorities will approve emergency use without Phase 3 trials, if their products are shown to be safe and to effectively stimulate kids’ immune systems.

Apples to apples: I highly recommend this article in The Atlantic magazine for its great job of comparing the 3 vaccines now available in the US. Including debunking the mediatic notion that they all completely prevent severe COVID-19 and death. 

 

Crescendo accelerando

 

Billboard: The gift you can't refuse. Funeral €1,250, casket free of charge.

Every day I update a graph of the state of the Italian pandemic to post on Facebook. Here are the current versions, with a hint that new cases may be slowing down:

After coping brilliantly with the first wave, Italy hadn't recovered fully from the second before sliding into a third. After a tiny Christmas surge the number of cases, then hospitalizations, then ICU patients, then deaths stopped falling and then, in sequence, began another steady climb.

What’s up? Mostly, covid fatigue. Italians are good about wearing masks and about distancing in shops and offices, but they can’t resist visiting each other at home. Even some of our own friends regularly invite dinner guests. Plus buses and subway cars stay crowded. And young people break all the rules they can, thronging streets until the curfew falls at 10, when some flock to clandestine all-night parties. Enforcement of capacity limits and anti-movida rules has been spotty at best.

It doesn’t help that the more contagious, possibly more virulent English variant is taking over.

But even worse, in my book, is the blind eye turned by Mario Draghi’s brand-new government. Instead of imposing a several-week countrywide lockdown when the emergency began unspooling in early February, as 44% of Italiansdemanded, they kept fiddling around with the same failing three-tier restrictions. Why? Mostly because rigor would mean having to shell out emergency relief funds, partly because of right-wing open-it-up’ers in the government. On March 15^th the rules were finally tightened up some, though far short of a real lockdown – we’ll see.

For once my hero Anthony Fauci gets it wrong, about his own country of origin. “”They had a diminution of cases, they plateaued, and they pulled back on public health measures,” he said. Restaurants and some bars reopened, he said, and “the younger people particularly stopped wearing masks, and then, all of a sudden, you have a surge that went right back up.”” No! Italy is not the US! You rarely see anybody of any age unmasked on the street here, and never indoors. Italian bars are for knocking back an espresso, not for getting drunk, and nowadays they close at 6 pm anyway. And restrictions were not recently loosened. The problem was that the restrictions weren't strict enough – in yellow regions you could lunch inside restaurants, and until 2 weeks ago people everywhere were allowed to visit each other at home. Now the color-based rules have been made more rigorous, and virtually all of Italy went orange or red.

Italy hopes to let spectators back into theaters and movie houses around the end of the month. I say: dream on. Even before the current surge, attempts to reopen cultural institutions flopped. The famed La Scala opera house in Milan had to scrap its December opening when dozens of singers and instrumentalists tested positive for COVID-19. When La Scala tried ballet instead, a round of swabs turned up 50 positives: 35 dancers, 3 singers, 3 administrators, and a sprinkling of hairdressers and costumists.

 

The brightest spot may be on the vaccine front. Italy complains about how few doses they’ve received and how few are getting into arms, but the vaccination campaign is actually doing pretty well. Biden's million jabs a day, initially considered reaching for the moon, are equivalent to about 180,000 a day in Italy, the current average. About 11% of Italian adults have received a dose. Vaccination sites will soon spread beyond hospitals, concert halls, and the like to pharmacies, General Practitioners’ offices, and workplaces.

All the vaccine makers have sent many fewer doses than they promised. Now the newly-authorized Johnson & Johnson is threatening to do the same, with some predicting Europe won’t get any at all until May or even June. The United States is partly to blame, for blocking AstraZeneca and American manufacturers from exporting doses to Europe. 

Here’s the latest vaccine plan, with people getting vaccinated in category order: 0 = doctors, over-80s, etc. 1 = extremely high-risk at any age. 2 = ages 75-79. 3 = ages 70-74. 4 = ages 16-69 with high risk. 5 = healthy ages 55-69. 6 = healthy 18-54. Everyone over 55 or high-risk can get Pfizer or Moderna. The most efficient regions have only reached category 3. 

Lately, vaccinees are required to be enrolled in the National Health Service. This cuts out about a half million people, mostly undocumented immigrants but also Rom, homeless Italians, and United Nations retirees. 

Italian officials may be dragging their feet, but they're better than the governors of Texas, Mississippi, and the rest, who are lifting restrictions just as diagnoses plateau – at levels that during the first or second waves would have been considered awful. New cases are already on the rise in many states, though deaths are low because so many elderly have been vaccinated.

 

COVID hunkers down

 

Many infections drag on. Influenza can be followed by tenacious mental symptoms sometimes called the post-flu blues. Mononucleosis can trigger chronic fatigue syndrome. Ebola can leave cognitive problems that last years. Gastroenteritis can set off enduring irritable bowel syndrome. Rarely are there specific treatments. 

My own first hint that COVID-19 could do the same, like many other Americans’, came when we were marooned in California last spring, watching CNN anchor Chris Cuomo describe his COVID-19 experience day after day on live TV. Cuomo tested positive in March, at the end of May he was “still not 100%,” and in July he admitted having “brain fog that won't go away.”

Long COVID-19 = long-haul COVID = post-acute sequelae of COVID-19 (PASC) has already prompted specialized clinics, patient groups, a World Health Organization brief, and some superb commentary at Vox and The Atlantic.

The condition is extremely variable. Some long haulers have continuous symptoms, others first improve then deteriorate, still others have symptoms that come in waves every week or two – most commonly fatigue, shortness of breath, muscle weakness, and brain fog. Then come chest pain, lightheadedness, headaches, loss of smell, diarrhea, joint pain, insomnia, night sweats, fevers, anxiety, backache…. And, adding insult to injury, many patients find themselves disparaged as sissies or hypochondriacs.

How many COVID-19 patients become long haulers? Depends on who you ask. Staking out the lower end was one study that reported 4.5% of patients to have symptoms after 8 weeks and 2.3% after 12. The dominant statistic is one in 10 COVID-19 patients with symptoms after 3 months. But a more accurate figure is probably one out of 3, even for patients who are never hospitalized. Some report even higher percentages and longer durations. One Italian surveyfound that 45% still had symptoms after 7 months. In another, many stayed sick for as long as 9 months. A third reported that fully half of COVID-19 survivors met criteria for moderate-to-severe depression 4 months after their acute illness. 

We are not very good at predicting who will become long-haulers, except that patients who start out sicker are more at risk. In Italy one study found that half the patients hospitalized with severe COVID-19 had low oxygen levels 4 months after discharge, half flunked a 2-minute walking test, and 17% had post-traumatic stress disorder. Anotherreported that 87% of hospitalized patients were still unwell 60 days after going home. And a Chinese study found that 76% of COVID-19 patients hospitalized in Wuhan had symptoms six months later. 

We don’t really know what’s going on, though high-tech testing gives some hints. A German study of mostly healthy, young COVID-19 outpatients found that heart inflammation could be detected in 60% by sophisticated MRI techniques 2-3 months later. A third of patients with COVID-19 pneumonia still have abnormal CAT scans six months after they have cleared the virus, and many still breathe badly after 9 months.

For the sickest COVID-19 patients, long COVID may be a good outcome. One study found that 6.7% of patients die within 2 months of hospital discharge, and 15.2% need to be readmitted. Of ICU survivors, 10.4% died within 2 months. 

Though clinic after clinic is popping up for treating long COVID sufferers, nobody really has much to offer them. Perhaps graded exercise for fatigue, antiinflammatory drugs for pain, and asthma inhalers or breathing exercises for shortness of breath. The few published guidelines have taken special flak from physicians who themselves are long-haulers. A particular form of breathwork has been proposed to treat lightheadedness related to postural orthostatic tachycardia (POTS). And a few patients, paradoxically, have reported feeling strikingly better after receiving a dose of COVID-19 vaccine. Hopefully something will come out of the billion dollars the NIH is now investing in research. 

 

More perks of the jab

The Centers for Disease Control have come out with initial guidelines on what you can and can’t do once you’ve been fully vaccinated, i.e. 2 weeks after your final shot. They agree, as I’ve written, that fully vaccinated people can socialize indoors among themselves without masks or distancing, and can skip both quarantine and testing after exposure to someone who’s tested positive – unless they live in group settings such as a prison or a convent.

But in one glorious way the CDC has gone farther than I did. I suggested you might socialize indoors with unvaccinated people with everybody masked and distanced and the windows open. The guidelines are much more generous, allowing people to socialize indoors with unvaccinated people from one other household without masks, unless those people are at high risk. I’ve already jumped on that one, inviting a young violinist over for some chamber music as soon as the regional color code permits.

The CDC hasn’t yet loosened guidelines for travel, restaurants, movie theaters, concerts, or medical offices. And the European Union still hasn’t contemplated letting in American tourists, whatever their vaccination status, though I suspect it will soften up in late spring. People holding a “Digital Green Pass” should soon be able to travel within Europe – though an insane and highly European drive to make things as complicated as possible may block implementation for months.

Not to be a party pooper, but I see some complicating factors:

1)    Johnson & Johnson’s protection against variants and against severe disease doesn’t peak until 4 weeks after the shot. Should people who receive this vaccine wait 4 instead of 2 weeks?

2)    AstraZeneca is uniquely ineffective in preventing asymptomatic infection. Should AstraZeneca vaccinees be warned to keep wearing masks everyplace?

3)    No vaccine is 100% protective, but Johnson & Johnson and AstraZeneca are notably less so. Should people who received them take more precautions?

I suspect none of these considerations will ever be mentioned, because authorities everywhere are pushing the line that all vaccines are created equal.

Nominees for the No-vax Oscars

 

I grabbed this screenshot from a website that says it’s “A Beacon of Light Exposing the Truth in the Darkness of Deceit.” Curious who these guys are? Kaufman, a psychiatrist who says the coronavirus doesn’t exist, got fired for not wearing a mask. Adil shares videos calling COVID-19 a hoax “orchestrated by the elite”; he got fired too. De Smetclaims (falsely) that the vaccines were never tested on animals. Barre Lando, according to his LinkedIn profile, is a “Biological Terrain Specialist” in California. Madej is a QAnon adherent who on January 6^th told the Capitol rioters that COVID-19 vaccines were “a witches’ brew.” Cahill’s and de Klerk’s prime claim is that the pandemic doesn’t exist. Rubas’s, according to Google Translate, is “You have to be a psychopath to call the preparation taken out of the hat a vaccine!” Cancelo doesn’t believe people without symptoms can spread the coronavirus, and may have said that no one fears it except Freemasons.