Tuesday, April 21, 2020

COVID, and the Graphic Representations of Death, and Transmission

Let's do two curves today: the first is from the Journal of the New York Times, and shows what is likely to be a more accurate death toll from the COVID outbreak thus far. Counting, it turns out, is a hard business in medicine. What is often the "official" count of COVID mortality in any given country or smaller municipality is a count that a government officer tallies by receiving reports from professionals--usually but not always physicians--who note in a form that so-and-so died, and had a positive COVID test. But that excludes people who never got a COVID test, either because they died outside a hospital, or because testing was woefully inadequate and there simply weren't enough tests to go around, which might resemble a large, wealthy country located in North America.

Thus, a simple but different way of sizing up the impact of COVID is simply to compare all deaths to the averages in previous years (which are, generally speaking, roughly stable from year to year in most places in the US where there hasn't been mass influx or exodus). If the needle moves above the historical average, then that is a very strong indicator that COVID deaths are being missed. In the immortal words of Rasheed Wallace, the ball don't lie. Anyway, the article looks at 2020 compared to previous years, and each figure, from various parts of the world, all show the impact of the COVID outbreak in stark terms. Because the graphics at NYT can't be pulled and reproduced, a similarish graphic can be found in this piece from Reason:
The upper, flat, gray line, hovering around the number 2000, is the average number of deaths over the preceding seven days in New York City during the years 2015-2019--that is, it's an average of averages. The colored numbers toward the bottom are the seven-day averages of deaths from influenza in New York in any given year from the same period. Where this departs from the NYT piece is that these data only look at official COVID and flu deaths and compares them to the overall total. For 2020, you would also need to add in everyone else who has died, which now includes a sizable chunk of people, and the red spike would climb even higher. (It's also worth keeping in mind, in an apples-to-apples comparison, that the same issue applies to deaths from influenza, which is at least as hard to diagnose as COVID, so the total deaths from flu in any given year are also higher than the official number. Epidemiologists have various tricks to tease out a reasonably accurate picture of flu mortality in any given year. But as noted before, a very useful way to get a sense of how lethal an epidemic is in a given year, whether from flu or COVID, is to just look at the total number of deaths and compare it to recent years, and if the official number just from the infection exceeds the total mortality in previous years, it's a sure bet that the epidemic is especially severe. The ball don't lie.) The Times piece includes the observation that "the totals include deaths from Covid-19 as well as those from other causes, likely including people who could not be treated as hospitals became overwhelmed," and link to an article explaining this heartbreaking phenomenon. During the Ebola outbreak, for instance, pregnant women were unable to receive adequate prenatal care due to hospitals and clinics being closed, and a small percentage of women died from complications of routine problems that would have been handled had such facilities been open. Thus, Ebola killed those who never became infected with the virus, and as the COVID outbreak proceeds, there will be similar effects on overall mortality. Curve #2 is here:

It is from this paper, entitled "Temporal dynamics in viral shedding and transmissibility of COVID-19." The key here is that the zero of the x-axis is not at the left corner where it is normally found, but rather can be found four ticks in. The gist of this figure--which, to be clear, is like so many other things in COVIDland merely a model based on relatively limited data--is that people with COVID may actually be in their most infectious phase before they even know they might be infected. And that is one very serious problem as we collectively contemplate, at the local, national, and global levels, about how to resume economic and social activity that resembles something approaching normal. "Significant presymptomatic transmission would probably reduce the effectiveness of control measures that are initiated by symptom onset, such as isolation, contact tracing and enhanced hygiene or use of face masks for symptomatic persons," the authors state in the characteristic understatement of scientific communication (that's my emphasis; journals don't allow for italics). But make no mistake, this makes ongoing policy discussions, which have already become weaponized, not only among the violent nitwits and infants of the MAGA coalition in the US, but in various other locales as well, a good deal more challenging. The net result will almost certainly be even more graves, and those who will soon reside there.


Sunday, April 19, 2020

COVID, and Delayed Gratification

While a picture may be worth a thousand words, sometimes one word can stand alone without the assistance of the other nine hundred ninety nine.

In the case of this picture above, which displays the raw emotions of Midwestern Trumpistas as they literally shout about their states' governments decisions to maintain a lockdown policy in the face of the COVID outbreak, the one-word description can be: Brownshirts.

In case you aren't familiar with that reference, here's a primer on the Brownshirts. Money quote: "Violent and often disorderly, the SA were primarily responsible for the protection of leading Nazis and disrupting other political opponents’ meetings, although they often had a free rein on their activities." The picture above is from the Statehouse in Columbus, Ohio, but this could just as easily be from Berlin or Munich in 1932.

At any rate, as I have been thinking about this blood-chilling picture, and of how Trump has (again) whipped up his mob as a means of throwing a temper tantrum when confronted with the reality that his power is not, in fact, absolute, it occurred to me that these "protests" he has "encouraged" can be likened to one of the most famous experiments of psychology from the 20th century.

The research is commonly known as the marshmallow experiment. In the popular understanding, the experiment was designed to evaluate whether a child could delay the gratification of having one tasty treat (marshmallow, pretzel, cookie, whatever) by holding out a full fifteen minutes, at which point they would be given an additional one. The experimenters tracked the children through time, and what resulted was the surprising finding that those who were unable to delay gratification had worse outcomes in what the authors refer to as "cognitive and academic competence and ability to cope with frustration and stress in adolescence." In other words, the inability of some children to restrain themselves predicted a less happy and more troubled life.

It turns out that, as with many other popular understandings of psychological research (like, say, the infamous Milgram experiment), the story of the marshmallow experiment is not quite as straightforward as is often portrayed. For one, the researcher who designed the experiment, one Walter Mischel, has noted that what people have assumed about the experiment is almost the polar opposite of his philosophy of psychology. The point of the study, he argues, was to demonstrate that children could change their behavior with the proper help--that is, with a few mental tricks helpfully provided by the adult, they could in fact wait as long as their classmates. Moreover, other researchers have been unable to replicate Mischel's findings, casting doubt on whether the results, and the conclusions on which they were based, were valid.

None of which is especially relevant here. What is relevant is that the question of when to re-open the economy in the midst of the COVID outbreak has become, in effect, a giantic, multi trillion-dollar marshmallow experiment, and what we have witnessed, from the President to his thus-far-still-hapless-but-nevertheless-menacing MAGA/Sturmabteilung troops, is the need for instant gratification run amok. The parallels aren't perfect, of course: there will be nothing "tasty" to the one-marshmallow scenario of returning to life too soon, and even the "two marshmallows," for which the waiting is necessary, is merely a best-of-many-bad-options scenario. But it does frame the actions of the President and his horde of thugs as a massive, collective expression of infantilism of the most lethal sort.


Postscript: a friend writes, brilliantly, "Trump is the most dangerous kind of damaged-child-in-adult-body. He would've just stabbed the researcher, stuffed the whole bag of marshmallows down his pants, and gone home." Ha!

Thursday, April 16, 2020

What an Anti-Chinese Fox Piece Tells You About the Republican Party

Here's the piece, entitled, "Sources believe coronavirus originated in Wuhan lab as part of China's efforts to compete with US." The Cold War-era editors of правда--which we in English call Pravda, and was once the Soviet Communist Party's Official Newspaper--would be smiling upon the Fox News Division right now, content to know that the dark arts in which they made their mark, specifically, propaganda, still has a happy home. (Actually, they're still around, and though the Billy Rubin Blog staff is woefully under-educated about the details of Russian oligarchy, we wouldn't be surprised to learn that there isn't much truth to be found in the Pravda of Putin's Russia, either.)

Big shock coming: the Fox piece doesn't really tell you much about China, as it is effectively one big Lie wrapped in a cocoon of half-plausible journalistic conventions to provide the scantiest justification for being circulated to millions of rubes who will swallow the story without much fuss, happily scarfing down the news equivalent of canned tuna laden with mercury and PCBs.

But what such a story does tell you about is the increasing desperation of Donald Trump, the Republican Party, and its various subsidiaries to pin the tail on whatever donkey they can find, so as to distract from their own glaring incompetence in the COVID outbreak, which at this point is most appropriately described as "murderously stupid," the occasional competence of a Republican governor such as Charlie Baker, Mike DeWine, or Larry Hogan notwithstanding.

Let's start all the way back in early February--in other words, what seems like a lifetime ago--with the original irresponsible speculation about the Chinese origins of COVID to see just how feeble the current attempt at reportage really is. The full details can be found here in a piece by Foreign Policy, but the gist is that some Indian researchers working in a lab circulated a manuscript looking at the protein coat of the COVID virus, and noted some similarities to the outer surface of HIV. An Indian scientist and columnist named Anand Ranganathan, in what can only be described as a flight of fancy, wondered aloud in a Tweet on January 31 whether this could mean that Chinese scientists had been mucking about with HIV in a lab and somehow ended up with a version of Frankenvirusstein that got out on the loose. By later in the day, Ranganathan thought better of his armchair speculation, and withdrew the Tweet, which if you click on the link above, you will see. (The scientific paper was withdrawn before submitting to the peer review process, as well.)

But by that point, like the actual virus itself, the Chinese-bioweapons-lab origin story was on the loose and circulating across the globe, and causing only slightly less mayhem. Conspiracy theorists picked up the ball and ran with it, where it almost immediately found a happy home among Republican Party leaders; Oklahoma Senator Tom Cotton was so confident in its plausibility that he gave interviews suggesting "we need to at least ask the question" of whether the Chinese government was behind the whole thing.

That a high-ranking Republican politician would resort to base sophistry and rhetorical gimmickry in 2020 shouldn't have come as a surprise to anyone, given the Red Team's penchant for similar shenanigans in other charged topics where there's a clear scientific consensus, such as "teaching the controversy" of evolution (hint: there's no controversy) and encouraging denial about the reality of man-made fossil-fuel driven global warming (maybe the Republican consensus there might be beginning to crack, though no sane person should be holding their breath). Cotton could always claim he wasn't actually alleging this was a fact--since that would require outright lying, something even scalawags like Cotton hesitate to do--but merely noting that since a rumor existed, however ridiculous, it should be considered. Thus, the Senator from Arkansas was able to have his xenophobic cake and eat it too. (Of course, Trump lies without the slightest hesitation; Cotton might demur simply because he isn't sure he can pull it off as well as his master.)

Since the allegation was built on high-octane paranoia mixed with dark fantasy, it made the rounds for maybe 72 hours before submerging itself into the collective right wing id, and would have evaporated into nothingness. But Fox, along with other right wing media, appears to have regurgitated the story in what seems like a desperate attempt at pointing fingers at anywhere other than where they should be aimed, namely, at a fumbling and laughably inept White House. And it plays like a movie sequel in which a lazy producer simply pops a Roman numeral up, cycles through the same cast, and hopes for further profits to roll in. Since there's no new hard news, Fox News is required to truth-launder its claims by a reliance on "sources." Here's the key graf:

The “increasing confidence” comes from classified and open-source documents and evidence, the sources said. Fox News has requested to see the evidence directly. Sources emphasized -- as is often the case with intelligence -- that it’s not definitive and should not be characterized as such. Some inside the administration and the intelligence and epidemiological communities are more skeptical, and the investigation is continuing.

In other words: this stuff is still just made up, but it's made up by people inside the government, and therefore they can be considered "sources" to lend an air of legitimacy to the claims as if this were a well-sourced New York Times story. In reality, it almost certainly means that a Trumpparatchik sent an email to a Fox staffer after reading a feverish post on 4chan repeating the yarn. But now the Fox staffer can pass it along as coming from a secret government official who really knows their stuff. Fox even add the nice buyer-beware touch of noting that this story is not definitive and should not be characterized as such. In the immortal words of Sidney Morgenbesser: yeah, yeah.

To note that Fox News wants to whip up outrage against an un-American Other (which is to say, not white) like China, and that it considers innuendo to be no less important to their brand of journalism than reporting unassailable facts, is not precisely an earthshaking revelation. So why care at all? Because there are plenty of entirely legitimate reasons to criticize China. So much so that it's like shooting fish in a barrel. And yet, with the ammunition sitting out on the table, practically begging to be used, Fox chooses not only to hold their fire, they don't even lock-and-load.

If the Federal US response has been an abject embarrassment, China hasn't precisely coated itself in glory, either. When physicians and scientists, all of whom were working at great personal risk, tried to raise the alarm that a frightening new virus appeared to be circulating in Wuhan, local government leaders used their authority to silence or otherwise intimidate the experts as troublesome worry-warts whose interference might have negative effects on the economy. (Sound familiar?)

As the epidemic worsened, the US Government, along with the World Health Organization, offered help by sending leading virologists, physicians, and epidemiologists. China refused the offers until finally relenting and allowing in experts by the end of January.

As January progressed, the outbreak became out of control and could no longer be swept under the rug by local leaders. So the damage control response was to erase the evidence, as the "wet market" where the virus almost certainly originated was wiped clean, preventing any opportunity to fully understand the circumstances of the virus's jump into humans. (Side note: "wet market" is, at least according to one reporter, akin to the American concept of the Farmer's Market, and as such isn't particularly exotic; some wet markets, such as the Huanan Wholesale Market in Wuhan, do substantial traffic in exotic animals, and one of those animals, perhaps a pangolin, is highly likely to be the original host. All the early epidemiology points to the Huanan Market as Ground Zero, but the trail has been forever lost due to the local government's eagerness to cover it up.)

After reeling in January and early February, the national Chinese government responded in full force, and with a level of competence that has thus far put the Americans to shame. They famously built a large hospital for those with the virus in less than two weeks, shut down travel in Hubei Province, did reasonably well at feeding a locked-down population the size of New York, and, to use the parlance commonplace today, flattened its epidemic curve. But what pride it could have taken in a job well done was eclipsed by the Chinese government's worst authoritarian tendencies: they have prevented honest reporting of the outbreak, "investigated" critics of President Xi to the point where they simply disappear, and publish data about their epidemic that has increasingly strained credulity, suggesting that they are finding ways by which they are juking their stats to look more impressive than they really are.

So with all these easy targets out there in broad daylight, wagging their tails, why would Fox pick the tin-foil hat, kooky theory to promote? And to promote it in a way that anyone other than a total doofus could see was a con?

The answer, of course, is that Donald Trump approves of ignoring experts, silencing journalists, destroying evidence, intimidating opponents, protecting personal interests above those of the public good, and sidelining the civil servants who protect that public good. Trump's admiration of President Xi's worst dictatorial tendencies couldn't be more plain. These things constitute his political program, so of course Fox wasn't going to criticize China for that stuff.


postscript: Since the precise origins of COVID are not firmly established, could there be some kind of a link to a lab researcher who got infected doing research and then spread it? Perhaps it doesn't involve the fanciful bioweapon component, but could COVID have originated from a lab tech making a mistake simply in a scientific research institute? Similar accidents have occurred in the United States, so why not assume it could have happened there?

Two answers. The first is: yes, it's possible; some scientists acknowledge that possibility here. But if so, a lab accident simply becomes a different version of the wet market origin, which is to say, there may be human error at bedrock, but not the kind of nefarious Chinese world domination scheme that is driving episodes of nocturnal emissions among the Fox staff. One doesn't need to resort to science fiction to see evidence of China's imperial ambitions: they're making it perfectly obvious for anyone to see. And yet that, which is a legitimately concerning development years in the making, remains a relatively quiet story in American politics.

The second answer is, simply, that extraordinary claims require extraordinary evidence. After being fed a daily diet of Whoppers by the Republican party, not only in the form of Donald Trump although he is their most enthusiastic practitioner, the policy with respect to any of their pronouncements should be: where's the beef?

Monday, April 13, 2020

COVID: Randoms at the Easter/Passover Mark

I. Christianity has Easter. Islam has Eid al-Fitr, which is coming in a little late this year at the end of May, but for the purposes of this discussion we'll count it as their "spring" holiday. And Billy Rubin's people have Passover to celebrate, which like Easter we are in the midst of as this is written.

I note this simply to say that I belong to a people whose spring holiday commemorates a plague--ten of them, in fact--so this year I think we've got the inside track for Western religion with the most appropriately-themed holiday.

II. If I have to see another vent setting with a fucking PEEP of 10 or more, I'm going to break something.

III. Along those lines, it remains clear to me that COVID is a disease of inadequate oxygenation. Ebola, I came to realize, was a disease of fluid loss. Technically we call the COVID complication "ARDS," which stands for "Acute Respiratory Distress Syndrome," which is a very fancy, doctory-sounding way of effectively saying that people have inadequate oxygenation. Now, the term "inadequate oxygenation" is itself a complicated phrase, but you can only simplify so far, as understanding what oxygen does in the human body takes just a bit longer to explain.

 the oxygenation is inadequate--that is, what leads to ARDS--is, quite literally, a trillion-dollar question at this point. The oft-invoked explanation you hear in my circles is that it is the result of a "cytokine storm." What, you may ask, is a cytokine storm? There are two separate explanations. The first is that it is a complicated chain of biochemical signaling that results in edema (fluid going where it shouldn't be, like into the lungs) and the initiation of "the inflammatory cascade" (roughly, the process by which the body reacts to trauma and does its best attempt to heal itself, like when a person accidentally whacks their thumb with a hammer when trying to nail something to the wall). The thumb gets hot, red, and swollen, and in a cytokine storm, this thumb-swelling molecular process happens throughout the body, and in COVID, it seems to happen especially in the lungs.

The second explanation, which doctors are loath to admit, is that "cytokine storm" is a phrase designed to make us sound like we know what we're talking about when, to a large degree, we don't. It's akin to saying something like "the kinetic energy of air molecules as measured by kilojoules increases substantially in weather patterns, when increased levels of solar radiation reach the atmosphere due to the axis tilt of the earth." That is a fancier, dressed-up way of saying "it gets hot in the summer." To use the 25-cent words isn't being inaccurate, and it does express a general understanding of the process from a distance. But likewise it does not do an exceptionally good job of describing the mechanics of the process, and doesn't contribute much beyond the more pedestrian observation. It's just verbal strutting.

This is where we're at with COVID. To think of this disease in the blunt instrument, Mickey Mouse language of "inflammation activation" or "cytokine storm" is merely to say that Bad Shit Is Happening, but people who didn't go to medical school could have told you that. I don't mean to imply that my colleagues are wrong in using language like this, for the cytokine storm does, indeed, appear to be a useful general concept (not worth going into here, but there is much circumstantial evidence that this disease is associated with elevations of all kinds of "inflammatory markers" such as ferritin, ESR, CRP, IL-6 among others). It's what we know, give or take. That means we understand the phenotypic response, the end product of the molecular dysharmony, but we do not yet have a deep grasp of the genotypic mechanism of the disease: the actual, step-by-step process by which a tiny piece of nucleic acid wrapped in a protein coat kills a thing one trillion times its size.

No, my objection to the hand waving prevarications of "cytokine storms" and "inflammatory cascades" and "hyperactivation of the immune system" is that we portray ourselves as more knowledgeable about this than we are. Which means that, when we put forward some hopelessly simple hypothesis about what might make a difference for the better, we portray medicine, and the process by which it works, in a false light. It's a setup for heightened expectations, and since we don't really understand the mechanics of this virus at this point, it's a setup for failure, for having people lose faith in our ability to solve the problem.

And that is a pity, because our profession really is collectively competent enough to figure this out. It took more than two or three centuries of hard-won victories in creating the proper system by which we can solve the processes that drive disease, and the knowledge that we have gained in those two centuries have put the accomplishments of the preceding ten millenia to shame. But we don't know everything, and we're still figuring out this virus that we only just met three months ago. We're smart, and accomplished, but we shouldn't act smarter than we are.

This is the hydroxychloroquine story in a nutshell. But it could just as easily be the ACE-inhibitor story. Haven't heard of the speculation about the relationship between ACE inhibitors and COVID? That's because Donald Trump hasn't heard of it--and more importantly, because he has focused the public's attention on hydroxychloroquine by pouring so much kerosene on what was a slowly-burning dumpster fire about that drug that nobody outside of narrow medical circles has paid much attention to other investigations like this.

But in my opinion it's a similar story. Like hydroxychloroquine, it's built on seemingly reasonable observations: ACE inhibition might upregulate the expression of the ACE-2 receptor; ACE-2 happens to (apparently) be the receptor by which COVID gains entry into the body; thus people using ACE inhibitors might be at risk for more severe disease because they have so many more ACE-2 receptors, leading to increased susceptibility to infection.

It's speculation built on an untested hypothesis built on a highly simplified model. It might be right, but likewise it could be wrong in one, or more than one, step along the path. Thus, someone taking ACE inhibitors might be at increased risk of a poor outcome if infected with COVID...or they might actually be protected by taking the medication. (The authors in the link argue for the latter.) So who is right? Nobody knows. So until this is studied properly--and that is the gift of two centuries of hard work, the idea that proper study is the only good way to know what works and what doesn't--we shouldn't jump on or off any pharmaceutical bandwagons in the way that an oafishly dull politician might endorse some Highly Iffy medication.

And keep in mind hydroxychloroquine and ACE inhibitors are just the beginning. Should we be using low molecular-weight heparin to interfere with "microangiopathic thrombosis"? Should we be giving steroids for "inflammation activation" during the "cytokine storm" during the "second phase" of illness? Should we give the antiviral remdesivir early in the disease, or late? And so on. To my mind, the answer is that we can't know if we don't study them properly, and that requires not being emotionally invested in the outcomes of one or more of these medications. Narrow your eyes, and steel your emotions. Otherwise there may be more bodies in the ground at the end of the day.

IV. There's so much good journalism being done that this entry isn't going to even bother with finding appropriate links, something we normally take quite seriously at the Billy Rubin Blog. (Of course, one does need to make sure to find the good journalism, since there's so much shit circulating on the interwebs, too. This is a topic for a different day: the need for a Good Housekeeping Seal of Approval, although the short version of it is, when in doubt, look to the New York Times or the Washington Post in the US; the BBC or Al Jazeera are pretty good sources, too.) But with that said, one story that we haven't seen--yet--involves that quintessentially American penchant for violence. Here's the basics.

The President has decided, against increasing piles of evidence, to go all in and promoted the healing properties of the above-mentioned drug hydroxychloroquine. As regular readers of this blog know, we weren't fans of it ten days ago, which in COVIDland is equivalent to a few lifetimes, and several stories from the professional media were published in the days that followed that blog entry providing much-needed pushback against the anti-scientific boosterism that has accompanied hydroxychloroquine's star turn on the medical stage. But so far as I know, the President hasn't backed down, and there is no real reason to suppose that he will, since there is no downside to adding yet one more outrage into his catalog of misrepresentations, exaggerations, and overt falsehoods. Indeed, there is now strong evidence that Anthony Fauci will pay the price for telling truth to power, and specifically on the subject of hydroxychloroquine.

Why is the continued mention of hydroxychloroquine important, besides this being another instance of how thoroughly appalling Donald Trump and his enablers and supporters are? And what does this have to do with violence? Because there is a slowly emerging consensus that the drug really does do more harm than good--which is to say, it quite likely kills more people than it saves, if it saves anyone at all, which it probably doesn't. The reason is that in order for hydroxychloroquine to work, it has to be dosed in such a way that the side effects, which includes potentially lethal damage to the electrical system of the heart, prove more dangerous than any potential benefits. Many doctors clued into the medication, and who were appropriately skeptical of the phenomenon of bandwagon-jumping, were aware of this weeks ago, but now some hard evidence is trickling in to support the notion that it's a genuinely dangerous drug in COVID infection. The data is by no means definitive, but likewise there's been zero legitimate evidence, in well-designed trials, that it has any lifesaving benefit. So on balance, it strongly suggests that it's bad medicine to give this drug unless it's part of a study. I have never felt otherwise.

And thus, Trump has not only taken on Fauci in touting what may well be a worthless drug to stressed and frightened Americans terrified of losing a loved one to COVID, but he may well be taking on the entire medical establishment should the evidence become increasingly clear--as the Billy Rubin Staff believe it will--that there ain't no there there with this drug. I've already been hearing stories, in blue blue Massachusetts, which is not exactly Trump Country, of people asking doctors about "Trump's drug" to help with their mothers and fathers. How many of them will accept an explanation from one of those pointy-headed infectious disease doctors that there's no value and more than a little risk in the drug, when their main source of news--which is to say, a nightly diet of Donald Trump talking from a lectern--continues to insist that it's a miracle drug, and that there's a Deep State conspiracy against him? And when will there be one of his followers who decides to make his or her (though probably his) views known at the end of a shotgun barrel? We are as a nation armed to the teeth, and the stress of this event, and the dead that continue to mount, increases the chance that doctors as a group become a target of hatred and fear in the mind of a psychopath who finds himself at the Resolute Desk.

V. Not to depress you more, but this thing won't be over in May, no matter what Donald Trump and his not-so-lovable Republican scamps say to the contrary. I haven't a clue what the country, or the world, is going to look like after the various lockdowns and shelter-in-place orders are lifted, but what I can say with confidence is that my analogy to a snowstorm was an unfortunate choice, for the simple reason that snowstorms end. Eventually this will end, so perhaps in some sense it wasn't a total debacle to call it as such. But it's better to think in terms of a year rather than a few more weeks. We can't stayed locked down that long, and that means we are going to have to confront the question of just how many dead we can tolerate at the expense of worse instability.

VI. I saw a patient with COVID yesterday morning. He didn't look too bad. He shook his head at one point, noting, "It's crazy. I'm lying here in bed because one guy wanted to have bat soup." His joke wasn't literal, as it was clear from conversation that he understood the exact origins of COVID are murky, even if we are certain that the epidemic began in Wuhan. The point, he was trying to make--and making quite well--is that the only reason why he was in the hospital was because of an event that began on the other side of the world to one person, and that a chain of you-can't-believe-this failures ensued to land him where he was. We both laughed at the absurdity of the situation, an ice-breaking moment of black humor in the midst of the doctor-patient interaction.

I went home, slept, and came back this morning to discover that he was intubated hours before after the bottom fell out of his respiratory status, as it were. And the PEEP on his vent is set at ten.


Saturday, April 4, 2020

COVID: A Long Tale of the Hydroxychloroquine Mess

Originally this was going to be a multi-subject entry, but trying to explain hydroxchloroquine took a lot more words than I had anticipated, so for today I'm just going to try to tackle this one topic. Tomorrow, other randoms as we wrap up one hell of a week in COVID land.

The Billy Rubin blog staff had a bit of a temper tantrum earlier in the week on the subject of hydroxychloroquine, puzzling some of Billy's Facebook friends as they tried to understand why the innocent question of "why does this not work?" was met with replies that, to put it bluntly, were raving. The outbreak is bringing out the best and worst in Dr. Rubin, and among his worst traits is a lack of patience with what he would describe as "bad medicine." In professional circles, for the most part, he works very hard not to lose patience. On Facebook, though, he ranted a little without explaining himself properly. As a consequence, he's now a little embarrassed, and consequently is referring to himself in third person to make it look like it's someone else entirely.

Here is a more sober explanation of the problem. It's a long explanation. But let me note that absolutely nothing has changed my conviction that what has transpired on the subject of hydroxychloroquine is, from a professional standpoint, shameful. "Shame" is a strong word to use in the realm of medicine; we don't like throwing feces balls at each other like enraged chimpanzees. But it's unfortunately the right word, and unmasks a collective philosophical problem in medicine that irks all members of the Billy Rubin Blog staff.

Let's start at the beginning, all the way back to just over two whole months ago, in Wuhan, China, in the early days of the outbreak. As we now see in New York, the healthcare system in Wuhan was overwhelmed, and the doctors there lacked any known, specific therapy for an unknown virus that looked one hell of a lot like its genetic cousin SARS (what we know now but didn't then is that COVID is significantly less lethal than SARS, and for which the world should be breathing a deep sigh of relief). The doctors there, in a valiant but ultimately uncoordinated attempt at doing something, started trying out whatever they had in their arsenal that could be reasonably justified on biological grounds, and this included a variety of drugs used in treating other viral infections. (Side note: I'm no expert on the subject of the infrastructure of Chinese medicine, but based on reading years of medical papers out of China, and doing a brief sojourn to Beijing, Xi'an, and Luoyang a few years back, I'm reasonably confident that Chinese medicine in the urban areas is effectively indistinguishable from the West. The idea that China is third- or second-world in its living standards is well out of date at this point.)

The discussion of these drugs got a glancing mention in the report on the early outbreak issued by the WHO and Chinese CDC (see bottom of page 32 if interested). Because everyone was trying to play nice together, the language is careful to avoid judgement, and basically says, "well, doctors tried this stuff." The drugs included the following:

chloroquine: an antimalarial--not an antiviral, more on that in a second;
lopinavir/ritonavir: a drug used in treating HIV known as a protease inhibitor, more on that in a second, too;
alpha interferon: an old drug used mainly for treating Hep C until new drugs came along, now almost never used in the US;
ribavirin: an old drug used now mainly for two very different viruses, a respiratory virus called RSV, and a hemorrhagic fever virus called Lassa Fever

The paragraph ends with a nod to traditional Chinese medicines, where it was noted "the effects [of which] must be fully evaluated." No snark about Chinese medicines coming from me on this; the problem isn't the medicine itself, only how such compounds get evaluated so that we can know what works and what doesn't. And the same could be said of these "well, we tried this stuff" drugs. But the rationale behind using some of these drugs is, in my opinion, very thin.

Let's take the lopinavir/ritonavir example before getting to chloroquine and hydroxychloroquine. As I said, lopinavir is an HIV protease inhibitor. What's a protease? Well, when HIV reproduces, it starts out as this long strand of nucleic acid; the HIV strand then uses the body's own cellular machinery to "translate" that strand into one huge combination of all the proteins used in making an HIV particle. It would look like an Ikea set with every single piece of the furniture, from the big pieces to the individual screws, taped together. The function of the protease is to cut those pieces of tape to allow for assembly. Thus a protease inhibitor keeps everything glommed up together so that it can't be assembled. Protease inhibitors remain one of the mainstay drugs in treating HIV, though lopinavir is now a third-line drug in the US and Europe owing to very real and unpleasant side effects--side effects that could be lethal in a sick person.

Anyway, coronaviruses like COVID have their own proteases, so the basic reasoning was, "well, since both viruses have proteases, maybe it'll work." It wasn't that shot-in-the-dark, though: despite the fact that HIV is a very different virus and is far away from COVID on the evolutionary tree, the reasoning was based in scientific research, as this paper notes that lopinavir appeared promising as an anti-SARS drug as long ago as 2005. Every drug used by the doctors in Wuhan follows a similar rationale. They did their homework, for sure--and that they did so in the midst of being overrun by a plague that felled members of their own ranks, including a number of people who not only braved the virus but also told truth to power, should earn our eternal thanks, regardless of where we find ourselves on the ideological divide with respect to our governments.

Chloroquine is a drug whose formal development goes way back 1945, but its roots date much further back to the early seventeenth century, when European empires began their systematic program for extracting resources from the tropics in earnest. The earliest Western observations came from observing the medicinal properties of preparations from the bark of the Cinchona tree in the Andean region of South America. The Cinchona gave us quinine, the critical ingredient in the original Gin & Tonic, which in addition to being a delight to drink, provided legitimate protection against malaria. From there, the massively oversimplified story of chloroquine requires a fast forward to the early 19th century, when the foundations of modern medicine were being laid by the development, of all things, of the modern dye industry, because they eventually begat German biochemical and pharmaceutical companies like IG Farben. (If you're puzzled by seeing a reference to dye makers, the link is that 19th-century scientists discovered that some dyes like methylene blue had antimalarial properties, which led to further research. In fact, the story of the link between the dye industry and infectious disease is a pretty fascinating one, as the story of the development of Bactrim--still ubiquitous in modern medicine--cannot be told without explaining its origins in dye research and development. But we're getting far afield, and we still haven't gotten to the meat of this post.)

Anyway, chloroquine was the most promising of the antimalarials that came out of the mid-20th century research, and its mass production led to the first reliable industrial treatment of the disease. At the same time, physicians who were trying to understand the biological process of inflammation (which, one hundred years later, we're still trying to understand) noted that part of chloroquine's effectiveness seemed to reside not only in how it killed the malaria parasite, but also that it seemed to tamp down the human (or "host," in sciencespeak) inflammatory response. That is, it appeared that part of malaria's lethality was not only directly from the parasite, but also from the exaggerated host immune/inflammatory response, and chloroquine seemed in part to work by pulling the reins on inflammation. Which made people wonder whether it might be useful in other diseases where the body had an exaggerated immune response, but not in the setting of malaria. (Spoiler alert: it was.)

The upside was that chloroquine could save you from malaria; the downside was that it wasn't an entirely benign drug in its own right. Tinkering with the drug, chemists added a "hydroxyl" group onto chloroquine (which is to say, an oxygen atom attached to a hydrogen atom), and thus was born hydroxychloroquine. It was one of many different variants that was studied at the time and was found to be as effective against malaria as chloroquine, but with a much more favorable safety profile. This is the bread and butter of what drug companies do, and it's worth noting that chemists in these companies create hundreds of compounds, all slightly different, and run preliminary tests to identify the most promising compounds that might make it to a human trial. Hydroxychloroquine was just one of these hundreds of compounds at the start of the process, and many more drugs fail to get to a drug trial than those that don't--and most of those that make it to a drug trial end up failing as well.

Malaria falls out of this drama by the late 20th century owing to the fact that malaria got wise and developed resistance to chloroquine and hydroxychloroquine, such that there are now few malaria-endemic areas on earth where the drugs still work. Thus, by the time we arrive in the pre-COVID world of early December 2019, hydroxychloroquine's use mainly resided in its anti-inflammatory properties. And the principal diseases of inflammation where they have been found to be most effective have been in lupus and (to a more limited extent) in rheumatoid arthritis. Newer agents have begun to replace hydroxychloroquine, but particularly in lupus, hydroxychloroquine is still commonly used. Which means lupus patients need those drugs to be stockpiled for their use.

The use of chloroquine and hydroxychloroquine in the treatment of viral infections dates back to at least the early 1980s, again as virologists tinkered around labs seeing what drugs worked and what didn't against some pet virus. And chloroquine/hydroxychloroquine's record against viruses in the laboratory is pretty good. Poke around Pubmed for awhile and you can see promising results against influenza, Hepatitis C, HIV, and, of course, SARS--a virus that can be thought of as the raging beast relative of COVID, the Trump to COVID's George W Bush, as both are deadly, but one significantly more so. Since January, virologists were able to see the same antiviral effect against COVID, as well. But this is all "in vitro" data, which is to say, those experiments just looked at what the drug did with the virus on the battlefield of a few cells in a petri dish.

That was the background behind hydroxychloroquine's star turn on the COVID stage. But did it work? The most intellectually pure scientific answer is "we don't know." The most likely answer, in the opinion of the Billy Rubin Blog Editorial Staff, is "nope."

The original clinical evidence supporting hydroxychloroquine came from a study found here in the International Journal of Antimicrobial Agents. (Note: this study may be amended, or even withdrawn, but the point is where it moved the needle with respect to how it influenced the medical community, and ultimately, Donald Trump, in March 2020. Thus, post-hoc changes to the article matter little.) The study evaluated 42 patients: 26 got hydroxychloroquine, and 16 did not.

Before we get to just how bad a study it is, let's ponder that sample size for a second. And to get context for that, there needs to be a discussion about case fatality rates.

There is now spirited debate about just how lethal COVID is--is it one percent, or four, or zero-point-five? For my part, I'm going with two general numbers: the overall case fatality of everyone who gets infected is about one in two hundred (or 0.66 percent)--but this is only a rough estimate because we don't know how many people there who have very mild symptoms, or no symptoms at all, since they don't get tested. By contrast, the case fatality rate of people who develop obvious symptoms of illness is somewhere around four or maybe five in one hundred. Overall I think this is a sideshow except for the epidemiologists who need to figure out things like herd immunity in their modeling of just how bad this epidemic is going to get.

But from a clinician's standpoint, the latter number (ie CFR of 4-5%) is far more important, because what we really want to know when using a drug is: if I use this on someone, how likely am I to save a life? And to do that you have to know how many people would die from doing nothing at all. Hopefully everyone out there can see that, if you have a disease in which four people out of one hundred die, then recruiting 42 patients is not going to tell you what you need with any confidence, as all 42 could simply survive by chance. So that's strike one against the study--and it's a big strike, so kinda worth strike two as well.

But there can be clever ways to use a small sample size and get surrogate data to tell you whether doing a full, count-em-up clinical trial to look directly at mortality is worth it. In this case, the surrogate marker is the amount of virus people have in their bodies. This was the finding that got everyone's attention, and it was mainly due to this picture:

It purports to show that those who got hydroxychloroquine (the red line) had a much faster decline in their viral loads than those who didn't--and from that, the conclusion was that we should try this out clinically. The problem, or at least one among many, as extensively outlined in this extremely well-written blog by David Gorski, a surgical oncologist with a PhD and who writes often on clinical trials and the statistics that underlie the work, is that even this scant data is cherry-picked, as (for starters) patients who were moved to the Intensive Care Unit--which is to say, the sickest ones--got left out of the hydroxychloroquine group. This borders on scientific malpractice, and is a rookie error of clinical trial design. In fact, we don't even expect rookies to make mistakes like this.

But what happened in the medical world, even before Donald Trump came along and made everything much worse, was that only the punch line got repeated (hydroxychloroquine works!), and nobody took a direct look at the data to see just how shoddy it was. That's understandable in the layperson world, but for doctors who are trying out untested and potentially dangerous medications in critically ill people, it's the worst kind of laziness. Doctors were prescribing this drug (or, appallingly, hoarding it for their own use) because they read somewhere or heard from someone who spoke to someone who read something that "maybe this works." Well, maybe it does work. But maybe ozone therapy works for Ebola, too. (Hint: it doesn't, really.)

Hydroxychloroquine thus became the great hearsay drug in the early hours of the COVID epidemic. It had no proof, a vaguely plausible justification for its use, and ready availability. But by mid-March, there was still very much no there, there.

Then Trump's tweet came on March 21. I won't say much about this chapter of the saga other than to note that it should be self-evident that there is a high inverse correlation between any pronouncement Donald Trump makes and its truth value. Thus, the fact that he touted the drug (along with a second drug we don't have time to go into, azithromycin) could be reasonably regarded a priori as clinically useless, or at least wildly overblown, simply by dint of the fact that Trump endorsed it.

Meanwhile, in Fantasyland, tales from a "simple, country doctor" were filling the airwaves of the magical hydroxychloroquine elixir. The doctor in question is one Vladimir Zelenko, who noted that he was "seeing tremendous results" in patients using hydroxychloroquine, azithromycin, and zinc. How could such a simple country doctor outwit such heavyweights as Anthony Fauci, who seemed to remain stubbornly skeptical of hydroxychloroquine when doctors like Zelenko could see its obvious promise? Was Fauci secretly part of the Deep State trying to take down Trump by making things worse and withholding lifesaving, and readily available, drugs?

The answer to these questions are simple: Zelenko's simple. He is, like his President who took to the Twitterverse in enthusiastic endorsement, a living, breathing, perfect example of the Dunning-Kruger effect. He is so hopelessly in over his head that he has no mental tools to understand just how in over his head he really is. Maybe--maybe--if COVID were as lethal as Ebola, simple country doctors could see for themselves if a drug worked without having to resort to clinical trials, or troublesome issues like placebo controls and informed consent, or confidence intervals and power calculations. But with this virus? Not so much. You need the machinery of modern medicine, and the research tools that took two centuries to develop, to really know whether you're making an impact. But he has no clue that he has no clue. And so can be said for the followers of Donald Trump, who have been remarkably resistant to grasp his obvious buffoonery, despite it being on daily display over the past month. It's quite impressive, really. Denial is a powerful thing.

But let's end not on the cartoonish stupidity of the President and his Republican enablers, let's turn back to what under normal circumstances would a be solid place to find information, for even they can make the occasional slip-up. And this week, a piece in the New York Times described a new trial on hydroxychloroquine in which the results were favorable. It's certainly a better study than the one mentioned above, though that's a pretty low hurdle. But it's not substantially better: it once again enrolled too small a cohort to look directly at mortality, so it relies on surrogate data that make it hard to know whether the benefit is real or an optical illusion; the patient population studied never got very sick, making its relevance in saving lives of unclear significance; and people did suspiciously well in this cohort, potentially suggesting some unseen bias that shaped the numbers. Everyone in my division took a look at the paper: the reaction was swift, and it wasn't anywhere near as favorable as the warm coverage in the article.

The study hasn't been peer reviewed, where these and other troubling issues would be addressed. Perhaps upon peer review, the study might not even be published because it is found to be wanting. The question, then, is why did NYT pick it up? At the Billy Rubin Blog, we're scratching our heads on that one, because the publication of this article just made it harder for every ID doctor everywhere to try to do their jobs, in no small part because we have to continuously explain to stressed and worried families at length why these studies aren't really very good, and that these drugs come with side effects that might actually end their loved ones life, not save it. This blog entry, despite running to thousands of words, hasn't even taken a shot at explaining a heart-stopping effect called the long QT syndrome, which is almost certainly hydroxychloroquine's most deadly acute effect, and is even worse when used in conjunction with azithromycin, and which I've seen once already in a COVID patient.

Ultimately, there's an old saying in medicine that encapsulates the skepticism that we should be applying toward hydroxychloroquine's boosters, whether those boosters are motivated by naked partisan political considerations (which is to say, Trump, who wants this to go away for narrowly selfish reasons), or by a look-we're-trying-to-do-everything-we-can motivation (doctors who feel they just can't stand around and do nothing). The saying is really old, so old that it comes from a different language, and a different epoch, entirely. The language is Latin, and the saying is primum non nocere. It means, "first, do no harm," and is a caution to physicians who panic in the midst of an outbreak by trying to throw everything at the wall and seeing what sticks. With a four percent case fatal virus, you cannot see what sticks unless you do a clinical trial. With a drug like hydroxychloroquine, off-the-shelf use is a recipe for killing not only one patient--the COVID patient receiving the drug--but possibly a second as well. That person is the lupus patient who has been denied their drug. Because soon, stockpiles of hydroxychloroquine, like the ventilators that are crucial to the survival of the sickest COVID patients, will have dried up.

Among the many lessons that the West African Ebola outbreak had to teach was that physicians shouldn't lose their collective clinical head in a disaster. We should take a page from Douglas Adams, and conduct ourselves by the motto don't panic. We should treat patients by what we know works, not what we hope works, because we're probably going to kill somebody if we practice medicine that way, and we're no better than the Quacks of Old London in the 1600s. We do what we can, and in the meantime, we (urgently) do well-designed, adequately-powered clinical trials to learn what works and what doesn't. That includes a trial of hydroxychloroquine! But without doing good science, we're the same as doctors during the bubonic plague, or at least not as good as we could and should be.

There were no good clinical trials that came out of the West African Ebola outbreak. That failure was enough to get a group of experts together to work with US, European, and African countries so that they were more prepared to do quality clinical trials when the next Ebola outbreak came. Thus, it came to pass, that good clinical trials were conducted in a much more challenging Ebola outbreak in the Congo, so that now we have two therapies that dramatically reduce the mortality from Ebola.

There is no reason why we cannot do such research right now, and adjust our practices as fast as humanly possible, in the midst of this outbreak, especially as it may not be over anytime soon.