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.



  1. Dear bilirubin (yuk, yuk)

    "Along those lines, it remains clear to me that COVID is a disease of inadequate oxygenation." This is true.

    Don't covid patients typically present with bilateral ground-glass on the outer lobe scans? That's not typical of pneumonia, right?...not ARDS...but the patient is blue and his breathing muscles aren't distressed, right? So is the problem with the lungs or with the blood not carrying the O2? No reason to intubate, but maybe there's a reason to give some packed cells.

    Who typically prescribes Plaquenil for lupus patients? What was the regimen back when it was used to treat malaria? Can patients typically tolerate 200 mg HCQ bid for five days with no new cardiac arrhythmias occurring? How many years do lupus patients have to take Plaquenil before 1% of them develop arrhythmias?

    Why are covid mortality rates much lower in places like Utah and Tennessee than New York and Michigan and Louisiana and Kansas?

    Now hydroxychloroquine only mildly inhibits usage of the ACE2 receptor by coronavirus, right? Is the HCQ zinc-ionophoric activity high enough with the recommended dosages to actually get enough zinc into cells to inhibit the RNA-dependent RNA polymerase produced by coronavirus?

    No, I'm not a physician, although my daughter is and we discuss these things. Per my daughter, the Memphis docs are treating patients with Plaquenil/zinc at the hospital she works at. Taking Zpak with Plaquenil may be risky because of synergistic effect on QT, but maybe not at Zelenko's dosages and duration.

    If patients are dosing themselves with high levels of zinc without their doctor's knowledge, and the doc tries Plaquenil, might that give undeserved credit to Plaquenil as a mono-treatment?

    If someone can point me to a clinical study that shows that HCQ/zinc (using Zelenko's dosage and duration) provides no benefit, that would be much appreciated.

    Hope you are able to keep the covid mortality rate low in your patients.

    1. There's a lot to unpack there, theasdgamer--far too much for the time I have allotted in the day. The simplest answer I can give to cover all of your musings is that there is a big difference between casual observation and rigorous hypothesis-testing. The casual observation is that Utah has a lower mortality rate. (I don't know if this is true, but for the moment I'll take your word that current data suggests it is.) There are literally *dozens* of reasons why this may be a statistical optical illusion. It also might be real, and the real difference itself might have to do with all manner of variables that has nothing to do with whether someone got PRBCs, or azithro/Plaquenil, or zinc, and so forth. You can theorize to your heart's content; only a real study will tell you what's what.

      You mention Zelenko. He is a doofus who doesn't understand this process. You can't make casual observations in a clinical setting and follow with confident conclusions about a drug's effectiveness in a disease that kills one in a hundred. At the Billy Rubin Blog, we hate to resort to name calling, but for someone who has gotten paraded on the national stage as a (highly improbable) hero of the right wing, the word fits: he's an iggit. Pity we can't take his license to practice medicine away.

    2. I think ideology is clearly interfering with your role as a physician. I only hope your patient's family and love ones find this blog before is too late.

      Time will tell who the real "doofus" is.

    3. Thanks for the feedback, anon. Funny it should come today, given this headline in the Washington Post: "hydroxychloroquine, , an anti-malarial drug President Trump encouraged as a treatment for covid-19 patients, is not only ineffective but significantly increases the risk of death for some, new evidence suggests.

      “Alarmed by a growing cache of data linking the anti-malaria drug to serious cardiac problems, some drug safety experts are now calling for even more forceful action by the government to discourage its use,” The Post reported. Read about how some of those experts are calling for the Food and Drug Administration to revoke the emergency authorization it granted for use of the drug during Trump's sales pitches."

  2. At the risk of triggering a 'BillyRubin storm' (a.k.a. 'poking the bear'), dare I ask about the trial being run in South Dakota? :-)

  3. Thanks for replying.

    Zelenko says that he has treated 700 patients with zero deaths. And he only treats patients with hypoxia or if they are 60+. Zelenko says that early treatment with his regimen is critical. Zelenko states that he found a South Korean paper which covered a trial using HCQ/zinc, but I haven't been able to find it. Perhaps you have?

    What are the odds of zero deaths with those facts?

    Then there's Cardillo in LA who reports that he gives HCQ/zinc to patients who are "severely" ill and sees remission of symptoms in 8-12 hours.

    Best wishes to you and your patients.

    I would LOVE to see a clinical trial of HCQ/zinc, whether it disconfirms or confirms.

    1. I gave a somewhat testy reply about Zelenko on the previous blog post that is devoted exclusively to hydroxychloroquine. I apologize the slightest bit for the testiness, but not for holding Zelenko in contempt for utter irresponsibility. I've tried to explain in this post and the previous one why his claims should be greeted with absolute skepticism, and why stuff like this, where the phrase "DO NOT TRY THIS AT HOME" should be flashing to every doctor who thinks they want to experiment on their patients with some kitchen-counter concoction because they read about some study in France that "was intriguing." (I don't know if Zelenko used those precise words, but it conveys the general gist.)

      The fact that he mentions the French study is the tell that he's a rube and just got suckered. Every doctor worth a damn who knows something about clinical trial design didn't even laugh when they looked at that study, their jaws dropped as they said to themselves--and anyone else who would listen--"you mean to tell me someone as famous a Didier Raoult put his name to THAT? What the fuck's the matter with him?!" Now you may not know who Didier Raoult is, but in the world of infectious disease medicine, he's about as famous as it gets--only Paul Farmer and Anthony Fauci have greater fame off the top of my head. But this "study" is an embarrassment, and he should never have done anything as irresponsible as lend his name to this. I assure you that I am not alone in that assessment. It's simply not controversial. Nobody who understands clinical trial design thinks this is worthy of attention, and as such it's worse than armchair speculation because people like Zelenko hear the word "study" and think that, even if it isn't *perfect,* the results *might* be telling us something. But they don't. And the fact that he hasn't the foggiest clue about that should provide strong circumstantial evidence why we shouldn't swallow his claims about these pills, so to speak.

      Zelenko mentions a paper from South Korea. Here is a review paper from March 22 that looks at most or all existing studies of chloroquine and hydroxychloroquine, and mentions a trial there, the results of which do not appear to have been published yet. This paper itself is not peer reviewed, so use at your own risk, but its conclusion is that we are nowhere close to knowing whether either of these drugs work:

      I've never heard of "Cardillo in LA," but I would guess this is the same phenomenon, and I've no interest in playing Dumb Doc Whack A Mole.

      There are now millions of people infected, so if people with time on their hands want to do a trial of Plaquenil and Zinc, they can be my guest. The likelihood that it won't show benefit is extremely low, somewhere between zero and two percent, if you're being optimistic, and if it's conducted properly. MOST drug trials fail, even ones whose rationales are better than the reasons supporting hydroxychloroquine.

  4. Trump is a simple man who requires simple explanations for complex problems. He picks one idea and runs with it, and his fanboy base laps up whatever the says. Before plaquenil, it was something else/some piece of drivel without a shred of evidence that he repeated ad nauseam, and so on. There's basically turtles all the way down.