Ebola—  Sadly, there is an update this week.  Although there are no new cases in the Kivu region of the DRC, where the 2019 outbreak was located, there are now at least 8 cases of Ebola in Mbandaka.  Those of you who are OGs on this list may remember that town from two Congo outbreaks ago—and yes, this is the same place, and almost the same time of year, as the 2018 outbreak of Ebola in the DRC.  That one was contained much faster through early detection and effective contact tracing, allowing a ring vaccination strategy to work.  Hopefully, that happens again.  

On the plus side, Mbandaka is not quite so isolated a region, and is more politically stable (that being relative for the DRC), so contact tracing should hopefully be a little better and ring vaccination is reasonable to start out with.  

On the down side, Mbandaka is not quite so isolated a region, and as we discussed in 2018, sits right on the Congo River, which is a major thoroughfare for transportation and trade.  You are only a couple days by boat from Kinshasa, the capital of the DRC and a megacity of 11 million, sitting opposite Brazzaville, the capital of Congo, at 1.8 million. Most cargo (and less often people) still have to hop a rail line to get to the Atlantic in Matadi though.   Response to this new outbreak (which is either fruit bat migration, people migration from Kivu [as hopefully sequencing and comparison to the virus active in that region will determine], or those rare reactivations in previously infected people we call Ebola Janes here) may be hampered by the WHO’s newly reduced funding and necessary focus on COVID.  Depending on how hard the DRC is getting hit by COVID too, efforts may be a little slower.  They may also have to shift some vaccine back across the country to Mbandaka, and I’m not sure how efficient that is in the DRC, but I have some guesses.

So, once again, it looks like the Ebola portion of this update will keep rolling for a bit.

Coronavirus—We have lots again, and I may have to pick and choose to keep this manageable.  In fact, last week’s social issue comment is likely getting punted again.

—First, as I have said before, all predictions wrong or your money back.  Well, some of you may recall from the “Black Death” comparison update earlier into the outbreak that some of the parallels would likely not be 1:1.  For example, since coronavirus did not have the lethality of the Black Death, wholesale breakdown of social order with violence, rioting etc. would not be as likely.

With the benefit of hindsight, I -may- have been a little too optimistic when minimizing the chances of societal and institutional collapse.

My bad.

Goes to show you that I (we) should listen a little more when our great-great-great-great-great-great-etc. grandparents when they tell us how it all went down.

Song link selection is still on point though…  I stand by the Kaiser Chiefs.

—Worth noting that it was messy, but the societal restructuring of the Black Death in most of Western Europe weakened serfdom and set the table for the Renaissance.  So positive order from a little chaos is possible.  On the other hand, in some parts of Europe, Russia in particular, serfdom got stronger.  The balance of power between entrenched corruption and the people can tip the other direction as well.

—“Governments are instituted among Men, deriving their just powers from the consent of the governed, —That whenever any Form of Government becomes destructive of these ends, it is the Right of the People to alter or to abolish it, and to institute new Government”

—Consent wisely.

—The Pax Romana was not the end of history, although they looked it to those living in the Mediterranean and western Europe at the time.  History had merely paused, stooped, to take one heaving breath in a stolen moment.  Then the sprint began again.

—The end of the Pax Americana will likewise be a return to history.  Look again to your great-great-great-great-great grandparents for what that looks like where you are.  I suspect America will be setting its house in order for a bit, solving American problems the American way.  The rest of the world will likely be on its own during that time.    

—Secondly, following up the update to the update from last week and the Lancet publication of an observational study on a massive number of patients suggesting hydroxycholorquine may not be effective in the treatment of SARS-CoV-2.  I mentioned that immediately after publication, Australia questioned the numbers that the database used in that study, Surgisphere, assigned to them, and that Surgisphere was refusing to disclose the data.  “That’s not great” I think was my exact quote on that.

Well, it gets worse.  The Lancet has followed the New England Journal of Medicine and issued a formal “expression of concern” yesterday (the NEJM had published another study relying heavily on Surgisphere databases).  That’s a polite way of saying “there is a high chance this study is wrong, and will probably be retracted soon.”  

And lo, three of the authors retracted the study today after Surgisphere refused to let the authors of the paper review the source of their data.

The Guardian let loose some investigative reporters onto the case, and it’s clear that Surgisphere does not have the personnel needed to have reviewed the amount of data it claims, and no one seems to know where they got it from, as hospitals and universities keep claiming they have no known data sharing agreement with them.  

In fairness to the peer reviewers on the Surgisphere papers, they have no way to know if Surgisphere has the agreements in place or not.  All they get is the paper the authors wrote using whatever “data” Surgisphere provided them.  Thus, the onus is really on the co-authors of the paper to vet Surgisphere and its database for accuracy, before sending it out for peer review.  The failure of the authors to verify their data source before publishing will probably cause them to go down with the Surgisphere ship on this, retraction or no.  But the nice thing about science publication is that egregious errors like this do get corrected.  Unfortunately not before publication this time, but the example likely to be made will keep other authors, particularly those racing to get anything COVID related out as fast as possible, a little more careful checking their data and its source.

I know where I work data review for publication is one of -the- most tedious processes we have.  There is an entire scientific function here whose job, no joke, is to go through every paper anyone in the company writes before it is submitted line by line by line to find the exact lab notebook entry and exact location where every piece of data was generated and is stored.  Adds a lot of time, but this is why they do it.

—The good news is that, as I mentioned, the review of the paused hydroxychloroquine studies would be on the merits and data (so far) of those studies, and not the Lancet publication.  Those studies have resumed following those reviews, and will hopefully, finally, get some definitive data and end this love/hate relationship with hydroxychloroquine as a treatment for SARS-CoV-2.

—Donald Trump has still not caught malaria since he was reported to be taking hydroxychloroquine.

—Next major development.  Honestly, so far so good on the Great Memorial Day Weekend Experiment.  Yes, they found some positives partying out on the Lake of the Ozarks before they were symptomatic.  That’s no surprise.  But no major blowout in new cases–yet.  Still too early to claim victory, because lab turnaround time depending on where and how people are getting tested may cause the wave to appear a little later.  The first edges of that wave should have been visible by now though, and so far, we are not seeing it.  So I am cautiously optimistic.  You can view velocity of new cases across the states here:  https://coronavirus.jhu.edu/data/new-cases-50-states

—Where you are seeing “X state is seeing an increase in cases!” in the news is mostly confined to specific counties and locations in those states.  This again is reinforcement for the idea that the “second wave(s)” are likely to be more local and focal in nature, and why that has been our base case in this update.

—That said, if there is no major blowout in new cases by the end of June between the Great Memorial Day Experiment and the Best of The Kaiser Chiefs Experiment last week, I’m going to be looking a lot more closely at that CD4+ paper we discussed.  That’s the one that showed a high percentage of the population had CD4+ T-cells “trained” from previous exposure to other common cold coronaviruses that were reactive in vitro against SARS-CoV-2.  That may be consistent with a higher level of resistance, and asymptomatic “infection,” then we currently account for in many models.  

—If that is true, then I would also start to suspect that resistance and immunity to SARS-CoV-2 may not be adequately captured by antibody tests, and be driven by some of the less antibody dependent ways of fighting a virus available to your immune system.  

—No blowout by end of June makes the “largely over by end of July/August” case much more possible, but still not to our base case just yet.  There are still focal second waves breaking out in other countries further along the first wave than the US.

—So that’s the good news following the Great Memorial Day Experiment.  The bad news is we may well get that blowout yet, and good luck maintaining or re-quarantining now.  We will all be Sweden here, and their government is already under fire this week for a now higher than expected mortality for having NOT gone into some kind of strict social distancing and lock down.

—In other news, I cannot comment on Gilead’s latest Phase 3 data this week for remdesivir.  There are commentaries both ways in the public domain though if interested.  Same for press releases regarding drugs my employer is bringing forward.

—More on the underlying pathology from a tastefully named reader in Georgia, who sent this:  https://elemental.medium.com/coronavirus-may-be-a-blood-vessel-disease-which-explains-everything-2c4032481ab2

This is mostly an interview with an author associated with the following paper:  thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext

This paper was published in April, and showed definitively that in some patients, SARS-CoV-2 was not only infecting pneumocytes in the lungs, it was crossing into the small blood vessels carrying blood to the lungs to get oxygenated.  There, it was infecting the cells that make up the blood vessels called endothelial cells.  They have a really great electron microscopy shot showing the virus replicating within these endothelial cells, and endothelial cells do indeed express ACE2, which is the target for the virus to attach to cells it infects.  This line of research has been extended, and summarized well here:  nature.com/articles/s41577-020-0343-0.  

In short, they are proposing that attack on the endothelial cells by the virus is either the main cause, or at least a significant contributing cause, to the Ah-nold inflammatory over-reaction that we have been discussing as the increasingly likely culprit for severe SARS-CoV-2 disease.  What happens is illustrated in the following diagram, which I have taken from sciencemag.org/news/2020/06/blood-vessel-attack-could-trigger-coronavirus-fatal-second-phase:

So the idea here is that a patient catches SARS-CoV-2.  They get the standard symptoms for week 1, often bad enough to go to the hospital.  About 7 days after symptoms (when the immune system is likely to be highly engaged if not turning the tide on the virus itself) is where things start to go pear shaped for those patients likely to have an especially difficult time with SARS-CoV-2.  The endothelial driven hypothesis is that the infection has moved heavily into the endothelial cells, and direct damage to them causes them to get “leaky”.  This lets fluid across and into the air space in the lungs (shown in the picture) along with more immune cells.  The more fluid in the air space, the less space for actual air, and the patient requires more aggressive oxygenation support up to and including a vent.  Meanwhile, damage to the vessels also provokes the coagulation cascade, which is trying to do its job blocking leaks in blood vessels–of which there are now more.  This leads to intravascular coagulation, or clotting inside the vessels and in some patients what we call disseminated intravascular coagulation, or DIC.  Disseminated simply means “widespread”.  In DIC, clots are starting to form inside blood vessels (shown in the diagram above) so frequently that the patient will start to run short of clotting factors and platelets.  Thus, they may start to bleed at the same time they are clotting.  DIC is a real bad time and a medical emergency.  Some laboratory indications that the clotting cascade is being triggered include elevated d-dimer, which is frequently seen in COVID-19, and elevated fibrinogen, being produced to make all the clots.  vWF, or von Willebrand’s Factor, is also typically elevated in COVID-19—this is made and stored in endothelial cells, and elevated levels are consistent with very unhappy endothelial cells somewhere, which are now spilling vWF into circulation to be detected.  This damage also causes the endothelial cells to release cytokines—these are the snapping twigs that set the immune system off.  

All of this is consistent with vascular damage as a driver of the Ah-nold immune response that may be doing the majority of the actual COVID-19 pathology.  Certainly, direct invasion and damage of the endothelial cells by SARS-CoV-2 is not helping.  

Also worth mentioning that the Kawasaki-like syndrome seen in children would fit for this as well, as inflammation of the vessels is a major part of it.

The authors of these articles suggest several lines of treatment that may stabilize the endothelial cells, and thus stop this kind of cascading damage leading to Ah-nold and commandos blazing down acres of jungle.  I cannot comment on those, in large part due to a press release on April 10th from my employer regarding certain molecules that my employer is advancing to clinical trials as a potential treatment for COVID-19.

That being said, in some ways, this is like arguing if the fire in the kitchen or the garage, both occurring at the same time, was MOST responsible for the house burning down.  Massive and sudden damage to the pneumocytes, or even over-exuberant reaction to the damage to either or both of the endothelial cells and pnemocytes, can trigger a cytokine storm–snap the twig that sets Ah-nold off.  When Ah-nold and his commandos go off (called sepsis), part of that reaction will signal the endothelial cells to increase vascular permeability.  After all, the immune system, which lives in the blood stream, has mounted up to ride or die, and the endothelial cells move to let the cavalry charge through.  So, like in the diagram above, a cytokine storm from pneumocyte (and/or endothelial cell) damage lets more fluid and immune cells into the airspaces in the lungs.  Due to the close association of coagulation and inflammation, sepsis can start to trigger clotting in the blood stream, elevating d-dimer and fibrinogen, up to and including DIC as a frequent complication of sepsis.  All of that clotting and immune stimulation will perturb endothelial cells, stimulating release of vWF, which, sure enough, is elevated in sepsis in general.

So basically, you can start with pneumocyte damage, causing number 3 in that diagram FIRST and work your way back to 1, getting all the same changes but not requiring a lot of endothelial cell damage.

Is direct endothelial cell infection and damage THE cause of the sepsis?  Maybe.  Is it the MORE IMPORTANT cause of the sepsis?  Maybe.  Is it a significant contributor to the sepsis, while the main cause is damage to pneumocytes?  At least.  Could it be different in different patients as to which source of damage was the snap that caused Ah-nold to bring the forest down?  Absolutely.

From my perspective, that’s less important than knowing that the virus is triggering a response in some patients leading to sepsis with all the associated problems of sepsis.  Finding the balance and timing for when you can start to dial the immune system down enough that the virus does not get worse, and identifying earlier whose immune system is likely to go Ah-nold to better focus and moderate the response, and/or tying up the virus with antibody (either as a treatment or provoked by a vaccine) or antiviral early so a critical mass of damage to trigger Ah-nold never happens is the key.  At least in my opinion.  If you stabilize the endothelial cells, will it help?  Yeah, probably–especially in those patients where the endothelial damage is the more twig snap.  I don’t know that we can reliably tell those patients apart, and if the snap from the pneumocytes is still loud enough, they may still run into an issue anyway.

But that’s what clinical trials are for.

—You may have seen anecdotal observations about SARS-CoV-2 from Italian doctors treating the disease.  Basically, some quotes hit the media that the Italian docs are seeing “less severe” disease, as if it’s changing and becoming milder.  Encouraging if true and widespread, but anecdotes are not enough.  Could just be the patients now coming to this guy’s practice as Italy remains on a steady down slope of new cases.  In general though, a good way for a virus to mutate is to become -less- severe in the symptoms it causes, as less sick people are more inclined to go to parties, giving the virus access to more hosts.  So, plausible, but not definite, and keep an eye on it for now.  

—You may also have seen this last week, which mentions the Indiana experience:  https://www.npr.org/sections/health-shots/2020/05/28/863944333/antibody-tests-point-to-lower-death-rate-for-the-coronavirus-than-first-thought?utm_campaign=storyshare&utm_source=twitter.com&utm_medium=social

This is more suggestion that the case fatality rate is likely to land between flu and 1% overall.  However, keep in mind last week’s math, as this NPR article and the folks in it rely fairly heavily on antibody tests.  Continue to view these numbers more as estimates.  The true positive predictive values of the antibody tests are tough to discern right now.  Also, keep in mind the flip side is true.  I know of highly accurate antibody tests that have struggled to find antibodies in some patients who definitely HAD SARS-CoV-2 at one point—and especially in those with less than hospitalization worthy SARS-CoV-2.  There are biological reasons that might be.  If those biological reasons are very widespread, and not everyone who gets SARS-CoV-2 winds up making enough antibody for the tests to reliably detect, the total CFR gets even lower, and second waves, if they happen, may be less a threat to entire healthcare systems as more herd immunity than expected may already exist.

Again, though, the counterargument to that optimism is that second waves are still occurring at least loco-regionally around the world.

Again, what happens with the Great Memorial Day and Best of Kaiser Chiefs Experiments through the end of June will be very suggestive.

Love in the Time of Coronavirus:

Thanks to the many of you who sent this along:
https://news.sky.com/story/coronavirus-monkeys-escape-with-covid-19-samples-after-attacking-lab-assistant-11996752

Man, do I want that to be true.  But there’s what you read, and what really went down.

Turns out, that article leaves a few details out.  Details known only to a select few.

I’m happy to fill you in.

This was no accident.  I know you read “monkeys steal lab tests right out a lab workers hands” and think “hahaha…silly monkeys doing silly monkey things.”

Not this time.

No, that lab was doing cutting edge research on SARS-CoV-2, and had found the truth.  SARS-CoV-2 was developed in a secret bioweapons facility and released deliberately on all humanity as a weapon of mass destruction.  The evidence uncovered in that lab in India pointed to one, and only one, possible source with the resources, will, and capability to not only weaponize, but deliberately release, for political purposes, a disease like this:

That’s right–The Army of The Bioterrorist Monkeys.

By releasing SARS-CoV-2, a virus to which they are immune, they hoped to destabilize human society worldwide, creating the chaos, strife and discord from which would finally, FINALLY come the Planet of the Apes.
Unfortunately for humanity, posing as research animals, agents of the Army of the Bioterrorist Monkeys had infiltrated the lab and tipped off the Monkey Army that our researchers in India were on to them.  If the truth were known, the secret monkey plan might be thwarted!  They had to act fast, and that was no random group of monkeys conducting a grab and dash on that researcher.  No, that was military precision, timing and discipline in a carefully orchestrated, expertly conducted strike by elite monkey special forces.  Verifying the contents of the package as the incriminating samples, by taste of course, the monkeys raced the stolen samples back to the hidden lair and as the Army of the Bioterrorist Monkeys mustered for the final push.

The rise of the Planet of the Apes was at hand.

Or so they thought.

What they didn’t know is that one of their own had been flipped.  For peanuts.

Literally.  

Our finest, our best, our last hope against the Planet of the Apes was mobilized.

Into their sinister mountain lair…  And there, in the dark, and the deep, where the terrors lie in wait…there did the battle take place.  One human champion versus an entire army.  Hand to hand, inch by conquered inch.  Wordless intensity, only grunts and blows sounding the struggle.  Desperate in the shadows.  For at the end of that day, of that very hour, only one species would dominate primate-kind.

Only one.

So when the article so cavalierly mentions that “the specimens were later recovered”, realize, dear reader, that is to spare you and the rest of humanity from knowing just how close the monkeys were to their chilling objective.  How narrowly humanity avoided the long dark night.  Just how near prehensile tails came to ruling the world.

All but for one hero, and long live the name:

Your chances of catching coronavirus, at the moment, are good but fading in many places around the world.

Your chances of catching Ebola are equivalent to Jane Goodall, for so long as she breathes, ever letting the planet fall into the clutches of the damn, dirty apes.

<Paladin>