Ebola–  <sigh>.  We’re up to 69 confirmed cases and continued geographic spread within the Equateur Province of the DRC.  The treatment center in Bikoro is already over capacity.  Only 71% of known high risk contacts have been followed up by the time of WHO’s report this week.  65 known high risk contacts have either never been seen or have disappeared.  Only 143 new vaccinations were carried out, which is not remotely enough for either a ring strategy or “carpet bombing.”  Still no word about the case discussed previously with either vaccination failure or vaccinated too late to stop already present disease to know which of those possibilities it was.  The only good news this week is that cases are not exploding (yet) and spread is geographically contained to Equateur Province (so far).  I’m sure we’ll have more to say about Ebola in the weeks ahead.

In other “Reasons to Not Visit the DRC” news, the DRC -also- has a plague outbreak.  Starting in mid June, Ituri province (where plague is also endemic) began dealing with a small outbreak.  75 confirmed cases and 17 deaths. 

Hadn’t heard about that before now, huh? 

What about the Lassa fever outbreak that is currently going on in Nigeria?  Missed those headlines too?  Yeah, Lassa fever is a less well known hemorrhagic fever and is endemic in West Africa.  Since January across 129 separate regions of Nigeria, there have been 1,051 confirmed cases of Lassa fever and 233 deaths.  Lassa is contracted by contact with urine or feces of its reservoir multimammate mouse, which lives in West Africa

Although a different family of virus, there are some SARS-CoV-2 parallels.  Lassa can get into endothelial cells too, and Lassa is known to screw up the immune response to it deliberately to help the virus evade surveillance and replicate.  About 80% of those who catch Lassa don’t even know it or get only mild symptoms (that 20% mortality rate above is because there are undoubtedly more cases running around than they have confirmed).  Because the unlucky 20% with severe symptoms can have a real bad time though (2-3% mortality), and there is no known vaccine and only IV ribavirin has been shown to help, Lassa is considered a biosafety level 4 agent like Ebola. 

One that 300,000–500,000 people in West Africa will get just this year alone.
That mouse doesn’t get around much beyond West Africa, so unless Lassa finds a new way to move, there will be no lassa updates though, don’t worry.

However, to recap, a squirrel in Colorado tests positive for plague (as they do every year)–headlines around the world.

Meanwhile, this is probably the first that many of you have even heard of Lassa fever.  Which is actively spreading, infects hundreds of thousands, and kills thousands, every year.

What a world.

Fortunately, I may be the only active reader of the weekly WHO Africa surveillance report, thus sparing us the “LASSA FEVER TO DOOM US ALLLLLLLLLLL” headlines.

In better news from that report, the major African countries appear to be cresting the first COVID wave.  South Africa, for example, is clearly on the down slope of new cases.  Case Fatality Rate has been running a little lower in Africa in general (thank God for that) and is probably an overestimate anyways as testing is a little more restricted.  Considering Africa is far and away the youngest continent on the planet, that’s not a huge surprise.

–That’s a good segue into This Week in Coronavirus.

–First, the bad news.  Delayed first wave is now catching up in East Asia, as the Philippines have seen dramatic increases in new cases, and Victoria, in Australia, continues to climb the late first wave peak.  I bring those up specifically because they are currently under draconian lock downs that… well… do not appear to be having the intended effect upon new case numbers to put it politely.  I have no report on if the new cases are threatening the local healthcare systems through sheer force of numbers, but if the recent outbreaks are like the European delayed first wave, the patient population is younger and less apt to wind up in the hospital or for long.  There are likely some local/regional areas whose healthcare systems will be tested though, especially if they were relatively spared in March/April.

–In the good news, at least for those of Stateside, here is the current map of rate of new cases:

That’s a lot of green, from sea to shining sea.  That green is the fall in new cases we have been expecting, and arriving right about when we expected. 

“But wait!”  I hear you say.  “They have been doing less testing!  Plus the hurricane disrupted testing up and down the East Coast!  That’s why case numbers are falling!”

Nope.  Positivity rate overall is declining, and on the individual level, is flat to declining in nearly all states.  This really is a general drop in new cases.  Further, as less SARS-CoV-2 is around in general, one would expect fewer people to want to be tested.  Especially with the delays and hassles we have mentioned in some locations previously.

Also note that the Federalist experiment in various degrees of openness, re-closure, face mask mandates, compliance with all of those etc. among the many states pictured above has all wound up at the same green-ish color of declining cases.  Regardless of actual policy used.  I expect this drop will continue.  I suspect many places in the US are getting much closer to herd immunity (and that magic number is less than 50%).  I expect any recurrence with school re-opening etc. will be localized, and short lived, as the virus is running out of susceptible hosts fast.

The Rt data this week on rt.live are consistent with the drop in new cases and the decline in positivity as well.  The mean Rt for over half the states is currently at or below 1.0, indicating a virus running out of steam.

Maybe don’t book that Hawaiian vacation for this week though…

–Sweden’s numbers remain very stable.  That is the European bellweather for the next couple weeks.  If the glowing embers of the late first wave elsewhere in Europe cannot re-spark Sweden, that is a positive sign herd immunity can and will be reached once the first wave has crested.

–In May, we discussed the plethora of “FEAR THE SECOND WAVE” because “A TOTALLY UNRELATED VIRUS CALLED INFLUENZA DID THAT IN 1918” scare headlines.  We presented arguments against that then, since SARS-CoV-2 does not mutate like that, and its cousins MERS and SARS-CoV-1 did not have major second waves.  We have, for months, been laying a base case that “second waves” would be state/city level, and while possible to re-ignite an entire large nation, probably would not.  We expanded the base case to be once the first wave was over, most places would probably be at or close to herd immunity. 

Well, experts now agree:  https://www.yahoo.com/news/experts-no-longer-expect-seasonal-210100113.html

–So we will expand a little more.  See that coast to coast green map above?  Even if there are local/regional flares as schools re-open over the next couple months (at worst), those of you stateside will be able to vote in person in November.  Safely.

I say that not as a political statement (I’m voting for Kanye, and may God preserve the glorious Union), but solely as my opinion based on the current, and my expected, rate of transmission of the virus in the US over the next couple months.

–The Rt and the “sea of green” leave me unconcerned by the timing of any coronavirus vaccine. 

–That said, avoid complacency.  Especially if you are in a high risk category.  We are not at herd immunity yet.  The single biggest risk factor, independent of age, is your weight:

Continue to take healthy steps, eating right, sleeping right, exercising.

–Probably a good time to mention the first four weeks with the Zoe app, from the “personalized nutrition” study I participated in as a research subject, are in the books.  You may be interested in my experience, and the data I collected, and you can find it here.

–Finally, a reader submitted an article on hydroxychloroquine and the initial studies behind it.  I am not going to link the article itself, because I think it is too conclusive about hydroxychloroquine where the actual clinical trial results are mixed.  However, the article mentions a paper showing that the initial “petri dish” experiments that suggested HCQ might work may have not been using the best possible model.

Look, models of all kinds, from mathematical models, to biologic models of various diseases, are all wrong.  ALL of them.  Some are useful. 

Some of the OGs on here got an absolute rant from me in December on the shortcomings of the way we model cancer preclinically to decide which drugs go forward, and how we are probably missing some very good drugs.  Mostly because we don’t have many good models of cancer metastasis, and do not routinely look for anti-metastatic effects.

There is also a reason this cartoon, this specific cartoon hangs in every cancer research lab that I have been in:

https://imgs.xkcd.com/comics/cells.png

That’s not limited to cancer drugs.  The petri dish models, even the mouse models, for nearly every disease you can think of have limitations.  You will frequently cure cancer in a petri dish, and/or in mice, and then have that same drug fail gloriously in human trials.

Every model is wrong.  Some are useful.

The usefulness of these models, and why we still do them, is their negative predictive value.

If you think, for example, that HCQ will stop SARS-CoV-2 from replicating in infected cells, you can test that fast and cheap in a petri dish with some cells.  If HCQ cannot stop SARS-CoV-2 in a petri dish, the chance that it will stop SARS-CoV-2 in a person is tiny.  Not impossible, since cells in you are in a very different environment than a petri dish, but tiny.  So you are probably better off testing something else.

So the new publication shows that the early HCQ excitement was generated by petri dish experiments using rat kidney cells.  These are common for this kind of work.  But like all models, they are wrong.  “Not human” and “not lung” come immediately to mind.  The virus can replicate in them though, and HCQ blocked that replication.  The authors of the new publication showed that SARS-CoV-2 has a Plan A and a Plan B to get into new cells it wants to infect.  HCQ blocks Plan A, and importantly, rat kidney cells don’t leave it an option of Plan B.  Human lung cells can be invaded by Plan A or Plan B.  Using human lung cells not available to the first round of HCQ researchers, they found HCQ stopped SARS-CoV-2 from using Plan A on human lung cells in the petri dish–but the virus was able to use Plan B, and got around HCQ in human lung cells!

Does this explain the mixed clinical results with HCQ?  It helps.  Would that have stopped HCQ trials before they started?  Tougher question.  Again, even the human lung cells in a petri dish are imperfect.  What if, outside the petri dish and in you, Plan B was less available to SARS-CoV-2 than the petri dish makes it seem? HCQ is cheap, widely available, and has a known safety profile.  Someone would probably have taken the rat kidney cells results, damned the human lung cell torpedoes, and gone full speed ahead into at least a small clinical study.  With no alternative treatment, known risks (versus a completely new drug whose side effects might not be fully known yet), an improbable chance of wild success might have been enough. 

The new publication and the article covering it both fairly conclude that new preclinical, petri dish studies of SARS-CoV-2 should probably focus on human lung cells though.

–The article does mention another important issue.  The “covidization” of research, where a large number of scientists have rushed to get anything and everything COVID related out–even coronaviruses, antivirals, epidemiology etc. are far out of the realm of their usual field.  So an example would be HIV experts who want serial viral load testing to see how the virus is responding to a drug, because they can do that with HIV.   But HIV is a different virus, present for life, and not cleared within a week or two by most patients, like SARS-CoV-2.  Further, HIV is sampled in the blood, where it lives, while SARS-CoV-2 is sampled where it lives in the body by oral/nasal swab, bronchoavleolar lavage, or even spit testing in some newer methods coming out.  The accuracy of the “count” of virus cells is very different in all of those settings.  That may not stop some researchers from applying a model they are used to (HIV) even though it is not really appropriate for SARS-CoV-2, which is a different disease and virus.  Or using rat kidney cells because you have them and know them, and not testing human lung cells.

This has also plagued the literature in terms of various “rare” medical complaints associated with SARS-CoV-2.  Think back to our discussion of the “neurological disorders” following SARS-CoV-2 infection.  They only confirmed SARS-CoV-2 in what, half of them?  Even among the confirmed cases, some of that could very well still be coincidence.  It is absolutely possible that your first symptoms of schizophrenia will happen around a coronavirus infection right now.  Not because the coronarvirus caused schizophrenia, but because some people will get schizophrenia symptoms showing up for the first time this year and a lot of people will get SARS-CoV-2.  Those circles will inevitably cross on the ol’ Venn diagram–through nothing more than coincidence, random chance, and sheer force of numbers on the coronavirus side.  Be appropriately suspicious of all the many syndromes that pop up as “caused” by coronavirus.  We won’t sort out what was actually due to the virus (or the immune response to the virus) completely for some time.  Anything and everything will be published right now though, especially if you have a test that showed SARS-CoV-2 happened to be present right then and there in the patient.

Also remember our list of key takeaways from John Ioannidis’ “Why Most Published Research Findings Are False” paper.  Among them is that the “hotter” and newer the field, with more papers being published as fast as they can, the greater the chance that any given paper from them is wrong.  In part through random chance causing a finding to appear true, but also because the rush through to publication means preliminary results are more likely to be published before getting fully fleshed out.

This is going on in COVID research right now.  Absolutely.  And also in news reporting on COVID.

–Speaking of stepping out of their depth, I had hoped to not have to cover this, and it would stay Twitter rumor.  Then late this afternoon the following article popped up on Yahoo: 

https://www.yahoo.com/news/most-of-the-coronavirus-tests-the-us-does-are-worthless-but-theres-a-solution-that-could-actually-work-and-stop-the-spread-154815346.html

A couple things.  Yes, PCR is the gold standard for both specificity and sensitivity for SARS-CoV-2.  Yes, turnaround time has slowed because of demand, to the point that using it to trace cases is worthless.  But, as we have discussed, but the article has not, PCR is best reserved for patients sick enough to go to the hospital to allocate resources.  If you are sick, but not hospital sick, a SARS-CoV-2 test doesn’t change what you should do–stay home until you are better and warn everyone else.  If you are asymptomatic, a SARS-CoV-2 test shouldn’t change what you do, which is reasonable social distancing already anyways.  Plus, it’s not clear that asymptomatic people can even spread the virus where testing asymptomatic people is really all that useful, short of epidemiology purposes.  I would contend that a lot, if the not the majority, of the people currently being tested don’t really need to be getting tested, at least not from a symptoms and medical utility standpoint.  The article’s argument that you cannot effectively contact trace and isolate to control the spread with PCR is a fair one.  But as we have said, you are LOOOONG past the point where you contact trace this away anyways.  It’s simply too widespread.  The idea that we need rapid daily testing, at home, of the entire US population because we can contact trace and isolate to control the spread is ludicrous. 

This is the common cold.  It spreads like the common cold.  It is everywhere now, like the common cold.  You cannot contact trace away the common cold. 

Especially not with a test that is less accurate.  Now, I agree with the guys proposing this that, in theory, a less sensitive, but rapid antigen based test is fine.  You don’t need the 98%+ sensitivity of PCR (that can be a confirmatory test).  If it works at even 90% sensitivity, that may be good enough.

What the article misses, what the geniuses proposing this miss, is that sensitivity is not the problem with this approach.  It’s specificity. 

You are going to bring an antigen based test, which is NOT gene level identification, to a coronavirus.  Whose cousins are the common cold, and are everywhere.  Your immune system does antigen based testing–as we have mentioned, many people are likely resistant to coronavirus because there is enough cross reactivity among coronaviruses for those key antigens that the T-cells that beat one of SARS-CoV-2’s cousins can be repurposed to beat SARS-CoV-2.

In an antigen based lab test, that cross reactivity leads to what we call a “false positive.”  The test will tell you that you have SARS-CoV-2.  What you really have is a non-SARS-CoV-2 cousin that is juuuuust close enough to fool the test, and NOT SARS-CoV-2.  On top of that, we are expecting everyone to do the test exactly right and interpret it properly.  It’s great that they brought up home pregnancy tests as an example of these antigen based methods–there are people that misread their home pregnancy test.  People testing themselves at home will ABSOLUTELY misread this rapid SARS-CoV-2 antigen test too–I guarantee it.  So you will have false positives for that too.  But pregnancy tests are highly specific for pregnancy–in women of child bearing age.  There are conditions (mostly rare tumors) where men can produce enough hCG to pop a pregnancy test positive.  Perimenopausal women can produce enough hCG as part of The Change to sometimes pop a home pregnancy test positive too.  All of this is to say that the specificity of the assay depends on the patient population you are testing.

EVERY positive home pregnancy test in a male is a false positive for pregnancy (what you have detected is most likely a tumor).

So in someone taking this new test who has already been exposed to, and beat, SARS-CoV-2, but doesn’t know it (as a huge proportion of the population will be)–well, I would argue most, if not all, positives in those patients will be false positives. 

We will have no idea who they are.

But let’s just crush this idea with math.  We will assume that our antigen based SARS-CoV-2 test is 90% sensitive, and 99% specific.  That’s a pretty specific test, assuming that target antigen has almost NO cross reactivity with other viruses, coronaviruses especially, that might be out there.  Arguably best case.

300 million Americans wake up tomorrow and take this test.  1% of them actually have SARS-CoV-2:  3 million people.  The test detects that in 90% of them (2.7 million true positives).  Yay test!  Of the 297 million people who do NOT have SARS-CoV-2, the test gives them a correct negative 99% of the time.  So 294,030,000 Americans breathe easier (no pun intended)–at least for today. But that means 2.97 million Americans just got a false positive.

That’s right–at 99% specificity, if you test every American, even if you test POSITIVE with this test, the odds are actually BETTER THAN NOT that you do NOT actually have the virus!  (48% chance you actually have the virus with a positive test, to be specific)

In fact, our assay just picked up 5.67 million new cases in a single day (a little less than half of them real!).  For comparison, there were only about 260,000 new cases reported in the entire world today. 

This performance gets worse if you continue to screen everyone, but the virus is running out of hosts.

Now 300 million Americans wake up tomorrow and take this test.  Half as many of them as our previous example actually have SARS-CoV-2:  1.5 million people.  The test detects that in 90% of them (1.35 million true positives).  Yay test!  Of the 298,500,000 million people who do NOT have SARS-CoV-2, the test gives them a correct negative 99% of the time.  So 295,515,000 Americans breathe easier (pun intended now)–at least for today. But that means 2.985 million Americans just got a false positive.

Now, there is only a 31% chance that your positive result with this test is real, and you ACTUALLY have SARS-CoV-2.

How long do you think a test like this will really be used?

What of all those “false positives”?  Will they continue to screen themselves with this after they “got the ‘rona” and “got better”?  Didn’t this antigen test tell them so, even if it lied to them?

How is this a solution, restoring faith in government, and defeating the virus once and for all, unless it is the single most specific clinical assay in history–interpreted properly, performed properly, at home, by regular people?

The article, and the advocates of this method, are focusing on the wrong metric.  Sensitivity is not the major hurdle when you are talking MASSIVE screening for what is still a fairly rare disease (assuming our estimate of about 1% of the population per week actually getting it).

Specificity is the issue, and will be a challenge with this method.

Even then, you are too far gone for contact tracing to work. 

–Your chances of catching Ebola are slightly worse than your chances of catching Lassa fever.  Don’t play with mice in West Africa.

–Your chances of catching plague still exist.  Don’t touch dead marmots.  Or squirrels in Colorado.  Or anything, really, in the DRC.

–I know I make jokes in this section.  After all, covering various forms of epidemic and pandemic disease is pretty bleak–even for a pathologist.  A brief, light summary of the chances of the disease actually coming to you or yours always seems a good way to wrap.

My friends, now is not the time for jokes.

It’s back.

They’re back: 
https://www.thetimes.co.uk/article/safari-park-baboons-armed-with-knives-chhx8lf3l

The chances of you catching coronavirus this week are equivalent to the chances that you were NOT prepared for the return of the Army of the Bioterrorist Monkeys…

….but Jane Goodall was.

<Paladin>