The board exam went well–thanks for asking.

Ebola:

–Up to 98 confirmed cases, but this is likely an undercount.  Most Equateur Province now has at least one case.  Strikes among response workers mean that alerts, sample testing, and case and contact tracing are being under-reported.  Three treatment centers remain over capacity, and at least 7 patients with Ebola are still being treated in community health centers, and not the specialized treatment centers.  On the plus side, a little under 24,000 people total have been vaccinated so far, which is probably the only thing preventing exponential growth.  As it stands, the outbreak is likely to continue to at least muddle along, but travel down the Congo at some point remains very in play.

Coronavirus:

–Still plenty to talk about here too.

–Let’s start with this morning’s news, this week’s breakthrough testing innovation.  This comes courtesy of Abbott, on their BinaxNOW system.  This is the “$5, 15 minute” test in news reports this morning.  This still requires the equipment and a medical lab to do the testing.  Unlike last week’s gamechanger, this is antigen based assay.  Recall that PCR will look for the “genetic fingerprint” of SARS-CoV-2, and is very specific (and sensitive) for SARS-CoV-2.  Antigen tests, as we discussed before, have greater chance to recognize coronarviruses that are NOT SARS-CoV-2–a “false positive.”

In the testing submitted for their FDA EUA (available online at the FDA website), is at least 98.5% specific when compared to a PCR based method for SARS-CoV-2.  Their official, FDA approved intended use statement makes clear that the BinaxNOW assay does NOT discriminate SARS from SARS-CoV-2.  Which is fine.  The original SARS has not been heard from in a long, long time that we should worry much about that particular cross-reaction. 

But buried further down in their EUA data are a couple other little gems.  

First, they did look to see if the sequence of the antigen (protein) the test detects cross reacts with other coronaviruses too.  Specifically, they looked at MERS-CoV, which is a close cousin of SARS and SARS-CoV-2, and they looked at another human coronavirus, HKU1.  “Sequence of the antigen” is a fancy way of saying “looked at the order of amino acids.”  The more similar the order of amino acids, the greater the chance the test will cross react.  So MERS-CoV is a little over half identical to SARS-CoV-2 for this antigen, and HKU1 coronavirus is a little over a third identical.

“Is that enough for the test to cross react?”

No idea!  Depends on what specific part of the antigen is critical for the BinaxNOW test.  If it’s the part that’s identical among all those coronaviruses, that could be a problem.  Even then, the sequence is only part of the story.  Remember, the antigen is a protein.  Proteins work because they take a specific shape.  Don’t worry about the colors, but just take a look at the shape of the red, white and blue blobs in the figure below:

That figure is from a 2014 paper on the shape of nucleocapsid of coronaviruses, including the original SARS-CoV.  Again, this is the antigen used by the BinaxNOW assay.  See how it’s the same “blob with a handle on the right” shape for all the different coronaviruses in the figure?  They all take a similar shape because the nucleocapsid protein does roughly the same thing in all coronaviruses, even though the sequence of the nucleocapsid protein is a little different among them all.

The reason all this shape stuff is important is because BinaxNOW will recognize SARS-CoV-2 not by looking at the sequence of amino acids (unlike PCR, which looks for a specific genetic sequence) but by the shape of the nucleocapsid antigen.  To be specific for SARS-CoV-2, the BinaxNOW will have to be able to recognize the blob and handle that is different from the OTHER blob and handles in the figure above.  It’s possible to do that, if the test looks for a unique enough part of that shape.  But those shapes are all so broadly similar that the BinaxNOW may not always be able to pick SARS-CoV-2 out of the lineup. 

If the BinaxNOW assay CANNOT do that, it will have a false positive problem.  It will tell people they have SARS-CoV-2, when really, they may just have a common cold coronavirus present.

The best way to check that the BinaxNOW is well trained to look for ONLY the shape of the SARS-CoV-2 nucleocapsid antigen would be to get a bunch of other coronaviruses and test them with the BinaxNOW.  Sequence comparison on a computer is nice, but it’s not that real world, proof of shape recognition that is needed to determine how accurate the BinaxNOW will be.

If that test was done, the results are not in the publicly available data for the BinaxNOW.  It is not immediately obvious why that test would NOT be done (either by Abbott, or at the insistence of the FDA), nor immediately obvious why if it was done, the results are not part of the EUA disclosure.
You can go back to my recent updates for the consequences of a test taken by a lot of people, even with low false positive rates.  It takes a shockingly low false positive rate to make a “positive” result by the test a coin flip (or worse!) as to if you truly have the virus or not.

That said, this Abbott test has a role.  It is reasonably sensitive to detect a coronavirus, and a good use of this test would be to rapidly screen people.  It will pick up most people with SARS-CoV-2, but the problem is it may pick up other coronaviruses as well.  So you use this test as a screen.  Anyone who is negative is pretty likely to be negative for SARS-CoV-2 (or at least at -really- tiny viral load).  But you can then do the slightly slower, but much more SARS-CoV-2 specific PCR, to see if all the positives on the BinaxNOW have SARS-CoV-2 or some other coronavirus.  That still gets most of your negatives ruled out pretty quickly, and reduces the testing load on the PCR, focusing the PCR on the patients most likely to have the virus, where the test is most appropriate.  So still useful–if used appropriately.

We’ll see how appropriate the use turns out to be.

–Speaking of false positives, they have consequences too.  We already discussed the governor of Ohio getting a false positive antigen test earlier–that required two separate negative PCRs for him to clear him.  Just in the news this week is the NFL temporarily suspending testing with a NJ lab it contracted for rapid SARS-CoV-2 tests, after that lab discovered it had a contamination problem and 77 players were given a false positive result.  Sweden also reported today that something like 2,300 false positives were reported there, when a kit they purchased from China turned out to be less accurate than advertised.  That doesn’t affect Sweden’s numbers too much–but that’s 2300 people that may have been taking fewer social distancing precautions, figuring they already had it, and thus were at less risk to get the virus again (really, for the first time) or spread it to others.

–In terms of risk of getting the virus again, there are still occasional reports of people getting SARS-CoV-2 again.  Most of them appear to be similar to one of the more recent cases.  This was a guy in Southeast Asia who got the virus in March, with full COVID symptoms, but got better.  He recently traveled out of the country he lives in, and returned.  On return, he was screened in the airport and popped positive again.  As you might suspect, the second positive was for a slightly different strain of SARS-CoV-2.  But he never developed symptoms from this second positive result–his immune system had it under control.  This second strain was also the mutant that generated all the doom headlines lately as “10 TIMES MORE CONTAGIOUS THAN ORIGINAL SARS-COV-2!  OMG IT’S MUTATED!  WE IZ ALL GONNA DIE!”  That strain does appear to be more contagious, but consensus is that the disease itself is much less severe with this particular mutant.

–So this raises the question of if this guy really had SARS-CoV-2 reinfection on the second test.  After all, he had no symptoms and finished quarantine with subsequent negative tests having never developed symptoms.  Remember, antigen test or PCR test, all they tell you is if SARS-CoV-2 is there.  If the patient is sick with symptoms of COVID, pretty good chance SARS-CoV-2 is responsible.  But it’s possible this guy just dropped his mask for a moment on the plane or in the airport and was unlucky enough to inhale just enough SARS-CoV-2 to pop “positive” a second time–even though he did not get COVID (the respiratory disease caused by SARS-CoV-2) a second time.

–That conundrum is also why the CDC advised earlier this week (only to walk back some today) that asymptomatic patients, even if a known contact of a SARS-CoV-2 patient, don’t need to be tested if they do not wish to be.  This is something we have said in these updates for awhile–medically, the test result doesn’t change what you do as a known close contact of a SARS-CoV-2 patient.  If you have symptoms, particularly symptoms severe enough to go to the hospital, yes, the test is important because it changes your treatment.  Otherwise, we have a lot of tests for curiosity clogging the system and creating longer turnaround times for patients who actually need them.

–Indiana, for example, is moving to keep more of its testing within the state to improve turnaround time by shortening travel time for the specimen to the lab.  As we mentioned before, this is one of the major bottlenecks for turnaround time right now.

As a result, we are back doing limited testing for the state of Indiana again.

–Even though Indiana is muddling along at a plateau, and the Rt is at or a little less than 1.  Much like the rest of the nation.  Iowa and the Dakotas are the only areas of concern for a legit spike in cases right now.  Here in Indiana, it is the rural counties that are seeing most of the action–Indianapolis and its suburbs are at or below 5% positivity.  At least in the States, the numbers suggest a fire nearly extinguished.  A lot like a fire that is mostly white-grey ash and charcoal black wood, where the flames are out, but the heat remains.  What I see in the US data is that last big exhale over that fire, where some of the white-grey portions criss cross in glowing red-orange as your breath washes over them, and a few are just near enough unburned, though black wood, to sprout those last, temporary licks of flame. Once those die, though, only the slow and fading heat and ash will remain.

And life will move on, absent a SARS-CoV-2 fire.

We’ll have S’mores in its memory.

–But going back to reinfection.  Recent studies in monkey models of SARS-CoV-2 shows that following infection and recovery from SARS-CoV-2, there is, indeed, an effective immune response that stops the monkeys from getting sick from SARS-CoV-2 again:  https://science.sciencemag.org/content/369/6505/812

So true reinfection in humans is likely to be pretty rare, if it happens at all. 

–That also implies that once the first wave is over, and herd immunity is reached, your local area is not likely to see a whole lot of SARS-CoV-2 activity again.

–Speaking of which, Sweden’s numbers continue to stay low, and suggestion they may be at or near herd immunity is increasing:  https://www.marketwatch.com/story/sweden-has-developed-herd-immunity-after-refusing-to-lock-down-experts-claim-its-coronavirus-infection-rate-is-falling-2020-08-24

–Other places, not so hot.  Despite South Korea’s early containment success (which we talked about back in March/April–no one tested more, faster, than South Korea and they traced pretty effectively too), and continued mask protocols etc., new cases are rising there.  South Korea closed schools after its 12th consecutive day of increased cases. 

Some places still have a full stick, or good part of a stick, that the fire has not yet touched.  It will.  And then these too will subside.

–In the meantime, treatment and vaccine efforts continue.  Not too much to say on convalescent plasma.  This is a kitchen sink treatment that has been going on since March/April.  To do it, you needed a recovered patient, who you could prove via testing no longer had the virus, and could prove via testing was making SARS-CoV-2 antibodies, and could prove via testing that those antibodies neutralized the virus, and then could prove via testing that the plasma would not cause a transfusion reaction in the sick patient you wanted to treat with convalescent plasma.  The idea is to take the antibodies in that recovered patient’s plasma and give them to a sick patient in the hopes they would tie up enough virus to make the disease less severe.  The challenge is getting all of that testing done, and then done in time while the patient was still early in the infection where the plasma could make a difference.  The controversy is really over how many of those steps, and in how much detail, are really needed for a kitchen sink treatment.  I still think the logistical barriers to getting donors identified, donations collected and the minimum safety testing still necessary are high enough that convalescent plasma will still be a pretty uncommon treatment for SARS-CoV-2.  For what that’s worth.

–And in unrelated, but still medical news that may one day affect you:  https://www.linkedin.com/pulse/california-doctor-out-jake-novak/?fbclid=IwAR36h1qenXXZ_2vezcyFB78t0sFFSiOJ6yF4XuAhPvUN29xEhOf7hqdxz4Y

–Your chances of catching Ebola this week are remote, but still very much exist.

–Your chances of catching SARS-CoV-2 remain good in many places in the world, some places better than others.

<Paladin>