Ebola–

We are at 46 confirmed cases, with another health zone and more health areas being affected (so a slightly larger geographic region in the DRC).  Contact tracing remains inadequate.  Several of the confirmed patients remain in the community.  They have lost contact with several high risk close contacts.  The Ebola Treatment Center in Bikoro is nearly entirely full and a nearby general hospital is reported to be overcrowded (note:  this may be COVID and other disease–is not overcrowded with Ebola).  But they managed to vaccinate a few hundred more people in what looks suspiciously like a ring pattern, which you should read as “doomed to failure at this point.”  On the plus side, 11,237 people have been vaccinated, and the increase in cases remains slow, and not an exponential boom.  For the time being.  I suspect we will be updating on Ebola for many weeks to come though.

Bubonic plague– 

Thanks to everyone who sent the articles about the squirrel in Morrison, Colorado that tested positive for bubonic plague.  Morrison sits on the I-70 loop around Denver, on the west side, but has only about 400 people living in it.  Morrison’s big claim to fame is to be just south of the Red Rocks Park and Amphitheater.  It also abuts Mt Glennon park and is within reasonable rodent transmission distance of two large Denver golf courses.  That said, again, in this area, it’s not unusual to see bubonic plague.  It is endemic in this part of the United States–you can see the full range here:  https://www.cdc.gov/plague/maps/index.html  The one case in Illinois was a laboratory exposure, for the record.  So far, no reported cases in humans in Colorado.

DO NOT TOUCH DEAD RODENTS, ESPECIALLY IN THE WESTERN US, AND ESPECIALLY AROUND MORRISON COLORADO RIGHT NOW.

In news of actual human cases of bubonic plague, there appear to be two separate outbreaks around Mongolia.  One is a single case in an older farmer type who is apparently doing well on treatment.  There other is apparently three teenagers who ate marmot meat.  One of them recently died, having lost the war before the antibiotic battle could begin–the other two are responding to antibiotic therapy.

AGAIN, DO NOT TOUCH DEAD MARMOTS. 

Coronavirus–Again, I will be sticking to the high points.

–First, the White House wresting data reporting away from the CDC to HHS, and thus under more direct control of the executive branch does not make a great deal of sense to me.  The CDC has made mistakes in the response to the coronavirus pandemic, of that there is no doubt.  Falsifying data, particularly to somehow embarrass the current administration, is not one of them.  For example, hospitalization rates remain largely stubbornly flat, despite rising nominal cases.  The death rate (again, national average–your local will vary a bit) remains largely flat.  Those, on face to me at least, appear to be supporting the more frequent claims of the executive branch.  If there was some obvious deficiency in the data collection and reporting resulting in misinformation being spread by CDC, that case should be clearly made, and might justify this new reporting structure.  Otherwise, it will look (and be interpreted) by a sizeable portion of the population as controlling the data for political purposes.  When you have a response that has been marred by deliberate lies about masks to the general population (by Dr. Fauci, who admitted he felt compelled to lie to ensure supply for doctors and nurses early in the outbreak, but lied nonetheless), schizophrenic pronouncements by every level of local, state and national government, retractions of major studies on controversial treatments, making a move that would undermine confidence in COVID cases and outcomes for many is, well, not ideal.  It’s just more fuel to the fire that no one in charge, anywhere, has any idea what they are doing, and nothing is reliable.

This, exactly this, is why we are all Sweden now.

–In fairness, at least in Florida, there are problems with the data though.  Serious enough that I am not sure how many cases Florida actually has, and what their true positivity rate is.  But, there are definitely hospitals there getting overwhelmed, including by report today, Miami-Dade county.  So we can safely assume “a lot” still for Florida.  Projecting when they will turn the corner on the current outbreak is tough.  This error, which included issues like counting 100% of COVID test results as positive at the state aggregation level from some labs (they were not actually that high), and others as 98% positive and like 76% positive (which turned out to be 9.8% and 7.6% positive when reporters called the actual labs), also makes it tough to tell nominal positives and positivity rate at the national level.  Florida has been up to 25% of the entire US’ positive cases on some days recently, and that appears to be a bit of an overestimate.  How much of an overestimate and for how long is tough to say.

–That said, cases in the US overall continue to go up nominally.  The positivity rate is tracking up.  The death rate is ticking up.  These all remain VERY slight increases and WELL below March/April levels, even in many of the most heavily affected states.  Arizona appears to have hit its peak–new cases there have been falling since early this week.  That’s probably a little early for the new gym/bar measures to be driving that, but they will help bury this delayed first wave.  Texas looks to be right at the top, and I suspect they will announce a few extra measures soon.  Cali continues its long slow march higher though.  Alabama has become a new hot spot. 

–For US numbers, even though Florida is over-estimating, I still firmly believe the current numbers of active cases of SARS-CoV-2, counting people who are asymptomatic or have only very mild symptoms, is significantly undercounted.  The big national labs, given the broad mild increase in cases and tests across the US, are back up to an average 7-10 day turnaround time.  I cannot tell you how many times I have heard in the past two weeks that people with known exposure or mild symptoms have gone to get a test and one of the places sending to the national labs (like a CVS) has told them to expect results in 7-15 days.  If you are asking how getting a test result 15 days later for a virus with a quarantine period of 14 days helps, the answer is “it doesn’t.”

Unsurprisingly, many of the worried contacts and “walking wounded” are just not getting tested in the face of those turnaround times.  Some of them are positive, and are not being counted in the current numbers–they will move us closer to herd immunity, so my estimate last week may be dead on, or may be conservative.  We’ll see.  After all, this is the average American citizen at this stage in the pandemic:

—Internationally, you have worsening outbreaks in Hong Kong and Tokyo, among others.  The Eastern European states are seeing increases as well, with masks made mandatory in Croatia, new restrictions in Bulgaria, new daily highs in Romania, and riots in Serbia.  In short, geographic extensions of the first wave and/or aftershocks are not limited to the United States.  Expect things to continue like this.  Brazil, Mexico and South Africa may be at their peaks for the first big wave through.

–So yes, a couple bullets ago I said “herd immunity.”   The big question this week, both reader and in person, was reports primarily from Europe suggesting that herd immunity may be “impossible” as antibody testing in some hard hit regions in Italy suggested that antibodies to SARS-CoV-2 become undetectable in three months. 

Let’s talk about that.  The assumption is that you -need- antibody production to be immune.  I am not 100% convinced that is the case.  Per the coronavirus expert virologist across town here, coronaviruses on the whole do not invoke very strong antibody responses.  I would say that is true based on what I have seen and heard.  There are also more published reports, and news reports on those this week, that match the observation that the less symptomatic you are, the less antibodies you produce–if you produce them at all.  I think a lot of the response is cell based immunity, which relies on “highly trained” virus specific CD8+ T-cells to hunt down and eliminate virus infected cells before they can spew more virus.  We don’t have a good way to test for those and do not do so routinely.  CD8+ T-cells (and similar NK cells) don’t make antibodies to fight off infection.  Vaccines induce antibodies with the idea of having a swarm of antibodies already present, which should lock up a virus before it ever gets into a cell.  B-cells produce antibodies to infectious agents with the same idea–lock up the pathogen before it can cause too much trouble, and “flag” the antibody bound bug to be literally eaten by other white blood cells called macrophages.  Cell based immunity, CD8 and NK style, is more about taking out the virus AFTER it has made it to a cell.

So antibodies–stop the bug BEFORE it gets to a cell

T-cells (CD8 and NK)–stop the bug AFTER it gets into a cell.

Leprosy (remember that one?) is a disease of the immune system picking the wrong option to emphasize among those two.  Mycobacterium leprae and Mycobacterium lepromatosis are the bacteria that cause it–they are cousins of tuberculosis, but can ONLY live inside cells.  What -form- of leprosy you get (traditionally tuberculoid vs. lepromatous) depends entirely on how your immune system chose to fight the bacteria.  If the immune system went cellular immunity (T-cells and NK cells), the leprosy is very confined, bacteria in few number, and rarely gets into nerves.  If the immune system chooses to fight with antibodies, they can’t really reach the bacteria inside the cell, and the disease tends to be more widespread with more bacteria and more nerve damage. 

As a reminder, viruses HAVE to live inside cells.  Antibodies can block them from getting into new cells (so your body will make them), but often as part of a balanced response including CD8/NK cells, or biased towards those CD8/NK cells. 

So in a virus like this coronavirus, cellular immunity may be VERY important for resistance and immunity.  We just don’t have as accessible ways of testing it as we do antibodies, and we typically don’t design vaccines for this response, since a swarm of pre-existing antibodies is usually enough to keep whatever virus it is from getting into cells to get you sick in the first place if you are successfully vaccinated.
No/low antibodies does NOT necessarily mean no immunity, or waned immunity!

In addition, the European studies just show gradual loss of antibody titers.  This happens with every infection you get over, and in vaccines.  This is the reason you get booster shots!  When the body doesn’t need a lot of antibody around and is no longer running into that same virus, antibody production goes down.  The body says “haven’t needed these antibodies in awhile–let’s focus on the ones we do need, and mothball this guy.”  To do that, some B cells that make that antibody will be kept “stored” close on hand—for decades sometimes (that’s about how long between most adult booster shots for instance).  If you run into that same virus again, they get hauled out and cranked up quickly so you don’t get sick.  To my knowledge, those studies reporting falling titers did not re-challenge those patients with inactivated SARS-CoV2 or parts of the virus.  If they did, I would lay money that titers in most patients would come back to detectable levels quickly as the right B-cells get called back into action once more.

Further, these European studies also imply that three months after getting the virus, infections are so low in Europe that they are not encountering the virus again.  If the same patient was regularly running into SARS-CoV-2, the memory B-cells would be continually triggered, and would never go on mothballs.  They would be in action more frequently, and the decline in viral titer would not be seen.  That may be because the virus has truly been driven out of those regions of Italy and is no longer spreading there because it just hasn’t been back yet.  Alternatively, it hasn’t been back yet because herd immunity was reached and it can no longer get a foothold when someone with the virus stumbles into those Italian towns.  So if eliminated virus in Italy, causing early “mothballing” of antibodies is not the explanation, another plausible one is that you don’t need a -lot- of antibody to avoid getting sick again, and the immune critical threshold may be below the level of antibody we can reliably detect in the lab.  The virus is still moving at a low level in parts of Italy, but turns out, only a little antibody is necessary to prevent getting sick, and you never see a spike back into the detectable range, even when they run into the virus again.  That is possible, but less likely.

Perhaps the best argument for maintained immunity is states like New York and New Orleans.  These are high traffic, high visitor areas where the virus is likely to be coming back.  But they got hammer timed in March/April.  By now, if the European studies are correct, antibodies should be waning in their populations, and they should be seeing increasing cases in this gradual resumption of the first wave. 

They are not.

In fact, there are really only case reports (few among the millions to have been infected) of patients who have caught COVID more than once.  Some of them are not convincing–a few anecdotes where a low early positive was just the virus present, disease caused by something else, and SARS-CoV-2 got a better “bite” a few weeks later to cause actual COVID. 

All of this said, I will acknowledge I am on one side of a hot debate in medicine right now on what these falling titers really mean.  There are others who feel differently than me.

–So the vaccine of the week was Moderna again, this time with a full Phase 1 study.  You can find it here:  https://www.nejm.org/doi/full/10.1056/NEJMoa2022483?query=featured_home  and I am going to discuss it just a little.  Not too much, because again, competitor, but there are some salient points worth pulling out here.

First, vaccine, like the Pfizer vaccine from two weeks ago, is an mRNA vaccine.  So instead of injecting inactivated virus or part of the virus, the instructions for your cells to make a SARS-CoV-2 protein are injected instead.  They get shown to your immune system; your immune system should make antibodies to it.

This is a Phase 1 study, so the desired outcome is safety and dose.  Again, similar to Pfizer, there was a lot of fever, muscle aches and joint pain, especially at the higher doses (which likely will not move forward in development).  No screaming show stoppers.  Also like the Pfizer vaccine, they present data showing an increase in antibody titers to their target viral protein.  That’s what you saw in the headlines, even though that is not the purpose of this study.  It’s just a “bonus.”  The real goal is safety.

What you did not see was this gem in the methods of this study with the Moderna vaccine:

“Participants were not screened for SARS-CoV-2 infection by serology or polymerase chain reaction before enrollment.”

Now, the authors will probably tell you this is no big deal because the primary outcome for the study is safety and dose.  It is a Phase 1 study; that is technically true.

“But wait,” I can hear you say.  “If they didn’t find out if their volunteers had or got coronavirus, how do they know those antibody responses, and the fevers etc., were from the vaccine and NOT the volunteers catching the actual coronavirus?”

They don’t.  That’s the short answer.  So I will leave it to you as discerning reader to weigh the wisdom of conducting a vaccine trial but not ensuring that your volunteers neither had, nor contracted, the vaccine you were trying vaccinate against. 

But I mention this more for something Moderna did do right.  They measured T-cell responses in their study.  Whether it was vaccine or virus, what they found was that a Th1 response was much stronger than a Th2 response.  That’s a fancy way of saying that the immune system, in addition to making some antibodies, was actually revving up the part of the immune system that is mostly T-cells and NK cells–cellular immunity. 

Now, do I cite this because it happens to be evidence that agrees with where I land on the “cellular immunity may be more important than antibodies” debate?

Absolutely!

I’m as human as everyone else, and if something agrees with my opinion–yeah, that’s the good stuff right there.

But–it doesn’t falsify my hypothesis, and is expected if I am right.  What I would like to see is a bunch of patient samples tested for their T-cell responses (either checking Th1 vs Th2 or if we can find markers for SARS-CoV-2 specific CD8 cells that would be even better).  My suspicion is that in patients with LESS severe disease, a Th1/CD8/NK cell response is dominant.  Similar to leprosy, you may see a difference depending on which direction your immune system goes, and the reason antibody likelihood AND titer seems to increase the more severe disease you got may reflect your immune system “choosing” wrong and going too antibody heavy.  It is tempting to then speculate that your immune system goes Ah-nold when its antibody heavy approach does not appear to be working, it freaks, and just starts carpet bombing.  We’ll have to see how things develop.

–So this in turn leads into the -other- major topic of conversation this week (I am not going to wade into the “send them back to school” debate just yet):  scare articles on lingering symptoms and “permanent” damage.  Some of these claim that for every patient who dies, 18 will have “permanent” heart damage, and 10 will have permanent lung damage etc. 

Those numbers are extremely high versus studies following up on patients a few weeks to months after they are discharged from the hospital or their initial symptoms resolve.   The very best of these that I am aware of show a little under 2/3rds of outpatient cases are back to normal within 2-3 weeks of diagnosis; and about 40% of those requiring hospitalization are back to normal 2-3 weeks after diagnosis.  The common complaints in that period are fatigue, shortness of breath, joint pain and some lingering chest pain.  There is no indication that any of this is permanent damage. 

In fact, I am not even convinced that is unique to SARS-CoV-2.  Since fielding the question from a tastefully named reader earlier this week, it occurred to me to look into what long term, lingering symptoms, if any, are common to pneumonias (severe infection of the lungs similar to COVID) in general, no matter the cause of the pneumonia.  Turns out, there are studies that have been done on this.  Here is one in 576 patients with community acquired pneumonia (can be bacterial or viral) which followed up on symptoms up to 90 days after symptoms first started.  Check out not only the more frequent complaints, but just how frequent they are:

Fatigue, shortness of breath (dyspnea on the chart) and chest pain are all EXTREMELY common 30 days out–and even pretty common 90 days later.  Again, that’s for ANY pneumonia, in article decades before SARS-CoV-2!

And those lingering symptoms are more common, in fact, than the percentage reporting those symptoms lingering with SARS-CoV-2! 

It may just take a bit to completely get back to normal after any rip roaring pneumonia. 

Lingering symptoms may just be “aftershocks” of the immune system plus/minus recovery from a pretty sedentary downtime while seriously ill.  And again, quite a lot of patients are back to normal 2-3 weeks after resolution.  I don’t know for sure if lingering symptoms are more common if you actually needed the hospital, but I would suspect they are.  None of the positive UFC fighters, for example, have had any lingering issues, and none to my knowledge have been hospitalized when they popped COVID positive.  All three people I personally know who got it (non hospitalized) have recovered fully.  We have heard from only one patient who has had lingering low positive test results for about a month and intermittent symptoms with that.  We got contacted by that patient because that patient felt themselves to be a rarity compared to others they knew, and wanted some insight on what might be going on (if we could). 

So again, be cautious with some of the “WORST DISEASE EVAH” headlines and scare articles.  They have a persistently bad habit of cherry picking, or emphasizing only the worst and making the worst seem far more common than it appears to be thus far, with millions confirmed infected worldwide and many millions more on top of that likely also already exposed (and just never knew or never got tested). 

–Your chances of getting bubonic plague remain directly proportional to how often you touch marmots, squirrels in Denver, and other rodents in endemic plague areas.  Don’t touch rodents, especially dead ones, in endemic plague areas.

–Your chances of catching Ebola are equivalent to a squirrel in Denver catching bubonic plague because it picked up a dead marmot in Mongolia.

–Your chances of catching coronavirus are equivalent to the chances someone you know was feeling extra generous with the ol’ Bitcoin on Twitter yesterday. 

<Paladin>