Category Archives: Social issues ( be civil ! )

Welcome to the world of the physician


In a sense, the uncertainty about hematologic complications of the pandemic vaccines is good in that it is a real teaching moment for the public about what docs confront every day — balancing risk vs. reward. 

No drug is without side effects.  No surgery is without complications.  It is good to see the public  wrestle with these things.  

For a very good explanation of what those complications are and the risks and rewards of taking the vaccines please see — 

https://blogs.sciencemag.org/pipeline/archives/2021/04/14/vaccine-side-effects-q-and-a

Even more interesting are the 139 comments found at the end of  the article.  Some are from experts, some are from frightened lay people; as always there are people with an ax to grind.  As is usually the case in medicine, the data are not clear cut and sometimes contradictory.  As is always the case more data would be helpful, is desired and rarely available.  What is particularly interesting to me is the way some very knowledgable people wrestle with the data, interpreting the same data differently.  Welcome to the real world. 

On a more positive note, a friend who teaches at Hopkins sent me the a copy of the eMail below, with permission to share it.  This provides lots of excellent data on the protective effects of vaccination in a  group of people with a fairly high risk of exposure to the virus,  working at a major medical center where lots of very sick COVID-19 patients are being treated. 

35,000 were vaccinated.  Nonetheless 51 became infected at a time of maximum protection (5 weeks or more after the first shot), demonstrating that the vaccine isn’t 100% protective.  But no one ever claimed that it was.

 But only 2 of the 51 required hospitalization.  So the vaccine is effective in preventing serious illness from the virus (2/35,000).  So who cares if the other 49 had the symptoms of the flu.  They don’t and you shouldn’t.  The number of hematologic complications wasn’t stated. There were two at most, as they always result in hospitalization.  

To the Johns Hopkins Medicine community

 

Dear Colleagues,

 

As we continue to monitor COVID-19 infection and vaccination trends at Johns Hopkins Medicine (JHM), we want to share some data about the incidence of infection among JHM personnel following partial and full vaccination.

 

You are considered fully vaccinated, per the Centers for Disease Control and Prevention, two weeks or more after receiving the second dose of a two-dose COVID-19 vaccine regimen and two weeks or more after receiving a one-dose COVID-19 vaccine regimen. This is when the body has had a chance to produce the antibodies and immune response that protect against infection. Before this time, if you have started the vaccination series, you are considered partially vaccinated and you do not yet have the full amount of protection the vaccination provides against infection. While full vaccination has been found to be highly effective at preventing COVID-19, infection (the incidence is very low) is still possible even after being fully vaccinated.

 

We are monitoring the situation to determine how often infection seems to occur after partial or full vaccination, and the severity of those infections.

 

As of April 12, 2021, of the nearly 35,000 employees who were fully vaccinated (14 days or more after a second dose), 51 employees (0.14% of those who have been fully vaccinated) had tested positive for COVID-19. This demonstrates that SARS-CoV-2 infection is possible even after full vaccination, and it highlights the importance of continuing to practice basic infection prevention precautions after full vaccination. The good news is that acquiring COVID-19 after full vaccination appears to be relatively rare and, among these 51 cases, only two were severe enough to require hospitalization. This shows that the COVID-19 vaccine is highly protective against severe disease, hospitalization and death. If you have not yet been vaccinated, please schedule your appointment as soon as you can to protect yourself and others.

 

 

Some very disturbing pictures

Granted that these pictures look like microscope slides containing colored blobs, but once you understand what they show, the implications are quite frightening.

These images are biopsies of various portions of the gastrointestinal tract in a person who had become  symptomatic  three months earlier with COVID-19 from which the person  has now recovered).The green blobs represent fluorescent antibodies binding to the nucleocapsid protein of the pandemic virus (SARS-CoV-2).  They are found in the enterocyte cells which line the inside of the gut.  These are the enterocyte which live for just 5 days before they are shed.  

This is my first shot at getting pictures into my blog, and they do appear blurry (apologies !).  I will try to correct this. All you need view is in the first and second columns of rows a, c, and e as most  of the rest are controls. The pictures are from a Nature paper — here’s a link — https://www.nature.com/articles/s41586-021-03207-w.pdf

 

Why is this disturbing?  Because their presence implies that they have been made continually for the whole three months, as enterocytes are born and die. 

Well maybe it’s an artifact confined to one patient.  Unfortunately similar findings were present in 5/14 cases recovered COVID-19 patients who received GI tract biopsies for clinical reasons unrelated to COVID-19.  The 14 are from a larger series of recovered COVID19 patients (see the copy of the previous post below). Like Reverend Paley’s found watch, the presence of the viral nucleocapsid protein demands an explanation of what had to be present to put it there.

There are a series of requirement for this to happen.  The messenger RNA for the protein had to be made and present, which, in turn means at the least that the viral gene from which the mRNA for the nucleocapsid protein was made must also be present.  What mades nucleocapsid mRNA? The viral RNA dependent polymerase. So the polymerase must be present as well, along with the 3 genes coding for the 3 proteins making up the polymerase.  Not only that but all of the above must have been present in longer lived cells  than the enterocytes.

Defective viruses certainly appear during the course of viral infection (particularly as in AIDS), but it is very scary to realize just how much of the virus must be present and functioning to produce just these findings. Perhaps the fluorescent antibody was really binding to another protein, not from the virus at all.  After all, antibodies aren’t always as specific as we’d like them to be.  

However, the authors did something else which makes this much less likely. They wrote, “In addition, viral RNA was detected by in situ hybridization in biopsy samples from the two participants who were tested for it”

Further scariness:  Pictures e and f show the nucleocapsid protein is present at the far end of the terminal ileum (small intestine) a part of our GI tract which is 22 feet long

So this person although well, was literally crawling with both the viral protein and the machinery necessary to make it. 

Are many more, or all such people who are clinically recovered from clinical COVID-19 excreting infectious virus?  I’m sure people have looked, and if they haven’t they should be. 

I’m going to now insert the previous post on the subject.  It contains a link to the Nature paper, so feel free to follow it and look for yourself.  It contains a lot more detail. 

Is the virus still within you? Will it cause trouble?

Let’s say you’ve recovered from a bout with COVID-19. Is the virus still with you? Could it come back and cause trouble? Given the data in a recent paper [ Nature vol. 591 pp. 639 – 644 ’21 ] — https://www.nature.com/articles/s41586-021-03207-w.pdf, it’s quite possible.

But first a story about my grandmother.  She was born somewhere around the Baltic Sea in 1880 and came to America in 1893.  She died of undiagnosed (hence untreated) miliary Tuberculosis in a University Hospital in 1967.  Just about everyone in Europe in the 1880s was exposed to TB and just like SARS-CoV-2 many if not most were asymptomatic.  Their lungs walled off the organism in something called a Gohn complex — https://en.wikipedia.org/wiki/Ghon%27s_complex.  The organism didn’t die — and probably broke out of the complex as my grandmother aged and her immune system got weaker and weaker.  It is very unlikely that she picked it up by exposure in the 1960’s.  As they say TB is forgotten but not gone.  

Which brings me to the Nature paper.  At first I thought it was great and very optimistic.  Some 87 people from New York City who had symptomatic SARS-CoV-2 infection (proven by finding the viral genome using RT-PCR technique).  The authors studied the antibody responses at an average of 1.3 and 6.2 months after infection.  Although the antibody levels dropped (which always happens) they changed so they bound the virus more tightly.  This is called affinity maturation — https://en.wikipedia.org/wiki/Affinity_maturation.  

So that’s good? 

No that’s bad because it implies that the protein stimulating affinity maturation is still around. The authors note the persistent antigenic stimulation of the immune system is possible because an “antigen trapped in the form of immune complexes on follicular dendritic cells .. . . . can be long-lived, because follicular dendritic cells do not internalize immune complexes”.  

Well maybe, but the paper gives evidence for another mechanism of antigen persistence (which I find more persuasive). 14 of the people had intestinal biopsies for appropriate clinical indications (see Table 7 in the supplementary information of the article). In some of the biopsies they detect viral antigen in some of the enterocytes (cells which line the inside of the gut) — I’m assuming the antigen is the viral spike protein, but it’s hard to find exactly what it is. 

This is quite bad, as the lifetime of the enterocyte is 5 days.  This means that the antigen is being continually produced, which means that the mRNA for the antigen is being continually produced, which in turn means that the viral genome is still around.  The mean lifetime of cellular mRNAs is 10 hours although some hang around for days, however I doubt that the mRNA responsible for the viral antigen had lasted for 2.8 to 5.7 months which is the time after clinical infection when the biopsies were done. 

So it is possible, that like TB in the Gohn complex, the immune system has fought the virus to a draw, but that the intact organism could be still present.  As in my grandmother, it is possible that the virus will reappear as the immune system weakens with age (something that happens in all of us). 

In that case we wouldl have recrudescence not reinfection. 

PS:  My grandmother came to this country at age 13 alone and speaking no English.  Every time I feel sad at what the pandemic has put us all through, I think of that generation.  

PPS: When she got sick, I wanted to put her in the hospital where I was an intern, but our family GP (Dr. Richard A. Gove) told me taking care of my own family was a very bad idea and put her elsewhere.  I doubt that I’d have made the diagnosis, or that anyone at our hospital would have. 

PPPS:  I don’t know if they still do autopsies, but I was always able to get one after I’d tell families of the deceased about my grandmother.  It meant that my wife and I and our two little kids were all screened for TB. 

PPPPS — a friend brought up the following — Eleanor Roosevelt, who was thought to have aplastic anemia, was treated with prednisone and later found to have died of military tuberculous, probably the recurrence of tb acquired some 4 decades earlier.

 

 

Is the virus still within you? Will it cause trouble?

Let’s say you’ve recovered from a bout with COVID-19. Is the virus still with you? Could it come back and cause trouble? Given the data in a recent paper [ Nature vol. 591 pp. 639 – 644 ’21 ] — https://www.nature.com/articles/s41586-021-03207-w.pdf, it’s quite possible.

But first a story about my grandmother.  She was born somewhere around the Baltic Sea in 1880 and came to America in 1893.  She died of undiagnosed (hence untreated) miliary Tuberculosis in a University Hospital in 1967.  Just about everyone in Europe in the 1880s was exposed to TB and just like SARS-CoV-2 many if not most were asymptomatic.  Their lungs walled off the organism in something called a Gohn complex — https://en.wikipedia.org/wiki/Ghon%27s_complex.  The organism didn’t die — and probably broke out of the complex as my grandmother aged and her immune system got weaker and weaker.  It is very unlikely that she picked it up by exposure in the 1960’s.  As they say TB is forgotten but not gone.  

Which brings me to the Nature paper.  At first I thought it was great and very optimistic.  Some 87 people from New York City who had symptomatic SARS-CoV-2 infection (proven by finding the viral genome using RT-PCR technique).  The authors studied the antibody responses at an average of 1.3 and 6.2 months after infection.  Although the antibody levels dropped (which always happens) they changed so they bound the virus more tightly.  This is called affinity maturation — https://en.wikipedia.org/wiki/Affinity_maturation.  

So that’s good? 

No that’s bad because it implies that the protein stimulating affinity maturation is still around. The authors note the persistent antigenic stimulation of the immune system is possible because an “antigen trapped in the form of immune complexes on follicular dendritic cells .. . . . can be long-lived, because follicular dendritic cells do not internalize immune complexes”.  

Well maybe, but the paper gives evidence for another mechanism of antigen persistence (which I find more persuasive). 14 of the people had intestinal biopsies for appropriate clinical indications (see Table 7 in the supplementary information of the article). In some of the biopsies they detect viral antigen in some of the enterocytes (cells which line the inside of the gut) — I’m assuming the antigen is the viral spike protein, but it’s hard to find exactly what it is. 

This is quite bad, as the lifetime of the enterocyte is 5 days.  This means that the antigen is being continually produced, which means that the mRNA for the antigen is being continually produced, which in turn means that the viral genome is still around.  The mean lifetime of cellular mRNAs is 10 hours although some hang around for days, however I doubt that the mRNA responsible for the viral antigen had lasted for 2.8 to 5.7 months which is the time after clinical infection when the biopsies were done. 

So it is possible, that like TB in the Gohn complex, the immune system has fought the virus to a draw, but that the intact organism could be still present.  As in my grandmother, it is possible that the virus will reappear as the immune system weakens with age (something that happens in all of us). 

In that case we wouldl have recrudescence not reinfection. 

PS:  My grandmother came to this country at age 13 alone and speaking no English.  Every time I feel sad at what the pandemic has put us all through, I think of that generation.  

PPS: When she got sick, I wanted to put her in the hospital where I was an intern, but our family GP (Dr. Richard A. Gove) told me taking care of my own family was a very bad idea and put her elsewhere.  I doubt that I’d have made the diagnosis, or that anyone at our hospital would have. 

PPPS:  I don’t know if they still do autopsies, but I was always able to get one after I’d tell families of the deceased about my grandmother.  It meant that my wife and I and our two little kids were all screened for TB. 

PPPPS — a friend brought up the following — Eleanor Roosevelt, who was thought to have aplastic anemia, was treated with prednisone and later found to have died of military tuberculous, probably the recurrence of tb acquired some 4 decades earlier.

 

 

 

The United States lost the battle with the virus by March of 2020

Two papers published this February show that the USA had lost the ability to contain the pandemic virus by early April 2020.  The first paper was submitted in July 2020, the second in August.  They would have changed our perception of what we were up against in late 2020.  Here are links to both — they are not behind a paywall, and a friend who subscribes to neither was able to access them through these links.

The Nature paper is the most damning.  10,000 blood samples from Mt. Sinai hospital in New York City accumulated from February through July 2020 were studied for antibodies to the pandemic virus (whose presence implies previous infection)

Figure 1 p. 147 shows it best, with weekly numbers of tests and cases, in two groups — people attending urgent care and (more representative of the general population) patients who visited the obstetrics and gynecology department and visits for labour and deliveries, oncology-related visits, as well as hospitalizations owing to elective surgeries, transplant surgeries, pre-operative medical assessments and related outpatient visits, cardiology office visits and other regular office and/or treatment visits.

As you might expect the ER patients had a higher percentage of antibodies.  The first PCR confirmed case in the city was 1 March, with 1000 cases by the 15th. 

It was no secret that NYC was in the middle of the pandemic.  What is quite shocking is the number of people with antibodies (hence previously infected with the virus) in the presumably healthy group.  By 5 April 33/326  (10%) of tests were antibody positive, by 19 April 46/241 (19%) where it essentially remained to the end of the study in July.  Game over. Containment impossible. 

The second paper is from Boston where the virus genomes were sequenced from March through May of 2020.  The sequence of the viral genome tells you where the virus was coming from.  There were 120 separate introductions of the virus into the Boston area.  Most were from North America.  But of those from elsewhere how many do you think were from Asia?  Amazingly only 3.  How many from Europe?  19.  It’s like Wile. E. Coyote  peering earnestly toward Asia to nab the roadrunner, while a pack of roadrunners from Europe passes him from behind without him noticing a thing. 

It isn’t the fault of the authors that this information has just come out this month.  It would have changed our perception of the epidemic and what to do about it Trump or no Trump.  

20/20 hindsight is a wonderful thing.  Here’s Dr. Fauci doing the best he could with what he knew at the time — he is NOT to be faulted to saying this — he changed quickly. 

In the clip, Dr Fauci says “There’s no reason to be walking around with a mask. When you’re in the middle of an outbreak, wearing a mask might make people feel a little bit better and it might even block a droplet, but it’s not providing the perfect protection that people think that it is. And, often, there are unintended consequences — people keep fiddling with the mask and they keep touching their face.”

Fauci made this comment on an interview with 60 Minutes on March 8, a time when NYC proven cases were surging from 1 to 1000. 

Our vaunted intelligence service and the ‘situation room’ either did  not know or did not tell Dr. Fauci about the fact that the dean of a Hong Kong medical school wrote an article in the South China Morning Post 27 January 2020 stating that  “research shows self-sustaining human-to-human transmission is already happening in all major mainland cities.”  For details please see https://luysii.wordpress.com/2020/01/27/what-to-do-about-the-wuhan-flu/

Here are the links to the two papers cited above  https://www.nature.com/articles/s41586-020-2912-6.pdf

and https://science.sciencemag.org/content/sci.371/6529/eabe3261.full.pdf

Click to access 574.full.pdf

 

600,000 Pandemic deaths in the United Kingdom ! ! !

Yes, 600,000 pandemic deaths in the UK given their attack rate of 182/100,000 and a population the size of the USA (328 million) actually it’s even worse than that because their case fatality rate is 2.9 % and ours is 1.8% — so multiply the 600,000 deaths by 1.6 and you get a million deaths in the UK given their attack rate and case fatality rate (and scaling their population to match ours).

Where are these numbers coming from — the same place that those in the previous post came from — https://coronavirus.jhu.edu/data/mortality, Johns Hopkins. 

Here are the top ten attack rates per 100,000 population from the previous post

181.70, 180.83, 158.39, 155.25, 152.49, 143.61. 142.73, 140.98, 124.72, 118.50

You were asked to guess where the USA, and the UK were.  No the USA is not at the top, but in the middle (hardly great but not as bad as the 500,000 headline would imply).  The UK is at the top. 

Here are the 10 countries (alphabetized) from which these rates were drawn

Czech Republic, France, Italy, Mexico, Peru, Portugal, Slovakia, Spain, United Kingdom, USA

Here are the case fatality rates (in percent) from the same 10 countries

8.8, 3.5, 3.4, 2.9, 2.3, 2.2, 2.1, 2.0, 1.8, 1.7

The UK is 2.9 and the US among the lowest at 1.8  

Not what you’ve likely been led to believe.  

There are worse problems afoot for the USA.  Granted the following  are 3 small and nonrandomized samples, but the minorities who need it the most aren’t getting the vaccine (and not because it is being withheld from them).

Sample #1 Yrs Trly and wife second shot yesterday —

My wife and I received the booster dose of the Pfizer vaccine today. We live in a town that is 45% Latino (mostly Puerto Rican). Both times we were there, the vaccinees were almost all Caucasian, a disaster in the making. The nurse I spoke with said that what we’d seen about Latinos not getting vaccinated was typical in her experience. She also noted misinformation going around among them, such that vaccination would make you sterile.

Sample #2 a friend who was vaccinated elsewhere (but in the same metro area)- “That was my experience at the State Curative site at XXXXXXX. Large African-American population in that area; however, only caucasians getting the vaccines on both occasions. Puzzling.”

Sample #3 a college classmate and friend –Welcome to the club. I received my vaccine through Hopkins as a practicing clinician. My wife received hers as a DC resident through the DC Government in a Black neighborhood; all of the vaccinees there were whites from Foggy Bottom and Georgetown. the DC Government then got smart and has been allocating vaccine by specific neighborhood.

Now there was a giant article in the 4 January New Yorker by Lawrence Wright blaming the magnitude of the pandemic on Trump’s not pushing mask wearing. 

Well here’s our Vice President — https://abc7ny.com/vice-presidential-debate-vp-2020-kamala-harris/6852144/

Harris was asked if Americans should take the vaccine and if she would. Harris says that if doctors “tells us that we should take it, I’ll be the first in line to take it, absolutely. But if Donald Trump tells us that we should take it, I’m not taking it.”  Well he did tell us exactly that. 

Is it her fault that minorities aren’t taking the vaccine?  Don’t wait for the New Yorker to take up the issue. 

 

500,000 US deaths from the pandemic ! ! !

My wife and I received the booster dose of the Pfizer vaccine today. We live in a town that is 45% Latino (mostly Puerto Rican). Both times we were there, the vaccinees were almost all Caucasian, a disaster in the making.

The setup was a marvel of efficiency. The time of vaccination was written on a sticky, which was to be placed on the (widely separated) chairs we sat on for 15 minutes, watched by several nurses for any symptoms.  As soon as we got up, someone (a Latino wouldn’t you know) zoomed over and sterilized the chair. The nurse I spoke with said that what we’d seen about Latinos not getting vaccinated was typical in her experienced. She also noted misinformation going around among them, such that vaccination would make you sterile.

I asked her how she though the USA was doing vis a vis other countries, and she said she thought that we were the worst, and quoted the front page of the New York Times of 21 February.

Well, we have two sets of actual statistics available. The first is mortality from the pandemic per 100,000 population and the second is the mortality rate of symptomatic cases (case fatality ratio).

Here are the top ten mortality rates per 100,000 population

181.70, 180.83, 158.39, 155.25, 152.49, 143.61. 142.73, 140.98, 124.72, 118.50

Here are the 10 countries (alphabetized) from which these rates were drawn

Czech Republic, France, Italy, Mexico, Peru, Portugal, Slovakia, Spain, United Kingdom, USA

Here are the case fatality rates (in percent) from the same 10 countries

8.8, 3.5, 3.4, 2.9, 2.3, 2.2, 2.1, 2.0, 1.8, 1.7

Your job is to match the countries with rates based on what you’ve read and what you know.  At least guess where the USA and the UK fit in. 

Answers and further commentary tomorrow 

 

How to get vaccinated early

Here is a completely ethical way to jump to the head of the line and get vaccinated before you should have been. I did it quite unconsciously, taking my wife in for her scheduled vaccination 1 February in the midst of a blizzard whose intensity was impressive even by Montana standards. It was toward the end of the day and the place was pretty empty. I had an appointment for the 9th and my wife asked if I could get in if there had been cancellations (which there seemed to be). So they took me.

This turned out to be ethical because they were administering the Pfizer vaccine, which has to be used after being thawed out or thrown away (it can’t be refrozen). It really is a situation of use it or lose it.

So that’s what you do — go to a place administering the Pfizer vaccine (this won’t work if they’re giving the Moderna vaccine which can be refrozen) and ask there have been any cancellations.  Do this late in the day.

At last something useful from this blog.

Sad thoughts on Montana

Yesterday’s post about all the smart people in Montana (see below) wouldn’t be complete without the downside, which is Montana’s leading export — its smart young people. 

Lindsay’s down in Austin Texas, the physicist has a company making high tech optical instruments for physics research outside Boston, the engineer is out in Utah.

My son’s high school friends went on to Cornell, Harvard, Rice, Stanford, Yale and did well.  None remain in the state.  

Most of their parents were docs , who had to come from out of state (like I did) because Montana had no medical school back then.  

The educational system in Billings back then was superb.  Our son passed his language requirement at Cornell with 4 years of Billings high school French.  He didn’t need to take remedial writing thanks to a fabulous honors English teacher — Lowell Gorseth, unfortunately no longer with us. 

Good as it was, it didn’t stop teenagers from being bored.  One day a bunch of them were moping around in the living room, so I sat down to the piano and made up the “Billings is boring” song which we all sang. 

Here’s the old post 

Montana girl does good, real good !

Montana is flyover country. Nobody smart lives there. We all know that.

But when I got there in 1972 an issue of Science contained an article by State Legislator about a modification of general relativity — https://en.wikipedia.org/wiki/Kenneth_Nordtvedt.  MIT grad, Harvard Junior Fellow etc. etc. 

Then there was the son of a doc I practiced with in Billings.   Honors physics at Billings Senior high school placed him in 2nd year physics at Harvard, from which he graduated in 4 years obtaining a masters in physics as well. 

Then there was a local boy, the Thiokol engineer who predicted the Challenger disaster and was over-ruled. 

The great thing about Montana was that no one ever bragged about this sort of thing.  There were so few people, that no one felt compelled to tell you about themselves, you’d find out about them soon enough.  The classic example was an excellent surgeon and friend I practiced with for 15 years.  Only on reading his obituary last year did I find out that he had a Fulbright after college.

Which brings me to Lindsay, a girl I first met when she was a high school student.  The family were ranchers with a beautiful spread on the east face of the Crazy mountains north of Big Timber.  I’m not sure how we first met — I don’t think I saw any of them as a patient.  But we all became friends and the galactic premiere of a cello sonata I wrote with a 19 year old secretary in a lumberyard was in their living room. 

The two least important things about Lindsay are that she was a centerfold and an olympic silver medalist in woman’s two person crew.  Don’t get excited about the centerfold bit, she was fully clothed, but for some reason the Harvard Alumni magazine had a 2 page picture on a field of daisys of her back in the 80’s when she was there. 

Lindsay went on to get a PhD from Cambridge and her work and that of her husband may have come up with something useful for Alzheimer’s disease.  I’ll talk about the science behind it in a future post.  But when the news broke today, the stock of her company hit 70  (it was around 7 at the beginning of the year).  For details please see — https://finance.yahoo.com/m/49fa6153-4235-3866-bff2-5a35470e54da/why-cassava-sciences-stock.html.

Couldn’t happen to a nicer girl.  Of course it didn’t just happen.  Decades of hard work went into it.  So as you fly across the country, look down.  Some people down there might be even smarter than you are. 

 

Montana girl does good, real good !

Montana is flyover country. Nobody smart lives there. We all know that.

But when I got there in 1972 an issue of Science contained an article by State Legislator about a modification of general relativity — https://en.wikipedia.org/wiki/Kenneth_Nordtvedt.  MIT grad, Harvard Junior Fellow etc. etc. 

Then there was the son of a doc I practiced with in Billings.   Honors physics at Billings Senior high school placed him in 2nd year physics at Harvard, from which he graduated in 4 years obtaining a masters in physics as well. 

Then there was a local boy, the Thiokol engineer who predicted the Challenger disaster and was over-ruled. 

The great thing about Montana was that no one ever bragged about this sort of thing.  There were so few people, that no one felt compelled to tell you about themselves, you’d find out about them soon enough.  The classic example was an excellent surgeon and friend I practiced with for 15 years.  Only on reading his obituary last year did I find out that he had a Fulbright after college.

Which brings me to Lindsay, a girl I first met when she was a high school student.  The family were ranchers with a beautiful spread on the east face of the Crazy mountains north of Big Timber.  I’m not sure how we first met — I don’t think I saw any of them as a patient.  But we all became friends and the galactic premiere of a cello sonata I wrote with a 19 year old secretary in a lumberyard was in their living room. 

The two least important things about Lindsay are that she was a centerfold and an olympic silver medalist in woman’s two person crew.  Don’t get excited about the centerfold bit, she was fully clothed, but for some reason the Harvard Alumni magazine had a 2 page picture on a field of daisys of her back in the 80’s when she was there. 

Lindsay went on to get a PhD from Cambridge and her work and that of her husband may have come up with something useful for Alzheimer’s disease.  I’ll talk about the science behind it in a future post.  But when the news broke today, the stock of her company hit 70  (it was around 7 at the beginning of the year).  For details please see — https://finance.yahoo.com/m/49fa6153-4235-3866-bff2-5a35470e54da/why-cassava-sciences-stock.html.

Couldn’t happen to a nicer girl.  Of course it didn’t just happen.  Decades of hard work went into it.  So as you fly across the country, look down.  Some people down there might be even smarter than you are. 

The human species as a culture medium for the pandemic virus

Creationists or not, we are all about to get an unwanted lesson in natural selection and evolution, courtesy of the current pandemic virus (SARS-CoV-2).  This is going to be a long post, which will contain an incredible case of meningitis, thoughts on selfish genes in viruses, evolution, natural selection and why we’re in for a very, very long haul with the pandemic virus.

As you probably know, mutant pandemic viruses (all different) have emerged (in England, South Africa, Brazil).  Even worse they appear to be more infectious, and some are more resistant to our vaccines (all of which were made before they appeared).  

Here is lesson #1 in natural selection.  Viruses have no brains, they barely have a genome.  The human genome contains 3 billion positions, the pandemic virus 30,000.  So we have 100,000 times more information in our genome than the virus does. 100,000 is about the number of inches in a mile and half.  

So how is the virus outsmarting us?  Simply by reproducing like mad.  The molecular machines that copy our genome are very accurate, making about 1 mistake per 100,000,000 positions copied — that’s still enough for the average newborn to have 30 new mutations (more if the parents are older).  The viral machine is much less accurate.  So lots of genome mutations are made (meaning that the viral proteins made from the genome change slightly).  Those that elude the vaccines and antibodies we’re throwing at them survive and reproduce, most don’t.  This is natural selection in action. Survival of the fittest.  Darwin wasn’t kidding.

What is so remarkable about the British and the South African variants, is that they contain multiple mutations (23 in the British variant).  Usually its just one or two.

 You’ve probably heard about the mutation changing just one of the 147 amino acids  in hemoglobin to cause sickle cell anemia. Here’s another.  APOE is a 299 amino acid protein.  It comes in 3 variants  — due to changes at 2 positions.  One variant greatly increases the risk of Alzheimer’s disease, another decreases it.  So even single mutations can be quite powerful. 

So how did these multiple mutations come about?  We likely now have an answer due to one very well studied case [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia (CLL). She shed the virus for 70 days.  Even so, she wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and so its genome was always changing.  The authors were smart enough to continually sequence the viral genome throughout the clinical course and watch it change. 

Could this happen again.  Of course?   There are some 60,000 new cases of CLL each year in the USA.  Many of them have abnormal immune systems even before chemotherapy begins.

Here is an example from my own practice. The patient was a 40 year old high school teacher who presented with severe headache, stiff neck and drowsiness.  I did a spinal tap to get cerebrospinal fluid (CSF) for culture so we could find the best possible antibiotic to treat the organism.  This was 30+ years ago, and we had no DNA testing to tell us immediately what to do.  We had to wait 24 hours  while the bugs grew in culture to form enough that we could identify the species and determine  the antibiotics it was sensitive to. . 

As the fluid came out, I had a sinking feeling; as it was cloudy, implying lots of white cells fighting the infection. Enough white cells to make CSF cloudy (it normally looks like water) is a very bad sign. So after starting the standard antibiotic to be used in the first 24 hours before the cultures came back, I called the lab for the cell count.  They said there weren’t any.  I thought they’d seriously screwed up maybe losing what I’d sent or mislabeling it and looking at the wrong sample, and I unpleasantly stormed down to the lab (as only an angry physician can do) to see the spinal fluid.  They were right.  The cloudiness of the CSF was produced by hordes of bacteria not white cells.  This was even worse as clearly the bacteria were winning and the patient’s immune system was losing, and I never expected the patient to survive.  But survive he did and even left the hospital.  

Unfortunately, the meningitis turned out to be  the first symptom of an abnormal immune system due to a blood malignancy — multiple myeloma. 

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Addendum 2 February — I sent this post to an old friend and college classmate who is now a hematology professor at a major med school.  He saw a similar case —

“When I was a medical student I saw a pediatric sickle anemia patient (asplenic) with fever and obtundation. When I looked at the methylene-blue stained CSF, I thought that stain had precipitated. So I obtained a fresh bottle of stain and it looked the same. Only this time, I looked more closely and what I thought was precipitated stain were TNTC pneumococci.

I urge all my immunosuppressed patient to get vaccinated for covid-19. I worry that if many people don’t get vaccinated,  those who do will not be that better off.”

Addendum 3 February– I asked him if his patient had survived like mine —

answer 

“Unfortunately, no. With the pneumococcus, If antibiotics are not started within 4 hours after recognition, the train has left the station.”

 

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So there are millions of active cases of the pandemic, and tons of people with medical conditions (leukemia, multiple myeloma, chemotherapy for other cancer) with abnormal immune systems, just waiting for the pandemic virus to find a home and proliferate for days to weeks.  Literally these people are culture media for the virus. Not all of them have been identified, so don’t try to prevent this by withholding vaccination from the immunocompromised — they’re the ones who need it the most. 

I think we’re in for a very long haul with the pandemic.  We’re just gearing up to stay on top of the viral sequence du jour.   Genome sequencing is not routine (it should be).  The South African and British mutations were picked up because a spike in cases led people to sequence the virus from these patients.  Viral genome sequencing and surveillance should be routine in most countries  — not waiting on an infection spike.