#32 – Spanish Flu: Why It Also Killed the Young and Healthy

00:00:05: The virus originally came from birds and there are two scenarios that I debated.

00:00:10: One is, it jumped from birds into humans at the same time to pigs or... ...the other hypothesis is they jump from birds to pigs then from pigs to humans.

00:00:47: Yeah hello and welcome to this episode of Virological!

00:00:51: This was recorded on September fourteenth of twenty-twenty six in severe Spain.

00:01:00: And because I'm here in Spain at a conference, we're going to talk about something historic the Spanish flu or Spanish influenza which is actually pretty interesting pandemic that's worth discussing.

00:01:16: so Spanish flu as they name says was caused by influenza In this case an influenza A virus of the H-one N one subtype and happened long time ago, it started in nineteen eighteen.

00:01:31: We'll get to the historic details.

00:01:34: just a little bit about influenza viruses.

00:01:37: H one N-one is like all influenza A viruses or the myxovirus.

00:01:43: these are.

00:01:43: the myxoviruses have negative sense single stranded RNA genome and their genome segment that they have genomic segments.

00:01:53: Influenza A virus has eight genomic.

00:01:55: It's one of the issues with them because different influenza A viruses can exchange their genomic segments and that can lead to new combinations, which could be more problematic than their parental viruses.

00:02:10: Influenza viruses include Spanish flu in H-one N-one.

00:02:15: they are about eighty to hundred twenty nanometers in diameter.

00:02:19: They are blemorphic, many of them around.

00:02:22: Many virions that you can observe.

00:02:23: but specifically if a fresh patient isolates they also be filamentous.

00:02:29: and when we look at the composition of the virion We have RNA on the inside The eight genomic segments covered by nuclear protein to protect the RNA.

00:02:40: Each segment has limerase complex associated with it.

00:02:46: In this case it's a trimeric polymerase, so not just one polymerase protein.

00:02:49: It is three different ones that come together to form the polymerase.

00:02:54: and then we have matrix proteins which forms in a way shell on inside of lipid membrane.

00:03:02: And in the lipid membranes there are ion channels and two spike proteins.

00:03:08: One is called HA or hemagglutinin.

00:03:10: The other one is called neuraminidase.

00:03:14: The hemagglutinin is the receptor binding protein, it binds to C-alic acid.

00:03:19: That's a sugar residue that often found on proteins in our cell surfaces.

00:03:24: So basically all of us have that type of sugar on surface and so the virus can bind into these cells.

00:03:34: And then the neuraminidase second spike protein is actually a receptor destroying enzyme that cleaves off the sugar and so it allows the virus to leave infected cells.

00:03:50: As I said, Spanish flu, Spanish influenza was of H-one N-one subtype.

00:03:56: And when we say H one N-One.

00:03:58: That basically means types of hemagglutinin H and neuraminid SN that are encoded by this virus, it's important to know there is a huge diversity of these viruses out in the animal reservoir for influenza hemagglutinin.

00:04:15: Influenza A hemaggglutinine.

00:04:17: we know they're nineteen different sub-tapes out here.

00:04:21: For neuraminidase there are twelve different sub types out there but H one N one basically its one sub type and thats type one hemaggleutinin type on neuraminidae And these viruses cause respiratory infections.

00:04:35: I'll talk about the symptoms a little bit later.

00:04:38: and yeah, this virus, this H-one n-one virus caused really big and problematic pandemic in nineteen eighteen.

00:04:47: that's called the Spanish flu pandemic was the deadliest influenza pandemic has been recorded so far.

00:04:54: there have been other influenza pandemics afterwards In nineteen fifty seven nineteen sixty eight and two thousand nine but those were less deadly as compared to the nineteen eighteen each one and one pandemic.

00:05:07: So enough about the virus.

00:05:09: let's talk a little bit about history, how this all happened.

00:05:13: basically there are few hypothesis where these viruses came from.

00:05:17: it is certain that they come from animals.

00:05:20: we will discuss potential routes here in terms of where it comes from.

00:05:25: geographically I think the leading hypothesis is that it came from United States, from Haskell County in Kansas and that's a hypothesis that has been postulated by Alfred W. Crosby

00:05:41: Jr.,

00:05:43: he was an historian.

00:05:45: so based on historical records there were already some cases of respiratory disease.

00:05:57: There is another hypothesis and that this virus jumped into humans in the trenches of World War I, Europe.

00:06:06: And there's a hypothesis that was driven by John Oxford as British flu researcher who basically found records of influenza-like outbreaks in some areas in France.

00:06:23: There is another hypothesis that the virus was actually coming from Austria and emerged in nineteen seventeen.

00:06:32: That's a hypothesis that was driven by Andrew Bryce Smith, And then there is another Hypothesis to the viruses Actually Coming From China and Claude Anon from Pasteur Institute Was The Person Who Was Postulating This.

00:06:47: this Is all Based on Some Historic Records That Would Suggest There Was an Outbreak Here or There that could have started all of this.

00:06:56: What is clear, it's that the virus originally came from birds and there are two scenarios that I debated.

00:07:02: one is that they jumped from birds into humans in at the same time into pigs or roughly at the Same Time Into Pigs And This Nineteen Eighteen Virus was also found In Pigs.

00:07:15: Or The Other Hypothesis Is That They Jumped From Birds To Pigs Then From Pigs to Humans.

00:07:22: So it's not clear which way went, but we know that at some point in birds and it ended up in humans.

00:07:31: Keep the pigs in mind!

00:07:33: We'll get back to them.

00:07:35: The first official case was recorded on March fourth of nineteen eighteen in Keppfühl-Fanston in Kansas.

00:07:48: I think this is a man named Albert Getschel who was an army cook there in this fort.

00:07:55: And then the virus spread really quickly, which tells us that the virus is probably around before March fourth already humans.

00:08:03: on March eleventh of nineteen eighteen are already cases in Queens and New York.

00:08:09: by April There were widespread circulation under east coasts to United States in the Midwest but also already in France than in Great Britain Italy Poland, Ukraine and Spain.

00:08:23: And you can imagine if it started in the United States... I mean this was during World War One.

00:08:29: through troop movements and soldiers basically crossing the Atlantic could have easily moved to Europe.

00:08:37: Spain is important dimension here because that's where their name comes from.

00:08:41: so basically there was a world war going on participated in the war, right?

00:08:48: There was censorship and they didn't want to talk about massive disease outbreaks in their respective countries because that would have basically weakened the country.

00:09:00: And Spain was not in a war.

00:09:02: Spain was in a way neutral... ...and The Spanish Press was free to write this.

00:09:07: So they wrote it out about outbreak which is why its called Spanish Influenza.

00:09:12: Because They reported By May the virus had reached North Africa, India Japan and by June it was in China.

00:09:23: And this is basically a first wave.

00:09:25: so they started early spring depending on geographic region.

00:09:30: that took until June.

00:09:33: The first wave of the nineteen-eighth pandemic actually not very severe.

00:09:37: It's relatively mild similar to what people were used from regular influenza.

00:09:43: There were a lot of issues with troops because during the war, people lived in tightly-packed barracks or in trenches.

00:09:54: They had lots of interactions and there was a lot infections in their respective armies.

00:10:00: The estimates are that on the first wave it was already half... ...or at least one third of the military population who participated in the war in Europe infected.

00:10:11: Then there is second wave.

00:10:13: By the way, does this ring a bell?

00:10:15: This is exactly what we saw with COVID-IX in the beginning.

00:10:18: Right first wave second wave and here like actually COVID-IN in many countries The Second Wave was much more severe And it started already In August of nineteen eighteen Boston for example.

00:10:35: there are records Of the First Wave starting and this Is interesting because this isn't summer right.

00:10:40: usually influenza circulates during the winter season in the Northern Hemisphere, but the pandemic virus didn't seem to care.

00:10:47: It started a wave in summer and this wave led to large number of deaths.

00:10:55: there's for example one instance where they had a parade in Philadelphia Liberty Loans Parade.

00:11:01: it is famous example I think took place on twenty-eighth September of nineteen eighteen because lot people participated was a lot transmission And the estimate is that this one parade in Philadelphia resulted in twelve thousand deaths.

00:11:17: We'll come to a number of deaths later, but on the second wave lot people got infected and lots died.

00:11:27: The second wave was basically many places over by December of nineteen eighteen.

00:11:34: In early nineteen nineteen a third wave occurred which was milder than it lasted until February to May of nineteen-nineteen in Europe and then there was even a fourth wave in some countries which lasted until early into the early nineteen twenties.

00:11:56: And I think beginning with nineteen twenty people started to see seasonality again so that virus only infected during winter, it became milder.

00:12:10: Seasonal influenza is not necessarily mild.

00:12:12: It can be a pretty severe disease, but compared to the pandemic it was milder.

00:12:18: A little bit about the characteristics and the diseases that are not so The reproductive number of the nineteen eighteen h one n-one pandemic Is estimated to be two to three.

00:12:28: So that's above what we see with regular seasonal influenza.

00:12:31: That's more or less one point five.

00:12:34: And I think the transmission mode Was also similar to seasonal influenza.

00:12:38: then Respiratory droplets, but potentially also aerosol transmission.

00:12:43: So you know respiratory virus can spread pretty quickly and this one was more infectious than what we now from seasonal influenza.

00:12:52: There were a wide range of symptoms and severity of symptoms.

00:12:59: in some cases This just led to a source road, a headache and upper respiratory tract infections.

00:13:06: But in many cases the infection also resulted in pneumonia.

00:13:12: what is often reported for the nineteen eighteen pandemic are secondary bacterial infections that often lead pretty severe outcomes.

00:13:24: One syndrome I should mention here it's called heliotrope cyanosis.

00:13:30: So basically what happened here is that the lung was affected so much, there wasn't oxygen supply of the body anymore and people died with a blue face.

00:13:40: Basically black coloration of their extremities which sounds pretty bad.

00:13:45: but this can happen with influenza.

00:13:47: What's also described in that it's unusual for seasonal influences, hemorrhages on the mucosal surfaces or upper respiratory tract.

00:13:57: And we now know this virus can cause what is called the cytokine storm.

00:14:02: So a cytokines storm, it's basically an over-stimulation of the innate immune system and so a lot of innate immune molecules are released from cells And that is basically the body overdoses in terms of their response to the virus.

00:14:16: That then leads to severe disease and mortality.

00:14:20: If you look at the severity The case fatality rates are assumed to be around two or three percent.

00:14:26: Super high, I think in the worst case scenarios with COVID-IX that hasn't had a case for teledirate of maybe one point five to enlarge outbreaks where you know there was not enough medical personnel at the beginning.

00:14:42: and this really bad outbreak in New York.

00:14:45: For example or were in northern Italy so You know for the nineteen eighteen eight twenty nine one virus.

00:14:52: This was higher The estimates of how many people died in that pandemic, somewhere between twenty and hundred million people.

00:15:00: That's a lot!

00:15:02: And you have to also keep your mind at back then the world population was much smaller.

00:15:07: we're talking about the population of one point eight two-one point nine billion people... ...and that means that approximately depending on estimate One to six percent of global population died in this pandemic.

00:15:23: I know there's people out here that say, yeah one percent is not much.

00:15:25: That means ninety-nine percent lived?

00:15:28: Think again!

00:15:34: There are areas where it was more affected than others.

00:15:42: The case fatality rates in Tahiti were approximately thirteen percent.

00:15:47: Western Samoa reported to have had a case fatality rate of twenty two percent, and in some native populations the case-fatality rates went up to fifty percent.

00:15:59: In some settlements even higher.

00:16:02: so that's terrible.

00:16:05: what is interesting about fatalities?

00:16:07: also?

00:16:08: typically influenza affects very young and old most but people who are healthy are often less affected.

00:16:22: And that's not true for the nineteen eighteen pandemic, but if you look at this age distribution it looks like a W. there is basically lot of problems in terms of modality.

00:16:32: kids.

00:16:33: then The mortality rates go down with H and Then they go up again and they peak between twenty and forty years Of age and then he goes Down Again A little and then Goes Up In Very Old.

00:16:45: and That Super Unusual.

00:16:47: And people have wondered about that.

00:16:48: and one hypothesis is basically my hypothesis, but I've argued with people about it.

00:16:54: Not everybody believes that... ...is the may not been influenced around before nineteen eighteen?

00:17:01: in the years before there was another pandemic from eighteen eighty nine to eighteen ninety-one.

00:17:08: That's called The Russian Flu.

00:17:11: Maybe there was influenza before that, my hypothesis is that Russian flu was also for this coronavirus.

00:17:20: There's some supportive data but it's not proven... But the idea is maybe it is also for these three when they make kicked out the influenza viruses that were circulating before then.

00:17:29: and then there are years between eighteen ninety one in nineteen eighteen without any influence on people born during a period of time probably had no immunity to influence at all, and that's why they dieted a higher rate.

00:17:44: With little bit younger generation... Little bit younger people you could think the immune system is a little bit better than they were protected.

00:17:52: The older people maybe have immunity from period before in the year of eighteen ninety-one And this could explain W shape.

00:18:01: I'm not sure if it true but thats my hypothesis.

00:18:04: But its remarkable that there were a lot of deaths in people between twenty and forty years of age.

00:18:12: There are other risk factors, socioeconomic status was tied to mortality rates.

00:18:19: poor people died at much higher rates than wealthy people... ...there is also a lot more mortality in soldiers you can imagine during the war.

00:18:27: That's not easy, that suboptimal care that people receive And they live under terrible circumstances on the front.

00:18:36: That probably didn't help.

00:18:38: And another group that was really badly affected were pregnant women, and so for pregnant women case fatality rates between twenty-three and seventy one percent are reported at the time.

00:18:50: What might also be interesting.

00:18:52: is there long term effects described of survivors?

00:18:58: They're a little bit like Long Covid if you read into it.

00:19:02: the nineteen-eighteen pandemic also had a pretty big impact on people who survived it.

00:19:09: So all in all, pretty terrible pandemic and I should also say that after you know, nineteen twenty this virus as mentioned became seasonal virus And most circulating for quite some time until nineteen fifty seven Inhumans seasonal H-one admirers.

00:19:31: There was of course a lot of immunity already in the population and the virus started to antigenically drifted, became what we know now as typical seasonal influenza virus.

00:19:43: but I also wanted to mention is countermeasures.

00:19:47: people have of course understood in a way the nature of infectious diseases they want to stop.

00:19:53: these quarantines were used for that.

00:19:55: Australia was very successful with that.

00:19:57: in Iceland island nations are usually doing better with these pandemics because they can basically relatively easy, easily keep people out who are infected.

00:20:10: The other measures that were implemented where social distancing for example we noted also from covid-nineteen.

00:20:15: this was done during the nineteen eighteen pandemic.

00:20:18: two closing of schools restricting mass gatherings and restricting their use of public transportation.

00:20:26: so all Masks were used, people who are already smart back then and knew that masks can protect from respiratory infection.

00:20:38: But you also had already anti-mask leaks.

00:20:41: so there was protest against masks already.

00:20:44: And I have to admit during the COVID pandemic i read a book about it in all mention.

00:20:50: later John Berry wrote a really, really good book about the nineteen eighteen pandemic and so much that was done back then.

00:20:59: What's also done during COVID-nineteen?

00:21:02: And so many stupid things that were done back in nineteen eighteen.

00:21:05: we're all so done doing COVID-Nineteen.

00:21:08: So it's almost as nothing changed anyway.

00:21:12: People were also trying to make vaccines.

00:21:14: There was some misconception about the agent that was causing this, there was for example a vaccine made against hemophilus influenzae which you know is a bad bacterial pathogen but it wasn't.

00:21:26: because of this pandemic.

00:21:28: people used all kinds of potential medications.

00:21:32: aspirin was used probably That might have helped in some cases a little bit But other things like quinine which probably had no impact arsenic, but even like things that wouldn't work.

00:21:46: I've read the blood landing.

00:21:48: something was used in middle ages against infectious diseases without any success and it's also been used here as well.

00:21:56: It might be interesting to mention a few people who were affected back then by H-one N one.

00:22:06: there are some famous people died during this pandemic.

00:22:11: One of them is Gustav Klimt and also Egon Schiele.

00:22:15: And with Egon, it's interesting because his wife also died after the nineteen-eighteenth pandemic so he got sick.

00:22:23: first there was a famous drawing that he made of his wife basically in resting and dying already.

00:22:33: His wife was named Edith and the painting is called Edith Schiele Dying or Edith Dying and he died a few days later.

00:22:44: What's also interesting is Frédéric Trump, the grandfather of President Trump... ...also died during the H-one N-one pandemic due to an infection.

00:22:58: There are famous people who survived, got infected, got severe infections but survived.

00:23:03: Mahatma Gandhi had an H-One N-One.

00:23:08: Edward Munch, there's even a self-portrait that he painted of him with Spanish flu.

00:23:14: George O'Keefe had the Spanish influenza and then two U.S.

00:23:19: presidents Franklin D. Roosevelt and then to US president Franklin D., Roosevelt And Woodrow Wilson also survived infections with this virus.

00:23:32: in terms of research into these viruses Of course A lot of historic data and so on and so forth but is currently circulating as H-one and one that's different from what was causing this pandemic, right?

00:23:44: And back then there were no sequencing.

00:23:46: The virus couldn't be isolated so not a lot of knowledge about these viruses except you know it was deadly or highly problematic.

00:23:57: So people started to put effort into trying to get samples old samples in sequence potentially the virus or the virus genome that was still in these old samples.

00:24:10: And one person who started this was Jeffrey Daubenberger, at the point where US armed forces instituted pathology and so he was looking for samples from people who died back in nineteen eighteen.

00:24:26: Pathologists would take the lung for example then look at a tissue or damage but also fix this informally to preserve it.

00:24:37: tissue samples from people who had died in nineteen eighteen of the infection.

00:24:43: And he was able to sequence bits and pieces of the virus in there, this was published in nineteen ninety seven science I believe... ...and then another guy Johan Haltin Was taking a different approach to this and was digging up a corpse form the permafrosts in Alaska of a person who had died during the nineteen-eighteen pandemic in place called Prevac Mission.

00:25:08: And I believe that the pandemic back then killed more than eighty percent of population, but so he was able to find the corpse that was buried and burried at Bermphrost which means that dead body has been frozen since nineteen eighteen years ago from this lung.

00:25:28: it is also possible for him to get parts of the genome And with this genomic information you can of course look at how the virus potentially, or how these proteins of the virus potential looked like.

00:25:42: John Scale and Ian Wilson were actually able to get a structure for the hemagglutinine off the nineteen-eighteen virus that was published in two thousand four.

00:25:53: So they basically took the genomic for the hemagglutinin gene and then recombinantly expressed it, made a crystal structure from that.

00:26:02: That's kind of how you look at this structure of

00:26:05: proteins.".

00:26:06: And in two thousand five Darren Tampi at the CDC together with Adolfo-Gasius Astro and Peter Balasi at Monsignor actually reconstituted the virus.

00:26:22: There are systems where if you have the genomic information of influenza virus, You can basically reconstitute that in cell culture and get an infectious virus out again.

00:26:33: We call it rescuing The process.

00:26:36: It's pretty well established for many different viruses And they did with the Genomic Information from these samples From the lung pathology slides That were fixed informally into the permafrost material and that helped to learn a lot about this virus.

00:26:56: So initially there were only few sequences, now many people have gone back and sequenced more of these old samples.

00:27:03: There's pretty good understanding.

00:27:06: you know how the virus sequence looked in nineteen eighteen and how it evolved And as I said having that virus in laboratories being able study the virus in cells what it does in terms of damage to cells and what he does in animals allowed better understand this pandemic.

00:27:28: Aspect that I also wanted to mention is initially a set.

00:27:32: the virus ended up in humans and swine, right?

00:27:36: And in humans the virus circulates and infects people over-and-over leads to a lot of antibodies, neutralizing antibodies against the virus.

00:27:49: and these antibodies in the population put pressure on the virus.

00:27:52: And so the virus changes a lot.

00:27:53: for influenza we call this antigenic drift.

00:27:57: So in the human population because we get infected multiple times over our lives and we mount strong immune responses against the various, the virus has to change right?

00:28:09: It evolves relatively rapidly.

00:28:11: But in pigs, the situation is different.

00:28:13: So December has jumped into pigs in nineteen eighteen.

00:28:17: but pigs don't live that long.

00:28:19: they usually only get infected once with a certain influenza virus.

00:28:22: They make neutralizing antibodies, but they leave you know for few Sometimes a year sometimes shorter depending on when they gets slaughtered.

00:28:32: and so they don't put pressure on the virus.

00:28:34: And so the virus stays relatively conserved.

00:28:39: And this H-one, N-one virus specifically viruses that had the H one component of the nineteen eighteen pandemic virus.

00:28:47: That stayed in a big population and still there... ...and that hemagglutinin from these nineteen eighteen virus or one that is I mean it evolved little bit but one was relatively similar was part of the two thousand nine pandemic virus that caused a swine flu pandemic.

00:29:11: That is interesting for number reasons.

00:29:13: during this one flu pandemic older people were well-protected.

00:29:19: they often didn't get infected, it didn't gets sick and The reason for that is these other people.

00:29:26: specifically if you are born before nineteen fifty seven had already immunity to nineteen eighteen-like viruses and this new swine virus was actually a nineteen eighteen like virus.

00:29:40: And so they already had neutralizing antibodies.

00:29:42: that's what not true for young people, and so younger people were more affected during the night during two thousand nine pandemic because didn't have protection from immune memory form when you know from old infections before the nineteen sixties.

00:29:59: it is an interesting aspect I think that in one species, the virus doesn't change much because there's no pressure while humans it changes and then the virus that stayed preserved can cause another pandemic basically almost hundred years later.

00:30:18: So yeah... It is very interesting what these viruses sometimes do.

00:30:23: I'm coming to an end here but i wanted point out this book by John Berry.

00:30:27: I think it's really super nice summary of what happened during the pandemic.

00:30:32: It is really nicely investigated, there are a lot of historic sources in here called The Great Influencer and i really recommend that you put the link to this in the comment section on the podcast.

00:30:48: with that thats all for today.

00:30:50: as always if you have any questions comments or suggestions please write an email to Virological at podcastwerkstatt.com and if you like the podcast, please support us on Steady!

00:31:02: Thanks for listening in – until next time… Bye!