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19th century pandemic with long-covid-ME like symptoms, possibly caused by a now-seasonal coronavirus

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441924/

Clinical evidence that the pandemic from 1889 to 1891 commonly called the Russian flu might have been an earlier coronavirus pandemic Harald Brüssow and Lutz Brüssow

Summary

Contemporary medical reports from Britain and Germany on patients suffering from a pandemic infection between 1889 and 1891, which was historically referred to as the Russian flu, share a number of characteristics with COVID‐19. Most notable are aspects of multisystem affections comprising respiratory, gastrointestinal and neurological symptoms including loss of taste and smell perception; a protracted recovery resembling long covid and pathology observations of thrombosis in multiple organs, inflammation and rheumatic affections. As in COVID‐19 and unlike in influenza, mortality was seen in elderly subjects while children were only weakly affected. Contemporary reports noted trans‐species infection between pet animals or horses and humans, which would concur with a cross‐infection by a broad host range bovine coronavirus dated by molecular clock arguments to an about 1890 cross‐species infection event.
 

Pyrrhus

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Interesting- thanks for posting!

This paper is a perfect example of the well-recognized "pandemic-endemic transition" in epidemiology, where a new virus can initially show up as discrete outbreaks (pandemic), but later shows up just as isolated/sporadic cases (endemic).

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Sounds plausible. I wonder if it just went away or mutated into a form that became more or less harmless.

One of the evidence that it was indeed a coronavirus pandemic back then is analysis of currently existing human coronavirus that usually causes common cold and a bovine coronavirus that was similar enough. Then estimating their common ancestor gave the Russian flu pandemic dates.

But then usually causing common cold symptoms doesn't mean it won't cause CFS-like symptoms or indeed CFS in rare cases. This hypothesis was what initially led me to investigate "normal" coronaviruses, which then led me to finding this article.

Here's relevant quote that I paraphrased earlier:

Fifteen years ago, the discussion of the agent responsible for the Russian flu pandemic of 1889 took a new turn with an unexpected observation from virologists working at KU Leuven in Belgium. They sequenced the human coronavirus OC43 (HCoV‐OC43), a group 2 or Betacoronavirus like SARS‐CoV and SARS‐CoV‐2, which caused SARS and COVID‐19, respectively. Within the Betacoronaviruses, HCoV‐OC43 belongs to the Embecovirus Lineage A, while SARS‐CoV and SARS‐CoV‐2 belong to the Sarbeco Lineage B coronaviruses. This classification difference also reflects a clinical difference: HCoV‐OC43 causes mild upper respiratory tract infections and only rarely severe pneumonia in neonates and aged people with underlying illnesses. Together with human coronavirus HCoV‐229E, a group 1 or Alphacoronavirus, it causes up to 30% of seasonal cold infections (Killerby et al., 2018). According to serological studies, infections with these two coronaviruses occur frequently in young children and then repeatedly throughout life. Neutralizing antibodies to these coronaviruses are found in in 50% of school‐age children and 80% of adults (Pohl‐Koppe et al., 1995). KU Leuven scientists then showed that HCoV‐OC43 shared very high nucleotide sequence identity with bovine coronavirus (BCoV) across the entire genome length, ranging from 93.5% for the S (spike) gene to 98% for the E (minor envelope) gene. The bovine coronavirus was shown to be the closest relative of HCoV‐OC43, except for gene E which showed 99.6% nucleotide (nt) identity with porcine hemagglutinating encephalomyelitis virus (PHEV), suggesting a potential recombination event with another coronavirus. In addition, HCoV‐OC43 shows a 290‐nt deletion affecting two nonstructural genes from BCoV. The Belgian virologists suggested that this animal‐human zoonotic pair of coronaviruses should be analysed in order to gain insights into the processes of adaptation of a nonhuman coronavirus to a human host, which is important for understanding the interspecies transmission events that might lead to the origin of human epidemics. Notably, with an estimated 4.3 × 10‐4 substitutions per site per year, the time to the most recent common ancestor of HCoV‐OC43 and BCoV was dated by three methods to 1891, 1873 and 1890 (Vijgen et al., 2005). Recent re‐examination of the molecular clock data led to a narrower estimate around 1890.
 

Pyrrhus

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The Belgian virologists suggested that this animal‐human zoonotic pair of coronaviruses should be analysed in order to gain insights into the processes of adaptation of a nonhuman coronavirus to a human host, which is important for understanding the interspecies transmission events that might lead to the origin of human epidemics. Notably, with an estimated 4.3 × 10‐4 substitutions per site per year, the time to the most recent common ancestor of HCoV‐OC43 and BCoV was dated by three methods to 1891, 1873 and 1890 (Vijgen et al., 2005). Recent re‐examination of the molecular clock data led to a narrower estimate around 1890.

Such genetic dating of the emergence of new viruses could be an immensely important research tool in epidemiology. Essentially, this genetic dating shows how a worldwide coronaviral pandemic that started in 1890 as discrete outbreaks could become an endemic common cold virus over time, now showing up as isolated/sporadic cases instead of as discrete outbreaks.


A similar genetic dating was performed for the virus Enterovirus A71, which concluded that this virus first emerged around 1940:

Evolutionary Genetics of Human Enterovirus 71: Origin, Population Dynamics, Natural Selection, and Seasonal Periodicity of the VP1 Gene (Tee et al., 2010)
https://journals.asm.org/doi/epub/10.1128/JVI.01019-09
Excerpt:
Tee et al. 2010 said:
We estimated that the common ancestor of human EV-71 likely emerged around 1941 (95% confidence interval [CI], 1929 to 1952), subsequently diverging into three genogroups: B, C, and the now extinct genogroup A. Genealogical analysis revealed that diverse lineages of genogroup B and C (subgenogroups B1 to B5 and C1 to C5) have each circulated cryptically in the human population for up to 5 years before causing large [hand, foot, and mouth disease (HFMD)] outbreaks, indicating the quiescent persistence of EV-71 in human populations.
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Interestingly, this emergence of Enterovirus A71 at some point in the years around 1941 corresponds to the first recorded outbreaks of ME. Therefore, it has been suggested that the early outbreaks of ME might have been due to the emergence of this new virus Enterovirus A71. As time passed, this virus might have started to show up as isolated cases instead of as discrete outbreaks...
 
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Pyrrhus

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Here's another attempt to use genetic analysis to pinpoint the date of a past pandemic, but this analysis looks at how humans have evolved to resist coronaviruses, not the other way around.

It is also bit more speculative as the past pandemic in question is posited to have occurred over 20,000 years ago in East Asia:

An ancient viral epidemic involving host coronavirus interacting genes more than 20,000 years ago in East Asia (Souilmi et al., 2021)
https://dx.doi.org/10.1016/j.cub.2021.05.067

Excerpt:
Highlights
  • Ancient viral epidemics can be identified through adaptation in host genomes
  • Genomes in East Asia bear the signature of an ∼25,000-year-old viral epidemic
  • Functional analysis supports an ancient corona- or related virus epidemic
Summary
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors—pointing to which viruses have future pandemic potential.

Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that likely started more than 20,000 years ago. These adaptive events were limited to the population ancestral to East Asian populations. Multiple lines of functional evidence support an ancient viral selective pressure, and East Asia is the geographical origin of several modern coronavirus epidemics. An arms race with an ancient coronavirus, or with a different virus that happened to use similar interactions as coronaviruses with human hosts, may thus have taken place in ancestral East Asian populations.

By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to better predict the pandemics of the future. Importantly, adaptation to ancient viral epidemics in specific human populations does not necessarily imply any difference in genetic susceptibility between different human populations, and the current evidence points toward an overwhelming impact of socioeconomic factors in the case of coronavirus disease 2019 (COVID-19).
(spacing added for readability)
 

Pyrrhus

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A comment from another thread:

Two other factors should probably be considered when asking whether a given infection will present itself as outbreaks or as sporadic cases:

1) How recently a given infectious agent has been introduced into a given geographical population. When an infectious agent is first introduced into a given geographical population, it presents itself as an outbreak. As time goes on, more and more people in the geographical population develop antibodies to the infectious agent, and the infection becomes endemic to that given geographical population. As a result, the infectious agent ends up presenting itself as sporadic cases, rather than as an outbreak.

2) How much transportation of persons there is between different geographical populations. When transportation of persons is rare, it is more likely that a given geographical population will not have encountered the infectious agent. This makes it more likely that an outbreak will occur when the infectious agent finally arrives in that geographical population. When there is widespread transportation of persons between different geographical populations, then the probability of a given geographical population having been exposed to the infectious agent rises, and the infectious agent will likely have become endemic in that given geographical population, resulting in sporadic cases, rather than as an outbreak.

Polio started out in the 1800’s as rare outbreaks in relatively isolated locations. As time went on, human transportation from the industrial revolution resulted in more outbreaks in more places. Urban centers that had previously suffered an outbreak started to see sporadic cases. By the 1950’s, polio had become endemic in most of the United States, and most polio cases were sporadic cases.

Since the 1950’s, there has been an explosion in human transportation, largely thanks to air travel. This has brought previously rare, isolated infections to all parts of the world. Zika and Dengue viruses are just two examples that have caught the headlines.
 

Pyrrhus

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Interestingly, this emergence of Enterovirus A71 at some point in the years around 1941 corresponds to the first recorded outbreaks of ME. Therefore, some have suggested that the early outbreaks of ME might have been due to the emergence of the new virus Enterovirus A71. As time passed, this virus might have started to show up as isolated cases instead of as discrete outbreaks...

Wow. I just took another look at that paper. Apparently, a new strain of Enterovirus A71 appeared in 1984, the same time as the Incline Village/Lake Tahoe outbreak of ME/CFS! And a major outbreak of this new strain also occurred in 1997, the year that many others I know first fell ill.

The paper includes these two graphs, which uses grey shading to depict the major outbreaks of Enterovirus A71 over the last couple of decades:

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Pyrrhus

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For more information on the "pandemic-endemic transition", and what it might mean for Covid-19, see this excellent article from the journal Cell Immunology:


Transition to endemicity: Understanding COVID-19 (Antia and Halloran, 2021)
https://www.cell.com/immunity/fulltext/S1074-7613(21)00404-0
Here, we explain basic concepts underlying the transition from an epidemic to an endemic state, where a pathogen is stably maintained in a population. We discuss how the number of infections and the severity of disease change in the transition from the epidemic to the endemic phase and consider the implications of this transition in the context of COVID-19.
[...]
An epidemic refers to the rapid spread of a pathogen in a population, while the endemic state refers to the stable maintenance of the pathogen, typically at a lower prevalence. When a new virus emerges into a human population, it can ignite an epidemic. The virus can be introduced from a different part of the world (e.g., viruses brought by the conquistadors to the Americas), or it can be a newly emerged zoonosis (e.g., Ebola virus or severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). If the virus spreads worldwide, then the epidemic is a pandemic.
[...]
The epidemic can fade out (i.e., the virus can go extinct) if the population is below a critical size, as is frequently the case for epidemics in island populations. If the virus does not go extinct, it can persist for an extended period of time at a lower prevalence than at the peak of the epidemic. The latter is the endemic phase.
 

Pyrrhus

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And here's a fascinating example of genetic dating that suggests that the measles virus likely originated in the middle ages from a cattle virus called Rinderpest:


Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries (Furuse et al., 2010)
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2838858/pdf/1743-422X-7-52.pdf

Excerpt:
Furuse et al. 2010 said:
Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genus Morbillivirus and is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV.

We investigated divergence times using relaxed clock Bayesian phylogenetics. Our estimates reveal that MeV had an evolutionary rate of 6.0 - 6.5 × 10-4 substitutions/site/year. It was concluded that the divergence time of the most recent common ancestor of current MeV was the early 20th century. And, divergence between MeV and RPV occurred around the 11th to 12th centuries.

The result was unexpected because emergence of MeV was previously considered to have occurred in the prehistoric age. MeV may have originated from virus of non-human species and caused emerging infectious diseases around the 11th to 12th centuries. In such cases, investigating measles would give important information about the course of emerging infectious diseases.


Interestingly, the original rinderpest virus was declared eradicated in 2011, after centuries of killing any animal found to have the virus:
How Rinderpest was eradicated
https://ourworldindata.org/how-rinderpest-was-eradicated
 

Pyrrhus

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One of the evidence that it was indeed a coronavirus pandemic back then is analysis of currently existing human coronavirus that usually causes common cold and a bovine coronavirus that was similar enough. Then estimating their common ancestor gave the Russian flu pandemic dates.

Here's one paper that says that it might be a coincidence that coronavirus OC43 happened to emerge around the same time as the Russian Flu:

Dating the Emergence of Human Endemic Coronaviruses (Forni et al., 2022)
https://www.mdpi.com/1999-4915/14/5/1095

Specifically, we estimated that HCoV-OC43 split from the bovine coronavirus (BCoV) lineage [between 1872–1967], whereas HCoV-229E separated from the camel alphacoronavirus in the 18th century [between 1714–1791]. It should, however, be noted that the 95% intervals for the split of HCoV-OC43 from the animal virus were very large, and the inference should, therefore, be taken with caution.
[...]
Although there is no clear relationship between pandemic occurrence and human population size, the frequency of influenza pandemics seems to intensify starting around 1700, which corresponds with the initial phase of the exponential increase of human population [due to the industrial revolution and colonial expansion.]
[...]
It was previously suggested that the 1889–1890 flu pandemic (known as the Russian flu), which was characterized by pronounced central nervous system symptoms, was actually caused by HCoV-OC43. If we allow for credible intervals, our estimate of the timing of HCoV-OC43 emergence is still compatible with the hypothesis that the virus, which displays some neurotropism, was the causative agent of Russian flu.

However, the frequency of flu pandemics in the 19th century suggests the concurrence of HCoV-OC43 emergence and the Russian flu pandemic may be due to chance. Only the retrieval of historical samples from the pandemic will prove or refute this hypothesis.