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A well a everybody’s heard about the bird

B-b-b bird, bird, bird, b-bird’s the word

A well a bird, bird, bird, the bird is the word

A well a bird, bird, bird, well the bird is the word

A well a bird, bird, bird, b-bird’s the word

A well a bird, bird, bird, well the bird is the word

A well a bird, bird, b-bird’s the word

A well a bird, bird, bird, b-bird’s the word

A well a bird, bird, bird, well the bird is the word

A well a bird, bird, b-bird’s the word

– The Trashmen, “Surfin Bird“.

Bird is the Word. Indeed. Finest tribute to Charlie Parker ever, at least as I understand the lyrics. But then, didn’t Frank Zappa say something to the effect it is foolish to look for meaning in rock lyrics? I think so. Can’t quickly find the quote and don’t want to go down that rat hole. Wouldn’t be prudent.

I am a bit punk this month. My gallstones, after years of lying quietly, decided to try and kill me. Nothing like a gangrenous gallbladder to slow you down. I found it interesting in that for years I said the gallbladder was the second most difficult to understand organ, and it could go south with remarkably little lab and physical findings pointing to the gallbladder. Then you open the patient up based on CT findings and it is dead, Jim. Although green, rather than the usual red shirt. Like mine. I am getting better, but do not have my usual focus.

My long and storied career saw three pandemics. AIDS started when I was in medical school (remember, association is not causation), then H1N1 influenza, and finally COVID 45. At 67 I wonder if I will live long enough to see a fourth, or ironically, to die in one? Could be.

I never saw coronaviruses as a pandemic worry. It wasn’t discussed much in the journals or meetings that I remember, although there were the smart ones who were worrying about coronaviruses and there were a few coronaviruses that tried, and failed, to go full pandemic.

It was always influenza that kept that ball of anxiety alive, because we (by we I mean ID docs) remember the 1918 influenza that killed, in less than a year, more Americans than died of enemy action in all our wars combined. 600,000 or so. 0.5% of the population. Dead. Damn impressive. COVID killed around 0.3% in comparison, but in 3-ish times the population.

By the way, the descriptor ‘only’ never belongs in front of morbidity or mortality statistics, and is the marker of an uncaring asshole, an anti-John Donne. One death is not an “only” to the person dying or their friends and family. And please, if you find I did just such a faux pas in the past, I do not want to know about it. We all do foolish things in our youth, youth being defined as age less than current age.

Influenza has always been one of the more interesting infectious diseases, in part due to its history, in part due to its impact on society, and in part due to it pathophysiology. Which is like most of the ‘fun’ infectious diseases. Syphilis, TB, Malaria, and influenza are some of the pathogens that share those characteristics.

While it looked early in the outbreak that H1N1 was going to be the next Spanish flu, the reported initial high mortality rates out of Mexico were a reporting artifact. H1N1 probably killed 284,000 (range from 150,000 to 575,000) people, so not a particularly virulent by 1918 standards. Or COVID 45.

Of course, with H1N1 we had residual immunity from prior outbreaks, vaccines, medications to treat flu and its secondary infections, ICUs, and a better understanding of how to dose aspirin. So I would be surprised even if there was a new influenza outbreak it would kill at 1918 rates. But given the huge world population now, a death rate of 0.5% would kill a lot of people.

During most of my career, avian influenza has been wandering through the world, and I get the impression it is probing the barriers between birds and humans, looking for a way in. Of course, it is not really doing that, but a rule of infectious diseases, if it is possible to get infected by some weird, unusual route, someone will get infected by that route. And if there is an environmental niche that an infection can move into, it will. Evolution is a bastard. The question is whether it will be a one-off event (likely) or the start of something worse.

But first, let’s talk influenza A. As you know, flu is brought to you by the letters H and N. The H stands for the hemagglutinin and N the neuraminidase. H1, H2, and H3 are found in human strains. H4, H5, H6 etc. (18 have been isolated so far) are strains found in other animals, like bird influenzas. Similarly, there are human and non-human neuraminidases (11 total). They are important virulence factors where

HA initiates viral fusion by binding to sialic acid-containing receptors on the host cell and NA facilitates viral release by hydrolyzing the ketosidic bond of sialic acid. The balance of HA and NA activities is thought to be critical for influenza virus infectivity and transmissibility.

Generally, these enzymes are mostly species-specific, although humans and pigs are remarkably alike as far as influenza, and my wife, are concerned. She always wished she realized at a younger age that most men are pigs. The pig-human similarities are why outbreaks of human influenza often originate in pig farms.

In ID, it is traditional to mention if a given virus is DNA or RNA or single-stranded or double-stranded or circular or whatever. Much of the time it is information that does not help understand the virus. For some, like HIV, that information can be helpful. The key thing about influenza is that it is a segmented genome. Eight segments, in fact.

So what can happen, often in a pig, is the poor swine is infected with say, a human and a bird flu, and in forming a new virus it takes a segment from a pig flu and a segment from a human flu and, viola, you have a new strain of flu. The dreaded antigenic shift that usually happens every 30 to 50 years. That is different than the antigenic drift, where there is the gradual accumulation of mutations in the viral genome. For, like humans, influenza is a sloppy reproducer.

So right now the worry is H5N1. Where did it come from? Chinese poultry farms around 1996. As is typical of influenza. Farms the world over have a mix of humans, pigs, birds and other animals in high density, perfect for breeding a new strain of influenza. Since that time, by way of wild birds, it has spread across the world, killing uncountable birds, 900 or so humans with a 50%, yes 50%, death rate.

And, to my surprise given that viri are usually relatively species-specific, killing other animals. Lots of other animals. It has killed huge numbers of elephant seals and

Avian flu viruses tend to be picky about their hosts, typically sticking to one kind of wild bird. But this one has rapidly infiltrated an astonishingly wide array of birds and animals, from squirrels and skunks to bottlenose dolphins, polar bears and, most recently, dairy cows.

And that is odd. Cows? Cows have their own influenza D. But A? A Pubmed search suggests reports for influenza A in cows only started in the last decade. Cows do not die off like sea lions but get a mild illness. But the influenza is now widespread and spreading in dairy cows and, when tested (many farmers are evidently refusing not only to have the milk tested, but will not let their cows wear masks. Free the cow.) H5N1 is found in milk. And if raw milk from infected cows is fed to cats, the cats sicken and die from H5N1.

Feels like we should cue the music from Jaws.

But despite being widespread, there has been a paucity of human cases with one case in a dairy worker, suggesting that cows and cow milk are not that efficient at spreading H5N1. Yet. Why? Besides pasteurization? We lack the receptors in the upper airway for H5N1 to bind to. And the first, necessary, step in an infection is the pathogen binding to a very specific receptor on a cell:

Epithelial cells in the intestinal tract of birds (the major target organ of influenza viruses in avian species) express primarily sialic acid linked to the penultimate galactose residue by an α2,3-linkage, and avian influenza viruses have evolved to preferentially bind to this type of sialic acids. In contrast, epithelial cells in the respiratory tract of humans (the major target organ of influenza viruses in humans) express primarily α2,6-linked sialic acids. After they infect humans, influenza viruses therefore need to acquire mutations in HA that confer efficient binding to α2,6-linked sialic acids to enable efficient transmission among humans. The HA proteins of highly pathogenic avian H5N1 influenza viruses preferentially interact with α2,3-linked sialic acids (reviewed in [22]); human infections with these viruses may, in part, be explained by the finding of α2,3-linked sialic acids on type II pneumocytes lining the alveolar wall, and on nonciliated bronchiolar cells [23–26]. The lack of α2,3-linked sialic acids on epithelial cells of the upper respiratory tract of mammals may explain why highly pathogenic avian H5N1 influenza viruses do not transmit efficiently among mammals.

2-3 linked sialic acids are found in human intestines, so raw milk could be a potential source for H5N1. But who in their right mind would drink raw milk in the year 2024? Plenty, I would suspect.

Pasteurization, however, should take care of it. The lone case report of disease in the dairy worker suggests a respiratory route, and as is usual of H5N1 infections, it occurs in those with potentially massive exposures that allow the virus to reach the lower airway to start infection.

And as best I can tell, the alpha 2,3 linked sialic acids are plentiful in cat gut and the cow trachea. It turns out that cow udders have human and bird sialic acid and

human eyes contain the same H5N1 receptor found in ducks and cow udders.

Explaining why the one reported case of a human had conjunctivitis as a predominant symptom. Could have been a splash injury, they were certainly common enough in hospitals before widespread goggle use.

As an aside, I once had a question about HIV prophylaxis. The stripper was lactating and while spinning about the stage, her milk splashed in the eye of a patron. He wasn’t wearing goggles or glasses. But perhaps one should be cautious of lactating animals of all species infected with H5N1. As to my recommendation, I think I laughed too hard to give one.

Cool, huh? Know the receptor that the pathogen needs to get started and a lot of the disease manifestations are explained, be it flu, COVID 45, HIV, or Gonorrhea. That link has the best review of the distribution of sialic acid receptors you could possibly want. Or not want.

But humans seem to be protected. For now. Influenza is unstable, shifting and drifting, changing its genome. It will not take much for it to become transmissible by the air, maybe 3-5 mutations, a number that does deserve an only. Of course, becoming more transmissible doesn’t necessarily mean it will continue to have a 50% mortality rate. It might be more transmissible but less virulent. Or not. And note the N1 in H5N1. As in H1N1. A common human N. So we may have some immunity from H1N1 depending on how much antigenic drift has occurred:

Our results support experimental evidence that prior infection with H1N1 confers partial cross-immunity to H5N1.

It is likely that some preexisting immunity, vaccinations, medications, and bankrupting modern medical care (at least in the West) will attenuate the mortality of H5N1 when and if it becomes more transmissible. Hopefully, mortality will decrease a lot, as a 50% death rate would be a bit much.

I fully expect H5N1 to get those mutations, one way or the other. What can happen, will happen. As I said, H5N1 is very unusually pushing and prodding its way into many other animal species. And if it gets into our closest influenza and spiritual relative, the pig? Can’t see why humans would not be next, so invest in coffins. Something wicked this way comes, but with more or less 1918 levels of morbidity and mortality, got me.

All I know for sure is that since COVID 45, a tremendous number of people will do the wrong thing and die as a result. As the wise man noted, no one ever learns from past mistakes and so repeat the same damned thing over and over.

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Posted by Mark Crislip