Good stuff Eric. I've never before seen an ultrasound image of necrotizing fasciitis. Poor dog. And how in the world was a bone marrow aspirate indicated?!
For sure, even if you were concerned about the cytopenias, they are easily explained by sepsis, which is known to cause acute marrow wipeout. What we actually saw on the bone marrow aspirate cytology and core biopsy (we did BOTH, ugh) was lots of fat, bony trabeculae, and marked hypoplasia of the hematopoietic tissue. So "non-contributory" is probably more accurate than "non-diagnostic" (because the samples contained adequate specimen and revealed the expected finding), but that is way longer than I wanted to spend on that specific detail
And in terms of the comment about politics, we are certainly repeating a lot of past historical mistakes... 👀
Another really good piece, Dr. Fish. I felt like I was literally IN this with you, that’s how real and compellingly written this is.
I’m so glad you were able to make a difference for Lola and give her many more years with her mom, Dr. Harper.
And I particularly enjoyed the reference to Rush’s “Freewill.” Great line from that song, one of my all-time favorites. Good old Geddy Lee’s high falsetto singing away…
Rush is criminally underrated. I was fortunate to see them live in concert twice when they were still touring. Neil Peart is an insane drummer, but not as many people know he also penned the lyrics to almost all of their songs! He was deep into sci-fi, mysticism, and philosophy, and it shows
Brilliant piece, Dr. Fish. Exactly why it’s important for veterinary training to include specialty practice to see these cases that stay with them for life and spur an eagerness to consult literature. We can become complacent with our horses easily enough.
And-I thought you were going to make a parallel to democracy. In all - we need to be alert, informed, and have a growth mindset.
You are not the first reader to draw a parallel to current events & politics. That was not my intent or subtext, but I certainly agree "we" (or at least our nation's leaders) are repeating a lot of terrible mistakes from the 20th century that will haunt us in the history books...
Fascinating. I did not know that dogs could get necrotizing fasciitis from S. pyogenes, too!
So: technical question: so the virulence factor that's most responsible for streptococcal necrotizing fasciitis in humans is streptococcal pyrogenic exotoxin, a superantigen. Superantigens work by cross-linking major histocompatibility complexes and T-cell receptors into perpetuity. This is also why HLA subtype is tied to how bad an individual human's reaction to a particular superantigen is, since some HLAs have more affinity for superantigens than others.
But....dogs definitely have very different HLAs (or should I say "CLAs" for "canine leukocyte antigens"...?) than humans. But they must be similar enough that the same streptococcal superantigen would bind both? Do different breeds of dogs have different reactions to streptococcal superantigens --> necrotizing fasciitis because of "CLA" genotype differences? Or is it a different mechanism than a superantigen that leads to necrotizing fasciitis in dogs?
Relatedly, do other non-human animals (but with adaptive immune systems similar to ours, with MHCs and TCRs and such) get affected by superantigens too?
These are great questions! Unfortunately, I do not know the answers to them. In terms of clinical research, there is almost none. As the piece mentions, the largest study I could find is a retrospective case series (low quality evidence, not even a case-control, let alone a prospective study) of 23 dogs. Most of what we know is from one-off case reports and "anec-data". Some people suggest fluoroquinolone antibiotics may worsen outcomes, but we just don't know for sure. There may be some experimental model studies that investigate the mechanisms, nothing rings a bell offhand :/
Ooh! So, the gene for the streptococcal superantigen is an example of "lysogenic conversion"--where there's a gene in the bacterial chromosome because the bacterium is itself infected with a virus, so it's a viral gene that's actually responsible for the symptoms. And the viral genes get expressed the most when there's a threat to the bacterial DNA replication (meaning, it's time to get out of there and find another bacterium to infect.) And you know what screws with bacterial DNA replication? Fluoroquinolones. This is why some other lysogenic conversion-virulence diseases, like enterohemorrhagic E. coli, also get worse if you use fluoroquinolones.
So, that's consistent with streptococcal superantigens causing necrotizing fasciitis in dogs, anyway--which would imply that their CLAs are similar enough to our HLAs to allow the same protein to bind to both.
Ok, so: I have learned more. In humans, streptococcal necrotizing fasciitis is caused by S. pyogenes, but in dogs it's caused by S. canis. Both have similar pathogenicity mechanisms, in that S. canis strains can also have the virally-encoded streptococcal pyrogenic exotoxin, i.e., the superantigen that causes tons of inflammation by cross-linking antigen presenting cells and T-cells, previously described. Does it cross-link *dog* antigen-presenting cells and T-cells, though? Unclear.
But! S. canis can also have another gene, the gene for hyaluronidase, an enzyme that just chews right on through connective tissue. This would explain why the ultrasound of the dog's necrotizing fasciitis looks so much more damaged, with the big gaps in the tissue, than you'd see on a person with necrotizing fasciitis, where the damage is caused by inflammation.
Now here's where it gets cool: S. pyogenes, the one for people, used to have a functional copy of this gene, too. In humans, the hyaluronidase enzyme was the reason why S. pyogenes used to cause childbed fever, a very fatal infection in mothers who had just given birth--with damage to their uteruses that looks a lot like what you're seeing here in dogs. But these days, very, very few isolates of S. pyogenes make functional hyaluronidase, because of a variety of point mutations in hyaluronidase genes. In S. pyogenes, the streptococci that cause disease in humans, the adoption of hygiene practices like handwashing may have led to selection against strains of S. pyogenes with an intact hyaluronidase gene. There's a tradeoff between bacteria having a capsule--that protects them in the environment and allows spread from person to person--and having hyaluronidase. So as we got better at stopping them from persisting in the built human environment by washing surfaces, and from passing from person to person by washing our hands, only the hardiest, capsule-bearing S. pyogenes could really survive.
But it strikes me, based on much personal experience, that dogs are, uh, not great at hygiene on their own. So I'll speculate that's why the hyaluronidase enzyme--and not capsule--is still found in S. canis, and can thus cause this super-destructive tissue infection in dogs.
Good stuff Eric. I've never before seen an ultrasound image of necrotizing fasciitis. Poor dog. And how in the world was a bone marrow aspirate indicated?!
For sure, even if you were concerned about the cytopenias, they are easily explained by sepsis, which is known to cause acute marrow wipeout. What we actually saw on the bone marrow aspirate cytology and core biopsy (we did BOTH, ugh) was lots of fat, bony trabeculae, and marked hypoplasia of the hematopoietic tissue. So "non-contributory" is probably more accurate than "non-diagnostic" (because the samples contained adequate specimen and revealed the expected finding), but that is way longer than I wanted to spend on that specific detail
And in terms of the comment about politics, we are certainly repeating a lot of past historical mistakes... 👀
And I initially thought this was going to be a political article :-)
Another really good piece, Dr. Fish. I felt like I was literally IN this with you, that’s how real and compellingly written this is.
I’m so glad you were able to make a difference for Lola and give her many more years with her mom, Dr. Harper.
And I particularly enjoyed the reference to Rush’s “Freewill.” Great line from that song, one of my all-time favorites. Good old Geddy Lee’s high falsetto singing away…
Rush is criminally underrated. I was fortunate to see them live in concert twice when they were still touring. Neil Peart is an insane drummer, but not as many people know he also penned the lyrics to almost all of their songs! He was deep into sci-fi, mysticism, and philosophy, and it shows
Brilliant piece, Dr. Fish. Exactly why it’s important for veterinary training to include specialty practice to see these cases that stay with them for life and spur an eagerness to consult literature. We can become complacent with our horses easily enough.
And-I thought you were going to make a parallel to democracy. In all - we need to be alert, informed, and have a growth mindset.
You are not the first reader to draw a parallel to current events & politics. That was not my intent or subtext, but I certainly agree "we" (or at least our nation's leaders) are repeating a lot of terrible mistakes from the 20th century that will haunt us in the history books...
Fascinating. I did not know that dogs could get necrotizing fasciitis from S. pyogenes, too!
So: technical question: so the virulence factor that's most responsible for streptococcal necrotizing fasciitis in humans is streptococcal pyrogenic exotoxin, a superantigen. Superantigens work by cross-linking major histocompatibility complexes and T-cell receptors into perpetuity. This is also why HLA subtype is tied to how bad an individual human's reaction to a particular superantigen is, since some HLAs have more affinity for superantigens than others.
But....dogs definitely have very different HLAs (or should I say "CLAs" for "canine leukocyte antigens"...?) than humans. But they must be similar enough that the same streptococcal superantigen would bind both? Do different breeds of dogs have different reactions to streptococcal superantigens --> necrotizing fasciitis because of "CLA" genotype differences? Or is it a different mechanism than a superantigen that leads to necrotizing fasciitis in dogs?
Relatedly, do other non-human animals (but with adaptive immune systems similar to ours, with MHCs and TCRs and such) get affected by superantigens too?
Thanks!
These are great questions! Unfortunately, I do not know the answers to them. In terms of clinical research, there is almost none. As the piece mentions, the largest study I could find is a retrospective case series (low quality evidence, not even a case-control, let alone a prospective study) of 23 dogs. Most of what we know is from one-off case reports and "anec-data". Some people suggest fluoroquinolone antibiotics may worsen outcomes, but we just don't know for sure. There may be some experimental model studies that investigate the mechanisms, nothing rings a bell offhand :/
Ooh! So, the gene for the streptococcal superantigen is an example of "lysogenic conversion"--where there's a gene in the bacterial chromosome because the bacterium is itself infected with a virus, so it's a viral gene that's actually responsible for the symptoms. And the viral genes get expressed the most when there's a threat to the bacterial DNA replication (meaning, it's time to get out of there and find another bacterium to infect.) And you know what screws with bacterial DNA replication? Fluoroquinolones. This is why some other lysogenic conversion-virulence diseases, like enterohemorrhagic E. coli, also get worse if you use fluoroquinolones.
So, that's consistent with streptococcal superantigens causing necrotizing fasciitis in dogs, anyway--which would imply that their CLAs are similar enough to our HLAs to allow the same protein to bind to both.
Wow, very cool! Thanks for the microbiology perspective 🤓
Ok, so: I have learned more. In humans, streptococcal necrotizing fasciitis is caused by S. pyogenes, but in dogs it's caused by S. canis. Both have similar pathogenicity mechanisms, in that S. canis strains can also have the virally-encoded streptococcal pyrogenic exotoxin, i.e., the superantigen that causes tons of inflammation by cross-linking antigen presenting cells and T-cells, previously described. Does it cross-link *dog* antigen-presenting cells and T-cells, though? Unclear.
But! S. canis can also have another gene, the gene for hyaluronidase, an enzyme that just chews right on through connective tissue. This would explain why the ultrasound of the dog's necrotizing fasciitis looks so much more damaged, with the big gaps in the tissue, than you'd see on a person with necrotizing fasciitis, where the damage is caused by inflammation.
Now here's where it gets cool: S. pyogenes, the one for people, used to have a functional copy of this gene, too. In humans, the hyaluronidase enzyme was the reason why S. pyogenes used to cause childbed fever, a very fatal infection in mothers who had just given birth--with damage to their uteruses that looks a lot like what you're seeing here in dogs. But these days, very, very few isolates of S. pyogenes make functional hyaluronidase, because of a variety of point mutations in hyaluronidase genes. In S. pyogenes, the streptococci that cause disease in humans, the adoption of hygiene practices like handwashing may have led to selection against strains of S. pyogenes with an intact hyaluronidase gene. There's a tradeoff between bacteria having a capsule--that protects them in the environment and allows spread from person to person--and having hyaluronidase. So as we got better at stopping them from persisting in the built human environment by washing surfaces, and from passing from person to person by washing our hands, only the hardiest, capsule-bearing S. pyogenes could really survive.
But it strikes me, based on much personal experience, that dogs are, uh, not great at hygiene on their own. So I'll speculate that's why the hyaluronidase enzyme--and not capsule--is still found in S. canis, and can thus cause this super-destructive tissue infection in dogs.
Thanks again for helping me learn things, Eric!
Sources:
https://www.veterinaryworld.org/Vol.5/May%202012/Canine%20Streptococcal%20Toxic%20Shock%20Syndrome%20associated%20with.pdf
https://pmc.ncbi.nlm.nih.gov/articles/PMC4231703/