Thread by @evolutionarypsy

Really interesting (follows up on the case of two sets of brothers with severe COVID-19) sciencemag.org/news/2020/09/h…

We produce interferons in response to infections. These interferons “interfere” with viral replication. Coronaviruses have some protection against this because they have a replication checking enzyme (this is why coronaviruses mutate more slowly than some other viruses like flu)

Interferon is also used as an anti-viral agent (used to be a treatment for HIV and Hep C)

In these studies, a much higher percentage of patients (14%) with severe COVID than in the general population (less than 1%) had either inborn errors of metabolism affecting type 1 interferon production or autoantibodies to the type 1 interferons.

Autoimmune stuff is usually much more common in women, but patients with autoantibodies to type 1 interferons were 94% male.

This could explain part of why men are more vulnerable to severe infection than women.

It also could point to treatment changes (study interferon in these patients) and also could be a reason why convalescent plasma is a mixed bag...convalescent plasma from some patients could contain the interferon autoantibodies and make people worse.

These genetic differences and autoantibodies have been found from people of varying genetic backgrounds from all over the world 🌎

(@thehouseofpod 👆🏻 this is what we were talking about last week...while immunity to old diseases like tb, norovirus, and malaria tend to cluster in certain genetic populations, as those epidemics affected fitness/reproduction, it’s a mistake to assume for brand new disease)

Here’s the article about genetic errors in interferon production (I’m 7 years old because I saw the second author’s name and giggled) science.sciencemag.org/content/early/…

And he’s the first author on the “rogue autoantibody” paper science.sciencemag.org/content/early/…

Interestingly the pathology of #covidtoes is a type-1 interferonopathy vasculitis, which happens when you have too much interferon floating around. Maybe not a coincidence that it tends to happen in folks with mild illness ncbi.nlm.nih.gov/pmc/articles/P…

(I can quickly get into the weeds with this and there are differences in interferons and their production in lungs, mucous membranes, and systemic so it may not be that simple)

I have recurrent pernio/chilblains myself (if I don’t keep my feet warm) and if I did have COVID back in Feb had an extremely mild course, so if chilblains is a marker of high type 1 interferon, that could explain it. We’re even more in the weeds now. 😷

But I’m going to need the epi data on people with pre-existing chilblains crossed with severity of COVID disease course

Here was the original paper from July about the two sets of brothers hospitalized with COVID...so other groups looked for the same issues in severe COVID in a much larger sample because science is awesome. jamanetwork.com/journals/jama/…

just one nitpicky clarification, the inborn errors affecting interferon included not only production but also places where interferons act (several different rare alleles were found)...so synthetic interferon would only theoretically help the subset with low production

Damn this work is so thorough (pic is of some of the methods in one of the science papers)

I wrote the first part of thread really fast while walking the dog this morning because I was excited about the papers...but there are some minor errors/misspeaks I just want to fix because they are literally keeping me awake tonight lol.

“Inborn errors of metabolism” should just be inborn errors. It’s ribavirin that coronaviruses are protected against with their replication checking gizmo not interferon. And type 1 interferons should always be plural (there are a bunch of them)

Okay I feel better

One more fascinating thing about the autoantibodies...one of the handful of women in the sample positive for anti-interferon antibodies has a disorder where she has only one functional X chromosome. Having two X chromosomes is 👍🏻 👍🏻 protection against risk of severe COVID