"Were changes made to pulseaudio client & server configs?"
I don't remember, but since I replaced Pulseaudio with Pipewire, I thought pulseaudio played no role anymore? Well, there's probably a lot about these clients and servers I don't understand right.
Did you remember to stop and disable the native pulseaudio service when you installed pipewire?
Maybe I should upgrade from US 20.04 to 22.04. I haven't because 22.04 was criticized a lot. It had many drawbacks and bugs, but perhaps updates have improved it since then.
I haven't kept up with what those problems were but apart from a few weird differences compared to my older system 22.04 (I'm on Mint 21.1) seems to work OK for me so far. But it is early days and I haven't transferred everything across to it yet.
You mention you use Ubuntu Studio? Is there any particular reason why? I don't know much about it but it never seemed to be that well maintained or thought out to me, and DIY solutions seemed better? It's more work obviously to go through the long process of tuning everything and installing certain packages but once it's done (and make notes!) you'd be OK.
I'm using Mint and used to compile most packages myself but nowadays a lot (not all) of it can just be installed via KXStudio repo and for the rest I just block packages I don't want to use from there because they are really old (guitarix, linuxsampler etc) in apt preferences and compile those myself.
I could imagine the source of the problem is some combination of wrong software settings and perhaps incompatible, dated hardware. Maybe I should just bite the bullit and replace it all
Perhaps it's worth re-installing because the standard is now 22.04 anyway and chasing after the problem may not be worth the effort. Your old soundcard and PC should probably still be OK? I have lots of old hardware here which - after some tinkering - works well enough for my purposes. I recently also had a noise issue - funnily enough only on the headphone socket of a sound interface. I now suspect this was caused by interference generated by a faulty powerline ethernet adapter because since replacing that unit the noise issue magically disappeared.
What I would do is to just buy another drive (SSD or NVMe if your motherboard supports it) and remove the old drive and do a new installation with the rest of the hardware kept the same.
Then replace pulseaudio with pipewire (I cannot think of any reason to require pulseaudio any longer) and test again. Of course, you can also have jack installed and switch from pipewire to jack as well when you need to.