Follow-Up:

Although CPU & Memory usage are both significantly higher than previous versions, both still look to be within acceptable parameters.

I was able to resolve the "Category: Microsoft.AspNetCore.Server.Kestrel EventID:22" warnings by increasing the MAX INDEXING THREADS under TROUBLESHOOTING > OPTIONS > PERFORMANCE TUNING from 6 to 30 (server has 32 Cores). Have not had this warning appear in the Windows logs since.

The SETTINGS > GATEWAYS > SMARTERMAIL GATEWAY > WEB SERVICE VERIFICATION resulted in 100% of all inbound email to be rejected with "rsp: 550 No such user here". We immediately went back to "SMTP USER VERIFICATION" instead and will settle for the intermittent "rsp: 550 No such user here".

Almost all of the intermittent "rsp: 550 No such user here" appear to be from legitimate Bulk Mail providers such as MailChimp, Sailthru, MandrillApp, SparkpostMail (tough to troubleshoot as the SMTP logs show the same "rsp: 550 No such user here" for senders that are on the SETTINGS > SECURITY > BLACKLIST and SMTP BLOCKS).

Awhile back, I learned that if recipient verification encounters a processingy error, it is considered equivalent to a confirmed reject.   I consider this unacceptable because it could cause your exact problem. I  have never been convinced that recipient verification is even a good idea, and it is definitely a bad idea if it can produce false rejects.   Turn it off 

I recommend getting a ticket submitted for this so we can collect additional details. We'll want to look at the full SMTP sessions for some example sessions to confirm whether there were other failures happening concurrently (like bad recipients being specified) and look for patterns.