I saw you can use it with the CWC login, but can it pass to the guest machine login?

You are correct, proper 2FA is the requirement.

For a small business like us, the ease of implementing a PIV with Yubikey is very seamless and low cost. The yubikey is a 1 time cost and smart card authentication is built into the windows domain enviroment. Duo is nice, but brings in added complexity and subscription costs. If connectwise would pass the usb yubikey it would be an amazing feature.

NIST 800-171 is now rolling into CMMC and this will be a must. If this option is not added then it will prevent me from using it and a lot of MSPs out there.

With the NIST 800-171 requirements being fully enforced, 2-factor for privileged accounts is a must. This means that I need to pass my usb based Windows SmartCard (Yubikey) login to the remote machine. I agree that RDP does have this functionality and I use it already from my local machine into local remote servers.