Connection timed out

We frequently have in the nginx error.log

2020/11/20 00:23:32 [error] 31270#31270: *9219599 connect() failed (111: Connection refused) while connecting to upstream, client: 5.45.207.91, server: 0.0.0.0:443, upstream: "127.0.0.1:5349", bytes from/to client:0/0, bytes from/to upstream:0/0 2020/11/20 00:24:50 [error] 31271#31271: *9219608 upstream timed out (110: Connection timed out) while reading response header from upstream, client: 127.0.0.1, server: fairmeeting.net, request: "POST /http-bind?room=test1 HTTP/2.0", upstream: "http://[::1]:5280/http-bind?room=test1", host: "fairmeeting.net", referrer: "https://fairmeeting.net/test1"