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Simon died of plague, yes. Simon and Isidor are drastically different characters in Pathologic 2. That said, they do cause the outbreak on purpose in 2.
It's vague but I'm pretty sure this line implies he knew. Georgiy says similar things about the plague as Isidor in Marble Nest as well - A plague is just a type of death to you. But to me, it's essentially an exam. And one must not run away from exams forever. Sooner or later, one must take them.