In 90 AD it began with the North Atlantic Oscillation, followed by collapse of grain supplies in Egypt (The Bread Basket of the World in those days), followed by recurrent bouts of the Plague for the next 150 years or so.
Based on DNA evidence of mass burials in Rome, there were two forms of the plague: The Bubonic Plague and the Pneumonic Plague. The first allowed partial recovery after 3-4 weeks in some cases with acquired immunity, the later was deadly in 7-10 days without recovery.
These events depopulated the largest and wealthiest city in the world in those days, destroyed business, lead to increasing military failures until over run by the Barbarians. No suitable burial sites, no grave diggers, a disaster...
Remember keep you eyes open, and don't forget to duck when the unexpected takes place.