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Yellow fever was one of the dreaded diseases spread by mosquitoes. Yearly summer epidemics of yellow fever had plagued and devastated American cities as far north as Boston for years. Doctors of the Civil War era knew that the disease was brought to North America each year by infected seamen on ships from tropical ports, but they had no idea that the great plagues were spread by mosquitoes.

Once an infected mosquito bit a person, the onset of the disease began within a few days. The patient suffered head and body aches, along with high fever and nausea; damage to the liver resulted in a yellowing of the skin and eyes. More than half the victims of yellow fever died within a few days; those who survived gained an immunity against the disease. Southern ports established stations of quarantine where ships arriving from tropical ports were required to wait, often three or four weeks, until they were certified free of the disease and allowed to proceed to the wharves and unload their cargo.

There were many severe epidemics of yellow fever during the Civil War. The disease was common in the swamps around the Mississippi River as well as the Southern ports. Coastal North Carolina was swept by an epidemic in 1864; of the 763 cases reported in New Bern, 303 died. Wilmington traced its epidemic to the arrival of the blockade runner Kate. From October 20 to November 15, yellow fever claimed 710 lives, about 15 percent of Wilmington's population.