The Discovery of the Cause of Yellow Fever

Courtesy of the Walter Reed Medical Center

Yellow fever killed more men in the Spanish-American War than did the enemy. It appeared in Central America in 1596, probably imported from Africa by slave ships. It may have been the disease from which members of Columbus' second expedition suffered in 1495. Ninety epidemics struck the United States between 1596 and 1900. In 1793 an epidemic first hit Philadelphia, then the U.S. capital, causing the Government to flee as ten per cent of the population perished. Washington went to Mount Vernon while Jefferson fled the disorder caused by the onslaught of the disease. Because of frequent epidemics which destroyed ninety per cent of his expeditionary forces in 1802, Napoleon was influenced to sell the Louisiana Territory. It was chiefly because of "yellow jack," as the disease was nicknamed from the pennant which was flown during quarantine, that the French were unable to complete the Panama Canal. The danger of contaminating the southern states was considered to be a major factor in the annexation of Cuba.

The onset of yellow fever came with chills and a headache. Then followed severe pains in the back, arms and legs accompanied by high fever and vomiting. The feverish stage might last hours, days, or weeks. Jaundice, from which the fever derives its name, might then appear. Then came the so-called "stage of calm" when the severity of the symptoms subsided and the fever dropped. In less serious cases this stage indicated recovery. But in the main, this stage was followed by a return of the fever accompanied by internal bleeding which caused the dreaded "black vomit" when blood released into the stomach was ejected.

There were 300,000 cases in the United States between 1793 and 1900, which cost the nation almost $500,000,000 with a mortality rate usually at forty per cent but sometimes as high as eighty five per cent. The scourge of yellow fever had plagued the southeastern United States for two hundred years, but nowhere was it more prevalent than in Havana.

In early 1900, Dr. Walter Reed arrived at in Havana, Cuba to assist with research on the cause of Yellow Fever. Reed first tried to prove that there was a relationship between Bacillus icteroides, a member of the hog-cholera group, and yellow fever. But within months, those efforts failed. Then Reed turned his attention to the theory of Dr. Carlos Juan Finlay and examined it more carefully. For nineteen years this resident of Havana had contended that yellow fever was carried in the body of a common house mosquito which at that time was called Culex fasciatus, later Stegomyia fasciata, and is now known as Aedes aegypti. This theory had been expounded even earlier, but it was Finlay who was its staunchest exponent. However, after some 100 experimental inoculations had failed to produce any cases of the disease under strict laboratory control, Finlay was scoffed at; people referred to him as the "mosquito man." There was evidence, however, that tended to lend credence to this theory which even the Yellow Fever Board, optimistic though it was, had doubted. First of all, the disease skipped erratically from house to house, jumping around corners. One member of a household might contract the disease while others in close contact never became ill or did so after a period of about two weeks had elapsed. This was quite unlike any other infectious disease except malaria which had already been shown to be spread by the Anopheles mosquito.

Walter Reed then decided that the best way to study yellow fever was not by searching for a specific agent but rather by identifying the means by which the fever was transmitted. On of the scientist working with Walter Reed was Dr. Lazear. He had recently been working with malarial mosquitoes. Dr. Lazear had observed that generally there was a delay of two or three weeks between the first and the second case of Yellow Fever in a community. On the basis of this observation, he suspected that an insect might be the intermediary since this would account for the delay in transmission as the disease developed in the mosquito.

After Dr. Lazear's observations, Dr. Carroll, a scientist working with Walter Reed, volunteered to be bitten and promptly developed a case of yellow fever. Carroll luckily recovered and went on with his work in bacteriology. Next, Lazear asked Private William Dean of Ohio if he would consent to be bitten. Answering that he wasn't "afraid of any little old gnat" Dean permitted the female Aedes aegypti to bite him. He also developed a case of Yellow fever, from which he eventually recovered. Finally, Dr. Lazear allowed himself to be bitten and after several days of delirium and black vomit, he died - a true martyr to science.

Major Walter Reed, although grieved at Lazear's death, was hopeful at the prospect of successfully tracking down the secret of the fever. Dr. Lazear's notebook, found by Lieutenant Albert E. Truby (later Brigadier General), yielded the key. In it, through the carefully recorded controlled experiments, Walter Reed found that in order for a mosquito to become infected, it had to bite a yellow fever patient during the first three days of his illness; only during that time was the agent present in the bloodstream. Further, it required at least twelve days for the agent to ripen in the female mosquito (only the female aegypti draws blood) and migrate to her salivary glands before the fever could be passed to another person.

The original "experiments" were enough to sufficient convince Walter Reed that mosquitoes were probably the intermediary in Yellow Fever. However, Reed felt he had to be sure. As a result Reed decides that more experiments were needed. With the express permission of the Governor General of Cuba, a large number of American and Spanish volunteers were selected for a large experiment. Reed had already tested the "mosquito theory" on a wide variety of experimental animals. Reed also desired to disprove the seemingly fallacious belief that yellow fever could be transmitted through clothing and bedding soiled by yellow fever sufferers. These articles were known as fomites and were commonly thought to carry the disease. Just as "everybody knew" that the mosquito theory was foolish, so "everybody knew" that fomites were dangerous.

In November, 1900, Camp Lazear was established one mile from Quemados and placed under strict quarantine. At this experimental station Private John R. Kissinger permitted himself to be bitten and promptly developed the first case of controlled experimental yellow fever. This case has been deemed as important to medical science as Robert Koch's discovery of the tubercle bacillus and the development of the diphtheria anti-toxin. Kissinger and John J. Moran had volunteered on condition that they would receive no gratuities, performing their service "solely in the interest of science and the cause of humanity."

Then, in order to prove the theory for all time and to destroy the fomite myth, two specially constructed buildings were erected in Camp Lazear. Building Number One, or the "Infected Clothing Building," was composed of one room, 14 x 20 feet heated by a stove to ninety-five degrees. For twenty nights Dr. Robert P. Cooke and Privates Folk and Jernegan hung offensive clothing and beefing around the walls. They slept on sheets and pillows befouled by the blood and vomit of yellow fever victims. Not one of the volunteers contracted the disease. On December 19, 1900, they were relieved by Privates Hanberry and England who, in turn, were finally relieved by Privates Hildebrand and Andrus. From November 30, 1900 to January 10, 1901 the experiment ran to completion, disproving the fomite theory of transmission and thereby demonstrating the uselessness of destroying the personal effects of yellow fever victims, thus saving thousands of dollars in property.

The second building was similarly constructed and was called the "Infected Mosquito Building." It was divided into two parts separated by a screen with screens on the windows as well. Mr. John Moran, a clerk in General Fitzhugh Lee's office, was bitten by fifteen infected mosquitoes, developed the fever and recovered. The other volunteers who were separated, and thereby protected by the screen, escaped infection. Ten cases were produced in this manner. Yellow fever was produced in the bodies of twelve more American and Spanish volunteers either by direct mosquito bites or by injections of infected blood or blood serum. These injections proved that the specific agent of yellow fever is in the blood and that passage through the body of a mosquito is not necessary to its development.

The courage of the volunteers is tremendous. A unique honor helps keep alive the memory of the twenty-four gallant men who participated in this experiment. In 1929 Congress awarded a special gold medal to each man or his next of kin. Had it not been for Major Reed's fair and thoroughly scientific approach to the problem and misconceptions concerning the disease yellow fever might have continued for years. Soon a major effort was underway to destroy disease carrying mosquitoes. Inspection parties were organized to check all homes in Havana for possible breeding places, insuring that the only standing water in the homes was needed for family use and properly screened. All other water receptacles were to be emptied. Later the same techniques were applied in the Panama Canal Zone, freeing it of fever, permitting the United States to complete the Panama Canal so vital for commerce and deployment of the Pacific fleet. Thus the menace which had struck the United States every year since 1648, from Pensacola to Nantucket Island, was eradicated. There would be no more epidemics such as that in Memphis in 1878 which cost the country one hundred million dollars.

In the summer of 1901, Dr. Carroll proved that the specific agent of yellow fever was sub-microscopic and too small to be caught in the pores of the diatomaceous filter that retained bacteria. Thus the last key to the disease was found. Carroll had proved through a series of inoculations that a filterable virus could cause disease in man. In 1927 it was found that certain species of monkeys were susceptible to the virus, thereby eliminating the need for human subjects. In 1937 a vaccine against yellow fever, called 17-D, was produced by scientists of the International Health Division of the Rockefeller Foundation. The use of this vaccine became routine in the United States Army in 1942. Since yellow fever is still endemic in the jungles of Central America and Africa where anti-mosquito measures are almost impossible, the fever still exists. A distinction is therefore made between "urban" yellow fever which is under control and the jungle variety which persists. As yet there is no cure for the disease, only inoculation against it.

Through the efforts of Walter Reed and those that worked with him the mystery or Yellow Fever was solved and thousands of lives have been saved. However there are still many who argue whether the scientific methods used by Reed were ethical.

1. How did Yellow Fever affect the early history of the United States?
2. Why would many seriously ill patients think they had recovered from yellow fever?
3. What symptom of Yellow Fever gave it its name? Use the scientific name.
4. What was Walter Reed's original hypothesis about Yellow Fever?
5. What conclusion did Walter Reed make about his original hypothesis? Why
6. What did Dr. Carroll volunteer to do to test Walter Reed's new hypothesis? How ethical was Walter Reed in letting Carroll volunteer?
7. Explain the methods used in by Walter Reed to test his new hypothesis.
8. Explain how an experiment can be scientific, but unethical.
9. Define these words: mortality rate, theory, fomites, intermediary, and ethical.
10. Write a three sentence summary of this article.