Walter Reed established that yellow fever was caused by an unknown infectious agent being transmitted by the Aëdes mosquito, thereby laying the basis for experimental medicine in the twentieth century.
During the last thirty years of the nineteenth century, a new understanding of the role of microorganisms in disease, along with improvements in personal hygiene and public sanitation, led to a dramatic decrease in the incidence of diseases such as typhoid and cholera. Yellow fever, however, had foiled all attempts at control. The disease had been known for centuries along the west coast of Africa, where it showed little effect in the native population, probably because generations of exposure had resulted in a high degree of inherent resistance. Europeans, however, had virtually no resistance to yellow fever, and thousands died of the disease during efforts to develop the natural resources of Africa. So deadly was yellow fever to Europeans that the continent of Africa became known as the white man’s grave.
The Western Hemisphere remained free of yellow fever until the seventeenth century, when it was probably introduced as a result of the slave trade from western Africa. The first documented epidemics in the New World struck Barbados in 1647 and Yucatán in 1649. The first epidemic in the American colonies took place in New York in 1668. Severe epidemics continued periodically, with 135 major epidemics striking American port cities between 1668 and 1893.
Yellow fever was a particularly frightening disease. It attacked suddenly, causing a high fever, headache, and nausea. The eyes became inflamed and the skin took on a yellow pallor. Many victims hemorrhaged internally, producing a black vomit. The mortality rate ranged from 30 percent to 70 percent, with most deaths occurring on the sixth or seventh day after infection. During the Philadelphia epidemic of 1793, more than seventeen thousand cases were reported, with more than five thousand deaths. In 1802, an epidemic in Santo Domingo killed twenty-nine thousand of the thirty-three thousand troops sent there by Napoleon Bonaparte for a planned invasion of the United States up the Mississippi River. As a result of these devastating losses, Napoleon changed his plans and the next year negotiated the Louisiana Purchase with President Thomas Jefferson. An epidemic in the Mississippi Valley in 1878 caused the deaths of about thirteen thousand people. More than fifty-two hundred of these deaths were in Memphis, Tennessee, and the financial impact caused the city to lose its charter temporarily in 1879.
Walter Reed.
Two theories developed as to the cause and spread of yellow fever. Some considered it to be a contagious disease that could be spread directly from one person to another. Others believed it to be caused by a miasma, by filth, or by rotting vegetables. The Philadelphia epidemic of 1793 was attributed to a shipment of spoiled coffee beans. In 1881, Carlos Juan Finlay,
It was at this time that Walter Reed was appointed to head a commission to study yellow fever in Cuba. The U.S. Army’s Yellow Fever Board
The Yellow Fever Board’s initial work was aimed at identifying the cause of the disease. The U.S. surgeon general had discouraged pursuit of the mosquito transmission concept, so the investigators went to work to isolate a bacterial agent. They thoroughly studied eighteen severe cases of yellow fever but were unable to isolate any microbial cause for the disease. They thus quickly reached an impasse and were forced to take a new approach. Reed knew of an outbreak of yellow fever in a military prison where there had been no possible direct contamination. It was also known that a ship leaving an infected port might be free of the disease for two to three weeks before an outbreak would occur at sea. The cases in Cuba would jump from one house to another even though the inhabitants had had no contact. Carter also pointed out that a study he did in Mississippi showed an average of twelve days between the first case of yellow fever in an area and a larger second wave. All these facts forced Reed to reconsider Finlay’s mosquito hypothesis.
At the request of the Yellow Fever Board, on August 1, 1900, Finlay supplied mosquito eggs for Reed’s studies. Given that no animals were known to acquire yellow fever, the board members knew they must rely on human experimentation. It was agreed that the first humans involved in the experiments must include the members of the board. That same week, Reed was recalled to Washington to report on some earlier work he had done in Cuba on typhoid fever. The board agreed to carry on in his absence. Lazear took charge of the mosquitoes, which were fed on yellow fever patients and then on nine volunteers. None of these first volunteers became ill, probably because the initial patients were too advanced in their illness to have the yellow fever virus in their bloodstreams. On August 27, a mosquito that had twelve days earlier bitten a patient in his second day of illness was allowed to feed on Carroll. Within three days, Carroll became seriously ill with yellow fever. Although very near death for a time, he survived. A subsequent experiment on another volunteer led to a second experimental case; that volunteer also recovered.
On September 13, Lazear was feeding one of the experimental mosquitoes on a patient when another mosquito came through a window and landed on his hand. Rather than chance disrupting his experiment, he allowed the wild mosquito to feed on his blood. Five days later, Lazear developed symptoms of yellow fever. His condition deteriorated rapidly, and on September 25, 1900, he died. Reed returned to Cuba in October. He quickly realized that the experimental cases, although certainly important, did not completely settle the yellow fever issue, because either could have been exposed by some means other than by a mosquito. He requested approval to build an experiment station in an open field 1.6 kilometers from the town of Quemados, Cuba. The remaining board members named this site Camp Lazear, for their lamented colleague.
Established November 20, 1900, Camp Lazear consisted of seven floored hospital tents and support facilities. The tents were made mosquito-proof, and each was inhabited by one to three nonimmune volunteers. Each volunteer was paid one hundred dollars for participation and another one hundred dollars if he developed yellow fever as a result of the experiments. From November 20 through December 30, six volunteers were bitten by infected mosquitoes. Five developed yellow fever, and all survived. Even though these carefully controlled experimental cases provided strong evidence that mosquitoes could carry yellow fever, Reed set out to determine if there were other ways the disease could be transmitted. In his next series of experiments, three volunteers came down with yellow fever after being injected with blood from patients in the early stages of the disease. On November 30, Reed began a third set of experiments to determine whether contaminated clothing and bedding could transmit yellow fever: Seven men slept each night with soiled sheets, pillowcases, and blankets taken from the fellow fever ward of the hospital. All seven men remained completely healthy.
For his final experiment, Reed constructed a mosquito-proof frame building with a center wire screen partition. Each side of the building was occupied by a nonimmune volunteer, yet on one side of the partition mosquitoes that had fed on yellow fever patients were released. As expected, the volunteer bitten by the mosquitoes became ill while the one on the other side of the partition remained healthy. The Yellow Fever Board was now satisfied with its experiments. On February 4, 1901, Reed reported the results of the board’s findings at the Pan-American Medical Congress held in Havana. This report was then published in the February 16, 1901, issue of the Journal of the American Medical Association. The mosquito was clearly established as the vector in the transmission of some unknown agent that produced yellow fever. (The discovery of the yellow fever virus was almost thirty years away.)
Given the Yellow Fever Board’s findings, it was clear that the way to control yellow fever was to eliminate exposure to mosquitoes. Gorgas quickly set out to do just that by protecting infected patients from mosquito bites and by eliminating places that encourage mosquitoes to breed. In March, 1901, Gorgas launched a house-to-house attack on mosquitoes. All water containers were to be emptied, covered, or layered with kerosene. Failure to comply meant a ten-dollar fine. Gorgas’s tactics were first met with derision by the populace; however, during the summer of 1901, the number of yellow fever cases in Havana was drastically reduced, and by October, for the first time in decades, no cases were being reported. Within a few years, the entire Western Hemisphere was for the most part rid of yellow fever.
One of the most significant consequences of the elimination of yellow fever was that it again became possible to consider building a canal across the Isthmus of Panama.
The work of Reed and the Yellow Fever Board had impacts far beyond the reduction of morbidity and mortality from yellow fever. Yellow fever was the first human viral disease extensively studied, and the Aëdes mosquito was the first insect determined to transmit a virus to other organisms. Additionally, the board’s work marked the first time that medical experimentation was performed following a sound scientific method. The board members carried out human experimentation only after careful consideration of other alternatives. All experiments were carefully controlled, and the researchers kept meticulous records. Not only did Walter Reed’s work establish a basis for subsequent studies on yellow fever, but his methods also served as a model for medical experimentation throughout the early part of the twentieth century.
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Andrewes, C. H. “Yellow Jack.” In Natural History of Viruses. New York: W. W. Norton, 1967. This exhaustive book presents basic facts of the chemical makeup and nature of viruses in general and explains how viruses spread, how they perpetuate themselves in nature, and how they survive in hard times. The chapter on yellow fever includes the natural history of the virus in the jungle environment. -
Bean, William B. Walter Reed: A Biography. Charlottesville: University Press of Virginia, 1982. This very complete biography includes discussions of Reed’s childhood and work in the Indian wars. The information is taken from approximately fourteen thousand pages of letters, papers, and writings of Walter Reed as well as other sources. -
De Kruif, Paul. “Walter Reed: In the Interest of Science—and for Humanity.” In Microbe Hunters. 70th anniversary ed., with new introduction by F. Gonzalez-Crussi. New York: Harvest Books, 2002. De Kruif was a prolific writer on the historical backgrounds of numerous developments in medicine. Although short on details and full of fictional narrative, this volume presents the work of Walter Reed in a very readable, human manner. -
Kelly, Howard A. Walter Reed and Yellow Fever. 3d rev. ed. Baltimore: Norman, Remington, 1923. Kelly was the first biographer of Reed and provides some interesting insight into his early years. The major portion of the book deals with the work on yellow fever and its implications. -
Pierce, John R., and Jim Writer. Yellow Jack: How Yellow Fever Ravaged America and Walter Reed Discovered Its Deadly Secrets. New York: John Wiley & Sons, 2005. Focuses on the impact of yellow fever in the United States. Describes the debates that took place over the cause of yellow fever and Reed’s work to determine its mode of transmission. -
Reed, Walter, James Carroll, and Aristides Agramonte y Simoni. “The Etiology of Yellow Fever.” Journal of the American Medical Association 36 (February, 1901): 431-440. Reed presented this landmark article at the Pan-American Medical Congress in Havana on February 4, 1901. It provides some background as well as detailed information on all phases of the Yellow Fever Board’s experiments. The article was reprinted in the August 5, 1983, issue of JAMA (pages 649-658). -
Williams, Greer. “Part Three: Costly Victory—Yellow Fever.” In The Plague Killers. New York: Charles Scribner’s Sons, 1969. Greer has drawn on previously unpublished material from The Rockefeller Foundation archives for this volume. He catches the personalities of the scientists involved and imparts a sense of the massive human implications of their work.
Founding of the International Sanitary Bureau
Gorgas Develops Effective Methods of Mosquito Control
Construction Begins on the Panama Canal
Chlorination of the U.S. Water Supply Begins
Theiler Develops a Treatment for Yellow Fever