Yellow Fever
Yellow Fever
Disease History, Characteristics, and Transmission
Introduction
Yellow fever is an acute viral disease that is spread by mosquitoes and occurs in Africa and South America. Although a vaccine is available to prevent the disease, the incidence of yellow fever is growing, especially in South America. In this article, the virologist Jack Woodall discusses yellow fever and relates his first-hand experience in studying the disease. Woodall is the director of the Nucleus for the Investigation of Emerging Infectious Diseases at the Federal University of Rio de Janeiro in Brazil.
Disease History, Characteristics, and Transmission
From the seventeenth to the beginning of the twentieth century, the major ports of the United States suffered from periodic epidemics of yellow fever. New York was afflicted in 1668, Boston in 1691, and Philadelphia in 1793, where one in ten of its inhabitants died. Work on digging the Panama Canal was stalled because of the huge toll of yellow fever and malaria on the workers. The U.S. Army decided to do something about this. It set up a Yellow Fever Commission in Cuba, which was having an epidemic, and was at the time under U.S. control.
Jesse Lazear was a handsome young U.S. Army physician with a Vandyke beard, stationed in Baltimore at the start of the twentieth century. He and a colleague joined the Commission, and both volunteered to test a new theory, that the disease was transmitted by mosquitoes. They allowed themselves to be bitten by local mosquitoes; both came down with yellow fever, but only one survived; Jesse died of it.
Other soldiers, whose names have not gone down in history, volunteered to sleep in the sheets stained by the blood and vomit of yellow fever victims. Those who did so in mosquito-proofed huts did not get the disease, whereas others sleeping in clean sheets, but without mosquito netting became ill and some died. So without even knowing that yellow fever was caused by a virus, a control program could be put in place. U.S. Army General William C. Gorgas, who had himself survived yellow fever he caught in Texas, implemented mosquito control, and eradicated yellow fever from Havana, Cuba, and the Brazilian ports of Rio de Janeiro and Santos, and the Panama Canal was completed.
Before the isolation of the yellow fever virus, no vaccine could be made, and before the advent of the vaccine, yellow fever research was a hazardous undertaking. The International Health Division of the Rockefeller Foundation established yellow fever research laboratories in East and West Africa and South America to try to delimit the areas endemic (areas where the disease naturally occurs) for the disease. Six of their scientists died of yellow fever.
There are some basic things you need to know about yellow fever. First, it is the classic viral hemorrhagic fever, with sudden onset of fever, chills, headache, backache, nausea and vomiting, causing damage to the liver, kidneys and heart, and hemorrhage, with a death rate of 20–50 percent in severe cases. The liver damage produces the yellow jaundice that gives the disease its name. It is endemic in the jungles of Africa and South America, but every so often breaks out in the cities, especially in West Africa, for example in Nigeria between 1986 and 1991. The World Health Organization estimates that it still causes around 200 thousand cases with 30 thousand deaths every year.
Second, as it is a virus disease, antibiotics have no effect on it. The antiviral drug ribavirin, given within the first five days of infection, improved survival in hamsters, so might do the same for humans. Otherwise, there is only supportive treatment, and you either recover or you don't. Laboratory diagnosis is done by isolation of the virus in tissue culture from blood taken within the first five days of illness; this test takes a few days to produce a result. Rapid tests for specific components of the virus in blood samples take only hours. If these tests fail, diagnosis can still be made by finding specific antibodies in the serum later in the course of the illness. In Brazil in the days before these tests were available, a small block of tissue was removed from the liver of a victim's corpse using a steel punch to pierce the abdomen. The specimen was placed in formalin to preserve it and examined at the lab, often after days of canoe travel down the Amazon, under the microscope for characteristic stained spots inside the cells called Councilman bodies. Nowadays, we know that some other jungle viruses also produce Councilman bodies, but certainly in the majority of cases their presence proved that the victim had died of yellow fever.
Following the example of General Gorgas, other great public health figures such as Fred Soper of the Rockefeller Foundation, Cuba's Carlos Finlay and Brazil's Oswaldo Cruz spread the gospel, and by the end of 1924 yellow fever had been eradicated from the cities of Mexico, Central America, and Ecuador. In fact, there was hope that it could be eradicated from the Americas altogether, until researchers made the unwelcome discovery of an outbreak in a rural area of Brazil where the urban vector mosquito, Aedes aegypti, did not exist. The virus was cycling between monkeys and tree-top mosquito species, and infecting people who ventured into the forest to hunt, collect timber, or cut it down to make plantations.
This discovery ended the hope of continent-wide eradication. Even if you could kill every monkey in the jungle—and who would want to do that?—the virus would survive because it has been found that it is passed down by mosquitoes through their eggs, generation after generation. Some people have dreamed of replacing the vector (transmitter) mosquitoes in nature with the same species genetically engineered to be resistant to the virus, but the probability that this could be done is around zero. So in rural areas, yellow fever only gets into a human by accident, when an infected mosquito mistakes him for a monkey. But when it does, he goes back to his hut, runs a fever, and infects the Aedes aegypti there. After a few days incubation, the infected mosquitoes then transmit yellow fever to his family and neighbors.
The next thing that happens is that one of the people who falls ill in the village seeks hospital care in the nearest town. There he infects the local A. aegypti and starts an urban epidemic. Infected townspeople in turn carry the yellow fever to the country's capital and major ports. In the days of sailing ships, fresh water was carried on deck in open barrels, in which the mosquito bred. Passengers and crew coming on board after having been bitten by infected mosquitoes ashore would fall ill at sea, and the water-barrel mosquitoes would start an epidemic that would continue until the ship reached the U.S., Canada (Halifax in 1861), even Europe—Spain, France, England and Italy in the 1800s. There, it would be taken ashore by disembarking passengers, crew and mosquitoes, to start an epidemic.
The last outbreak of yellow fever in the United States was in 1905, when New Orleans and other Southern ports were affected. But since the demise of sailing ships, the last urban yellow fever epidemic in the western hemisphere occurred in Trinidad, West Indies, in 1954, unless you count some more recent cases on the outskirts of the town of Santa Cruz, Bolivia, which could actually have been contracted in the countryside.
A puzzling question is, why has yellow fever never spread to Asia? Its cities are full of dengue, which is carried there by the same mosquito species as in Africa and the Americas, and their jungles and temples are full of monkeys that are highly susceptible to it—the virus was first isolated by injecting the blood of a sick African into an Asian rhesus macaque. Passengers incubating the disease have jetted home from the jungles of Africa or South America to fall ill in the USA and Europe, where fortunately they did not spread the disease—but the same could occur with passengers to India or China; what a mess that would create. There is not enough vaccine in the world to cope with a wide-spread epidemic in either of those countries.
Explanations for Asia's exemption are not convincing. There is a theory that immunity against dengue, which is endemic in Asia, and related viruses, cross-protects against yellow fever. But there is plenty of dengue and related viruses in South America and Africa, and it doesn't seem to cross-protecton those continents. It was thought that the Asian strains of A. aegypti might not be as efficient in carrying the virus, but lab experiments have proved that they are.
So, yellow fever cannot be eradicated, and there is no cure. Fortunately, there is a vaccine, possibly the most successful vaccine ever developed; one painless shot and you are protected for life, although it is best to get a booster every ten years. I was privileged to know the vaccine's developer, Max Theiler, a long-faced South African with bruised-looking eyes who worked at the Rockefeller Foundation Virus Laboratory on New York City's Upper East Side, and was an ardent baseball fan. He passed the yellow fever virus through lab animals and then embryonated chicken eggs until it lost the ability to attack the nervous system. The attenuated strain, code-named 17D, was field-tested in Brazil in 1937, and had since protected many millions of people, saving countless lives. It won him the Nobel Prize many years later. The French also developed a vaccine in the brains of mice, which had side effects, but did protect millions in their West African colonies. Theiler's 17D vaccine or derivatives are now routinely incorporated in the childhood vaccination schedule of many endemic countries.
Impacts and Issues
Where are we now, at the start of a new century? The big cities of Brazil suffer dengue outbreaks every year, which as mentioned above is spread by the same mosquito that carries yellow fever. Mosquito control has not been successful, since it is not pursued as rigorously as in the days of Oswaldo Cruz, 100 years earlier.
Since the A. aegypti mosquito breeds in domestic and peridomestic containers holding water—water jars, rain-water barrels, drums, discarded tires, cans and plastic containers, drinking vessels for domestic animals, flower vases—getting rid of those should be easy. All you have to do is to throw out those that you can, empty out the water from those you cannot, or change the water in your pet's dish and flower vases every three days, before any mosquito larvae in there can turn into adults. But in places where trash collection is intermittent or non-existent, and the public is apathetic, this just doesn't happen. People like to see trucks and sanitary agents going through the streets with insecticide fogging machines, but all that does is knock out that day's mosquitoes—plenty more will hatch tomorrow.
At the end of 1999, hundreds of Brazilian tourists went to celebrate the New Year at a popular resort at the edge of the jungle called Chapada de Veadeiros. Not all had been vaccinated against yellow fever. Some were bitten by infected jungle mosquitoes and returned home only to be hospitalized with the disease in the major cities of Rio de Janeiro, Sao Paulo, Brasilia, and Goiania. By some miracle, there was no epidemic, but we might not be so lucky next time.
So even if you have no plans to travel outside the cities of countries in the yellow fever belts of Africa or South America, it is prudent to get vaccinated, no matter what it costs. The only exceptions would be infants less than nine months old, pregnant women, those with egg allergy (since the vaccine is made in eggs), and people who are immunosuppressed for any reason (for example, those undergoing cancer therapy or organ transplants, carriers of HIV). Also if you are over 65 you should consult your doctor before getting the shot, because you are at higher risk of rare side effects of the vaccine. He or she will probably tell you not to have it if you promise to stay in the cities, and if an epidemic breaks out to come straight home, where, if you should get a fever within two weeks of returning, you should inform your doctor that you may have been exposed to yellow fever.
But I really worry about Asia.
WORDS TO KNOW
ATTENUATED STRAIN: A bacterium or virus that has been weakened, often used as the basis of a vaccine against the specific disease caused by the bacterium or virus.
ENDEMIC: Present in a particular area or among a particular group of people.
HEMORRHAGIC FEVER: A hemorrhagic fever is caused by viral infection and features a high fever and a high volume of (copious) bleeding. The bleeding is caused by the formation of tiny blood clots throughout the bloodstream. These blood clots—also called microthrombi—deplete platelets and fibrinogen in the bloodstream. When bleeding begins, the factors needed for the clotting of the blood are scarce. Thus, uncontrolled bleeding (hemorrhage) ensues.
VECTOR: Any agent, living or otherwise, that carries and transmits parasites and diseases. Also, an organism or chemical used to transport a gene into a new host cell.
Primary Source Connection
Dr. Carlos Finlay began studying yellow fever in the 1870s and in 1881 was the first to assert that the Aedes mosquito was the vector of disease for yellow fever. Finlay's research was largely ignored for decades until a team of United States researchers posited a substantially similar theory in 1900. The following article from the New York Times discusses the scientific community's belated recognition of Finlay's contributions to yellow fever research.
Dr. Finlay Gets Full Credit Now
HAVANA PHYSICIAN WHO SOLVED THE YELLOW FEVER PROBLEM IS EXTOLLED HERE AND ABROAD
Said Mosquitos Carried It
And Allowed a Contaminated Insect to Sting Him to Prove It—Theory Ridiculed at First Reversing the usual order of things, scientists are determined that the rest of the world shall recognize in his lifetime the inestimable boon that Dr. Charles (or Carlos) J. Finlay of Havana conferred upon mankind when he formed the correct idea of how yellow fever is transmitted, proved his theory by self-inoculation, and forced it upon enlightened physicians and sanitarians after it had been rejected by contemporaries who regarded him as a nuisance.
Thousands of physicians who are well acquainted with the experiments of Reed, Carroll, and Lazear, who lost their lives in yellow fever investigations, never heard of Finlay. And yet he was their inspiration, and his experiments antedated theirs by a score of years. They succumbed, willing martyrs to the great cause; but he still lives and labors, revered by those working in the higher plains of science, regarded with something akin to awe by those who hear of him casually for the first time, and now, it seems, about to receive full credit, belated though it is, from the wide world.
It is now just thirty years and two weeks since Dr. Finlay read a paper before the Royal Academy of Havana, in which he propounded the novel theory that yellow fever was propagated by through the agency of mosquitos. And it is just six weeks ago that a physician in Edinburgh, commenting on Dr. Finlay and his discover, in the course of a letter wrote:
“Considering the times, it will eventually be considered one of the most wonderful pieces of constructive work in the history of medicine, but, like every other advance, it was rejected by contemporaries. Unlike nearly all other great medical discoverers, however, he has lived to see the acceptance of his facts and has not had to die of a broken heart; but it has been enough to break any one's heart to see himself so utterly ignored while the world has been singing the praises of the men upon whom he forced his ideas.”
Further along the same physician writes:
“No doubt Reed himself, if alive, would blush at the methods used, and would continue to insist upon giving Finlay full credit for the great conception. Too high praise cannot be given also to Lazear and Carroll for their bravery, but Finlay did the self-same inoculation twenty years earlier. Finlay, indeed, used these Americans as one would a tool, and he had to force them, for they, too, laughed at him.
“It seems to me that the credit for initiating the experiments confirming Finlay's discovery is due to Leonard Wood, who, as Governor, forced the matter along in the very city where Spanish generals had positively prohibited such work.”
History of the Discovery The Medical Record, which has all the facts in its possession, has undertaken to establish the brilliant work of Dr. Finlay in such a manner that all may know of it. The editor has written an article embodying the history of the discovery. After relating that Dr. Finlay's theory, was received with incredulity and more or less good-natured ridicule, he says;
“Nothing daunted, however, with true grit he continued his observations on the remarkable coincidence between the prevalence of yellow fever and the temporary increase in the number of mosquitos—studied the anatomy, the manner of breeding, and the habits of the mosquitos, and also continued his inoculation experiments. These were begun in July, 1881, at which time he obtained a well-marked attack of yellow fever following a bite by a contaminated mosquito.
“In a paper published in The American Journal of the Medical Sciences in October, 1886, Finlay describes the mosquito which he regarded as the agent in the spread of yellow fever. It had a dark-colored body with ventral surface coated thick skin and marked with gray or white rings; on each side of the abdomen was a double row of white spots; its most striking feature was five white rings on the hind legs, present but less marked on the anterior and middle legs; white spots were visible on the side of the thorax and front of the head, while the corselet presented a combination of white lines in the figure of a two-stringed lyre; the wings when closed did not cover the body.”
Dr. Finlay made further close observations of this mosquito, which is now known to science as Stegomyia calopus (the yellow-fever mosquito,) finding that it did its flying and biting between between 9 and 10 o'clock in the morning.
“In the same article,” continues the writer, “Finlay argues with much acuteness in support of his theory, and he concludes with the passage, which we quote at length, since it sets forth so clearly the views as to the spread of yellow fever that are universally held to-day.
Dr. Finlay's Argument “From the evidence adduced in the preceding pages,’ he writes, ‘I conclude that while yellow fever is incapable of propagation by its own unaided efforts, it might be artificially communicated by inoculation, and only becomes epidemic when such inoculation can be verified by some external natural agent, such as the mosquito’”.
“The history and etiology of yellow fever exclude from our consideration as possibly agents of transmission other blood-sucking insects such as fleas &c., the habits and geographical distribution of which in no wise agree with the course of that disease; whereas a careful study of the habits and a natural history of the mosquito shows a remarkable agreement with the circumstances that favor or impede the transmission of yellow fever.”
“So far as my information goes this disease appears incapable of propagation wherever tropical do not or are not likely to exist, ceasing to be epidemic at the time limits of temperature and altitude which are incompatible with the functional activity of these insects; while, on the other hand, it spreads readily wherever they abound. From these considerations, taken in connection with my successful attempts in producing experimental yellow fever by means of the mosquito's sting, it is to be inferred that these insects are the habitual agents of transmission.”
In an article running through several numbers of The Edinburgh Medical Journal in 1894, Dr. Finlay again set forth his mosquito theory, and once more in The Medical Record, on May 27, 1899, before the United States Army Commission had proved its correctness in such a manner that there could be no denial. In the latter article he asks:
“Why should not the houses in yellow fever countries be provided with mosquito blinds, such as are used in the United States as a matter of comfort, while here it might be a question of life or death?”
He next went on to tell how the larvae might be destroyed and the mosquitos exterminated, and described ideal sanitary measures and hospital construction. In brief, he foreshadowed conditions which afterward became realities and converted hot-beds of yellow fever into delightful health resorts.
“There can be not doubt that yellow fever might be stamped out from Cuba and Puerto Rico,” he said, “and malaria reduced to a minimum. It would then be the business of the port and quarantine officers to prevent the introduction of fresh germs.”
His Dreams Realized “When the United States Army occupied Havana,” the writer continues, “Finlay saw his opportunity, and went to the sanitary authorities with his mosquito and his theory, and urged them to investigate the subject and prove the theory which he knew to be a fact. He was received with polite toleration, but without great enthusiasm. He persisted, nevertheless, in season and out of season, and in fact made such a nuisance of himself that an investigation was finally decided upon, his confidence arousing a suspicion that he might, after all, be on the right track.
“The results of this investigation are well known. Major Reed and his associates, Agramonte, Carroll, and Lazear, took Finlay's mosquito and his data and by a series of experiments, the equal of any in the annals of scientific investigation, established beyond cavil the mosquito doctrine of yellow fever transmission.
“Some of his views were found to be erroneous, which is not surprising when one considers the disadvantages under which he labored single-handed, but his basic idea was found to be absolutely correct. Making a practical application of this doctrine and perfecting the measures outlines by Finlay in his Medical Record article, the genius of Gorgas converted the two notorious pestholes, Havana and Panama, into health resorts.
“This is all ancient history, but for that very reason it is in danger of being forgotten. Even such a master of medical history as Osler forgot it in an address on the transmission of disease through the agency of blood-sucking insects, which he delivered before the London School of Tropical Medicine last Spring. In this address he omitted all mention of Finlay's work, and only when he was reminded of it by a letter from Guiteras of Havana in The Lancet did her apparently recall the great part which this pioneer has taken in the establishment of the mosquito doctrine.”
Dr. Finlay was born in Cuba and has devoted his life to the inhabitants of that island, although his work has extended to a wide sphere, but the Scotch really claim and are justly proud of him and his achievements.
“DR. FINLAY GETS FULL CREDIT NOW: HAVANA PHYSICIAN WHO SOLVED THE YELLOW FEVER PROBLEM IS EXTOLLED HERE AND ABROAD,” NEW YORK TIMES, SEPTEMBER 3, 1911.
See AlsoArthropod-borne Disease; Hemorrhagic Fevers; Host and Vector; Tropical Infectious Diseases.
BIBLIOGRAPHY
Books
Dickerson, James L. Yellow Fever: A Deadly Disease Poised to Kill Again. New York: Prometheus, 2006.
Periodicals
Woodall, Jack. “Why Mosquitoes Trump Birds.” The Scientist. (January 2006).
Web Sites
Centers for Disease Control and Prevention (CDC). “Yellow Fever - Disease and Vaccine.” <http://www.cdc.gov/ncidod/dvbid/yellowfever/index.htm> (accessed June 13, 2007).
World Health Organization. “Togo: Yellow Fever Vaccination Campaign Protects 1.3 Million People.” <http://www.who.int/features/2007/yellow_fever/en/index.html> (accessed June 13, 2007).
Jack Woodall