158 Yellow Fever

Yellow fever is an acute group B virus disease of short duration transmitted to humans by different genera of mosquitoes, but especially by the Aedes aegypti (known previously as the Stegomyia fasciata).

Known early in the New World as the “Barbados distemper,” “bleeding fever,” the “maladie de Siam,” “el peste” vomito negro, and later yellow jack (be­cause of the yellow quarantine flag flown by ships), the disease has been called by some 150 names. It was first termed “yellow fever” apparently by Grif­fin Hughes in his Natural History of Barbados (1750).

Etiology and Epidemiology

Generally speaking, humans suffer most from those illnesses for which they are not the intended host. Bubonic plague, for example, is normally a disease of rodents that has, from time to time, incidentally infected humans with devastating consequences. Similarly, yellow fever is normally a disease of non­human primates, particularly monkeys. The disease is transmitted among them by mosquito vectors, but not mosquitoes that are ordinarily attracted to hu­man beings.

When the disease leaves the treetops (as, for exam­ple, when a tree is felled), and when mosquitoes such as Aedes africanus and Aedes simpsoni in Africa and Haemogogus genera in the Americas link jungle yel­low fever with humans and begin a cycle of transmis­sion from nonhuman primate to mosquito to human, the disease is often called endemic; when the yellow fever virus is taken in the blood of an infected hu­man to heavily populated areas where the cycle is one of human to the female A. aegypti mosquito to human, the disease is termed epidemic or urban yellow fever.

The habits of the female A. aegypti have much to do with shaping the characteristics of an epidemic. She is a domestic mosquito that lives close to hu­mans, depending on them for blood meals and breed­ing in puddles or containers of water in and around their places of dwelling. Her range is very short, generally a few hundred yards at most, which means that A. aegypti requires a fairly closely packed human population. Because A. aegypti can survive only a few days without water (although her eggs can survive for years in dehydrated form) and requires water in which to breed, adequate rainfall is a prerequisite for urban yellow fever, and indeed, many of the classic epidemics have taken place shortly after a period of extended rainfall. Warm weather is another prerequisite, for A. aegypti will not bite when the temperature falls below 62^oF (or 17^oC), and extended chilly weather will send her into hibernation.

The virus also has some distinctive requirements, especially for transmission - a process in which hu­mans are best thought of as the site where the virus changes mosquitoes. This exchange can take place only during the first 3 to 6 days of infection of the yellow fever victim while the virus still remains in the blood (viremia); after the virus has entered the mosquito, it must incubate for another 9 to 18 days before the mosquito can infect another human being.

Although it has generally been thought that mon­keys serve as the reservoir for the virus, other mam­mals (marsupials and armadillos) are also suspected of carrying the virus in endemic areas, and for short periods of time the mosquito populations can act as a reservoir.

Distribution and Incidence

In the Americas epidemic yellow fever has been in rapid decline during the twentieth century, essen­tially due to efforts aimed at eradicating A. aegypti from major population centers. The last outbreak of urban yellow fever took place in Trinidad in 1954.

Nonetheless the yellow fever virus remains very much alive in the monkeys that inhabit the forests of Central and South America, and consequently a small number of human cases (between 50 and 300) continue to be reported annually among individuals who work in or live in close proximity to those for­ests. The vast majority of the cases occur in regions of Brazil, Ecuador, Venezuela, Colombia, and Peru that are drained by river networks contributing to the Orinoco, Magdalena, and Amazon systems. A bit earlier in the century, human cases of the disease were also reported with some regularity in Central America, Bolivia, Argentina, and Paraguay.

In Africa, severe epidemics of urban yellow fever still occur from time to time; a notable recent exam­ple is the Ethiopian epidemic of 1961, which cost thousands of lives. Still more recently a major out­break in western and southwestern Nigeria claimed thousands of lives. Isolated human cases, however, are not reported with systematic regularity despite the vast belt of endemic yellow fever that stretches across much of that continent, and despite the pres­ence of antibodies in a great number of the in­habitants of that belt, indicating past yellow fever infection.

One mystery Sinrounding yellow fever is that it has never occurred in Asia, despite the presence there of the Aedes mosquito vector. Some think that the mosquitoes themselves in that part of the world are resistant to infection. Others suspect that a popula­tion may be able to support only so many group B arboviruses and that entrenched illnesses in this cate­gory such as dengue and Japanese encephalitis may have forestalled the advance of the yellow virus.

Immunology

An attack of yellow fever confers on the host a life­time of immunity against reinfection. Because the disease generally reserves its most severe symptoms for young adults and (as some illnesses) treats chil­dren more gently, whole populations in endemic ar­eas or in areas frequently visited by yellow fever can become more or less quietly immune as children expe­rience the illness as just one more in a train of child­hood ailments. Under such circumstances an epi­demic is never seen, unless or until large groups of newcomers suddenly arrive, such as was so often the case with immigrants, soldiers, and sailors reaching the Americas. It was this phenomenon that gave rise to yellow fever nicknames such as “strangers’ fever,” the “disease of acclimation,” and “patriotic fever.”

On the basis of the experience of both slave and free black populations in the hemisphere, however, many came to believe that blacks possessed a special (today some would say innate) ability to resist the disease. The question remains unresolved. Some have denied this ability, by pointing to urban epidem­ics in Ethiopia or Sudan and western Nigeria in which thousands of blacks lost their lives. These regions are on the edge of the endemic belt where many presumably would not have been exposed regu­larly to yellow fever, and thus would have included many with no acquired immunity. By contrast, most of the slaves reaching the Americas originated from deep within the endemic zone, and consequently would have acquired immunity to yellow fever be­fore they ever stepped aboard a slaving ship.

On the other hand, genetic selection for yellow fever resistance as a result of prolonged exposure cannot be discounted, for many of the West African descendants of those first arrivals to the Americas lived for generations in areas untouched by yellow fever, yet, without any opportunity to acquire immu­nity in advance, suffered much less than whites when the disease finally did make an appearance. It has been suggested that related arboviruses or Aaviviruses (dengue or Japanese encephalitis, for example) may confer some cross-protection against yellow fever, whereas others believe that certain strains of the illness may vary in mildness or sever­ity, depending on the groups of individuals under attack. In this latter connection it may be significant that Chinese in the New World were reputed to be almost as resistant to the illness as blacks because although yellow fever has never invaded Asia, dengue and Japanese encephalitis are endemic to much of the region.

Forttmately today one need not suffer through the illness in order to ensure resistance to it. Rather immunization can be gained with a strain of living virus called 17D, and immunization projects have been in effect since the 1930s in many regions of endemic yellow fever.

Clinical Manifestations and Pathology

The onset of symptoms generally occurs 3 to 6 days after the virus is injected into the blood. In the range of moderately severe to malignant cases, the symp­toms arrive suddenly with flushed features, severe chills, high fever, intense headache, and perhaps a backache and other muscular aches and pains. Quite often there is nausea. These symptoms continue

VIIL Major Human Diseases Past and Present throughout a restless, agitated 2 or 3 days, after which the patient characteristically experiences a remission.

From this point forward, most patients fortunately will recover, but for others, the remission will be short-lived, jaundice may set in, hallucinations fre­quently will take place, and internal hemorrhaging will occur, with the victim vomiting huge quantities of black vomitus.

Early in the course of the illness the virus sets up an infection - primarily in the liver - and multiplies to the extent that just one drop of blood contains millions of virus particles. This volume of foreign matter in the blood quickly summons an antibody response, which, if the patient recovers, remains in the blood for a lifetime to ensure that he or she never will be called upon to repeat the experience. If the patient dies, pathological findings usually reveal ex­tensive internal damage such as cardiac enlarge­ment and kidney congestion; hemorrhages of the stomach, duodenum, bladder, and mucous mem­branes; and liver necrosis.

Diagnosis

Because of its wide range of symptoms, diagnosis of yellow fever has always been difficult, and in the past the disease has doubtless been confused with many other ailments that present similar symp­toms. Examples of such illnesses are infectious Weil’s disease, dengue, tick-borne relapsing fever, Iassa fever, malaria (especially blackwater fever), scurvy, and typhoid and typhus; even illnesses such as influenza easily could have camouflaged mild yel­low fever.

History and Geography

American Versus African Hypothesis of Origin Much historical interest in yellow fever has focused on its place of origin: Africa or the Americas? Those who believe it to have been the latter have empha­sized that the disease was described and epidemics were recorded in the Western Hemisphere well over a century before it was recognized in Africa, with the first recognizable epidemic striking Barbados in 1647 and then spreading during the next 2 years to Guadeloupe, St. Kitts, Cuba, and the Yucatan Penin­sula. Moreover, Amerindian accounts and records of the early Spanish Conquistadores make mention of diseases that could have been yellow fever, such as an epidemic of 1454 on the Mexican plateau, a 1477-

97 epidemic that raged in the Yucatan, and an out­break of disease in Santo Domingo that assaulted the men of Columbus in 1493.

By contrast, the protagonists of the African hy­pothesis dismiss these outbreaks as typhus, malaria, or some other disease but not yellow fever, in large part because of immunologic evidence. Whatever the illnesses might have been they argue, the Indians were very susceptible to them; however, any en­demic presence of yellow fever should have created a high degree of immunity to it. In addition, American monkeys are demonstratively susceptible to the ill­ness, whereas West African populations of both hu­mans and monkeys have shown themselves to be quite resistant to it, suggesting a history of long exposure.

Indeed, the West Africans’ ability to resist yellow fever would explain why recognition of the disease was so slow in coming to that region. In the case of Europeans in Africa, it was difficult to distinguish among the “fevers” that fell upon them (and, in the case of portions of the British army during the early nineteenth century, were eliminating more than half of the troops annually). But judging from the extraordinarily low (by comparison) death rates of black troops serving alongside the Europeans, yel­low fever must have been prominent among them, and in this connection it is worth noting that even in this century, physicians in Africa have almost rou­tinely misdiagnosed yellow fever as malaria. Inter­estingly, too, J. P. Schotte, who is credited with first describing yellow fever in West Africa in 1778, did not claim that it was the first epidemic of the disease in the region. Rather, he discussed previous epidem­ics, in which he reported (significantly) that only the Europeans had suffered greatly.

A final piece of evidence that may point to an African cradle of yellow fever has to do with the prevalence of its A. aegypti vector. In Africa, many species of mosquitoes are more or less closely allied to the Aedes, whereas very few are thusly related in the Americas, suggesting that the vector, at least, is an import. On the other hand, it is possible (al­though unlikely) that the yellow fever virus was present in the monkey populations of the New World prior to the arrival of the Europeans but had to await the arrival of the vector in order to be trans­mitted to humans.

Certainly the timing of yellow fever’s recorded appearance in the New World does nothing to detract from the case for an African origin of the vector, and probably of the virus as well, for the decade of the 1640s was one of accelerated slave trade activity to Barbados as that island was converting its economy to one of a sugar plantation system based on slave labor. The same slave ships that could have deliv­ered the virus in black bodies doubtless did carry the mosquito in their water casks. However, whether the disease achieved endemicity by establishing it­self in the monkey populations of those few Carib­bean islands that contained monkeys can only be speculated upon, for so many of the serious out­breaks to follow also seem to be traceable directly back to Africa via the slave trade. It does seem, however, that the Yucatan Peninsula and the region around Vera Cruz became endemic foci.

Disease Outbreaks: Seventeenth Through Nineteenth Century

Having reached the Caribbean, the disease began making summer visits northward, striking New York in 1668, Philadelphia and Charleston in 1690, and Boston in 1691, while to the south, yellow fever became a regular visitor to the port cities of Colom­bia, Ecuador, and Peru. Interestingly, it disappeared from Cuba in 1655 after raging there since 1649 and, save for a visit to Santiago de Cuba in 1695, did not return until 1761, apparently because of the islands’ sparse population during this century-long period.

A similar phenomenon appears in the medical lit­erature on Brazil. There seems no doubt that the bichα or molestia da terra that struck Pernambuco in November of 1685 was yellow fever. It killed thou­sands in Recife and Olinda and spread into Cearfi before burning out about 5 years later. As was the case in the Caribbean, the outbreak in Brazil has been attributed to a ship that arrived from the Afri­can coast. However, despite a thriving slave trade that presumably could have brought the vector and virus to Brazil in countless ships, and a monkey population that some believe already harbored the virus, the region reputedly was free of the disease for the next century and a half. It is true that many slaves reaching Brazil came from Angolan and, to a lesser extent, East African regions that were outside the endemic zone of yellow fever. But many also came from regions within that zone, which makes it so perplexing that when yellow fever was allegedly reintroduced, some say that it arrived not from Af­rica but from North America, in 1849, on the brig Brazil, whose crew had been infected either in New Orleans or Havana when the ship had put in to those ports.

Equally perplexing is the selectivity yellow fever demonstrated in seeking out victims as the disease spread from Bahia to other coastal cities, for, al­though it fell upon European newcomers with consid­erable fury, it treated local blacks and whites far more gently, suggesting, of course, that the disease may have been present in the region all along — in its jungle or sylvan form - quietly immunizing the population by periodically producing mild cases in the young. Significantly, in the years immediately prior to the outbreak of the 1849 epidemic, Brazil had been the recipient of a sizable influx of Euro­pean immigrants, in addition, the population of Rio de Janeiro still included a number of individuals on their way to California. Thus in this epidemic, as in the countless ones to follow, it would be the newcom­ers who were the chief sufferers of the illness.

Yet yellow fever did not limit its assaults on Euro­peans to Africa and the Americas, but rather on notable occasions sought them out in their home­lands as well, apparently reaching the continent from the Caribbean. The Iberian Peninsula was the most common target, with periodic epidemics re­ported there throughout the eighteenth and nine­teenth centuries. The coastal cities of Oporto, Lis­bon, and Barcelona bore the brunt of these attacks, although the disease did penetrate to the heart of the peninsula from time to time, even reaching Ma­drid in 1878. Small outbreaks also occurred on occa­sion in France, England, and Italy.

Without doubt, however, yellow fever gained its most fearsome reputation in the Caribbean because of Europeans on hand to host it, often in the form of military personnel who provided the disease with a seemingly endless stream of nonimmunes. In 1655, of the 1,500 French soldiers sent to occupy Saint Lucia, only 89 were reported to have survived an onslaught of disease led by yellow fever. The decade of the 1690s saw yellow fever sweep much of the Caribbean, and whole populations of many islands thinned considerably. In 1693 the English attack on the French at Martinique collapsed in face of yellow fever, whereas in 1741, Admiral Edward Vernon’s abortive attack on Cartagena saw the loss of close to half of an original landing force of 19,000 (including many North Americans) to yellow fever.

Prisoners sent as workmen from Vera Cruz to Ha­vana in 1761 are credited with reintroducing yellow fever to Cuba where it proved a formidable ally of the Spaniards the following year in a nearly success­ful effort to deny Havana to the English. However, it was during European attempts to invade St. Dom­ingue around the turn of the century that yellow fever deaths really peaked in the Caribbean. Over the years 1793-6 the British army in the West In­dies lost some 80,000 men, with over half of the deaths attributed to yellow fever. The disease also decimated the French soon after they began their invasion of Hispaniola in 1802 and accounted for a sizable portion of the 40,000 men lost in the first 10 months of the war. After the French retreat to the islands of Martinique and Guadeloupe, yellow fever destroyed any French notions of attempting a second assault by raging among the survivors for another 3 years. It was this tremendous loss OfEuropean life to yellow fever (and to malaria) that prompted the En­glish to begin to fill West Indies regiments with black troops who were thought to be immune to the disease and demonstrated over and over again that, indeed, many were.

Because of Philadelphia’s brisk trade with the West Indies, yellow fever found its way frequently to that port city during the eighteenth century, with epidemics recorded for the years 1741, 1747, 1762, 1793, 1794, and 1797. The epidemic of 1793 was car­ried to the city by French refugees from revolution- torn San Domingue. With the turn of the nineteenth century, however, as the West Indian trade was shared to a greater extent by southern ports, it was the South that began to receive most of yellow fever’s attention, with New Orleans, Savannah, Mobile, and Charleston the most frequent ports of call for the disease.

During the first 6 decades of the nineteenth cen­tury, Savannah suffered from 15 epidemics, Charles­ton had 22, and New Orleans at least 33. The most notable of the New Orleans epidemics occurred in 1853 during which the city lost almost 8,000 indi­viduals to the disease. Chief among the victims of this and all other epidemics were Northerners and foreigners (especially the Irish), along with white Southerners from the interior. Permanent white resi­dents, however, seldom suffered from fatal yellow fever. Among blacks, it was reported by physicians that mulattoes were the most susceptible (to about the same degree as local whites), and until late in the antebellum period, “pure” blacks were believed to be totally immune. Yet in the decade or so before the Civil War, physicians began to notice that blacks did take the disease in a very mild form during epidemics - so mild that it had heretofore escaped notice.

In Brazil, too, blacks were reputed to be extraordi­narily resistant to yellow fever, whereas the Euro­pean immigrants flocking to South America in large numbers became the primary target. With the end of the slave trade in 1850, the chances of the disease entering the country from Africa were reduced. There was always the possibility that the disease would be imported from the Caribbean or North America as supposedly occurred in 1849, but in view of the almost continual epidemic onslaught of yellow fever on Bra­zilian coastal cities for the remainder of the century, it seems a reasonable supposition that the disease was endemically established in the country.

Cuba, too, was the nineteenth-century destination of European laborers (from Catholic Europe and the Canary Islands), and these, as well as numerous refugees from Spanish America and numerous Span­ish soldiers, assured yellow fever a plenitude of hosts on that island. Moreover, a contraband slave trade continued contact with the reservoir of yellow fever in Africa, and regular trade with Vera Cruz kept Cuba in touch with another endemic focus of the disease. Thus it is not surprising that Cuba became the yellow fever capital of the Caribbean. By con­trast, the disease began to wane in most of the rest of the islands as the end of the British and French slave trades and the decline of the sugar industry turned them into economic backwaters seldom vis­ited by outsiders.

The northern blockade of southern ports during the American Civil War, rather ironically, kept the South free of yellow fever for the duration by curtail­ing West Indian shipping traffic. However, the dis­ease returned to New Orleans in 1867, assaulted inland Montgomery in 1873 and Savannah in 1876, before beginning an ascent of the Mississippi River in 1878 that left countless yellow fever dead in a wake that stretched from New Orleans to Memphis, Tennessee, where 5,000 alone went to a yellow fever grave.

This 1878 epidemic almost certainly reached the United States from Cuba, where the influx of Spanish soldiers sent since 1876 to end the Ten Years’ War had provided the tinder for an epidemic that raged on that island from 1876 until 1879. Whether the Cuban epidemic also reached out to slaughter French work­ers arriving in Panama from 1878 onward to work on Ferdinand de Lesseps' abortive attempt to build a canal across the isthmus, or whether that outbreak came from an endemic jungle source is a matter of speculation. But like their predecessors, who be­tween 1851 and 1855 lost thousands of their numbers to yellow fever in building the Panamanian railroad for American financiers, the French canal workers died in droves, many even bringing their own caskets with them to the isthmus.

Transmission and Control: Twentieth Century The beginning of the end of yellow fever’s seemingly endless onslaughts on the Atlantic coastal regions of the hemisphere came just 3 years after the disas­trous yellow fever year of 1878, when Carlos Finlay y Barres of Cuba put forth his theory that the A. αegypti mosquito transmitted the disease. The theory was confirmed in 1900 through the use of human volunteers (three of whom died) by the U.S. Army Commission on Yellow Fever in Havana headed by Walter Reed. Armed with this knowledge, William Gorgas was able, by eradicating the A. αegypti, to rid Havana and consequently much of Cuba (which just 3 years previously had registered 6,000 yellow fever deaths) of the disease. Following this, Gorgas applied the same mosquito eradication methods in Panama, making it possible for workers on the American canal to avoid the fate of so many of their French predecessors. The measures were also quickly applied elsewhere so that the 1905 outbreak of yellow fever in New Orleans and the 1908-9 ap­pearance of the disease in Barbados represented, respectively, the last of the disease on North Ameri­can soil, and the last reported appearance in the Caribbean for decades.

Plans for eradicating the disease from the entire globe were put forth by Gorgas, and in 1915 the Rockefeller Foundation launched this effort with the creation of its Yellow Fever Commission. The com­mission began by concentrating on sites in Latin America, but in 1920 shifted much of its attention to Africa. In 1925 the Second Commission to West Af­rica established itself at Lagos, Nigeria, where, among other things, it was discovered that the rhe­sus monkey from India, unlike African monkeys, was susceptible to yellow fever. With that discovery, it became possible to use monkeys rather than hu­man volunteers for yellow fever experiments. None­theless, yellow fever research remained a dangerous affair, and Adrian Stokes, Hideyo Noguchi, William A. Young, and Theodore B. Hayne all perished from the disease in Africa during these “heroic days” of yellow fever research, which by 1929 had demon­strated beyond doubt that yellow fever was the re­sult of infection by a virus.

In Brazil, the knowledge gained by the Reed Com­mission in Havana was quickly applied by Oswaldo Cruz to a mosquito eradication campaign that freed major coastal cities from the terror of almost unre­mitting yellow fever assaults for the first time in over a half-century. Despite the campaign, however, the disease stubbornly refused to disappear from Brazil. Sporadic outbreaks continued with puzzling frequency in that country, and in Peru, Ecuador, and Venezuela and Colombia as well, all of which shared portions of South America’s great rain forest.

In 1923 the International Health Division of the Rockefeller Foundation accepted Brazil’s invitation to administer the Brazilian Yellow Fever Service and, under the direction of Fred Soper, conducted immunologic surveys which showed that many Bra­zilians residing close to the forest regions had hosted yellow fever in the past. In 1928 a yellow fever epidemic in Rio, which had been free from the dis­ease for over two decades, triggered investigations revealing that yellow fever could spread in the ab­sence of the A. aegypti mosquito, and that the dis­ease was very much alive in the monkey inhabitants of the great South American rain forest. Jungle yel­low fever had been discovered, and with that discov­ery most of the final riddles connected with yellow fever transmission were resolved.

Meanwhile, as mentioned previously, by the late 1920s workers in Africa had demonstrated that the rhesus monkey was susceptible to yellow fever; thus with an animal that could be used in laboratory experiments, efforts to isolate the yellow fever virus were begun. Shortly afterward Max Theiler discov­ered that the disease could also be transmitted to white mice, which were less expensive and certainly easier to handle experimental animals. Next Theiler showed that if the virus was transmitted from mouse to mouse, it became sufficiently weakened that it could be used to inoculate and immunize monkeys against yellow fever. More effort on the part of Theiler and co-workers led, by the late 1930s, to a further attenuation of the virus, called the 17D Valline strain, which is a mutation of the virus achieved by successive passage of virus in cultures and chick embryo tissues. It is harmless to humans, but immunizes them against the disease.

The development of a vaccine against yellow fever was crucial, for with the discovery of jungle yellow fever came the realization that yellow fever could not be wiped out after all. This vaccination became the only method of yellow fever prevention in re­gions where mosquito eradication was not practical. The virus is always present in monkeys and perhaps other wild creatures of the forests, and consequently cannot be pinpointed.

For this reason epidemiologists are particularly alarmed at the relaxation of mosquito control mea­sures in the Western Hemisphere, where very few have been vaccinated. In the southern portions of the United States and much of the Caribbean and Central America, A. aegypti has reestablished it­self, and Brazil, once apparently free from the mos­quito, has reimported it from North America. With modern air travel, an infected individual - or even mosquito - could easily be whisked from the South American or African forests to any number of large cities where A. aegypti again resides in large num­bers, and stands ready to spread the disease throughout nonimmune populations. In addition, Aedes albopictus, a close relative of A. aegypti, has recently (within the last decade) been introduced to the United States from its native habitat in the Orient. Laboratory studies have revealed A. albopic­tus to be fully susceptible to the yellow fever virus and capable of transmitting it to vertebrates, and it is known to be a prominent vector of dengue as well. Its habits, feeding preferences, and general biology closely resemble those of its more famous congener, and both can inhabit the same areas. Moreover, the newcomer is more tolerant of cold weather, and it has spread widely in the United States. Its spread to the West Indies, and Central and South America is feared. As Wilbur Downs stated in a personal communication, “It could prove to be a most unwelcome contributor to yellow fever epidemiology in coming decades.”

Donald B. Cooper and Kenneth F. Kiple

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