The Plagues Are Flying

No other disease—indeed, no other force of nature—did more to shape the evolution of American life than yellow fever. HIV-AIDS may, in a century or so, come to be regarded as an equal influence. But it was yellow fever that set the modern rules of engagement—emotional, political, scientific, and medical—in confrontations between disease and humankind. As is often the way with pathologies suppressed and illnesses prevented, the threat that yellow fever posed to society is now largely and happily forgotten. The apparent victory over a temporarily prevalent mosquito is part of the gilt-edged human history of the New World. Such are the repressions of memory, the distractions of the present.

The inquisitive reader is therefore forced to rely on primary sources to recover the sense of terror brought about by yellow fever in nineteenth-century proto-urban America. One example: Elizabeth Drinker, a Philadelphia Quaker born in 1734. She wrote a diary until six days before she died on November 24, 1807.¹ Her chronicle of domestic living provides grisly insight into the drama of yellow fever in America’s then most significant city.

The fever first struck Philadelphia in 1699. In September 1762, Drinker noted its comeback: “A Sickley time at Philada. many Persons are taken down, with Something very like the Yallow-Feaver.” During the frequent epidemics of the 1790s, she called part of her diary the “Book of Mortality.” In 1793, for instance, she described “an unusual number of funerals,” the escape of families as the “fever prevails in the City,” and the burning of tar in the streets to ward off disease. Five thousand people died during that single outbreak, 10 percent of Philadelphia’s population. Drinker recounts stories of harrowing tragedy:

…G Hesser told a sad story, of Robt. Ross Broker that he died in the night of the Yallow fever, no Body with him but his wife who was taken in labour while he was dying, she opend the window and call’d for help, but obtain’d none, in the morning some one went in to see how they fair’d, found the man and his wife both dead, and a new born infant alive….

The number of dead exceeded all expectations. In September 1793, Drinker reported:

…it is said that many are bury’d after night, and taken in carts to their graves…. we have also heard to day that the dead are put in their Coffins just as they die without changing their cloths or laying out, are buried in an hour or two after their disease…. Coffins were keept ready made in piles.

The marks of these epidemics have been erased from the city’s public exterior. When I was there recently the only visible memorial—pointed out to me by an elderly man sitting beneath the Bicentennial Bell—was a U-shaped depression in the ground beside Carpenters’ Hall. An old sewer. And this for an epidemic about which, during fierce public petitioning for George Washington to declare war in support of the French Revolution, John Adams claimed that “nothing but the yellow fever…could have saved the United States from a total revolution of government.”

1.

Yellow fever is caused by a virus transmitted to human beings in villages and towns by a delicate-looking mosquito called Aedes aegypti, although the connection between mosquitoes and the fever wasn’t established until 1900. When the yellow fever–infected mosquito enters a human settlement, outbreaks of disease tend to be explosive—and mortal. An epidemic in Ethiopia between 1960 and 1962 killed as many as 30,000 people. The disease itself is particularly horrible. Illness begins abruptly with fever, headache, and muscle pain. The victim is extremely ill with bleeding and violent episodes of vomiting. Within a few days, the pulse slows, blood pressure falls, and the kidneys fail. Blood oozes from every tissue surface. When the infection is severe, half of those affected die.

Margaret Humphreys, a respected historian of science, has shown how the human slaughter brought about by yellow fever almost by itself precipitated the creation of important US public health institutions, including the US Public Health Service, which was set up, Humphreys argues, largely in response to yellow fever’s effects on American commerce.² Each epidemic in the nineteenth century—and New Orleans took the brunt of the disease—“stopped trains and bottled up ports, keeping cotton from the mills and preventing the movement of basic merchandise from distribution points in cities to the countryside.” Boards of health were set up to combat yellow fever’s threat. Thus,

Yellow fever was crucial to the expansion of federal public health involvement in the late nineteenth century, largely because, unlike any other disease that steadily afflicted the country, it was fundamentally a national problem.

In her powerful and original analysis, Humphreys tried to lay down universal criteria that any new health threat must meet in order to command serious political attention. Her conclusions remain relevant today. The theory surrounding the disease, she writes, should be agreed upon by scientists; proposed intervention measures should be affordable; the rights of citizens should be disrupted only minimally by those measures; the risk of disease should hang over a substantial proportion of the population; and the actions to be taken must be understandable and acceptable to the public. A public health movement arose in response to yellow fever. The Public Health and Marine-Hospital Service—marine hospitals were responsible for the seamen’s well-being—was finally enacted into federal law in 1902. The disease was extinguished from North American shores by 1905.

Yellow fever also galvanized an unusually public debate about the epistemology of disease. The issue mattered because of a prevailing medical view that the yellow fever epidemic of 1793 had been imported from the West Indies. If correct, extensive quarantine measures at ports and in major cities would have been the only means of future protection. Such interventions would have seriously damaged expanding but fragile commercial networks. The dispute could not be left to sterile musings within the salons of academic medicine. Instead, Noah Webster, lawyer, journalist, lexicographer, and the first historian of epidemic diseases, took the debate out of doctors’ hands and made it a public issue. He pieced together information from medical and philosophical societies to construct a new theory to explain yellow fever as depending “wholly on the constitution of our own atmosphere,” and perhaps most of all on “the poisonous acids, extricated from every species of filth in hot weather.”

As a layman with extraordinary forensic skills, Webster challenged physicians of the time—in particular, Dr. William Currie of Philadelphia, a man described by Dr. Benjamin Rush as “the oracle of our city upon the subject of yellow fever.” Webster set out his contrary ideas in twenty-five letters published in the New York Commercial Advertiser in 1797.³ It is one of the earliest and most important examples of investigative journalism provoking discussion about a subject of crucial civic and public health significance.

One freakish modern branch of this history concerns American enthusiasm for yellow fever as a biological weapon. In now declassified government documents, a glimpse can be had of the US biological warfare program between 1945 and 1960.⁴ Yellow fever, together with its urban mosquito vector Aedes aegypti, was a great military hope. Work began on offensive mosquito strategies in 1953 at Camp Detrick. The advantages of a mosquito attack were plain—the virus is injected into the human body directly; as long as the mosquito is alive, the release area is dangerous; there is no known cure for yellow fever; the population of the USSR would be highly susceptible; and vaccination programs would be impossible to organize quickly enough. In 1956, field trials using uninfected mosquitos began in Georgia and Florida. These insects were good carriers: mosquitos spread over several square miles. Fort Detrick could produce up to half a million mosquitos each month.

Part of this early work was completed by Dr. Lewis Gebhardt, a scientist at the University of Utah. Together with colleagues elsewhere, Gebhardt defined the requirements for a successful urban yellow fever attack. His team studied the advantages and drawbacks of several mosquito species, the complexities of Eurasian meteorological conditions (notably around Moscow, Stalingrad, and Vladivostok), and the defensive capacities of these regions, and they appraised plans for mosquito attack. Their analyses were followed by Project Bellwether and Operations Big Buzz and Magic Sword. Bellwether, conducted in 1959 and 1960, centered on studying the biting potential of starved female mosquitos at various distances, wind speeds, temperatures, and humidities, together with experiments in several simulated urban settings. Big Buzz set out to assess the feasibility of mass production of mosquitos and their use in munitions. (In these documents, China crops up as another US target.) Magic Sword took Bellwether a step further by detailing precise attack rates per thousand mosquitos released. President Nixon eventually terminated US research into offensive biological warfare in 1969.

In Mosquito, Andrew Spielman, a distinguished Harvard investigator into mosquito-borne diseases and a professor of tropical public health, summarizes the history of yellow fever’s discovery and the complex interplay of Cuban and American scientific rivalry that tied the infection to the Aedes species. After twenty years of research and debate between scientists in Havana and Washington, D.C., it fell to Walter Reed in 1900 to announce yellow fever’s true source of transmission. (The virus was eventually isolated in 1927.) A century later, as Spielman notes ruefully, “after a person is infected, there is little even today that physicians can do.” Indeed, as the Ethiopia epidemic underlines, there was a fatal slackening of interest in yellow fever during the twentieth century, so much so that only in 1983 did the World Health Organization gather yellow fever experts together in Dakar, Senegal, to reach a consensus on how to deal with this emerging global menace.⁵

Since 1983, yellow fever has ignored the efforts of these scientists. In Africa, almost five hundred million people live at risk for the disease. The virus is endemic in nine South American nations, including much of Brazil, Venezuela, Colombia, Peru, and Bolivia. And the threat is spreading. Yellow fever epidemics are occurring more frequently and the numbers of mosquitos are increasing. A yellow fever outbreak occurred in Kenya for the first time in 1992.⁶ The worst outbreak in Brazil during the past twenty years took place in 1993. Yellow fever reemerged in Senegal in 1995. And the first instance of urban yellow fever in the Americas for half a century was described in 1999.⁷ WHO again convened its expert forces in 1998 to examine why the disease was reemerging.

The reasons are twofold. First, the relation between human settlements and the forests from which yellow fever emerges is changing fast. In the Kerio Valley, where the Kenyan epidemic began, a road had recently been cut through the bush. Opportunities for mosquitos to be transported out of the valley, or for humans to come into the region at risk, have widened significantly. With high birth rates in many of these regions, forests have been destroyed to make way for human habitation, thereby opening up new contact points between susceptible humans and virus-loaded mosquitos.

Second, although there is an effective vaccine against yellow fever, coverage of the populations at risk is low. For successful prevention, vaccination rates need to exceed 80 percent. They never do. The outbreaks in Brazil and Senegal were largely owing to a lack of vaccination. Part of the difficulty is practical. The yellow fever vaccine contains a live but attenuated virus, and so has a short shelf-life. It is easily damaged if removed from reliable refrigeration. But there is also the issue of political will. Vaccination campaigns are often poorly planned and usually do not form part of a coherent regional or national strategy against yellow fever. The motivation to deploy yellow fever vaccine is likely to be questioned still further with recent reports of serious (but rare) adverse reactions associated with the only vaccine currently available.⁸ African and South American governments have repeatedly failed to appreciate the damaging effects of the disease on their own country’s economic and social development. Meanwhile, in 2001, WHO continues to report new outbreaks in Guinea, Brazil, and the Ivory Coast. The lessons of yellow fever in the southern United States remain to be learned elsewhere.

2.

Search your house for the corpse of a common mosquito—Culex pipiens —and take a look at it under a microscope or a powerful hand lens. The image you will see is one of frightening beauty. The head is a compact black bullet from which emerge long thick spikes of hair, two segmented antennae, and clamp-like mandibles. A thin rod of a neck joins the head to the thorax, which is hunched and anchors the wings firmly in place. These wings are variegated and flecked with pigment, taking on the radiant transparency of monochrome stained glass. The six legs are long, bristled, and jointed. The mosquito’s back is arched into spring-like readiness; the entire body is shaped for attack.

Whatever its human cost, Spielman clearly admires the mosquito. He is captivated by its power: “No animal on earth has touched so directly and profoundly the lives of so many human beings.” He considers our position toward the mosquito nothing less than a “relationship.” Indeed, “It may be difficult to love the mosquito but anyone who comes to know her well develops a deep appreciation.” Spielman’s adjectives are telling: the mosquito is, variously, iridescent, beautiful, exquisite, hardy, clever, relentless, elegant, fascinating, and bizarre. He eventually throws biological caution to the wind: this insect “thinks with her skin.” Spielman is not naive in his admiration. He readily admits that the mosquito is brutally “self-serving.” It lives to eat and copulate. Nothing more.

The mosquito is an evolutionary exercise in subtle biological engineering. Its anatomy boasts trumpets and siphons. Culex pipiens must beat its wings up to five hundred times a second to fly at a modest three miles per hour. Yet its life is visceral in the extreme. One New Zealand male mosquito loiters around developing adults in their pupae, awaiting the emergence of virgin females on which it pounces with only one thought in its insect mind—“essentially a rape,” Spielman concludes. Sometimes a male Culex is so firmly engaged with its female partner that withdrawal can only be achieved by tearing off the male sex organ. Spielman also debunks common myths. While a female mosquito may like to feed on human blood, a more likely source of food is sugary plant nectar. Blood is only necessary to help drive egg production. (One myth that is true: only females bite.)

To such information one could add that there are well over two thousand species of mosquito (seventy-three of which live in Florida); salt-marsh mosquitos can migrate up to a hundred miles; a mosquito can smell a host up to thirty miles away; and there is a board game for children called “Know Mosquitos.”

But the theme of Spielman’s book is far more than a natural history of the lives and loves of mosquitos. He tells the story of how human beings have tried to control and eradicate mosquito-borne diseases, and how these campaigns have frequently failed. He does not revel in human defeat. Rather, he wishes to draw attention to the extraordinary adaptability of these insects. They live in a state of total war with predatory microbes, worms, ants, beetles, dragonflies, bats, and geckos. But human beings have become their chief enemy. And what we do commonly gives fresh life to mosquitos and their accompanying diseases.

Spielman’s best example is Aedes albopictus, the Asian tiger mosquito that transmits dengue and other viral encephalitides. The Asian tiger was discovered in the US in 1983. It had most likely traveled to its new home—Memphis, Tennessee—from abroad. By 1985, Aedes albopictus had taken root in Texas. The origin of this unusual mosquito species was the importation of billions of tires into the US from Asia. A disturbance in the ecological balance created the conditions for a new mosquito to bring new diseases before us. Spielman argues that the mosquito has a “remarkable ability to adapt and specialize,” and that we humans are the main force behind this sometimes dangerous adaptation.⁹ New species of mosquito are still discovered in the US every few years.

West Nile virus is a good example of how a new mosquito-borne infection can come from nowhere, or so it seems, to threaten an unsuspecting urban population. The virus leaped to New Yorkers’ attention in August 1999. By September there had been sixty-two cases and seven deaths. The characteristic illness was an encephalitis, a meningitis, or both. Older peo-ple were especially vulnerable. Infections centered on northern Queens and the South Bronx, although the entire city was gripped with panic. Mayor Rudolph Giuliani promised “to wipe out the mosquito.” Public health officials took thousands of specimens and isolated twenty-four species of mosquito. But Spielman believes that scientists should have done better: they “could have subjected the samples that were sent to more thorough testing.” Indeed, these experts thought they were dealing with an entirely different virus. They were wrong.

The primary hosts for West Nile virus are birds. Human beings become infected incidentally when the infection spills over from badly stricken bird communities. In the Bronx Zoo, for example, a Chilean flamingo, a bald eagle, and assorted cormorants, herons, gulls, and mallards were all struck down. The message to the public during the outbreak of 1999 was to avoid bites. While New Yorkers were hastily rolling down their sleeves and covering up their ankles, the city’s response was to begin ground and aerial insecticide spraying to reduce the density of adult mosquito populations. This chemical cull was readily embraced by politicians and the public alike. The criteria cited by Humphreys for mounting an acceptable response to these sudden mosquito attacks were all satisfied. By the end of the year, a survey of Queens residents suggested that as many as one in five people with evidence of West Nile virus contact had developed an abnormal fever in the previous months, a surprisingly high frequency. As a recent report points out, this outbreak of West Nile virus is the first ever to have been detected in the Western Hemisphere.¹⁰ The virus was originally discovered in the West Nile district of Uganda in 1937. Genetic analysis of the New York strain indicated that it may have originated from the Middle East, perhaps via an infected migratory or imported bird.¹¹

By 2000, the New York public health department was ready for a return of the virus—and it came. But this time only twenty-one New Yorkers contracted the infection, although two people died. The epicenter of the outbreak shifted to Staten Island, and the virus spread out to New Jersey (six cases) and Connecticut (one case). The smaller number of infections may have reflected successful efforts to control mosquito populations. Insecticide spraying schedules began early to cut down the numbers of adult mosquitos. To allay additional public anxiety about an atmosphere full of toxic insecticide, advance warnings of spraying were given on local radio networks. Whatever the reason for the smaller outbreak—and it could have been natural variability in infection rates—nobody is taking any chances in 2001. New York State has set aside $20 million for West Nile virus research and control programs, and the Centers for Disease Control and Prevention have added a further $4 million.¹² A new research group has been established near Albany.

Since birds are the natural hosts for West Nile virus, a dead bird is an ominous warning—an indicator that the virus might be prevalent once again. When a dead bird is stumbled across, and tests positive for West Nile virus, the area around the site becomes a center for intensive mosquito-control strategies. In 2000, dead birds were discovered in late June, and virus-carrying mosquitos were subsequently found in July.

On May 8 of this year, I attended a lecture given by Roger Nasci, a research entomologist at the Centers for Disease Control and Prevention. He was speaking at the annual Washington, D.C., conference of the American Mosquito Control Association. To the audible gasps of an obviously agitated audience, he announced that the first two dead West Nile virus–positive crows had recently been found in New Jersey—one in Bergen County on April 30, and one in Middlesex County on May 2. The West Nile virus season had started early. Since then, a virus-positive dead crow has been reported in Westchester County, New York. Pennsylvania expects West Nile virus to spread across its state borders too, and is spending over $11 million on West Nile virus detection and eradication schemes.¹³ Eastern seaboard newspapers carry regular articles on how to keep the virus at bay.¹⁴ Nobody knows yet how this year’s outbreak will turn out. But West Nile virus should be considered in anyone on the east coast of the US who develops an unexplained summertime fever, especially if it is accompanied by a headache.

3.

Is it time to award victory to mosquitos? Not quite yet, perhaps, although the outlook for human beings is far from encouraging. Take malaria. Ronald Ross pinned the blame for malaria transmission on the Anopheles mosquito in 1897, and he received the Nobel Prize for his efforts in 1902. By the 1930s, leading malaria experts were focusing on the mosquito as the target for disease control. According to Spielman, they “had come to see the mosquito as a formidable but vulnerable enemy that should be subjected to an all-out war.”¹⁵

But public health policies of zero tolerance toward mosquitos—the principal instrument being the insecticide DDT—failed. Spielman’s experience working for the Tennessee Valley Authority in the 1950s taught him that “economic development, especially improvements in rural communities, had been the keys to a positive cycle of wealth and health.” The mosquito was too simple a target:

In reality, mosquitos are a pest and a threat that require people to mount a consistent, sophisticated, and even strategic defense. The impulse to smash the enemy must be measured against the knowledge that, in the case of a weapon like DDT, it is possible to go too far.

The 1990s have seen a return of optimism to malaria control programs. Facing an annual death toll of one million people, together with three hundred million new acute infections each year, the director-general of WHO, Gro Harlem Brundtland, launched a Roll Back Malaria campaign in 1998. Her target is more modest than the earlier goal of total eradication—to halve the world’s malaria burden by 2010. This will be immensely difficult. Ninety percent of deaths take place in Africa, and so commitment from African nations is an absolute prerequisite for success. The 2000 Abuja Declaration was signed by forty-four African governments. It advocated new efforts to strengthen health systems, thereby assisting anti-malaria initiatives, such as drug treatment, provision of insecticide-impregnated mosquito nets, and other preventive measures.

April 25, 2001, was designated Africa Malaria Day to reinforce the promises of a year earlier. The signs are hopeful for this renewed global effort.¹⁶ But hubris is always close at hand. Writing almost a decade ago about anti-malaria programs, Spielman cautioned that grandiose “global solutions tend to be the most dangerous.”¹⁷

One variable is outside even WHO’s control—namely, climate change. Despite President Bush’s wobbling on the subject, glaciers are shrinking, permafrost is thawing, Arctic ice is thinning, the land surface is warming, and ocean temperatures are rising.¹⁸ Climate clearly influences malaria, together with many other mosquito-borne infections. Higher temperatures support the malaria life cycle. The amount, intensity, and timing of rainfall affect breeding sites. Humidity shapes mosquito behavior. Strong wind stops mosquitos from biting. It is not surprising that some scientists have predicted a heightened threat from “vector-borne” diseases such as malaria with the acceleration of global warming. But is there any substance to these claims?

Paul Reiter, a respected American entomologist, calls forecasts of this sort “indefensible.”¹⁹ A federally mandated review of climate change and health concluded that “the levels of uncertainty preclude any definitive statement on the direction of potential future change…. Most of the US population is protected against adverse health outcomes associated with weather.”²⁰ But in a recent study of how malaria will be affected by a warmer planet, the zoologists David Rogers and Sarah Randolph find changes, although small, in expected malaria distribution.²¹ By 2050 malaria may have spread northward into the southern United States, southward in Brazil, westward in China, and across into Central Asia. Malaria transmission may also be enhanced by the El Niño Southern Oscillation, a periodic variation in Pacific Ocean temperature and atmospheric pressure that occurs every two to seven years.²² The UK government issued a warning this year that malaria could return to the English landscape by 2020. And dengue, another mosquito-borne disease, which currently places 1.5 billion people at risk of infection, is projected to put 4.1 billion people at risk by 2055.²³

What new measures might be taken to block the mosquito’s incursions on human health? Inevitably, much fashionable emphasis is being placed on genomics. In March 2001, an international group of scientists met in Paris to agree on principles for sequencing the genome of Anopheles gambiae, the most important carrier of malaria in sub-Saharan Africa. The hope is that the mosquito’s DNA sequence, which stretches the length of about one large human chromosome, will open up new possibilities for neutralizing the increasingly drug- and insecticide-resistant malaria parasite. A rough draft of the genome is expected by the end of this year. A similar research project is planned for the genome of Aedes aegypti.

Spielman is not especially impressed by these initiatives. As an old entomological hand who learned his craft in swampy salt pools and on exotic islands rather than in the laboratory, he writes:

For nearly twenty years, those who set the agenda for science funding have taken an optimistic view of the myriad obstacles to the genetic approach to disease-bearing mosquitos. They felt that the power of modern science is limitless. The practice of molecular biology is wonderfully exciting, involving ingenious experiments based on technology that can, at times, seem almost magical. But laboratory work is reductionist.

So while he supports realistic programs like Roll Back Malaria, Spielman wants to plan for a “permanent fix” beyond 2010. The answers will lie in reversing poverty and encouraging intelligent development—education, primary health care, housing, and roads. In the end, it comes down to our “relationship” with the mosquito, and the key to this relationship “is getting to know it better.” Research is important, but it should aim “to create fundamental changes in the relationship between human and mosquito populations.” In a paper written in 1994, Spielman said: “Efforts to suppress or contain a vector-borne infection should select research directions on the basis of health relevance rather than technological opportunity.”²⁴ In his new book he argues that simple measures work well, such as quickly detecting and diagnosing new outbreaks of mosquito-borne infection. They must form the basis for any successful public health strategy.

Ronald Ross would probably have agreed with Spielman. A hundred years ago, Ross wrote:

It is, of course, very desirable to make as many theoretical investigations as possible on the mosquito theory, but we must not forget that while we are considering academical details valuable lives are constantly being lost and that we are already in possession of facts solid enough to form a basis for practical action…. The duty …is distinctly one which belongs to the Governments of our malarious dependencies.²⁵

With the recent UN declaration of commitment to a US $7 to $10 billion global health fund to fight HIV-AIDS and other infectious diseases, including malaria, this lesson is a timely reminder of the urgent challenge ahead.