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Disease Forecasting

Relying on satellites, computers, African hunters and even the humble chicken, researchers are building disease warning systems to catch viruses on the verge of sparking epidemics.

By Jim Duffy

Nathan Wolfe has spent his share of time in Central Africa. As an assistant professor of Epidemiology, he's also done his share of thinking about the AIDS pandemic that emerged from the African jungle to take 20 million—and counting—lives around the world.

Is this the way things had to turn out?

"Think about what an earlier warning of just five years or 10 years on that pandemic could have meant," says Wolfe, DSc. "It would have been monumental in terms of the lives and the billions of dollars it would have saved."

The emergence of new threats—whether AIDS or Ebola in recent years or cholera or smallpox in the past—is nothing new to public health. AIDS has been deadlier than most scourges, to be sure, but public health developed over the centuries in response to an ever-changing cast of diseases. It is always scrambling to learn the workings of a strange new foe in time to stem a rising tide of disease.

In this sense at least, the fieldwork is reactive. The question Wolfe and a number of fellow researchers are now asking is this: What if public health fieldwork could be proactive as well? What if it could anticipate emerging diseases before they gain a foothold? What if it saw where the next pandemic-ready killer would likely come from? What if it knew how the next one would likely behave and evolve?

Such a future may not be so far out of reach. Don Burke, a professor of International Health, has been a pioneer in forecasting emerging diseases, advocating for the importance of prediction and prevention, and assembling a cadre of like-minded faculty (including Wolfe), postdocs and graduate students. The scientific world glimpsed the power of scientific prediction in 1997, when Burke examined the relative levels of future threats posed by various viruses. His stock lecture around that time featured a memorable laugh line.

"If I were king," he said time and again, "I'd be investing in coronaviruses."

Previously, coronaviruses (gene-swapping viruses common in animal populations) had been known only to cause sporadic minor illnesses in humans, like colds—never a major epidemic. That changed in 2003, when the SARS epidemic caught everyone by surprise, or at least everyone who hadn't heard one of Burke's lectures.

This work of forecasting emerging disease threats remains a rather novel undertaking. But it's one that Burke, Wolfe and other Bloomberg School researchers and alumni are pursuing in places as far-flung as Cameroon, Thailand and Chile. The projects described in this story all have the potential to boost human health in the here and now. But all also aim to spur the development of public health toward a future in which it gains powerful new predictive tools.

The work is full of unknowns. Science knows surprisingly little about zoonosis, the emergence of human disease from other animals. It knows little about the reservoir of diseases in animals or how those diseases move among species. Much remains mysterious, too, about how viruses fit into the broader ecological environment.

"But all these things are knowable, to some degree," says Burke, MD. "It could very well be that we're entering a phase—especially in microbiology— where we can seriously start tracking individual virus strains and how they interact with each other, where we can finally start to measure the right things and ask the right questions."

Tracking Hunters

Nathan Wolfe expected that he'd prove his point eventually, but he didn't expect to do it so quickly. His initial batch of blood samples covered only 1,000 hunters in Central Africa, and that's a small window to peer through while looking at the population-level risk of contracting chronic retroviruses from nonhuman primates. (Retro-viruses like HIV insinuate themselves in a host cell's DNA and then replicate, making it difficult for the immune system to destroy them.)

Wolfe had long harbored doubts about the conventional but unproven wisdom that such viruses cross into humans only rarely. In 1998, while a doctoral student at Harvard, he mused in the journal Emerging Infectious Diseases about the surprises that might turn up if scientists looked closely at hunters working in a biodiversity hotspot.

"Shortly after that came out—I was in Borneo at the time—I got this strange email from my mother," Wolfe recalls. "Some general from the U.S. military was calling for me, and my mother wanted to know what sort of trouble I was in."

That "general" turned out to be Colonel Don Burke, then a public health officer with the U.S. Army's Walter Reed Hospital. When Wolfe got in touch, Burke dangled before him the prospect of postdoctoral fieldwork in Cameroon. The jungles there boast all the biodiversity—and hence, viral diversity—Wolfe could ask for. And as primate hunting makes for a lot of bloody mixing among the species, why shouldn't viruses jump from one to another?

"These are basic biological phenomena we're talking about," Wolfe says. "All sorts of things have the potential to move back and forth."

Initially, Wolfe set out to develop a cross-sectional picture of hunters' exposures to primate retroviruses. Hunters have drawn scant scientific interest over the years, in part because they are seen by many as a threat to endangered animals.

Primate hunting in the biologically diverse jungles of Central Africa makes for a lot of bloody mixing among the species. Why shouldn't viruses jump from one to another?

"When we go in these villages, what we find is that no one has ever showed any interest in their health or in their work," Wolfe says. "Nobody has even come in to talk with them."

Wolfe learned early on that the ways his hunters interact with their ecosystem have changed recently, increasing their exposures to other primates. Greater access to firearms has made hunters more efficient. New logging roads have opened the way into previously inaccessible hunting grounds and simultaneously connected hunters with new urban bushmeat markets.

When Wolfe gathered blood from hunters, he divided each sample proactively into plasma and lymphocyte collections to facilitate tracking the genetic lineage of any viruses that popped up. Last year, in The Lancet, Wolfe reported that 10, or 1 percent, of his 1,000 samples had antibodies to simian foamy viruses (SFV), one of the three classes of retroviruses found in African primates. Among the 10 were SFVs from three different primates: the mandrill, the gorilla and the DeBrazza's guenon.

Such transmissions had never before been documented in the wild.

Next, Wolfe turned to the deltaretroviruses. Unlike SFVs, these have been known to cause human illness. Only two deltas—HTLV-1 and HTLV-2—had been detected in humans until earlier this year when Wolfe, Burke and others announced in the Proceedings of the National Academy of Sciencesthat they had doubled that total by discovering two more.

Wolfe and University of Yaoundé doctoral student Cyrille Djoko are now combing the samples for the lentiviruses that include the simian immunodeficiency viruses (SIV), the source in humans of HIV-1 and HIV-2. Wolfe sees no reason to expect anything different in this class, so look for him to report soon that some of his hunters are carrying SIVs.

"And all of these discoveries have come out of those first 1,000 samples," Wolfe says. "We've only looked at 20 or 30 percent of our existing collection."

Wolfe is now aiming to develop a longitudinal portrait of the workings of zoonosis in the Central African jungle. In addition to donating their own blood, hunters are gathering filter-paper samples from animals they kill.

One of Wolfe and Burke's doctoral students, David Sintasath, is analyzing these for prevalence data on retro-viruses among nonhuman primates. (Another, Amy Peterson, is screening for similar numbers on primate malarias.)

Wolfe is well-positioned, then, to boost basic knowledge about primate viruses and their movement into humans. He's hopeful that his work will shed light on lingering mysteries surrounding the precise origins of the AIDS epidemic. And he has a chance, too, at an exciting scientific first: capturing the "actual moment" of a virus transmission via samples from both hunted and hunter.

"That's not going to be easy," he says, "but it's something we have the potential to do."

Smallpox's Lethal Cousin

But Wolfe is not waiting until all this basic science is sorted out before pursuing a future in which science can see the next AIDS coming in enough time to make a monumental difference. It's the driving force behind a just-off-the-ground collaboration with Anne Rimoin, an assistant professor of Epidemiology at the UCLA School of Public Health and adjunct assistant professor in International Health at the Bloomberg School.

Rimoin, too, studies African hunters. Her hunters are even more isolated than Wolfe's, as she spends half of each year in a stretch of the Democratic Republic of Congo (DRC, formerly Zaire) accessible only by cargo plane.

"Basically, I'm the only person crazy enough to go out there," says Rimoin, PhD '03. Her research centers on monkeypox. The relative of smallpox was discovered in 1958 in laboratory monkeys, though its real animal reservoir remains unknown. It was first observed in humans in 1970, at the tail end of the smallpox eradication campaign. While rarely fatal in the developed world, according to the Centers for Disease Control (CDC), monkeypox can kill as many as 10 percent of its victims in less developed countries.

Most experts who looked at monkeypox early on in places like DRC weren't overly concerned. They saw a rural disease in countries that were urbanizing. They saw a hunter's disease in countries increasingly using domesticated livestock.

But neither trend survived the onset in the late 1990s of the Second Congo War, which claimed millions of lives and is considered the world's deadliest conflict since World War II. The military forces that occupied the area where Rimoin now works slaughtered livestock, burned fields and brutalized the local populace, driving them into the rainforest. "People are now exclusively reliant on bushmeat," reports Rimoin.

Big picture, eye-in-the-sky technology now chases epidemiological mysteries: Satellite imagery of the southwestern U.S. uncovered a chain of natural events that culminated in a 1993 hantavirus outbreak.

When reports of monkeypox cases began filtering out of the jungle, Rimoin got in touch with DRC's public health officials and volunteered to investigate. The disease had always been regarded as one that appeared only in brief, sporadic outbreaks, but what Rimoin found was something else: endemic monkeypox.

Her research is an attempt to sort through the biological, ecological, epidemiological and sociological factors behind this surprise. How much of the monkeypox that she is finding can be attributed to increased exposures? Is its resurgence related to the disappearance of smallpox, an ecological competitor? Why does the disease predominantly strike young adolescents?

"There are lots of reasons why this is a very, very interesting disease," Rimoin says.

In her collaboration with Wolfe, Rimoin will gather information on Wolfe's retroviruses from her hunters, while Wolfe will bring Rimoin's acute disease surveillance techniques to Cameroon.

But their goal is bigger than this simple swap of information and techniques. They're out to create a pair of pilot "hunter networks" to serve as sentinel stations that could warn of the emergence of new viral disease.

Key to the project will be building a strong relationship with hunting communities. "In the past, they've been considered the enemy of conservation," Rimoin says. "But we're looking at them as an untapped resource. We're not just going to engage them as study participants. We'll also work with them as active collaborators."

Hunters will monitor the jungle for animal die-offs, often a precursor to human disease. They will alert researchers to new and virulent human disease events. In addition, researchers and hunters will look together at hunting behaviors such as butchering, with an eye toward developing techniques that protect hunters' health.

These networks are prototypes for the sort of sentinel disease surveillance stations that may someday operate in disease hotspots around the world, sounding alerts to the appearance of new pathogens. To Wolfe, this is a critical next step for public health.

"In a hundred years," he says, "I [don't want] people to look back at the way we do things today and say, 'They went chasing after diseases too late. They didn't pay attention until the diseases were global.' That's not doing it the right way."

Viruses on the Move

Greg Glass, PhD, worked backward to find his way to disease forecasting. In 1993, a colleague aware of Glass's expertise tracking viruses spread by rats asked him to look at an outbreak of hantavirus pulmonary syndrome (HPS) in the southwestern United States' Four Corners region (where New Mexico, Colorado, Utah and Arizona meet). Rare but potentially deadly, HPS is caused by a virus that makes its way to humans through air they breathe near rodent droppings, urine or saliva.

Trained as an ecologist, Glass looked first at the big environmental picture. "Basically, all infectious diseases are two or more populations—humans and pathogens—coming together," he says. "The pathogens might be in mice or in monkeys, whatever. If you find where things overlap, you find where the action is."

Countless factors—weather fluctuations, vegetation patterns, insect abundance, predator populations and the like—can drive shifts in mice populations. Glass, a professor of Molecular Microbiology and Immunology, needed to identify which ones were both in common among and exclusive to the outbreak's hotspots.

This involved extensive fieldwork, of course, but Glass's specialty is using satellite imagery to chase epidemiological mysteries. This was still regarded as a newfangled tool; not long before, Glass had applied for a grant to study rodents linked to Argentine hemorrhagic fever.

"Nobody thought it would work," he says. "One of the reviewers' comments was, 'I don't know how they expect to see mice with a satellite.'"

Not all reactions were so laughably uninformed. With Lyme disease erupting in the northeastern United States, public health officials in Maryland developed an interest in Glass's technique.

"It was quite successful," Glass says. "We took a straightforward epi approach, and by the time we got done, we'd discovered that people living in high-risk areas identified with the satellite were 20 times more likely to get Lyme disease than people living somewhere else."

In the Four Corners, the HPS outbreak at first stumped even researchers who had studied the region's rodents for decades. They were unable to differentiate in the field between sites where people were getting sick and sites where they weren't.

Satellite images told a different story. They helped Glass track the 1993 outbreak to a chain of natural events ecologists term a "trophic cascade." This particular cascade commenced with heavy 1992 rains associated with an El Niño climate variation, spurring plant growth in certain pockets of the landscape, which in turn boosted insect numbers. The next year, mice numbers were booming.

"As far as the mice are concerned, this was Garden of Eden stuff," Glass says.

The avian flu strain known as H5N1 has more than once leapt from Asia's poultry population to infect humans. Could it lead to a pandemic as deadly as the 1918 flu?

Under ordinary conditions, most Four Corners mice live at elevations higher than humans. But the population explosion of 1993 sent them into new territories and lower elevations.

"It's the reverse of the story Nathan [Wolfe] has to tell," Glass says. "What he's found is people moving into places where retroviruses are. Here, the virus is on the move, going to where people are."

It was after solving this mystery that Glass began to work backward. Had his retrospective discoveries provided him with enough information to travel back in time and predict the outbreak?

Though still a work in progress, the strategy shows great promise. Backed by a five-year NIH International Collaborations in Infectious Disease grant, Glass is embarking on a new project with colleagues in New Mexico and Chile. He is taking the satellite technique to Chile, where hantavirus is a much bigger problem than it is in the United States.

Meanwhile, Glass continues to develop predictive maps for the Four Corners. On his computer screen, the map for last summer shows one lone danger zone, a jagged stretch of yellow across a deep blue backdrop. Earlier, Glass had reported this finding in an e-mail to three colleagues in the Southwest.

"We told them the only place that's likely to light up this year is northeast Arizona," he says. "It was about two days later that I got an e-mail from a fourth person saying, 'Have you tracked any mice up in northeast Arizona? We're getting some cases up there.'

"That's the perverse aspect of all this," Glass continues. "At the moment, being right means somebody's getting sick, and that's a bad deal. But on the other hand, it makes you feel like maybe we're really onto something."

Model Epidemics

"Viral chatter" is a phrase Don Burke uses often in talking about emerging zoonotic diseases. It describes the way a virus on the verge of sparking an epidemic might behave in an almost hyperactive manner, generating one surge after another in reports of human infections. Burke intends the phrase to echo its war-on-terrorism counterpart, "intelligence chatter."

"It's the same idea," he says. "You have these multiple introductions, and taken all together they lend credence to this idea that something is about to happen. But we can't pinpoint exactly the whens and wheres of what that might be."

In recent years, Southeast Asia has been a hotbed of viral chatter from the avian flu strain H5N1 (the name describes its surface array of hemagglutin and neuraminidase proteins). First isolated from birds in 1961, H5N1 didn't cause a public health scare until 1997 when it bounced out of the poultry population in Hong Kong and infected 18 people, killing six, before fading.

By early 2004, however, H5N1 had again exploded, killing an estimated 100 million birds in eight countries. Human infections and deaths have been documented recently in Thailand, Vietnam, Cambodia and Indonesia.

Uncommonly virulent, the virus has stirred fears of an outbreak on the order of the major influenza pandemics of the 20th century. In 1918, the flu killed as many as 50 million people worldwide, including 500,000 in the United States. Less lethal pandemics in 1957 to 1958 and 1968 to 1969 still managed to cause 70,000 and 34,000 U.S. deaths, respectively, according to the CDC.

Scott Dowell, MD, MPH '90, is familiar with H5N1 chatter. As former director of the Bangkok-based International Emerging Infections Program (IEIP), a joint effort of the CDC and Thailand's Ministry of Public Health, he's been on the front lines, confirming human infections and tracking reported transmissions.

"What we're doing on the ground isn't really about any new advanced techniques," Dowell says. "At this point, we're falling back on traditional approaches."

Because it's so easy for physicians to miss a new, virulent strain amid outbreaks of regular flu, it's critical to identify clinical features clearly enough to ensure timely recognition of cases. So far, Dowell says, this flu has a tendency to infect young people who've been in contact with sick poultry. Patients show signs of pneumonia and lymphopenia, then progress quickly into acute respiratory distress syndrome.

Dowell and IEIP also collaborated with Thai authorities on preparations for a potential epidemic. While this work incorporates tried-and-true public health strategies as well, it's also been strongly influenced by research undertaken by Burke and Derek Cummings, a research associate in International Health. Their work has "had a big impact on the way we've been thinking," says Dowell, who moved back to the CDC in Atlanta in July to become a senior advisor to the director at the Coordinating Center for Infectious Diseases.

Working with an international team, Burke and Cummings recently published a paper in the journal Nature in which they projected via a computer model the various courses H5N1 might take in Thailand on a path from viral chatter to global threat. They then tested a range of scenarios to see whether an epidemic could be held in check so effectively that it would never escape Thailand.

Cummings, who has studied the 1918 flu in some detail, wasn't optimistic at the outset. "Given what's happened in past pandemics, there wasn't a lot of hope," he confesses.

Computer models can predict various scenarios of how an epidemic may unfold, yielding clues for how best to respond. But one situation never varies: when infection numbers get too high, the cause is lost.

In search of reliable data sets, Cummings scoured Thai government offices, academic institutions and international organizations. The model encodes each one of 85 million individuals in Thailand. It distributes them in line with real-world population densities and in accord with the size, age and gender distribution of households. It also includes measures of the distance each travels to work or school and their number of co-workers or classmates.

The modeling team first ran a simulated epidemic with no public health protections in place. That flu followed a classic epidemic curve and reached into every corner of the country within five months, on its way to becoming a global threat.

Next, they tested an overly optimistic scenario, assuming that this new flu would be relatively easy to identify and would spread at a rate in accord with "run-of-the-mill" flu. In addition, the public health response would be fast, effective and would focus on administering prophylactic doses of antiviral medicines to broadly defined contact rings of infected individuals. Under these conditions, the epidemic was contained in Thailand nearly 100 percent of the time.

Then Cummings, Burke and their collaborators devised and tested a range of scenarios with the sorts of surprises and complications inevitable in the real world. It was here that they braced for the worst outcomes, but that's not what the model delivered. As long as the new strain didn't quickly gain a supercharged level of transmissibility (in the 20th century, only the 1918 flu seems to have pulled this trick) and as long as the public health response was reasonably efficient, the containment strategy showed as much likelihood of success as failure under most scenarios.

A key and somewhat counterintuitive finding concerned antiviral medicines. Successful outcomes in any scenario emerge only if overall infection numbers are kept quite low. Once the numbers get out of hand, the cause is lost. In a sense, however, this is good news. It means that the antiviral stockpile needed to fight a transmissible H5N1 doesn't need to be as large—or as prohibitively expensive—as previously feared.

"You're looking at something in the high hundreds of thousands of antiviral courses," Cummings says. "It could go up to 1 million, maybe 2 million"—figures much lower than the many millions of doses that had originally been anticipated.

The finding opened eyes at CDC. Dowell says that new funding anticipated from the U.S. Congress will enable IEIP to begin training and outfitting as many as 100 rapid-response influenza teams and to start building an antiviral stockpile.

"The implications of this new way of thinking are enormous," he says. "There have been debates here about whether this is really feasible. One of my Thai colleagues said, 'You know, it may or may not work. But there is little lost in trying. And there is such a big potential loss if we don't try.' I think he's got it right."

So does Cummings.

"Without a doubt, the best hope we have is that a human-to-human transmissible agent never develops," he says. "But this research shows that there's a second hope. At least at the early stages, an agent is probably not going to be all that well adapted to human transmission. That gives us a chance. It's still a long shot. But it's worth pursuing."