Hazardous Duty


Within a week of September 11, the first anthrax letter was already in the mail.

Then on October 2, a tabloid magazine editor was wheeled into a Florida emergency room, confused and feverish, showing signs of meningitis. The symptoms were puzzling at first, but the man's cerebrospinal fluid quickly led to a working diagnosis. On close examination, the unusually cloudy sample showed telltale chains of big, boxy bacteria. The sample was sent on to local and then state health departments, which confirmed the presence of anthrax.

The Florida Department of Health called the Centers for Disease Control and Prevention's meningitis and special pathogens branch, which called its consultant, David Stephens, director of infectious diseases for the Emory School of Medicine.

"I walked up Clifton Road to CDC, and the place was very quiet," he recalls. "It was eerie. It seemed like everyone had gone to Florida."

Eerie indeed. The drama unfolding in Florida was the first case of inhalational anthrax in the United States in 25 years, and in the aftermath of September 11, it reeked of bioterrorism. It was only the beginning of a strange story that has yet to reach a conclusion.

For the next two months, Stephens spent most of his waking hours at CDC. The federal agency depended on him to lead its clinical team in diagnosing and treating patients with anthrax in Florida, New York, and Washington, DC, and preventing the disease among 40,000 potentially exposed people.

"All we had to work with were 25-year-old treatment guidelines, so we practically had to start from scratch," he says. "Our arsenal of drugs is completely different now, and we had to decide which would work best against a disease that we had never treated. We used a multi-drug approach, focusing on antibiotics that work by entering affected cells in high concentrations. To start with, we had to rely on animal and in vitro [test tube] data to decide which drugs to use. We put together recommendations for treatment very quickly and revised them as information came in from additional cases."

By the time anthrax hit DC, more information was available from a second inhalational case in Florida and several cutaneous cases in New York and New Jersey. Stephens' team continued to update treatment recommendations in the CDC's Morbidity and Mortality Weekly Report.

By year's end, five people had died from inhalational anthrax, 11 survived cutaneous and inhalational infections, and nearly 40,000 were taking protective antibiotics. The results were much better than anticipated. In the past, about only 15% of patients with inhalational anthrax survived. Last fall, 60% survived, thanks to a combination of speedy diagnosis, aggressive treatment, and high-tech care.

Although life has returned to some semblance of normal, Stephens continues to work closely as a consultant with CDC, refining treatment recommendations and studying what happens when so many people are placed on long-term antibiotics.

by Valerie Gregg




Just months ago, bioterrorism seemed far-fetched. Its threat is now an accepted fact of American life. And Emory's position in the "public health capital of the world," right next door to CDC, puts the university in a unique position to guard against future bioterrorism, says James Curran, dean of the Rollins School of Public Health (RSPH).

"During the public health response to September 11 and the subsequent anthrax outbreak, we saw a seamless integration of the best of academic and institutional public health, as Emory faculty and CDC employees worked hand in hand," says Curran. "We watched lab and clinical capacity accelerate with a speed rarely seen either in academia or government, all while public policy related to the outbreak was being developed. That is absolutely unprecedented."

Ironically, because of 9/11 and the anthrax letters, the country's perception of public health appears to have changed for the better. "Before our national tragedy, people either misunderstood our profession or didn't understand it at all," he says. "Now we're on the nation's radar screen, and a strong public health system is recognized as crucial to our national security."

After decades of funding neglect, the situation is dire. "Whether it's buildings at CDC or staffing for disease surveillance and response at state and local health departments, we are not well equipped for intentional epidemics or unintentional epidemics," he says. "Only a small fraction of public health workers have formal public health training."

The $2.5 billion bioterrorism bill passed by the US Congress should help, but much more is necessary. Hospitals nationwide must prepare to handle large disease outbreaks caused by bioterrorism. Schools of medicine and public health must train public health, medical, and law enforcement workers about bioterrorism recognition and response. Infectious disease laboratories at CDC and state health departments must be strengthened. And in many cases, the ability for all these links in the public health chain to communicate and work together must be improved or, in some cases, invented.

A task force assembled by Michael Johns, director of the Woodruff Health Sciences Center, is now seeking to define how Emory can help the nation accomplish all of these objectives. The group is taking stock of the vast breadth of bioterrorism-related work ongoing at Emory and Grady hospitals, the RSPH, the Veteran's Administration, the schools of medicine and nursing. A plan is being drafted to guide Emory efforts to contain the threat and work effectively with state, local, and national agencies.

Apocalypse averted



It took more than 20 years, unspeakable suffering, and nationwide anxiety for the public health system to receive its due. By 1980, the nation's public health early-warning systems had begun a downward spiral. The success of antibiotics and childhood vaccines turned attention, funding, and staffing away from a system created to contain infectious diseases like smallpox, tuberculosis, measles, and mumps.

Meanwhile, the threat of bioterrorism quietly mounted. Military scientists and Soviet defectors warned of massive amounts of smallpox and anthrax genetically engineered to resist vaccines and antibiotics. Until recently, anyone could order plague bacteria or anthrax through the mail. Early last year, the Commission on National Security in the 21st Century described bioterrorism as the greatest national security threat facing this country during the next century.

National security was surely threatened October 16, when a letter filled with weapons-grade anthrax shut down Congress. But long before the recent crises, many Emory medical school and public health faculty members were quietly working on issues relating to bioterrorism. Last December, a $4.2 million gift from the O. Wayne Rollins Foundation for a new Center for Public Health Preparedness and Research at RSPH put those efforts on a fast track.

Led by former US assistant surgeon general and infectious disease expert Ruth Berkelman, the center will address research and policy issues related to bioterrorism and other public health threats, including emerging infectious diseases. Faculty across the health sciences center will collaborate on projects to deter and respond to terrorism and naturally occurring diseases. The center is already working closely with the CDC and the Georgia Division of Public Health. Faculty are serving on senior policy-making groups in Washington, DC, including the National Academy of Sciences. RSPH is ramping up efforts to train public health workers in the field as well as public health students.

Shoring up the nation's flagging public health system is a mammoth undertaking, says Berkelman. "Bioterrorism must be on clinicians' radar screens. As the first responders in a bioterrorist attack, physicians must know how to spot the signs of an intentional attack and report unusual cases to their local health department. The right information must then travel quickly from local to state and federal health departments. They must all work together seamlessly to identify and contain an epidemic before it gets out of hand."

Ensuring the strength of each link in the nation's public health system is essential to controlling any infectious disease, including those caused by bioterrorism. "Surveillance for diseases caused by bioterrorism requires similar systems to those for naturally occurring infectious disease. If we make our public health departments stronger to prepare for bioterrorism, they will be better able to deal with other health threats."

Downward spiral



Many other Emory faculty members are playing crucial roles in containing the bioterrorist threat. Arthur Kellermann, chair of emergency medicine, is seeking ways to build surge capacity needed to cope with a terrorist event in a strapped emergency medical system. Harry Keyserling, family and preventive medicine, is supervising clinical trials of a new anthrax vaccine course. Keith Klugman, international health, tested a new class of drugs against antibiotic-resistant strains of anthrax. Biostatistician Ira Longini is modeling the potential spread of a smallpox outbreak.

And for scientific expertise on anthrax during the recent crisis, the media turned to Philip Brachman, professor of international health and retired CDC epidemiologist, who in 1957 investigated the only other anthrax outbreak in US history. This past fall, he was the sole expert on human anthrax infections willing and able to speak freely.

"Schools of public health have an obligation to alert and educate the public," he says. "We may feel powerless, but in fact there's a lot we can do. The way we react to an incident of bioterrorism can contain the results before too many lives are destroyed."

As recent events have transformed the national psyche, public health priorities have changed, says Curran. "We are living in a time when a far-off threat now seems imminent. We're learning new things every day, including that bioterrorism can work using anthrax. We've been in the midst of a national public health crisis, and Emory's faculty has done yeoman's work under incredible pressure."


Valerie Gregg is editor of Emory's Public Health magazine.

 

Different kind of war

Preparing for bioterrorism requires a public health system that is strong and coordinated at every level.

Following the anthrax trail



Bacillus anthracis' stability, portability, and killing power make it an attractive bioweapon, says Philip Brachman, whose acquaintance with anthrax dates back to the 1950s, when the Army was developing an anthrax vaccine to protect soldiers during the Korean War. One of his first assignments was to look at past anthrax data and develop a more sensitive surveillance program for new cases. "The Army had tested its anthrax vaccine for safety, but never studied if it would prevent disease," he says.

Brachman identified four goat hair processing mills in New Hampshire and Pennsylvania that averaged 1.2 cases of cutaneous anthrax per 100 employees a year. "So we decided to proceed with vaccine field trials in that population," he says. The vaccine proved 92.5% effective.

During the vaccine trials, an anthrax epidemic in a New Hampshire mill provided an invaluable test of the vaccine. No one who fell ill had received the actual vaccine.

Goat hair, which was used for linings of men's suits and carpet pads, went out of vogue with the advent of synthetic fabrics, and occupational anthrax became harder to find. Before this past fall, the last case of inhalational anthrax was in 1976 in a California tapestry artist using imported yarn containing goat hair. "The mills never had any more cases among vaccinated employees," says Brachman. "They made vaccination a condition of employment. Today the goat hair industry no longer exists in the United States, and we only see rare cutaneous cases in people working with animals in other industries like tanning and agriculture."

After the Army's anthrax vaccine trials concluded, Brachman continued to investigate isolated reports of anthrax. One case parallels the recent death of a 94-year-old Connecticut woman thought to have contracted inhalational anthrax from cross-contaminated mail. Brachman theorizes that small doses may sicken those with suppressed immune systems more easily.

"During the 1950s, a young Philadelphia man with a compromised immune system contracted inhalational anthrax through a very small dose of bacteria. He had sarcoidosis, an inflammatory lung condition and was on a small dose of steroids, which inhibit the immune response. On his daily walk to work, he passed by a tannery. It was summer time, and it's possible that a breeze came out the open tannery door just as he was walking by. That breeze could have carried a cloud of B. anthracis from hides being processed, and he may have inhaled at just the wrong time. I cultured the environment in the tannery and found B. anthracis."

Following the trail of anthrax spread intentionally through the mail is "a different bag," says Brachman. "This is the first bioterrorist attack ever in which anthrax was successfully used. We have learned a lot about anthrax as an infectious agent and a lot more about bioterrorism than we knew before. We also know firsthand the fear and disruption that bioterrorism can cause."


Imposing order upon chaos



Earthquakes in Los Angeles and Armenia. The eruption of Mt. Pinatubo in the Philippines. Hurricanes Hugo, Andrew, and Iniki. Eric Noji has stood in the aftermath of them all and tried to impose order upon chaos.

On September 12, standing amid the rubble of the World Trade Center, he knew that the public health effects of this disaster would be different.

Controlling the aftermath of a natural disaster usually assumes a predictable rhythm, says CDC disaster response expert Noji. Illness and death rates are high early on, ebbing as the population's needs for food, shelter, and clean water are met. The intensity of the public health response rises and falls along with morbidity and mortality.

September 11 and the ensuing anthrax outbreaks turned that paradigm on its head. "Natural and humanitarian disasters usually have an end in sight," Noji says. "These recent events are the strangest disasters I've ever been involved in because the crisis just goes on and on."

The author of the preeminent text, The Public Health Consequences of Disaster, has taught a course with the same name at Rollins School of Public Health (RSPH) for more than a decade. Since September 11, he has literally been on call day and night and is now detailed from CDC as senior medical adviser to the US Office of Homeland Security.

"We'll go full steam," he says, "until the anthrax cases are solved and the perpetrator is caught." But this state of chronic expectancy is nerve-racking, as is responding to an emergency while simultaneously formulating policy. "As scientists, we're accustomed to a more methodical way of making policy. There's no time now to ruminate on the evidence. We have to think on our feet."

Public health workers must also be versatile. "When you have a major emergency like the anthrax events, people have to switch gears and help," Noji says. "The barriers between disciplines blur."

Just as disaster response requires a little bit of everything, Noji's classes have drawn students from every RSPH department as well as the nursing and medical schools. After the sarin gas attacks on the Tokyo subway system and the Oklahoma City bombing in the mid-1990s, Noji added lectures on the public health response to terrorism to his curriculum. His CDC colleagues are teaching the course this semester, but when his stint in the White House is over, he surely will have more unique lessons to share with his RSPH students.


An impossible possibility



When Stan Foster considers the possibility of bioterrorists unleashing smallpox upon an unvaccinated world, his thoughts travel back to 1975, to a desperately ill Bangladeshi girl named Rahima Banu, 3 years old and covered with painful pox.

"We found her hidden under a burlap sack," he says. "Hers was the last case of variola major seen in the world. Luckily she survived."

A few years ago, Foster traveled with a BBC film crew to her village to meet Banu, her husband, and her two young daughters. It was a joyous celebration, a time to look back and celebrate a public health victory that required the astronomical efforts of thousands of people.

The World Health Organization's declaration in 1980 that smallpox had been eradicated from the globe was perhaps the high point of a wave of confidence that medical advances had conquered the scourge of infectious diseases. Remaining supplies of the virus were distributed to the United States and Soviet governments, which agreed to use the virus only to advance science. But unbeknownst to the world, the Soviet Union manufactured smallpox virus for the purpose of bioterrorism. With the breakup of the Soviet Union into separate countries and the ensuing economic chaos, did some virus and the technologies to produce it fall into the hands of terrorists or unfriendly regimes?

Foster shudders to imagine terrorists turning back the clock to the days when smallpox raged. "We must realize that a bioterrorist attack on the United States using smallpox would reintroduce the virus into the world," he says. "Here, we have the facilities and vaccine to control it. But it would be especially tragic should smallpox be reintroduced into Asia and Africa. We could see possibly 100 million cases and 15 to 20 million deaths."

After 9/11 and the ensuing anthrax outbreaks, what once seemed impossible became possible. Stan Foster dusted off his slides of crying babies with horrific rashes and now spends much of his time teaching federal, state, and local health officials and clinicians the intricacies of smallpox diagnosis. He and William Foege, presidential professor emeritus at RSPH, are among a small number of physicians nationwide who know from experience -- not just pictures -- what smallpox looks like and the devastation it wreaks.


Beyond Cipro



Prescriptions for Ciproflaxin have been going like hotcakes. This past fall, nearly 40,000 were dispensed to those potentially exposed to anthrax-laced letters.

But what if the anthrax sent to the Senate and media outlets had been resistant to Cipro and other antibiotics commonly kept on hand? The illness and death toll could have been much higher.

Such a scenario is not so far-fetched, says Keith Klugman, an expert in antibiotic-resistant bacterial infections. During the Cold War, military scientists genetically engineered anthrax to resist antibiotics. And many old infections now are re-emerging with the natural ability to resist antibiotics.

As the anthrax crisis unfolded this past fall, Klugman set to work. He knew that Abbott Laboratories was developing a new class of antibiotics called ketolides to counter infections resistant to erythromycin and other antibiotics. A native South African, Klugman also knew that natural anthrax runs rampant among wild animals such as zebra on the African continent.

"The possibility of attack with resistant strains of anthrax brings a new urgency to the issue," says Klugman. "It's very important for the public health community to know about new drugs under development. Bacteria would more likely resist older drugs, not drugs that hadn't been discovered when the former USSR was developing its bioarsenal. These new drugs have different mechanisms of action that military scientists would not have prepared against."

Klugman tested ketolides against anthrax from infected patients in Zimbabwe and South African veterinary labs. The drugs were effective in cases in which erythromycin and some other antibiotics failed.

His work, funded by Abbott Laboratories, was carried out in cooperation with the National Health Laboratory Service in South Africa. Klugman presented his findings this past December at a conference organized by the American Society for Microbiology.

Such drug studies are among the many preliminary steps toward approval by the US Food & Drug Administration. As part of his ongoing work to solve problems related to microbial resistance to antibiotics, Klugman continues testing other drug candidates now under development.


Testing vaccine safety



Between the 1950s and 1990s, only some goat hair mill workers and the lab scientists who studied anthrax were vaccinated against it. That changed in 1991, with the threat of Iraqi bioweapons during the Persian Gulf War. The military decided to vaccinate soldiers heading there, but a shortage of vaccine and an exhaustive vaccination schedule that stretched over several years left many soldiers to complete their anthrax immunizations on the battlefield.

By 1998, after assessing the threat of biological weapons, the US Department of Defense required all armed forces to receive the anthrax vaccine. Confusion, complaints, lawsuits, and court martials followed, as some soldiers either refused immunization or blamed vague symptoms of Gulf War syndrome on the vaccine.

The anthrax outbreaks of this past fall conceivably put anyone who opens their mail at risk.

Since the FDA licensed the vaccine in 1970, more than 2 million people have been successfully immunized. Still questions remain. Should those already exposed or at risk of future exposure be vaccinated? Is the vaccine safe? Does it work?

Harry Keyserling, professor of pediatric infectious diseases, does not have all the answers, but he knows the vaccine has an excellent safety record in numerous studies.

The Woodruff Health Sciences Center is now a key study site for the first clinical trial of anthrax vaccine to be conducted among US civilians since the 1950s. Keyserling, the principal investigator, hopes the study results will simplify the existing dosing and shot regimen and provide more data to convince an anxious public that the vaccine is safe. The study, now enrolling volunteers, will test whether changing the injection method from subcutaneous (under the skin) to intramuscular (in the muscle) or decreasing the number of doses affects immune response or reactions to the vaccine.

The current FDA-approved course requires an initial dose followed by injections after two weeks, four weeks, six months, 12 months, and 18 months and a yearly booster thereafter. These injections are given subcutaneously.

Emory is one of five sites for the new CDC-led study. Enrollees in six study groups will be vaccinated over 43 months. One group will receive the licensed regimen of eight vaccinations under the skin, including annual boosters for two years. Another group will receive eight vaccinations of a placebo. The remaining groups will be vaccinated in the muscle rather than under the skin and will receive fewer vaccine doses. Blood will be drawn following each vaccine to evaluate the protective immune response.

For additional information about the study, call Keyserling's research staff at 404-727-4044.


Genetic clues to slaying a killer



Last fall, when scientists needed it most, expertise on the microbiology of anthrax was hard to find. But Science magazine found the expert they needed at the Emory School of Medicine.

When editors needed a late-breaking article on the cellular workings of Bacillus anthracis, they called on Kathryn Beauregard, a postdoctoral fellow in human genetics. Now deputy editor of the American Journal of Human Genetics, she spent the late 1990s studying anthrax while earning her doctorate at Harvard.

Her work there focused on the deadly toxin that anthrax produces in infected mammals. "Our lab was trying to figure out how the toxin knows where to go once it's in the bloodstream, and how it crosses cell membranes," says Beauregard. "These factors can greatly influence the virulence of bacteria."

Her November 15 Science article, "Evolution of a Killer," focuses on how the genetic code of anthrax will help scientists better understand why it is so deadly and identify new ways to fight it. The anthrax genome sequence was completed this past December, far ahead of schedule.

The genetic sequence may take basic research needed to develop new antitoxin drugs and vaccines in completely new directions. "We already know that the toxin is key with anthrax. New genetic tools allow you to observe which genes are turned on when anthrax bacteria enter infected cells. You could then figure out a way to turn certain genes off with drugs or vaccine.

"One of the interesting things I found when I researched the Science article is that anthrax is genetically very similar to other bacteria that aren't nearly as lethal," she says. "The genome will help us tease apart the similarities and differences between anthrax's less dangerous genetic relatives to find out what makes anthrax more deadly."


Figuring the odds



Suppose a suicidal terrorist with contagious smallpox were to amble down a crowded city street, run through a residential neighborhood, or pass through the busiest airport in the world. Random chance would have a lot to do with how many others that person might infect and how many new infections they, in turn, would pass on, and so on down the line.

The same laws of probability that govern the odds of coming up heads or tails in a coin toss can help predict the spread of infectious diseases among a population. That's why the NIH has contracted with some Emory biostatisticians to predict the spread of smallpox and help the nation prepare for a bioterrorist attack.

Although smallpox disappeared from the globe in 1979, the virus may have fallen into the hands of rogue states or terrorists. "In an outbreak of any infectious disease, chance plays a big role in what happens," says Ira Longini, who leads the project along with Rollins School of Public Health (RSPH) faculty Elizabeth Halloran and Azhar Nizam.

Their statistical model takes the structure of the population at risk into account, following individuals as they move through the day -- in their households, neighborhoods, schools, and places of work. After crunching the numbers, the computer program offers a scenario of how an outbreak would progress before it reaches a peak and tapers off.

RSPH researchers have used this statistical method for years to help CDC plan vaccination strategies for influenza. The smallpox simulation could help shape vaccination and quarantine strategies during a potential outbreak.

"There are serious questions about how public health officials should distribute limited quantities of smallpox vaccine should there be an outbreak," says Longini. "Should there be widespread vaccination, or should we stockpile vaccine and ring-vaccinate if a case shows up? How big should the rings be? Should the rings include households or neighborhoods? Should we vaccinate based on contact tracing? Would quarantine help?"

A statistical model could theoretically answer those questions.

"The results could be used like a playbook in a smallpox simulation, where various public health agencies would compete against the computer," he says. "In past exercises like Dark Winter, which simulated possible US reaction to the deliberate introduction of smallpox, the spread of the disease was calculated on the back of an envelope. Our model would yield much more precise results. Good data will give us a much better chance of containing an outbreak before it mushrooms into an epidemic."


First alert




In this Issue


From the Director  /  Letters

Hazardous duty

Code blue

Dropping Pulaskis

Class 'A' space

Moving Forward  /  Noteworthy

On point: Very private matters

Cleaning Mickey's mess


It's a modern-day canary in a coal mine -- living tissue interfaced with microchip circuits that function as a sentinel for bioterrorist threats.

Biomedical engineers William Ditto and Steve DeWeerth have been working on the biosensor concept for years. Since September 11, they've turned their efforts up a notch.

"The first line of defense against biological warfare is a person's body," explains Ditto, a professor in the Coulter Department of Biomedical Engineering at Georgia Tech and Emory. "But we don't want people to get sick. If devices could get sick well before people, they would provide an early warning -- like a smoke alarm."

Funded by the US Department of Defense, Ditto and his colleagues are using two complementary approaches. The first is to connect rat muscle cells to electronic circuits. These would detect chemicals that attack nerve and muscle cells, as well as germs like smallpox, Ebola, or anthrax that damage all tissues.

"Any agent that attacks cells has the potential of affecting the electrical behavior of neural and muscular cells," says DeWeerth, professor of biomedical engineering. "We can use that change in behavior to measure adverse activity."

The second approach uses "cycling probe" technology, licensed from ID Biomedical Corporation in Vancouver, Canada, to rapidly examine the DNA fingerprint of air particles or fluids. When placed on microchips, the microscopic probes amplify snippets of DNA. They then target particular DNA fingerprints through thousands of cycles that eventually decompose the probe. As the probe decomposes, it identifies fingerprints that match known viruses or bacteria.

Both kinds of devices are still under development, but Ditto expects them to be ready for use as a building sensor in the near future. The concept has been well received by federal officials, he says. "Early warning devices are highly preferable to early warning sickness in people."

 


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Web version by Jaime Henriquez.