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Last Updated

06 May 2003

Source: Washington Post, May 6, 2003

Germ Warfare

At the Centers for Disease Control, Hundreds of Scientists Have a Singular Mission: Crack the Case of the SARS Epidemic

By David Brown, Washington Post Staff Writer

ATLANTA

Most of the headquarters complex for the Centers for Disease Control and Prevention looks like the world's biggest high school -- hundreds of numbered rooms opening into corridors clad in concrete block and linoleum. The Emergency Operations Center, however, looks like a movie set. Perhaps something from "Independence Day."

The center opened last month, and the furniture, carpets and paneling are still off-gassing their heady hydrocarbons. Built below ground, it might be called a bunker except that it's the most stylish space on the 28-acre campus. Four long counters arc in front of a raised dais. Dozens of workstations are outfitted with computers, telephones, microphones and draftsman's lamps. On the front wall, plasma screens cycle data-rich maps and the giant heads of news anchors talk silently. Forty people, voices instinctively hushed, can work here without making the place feel crowded.

In the movies, this is the kind of place where the smartest men and women of the not-too-distant future plan battle against alien and implacable foes. The funny thing is, that's exactly what's happening here.

It is nearly two months into the epidemic of SARS, severe acute respiratory syndrome. The CDC is working at a pitch without precedent in the six decades since it evolved from the federal government's malaria laboratory into the main public health institution in the United States. More than 300 of its 1,600 people in Atlanta are working full time on a disease that was unknown to everyone here at Christmas, and whose name wasn't coined until February. An additional 200 people are working on it part-time.

The anthrax bioterror attacks of 2001 also stimulated an instantaneous and nearly full-tilt response from the agency. But that event was a weird hybrid of biology and crime. It didn't follow the natural course of infectious outbreaks, and consequently invoked only some of the classical measures for finding and containing disease.

SARS, though, has it all. It is contagious, deadly and highly variable in its pattern of transmission. It is spreading most easily in a distant country that has touchy relations with the rest of the world but probably lacks the capacity to contain it alone. At the same time, cases are found in substantial numbers in one of the only two countries that border the United States.

The cliched warning from experts on "emerging infections" -- that an exotic disease is only a plane flight away from any place on Earth -- appears to be true with SARS. And just to make things interesting -- this is an entirely new germ.

It's a great script. Unfortunately, it's not fiction.

But if the people at CDC are cold-sweat scared, they are not showing it. It may be they're simply too busy.

'They Are Desperate Now'

"Dr. Gerberding is going to be a little late," Vicki Freimuth, the CDC's associate director of communication, says to people drifting into the director's conference room for the daily 9:30 a.m. update on SARS.

"Do we go or do we wait?" asks Gene Matthews, legal counsel.

"We wait."

Representatives of CDC's core divisions take seats at leather chairs around a large table. On one wall are clocks set to Geneva and Hong Kong time. Between them is a narrow illuminated display of the hour in each of the American time zones, terminating in Zulu, the military designation for Greenwich Mean Time. On another wall are four portraits -- the president, the vice president, the secretary of health and human services, and Julie Louise Gerberding, CDC's director. Her black hair has a white forelock, a dramatic feature that millions of Americans now recognize.

In a few minutes, Gerberding arrives and takes the seat at the head of the table. The two handsome wood-panel and frosted-glass doors are closed. She nods to James LeDuc, 57, head of the division of viral diseases.

"I have some bad news to report," he says. "The situation in Taiwan seems to have turned sour."

LeDuc has a long face, a slow voice and a demeanor of houndlike placidity. He gives a synopsis of the SARS outbreak in Asia, noting unusual facts about the age or health histories of the newest fatalities. When he's done, he adds: "We have received a formal invitation to visit the Chinese CDC."

"What is the purpose of that mission?" Gerberding inquires.

Stephen B. Blount, head of global health, answers.

"There's not very much detail. It said that they wanted help in establishing their research agenda, and that this visit there will precede a visit here by some of their scientists," says Blount. "We do certainly think this is a gesture of solidarity and I won't say desperation but, yes, they are desperate now, given the sacking of their minister. Li Liming [head of the China CDC] needs political support to remain at his post."

After a little discussion, LeDuc picks up the latest count again, this time for the United States -- suspect cases, probable cases, new states affected. When he's finished, Gerberding calls on Martin S. Cetron, head of global migration and quarantine. He names the four main crossing points on the border between the United States and Ontario, the province where Toronto, the city hit by the disease, is located. Soon, drivers there will be handed "health notices" -- a folded piece of yellow paper that accordions out to show a message, in eight languages, advising people what to do if they have symptoms suggesting SARS. (Similar notices are already being handed to air travelers.) The printer will deliver a huge batch the next day.

"Terrific. So the show's on the road," Gerberding says.

A few minutes later, conversation turns to the question of how good the evidence is that a newly discovered coronavirus causes SARS. The director of Canada's National Microbiology Laboratory has publicly stated he doubts the new pathogen alone can cause the disease. LeDuc says the strongest evidence for the one-bug theory comes from experiments in which monkeys infected with the virus get a SARS-like illness. When the animals are also given human metapneumovirus -- another bug found in some SARS patients -- the disease didn't get worse, suggesting that infection with both viruses isn't necessary to produce the disease.

James M. Hughes, who heads CDC's National Center for Infectious Diseases, notes that the experiments haven't looked into whether things are different when metapneumovirus is given to the animals first and the coronavirus second.

"Are they going to do that?" Gerberding asks.

"Yes."

A diagnostic test for the new coronavirus will answer a lot of questions including, at least indirectly, the causation issue. The CDC is making a test that will be distributed to state health departments. Part of it requires blood plasma loaded with antibodies from someone who has survived SARS. One unit of plasma has arrived from a patient in Pennsylvania, a second is expected from Hong Kong today, LeDuc says.

"When will it be ready?" the director inquires.

"The first part of next week," he answers.

Gerberding moves on. Can someone make an inventory of what sort of screening of air travelers is being done in Asia? Is anyone looking into what effect Chinese and herbal medicines have on the coronavirus? What outreach is being done to Asian communities in the United States? What's being done to educate the CDC's disease investigators -- the Epidemic Intelligence Service -- about the control of community-wide outbreaks, should the worst-case scenario develop?

And how about truckers? Anyone establishing liaisons with them? And who's reminding the public that N95 masks -- the masks that lots of people may be wearing if SARS breaks loose -- need to be fit-tested to work?

"Sorry, I'm in a potpourri mode here," Gerberding says.

Just before the meeting ends, Blount tells Gerberding from the far end of the table: "I have an urgent request from the U.S. ambassador to Vietnam to speak with you this morning about the situation." She says she'll call after her morning teleconference with Health and Human Services, which will start in a few minutes.

The frosted-glass doors slide open. "Thank you, everyone. Good work," the director says. Before he gets up LeDuc notes mordantly in a stage whisper: "We're playing by the rules. We're supposed to be winning by now."

Outside in the EOC, the workstations are filling up. On one wall an illuminated sign announces: "Homeland Advisory Elevated Yellow," a reminder that elsewhere in the world the hand of man is the agent of fear.

Charting the Nucleotides

Paul A. Rota spends most of his time engaged in molecular epidemiology, one of the most clever advances in medicine in the last dozen years. He tracks outbreaks of measles (800,000 deaths annually worldwide) by following the genetic fingerprints of viruses swabbed from the throats of children thousands of miles from his windowless office in Atlanta. He sequences snippets of virus -- 450 nucleotides, or genetic letters. That's usually enough to tell him what he's got.

On March 23, researchers at CDC found a coronavirus in the lung fluids of a dead SARS patient from Hong Kong. Coronaviruses are so named because they have spiky surfaces that make them resemble stars with coronas when viewed with an electron microscope. Soon after, the virus was grown into workable quantities in cell cultures.

On March 31, "I brought everyone a little vial," Rota recalls.

"Everyone" in this case was about 20 other molecular biologists from the polio, enterovirus, gastroenteritis, and measles groups. Over the next two weeks, they sequenced the new bug in pieces, checked and rechecked the sequence, and then assembled the pieces into one genetic sentence 29,727 nucleotides long. They worked 16 hours a day, with some tasks running by automation in the down hours. The last bit of data came to Rota about 2 a.m. Monday, April 14. He ran a few final quality checks and went home to bed.

As it happens, the CDC team came in second. ("It wasn't a race," he says, not entirely convincingly.) A Canadian team posted its sequence on a public Internet site two days earlier. Curiously, its virus -- taken from a different patient -- was 15 nucleotides shorter at one end. And over the rest of the nearly 30,000 letters there were nine differences. Could these be meaningful? Nobody knows.

The Clean Room

Inside the building where investigators are working on live SARS virus, a color picture is taped to a corridor door. It shows two bottles of beer sitting on a beach with the ocean in the background. The caption reads: "This is what I meant when I asked for a Corona."

In the labs, workers are masked and gowned from head to foot, handling the virus only in special cabinets that vent the air through special filters. The new microbe is not a "Hot Zone," biosafety Level 4-bug like Ebola or smallpox. It's a Level 3, like West Nile, yellow fever and St. Louis encephalitis.

Thomas G. Ksiazek, a virologist and veterinarian, is the lord of this section, called Special Pathogens, a Cold War name resonating hazard and secrecy. Ksiazek is imposingly tall, outfitted today in a checked shirt and cargo pants, and cordially untalkative.

About seven of his people are working on the virus, and an equal number have been detailed from other sections. They're very busy. Since the epidemic began, the lab has received "six or seven thousand samples from several hundred patients," he says. Blood, throat swabbings, lung fluid, feces, autopsy tissue -- all will be probed for the new microbe or antibodies to it.

What's the biggest question Special Pathogens is facing? Ksiazek is asked.

"Who's got this virus?" he answers.

Team B Gearing Up

Everyone at CDC hopes SARS can be controlled by the tools of public health -- surveillance for disease, rapid diagnosis of infection, isolation and treatment of the ill, and quarantine of the well (or not-yet-ill) the infected people have been around. This is Plan A.

If Plan A doesn't work, there's Plan B -- the prolonged, global fight against a germ moving through communities in chains of transmission that can't be easily traced. For Plan B, CDC has Team B -- the Big Picture people, the long-range planners.

Team B doesn't meet every day. But on this day it's meeting at 2:30 for a telephone conference addressing, among other things, this question: What do the veterinary vaccines for coronavirus tell us about the feasibility of a human vaccine for SARS?

About a dozen people are jammed into the tiny office of Jonathan Kaplan, acting director of the division of AIDS. It's uniform day at CDC, the one day a week when members of the quasi-military United States Public Health Service put on their blues, whites and epaulets. The office looks like a shipboard ward room the night before battle.

The disembodied voice of Niels C. Pedersen, a professor of veterinary medicine at the University of California, Davis, begins by telling the people in the office and at least a dozen more on the phone that there are many coronavirus vaccines on the market. There are ones to prevent infections in dogs, cats, pigs, cattle and chickens.

(This isn't surprising. Many microbes attack both animals and humans -- and in general the animals are more likely to have a vaccine against the bugs. For example, horses have a West Nile virus vaccine, but people don't. The reason for the disparity is simple. Human vaccines must have a near-perfect track record. On the other hand, animals don't require informed consent, deaths in vaccine studies are tolerable if regrettable, and better-than-nothing finished products can find a place in animal husbandry.)

Another voice on the phone, Linda J. Saif, a veterinarian at Ohio State University, tells the group she's worked on coronavirus vaccines for pigs and cattle for 25 years. Her message: They don't work very well.

"They offer only partial protection."

She explains why, using the example of pigs. That animal can get an intestinal infection from a coronavirus that, if it loses a single gene through mutation, suddenly develops a predilection for infecting the lungs. And vaccinating with the lung strain doesn't protect against the intestinal strain.

Does the SARS virus grow in both organs? If it does, will a vaccine have to protect against infection in those two quite different tissues? Might two vaccines be required? These are all questions that must be answered, she says.

Which are better, live or killed vaccines? someone asks.

Killed coronavirus vaccines, which are relatively safe, don't work well, an expert answers. Vaccines made from live, weakened virus work better. But the one given to chickens to prevent bronchitis sometimes "reverts" to a dangerous form -- a very undesirable outcome.

For more than a half-hour, ideas spill forth. Both the uniformed people at the table and the voices on the phone pose questions and throw out theories like eager graduate students.

Is the rare "super spreader" patient who infects a dozen or more people shedding the SARS virus in his or her digestive tract? Could the fact that some coronaviruses attack two organs explain why many SARS victims in the Amoy Gardens housing block in Hong Kong had intestinal complaints? Is there something in all of this that explains why so few children have come down with SARS?

Eventually, Kaplan ends the call. "It doesn't seem like this is going to be easy," he says as the room empties.

The CDC's Shock Troops

Back in the Emergency Operations Center, the evening shift of Epidemic Intelligence Service officers are coming on duty about 6 p.m.

EIS officers spend two years learning practical epidemiology as the CDC's shock troops. They are known for being smart, hard-working, and willing to take any job assigned. In the SARS outbreak, they're manning the phones.

When a state health department official calls to report a suspected case of SARS, the EIS officers log the call, fill out a brief intake form, e-mail a six-page case report form to the caller, and provide general advice and counsel. During the day it's a busy place. The three-person evening shift, fielding calls from hospital emergency rooms and West Coast health departments, has more time to keyboard information from the case report forms into the CDC's SARS database.

This is nobody's regular job. All EIS officers have assignments elsewhere, mostly in CDC's Atlanta branches or as the agency's representative in one of the states.

Hardeep Sandhu, a 40-year-old physician from India, is on this shift. Before coming to the United States, he worked in polio eradication in his home country. When his two years in the EIS is up, he's going to work with the CDC in the final stage of the global eradication campaign, scheduled to end in 2005.

While he waits for calls, he enters the details of a case he took the night before from Virginia. It's unusual mostly because the physician called to report it as a possible SARS case before she'd even seen the patient.

"She was asking me what to do when the patient comes in. It was a Chinese patient who said he had a temperature. She asked, 'Should I send him to X-ray with a mask?' " he said. His advice: Use your clinical judgment. Don't preemptively put a mask on someone you've never seen.

Now, he has the facts: A 35-year-old Chinese man, recently returned from a fortnight in Beijing, has a cough and a fever high enough to qualify as SARS. A chest X-ray has been taken but has not been read by a radiologist. It's a suspect case, not a probable one. Blood, throat swabbing and fecal samples will be sent to CDC to be tested for the SARS virus. Tests for other diseases will be done locally.

"People are really aware of it now," he says of the new disease. "It is not something that is likely to be overlooked." In fact, things are verging on excessive vigilance. "We'll be overwhelmed if every clinician calls us before they see the patient."

Nevertheless, he's not going to tell people to hold back. In the polio campaign, the constant message to doctors is: Report every case of paralysis. Do not think we will be overwhelmed. You report it, let us decide.

"Finally what comes out is the true number of cases," he says.

Nearby, 30-year-old Neely Kaydos-Daniels is also keying in cases. She is the EIS officer in West Virginia and has a doctorate in epidemiology. She's scheduled to give a lecture at CDC headquarters in the next week on an outbreak of rashes and breathing problems at an indoor swimming pool. The cause turned out to be chloramines -- irritating compounds produced by the reaction of chlorine and bodily fluids in the water. She was asked to come down early, and was happy to oblige. It would give her a chance to visit her husband, a structural engineer in Raleigh, N.C., on the drive down and back.

Her phone rings. It's an emergency room doctor in Pennsylvania.

"I have a form I'd just like to fill out. Temperature greater than 100.5? Okay. Fever onset date? The 20th. Okay. Respiratory complaints? Okay. Travel history?" There's a long pause. "It sounds like it could be, but it doesn't strictly fit the case definition."

When the call is over, she describes the scenario: a 60-year-old woman with cough and fever whose daughter had been in Hong Kong in February. The daughter had had a cough for four weeks, and had been treated for bronchitis. But her daughter had never had a fever, a hallmark of SARS.

"We seem to have a lot of cases falling into this gray area," she says. In fact, a category of "special interest" has been added to "suspect" and "probable" in the SARS universe. The near-misses.

As she writes up the information, Sarah Park, an EIS officer coordinating data collection, looks into the room. It's about 7:30 p.m. and uniform day is over. Park, here only an hour ago, has changed into civilian clothes. She asks Kaydos-Daniels how long she will be in Atlanta.

"Through next week."

"Were you planning on doing anything on the weekend?"

"I was going to head back home. I was hoping to see my husband."

"Oh. Is there any chance you could come back and work here the week after that?"

"Sure, if West Virginia will let me."

Park disappears. Kaydos-Daniels goes back to work.

"They are desperate for people to work here," she says. "I don't know why people don't want to come. It's actually very interesting."

The Long Night Ahead

The person running the CDC's response to SARS is James Hughes, the 57-year-old chief of the National Center for Infectious Diseases.

It's 8:30 at night and he still has 26 e-mails to read and respond to. His black uniform tie is not yet loosened. His gold epaulets indicate he's an admiral in the obscure ranking of the Public Health Service. The office floor is decorated with cairns of scientific journals. Hughes has a thin face and a demeanor that's energetic but not nervous -- a pointer to LeDuc's hound.

The big challenges now, he says, are to maintain vigilance, keep the agency's response rapid, and get the CDC's homegrown SARS test out to state health departments as soon as possible. He's already asked the Food and Drug Administration for an exemption that will allow it to be used immediately.

"People have really risen to the occasion," he says. "It's a pretty special experience in many ways."

Hughes stayed home the previous Sunday. It was his first day off in six weeks. Tomorrow he's flying to San Francisco to deliver a lecture, "a long-standing commitment," he says without elaborating. It will be five hours in which his cell phone doesn't ring and he can't answer e-mail. Five hours of quiet. He might even sleep.