Liz Borkowski writes: Mark Pendergrast's Inside the Outbreaks: The Elite Medical Detectives of the Epidemic Intelligence Service is a fast-paced tour through nearly six decades of epidemiology achievements by this relatively small program of the Centers for Disease Control and Prevention. It's a fast and fascinating read, and its episodic structure makes it an easy book to carry around and dip into whenever you've a got a few minutes of free time.
The public-health professionals who join the EIS - usually for two-year stints, though some stay longer - are often young and willing to take risks, from giving smallpox vaccinations in a war zone to taking controversial positions on issues like gun control. It's easy to envision them dashing from one outbreak to the next, using their time in transit to read up on anthrax, smallpox, or whatever other agent is suspected of sickening people in the places they're heading. Reading Inside the Outbreaks is kind of like watching a season of a superhero TV show - there's always a new villain threatening an innocent community (salmonella in cake mix one week, tapeworm from sheep the next), plus an old nemesis or two that can be weakened but not killed off (malaria, influenza). Not every episode ends in victory, but after reading the book I'm in awe of all the EIS has achieved.
As exciting as that is, though, it's clear that there's a lot of grunt work involved. Pendergrast uses the phrase "shoe-leather epidemiology" often - it's a concept EIS founder Alexander Langmuir drummed into EIS officers' heads. When EIS investigators arrive on the scene of an outbreak, they often start by taking lots of samples - of blood, stool, air, soil, and any other substances that might give them a clue. They survey people about what they've eaten, what activities they've been engaged in, and which parts of a building they walk through. Then they crunch the data - and if that doesn't yield an answer, they have to go back and ask more questions. Here's one description of an approach Langmuir taught to EIS recruits:
In tracing epidemics, Langmuir espoused what came to be called a cohort study of a carefully defined group of people (Who attended the church supper?), comparing their behavior (What did they eat? Where did they go? Who did they associate with?) and looking for key differences between those who had become ill and those who had not. Sometimes through such comparisons, the cause of an epidemic became obvious. It was the potato salad!
Langmuir stressed the importance of long division. To find the rate of a given disease in a particular population, you needed a numerator (number of ill over a defined period of time) and a denominator (the population at risk). "Stripped to its basics," he said, "epidemiology is simply a process of obtaining the appropriate numerator and denominator, determining a rate, and interpreting that rate." Thus, the three essential elements were time (when were people exposed and when did they become ill?), person (who was affected in what defined population?), and place (where did the epidemic take place?).
But how do you know that an epidemic is occurring? First, you establish the "normal" rate of disease for that area. Langmuir talked about the importance of routine disease surveillance to establish baseline data and to look for anomalous blips.
Traced on a time-line, tracking the number of accumulating daily cases, most epidemics form a classic epidemic curve, a bell-shaped hump. In the simplest version, an outbreak begins in a particular community with an index case, spreads to others, reaches a peak, and then gradually burns itself out, as susceptibles either survive and become immune or die. Looking at this epi-curve, the disease detective could deduce a fair amount. A common source epidemic, such as bad potato salad at a picnic, would have a sudden onset, sharp peak and rapid resolution among a limited population, whereas an ongoing problem such as a contaminated water supply might affect an entire community for a longer time. Once a likely moment of exposure was determined, i.e., the time of the picnic, the epi-curve also revealed the average incubation period, the time between infection and disease onset.
Classic examples like food poisoning at a church supper tend to be relatively straightforward for shoe-leather epidemiologists, but in many other cases it's not clear what kind of agent is at work. Investigators may have to ask about potential agents that aren't obvious, and initial data sets may be too small to show an effect. Persistence and creativity are often necessary, and there are plenty of examples of both throughout the book. One of the stories I found particularly interesting was that of Reye's Syndrome, the often-fatal pediatric illness that an EIS officer first studied in 1962 in North Carolina (though it wasn't named Reye's Syndrome until the following year) and that continued to stump the medical community for decades. Here's Pendergrast's description of early EIS efforts to study the disease:
Reye's syndrome, the childhood killer, had been investigated by several EIS officers who had established that most of the cases were preceded by influenza or chickenpox. EIS officer Tom Glick set up the first informal surveillance system for Reye's syndrome. Over a 30-month period 1967-1969, he found 62 cases of Reye's syndrome, with a median age of six. Only fifteen survived. Thirty-three children had been treated with aspirin. "Most, if not all, cases of Reye's syndrome," Glick concluded, "are etiologically unrelated to exogenous toxins or common medications."
On November 3, 1971, EIS officer Larry Schonberger got a call from Duke Hospital where three infants with Reye's syndrome had been admitted in the previous 11 days. Two had died, and the third was clinging to life on a respirator. Schonberger set up a surveillance system at Duke and three other North Carolina hospitals. By Christmas, he had found ten patients with Reye's syndrome. Surprisingly, none had predisposing influenza B or chickenpox, though eight had some kind of cough, cold, sore throat, or congestion. Six survived. Schonberger conducted a study, as controls using children of similar ages admitted to the hospital for nonviral diseases. The results were inconclusive.
One of the surviving patients was a two-month-old girl. Schonberger gathered all of her medical records and questioned the mother intensely. "I left still puzzled," he remembered, "but I kept those records."
It wasn't until several years later that another EIS officer was finally able to gather more data and make the connection that solved the puzzle:
In December 1978, a flu epidemic hit Phoenix. The day after Christmas, EIS officer Karen Starko, working at the Arizona Department of Health Services, got a call from EIS alum John Sullivan-Bolyai, who was doing his pediatric residency in Phoenix. He had learned of seven cases of Reye 's syndrome in children in three Phoenix hospitals and thought she might want to investigate this cluster.
Starko visited several of the children - five girls, two boys -- in the hospital. They were in comas, on life support, holes drilled in their skulls to relieve the pressure. Within days, two were dead. She spoke to their parents. These had all been healthy, normal children who had had apparently routine bouts of influenza. After a day or two, the kids were out of bed, feeling better. Suddenly they began to vomit relentlessly, then became sleepy, delirious or combative, and finally fell into a coma.
Starko initiated a case-control study in January 1979, choosing as controls 16 of the victims' elementary school classmates who had come down with flu and recovered uneventfully. Her questionnaire focused on the week prior to illness, asking about symptoms, medications, type of home heating, pets, and immunizations. In February, she began to analyze the results, but figuring out what was in the various medications proved to be a challenge. There were decongestants, gum, lozenges, and Pepto-Bismol, as well as aspirin (acetylsalicylic acid) and Tylenol (acetaminophen). After research and several visits to drug stores to study labels, Starko compiled her results.
Aspirin. All seven children who developed Reye's syndrome had taken aspirin (salicylates) in one form or another, compared to half of the controls, and the cases took it in heavier doses.
Starko did some research. She found that EIS officer David Reynolds had investigated 11 fatal cases of Reye's syndrome in Oklahoma from October 1968 through June 1970. EIS alum Calvin Linnemann had reported in 1974 on 24 Ohio children with Reye's syndrome. All of the victims in both studies had taken aspirin. Starko brought her data to Larry Schonberger in Viral Diseases, but he said, "Gee, I think previous EIS officers looked at aspirin before in some studies and it was dismissed." Stunned, she asked him to find the paper that ruled out aspirin.
A few weeks later, Schonberger called. He had reviewed studies by EIS officers Tom Glick (1967-1969) and Larry Corey (1973-1975). Over half of the victims in Glick's study had taken aspirin, and he had not looked in brand-name medications. Corey had studied hundreds of cases during a nationwide influenza B epidemic, and 78 percent had taken aspirin. Schonberger had also looked at the medical records of the baby with Reye's syndrome from his EIS days. She had been given aspirin.
Starko's Arizona case-control study was compelling, but with only seven cases, it hardly constituted proof. Schonberger advised Gene Hurwitz, his EIS officer already working on a Reye's case-control study in Ohio, to focus on aspirin use. Michigan-based EIS officer Ron Waldman, working on his own study, did the same.
One missing piece nagged at Starko - the unusual pathology findings of cerebral edema combined with tiny fat drops within liver cells. Perhaps salicylate poisoning produced something similar. Her supervisor Lyle Conrad suggested she write to the Armed Forces Institute of Pathology in Washington, DC. Within two weeks, on September 24, 1979, she received details of 11 cases of "acute salicylism in infants and children." All had "small cytoplasmic fat vesicles." Starko's hands trembled as she read the letter. "I wanted to scream," she recalls. "This was it!" Seven of those cases had antecedent upper respiratory infections. In other words, they were probably Reye's syndrome cases.
Starko and her colleagues had more obstacles to surmount before it was possible to declare victory over Reye's Syndrome, but this story of putting together different pieces - a case-control study with an extensive questionnaire, ingredient information gathered in drugstore aisles, pathology reports from another source - is a great example of the kind of persistence and creative thinking that have to come together to solve medical mysteries.
Inside the Outbreaks does a great job celebrating the combination of heroic and mundane work that goes into identifying and preventing disease. It's also a great way to learn about epidemiology and why it's so important. While the book is a fitting tribute to the EIS, it also reminded me how important it is to have strong state and local public health departments that can collect surveillance data year after year and spot outbreaks (like these) as they emerge.
So, go read Inside the Outbreaks and develop a new (or renewed) appreciation for epidemiology superheroes!
I was a Pediatric neurology resident from 1978 to 1981 and treated 9 cases of Reyes Syndrome. Discovering the aspirin association was a major breakthrough and saved many lives. What is even more impressive is the fact that kids had taken aspirin for generations and Reye's syndrome wasn't reported until 1963. Initially acetaminophen was suspected since it came on the market about the time that Reye's syndrome became epidemic. This all comes down to good epidemiology.