I don’t regard this as the end of the blog but as the beginning of your reading and thinking about public health and the impact of the Epidemic Intelligence Service. So, as food for thought, here are three sections of the book involving EIS officer Richard Levine, who was a bit of a troublemaker. These sections all involve important issues: environmental toxins, politics and business, mass psychosomatic illness, and iatrogenic illness (cholera spread by the cholera treatment center itself):

The Dusty, Leaden Streets of El Paso

When an El Paso, Texas, health officer called to ask for help evaluating a possible lead contamination problem, Phil Landrigan and fellow EIS officer Stephen Gehlbach met in Texas on March 27, 1972.

The 828-foot tower of the American Smelting and Refining Company (ASARCO) had dominated the El Paso skyline since 1887. ASARCO transformed ore into lead, copper, and zinc, and in the process spewed 313 tons of tiny lead particles into the air in 1971 alone. A local study had revealed heavy metal pollution of the soil.

When Landrigan and Gehlbach analyzed blood from children in El Paso’s nursery schools, they found that twelve of the 485 children had levels above 40 micrograms per 100 milliliters, at that time considered the health danger threshold.∗ Eleven of those children lived within three miles of ASARCO. Four Mexican-American toddlers who lived in Smeltertown in the shadow of the ASARCO tower had levels above 80 micrograms, though none had symptoms of acute lead poisoning.

Over the next few months, Landrigan directed randomized studies around the ASARCO plant. Household dust in Smeltertown was found to contain up to 22,000 lead particles per million. Air sampling revealed lead particles in the air near the plant, but they rapidly decreased to background levels three miles away. Most of the particles were smaller than 5 microns, so they could penetrate and remain in the lungs. The children of Smeltertown were swallowing and breathing excessive amounts of lead.

In June 1973, Landrigan returned to El Paso where he and Randy Whitworth, a University of Texas psychologist, studied a group of Smeltertown children with blood-lead concentrations over 40 micrograms per 100 milliliters, comparing them to other local children with lower lead levels. They gave them IQ tests (in Spanish when appropriate) and measured their wrist reflexes. The children with higher blood-lead levels had lower IQ and slower reflexes. Lead poisoning represented a continuum of health problems.∗

Landrigan stayed at the CDC following his EIS experience and eventually headed a new environmental health section. As a result of his work, the new U. S. Environmental Protection Agency eventually tightened industry standards.

EIS officer Richard Levine, stationed in Alabama, had helped Landrigan with the initial El Paso smelter investigation. Fired up about the lead issue, Levine called Alabama’s air pollution section in the summer of 1972. Employees there showed him letters from a farmer adjacent to a secondary lead smelter in Troy, Alabama, that reprocessed car batteries. The farmer wrote that his cows were sick. Some had died.

In September 1972, Levine discovered that nine employees of the Troy plant had been hospitalized over the previous two years with symptoms of lead poisoning. Roscoe Moore, a veterinary EIS officer, came to help with the investigation. Levine, an aggressive New Yorker, and Moore, an African-American, annoyed conservative white Alabama officials. Their findings irritated them even more. “The families living adjacent to the smelter reported that since 1971 at least 21 dogs and cats had died after several days of vomiting, ataxia, irritability, apparent blindness, and convulsions,” Levine and Moore reported. Thirty out of 37 plant employees had blood lead levels over 80 micrograms per 100 milliliters.

Levine wrote a damning report and distributed copies to his boss and other state health authorities. “When I came in the next day, my desk had been ransacked,” Levine recalls. “All my notes and copies had been destroyed.” Alabama State Health Officer Ira Myers, an EIS alum, tried to have Levine recalled to Atlanta. Levine was sued by the lead company for libel and slander but was cleared in court.

Levine and Moore were finally able to publish their lead smelter investigation in 1976. “A disturbing postscript to the present episode,” they wrote, “was the discovery that between July 1973 and January 1975, 21 additional workers from the Troy smelter were diagnosed as having had lead poisoning and six were hospitalized.”

∗ The safe level is now considered 10 micrograms or lower.

………………………

Visual Chain of Transmission

Friday afternoon, May 11, 1973, the Fayette County, Alabama health officer reported an outbreak of violent itching and rash at an elementary school. About a quarter of the 366 students had become ill, and 48 students and three teachers had been taken to the hospital. Aside from the rashes, victims suffered a variety of ailments, including headaches, cough, nausea, vomiting, weakness, sore throat, burning eyes, abdominal pain, numbness, shortness of breath, and diarrhea. Twenty-one students lost consciousness for a time. Most recovered quickly, but a few remained hospitalized overnight.

The following morning, Alabama-based EIS officer Richard Levine drove to Fayette County Hospital in the town of Berry. Levine examined the patients, including a teacher who told him, “It was like there was Red Devil Lye splashed all over my skin.” The victims had no fever, no abnormal white cell count. The fading rashes were mostly on the patients’ extremities, in areas where they had scratched. Levine told the school principal that he saw no reason to cancel school on Monday.

The EIS officer went home, and then returned on Tuesday to find the school nearly empty. There had been another outbreak. Eighteen students were afflicted. Most had also been in the first epidemic.

Levine called the CDC for help. EIS officer Fred Romm came from Atlanta with a sanitary engineer. EIS officer Dan Sexton came from Mississippi with John Kaiser, a fourth-year medical student taking an epidemiological elective. The CDC engineer set off smoke bombs to study air circulation. The investigators examined seating charts to see who sat next to an open window. No meaningful patterns emerged.

The outbreak appeared to be limited to the elementary school. Because of the rapid onset and lack of fever, it probably wasn’t an infectious disease. Investigators collected information on chemicals used at the school but found no answers.

Levine and Sexton gradually pieced together the story. Shortly before the morning recess on May 11, two sixth grade girls, both vigorously scratching themselves, were sent out of class to sit on a bench at the end of the main hallway. During recess, their concerned friends from the 5th and 6th grades gathered around them. They, too, began to itch and scratch. Some ran into the restroom to splash water on their burning skin. Students already in the bathroom became affected. “A few minutes later the 4th grade recessed and joined the commotion at the end of the hallway,” Levine wrote in his Epi-aid report. Soon fourth graders also began to scratch themselves.

Third graders waiting for lunch caught the itching plague as well. The first and second graders, already at lunch, were mostly kept free of the ailment, while the special education students in a distant classroom remained totally unaffected. Shortly after noon, the desperate principal evacuated the school. The skin of several teachers began to burn as well.

On Friday, May 18, Levine was interviewing seven 5th and 6th grade girls who had suffered repeated attacks. “I’ve got an itch!” a fifth grader announced. She began scratching herself violently. The other girls followed suit, scratching so hard that they began to bleed. Two fifth grade boys came into the room. One began to scratch. The other developed a sympathetic rash without touching himself.

Having witnessed this third epidemic himself, Levine was convinced that it was mass hysteria. Those who came down with the ailment simply had seen someone else suffering from it — a “visual chain of transmission,” as Levine eventually wrote in a published article. As with most such episodes, the majority of the victims were female.∗ The only ones exempt were the special education students – perhaps because they were not “smart” enough to become ill. After the third outbreak, the local board closed the elementary school for the rest of the year, which was nearly over anyway.

∗ Industry and regulatory officials often assume no toxic effect below certain levels, leading to a “hockey stick’” graph with a straight line showing no effects until the critical level is reached, then the “stick” part of the graph with a straight line rising above that level.

……………………………

The Cholera Center

After a little over a year in Alabama, having witnessed a hysterical epidemic and enraged state officials with his reports on lead, Richard Levine took a position at the Cholera Research Lab in Bangladesh conducting vaccine trials for the balance of his EIS service.

Day or night, speedboats brought patients from 234 nearby villages. From the upper deck of the old prison barge where he lived three days a week, Levine “saw the boats come in with cholera patients and their family members. People would be pooping in the boat on the way down.” Employees flipped the boats over and washed the diarrhea, replete with cholera vibrio, into the adjacent canal. Family members, often asymptomatic cholera carriers, excreted directly into the canal. In addition, the hospital sewage system leaked into the waterway.

Examining hospital records, Levine found that during five epidemics occurring from November 1968 through February 1971, the cholera hospitalization rate in “area C” on the canal was 15.6 cases per 1000 people a year, compared to a rate of 2 cases per 1000 in all villages. The re-infection rate for area C was 13 times as high as other villages. “Contamination of canal water can overcome any immunity resulting from repeated exposure,” Levine wrote in one of two papers reporting his results.

Once again, Levine was the bearer of controversial news. Even though he carefully concluded, “The benefit of the hospital to the community in terms of lives saved greatly outweighs the few extra cases in the hospital vicinity,” CDC authorities would not approve the papers. So Levine and his co-authors submitted them to the British journal, The Lancet, which published them. Soon thereafter, new sanitary precautions were initiated.

∗ Why females appear to be more susceptible to psychosomatic disorders is a contentious issue. Explanations include: 1) Women are more emotional and sensitive. 2) The imagined ailments stem from women’s oppression. 3) It is a cultural phenomenon. 4) It is genetic.

That said, it is hard not to be envious of the bright, dedicated, indeed courageous EIS officers who have been able directly or indirectly to remove pump handles. In contrast, most of my activities as an EIS officer were related to influenza epidemiology. Although I was in the amazing position of being the only EIS officer who was assigned to this area in 1967-1969 and as a result got the opportunity to play a major role in documenting the last U.S. epidemic of H2N2 influenza (“Asian flu”) and the first U.S. epidemic, indeed pandemic, of H3N2 influenza (“Hong Kong flu”), there was no simple control measure and no opportunity to remove a pump handle. Nonetheless, as Mark Pendergrast documents, I had the good fortune to participate in a series of controlled trials of influenza vaccines in both the 1967-1968, Asian flu, and the 1968-1969 Hong Kong flu epidemics. I worked closely with the late Steve Mostow, a young physician who served for three years in the respiratory viral diseases laboratory at CDC; and we both worked under the expert leadership and guidance of Walter Dowdle, then head of the viral diseases laboratories at CDC and later deputy director of CDC, and Marion Coleman, the head of the respiratory viral diseases laboratory. Both were excellent virologists. Unfortunately Marion died at a young age of a brain tumor. I consider Walt, who retired many years ago from CDC but continues as a consultant to WHO’s Task Force on Global Health and for many years worked on polio eradication at the Carter Center in Atlanta, to be one of the most level-headed thinkers and best teachers I have ever encountered. I had the good fortune to be able to learn from occasional interactions with him even a few decades after I was no longer affiliated with CDC.

Until the late 1960s, commercially-prepared influenza vaccines employed the Sharples centrifugation process to try to purify viral particles from the embryonated egg fluids in which the vaccine virus was grown. When electron micrographs became available it was apparent that these products were not very pure. The number of inactivated viral particles in a given amount of vaccine varied, and the impurities were associated with a high reaction rate, which limited the total dose that could be given. Efficacy, while said to be on the order of 70 percent for a vaccine made with a virus similar to the prevailing epidemic strain, was often much less and could be zero. New zonal ultracentrifugation methods led to much purer vaccine preparations, and a larger amount of virus could be given without so many reactions. Demonstrating the properties of the new vaccines vs. the old – reactions, efficacy – was the object of the vaccine trials being conducted by us in those years.

Having an influenza vaccine with reasonable efficacy, which actually was only on the order of about 70 percent, is just the first step in achieving control of the disease. Getting it to people in time, especially in the years in which it is most needed such as an anticipated pandemic, involves a whole process ranging from the mechanics of manufacturing a new vaccine to organizing an immunization program at the national and all local levels. In our complex health system, this is a formidable task and one that had not been considered systematically back in the 1960s. “Inside the Outbreaks” documents the “over-reaction” to swine flu in 1976. Others have called it the “Swine Flu Fiasco”; but in my opinion it represented a reasonable approach to a problem given what was known at the time and was an important milestone. Going into that issue would require much more discussion that is possible here. I raise it, however, because some of the fall-out from 1976, such as concern about possible future association of influenza vaccine with Guillain-Barré syndrome and general apathy about influenza immunization among the public and health care professionals, led to persistence of very low immunization rates even in the so-called “high-risk” population for whom vaccine was particularly recommended – i.e., persons age 65 and over and persons with various chronic conditions, especially heart disease, lung disease, and diabetes.

In the early 1980s, Alan Kendal, then head of the influenza laboratory at CDC, decided that it was important to revise the influenza recommendations. At the time, I and Fred Ruben, a former EIS officer then at the University of Pittsburgh who had done a lot of work on influenza and influenza vaccine over the years, were both members of the Immunization Practices Advisory Committee (ACIP). Alan asked Fred and I to join him and EIS officer Peter Patriarca who worked on influenza to join him in drafting revised recommendations. We recognized that it was important not just to have recommendations that were “sensible”, which the old ones were, but ones that were likely to be followed. In addition, the objective was to assure that people who needed it got into the habit of annual influenza immunization. Why? At one time, it was thought that influenza A epidemics occurred in the U.S. only every two to three years; but with the advent of H3N2 (Hong Kong) influenza in 1968-1969 and the return of H1N1 (Russian) influenza in 1977, and careful analysis of mortality data, it was now apparent that on average influenza A was leading to 30-40,000 excess deaths in the U.S. each year!

In drafting the revisions to ACIP’s influenza vaccine recommendations, we focused first on “highest risk” persons – e.g., older people with chronic conditions who were most likely to be hospitalized or die during an influenza epidemic. Our reasoning was that one needed target groups for whom one could set high, but achievable immunization goals. The “highest risk” group consisted of persons most likely to be seeing physicians regularly – i.e., persons who could be immunized during office visits. We went a step further and recommended that the medical personnel caring for them, physicians, office nurses, and hospital workers, be immunized since they would be most exposed to influenza at a time that they most needed to be healthy and help others. I confess that there was not, at that time, any evidence, just “common sense”, to support the recommendation for health care workers, and such evidence only developed later. But, there was evidence to show that commercially-available influenza vaccines could be effective at decreasing major morbidity due to influenza such as hospitalization; and that evidence was first developed in the 1970s by former EIS officer William H. Barker who teamed up with John P. Mullooly to study members of Kaiser Permanente in Portland, Oregon. So, there was major morbidity such as hospitalization and mortality that could be prevented with more effective immunization recommendations and practices.

Anyway, starting with the revised influenza immunization recommendations from ACIP, the efforts of CDC to track immunization and suggest ways to improve it, and a series of international conferences called “Options for the Control of Influenza” which Alan Kendal initiated in about 1984, some attention began to be paid to influenza. As annual immunization rates increased in the U.S., albeit still relatively low, more and more evidence accumulated about who might benefit from influenza immunizations, ACIP considered more and more evidence, and immunization recommendations again became more inclusive.

That said, only a handful of people in the U.S. and around the world seemed interested in how a next pandemic – the last being the Hong Kong (H3N2) pandemic of 1968-1969 – might be blunted. Influenza may not be predictable from year to year, but the idea that it will disappear and not trouble us again is unthinkable. Yet, we were doing relatively little about it. When the first outbreak of “Avian flu” (H5N1) occurred in Hong Kong in 1997, we would have been totally unprepared as a nation to develop and apply widespread control efforts had a pandemic occurred. That outbreak was controlled in Hong Kong by killing the large populations of live chickens and ducks that were harboring the virus. With the reappearance of H5N1 a few years later, the world as a whole and the U.S. paid more attention. Significant resources have been devoted to influenza control, developing and testing new vaccines and antivirals, and formulating plans for deployment of control efforts of many types. Although scientific “breakthroughs” are still needed, promising avenues are being pursued, and there is now a large group of scientists working on influenza and influenza control.

The recent H1N1 (swine flu – “again”) pandemic has been a fortunate test of pandemic planning. Though the country and world are still far from prepared, and there is still no chance to remove the pump handle completely, we are much better prepared than just a decade ago and because H1N1 has been “relatively mild”, it has provided an opportunity to find holes and consider ways to plug them rather than providing a tragic relearning of the lesson that influenza epidemics can cause massive societal disruption.

On a personal level, I was involved as an “amateur” in influenza control for many of the past 40 years. I say “amateur” since it was not my main activity at any time after leaving CDC and I never was supported to do work in the field. I realized a year or two ago that there are now enough “professionals” in the field that I can think of the tide in the battle to control influenza having turned and turn my personal attention to other pressing problems. Influenza control isn’t as instantly gratifying as pump handle removal, but the progress is satisfying nonetheless. And, while it is common to think of EIS officers arriving at epidemics or getting involved with diseases after they have peaked and “riding the downhill tail of the epidemic curve to glory”, in fact, it is remarkable to see the degree to which EIS officers have, sometimes alone and more often in concert with teams even huge numbers of others, successfully participated in both short-term and long-term disease control efforts.

Fears of bioterrorism are overblown. We should be spending much more money, time, effort, and print (including e-print) on naturally occurring outbreaks, epidemics, and human behavioral risk factors. At least, that is one of my conclusions after researching and writing the history of the Epidemic Intelligence Service, which is a kind of microcosm of public health events over the past half century.

The EIS was created in 1951 in the crucible of Cold War paranoia during the Korean War. Alexander Langmuir masterfully played the fear card in order to fund the EIS, and he named it in a suitably military-type way, with “intelligence” meaning the same thing for outbreaks that it did for the then-recently created Central Intelligence Agency. One could say that the EIS is a kind of medical CIA, except that EIS officers do not usually act under the cloak of secrecy.

There is no question that Langmuir took the threat of biological warfare extremely seriously. But he was also savvy enough to realize that by playing up such Cold War fears, he was more likely to secure funding. Thus the earliest EIS officers were on a sharp lookout for any indication of unusual outbreaks that might have been caused intentionally. Over the years, a few incidents have been considered as possible bioterrorism events. One of the earliest was investigated by EIS officer Jerry Barondess (EIS 1951-1953), who was stationed in Philadelphia, “where putatively I was defending the Northeast,” he recalled.

“One day I got a call from Atlanta. Alex said there was an epidemic of fox rabies in Broadax, PA. Go and look into that. I was a smart aleck. I said, ‘Do you think the Communists are coming into the foxes in Broadax?” He told me to just shut up and go. It turned out, a couple of weeks before, in broad daylight, near Valley Forge, a fox came out of trees, teetered across a quarter mile of open ground, approached an elderly woman knitting on her porch, and snarled at the old lady, who shouted Shoo and he ran away. A couple of days after that, a fox worried a cow. A few days later, a dead fox was found to be rabid. There were no human cases yet. So I was called in. It turned out that nearby there was an old very distinguished and highly fumigated hunt club, the White Marsh Hunt, that hunted foxes. This was a faux British kind of thing, bugles and horns. Having reduced the fox population to an unacceptable level, they had imported a bunch of foxes from somewhere near Utica, I think, a few weeks before. So it was not the Russians, it was the White Marsh Hunt.”

In 1984, EIS officers investigated a Salmonella outbreak in The Dalles, Oregon. Their case control study implicated the salad bars in various restaurants around town, but they couldn’t link them epidemiologically. The restaurants didn’t purchase produce from the same farms, and there were no employees who worked at multiple restaurants. Nor did customers roam from eatery to eatery. That turned out to be bioterrorism, committed by the nearby Rajneeshee cult in a dress rehearsal for a larger event in which they hoped to debilitate local voters in order to maintain the cult’s tax-exempt status. Excerpt from Inside the Outbreaks:

EPO director Carl Tyler refused to allow [EIS officers] Török and Tauxe to publish their article on the investigation, afraid that it would provoke “copy-cat” events, as the Tylenol-cyanide poisonings had in 1982.
A decade later, in the wake of the 1995 Aum Shinrikyo sarin gas attacks in the Tokyo subways, Török and Tauxe were finally allowed to publish their paper on the salad bar contamination, the first major bioterrorism event in the United States.

As the turn of the 21st century approached, there were widespread fears of bioterrorism as part of the millennial fever. From the book:

On October 30, 1998, EIS officer Marshall Lyon got a call from a worker at a Planned Parenthood clinic in Knoxville, Tennessee, which had received a letter that said, “You’ve just been exposed to anthrax. You will die within 24 hours.” Over the next hour, he got calls about identical letters sent to clinics in Louisville, Kentucky, and Indianapolis, Indiana. Lyon tried to calm the callers, telling them that if there was nothing in the envelope but the letter, anthrax exposure seemed unlikely.
All the centers had also called 911, bringing police, firefighters, emergency medical services, the FBI, and Hazardous Materials (HAZMAT) units to the clinics. By the time Lyon flew to Indianapolis on Monday to assess the situation, it was clear that the letters were hoaxes. Yet when another Indianapolis clinic received a similar letter that day, the scenario repeated itself. Then in Los Angeles on December 17, 1998, two anthrax letters were mailed to city offices, followed within the next week by phone warnings to a private business and a large federal building, from which 1,500 employees were evacuated. Lyon flew out. “It kind of boggled my mind,” he recalled. “There was no assessment of the threat credibility.” Lyon tried to preach some common sense. “You have to temper your response,” he said, “or you will go broke.”
Over the next few months, dozens of hoax letters, many containing talcum powder or white flour, arrived at schools, courthouses, media outlets, abortion clinics, and an IRS office.

Fortunately, this rash of hoax letters spurred the CDC to form a bioterrorism task force and to create a state-of-the art anthrax lab. My favorite non-bioterror scare occurred in conjunction with New Year’s Eve. Here is that little section.

In October 1999, the FBI issued a warning about terrorism linked to the turn of the century. The same month, Hot Zone author Richard Preston published an article in the New Yorker, speculating that the recent West Nile virus outbreak might have been the work of a terrorist. Preston quoted an Iraqi defector who said that Iraqi dictator Saddam Hussein had boasted that his labs could produce a West Nile virus “capable of destroying 97 percent of all life in an urban environment.”
EIS officer Kristy Murray had already concluded that the West Nile epidemic in New York City was not premeditated and she knew that a 97 percent mortality rate was absurd. With near-hysteria in the air over the Y2K bug that would supposedly wipe out computers as dates turned on Jan. 1, 2000, Murray got a call from Pennsylvania health authorities. The trucker who had delivered the ball to Times Square for the New Year’s Eve celebration had just died of a rapidly fatal pneumonia, and so had his wife. Murray had nightmare visions of the giant glittering ball slowly descending at midnight, spraying deadly fumes over thousands of celebrants. But she learned, to her relief, that the trucker had carried a wall, not a ball – someone had misheard the word and panicked. The trucker and his wife were already unhealthy and morbidly obese. The 20th century went out with a routine bang, not a fatal hiss.

We know, of course, that exactly 50 years after the creation of the EIS, its officers did investigate a major bioterror event when real anthrax letters began to kill and sicken people. In my chapter, “Full Circle,” I wrote in detail about that investigation. At chapter’s end, I concluded:

Ottilie Lundgren was the last anthrax victim of the 2001 bioterror spree. A total of 22 people had been infected, half of them with inhalational anthrax, and five inhalational victims had died. Of the 146 then-current EIS officers, 136 helped with at least one part of the investigation. Nearly a third of them went out twice, and some were redeployed four or five times.
Prompt investigation and prophylaxis undoubtedly prevented other anthrax infections and deaths. No health authorities had any way of knowing how many letters had been sent out to what locations, or whom they would infect. “What shook me,” EIS officer Kevin Winthrop said, “is how one individual could drop a few letters in a mailbox and nearly shut down a country.”
As a result of the anthrax investigation, blowers were no longer used to clean sorting machines, letters were irradiated, and other safety measures put in place. There was some good news, too. Untreated, the case fatality rate for inhalational anthrax from the letters approached 50 percent — less than the expected 85 percent rate – but when promptly treated, all but a few patients survived. …[A FEW CUT PARAGRAPHS HERE]
In the wake of the anthrax letters, the Bush administration and Congress threw billions of dollars into bioterror preparedness, much of it going to the CDC and to state health departments. HHS Secretary Tommy Thompson called for an EIS officer in every state, but some states had weaker public health infrastructure and lacked good supervisors. Instead, EIS alums called Career Epidemiology Field Officers (CEFOs) were posted to such states, though they focused primarily on terrorism and emergency response.
The new bioterror money undoubtedly improved preparedness for many potential public health emergencies, but other problems were underfunded, according to EIS alum Barry Levy, editor of the 2003 book, Terrorism and Public Health. “These bioterror initiatives have, in general, distorted public health priorities,” complained Levy, “and drained human and financial resources away from addressing current public health problems, including tobacco- and alcohol-related diseases, gun-related injuries and deaths, HIV/AIDS, and mental health disorders.”

So, I repeat, bioterrorism fears are overblown. I think this is because of bioterrorism’s sexy nature, not only for the media, but for public health figures. It’s exciting to worry about. And there are certainly realistic fears that some of the smallpox that the Soviets were secretly brewing may get into terrorist hands, and it could be released in a way that would create an epidemic and cause many deaths.

Even if that bleak scenario were to come true, however, we would probably be able to contain the epidemic relatively quickly. We know how to conduct surveillance-containment, and we know how to vaccinate against smallpox.

Then there is the idea that some mad scientist is going to use genetic engineering to create a new killer strain that will cause a pandemic. The June 2010 issue of Scientific American ran an article, “Terror in a Vial,” asserting that the concern over nuclear bombs is old-fashioned, “an approach unsuited to the modern reality.” Instead, the authors believe we should be worried about bioterrorism. “Terrorists no longer need to steal deadly pathogens when common-place genetic engineering techniques could turn a benign microbe into a killer or synthetic biology tools might be used to build a virus from scratch.”

Maybe, but I think natural selection is a far more potent device to create microbes to take advantage of the burgeoning human herd. There will be 9 billion of us in another 40 years. I don’t think terrorists or any humans are smart enough to create a microbe that could do worse than nature already does. And if they did, it would be likely to be treatable and not easily transmissible. Much better to worry about nuclear bombs.

What we really need is a well-funded public health system that conducts comprehensive surveillance for infectious as well as toxic agents. Bioterrorism will be spotted as part of that effort. Every year approximately 36,000 people die of seasonal flu-related causes. Yet no one seems unduly concerned.

And as I pointed out near the end of Inside the Outbreaks, our biggest challenges are modifying our own behaviors:

Humanity’s worst problems are self-inflicted. Why do members of Homo sapiens self-destruct? According to World Health Organization, the top two global killers, accounting for nearly a third of all mortality, are ischaemic heart disease (blocked arteries) and cerebrovascular disease (insufficient blood to the brain, strokes), both of which are often caused by smoking, obesity/poor diet, and lack of exercise.
In 2004, four authors (including EIS alum Jim Marks) estimated recent “actual causes of death” in the United States – i.e., the underlying behavior or agent responsible for human demise. The top culprit was tobacco, accounting for 18.1 percent of all U. S. deaths, followed by obesity and poor diet (15.2 percent), with excessive alcohol consumption third (3.5 percent). …. [SNIP]
How could EIS officers get people to modify their drinking habits and diets, get more exercise, and quit smoking? They could provide important surveillance data and studies, but ultimately, argued EIS alum Tom Farley in his co-authored 2005 book, Prescription for a Healthy Nation, the cure would involve modifying our environment to make it easier and more appealing to walk, run, bike, and buy or grow healthy foods. “Health is political,” he wrote, advising that “it will take fighting in Congress to get the booze ads off television, arguing in the town council to build sidewalks or fix the recreation equipment in the park, or calling state legislators to ban smoking in all restaurants.”…. [SNIP]
And so EIS officers continue to engage with such problems, confirming that poverty, social injustice, and frustration are at the root of many health issues. Those who are most vulnerable are the underprivileged, the malnourished, the unvaccinated, refugees. …[SNIP]
Looming over all other problems is global warming. …In 2008, EIS alum Mike St. Louis co-authored a summary article on the potential public health impacts of global warming. “The most severe consequences of climate change will accrue to the poorest people in the poorest countries,” he wrote, “despite their own negligible contributions to greenhouse gas emissions.” Malnutrition, unsafe water, and heat waves will increase. Coastal megacities – Mumbai, Lagos, Shanghai, Dhaka, Tokyo, New York – will be vulnerable to sea-level rise and infiltration of freshwater with saltwater.• Diseases carried by mosquitoes may shift to currently temperate climes. Waterborne infections such as cholera could spread. Armed conflict is likely to escalate as people fight over scarce resources or ban desperate refugees. Also, by 2050, the human population is projected to grow from its current 6.8 billion to over 9 billion.

So that’s why I am not unduly concerned about bioterrorism, though that does not mean I think we can afford to ignore its possible occurrence, either. -Mark Pendergrast

Is an influenza or chickenpox infection necessary to acquire RS?
The answer is no. RS generally has two phases: the antecedent illness and usually, within a few days of this, the syndrome of vomiting and encephalopathy. While viruses are the most common antecedent event, other illnesses may precede RS such as teething and connective tissue diseases. Some antecedent viruses are influenza A and B, adenovirus, Coxsackie virus, Epstein-Barr virus, ECHO virus, polio, parinfluenza, reovirus, rubella virus, measles, herpes simplex. (Corey, Am J Med, 1975)

Is fever in the antecedent illness necessary to acquire RS?
No. In the U.S. Public Health Service Study (Hurwitz, NEJM, 1985) fever was reported less often by RS cases (54%) than by any of the four control groups (59% to 89%).

Was RS truly more common after influenza B than other viruses?
Currently available data are not sufficient to answer this question. (Any data on this would be welcome). Outbreaks of RS associated with influenza B infection were reported to CDC starting in 1967 when 6 cases were reported from Tampa, Florida. Other subsequent outbreaks included: Oklahoma 1969 (6 cases), Atlanta 1969 (6 cases), Massachusetts and Vermont 1970 (24 cases), and Guam 1971(6 cases). (Hochberg, JAMA, 1975)

The largest study (Corey, Am J Med, 1975) addressing the association was performed between December 15, 1973 and June 30, 1974. In anticipation of substantial influenza B activity after identification of a new variant of influenza B, both CDC through state health departments and the American Academy of Pediatrics urged physicians to report cases. 379 cases fitting the CDC case definition were reported. While it was hoped that laboratory evidence of the type of infection would be obtained from many, attempts at viral isolation or properly spaced serology were conducted in only 21%. However, many cases did cluster temporally and geographically with influenza B. 340 cases reported an upper respiratory infection. 58 (17%) had evidence of influenza B infection. Serology or viral isolation identified influenza A/Port Chalmers (2 cases), adenovirus (1 case), parainfluenza virus (1 case), double virus infections (3 cases), and no evidence for a virus (5 cases). 28 patients had an antecedent varicella infection and 15 patients had a gastrointestinal infection.

Also, more RS cases were reported to CDC during influenza B years as follows: (Hurwitz, Pediatrics, 1982)
Year Major influenza activity Number of RS Cases
1973-74 B 379
1976-77 B 454
1977-78 A 237
1978-79 A 389
1979-80 B 548

Thus, the association with influenza B is a descriptive one. It may be real (influenza B is an independent risk factor), a confounder (influenza B is a reason to give aspirin), or an artifact of surveillance. Reporting RS to CDC was for the most part voluntary. Once the early small outbreaks associated with influenza B were reported and CDC and the AAP called for RS cases during an influenza B year (and found them!) the impression that the illness was associated with influenza B was furthered. Interestingly, after 1990, although the number of RS cases had fallen, no association was noted with influenza B (Belay, NEJM, 1999). Thus the question of whether or not influenza B predisposed to RS is still up in the air. To my knowledge, there are no data addressing the question of whether children with influenza B are at greater risk of RS than children with influenza A or other viral illnesses.

Are influenza and chicken pox independent risk factors for RS or are they simply a trigger for the administration of aspirin?
Unfortunately, this question has not been addressed directly. While temporal and geographic associations with viruses have been identified, these are only descriptive. It remains unclear if these viruses possess some characteristic that promotes the development of RS or whether they are simply the trigger for the administration of aspirin.

On the other hand, there is pharmacology evidence that aspirin alone can accumulate to toxic levels at the doses recommended at the time in children. In 1906 Langmead (Lancet, 1906) reported a child hospitalized with rheumatic fever who received 325mg of a salicylate every 6 hours and on day 4 developed vomiting, fever, dyspnea, cyanosis, and coma and died. He suggested the salicylate might have accumulated. Yet, it wasn’t until 1947 and the development of a test to measure salicylate in the blood that Erganian (J Pediatrics, 1947) showed that indeed salicylate levels progressively increased over several days in some children given commonly recommended doses. In 1965 Levy showed that when the body level of salicylate reaches 360 mg, metabolism changes from first order (when the body can metabolize whatever amount of drug it is given) to zero order (when only a certain amount can be metabolized at a time). In other words, metabolism becomes rate limited and the drug can easily accumulate. Any one of a number of factors will predispose to salicylate accumulation: too much, doses too close together, dehydration (as with fever), reduced renal excretion, low urine pH, and individual variation in speed of metabolism. Other factors such as acidosis and hypoproteinemia increase brain uptake. In addition, individual differences in level at which toxicity occurs have been noted. (Reviewed in Starko, CID, 2009)

Pinsky and colleagues (JAMA, 1988) at the CDC provided evidence that suggests that accumulation happens in RS. They showed that RS cases generally took more salicylate than did controls (although for the most part within recommended amounts) and more importantly that RS cases continued to take salicylate for more days than controls. On day 3 for example, 18 (78%) of 23 RS cases were still taking aspirin whereas only 12 (9%) of 134 controls were doing so. This pattern is consistent with accumulation similar to that reported by Langmead in 1906 and Erganian in 1947.

Congress’s creation of federal agencies is clearly a huge achievement, and they’ve also periodically given new powers to already existing agencies. For instance, Mark Pendergrast tells the story of the Dalkon Shield, an IUD that turned out to cause infections while failing to prevent pregnancy in many of the women who used it; at least 17 pregnant women died with IUDs in their uteruses. The manufacturer, facing lawsuits, eventually took the product off the market, but the episode demonstrated the need to prevent similar problems in the future. Congress responded by passing the Medical Devices Amendment Act, which mandates that medical devices receive FDA approval before being marketed.

Agencies also rely on Congress for their annual appropriations, and public health isn’t often the top Congressional priority when it comes to dividing a limited pool of revenue. There are times when Congress responds to a growing health threat by giving an agency more money to address the problem; for instance, after several outbreaks of food-borne illnesses, Congress gave FDA’s FY 2010 budget a large increase to help it hire more food inspectors. It seems like more often, though, Congress makes funding decisions that run counter to the advice of public health professionals.

Of course, those of us in the public health field would like to see much larger amounts of money overall going to preventing death and disease – as Karen Starko pointed out in her post last week, public-health efforts bring enormous benefits, but are miserably underfunded compared to other areas. Then there are the problems with Congressional priorities, which can be shaped more by current news coverage or a small-but-vocal group of constituents than by a broad understanding of our nation’s health challenges. Inside the Outbreaks includes a few examples of this, including post-9/11 Congressional decisions to increase appropriations for bioterror while cutting other health-related budget items.

In addition to Congress and CDC having different ideas about the relative importance of different public health priorities, there can also be times when members of Congress flat out oppose a CDC effort to tackle a particular public health problem and eliminate funding for that area altogether. Mark Pendergrast gives this example in Chapter 18:

In November 1994, conservative Republicans had won both houses of the U. S. Congress, which spelled trouble for the CDC National Center for Injury Prevention and Control, where EIS alums Mark Rosenberg and Jim Mercy continued to study the impact of firearms. As their EIS officer for the incoming class of 1995, they recruited Etienne Krug, a 34-year-old Belgian.

“I grew up in Europe,” Krug said, “where firearms are not available at all. They are considered very unsafe to have in your home.” So he decided to compare the rate of firearms deaths in the United States with other developed countries. The results showed children under the age of 15 were twelve times more likely to be killed with a gun in the United States than in the other countries’ combined average rates. Krug’s study also pointed out that while the overall annual death rate for children in the United States had declined substantially since 1950, the child homicide rate had tripled.

When the MMWR published his findings in February 1997, Krug was interviewed on international TV and radio, resulting in an anonymous death threat. The Republican Congress had just passed a bill eliminating the $2.6 million Division of Violence Prevention budget for firearms research and ordering the CDC never to advocate gun control. Thus, when pressed by reporters about whether tougher laws should be passed, Krug answered, “That is up to legislators to determine based on the data.” The Congressional ban on CDC gun control advocacy remains in place.

This is troubling. If scientists think that Congress will eliminate research efforts that yield results Congress dislikes, they’re likely to steer clear of investigations that might draw Congressional ire, even if that research could save many lives. This was also something that my colleagues and I found in our Scientists in Government research, when we interviewed scientists from federal agencies to identify policies and practices that could be improved in order to strengthen federal science. In particular, several scientists from the National Institute for Occupational Safety and Health (which is part of CDC) told us that the 104th Congress’s threat to eliminate NIOSH still informs agency decisions about research topics, and that new initiatives have been “noticeably in non-controversial areas.”

Congress has a responsibility to exercise oversight over the agencies it has created, but its micro-managing has the potential to impede agencies in their work to carry out their Congressionally mandated missions – which in CDC’s case is “Collaborating to create the expertise, information, and tools that people and communities need to protect their health – through health promotion, prevention of disease, injury and disability, and preparedness for new health threats.” There will be times when the tools and information communities need to protect their health do not sit well with a group of voters, and Congressional (or presidential) pandering to those voters will impede disease prevention.

Inside the Outbreaks‘ description of CDC’s work on HIV/AIDS illustrates just how much is at stake when lawmakers, executives, and agencies themselves let political considerations interfere with research and prevention efforts. I knew the US had been too slow to respond to AIDS, but reading about multiple instances when EIS officers recommended specific actions but authorities declined to act was depressing. As early as 1982, EIS officer Jim Curran’s was recommending that blood donations from high-risk groups be deferred – and his advice wasn’t being heeded. Because of how AIDS is spread (sexual contact, injection drug use) and because it initially affected marginalized populations, many people were reluctant to discuss or investigate it, and then resisted the kinds of prevention efforts (condom distribution, needle exchanges, etc) that could best prevent its spread.

Aside from reminding Congress (and the White House) just how many lives are at stake from public health problems it would rather not acknowledge, what are good ways to ensure that Congressional actions towards health-related federal agencies don’t hinder agencies in fulfilling their Congressionally mandated missions?

The Ogemaw County epidemic has been well described first in a story that Berton Roueche did for the New Yorker, which I found particularly exciting since I had originally been attracted to epidemic investigations and the EIS by reading some of Roueche’s collected stories in “Eleven Blue Men”. The description of Ogemaw remains in print in another collection of Roueche stories, “Medical Detectives”, and is entitled “The West Branch Study” – West Branch being the largest town in Ogemaw County. It is described more formally/scientifically in the following reference: Schoenbaum SC, Baker O, Jezek Z. “Common-source epidemic of hepatitis due to glazed and iced pastries.” American Journal of Epidemiology. 1976; 104:74-79.

Back in 1968, Ogemaw County had a population of about 12,000. A worker in the local bakery and another local resident who happened also to be a food handler at an ice-cream stand had had hepatitis in early April. Then over one month from late April to late May, there were 61 more cases of hepatitis. Since hepatitis A, which in those days was called infectious hepatitis, has an incubation period of about 15-45 days, the whole outbreak was consistent with a common source of exposure back in the early part of April – i.e., sometime in the first two weeks.

Now, cohort studies are based on the idea that the investigator wants to find out if exposure to something causes disease. So, to do a cohort study you start with a group of people who are well but have an exposure of interest – for example, smoking. You find a similar group of people who are well and do not have that exposure – i.e., are non-smokers. Then you follow both groups over time and determine how many in each group become ill from various illnesses. That allows you to calculate the “relative risk” of developing a specific illness, e.g., lung cancer, heart disease, etc, if you are exposed (a smoker) vs. non-exposed (a non-smoker). An advantage of cohort studies is that they allow you to study the occurrence of multiple illnesses in relation to a single type of exposure. Since you start with people who are well and the illnesses develop over time, cohort studies take a lot of time. They are “prospective” studies. It is also the model for clinical trials, i.e., for drugs or other medical interventions. One starts with a group of people and gives some of them a drug, or “exposure”, and compares what happens to the treated group over time vs. the non-treated or non-exposed group.

In contrast, case-control studies are “retrospective”. They work backwards in time. One starts with a group of people who have an illness, the cases, and a group who do not have it, the controls. Then one determines if the members of each group might have or have had a variety of exposures. By comparing the frequency of each exposure in each group one can calculate a statistic known as the “relative odds” of getting the illness in the face of each specific exposure.

When I started the EIS course back in July 1967, the first case study was a church supper or pot-luck supper in Oswego County, New York. The epidemic was due to staphylococcal enterotoxin which has a very short incubation period between the time its victims eat it and the time they become ill. In a church supper in a small town it is possible to determine who was present, who became ill or stayed healthy, and what each person ate. That actually makes it possible to approach the analysis of the information either from a cohort approach – i.e., consider each food on the buffet table an exposure, calculate, and compare the relative risk of illness for those who consumed the food and those who didn’t – or pursuing the case-control approach one could start with the groups of people who got ill vs. those who didn’t, calculate the frequency with which the persons in each group ate each food and then calculate the relative odds of illness for eaters of each food. The cohort approach to analysis is preferred in this situation; and a study in which all the data about the exposures and illness can be obtained at one time is called a “cross-sectional” study.

OK – so back to Ogemaw County: Hepatitis has a relatively long incubation period, especially compared to staph enterotoxin. By the time the epidemiologist learns about the outbreak it really isn’t possible to know the cohorts of persons who were exposed to each possible source of such outbreaks – foods of various types from various sources, water, etc. But, it is easy to know who is sick, the cases. Then one has to pick a suitable group of controls and try to find out from each group what they might have been exposed to. In short, evaluation of such epidemics fits quite naturally into the case-control methodology. There is an issue, however, and it involves selection of an “appropriate” group of controls. This isn’t trivial, and sometimes one even picks a couple of different kinds of controls. Also, one can just pick a group of suitable controls for the group of cases as a whole, or one can try to match a specific control to each case or patient. The theory is that one wants the controls to be as similar as possible to the cases except for the exposures that might have been associated with the development of the illness. So if the cases were all young women, one wouldn’t pick a group of controls that were all old men. On the other hand, if one matches each ill woman who is a specific age with a healthy woman of exactly the same age, then one can no longer study whether gender or age are factors in developing the illness. In Ogemaw County we took a chance in picking the controls. Forty-one of the 61 cases were age 10-19. To have a control group that came close to the case group in demographics, we chose all the household members of cases who were age 10-19 and ended up with 56 of them. The chance that we took was that not everyone who gets infected with the hepatitis A virus becomes ill. So, it was possible that by picking household members of cases we were picking some people who actually had had exposure to the hepatitis virus. In considering them controls we were increasing the likelihood that a high rate of exposure to the culprit would occur in the control group and we wouldn’t be able to identify the culprit since there wouldn’t be enough difference in reported exposure between cases and controls. Nonetheless, it was convenient to be able to interview the cases and controls about exposures on just one contact with a household. So we took the chance. And, it worked out: 92 percent of the patients 10-19 years old had eaten glazed or iced pastries from the local bakery during the first two weeks of April 1968, the likely time of exposure given the body of the epidemic occurring in late April/May; whereas, only 47 percent of the controls reported a similar exposure. The only other frequent exposure reported by cases was West Branch’s municipal water, but the controls reported consuming water from the municipal supply even more frequently than the cases. So, it was just a frequent exposure for anyone living in the Ogemaw County area.

There were many other interesting features to the epidemic in Ogemaw County; and since they are well-described in the journal article and story in Roueche’s “Medical Detectives” I won’t go into them here. What I would like to mention is that like most epidemic investigations, Ogemaw was a team effort. I was sent out from Atlanta where I had been working on influenza. In line with some of the stories in “Inside the Outbreaks”, I needed to learn about the epidemiology of hepatitis A on the flights up to Michigan. I got to work closely with the county health officer, Ophelia Baker; and two other EIS officers were sent up after a few days to help in the investigation – Jim Gardner, the EIS officer in my class who had been assigned to the state of Michigan, and Eugene Page, the EIS officer in Florida. Then one day I got a call from Atlanta. There was a visitor at CDC, a seasoned infectious disease epidemiologist from Czechoslovakia, Dr. Zdenek Jezek. He had had several times as much experience as the three of us EIS officers combined! In fact, at the time he came to visit CDC, he was working for WHO and had just come back from a couple of year assignment in Mongolia. Without the team and Zdenek Jezek’s experience, I doubt we would have been able to pin down the exposure quite so neatly to the worker in the bakery who had become ill in early April. When we observed the bakery operations directly, we saw that he would dip pastries with his bare hands into a pan of glaze, a thick sugar-water mix, and put icing onto other pastries with his hands. Dr. Baker, in her role as the health officer, instituted some food-handling rules for the local businesses that prepared foods on site such as the bakery, and proceeded to inspect them over time. Michigan, which used to manufacture immune serum globulin, had a large supply, and Dr. Baker ran clinics to give globulin to anyone who wanted it which turned out to be the majority of residents of the county. There was no newly reported case of hepatitis in Ogemaw County for over a year after the epidemic.

As I read Mark’s book, I began thinking about whether we are in the same situation with our physical and mental health. Are we paying enough attention to that which produces real value, like prevention, a key strategy of the EIS and other prevention-oriented organizations?

First, a little perspective…CDC’s budget request for 2010 was 10.1 billion. (http://www.cdc.gov/fmo/topic/Budget%20Information/index.html) including:
3.3 B for childhood vaccines
2.0 B for infectious diseases
1.5 B for terrorism
1.0 B for health promotion

In 2006, it was estimated that bringing a single drug to market costs 0.5 to 2 billion. (http://content.healthaffairs.org/cgi/content/full/25/2/420). A Reuters report in April 2010 (http://www.reuters.com/article/idUSLDE63C0BC20100413) indicated that consensus forecasts for sales figures for the top selling drugs ranged from 11.7 billion for Lipitor to 5.8 billion for Crestor with Plavix, Advair, Remicade, Enbrel Humira, Avastin, Rituxan, Diovan in between.

So we spend almost 12 B on our top selling drug and 10 B on the entire CDC budget. Is this how we want to spend our money? Now don’t get me wrong I am all for drugs (medical). And I am not implying that a 12 billion for one drug isn’t worth it. Rather, the relative amount spent for the prevention and health promotion work of CDC seems a bit low.

An important question then is: How do you understand the value of prevention efforts? While we do a pretty good job measuring the benefit we get from each drug in its formal clinical trials, can calculate cost benefit, and can use this information to make choices about how we spend our dollars, measuring what didn’t happen (what we prevented) is much more difficult involving projections, assumptions, and discounting.

Here is where Mark’s book comes in. Inside the Outbreaks is the first book chronicling the work of the EIS. Each sub-section tells a brief story and as you read through the book, you develop a growing knowledge and appreciation for what illnesses did and, importantly, didn’t happen. For example, for each of these diseases, it is clear that many illnesses and deaths were prevented.

–In 1965, a Salmonella outbreak afflicted about 200,000 people in Riverside, California killing an infant and several others before the CDC team found that water was the source and stopped the outbreak.
– In 1966, the World Health Organization passed a vote to fund a worldwide small pox elimination program. CDC played an important role in the subsequent eradication program.
–CDC was a leader in identifying infections that originated in hospitals and in instituting surveillance and preventive programs.
–Lead poisoning, vinyl chloride associated liver cancer, toxic shock syndrome and tampons, Accutane-associated birth defects, and many other links between an environmental cause and health were identified or characterized by CDC studies.

How many thousands or millions of us are healthy today because of this work? And how many suffer because we didn’t do more of this kind of work? I suggest that a general appreciation and awareness is a first step in placing value. Pendergrast’s book goes a long way in providing this. Once we truly understand and appreciate, we can think about measuring value. Was the money we spent worth it? Could we have done more with more? If we have a dollar for our health today, where do we think we will get the most value? Would more funds toward prevention give us more of the health value we want?

Are we headed for another crisis, one caused by spending dollars on health products of lesser (or no) value rather than those of more value resulting in slowing improvements or decreases in our health…a health recession?

Although Karen’s and subsequent CDC studies clearly demonstrated that giving children aspirin caused the vast majority of Reye syndrome cases, the CDC has no regulatory power. The FDA gave in to pressure from the aspirin industry and delayed a warning label on children’s medicine containing aspirin for five years, during which nearly 300 more children died of Reye syndrome in the United States.

He follows up the Reye’s Syndrome story by asking “Should the CDC have regulatory power?” In considering that question, it’s instructive to look at some of the many episodes in the book where EIS officers either were or weren’t able to use their discoveries about the source of disease outbreaks to get necessary large-scale changes made.

Because there’s such a range of causes of disease outbreaks, I’m going to confine my comments today to food. Food-borne diseases were a constant thread running through the book, and the EIS officers were usually able to identify a source, like a producer or food preparer failing to take proper sanitary precautions or a production facility being contaminated with bacteria. In many cases, an EIS officer to pinpoint a cause that was simple to fix – a food handler putting potato salad in containers that had held raw chicken, for instance. In other cases, as with an entire shipment of toxin-laden smoked whitefish or contaminated canned mushrooms from China, the FDA was able to issue a recall or ban importation. Our overall food safety system would be stronger if we devoted more resources to inspections and surveillance, but my impression when I finished the book was that a lack of regulatory authority isn’t the problem in these situations.

In terms of preventing food-borne illnesses, CDC findings on eggs that were described in the book also seemed to translate into policy with relative ease. After a string of mid-1960s salmonellosis cases being traced to products containing eggs, Philip Brachman, head of the Salmonella Surveillance Unit, sent recommendations to state health departments. Following his recommendations, FDA “passed regulations requiring that eggs be inspected (and diverted for pasteurization if cracked), then graded and sanitized on the outside.” This policy was based on the knowledge that cracked or soiled eggs could be contaminated with Salmonella-containing chicken feces. In the late 1980s, a multi-state outbreak of Salmonella eteritidis from products from a Rotanelli Foods plant sent EIS officer Mike St. Louis on the Salmonella trail:

EIS officers had made the egg-Salmonella link 25 years before, but past outbreaks had been traced to fecal contamination of cracked or soiled eggs. The modern Rotanelli plant had purchased unblemished large white eggs and then disinfected their exteriors. St. Louis buried himself in poultry research and found a 1944 article in the British Medical Journal stating that S. enteritidis could persist in the ovaries of chickens. Could the hens actually be depositing bacteria inside the intact eggs they laid? He published the suggestion in the Journal of the American Medical Association, raising a storm of protest from the egg industry.

Illinois-based EIS officer Sue Trock incubated whole eggs from an implicated farm, washed and flame-sterilized them, then cracked and cultured them. She found an abundance of S. enteritidis. Until then, eggs had been considered perfectly packaged natural products requiring no refrigeration. Illinois was the first state to demand chilled eggs (to prevent bacterial proliferation), even in transport, and the FDA soon followed suit.

Food on cruise ships is another recurring agent of disease outbreaks. Here’s how EIS officers went about tackling that:

In October 1973, 16 recently returned passengers from the S/S Statendam, operated by Holland-American Cruises, had experienced diarrheal illness due to Salmonella bareilly or S. senftenberg, both relatively rare serotypes. On December 19, 1973, the Statendam sailed on a nine-day Caribbean Christmas cruise, during which 55 of the 750 passengers complained of diarrhea. For the next five cruises, a CDC team, including EIS officers Mike Merson and Dale Lawrence, distributed a diarrhea questionnaire to all passengers. On each cruise, between six and ten percent reported a diarrheal illness. Swabs from crew members revealed ten salmonella varieties. Many of the afflicted crew worked in the ship’s galley.

Food preparation methods were alarming. Raw and cooked poultry were cut on the same butcher block with the same knives. Food handlers rarely washed their hands. Food was left at room temperature for two or three hours for breakfast and lunch buffets, then returned to the refrigerator. Leftovers were reworked and set out again for a midnight buffet. Once the problems were addressed, the number of Salmonella isolates declined, but on the eighth monitored cruise, there were still two senftenberg rectal isolates, and nine percent of the passengers reported illness.

EIS officers boarded nine other cruise ships at random during January and February 1974, administering questionnaires. The diarrhea rate ranged from 1.9 percent to 10.2 percent of the passengers, averaging 5.7 percent — not much different from the Statendam‘s record.

“We recommended that shipboard disease data be made public to put pressure on the cruise companies,” Merson recalled. The New York Times and Miami Herald ranked ships by illness records. Swiftly, the ships changed their food preparation and water storage practices, but cruise outbreaks have continued to plague tourists periodically.

This wasn’t the only instance in the book where a publicity campaign proved a swift and effective way to get companies whose products were implicated in disease outbreaks to improve their practices.

Between CDC’s ability to draw media attention to health problems and its apparently effective working relationship with FDA, it’s succeeded in addressing lots of food-related illnesses. However, Inside the Outbreaks includes plenty of examples where CDC wasn’t able to translate its findings into prevention, and the case of antibiotic use in livestock is one of those.

In 1983 EIS officer Scott Holmberg found victims in Minnesota and South Dakota to be suffering from a strain of Salmonella that was resistant to several antibiotics. He traced it to a farmer who “told Holmberg that he always threw in a handful of tetracycline per ton of feed to promote growth and prevent disease in his livestock.” Holmberg’s discovery spurred a push for regulation:

This outbreak was proof that resistant organisms developed in animals fed antimicrobials (primarily to fatten them faster) and then caused disease in humans. Holmberg documented that the fatality rate for people infected with drug-resistant Salmonella was 21 times greater than for regular strains. His investigation spurred FDA hearings and calls for a federal ban on adding antibiotics to animal feed. Although some breeders voluntarily stopped the practice, there is still no regulation in place. “If you want to buy antibiotics for yourself,” Holmberg observed, “you need a prescription, but not if you go to the feed store.”

More than a decade later, EIS officer Fred Angulo created a surveillance system whose information then spurred FDA action on a single antibiotic used for livestock:

In 1995, the FDA authorized the use of fluoroquinolones (i.e., Cipro) in chickens and turkeys, to promote growth and prevent disease. In response, Angulo created the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS). Launched in 1996, it documented an alarming increase in fluoroquinolone resistance in the ensuing years. The FDA finally reversed its approval of the drug for poultry, but limiting antibiotic use in U. S. food animals remained a challenge.

When it comes to limiting the use of antibiotics in livestock in order to reduce the risk of antibiotic-resistant infections in humans, FDA probably gets more pressure from livestock producers – and the members of Congress who look after their interests – than from the public health community. FDA has the regulatory authority to withhold or revoke approval of antibiotics for routine use in livestock (as opposed to targeted use to combat actual infections), but the political environment is another matter.

There book contains many other examples of problems that CDC has identified but been unable to solve, for a wide range of reasons. Within CDC itself, a director’s reluctance to address sexually transmitted diseases can hobble prevention efforts recommended by agency staff. It may be up to another regulatory agency to ban or recall a product CDC has identified as being dangerous, and the agency may want to avoid the wrath of manufacturers. In some cases, Congress forbids an agency from tackling a particular issue – like refusing to let FDA regulate herbal supplements – or from making recommendations that would upset an interest group, like prohibiting CDC from advocating for gun control.

To return to Mark’s question, I doubt that giving CDC regulatory authority would make the agency dramatically more effective at solving the problems it identifies. For all of the examples I can think of, there’s another agency that does have the power to regulate the product or practice in question, but political or budgetary pressures keep them from doing so. Would CDC be any less subject to such pressures?

Let me respond first to a blog comment from John Willis, who wrote: “This sounds like the basis for the show Medical Investigation, which is just the kind of superhero style TV show about the CDC that you imagine. I thought when I watched the show that it was far-fetched – a kind of House for epidemiologists with as much connection to the real world of outbreak investigation as House does to internal medicine – but perhaps I judged it too soon.”

Well, Inside the Outbreaks has indeed been optioned for a television series, though that apparently doesn’t mean that it will necessarily happen. I watched a few episodes of the short-lived Medical Investigation and was disappointed in the show, since it was, as Willis thought, pretty unrealistic. In fact, the Epidemic Intelligence Service folks told me that at first they were distressed that (for unknown reasons) the TV show placed the EIS-type officers at the National Institutes of Health instead of the CDC. But when they saw the show, they were relieved. My main problem with Medical Investigation was that they often presented the epidemiologists as superhero clinicians who were actively caring for the patients. While some EIS officers have helped to care for patients during the course of an investigation, that isn’t their job, and it is rare.

The super-hero cover of Inside the Outbreaks is misleading as well, showing a Clark Kent/Superman look-alike dressed in a lab coat, triumphantly holding up a test tube in a Eureka moment. That too rarely happens, since most EIS officers do not do lab work. In fact, if they had shown a realistic cover, it would have perhaps featured a photo such as this picture of Brad Hersh during a 1991 measles outbreak in Colorado. He stayed up most of the night crunching data in his lonely motel room, with papers spread all over the bed.

As mundane as that sounds, such number-crunching (“grunt work,” as Liz puts it) lies at the heart of disease detection and epidemiology in general, and it often is quite urgent and dramatic, as Karen points out – it can mean life or death for someone you have never met. Take, for instance, the story of E-Ferol. Here is an excerpt from Inside the Outbreaks:

Vitamin E Shots

In March 1984, an Ohio hospital notified the CDC that three premature babies had yellow skin, bloated stomachs, low platelet counts, enlarged livers, and kidney failure. Two had died. Despite extensive testing, no infectious cause could be found. Then a Tennessee hospital notified the CDC of a similar outbreak in its neonatal intensive care unit. Three of the eight premature babies had died. Walter Williams, a recent EIS graduate, was dispatched on April 3.
At the Tennessee hospital, Williams pored over the premature babies’ charts. Working 18-hour days, he finally found what he was looking for. All of the sick infants had received a new intravenous vitamin E preparation called E-Ferol. Born with low vitamin E levels, premies had traditionally received supplements by intramuscular injection. E-Ferol, licensed in December 1983, allowed easier administration through an IV tube. Williams notified EIS officer Bob Gaynes, who was still working the Ohio cases, in which he soon found an association with E-Ferol. A few days later, a third hospital called the CDC from Spokane, Washington, to say that four premature babies had died there. They too had been given E-Ferol.
A national recall halted the epidemic. The FDA had approved E-Ferol without testing because its constituents were similar to other harmless products. “The pharmaceutical industry and federal regulatory agencies should give special consideration to evaluating the safety of new medications that will be used to treat infants,” Williams and Gaynes wrote in their paper on the outbreak.

You can see how urgent this matter was, but Walter Williams solved it by painstakingly compiling notes from hospital charts. One of the problems I had with writing this history of the EIS was space. I simply didn’t have room for so many personal quotes and observations. Here is what Williams told me: “I found the answer late at night, in a room with no windows. My eyes were gritty. Every night had been that way. I called my supervisor at CDC that night, then redid the calculations back in my hotel room. I had a programmable calculator made by Texas Instruments, which had a card reader, but it wasn’t working. So I had to plug in the numbers for it. It didn’t look right to me. When I did it the last time and confirmed all numbers, the statistical significance was very high. It was this product and nothing else.” So there are indeed plenty of Eureka moments for disease detectives.

Liz wrote that EIS officers are “often young and willing to take risks.” True. When the program began in 1951, most were in their late twenties. Nowadays they are more likely to be in their mid-thirties, but many do appear to have a “certain immortality complex,” as EIS alum Jim Gale put it in the book (he was talking about jumping into a grave to take a sample from someone who had died of a particularly virulent plague bacillus). Although quite a few EIS officers have caught the diseases they were investigating, only one EIS officer has died in the line of duty, and that was Paul Schnitker, who died in 1969 as his airplane blew up while approaching Nigeria, probably from a terrorist bomb in luggage.

I recently had dinner with John Schnitker, Paul’s brother, in Washington, DC, where he works for the State Department. There is a Schnitker award given each year to an EIS officer who has made a major contribution in international health. John told me that he has kept tabs not only on the accomplishments of each winner, but the nominees, and he is continually amazed at what EIS officers have done.

Near the end of her post, Liz quoted the beginning of my section on Karen Starko’s Reye syndrome investigation, which was particularly nice, since Karen turned out to be the first EIS alum to chime in here. And Liz concluded: “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.”

I certainly agree, but I wanted to point out something else about that Reye syndrome affair that is frustrating. Although Karen’s and subsequent CDC studies clearly demonstrated that giving children aspirin caused the vast majority of Reye syndrome cases, the CDC has no regulatory power. The FDA gave in to pressure from the aspirin industry and delayed a warning label on children’s medicine containing aspirin for five years, during which nearly 300 more children died of Reye syndrome in the United States. Here is that section, followed by a cartoon from the book:

The aspirin industry demanded more studies and successfully delayed a warning label on salicylate-containing medication until 1986. From 1981 through 1985, over a thousand U. S. children contracted Reye’s syndrome, with 291 deaths. Up to a third of the survivors probably suffered permanent brain damage.
Publicity about the hazards of aspirin, including that generated by the EIS officers, gradually reduced its use for children, so that Reye’s cases in the United States fell from a peak of 555 in 1980 to 36 in 1987, and finally to just two cases in 1997, by which time most children’s medication no longer contained aspirin.

So let me throw out a question to readers. Should the CDC have regulatory power? That would mean that those responsible for investigations would also be responsible for regulations, which might lead to conflicts of interest. That issue arose over whether the CDC should not only advise on vaccine administration but should also investigate adverse reactions to vaccines. Some argued that this was like letting the airlines run the FAA (Federal Aviation Administration.)

I don’t have much to add to Karen’s post on the importance of the case study method. Amen! In July 2005 I sat in on most of the EIS training, and it was the afternoon case studies that really had an impact. The new officers were fed information a little at a time, then asked for conclusions. It really made everyone think so hard that I could practically see the smoke was coming out of their ears. I must admit that I hope Inside the Outbreaks will be picked up as a supplementary textbook by universities and schools of public health to be used as a treasure trove of such case studies, or at least as the basis of intense discussion.

Steve Schoenbaum observed that the 2 x 2 table (who ate or didn’t eat? Who got sick and who didn’t) lies at the heart of epidemiological investigations. “The method may sound simple, but there are several varieties of epidemiologic studies – the book predominantly mentions cohort and case-control – and one can spend a lifetime coming to an understanding of how best to use epidemiologic methods to address important issues.” That is certainly true, and even after five years of researching and writing about the EIS, I am certainly no expert on it all. But it might be worthwhile to discuss the difference between cohort studies and case control studies, if anyone wants to take that on. I would be willing to give my short version to kick it off.

Steve also observes: “It was beginning to dawn on me that my work and experiences as an epidemiologist were informing my management career. Indeed, I believe that most epidemiologic projects require developing and managing teams – a theme that is nicely and plentifully illustrated in Inside the Outbreaks.” That’s an interesting and important point. I was afraid, in writing the book, that it would make it sound as if EIS officers came in like the Lone Ranger and solved everything alone. Instead, they have to function as members of a team. They must be culturally sensitive, establishing good working relationships quickly. That doesn’t always happen, of course, and some state health departments resisted calling “Langmuir’s storm troopers,” as one famously put it. By and large, though, EIS officers learn a great deal about management skills by necessity.

“Translating epidemiologic information into action” is, as Steve notes, the heart of the enterprise. Yes, you need to conduct surveillance, to find baseline data. You need to trace epidemic curves, to figure out how the disease was transmitted. But then you have to make recommendations about stopping it in its tracks, if possible. As I pointed out in the concluding chapters of the book, that becomes more and more difficult when you are dealing not just with microbes, but with human behavior, which is a good deal more difficult to combat or modify. That, too, is another good discussion-starter.

Steve makes another invaluable point. “CDC programs and thus the experiences of EIS officers have certainly been affected by higher level decisions.” That’s putting it mildly! Here’s a funny story. I want to speak to Rotary Clubs about the book, since they are such strong and important supporters of polio eradication, one of the things I wrote about. But when I called a local Rotary Club in the Atlanta area, the president said, “We usually have political speakers,” and he declined. I tried to explain that public health is politics, and some of the most important (and frustrating) politics you can encounter. Comments and specific examples, folks?

Early on in “Inside the Outbreaks”, Alex Langmuir’s description of epidemiology as the science of long division gets mentioned as does the classic four-fold table (e.g., in the context of common source epidemics such as pot-luck suppers, a matrix for each food item served would have two columns – “ill”, “not ill” – and two rows – “ate the item”, “did not eat the item”). What comes through by implication in the book is the extraordinary inventiveness that EIS officers and other epidemiologists have exhibited over the years in getting usable numerators and denominators. The method may sound simple, but there are several varieties of epidemiologic studies – the book predominantly mentions cohort and case-control – and one can spend a lifetime coming to an understanding of how best to use epidemiologic methods to address important issues. And, the fact that the EIS has been able to foster so many contributions from people who start out with a two-year term of service and a one-month introductory course, generally taught by peers who have been in the program for just a year themselves, speaks to the robust organization of the program itself including to mention a few, its selection process, development of tools such as the course itself including its use of the case-method type of teaching that Karen Starko describes in her blog post (June 23, 2010), as well as software and other resources EIS officers can use in the field, consultative backup, and development of reports that do not just lead to publications about the issue at hand but also provide the basis for program evaluation.

Some years ago Alex Langmuir was asked to participate in an oral history project, I believe by the National Library of Medicine. When his contribution was completed, there was a ceremony in Boston at the Countway Medical Library, and several of his associates and friends were asked to speak in his honor. I, in turn, was honored to be one of those. At that point, most of my activities were related to management in a large HMO. I had left academia and had taken my first major management position after almost a decade and a half of being an epidemiologist. It was beginning to dawn on me that my work and experiences as an epidemiologist were informing my management career. Indeed, I believe that most epidemiologic projects require developing and managing teams – a theme that is nicely and plentifully illustrated in “Inside the Outbreaks”. In preparing remarks for Alex’s ceremony, I was able to reflect on the fact that in my opinion he was an excellent manager. None of us is perfect; and “Inside the Outbreaks” does a nice job at painting a portrait of Alex both at home and in the workplace “warts and all”. But, I think that readers of the book will recognize that the EIS was a classic start-up/entrepreneurial venture and that its founder was able to grow it into a significant enterprise, many of whose activities and processes have proven durable for decades.

One thing that goes back to the earliest days of the EIS and Alex’s influence, and comes across well in the book, is the notion of translating epidemiologic information into action. Alex had a strong bias towards action, a characteristic of good managers, and that bias fortunately has also persisted over the decades. I believe it has also been injected into many EIS officers, or if already present in our personalities, enhanced by the EIS experience and the opportunities to act that it presents.

In my opinion, Mark Pendergrast has done an excellent job in showcasing the EIS and its history without overly confounding it with the “co-history” of the Centers for Disease Control or the US government as a whole. Yet, these larger forces not only provided the environment in which the EIS did and does function, but also directly affected programs, decisions, and possibly attitudes. The book describes some of the issues around public disclosure of information learned by EIS officers, but it would take a separate analytic vs. an historical approach to really get at the degree to which some of the specific incidents recounted, e.g., what gets included in the MMWR, how to handle the (dis)continuation of a clinical trial, etc, reflect decisions at the level of the EIS vs. CDC vs. some higher level of government. CDC programs and thus the experiences of EIS officers have certainly been affected by higher level decisions. Although CDC still published abortion surveillance reports, I believe that activities recounted in the book that are related to abortion surveillance in the period following Roe v. Wade (1973) changed dramatically as a result of U.S. government policies related to family planning and abortions. Similarly, I suspect that CDC could have, and EIS officers could be involved in, more activities related to injuries resulting from handgun use were it not a controversial area of public policy. CDC is not the only federal agency that is tractable to pressures from strong outside interests. Some readers of this blog may recall that the former Agency for Health Care Policy and Research (AHCPR) was threatened with total loss of funding and almost went out of existence in the mid-1990s because of controversy about its clinical guidelines activities, particularly one for management of back pain, and was reorganized into what is now the Agency for Healthcare Research and Quality (AHRQ), an agency that funds the development of evidence about clinical practices but does not synthesize that evidence into clinical guidelines.

Another theme that comes across well in “Inside the Outbreaks” is that while it is now trendy to talk about globalization, the EIS has had a global perspective since its earliest days in the 1950s and continues to operate and have a global influence directly or through its alumni and “friends” in other countries. That said, I also sensed, probably reflecting my EIS experience, the objective of epidemiologists mentioned in the book about going upstream to find problems that need addressing at their source, and the incidents described in the book, an opportunity for action that has not yet been taken: Beginning with CDC’s assistance in the 1950s for a tidal wave or tsunami to the malnutrition evaluations in what had been Biafra to very recent involvement in the earthquake in Haiti, not described in the book, it has been common to include epidemiologists in aid efforts when responding to disasters around the world. Yet, as Hurricane Katrina showed within this country and as appears to be the case with events in other countries, both the national and international responses appear to be developed ad hoc and often appear uncoordinated. Just as we finally began to recognize a little more than a decade ago with the appearance of H5N1 (Avian) influenza that it was likely that someday there would be another influenza pandemic and that general pandemic preparedness/planning was an important priority, in reading through “Inside the Outbreaks” it dawned on me that international planning for responses to various types of disasters – e.g., floods and earthquakes – makes enormous sense. We may not know when the next will occur, but we know there will be another; and it would be prudent to have designated leaders of the relief efforts. Epidemiologic analysis of prior events would make it clear what the priorities would be for providing certain types of services in a logical order – e.g., arranging for control of air, sea and land traffic to the affected area, handling the press that will predictably arrive, assuring that the type of goods sent are appropriate to the type of disaster and local conditions (hot/cold climate, etc, etc).

I could go on, but I suspect that readers have already gotten my main messages that “Inside the Outbreaks” is an excellent recounting of the history of the EIS, an important U.S. government-sponsored activity that has influenced the lives of a few thousand persons lucky enough to have been in it, and also a highly provocative book. Readers get an extremely clear picture of the contributions possible from the social science of epidemiology and how that science is applied by its practitioners. I would recommend it as interesting, informative, even entertaining, reading.