Legionnaires’ disease – finally, a suspect is found

March 2006

By December 1976, the public health investigators had taken a lot of samples, talked with hundreds of people and considered and rejected many theories. They had written reports and papers and performed endless laboratory tests. Congress had investigated some of the investigators, and all of them were pretty down about not being able to find the source of the mysterious outbreak of pneumonia, in which 221 people were sick and 34 had died.

Joseph McDade, PhD, microbiologist in the rickettsia laboratory, who had processed some of the original specimens in August, returned to his laboratory in December to re-examine them. He was mulling over a report by David Fraser, MD, who had headed the field investigation.

“[McDade] had just come from a holiday party and got an earful from somebody who said you folks at the CDC don’t known how to solve problems. He was a little insulted and proud, and he went back and decided to look some more,” said Fraser.

McDade said there were several reasons he decided to review his work. “After a time, when no one finds anything, the idea of seeing something in the guinea pig that was never explained, because you could never grow it out, kind of gnaws at you. So, I was thinking about that all along.

“Then Dave sent his report around, which made me just think of the whole episode again, but it wasn’t necessarily anything in particular in that report; I was just thinking in general, and then you have someone chewing at you at a Christmas party —

“It was just something that was left unresolved, and I needed to take a look at that,” McDade said.

Q fever

“Whenever something like this happens — where you have a very large outbreak investigation — most everybody in the laboratory is involved, one way or another, directly or indirectly,” explained McDade. “At that time, they had asked people who were familiar with diseases that usually had a pneumonia-type component to them to do whatever testing was useful and necessary to try to determine whether or not the outbreak was caused by one of the known pathogens. Well, the organism or the disease that we were asked to rule out was the agent for Q fever,” he said.

Q fever is a disease that is found in humans, but transmitted by domestic animals, mostly livestock, such as sheep, goats and cattle. “There wasa fairly low probability at that time [that it was Q fever],” he said, “because obviously, there was no livestock involved in downtown Philadelphia.”

The first time McDade tried to isolate the organism, he inoculated guinea pigs and found stray bacterium in the spleens, but he could not grow it in embryonic eggs.

“When I tried to grow it in embryonic eggs the first time – remember I’m trying to grow Q fever rickettsiae, which are a special kind of intracellular gram-negative coccobacillary – I actually added antibiotics to the suspension to make sure that no bacterial contamination would occur,” he said.

He re-examined slides of the spleen of the guinea pigs that were inoculated in August and found a cluster of organisms. This time, he attempted to isolate them in embryonated eggs, but did not add any antibiotics. He did an analysis and took his findings to his boss, Charles Shepard, MD, who developed the first laboratory test for leprosy on the footpad of an armadillo.

“Dr. Shepard was a low-key sort of guy, and a very pristine scientist,” said Stephen Thacker, MD, who was a young Epidemic Intelligence Service (EIS) officer during the outbreak. McDade describes Shepard as very collegial.

“They went back to some unsolved investigations: one in the 1965 at St. Elizabeths Hospital in Washington and one in 1968 at the health department in Pontiac, Mich., where three EIS officers got sick. It turns out they were the same etiologic agent because the bacterium, the gram-negative pleomorphic rod, was the legionnaires’ bacterium,” Thacker said.

McDade said he and Shepherd wanted to find an animal model and isolate the agent in the animal. They inoculated guinea pigs, which developed fever. “At the time that they developed fever, we euthanized those animals and collected the tissue from the ill animals. Those tissues we subcultured into embryonated hen’s eggs,” McDade said.

“But just because you isolate a microorganism doesn’t necessarily mean that it has anything to do whatsoever with the outbreak. But we were able to make three independent isolations of the same microorganism from stored specimens from different patients. That was fairly convincing evidence,” McDade said.

In addition, since the epidemiologists had taken blood samples both from patients who were sick and who recovered, the investigators were able to find antibodies to the bacterium. “By doing so, we were able to show that like 90% of the patients either had a very high level of antibodies to the organism or developed high levels of the antibodies during the course of their illness,” he said.

Shepard and McDade told David Sencer, MD, then-CDC director, that they identified the causal bacterium for the outbreak of pneumonia in Philadelphia. Subsequently, it was called Legionella pneumophila.

With this information, CDC officials were able to do experiments that allowed them to make recommendations for treatment, which they had been reluctant to do during the outbreak because there was no scientific proof that anything would work. They found that rifampin and erythromycin cured the infection in guinea pigs, and it became the standard of care, according to Fraser, who wrote a retrospective article about the outbreak in The Lancet Infectious Diseases.

In addition, the CDC said that the organism grew in water and could be aerosolized, which reinforced the investigators’ idea that the source of the organism was the air conditioning unit and that people became infected while standing in the lobby of the Bellevue-Stratford Hotel.

“We never did prove it was the air handling system,” admitted Thacker, because the hotel staff had cleaned the filters, right before the CDC arrived, not realizing it could be the source of infection. “We just suspected that it was.”

There are at least 46 species of Legionella and 70 serogroups, according to the CDC. L. pneumophila, an aquatic organism that thrives in warm watery environments, causes 90% of the cases of disease in the United States. Most occur over the summer. The CDC estimates that 8,000 to 18,000 cases of legionnaires’ disease occur every year in the United States; cases are seen worldwide. Most are sporadic, 23% are nosocomial and up to 20% can be linked to outbreaks, according to the CDC. Up to 15% of cases are fatal. Inhalation of contaminated aerosols from devices, such as cooling towers, is the primary means of infection. Those most at risk are the elderly, smokers and those with chronic lung disease or immunocompromised conditions.

The organism is easier to isolate and identify today. Eventually, a direct fluorescent antibody test was developed that allowed one to detect the organism in lung specimens, McDade explained. “Bob Weaver and some other people in the bacteriology laboratory in the old Bureau of Laboratories were able to develop a technique for growing it on agar, just as any other bacterium is grown. So, now you can do a routine culture if you want, and they have some other kinds of tests, where they can look for it, for example a urinary antigen test,” McDade said.

Although legionnaires’ disease is a reportable condition in most states, cases are underreported, according to the CDC.

Honor our comrades

In his report in The Lancet Infectious Diseases, Fraser called the investigation a “seminal experience for nearly everyone involved.” Distinguished careers followed many of the 25 field officers, including Fraser, who eventually became president of Swarthmore College.

Thacker, who described an EIS investigation as “being like Sherlock Holmes,” headed two centers and the Epidemiology Program (including EIS), and became director of the Office of Workforce and Career Development at the CDC. Walter Orenstein, MD, headed the National Immunization Program at the CDC, before going to Emory University. James Marks headed two centers at the agency before becoming health director of the Robert Wood Johnson Foundation. David Heymann became executive director of communicable diseases at WHO. McDade became the assistant director for science at the CDC, and still does consulting for the agency. Ted Tsai, MD, became assistant director for medical science at the CDC’s vector-borne diseases division before moving to Wyeth Laboratories. Mitch Cohen is currently director of the Coordinating Center for Infectious Diseases at the CDC, after many years as director of bacterial and mycotic diseases.

The Bellevue, however, did not fair so well. It was on the decline when legionnaires’ disease hit, and it could not survive the blow. It reopened several times, and now lives life as the Park Hyatt Philadelphia at the Bellevue, renovated to all its swanky glory.

Brachman said the name of the disease was a curious after story. “Once the agent was identified, we held a meeting at the CDC, in which representation from the state and from various groups, including the American Legion, were there to review what had happened,” he said. Although the press had labeled it legionnaires’ disease, the CDC did not expect officials to take to the name.

“If there was a problem in Denver, and you had a lot of deaths and they called in Denveritis, I don’t think the mayor of Denver would be very happy, or if you called it Las Vegasitis or something,” Brachman said. “In this case, we were dumbfounded. I can’t remember, but I think we came up with some other names, but the American Legion said, ‘Absolutely not. We want to honor our fallen comrades. We want you to call it legionnaires’ disease.’”

For more information:

• Fraser DW. The challenges were legion. Lancet Infect Dis. 2005;5:237-241.
• Thomas G, Morgan-Witts M. Anatomy of an Epidemic. Garden City, NY: Doubleday; 1982.