Despite only having been identified some 25 years ago, Legionella pneumophila (the causative agent of Legionnaires' Disease) is no new organism. Medical history is littered with evidence that this organism has wreaked havoc long before people knew its identity. Every year about 5 - 10% of pneumonia cases are caused by this creature, and the mortality rate can soar to as high as 30% if untreated.
Despite its modern-day infamy, Legionella pneumophila might never have been found, if not for a celebration that took place in Philadelphia a quarter of a century ago...
The Philadelphia Tragedy
It is 21 July, 1976. The place is Bellevue Stratford Hotel, Philadelphia. The occasion is an historical one - the US Bicentennial Convention of the American Legion - although, by an ironic twist of fate, it would go down in the annals of history as one of the biggest medical tragedies of the 20th Century.
More than 4000 World War II Legionnaires, along with their families and friends, have assembled here to participate in the 58th American Legion's convention, about 600 of whom are staying at the hotel at which this convention is hosted. It is a joyous, merry-making occasion that is all about reunion, fellowship, even a parade of sorts.
The day after the opening of the convention, some of the participants begin falling ill. The symptoms are the same: fever, coughing and breathing difficulties - all of which are dismissed as the celebration carries on at full swing. On Tuesday 27 July, four days after the convention, however, things begin to turn sour. There is one death at a hospital in Sayre - that of an Air Force veteran who attended the Philadelphia convention.
And for no explicable reason, the American Legionnaires start dying, one by one, of a mysterious illness...
Prelude to Disaster
1976 was not a good year for everyone. It started in January with an influenza epidemic which claimed the life of a soldier at Fort Dix, New Jersey. Nine unidentified influenza viruses were isolated and sent to the Centre for Disease Control (CDC). Five were identified as the common influenza A virus; four, shockingly, were swine influenza viruses. The last time a pandemic was caused by human-to-human transmission of a virus of this sort was in 1918, and it had caused more than 20 million deaths. To everybody's dismay, the results from the tests carried out on the paired sera1 from Fort Dix clearly indicated that this, too, was a human-to-human transmission case.
Meetings carried out between the CDC and the Food and Drug Administration (FDA), the Army, the National Institutes of Health, and the New Jersey Health Department eventually led to a meeting between Jonas Salk (of the famous Salk vaccine), Albert Sabin and a number of other members of the Advisory Committee on Immunization Practices with President Ford in March. Ford was advised to request $135,000,000 from Congress to develop and mount an immunization campaign against a virus that possibly threatened an outbreak on the scale of the 1918 pandemic. They justified this course of action with the following arguments:
That emergence of totally new influenza A viruses occurred about every ten years to replace the current strain, each time causing a pandemic.
That the last two cycles had been 1957 and 1968, and that it was high time for a new cycle.
That old influenza viruses could return, and this one could be the 1918 swine flu virus-like pathogen coming back.
That since nobody was an oracle where predicting swine influenza pandemics was concerned, the public health agencies had better get ready.
This campaign was met with mounting criticism in the summer of 1976 when further evidence of the virus had failed to appear2, leading to a new host of troubles. The insurance companies refused to insure the manufacturers of the vaccine because of possible side effects; the manufacturers themselves in turn refused to produce the vaccine without insurance. In an attempt to ameliorate the situation, President Ford introduced the Tort Claims Act3; the bill failed to move through Congress, however, and things became increasingly hostile for those who were caught in the middle.
And then came the reports of three deaths from Pittsburgh. Deaths that were caused by influenza-like illness.
A Basic Misunderstanding
By Monday, 2 August, Pittsburgh, Harrisburg and Philadelphia were crawling with Environmental Information Systems (EIS) officers and CDC epidemiologists, all of whom were seeking answers to this strange disease whose victims were American Legionnaires who had attended the 21 July American Legion convention. All the patients had the same complaint: chest pains, high fever, lung congestion and pneumonia. Epidemiological studies and laboratory data did not suggest influenza; however, the members of Congress who read the papers got it into their heads that it was and consequently passed the Tort Claim Act in a hurry because they didn't want to be made responsible for holding up the immunization campaign should anything awful happen.
With no more juicy news about the swine flu 'pandemic', attention was shifted to the peculiar disease that had struck the American Legionnaires in July (by then 221 people had been infected, and 34 had succumbed to it). Come September, however, things were starting to get nasty again because the CDC, who had initially been revered as a hero in this cause, had failed to identify the elusive aetiological agent responsible for this peculiar disease. The only thing the CDC had to report was that the only thing they were sure of was that what had happened in Philadelphia had happened either in the lobby or just outside the Bellevue Stratford Hotel. Needless to say, this was met with general derision and disbelief.
A Twisted Plot?
With the CDC as confused as the general public, crackpot theories regarding the origins of the disease began to emerge. Some insisted that nickel carbonyl intoxication was the cause. Wilder allegations included conspiracy theories - that communists or pharmaceutical companies were conspiring to wipe out American veterans. Others, in their eagerness to find fault, claimed that the agent was obviously a toxin, that the wrong specimens had been taken, or that there were just not enough of them. In fact, as Scott Robertson MD claimed, the only real consensus to develop among scientists was that this was not a bacterial disease!
The vaccination programme began on 1 October, amid meetings, arguments and congressional hearings. Within ten weeks, nearly 50,000,000 doses of vaccine had been administered to both young and old. In fact, this programme had run into an enormous trouble when three elderly people died ten days after being vaccinated - it was in danger of being aborted until the CDC managed to convince the media that 80 and 90-year-old people died every day, with or without the vaccination. Eventually, however, this immunization programme had to be stopped when the CDC discovered that the vaccine was associated with the late November and early December reports of Guillain-Barré Syndrome (GBS).
Workaholic to the Rescue
The world has Dr Joseph McDade to thank for the discovery of the bacteria responsible for Legionnaires' Disease. He was a rickettsiologist at the CDC, whose team eventually discovered the evidence for the existence and pathogenesis of the Legionnaires' Disease bacteria from clinical specimens in early 1977. This was what happened...
McDade had been asked to rule out Q-fever as a causative agent. Thus, in his search for the Legionnaires' Disease bacteria, he used the same techniques for isolating rickettsial pathogens. Guinea pigs that were inoculated with material from victims all died of a febrile illness. Peering into a microscope, McDade observed several cocci and several small bacilli, none of which seemed significant at the time. He decided to inoculate embryonated eggs with suspensions of the guinea pig spleen tissue that had been treated with antibiotics to inhibit the growth of contaminating bacteria. The eggs grew nothing, causing McDade to suspect that the rickettsiae had been killed along with the rest of the microbes.
28 December, 1976, saw a year-end party that Joseph McDade did not particularly desire to attend. Uncomfortable with the crowd, he decided to return to the laboratory to wrap up some things before the end of the year. He took out his guinea pig slides again and put them under the microscope for review. This time he noticed something he had not noticed before: a cluster of the bacilli he'd seen previously were engulfed by a white cell.
Excited, McDade and his team of researchers plunged into the mystery afresh. New batches of inoculated eggs were prepared, this time without the antibiotics. Guinea pigs were then injected with yolk sac extracts, and developed the typical symptoms of Legionnaires' Disease. Blood samples taken from the survivors were mixed with the yolk sac isolates, and subsequently reacted. The Legionnaires' Disease bacteria had been found.
Why it Took so Long to Find the Bacillus
The Legionnaires' Disease bacillus, later named Legionella pneumophila, was no ordinary microbe. It could not be grown under typical conditions, being dependent upon ridiculous demands: high levels of the amino acid cysteine and inorganic iron supplements, low sodium concentrations, as well as activated charcoal to absorb free radicals. In addition, it preferred elevated temperatures, which was highly abnormal among pathogens, who preferred near-body temperatures. It did not help that the team of CDC researchers had been using the wrong animal model at the start, and had only gotten results when they switched from mice to guinea pigs4.
Once the etiological agent had been determined, however, another question popped up: where exactly was this bacteria from, and how did it come to infect the World War II veterans?
Dr Carl Fliermans solved the first part of the puzzle when he discovered that L pneumophila lipids resembled those of the thermophilic bacteria he'd found in the thermal regions of the Yellowstone National Park, and that this bacteria tended to live as biofilm (scum) associated with certain species of algae. Subsequently, Fliermans began poking around aquatic habitats and found - guess what? - this bacteria residing in thermal waters discharged from a nuclear reactor at Savannah River Laboratory. This bacteria was later found to be living in natural hot springs all over the United States and, most importantly, in air-conditioning cooling towers.
The Mystery Solved
One very important clue pertaining to the nature of the cause of Legionnaires' Disease, one that would have pointed researchers in the right direction, had earlier been overlooked. The clue was this: of the 221 people who became sick, 72 were people who were not involved in the American Legion convention - people who had either been inside the Bellevue Stratford Hotel, or had walked past it. Later when it was discovered that the organism resided in the water of cooling towers, the pieces fell into place. The Legionnaires' Disease bacillus was actually being spread by the air-conditioning system itself, in aerosolised water droplets. People who inhaled the aerosols inevitably inhaled the micro-organisms, which were subsequently brought into the respiratory tract. Here, they multiplied in patrolling macrophages, safe from other hostile mechanisms of the human immune system, causing flu-like symptoms and, where untreated, pneumonia that resulted in death.
Once this fact had been discovered, it struck scientists that this Legionnaires' Disease bacteria, that bred unchecked both in natural freshwater sources and in that of manmade containers, could not possibly be a new organism5. Scientists scrambled to dig through the medical archives in pursuit of evidence that this bacteria had wreaked havoc before. Sure enough, they discovered that a number of previously unresolved outbreaks, including the one in 1968 where 95 out of 100 people working in a building in Pontiac, Michigan contracted respiratory disease, had been actually caused by Legionella pneumophila. They would later find that although L pneumophila was responsible for 90% of sporadic outbreaks, other (later discovered) species were also fully capable of assaulting the immune system. Other outbreaks and epidemics occurring throughout the world since then would eventually show them that occurrence of Legionella in manmade environments was not restricted to cooling towers alone - that wherever on earth there was a machine that could produce mist, there was Legionella and Legionnaires' Disease.
1 'Sera' is plural for serum.
2 Interestingly enough, a new influenza virus did appear eventually; however, it was not swine flu virus, and did not cause a pandemic or displace the current influenza A virus. But that's altogether a different story.
3 This was to indemnify the pharmaceutical companies against claims arising from the swine flu programme.
4 The team had initially used mice, which are commonly used in laboratory studies. However, L pneumophila was an intracellular parasite that resided and multiplied primarily inside macrophages, and it was highly unfortunate for the team that mice macrophages are highly inefficient at ingesting L pneumophila. Oh, and in case you're wondering, macrophages are a white blood cell component of the immune system that destroy invading micro-organisms by gobbling them up. The mechanics are much more complicated than that, but this isn't an immunology class.
5 Indeed, it was because Fliermans realised that L pneumophila was probably not a new microbe that he found it in the thermal waters from Savannah River Laboratory. Prior to his discovery, he had been reading the Bible, and Ecclesiastes 1:9 kept on jumping out at him: 'The thing that hath been, it is that which shall be; and that which is done, is that which shall be done: and there is no new thing under the sun.' He believed it to be true, and let it lead him.