PART 1: THE HISTORY OF LEGIONNAIRES’ DISEASE

The Philadelphia Tragedy

It is July 21st, 1976. The place is Bellevue Stratford Hotel, Philadelphia. The occasion is an historical one – the U.S. Bicentennial Convention of the American Legion – although, by an ironic twist of fate, would go down in the annals of history as one of the biggest medical tragedies of the twentieth century.

More than 4,000 World War II Legionnaires, along with their families and friends, have assembled here to participate in the fifty-eighth American Legion’s convention that spans four days, 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 and coughing and breathing difficulties – all of which are dismissed as the celebration carries on at full swing. On Tuesday, July 27th, 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 explainable 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 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 sera 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, where President Ford was advised to request $135 from Congress to develop and mount an immunization campaign against a virus that possibly threatened an outbreak on the scale of the 1918 pandemic (1). They justified this course of action with the following arguments:

This campaign was met with mounting criticism in the summer of 1976 when further evidence of the virus had failed to appear*, 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 Act*; 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, August 2nd, Pittsburgh, Harrisburg and Philadelphia were crawling with EIS officers and CDC epidemiologists, all of whom were seeking answers to this strange disease whose victims were American Legionnaires who had attended the July 21st 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 bill 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 pharmaceautical 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 (2)!

The vaccination program began on the 1st of October, amid meetings and arguments and congressional hearings. Within 10 weeks, nearly 50 million doses of vaccine had been administered to both young and old. (In fact, this program had run into an enormous spot of trouble when three elderly people died ten days after being vaccinated, and 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 program 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 (2). 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.

December 28th, 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 pigs*.

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 that 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 (3). 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: that of the 221 people who became sick, 72 were people who were not involved in the American Legion convention – people who had 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 aerosolized water droplets. People who inhaled the aerosols inevitably inhaled the microorganisms, which were subsequently brought into the respiratory tract where they multiplied in patrolling macrophages, safe from other hostile mechanisms of the human immune system, causing flulike 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 organism*. 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.

PART 2: LEGIONNAIRES’ DISEASE FAQ

What is Legionella?

Legionella is a Gram negative *, rod-shaped bacteria measuring about 0.3-0.9 microns by 1.5-5 microns (one micron/micrometre is 0.000001 metres or 0.0001 centimetres). It is an aerobic microbe, meaning that it requires oxygen to live, and has unusual nutritional requirements – high levels of the amino acid cysteine, inorganic iron and low concentrations of salt – as opposed to a large number of other pathogens. It is also unusually tolerant to high levels of chlorine, low pH and high temperatures (they grow nicely at temperatures between 28 and 45 degrees Celsius) – all of which would strike down the normal pathogen.

There are currently at least 34 species of Legionella, and more than 23 serogroups of L. pneumophila. L. pneumophila serogroup 1 is responsible for more than 80% of all Legionella infections; however serogroups 4-6 and other species such as L. bozemanii, L. longbeachae, and L.maceachernii have been known to cause Legionnaires’ Disease as well.

Where can Legionella be found?

Legionella is ubiquitous in natural freshwater sources such as rivers, ponds and hot springs, usually living as parasites of a number of amoebae. They can also be found in the waters of air-conditioning cooling towers, spas, fountains and potable water sources such as taps, faucets and showerheads. L. longbeachae is usually found in soil, and is transmitted in a most fascinating fashion, which will be discussed later.

Who does Legionella infect?

In the environment, Legionella parasitizes free-living amoebae such as Naegleria and Hartmanella. It also infects macrophages and a number of other components of the human cell-mediated immune system.

Scientists have also isolated L. pneumophila from calves who had died of pneumonia (4, 5). In the second case, fatal pneumonia caused by L. pneumophila was determined as the cause of death.

How does Legionella infect us?

The primary mode of transmission is by inhalation of aerosolized water droplets containing Legionella*. Once inside, it is gobbled up by patrolling alveolar macrophages, who extend a single pseudopod from their cell surface and drag Legionella into them *(8). Now, under normal circumstances, a ‘captured’ bacteria is subsequently packaged inside a membrane called a ‘phagosome’, which will then fuse with a lysosome. (A lysosome is essentially a bag containing an arsenal of deadly enzymes that will, upon release, kill the bacteria) However, Legionella has found a way to stop this fusion from occurring, which means that now this parasitic little bacteria is safely tucked away in a little parcel in a large white blood cell that restlessly roams about the lungs. And now that it does not need to fear being attacked by other components of the immune system, it can begin to multiply inside the macrophage, using the cell as a mobile home and the stuff inside it as food. Eventually, when the children and great-grandchildren of the original Legionella have exhausted the food supply, they burst open the macrophage, thus killing it, and surge out in search of new homes. This will continue to go on and on until they are stopped, or until they have done immense damage to the human host.

What are the symptoms of infection by Legionella?

The less severe form of Legionella infection is Pontiac Fever, which manifests itself as a self-limiting flu-like illness. The incubation period is remarkably short – in terms of hours to several days (9) – and symptoms will include malaise, muscle aches (myalgia), fever, chills and headache. Patients will, however, typically recover completely within one week.

Legionnaires’ Disease is the more severe manifestation of Legionella infection. The incubation period for Legionnaires’ Disease is 2 to 10 days. Symptoms typically include a dry (nonproductive) cough and difficulty in breathing, as well as flu-like symptoms such as fever, headache, chills, myalgia and overwhelming lethargy. The onset of pneumonia is abrupt. Chest x-rays will reveal signs of pneumonia, either in a distinct area (“lobar”) or in a “patchy” pattern throughout the lungs (10). Sputum is occasionally produced, often containing inflammation, but Gram staining will reveal no bacteria in the sputum (9). Failure of the pneumonia to respond to traditional pneumonia-combating antibiotics such as expanded-spectrum cephalosporins and aminoglycosides usually confirms the disease. If the patient is not treated by this stage, prognosis is poor.

Occasionally, other complications may arise from infection by Legionella, including:

Lately, infection by Legionella has also been linked to acute purulent arthritis (11).

How common is Legionella infection?

Infection by Legionella, despite its recent discovery, is fairly common. Most of us have, at some point in our lives, encountered this bacteria and have subsequently built up antibodies against it. 95% of those who come into contact with it will develop Pontiac Fever, which can easily pass for normal influenza. It has also been speculated that infection by Legionella is responsible for suburban neurosis a.k.a. Sick Building Syndrome (sore throat, slight headache, tiredness), although findings are, at this time, inconclusive (12). Most of those who develop full-blown Legionnaires’ Disease are those who are old, very young or whose immune systems have been compromised by disease or the environment.

Some major outbreaks of Legionnaires’ Disease and other Legionella-caused diseases are summarized in the table below:

How dangerous is Legionnaires’ Disease?

Research has indicated that Legionella is an opportunistic pathogen, which (theoretically) means that under normal circumstances, it does not cause full-blown Legionnaires’ Disease, and will only strike when conditions are right. Originally, it was reported that Legionnaires’ Disease is usually contracted through inhalation of aerosols of water droplets containing the organism, and that those who get the disease are primarily the old, the very young, and the immunocompromised, with death occurring in 15-30% of the cases. However, there have been several intriguing cases throughout the history of this disease. Four supposedly healthy middle-aged men who worked at an automotive plant in Ohio contracted Legionnaires’ Disease in 2001, two of whom died (13). A medical practitioner supposedly caught Legionnaires’ Disease from his pneumonic patient in what was possibly the first person-to-person transmission case of the disease (14). In the U.S., three people came down with the disease, and the source of the organism (L. longbeachae) was traced back to commercial potting soil, which all three had been using (15). This was not the first case where the organism originated from soil – in 1984, a gravedigger contracted the disease, and Legionella was isolated from the graveyard soil (14). This suggests that Legionella may be found in more habitats and spread in more ways that we have not yet discovered, and that even supposedly healthy individuals may fall victim to Legionnaires’ Disease *.

It would be ridiculous to say that Legionnaires’ Disease is not important, or that it does not – and never will – pose as significant a threat as, say, Bubonic Plague or tuberculosis. For just as the plague thrived at a time when regulations on sanitation did not exist and hygiene was practically nil, and that the typhoid fever and cholera organisms still glory in contaminated waters, Legionnaires’ Disease is an important disease of the modern world, encouraged and spread by modern technology itself. Even if we try to comfort ourselves by saying that Legionnaires’ Disease will only plague the aged and the sick, the fact remains that our modern environment is no longer friendly to our immune system. Smog and haze and noxious fumes emitted by vehicles and machines are among the biggest threats to our lungs’ primary defence systems., thus making even the most healthy of us susceptible to infection (of course the degree of susceptibility will differ). Even as children are being born everyday, our citizens grow old and become increasingly prone to disease. The water supply in many places such as Melbourne, Australia have already become tainted with Legionella infestation, and conditions are hard to reverse. The emergence of high-rise buildings with centralized air-conditioning systems and the increasing usage of misting machines, spas and air-conditioning (among others) facilitate propagation of the agents of this disease. And even if the people are healthy enough not to develop Legionnaires’ Disease, more than 90% of them will get Pontiac Fever or Sick Building Syndrome, thus contributing to ill-productivity in the workplace and, by extrapolation, posing as an economic problem if not a health one.

However, there is no reason to panic unnecessarily. If detected early, Legionnaires’ Disease can be treated successfully by antibiotic therapy, usually erythromycin (which is a common antibiotic and has no nasty side effects) alone, but sometimes used in conjunction of rifampicin – although in more severe cases, organ damage may occur due to the spread of disease. Besides, the chances of you catching it from someone else who has it are very, very, very small – which you should be extremely thankful for, seeing as it’s a respiratory disease and is transmitted by air.

How do I reduce the risk of catching Legionnaires’ Disease?

REFERENCES

1. Dowdle, WR. 1993. 1976: Lessons Learnt. IN Legionella: Current Status and Emerging Perspectives. American Society for Microbiology, Washington D.C.

2. Robertson, Scott. 1996. Legionnaires’ Disease. http://hsc.virginia.edu/medicine/clinical/internal/conf/chiefs/legion.htm

3. Gillen, AL and CB Fliermans. 2002. Creation biologist Carl B. Fliermans, solves mystery of Legionnaires’ Disease. http://www.icr.org/headlines/legionnairesdisease.html

4. Boldur, I, A Cohen, R Tamarin-Landau et al. 1987. Isolation of Legionella pneumophila from calves and the prevalence of antibodies in cattle, sheep, horses, antelopes, buffaloes and rabbits. Veterinary Microbiology 13:313-20.

5. Fabbi, M, MC Pastoris, E Scanziani et al. 1998. Epidemiological and environmental investigations of Legionella pneumophila infection in cattle and case report of fatal pneumonia in a calf. Journal of Clinical Microbiology, July 1998; 36(7): 1942-47.

6. Frequently asked questions: Legionella control. http://www.ems-online.co.uk/environmental/legionella_questions.shtml

7. Breiman, RF. 1993. Epidemiologic aspects of Legionellosis. IN Legionella: Current Status and Emerging Perspectives. American Society for Microbiology, Washington D.C.

8. Marra, A and H Shuman. 1992. Genetics of Legionella pneumophila virulence. Annual Review of Genetics 26:51-69.

9. Winn, Jr, WC. 1995. Legionella. IN Manual of Clinical Microbiology, 6th edition. Eds. Murray, PR, EJ Baron, MA Pfaller, FC Tenover, RH Yolken. ASM Press, Washington DC.

10. Signs and Symptoms of Legionnaires’ Disease. http://medicine.creighton.edu/forpatients/Legion/Legion.html

11. Bemer, P, S Leautez, E Ninin et al. 2002. Legionella pneumophila arthritis: Use of medium specific for Mycobacteria for isolation of L. pneumophila in culture of articular fluid specimens. Clinical Infectious Diseases 35:e6-e7.

12. Dixon, B.1994. Legionella pneumophila and Sick Building Syndrome. IN Power Unseen: How microbes rule the world. WH Freeman and Company Limited, New York.

13. Allan, T, H Horgan, H Scaife et al. 2001. Outbreak of Legionnaires’ Disease among automotive plant workers --- Ohio, 2001. MMWR Weekly, May 11; 50(18):357-9. (you can also find it in the CDC website at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5018a1.htm)

14. Legionnaires’ Disease: Unusual Cases. http://q-net.net.au

15. Duchin, JS, J Koehler, JM Kobayashi et al. 2000. Legionnaires’ Disease associated with potting soil --- California, Oregon and Washington, May-June 2000. MMWR Weekly, September 1; 49(34):777-8. (you can also find it in the CDC website at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4934.htm

16. Horwitz, MA, SC Silverstein. 1981. Interaction of the Legionnaires’ disease bacterium (Legionella pneumophila) with human phagocytes. II. Antibody promotes binding of L. pneumophila to monocytes but does not inhibit intracellular multiplication. Journal of Experimental Medicine 153:398-406.

17. Anonymous. 1987. Minimising the risk of Legionnaires’ disease. Technical Memorandum (TM13). The Chartered Institution of Building Services Engineers, London.

18. Grosserode, M, R Wenzel, M Pfaller et al. 1993. Continuous hyperchlorination for control of nosocomial Legionella pneumophila pneumonia: A ten-year follow-up of efficacy, environmental effects, and costs. IN Legionella: Current Status and Emerging Perspectives. American Society for Microbiology, Washington D.C.

19. Kuchta, J, JS Navratil, RM Wadowsky et al. 1993. Effect of chlorine on the survival and growth of Legionella pneumophila and Hartmanella vermiformis. IN Legionella: Current Status and Emerging Perspectives. American Society for Microbiology, Washington D.C.

20. Edelstein, PH, RE Whittaker, RL Kreiling et al. 1982. Efficacy of ozone in eradication of Legionella pneumophila from hospital plumbing fixtures. Applied and Environmental Microbiology Dec; 44(6):1330-4.