78 Legionnaires’ Disease

Legionnaires’ disease is an acute infection of hu­mans, principally manifested by pneumonia, that occurs in a distinctive pattern in epidemics and is caused by bacteria of the genus Legionella.

Legionnaires’ disease is one form of presentation of Legionella infections, which are generally re­ferred to by the umbrella term legionellosis. Another distinctive Clinicoepidemiological pattern of legionel­losis is Pontiac fever. Pontiac fever affects 45 to 100 percent of those exposed and has an incubation pe­riod of 1 to 2 days. Pneumonia does not occur, and all patients recover. More than 20 species of Legionella have been identified, 10 of which are proven causes of legionellosis in humans. The most common agents of human infection are Legionella pneumophila, Le­gionella micdadei, Legionella bozemanii, Legionella dumoffii, and Legionella Iongbeachae.

Legionellae are distinguished from other bacteria in being weakly staining, gram-negative, aerobic rods that do not grow on blood agar or metabolize carbohydrates, and have large proportions of branched-chain fatty acids in their cell walls and ma­jor amounts of ubiquinones with more than 10 iso­prene units on the side chain.

Distribution and Incidence

staining and other diagnostic culture procedures was identified, Legionella was found to cause 1 to 2

Legionellosis is easily overlooked, but has been found essentially wherever it has been sought. The weak staining of Legionella and its failure to grow on the usual bacterial diagnostic media allowed it to be missed for many years in the evaluation of per­sons with pneumonia.

Formal surveys of the incidence of legionellosis have not been done in most countries, but large numbers of cases have been identified in Great Brit­ain and several European countries, and cases have been reported on all continents.

Epidemiology and Etiology

Legionellae live in unsalty water and are widely dis­tributed in nature. They thrive particularly well at or slightly above human body temperature, and thus are commonly found on the hot water side of potable water systems and in the recirculating water in cool­ing towers and other heat exchange devices.

The various ways in which Legionellae can go from their watery environment to infect humans are not all worked out, but one method is clear. Aerosols created by some mechanical disturbance of contami­nated water, such as in the operation of a cooling tower, can on occasion infect people downwind. It is likely that, after the aerosol is generated, the drop­lets of water evaporate, leaving the bacteria air­borne. Once airborne, they can travel a considerable distance, be inhaled, and then be deposited in the lungs. Potable water systems also can act as the source of legionellosis outbreaks, but it is not known whether this occurs through aerosols (as might be generated by sinks, showers, or toilets), by coloniza­tion of the throat and then aspiration into the lungs, by direct inoculation (as into the eye or a wound), or by ingestion.

Many outbreaks have been recognized, but most cases occur individually (or sporadically). The risk of Legionella pneumonia (including Legionnaires’ dis­ease) increases with age and is two to four times higher in men than in women. No racial predisposi­tion has been seen. Cigarette smokers are more sus­ceptible, as are people whose cellular immune sys­tem is compromised — for example, by medication (such as corticosteroids) or underlying illness.

Few children have been shown to have legion­ellosis, but one prospective study showed that one- half developed serum antibodies to L. pneumophila before 4 years of age, indicating that inapparent infection may be common, at least at that age. In contrast, studies of adults during Legionnaires’ dis­ease outbreaks have generally shown that fewer than one-half of the Legionella infections are inapparent.

Legionellosis can occur throughout the year but is most common from June through October in the Northern Hemisphere. The summer season predomi­nates even in outbreaks unrelated to air-conditioning systems, but whether warmer weather causes the bacteria to flourish or, rather, humans to increase contact with their environment is not known. The fact that most bacterial and viral pneumonias are most common in the winter makes the seasonality of legionellosis one clue in diagnosis. Legionellosis does not seem to spread from one person to another.

Travel and certain occupations put people at in­creased risk oflegionellosis. Several outbreaks have occurred in tourist hotels, and a disproportionate number of sporadic cases are in people who recently have traveled overnight. Disease caused by Le­gionella and serologic evidence of previous Le­gionella infection are more common in power plant workers who have close exposure to cooling towers. Other outbreaks have occurred in people who used compressed air to clean river debris out of a steam turbine condenser, and in workers exposed to aero­sols of contaminated grinding fluid in an engine assembly plant.

Legionellosis outbreaks can be stopped by turning off the machinery that is making infectious aerosols, disinfecting that machinery, and heating or rechlor­inating contaminated drinking water. Several chemi­cal additives that are used in the routine mainte­nance of cooling towers and evaporative condensers can limit the growth of Legionella if used in combina­tion with regular cleaning.

Immunology

Legionella organisms live inside cells of all types, from various protozoa and freshwater amoebae in the external environment to various phagocytic cells in the human body. Given the location of Legionella in­side cells, it might be expected that cell-mediated im­munity is more important tl^ιn humoral (antibody- mediated) immunity, and such seems to be the case in legionellosis.

This may explain why people with defective cellu­lar immunity are particularly susceptible to le­gionellosis and why so few people exposed in an epidemic of Legionnaires’ disease become sick even though usually fewer than 20 percent (and often fewer than 5 percent) have preexisting elevations of titers of specific antibody to Legionella.

Clinical Manifestations and Pathology

Two distinct clinical and epidemiological syndromes of legionellosis have been identified: Legionnaires’ disease and Pontiac fever. Legionnaires’ disease is a multisystem disease, characterized by pneumonia, high fever, chills, muscle aches, chest pain, head­ache, diarrhea, and confusion. Chemical evidence of involvement of the liver and kidneys may also be found. Pneumonia usually worsens over the first week of illness and resolves gradually thereafter. Without specific antibiotic therapy, the disease is fatal in about 15 to 20 percent of otherwise healthy people, and in up to 50 percent of those with compro­mised cellular immunity. It is not readily distin­guished on clinical observation alone from several other forms Ofbacterial pneumonia.

Pathological changes are usually confined to the lungs, which often show a pattern of lobar pneumo­nia.

Pontiac fever is characterized by fever, chills, mus­cle aches, and headache. Cough and chest pain are much less common than in Legionnaires’ disease, and no cases have pneumonia. Victims are very ill for 2 to 7 days, but all recover.

History and Geography

From July 21 through 24, 1976, the Pennsylvania Department of the American Legion, a fraternal or­ganization of military veterans, held its annual meeting in Philadelphia, with headquarters in the Bellevue Stratford Hotel. Within days of the end of the convention, reports began to reach Legion head­quarters of conventioneers who had developed pneu­monia and died. A massive investigation, begun on August 3, uncovered 221 cases in Legionnaires who had attended the convention and others who had been in or near the headquarters’ hotel. The earliest case had its onset on July 20, the peak occurrence extended from July 24 through August 1, and de­creasing numbers of cases continued through Au­gust 16. Ninety percent of those who became ill developed pneumonia, and 16 percent died.

Diagnostic tests for all known agents of pneumo­nia, infectious and otherwise, were negative. The epidemiological investigation suggested airborne spread of the agent, because risk of “Legionnaires’ disease,” as the press had dubbed it, increased with the amount of time spent in the lobby of the hotel and on the nearby sidewalk, but was unrelated to contact with other sick people or animals, eating, or participation in specific events at the convention. Those who drank water at the Bellevue Stratford had a higher risk than others, suggesting the possi­bility of a waterborne agent, but 49 of the cases had only been on the sidewalk outside and had drunk no water there.

The outbreak received considerable notoriety and prompted a congressional investigation. The failure to find immediately the agent led to much public speculation about toxic chemicals and sabotage, but the answer came through the more usual route of persistent scientific work.

In August, Joseph McDade, who worked on rickett­sia at the U.S. Public Health Service Centers for Disease Control, had tested specimens from Legion­naires for evidence of rickettsia by inoculating lung specimens into guinea pigs and, if the animals died, putting tissue from them into embryonated eggs. The experiments were complicated by what seemed to have been some bacterial contamination, but over­all the results appeared clearly negative. In late November, McDade received a draft report of the status of the investigation to that point. He noted that the liver was involved in many of the cases, a fact that was reminiscent of Q fever, the rickettsial infection most commonly associated with pneumo­nia. After mulling upon that coincidence, he re­turned to his laboratory over the Christmas holidays to reexamine the specimens from his August experi­ments. After some hours, he came across a cluster of what looked to be large rickettsiae or small bacteria in a section of liver from a guinea pig that had been inoculated with lung tissue from a fatal case of Le­gionnaires’ disease. Repeating the inoculation of eggs, he was able to grow these organisms in the yolk sacs. Using the infected yolk sac suspension as the antigen in an indirect fluorescent antibody (IFA) test, he was then able to show that the serum col­lected during the field investigation from patients who had recovered from Legionnaires’ disease (but not that from unaffected people) had sharply rising titers of specific antibody to the yolk sac organism - indicating convincingly that this (which has since become known as Legionella pneumophila) was the causative agent.

In the 11 years before the Legionnaires’ disease outbreak, the Centers for Disease Control had inves­tigated two other large epidemics of respiratory dis­ease for which an agent had not been found. One, in 1965, had involved 81 patients at St. Elizabeth’s Hospital, a psychiatric institution in Washington,

D. C. John V. Bennett, the epidemiologist who had led the original St. Elizabeth’s investigation, commu­nicated to the author in the early fall of 1976 that he was certain that the two outbreaks were caused by the same agent. Fortunately, serum specimens from the St. Elizabeth’s outbreak had been stored at the Centers since 1965. When tested in early January of 1977, they unequivocally proved Bennett right.

In 1968, a remarkable outbreak of a severe, self­limited illness involved 95 of 100 employees in a health department building in Pontiac, Michigan. Some of the investigators from the Centers for Dis­ease Control succumbed also, but only those who en­tered the building when the air conditioning system was turned on. Guinea pigs were placed in the build­ing without any protection, with antibiotic prophy­laxis, or in an isolator that filtered the air, and then were killed to look for evidence of pneumonia or other ill effects. Inspection of the air conditioning system showed two major defects. The exhaust from the evaporative condenser discharged on the roof just a few feet from the fresh air intake. In addition, the exhaust duct and a horizontal chilled air duct that was adjacent to the exhaust duct had defects that allowed water droplets from the exhaust to puddle in the chilled air duct. Water recirculating in the evapo­rative condenser was aerosolized (with or without prior attempts to sterilize it) in laboratory tests to expose guinea pigs in an attempt to induce disease.

When materials from the 1968 investigation of Pontiac fever were used in the tests that succeeded for Legionnaires’ disease, scientists were intrigued to find positive results. Not only did people recover­ing from Pontiac fever show rising titers of specific antibody to L. pneumophila, but also L. pneumophila could be recovered from the stored lung tissue of guinea pigs that had been exposed, unprotected, to the air in the health department building or to the evaporative condenser water. Thus a very different disease - both epidemiologically and clinically - was shown to be caused by a bacterium which, to this day, cannot be distinguished from the one that caused Legionnaires’ disease.

Within a few weeks of the isolation of L. pneu­mophila in embryonated eggs, Robert Weaver found a way to grow it on agar plates. Subsequent improve­ments led to the development of charcoal yeast ex­tract agar, which greatly facilitates the isolation of Legionella.

Investigations of legionellosis proceeded both for­ward and backward in time. In the summer of 1977, outbreaks of Legionnaires’ disease were quickly rec­ognized in Vermont, Ohio, and Tennessee. In 1978 an outbreak of 44 cases at a hospital in Memphis, Tennessee, started shortly after a flood knocked out the usual cooling tower, and required turning on an auxiliary that had been out of use for 2 years. Cases clustered downwind from the auxiliary cooling tower but stopped occurring 10 days after it was shut off. L. pneumophila was isolated from both patients and the cooling tower water, confirming the epi­demiological evidence that Legionnaires’ disease, like Pontiac fever, could be caused by L. pneumo­phila contamination of heat-rejection devices in air­conditioning systems.

But air conditioning systems were not the whole answer. Public health authorities in Scotland and Spain were investigating a series of pneumonia cases acquired by Scottish visitors to a hotel in Benidorm, Spain, over several seasons. The hotel was not air-conditioned, but the cases proved to be Legionnaires’ disease. It would be some time before the source was found.

Other previously “unsolved” outbreaks were found to have been legionellosis. In 1973, all 10 men involved in cleaning a steam turbine condenser at a power plant on the James River in Virginia had developed what in retrospect seemed to have been Pontiac fever. Testing of stored serum specimens confirmed this. An outbreak of 78 hospitalized cases of pneumonia in Austin, Minnesota, in the summer of 1957 had been investigated at the time. Although the records had been preserved, the serum speci­mens had been lost in a refrigeration mishap. Survi­vors were recontacted in 1979, and they and the appropriate controls were bled to confirm the diagno­sis of Legionnaires’ disease in what is to date the earliest documented epidemic of legionellosis.

In 1979 reports began to appear of agents, some of which caused pneumonia, that resembled the L. pneumophila type strain in some ways but were clearly distinct, McDade and colleagues isolated an organism on artificial media that Hugh Tatlock had recovered in 1943 by inoculating into guinea pigs blood from a soldier at Fort Bragg, North Carolina, who seemed to have a case of “pre-tibial fever,” an illness subsequently shown to be caused by Lepto­spira. Later that year, A. William Pasculle and col­leagues isolated the “Pittsburgh pneumonia agent” in embryonated eggs but could not grow it in artifi­cial media. Subsequently, the Tatlock organism and the Pittsburgh pneumonia agent were shown to be the same, and were named L. micdadei.

McDade and colleagues also grew the OLDA strain on artificial media. OLDA was another organ­ism that resembled a rickettsia and had originally been isolated in 1947 by E. B. Jackson, by inoculat­ing a guinea pig with blood from a patient with fever of unknown origin. When characterized in 1979, it turned out to be L. pneumophila. It remains the earliest documented isolate of that species.

In 1959 F. Marilyn Bozeman and colleagues iso­lated a rickettsia-like organism in guinea pigs from a navy man who developed pneumonia after practic­ing with scuba gear in freshwater swimming pools. Lester G. Cordes and colleagues isolated it on artifi­cial media in 1979 and showed that it was distinct from L. pneumophila. It was subsequently named L. bozemanii.

Another line of discovery first reported in 1979 had important consequences in defining the biology of Legionella. George K. Morris and his colleagues reported the recovery of L. pneumophila from envi­ronmental water specimens, collected in the course of investigation of outbreaks of Legionnaires’ dis­ease. This quickly led to the discovery that Le­gionella organisms were widespread in nature, and could be found in about one-half of cooling towers. It also, for example, led to the discovery of additional Legionella species, not previously recognized to cause human disease.

In 1980, John O. H. Tobin reported the first isola­tion of Legionella from potable water systems, as part of an investigation of two kidney transplant patients who acquired Legionnaires’ disease while in the same hospital room in England. Subsequent studies in hospitals in England and in the United State showed the importance of such systems as the sources for dissemination of Legionella.

As these studies were reported, the picture emerged of Legionella as a group of freshwater- associated bacteria widely distributed in nature, causing pneumonia in humans when particularly susceptible people are exposed by aerosols, or per­haps otherwise, to contaminated water. The pres­ence of running hot water and other thermal pollu­tion, often from industrial processes, favors its growth, suggesting that legionellosis may be ex­pected to be particularly common in the developed world. However, the disease appears to be worldwide in its distribution.

David W. Fraser

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