These organisms are visualized poorly if at all by Gram stain. In tissue, silver impregnation stains such as the Dieterle or Warthin–Starry method allow visualization of the organisms.

To date the genomes of 6 strains of L. pneumophila have been sequenced. They range in size from 3.34 to 2.52 MB. The GC content ranges from 86% to 88% and 86% to 87% of the genes are coding genes. Recently whole genome sequencing has been applied to the investigation of an outbreak of LD.

Epidemiology and pathogenesis

Legionellae are aquatic microorganisms and thus the epidemiology of infections due to these organisms is linked to water systems that are contaminated with these bacteria. The earliest known outbreak of LD occurred in 1965 at St. Elizabeth’s Hospital in Washington, DC. The outbreak that gave this illness its name and led to the isolation of the causative microorganism was associated with the 58th Annual Convention of the American Legion held at a hotel in Philadelphia from July 21 to July 24, 1976. One hundred and eighty-two of the attendees at the convention developed pneumonia. One hundred and forty-seven (81%) were hospitalized, and twenty-nine (16%) died. This outbreak of pneumonia of apparent unknown cause triggered an extensive epidemiologic and microbiologic investigation by the Centers for Disease Control and Prevention (CDC), culminating in the isolation of a new microorganism, Legionella pneumophila, about 6 months later.

We now know that legionellosis can occur as sporadic (endemic) cases or as outbreaks in the community or in healthcare facilities. We have learned a lot about legionellosis by studying outbreaks. Outbreaks have varied in size from a few cases to the largest outbreak yet reported of 800 suspected and 449 confirmed cases in Murcia, Spain, in July 2001. A study from Europe from 2000 to 2002 indicated that there were 10 322 cases of LD with infection rates among the reporting countries from 0 to 34.1 cases per million population. Thirty-six outbreaks involving 211 persons were linked to hospitals; 38 outbreaks with 1059 cases occurred in community settings; 2 outbreaks were linked to private homes; and 113 outbreaks were travel-associated clusters involving 315 persons. Travel within Europe accounted for 88% of the cases. The remainder were associated with travel to the Americas, Caribbean, Far East, Africa, and Middle East. Continuing studies show that 20% of legionellosis in Europe is travel related. In 2009 there were 607 cases of LD possibly associated with 825 accommodation sites for an overall risk of 0.3 cases/million nights. Travel to Greece was associated with the highest risk.

With the use of geographic information systems it has been shown that the dispersion distances of Legionella from a contaminated cooling tower is about 11.6 km.

When data on 3254 patients with LD reported to the CDC from 1980 through 1989 were analyzed, investigators found that disease rates did not vary by year but were higher in northern states and during the summer. The mean age of patients with LD was 52.7 years compared with 34.7 years for the US population. In contrast to earlier reports, persons with LD were now more likely to be black. They were also more likely to be smokers, or have diabetes, cancer, acquired immunodeficiency syndrome (AIDS), or end-stage renal disease. Indeed, the observed number of cases among patients with AIDS was 42-fold higher than expected. Twenty-three percent of the cases were nosocomially acquired.

Some of the features noted in a review of the first 1000 cases of LD in the United States were that 71% of the cases were male and states with the highest attack rates were east of the Mississippi River. In addition, in the 2 weeks before onset of illness 37% of the patients had traveled overnight; 29% had been a hospital visitor, and 5% had been hospitalized for 2 days or fewer before onset of illness. The most recent update on LD in the United States in 2012 shows that legionellosis increased 217% from 2000 to 2009 with a total of 22 410 cases being reported to the CDC. The highest rates were in mid Atlantic States, lowest in West and South Central States. The rate was higher in males than in females and higher in African Americans. The highest rates were in those ≥80 years of age at 2.66/100 000 compared with 0.13/100 000 for those in the 20- to 29-year age group.

Only 5% of the cases were confirmed by culture, the rest by urinary antigen. Cases peaked in July and August, and were lowest in January through April.

Other risk factors for LD in the setting of an outbreak are cigarette smoking (relative risk 1.7 to 3.4) (smoking cannabis and tobacco may be a risk factor for severe LD) and consumption of three or more drinks of alcohol per day (confers a relative risk of 3.5). More recently investigators have begun to combine studies of traditional risk factors with a dissection of host susceptibility using molecular biology tools. A mutation leading to a stop codon at position 392 results in a dysfunctional toll-like receptor (TLR) 5 protein unable to recognize flagellin and is a risk factor for L. pneumophila infection in nonsmokers. Reduced interferon-γ release has been noted in patients who have recovered from LD. More recently it has been observed that treatment with a tumor necrosis factor antagonist can predispose to LD, with now more than 22 cases reported. It is interesting in light of the above information about the role of cell-mediated immunity in LD that patients with human immunodeficiency virus (HIV) infection who have a defect in cell-mediated immunity are relatively infrequently infected with Legionella spp. However, when they do develop Legionella infection, they take longer to become afebrile, have more respiratory symptoms, and have a higher rate of respiratory failure and mortality when compared with patients with Legionella but without HIV infection.

Outbreaks provide an opportunity to learn about the mechanisms of transmission of LD. In most instances, Legionella is transmitted to humans by inhalation of aerosols containing the bacteria. Outbreaks have been associated with exposure to a variety of aerosol-producing devices, including showers, a grocery store mist machine, cooling towers, whirlpool spas, decorative fountains, and evaporative condensers. Other water sources implicated in transmission of LD include showers and spas in wellness centers, water on trains, birthing pools, dental units, asphalt paving machines, and windscreen wiper fluid without added screen wash. New reservoirs for Legionella continue to be identified such as compost facilities. It is also likely that aspiration of contaminated potable water by immunosuppressed patients is a mechanism whereby infection with Legionella is acquired. Legionellosis is believed to occur worldwide, but data are limited or nonexistent for many countries. It is likely that legionellosis is uncommon in areas without hot-water heaters and complex water distribution systems. However, even in these areas, aspiration of contaminated natural water, as, for example, following boating accidents, can result in LD. Legionnaires’ disease has been found throughout North America, Europe, the United Kingdom, Argentina and Brazil in South America, Singapore, Thailand, and Australia. A few cases of LD have been reported from India.

Pathogenesis

Our knowledge of the pathogenesis of Legionella infections in humans is still incomplete. The alveolar macrophage is the target cell for Legionellae in the lower airways. Both E-cadherin and b1 integrin receptors mediate filamentous L. pneumophila attachment to lung epithelial cells. Only virulent strains of Legionella are capable of initiating parasite-directed endocytosis. Following phagocytosis or endocytosis, there is abrogation of phagosome–lysosome fusion, which is essential for the intracellular growth of this microorganism. The replicative phagosome becomes associated with the endoplasmic reticulum.

Following a latent period of about 12 hours, the bacteria start dividing. During this latent period, there is synthesis of up to 35 proteins and repression of 32 proteins. Iron must be available in the phagosome for growth. Virulent L. pneumophila strains are sensitive to sodium chloride.

Once the replicative phagosome has been established, the bacteria begin to multiply with a doubling time of 2 hours. Heat shock protein 60 (Hsp 60), a chaperone protein, is a dominant protein during this intracellular phase, suggesting that it has an essential role in the viability of the microorganism. Several morphologic changes occur as the number of bacteria increase: They become shorter and accumulate intracytoplasmic membranes and vesicles.

It is likely that Legionella behave differently while multiplying in macrophages than they do while multiplying in amebae, their natural hosts. Because airborne amebae have been found in water aerosols, this finding may have implications for LD in humans.

Infectious syndromes

Pneumonia is the most common manifestation of infection with Legionella spp. It may occur in the community as sporadic cases or as outbreaks. In addition, Legionella is one of the agents of healthcare-associated pneumonia. There may be a variety of extrapulmonary manifestations and sometimes the clinical picture is dominated by these.

Pontiac fever is a syndrome related to inhalation of Legionella spp. lipopolysaccharide.

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