Microbiology, epidemiology, and pathogenesis of Legionella infection

INTRODUCTION — Legionella bacteria are aerobic, gram-negative, intracellular pathogens that are important causes of community-acquired and nosocomial pneumonia. Legionella infections can be acquired sporadically or during outbreaks. Legionella bacteria are typically transmitted via inhalation aerosols from contaminated water or soil.

The microbiology, epidemiology, and pathogenesis of Legionella infections will be reviewed here. Clinical manifestations, diagnosis, and treatment of this entity are discussed separately. (See "Clinical manifestations and diagnosis of Legionella infection" and "Treatment and prevention of Legionella infection".)

DEFINITIONS — The term legionellosis refers to any clinical syndrome associated with Legionella infection. The two most common syndromes associated with Legionella infection are:

●Legionnaires' disease, which refers to pneumonia caused by Legionella spp

●Pontiac fever, which is an acute, self-limited febrile illness that is typically acquired during outbreaks

Extrapulmonary legionellosis refers to infection outside the lung (eg, cellulitis, endocarditis, peritonitis) and is rare but reported. (See "Clinical manifestations and diagnosis of Legionella infection".)

MICROBIOLOGY

Pathogen — Legionella bacteria are aerobic, nutritionally fastidious, gram-negative bacilli and facultative intracellular pathogens [1].

The bacterial family Legionellaceae consists of >60 species and >70 serogroups [2,3]. Legionella pneumophila, the most common cause of human disease, is divided into >15 serogroups [3,4]. L. pneumophila serogroup 1 is the most prevalent, although nearly all serogroups have been reported to cause human disease [4,5].

At least 26 other Legionella species are pathogenic in humans. L. longbeachae is the second most common cause of human disease [4,6]. L. micdadei, L. bozemanii, L. feeleii, L. anisa, and L. dumoffii are also established human pathogens [3].

Environmental reservoir — Legionellae are environmental organisms found in water and soil [1]. Environmental reservoirs vary among species.

L. pneumophila and most other Legionella species mainly reside in bodies of water, such as lakes, streams, and artificial water reservoirs. Within water, Legionellae can live planktonically, in biofilms, or as intracellular parasites within protozoa (eg, free-living amoeba and ciliates) [7]. Replication within protozoa protects the organism from temperature shifts, pH changes, and nutrient-poor environments. Additional factors that promote growth in water include warm temperatures (25 to 42°C), stagnation, and sedimentation.

By contrast, L. longbeachae is genetically adapted to invade plant material and primarily resides in soil and compost [8-11]. While Legionella species have preferred growth environments, their habitats are not discrete. L. pneumophila and other Legionella species can occasionally be found in soil and compost [12]. Conversely, L. longbeachae has been found in water sources [13,14].

Transmission — Legionella bacteria are typically transmitted to humans via inhalation of aerosols derived from water or soil [8,15]. The infectious dose for humans has not been precisely quantified but is likely high, requiring >1000 organisms to cause infection [1,16].

Contamination of water sources with concentrations of Legionella high enough to cause human infection can occur when changes in water flow or pressure disrupt biofilms, releasing large amounts of bacteria into the surrounding water [1]. Legionella's ability to grow intracellularly within free-living amoeba may also facilitate transmission from either water or soil [1,17,18]. A single infected amoebal cyst may contain thousands of Legionella bacteria and, if aerosolized, could easily deliver an infectious dose.

Laboratory and person-to-person transmission generally do not occur, likely due to the high infectious dose. However, a single case of possible person-to-person transmission has been reported [19].

The incubation period ranges from 2 to 10 days (median 4 to 6 days) for Legionnaires' disease and from approximately 4 hours to 3 days (median 32 to 36 hours) for Pontiac fever [1].

EPIDEMIOLOGY

Incidence and prevalence

Legionnaires' disease — The reported incidence of Legionnaires' disease is approximately 1.4 to 1.8 cases per 100,000 persons in the United States, Europe, and Australia [20-22]. Within these regions, local rates range from approximately 0.4 to 5.0 cases per 100,000 persons. The highest reported incidence (5.4 cases per 100,000 persons) is in New Zealand, where L. longbeachae causes the majority of disease [23,24]. Across these regions, reported incidences are rising [20,21,25,26]. However, this rise in incidence may reflect increased awareness, improved diagnostic tests, and/or changes in reporting standards rather than a true rise in incidence.

Legionnaires' disease may be community acquired or acquired in health care facilities.

●Community-acquired pneumonia – Legionnaires' disease accounts for approximately 1 to 10 percent of cases of community-acquired pneumonia (CAP) [27-32]. CAP caused by legionellae is most often diagnosed in hospitalized patients and can be severe. Up to 44 percent of patients have been reported to require intensive care unit admission, and the associated mortality is approximately 1 to 10 percent [20,33,34].

●Nosocomial pneumonia – The prevalence of Legionnaires' disease in patients with nosocomial pneumonia is linked to presence and concentration of legionellae in the facility's water supply [35,36]. In the United States in 2015, approximately 20 percent of cases of Legionnaires' disease was acquired in hospitals or long-term care facilities [37].

Pontiac fever — The incidence of Pontiac fever is not well established because the syndrome is typically nonspecific and self-limited. However, outbreak investigations suggest that Pontiac fever may be more common than Legionnaires' disease during outbreaks [38,39].

Outbreaks — Legionella species cause both sporadic and epidemic infections. While the great majority of cases are sporadic, outbreaks are common.

Legionella bacteria were first identified as a result of the investigation of an outbreak of severe pneumonia among attendees at an American Legion convention in 1976 [40-42]. The initial outbreak involved 182 persons and was linked to contamination of the air conditioning system at the hotel where the convention was held.

Subsequently, Legionella has been identified as a common cause of waterborne disease outbreaks. During 2015, there were 54 reported Legionnaires' disease outbreaks in Europe alone, involving 559 cases from 11 countries [21]. While the largest of these outbreaks involved 304 persons, most affected <10 persons. Large outbreaks are often associated with contaminated industrial cooling towers or water systems that supply communities or facilities such as hospitals, hotels, cruise ships, or apartment buildings [43-49].

As examples, contaminated cooling towers were responsible for an outbreak at the Melbourne Aquarium that involved 125 visitors [47]. Seventy-six percent of patients required hospitalization, and the case-fatality rate was 3 percent. In an outbreak at a Dutch flower show, 188 visitors became ill after exposure to a contaminated whirlpool spa in the exhibition hall [50]. However, contamination of any water source can also lead to infection. (See 'Environmental exposures' below.)

L. pneumophila is by far the predominant species associated with outbreaks.

Geographic variation — Globally, L. pneumophila is the most commonly reported cause of Legionnaires' disease, causing over 90 percent of community-acquired cases [4]. Within L. pneumophila species, serogroup 1 predominates, causing approximately 85 percent of cases overall.

L. longbeachae is the second most commonly reported cause of Legionnaires' disease [6]. Although L. longbeachae accounts for approximately 4 percent of reported cases overall, its prevalence appears to be significantly higher in Australia and New Zealand, where it is reported to cause >50 percent of cases [24].

It is unclear how much of the global predominance of L. pneumophila is due to the widespread use of the urinary antigen test as the sole diagnostic, as this test only detects L. pneumophila serogroup 1.

Seasonality — Legionnaires' disease caused by L. pneumophila is possibly more common in late summer and early autumn [21,51,52], whereas that caused by L. longbeachae peaks in spring and early summer [33]. It is thought that these patterns reflect warmer, wetter weather and gardening activity, respectively [33,53].

Risk factors — Although Legionella bacteria are widespread in the environment, human infection is relatively rare. Even during large outbreaks, only a minority of persons in affected areas develop disease.

Host risk factors — Older age is strongly associated with Legionnaires' disease. In most cohort studies, >75 percent of patients with Legionnaires' disease are >50 years old [51,54,55]. Pediatric Legionnaires' disease does occur but is rare [56].

Immunocompromise, particularly impaired cellular immunity, has also been identified as a risk factor for Legionella infection. Acquired immunodeficiency syndrome (AIDS), hematologic malignancies, and diabetes mellitus have each been shown to be independent risk factors Legionnaires' disease in a large case-control study [51]. Solid organ transplantation, tumor necrosis factor-alpha inhibitors, and anti-CD52 agents have also been reported to increase the risk of infection [57-59].

Other commonly described risk factors include smoking (current or past), chronic respiratory disease, cardiovascular disease, and end-stage kidney disease [8,47,51,54]. Male sex and alcohol use have also been associated with increased risk of infection [60].

Environmental exposures — Most Legionella infections are associated with exposure to contaminated manmade water reservoirs. Reported sources of infection are diverse and include showers [61], pools [62], hot tubs [63], aquariums [47], fountains [64], birthing pools [65,66], drinking water systems [15,55], air conditioning systems and cooling towers [67,68], and other water collection systems [69,70]. Natural water systems, such as rivers and streams, are less common sources of infection [71].

Soil, potting mix, and compost exposure is also a risk factor for Legionella infection, particularly for L. longbeachae [8,72]. Gardening and specifically not washing one's hands after gardening are associated with an increased likelihood of infection with L. longbeachae [8,72].

PATHOGENESIS — The pathogenesis of L. pneumophila has been most comprehensively studied for Legionnaires' disease caused by L. pneumophila. Relatively little is known about the pathogenesis of Pontiac fever or Legionnaires' disease caused by non-pneumophila Legionella species.

Legionnaires' disease

L. pneumophila infection — L. pneumophila typically reaches the lung via inhalation and, less commonly, via microaspiration [73-75]. Within the alveoli, the bacteria attaches to alveolar macrophages and epithelial cells using flagella, pili, and outer membrane porins [76-81]. Phagocytosis is mediated by human complement component C3 and macrophage infectivity potentiator protein, a virulence factor expressed on L. pneumophila's cell surface.

Following phagocytosis, L. pneumophila uses a Dot/Icm type IV secretion system to translocate hundreds of effector proteins into the phagocytic vacuole [82-86]. These effector proteins inhibit phagosome-lysosome fusion, thereby allowing L. pneumophila to survive within the host cell. Effector proteins also recruit vesicles from the host cell's endoplasmic reticulum, which transform the phagocytic vacuole into an organelle that is competent for intracellular bacterial replication.

As L. pneumophila replicates, the vacuole expands to fill the cell. Upon exhaustion of host cell nutrients, the bacteria enter a stationary growth phase and develop flagella [87]. The flagella trigger caspase-1, which induces apoptosis, and progeny bacteria exit the cell, initiating a new amplification cycle [88]. While multiple other virulence factors and immune evasive mechanisms have been described for L. pneumophila, their role in pathogenesis is not clearly established. These include heat-shock protein Hsp60, which enhances epithelial cell invasion [89]; a lipopolysaccharide containing endotoxic activity; and the rcp gene, which appears to encode a lipid A-modifying enzyme, confers resistance to cationic peptides, and promotes macrophage and lung infection [90]. L. pneumophila also secretes a variety of proteins, degradative enzymes, and toxins primarily via a type II secretion system [85,91-96]. Additional immune-evasive mechanisms include the bacteria's ability to resist complement and cationic peptides in the extracellular space and ability to withstand free radical assault [80,81,90].

Infection with other Legionella species — Like L. pneumophila, most other Legionella species are transmitted via aerosol inhalation, invade alveolar macrophages, and replicate intracellularly, usually relying on a Dot/Icm type IV secretion [97-100]. However, specific virulence factors and effector proteins vary among species [82,100-103].

As an example, L. longbeachae is encapsulated and lacks flagella. The genome size is approximately 40 percent larger than L. pneumophila. Some of the added genetic sequences are believed to encode effector proteins derived from soil- and plant-dwelling microorganisms, which may enhance L. longbeachae pathogenicity [11,99,104]. In vitro and animal models also suggest that L. longbeachae infection might be more virulent than L. pneumophila infection [105]. In mice, infection with L. longbeachae is immunologically silent and causes lethal acute respiratory failure. By contrast, L. pneumophila infection is typically self-limited.

Host immune response — Th1 cell-mediated immunity is the primary means of immune control of Legionella infections. Macrophage activation, triggered by the innate immune system, also plays an important role in clearing infection [106-110]. The cytokines produced by infected alveolar macrophages are essential for the recruitment of neutrophils and for stimulating interferon-gamma production by natural killer cells, which are both needed for sterilization in the lung [109,111]. Although Legionella-specific antibodies develop during the course of infection, the humoral immune response does not appear to be critical for host defense.

Pontiac fever — The pathogenesis of Pontiac fever is not well characterized. The syndrome can be caused by most Legionella spp and is acquired by inhalation of the organism from the environment. Because the incubation period is short (four to six hours) and recovery is typically rapid, Pontiac fever is hypothesized to be a toxin-mediated illness.

SUMMARY

●Microbiology − Legionella bacteria are aerobic, gram-negative, intracellular pathogens that are commonly found in water and soil. Human infection is typically acquired through inhalation of aerosols from these substances. (See 'Microbiology' above.)

●Common serotypes − Legionella pneumophila serotype 1 is the most commonly reported cause of human Legionella infections worldwide. Legionella longbeachae is the second most common cause of human Legionella infections and is predominantly reported in Australia and New Zealand. (See 'Incidence and prevalence' above.)

●Sporadic and epidemic infections − Most Legionella infections are sporadic; however, epidemics can occur and are often associated with exposure to contaminated communal water supplies in large facilities such as hospitals, hotels, or apartment buildings. (See 'Outbreaks' above and 'Environmental exposures' above.)

●Clinical manifestations − The two major clinical syndromes association with Legionella infections are Legionnaires' disease (pneumonia) and Pontiac fever, an acute, nonspecific, self-limited febrile illness. (See 'Definitions' above and "Clinical manifestations and diagnosis of Legionella infection".)

●Prevalence and age association − Legionella spp are estimated to cause about 2 to 10 percent of cases of community-acquired pneumonia, with over 75 percent of cases occurring in adults >50 years old. (See 'Incidence and prevalence' above and 'Risk factors' above.)

●Risk factors − In addition to older age, risk factors for Legionnaires' disease include smoking, chronic respiratory disease, diabetes mellitus, and other immunocompromising conditions. (See 'Host risk factors' above.)

●Pathogenesis of Legionnaires’ disease − The pathogenesis of Legionnaires' disease is complex but involves invasion of alveolar macrophages and epithelial cells, intracellular replication, and apoptosis of infected cells. Cell-mediated immunity is the primary means of immune control. (See 'Pathogenesis' above.)

●Pathogenesis of Pontiac fever − Because of the self-limited and nonspecific nature of Pontiac fever, the epidemiology and pathogenesis of this disease have not been well characterized. (See 'Pontiac fever' above and 'Pathogenesis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Victor Yu, MD, Janet Stout, PhD, Nieves Sopena Galindo, MD, and Patricia Priest, MBChB, DPhil, who contributed to earlier versions of this topic review.