Legionnaires’ Disease and 232 Pontiac Fever Paul H. Edelstein and Craig R. Roy

SHORT VIEW SUMMARY

Definition } Pontiac fever is associated with inhalation of highly sensitive in all settings. Urine antigen } Legionnaires’ disease is a noncontagious type Legionellaa spp.–containing water but not testing, the most commonly used test, is about of bacterial pneumonia caused by Legionella necessarily caused by the bacterium. It occurs 70% and 30% sensitive in spp. bacteria, most commonly Legionella in sporadic and epidemic form at apparently community-acquired and nosocomial disease, pneumophila. low incidence but may be more common than respectively. is reported. } Pontiac fever is a several-day-long, Therapy nonpneumonic, febrile, influenza-like illness Microbiology } Macrolides, tetracyclines, and quinolone associated with exposure to Legionellaa spp. } Constituted of more than 60 known species, the antimicrobials can all be used to successfully that resolves spontaneously. Legionellaa bacteria are ubiquitous in the treat the disease, with azithromycin and Legionellosis includes legionnaires’ disease, } aqueous environment and probably moist soils. levofloxacin being the most active. Pontiac fever, and extrapulmonary Legionella } Optimal bacterial growth requires specialized Tetracyclines may not be active for L. spp. infection not associated with pneumonia. media that contain cysteine and iron. longbeachaee–caused disease. Epidemiology } The bacteria are facultative intracellular } For cure, 3 to 14 days’ therapy is required, } Legionnaires’ disease is acquired by inhaling a parasites of free-living amebae and human depending on disease severity, host factors, water aerosol containing Legionellaa spp. monocytes and macrophages that use hostlike and type of therapy used. proteins to masquerade as host and to avail bacteria, and possibly by microaspirating Prevention Legionellaa spp.–containing water. themselves of intracellular resources. } No vaccine is available. } About 20 to 80 cases annually per million Diagnosis } Proper environmental design and maintenance population occur in most developed countries, } Clinical and roentgenographic differentiation reduce disease risk. with the elderly, males, cigarette smokers, and of legionnaires’ disease from common causes immunosuppressed patients most at risk. of pneumonia is not generally possible. } About 1% to 5% of patients hospitalized for } Specific and specialized laboratory testing can community-acquired pneumonia have be helpful for disease diagnosis but is not legionnaires’ disease.

HISTORY before, but major advances in technology were required to properly Legionnaires’Legionnaires’ disease (LD) is an acute pneumonic illness caused by determine its cause. gram-negative bacilli of the genus Legionella, the most common of Even with identification of Lp in 1977 as the cause of LD, how best which is Legionella pneumophila (Lp). Pontiac fever (PF) is a febrile, to diagnose the disease and ways to abort epidemics of LD remained nonpneumonic, systemic illness closely associated with, if not caused uncertain for several years. Epidemics of the disease, especially noso- by, Legionella spp. Legionellosis is the term that encompasses all diseases comial ones, commonly lasted for years.16–22 It was discovered that Lp caused by, or presumed to be caused by, the Legionella bacteria, including and other Legionella spp. were naturally occurring aquatic bacteria that LD, focal nonpulmonary infections, and PF. grew in warm water, in cooling towers, water heaters, and potable water LD was first recognized when it caused an epidemic of pneumonia plumbing. These discoveries led to the end of several multiyear outbreaks at a Pennsylvania State American Legion convention in Philadelphia of the disease.23 It is now unusual for LD outbreaks to last more than in 1976; 221 people were affected, and 34 died. Despite intensive labora- a week or two. tory investigation, the cause of the outbreak went undetected for many LD occurs in both sporadic and epidemic forms, sometimes involving months. Epidemiologic investigation concluded that the disease was many hundreds of victims.24–27 The disease, while a relatively rare (1%–5%) most likely airborne, and focused primarily at one convention hotel, cause of community-acquired pneumonia that is often easily treated which closed because of adverse publicity.1,2 About 6 months later, Joseph and relatively mild, can cause severe, and fatal, disease. McDade and Charles Shepard, investigators at the Centers for Disease Control and Prevention, discovered the etiologic agent, a fastidious THE ETIOLOGIC AGENT gram-negative bacillus.3 Because of the historical association with the The LegionellaLegionella spp. aarere ssmallmall ggram-negativeram-neg bacilli with fastidious growth American Legion convention, this disease is now called “legionnaires’ requirements. Amino acids are the main energy source for extracellular disease,” and the etiologic agents belong to the family Legionellaceae, growth, with glycerol or glucose used during intracellular growth.28 with Lp being the agent responsible for the 1976 Philadelphia epidemic. Obligate aerobes, the bacteria grow at temperatures ranging from 20°C Several past unsolved outbreaks of pneumonia in the 1950s to the early to 42°C. Coxiella burnetii, an obligate intracellular parasite and the 1970s had been LD.4–6 An unsolved epidemic of a nonpneumonic febrile etiologic agent of Q fever, is the closest relative of the Legionellaceae. illness in Pontiac, Michigan, was found to be associated with Lp exposure; l-Cysteine is required for the growth of all but one of the clinically this illness was termed “Pontiac fever”.7,8 Prior epidemics of PF occurred important Legionella spp., and this amino acid is needed for the initial as early as 1949.9 Bacterial isolates from the 1940s through the 1960s, growth of all described Legionella spp. from environmental or clinical previously thought to be rickettsial agents, were found to be Legionella sources. Soluble iron is required for optimal growth, and for initial bacteria.10–15 Both the organism and the disease had been studied decades isolation of the bacterium from both clinical and environmental sources. 2807 2808 s ent g ic A g tiolo E

A B

FIG. 232.1 Cultures of Legionella pneumophila. (A) Typical opal-like colony of L. pneumophila grown on BCYEα agar. (B) Gram stain of L. pneumophila taken from culture plate. Basic fuchsin should be used as the counter-stain as safranin stains the bacterium poorly. ectious Diseases and Their f In I

A yeast extract agar containing iron, l-cysteine, α-ketoglutarate, and

Part II charcoal and buffered with an organic buffer (buffered charcoal-yeast extract [BCYEα] agar) is the preferred growth medium for clinical isolation. Clinically important Legionella spp. grow best at 35°C in humidified air on BCYEα medium, usually in 3 to 5 days after inoculation of plates. Up to 14 days’ incubation may very rarely be required for the isolation of unusual Legionella spp. More than 60 different Legionella spp. have been described, about half of which have been reported to infect humans.29 Lp serogroup 1 (Lp1) caused the 1976 Philadelphia outbreak, and is the cause of 65% to 90% of all cases of LD for which there is a bacterial isolate.30–32 Lp1 dominance is not universal. For example, Lp1 constituted only 66% of Legionella spp. isolates in LD patients in Ontario Province, Canada, with Lp serogroup 6 being a relatively common isolate in that province.32 Also, L. longbeachae (Llb) causes 50% to 85% of LD cases in New Zealand, and a similar fraction in Australia.33 Lp1 can be divided into multiple subtypes using a variety of serologic, other phenotypic, and genetic FIG. 232.2 Gimenez stain of L. pneumophila growing in an ameba. methods. One particular subtype of Lp1 causes 55% to 76% of cases of Note that the bacteria are much smaller and more uniform in morphology LD due to Lp, and 85% of cases due to Lp1. This “Pontiac” subtype than when the bacteria are taken from a culture plate (see Fig. 232.1B). reacts with a specific monoclonal antibody and contains the lag-1 gene encoding a lipopolysaccharide acetyl transferase.34,35 The most common non-Lp species that are isolated from humans are Llb, L. micdadei, L. In addition to intraamebal survival, free-living Legionella bacteria bozemanae, and L. dumoffii,31 which, with the exception of Australasia, can enter a low metabolic state termed “viable but not cultivatable”, constitute fewer than 5% of culture-proven cases.36,37 making them difficult to recover from the environment and biocide- Most clinical microbiology laboratories should be able to identify resistant.42 The Legionella bacteria, amebae, and other microorganisms Legionella bacteria to the genus level (Fig. 232.1). Identification of Lp constantly escape from the biofilm because of pressure fluxes into a and Lp1 can be accomplished by sophisticated laboratories. Identification freely moving phase. Environmental changes that disrupt the biofilm of other Lp serogroups and other Legionella spp. is more difficult, can result in the sudden and massive release of Legionella bacteria into requiring molecular testing for accurate identification.38 Matrix-assisted the surrounding water. If this water is then aerosolized or aspirated, laser desorption/ionization time-of-flight (MALDI-TOF) mass spec- the bacteria can cause illness in a susceptible host. Almost all cases of trometry identification of bacterial colonies can be useful for the LD result from Legionella contamination of warm man-made water identification of commonLe gionella spp., but may not be completely sources. Legionella is one of several opportunistic pathogens that are accurate depending on the validity of the database, with custom databases found in the built plumbing environment.43 Some recently reported increasing the accuracy of bacterial identification. novel water sources include rain puddles in tropical regions, tsunami- related water exposure, windshield wiper fluid, water from truck tankers MICROBIAL ECOLOGY used to clean or maintain roads, and corroded domestic water pipes.44–48 The LegionellaLegionella bacteriabacteria areare foundfound ini our natural aqueous environment, One exception to water as a risk factor is that Llb appears to be transmitted in lakes, streams, and even coastal oceans, at temperatures ranging mainly through potting soil used by gardeners.49 Water treatment of from 5°C to greater than 50°C.39 Warm water (25°C–40°C) supports source water to make potable water may increase the concentration of the highest concentration of these bacteria, with warm water being the Legionella bacteria (and mycobacteria) in the water.50 Legionella bacteria major bacterial reservoir leading to LD. Free-living amebae in the same are present in very low concentrations in disinfectant-treated cold potable waters support the intracellular growth and survival of the Legionella water, usually at levels of less than 1 bacterium per liter. The bacterial bacteria40,41 (Fig. 232.2). When faced with inimical environmental factors density can be amplified by growth in biofilm within water distribution the Legionella-infected amebae encyst, allowing the survival of both pipes, especially older pipes with low or no water flow. The bacteria the host and parasite. In both natural and man-made waters, Legionella- can be further amplified in the presence of warm conditions, such as infected amebae are found in consortia of many different microorganisms, those found in many buildings or heat rejection devices. Legionella all of which exist in a biofilm. bacteria concentrations in air-conditioning cooling towers range from 2809 102 to 108 colony-forming units (CFU)/L. Up to 80% of air-conditioning as in TLR2-deficient mice.65 Epidemiologic data indicate that humans cooling towers tested contain the bacterium, as do 5% to 30% of home with a TLR5 stop polymorphism are more susceptible to LD; for unclear and industrial water heaters and hot water plumbing.39 Contaminated reasons human TLR4 polymorphisms are protective67–70 even though Cha water that is aerosolized serves as a disseminator of the bacteria into the lipid A moiety produced by Lp has an atypical structure and is less the environment. The concentration of Legionella bacteria in a particular stimulatory toward TLR4 than the classic lipid A molecule produced p environmental site may spontaneously fluctuate over a wide range. by Enterobacteriaceae.71 ter 232 The delivery of microbial products into the macrophage cytosol by PATHOGENESIS virulent Lp contributes significantly to the robust inflammatory response. OverviewOverview The mouse protein caspase 11 and the human homologues caspase 4 Legionnaires’ Disease and LD is initiated by inhalation, and probably microaspiration, of Legionella and caspase 5 bind directly to cytosolic lipopolysaccharide (LPS) during bacteria into the lungs. Although Legionella bacteria are ubiquitous in Lp infection of macrophages,72–74 and caspase 11 has been shown to be our environment, they rarely cause disease. A confluence of a number essential for septic shock, implicating this pathway as being critical for of factors must occur simultaneously before LD is possible. These factors LD pathology. Many responses are activated by host nucleotide-binding include the presence of virulent strains in an environmental site; a oligomerization domain (NOD)–like receptor (NLR) proteins. The mouse means for dissemination of the bacteria, such as by aerosolization; and NLR protein NAIP5 detects bacterial flagellin to activate caspase-1– proper environmental conditions allowing the survival and inhalation dependent processing and secretion of the cytokines IL-1b and IL-18, of an infectious dose of the bacteria by a susceptible host. Strains of and animals that are defective for NAIP5 are significantly more susceptible P different virulence exist for the same ps ecies, and some species and to Lp infection. The NLR proteins NOD1 and NOD2 respond to ontiac Feve serogroups are more virulent than others.51–53 Possible strain virulence peptidylglycan fragments delivered into the cytosol by virulent Lp, and factors include aerosol stability, ability to grow within macrophages, sustain activation of innate immune signaling pathways. Lastly, the possession of eukaryotic gene homologs, and surface hydrophobicity. proteins RIG-I and MAVS respond to bacterial nucleic acid delivered The infectious form of the bacterium is not known, but in all cases into the cytosol during Lp infection to activate type I interferon r the bacteria originate from water or soil. Several possibilities exist for production.65 the infectious particle, including bacteria contained within an amebal Although the severe Th1 response induced by Lp can be detrimental cyst, a sporelike form,54 a biofilm particle containing Legionella bacteria to the host under high bacterial loads, these cytokines are crucial for and other bacteria, and freely dispersed extracellular Legionella bacteria. the clearance of Legionella organisms.75 Cytokines produced by infected Virulence increases when the bacterium is grown in amebae, in the late alveolar macrophages are essential for the recruitment of neutrophils stationary phase in vitro, or as the sporelike form.55–57 The bacterial and for stimulating IFN-γ production by natural killer cells, which are inoculum required to cause LD is unknown. Guinea pigs develop both needed for sterilization in the lung.76 Neutrophils are efficient at asymptomatic infection, disease, and death with inocula of 10 to 100, clearing extracellular Lp from the lungs. Macrophages activated by IFN-γ 1000, and 10,000 bacteria, respectively.58,59 Bacteria in amebal cysts or kill Lp.77 This change in macrophage permissiveness involves, among in a biofilm fragment contain greater than 1000 bacteria, making it other things, a reduction in intracellular iron, a factor that is necessary possible that inhalation of an infected amebal cyst or biofilm fragment for Lp replication.78 Indeed, the majority of legionellae seen in lung could cause disease.60 Survival of aerosolized extracellular Lp is dependent samples are associated with alveolar macrophages. Furthermore, the on relative humidity.61 Relative humidity may be a key factor in disease susceptibility of an animal species correlates with the ability of Lp to transmission.25,62 LD is a seasonal disease in some regions, with most infect its macrophages, and bacterial mutants that are impaired for in cases occurring in the warmer months. For example, in the northeastern vitro infection of macrophages have reduced virulence. Antibodies United States, the majority of cases occur from June through early develop during the course of Lp infection, but the humoral immune October. This is probably because of elevated ambient temperature and response does not appear to be critical for host defense. humidity.63 It is widely believed that the adaptation of Lp to protozoan niches After bacteria enter the lung, they are phagocytosed by alveolar in nature engendered it with the ability to infect mammalian phagocytes.79 macrophages. The bacteria produce virulence factors that enhance Lp enters the macrophage by conventional or coiling phagocytosis,80–82 phagocytosis and promote intracellular survival and replication (see processes that utilize the host cell actin cytoskeleton.83 Opsonization “Legionella pneumophila Virulence Factors” below). After sufficient with the C3 component of complement can promote phagocytosis,84 intracellular replication, the bacteria kill the macrophage, escape into but entry by this pathway dampens the oxidative burst and thereby may the extracellular environment, and are then rephagocytosed by mac- enhance bacterial intracellular survival. However, opsonin-independent rophages. The bacterial concentration in the lung increases due to phagocytosis also appears to be important.57 Even in the event that the amplification of the bacteria within macrophages. oxidative burst is triggered, Lp strains may be resistant to hydrogen Following this intracellular multiplication, neutrophils, additional peroxide, superoxide anion, and hydroxyl radicals. macrophages, and erythrocytes infiltrate the alveoli, and capillary leakage After entry, legionellae reside within a nascent phagosome (Fig. results in edema.64 Chemokines and cytokines released by infected 232.3) that does not fuse with endosomes or lysosomes,85–87 thereby macrophages help trigger the severe inflammatory response. In the avoiding acidification and degradative enzymes. The phagosome subverts mouse model of LD, the relevant proinflammatory chemokines and host vesicles in the early secretory pathway using proteins produced cytokines include keratinocyte-derived chemokine (KC), macrophage by Lp.88 The vacuole containing Lp rapidly recruits membrane from the inflammatory protein-2 (MIP-2), tumor necrosis factor-α (TNF-α), endoplasmic reticulum and develops into an organelle that resembles interleukin (IL)-12 and IL-18, and interferon-γ (IFN-γ).65 Humans with the host rough endoplasmic reticulum.89–91 This specialized Legionella- LD had elevated levels of TNF-α and IL-8 in relation to other bacterial containing vacuole supports intracellular replication. This vacuole pneumonias in one study.66 Systemic spread of the bacteria may be expands during replication and ultimately fills the host cell. Upon nutrient accomplished by infection of circulating monocytes. depletion (e.g., amino acid depletion), Lp enters stationary phase and The mechanisms for systemic toxicity of the disease are unclear, but converts to a flagellated form that is primed to seek out and infect new it involves the severe inflammatory response to virulent Lp. Cytokine host cells.55,92 Egress of Lp from the expended host cell is not well production is mediated by detection of microbial products by receptors understood, but in macrophages this involves pathogen-induced apoptosis of the innate immune system. Toll-like receptors (TLRs) on macrophages that leads to cellular necrosis.93,94 and other cells initiate host responses to both virulent Lp and avirulent Neither the pathogenesis nor the etiology of PF is known with mutants by detecting common pathogen-associated molecular patterns certainty. PF is caused by inhalation of a disease-causing environmental (PAMPs). TLR2 detects lipoproteins and lipopeptides, TLR5 flagellin, aerosol derived from water containing microorganisms including and TLR9 bacterial DNA.65 Replication of Lp is greater in the lungs of Legionella bacteria. Thirty percent to 85% of patients with this disease mice deficient for TLR2 or the TLR adapter protein MyD88, resulting have serum anti-Legionella antibody in higher concentrations than is in higher mortality; and mice lacking TLR5 or TLR9 have delayed found in the normally healthy population.95 The prevalent assumption innate immune responses but disease susceptibility is not as pronounced is that the illness is caused by inhalation of the Legionella bacteria. Since 2810 prolyl isomerase that is required for the early stages of intracellular infection and for full virulence in animals.102–104 Legionella LPS contains some endotoxic activity, and changes in LPS have correlated with increases s in serum resistance, intracellular growth, and virulence.105 Finally, the ent rcp gene, which appears to encode a lipid A–modifying enzyme, confers g resistance to cationic peptides and promotes macrophage and lung 106 ic A infection. g Lp secretes a variety of proteins, degradative enzymes, and putative toxins. The release of proteins yb Lp into the extracellular milieu is tiolo E mediated primarily by a type II secretion system.107 Genome sequencing also suggests the existence of type I and type V secretion systems.108 A number of enzymes and novel proteins are all secreted via the Legionella type II system.107 Mutations within the genes encoding the type II secretion system diminish infectivity for macrophages, protozoa, and animals.109,110 A secreted zinc protease is produced during infection and promotes pathology in the guinea pig model of disease as well as intracellular infection of some amebae hosts.111,112 A Legionella type IVb secretion system called Dot/Icm is essen- tial for intracellular replication and virulence in animal models of disease.113,114 It is essential for the ability of the Legionella parasite to ectious Diseases and Their f modulate host vesicular transport to avoid delivery to lysosomes and

In FIG. 232.3 Electron micrograph of L. pneumophila growing within promote vacuole biogenesis. Mutations in dot/icm loci lead to loss of I a phagosome of an alveolar macrophage. Note the characteristic 115,116 ribosomal studding of the phagosome. virulence. More than 300 proteins are secreted by the Dot/Icm system and in most cases these “effector” proteins translocate from the 114 Part II Legionella-containing vacuole into the host cell cytoplasm. Some of the aerosols contain a mixture of microorganisms and endotoxins, it these have been implicated in bacterial evasion of lysosome fusion.117–119 is unclear whether the disease is due to inhalation of endotoxin, of a Others, such as RalF, DrrA (SidM), LepB, LidA, and SidJ, play roles polymicrobial aerosol, or of Legionella bacteria alone or to a combination in the recruitment of endoplasmic reticulum–derived membranes to of all these agents.95 A study of the virulence for guinea pigs of the Lp the Legionella-containing vacuole.120–123 The effector SdhA is important strain that caused the 1976 Philadelphia LD epidemic and the PF for maintaining the integrity of the vacuole in which Lp resides,124 and environmental isolate from the Pontiac, Michigan, epidemic showed effectors SidF, SidP, and LepB directly modulate phosphatidylinositol no differences between the two bacterial strains.96 The incubation period phosphate signatures on the cytosolic surface of the vacuole that are of 4 to 6 hours of some PF patients supports a toxin-mediated illness, important for the binding of other effectors.125 Lp expresses several while the median incubation period of around 35 hours is more suggestive effectors that function as glucosyltransferases that are capable of inhibiting of initial bacterial multiplication causing illness. Infections with non- host cell protein synthesis (elongation factor 1A).126,127 Although Dot/Icm Legionella bacteria can produce Legionella antibodies, so the presence is essential for Lp infection, a second type IV secretion system known of such antibodies does not prove that PF is due solely to Legionella as Lvh is found in addition to Dot/Icm in many strains; however, this infection or intoxication. Bath water fever, a clinical syndrome thought system does not appear to deliver effector proteins into host cells but to be due to endotoxin inhalation, is very similar to PF, suggesting that retains the ability to promote DNA conjugation, which could facilitate PF may also be caused by endotoxin inhalation.95 Several reports exist horizontal transfer of genes encoding effectors.128 Interestingly, many of in which exposure to the same environmental source led to PF in most the type II and type IV secreted proteins as well as other mediators of exposed people, but to LD in a few people; whether the milder illness infection (e.g., LpnE and Lpg0971) bear striking sequence similarity to was really PF or mild LD is open to question, and does not help answer eukaryotic proteins, suggesting that they were acquired by horizontal gene the question of etiology and pathogenesis.95 Perhaps the strongest transfer from a eukaryotic host and use similar biochemical activities evidence implicating systemic infection with Legionella bacteria as the to facilitate Lp infection.108,117,129–134 cause of PF has been the very rare reports of positive Lp urinary antigen Several infectivity factors have been localized to the Lp periplasm tests or positive cultures in patients with PF.95 The rarity of such cases or cytoplasm. A Cu-Zn superoxide dismutase resides in the periplasm, and the rapid recovery without antibiotic therapy argue against systemic affording resistance to toxic superoxide anions, and the KatB catalase- infection as the cause of PF. peroxidase is needed for optimal intracellular infection.135,136 The Legio- nellaa phosphoenolpyruvate phosphotransferase and HtrA protein promote Legionella pneumophila Virulence Factors intracellular growth and virulence, and the phosphotransferase regulates Studies of Lp grown in mammalian eukaryotic cells and in its natural expression of the transcriptional activator PmrA.137–139 Lp iron acquisition, environmental host, free-living amebae, show that the bacterium changes important for intra- and extracellular replication, involves, among other dramatically within cells as the intracellular infection progresses, things, a secreted ferric iron chelator (the siderophore legiobactin), a becoming very small and highly motile as the cell loses its ability to secreted pyomelanin with ferric reductase activity, and an inner mem- sustain bacterial multiplication. These small motile forms, termed the brane ferrous iron transporter (FeoB).140–143 “transmissive” type of bacteria, have increased virulence for eukaryotic In addition to the identification of eukaryotic-like proteins in the cells. Once inside the cells, a nonmotile “replicative” phase predominates. Lp genome, another outcome of sequencing bacterial genomes is the The transmissive bacteria can be produced in vitro under nutrient-limiting realization that there are large segments of DNA, including plasmids conditions. Multiple bacterial factors control this transition between and chromosomal “islands”, that can vary between Lp strains.108,144–146 the transmissive and replicative phases, with some of the most important It is possible that these variable regions of the genome will help explain ones being production of ppGpp and activation of LetA/S and RpoS. differences in virulence that may exist between strains. Indeed, large CsrA plays an important role in the posttranscriptional regulation of deletions of the chromosome that remove individual islands can decrease this process.97,98 Lp replication in specific protozoan hosts.147 A variety of surface structures have been implicated in Lp patho- genesis. Type IV pili modestly promote bacterial attachment to mac- Virulence Factors and Pathogenesis of Other rophages and epithelial cells,99 and flagella promote invasion independent Legionella Species of adherence.100 The major outer membrane protein is a porin that also Relatively little is known about the virulence mechanisms, molecular serves as a binding site for complement components and thus mediates pathogenesis, and cell biology of infections caused by Legionella spp. opsonophagocytosis.101 The Mip protein is a surface-exposed peptidyl other than Lp. With the major exception of Llb, infections caused by 2811 the other Legionella spp. are rare and found almost exclusively in severely cases of LD occur annually. The incidence of LD causing community- immunocompromised patients. Genome sequencing of 38 different acquired pneumonia not requiring hospitalization is not known. One Legionella species revealed that there are over 5000 different effector small regional US study estimated that the incidence of LD among Cha proteins encoded by the genus and only seven Dot/Icm effector proteins outpatients treated for pneumonia was 40 to 280 per million population 148 170 that are shared by all species. Thus effector plasticity, which facilitates per year. Thus somewhere between 18,000 and 88,000 cases of LD p adaptation of Legionella to different environmental hosts, likely influences are estimated to occur per year in the United States, the majority of ter 232 human virulence potential. Despite unrestricted growth in otherwise which are neither epidemic nor hospitalized. A German study of nonpermissive macrophages, some non-Lp species fail to promote community-acquired LD found that the annual rate was 180 to 360 inflammatory cell death,149 which could be correlated to a failure to cases per million population, which if extrapolated to the United States Legionnaires’ Disease and cause disease in nonimmunocompromised people, although this is would mean that 56,000 to 113,000 LD cases occur per year in the unstudied. Llb resides within a ribosome-studded phagosome, albeit United States.171 Some geographic regions appear to have more LD than with markers of late endosomal maturation, unlike Lp, which is able others.63 The incidence of LD in the United States and elsewhere appears to block endosomal maturation at an early stage.150–152 In contrast, L. to be increasing, based on the numbers of reported cases; whether this micdadei resides in a smooth phagosome, and morphologic data suggest is due to more widespread use of the urine antigen test, better reporting L. dumoffii grows within the cytoplasm rather than in a phago- and surveillance, or a true disease increase is unknown.172 Estimates of some.150,153–155 Analysis of the genome of several different Llb strains LD as a cause of community-acquired pneumonia requiring hospitaliza- has shown that this species has and utilizes the Dot/Icm system for tion in adults range from 0.5% to 10% of all admitted pneumonia cases; P causing infection, that it is nonflagellated, and that it possesses a wide an average value is probably approximately 2%, even in geographic ontiac Feve range of eukaryotic effectors different from those found in Lp.156,157 regions with excellent diagnostic capabilities.173–177 Many of the Llb effectors appear to have been derived from plants and LD in children is uncommon, representing 1% or less of causes of soil organisms, suggesting that it has evolved as primarily a soil-adapted pneumonia, and occurs as a nosocomial disease of immunosuppressed bacterium. Experimental virulence of Llb for macrophages appears to children, and in neonates.178 Nosocomial and domestically acquired r be relatively independent of growth phase, in contrast to Lp,151,158 and cases of LD have been reported in apparently immunologically normal studies in mice and explanted human macrophages show that host newborns exposed to Legionella-contaminated water in incubators and antibacterial cytokines are suppressed.157 bath tubs, and during birth.178–180 Shortly after the 1976 Philadelphia outbreak, nosocomial LD outbreaks EPIDEMIOLOGY were reported in several cities throughout the United States and Europe. IncubationIncubation PeriodPeriod and Contagiousness Because relatively little was known about the environmental ecology The incubation period during most outbreaks of LD is between 2 and of Lp, or about optimal diagnostic methods, these outbreaks were 10 days, with up to 10% of epidemic cases having incubation periods characterized by long durations, often years in length, and high numbers longer than 10 days. The median values are 4 to 6 days, with some of cases and fatalities. For example, the LD outbreak at the Wadsworth outliers of from 1 up to 28 days.1,159,160 A 2-month incubation period Veterans Administration Hospital in Los Angeles, California, resulted was reported for one nosocomial case.161 The incubation period of PF in more than 250 cases of disease in both patients and visitors over an is from 4 hours to 3 days, with a median of around 32 to 36 hours, 8-year period.16,23,181 Nosocomial LD epidemics continue to occur although incubation periods of up to 5 days have been reported.7,162,163 worldwide, albeit with durations measured in weeks rather than years.182,183 The incubation period of LD due to Legionella species other than Lp Nosocomial pneumonia usually affects a relatively small number of is not known with certainty; based on case reports from nosocomial hospitalized patients, with attack rates less than 1% of patients.16,184 cases of the disease, the incubation period after onset of immunosup- During nosocomial outbreaks of LD, the minority (5%–11%) of patients pression appears to similar to that of LD due to Lp.164 with nosocomial pneumonia of all etiologies have been reported to Person-to-person transmission of LD or PF does not occur. A report have LD.16,185–187 of “probable” person-to-person transmission, the only such case ever Some recent large community-based LD outbreaks have been in reported, lacked sufficient scientific evidence to support this conclusion.165 New York City in 2015 (138 people, 16 deaths) and Flint, Michigan, in Laboratory transmission to humans has not been documented. 2015 (91 people, 12 deaths). Several large outbreaks involved people visiting a town center, rather than being inside a certain building. Patterns and Rates of Disease Long-distance spread of disease from industrial aerosols has been and Mortality reported.25,188 LD occurs in both sporadic and epidemic forms. For the years 2013–2014, LD affecting travelers constitutes up to half of reported cases in about 3% of reported US cases were clustered, whereas in England and some countries. In many cases, a common source outbreak has been Wales from 2013 to 2015, about 20% of reported cases were clustered.166–168 found, but for others the cases appear to be sporadic. Multiple common About 2% of reported cases are health care associated. In England and source outbreaks have been uncovered in travelers by a cooperative Wales for the same time periods, 40% of cases were acquired while European reporting system that collects and analyzes LD cases in traveling abroad. In the United States, about half the clustered cases Europeans.189 were acquired by exposure to contaminated drinking water and the Sporadic cases of the disease are about 5-fold to 20-fold more common remainder by exposure to environmental water, such as from cooling than linked cases of the disease. Some sporadic cases are undoubtedly towers. Underreporting of the disease is likely because of empirical the result of common source exposures. This is especially true of travelers treatment without laboratory testing, insensitive diagnostic tests, and who return to their homes during the incubation period, or while they the use of passive surveillance systems. Only 5166 cases of LD were are ill but still well enough to travel. Evidence for common source links reported in 2014 (16.2 per million population) to the Centers for Disease for apparently unrelated cases comes from observations that proximity Control and Prevention (CDC). This rate is lower than that reported of residence to wet cooling towers is a risk factor for LD.190,191 Residential in Denmark, France, and Portugal in 2014, with 28.1, 20.5, and 56.4 acquisition from drinking and bathing water, which rarely results in cases per million population, respectively, and higher than that reported more than a single case, accounts for less than 10% to 15% of sporadic for England and Wales (5.8 per million).36 LD.192–194 Prospective studies of both sporadic community-acquired and The reported incidences of LD in the United States rose almost nosocomial LD have reported far more cases in the United States than fivefold from 2000 to 2016 (19 per million per year), and almost twofold would be expected based on the number of cases reported to the CDC. from 2006 to 2016. The relative contributions of increased testing, aging One study in Ohio of adults with community-acquired pneumonia of the population, increased immunosuppression of the population due requiring hospitalization found that 2.4% of such patients had LD, and to advances in medical care, and global warming are uncertain. that the disease incidence was approximately 80 per million population PF often causes explosive outbreaks of disease with high attack rates. per year.169 When extrapolated to the entire population of the United Attack rates of 70% to 90% have been reported from several States, the authors estimated that between 8000 and 18,000 hospitalized epidemics.7,162,195–197 2812 LD mortality rates are variable, ranging from less than 1% to as high A wide range of nosocomial exposures can result in LD. Almost all as 80%, depending on the underlying health of the patient, promptness involve delivery of Legionella-contaminated water into the respiratory of specific therapy, and whether the disease is sporadic, nosocomial, tract, and include the use of tap water filled or rinsed nebulizers, s or part of a large outbreak.30,198–201 The lowest mortality rates (approxi- humidifiers, oxygen humidifiers, ventilator tubing, and nasogastric 223–226 ent mately 1%), were observed in large outbreaks of the disease, whereas feedings or lavages. Proximity to a contaminated decorative fountain g the highest mortality rates were reported in untreated nosocomial disease has transmitted nosocomial LD in several outbreaks.26,227 Consumption 202 ic A in patients with severe underlying diseases. The average fatality rates of Legionella-contaminated ice can also be a risk factor for nosocomial g for sporadic disease are estimated to be approximately 10% to 15%. LD.228 These are in addition to exposure to Legionella-contaminated air Fatality rates of nosocomial disease have declined by more than 50% originating from a cooling tower.229–231 Rare cases of nosocomial Legionella tiolo E in the United States over the last 20 years; a similar but less dramatic wound infection have resulted from irrigation or bathing of wounds decrease in death rates of community-acquired cases has also been in Legionella-contaminated water.232,233 observed.30 The decline in mortality rates appears to be due to better and faster disease recognition and more widespread use of LD-effective Modes of Transmission empirical therapy for pneumonia.30,202 LD is transmitted from the environment to humans by inhalation of an infectious aerosol.234 In an unknown fraction of cases microaspiration Risk Factors of contaminated water into the lungs is the mode of transmission.226,235 Because of the ubiquity of Legionella spp. in our natural and man-made Multiple examples of exclusive aerosol transmission of LD exist, environments, most people encounter these bacteria frequently. Yet especially in epidemics having a cooling tower, water spa, water fountain, most of those exposed do not get the disease. This is attributed to largely or water mister as the source of disease.1,219,229,230,236–238 Drinking of water unknown host immune mechanisms and to the lack of sufficient at the epidemic site has not been demonstrated to a be risk factor ectious Diseases and Their f concentrations of virulent Legionella spp. bacteria in small aerosol for LD. In particles. The known host risk factors for LD are those that result in The data supporting microaspiration of water as a major mode of I decreased local or systemic cellular immunity, and those activities that transmission are less convincing. These data include examples of noso- increase the chances of exposure to an infectious aerosol or microaspira- comial disease in patients whose major risk factor was nasogastric tube

Part II tion of contaminated water. Also important are environmental and irrigation with tap water, and interruption of nosocomial outbreaks by bacterial factors such as relative bacterial virulence, bacterial aerosol substituting sterile water for tap water for drinking and nasogastric stability, organism growth conditions, and factors that facilitate the tube irrigation.226,235 Whether microaspiration is the major transmission spread of the bacterium from contaminated water to the host, such as mode for nosocomial disease is controversial and unproven.239 wind direction, relative humidity, and aerosol formation. Rare reports of peritonitis or bowel abscesses caused by Lp have Male gender, cigarette smoking, chronic heart or lung disease, diabetes, led to speculation that oral ingestion may be a mode of disease end-stage renal failure, organ transplantation, immunosuppression, transmission.240–242 In all these cases, Lp pneumonia or empyema occurred some forms of cancer, and age greater than 50 years are LD risk concurrently, making unclear which organs were the ones primarily factors.184,193,203,204 The approximately twofold greater risk for men may infected. It is very unlikely that oral ingestion of Legionella-contaminated be due to the greater prevalence of cigarette smoking and its complications water is more than a very minor mode of transmission of the disease. in males. As the population ages in developed countries, LD incidence will rise, based on the very high attack rates in the elderly, in the range Outbreak Investigation of 800 to 1500 per million per year for those age 80 years and older.32 Prompt notification of public health authorities of any strongly suspected Poverty, at least in large cities, is a risk factor for LD.205 There may be or confirmed case of LD is critically important for detecting epidemics racial disparities in LD incidence, with African Americans having a of the disease, and is legally required in many regions. What appears higher attack rate than whites, even after accounting for socioeconomic to be only a single case of the disease may be part of an epidemic, or status.205,206 Cigarette smoking and glucocorticoid administration both the index case. separately increase risk by approximately twofold to sevenfold. Medical institutions should embark on extensive investigation of Anti-TNF-α therapy is a significant risk factor for LD, especially including even a single case of nosocomial LD.243 More cases may have occurred TNF-α antibodies, but also thalidomide and lenalidomide.207,208 previously, or will appear subsequently. Retrospective review of noso- Anti-CD52 therapy can result in severe LD.209 Lung, but not gastro- comial pneumonia cases for a 3- to 6-month period may yield more intestinal tract, cancer is an LD risk factor.203 A variety of hematologic cases. Prospective laboratory testing of all patients with nosocomial malignancies have also been shown to be important risk factors, especially pneumonia for LD for a 3- to 6-month period also can be useful. Hospital hairy cell leukemia.185,203 Small single studies of genetic predisposition physicians should be notified to consider LD when making diagnostic to LD have shown that polymorphisms in TLR4, TLR5, and mannose- and therapeutic decisions in patients with nosocomial pneumonia until binding lectin produce minor predispositions to the disease.67,69,210,211 it is clear that any ongoing nosocomial outbreak has been eradicated. Recent surgery has been an important risk factor for nosocomial Investigation of both community-acquired and nosocomial outbreaks disease.212,213 Alcoholism is a predisposing condition in only some of LD requires a thorough epidemiologic investigation. Environmental studies.184,185,193,214 Host risk factors for non-Lp LD appear to be similar testing without concurrent epidemiologic investigation can result in to those for Lp infection; most patients with these infections are misleading findings, even when molecular fingerprinting is used to immunosuppressed or have cancer, with the exception of LD due to compare clinical and environmental isolates.244–247 Not all environmental Llb.215,216 There appear to be no predisposing host factors for PF. microbiology companies are competent in the proper collection, Activities that increase the chances of exposure to Legionella bacteria processing, and culturing of water specimens for Legionella spp. bacteria; in water increase the risks of disease acquisition. Recent overnight certification is required in some countries, with a voluntary certification travel, use of well water in the home, recent plumbing work inside program available in the United States.248 It is crucially important to the home, disruptions of water supply resulting in “brown” water at obtain Legionella bacteria clinical isolates as part of an epidemiologic the water tap, and living in a water distribution network with older investigation; this allows molecular fingerprinting and comparison of plumbing all increase the acquisition risk of community-acquired clinical and environmental isolates. Environmental sampling protocols LD.191,193,194,217,218 Increased risk activities include exposure to whirlpool for outbreak investigation are available.249,250 or hot spring spas; living close to a cooling tower; and being near Rough clues to the environmental source of an LD epidemic can be decorative fountains.190,191,204,219,220 Rarely reported risks are near- found in the pace of the outbreak and its geographic distribution. drowning10,44,220,221 and delivery by water birth.222 Exposure risk factors Explosive outbreaks involving tens to hundreds of people over a several- for LD due to Llb are much different than for Lp infection, with handling day period are most often due to a contaminated massive aerosol genera- of potting soil or compost, cigarette smoking, chronic obstructive tor, usually a cooling tower but sometimes a whirlpool spa or misting lung disease, and not washing hands after use of the soil being major device. Potable water–associated outbreaks may produce as many cases, risk factors.49 but generally over a much longer period of time, such as many weeks 2813 or months. Cooling tower–related epidemics often affect both building such as drug therapy. Symptoms of rhinorrhea, chronic afebrile fatigue, visitors and people who are within several hundred meters up to a and fever without pneumonia lasting for many weeks are either not 10-km distance from the tower.25 seen or so rare as to make the diagnosis unlikely. Cha Nonspecific laboratory test abnormalities may occur in LD270 that

Environmental Decontamination are consistent with having a severe case of pneumonia. These include p for Outbreaks hyponatremia, hypophosphatemia, increased liver-associated enzymes, ter 232 All aerosol-generating sources implicated or highly suspected of being hyperbilirubinemia, leukopenia, thrombocytopenia, disseminated a source of epidemic LD should be taken out of operation as soon as intravascular coagulation, leukocytosis, pyuria, elevated creatine kinase, possible. A number of guidelines exist for emergency disinfection of and elevated lactate dehydrogenase. Patients with LD are more likely Legionnaires’ Disease and such sources, and these may differ according to local regulations or to have hyponatremia than do those with other causes of pneumonia, guidelines.249–251 Long-term remediation can be complex and requires but the range of serum sodium values is too broad for this abnormality expert engineering and public health advice. to be diagnostic in an individual patient.271 Laboratory markers of pancreatitis are detected if this is a complication of LD. Renal disease CLINICAL PRESENTATION caused by LD may result in the presence of urine casts and white blood LegionnairesLegionnaires’ DiDiseasesease cells, elevated serum creatinine levels, or both types of abnormalities. LD causes acute consolidating pneumonia that cannot be accurately Myoglobinuria is a relatively common finding as indicated by a positive differentiated from pneumococcal pneumonia based on clinical or dipstick test for “blood” in the absence of significant numbers of red P roentgenographic findings on initial presentation.252–254 Initial clinical blood cells in the urine. ontiac Feve findings of both community-acquired and nosocomial epidemic LD in Clinical diagnosis may be more specific if the patient’s clinical course the 1970s seemed to show that a distinct clinical syndrome was after treatment has been given is taken into account, and if epidemiologic observed.255 This syndrome was characterized by fever with pulse- and immunologic risk factors are considered. The chances of a patient temperature dissociation, myalgia, nonproductive cough, few pulmonary having LD are increased if an acute consolidating pneumonia fails to r symptoms, diarrhea, confusion, hyponatremia, hypophosphatemia, and respond to several days of β-lactam antimicrobial therapy, or if the elevated liver-associated enzymes. While this symptom complex does pneumonia is severe enough to require intensive care unit hospitalization. occur in LD, it is neither specific nor frequent enough to allow differentia- Important epidemiologic clues include use of a hot tub or recreational tion of LD from other common causes of community-acquired spa; travel outside the home for one or more days; recent pneumonia pneumonia. Clinical scoring systems to help increase diagnostic accuracy of a coworker, fellow conference attendee, or fellow traveler; and recent have not performed well enough to be used to guide proper therapy.256–258 plumbing work done at home or work. The clinical findings of non-Lp LD do not differ significantly from The nonspecific presentation of LD can make clinical diagnosis very those caused by Lp.216,259 Llbb LD occurs predominantly in nonimmunosup- difficult, and mandates empirical therapy for this disease in most patients pressed patients, whereas the reverse is true for LD caused by the other with community-acquired pneumonia of uncertain etiology. Diagnosis non-Lp Legionella spp.33 Those with immunosuppression and non-Lp of the index or sporadic case of nosocomial LD is difficult because of LD tend to have a more severe course and greater likelihood of non- the rarity of nosocomial LD in most hospitals, and because laboratory pulmonary LD, but this is similar to the findings of immunosuppressed testing for nosocomial LD is uncommon in such settings. patients with Lp LD. A prodromal illness may occur, lasting for hours to days, with Extrapulmonary Infections symptoms of headache, myalgia, asthenia, and anorexia. Fever accom- Extrapulmonary infections are rare and usually occur as metastatic panies this prodrome, except in severely immunocompromised patients complications of pneumonia in immunocompromised patients. Metastatic and sometimes in the elderly. Multiple rigors may occur, as well as infection has been reported almost exclusively in immunocompromised diarrhea and abdominal pain. Cough, with or without chest pain, may patients, or patients with fatal LD, who may develop abscesses and develop hours to days after onset of the prodrome; the cough produces other infections of the brain, the spleen or extrathoracic lymph nodes, purulent sputum in only approximately 50% of patients. The initial and skeletal and myocardial muscles.272–276 Other reported sites of clinical picture may be confusing because the systemic symptoms can metastatic infection have been the intestines and liver, the kidneys, the be more impressive than ones referable to the lower respiratory tract, peritoneum, the pericardium, vascular shunts and grafts, bone marrow, leading some physicians to diagnose “influenza”, ag astrointestinal illness, joints, surgical wounds (including those related to prosthetic heart valves “sepsis”, and in some cases an acute abdomen syndrome. These prodromal and the aorta), native heart valves, the perirectal area, and the skin and symptoms escalate in severity as the disease progresses, which may subcutaneous tissues.240,277–288 Both reported cases of culture-confirmed result in a several-day delay before presentation; the median time to native valve endocarditis were in immunocompromised patients with presentation after onset of illness is approximately 4 days.260 Careful LD.288,289 In some of these cases the onset of symptoms of the metastatic physical examination of the chest, and chest roentgenography, almost infection preceded the recognition of pneumonia by several days, and always demonstrates findings of consolidating pneumonia.261,262 Chest in other cases the metastatic infection presented days to weeks subsequent computed tomography findings include ground-glass opacities and to onset of the pneumonia. A metastatic infection site may be the only consolidation.263,264 Pleuritic chest pain, sometimes in concert with evidence of relapse of infection. Three cases of metastatic infection have hemoptysis, can occur and may result in an incorrect diagnosis of been reported in apparently previously healthy patients,274,290,291 but pulmonary infarction. Headache may be the most prominent feature, otherwise immunosuppression is found in such patients. and so severe as to suggest subarachnoid hemorrhage. Mental confusion Very rare cases of primary infection not preceded or accompanied is commonly reported; obtundation, seizures, and focal neurologic by pneumonia have been reported. Some of these appear to be the findings occur less frequently.265–267 Some patients may have negative result of direct inoculation of Legionella-contaminated water into various chest x-ray films on presentation but chest films taken a yda later may tissues, usually in hosts with immune compromise. Some infections were show focal or diffuse pulmonary infiltrates; as with other causes of introduced by bathing postoperative patients with contaminated tap water, community-acquired pneumonia, plain chest films may be less sensitive by the use of therapeutic baths, and by inadvertent tap water irrigation than chest computed tomography examination at presentation.268 Lung of the mediastinum after esophageal perforation. Culture-proven sites cavitation is seen almost exclusively in immunosuppressed patients.269 of such infections have been surgical or other wounds, subcutane- Pleural effusion without pulmonary infiltrates is rarely observed. ous tissues, prosthetic and native joints, prosthetic heart valves, the Bronchoscopic findings in LD patients are often remarkable for the mediastinum, and the respiratory sinuses.232,233,286,291–303 In contrast to the absence of inflammation or purulent secretions in the large airways. case of native valve endocarditis, almost all patients with prosthetic valve Abdominal examination may reveal generalized or local tenderness endocarditis were neither immunosuppressed nor had LD.292,293,296,297,304–306 and, in rare cases, evidence of peritonitis. Splenomegaly is uncommon. Native and prosthetic joint infections have been reported uniformly Findings of pericarditis, myocarditis, and focal abscesses are rare. No in immunocompromised patients with preexisting arthritis, with one rash is associated with this disease, except that caused by other factors exception of a patient who was not immunocompromised but did have 2814 underlying arthritis.286,291,301–303,307 With one exception all joint infections culture for Legionella should always be performed regardless of the occurred in the absence of LD. Polymerase chain reaction (PCR)–positive, results of an antigen or PCR test. Many clinical laboratories have neither but culture-negative, meningoencephalitis has been reported in patients the expertise nor the ability to properly perform these specialized s without LD.308 cultures. ent Urine antigen testing is the most common laboratory test ordered g Pontiac Fever for LD diagnosis.30,311 This very specific test is easily performed by those ic A PF is a self-limited, short-duration febrile illness, usually diagnosed without special skills and is often positive when other tests are negative. g only during an outbreak of the disease.7,95,162,163 Symptom onset is 4 to The test is not perfect because it is most sensitive for the detection of 60 hours after exposure to a bacteria-contaminated aerosol, either in a the Pontiac subtype of Lp1 (up to 90%), less sensitive for other monoclonal tiolo E workplace or some other group setting. More than 80% to 90% of exposed antibody types of Lp1 (60%), and very poorly sensitive (<5%) for other people become ill. Unlike LD, children commonly get the disease.95,162,163 Lp serogroups and other species.312 Since the majority (approximately The sources of contaminated aerosol have included industrial processes 90%) of cases of community-acquired LD are due to the Pontiac subtype, using sprayed water, recreational spas, decorative water fountains, and the average sensitivity of this test is in the range of 70% to 80%. cooling towers. Fever, myalgia, headache, and asthenia are the dominant Immunocompromised patients, patients with nosocomial LD, and patients symptoms. Cough, dyspnea, anorexia, arthralgia, and abdominal pain in some geographic regions are more likely to have LD caused by other occur less frequently. Most patients are not ill enough to seek medical serogroups and species, and hence a negative urine antigen test.313 Yield attention, recovering without specific therapy 3 to 5 days after disease can be increased by urine concentration, and for one assay type by onset. There is little information about physical examination findings prolonging the incubation time. Rare false-positive tests may be due in the first day of illness; examination 2 to 5 days after onset may show to rheumatoid-like factors, easily inactivated by boiling; most laboratories fever and tachypnea. Pneumonia does not occur. Fatigue and nonfocal do not use an inactivation step. A common clinical error is to order ectious Diseases and Their f neurologic complaints may persist for up to several months in the only urine antigen testing and to stop therapy for LD if the urine test In minority of affected patients.7 Because the clinical findings are nonspecific, is negative, because the urine test can be insensitive. Positive tests are I it is very difficult, if not impossible, to accurately diagnose this disease associated with more severe disease.214 Patients with extensive bilateral in the absence of similar illnesses in coworkers or others with a common LD may excrete urinary antigen for weeks to months after recovery;

Part II source exposure. Inquiries regarding the health of coworkers and this should not cause confusion over whether a positive test is the result acquaintances may help to confirm the diagnosis, but this can be of new or old pneumonia in the absence of a history of recent hospitaliza- nonspecific and insensitive.309 tion for severe pneumonia. Antibody detection is insensitive and of low specificity unless paired LABORATORY DIAGNOSIS acute and convalescent sera are tested.314 For optimal yield, convalescent Specific,Specific, butbut rrelativelyelatively ininsensitive,sensitive, teststests aare available for the diagnosis sera should be collected at 4, 6, and 12 weeks after disease onset. Only of LD (Table 232.1). Culture yield depends on the severity of illness, approximately 75% of patients with culture-proven LD will seroconvert with the lowest yield (15%–25%) for mild pneumonia and the highest at all, even with optimally timed and tested sera. Commercially available yield (>90%) for severe pneumonia causing respiratory failure.38 Prior serologic tests lack specificity or sensitivity because of deviations from specific antimicrobial therapy affects yield adversely, although some the standardized test methods. Only seroconversion to Lp1 is of high patients have positive sputum cultures for days to weeks after initiation enough specificity for clinical use; measurement of antibodies to other of specific therapy. Expectorated sputum or, even better, endotracheal serogroups and species is plagued by low specificity and is not aspirates are good specimens for culture; neither bronchoscopy nor recommended. lung biopsy is required for good culture yield, assuming a good-quality Detection of Lp in respiratory tract tissues and fluids using immu- sputum specimen is obtained. Sputum Gram stain is insensitive. Legionella nofluorescent microscopy (direct fluorescent antibody [DFA] test) is micdadei, and rarely Lp, may be acid fast or weakly acid fast.310 Sputum very specific if a monoclonal antibody to this species is used and the cultures may be positive despite the presence of epithelial cells and lack test is performed by experts.315 Use of other reagents, or testing by of leukocytes, making suspicion of LD an exception to the usual sputum nonexperts, can result in many false-positive test results. The test is adequacy screening criteria. Blood culture is positive in approximately insensitive. Most laboratories do not perform this test because of its 10% of critically ill or severely immunocompromised LD patients, and low yield and complexity. DFA staining can be useful for the detection in most patients with prosthetic valve endocarditis; specialized culture of LD in fixed lung specimens. techniques are required to detect the bacteremia. Culture diagnosis is Molecular amplification (PCR) and detection of Lp and non-Lp not dependent on Lp serotype or on Legionella spp., a fault of all of species is available at reference and public health laboratories.38 No antibody and urine testing. Culture is also often the only test positive commercial PCR test approved by the US Food and Drug Administration in cases of LD caused by other Legionella species. Culture media and is marketed in the United States. Most evaluations have shown that the selective conditions are optimized for the detection of Lp, with unknown molecular methods are about as sensitive as culture, with more recent performance for the detection of non-Lp species. Since a clinical isolate studies showing that molecular methods are approximately 30% more may be required for complete investigation of the source of an outbreak, sensitive than culture. The addition of PCR testing for Lp and Legionella

TABLE 232.1 Specific Diagnostic Tests for Legionnaires’ Disease Caused by Legionella pneumophilaa TEST SPECIMEN TYPES SENSITIVITY SPECIFICITY NOTES Culture Sputum, other lower respiratory tract secretions; lung; 20%–95% 100% May be positive up to several days after pleural fluid; blood; extrapulmonary tissues, fluids treatment; requires special media and expertise Antigenuria Urine 60%–95% >99% Highest sensitivity for L. pneumophila serogroup 1, Pontiac type; may remain positive for days to months Immunofluorescent Same as culture 20%–50% 99% Highest specificity with monoclonal antibody; microscopy requires very high level of technical expertise Antibody Paired serum 20%–70% 95%–99% Highest specificity for L. pneumophila serogroup 1 Molecular Sputum, other lower respiratory tract secretions; urine 70%–95% 95%–99% Excellent performance in some reference amplification laboratories aPertains only to L. pneumophila infections. The yield of diagnostic tests is lower for infection caused by other species, especially those tests based on immunoassay. 2815 spp. increases diagnostic yield by 10% to 100% over that for urine a tetracycline should not be used for the therapy of LD caused by this antigen testing, and appears to be most useful for the diagnosis of species, and that in regions where Llb infection is common tetracyclines milder cases of the disease and for the detection of Llb infection.316 A are not drugs of choice for the empirical therapy of community-acquired Cha genus-specific PCR test, which can detect all known Legionella spp., pneumonia suspected to be LD. None of the β-lactams, monobactams, 199 can be quite useful for testing specimens from immunocompromised aminoglycosides, or phenicols is active for LD. p and other patients who may not be infected with Lp. Some studies have Prospective adequately sized clinical trials of antimicrobial therapy for ter 232 reported nonspecific PCR results; some reagents and nucleic acid LD have not been performed.199,257,321 Patients treated with erythromycin extraction kits may be contaminated with Legionella DNA. Use of PCR or a tetracycline drug had significantly lower fatality rates than did those for clinical purposes should only be undertaken for very well-validated treated with β-lactam or aminoglycoside agents in the 1976 Philadelphia Legionnaires’ Disease and and controlled assays, but when they are available these assays can epidemic.1 In one outbreak of nosocomial disease, immunosuppressed increase diagnostic yield. Genetic sequencing of positive PCR products, patients treated with erythromycin had a 24% fatality rate, in comparison or the use of whole-genome sequencing, in the absence of a positive to an 80% rate for otherwise-treated patients, and erythromycin-treated culture, can be used in many cases for species-level identification and nonimmunocompromised patients had a 7% fatality rate in comparison molecular fingerprinting.317,318 to 25% for those otherwise treated.255 Small numbers of patients with Optimal test yield requires performing more than one type of test; LD have been reported to responded very well to erythromycin, a PCR (when available), sputum culture, and urine antigen testing are tetracycline, azithromycin, dirithromycin, clarithromycin, pefloxacin, the preferred tests. If these are negative, and there are clinical or epi- ciprofloxacin, gatifloxacin, and levofloxacin. One retrospective study P demiologic reasons for making a retrospective diagnosis weeks to months of LD with severe pneumonia showed that patients treated with a ontiac Feve later, then antibody testing should be ordered. For patients who may fluoroquinolone antimicrobial agent within 8 hours of ICU admission be more likely to have LD caused by Legionella spp. other than Lp1, had significantly better outcomes than did those treated later, or with the best laboratory tests are sputum culture and PCR rather than urine other drugs, including erythromycin.322 Some more recent uncontrolled antigen and serum antibody testing. studies showed that erythromycin and clarithromycin were inferior to r The yield of all tests except perhaps antibody determination is levofloxacin therapy for LD in terms of hospital length of stay, time diminished by specific therapy, requiring testing before, or within a few to become afebrile, and complications, but not mortality323,324; of note, days, of the start of antimicrobial therapy. Therapy should not be withheld no comparison with azithromycin, the most potent anti-Legionella pending collection or testing of specimens, and should not be stopped macrolide, was performed. Addition of rifampin to levofloxacin led to based solely on the result of a negative laboratory test. worse outcomes than levofloxacin alone in another uncontrolled study.325 One study showed no significant difference in outcome for 104 patients THERAPY AND RESPONSE treated with either levofloxacin, clarithromycin, or azithromycin.326 Two TO THERAPY recent large retrospective, propensity-adjusted studies showed that there LegionellaLegionella bactebacteriaria areare intracellular parasites of monocytic phagocytes. is no significant difference in outcome for hospitalized LD patients This means that all antimicrobial agents efficacious for LD must be treated with either azithromycin or levofloxacin, including in critically ill concentrated and bioactive in the correct subcellular location within patients,327,328 and a third large retrospective study of critically ill patients these cells. The macrolides, quinolones, and tetracyclines all meet these showed that levofloxacin therapy reduced mortality in comparison to criteria for Lp infection. Some of the non-Lp bacteria (e.g., L. dumoffii, non-azithromycin macrolides.329 Combination antimicrobial therapy L. feeleii, L. jordanis) are known not to reside in a phagosome,154 making for LD is not beneficial, even in critically ill patients.329 The available it possible that some of these drugs, which are differentially distributed evidence supports the use of either azithromycin (500 mg daily for 3–7 within cells,319 may be less effective than others for infections caused by days) or levofloxacin (500–750 mg daily for 5–10 days) for hospitalized these Legionella species. Tet(56), a tetracycline destructase that confers patients with LD, with neither erythromycin nor clarithromycin being tetracycline resistance, has been reported to be present and active in preferred therapies (Table 232.2). one strain of Llb.320 Proteins with sequence homology to Tet(56) are Acquired resistance to antimicrobial drugs used to treat LD has not present in other Llb strains, L. clemsonensis, L. massiliensis, L. nautarum, been detected in multiple in vitro susceptibility studies, including in L. feeleii, L. quinlivanii, and L. geestiana; apart from Llb, these other unpublished studies of isolates from patients who had poor responses Legionella spp. either have not been reported to cause LD or are very to therapy. Lp is known to develop drug tolerance when grown in rare causes of the disease. The presence of Tet(56) in Llb suggests that macrophages,330 and studies in guinea pigs show evidence of drug

TABLE 232.2 Preferred Therapy for Legionnaires’ Disease CLINICAL CONDITION FIRST CHOICES DOSAGEa,b SECOND CHOICES DOSAGEa,b Mild pneumonia inpatient or Azithromycin 500 mg qd for 3–5 d Doxycyclinec 200 mg loading dose, then 100 mg bid for outpatient, not immunocompromised or or 10–14 d Levofloxacin 500 mg qd for 7–10 d Erythromycin 500 mg qid for 10–14 d or Ciprofloxacin 500 mg bid for 7–10 d or Moxifloxacin 400 mg qd for 7–10 d or Clarithromycin 500 mg bid for 10–14 d Moderate to severe pneumonia or Azithromycin 500 mg qd for 5–7 d Ciprofloxacin 400 mg IV tid initially, then 750 mg PO bid immunocompromisedd or or for 10–14 d Levofloxacin 500 mg qd for 7–10 d Moxifloxacin 400 mg qd for 10–14 d or or 750–1000 mg IV qid for 3–7 d, then 750 mg qd for 5–7 d Erythromycin 500 mg PO qid for a total course of 21 d aDosage adjustments must be made for some of these drugs for patients with renal insufficiency. Patients with mild disease may be treated entirely with oral therapy, whereas for severely ill patients parenteral therapy is advised until improvement is seen and oral absorption is sufficient. Unless otherwise noted, all dosages given are for either IV or oral routes. bTherapy duration may need to be considerably longer for patients with lung abscesses, empyema, endocarditis, or extrathoracic infection. cDoxycycline should not be used to treat suspected or known L. longbeachae infection. dSeverely immunocompromised patients may require courses of therapy at the high end of the duration ranges given, or even longer. Close clinical follow-up is required to detect possible relapse after antibiotics have been discontinued. 2816 tolerance for erythromycin and several other drugs.331–333 Drug tolerance, examination, and especially by roentgenography, takes considerably possibly due to induction of efflux pumps,334 was thought to be the longer to resolve. It is common to observe apparent increases in the cause of relapses in immunocompromised patients treated with eryth- sizes of the original pulmonary infiltrates despite substantial clinical s romycin, and the overall poorer performance of erythromycin and improvement over the first several days of therapy; this is not a cause 350 ent clarithromycin therapy in critically ill patients. More recently, the for alarm as long as by other measures the patient is improving. g preexistence and emergence of low-level quinolone heteroresistance Complete clearing of the chest roentgenograph may not occur for up ic A during treatment for LD was reported, based on molecular studies during to 4 months after initiation of specific antimicrobial therapy, with the g quinolone and other therapies.335,336 There is also one report of the majority of patients having complete clearing by 2 months.261,351,352 isolation of a clinical isolate with elevated ciprofloxacin and levofloxacin Severely immunocompromised patients, or those with severe pneumonia tiolo E minimal inhibitory concentrations, but the relationship between these requiring artificial ventilation, may take longer to improve after initiation results and the response of the patient to ciprofloxacin therapy is of specific therapy, or may not respond at all because of irreversible uncertain,337 with no apparent outcome difference between those patients acute respiratory distress syndrome (ARDS); Even in such patients many with a heteroresistant population and those without one.335 Since of the systemic signs of infection (e.g., fever) improve, although the quinolone therapy is quite effective for the treatment of LD, and since respiratory failure itself may worsen. dual quinolone-macrolide therapy does not improve outcome in critically Failure to respond to specific therapy for LD should bring into ill patients, it is difficult to suggest combination therapy or nonquinolone question the validity of the diagnosis, the possibility of coinfection or therapy to counter the emergence of resistance to quinolone superinfection, and the possibility of extrapulmonary disease complicating therapy. the LD. Up to 10% of patients with LD have coinfections or superinfec- The decision regarding which antimicrobial agent to administer for tions with other respiratory pathogens or other pathogens, such as LD should be guided by severity of illness, degree of immunocompromise, Pneumococcus, Haemophilus influenzae, Staphylococcus aureus, Entero- ectious Diseases and Their f drug cost, drug toxicity, and drug availability (see Table 232.2). Nonim- bacteriaceae, Listeria, Nocardia, Pneumocystis, Aspergillus, tuberculosis, In munocompromised outpatients with mild LD can be treated with any Cryptococcus, and a variety of viruses.257,353,354 Superinfection with I of the drugs listed in Table 232.2, with drug cost, availability, and toxicity opportunistic pathogens is generally seen in severely immunocompromised being the main deciding factors. Hospitalized or immunocompromised patients and in those in nosocomial LD, whereas coinfection with

Part II patients with LD should be treated with one of the listed quinolones common respiratory pathogens may be seen in patients with community- or azithromycin, unless drug unavailability or cost prevents their use. acquired LD, based on positive blood or sputum cultures at the time Initial intravenous antimicrobial therapy may be required in severely of diagnosis of LD.353–357 Drug fever, pancreatitis, myocarditis, hepatitis, ill patients. Even in such patients, oral antimicrobial therapy can be pericarditis, metastatic infection, and pleural empyema may rarely be used as soon as there is clinical improvement and intestinal drug complications of LD, or its treatment, and causes of prolonged fever or absorption is adequate. Immunocompromised patients treated with poor response to therapy. erythromycin or clarithromycin, with or without rifampin, may suffer Ancillary therapy of LD has not been studied systematically. Cor- relapse days to months after cessation of therapy, especially if the level rection of fluid and electrolyte abnormalities, and hypoxemia, is useful. of immunosuppression is subsequently increased. In cases in which Corticosteroid therapy for LD-caused ARDS is advocated by some,257 severe immunosuppression is chronic, thought should be given to but is of unproven benefit and could be detrimental to control of the continued suppressive therapy with a drug such as azithromycin, which infection.260,358,359 A clinical response to administration of azithromycin has a very long intracellular half-life.298 or a quinolone is mandated before the administration of such immu- The optimal duration of antibiotic therapy for LD has not been nosuppressive therapy, as well as continuation of the antimicrobials determined conclusively.338 Use of short courses of azithromycin (500 mg/ during and after steroid therapy. Corticosteroid therapy may be indicated day), ranging from 3 days to 7 days in outpatients and inpatients, for postpneumonic lung diseases such as cryptogenic organizing respectively, has been very effective, with only one relapse reported in pneumonia, and perhaps pulmonary fibrosis.360–362 Extracorporeal a severely immunosuppressed patient.339–341 Those with extensive membrane oxygenation therapy can be lifesaving in patients with pneumonia or with severe immunocompromise may profit yb longer severe LD.363 administration of azithromycin. Neither erythromycin nor clarithromycin are as active, or persistent in macrophages, as is azithromycin, requiring PREVENTION treatment durations of 14 to 21 (if immunosuppressed) days. Five days ImmunizationImmunization and Chemoprophylaxis of treatment with levofloxacin (750 mg/day) has been shown to be very No human vaccine for LD exists, and prior infection does not necessarily effective without relapses, and as effective as a 7- to 14-day course with prevent reinfection.354 Antibiotic prophylaxis has prevented LD in 500 mg/day.342 Overall, except for severely immunocompromised patients, immunocompromised patients during nosocomial epidemics of the the duration of antibiotic therapy should follow the general guidelines disease.364,365 for all forms of community-acquired pneumonia.343 Rifampin should not be used to treat LD unless there are no other Engineering Modifications and options available. Coadministration of rifampin with any of the drugs Maintenance listed may be harmful, and has negligible benefit.325 Rifampin dramatically Proper building, cooling tower, and plumbing design and construction reduces serum and lung concentrations of all of the macrolide drugs can reduce the frequency and intensity of Lp contamination of potable due to induction of drug clearance, with the enhanced clearance persisting water systems.366 Risk assessment and a water management program for weeks after stopping the rifampin.344–346 are important parts of environmental control, and required by many Most LD patients treated with one of the recommended antimicrobial governmental organizations.367–369 agents respond promptly to the therapy, sometimes within hours. Within Use of monochloramine to treat public drinking water reduces 12 to 24 hours, most patients have improvement or complete clearance Legionella spp. colonization of water, as well as rates of nosocomial of myalgia, confusion, headache, abdominal pain, diarrhea, nausea, LD.370–372 Secondary disinfection with monochloramine also appears to vomiting, and anorexia. Four to 7 days may be required for complete be highly effective.373,374 resolution of fever, with a steady decrease in fever over that period and with the most improvement being seen in the first day or two. Cough, Environmental Cultures for sputum production, shortness of breath, and pleuritic chest pain respond Legionella Bacteria more slowly to therapy, but major improvements usually occur within There is little national or international consensus regarding the benefit the first several days. As with most types of bacterial pneumonia, of routine environmental cultures to prevent LD. The Legionella bacteria convalescence may be prolonged for months and complicated by present in our aqueous environment almost never cause disease. That, neuropsychiatric disease, including chronic fatigue347,348; in addition combined with natural fluctuations, imprecision in measuring bacterial there can be persistent (months) pulmonary physiologic abnormalities concentrations, and extreme heterogeneity in Legionella environmental that may be symptomatic.349 Evidence of chest consolidation on physical concentrations, make it difficult to define a specific and sensitive bacterial 2817 concentration target for remediation. Many, but not all, government areas. Other organizations suggest that all hospital water supplies be and other organizations recommend against the routine use of envi- checked.377–380 Evidence from several LD nosocomial outbreaks shows ronmental cultures in risk assessment.243,375–378 that detection of any Legionella spp. in a hospital water distribution Cha Many bodies recommend that hospital water systems supplying wards may be a cause for concern, and that a guideline previously used by

housing immunocompromised patients be cultured for Lp, and that some for remediation if 30% or more of cultured sites are positive is p remediation be carried out if any positive cultures are found in these insensitive.381,382 ter 232 Legionnaires’ Disease and Key References regions involved in host range expansion. Proc Natl Acad 313. Helbig JH, Uldum SA, Bernander S, et al. Clinical utility Sci USA. 2011;108:14733–14740. of urinary antigen detection for diagnosis of The complete reference list is available online at Expert Consult. 148. Burstein D, Amaro F, Zusman T, et al. Genomic analysis community-acquired, travel-associated, and nosocomial 1. Fraser DW, Tsai TR, Orenstein W, et al. Legionnaires’ of 38 Legionella species identifies large and diverse Legionnaires’ disease. J Clin Microbiol. 2003;41:838–840. disease: description of an epidemic of pneumonia. N Engl effector repertoires. Nat Genet. 2016;48:167–175. 318. Mentasti M, Afshar B, Collins S, et al. Rapid investigation J Med. 1977;297:1189–1197. 160. European Centre for Disease Prevention and Control. of cases and clusters of Legionnaires’ disease in England 3. McDade JE, Shepard CC, Fraser DW, et al. Legionnaires’ Legionnaires’ disease incubation period; 2017. https:// and Wales using direct molecular typing. J Med Microbiol. disease: isolation of a bacterium and demonstration of its legionnaires.ecdc.europa.eu/?pid=107. Accessed 2016;65:484–493. role in other respiratory disease. N Engl J Med. November 18, 2017. 322. Gacouin A, Le Tulzo Y, Lavoue S, et al. Severe pneumonia 1977;297:1197–1203. 166. McClung RP, Roth DM, Vigar M, et al. Waterborne due to Legionella pneumophila: prognostic factors, impact 7. Glick TH, Gregg MB, Berman B, et al. Pontiac fever. An disease outbreaks associated with environmental and of delayed appropriate antimicrobial therapy. Intensive

epidemic of unknown etiology in a health department: I. undetermined exposures to water - United States, Care Med. 2002;28:686–691. P ontiac Feve Clinical and epidemiologic aspects. Am J Epidemiol. 2013-2014. MMWR Morb Mortal Wkly Rep. 327. Garcia-Vidal C, Sanchez-Rodriguez I, Simonetti AF, et al. 1978;107:149–160. 2017;66:1222–1225. Levofloxacin versus azithromycin for treating Legionella 17. Fisher-Hoch SP, Bartlett CL, Tobin JO, et al. Investigation 167. Benedict KM, Reses H, Vigar M, et al. Surveillance for pneumonia: a propensity score analysis. Clin Microbiol and control of an outbreaks of legionnaires’ disease in a waterborne disease outbreaks associated with drinking Infect. 2017;23:653–658. district general hospital. Lancet. 1981;1:932–936. water - United States, 2013-2014. MMWR Morb Mortal 328. Gershengorn HB, Keene A, Dzierba AL, et al. The r 25. Nygard K, Werner-Johansen O, Ronsen S, et al. An Wkly Rep. 2017;66:1216–1221. association of antibiotic treatment regimen and hospital outbreak of legionnaires disease caused by long-distance 168. Public Health England. Legionnaires’ Disease in England mortality in patients hospitalized with Legionella spread from an industrial air scrubber in Sarpsborg, and Wales – 2015. London: Public Health England; pneumonia. Clin Infect Dis. 2015;60:e66–e79. Norway. Clin Infect Dis. 2008;46:61–69. 2016:1–42. 329. Cecchini J, Tuffet S, Sonneville R, et al. Antimicrobial 27. Weiss D, Boyd C, Rakeman JL, et al. A large community 189. European Centre for Disease Prevention and Control. strategy for severe community-acquired legionnaires’ outbreak of Legionnaires’ disease associated with a European Legionnaires’ Disease Surveillance Network disease: a multicentre retrospective observational study. J cooling tower in New York City, 2015. Public Health Rep. (ELDSNet); 2017. https://ecdc.europa.eu/en/about-us/ Antimicrob Chemother. 2017;72:1502–1509. 2017;132:241–250. partnerships-and-networks/ 336. Hennebique A, Bidart M, Jarraud S, et al. Digital PCR for 33. Isenman HL, Chambers ST, Pithie AD, et al. Legionnaires’ disease-and-laboratory-networks/eldsnet. Accessed detection and quantification of fluoroquinolone resistance disease caused by Legionella longbeachae: clinical features November 19, 2017. in Legionella pneumophila. Antimicrob Agents Chemother. and outcomes of 107 cases from an endemic area. 202. Sopena N, Force L, Pedro-Botet ML, et al. Sporadic and 2017;61:e00628-17. Respirology. 2016;21:1292–1299. epidemic community legionellosis: two faces of the same 347. Lettinga KD, Verbon A, Nieuwkerk PT, et al. 38. Edelstein PH. Legionella. In: Carroll K, Pfaller M, Landry illness. Eur Respir J. 2007;29:138–142. Health-related quality of life and posttraumatic stress ML, et al, eds. Manual of Clinical Microbiology. 12th ed. 208. Tubach F, Ravaud P, Salmon-Ceron D, et al. Emergence disorder among survivors of an outbreak of Legionnaires Washington, D.C.: ASM Press; 2019. of Legionella pneumophila pneumonia in patients disease. Clin Infect Dis. 2002;35:11–17. 43. Falkinham JO III, Hilborn ED, Arduino MJ, et al. receiving tumor necrosis factor-alpha antagonists. Clin 354. Meyer RD, Edelstein PH, Kirby BD, et al. Legionnaires’ Epidemiology and ecology of opportunistic premise Infect Dis. 2006;43:e95–e100. disease: unusual clinical and laboratory features. Ann plumbing pathogens: Legionella pneumophila, 226. Marrie TJ, Haldane D, MacDonald S, et al. Control of Intern Med. 1980;93:240–243. Mycobacterium avium, and Pseudomonas aeruginosa. endemic nosocomial legionnaires’ disease by using sterile 363. Noah MA, Ramachandra G, Hickey MM, et al. Environ Health Perspect. 2015;123:749–758. potable water for high risk patients. Epidemiol Infect. Extracorporeal membrane oxygenation and severe acute 49. Kenagy E, Priest PC, Cameron CM, et al. Risk factors for 1991;107:591–605. respiratory distress secondary to Legionella: 10 year Legionella longbeachae Legionnaires’ disease, New 234. Fraser DW. Legionellosis: evidence of airborne experience. ASAIO J. 2013;59:328–330. Zealand. Emerg Infect Dis. 2017;23:1148–1154. transmission. Ann N Y Acad Sci. 1980;353:61–66. 366. World Health Organization. Legionella and the Prevention 53. Cazalet C, Jarraud S, Ghavi-Helm Y, et al. Multigenome 246. David S, Afshar B, Mentasti M, et al. Seeding and of Legionellosis. Geneva: World Health Organization; analysis identifies a worldwide distributed epidemic establishment of Legionella pneumophila in hospitals: 2007. Legionella pneumophila clone that emerged within a implications for genomic investigations of nosocomial 373. Duda S, Kandiah S, Stout JE, et al. Evaluation of a new highly diverse species. Genome Res. 2008;18:431–441. Legionnaires’ disease. Clin Infect Dis. 2017;64:1251–1259. monochloramine generation system for controlling 63. Simmering JE, Polgreen LA, Hornick DB, et al. 247. Bacigalupe R, Lindsay D, Edwards G, et al. Population Legionella in building hot water systems. Infect Control Weather-dependent risk for Legionnaires’ disease, United genomics of Legionella longbeachae and hidden Hosp Epidemiol. 2014;35:1356–1363. States. Emerg Infect Dis. 2017;23:1843–1851. complexities of infection source attribution. Emerg Infect 376. Health & Safety Executive. HSE 2013 L8, Legionnaires’ 64. Winn WC Jr, Myerowitz RL. The pathology of the Dis. 2017;23:750–757. disease. The control of legionella bacteria in water Legionella pneumonias. A review of 74 cases and the 249. Centers for Disease Control. Legionella (Legionnaires’ systems. In: Executive HS, ed. 2013 L8. 4th ed. London, literature. Hum Pathol. 1981;12:401–422. Disease and Pontiac Fever); 2017. http://www.cdc.gov/ UK: Health and Safety Executive; 2013:1–28. 88. 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J Comput Assist Tomogr. 2007;31:125–131. legionnaires’ disease outbreaks: a large outbreak in a enigmatic chimera. Curr Opin Microbiol. 2016;29:22–29. 266. Johnson JD, Raff MJ, Van Arsdall JA. Neurologic hospital with a Legionella disinfection 147. O’Connor TJ, Adepoju Y, Boyd D, et al. Minimization of manifestations of Legionnaires’ disease. Medicine system-Pennsylvania, 2011-2012. Clin Infect Dis. the Legionella pneumophila genome reveals chromosomal (Baltimore). 1984;63:303–310. 2015;60:1596–1602. Chapter 232 Legionnaires’ Disease and Pontiac Fever

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