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Management of Legionella in Water Systems (2019)

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2019. Management of Legionella in Water Systems. Washington, DC: The National Academies Press. doi: 10.17226/25474.
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1 Introduction The leading cause of reportable waterborne disease outbreaks in the United States today is Le- gionnaires’ disease, a pneumonia caused by the Legionella bacterium. Legionella was first documented as a cause of human disease in 1976, after an outbreak of pneumonia of unknown origin was described among members of the American Legion who had attended a conference at the Bellevue-Stratford Hotel in Philadelphia. Of the nearly 2,000 conference attendees, 182 people developed clinical disease and 29 died from their illness. This large outbreak generated national alarm, as public health experts, labora- tory scientists, and clinicians raced to define the pathogen (Winn, 1988). A subsequent epidemiological investigation revealed a relationship between the attack rate and the time spent in the hotel lobby and consequently, the route of exposure was surmised to be airborne. The high attack rate coupled with dis- ease severity may have reflected the prevalence of pre-existing conditions among those exposed: of the 94 hospitalized cases, 58 had pre-existing conditions (Fraser et al., 1977). Once the etiologic agent was identified, antibody titers of hotel employees suggested they had been exposed to the bacterium intermit- tently over a long period. In 1978 Dr. Joseph McDade and colleagues at the U.S. Centers for Disease Control and Prevention (CDC) discovered the etiologic agent of the Philadelphia outbreak (McDade et al., 1979). The bacterium responsible was named Legionella pneumophila, reflecting the patients initially diagnosed with disease and the respiratory complications seen with infection. The first to isolate Legionella species (spp.) is thought to be Hugh Tatlock in 1943 (Tatlock, 1944); subsequently, in 1959 F. Marilyn Bozeman isolated these bacte- ria from individual human cases. Retrospectively, the Philadelphia infectious agents were determined to be similar to the L. pneumophila seen previously by Bozeman in 1959 (Bozeman et al., 1968), as judged by immunological assay and similarity of guanine-cytosine DNA composition (McDade et al., 1979). As news of the Philadelphia outbreak and the identification of L. pneumophila as a human pathogen spread, legionellosis became recognized throughout the world. Legionella spp. were retrospectively linked to previous enigmatic outbreaks of respiratory disease, including one dating back to 1957 in Minnesota. Thus, legionellosis was present in the United States for years prior to its detection in 1978 (Osterholm et al., 1983; Thacker et al., 1978). Another retrospective study linked L. pneumophila to a previously un- diagnosed cluster of patients in a county health department facility in Pontiac, Michigan, struck by a “flu-like,” less severe form of the illness associated with fever, headaches, and myalgias—a syndrome termed Pontiac fever (Glick et al., 1978). As culture techniques were improved and adopted by the mi- crobiology community, the number of reported Legionella spp. grew to include L. micdadei, L. bozemanii, and L. longbeachae, among others. At the time of this publication, more than 61 Legionella spp. have been identified, of which more than half are associated with human disease (Cunha et al., 2016). 11 Prepublication Version - Subject to further editorial revision

12 Management of Legionella in Water Systems In the period following the Philadelphia outbreak, knowledge surrounding legionellosis expand- ed rapidly (see Figure 1-1). In the first few years after the outbreak, scientists identified the pathogen, procedures critical for laboratory isolation, common environmental sites of exposure (e.g., air condi- tioning units, cooling towers, potable water), and the underpinning to new methods for diagnosis (e.g., the urinary antigen test) (Berdal et al., 1979; Feeley et al., 1978; Politi et al., 1979; Shands et al., 1985). Importantly, epidemiologic and laboratory animal models demonstrated the benefits of macrolides and flouroquinolones as antibiotic therapy for legionellosis (Fraser et al., 1978). Epidemiologic studies also identified Legionella spp. as primarily waterborne pathogens. In the 1976 Philadelphia outbreak, the ho- tel’s cooling tower was the source of water droplets contaminated with Legionella that spread through the air in and around parts of the hotel. Subsequently, many Legionella outbreaks have been linked to water exposures, including clusters caused by potable water sources in hospitals (Broome et al., 1979; Tobin et al., 1980, 1981). A timeline of Legionella-related events since 1943 is provided by Figure 1-1. Medical and epidemiological terms related to Legionnaires’ disease and used throughout this report are defined in Box 1-1. CLINICAL DISEASE AND EPIDEMIOLOGIC STUDIES Legionnaires’ disease is caused by bacteria of the Legionella genus—small aerobic Gram-negative rods that are facultative intracellular pathogens. Humans are primarily exposed to Legionella through in- halation into the respiratory system, after which the organism replicates in pulmonary macrophages and monocytes. Incubation periods are thought to range from two to twelve days, but may be longer, partic- ularly in immunosuppressed patients. Patients with Legionella pneumonia have fever, cough, shortness of breath, and myalgias (i.e., soreness or aching of the muscles)—common symptoms in other respiratory infections. Unlike most people with community-acquired pneumonias, however, patients with Legion- naires’ disease more frequently have gastrointestinal symptoms and altered mental status and neurologic abnormalities. Patients with Pontiac fever present with fever, myalgias, chills, and headache, but by definition do not have pneumonia; most patients recover without treatment. Because both diseases have symptoms that are similar to other infections, the legionellosis diagnosis may be delayed or missed, which can lead to severe consequences in those with Legionella pneumonia. Legionellosis is most common among the elderly and those who are immunosuppressed. Inci- dence is also higher in men and in people who smoke cigarettes. While disease from non-pneumophila Legionella spp. is more common in immunosuppressed patients, the majority of reported cases are caused by L. pneumophila and most frequently serogroup 1 (although this varies by country). Legionella spp. have been found on every continent (Aranciba et al., 2014; Beauté, 2017; Carvalho et al., 2008; Chaudhry et al., 2017; Chedid et al., 2005; Guo et al., 2015; Wolter et al., 2016; Yu et al., 2002), but most currently available epidemiologic data focus on legionellosis in large metropolitan areas in developed regions. In the United States, incidence of Legionnaires’ disease increased more than five-fold from 2000 to 2017 (see Figure 1-2). Legionnaires’ disease is acquired by exposure to contaminated aerosols of water generated by manufactured devices such as showerheads and faucets, cooling towers, fountains, hot tubs, and oth- er building water systems. Despite numerous reports of common-source outbreaks in the community, through travel or through hospital exposures, and despite improvements in epidemiologic and laboratory tools, the vast majority of Legionella cases remain sporadic, community-acquired cases for which the pri- mary exposure source is never identified. Prepublication Version - Subject to further editorial revision

1976 Legionnaires’ disease becomes a reportable disease by the CDC 1979 First detection of L. pneumophila antigen in urine10 2013 Outbreak of community legionellosis cases linked to wastewater from German brewery 1979 Legionella first linked to cooling towers11 2014-2015 1968 2001 Outbreak in Flint, MI, related to First description of Pontiac fever 1978 Legionella formally added to the change in city water to Flint in Pontiac, Michigan, which was First evidence of macrolide antibiotics for CDC’s waterborne disease River. Led to involuntary later linked to treatment of legionellosis8 and development of surveillance program manslaughter charges for state L. pneumophila6 early guinea pig model for antibiotic therapy9 and city officials22 1949 1976 1985 2014 First L. pneumophila strain Outbreak of pneumonia at an American Legionella linked to potable Outbreak in Bronx, NY, related identified by Bozeman and Legion Conference Bellevue-Stratford Hotel in 2004 to cooling towers.21 Led to water12 colleagues2 Philadelphia, PA, and designation of disease L. pneumophila genome cooling tower regulation in NYC at Legionnaires’ disease8 sequenced13,14 in 2015. 1977 2001 Largest documented 2016 L. pneumophila cultured in guinea pigs by 1965 legionellosis outbreak to date First documented case of 1943 McDade and colleagues at the CDC from Outbreak of legionellosis in (>800 cases) in Murica, Spain15 probable person-to-person A “Rickettsia-like organism” patient samples from the American Legion St. Elizabeth’s Hospital in transmission of legionellosis17 discovered in guinea pigs in a Conference, designating the organism as Washington, DC7 patient by Tatlock1 L. pneumophila 2013 Congressional committee 2016 1978 1999 holds oversight hearing on “From Watersheds to Shower 1954 Legionella spp. isolated on laboratory Outbreak at flower show in Legionnaires’ disease heads: A Workshop on Legionella first isolated from soil media (BCYE with cysteine and α- the Netherlands linked to outbreak at Pittsburgh, PA, Legionella” sponsored by the amoeba by Dronsanki3 ketoglutarate) by Feeley5 hotel whirlpool spa19 Veteran’s Affairs hospital Sloan Foundation at Emory University 1978 2000 1957 First international Outbreak linked to cooling 2014 First documented outbreak of symposium on Legionella towers at aquarium in Large outbreak near Lisbon, legionellosis in Minnesota4 held at CDC Melbourne, Australia.20 Led Portugal linked to cooling Australia to make Legionella a towers18 1981 reportable disease and the L. longbeachae isolated introduction of stricter from a patient in Long regulations. 2015 - 2016 Beach, CA16 Outbreak at Quincy Illinois veterans home. Prepublication Version - Subject to further editorial revision FIGURE 1-1 Timeline of important Legionella related events. NOTES: Broken lines are outcomes determined through retrospective analysis. First Legionella spp. reported by Tatlock was Tatlockia micdadei, a synonym for Legionella micdadei. Blue indicates first reported cases of Legionella pneumonia and Pontiac fever respectively; orange indicates a large and historically signifi- cant outbreak. Citations indicated are listed at the end of the chapter. Timeline not to scale. 13

14 Management of Legionella in Water Systems BOX 1-1 Legionnaires’ Disease Definitions Attack rate: The proportion of exposed people who become ill with (or who die from) a disease in a population initially free of the disease. Case: An individual with a specified disease, illness, or condition who meets specific clinical, laboratory, and/or epidemiologic criteria. Cluster: Cases of a disease, illness, or other health-related condition, grouped together in time and/or place. Disability-adjusted life years (DALYs): A common health metric used to quantify the number of healthy years lost to disability, illness, and/or death due to a particular disease. Often used to compare the health burden of different diseases or in diseases among specific populations and to inform public health policy or decisions. Disease burden: Measure of a health problem’s impact that combines financial cost, mortality, morbidity, and/or other indicators. Incidence: The occurrence of new cases of a given medical condition or illness in a population within a specified period of time. Legionellosis: Disease caused by Legionella bacteria. Legionellosis includes both lung infec- tions (Legionnaires’ disease) and milder syndromes (Pontiac fever). Legionnaires’ disease (also known as Legionella pneumonia): Lung inflammation caused by Legionella infection, in which the lung’s air sacs fill with inflammatory cells fighting the infection. Patients with pneumonia have evidence of lung involvement on radiologic images and have pos- itive cultures or other tests (e.g., urinary antigen) for Legionella. Mortality rate: a measure of the frequency of occurrence of death in a defined population (e.g., all individuals diagnosed with a specific disease) during a specified interval. Nosocomial: A disease originating or acquired in the hospital, most commonly in reference to infections. Outbreak: The occurrence of cases of disease or illness in excess of what would normally be expected in a defined community, geographical area, or season (World Health Organization definition). Pontiac fever: A self-limiting “flu-like” illness caused by exposure to Legionella bacteria, defined by lack of pneumonia. Named after site (Pontiac, Michigan) of first description. Sporadic: A disease or illness that occurs infrequently and irregularly. With regard to Legionella, those cases not associated with an outbreak. Waterborne disease: A disease transmitted or propagated by contaminated water. Prepublication Version - Subject to further editorial revision

Introduction 15 FIGURE 1-2 Increasing incidence of legionellosis in the United States from 2000 to 2017. SOURCE: Adapted from Shaw et al. (2018) with 2016 and 2017 data from the National Notifiable Disease Surveillance System (NNDSS). The medical establishment has not optimized the diagnosis of Legionnaires’ disease for many rea- sons. When patients present with pneumonia, most physicians choose empiric therapies that adequately treat the disease, so these cases are never counted. If a patient is tested using the urinary antigen test on site, results for infections caused by L. pneumophila serogroup 1 can be received in one day. However, when a patient is culture-tested for Legionella, it can be at least a week or longer before the results are known, making it difficult to diagnose cases in a timely manner. Worldwide, the actual burden of Legion- naires’ disease is generally acknowledged to be underreported by as much as eight- to ten-fold (Dooling et al., 2015; Mercante and Winchell, 2015; Phin et al., 2014; St-Martin et al., 2013; von Baum et al., 2008). Among common waterborne pathogens, Legionella is now the most common cause of reported drinking water-associated outbreaks (see Figure 1-3). Etiologic shifts from the 1970s to the modern era likely reflect successful efforts mandated by the Safe Drinking Water Act of 1974 to control fecal and enteric bacterial pathogens and parasites (primarily Cryptosporidium spp. and Giardia lamblia). Waterborne infections account for $3 to 4 billion in excess costs in the United States per year (Adam et al., 2017). Nearly $1 billion per year goes to the top five primarily waterborne diseases (i.e., giardiasis, cryptosporidiosis, Legionnaires’ disease, otitis externa, and non-tuberculous mycobacterial in- fections), including $430 million in hospitalization costs to Medicare and Medicaid (Collier et al., 2012). Proven Legionella cases are estimated to lead to a median cost of $26,000 to $38,000 per admission (Col- lier et al., 2012). European data paint a more ominous picture; Cassini and colleagues (2018) suggest that Legionella spp. are one of the top five pathogens leading to the most disability-adjusted life years (DALYs) and one of only four infections (including HIV, tuberculosis, and invasive pneumococcal disease) consid- ered to have both a high population and high individual burden of disease (see Figure 1-4). Numerous sources worldwide have documented increasing incidence of Legionella cases, suggesting little progress in decreasing risk for Legionella. Incidence is generally thought to be underestimated, such that the true financial and human costs of legionellosis are also likely underestimated. Prepublication Version - Subject to further editorial revision

16 Management of Legionella in Water Systems FIGURE 1-3 Etiology of reported drinking water associated outbreaks in the United States (n=298) by year, 1971 to 2014. SOURCE: Benedict et al. (2017). FIGURE 1-4 Scatterplot of the burden of selected infectious diseases in disability adjusted life years (DALYs) per case and DALYs per 100,000 population per year, European Union/European Economic Area countries, 2009 to 2013. SOURCE: Cassini et al. (2018). NOTE: EU/EAA: European Union/European Economic Area; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HIV/AIDS: Human immunodeficiency virus infection; IHID: Invasive Haemophilus Influenzae disease; IMD: Invasive meningococcal disease; IPD: Invasive pneumococcal disease; STEC/VTEC: Shiga toxin/verocytotoxin-producing Escherichia coli; TBE: Tick-borne encephalitis; vCJD: variant Creutzfeldt-Jakob disease. Diseases were arbitrarily subdivided according to burven in DALYs per 100,000 population and DALYs per case. Prepublication Version - Subject to further editorial revision

Introduction 17 Table 1-1 lists waterborne bacterial pathogens associated with human sinopulmonary disease. Acquiring pneumonia from waterborne pathogens is uncommon, as most lead to gastrointestinal illness. Nonetheless, pneumonia can occur from waterborne pathogens, most notably Legionella spp., Pseudomonas spp., and non-tuberculous mycobacteria. Some of the listed bacteria grow opportunistically in building water systems, but only Legionella causes a reportable illness. Hundreds of organisms associated with waterborne disease are not discussed in detail in this report, including common waterborne pathogens such as Pseudomonas spp., non-tuberculous mycobacteria, Campylobacter spp., Cryptosporidium, and some E. coli infections. Nor does this report discuss other clinical illnesses linked to water, including otitis externa (an ear infection involving the external ear canal), diarrheal disease and their etiologic agents, and skin and soft-tissue infections, among others. Finally, Table 1-1 does not include a large number of important viruses, fungal spp., and parasites causing sinopulmonary infections that have been linked to water sources. BUILT ENVIRONMENT IS A MAJOR ECOLOGICAL NICHE Legionella bacteria naturally reside in many freshwater and soil environments, such as lakes, streams, and sediments, and many different species potentially cause disease. However, it is the un- checked growth of pathogenic legionellae in human-made water systems that typically leads to human exposures and causes disease. Humans are exposed to Legionella after inhaling or aspirating contaminat- ed water aerosolized from a variety of sources. L. pneumophila appears to grow poorly as individual, free-living cells in natural environments; instead, its growth is optimal within amoebae (Kuiper et al., 2004) and other free-living protozoa that are associated with biofilms (Buse et al., 2012; Hellinga et al., 2015). Indeed, the bacterial growth re- quirements are consistent with a natural, parasitic lifestyle. For example, replicating Legionella require external sources of certain amino acids and minerals (Reeves et al., 1981; States et al., 1985), low levels of oxygen (optimum below 1 mg/L) (Mauchline et al., 1992), and a temperature range between 25°C and 43°C (Garrity et al., 2005). During the Legionella life cycle, its physiological state switches between infec- tious and replicative forms as well as more hardy, dormant cell forms. Although Legionella can survive and persist in the absence of a host cell, in nature significant amplification appears to require protozoan hosts (Fields et al., 2002). Sometimes pathogenic legionellae replicate within free-living amoebae to lev- els that elevate risks to the people who are exposed (Ashbolt, 2015b; Declerck, 2010). Accordingly, the ecology of L. pneumophila is directly linked to that of protozoa, whose primary habitat is biofilm (Declerck, 2010). A biofilm is a community of microorganisms within a self-produced hydrated gel matrix attached to moist soil, sediment, and other solid surfaces that accumulates organic and inorganic material (Characklis and Marshall, 1990). Biofilms typically form on all moist surfaces, in- cluding engineered surfaces such as pipes, tanks, appurtenances, filters, and gaskets—virtually everything that contacts water. Biofilm communities growing on pipes can include bacteria/archaea (including round, rod-shaped, filamentous, and appendaged forms), fungi, and higher organisms such as amoebae, ciliates, nematodes, larvae, and crustaceans (see Figure 1-5). The pipe material can exert a strong influ- ence on the composition and activity of the biofilm’s microbial community. Both surface materials and temperature influence the complex interactions among Legionella, host amoebae, and biofilm community members. (More detailed discussion on this ecology is found in Chapter 2.) In general, at moderate to warm temperatures, surfaces wetted with water that contains nutrients provide a favorable habitat for biofilm growth, grazing protozoa, and Legionella growing within the protozoa. Prepublication Version - Subject to further editorial revision

18 TABLE 1-1 Common Waterborne Bacterial Pathogens Associated with Human Sinopulmonary Disease Pathogen Associated Disease(s) Source* Comments • High resistance to chlorine (Karunmathil et al., 2014) bacteremia, pneumonia, skin Healthcare- Acinetobacter spp. • Associated with hospital outbreaks and soft-tissue infections acquired • Can grow in building water systems bacteremia, pneumonia, skin Communi- • Primarily A. hydrophila Aeromonas spp. and soft-tissue infections ty-acquired • Can grow in building water systems Burkholderia cepacia Healthcare- • Can grow in building water systems bacteremia, pneumonia complex acquired • More frequent in patients with weakened immune systems bacteremia, pneumonia, • Associated with hospital outbreaks Healthcare- Burkholderia pseudomallei skin and soft-tissue infec- • Resistance to multiple forms of disinfection acquired • Can grow in building water systems tions • Consider in community wells or if fecal contamination is present E. coli and other selected bacteremia, pneumonia, diar- • Associated with groundwater and surface water contamination Both Enterobacteraciae spp. rhea, gastroenteritis • Multidrug-resistant Enterobacteraciae associated with pneumonia in hospital water systems (e.g., Klebsiella pneumonia) • Common cause of outbreaks • Species vary by location and host; L. pneumophilia make up majority • Largest number of cases are community-acquired with no source identified Legionella spp. pneumonia Both • Can grow in building water systems • Non-water-based exposures can also lead to legionellosis • Pontiac fever patients do not have pneumonia Healthcare- • Primarily occurs in patients with compromised immune systems Methylobacterium spp. bacteremia, pneumonia acquired • Can grow in building water systems • Primarily Mycobacterium avium-intracellulare, but others also reported (Falkingham, Non-tuberculous mycobac- 2011) bacteremia, pneumonia Both teria • Can grow in building water systems • High resistance to chlorine Prepublication Version - Subject to further editorial revision bacteremia, pneumonia, skin • Primarily P. aeruginosa Pseudomonas spp. Both and soft-tissue infections • Can grow in building water systems • Known intrinsic resistance to multiple antibiotics Stenotrophomonas maltophil- bacteremia, pneumonia, skin Healthcare- • More frequent in patients with weakened immune systems ia and soft-tissue infections acquired • Can grow in building water systems *Probable source location designation (community or healthcare associated) is based on published data regarding documented water source links.

Introduction 19 A B FIGURE 1-5 (A) Schematic of a biofilm growing on pipe walls, including the various microbial cells associated with the biofilm. (B) Corroded iron pipe showing the uneven surface that promotes the accumulation of biofilms. NOTE: BDOC =biodegradable dissolved organic carbon. BDOC can leach out of plastic pipe walls and can also be provided by microorganisms. SOURCE: Courtesy of Paul van der Wielen. The main mode of human exposure to Legionella is via inhalation of aerosols. Aerosols are small (typically <100 µm) drops of liquid formed by the action of turbulence on fluids, although only those less than 10 µm can reach deep into the human lung. Any materials suspended within the liquid, such as bac- teria and protozoa, can be transported within these droplets. The aerosol particles have a large surface area-to-volume ratio and may selectively accumulate hydrophobic materials, including bacteria (Parker et al., 1983). Aerosolization is distinct from volatilization, which is a chemical phase change wherein either a dissolved solute, or the solvent itself, exits the liquid to form a true vapor state. Sites with both biofilm growth and potential for aerosolization are possible sources of Legion- naires’ disease risk. Many such areas exist in the built environment, including components of heating, ventilation, and air conditioning (HVAC) systems such as cooling towers and humidifiers; indoor plumb- ing (called premise plumbing) including outlets such as showerheads and faucets; and spas, hot tubs, and Jacuzzis (collectively called hot tubs in this report) (see Figure 1-6). Additional known sources of infection are fountains, misters, nebulizers, car washes, and industrial wastewater treatment plants. FIGURE 1-6 Built locations where Legionella growth can occur. NOTE: Thinner black arrows indicate water path- ways to premise plumbing and thicker grey arrows indicate wastewater. SOURCE: Adapted from Exner (2018) by Kyoko Kurosawa. Prepublication Version - Subject to further editorial revision

20 Management of Legionella in Water Systems Building- and industrial-scale (e.g., power plants, industries) wet cooling towers have been impli- cated in many outbreaks of Legionnaires’ disease (see Figure 1-7). Cooling towers remove heat from re- circulating water used in water-cooled chillers, heat pumps, air compressors and other equipment. Heat is rejected from recirculating water in the cooling tower primarily through evaporation. Under certain conditions, biofilms can develop within water-associated piping, heat exchangers and other component surfaces. Furthermore, the warm temperatures of the bulk water in cooling towers are also conducive to Legionella growth. These towers may generate bacteria-laden aerosols that drift away from the building or facility and then are inhaled by people working and living in the building as well as passersby. Expo- sure can also occur indoors if the downdraft from cooling towers is transported into building interiors, via air intakes or infiltration. In the United States, there are estimated to be two million cooling towers including both individual and industrial towers.1 Legionella can also contaminate drinking water, either in distribution systems or premise plumb- ing. In the United States, more than 322 million people are served by 152,000 public drinking water systems with more than 1.2 million miles of water supply mains. The total length of premise plumbing, which refers to all piping downstream of the service line connection and within buildings, is thought to be more than 6 million miles (NRC, 2006). Compared with the main distribution system, premise plumbing uses relatively long sections of small diameter tubing with about ten times more surface area per unit length (NRC, 2006). Thus, premise plumbing provides extensive interior surface area for biofilm growth. Moreover, because of stagnation, premise plumbing is frequently devoid of a disinfectant residual. If water in the pipes becomes enriched with pathogens such as Legionella, occupants may be exposed to aerosols created by showerheads or faucets (see Figure 1-8). Other home appliances such as hot-water heaters (see Figure 1-9) and humidifiers (see Figure 1-10) can also provide habitats for biofilm growth and enrichment. In 2018, there were estimated to be over 127 million households in the United States.2 Biofilm and Legionella growth can also be enhanced by water age, which depends on the building type and use, occupancy, and water use. Indeed, the water residing in premise plumbing has a much wid- er age distribution than the water entering a home from the distribution system (NRC, 2006). Although in the United States the average hotel occupancy is about 66 percent, it can fluctuate seasonally between less than 50 percent to more than 75 percent,3 creating significant potential for water stagnation. There are over 5 million hotel rooms in the country4. Green buildings may provide additional areas for growth of pathogens because of lower hot-water temperatures, lower flows, and longer building water ages (Rhoads et al., 2016). 1 See https://energytrendswatch.com/2017/11/21/cooling-towers-not-so-cool/. 2 See https://www.statista.com/statistics/183635/number-of-households-in-the-us. 3 See https://www.statista.com/statistics/206546/us-hotels-occupancy-rate-by-month. 4 See https://www.statista.com/statistics/245864/us-hotel-rooms-by-chain-scale-segment. FIGURE 1-7 Photo and schematic of a cooling tower. SOURCES: Shutterstock and ASHRAE (2016). Prepublication Version - Subject to further editorial revision

Introduction 21 FIGURE 1-8 A faucet and a fine-mist showerhead showing the potential for aerosolization. SOURCE: Shutterstock. FIGURE 1-9 Schematic of an electric hot water heater and photo of a gas hot-water heater. SOURCES: https://buildingsfieldtest.nrel.gov/electric_resistance_water_heaters. © Government of Yukon (diagram) and WikiCommons (photo). FIGURE 1-10 A hot tub, a humidifier, and a fountain. SOURCE: Shutterstock. Prepublication Version - Subject to further editorial revision

22 Management of Legionella in Water Systems In addition to the premise plumbing and fixtures typical of residential and commercial buildings, healthcare and medical facilities provide additional opportunities for both biofilm colonization and aero- solization due to specialized medical devices, such as dental units and hydrotherapy units. Moreover, compared with the general public, their susceptible patient populations are at risk of Legionnaires’ dis- ease of greater intensity or severity. In the United States there are more than 6,200 hospitals, with more than 930,000 beds5. In 2015 there were about 1.7 million nursing home beds in the United States6. Ac- cording to the American Dental Association, there are almost 200,000 dentists in the United States7. Another major type of built environment that can generate Legionella risk are recreational water features, both outdoor and indoor. These include swimming pools, hot tubs, hot-spring baths, fountains (see Figure 1-10), and water parks, as biofilms can form on surfaces and contaminated aerosols can be generated. Recreational sources have resulted in several Legionnaires’ disease outbreaks (Leoni et al., 2018). In the United States, there are an estimated 9 million swimming pools and 5 million hot tubs.8 Other less common locales in the built environment can provide conditions suitable for biofilm growth, and hence colonization by pathogens such as Legionella and their protozoan hosts. Among these locales are interior water features such as green walls and waterfalls (den Boer et al., 2002; Haupt et al., 2012) and external building features that introduce additional wetted and irrigated surfaces includ- ing green walls or roofs, particularly when collected or harvested water is used for domestic purposes (Hamilton et al., 2017). Irrigating, lawn sprinkling, and spray washing with stagnant water from hoses or fixtures may be of concern as well, especially when using recycled water treated to non-potable standards (Hamilton et al., 2018; Johnson et al., 2018). In several countries, wastewater treatment plants receiving industrial wastewaters with temperatures higher than 25°C have also been identified as sources of Le- gionnaires’ disease (e.g., Loenenbach et al., 2018; Olsen et al., 2010) and Pontiac fever (e.g., Castor et al., 2005; Gregersen et al., 1999). ORIGIN OF THE STUDY In the 40 years since the discovery of L. pneumophila, much has been learned about its ecology; in contrast, less progress has been made toward preventing Legionnaires’ disease or understanding the ecol- ogy of different species of pathogenic Legionella and their protozoan hosts. Most knowledge regarding Legionnaires’ disease comes from investigations of disease outbreaks, in which two or more people are infected at the same time by the same source. Yet, only 4 percent of Legionnaires’ disease cases are as- sociated with known outbreaks and are thoroughly investigated (Hicks et al., 2011). Whether outbreaks accurately represent the exposure route of the numerous sporadic cases that go unreported remains un- clear. Thus, improved monitoring of Legionnaires’ disease in patient populations and of Legionella pres- ence in water systems is critical to better understanding the disease burden and the likelihood for partic- ular water systems to be sources of infection. Though monitoring the disease incidence and the presence of L. pneumophila in water samples has evolved considerably over the past 20 years, controversies associated with each persist. For Legionnaires’ disease, a urine antigen test or a (more difficult) sputum test are considered diagnostic, and yet such tests are not commonly performed for hospital patients with pneumonia. Furthermore, the urine antigen test only detects one of the 14 known serogroups of L. pneumophila. Because of these reasons, among oth- ers, the number of cases of Legionnaires’ disease is grossly underestimated in the United States as well 5 See https://www.aha.org/statistics/fast-facts-us-hospitals. 6 See https://www.statista.com/statistics/323196/number-of-licensed-nursing-home-beds-in-the-us. 7 See https://www.ada.org/en/science-research/health-policy-institute/data-center/supply-and-profile-of-dentists. 8 See http://www.apsp.org/Portals/0/2016%20Website%20Changes/2015%20Industry%20Stats/2015%20Industry%20Stats.pdf. Prepublication Version - Subject to further editorial revision

Introduction 23 as in other countries that conduct surveillance. Water systems have traditionally been sampled using culture-based methods, which can take many days to detect growth and can be biased toward certain bacterial types. Polymerase chain reaction (PCR) methods exist, but their ability to differentiate between viable and nonviable organisms is still evolving. If routine monitoring of water systems for Legionella is to become standard practice for determining the risk of Legionnaires’ disease for a given building or wa- ter system, accurate and quantitative microbiologic environmental testing is needed. Finally, although there is general agreement about the levels of detected Legionella that require remedial actions within a water system, there is no consensus on whether there is a threshold level of detected Legionella below which there is no risk of infection. The treatment of water systems to reduce colonization by Legionella is further complicated by the bacterium’s complex ecology. Legionella have developed multiple strategies to survive in the environment, including entering into a viable-but-non-culturable-like state, multiplying within a variety of protozoa including amoebae, and persisting within microbial biofilms. Indeed, its evolution of mechanisms to avoid digestion by its natural predatory hosts is thought to account for the virulence of certain strains of Legionella within human lung macrophages. Compared with bacteria in suspension, biofilms are rel- atively resistant to biocides and disinfectants, a primary means of treating built water systems. Other treatment methods involve raising water temperature beyond the growth range for the bacterium and host protozoa, reducing organic carbon levels in source water, altering pipe materials to discourage bio- film formation, and maintaining flow regimes in premise plumbing. At best, a patchwork of laws, codes, policies, and guidance documents dictate how Legionella is managed in U.S. water systems and buildings. Healthcare facilities that are part of the Veterans Health Administration (VHA) system or that receive funding from the Centers for Medicare & Medicaid Ser- vices (CMS) must manage for Legionella contamination, but with varying requirements and oversight. Regulations to register, monitor, and treat cooling towers were put in place in New York City in the wake of the Bronx legionellosis outbreaks in the summer of 2015. New York State regulations now require all general hospitals and residential healthcare facilities to perform an environmental assessment, prepare and implement a sampling and management plan to test their potable water systems for Legionella, and institute control measures in the event of an exceedance. Similar and more widespread regulations for both cooling towers and buildings have existed in Australia, Canada, and some European countries for the past few years, and some are thought to have reduced the risk of Legionnaires’ disease. Beyond those buildings affected by the VHA and CMS requirements, management of legionellosis in the United States is mainly dictated via voluntary guidance documents from the American Industrial Hygiene Association, the American Society of Heating, Refrigerating, and Air-Conditioning Engineers, and the National Sanitation Foundation International, among others. Hence, Legionella management can be enforced only for a small subset of vulnerable buildings across the country. There is no federal law specifically targeting Legionella. The Surface Water Treatment Rule of the Safe Drinking Water Act only indirectly addresses Legionella via the requirement for maintaining a disinfectant residual in public water supply distribution systems that use surface water sources, and it does not extend to groundwater supplies or to building premise plumbing. STUDY PURPOSE AND APPROACH Following a May 2016 workshop on Legionella attended by representatives from around the world with expertise in public health, microbiology, and environmental engineering (Emory University, 2016), participants representing the National Academies of Sciences, Engineering, and Medicine sought to Prepublication Version - Subject to further editorial revision

24 Management of Legionella in Water Systems commence a consensus study on Legionella that could address the shortcomings previously mentioned. CDC, VHA, the U.S. Environmental Protection Agency (EPA), and the Sloan Foundation provided the funding for a project to address the Committee on Management of Legionella in Water Systems’ statement of task (see Box 1-2). BOX 1-2 Statement of Task There are many questions and gaps in information concerning Legionella pneumophila and Le- gionnaires’ disease that the proposed National Academies of Sciences, Medicine, and Engineer- ing project would confront. An ad hoc committee of the National Academies will review the state of science with respect to Legionella contamination of water systems and issue a report that addresses the following: Ecology and Diagnosis: Describe the microbial ecology of water supplies (from the source to the tap and within built systems) as it relates to Legionella. What strains of L. pneumophila are of most concern and how can their diagnosis be improved (e.g., in terms of increased specificity, simplicity, and speed)? Transmission via Water Systems: What are the primary sources and routes of human expo- sure to Legionella? What features/characteristics of water systems make them more or less likely to support growth of Legionella? Quantification: Considering surveillance data, case studies of outbreaks, hospital data, other routine testing of water systems, what is known about the concentration of Legionella in water systems and the prevalence of Legionnaires’ disease over the last 20 years? How uncertain are these estimates and what can be done to reduce this uncertainty? How can quantitative risk assessment be improved? Prevention and Control: What are the most effective strategies for preventing and controlling Legionella amplification in water systems? What are the best methods to prevent exposure to Legionella, especially in at-risk populations? Is there a minimum level of contamination required to cause disease? What are the benefits, risks, gaps in implementation, and barriers to uptake of Legionella control programs? Policy and Training Issues: What policies, regulations, codes, or guidelines affect the inci- dence, control, quantification, and prevention of Legionnaires’ disease? How might they be built upon to better protect the public? How can Legionella control be best balanced with other water priorities? Research: For the sections above, what additional information gaps exist and what knowledge must be gathered to fill these gaps? Prepublication Version - Subject to further editorial revision

Introduction 25 ORGANIZATION OF REPORT Chapter 2 discusses the diagnosis of Legionnaires’ disease, the life history and complex ecology of Legionella in both natural and built water environments, and common exposure pathways. These active areas of research will require continued investment in order to improve the management of Legionella in water systems. Chapter 3 focuses on the surveillance of Legionnaires’ disease in the United States and Europe, as well as the environmental monitoring of Legionella that is becoming more common in built water systems. The need for a quantitative threshold of Legionella concentration above which action must be taken, and the role of quantitative microbial risk assessment, are extensively discussed in this chapter. Chapter 4 considers the many strategies used to control Legionella, including the use of heat, bio- cides, flow control, aerosol formation prevention, and distal devices, along with their application in sev- eral typical built environments. The chapter also describes what is known about the efficacy of different control methods and their potential unintended consequences. Finally, Chapter 5 reviews the array of laws, regulations, codes, standards, and guidance docu- ments that relate to Legionella management, both in the United States and abroad. It includes suggestions for how these various policy tools can be strengthened to better protect the public from legionellosis. Each chapter ends with conclusions and recommendations that synthesize more technical and specific statements found within the body of each chapter. The most important conclusions and recom- mendations are compiled in the report summary. REFERENCES Adam, E. A., S. A. Collier, K. E. Fullerton, J. W. Gargano, and M. J. Beach. 2017. Prevalence and direct costs of emergency department visits and hospitalizations for selected diseases that can be transmitted by water, United States. J. Water Health. 15(5):673-683. American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE). 2016. 2016 ASHRAE Handbook : HVAC Systems & Equipment (S-I Edition). Chapter S40 Cooling towers. Pp 40.2. American Society of Heating, Refrigerating and Air-Conditioning Engineers, Atlanta, GA. Arancibia, F., C. P. Cortes, M. Valdés, J. Cerda, A. Hernández, L. Soto, and A. Torres. 2014. Importance of Legionella pneumophila in the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest 145(2):290-296. Ashbolt, N. J. 2015a. Microbial contamination of drinking water and human health from community water systems. Curr. Environ. Health Rep. 2(1):95-106. Ashbolt, N. J. 2015b. Environmental (saprozoic) pathogens of engineered water systems: Understanding their ecology for risk assessment and management. Pathogens 4(2):390-405. Beauté, J. 2017. Legionnaires’ disease in Europe, 2011 to 2015. European Legionnaires’ Disease Surveillance Network. Euro Surveill. 22(27):pii=30566. https://doi.org/10.2807/1560-7917.ES.2017.22.27.30566. Benedict, K. M., H. Reses, Vigar M., D. M. Roth., V. A. Roberts, M. Mattioli, L. A. Cooley, E. S. Hilborn, T. J. Wade, K. E. Fullerton, J. S. Yoder, and V. R. Hill. 2017. Surveillance for waterborne disease outbreaks associated with drinking water—United States, 2013–2014. Morb. Mortal. Wkly. Rep. 66:1216-1221. Berdal, B. P., C. E. Farshy, and J. C. Feeley. 1979. Detection of Legionella pneumophila antigen in urine by enzyme-linked immuno-specific assay. J. Clin. Microbiol. 9(5):575-578. Bozeman, F. M., J. W. Humphries, and J. M. Campbell. 1968. A new group of rickettsia-like agents recovered from guinea pigs. Acta Virol. 12:87-93. Broome, C. V., and D. W. Fraser. 1979. Epidemiologic aspects of legionellosis. Epidemiol. Rev. 1:1-16. Buse, H., M. E. Schoen, and N. J. Ashbolt. 2012. Legionellae in engineered systems and use of quantitative microbial risk assessment to predict exposure. Water Research 46:921-933. Prepublication Version - Subject to further editorial revision

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Introduction 27 Fraser, D. W., T. R. Tsai, W. Orenstein, W. E. Parkin, H. J. Beecham, R. G. Sharrar, J. Harris, G. F. Mallison, S. M. Martin, and J. E. McDade. 1977. Legionnaires’ disease: Description of an epidemic of pneumonia. New England Journal of Medicine 297(22):1189-1197. Fraser, D. W., C. Bopp. I. K. Wachsmuth, J. C. Feeley, and T. F. Tsai. 1978. Antibiotic treatment of guinea pigs infected with agent of Legionnaires’ disease. Lancet 1:175-178. Garrity, G. M., J. A. Bell, and T. Lilburn. 2005. Legionellales ord. nov. Pp. 210-247. In Bergey’s manual® of systematic bacteriology: Volume two, the proteobacteria, part B, the gammaproteobacteria. D. J. Brenner et al., Eds. Springer, United States: Boston, MA. Glick, T. H., M. B. Gregg, B. Berman, G. Mallison, W. W. Rhodes, Jr., and I. Kassanoff. 1978. Pontiac fever: An epidemic of unknown etiology in a health department. I. Clinical and epidemiologic aspects. Am. J. Epidemiology 107:149-160. Gregersen, P., K. Grunnet, S. A. Uldum, B. H. Andersen, and H. Madsen. 1999. Pontiac fever at a sewage treatment plant in the food industry. Scandinavian Journal of Work, Environment & Health 25(3):291- 295. Guo, J., T. Liang, C. Hu, R. Lv, X. Yang, Y. Cui, Y. Song, R. Yang, Q. Zhu, and Y. Song. 2015. Sequence types diversity of Legionella pneumophila isolates from environmental water sources in Guangzhou and Ji- angmen. Chin. Infect. Genet. Evol. 29:35-41. Hamilton, K. A., M. T. Hamilton, W. Johnson, P. Jjemba, Z. Bukhari, M. LeChevallier, and C. N. Haas. 2018. Health risks from exposure to Legionella in reclaimed water aerosols: Toilet flushing, spray irrigation, and cooling towers. Water Research 134:261-279. Hamilton, K. A., W. Ahmed, S. Toze, and C. N. Haas. 2017. Human health risks for Legionella and Mycobac- terium avium complex (MAC) from potable and non-potable uses of roof-harvested rainwater. Water Research 119(August):288-303. Haupt, T. E., R. T. Heffernan, J. J. Kazmierczak, H. Nehls-Lowe, B. Rheineck, C. Powell, K. K. Leonhardt, A. S. Chitnis, and J. P. Davis. 2012. An outbreak of Legionnaires’ disease associated with a decorative water wall fountain in a hospital. Infection Control and Hospital Epidemiology 33(February):185-191. Hellinga, J. R., R. A. Garduno, J. D. Kormish, J. R. Tanner, D. Khan, K. Buchko, C. Jimenez, M. M. Pin- ette, and A. K. Brassinga. 2015. Identification of vacuoles containing extraintestinal differentiated forms of Legionella pneumophila in colonized Caenorhabditis elegans soil nematodes. Microbiology Open 4(4):660-681. Hicks, L., L. E. Garrison, G. E. Nelson, and L. M. Hampton, 2011. Legionellosis—United States, 2000–2009. Morb. Mortal. Wkly. Rep. 60(32):1083-1086. Hines, S. A., D. J. Chappie, R. A. Lordo, B. D. Miller, R. J. Janke, H. A. Lindquist, K. R. Fox, H. S. Ernst, and S. C. Taft. 2014. Assessment of relative potential for Legionella species or surrogates inhalation exposure from common water uses. Water Research 56:203-213. Johnson, W. J., P. K. Jjemba, Z. Bukhari, and M. LeChevallier. 2018. Occurrence of Legionella in non-potable reclaimed water. Journal of the American Water Works Association 110(3):15-27. Karumathil, D. P., H. B. Yin, A. Kollanoor-Johny, and K. Venkitanarayanan. 2014. Effect of chlorine expo- sure on the survival and antibiotic gene expression of multidrug resistant Acinetobacter baumannii in water. Int. J. Environ. Res. Public Health 11(2):1844-1854. Kuiper, M. W., B. A. Wullings, A. D. L. Akkermans, R. R. Beumer, and D. van der Kooij. 2004. Intracellular proliferation of Legionella pneumophila in Hartmannella vermiformis in aquatic biofilms grown on plas- ticized polyvinyl chloride. Appl. Environ. Microbiol. 70:6826-6833. Leoni, E., F. Catalani, S. Marini, and L. Dallolio. 2018. Legionellosis associated with recreational waters: A systematic review of cases and outbreaks in swimming pools, spa pools, and similar environments. International Journal of Environmental Research and Public Health 15(8):1612. https://doi.org/10.3390/ ijerph15081612. Loenenbach, A. D., C. Beulens, S. M. Euser, J. P. G. van Leuken, B. Bom, W. van der Hoek, A. M. de Roda Husman, W. L. M. Ruijs, A. A. Bartels, A. Rietveld, J. W. den Boer, and P. S. Brandsema. 2018. Two community clusters of Legionnaires’ disease directly linked to a biologic wastewater treatment plant, The Netherlands. Emerging Infectious Diseases 24(10):1914-1918. Prepublication Version - Subject to further editorial revision

28 Management of Legionella in Water Systems Mauchline, W. S., R. Araujo, R. Wait, A. B. Dowsett, P. J. Dennis,and C. W. Keevil. 1992. Physiology and morphology of Legionella pneumophila in continuous culture at low oxygen concentration. Microbiol- ogy 138:2371-2380. McDade, J. E., D. J. Brenner, and F. M. Bozeman. 1979. Legionnaires’ disease bacterium isolated in 1947. Ann. Intern. Med. 90:659-661. Mercante, J. W., and J. M. Winchell. 2015. Current and emerging Legionella diagnostics for laboratory and outbreak investigations. Clinical Microbiology Reviews 28(1):95-133. NRC (National Research Council). 2006. Drinking water distribution systems: Assessing and reducing risks. Wash- ington, DC: National Academies Press. Olsen, J. S., T. Aarskaug, I. Thrane, C. Pourcel, E. Ask, G. Johansen, V. Waagen, and J. M. Blatny. 2010. Alter- native routes for dissemination of Legionella pneumophila causing three outbreaks in Norway. Environ. Sci. Technol. 44:8712-8717. Osterholm, M. T., T. D. Y. Chin, D. O. Osborne. H. B. Dull, A. G. Dean, D. W. Fraser, P. S. Hayes, and Wil- liam N. Hall. 1983. A 1957 outbreak of Legionnaires’ disease associated with a meat-packing plant. American Journal of Epidemiology 117(1):60-7. Parker, B. C., M. A. Ford, H. Gruft, and J. O. Falkinham, III. 1983. Epidemiology of infection by nontu- berculous mycobacteria. IV. Preferential aerosolization of Mycobacterium intracellularae from natural waters. American Review of Respiratory Disease 128(4):652-656. Phin, N., F. Parry-Ford, T. Harrison, H. R. Stagg, N. Zhang, K. Kumar, O. Lortholary, A. Zumla, I. Abubakar. 2014. Epidemiology and clinical management of Legionnaires’ disease. Lancet Infect. Dis. 14:1011- 1021. Politi, B. D., D. W. Fraser, G. F. Mallison, J. V. Mohatt, G. K. Morris, C. M. Patton, J. C. Feeley, R. D. Telle, and J. V. Bennett. 1979. A major focus of Legionnaires’ disease in Bloomington, Indiana. Ann. Intern. Med. 90(4):587-591. Reeves, M. W., L. Pine, S. H. Hutner, J. R. George, and W. K. Harrell. 1981. Metal requirements of Legionella pneumophila. Journal of Clinical Microbiology 13:688-695. Rhoads, W. J., A. Pruden, and M. A. Edwards. 2016. Survey of green building water systems reveals elevated water age and water quality concerns. Environmental Science: Water Research and Technology 2(1):164- 173. Shands, K. N., J. L. Ho, R. D. Meyer, G. W. Gorman P. H. Edelstein, G. F. Mallison, S. M. Finegold, and D. W. Fraser. 1985. Potable water as a source of Legionnaires’ disease. JAMA 253:1412-1416. Shaw, P., A. Barskey, A. Binder, C. Edens, S. Lee, J. Smith, S. Schrag, C. Whitney, and L. Cooley. 2018. Legion- naires’ disease surveillance summary report, United States, 2010–2015. Atlanta, GA: CDC. States, S. J., L. F. Conley, M. Ceraso, T. E. Stephenson, R. S. Wolford, R. M. Wadowsky, A. M. McNamara, and R. B. Yee. 1985. Effects of metals on Legionella pneumophila growth in drinking water plumbing systems. Applied and Environmental Microbiology 50(5):1149-1154. St-Martin, G., S. Uldum, and K. Mølbak. 2013. Incidence and prognostic factors for Legionnaires’ disease in Denmark, 1993–2006. ISRN Epidemiology Volume 2013, Article ID 847283, 8 pages. Tatlock, H. 1944. A Rickettsia-like organism recovered from guinea pigs. Proc. Soc. Exp. Biol. Med. 57:95. Thacker, S. B., J. V. Bennett, T. F. Tsai, D. W. Fraser, J. E. McDade, C. C. Shepard, K. H. Williams, Jr., W. H. Stuart, H. B. Dull, and T. C. Eickhoff. 1978. An outbreak in 1965 of severe respiratory illness caused by Legionnaires’ disease bacterium. Journal of Infectious Diseases 138:512-519. Tobin, J. O’H., M. S. Dunnill, M. French, P. J. Morris, J. Bear, S. Fisher-Hoch, R. G. Mitchell, and M. F. Muers. 1980. Legionnaires’ disease in a transplant unit: Isolation of the causative agent from shower baths. Lancet 316(8186):118-121. Tobin, J. O’H., R. A. Swann, and C. L. R. Bartlett. 1981. Isolation of Legionella pneumophila from water sys- tems; methods and preliminary results. Br. Med. J. 282:515-517. von Baum, H., S. Ewig, R. Marre, N. Suttorp, S. Gonschior, T. Welte, and C. Lück for the Competence Network for Community Acquired Pneumonia Study Group. 2008. Community-acquired Legionella pneumonia: New insights from the German Competence Network for Community Acquired Pneu- monia. Clinical Infectious Diseases 46:1356-1364. Prepublication Version - Subject to further editorial revision

Introduction 29 Winn, W. C. 1988. Legionnaires’ disease: Historical perspective. Clin. Microbiology Reviews 1(1):60-81. Wolter, N., M. Carrim, C. Cohen, S. Tempia, S. Walaza, P. Sahr, L. de Gouveia, F. Treurnicht, O. Hellferscee, A. L. Cohen, A. J. Benitez, H. Dawood, E. Variava, J. M. Winchell, and A. von Gottberg. 2016. Legion- naires’ disease in South Africa, 2012–2014. Emerg. Infect. Dis. 22(1):2012-2014. Yu, V. L., J. F. Plouffe, M. C. Pastoris, J. E. Stout, M. Schousbo, A. Widmer, J. Summersgill, T. File, C. M. Heath, D. L. Paterson, and A. Chereshsky. 2002. Distribution of Legionella species and serogroups isolated by culture in patients with sporadic community-acquired legionellosis: An international col- laborative survey. J. Infect. Dis. 186:127-128. Figure 1-1 citations: 1. Tatlock, H. 1944. A Rickettsia-like organism recovered from guinea pigs. Proc. Soc. Exp. Biol. Med. 57:95. 2. McDade, J. E., D. J. Brenner, and F. M. Bozeman. 1979. Legionnaires’ disease bacterium isolated in 1947. Ann. Intern. Med. 90:659-661. 3. Drozanski, W. 1956. Fatal bacterial infection in soil amoebae. Acta Microbiol. Pol. 5:315-317. 4. Osterholm, M. T., T. D. Y. Chin, D. O. Osborne. H. B. Dull, A. G. Dean, D. W. Fraser, P. S. Hayes, and W. N. Hall. 1983. A 1957 outbreak of Legionnaires’ disease associated with a meat packing plant. American Journal of Epidemiology 117(1):60-67. 5. Feeley, J. C., G. W. Gorman, R. E. Weaver, D. C. Mackel, and H. W. Smith. 1978. Primary isolation media for Legionnaires’ disease bacterium. J. Clin. Microbiol. 8:320-325. 6. Glick, T. H., M. B. Gregg, B. Berman, G. Mallison, W. W. Rhodes, Jr., and I. Kassanoff. 1978. Pontiac fever. An epidemic of unknown etiology in a health department. I. Clinical and epidemiologic aspects. Am. J. Epidemiology 107:149-160. 7. Thacker, S. B., J. V. Bennett, T. F. Tsai, D. W. Fraser, J. E. McDade, C. C. Shepard, K. H. Williams, Jr., W. H. Stuart, H. B. Dull, and T. C. Eickhoff. 1978. An outbreak in 1965 of severe respiratory illness caused by Legionnaires’ disease bacterium. Journal of Infectious Diseases 138:512-519. 8. Fraser, D. W., T. R. Tsai, W. Orenstein, W. E. Parkin, H. J. Beecham, R. G. Sharrar, J. Harris, G. F. Mallison, S. M. Martin, and J. E. McDade. 1977. Legionnaires’ disease: Description of an epidemic of pneumo- nia. New England Journal of Medicine 297(22):1189-1197. 9. Fraser, D. W., C. Bopp. I. K. Wachsmuth, J. C. Feeley, and T. F. Tsai. 1978. Antibiotic treatment of guinea pigs infected with agent of Legionnaires’ disease. Lancet 1:175-178. 10. Berdal, B. P., C. E. Farshy, and J. C. Feeley. 1979. Detection of Legionella pneumophila antigen in urine by enzyme-linked immuno-specific assay. J. Clin. Microbiol. 9(5):575-578. 11. Politi, B. D., D. W. Fraser, G. F. Mallison, J. V. Mohatt, G. K. Morris, C. M. Patton, J. C. Feeley, R. D. Telle, and J. V. Bennett. 1979. A major focus of Legionnaires’ disease in Bloomington, Indiana. Ann. Intern. Med. 90(4):587-91. 12. Shands, K. N., J. L. Ho, R. D. Meyer, G. W. Gorman P. H. Edelstein, G. F. Mallison, S. M. Finegold, and D. W. Fraser. 1985. Potable water as a source of Legionnaires’ disease. JAMA 253:1412-1416. 13. Chien, M., I. Morozova, S. Shi, H. Sheng, J. Chen, S. M. Gomez, G. Asamani, K. Hill, J. Nuara, M. Feder, J. Rineer, J. J. Greenberg, V. Steshenko, S. H. Park, B. Zhao, E. Teplitskaya, J. R. Edwards, S. Pampou, A. Geroghiou, I. C. Chou, W. Iannuccilli, M. E. Ulz, D. H. Kim, A. Geringer-Sameth, C. Goldsberry, P. Morozov, S. G. Fischer, G. Segal, X. Qu, A., Rzhetsky, P. Zhang, E. Cayanis, P. J. De Jong, J. Ju, S. Kalachikov, H. A. Shuman, and J. J. Russo. 2004. The genomic sequence of the accidental pathogen Legionella pneumophila. Science 305:1966-1968. 14. Cazalet, C., C. Rusniok, H. Brüggermann, N. Zidane, A. Magnier, L. Ma, M. Tichit, S. Jarraud, C. Bourch- ier, F. Vandenesch, F. Kunst, J. Etienne, P. Glaser, and C. Buchreiser. 2004. Evidence in the Legionella pneumophila genome for exploitation of host cell functions and high genome plasticity. Nat. Genet. 36:1165-1173. Prepublication Version - Subject to further editorial revision

30 Management of Legionella in Water Systems 15. García-Fulgueiras, A., C. Navarro, D. Fenoll, J. García, P. González-Diego, T. Jiménez-Buñuales, M. Rodriguez, R. Lopez, F. Pacheco, J. Ruiz, M. Segovia, B. Baladrón, and C. Pelaz. 2003. Legionnaires’ disease outbreak in Murica, Spain. Emerg. Infect. Dis. 9(8):915-921. 16. McKinney, R. M., R. K. Porschen, P. H. Edelstein, M. L. Bissett, P. P. Harris, S. P. Bondell, A. G. Steiger- walt, R. E. Weaver, M. E. Ein, D. S. Lindquist, R. S. Kops, and D. J. Brenner. 1981. Legionella long- beachae species nova, another etiologic agent of human pneumonia. Ann. Intern. Med. 94:739-743. 17. Correia, A. M., J. S. Ferreira, V. Borges, A. Nunes, B. Gomes, R. Capucho, J. Gonçalvez, D. M. Antunes, S. Almeida, A. Mendes, M. Guerreiro, D. A. Sampaio, L. Viera, J. Machado, M. J. Simões, P. Gonçalves, and J. P. Gomes. 2016. Probable person-to-person transmission of Legionnaires’ disease. N. Engl. J. Med. 374(5):497-498. 18. Russo, A., C. M. Gouveia1, P. M. M. Soares, R. M. Cardoso, M. T. Mendes, and R. M. Trigo1. 2018. The unprecedented 2014 Legionnaires’ disease outbreak in Portugal: Atmospheric driving mechanisms. Int. J. Biometeorol. 62(7):1167-1179. 19. den Boer, J. W., E. P. Yzerman, J. Schellekens, K. D. Lettinga, H. C. Boshuizen, J. E. Van Steenbergen, A. Bosman, S. Van den Hof, H. A. Van Vliet, M. F. Peeters, R. J. Van Ketel, P. Speelman, J. L. Kool, and M. A. Conyn-Van Spaendock. 2002. A large outbreak of Legionnaires’ disease at a flower show, The Netherlands, 1999. Emerging Infectious Diseases 8:37-43. 20. Grieg, J. E., J. A. Carnie, G. F. Tallis, B. Zwolakz, W. G. Hart, C. S. Guest, N. J. Ryan, J. A. Leydon, A. G. Tan, and I. R. Gordon. 2004. An outbreak of Legionnaires’ disease at the Melbourne Aquarium, April 2000: Investigation and case-control studies. Med. J. Aust. 180(11):566-572. 21. Lapierre, P., E. Nazarian, Y. Zhu, D. Wroblewski, A. Saylors, T. Passaretti, S. Hughes, A. Tran, Y. Lin, J. Kornblum, S. S. Morrison, J. W. Mercante, R. Fitzhenry, D. Weiss, B. H. Raphael, J. K. Varma, H. A. Zucker, J. L. Rakeman, and K. A. Musser. 2015. Legionnaires’ disease outbreak caused by endemic strain of Legionella pneumophila, New York, New York, USA, 2015. Emerg. Infect. Dis. 223(11):1784- 1791. 22. Nelson, R. 2016. Crisis in Flint: Lead and Legionnaires’ disease. Lancet Infect. Dis. 16:298-299. Prepublication Version - Subject to further editorial revision

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Legionnaires’ disease, a pneumonia caused by the Legionella bacterium, is the leading cause of reported waterborne disease outbreaks in the United States. Legionella occur naturally in water from many different environmental sources, but grow rapidly in the warm, stagnant conditions that can be found in engineered water systems such as cooling towers, building plumbing, and hot tubs. Humans are primarily exposed to Legionella through inhalation of contaminated aerosols into the respiratory system. Legionnaires’ disease can be fatal, with between 3 and 33 percent of Legionella infections leading to death, and studies show the incidence of Legionnaires’ disease in the United States increased five-fold from 2000 to 2017.

Management of Legionella in Water Systems reviews the state of science on Legionella contamination of water systems, specifically the ecology and diagnosis. This report explores the process of transmission via water systems, quantification, prevention and control, and policy and training issues that affect the incidence of Legionnaires’ disease. It also analyzes existing knowledge gaps and recommends research priorities moving forward.

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