1251CHAPTER 159 Legionella Infections

towers or fountains) or to large building structural water systems that

cause multiple prolonged exposures (e.g., those in hospitals, hotels, or

apartments). The most commonly reported sources include not only

cooling towers and fountains but also water misters; centralized heating, ventilation, and air-conditioning systems; hot tubs/spas; pools; ice

machines; and showerheads and sinks in large premise plumbing structures (Fig. 159-2). When used as primary sources of water, groundwater and wells have also been associated with Legionella exposures.

The majority of exposures are related to engineered hot-water systems,

which are often maintained at temperatures that limit scalding but are

ideally suited for Legionella’s growth. Legionella can also be found in

cold water, particularly in warmer summer months, as a consequence

of the warming water temperature; engineering issues (e.g., heating

lamps in fountains); or unexpected breaks in plumbing systems (e.g.,

malfunctioning thermostatic mixing valves), which can lead to hot-water contamination of cold-water systems.

Buildings with inconsistent use patterns, such as hotels in seasonal

travel destinations, can be linked to outbreaks of legionellosis, as water

stagnation leads to low chlorine/disinfectant levels and organism

proliferation can reach high enough levels to cause disease. Outbreaks

have also been linked to cruise ships and boats. Because of stay-athome orders related to the SARS-CoV-2 pandemic, there is concern

that, once the affected buildings (e.g., hotels) are reopened, limited

water movement and stagnation could lead to increases in cases of

legionellosis. Modern buildings with water-saving devices, which aim

to limit water and energy use, may increase the risk of legionellosis, as

they can decrease water temperatures and limit water flow.

Outbreaks in health care and long-term care facilities are identified

more frequently than outbreaks in other facilities, as they often bring

together at-risk patients, prolonged water exposures, accessible testing,

elevated awareness, and regulations that help ensure that cases are

more easily linked to common sources. The outbreak examples listed

in Table 159-1 demonstrate the wide variety of common sources and

the number of cases associated with such factors. As previously mentioned, most large outbreaks involve cooling towers, which can spread

aerosol droplets over a wide area. The largest outbreak reported to date

Year

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

Number of Cases

10,000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

FIGURE 159-1 Increasing Legionella disease incidence in the United States over the past two decades (2000–2018). (From https://www.cdc.gov/legionella/about/history

.html.)

Common

source/outbreak

Sporadic

Water

features

Cooling towers

Travel

Premise

plumbing

Aspiration

FIGURE 159-2 Sources of waterborne Legionella exposures and spectrum of presentation. The spectrum of sporadic to common-source outbreaks is a continuum. For

example, premise plumbing in a large office building can lead to a large outbreak, and travel exposures can be related to large outbreaks. Most sporadic cases have

no documented source of exposure, while outbreaks often involve mechanisms that spread water aerosol droplets over long distances (e.g., cooling towers), with a

consequent ability to infect more individuals. (Reproduced with permission from Kyoko Kurosawa.)

1252 PART 5 Infectious Diseases

involved a cooling tower in Spain that was linked to 449 documented

cases of Legionnaires’ disease. Outbreaks are increasingly discussed

in the media, such as outbreaks linked to cooling towers in the Bronx

neighborhood of New York City, a large hotel outbreak in Atlanta,

and outbreaks associated with the Flint, Michigan, water crisis. It is

not uncommon for lawsuits to be initiated when deaths are linked to

outbreaks.

Sporadic Cases The vast majority of cases of Legionnaires’ disease

occur sporadically in the community, manifesting as communityacquired pneumonia. Identification of the transmission source is

more difficult in community-acquired cases than in nosocomial cases,

despite reporting and review by local public health jurisdictions. In

nearly 90% of all cases of legionellosis, a source of exposure is never

identified. Since the spectrum of water exposures in the community

is so broad and incubation periods can be long, identifying individual exposures often is not possible. Transient exposures to common

sources, travel-related exposures, and exposures to less commonly

linked sources (e.g., potting soil and compost) may also be hard to

identify. Furthermore, studies of domestic hot water have demonstrated that 5–30% of households may have Legionella species detected,

but the role that households play in clinical legionellosis is hard to

determine, as home water testing is infrequently a part of usual contact

investigations. Because of underdiagnosis, it is likely that diagnosed

sporadic community-acquired cases represent only patients who are ill

enough to present to health care for evaluation.

Risk Factors A number of epidemiologic and demographic risk

factors are associated with legionellosis. Older age is a risk factor; most

studies suggest that risk begins to increase at an age of ~40 years. Furthermore, elderly patients are at the highest risk for major complications. Males are at approximately three times greater risk for Legionella

disease than are females in most large epidemiologic studies. Children

are thought to be less likely to develop severe infections. However,

since routine testing is less common among children, cases may be

underreported.

Smoking has been strongly linked to legionellosis. Inhalation of

smoke leads to anatomic changes in the airway epithelium, impairs

neutrophil and monocyte phagocytosis, and has negative effects on

airway ciliary clearance—all of which can increase the risk of pneumonia. Studies have shown that cigarette smoking is a dose-dependent risk

factor. Smoking cannabis has also been associated with increased risk.

Risk and severity of illness are further associated with smoking-related

pulmonary diseases such as chronic obstructive pulmonary disease or

emphysema, which in turn lead to increased risk for complications.

Patients with other organ dysfunction/failure, such as those with renal

disease (including those on dialysis), hepatic disease, nonsmoking

pulmonary disease, and cardiac disease, are at increased risk for legionellosis, although it is unclear whether these factors are related to disease

severity or to greater awareness and consequent recognition by health

care providers.

Immunosuppressed patients are at increased risk for legionellosis

and Legionella-related complications. Patients undergoing treatment

for cancer (including recipients of hematopoietic cell transplantation)

and solid organ transplant recipients are at high risk for legionellosis

due to immunosuppression as well as disease- and treatment-related

comorbidities. Use of prednisone and other glucocorticoids is strongly

associated with legionellosis; however, in light of the heterogeneity of

immunosuppressive agents and their use, it remains unclear whether

most other single agents are as strongly associated with the disease.

Combination immunosuppressive regimens increase risk. Patients

treated with these regimens are more likely to develop non-pneumophila

legionellosis and non–serotype 1 L. pneumophila infections that may

be missed by routine urinary antigen testing. Patients with autoimmune diseases receiving tumor necrosis factor inhibitors, either with

or without concomitant glucocorticoid use, are also at increased risk

for legionellosis. Furthermore, studies suggest a possible association of

legionellosis with genetic polymorphisms in components of the innate

immune system that are important in recognizing and responding to

intracellular pathogens (e.g., Toll-like receptors and interferon genes).

Transmission The Legionella species involved in human disease are

usually waterborne pathogens. However, disease development requires

sufficient levels of the organism at the exposure site, the formation of

small particles that can be inhaled or aspirated into pulmonary alveoli,

and an at-risk host. Legionella-containing aerosol particles <10 μm in

diameter are needed for deposition into the alveoli. The infective dose

during exposures is unknown but likely depends on the host: disease

development in at-risk individuals may require a more limited exposure. Strain virulence is also thought to be important in disease development: L. pneumophila serotype 1 is more apt to lead to outbreaks and

disease than, for example, Legionella anisa, which has only rarely been

associated with disease in high-risk patients. Because of the necessity

for these various factors, estimated attack rates during an exposure are

only ~5% for pneumonic presentations. Attack rates for Pontiac fever

are thought to be higher—up to 90% among those exposed.

Most exposures occur through the inhalation of contaminated

aerosols from mists, sprays, or other mechanisms that produce small

water droplets that can be inhaled into the distal alveoli. In homes,

the most common sites of exposure are showerheads and sinks, which

are especially apt to produce particles small enough for inhalation.

The role played by aspiration or microaspiration in exposures is

more controversial but is hypothesized to be a secondary route for

TABLE 159-1 Examples of Common-Source Outbreaks of Legionella pneumophila Infections Indicate the Wide Variety of Sources and Cases

SITE YEAR SPECIES/SEROTYPE REPORTED SOURCE(S) CASES

Hotela 2012 L. pneumophila serotype 1 Potable water, fountain, spa 85 (plus 29 suspected)

Hospitalb 2012 L. pneumophila Potable water 22

Communityc 2014 L. pneumophila serotype 1 Cooling tower 334

Hospital/communityd 2014–2015 L. pneumophila Potable water, household, cooling towers 86

Long-term care facilitye 2015 L. pneumophila Potable water 74

Communityf 2015 L. pneumophila Hotel cooling towers 128

Hospitalg 2018 L. pneumophila serotype 1 Potable water, showers 13

Hotelh 2019 L. pneumophila Fountain 13 (plus 66 suspected)

Communityi 2019 L. pneumophila Hot tub display 141

Note: Large community outbreaks were most commonly linked to cooling towers. Not all serotypes reported.

a

Smith SS et al: Open Forum Infect Dis 2:ofv164, 2015. b

Office of the Inspector General, Department of Veterans Affairs, 2013. Available at https://www.va.gov/oig/pubs/

VAOIG-13-00994-180.pdf. Accessed May 19, 2021. c

Shivaji T et al: Euro Surveill 19:20991, 2014. d

Smith AF et al: Environ Health Perspect 127:127001, 2019. e

Auditor General,

State of Illinois, Auditor General, 2019. Available at https://auditor.illinois.gov/Audit-Reports/Performance-Special-Multi/Performance-Audits/2019_Releases/19-QuincyLegionnaires-Disease-Perf-Digest.pdf. Accessed May 19, 2021. f

Commissioner, New York City Department of Health and Mental Hygiene, 2015. Available at https://www1.

nyc.gov/assets/doh/downloads/pdf/han/alert/legionella-in-bronx-source-identified.pdf. Accessed May 19, 2021. g

Kessler MA et al: Am J Infect Control S0196-6553(21)00091-2,

2021. Online ahead of print. h

Brown E: New York Times, 2019. Available at https://www.nytimes.com/2019/08/16/us/legionnaires-disease-atlanta-hotel-reopen.html. Accessed

May 14, 2021. i

North Carolina Department of Health and Human Services, 2019. Available at https://epi.dph.ncdhhs.gov/cd/legionellosis/MSFOutbreakReport_FINAL.pdf.

Accessed May 19, 2021. j

Not serotype 1.

1253CHAPTER 159 Legionella Infections

developing pneumonia. Although human-to-human transmission is

not a common pathway, a single presumptive case has been reported.

After exposure, L. pneumophila has an incubation period of ~2–10

days; this period has been reported to be longer in immunosuppressed

hosts. In contrast, symptoms of Pontiac fever occur within 24–48 h

after exposure.

■ CLINICAL PRESENTATIONS

Legionella Pneumonia Legionella pneumonia is the most common

manifestation of legionellosis. In clinical practice, Legionella pneumonia is often referred to by clinicians as an “atypical pneumonia” (i.e.,

pneumonia that lacks the classic signs and symptoms of bronchopneumonia), and other bacterial pathogens, such as Chlamydia pneumoniae

and Mycoplasma pneumoniae, are also considered as etiologic agents.

Initial symptoms of Legionella pneumonia are nonspecific and include

fever, myalgias, headache, shortness of breath, and either a dry or a

productive cough (Table 159-2). Patients with pneumonia who present

with neurologic or gastrointestinal symptoms such as anorexia, nausea, or vomiting may be more likely than others to have legionellosis.

Immunosuppressed patients may present without typical symptoms

such as fever. Patients who have recently traveled, who present during

a known or possible Legionella outbreak, or who develop pneumonia

while hospitalized should undergo testing for legionellosis. Patients

with severe pneumonia presentations, including acute respiratory failure, and those with pneumonia and sepsis-like presentations should

undergo testing for Legionella as per current community-acquired

pneumonia guidelines.

On clinical examination, patients with Legionella pneumonia classically present with rales, rhonchi, and—when consolidation is present—

egophony and dullness to percussion. Not all patients, particularly

immunosuppressed patients, present with pulmonary findings on

clinical examination. Initial laboratory findings in patients with

Legionella pneumonia include leukocytosis or leukopenia, thrombocytopenia, and elevated liver enzyme levels; hyponatremia and/or renal

dysfunction are frequent findings. Levels of nonspecific laboratory

markers of inflammation, such as C-reactive protein, can also be

elevated; however, procalcitonin levels may not be as useful as a diagnostic tool. Although clinical symptoms and laboratory findings tend

to be nonspecific, a number of clinical prediction tools, such as the

Winthrop-University Hospital Criteria and the Legionella Score, have

been developed to assist with the diagnosis of Legionella pneumonia.

These scoring systems may be more useful for their negative than for

their positive predictive value.

An important subset of Legionella pneumonia cases are those that

are linked to health care systems—i.e., nosocomial cases. Although

cases of hospital-acquired legionellosis are rare, their identification is

necessary as they may be harbingers of contamination of water systems,

devices, and/or potable water sources. Because of the rarity of nosocomial cases, outbreaks have sometimes occurred over years before the

source is identified within the health care system. In this regard, the

CDC offers the following definitions: (1) A presumptive health care–

associated case of Legionnaires’ disease is one developing in a patient

with Legionella pneumonia after ≥10 days of continuous stay at a health

care facility during the 14 days before onset of symptoms. (2) A possible

case is one that develops in a patient with Legionella pneumonia who

has spent a portion of the 14 days before symptom onset in one or more

health care facilities but not enough time to meet the criteria for a presumptive case. To ensure that singular cases lead to more system-wide

evaluations, the CDC also recommends an investigation if a health

care system detects one or more cases of presumptive health care–

associated Legionnaires’ disease at any time or two or more possible

cases within 12 months of one another.

■ PONTIAC FEVER

Pontiac fever is described as an influenza-like illness whose primary

symptoms are fever, headache, myalgias, chills, vertigo, nausea, vomiting, and diarrhea (Table 159-2). Compared with Legionella pneumonia, Pontiac fever is a milder, self-limited illness that is defined by the

absence of pneumonia. Although studies have shown that Pontiac fever

is associated with exposure to higher counts of colony-forming units

in water sources, the role of the pathogen in the disease is not clear.

Symptoms usually develop 24–48 h after exposure and can last for 2–5

days. Since many other illnesses resemble Pontiac fever, the diagnosis

usually relies on the recognition of typical clinical features during an

outbreak situation; therefore, cases are likely to be missed even when

patients present for health care. Studies documenting specific Legionella species as the cause of Pontiac fever clusters find that most are due

to L. pneumophila exposure; however, non-pneumophila species such

as L. anisa have also been associated with this presentation.

Extrapulmonary Disease A number of rare presentations for

legionellosis have been described. Skin and soft tissue infections that

resemble cellulitis, including cases due to tap water contamination

of postsurgical wounds, have been reported. Endocarditis, primarily

culture-negative prosthetic valve endocarditis, and myocarditis and

pericarditis have also been reported. Rarely, Legionella species have

been associated with septic arthritis and sinusitis.

■ DIAGNOSIS

The diagnosis of legionellosis on the basis of clinical findings alone is

difficult. Additional workup is needed to make a definitive diagnosis,

even when cases are potentially linked to a possible outbreak. To make

TABLE 159-2 Clinical and Epidemiologic Features of Legionella

Pneumonia (Legionnaires’ Disease) and Pontiac Fever

FEATURE

LEGIONELLA

PNEUMONIA PONTIAC FEVER

Incubation period 2–10 daysa 24–72 h

Pathogenesis Legionella infection Legionella infection or

exposure

Common symptoms Abdominal or chest pain

Anorexia

Cough, sputum

production

Confusionb

Diarrheab

Fatigue

Fever/chills

Headache

Myalgias

Nausea/vomitingb

Shortness of breath

Cough

Diarrhea

Fatigue

Fever/chills

Headache

Myalgias

Nausea/vomiting

Vertigo

Risk factors Age >40 years

Male

Smoker

Immunosuppressed host

Neurologic disease

Chronic lung disease

Organ dysfunction/

chronic illness

Factors associated with

increased exposure

Attack rate among

exposed individuals

~5%c ~90%

Hospitalization rate >90% <1%

ICU admission rate 30–50% Extremely low

Treatment Antibiotics (macrolide or

fluoroquinolone)

Supportive care

Case-fatality rated 10% Extremely low

a

Incubation period in immunosuppressed hosts may be longer than 14 days. b

This

symptom is strongly associated with Legionella pneumonia. c

Attack rates are highly

dependent on method of exposure, level of the pathogen in source water, and

host’s level of risk. d

Case-fatality rates are much higher among immunosuppressed

patients and those with severe underlying lung disease, ranging from 30 to 50%.

Abbreviation: ICU, intensive care unit.

Source: Modified from https://www.cdc.gov/legionella/clinicians/clinical-features

.html.

1254 PART 5 Infectious Diseases

a diagnosis, laboratory confirmation is needed, and invasive procedures may be required—e.g., bronchoscopy, particularly for patients

whose results on urinary antigen testing are negative and who cannot

produce sufficient sputum for testing or for patients with severe disease

requiring intensive care unit (ICU) admission. As current treatment

guidelines for community-acquired pneumonia recommend empirical

coverage that includes antibiotics active against Legionella species,

diagnostic testing is not routine even among persons who meet the

criteria for Legionella-specific testing. Furthermore, not all currently

available diagnostic laboratory assays are accessible or rapidly available

in primary care clinics, urgent care facilities, and emergency rooms

where patients may present with their initial symptoms.

Radiologic Findings On chest radiography, Legionella pneumonia

presents as focal infiltrates or consolidations, most frequently in the

lower lobes, that are indistinguishable from those due to other causes

of pneumonia (Fig. 159-3). On CT, air-space disease in one or more

lobes is often with associated ground-glass opacities (Fig. 159-4);

pleural effusions and lymphadenopathy are less frequently seen. In

immunocompromised patients, Legionella can present with similar

lower-lobe consolidations or atypically as pulmonary nodules—with or

without cavitation—that mimic fungal infections (Fig. 159-5) or even

as lung abscesses. Progression during early therapy is not uncommon

in immunosuppressed patients.

Laboratory Diagnostics •  CULTURE Cultures—of sputum,

bronchoalveolar lavage fluid, lung tissue, or extrapulmonary sites—are

the gold standard for diagnosis of Legionella pneumonia because they

are critical for epidemiologic investigations. Legionella species require

special nutrients, such as cysteine, for growth and therefore require

specialized media, such as buffered charcoal yeast extract (BCYE) agar.

Legionellae grow slowly, usually over 3–5 days, with non-pneumophila

species often requiring longer incubation times. Once growth is seen,

Legionella can be stained with standard Gram’s stain, and colonies often

fluoresce blue or white under ultraviolet light. L. micdadei is the only

Legionella species that is also modified-acid-fast positive. Sensitivity

varies with the sample but is highest among lower respiratory tract

samples. At some referral centers, lower-tract samples from high-risk

immunosuppressed patient populations are routinely sent for culture.

Unfortunately, because of current community-acquired pneumonia

guidelines, patients are often treated empirically, and many either never

have samples sent for Legionella-specific cultures or have such samples

collected only after antibiotic administration, which decreases sensitivity. Respiratory cultures from patients with legionellosis are crucial

during outbreak investigations, as clinical and environmental cultures

can be compared by pulsed-gel electrophoresis or molecular sequencing to help identify common-source outbreaks; cultures are also used

for serotyping of L. pneumophila.

FIGURE 159-3 Chest x-ray of a patient with Legionella pneumonia and rightlower-lobe consolidation. A 64-year-old woman presented with fever, dry cough,

and shortness of breath 7 days after returning from international travel. Legionella

urinary antigen testing was positive for L. pneumophila serotype 1.

A B

FIGURE 159-4 Right-upper-lobe infiltrate in a patient with L. pneumophila pneumonia on chest x-ray and CT. An immunosuppressed patient from a long-term care facility

presented with cough, sputum production, fever, and chills. New renal insufficiency and hyponatremia were documented. A chest x-ray (A) was consistent with a small

right-upper-lobe infiltrate (white arrow), which was confirmed by CT (B). Urinary antigen testing for L. pneumophila serotype 1 was negative, but polymerase chain reaction

on bronchoaveolar lavage fluid was positive for L. pneumophila.

1255CHAPTER 159 Legionella Infections

URINARY ANTIGEN TESTING Legionella urinary antigen tests are

widely available at many hospitals and commercial laboratories and

are characterized by ease of use, simple specimen collection, rapid

turnaround time, high sensitivity, and the ability to detect the most

prevalent Legionella species associated with clinical disease—L. pneumophila serotype 1. Urinary antigen testing has limitations, however: it

detects only L. pneumophila serotype 1 and gives false-negative results

in most cases caused by clinically important non–serotype 1 L. pneumophila and non-pneumophila species. Sensitivity for L. pneumophila

serotype 1 is ~70% for most assays, but specificity is very high. The

urinary antigen test can be negative very early in the disease and can

remain positive for months after an infection, particularly in immunosuppressed patient populations; it cannot be used for patients who are

anuric. Urinary antigen testing is not recommended for routine use

in screening for exposures among asymptomatic patients in outbreak

investigations.

SEROLOGY Acute- and convalescent-phase titers of antibody to Legionella have limited sensitivity in diagnosing acute Legionnaires’ disease

but can be useful during outbreak investigations. A case is confirmed by

documenting a fourfold or greater rise in titer of specific serum antibody to L. pneumophila serogroup 1. A case is suspected in tests using

pooled antigens by (1) a fourfold or greater rise in antibody titer to specific species (e.g., L. longbeachae) or non–serogroup 1 L. pneumophila

or (2) a fourfold or greater rise in antibody titer to multiple species of

Legionella. Some experts think that a single antibody level of ≥1:256

may be an adequate basis for diagnosing a presumptive case, but most

prefer paired serology for confirmation. Serology is an imperfect tool;

data suggest that as many as 20–30% of patients with proven legionellosis may not mount an antibody response that is sufficient for diagnosis,

and the sensitivity and specificity of seroconversion with regard to

non-pneumophila Legionella species are unclear among patients with

altered immunity. Serology can provide important information for epidemiologic investigations, helping to identify additional cases missed

by other diagnostic methods. In addition, the use of serologic testing

during outbreak studies allows the investigation of patients without

severe disease (e.g., those with Pontiac fever).

DIRECT FLUORESCENT ANTIBODY TESTING The sensitivity of direct

fluorescent antibody (DFA) testing of sputum is lower than that of

other testing modalities, ranging from 20 to 70% depending on the

assay used. Most available assays target specific species (e.g., L. pneumophila) or serotypes. DFA testing may have a higher positive predictive value in patients with severe pneumonia or symptoms consistent

with Legionnaires’ disease, but it is not recommended for screening

of low-risk patients because of the frequency of false-positive results.

MOLECULAR TESTING Polymerase chain reaction (PCR), loopmediated isothermal amplification (LAMP), and other nucleic acid

amplification tests are highly sensitive for lower respiratory tract

specimens (e.g., sputum) and are becoming more widely available.

Molecular methods can detect Legionella from multiple sources but

are most commonly used for respiratory specimens such as sputum

and bronchoalveolar lavage fluid. PCR is more sensitive than culture; in some studies, up to two to four times as many cases of lower

tract disease were detected only by molecular methods. Molecular

techniques also are useful in diagnosing infection in patients during

antibiotic therapy. However, PCR methods are not used to determine

L. pneumophila serotypes—information that is needed for epidemiologic

investigations—and most commercially available assays target only L.

pneumophila. Multiplex PCR tests for pneumonia and other respiratory

pathogens are increasingly available and may include L. pneumophila.

TREATMENT

Legionella Pneumonia

Treatment of Legionella pneumonia involves antibiotics that target

intracellular pathogens, whereas patients with Pontiac fever do not

require antibiotic therapy. Macrolides and fluoroquinolones are

the first-line agents for Legionella pneumonia according to guidelines in the United States and Europe (Table 159-3). Macrolides

disrupt protein production critical for survival of the organism.

Although erythromycin or clarithromycin is effective, azithromycin is the preferred agent, as it is easier to tolerate and is involved

A B

FIGURE 159-5 Nodular disease presentation on CT in an immunosuppressed patient infected with L. micdadei. A. Presenting CT scan in a hematopoietic cell transplant

recipient presenting with fever and cough. A pulmonary nodule was noted in the right upper lobe. Bronchoscopy was performed; cultures were positive on day 5 for

small white colonies on buffered charcoal yeast extract plates, and these colonies were eventually identified as L. micdadei. B. Repeat CT scan at day 12 demonstrated

an enlarging nodule, diffuse infiltrates, and possible cavitation. The patient required intensive care unit admission and intubation despite appropriate targeted antibiotic

therapy.

1256 PART 5 Infectious Diseases

TABLE 159-3 Treatment Options for Legionella Disease

DISEASE 

OPTIONS FOR INDICATED DISEASE SEVERITYa

MILD MODERATE/SEVEREb

Pontiac fever None N/A

Legionella

pneumonia

Either

A fluoroquinolone

 Levofloxacin, 750 mg PO

once daily; or

 Ciprofloxacin, 500 mg PO

bid; or

 Moxifloxacin, 400 mg PO

once daily

or

A macrolide

 Azithromycin, 500 mg PO

daily; or

 Clarithromycin, 400 mg

PO daily; or

 Erythromycin, 500 mg

PO daily

Either

A fluoroquinolone

 Levofloxacin, 750 mg IV once

daily; or

 Ciprofloxacin, 500 mg IV bid; or

 Moxifloxacin, 400 mg PO bid

or

A macrolide

 Azithromycin, 500 mg IV daily;

or

 Clarithromycin, 400 mg IV

bid; or

 Erythromycin, 1000 mg IV qid

or

Combination therapyc

a

Agents in bold type are considered first-line treatments. b

All immunosuppressed

patients should be considered to have moderate or severe disease and should be

started on IV therapy if possible. All patients requiring inpatient care should receive

IV therapy until their condition improves, at which point they can be switched to an

oral agent. c

Can consider combination therapy despite limited data demonstrating

improved outcomes in severely ill patients. Combinations include either (1) a

fluoroquinolone plus a macrolide or (2) a fluoroquinolone or a macrolide with a

secondary agent. Secondary agents include doxycycline, minocycline, rifampin, and

trimethoprim-sulfamethoxazole, all with varying efficacy for treatment.

Abbreviation: N/A, not applicable.

in fewer drug-drug interactions. Azithromycin and clarithromycin

also reach higher intracellular concentrations than erythromycin.

Fluoroquinolones are potent agents against Legionella species.

Data from both in vitro and in vivo models of infection suggest that

fluoroquinolones may be more effective than macrolides, but no

randomized clinical trials have yet compared the two drug classes

for treatment of legionellosis. In nonrandomized observational

studies, fluoroquinolones have been shown to be more effective

than macrolides (erythromycin and clarithromycin) in terms of

fever resolution and decreased duration of hospitalization; other

such studies have shown no difference in outcome.

Both macrolides and fluoroquinolones are available as IV and

oral formulations. Most experts prefer IV therapy during the first

few days of treatment for patients with severe Legionella pneumonia. Secondary agents, such as rifampin, doxycycline, minocycline,

and, less frequently, trimethoprim-sulfamethoxazole, have also

been used, with mixed responses. Tigecycline, a third-generation

glycylcycline related to tetracyclines, has been used for treatment of

patients with significant antibiotic allergies. The novel aminomethylcycline antibiotic omadacycline appears to be efficacious in vitro,

but its clinical efficacy has not been studied to date, and it is not

currently recommended for routine use. Although data are limited,

combination therapy does not appear to improve outcomes.

The duration of treatment for patients with mild disease is usually 10–14 days, but most symptoms will improve within the first

3–5 days of therapy. For immunosuppressed patients and patients

with severe disease, a 3-week course of therapy is recommended.

The duration of therapy for extrapulmonary manifestations of

Legionella infection is unknown and depends on the site involved

and clinical improvement. Resistance to macrolides and fluoroquinolones has been reported only rarely. Susceptibility testing is

not routinely performed but is available in specialized laboratories

and public health departments.

■ OUTCOMES

Legionella infections are associated with significant morbidity and

mortality, leading to hospitalization and ICU admission of most

patients who develop pneumonia. Case-fatality rates of Legionella

pneumonia are reported to be ~10%, with death more likely among

patients who are admitted to the ICU or have major comorbidities.

Among patients in whom antibiotic treatment is delayed, mortality

rates are approximately three times higher than among those treated

earlier. Patients who develop nosocomial pneumonia attributable

to health care–associated exposures, particularly those due to L.

pneumophila, have case-fatality rates of ~25%. Death is a much more

common outcome among immunocompromised hosts, whose mortality rates can reach ~30–50%. Assessment of long-term follow-up

among patients who survive Legionella pneumonia demonstrates that

more than one-quarter have ongoing complications after recovery,

including recurrent hospitalizations, acute renal failure, respiratory

complications, and recurrent pneumonias, among those who recover

from severe disease. In contrast, recovery from Pontiac fever usually

takes place within 3–5 days, as the disease is self-limiting; hospitalization, complications, and death related to Pontiac fever are extremely

rare.

■ PREVENTION

Prevention of legionellosis starts with addressing water systems. Large

municipal water systems provide water throughout the globe, but the

quality of these systems varies regionally; many areas have limited

access to potable water. Only limited regions have the resources to

address Legionella water contamination; most water-monitoring agencies focus on control of enteric pathogens, such as Escherichia coli and

other coliform bacteria, and do not have an adequate infrastructure

to address Legionella. Even in countries and cities with more complex

water systems, there is wide variation in how waterborne pathogens

are addressed, and rules and regulations are often country dependent.

In the Netherlands, for example, chlorination is not routine, whereas

the United Kingdom and most countries in the European Union use

chlorine routinely as the primary mode of disinfection for public water

systems. Although regulated by the Environmental Protection Agency,

management and treatment strategies in the United States vary by state

and, in some instances, by city.

Prevention in the United States focuses on health care organizations

and hospitals, where water-based exposures are more often linked to

case fatalities. Federal requirements to reduce Legionella risk in the

United States were first established in June 2017, when the Centers

for Medicare and Medicaid Services required that all health care

organizations develop and adhere to water management plans. These

plans require the development of multidisciplinary teams, an understanding of the organization’s water system, identification of high-risk

areas (e.g., transplant units, oncology floors), identification of at-risk

structures for Legionella growth, implementation and monitoring of

control measures, methods for intervention if control measures fail,

and procedures to assure documentation that policies are followed. All

medical centers are required to have an awareness of water quality and

to have systems in place to help prevent nosocomial Legionella pneumonia. Such policies leave water quality assessment, including testing

for Legionella, up to the individual facility. In addition to hospitals, an

increasing number of cities, including New York City, require similar

water-management plans for cooling towers, with registration, testing,

and mitigation options.

Even if detected in regional water systems, Legionella becomes a

human pathogen only after replication in premise plumbing systems.

In buildings, Legionella finds the ideal environment for logarithmic

growth, which leads to exposures and subsequent disease. An important first step in prevention within hospitals is a review of plumbing

systems to identify areas of concern and a review of impact areas

such as dental clinics, ICUs, rehabilitation units, and units that house

high-risk patients. Specific water features, such as therapy pools, ice

machines, and decorative fountains, need policies for cleaning and

disinfection. Targeted approaches to management of cooling towers,

1257CHAPTER 160 Pertussis and Other Bordetella Infections

such as high-efficiency drift eliminators and routine maintenance,

are important considerations. In addition, areas that have undergone

recent construction or renovation should be flagged, with prevention

policies in place to address the associated risks. New construction or

structural updates can lead to water stagnation, while modifications to

plumbing can disrupt biofilms. Units with older premise plumbing are

thought to be at higher risk, but even brand new facilities can become

colonized during construction, with consequent outbreaks.

Testing for Legionella is an important step when presumptive or

possible nosocomial pneumonia cases occur and can help address a

facility’s potential risks. There are a number of methods for environmental testing for Legionella, but environmental cultures are used in

most hospitals because they quantify Legionella levels, allow species

identification/serotyping, and can link environmental sources to

nosocomial outbreaks. Testing usually focuses on locations where the

index patient(s) may have had potential waterborne exposures (e.g.,

at showers and sinks). Other adjacent areas, along with those noted

to be high-risk locations within the hospital, should be considered for

additional testing; positive results should widen the testing area. Proactive testing is increasingly being used to preclude nosocomial cases;

however, if testing is planned, it should be coupled with a management

plan that addresses how Legionella will be dealt with if it is found in the

water system and where and how frequently testing should be done; we

recommend biannual or quarterly testing of select sites within hospital

systems.

If a common-source outbreak is discovered, a number of approaches

can be used to address Legionella. Regardless of source, immediate

limitation of ongoing water exposures for patients in the affected room,

unit, or floor is a crucial step in avoiding additional cases. Removing or

replacing water features associated with exposures, such as decorative

fountains and affected equipment or plumbing devices, may be needed.

Immediate interventions such as heat shock (increasing water temperatures for a limited period) and hyperchlorination may also be useful as

short-term steps in addressing an outbreak.

The addition of a disinfectant to the water system is one of the most

common ways to address the presence of Legionella. Chemical disinfection with agents such as chlorine or monochloramine and copper

and silver ionization are commonly used for secondary disinfection.

Use of disinfectants requires routine maintenance and monitoring of

chemical or ion levels to assure that they are sufficient for prevention.

Lack of monitoring and system failures have led to breakthrough

nosocomial Legionella cases. Another option is water filtration, which

either can serve as a primary method for prevention or can be used

in combination with secondary disinfection. Filters—either in-line

with plumbing or at point-of-use sites—can be considered for either

short- or long-term prevention during an outbreak. However, filters

have a limited life span, can weaken water pressure, and are costly to

maintain.

■ FURTHER READING

Cassell K et al: Estimating the true burden of Legionnaires’ disease.

Am J Epidemiol 188:1686, 2019.

Centers for Disease Control and Prevention: Developing a

water management program to reduce Legionella growth and spread

in buildings: A practical guide to implementing industry standards.

June 5, 2017. Available at https://www.cdc.gov/legionella/wmp/toolkit/

index.html. Accessed May 19, 2021.

Centers for Disease Control and Prevention: Legionnaires’ disease surveillance summary report, United States 2016–2017. Available

at https://www.cdc.gov/legionella/health-depts/surv-reporting/2016-17-

surv-report-508.pdf. Accessed May 19, 2021.

National Academies of Sciences, Engineering, and Medicine:

Management of Legionella in Water Systems. Washington, DC, The

National Academies Press, 2020.

Pierre DM et al: Diagnostic testing for Legionnaires’ disease. Ann Clin

Microbiol Antimicrob 16:1, 2017.

Pertussis is an acute infection of the respiratory tract caused by

Bordetella pertussis. The word pertussis means “violent cough,” which

aptly describes the most consistent and prominent feature of the illness.

The inspiratory sound made at the end of an episode of paroxysmal

coughing gives rise to the common name for the illness, “whooping

cough.” However, this feature is variable: it is uncommon among

infants ≤6 months of age and is frequently absent in older children and

adults. The Chinese name for pertussis is “the 100-day cough,” which

describes the clinical course of the illness accurately. The identification

of B. pertussis was first reported by Bordet and Gengou in 1906, and

vaccines were produced over the following two decades.

■ MICROBIOLOGY

Of the 10 identified species in the genus Bordetella, only four are of

major medical significance. B. pertussis infects only humans and is the

most important Bordetella species causing human disease. B. parapertussis causes an illness in humans that is similar to pertussis but is typically milder; co-infections with B. parapertussis and B. pertussis have

been documented. With improved polymerase chain reaction (PCR)

diagnostic methodology, up to 20% of patients with a pertussis-like

syndrome have been found to be infected with B. holmesii, formerly

thought to be an unusual cause of bacteremia. B. bronchiseptica is an

important pathogen of domestic animals that causes kennel cough

in dogs, atrophic rhinitis and pneumonia in pigs, and pneumonia

in cats. Both respiratory infection and opportunistic infection due

to B. bronchiseptica are reported occasionally in humans. B. petrii,

B. hinzii, and B. ansorpii have been isolated from patients who are

immunocompromised.

Bordetella species are gram-negative pleomorphic aerobic bacilli

that share common genotypic characteristics. B. pertussis and B.

parapertussis are the most similar of the species, but B. parapertussis does not express the gene coding for pertussis toxin. B. pertussis

is a slow-growing fastidious organism that requires selective medium

and forms small, glistening, bifurcated colonies. Suspicious colonies are

presumptively identified as B. pertussis by direct fluorescent antibody

testing or by agglutination with species-specific antiserum. B. pertussis

is further differentiated from other Bordetella species by biochemical

and motility characteristics.

B. pertussis produces a wide array of toxins and biologically active

products that are important in its pathogenesis and in immunity. Most

of these virulence factors are under the control of a single genetic locus

that regulates their production, resulting in antigenic modulation

and phase variation. Although these processes occur both in vitro

and in vivo, their importance in the pathobiology of the organism is

unknown; they may play a role in intracellular persistence and personto-person spread. The organism’s most important virulence factor is

pertussis toxin, which is composed of a B oligomer–binding subunit

and an enzymatically active A protomer that ADP-ribosylates a guanine nucleotide–binding regulatory protein (G protein) in target cells,

producing a variety of biologic effects. Pertussis toxin has important

mitogenic activity, affects the circulation of lymphocytes, and serves

as an adhesin for bacterial binding to respiratory ciliated cells. Other

important virulence factors and adhesins are filamentous hemagglutinin, a component of the cell wall, and pertactin, an outer-membrane

protein. Fimbriae, bacterial appendages that play a role in bacterial

attachment, are the major antigens against which agglutinating antibodies are directed. These agglutinating antibodies have historically

been the primary means of serotyping B. pertussis strains. Other virulence factors include tracheal cytotoxin, a peptidoglycan fragment,

which causes inflammatory respiratory epithelial damage; adenylate

160 Pertussis and Other

Bordetella Infections

Karina A. Top, Scott A. Halperin