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Legionella Infections

Chapter 164 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Legionella species cause two primary human diseases: Legionella pneumonia (Legionnaires' disease) and Pontiac fever; collectively referred to as legionellosis.
  2. L. pneumophila serotype 1 is the most frequently isolated pathogen, responsible for >80% of cases of Legionnaires' disease.
  3. Diarrhea, hyponatremia, and neurologic symptoms (confusion) are strong clinical predictors of Legionella pneumonia compared to other atypical pneumonias.
  4. Urinary antigen testing is the most widely available diagnostic tool but detects only L. pneumophila serotype 1; it has high specificity but variable sensitivity (~70%).
  5. Culture on buffered charcoal yeast extract (BCYE) agar is the gold standard but requires specialized media and slow growth (3-5 days).
  6. First-line treatment involves macrolides (azithromycin preferred) or fluoroquinolones (levofloxacin, moxifloxacin); duration is typically 5-10 days for stable patients.
  7. Pontiac fever is a self-limited influenza-like illness defined by the absence of pneumonia and does not require antibiotic therapy.
  8. Outbreaks are most commonly linked to water sources dispersing aerosol droplets (cooling towers, fountains, showers) in large buildings.
  9. Risk factors include age >40 years, male sex, smoking, immunosuppression, and chronic lung or organ dysfunction.
  10. Case-fatality rates for Legionella pneumonia are ~10%, but can range from 30-50% in immunosuppressed patients or those with severe underlying lung disease.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Increasing Legionella disease incidence in the United States over (2000–2019)
2 🖼 Figure CHAPTER 164 FIGURE 164-3 Chest x-ray of a patient with Legionella pneumonia...
3 🖼 Figure Right-upper-lobe infiltrate in a patient with L
4 🖼 Figure Sources of waterborne Legionella exposures and spectrum of to common-source outbreaks is...
5 🖼 Figure Right-upper-lobe infiltrate in a patient with L
6 🖼 Figure Right-upper-lobe infiltrate in a patient with L

1. DEFINITION & OVERVIEW

  • Legionella species cause two primary human diseases: Legionella pneumonia (often referred to as Legionnaires' disease) and Pontiac fever; collectively, these diseases are referred to as legionellosis.
  • Legionnaires' disease was first described in 1976 in an outbreak among members of the American Legion participating in a conference at a hotel in Philadelphia, Pennsylvania.
  • Legionella pneumonia is often referred to by clinicians as an 'atypical pneumonia' (i.e., pneumonia that lacks the classic signs and symptoms of bronchopneumonia).
  • Other bacterial pathogens, such as Chlamydia pneumoniae and Mycoplasma pneumoniae, are also considered as etiologic agents of atypical pneumonia.
  • Harrison's defines this as: 'Legionella species are responsible for >50% of all waterborne outbreaks and >10% of disease related to drinking water in the United States.'
  • Most cases of legionellosis are linked to waterborne exposures.
  • These infections can be either sporadic or due to common-source community or nosocomial exposures.
  • Outbreaks of legionellosis are well described.
  • After exposure, legionellosis occurs primarily among persons with risk factors for disease, including older adults and those with primary organ dysfunction, immunocompromise, or other chronic illnesses.
  • Clinical awareness is important, as the similarity of signs and symptoms of legionellosis to those of other respiratory illnesses can lead to delayed treatment.
  • Despite appropriate therapy, Legionella pneumonia is associated with significant morbidity and mortality.

1.1 Disease Classification

  • Legionnaires' disease: Severe pneumonia with systemic symptoms.
  • Pontiac fever: Milder, self-limited influenza-like illness without pneumonia.
  • Extrapulmonary disease: Rare presentations including skin and soft tissue infections, endocarditis, myocarditis, pericarditis, septic arthritis, and sinusitis.

2. EPIDEMIOLOGY

  • Steven A. Pergam, Thomas R. Hawn estimates that 50,000–70,000 Americans develop Legionnaires' disease per year.
  • Incidence rates of legionellosis in the United States are reportedly 2–3 cases per 100,000 persons, but higher rates have been reported in other parts of the world.
  • Numerous global epidemiologic studies have shown an increasing prevalence over the past few decades; this increase has been hypothesized to be due to a variety of causes, including an aging population, improved diagnostics, global temperature changes, and an aging water infrastructure.
  • Legionella species are found throughout the world, but most epidemiologic data focus on legionellosis in large metropolitan areas in Australia/New Zealand, Europe, and North America.
  • Rates of infection in other parts of the world are unknown, as surveillance systems and laboratory testing are less readily available in large portions of Africa and Asia.
  • More than 80% of cases of Legionnaires' disease are linked to L. pneumophila—in particular to serotype 1, which is the most frequently isolated Legionella pathogen.
  • In Australia and New Zealand, for example, the rate of disease due to Legionella longbeachae approaches or exceeds that for L. pneumophila.
  • Despite increases in cases in the United States and throughout the world, incident cases are still thought to be underreported.
  • Many cohort studies of community-acquired pneumonia do not require routine testing for Legionella or assess only for L. pneumophila serotype 1 (by urinary antigen testing) and therefore may underestimate true prevalence.
  • In studies that routinely assess for legionellosis, the prevalence of Legionella pneumonia ranges between 2 and 10% of all community-acquired pneumonia cases.
  • Seasonality and Climate: The incidence of Legionella disease increases in the summer and fall—specifically, in warmer weather and with increased rain and humidity.
  • Seasonal storms, which may disrupt water pipes or cause increased flooding, can result in contamination of water systems with soil and lead to Legionella exposures.
  • There is concern that, with ongoing climate shifts and rising global temperatures, cases of legionellosis may continue to increase.
  • Community and Health Care–Associated Outbreaks: Small and large clusters and point-source outbreaks of Legionella cases lead to public health investigations, but these situations account for only ~5–10% of all Legionella cases yearly.
  • Outbreaks occur when two or more people become ill after shared exposures in a community.
  • In health care systems, a single proven case should trigger a Legionella investigation.
  • The Centers for Disease Control and Prevention (CDC) recommends an outbreak investigation if a single patient with Legionella is identified who did not leave the facility/campus for the 10 days prior to illness onset.
  • Additionally, an outbreak investigation within a health care system is warranted if there are at least two possible Legionella patients who spent any time in the hospital/long-term care facility within 12 months of each other.
  • Most common outbreaks are linked to water sources dispersing aerosol droplets that increase the area of particle spread (e.g., cooling towers or fountains) or to large building structural water systems that cause multiple prolonged exposures (e.g., those in hospitals, hotels, or apartments).
  • 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.
  • 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.
  • Following stay-at-home orders during the SARS-CoV-2 pandemic, when buildings (e.g., hotels) were reopened, limited water movement and stagnation led 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.

2.1 Risk Factors

  • Older age is a risk factor; most studies suggest that risk begins to increase at an age of ~40 years.
  • 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).
  • There has also been transmission to lung transplant recipients from donor lungs.

2.2 Outbreak Examples

  • Table 164-1 Examples of Legionella Common Source Outbreaks, Indicating the Wide Variety of Sources and Cases.
  • Large community outbreaks most commonly linked to cooling towers.
  • Cases not noted to be a specific serotype, were not reported.

Table 1 — Table 164-1 Examples of Legionella Common Source Outbreaks, Indicating the Wide Variety of Sources and Cases

SITE YEAR ORGANISMa REPORTED SOURCE(S) CASES
Hotelb 2012 L. pneumophila serotype 1 Potable water, fountain, spa 85 (29 suspect)
Hospitalc 2012 L. pneumophila Potable water 22 cases
Communityd 2014 L. pneumophila serotype 1 Cooling tower 334 cases
Hospital/communitye 2014-15 L. pneumophila Potable water, household, cooling towers 86 cases
Long-term care facilityf 2015 L. pneumophila Potable water 74 cases
Communityg 2015 L. pneumophila Hotel cooling towers 128 cases
Hospitalh 2018 L. pneumophila serotype 1 Potable water, showers 13 cases
Hoteli 2019 L. pneumophila Fountain 13 LP (66 suspect)
Communityj 2019 L. pnuemophilak Hot-tub display 141 cases
Communityl 2022 L. pneumophila serotype 1 Cooling tower 17 cases

3. ETIOLOGY & PATHOPHYSIOLOGY

  • Legionellae are aerobic gram-negative bacteria that are ubiquitous in aquatic environments, damp soil, and compost.
  • Of the more than 60 Legionella species, approximately half have been documented to lead to clinical disease, but most clinical disease is driven by Legionella pneumophila, primarily serotype 1.
  • The primary habitats for growth and replication of Legionella are amoebae and other free-living protozoa, in which these bacterial species can thrive intracellularly; humans are accidental hosts.
  • Legionellae are reliant on host-derived amino acids and nutrients for intracellular replication.
  • The organisms have a biphasic life cycle: a replicative phase in nutrient-rich conditions (e.g., in their protozoal hosts) and a noninfective transmissive phase under scarcity of resources.
  • Therefore, they can persist in complex biofilms in both natural and engineered water systems (e.g., premise plumbing—a building's hot and cold water piping systems) and are phagocytized by waterborne protozoa.
  • In premise plumbing systems, where temperature and nutrients support the protozoal hosts of legionellae, the bacteria can replicate to concentrations sufficient to cause human infection.
  • After exposure to Legionella through inhalation or aspiration of small aerosol particles, the organisms attach to immune cells and are phagocytized.
  • After phagocytosis, they can evade intracellular defenses and replicate in human alveolar macrophages and monocytes.
  • Pathogenic Legionella species have numerous virulence systems that they use to evade the human immune system, including the development of Legionella-containing vacuoles within immune cells, downregulation of cytokine receptors, inhibition of host protein synthesis, and avoidance of lysosomal degradation.
  • Despite their ability to replicate and persist in an intracellular environment, innate immune components that target intracellular pathogens—specifically, pattern recognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain–like receptors—activate immune responses.
  • Adaptive CD4 and CD8 cytotoxic T-cell involvement and these innate immune responses eventually lead to the production of interferon γ and tumor necrosis factor, the promotion of neutrophil recruitment into the lung, and other proinflammatory responses.
  • This cascade can be beneficial and result in clearance of the pathogen.
  • However, these inflammatory responses can also cause immunopathology and adverse outcomes.
  • L. pneumophila is more cytopathogenic than most non-pneumophila Legionella species, a characteristic that may be partially responsible for its association with severe disease.

3.1 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 must be <10 μm in diameter 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 (see below) 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 developing pneumonia.
  • Although human-to-human transmission is not a common pathway, a single presumptive case has been reported.

4. CLINICAL FEATURES

  • Legionella Pneumonia: Legionella pneumonia is the most common manifestation of legionellosis.
  • Initial symptoms of Legionella pneumonia are nonspecific and include fever, myalgias, headache, shortness of breath, and either a dry or a productive cough (Table 164-2).
  • 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.
  • 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.
  • 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.
  • Pontiac Fever: Pontiac fever is an influenza-like illness whose primary symptoms are fever, headache, myalgias, chills, vertigo, nausea, vomiting, and diarrhea (Table 164-2).
  • 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, sporadic 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.

4.1 Clinical and Epidemiologic Features

  • Table 164-2 Clinical and Epidemiologic Features of Legionella Pneumonia (Legionnaires' Disease) and Pontiac Fever.
  • Incubation period: Legionella pneumonia (2–10 days), Pontiac fever (24–72 h).
  • Common symptoms: Legionella pneumonia (Abdominal or chest pain, Anorexia, Cough, sputum production, Confusion, Diarrhea, Fatigue, Fever/chills, Headache, Myalgias, Nausea/vomiting, Shortness of breath), Pontiac fever (Cough, Diarrhea, Fatigue, Fever/chills, Headache, Myalgias, Nausea/vomiting, Vertigo).
  • Risk factors: Legionella pneumonia (Age >40 years, Male, Smoker, Immunosuppressed host, Neurologic disease, Chronic lung disease, Organ dysfunction/chronic illness), Pontiac fever (Factors associated with increased exposure).
  • Attack rate among exposed individuals: Legionella pneumonia (~5%), Pontiac fever (~90%).
  • Hospitalization rate: Legionella pneumonia (>90%), Pontiac fever (<1%).
  • ICU admission rate: Legionella pneumonia (30–50%), Pontiac fever (Extremely low).
  • Treatment: Legionella pneumonia (Antibiotics (macrolide or fluoroquinolone)), Pontiac fever (Supportive care).
  • Case-fatality rate: Legionella pneumonia (10%), Pontiac fever (Extremely low).
  • Abbreviation: ICU, intensive care unit.
  • Source: Modified from https://www.cdc.gov/legionella/clinicians/clinical-features.html.
  • Incubation period in immunosuppressed hosts may be longer than 14 days.
  • This symptom (Confusion) is strongly associated with Legionella pneumonia.
  • Attack rates are highly dependent on method of exposure, level of the pathogen in source water, and host's level of risk.
  • Case-fatality rates are much higher among immunosuppressed patients and those with severe underlying lung disease, ranging from 30 to 50%.

Table 2 — Table 164-2 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
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 rate 10% Extremely low

5. DIFFERENTIAL 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 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 empiric 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, including urinary antigen testing, are accessible or rapidly available in primary care clinics, urgent care facilities, and emergency rooms where patients may present with their initial symptoms.
  • Other bacterial pathogens, such as Chlamydia pneumoniae and Mycoplasma pneumoniae, are also considered as etiologic agents of atypical pneumonia.
  • 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.

5.1 Diagnostic Criteria

  • CDC definitions for health care–associated cases:
  • (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.

6. INVESTIGATIONS & DIAGNOSIS

  • 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. 164-3).
  • On computed tomography (CT), air-space disease in one or more lobes is often with associated ground-glass opacities (Fig. 164-4); 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. 164-5) 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 stain, and colonies often fluoresce blue or white under ultraviolet light.
  • L. micdadei is the only non-pneumophila 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 molecularly to help identify common-source outbreaks; cultures are also used for serotyping of L. pneumophila.
  • 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), loop-mediated 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.

6.1 Diagnostic Algorithm

  • Step 1: Clinical suspicion based on symptoms (fever, cough, GI symptoms, confusion) and risk factors (age >40, smoking, immunosuppression).
  • Step 2: Urinary antigen testing for L. pneumophila serotype 1 (rapid, high specificity).
  • Step 3: If urinary antigen negative but suspicion remains high: Obtain respiratory cultures (sputum, BAL) on BCYE agar.
  • Step 4: If cultures negative and patient is immunocompromised or severe disease: Consider PCR on respiratory specimens.
  • Step 5: Serology for outbreak investigations or if other tests are negative.
  • Step 6: Environmental sampling for outbreak investigations.

7. MANAGEMENT & TREATMENT

  • 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 164-3).
  • Macrolides disrupt protein production critical for survival of the organism.
  • Although erythromycin and clarithromycin are both effective, azithromycin is the preferred agent, as it is easier to tolerate and has 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 been conducted to compare the two classes.
  • Fluoroquinolones may be more effective than macrolides, but no randomized clinical trials have been conducted to compare the two classes.
  • 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 aminomethycycline 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 optimal duration of treatment for Legionnaire's disease is unknown.
  • For community-acquired pneumonia, guidelines recommend treatment until the patient achieves clinical stability and for a minimum of 5 days.
  • In the absence of data, a similar duration of treatment for Legionella is a reasonable approach.
  • For immunosuppressed patients and patients with severe disease, a more protracted 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.

7.1 Treatment Guidelines

  • First-line agents: Macrolides (Azithromycin, Clarithromycin) or Fluoroquinolones (Levofloxacin, Moxifloxacin).
  • Azithromycin is preferred due to tolerability and fewer drug-drug interactions.
  • Fluoroquinolones are potent agents against Legionella species.
  • Secondary agents: Rifampin, Doxycycline, Minocycline, Trimethoprim-sulfamethoxazole.
  • Tigecycline for significant antibiotic allergies.
  • Combination therapy does not appear to improve outcomes.
  • Duration: Minimum 5 days for community-acquired pneumonia, until clinical stability.
  • Immunocompromised/Severe disease: More protracted course of therapy recommended.

8. PROGNOSIS & COMPLICATIONS

  • 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 immunosuppressed patients and those with severe underlying lung disease, ranging from 30 to 50%.
  • 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.
  • Despite appropriate therapy, Legionella pneumonia is associated with significant morbidity and mortality.

8.1 Risk Factors for Mortality

  • Immunocompromised patients (cancer, transplant recipients).
  • Severe underlying lung disease.
  • Age >40 years.
  • Male sex.
  • Smoking.
  • Organ dysfunction/chronic illness.

9. SPECIAL CONSIDERATIONS

  • Immunocompromised patients: 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.
  • 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.
  • Children: Children are thought to be less likely to develop severe infections. However, since routine testing is less common among children, cases may be underreported.
  • Travel: 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.
  • Outbreaks: 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.

9.1 Outbreak Management

  • CDC recommends an outbreak investigation if a single patient with Legionella is identified who did not leave the facility/campus for the 10 days prior to illness onset.
  • Additionally, an outbreak investigation within a health care system is warranted if there are at least two possible Legionella patients who spent any time in the hospital/long-term care facility within 12 months of each other.
  • 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.

10. KEY PEARLS & CLINICAL TRAPS

  • Clinical awareness is important, as the similarity of signs and symptoms of legionellosis to those of other respiratory illnesses can lead to delayed treatment.
  • 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.
  • Diarrhea is a strong predictor of Legionella pneumonia.
  • Hyponatremia and/or renal dysfunction are frequent in Legionella pneumonia.
  • Urinary antigen testing is the most widely available diagnostic tool but detects only L. pneumophila serotype 1; it has high specificity but variable sensitivity (~70%).
  • Pontiac fever is a milder, self-limited illness that is defined by the absence of pneumonia and does not require antibiotic therapy.
  • Most cases of legionellosis are linked to waterborne exposures.
  • Outbreaks are most commonly linked to water sources dispersing aerosol droplets (cooling towers, fountains, showers).
  • Risk factors include age >40 years, male sex, smoking, immunosuppression, and chronic lung or organ dysfunction.
  • Case-fatality rates for Legionella pneumonia are ~10%, but can range from 30-50% in immunosuppressed patients or those with severe underlying lung disease.

10.1 Diagnostic Clues

  • 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.
  • Diarrhea is a strong predictor of Legionella pneumonia.
  • Hyponatremia and/or renal dysfunction are frequent in Legionella pneumonia.
  • 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.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Increasing Legionella disease incidence in the United States over (2000–2019)

Caption: FIGURE 164-1 Increasing Legionella disease incidence in the United States over (2000–2019). (From https://www.cdc.gov/legionella/about/history.html.) — Figure 164-1: Line graph showing the increasing incidence of Legionella disease in the United States over the past two decades (2000–2019), reflecting improved diagnostics and aging population.

Figure 2

CHAPTER 164 FIGURE 164-3 Chest x-ray of a patient with...

Caption: CHAPTER 164 FIGURE 164-3 Chest x-ray of a patient with Legionella pneumonia and right- lower-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. Legionella species that is also modified-acid-fast positive. Sensitivity varies with the sample but is highest among lower respiratory tract is samples. At some referral centers, lower-tract samples from high-risk immunosuppressed patient populations are routinely sent for culture. — Figure 164-2: Diagram illustrating the spectrum of waterborne Legionella exposures and sources, ranging from sporadic cases to common-source outbreaks, including cooling towers, fountains, and premise plumbing.

Figure 3

Right-upper-lobe infiltrate in a patient with L

Caption: FIGURE 164-4 Right-upper-lobe infiltrate in a patient with L. pneumophila pneumonia on a long-term care facility presented with cough, sputum production, fever, and chills. consistent with a small right-upper-lobe infiltrate (white arrow), which was confirmed polymerase chain reaction on bronchoalveolar lavage fluid was positive for L. proven legionellosis may not mount an antibody response that is suf- ficient for diagnosis, and the sensitivity and specificity of seroconver- sion 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 addi- — Figure 164-3: Chest x-ray of a patient with Legionella pneumonia showing right-lower-lobe consolidation in a 64-year-old woman with fever and shortness of breath after travel.

Figure 4

Sources of waterborne Legionella exposures and spectrum of to common-source...

Caption: FIGURE 164-2 Sources of waterborne Legionella exposures and spectrum of to common-source outbreaks is a continuum. For example, premise plumbing in a large large outbreak, and travel exposures can be related to large outbreaks. Most sporadic source of exposure, while outbreaks often involve mechanisms that spread water aerosol (e.g., cooling towers), with a consequent ability to infect more individuals. (Reproduced Kurosawa.) — Figure 164-4: Computed tomography (CT) images showing a right-upper-lobe infiltrate in a patient with L. pneumophila pneumonia, confirming consolidation seen on x-ray.

Figure 5

Right-upper-lobe infiltrate in a patient with L

Caption: FIGURE 164-4 Right-upper-lobe infiltrate in a patient with L. pneumophila pneumonia on a long-term care facility presented with cough, sputum production, fever, and chills. consistent with a small right-upper-lobe infiltrate (white arrow), which was confirmed polymerase chain reaction on bronchoalveolar lavage fluid was positive for L. proven legionellosis may not mount an antibody response that is suf- ficient for diagnosis, and the sensitivity and specificity of seroconver- sion 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 addi- — Figure 164-5: CT scan demonstrating nodular disease presentation in an immunosuppressed patient infected with L. micdadei, showing an enlarging nodule and possible cavitation.

Figure 6

Right-upper-lobe infiltrate in a patient with L

Caption: FIGURE 164-4 Right-upper-lobe infiltrate in a patient with L. pneumophila pneumonia on a long-term care facility presented with cough, sputum production, fever, and chills. consistent with a small right-upper-lobe infiltrate (white arrow), which was confirmed polymerase chain reaction on bronchoalveolar lavage fluid was positive for L. proven legionellosis may not mount an antibody response that is suf- ficient for diagnosis, and the sensitivity and specificity of seroconver- sion 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 addi- — Figure 164-6: Schematic representation of the Legionella biphasic life cycle, showing replication in nutrient-rich protozoal hosts and transmission phase under scarcity of resources.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.