Version May 2024
INTRODUCTION — Pneumonia is the most commonly described manifestation of Legionella infection and is termed Legionnaires' disease. Legionella can also cause a self-limiting acute febrile illness, termed Pontiac fever. Rarely, Legionella causes extrapulmonary infections such as cellulitis, abscesses, endocarditis, or meningitis.
The clinical manifestations and diagnosis of Legionella infection will be reviewed here. The epidemiology, pathogenesis, treatment, and prevention are discussed separately. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection" and "Treatment and prevention of Legionella infection".)
LEGIONNAIRES' DISEASE (LEGIONELLA PNEUMONIA)
Clinical features — Pneumonia caused by Legionella is clinically and radiographically similar to other forms of pneumonia. Predominant symptoms include fever, cough, and shortness of breath [1-10]. Symptoms typically arise 2 to 10 days after exposure to contaminated water or soil. Fever and fatigue often precede the onset of cough. Rales and/or other signs of consolidation can be present on physical examination. Sputum may be difficult to obtain. Radiographic findings are varied and nonspecific; however, the most common findings are patchy unilobar infiltrates, which can progress to consolidations [11-13].
Although no clinical features reliably distinguish Legionnaires' disease from other types of pneumonia, certain features may raise the index of suspicion [1-6,10,14-17]. These include:
●Gastrointestinal symptoms such as nausea, vomiting, and diarrhea
●Hyponatremia
●Elevated hepatic transaminases
●C-reactive protein levels >100 mg/L
●Failure to respond to treatment for pneumonia with beta-lactam monotherapy
Scoring systems combining these clinical and laboratory features have been developed, but none have been validated or proven to have adequate predictive value for diagnosis. A scoring system, developed from a large cohort of cases in the United States using clinical parameters only that could be added to electronic health records and may alert clinicians to consider testing [8,15,17-19].
Legionnaires' disease ranges from mild to severe. In a case series of 214 hospitalized patients with Legionnaires' disease, 47 percent had moderate/severe pneumonia (Pneumonia Severity Index IV to V) and 18 percent required intensive care unit (ICU) admission [20]. In other case series, ICU admission was required in 44 percent. Mortality, even in tertiary care centers, ranges from about 1 to 10 percent [4,20,21]. Mortality after admission to ICU may be over 30 percent with some patients requiring extracorporeal membrane oxygenation [22]. Local complications are uncommon but include empyema and lung abscess. Extrapulmonary complications are rare. (See 'Extrapulmonary Legionella disease' below.)
Clinical features of Legionnaires' disease do not appear to vary with the infecting species or serotypes. In a case series evaluating over 100 patients with Legionnaires' disease, signs and symptoms of Legionella longbeachae pneumonia were largely similar to those of Legionella pneumophila pneumonia [4]. Key differences between these species are epidemiologic. L. pneumophila is found worldwide and typically acquired from contaminated water sources in late summer and early fall. By contrast, L. longbeachae is primarily acquired from soil in late spring and early summer and may have a more restricted geographic distribution (eg, most often reported in Australia and New Zealand). (See "Microbiology, epidemiology, and pathogenesis of Legionella infection", section on 'Epidemiology'.)
Diagnosis
When to suspect Legionella — Legionella infection should be considered in any patient presenting with pneumonia. While the majority of Legionella infections occur sporadically in patients with community-acquired pneumonia (CAP), infection can also be acquired in health care settings.
The index of suspicion for Legionella infection should be particularly high during known outbreaks, which are often associated with contamination of water supplies in large facilities such as hospitals, hotels, or apartment buildings. Other epidemiologic factors that should heighten suspicion for Legionella infection include season, known or potential exposure to a contaminated water source (eg, hot tubs, birthing pools, fountains), travel, and exposure to soil or potting mix in areas where the incidence of L. longbeachae is high. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection", section on 'Geographic variation'.)
Patient risk factors include older age, smoking, and chronic lung, cardiovascular, or renal disease [23-26]. Immunocompromise, particularly impaired cell-mediated immunity, increases both the likelihood of infection and poorer outcome [27-29]. Failure to respond to beta-lactam monotherapy in a patient with pneumonia should also raise suspicion for Legionella infection. Concern may also be raised when the course of a viral infection follows an unexpected course. Fatal cases of coinfection with severe acute respiratory syndrome coronavirus 2 have been reported but these are rare and the association is unclear [30]. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection", section on 'Risk factors'.)
Although certain clinical features (eg, altered mental status, gastrointestinal symptoms, and hyponatremia) might raise suspicion for Legionella infection, no individual symptom or sign or combination is pathognomic. Laboratory testing is necessary for diagnosis.
Whom to test — Because early diagnosis and administration of appropriate antimicrobial therapy is associated with improved outcomes in patients with Legionnaires' disease [31,32], we take an inclusive approach to diagnosis and generally test the following patients:
●All patients with moderate to severe CAP or patients with CAP who require hospitalization
●Any patient with CAP or nosocomial pneumonia who has a known or possible exposure to Legionella (eg, during an outbreak)
●Immunocompromised patients (who are at higher risk for Legionella infection and severe disease)
Our approach is largely consistent with recommendations from the Infectious Diseases Society of America (IDSA), the American Thoracic Society (ATS), the British Thoracic Society (BTS), and the National Institute for Health and Care Excellence (NICE) [33-35]. Each organization recommends testing for Legionella infection in all patients with severe CAP or those who require hospitalization. In addition, IDSA/ATS and BTS guidelines recommend testing for patients with nonsevere CAP who have specific risk factors or epidemiologic exposures [33,35-38].
Approach to testing — The main testing options for Legionella infection include nucleic acid detection (eg, polymerase chain reaction [PCR]), urine antigen tests, and culture (table 1).
Because the urinary antigen test only detects L. pneumophila serotype 1, we generally send PCR or culture on a lower respiratory tract sample when urine antigen assays are negative and Legionella infection is still suspected. For patients with positive Legionella urinary antigen tests or PCR, we generally also obtain a culture from the lower respiratory tract for epidemiologic purposes (eg, comparison with isolates from other patients or potential sources).
Testing methods
Polymerase chain reaction — PCR is the preferred test for the diagnosis of Legionnaires' disease. PCR can be performed on nearly any sample type and detects all clinically important Legionella species and serotypes. The diagnostic accuracy of PCR appears to be high and exceeds that of culture but is difficult to determine because there is no reliable reference standard [39-43]. The major limitation of PCR is the inability to obtain adequate sputum samples from patients with Legionnaires' disease. For some patients, inducing sputum for testing may enhance diagnostic yield [44]. Testing for upper respiratory samples by PCR is also an alternative; however, the sensitivity is low [44]. Metagenomic next generation sequencing of blood other bodily fluids is under investigation but the sensitivity and specificity is yet to be determined [45].
Urine Legionella antigen testing — The Legionella urinary antigen test is a commonly used alternative test for Legionnaires' disease. The sensitivity of urine antigen tests ranges from approximately 70 to 80 percent and the specificity approaches 100 percent in patients with Legionnaires' disease caused by L. pneumophila serotype 1 [39,46,47]. Legionella antigens can be detected in urine as early as one day after symptom onset and persist for days to weeks. The turnaround time for the assay is a few hours. Lateral flow devices are simple can be used in most clinical laboratories [48].
The major disadvantage of the assay is that it only detects L. pneumophila serotype 1. While L. pneumophila serotype 1 causes over 80 percent of reported cases of Legionnaires' disease in most regions of the world, L. longbeachae is common in some regions, such as Australia and New Zealand, which limits the utility of the assay [49]. Other urinary antigen systems that detect a broader range of species are under are under investigation [50].
Culture — Culture on special media is considered the gold standard for diagnosis of Legionella infections. Culture can be performed on nearly any sample type and results are typically obtained in approximately three to five days.
For Legionnaires' disease, the sensitivity of sputum cultures is variable with a reported range of <10 to 80 percent [39,46,51]. The specificity of culture nears 100 percent as colonization with Legionella species does not occur. A major limitation of sputum culture is that only about one-half of patients with Legionnaires' disease produce sputum [2-6]. As with other types of pneumonia, induced sputum and bronchoscopic samples appear to have greater diagnostic yield.
Legionella species can be cultured from blood, but the yield is poor and the growth may not activate the alarm on some commercial blood culture machines [52].
The sensitivity of culture also varies with the experience of the microbiology laboratory. Respiratory samples require prompt processing because Legionella bacteria do not survive for prolonged periods in respiratory secretions. In addition, some laboratories reject sputum samples with low polymorphonuclear leukocyte counts [53]. Because lack of purulent sputum is a common finding with Legionnaires' disease, rejection criteria should not be applied when Legionella infection is suspected, and the same applies to PCR testing [54]. Special media, typically buffered charcoal yeast extract (BCYE) agar, is required for culture. BCYE is supplemented with alpha-ketoglutarate and is rich in iron and L-cysteine, both of which are essential for Legionella growth (picture 1).
Antimicrobial susceptibility testing is not routinely performed because there are no standard methods or interpretative criteria [55-58]. The identification of an azithromycin resistance gene (lpeAB genes encoding a macrolide efflux pump) and point mutations in the L. pneumophila 23S rRNA, which mediate intermediate to high levels of macrolide resistance, and a tetracycline destructase gene in L. longbeachae have raised the need for a standardized resistance testing system [58].
Other testing methods — Direct fluorescent antibody (DFA) staining and serology are available but are generally not used in clinical practice. DFA staining has poor sensitivity and cross reacts with other respiratory pathogens. Serology requires collection of acute and convalescent samples spaced four weeks apart, which is clinically impractical. Serology is thus primarily used for retrospective diagnosis in epidemiologic investigations.
OTHER LEGIONELLA INFECTIONS
Pontiac fever — Pontiac fever is an acute, self-limited febrile illness, which can follow exposure to several Legionella species [59]. Symptoms are nonspecific and include fever, headache, chills, myalgias, nausea, vomiting, and diarrhea [60-62]. Symptom onset occurs approximately 4 to 60 hours after exposure (median 36 hours). The duration of illness ranges from approximately one to nine days (median four days) and typically resolves without specific therapy. In contrast with Legionnaires' disease (Legionella pneumonia), signs and symptoms of lower respiratory tract infection are absent.
Clinical suspicion for Pontiac fever is usually based on epidemiologic exposures (eg, current known outbreak or a cluster of cases with similar symptoms, particularly when a common potential source is evident). Because Pontiac fever is typically self-limited, testing is usually not performed unless part of an epidemiologic investigation.
Extrapulmonary Legionella disease — Extrapulmonary Legionella disease is rare and can occur as a complication of Legionella pneumonia or can occur independently. Most cases have been reported in immunocompromised patients [63]. In contrast with Legionnaires' disease and Pontiac fever, many cases of extrapulmonary Legionella disease are caused by Legionella species other than L. pneumophila [64,65].
The range of reported extrapulmonary manifestations is wide and includes cellulitis [66-70], skin and soft tissue abscesses [64,71-73], septic arthritis [74-77], prosthetic joint infection [78], osteomyelitis [79,80], myocarditis [81-85], pericarditis [86-88], native valve and prosthetic valve endocarditis [89-94], peritonitis [95,96], pyelonephritis [97], meningitis [98], brain abscesses [99-101], and surgical site infections [102].
The diagnosis of extrapulmonary disease requires detection of Legionella at the affected site, usually by culture or polymerase chain reaction.
SUMMARY AND RECOMMENDATIONS
●Legionnaire's disease (Legionella pneumonia) − Pneumonia is the most commonly described manifestation of Legionella infection and is termed Legionnaires' disease. Legionnaires' disease can be acquired sporadically or during outbreaks, which are often associated with contamination of water supplies in large facilities such as hospitals, hotels, or apartment buildings. (See 'Legionnaires' disease (Legionella pneumonia)' above and "Microbiology, epidemiology, and pathogenesis of Legionella infection", section on 'Epidemiology'.)
●Clinically similar to other forms of pneumonia − Pneumonia caused by Legionella is clinically and radiographically similar to other forms of pneumonia. Although there are no signs or symptoms that clearly distinguish Legionnaires' disease from other forms of pneumonia, suggestive clinical features include (see 'Clinical features' above):
•Gastrointestinal symptoms such as nausea, vomiting, and diarrhea
•Hyponatremia
•Elevated hepatic transaminases
•C-reactive protein levels >100 mg/L
•Failure to respond to treatment for pneumonia with beta-lactam monotherapy
●Wide range in severity − Legionnaires' disease ranges from mild to severe. Mortality estimates range from approximately 1 to 10 percent. (See 'Clinical features' above.)
●Indications for testing
•All hospitalized patients with CAP − Because early diagnosis and administration of appropriate antimicrobial therapy is associated with improved outcomes in patients with Legionnaires' disease, we generally test for Legionella in all patients with moderate to severe community-acquired pneumonia (CAP) or patients with CAP who require hospitalization. (See 'Whom to test' above.)
•Patients with pneumonia and known or possible exposure − We also test any patient with CAP or nosocomial pneumonia who has a known or possible exposure to Legionella (eg, during outbreaks) as well as immunocompromised patients with CAP who are at higher risk for infection and/or adverse outcomes. (See 'When to suspect Legionella' above and 'Whom to test' above.)
●Test selection
•PCR (preferred) − When testing for Legionella in patients with pneumonia, we prefer to use polymerase chain reaction (PCR) on a lower respiratory tract sample (eg, sputum or bronchoalveolar lavage specimen) because PCR has high diagnostic accuracy and detects all Legionella species and serogroups (table 1). (See 'Approach to testing' above and 'Polymerase chain reaction' above.)
•Urine antigen testing (alternative) − If PCR is not available or if sputum cannot be obtained, urine antigen testing is an acceptable alternative, especially in regions such as the United States where the prevalence of L. pneumophila serogroup 1 is high. (See 'Approach to testing' above and 'Urine Legionella antigen testing' above.)
•Limitations of urine antigen testing − Because the urinary antigen test only detects L. pneumophila serotype 1, we generally send PCR or culture on a lower respiratory tract sample when urine antigen assays are negative and Legionella infection is still suspected. (See 'Approach to testing' above and 'Culture' above.)
●Pontiac fever − Pontiac fever is typically diagnosed clinically during outbreaks. Microbiologic confirmation is generally not needed because symptoms are self-limited. (See 'Pontiac fever' above.)
●Extrapulmonary infections − Extrapulmonary infections caused by Legionella are rare but reported and include cellulitis, skin abscesses, septic arthritis, myopericarditis, endocarditis, meningitis, and peritonitis. Most extrapulmonary infections occur in immunocompromised patients. Diagnosis requires detection of the organism by culture or PCR from tissue at the affected site. (See 'Extrapulmonary Legionella disease' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledges Victor Yu, MD, Janet Stout, PhD, Nieves Sopena Galindo, MD, and Patricia Priest, MBChB, DPhil, who contributed to earlier versions of this topic review.
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