Continuing Education Activity

Legionellosis refers to infections caused by Legionella species, including Pontiac fever and Legionnaires' disease. Pontiac fever is a self-limited, influenza-like illness without pneumonia, whereas Legionnaires' disease is a severe, atypical pneumonia most commonly caused by Legionella pneumophila. Legionnaires' disease can progress rapidly to respiratory failure, shock, acute kidney injury, and multiorgan dysfunction. Approximately one-third of patients require intensive care, with mortality ranging from 4% to 40%. Although the global incidence is rising, legionellosis remains underdiagnosed and underreported. A high index of suspicion, prompt diagnostic testing, and early initiation of appropriate antimicrobials are critical to improving outcomes. Effective management also includes providing supportive care and implementing prevention and control measures to reduce transmission.

This activity reviews the epidemiology, clinical features, diagnosis, management, and prevention of legionellosis, with an emphasis on Legionnaires' disease. This activity also enhances healthcare professionals’ knowledge of risk factors, early recognition, and diagnostic strategies, while promoting the implementation of guideline-concordant therapy. The activity also emphasizes the importance of supportive care and preventive measures, including environmental monitoring and outbreak response, and highlights how coordinated, multidisciplinary care can improve patient outcomes. In addition, this activity emphasizes the value of interprofessional collaboration among healthcare providers to ensure timely diagnosis, appropriate treatment, and effective control of potential exposure sources. This activity equips healthcare professionals to recognize legionellosis early, select appropriate diagnostic tests, initiate effective therapy, and implement preventive measures to reduce disease transmission.

Objectives:

• Identify key clinical features and risk factors associated with Legionnaires' disease.
• Implement guideline-based empiric antimicrobial therapy for suspected or confirmed Legionnaires' disease.
• Apply evidence-based infection prevention and control measures in healthcare and community settings.
• Collaborate with interprofessional healthcare teams to ensure coordinated patient care, identify potential outbreaks, and implement measures to prevent further transmission of Legionnaires' disease.

Introduction

Legionellosis, and more specifically Legionnaires' disease, refers to human infections caused by bacteria of the genus Legionella. Legionellosis primarily presents as 2 primary syndromes: Pontiac fever (a self-limiting, nonpneumonic influenza-like syndrome) and Legionnaires' disease.[1] Legionnaires' disease is a potentially severe, often fatal, atypical pneumonia caused by bacteria of the genus Legionella, most frequently Legionella pneumophila.

L pneumophila was first identified after a large outbreak of a respiratory illness at an American Legion convention in a hotel in Philadelphia, United States, in 1976, which led to 182 cases and 29 deaths.[2][3] The causative agent, L pneumophila, was detected in the hotel's air-conditioning system, indicating contamination.[2][3] 

Legionellosis remains underdiagnosed and underreported, and its true incidence is unknown. However, studies over the past few decades have shown an increasing incidence of Legionnaires' disease worldwide, most likely due to enhanced clinical awareness, improved diagnostic techniques, and better surveillance systems.[4] Despite an incomplete epidemiological picture, studies report that Legionella spp are among the most common causes of severe community-acquired pneumonia (CAP), with Streptococcus pneumoniae being the most frequent cause.[5] 

L pneumophila can cause rapidly progressing, severe, atypical pneumonia, resulting in respiratory failure, shock, acute renal failure, and multiorgan dysfunction within days. Almost all patients with Legionnaires' disease require hospitalization, and approximately one-third of cases are admitted to the intensive care unit; reported mortality rates range between 4% and 40%.[6][7]

Legionnaires' disease is a well-recognized but increasingly prevalent global health problem. Healthcare professionals should maintain a high index of suspicion in patients with compatible clinical features, as timely diagnosis is essential for early initiation of appropriate therapy and improved outcomes. Early recognition, accurate diagnosis, and prompt treatment are critical, and optimal patient care is best achieved through a multidisciplinary approach to health care.

Etiology

Legionella spp are ubiquitous, aerobic, gram-negative, intracellular, motile bacilli that cause legionellosis worldwide. Since their identification in 1976 as the causative agents of an atypical pneumonia later termed Legionnaires' disease, more than 60 species and 70 serogroups of Legionella have been identified. Among these, L pneumophila is the most common cause of legionellosis and Legionnaires' disease.[1]

L pneumophila serotypes 1 to 6 are responsible for the majority of human infections. Other species, including L micdadei, L bozemanae, L longbeachae, and L dumoffii, account for the remaining 10% of human Legionella pneumonia cases.[8][9] Legionella spp are found worldwide in aquatic environments and ecosystems, including soil and natural and artificial water sources, such as rivers, ponds, cooling towers, and water supply systems.[10] Following colonization within a water system, eradication is exceedingly difficult to achieve, as these organisms form biofilms that can enhance their survival and persistence.[11]

Epidemiology

Legionella spp are ubiquitous environmental bacteria that can infect humans through various transmission routes. Legionellosis is a clinical entity that encompasses infections caused by Legionella spp, ranging from the mild, self-limiting, influenza-like Pontiac fever to the more severe Legionnaires' disease. This atypical pneumonia can be CAP or health care–associated (HAP) and mainly affects vulnerable patients.[7] Since its recognition in 1976, over 60 Legionella species and more than 70 serogroups have been characterized, with L pneumophila serogroup 1 being the most frequently implicated in human disease globally.[1] L longbeachae is the predominant species in New Zealand, the state of Western Australia, and the Northern Territory in Australia, whereas L pneumophila is predominant in the eastern Australian states of Queensland, New South Wales, and Victoria.[12][The Department of Health and Aged Care. Australia's notifiable disease status, 2014: Annual report of the National Notifiable Diseases Surveillance System. 2016]. Typically, L pneumophila has been implicated with cooling tower and other artificial water system exposures, whereas L longbeachae has been more associated with potting mix and gardening.

Risk factors for infection with Legionnaires' disease include male sex, older age, smoking, immunosuppression, malignancy, alcohol misuse, iron overload, treatment with antitumor necrosis factor-α agents, and living in areas of high poverty.[13]

Legionella spp are found worldwide in aquatic environments and ecosystems, including soil and natural and artificial water environments, such as rivers, ponds, cooling towers, and water supply systems in buildings.[10] Any aerosol-generating device that uses contaminated water serves as a vehicle for pathogen dissemination and can facilitate and cause human infection. These bacteria have been recovered from showerheads, faucets, whirlpool spas, and respiratory ventilators.[14] Following the establishment of colonization within a water system, eradication is exceedingly difficult to achieve. Legionella spp are known to form biofilms, which can enhance their survival.[11] Legionnaires' disease also exhibits a seasonal pattern, with an increased incidence linked to higher rainfall and temperatures.[15]

Human-to-human transmission of Legionella spp is infrequent, and there is no evidence of zoonotic transmission. The dominant transmission pathway, especially in community and outbreak settings, is through inhalation of aerosols generated by water systems, such as showers in buildings, faucets, whirlpool spas, cooling towers, humidifiers, and nebulizers, which carry Legionella spp that are then inhaled into the lungs. Once inhaled, L pneumophila subsequently invades alveolar macrophages, thereby causing infection.[16][17] Other modes of transmission include microaspiration of contaminated fluids, especially in hospitalized patients at increased risk of aspiration. 

Distinguishing between CAP and HAP cases is crucial.[18] The incubation period in Legionnaires' disease ranges from 2 to 10 days. Patients who develop Legionella infection after being hospitalized continuously for 10 or more days before the onset of illness are classified as having definite HAP Legionnaires' disease.[19] Legionella HAP cases typically occur in clusters, reflecting point-source exposure within healthcare facilities, such as contaminated water systems or medical equipment. Recognizing these patterns is crucial for implementing timely infection control measures and preventing further transmission of Legionella. 

Both the pneumonia severity index and nosocomial acquisition are independent predictors of increased mortality in patients with Legionella pneumonia.[20] In particular, nosocomially acquired infection due to Legionella spp carries a significantly higher risk of death compared with CAP caused by the same pathogen. Several factors may contribute to this excess mortality, including delayed recognition of the infection, the frequent absence of classical clinical features, and postponement of appropriate antimicrobial therapy. In addition, patients with HAP are more likely to be immunocompromised, have multiple comorbidities, or be exposed to invasive procedures, all of which further worsen outcomes.[20] 

Legionellosis or Legionnaires' disease remains underdiagnosed and underreported; therefore, its true incidence is unknown. In recent decades, however, studies have shown an increasing incidence of Legionnaires' disease worldwide, likely associated with enhanced clinical awareness, improved diagnostic techniques, and better surveillance systems.[4] Despite the incomplete epidemiological picture, studies report that Legionella spp are among the most common causes of severe CAP, with S pneumoniae being the most frequent cause.[5] Recent study results on seroprevalence were analyzed in a systematic review, providing the first comprehensive summary of the global epidemiology of legionellosis.[1] The review found marked heterogeneity across the included studies, and the overall random-effects pooled Legionella seroprevalence was 13.7% (95% CI: 11.3% to 16.5%).[1]

Most cases of Legionnaires' disease are sporadic, with over 70% being community-acquired, whereas others are linked to travel or healthcare settings. Legionnaires' disease accounts for an estimated 2% to 15% of CAP and ranks among the top 4 causes of CAP.[7][21] L pneumophila can result in a rapidly progressive and severe atypical pneumonia, leading to respiratory failure, shock, acute renal failure, and multiorgan dysfunction within days. Admission of hospitalized individuals to the intensive care unit remains high at 20% to 27%, and mortality ranges from 4% to 40%.[6][7][20]

Pathophysiology

Legionnaires' disease is primarily caused by L pneumophila—a gram-negative, waterborne bacillus that thrives in aquatic environments and gains access to the human lung via inhalation or aspiration of aerosols from contaminated water sources.[16] Once in the alveoli, the organism enters alveolar macrophages, inhibits their bactericidal activity, and converts them into sites for replication and growth. Through multiple virulence mechanisms, L pneumophila survives and replicates intracellularly.[22] The susceptibility of patients to Legionella infection is increased by factors that impair innate or adaptive immunity, such as older age, smoking, chronic lung disease, immunosuppression, or comorbid conditions such as diabetes.[23]

In severe disease, evidence suggests an initial hyperinflammatory phase, followed by immunoparalysis, which is characterized by a reduced capacity of immune cells to respond to further stimulation.[16][24] Virulence mechanisms of L pneumophila include flagella, fimbriae, secretion systems, and iron-acquisition systems.[11] The resulting intense inflammatory response damages alveolar and capillary structures, leading to exudation, consolidation, and impairment of gas exchange. Histopathologic studies demonstrate diffuse alveolar damage, involvement of alveolar ducts and respiratory bronchioles, and varying degrees of necrosis and neutrophilic infiltrates.[25]

Histopathology

Histopathological studies of Legionnaires' disease reveal predominant involvement of the terminal bronchioles, characterized by intra-alveolar exudates and edema-induced septal thickening. Legionella primarily replicates in macrophages, causing necrotic lung injury, and infected macrophages act as intracellular reservoirs that support bacterial growth.[16][17] 

Severe confluent lobular or lobar pneumonia is common, and abscess formation may occur. Histopathologic findings typically include a leukocytoclastic inflammatory infiltrate composed of neutrophils and macrophages, septic vasculitis affecting small blood vessels, coagulative necrosis, and focal septal disruption. These features are characteristic but not pathognomonic.[26] Please see StatPearls' companion resource, "Bacterial Pneumonia," for further information.

History and Physical

The history of a patient with suspected Legionnaires' disease typically includes recent exposure to potential sources of contaminated water, such as showers, hot tubs, fountains, cooling towers, or hospital water systems. Travel history is particularly important, especially recent stays in hotels, cruise ships, or healthcare facilities, as are occupational exposures among maintenance and plumbing workers. Symptom onset typically occurs 2 to 10 days after exposure and often begins gradually, characterized by fever, chills, malaise, and myalgias.

Respiratory symptoms commonly include dry cough, dyspnea, and pleuritic chest pain. Gastrointestinal complaints such as diarrhea, nausea, vomiting, and abdominal pain may also occur, and neurological manifestations such as headache, confusion, or ataxia can also be present. Underlying conditions such as chronic lung disease, diabetes mellitus, immunosuppression, or recent hospitalization increase the risk of infection and disease severity.[16][27] Legionnaires' disease should be suspected in all patients with CAP, especially in those with severe illness, poor response to β-lactam antibiotics, or prominent extrapulmonary features.[28]

On physical examination, patients are often ill-appearing with fever, sometimes accompanied by relative bradycardia. Respiratory findings can include crackles or rales, and occasional consolidation, although classic lobar signs may be absent. Tachypnea and hypoxia may indicate severe disease. Additional findings may include confusion, focal neurological deficits, abdominal tenderness, and, rarely, dermatologic or musculoskeletal involvement. Cardiovascular examination is typically unremarkable, although myocarditis or arrhythmias may occur. Awareness of these characteristic signs and symptoms, combined with a patient's exposure history, is critical for the timely recognition and management of Legionnaires' disease.[16]

Evaluation

Diagnosis

The diagnosis of Legionnaires' disease is based on a combination of epidemiological history, clinical assessment, laboratory findings, and radiological abnormalities, as clinical features alone are nonspecific and may resemble those of other forms of pneumonia.[28] Legionnaires' disease should always be considered in the differential diagnosis of all patients with CAP, particularly in severe cases, because early diagnosis and prompt initiation of appropriate therapy are associated with improved outcomes.[28] 

Patient-related and environmental risk factors must also be considered, including recent hospitalization, exposure during outbreaks, prevailing weather conditions, and seasonal trends. The latter are particularly important because, unlike many other pathogens, the incidence of Legionnaires' disease correlates strongly with rainfall and seasonality.[27] Relative bradycardia is regarded as a supportive clinical sign of Legionnaires' disease, particularly in febrile patients who are not receiving bradycardia-inducing medications and do not have a pacemaker.[29]

Laboratory Studies

Laboratory abnormalities in Legionnaires' disease are often nonspecific and may include hyponatremia, hypophosphatemia, elevated creatine kinase levels due to rhabdomyolysis, renal impairment, microscopic hematuria, leukocytosis with lymphopenia, and increased levels of ferritin or C-reactive protein. Although these abnormalities are not diagnostic, they may raise suspicion for Legionnaires' disease.[27][28] 

Microbiological Diagnosis

The urinary antigen test is widely used for its rapid turnaround and high sensitivity; however, it detects only L pneumophila serogroup 1, which remains the most common cause of Legionnaires' disease.[27][28] Culture of respiratory specimens, such as sputum or bronchoalveolar lavage, remains the gold standard, as it allows definitive species identification and epidemiologic typing. Limitations include low sensitivity, the need for specialized media, and, in some cases, invasive sampling procedures. However, standardized protocols are lacking in some settings.[27][28] 

Polymerase chain reaction (PCR) is a validated test for Legionella at many reference labs worldwide, but its use has been restricted due to cost and the laboratory expertise required to perform PCR testing.[30][European Centre for Disease Prevention and Control. Legionnaires' disease - Annual Epidemiological Report for 2023] PCR testing has also been technically employed in the detection of Legionella in immunocompromised individuals. 

Less frequently used methods, such as direct fluorescent antibody staining, are less sensitive and are technically demanding.[28] Optimal diagnostic yield is achieved by combining these methods to guide timely, accurate management of patients with Legionnaires' disease.[27]

Radiological Findings

Radiological findings in Legionnaires' disease are not pathognomonic. Chest radiographs typically demonstrate early patchy alveolar infiltrates with consolidation, most often in the lower lobes, although any lobe may be affected.[27][28] These infiltrates may progress rapidly to bilateral interstitial pneumonia, and pleural effusion occurs in 15% to 50% of cases.[27] Radiographic progression may continue during the first week even as clinical improvement is observed.[27][28] Cavitation and abscess formation are rare but may occur in immunocompromised hosts.[27] Please see StatPearls' companion resource, "Atypical Bacterial Pneumonia," for further information.

Treatment / Management

For patients hospitalized with severe CAP, prompt testing for L pneumophila is recommended. Empirical therapy should include coverage for Legionella spp, as delays in initiating appropriate antimicrobials are associated with poorer outcomes and increased intensive care unit admissions.[28][31][32][33] Fluoroquinolones, such as levofloxacin or moxifloxacin, and macrolides, such as azithromycin, remain first-line therapies for the empirical treatment of Legionella CAP, according to European and United States guidelines. A 2020 meta-analysis found no significant difference in mortality reduction between the 2 classes of antibiotics.[28][34] 

Due to the smaller proportion of overall CAP cases encompassing Legionella infections in various randomized trials, data are limited on the optimal treatment duration. The synergistic effect of combination macrolide/fluoroquinolone therapy has not been adequately studied beyond observational trials and case studies, but it has shown success in severe cases or in cases of treatment failure.[35][36] The consensus is for a 7- to 21-day course of treatment, with prolonged durations reserved for individuals who are immunocompromised or vulnerable to deterioration, including those in the intensive care unit setting.[37] Please see StatPearls' companion resource, "Atypical Bacterial Pneumonia," for further information.

Differential Diagnosis

The differential diagnosis of Legionnaires' disease includes a broad spectrum of respiratory infections and noninfectious conditions that present with pneumonia-like syndromes. Typical bacterial pneumonias, such as those caused by S pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, generally present with an acute onset, productive cough with purulent sputum production, pleuritic chest pain, and lobar consolidation on imaging. In contrast, atypical agents such as Mycoplasma pneumoniae and Chlamydia pneumoniae often cause a milder, subacute illness characterized by pharyngitis, hoarseness, or extrapulmonary findings such as hemolytic anemia or bullous myringitis.[9][28]

Viral pneumonias, including influenza and SARS-CoV-2, are characterized by prominent upper respiratory tract symptoms, myalgias, or anosmia, and often follow seasonal or epidemic patterns. In contrast, Legionnaires' disease is characterized by systemic involvement, with patients frequently presenting with high fever; relative bradycardia; gastrointestinal symptoms, particularly diarrhea and abdominal pain; neurological manifestations, such as confusion, headache, or encephalopathy; and hepatic dysfunction with elevated transaminases.[27] Pontiac fever, the milder form of Legionnaires' disease, is associated with constitutional symptoms such as myalgia, fever, and rigor, but typically resolves without the onset of pneumonia with a shorter recovery period.

Prognosis

Both the pneumonia severity index and nosocomial acquisition are independent predictors of increased mortality in patients with Legionella pneumonia.[20][38] In particular, HAP infections carry a significantly higher risk of death compared with CAP caused by the same pathogen. Several factors may contribute to this excess mortality, including delayed recognition of the infection, the frequent absence of classical clinical features, and postponement of appropriate antimicrobial therapy. In a French observational study, risk factors associated with mortality in legionellosis include intensive care unit admission, renal failure, elevated C-reactive protein levels, and corticosteroid treatment. Typical clinical findings associated with more severe disease include confusion at presentation, hepatic injury, hyponatraemia, and renal failure.[38]

In addition, patients with HAP are more likely to be immunocompromised, have multiple comorbidities, or be exposed to invasive procedures, all of which further worsen outcomes.[20] Infection with L pneumophila can cause rapidly progressive and severe atypical pneumonia, leading to respiratory failure, shock, acute renal failure, and multiorgan dysfunction within days. Admission of hospitalized patients to the intensive care unit remains high at 20% to 27%, and mortality ranges from 4% to 40%.[6][7][20]

Complications

Pulmonary complications may include the development of acute respiratory distress syndrome and interstitial pneumonia with pulmonary fibrosis.[39]

Extrapulmonary manifestations of Legionnaires' disease are mentioned below.

• Cardiovascular: Myopericarditis and endocarditis [40][41][42]
• Neurological: Encephalitis, brain abscess, and cerebellar ataxia [43][44][45]
• Gastrointestinal: Pancreatitis, colitis, hepatic, and splenic involvement, and small bowel obstruction [46][47][48][49]
• Musculoskeletal: Arthritis and rhabdomyolysis [50][51]
• Dermatological: Cellulitis, panniculitis, and necrotizing fasciitis [52][53]
• Hematologic: Disseminated intravascular coagulation, septic shock, and multiple organ dysfunction syndrome [40][39]
• Renal: Acute kidney injury [54]

Consultations

Consultations in Legionnaires' Disease

The specialties involved in managing Legionnaires' disease depend on the severity of the patient's illness and the presence of underlying conditions.

• Mild or early disease: Management is typically led by the primary clinician or hospitalist, with input from an infectious disease specialist for diagnosis and antibiotic selection. Pulmonology may also be involved, especially in patients with chronic lung disease.

• Severe or worsening disease: When patients develop hypoxemia, respiratory failure, sepsis, or multiorgan dysfunction, care becomes multidisciplinary. Patients may first present to their local emergency department, with initial review by emergency physicians. Infectious disease specialists have an essential role and should be consulted early. In contrast, intensivists oversee management in the intensive care unit, including providing support with mechanical ventilation or extracorporeal membrane oxygenation, if needed. Cardiology may be consulted for myocarditis or arrhythmias, nephrologists for acute kidney injury or rhabdomyolysis, and geriatrics or oncology specialists for high-risk older or immunocompromised individuals. Neurologists may need to be involved to manage neurological complications, including cerebellar ataxia, encephalitis, and embolic complications from infective endocarditis. Gastroenterologists and general surgeons may need to be consulted if Legionnaires' disease results in complications such as gastrointestinal bleeding and bowel obstruction.

Deterrence and Patient Education

Patients should be aware that Legionnaires' disease (caused by L pneumophila) is caused by bacteria that grow in warm, stagnant water and can be inhaled through aerosols. Patients at higher risk include older adults, smokers, and individuals with chronic illnesses or weakened immune systems. Preventive measures include regularly cleaning and disinfecting showers, faucets, and humidifiers; avoiding stagnant water; and using point-of-use filters if necessary. Patients should seek medical attention promptly if they develop a fever, cough, shortness of breath, or gastrointestinal symptoms, especially after potential exposure to contaminated water sources. To limit exposure to L longbeachae, appropriate mask and glove use is important when gardening or handling potting mix. Maintaining good overall health and avoiding smoking can also help reduce susceptibility.

Pearls and Other Issues

Preventing Legionnaires' disease (caused by L pneumophila) relies on keeping water systems, cooling towers, and plumbing clean and well-maintained, controlling water temperatures, and regularly flushing unused taps to prevent stagnant water. Point-of-use filters can also help reduce risk. Common challenges include missing early signs because symptoms are often nonspecific, failing to adequately maintain water systems, not identifying the source of infection, and using antibiotics that do not cover the intracellular Legionella pathogen. Educating high-risk individuals and following these precautions can help prevent disease and ensure timely treatment when needed. Although L longbeachae has different exposure risks, it is treated similarly to L pneumophila, with macrolide or fluoroquinolone antibiotics.

Enhancing Healthcare Team Outcomes

Legionnaires' disease can progress rapidly to severe illness with high mortality. Clinicians should collaborate closely with the broader healthcare team to ensure optimal patient care and outcomes. Public health authorities play a key role in identifying cases and preventing outbreaks from point sources, such as contaminated water systems or potting mix in the case of L longbeachae. These individuals can also provide broader public health messaging to prevent susceptible individuals from being exposed to L pneumophila.

Healthcare teams should work closely with the hospital infection control team, particularly if there have been HAP cases in the past 12 months, recent changes in the healthcare facility water supply, or positive results from periodic environmental Legionella testing. Liaising with relevant stakeholders outside a hospital setting is critically important to prevent further illness among vulnerable individuals, such as in aged care or veterans' facilities. 

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Disclosure: Siham Mahgoub declares no relevant financial relationships with ineligible companies.

Disclosure: Ayoola Awosika declares no relevant financial relationships with ineligible companies.

Disclosure: Andrew Nguyen declares no relevant financial relationships with ineligible companies.

Disclosure: Ellis Tobin declares no relevant financial relationships with ineligible companies.