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Legionnaires' Disease
Sean R. Wise, MD
Alex P. Houser, DO
image BASICS
DESCRIPTION
  • Legionnaires' disease was named for an epidemic of lower respiratory tract disease at an American Legion convention in Philadelphia in 1976. The causative bacterium was previously unrecognized. It was isolated, identified, and named Legionella pneumophila. The organism primarily causes pneumonia and flulike illness. Legionella preferentially colonizes man-made water systems (e.g., hotels, hospitals, air conditioning cooling towers).
    • Among the three most common clinical pneumonias
    • Most common atypical pneumonia
  • System(s) affected: gastrointestinal, pulmonary
  • Synonym(s): Legionella pneumonia; legionellosis
EPIDEMIOLOGY
  • Predominant age: 15 months to 84 years; 74-91% of patients are >50 years old
  • Predominant gender: male > female
Incidence
  • Reported cases in the United States from 2000 to 2009 increased from 3.9 to 11.5 cases per million.
  • Outbreaks occur most often at the end of the summer and early fall.
  • Represents 2-9% of all cases of pneumonia in the United States.
ETIOLOGY AND PATHOPHYSIOLOGY
  • L. pneumophila is a weak gram-negative aerobic saprophytic freshwater bacterium. It is widely distributed in soil and water. Bipolar flagella provide motility; grows optimally at 40-45°C
  • Exists as an intracellular protozoan parasite, colonizing surfaces and growing in biofilms, which persist in nematodes.
  • Serogroups 1 to 6 account for clinical disease.
  • Serogroup 1 represents 70-92% of all clinical cases of Legionella in the United States.
  • In the lung, Legionella infects alveolar macrophages.
  • The organism is transmitted by aspiration, direct transmission (e.g., contaminated respiratory equipment), and (most importantly) by airborne dissemination and aerosolization of contaminated water sources (e.g., contaminated shower water—felt responsible for the inaugural Philadelphia outbreak).
  • Recently, community outbreaks have been associated with whirlpools, spas, fountains, and also aboard cruise ships.
RISK FACTORS
  • Impaired cellular immunity (Legionella are intracellular pathogens)
  • Male gender
  • Smoking
  • Alcohol abuse
  • Immunosuppression/HIV
  • Chronic cardiopulmonary disease
  • Advanced age
  • Transplant recipients
  • Diabetes mellitus
  • Use of antimicrobials within the past 3 months.
GENERAL PREVENTION
  • Not transmitted person to person (respiratory isolation is unnecessary.)
  • Superheat and flush water systems: Heat water to 70°C, and flush outlets with hot water for 30 minutes (1)[C].
  • Ultraviolet light or copper-silver ionization are bactericidal.
  • Monochloramine disinfection of municipal water supplies decreases risk for Legionella infection.
  • No person-to-person transmission has been previously documented.
COMMONLY ASSOCIATED CONDITIONS
Pontiac fever: self-limited flulike illness without pneumonia caused by Legionella species
image DIAGNOSIS
  • Illness ranges from asymptomatic seroconversion and mild febrile illness to severe pneumonia.
  • Wound infections with Legionella have also been reported.
  • Incubation period is 2 to 14 days.
PHYSICAL EXAM
  • Fever
  • Relative bradycardia (key sign)
    • Defined as a temperature ≥102°F with an inappropriately low pulse pressure <100 beats/minute (normal compensatory reaction to fever is tachycardia >110 beats/minute)
  • Rales and signs of consolidation (egophony; tactile fremitus)
DIFFERENTIAL DIAGNOSIS
  • Other bacterial pneumonias, especially atypical pneumonias: Mycoplasma pneumoniae, Q fever (Coxiella burnetii), Chlamydophila pneumoniae, Chlamydophila psittaci, Francisella tularensis
  • Viral pneumonias, such as adenovirus, influenza (human, avian, swine), cytomegalovirus (CMV)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Diagnosis:
    • Gold standard is sputum culture for Legionella. Alert lab about diagnostic possibility (sample needs buffered charcoal yeast extract agar). Variable sensitivity (10-80%) and time consuming (up to 7 days for results). Hampered by lack of sputum production in >50% of patients.
    • Urinary antigen test (UAT) detects serogroup 1 (which causes most human disease). UATs are highly specific (95-100%) but variably sensitive. Legionella antigenuria can be detected 1 to 2 days after onset of disease and persists for up to 10 months. Limited by only detecting serogroup 1 (may miss 40% of cases) (2)[C].
      • Indications for UAT: severe pneumonia, ICU admission, failure of outpatient antibiotic treatment, current alcohol abuse, recent travel (within past 2 weeks), pleural effusion
    • Combination of respiratory cultures and urine Legionella antigen is optimal for diagnosis (3)[C].
    • Monoclonal direct fluorescence assay (DFA) on respiratory secretions is diagnostic:
      • Sensitivity 25-75%
      • Limited by lengthy (4 to 6 weeks) seroconversion
    • Silver/Gimenez stains used for lung specimens.
    • Disorders that may alter lab results: Direct immunofluorescence can cross-react with Pseudomonas and Bacteroides sp., Escherichia coli, and Haemophilus sp.
  • Other lab abnormalities (seen less commonly with other forms of pneumonia):
    • Hyponatremia
    • Hypophosphatemia (transient)
    • Lymphopenia
    • Mildly elevated serum transaminases
    • Elevated LDH
    • Elevated creatinine kinase
    • Microscopic hematuria
    • Highly elevated C-reactive protein (CRP) (>30)
    • Highly elevated ferritin (≥2 times normal)
  • Chest radiograph
    • Not specific for Legionella
    • Commonly shows unilateral lower lobe patchy alveolar infiltrate with consolidation
    • Cavitation and abscess formation is more common in immunocompromised patients.
    • Pleural effusion occurs in up to 50%.
    • May take 1 to 4 months for radiographic findings to resolve. Progression of infiltrate on x-ray can be seen despite antibiotic therapy.
Diagnostic Procedures/Other
Transtracheal aspiration/bronchoscopy occasionally necessary for sputum/lung samples
Test Interpretation
  • Multifocal pneumonia with alveolitis and bronchiolitis, and fibrinous pleuritis; may have serous or serosanguineous pleural effusion
  • Abscess formation occurs in up to 20% of patients.
  • Progression of infiltrates on x-ray (despite appropriate therapy) suggests Legionnaires' disease. Radiographic improvement may not correlate with clinical findings (longer lag times).
image TREATMENT
GENERAL MEASURES
  • Severity of illness and available support dictate the appropriate site for care.
  • Supportive care:
    • Oxygenation, hydration, and electrolyte balance with antibiotic therapy
  • P.597

  • Extrapulmonary complications and higher mortality in patients with AIDS.
  • In severe pneumonia, guidelines recommend obtaining a UAT and starting empiric antibiotics to include coverage for Legionella (4)[C].
MEDICATION
First Line
  • Antibiotics that achieve high intracellular concentrations (e.g., macrolides, tetracyclines, fluoroquinolones) are most effective; first-line treatment is levofloxacin; however, no prospective randomized controlled trials have compared fluoroquinolones to macrolides for the treatment of Legionella. Levofloxacin was associated with more rapid defervescence, fewer complications, decreased hospital stay by 3 days, and decreased mortality (4% vs. 10.9%) compared with macrolide antibiotics (4)[A].
  • Start antibiotics parenterally if sufficiently ill due to the GI symptoms associated with Legionella:
    • Levofloxacin is the preferred agent:
      • Levofloxacin 750 mg/day IV (switch to PO when patient is afebrile/tolerating PO) for 5 days or 500 mg/day for 10 to 14 days
    • Azithromycin may also be used first line. It requires a shorter duration of treatment than levofloxacin due to a longer half-life:
      • Azithromycin 500 mg/day IV (switch to PO when afebrile/tolerating PO) for 7 to 10 days
  • Contraindications: hypersensitivity reactions
  • Precautions: liver disease
  • Significant possible interactions:
    • Can increase theophylline, carbamazepine, and digoxin levels; can increase activity of oral anticoagulants
    • May decrease the effectiveness of digoxin, quinidine, oral contraceptives, and hypoglycemic agents
  • Longer courses of treatment (up to 21 days) may be needed in immunocompromised patients.
Second Line
  • Doxycycline 100 mg IV/PO q12h for total 14 days; for severe infections, initial dose is 200 mg IV/PO q12h.
  • Doxycycline cannot be used in pregnant patients and is not approved for children <8 years of age.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Inability to tolerate oral antibiotics
  • Hypoxemia
  • Criteria for direct admission to the ICU:
    • Any of the major criteria for severe CAP:
      • Septic shock requiring vasopressor support
      • Acute respiratory failure requiring intubation and/or mechanical ventilation
    • Three or more of the minor criteria for severe CAP:
      • RR ≥30 breaths/min; PaO2:FiO2 ratio ≤250; multilobular infiltrates; confusion/disorientation; uremia (BUN ≥20 mg/dL); leukopenia (WBC <4,000 cells/mm3); thrombocytopenia (PLT <100,000 cells/mm3); hypothermia (temperature <36°C); hypotension requiring aggressive fluid resuscitation
Discharge Criteria
  • Afebrile
  • Able to tolerate oral antibiotics
  • Normal oxygen saturation
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monitor respiratory status, hydration, and electrolyte status closely.
  • Chest radiography does not help with monitoring clinical response.
PATIENT EDUCATION
  • Disease prevention: Eliminate pathogens from water supplies, low-emission cleaning procedures of cooling towers with control measurements of water and air samples.
  • Legionella is not spread person-to-person.
PROGNOSIS
  • Improved prognosis when appropriate antibiotics are started early in the disease course.
  • Recovery is variable:
    • Patients may clinically worsen despite appropriate treatment early in the course of therapy (first 1 to 2 days).
    • Improvement with defervescence in 3 to 5 days and complete recovery in 6 to 10 days is typical. Some may have a more protracted course.
  • Mortality in nosocomial infections ranges between 15 and 34%.
REFERENCES
1. Walser SM, Gerstner DG, Brenner B, et al. Assessing the environmental health relevance of cooling towers—a systematic review of legionellosis outbreaks. Int J Hyg Environ Health. 2014;217(2-3):145-154.
2. Bartlett JG. Diagnostic tests for agents of community-acquired pneumonia. Clin Infect Dis. 2011;52(Suppl 4):S296-S304.
3. Tronel H, Hartemann P. Overview of diagnostic and detection methods for legionellosis and Legionella spp. Lett Appl Microbiol. 2009;48(6):653-656.
4. Burdet C, Lepeule R, Duval X, et al. Quinolones versus macrolides in the treatment of legionellosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(9):2354-2360.
Additional Reading
&NA;
  • Cunha BA, Klein NC, Strollo S, et al. Legionnaires' disease mimicking swine influenza (H1N1) pneumonia during the “herald wave” of the pandemic. Heart Lung. 2010;39(3):242-248.
  • Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27-S72.
  • Mercante JW, Winchell JM. Current and emerging Legionella diagnostics for laboratory and outbreak investigations. Clin Microbiol Rev. 2015;28(1):95-133.
  • Phin N, Parry-Ford F, Harrison T, et al. Epidemiology and clinical management of Legionnaires' disease. Lancet Infect Dis. 2014;14(10):1011-1021.
  • Shimada T, Noguchi Y, Jackson JL, et al. Systemic review and metaanalysis: urinary antigen tests for legionellosis. Chest. 2009;136(6):1576-1585.
See Also
&NA;
Pneumonia, Bacterial
Codes
&NA;
ICD10
  • A48.1 Legionnaires' disease
  • A48.2 Nonpneumonic Legionnaires' disease [Pontiac fever]
Clinical Pearls
&NA;
  • Consider Legionnaires' disease in patients with pneumonia, extrapulmonary findings (atypical CAP) and relative bradycardia, and any three of the following: relative lymphopenia, mildly elevated serum transaminases (aspartate aminotransferase/alanine aminotransferase), highly increased ferritin levels, or hypophosphatemia.
  • Consider Legionnaires' disease in cases of nosocomial pneumonia.
  • Legionella is an intracellular organism that must be grown on buffered charcoal yeast extract agar.
  • Because an increase in Legionella antibody titers cannot be detected >3 to 4 weeks, serology is not useful in early stages of the disease.
  • Respiratory specimen cultures combined with urine Legionella antigen testing is the preferred strategy for definitive diagnosis.