Legionella/Legionellosis

Legionella is a facultative intracellular, gram-negative bacilli. Legionella does not grow on common culture media because it requires certain supplementation (cysteine and iron). Legionella can be isolated on a buffered charcoal yeast extract (BCYE) medium. The habitat for Legionella is aquatic systems including human-constructed reservoirs, such as cooling towers and hot water tanks. Transmission occurs primarily through inhalation of aerosolized water droplets, causing pulmonary infection. Legionella pneumophila (L. pneumophila) accounts for the majority of human infections. The clinical presentation includes Legionnaires’ disease, atypical pneumonia, and Pontiac fever. Diagnosis is by culture, urine antigen test, and/or polymerase chain reaction (PCR). Fluoroquinolones and macrolides are the main treatments.

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Classification

Gram negative bacteria classification flowchart

Gram-negative bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thin layer of peptidoglycan do not retain the crystal violet stain utilized in Gram staining. These bacteria do, however, retain the safranin counterstain and thus appear as pinkish-red on the stain, making them gram negative. These bacteria can be further classified according to morphology (diplococci, curved rods, bacilli, and coccobacilli) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The bacteria can be more narrowly identified by growing them on specific media (triple sugar iron (TSI) agar) where their enzymes can be identified (urease, oxidase) and their ability to ferment lactose can be tested.
* Stains poorly on Gram stain
** Pleomorphic rod/coccobacillus
*** Require special transport media

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General Characteristics

Legionella

  • General characteristics:
    • Structure: thin, pleomorphic rods/bacilli
    • Gram stain: gram negative (poor Gram staining)
    • Other stain(s): usually with silver stain 
    • Oxygen requirement: aerobic
    • Invasion and replication in relation to host cell(s): facultative intracellular
    • Enzyme(s): 
      • Catalase positive
      • Oxidase positive (Legionella pneumophila (L. pneumophila))
  • Culture medium: grown on buffered charcoal yeast extract (BCYE) medium with iron and cysteine supplementation
  • Legionellosis (the disease caused by Legionella):
    • Legionnaires’ disease: atypical pneumonia
    • Pontiac fever: fever and myalgias

Clinically relevant species

  • L. pneumophila (causes 80%–90% of human infections)
  • L. micdadei (Pittsburgh pneumonia agent)
  • L. anisa
  • L. feeleii
  • L. longbeachae
Legionella Silver Stain

A silver stain of L. pneumophila

Image: “Legionella Silver Stain” by William Cherry. License: Public domain.

Pathogenesis

Epidemiology

  • Incidence: 8,000–18,000 cases of Legionnaires’ disease per year in the United States
  • More common and more severe in older adults 

Reservoir

  • Natural habitat:
    • Aquatic systems (e.g., lakes, streams)
    • Soil
  • In human-constructed aquatic reservoirs:
    • Hot water tanks
    • Dental equipment
    • Drinking water systems
    • Cooling towers
    • Pools/hot tubs
  • In water, Legionella exists within biofilms or as intracellular parasites in protozoa.
  • Warm temperatures (25°C–42°C (77℉–107℉)) enhance growth.

Transmission

  • Inhalation of aerosolized water droplets (primary route)
  • Aspiration
  • No person-to-person transmission

Virulence factors

  • Main feature of Legionella pathogenicity: ability for intracellular multiplication
  • Adherence and phagocytosis of Legionella:
    • Bacteria attach to the host cell (alveolar macrophages and monocytes) promoted by factors including:
      • Pili 
      • Lipopolysaccharide 
      • Outer membrane proteins
    • Phagocytosis facilitated by:
      • Human complement 3 (C3)
      • Macrophage infectivity potentiator (Mip) protein
  • Legionella survival and replication by forming Legionella-containing vacuole (LCV) facilitated by:
    • Defective organelle trafficking/intracellular multiplication (Dot/Icm) type IV secretion system (T4SS):
      • Recruits the endoplasmic reticulum to the bacterial vacuole
      • Translocates effector proteins to avoid phagolysosomal fusion
    • Type II secretion system (T2SS):
      • Dampens the cytokine response from infected cells
      • Releases degradative enzymes and toxins 

Disease process

  1. The bacteria multiply within the vacuoles, secreting siderophores, allowing the uptake of iron needed for Legionella growth.
  2. Eventually, flagella develop, which triggers caspase-1, leading to apoptosis.
  3. The cell is destroyed, liberating the bacteria and allowing infection of other cells.
Pathogenesis of Legionella infection

Pathogenesis of Legionella infection
The bacteria are opsonized by C3b (a cleaved component of C3) and are incorporated into the macrophages. Once inside the phagosome, the Legionella inhibits phagolysosomal fusion, which allows growth of the bacteria, producing degradative enzymes and toxins, eventually leading to apoptosis of the infected cell. The destroyed cell releases the bacteria, spreading the infection to other cells.

Image by Lecturio.

Host risk factor

  • Age > 50 years
  • Immunocompromised state: 
    • Diabetes
    • Acquired immunodeficiency syndrome (AIDS)
    • Hematologic malignancies
    • Solid organ transplant recipients
    • Patients on immunosuppressive treatment
  • Chronic lung disease
  • End-stage kidney disease
  • Smoking (impairs the mucociliary action that clears Legionella)
  • Alcohol use

Clinical Presentation

Infection with Legionella is known as legionellosis. 

Pontiac fever

  • Very common
  • Self-limiting, mild flu-like syndrome
  • Resolves spontaneously (no antibiotics needed) and often goes undiagnosed

Legionnaires’ disease

  • Presents as atypical pneumonia: 
    • Cough, fever, dyspnea 
    • Gastrointestinal symptoms: diarrhea, vomiting 
    • Neurologic symptoms: headache and confusion
  • Associated with hyponatremia
  • Illness occurs in certain settings:
    • Travel: cruise ships, resorts, hotels
    • Healthcare facilities: hospitals, nursing homes/long-term care facilities
  • Sporadic infection, but can also be associated with epidemic outbreaks
Table: Comparison of the clinical presentations of Legionella infection
Pontiac fever Legionnaires’ disease
Infection rate> 90%< 5%
Time of onsetThroughout the yearSporadic cases or outbreaks in late summer and early autumn
Incubation period1–2 days2–10 days
Manifestations
  • Mild flu-like illness (headache, fever, chills, muscle aches)
  • No pneumonia 
  • Unilateral lobar pneumonia or atypical pneumonia (fever, chills, dyspnea, dry or productive cough)
  • GI: nausea, vomiting, diarrhea (50%)
  • CNS: confusion, stupor, ataxia (50%)
  • Cardiac: relative bradycardia (rare)
Resolution
  • Self-limited
  • Requires antibiotic therapy
  • May present with failure to respond to beta-lactam monotherapy
Mortality rate< 1%15%–20% (if untreated)
GI: gastrointestinal
CNS: central nervous system

Diagnosis

Clinical examination

  • Unilateral lobar pneumonia: 
    • Crackles, decreased breath sounds, enhanced bronchophony on auscultation
    • Tactile fremitus upon palpation
    • Dullness on percussion (represents localized consolidation)
  • Atypical pneumonia: bilateral crackles or unremarkable findings

Diagnostic tests

  • Legionella urinary antigen: rapid method (detects L. pneumophila serogroup 1)
  • Polymerase chain reaction (PCR) (e.g., sputum or bronchoalveolar lavage specimen)
  • Culture: 
    • BCYE medium with iron and cysteine 
    • Legionella spp. grow slowly; visible colonies are usually present after 3 days of incubation.
    • Specimen(s):
      • Lower respiratory secretions
      • Lung tissue
      • Pleural fluid
  • Smears of clinical specimen(s):
    • Organism not well demonstrated on a Gram stain
    • Silver stain (Warthin-Starry and Dieterle)
    • Direct fluorescent antibody (DFA) staining (rapid but less sensitive than a culture) 
Legionella Pneumophila Immunfluoreszenz-Färbung

Legionella pneumophila: direct immunofluorescence staining with fluorescence-labeled antibodies

Image: “Legionella Pneumophila IF” by CDC-PHIL. License: Public domain.

Blood tests

  • Hyponatremia (rare in other types of pneumonia)
  • Leukocytosis
  • ↑ Erythrocyte sedimentation rate (ESR)
  • ↑ C-reactive protein (CRP)
  • ↑ Procalcitonin (may not occur in atypical pneumonia)

Chest imaging

  • Chest X-ray and chest computed tomography (CT) scan
  • Changes consistent with atypical pneumonia: diffuse reticular opacity with absent or minimal consolidation 
  • May include unilateral infiltrates, pleural effusion

Management

  • Empiric treatment follows guidelines for community-acquired pneumonia.
  • Directed treatment uses the following antibiotics: 
    • Fluoroquinolones: levofloxacin preferred
    • Macrolides: azithromycin preferred; drug of choice for children
  • Alternative antibiotic options:
    • Doxycycline
    • Trimethoprim-sulfamethoxazole
    • Combination therapy (some regimens include rifampin)
  • Legionella is resistant to beta-lactam antibiotics.
  • Legionnaires’ disease is a notifiable disease.

Differential Diagnosis

  • Atypical pneumonia (other etiology): pulmonary infection that presents typically in elderly or immunocompromised patients with dyspnea, non-productive dry cough, and extrapulmonary symptoms. Other causes include: Mycoplasma pneumoniae and Chlamydophila pneumoniae.
  • Influenza: a highly contagious, viral infection caused by ribonucleic acid (RNA) viruses. Influenza presents with sudden-onset high fever, headache, rhinorrhea, non-productive cough, malaise, and myalgia. Rapid influenza diagnostic tests (RIDTs) detect viral antigens. 
  • Acute respiratory distress syndrome: a severe inflammatory reaction characterized by non-cardiogenic pulmonary edema. The condition is due to injury to the alveolar-capillary membrane, causing fluid to flood the lungs. Multiple possible causes include trauma, sepsis, pneumonitis, pulmonary infarction, and transfusion-related acute injury.
  • Bronchitis: a lower respiratory tract infection that causes inflammation of the bronchi. Bronchitis is most frequently caused by a viral infection and presents with a self-limited cough.
  • Heart failure: a condition in which the heart is unable to pump enough blood to meet the metabolic needs of the body. Heart failure can present with pulmonary edema, causing dyspnea and cough.

References

  1. No author: Legionella (Legionnaire’s disease and Pontiac fever). (2018). CDC. Retrieved from https://www.cdc.gov/legionella/index.html
  2. Murdoch, D., Chambers, S. Priest, P., Ramirez, J., & Bond, S. (Eds.) (2020). Microbiology, epidemiology and pathogenesis of Legionella infection. UpToDate. Retrieved Dec 9, 2020, from https://www.uptodate.com/contents/microbiology-epidemiology-and-pathogenesis-of-legionella-infection?search=legionella&source=search_result&selectedTitle=3~102&usage_type=default&display_rank=3
  3. Rathore, M., & Bragg, L. (2018). Legionella infection. Medscape. https://emedicine.medscape.com/article/965492-overview
  4. Riedel S, Hobden J.A., et al. (Eds.) (2019). Legionella, bartonella, and unusual bacterial pathogens. In Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill.
  5. White, R., & Cianciotto, N. (2019). Assessing the impact, genomics and evolution of type II secretion across a large, medically important genus: The Legionella type II secretion paradigm. Microbial Genomics, 5(6),e000273. https://doi.org/10.1099/mgen.0.000273
  6. Yu V.L., Pedro-Botet M, & Lin Y.E. (2018). Legionella infections. In Jameson J.L., et al. (Eds), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
  7. Zhan, X., Hu, C., & Zhu, Q. (2015). Legionella pathogenesis and virulence factors. Annals of Clinical and Laboratory research, 3(2),15. https://www.aclr.com.es/clinical-research/legionella-pathogenesis-and-virulence-factors.pdf

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