Legionnaires Disease

Infectious Disease MONDO:0005824 Pathograph 7 Show in embeddings browser Bacterial Respiratory Infection

Legionnaires' disease is the severe pneumonic form of legionellosis, caused by inhalation of aerosols contaminated with Legionella (most often Legionella pneumophila). After inhalation, the bacterium replicates inside alveolar macrophages within a specialized Legionella-containing vacuole, producing a severe lobar pneumonia frequently accompanied by extrapulmonary features (gastrointestinal and neurologic abnormalities, relative bradycardia, and hyponatremia). Because the organism is intracellular, effective therapy requires cell-penetrant antibiotics (macrolides or fluoroquinolones) rather than beta-lactams. It is the severe counterpart of the self-limited, non-pneumonic Pontiac_Fever, the other clinical manifestation of Legionella infection.

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5
Pathophys.
8
Phenotypes
7
Pathograph
2
Medical Actions
⚙

Pathophysiology

5
Inhalation and Intracellular Replication in Alveolar Macrophages
Legionnaires' disease results from inhalation of Legionella-contaminated aerosols followed by bacterial replication inside alveolar macrophages, where the organism establishes a replication-permissive intracellular compartment (the Legionella-containing vacuole). This obligate intracellular lifestyle is the basis for the requirement for cell-penetrant antibiotics, because beta-lactams cannot reach the cytoplasmic organism.
alveolar macrophage CL:0000583
symbiont entry into host cell GO:0046718 biological process involved in interaction with host GO:0051701 Dot/Icm type IV secretion of effector proteins GO:0030255
Downstream
Severe Lobar Pneumonia with Extrapulmonary Features Intracellular replication in alveolar macrophages drives a severe pneumonic and systemic inflammatory illness.
Requirement for Cell-Penetrant Antimicrobials The intracellular niche dictates that only cell-penetrant antibiotics can reach and kill the organism.
Show evidence (3 references)
PMID:33843434 SUPPORT Other
"Human disease results from inhalation of Legionella-contaminated aerosols and subsequent bacterial replication within alveolar macrophages."
Establishes the core pathogenic mechanism — inhalation followed by intracellular replication in alveolar macrophages. Evidence source is OTHER as this is a review article.
PMID:33843434 SUPPORT Other
"To replicate intracellularly, Legionella generates a replication-permissive compartment called the Legionella-containing vacuole (LCV) through the concerted action of hundreds of Dot/Icm-translocated effector proteins."
Documents the Dot/Icm type IV secretion system and its effector-driven biogenesis of the Legionella-containing vacuole, the intracellular replicative niche this node represents. Evidence source is OTHER as this is a review article.
PMID:34750083 SUPPORT Other
"most atypical pathogens do not have a bacterial cell wall, some are intracellular (e.g., Legionella), and some are paracellular (e.g., M. pneumoniae)"
Confirms Legionella as an intracellular atypical pathogen, the basis for the intracellular-niche conformance. Evidence source is OTHER as this is a review article.
Severe Lobar Pneumonia with Extrapulmonary Features
Legionella replication in the lung produces a severe lobar pneumonia that frequently requires intensive care. A characteristic feature is prominent extrapulmonary involvement — gastrointestinal and neurologic abnormalities and relative bradycardia — that helps distinguish Legionnaires' disease from other community-acquired pneumonias.
inflammatory response GO:0006954 ↑ INCREASED
lung UBERON:0002048
Show evidence (2 references)
PMID:20955914 SUPPORT Human Clinical
"Gastrointestinal or neurologic abnormalities were found approximately in two-thirds and relative bradycardia in 9 (52.9%)."
Clinical case series documenting the extrapulmonary features (GI/neurologic abnormalities, relative bradycardia) characteristic of Legionnaires' disease. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
PMID:20955914 SUPPORT Human Clinical
"LD was severe in 11 (64.7%) patients, which required intensive care unit follow-up."
Supports the severity of Legionnaires' disease, with most cases requiring intensive care. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Requirement for Cell-Penetrant Antimicrobials
Because Legionella replicates inside host cells, effective treatment requires antibiotics that accumulate intracellularly — macrolides (e.g., azithromycin) and fluoroquinolones (e.g., levofloxacin) — whereas beta-lactams, which penetrate cells poorly, are ineffective. This pharmacokinetic gating, rather than a single enzyme target, governs drug selection.
response to antibiotic GO:0046677
Show evidence (2 references)
PMID:34750083 SUPPORT Other
"The therapeutic approach for atypical pneumonias is different than that for typical pneumonia."
Supports that intracellular/atypical pathogens such as Legionella require a different therapeutic approach than cell-wall-targeting beta-lactams. Evidence source is OTHER as this is a review article.
PMID:34750083 SUPPORT Other
"Typical bacterial pathogens classically respond to β-lactam antimicrobial therapy because they have a cell wall amenable to β-lactam disruption."
Explains why beta-lactams work against cell-walled typical pathogens but fail against the intracellular, atypical Legionella — the basis for the cell-penetrant-antibiotic requirement. Evidence source is OTHER as this is a review article.
Ribosomal Protein Synthesis Inhibition by Macrolides
Macrolides such as azithromycin, a first-line therapy for Legionnaires' disease, accumulate intracellularly and inhibit bacterial protein synthesis by binding the 50S subunit of the Legionella 70S ribosome — the conserved bacterial-translation target this node represents.
Translation GO:0006412
Show evidence (1 reference)
PMID:24336183 SUPPORT Other
"The ribosome is one of the main antibiotic targets in the bacterial cell."
Review establishing the bacterial ribosome as a principal antibiotic target, the macrolide target this node represents in Legionella therapy. Evidence source is OTHER as this is a review article.
DNA Gyrase and Topoisomerase IV Inhibition by Fluoroquinolones
Respiratory fluoroquinolones such as levofloxacin, a first-line alternative for Legionnaires' disease, are cell-penetrant and kill intracellular Legionella by trapping the DNA gyrase/topoisomerase IV cleavage complex — the bactericidal fluoroquinolone target this node represents.
DNA Topological Change GO:0006265
Show evidence (1 reference)
PMID:27449972 SUPPORT Other
"Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity."
Review establishing DNA gyrase and topoisomerase IV as the dual fluoroquinolone target and cleavage-complex mechanism, the levofloxacin target this node represents in Legionella therapy. Evidence source is OTHER as this is a review article.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Legionnaires Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Cardiovascular 1
Relative Bradycardia Bradycardia HP:0001662
Show evidence (1 reference)
PMID:20955914 SUPPORT Human Clinical
"relative bradycardia in 9 (52.9%)"
Documents relative bradycardia in about half of cases. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Digestive 1
Diarrhea Diarrhea HP:0002014
Show evidence (1 reference)
PMID:20955914 SUPPORT Human Clinical
"Gastrointestinal or neurologic abnormalities were found approximately in two-thirds and relative bradycardia in 9 (52.9%)."
Documents gastrointestinal abnormalities in about two-thirds of cases. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Immune 1
Pneumonia Pneumonia HP:0002090
Show evidence (1 reference)
PMID:33843434 SUPPORT Other
"Bacteria of the genus Legionella are natural pathogens of amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease."
Establishes severe pneumonia as the defining manifestation. Evidence source is OTHER as this is a review article.
Metabolism 2
Fever Fever HP:0001945
Show evidence (1 reference)
PMID:27906087 SUPPORT Human Clinical
"with fever >38 °C (71 %), heart rate >90 beats per minute (71 %)"
Case series documenting fever above 38 °C in 71% of hospitalized Legionnaires' disease patients. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Hyponatremia Hyponatremia HP:0002902
Show evidence (1 reference)
PMID:12415472 SUPPORT Human Clinical
"lower sodium blood levels (mean, 132.6+/-4.8 mmol/l vs. 135.7 mmol/l; P<0.01)"
Comparative outbreak study showing significantly lower serum sodium in Legionnaires' disease than in other pneumonias. Evidence source is HUMAN_CLINICAL as this is a comparative clinical study.
Nervous System 2
Confusion Confusion HP:0001289
Show evidence (2 references)
PMID:20955914 SUPPORT Human Clinical
"Gastrointestinal or neurologic abnormalities were found approximately in two-thirds and relative bradycardia in 9 (52.9%)."
Documents neurologic abnormalities in about two-thirds of cases. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
PMID:27906087 SUPPORT Human Clinical
"Confusion or a change in mental status was present in 50 % of patients at presentation."
Case series documenting confusion or altered mental status in 50% of hospitalized Legionnaires' disease patients. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Headache Headache HP:0002315
Show evidence (1 reference)
PMID:12415472 SUPPORT Human Clinical
"The presence of headache, high fever, hyponatremia, scanty or null expectoration, and current cigarette smoking provides physicians with important clues for a high suspicion of Legionella pneumonia"
Comparative outbreak study identifying headache as a distinguishing clinical clue for Legionella pneumonia. Evidence source is HUMAN_CLINICAL as this is a comparative clinical study.
Respiratory 1
Cough Cough HP:0012735
Show evidence (1 reference)
PMID:27906087 SUPPORT Human Clinical
"Twelve patients (86 %) reported cough, with 50 % of the patients reporting sputum production."
Case series documenting cough in 86% of hospitalized Legionnaires' disease patients. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
💊

Medical Actions

2
Azithromycin
Action: Pharmacotherapy NCIT:C15986
Agent: azithromycin CHEBI:2955
Macrolide antibiotic that accumulates intracellularly and inhibits bacterial protein synthesis at the ribosome; a first-line treatment for Legionnaires' disease because it reaches the intracellular organism.
Mechanism Target:
INHIBITS Requirement for Cell-Penetrant Antimicrobials — Azithromycin accumulates intracellularly and so reaches the cytoplasmic Legionella that beta-lactams cannot, satisfying the cell-penetrant requirement.
INHIBITS Ribosomal Protein Synthesis Inhibition by Macrolides — Azithromycin binds the 50S ribosomal subunit and inhibits bacterial protein synthesis, the molecular target represented by this node.
INHIBITS Inhalation and Intracellular Replication in Alveolar Macrophages — By inhibiting ribosomal protein synthesis in the intracellular organism, azithromycin arrests replication within alveolar macrophages.
Show evidence (1 reference)
PMID:27906087 SUPPORT Human Clinical
"antimicrobial therapy with newer macrolides or respiratory fluoroquinolones should be initiated for severe community-acquired pneumonia requiring intensive care unit admission, prior to laboratory confirmation of diagnosis, especially when a clinical suspicion of Legionella infection exists."
Case series supporting newer macrolides such as azithromycin as first-line therapy for severe Legionnaires' disease. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
Levofloxacin
Action: Pharmacotherapy NCIT:C15986
Agent: levofloxacin CHEBI:63598
Respiratory fluoroquinolone that penetrates host cells and inhibits bacterial DNA gyrase/topoisomerase IV; a first-line alternative to macrolides for Legionnaires' disease.
Mechanism Target:
INHIBITS Requirement for Cell-Penetrant Antimicrobials — Levofloxacin is cell-penetrant and reaches the intracellular organism, satisfying the cell-penetrant-antibiotic requirement.
INHIBITS DNA Gyrase and Topoisomerase IV Inhibition by Fluoroquinolones — Levofloxacin traps the DNA gyrase/topoisomerase IV cleavage complex, generating lethal double-strand breaks — the molecular target represented by this node.
Show evidence (1 reference)
PMID:27906087 SUPPORT Human Clinical
"antimicrobial therapy with newer macrolides or respiratory fluoroquinolones should be initiated for severe community-acquired pneumonia requiring intensive care unit admission, prior to laboratory confirmation of diagnosis, especially when a clinical suspicion of Legionella infection exists."
Case series supporting respiratory fluoroquinolones such as levofloxacin as first-line therapy for severe Legionnaires' disease. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
{ }

Source YAML

click to show 
name: Legionnaires Disease
creation_date: "2026-06-28T00:00:00Z"
description: >
  Legionnaires' disease is the severe pneumonic form of legionellosis, caused by
  inhalation of aerosols contaminated with Legionella (most often Legionella
  pneumophila). After inhalation, the bacterium replicates inside alveolar
  macrophages within a specialized Legionella-containing vacuole, producing a
  severe lobar pneumonia frequently accompanied by extrapulmonary features
  (gastrointestinal and neurologic abnormalities, relative bradycardia, and
  hyponatremia). Because the organism is intracellular, effective therapy requires
  cell-penetrant antibiotics (macrolides or fluoroquinolones) rather than
  beta-lactams. It is the severe counterpart of the self-limited, non-pneumonic
  Pontiac_Fever, the other clinical manifestation of Legionella infection.
category: Infectious Disease
parents:
- Bacterial Respiratory Infection
synonyms:
- Legionellosis (pneumonic)
- Legionella pneumonia
- Legionella pneumophila pneumonia
disease_term:
  preferred_term: Legionnaires' disease
  term:
    id: MONDO:0005824
    label: Legionnaires' disease
pathophysiology:
- name: Inhalation and Intracellular Replication in Alveolar Macrophages
  role: trigger
  conforms_to: "intracellular_pathogen_persistence#Intracellular Niche and Beta-Lactam Exclusion"
  description: >
    Legionnaires' disease results from inhalation of Legionella-contaminated
    aerosols followed by bacterial replication inside alveolar macrophages, where
    the organism establishes a replication-permissive intracellular compartment
    (the Legionella-containing vacuole). This obligate intracellular lifestyle is
    the basis for the requirement for cell-penetrant antibiotics, because
    beta-lactams cannot reach the cytoplasmic organism.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  biological_processes:
  - preferred_term: symbiont entry into host cell
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  - preferred_term: biological process involved in interaction with host
    term:
      id: GO:0051701
      label: biological process involved in interaction with host
  - preferred_term: Dot/Icm type IV secretion of effector proteins
    term:
      id: GO:0030255
      label: protein secretion by the type IV secretion system
  evidence:
  - reference: PMID:33843434
    reference_title: "Pathogenicity and Virulence of Legionella: Intracellular replication and host response."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Human disease results from inhalation of Legionella-contaminated aerosols
      and subsequent bacterial replication within alveolar macrophages.
    explanation: >-
      Establishes the core pathogenic mechanism — inhalation followed by
      intracellular replication in alveolar macrophages. Evidence source is OTHER
      as this is a review article.
  - reference: PMID:33843434
    reference_title: "Pathogenicity and Virulence of Legionella: Intracellular replication and host response."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To replicate intracellularly, Legionella generates a replication-permissive
      compartment called the Legionella-containing vacuole (LCV) through the
      concerted action of hundreds of Dot/Icm-translocated effector proteins.
    explanation: >-
      Documents the Dot/Icm type IV secretion system and its effector-driven
      biogenesis of the Legionella-containing vacuole, the intracellular
      replicative niche this node represents. Evidence source is OTHER as this is
      a review article.
  - reference: PMID:34750083
    reference_title: "Atypical pneumonia: Pathophysiology, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      most atypical pathogens do not have a bacterial cell wall, some are
      intracellular (e.g., Legionella), and some are paracellular (e.g., M.
      pneumoniae)
    explanation: >-
      Confirms Legionella as an intracellular atypical pathogen, the basis for the
      intracellular-niche conformance. Evidence source is OTHER as this is a review
      article.
  downstream:
  - target: Severe Lobar Pneumonia with Extrapulmonary Features
    description: >-
      Intracellular replication in alveolar macrophages drives a severe pneumonic
      and systemic inflammatory illness.
  - target: Requirement for Cell-Penetrant Antimicrobials
    description: >-
      The intracellular niche dictates that only cell-penetrant antibiotics can
      reach and kill the organism.

- name: Severe Lobar Pneumonia with Extrapulmonary Features
  description: >
    Legionella replication in the lung produces a severe lobar pneumonia that
    frequently requires intensive care. A characteristic feature is prominent
    extrapulmonary involvement — gastrointestinal and neurologic abnormalities and
    relative bradycardia — that helps distinguish Legionnaires' disease from other
    community-acquired pneumonias.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:20955914
    reference_title: "Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal or neurologic abnormalities were found approximately in
      two-thirds and relative bradycardia in 9 (52.9%).
    explanation: >-
      Clinical case series documenting the extrapulmonary features (GI/neurologic
      abnormalities, relative bradycardia) characteristic of Legionnaires'
      disease. Evidence source is HUMAN_CLINICAL as this is a clinical case series.
  - reference: PMID:20955914
    reference_title: "Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LD was severe in 11 (64.7%) patients, which required intensive care unit
      follow-up.
    explanation: >-
      Supports the severity of Legionnaires' disease, with most cases requiring
      intensive care. Evidence source is HUMAN_CLINICAL as this is a clinical case
      series.
  downstream: []

- name: Requirement for Cell-Penetrant Antimicrobials
  role: therapeutic_vulnerability
  conforms_to: "intracellular_pathogen_persistence#Requirement for Cell-Penetrant Antimicrobials"
  description: >
    Because Legionella replicates inside host cells, effective treatment requires
    antibiotics that accumulate intracellularly — macrolides (e.g., azithromycin)
    and fluoroquinolones (e.g., levofloxacin) — whereas beta-lactams, which
    penetrate cells poorly, are ineffective. This pharmacokinetic gating, rather
    than a single enzyme target, governs drug selection.
  biological_processes:
  - preferred_term: response to antibiotic
    term:
      id: GO:0046677
      label: response to antibiotic
  evidence:
  - reference: PMID:34750083
    reference_title: "Atypical pneumonia: Pathophysiology, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The therapeutic approach for atypical pneumonias is different than that for
      typical pneumonia.
    explanation: >-
      Supports that intracellular/atypical pathogens such as Legionella require a
      different therapeutic approach than cell-wall-targeting beta-lactams.
      Evidence source is OTHER as this is a review article.
  - reference: PMID:34750083
    reference_title: "Atypical pneumonia: Pathophysiology, diagnosis, and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Typical bacterial pathogens classically respond to β-lactam antimicrobial
      therapy because they have a cell wall amenable to β-lactam disruption.
    explanation: >-
      Explains why beta-lactams work against cell-walled typical pathogens but
      fail against the intracellular, atypical Legionella — the basis for the
      cell-penetrant-antibiotic requirement. Evidence source is OTHER as this is
      a review article.
  downstream: []

- name: Ribosomal Protein Synthesis Inhibition by Macrolides
  role: therapeutic_vulnerability
  conforms_to: "bacterial_protein_synthesis_inhibition#Bacterial mRNA Translation by the Ribosome"
  description: >
    Macrolides such as azithromycin, a first-line therapy for Legionnaires'
    disease, accumulate intracellularly and inhibit bacterial protein synthesis by
    binding the 50S subunit of the Legionella 70S ribosome — the conserved
    bacterial-translation target this node represents.
  biological_processes:
  - preferred_term: Translation
    term:
      id: GO:0006412
      label: translation
  evidence:
  - reference: PMID:24336183
    reference_title: "Ribosome-targeting antibiotics and mechanisms of bacterial resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The ribosome is one of the main antibiotic targets in the bacterial cell.
    explanation: >-
      Review establishing the bacterial ribosome as a principal antibiotic
      target, the macrolide target this node represents in Legionella therapy.
      Evidence source is OTHER as this is a review article.
  downstream: []

- name: DNA Gyrase and Topoisomerase IV Inhibition by Fluoroquinolones
  role: therapeutic_vulnerability
  conforms_to: "bacterial_dna_topoisomerase_inhibition#DNA Gyrase and Topoisomerase IV (Fluoroquinolone Target)"
  description: >
    Respiratory fluoroquinolones such as levofloxacin, a first-line alternative
    for Legionnaires' disease, are cell-penetrant and kill intracellular
    Legionella by trapping the DNA gyrase/topoisomerase IV cleavage complex — the
    bactericidal fluoroquinolone target this node represents.
  biological_processes:
  - preferred_term: DNA Topological Change
    term:
      id: GO:0006265
      label: DNA topological change
  evidence:
  - reference: PMID:27449972
    reference_title: "Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Quinolones dually target DNA gyrase and topoisomerase IV binding to
      specific domains and conformations so as to block DNA strand passage
      catalysis and stabilize DNA-enzyme complexes that block the DNA replication
      apparatus and generate double breaks in DNA that underlie their bactericidal
      activity.
    explanation: >-
      Review establishing DNA gyrase and topoisomerase IV as the dual
      fluoroquinolone target and cleavage-complex mechanism, the levofloxacin
      target this node represents in Legionella therapy. Evidence source is OTHER
      as this is a review article.
  downstream: []
phenotypes:
- category: Respiratory
  name: Pneumonia
  description: >
    Severe lobar pneumonia is the defining manifestation of Legionnaires' disease.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:33843434
    reference_title: "Pathogenicity and Virulence of Legionella: Intracellular replication and host response."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Bacteria of the genus Legionella are natural pathogens of amoebae that can
      cause a severe pneumonia in humans called Legionnaires' Disease.
    explanation: >-
      Establishes severe pneumonia as the defining manifestation. Evidence source
      is OTHER as this is a review article.
- category: Constitutional
  name: Fever
  description: >
    High fever is typical of Legionnaires' disease.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:27906087
    reference_title: "Legionella pneumonia in the Niagara Region, Ontario, Canada: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with fever >38 °C (71 %), heart rate >90 beats per minute (71 %)
    explanation: >-
      Case series documenting fever above 38 °C in 71% of hospitalized
      Legionnaires' disease patients. Evidence source is HUMAN_CLINICAL as this is
      a clinical case series.
- category: Respiratory
  name: Cough
  description: >
    Cough is a common respiratory symptom of Legionella pneumonia.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:27906087
    reference_title: "Legionella pneumonia in the Niagara Region, Ontario, Canada: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve patients (86 %) reported cough, with 50 % of the patients reporting
      sputum production.
    explanation: >-
      Case series documenting cough in 86% of hospitalized Legionnaires' disease
      patients. Evidence source is HUMAN_CLINICAL as this is a clinical case
      series.
- category: Gastrointestinal
  name: Diarrhea
  description: >
    Gastrointestinal abnormalities including diarrhea are common extrapulmonary
    features.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:20955914
    reference_title: "Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal or neurologic abnormalities were found approximately in
      two-thirds and relative bradycardia in 9 (52.9%).
    explanation: >-
      Documents gastrointestinal abnormalities in about two-thirds of cases.
      Evidence source is HUMAN_CLINICAL as this is a clinical case series.
- category: Neurologic
  name: Confusion
  description: >
    Neurologic abnormalities such as confusion are characteristic extrapulmonary
    features of Legionnaires' disease.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: PMID:20955914
    reference_title: "Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gastrointestinal or neurologic abnormalities were found approximately in
      two-thirds and relative bradycardia in 9 (52.9%).
    explanation: >-
      Documents neurologic abnormalities in about two-thirds of cases. Evidence
      source is HUMAN_CLINICAL as this is a clinical case series.
  - reference: PMID:27906087
    reference_title: "Legionella pneumonia in the Niagara Region, Ontario, Canada: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Confusion or a change in mental status was present in 50 % of patients at
      presentation.
    explanation: >-
      Case series documenting confusion or altered mental status in 50% of
      hospitalized Legionnaires' disease patients. Evidence source is
      HUMAN_CLINICAL as this is a clinical case series.
- category: Cardiovascular
  name: Relative Bradycardia
  description: >
    Relative bradycardia (a pulse-temperature dissociation) is a classic sign.
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:20955914
    reference_title: "Travel-associated Legionnaires disease: clinical features of 17 cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      relative bradycardia in 9 (52.9%)
    explanation: >-
      Documents relative bradycardia in about half of cases. Evidence source is
      HUMAN_CLINICAL as this is a clinical case series.
- category: Neurologic
  name: Headache
  description: >
    Headache is a frequent and often severe extrapulmonary symptom of
    Legionnaires' disease and is one of the clinical clues that distinguishes it
    from other community-acquired pneumonias.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:12415472
    reference_title: "Clinical study of an outbreak of Legionnaire's disease in Alcoy, Southeastern Spain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of headache, high fever, hyponatremia, scanty or null
      expectoration, and current cigarette smoking provides physicians with
      important clues for a high suspicion of Legionella pneumonia
    explanation: >-
      Comparative outbreak study identifying headache as a distinguishing
      clinical clue for Legionella pneumonia. Evidence source is HUMAN_CLINICAL as
      this is a comparative clinical study.
- category: Metabolic
  name: Hyponatremia
  description: >
    Hyponatremia is a recognized laboratory association of Legionnaires' disease.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:12415472
    reference_title: "Clinical study of an outbreak of Legionnaire's disease in Alcoy, Southeastern Spain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lower sodium blood levels (mean, 132.6+/-4.8 mmol/l vs. 135.7 mmol/l;
      P<0.01)
    explanation: >-
      Comparative outbreak study showing significantly lower serum sodium in
      Legionnaires' disease than in other pneumonias. Evidence source is
      HUMAN_CLINICAL as this is a comparative clinical study.
treatments:
- name: Azithromycin
  description: >
    Macrolide antibiotic that accumulates intracellularly and inhibits bacterial
    protein synthesis at the ribosome; a first-line treatment for Legionnaires'
    disease because it reaches the intracellular organism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  target_mechanisms:
  - target: Requirement for Cell-Penetrant Antimicrobials
    treatment_effect: INHIBITS
    description: >-
      Azithromycin accumulates intracellularly and so reaches the cytoplasmic
      Legionella that beta-lactams cannot, satisfying the cell-penetrant
      requirement.
  - target: Ribosomal Protein Synthesis Inhibition by Macrolides
    treatment_effect: INHIBITS
    description: >-
      Azithromycin binds the 50S ribosomal subunit and inhibits bacterial protein
      synthesis, the molecular target represented by this node.
  - target: Inhalation and Intracellular Replication in Alveolar Macrophages
    treatment_effect: INHIBITS
    description: >-
      By inhibiting ribosomal protein synthesis in the intracellular organism,
      azithromycin arrests replication within alveolar macrophages.
  evidence:
  - reference: PMID:27906087
    reference_title: "Legionella pneumonia in the Niagara Region, Ontario, Canada: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      antimicrobial therapy with newer macrolides or respiratory fluoroquinolones
      should be initiated for severe community-acquired pneumonia requiring
      intensive care unit admission, prior to laboratory confirmation of
      diagnosis, especially when a clinical suspicion of Legionella infection
      exists.
    explanation: >-
      Case series supporting newer macrolides such as azithromycin as first-line
      therapy for severe Legionnaires' disease. Evidence source is HUMAN_CLINICAL
      as this is a clinical case series.
- name: Levofloxacin
  description: >
    Respiratory fluoroquinolone that penetrates host cells and inhibits bacterial
    DNA gyrase/topoisomerase IV; a first-line alternative to macrolides for
    Legionnaires' disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levofloxacin
      term:
        id: CHEBI:63598
        label: levofloxacin
  target_mechanisms:
  - target: Requirement for Cell-Penetrant Antimicrobials
    treatment_effect: INHIBITS
    description: >-
      Levofloxacin is cell-penetrant and reaches the intracellular organism,
      satisfying the cell-penetrant-antibiotic requirement.
  - target: DNA Gyrase and Topoisomerase IV Inhibition by Fluoroquinolones
    treatment_effect: INHIBITS
    description: >-
      Levofloxacin traps the DNA gyrase/topoisomerase IV cleavage complex,
      generating lethal double-strand breaks — the molecular target represented by
      this node.
  evidence:
  - reference: PMID:27906087
    reference_title: "Legionella pneumonia in the Niagara Region, Ontario, Canada: a case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      antimicrobial therapy with newer macrolides or respiratory fluoroquinolones
      should be initiated for severe community-acquired pneumonia requiring
      intensive care unit admission, prior to laboratory confirmation of
      diagnosis, especially when a clinical suspicion of Legionella infection
      exists.
    explanation: >-
      Case series supporting respiratory fluoroquinolones such as levofloxacin as
      first-line therapy for severe Legionnaires' disease. Evidence source is
      HUMAN_CLINICAL as this is a clinical case series.
notes: >
  Created as part of the Respiratory Infections project. Severe pneumonic
  counterpart of the existing Pontiac_Fever entry (same organism, Legionella
  pneumophila; distinct pathomechanism). Conforms to the
  intracellular_pathogen_persistence module (intracellular niche and
  cell-penetrant-drug requirement). The infectious_agent (NCBITaxon) block was
  omitted at creation and the organism is described in the text.