Legionella/Legionellosis

Classification

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 Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Pontiac fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and myalgias

Clinically relevant species

• L. pneumophila (causes 80%–90% of human infections)
• L. micdadei (Pittsburgh pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia agent)
• L. anisa
• L. feeleii
• L. longbeachae

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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and toxins 

Disease process

1. The bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview 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 Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and allowing infection of other cells.

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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever

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

Legionnaires’ disease

• Presents as atypical pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: 
  • Cough, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea 
  • Gastrointestinal symptoms: diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, vomiting 
  • Neurologic symptoms: headache and confusion
• Associated with hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. 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

Diagnosis

Clinical examination

• Unilateral lobar pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: 
  • Crackles, decreased breath sounds, enhanced bronchophony on auscultation
  • Tactile fremitus upon palpation
  • Dullness on percussion (represents localized consolidation)
• Atypical pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: bilateral crackles or unremarkable findings

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of 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) 

Blood tests

• Hyponatremia (rare in other types of pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia)
• Leukocytosis
• ↑ Erythrocyte sedimentation rate (ESR)
• ↑ C-reactive protein (CRP)
• ↑ Procalcitonin (may not occur in atypical pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia)

Chest imaging

• Chest X-ray and chest computed tomography (CT) scan
• Changes consistent with atypical pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: diffuse reticular opacity with absent or minimal consolidation 
• May include unilateral infiltrates, pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion

Management

• Empiric treatment follows guidelines for community-acquired pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia.
• Directed treatment uses the following antibiotics: 
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones: levofloxacin preferred
  • Macrolides: azithromycin preferred; drug of choice for children
• Alternative antibiotic options:
  • Doxycycline
  • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and 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 Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (other etiology): pulmonary infection that presents typically in elderly or immunocompromised patients with dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, non-productive dry cough, and extrapulmonary symptoms. Other causes include: Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumoniae and Chlamydophila pneumoniae.
• Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza: a highly contagious, viral infection caused by ribonucleic acid ( RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure) viruses. Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza presents with sudden-onset high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, rhinorrhea, non-productive cough, malaise, and myalgia. Rapid influenza diagnostic tests (RIDTs) detect viral antigens. 
• Acute respiratory distress syndrome Acute Respiratory Distress Syndrome Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome: a severe inflammatory reaction characterized by non-cardiogenic pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema. The condition is due to injury to the alveolar-capillary membrane, causing fluid to flood the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs. Multiple possible causes include trauma, sepsis, pneumonitis, pulmonary infarction, and transfusion-related acute injury.
• Bronchitis: a lower respiratory tract infection that causes inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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 Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema, causing dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and cough.