What is the pathophysiology of leptospirosis?

Pathophysiology of Leptospirosis

Leptospirosis is a systemic infectious and inflammatory disease characterized by a biphasic clinical course, where pathogenic Leptospira species invade through mucosal/skin barriers, rapidly enter the bloodstream causing septicemia, and disseminate to multiple organs leading to multi-organ dysfunction and potential cytokine storm. 1, 2

Invasion and Dissemination

• Entry mechanism: Pathogenic leptospires enter the body by:

  • Penetrating intact or abraded mucous membranes or skin
  • Primarily transmitted through contact with water or soil contaminated with urine from infected animals (especially rodents) 1, 3

• Systemic spread: After entry, leptospires:

  • Rapidly enter the bloodstream (septicemic phase)
  • Use powerful invasiveness to disseminate throughout the body
  • Utilize cellular endocytic recycling and vesicular transport systems for intracellular migration 2
  • Discharge through renal tubules into urine (creating infectious source) 2

Biphasic Clinical Course

1. Septicemic phase (first 4-7 days):

   • Characterized by leptospiremia (bacteria in blood)
   • High fever, headache, myalgia, and influenza-like symptoms
   • Initial bacterial multiplication and spread 1

2. Immune phase (after 7-10 days):

   • Appearance of circulating antibodies
   • Immune-mediated manifestations (meningitis, uveitis, exanthema)
   • Potential for severe complications 1

Pathogenic Mechanisms

• Adhesion factors: Outer membrane proteins bind to:

  • Fibronectin
  • Laminin
  • Collagens in extracellular matrix 2

• Invasive factors contributing to pathogenicity:

  • Collagenase
  • Metallopeptidases
  • Endoflagellum for motility 2

• Vascular damage:

  • Leptospires damage endothelial cells
  • Disrupt adherens junctions (VE-cadherin and catenins)
  • Alter actin filaments
  • Increase vascular permeability 4

Inflammatory Response and Cytokine Storm

• Inflammatory cascade:

  • Leptospiral lipopolysaccharide and multiple hemolysins trigger inflammation
  • Induce pro-inflammatory cytokines (IL-6, TNF-α)
  • Can lead to cytokine storm in severe cases 5

• Immunological consequences:

  • Initial cytokine storm followed by immunoparalysis
  • Contributes to sepsis-like phenotype in severe cases
  • Poor recognition of leptospiral LPS by human TLR4 may contribute to high bacteremia 5, 6

Organ-Specific Pathology

• Renal involvement:

  • Leptospires colonize renal tubules
  • Cause tubular damage and interstitial nephritis
  • Can lead to acute kidney injury and renal failure 3

• Hepatic dysfunction:

  • Hepatocellular damage
  • Disruption of intercellular junctions between hepatocytes
  • Leakage of bilirubin from bile canaliculi causing jaundice 6

• Pulmonary manifestations:

  • vWA and platelet activating factor acetylhydrolase-like proteins induce pulmonary hemorrhage
  • Severe pulmonary hemorrhage syndrome has >50% fatality rate 2, 6

• Hemorrhagic complications:

  • Associated with coagulation abnormalities
  • Vascular damage contributes to bleeding tendencies 6

Risk Factors for Severe Disease

• Host factors:

  • Advanced age (>60 years)
  • HLA DQ6 allele carriers
  • Immunosuppression 6

• Pathogen factors:

  • High levels of bacteremia
  • Virulence of specific Leptospira strains 6

• Environmental factors:

  • Inadequate sanitation
  • Poor housing
  • Urban slum environments 6

Clinical Implications

Understanding the pathophysiology of leptospirosis is crucial for early diagnosis and treatment, as early antibiotic therapy (within 4-5 days of illness onset) significantly improves outcomes and reduces mortality from the severe forms of the disease 1.

Human-to-human transmission is rare, making this primarily a zoonotic disease with environmental exposure being the key risk factor for infection 3.

Human immunity to leptospirosis is primarily humoral (antibody-mediated), and protective immunity is generally serovar-specific, explaining why reinfection with different serovars can occur 3.

Human cases can range from asymptomatic to severe, with approximately 10% developing into severe forms with multi-organ failure and increased mortality 5.

Human Pathophysiology of Leptospirosis