What is the pathophysiology of acute leptospirosis leading to death?

Pathophysiology of Acute Leptospirosis Leading to Death

The pathophysiology of acute leptospirosis leading to death primarily involves a biphasic disease progression with initial bacteremia followed by an immune-mediated phase characterized by multi-organ dysfunction, particularly affecting the kidneys, liver, lungs, and vascular system. 1

Initial Infection and Bacteremic Phase

• Leptospirosis begins when pathogenic Leptospira spirochetes enter the body through mucous membranes or breaks in the skin after exposure to water or soil contaminated with urine from infected animals (particularly rats, cattle, pigs, and dogs) 2, 3
• The initial bacteremic phase lasts 4-7 days and presents with flu-like symptoms as the bacteria rapidly multiply in the bloodstream 1
• During this phase, leptospires disseminate hematogenously throughout the body, with high levels of bacteremia associated with poor clinical outcomes 3
• Human TLR4 poorly recognizes leptospiral LPS, contributing to inadequate immune response and higher bacterial loads 3

Immune-Mediated Phase and Organ Damage

• Following the bacteremic phase, a 1-3 day interval occurs before the immune phase begins, characterized by antibody production and immune complex deposition 1
• Severe disease (Weil's syndrome) develops as a result of both direct tissue invasion by spirochetes and dysregulated host immune responses 4, 5
• A cytokine storm occurs with elevated levels of pro-inflammatory mediators (IL-6, TNF-alpha) and anti-inflammatory cytokines (IL-10), contributing to tissue damage 3
• Genetic factors may influence disease severity, with HLA DQ6 allele carriers at higher risk of severe disease 3

Multi-Organ Dysfunction Leading to Death

Renal Failure

• Leptospires directly infiltrate kidney cells via renal tubules and interstitium 6
• LipL32 (bacterial outer membrane protein) binds to TLR-2 on renal tubular epithelial cells, triggering inflammatory pathways 6
• This leads to acute tubular necrosis, interstitial nephritis, and potentially acute kidney injury progressing to renal failure 6
• Urinalysis typically shows proteinuria and hematuria, with biochemical evidence of renal dysfunction 1

Hepatic Dysfunction

• Hepatocellular damage occurs with disruption of intercellular junctions between hepatocytes 3
• This results in elevated bilirubin levels and jaundice as bilirubin leaks from bile canaliculi 3
• Laboratory findings include high bilirubin with mild elevation of transaminases 1

Pulmonary Hemorrhage

• Severe pulmonary hemorrhage syndrome due to extensive alveolar hemorrhage carries a fatality rate exceeding 50% 3
• Capillary fragility contributes to pulmonary bleeding and respiratory failure 1

Hemorrhagic Complications

• Bleeding occurs due to capillary fragility rather than coagulation disorders, with tests of clotting often normal 1
• Thrombocytopenia and anemia may develop if significant hemorrhage occurs 1

Cardiovascular Collapse

• Hypovolemic shock can develop from severe dehydration and capillary leakage 7
• Myocardial dysfunction may occur, contributing to circulatory failure 1

Metabolic Derangements

• Hyperglycemia is initially observed, redirecting glucose to immune cells and promoting aerobic glycolysis 1
• Later stages of severe infection may be characterized by hypoglycemia due to peripheral glucose usage and anorexia 1
• Lipolysis is induced by inflammatory cytokines, leading to elevated plasma triglycerides and free fatty acids 1
• Inflammation simultaneously down-regulates utilization of free fatty acids, potentially causing toxic accumulation in organs 1

Progression to Death

• Mortality increases with age, particularly in patients older than 60 years 3
• Death typically results from:
  1. Progressive renal failure with uremia 1, 6
  2. Massive pulmonary hemorrhage leading to respiratory failure 3
  3. Hepatorenal syndrome 1
  4. Septic shock and multi-organ dysfunction 1, 3

Clinical Pearls and Caveats

• Early recognition and treatment with appropriate antibiotics during the bacteremic phase is crucial, as antibiotics are less effective during the immune-mediated phase 1
• Severe disease is primarily immunologically mediated, explaining why antibiotic effectiveness decreases in established leptospirosis 1
• Adequate hydration is essential to prevent renal failure, with oral rehydration solution recommended for mild to moderate dehydration and IV fluids for severe cases 7
• Prompt initiation of dialysis can be life-saving when oliguric renal failure occurs 3
• The development of ARDS in patients with sepsis is reported to occur in 25-42% of patients, increasing with persistent arterial hypotension 1