Leptospirosis: Approach, Diagnosis, Management and Treatment

1. Overview

• Harrison's Principles of Internal Medicine, 22E
• Goldman-Cecil Medicine

2. Microbiology

• Thin, coiled, highly motile spirochetes (0.1 µm diameter, 6-20 µm long)
• The trailing end forms a hook/question mark shape in fluid - hence "L. interrogans"
• Gram stain does not work; visible only by dark-field microscopy or silver impregnation staining
• Require special media for culture (weeks to months to grow)

• 260 pathogenic serovars arranged in 26 serogroups

• Key serovar-host associations:
  • Icterohaemorrhagiae/Copenhageni - rats (most important urban reservoir)
  • Hardjo - cattle
  • Canicola - dogs
  • Pomona - pigs

3. Epidemiology & Transmission

• Contact with water/soil contaminated with infected animal urine
• Through broken skin, cuts, abrasions, or mucous membranes (conjunctival, oral)
• Rarely: direct animal bites, laboratory accidents

• Farmers, slaughterhouse workers, veterinarians, sewer workers, rodent exterminators
• Recreational exposure: swimming, waterskiing, mud-runs, whitewater rafting
• Travelers to Southeast Asia, India, Malaysia, Brazil
• Populations in flood-prone, low-income settings

4. Pathogenesis

1. Entry via abraded skin or mucous membranes
2. Leptospires proliferate, cross tissue barriers, and disseminate hematogenously
3. Outer membrane contains LPS, cytotoxic glycolipoprotein (GLP), and lipoproteins (especially LipL32) - these drive endothelial injury and organ damage
4. GLP disrupts tubular Na+/K+-ATPase - explaining AKI and paradoxical hypokalemia
5. Glycocalyx and endothelial injury cause capillary leak and multi-organ failure
6. Leptospires have special tropism for the kidneys - AKI is nearly universal in severe disease

5. Clinical Manifestations

Phase 1: Leptospiremic Phase (Days 1-7)

• Abrupt onset high fever (38.5-40°C), severe headache, myalgia (especially calf muscles - characteristic)
• Conjunctival suffusion (without discharge) - highly characteristic sign
• Nausea, vomiting, diarrhea
• Non-productive cough
• Leptospires detectable in blood and CSF

Phase 2: Immune/Leptospiruric Phase (Days 7-14)

• Most patients improve spontaneously
• ~10% progress to severe disease (Weil's disease or pulmonary hemorrhage syndrome)
• Leptospires detectable in urine; antibodies appear

Weil's Disease (Severe Leptospirosis)

• Jaundice (conjugated/direct hyperbilirubinemia; transaminases only moderately raised - unlike viral hepatitis)
• Oliguric AKI (AKI incidence 10-80%; oliguric in 60%)
• Bleeding: petechiae, ecchymoses; severe GI or pulmonary hemorrhage
• Thrombocytopenia + coagulopathy (elevated INR, aPTT, D-dimer)
• Cardiac arrhythmias
• Aseptic meningitis (CSF: lymphocytic pleocytosis, elevated protein, normal glucose)
• Case fatality rate up to 10% overall; higher with multiorgan involvement

Severe Pulmonary Hemorrhage Syndrome (SPHS)

• Diffuse alveolar hemorrhage, ARDS
• Chest CT: ground-glass opacities and airspace nodules
• High mortality; may occur without jaundice

6. Diagnosis

Approach

"A provisional diagnosis of acute leptospirosis should be based primarily on clinical and epidemiologic grounds so as to enable early treatment." - Goldman-Cecil Medicine

• Acute febrile illness (≥38.5°C) + severe headache
• Relevant exposure history (animals, floods, travel to endemic area)
• Conjunctival suffusion + calf muscle tenderness (highly specific combination)
• Cough with hemoptysis, jaundice, oliguria, meningismus

Case Definitions (WHO/National)

Laboratory Tests

• PCR (blood, urine, or CSF) - most sensitive; now feasible even in resource-poor settings; test of choice in first week
• Blood culture in special media (EMJH medium) - takes weeks; low yield after antibiotics
• Urine culture - positive from day 7 onwards

• MAT (Microscopic Agglutination Test) - gold standard; serogroup-specific; single titer ≥1:400 (or ≥400) OR 4-fold rise in paired samples = diagnostic
• IgM ELISA (Leptocheck, Lepto lateral flow) - rapid, early detection; becomes positive in week 1
• Note: Serology may be negative early - do not rely on it to rule out acute infection

• Leukocytosis (>80% neutrophils)
• Thrombocytopenia
• Elevated CRP and procalcitonin (helps differentiate from dengue)
• Elevated direct bilirubin with only moderate transaminase elevation
• Elevated creatinine/BUN, pyuria, hematuria, proteinuria
• CSF: aseptic meningitis pattern
• Chest CT in suspected SPHS: ground-glass + airspace nodules

Differential Diagnosis

Useful diagnostic clues distinguishing leptospirosis: conjunctival suffusion, calf/muscle tenderness, pulmonary hemorrhage - Goldman-Cecil Medicine

7. Treatment

Antibiotics (Table 189-1, Harrison's 22E)

• Leptospira susceptible to: beta-lactams, cephalosporins, aminoglycosides, macrolides, tetracyclines
• Leptospira NOT susceptible to: vancomycin, rifampicin, metronidazole, chloramphenicol
• No antibiotic resistance reported to date
• No significant difference in outcomes between penicillin, ceftriaxone, cefotaxime, and doxycycline for severe disease (open-label RCTs)
• Jarisch-Herxheimer reaction may occur hours after starting antibiotics (fever, chills, tachycardia, hypotension) - manage supportively

8. Supportive Management

Fluid & Electrolyte Management

• Aggressive IV fluid resuscitation to correct dehydration and prevent oliguric AKI
• Hypokalemia is characteristic and common - supplement potassium
• Monitor urine output closely

Renal Replacement Therapy

• Prompt initiation of peritoneal dialysis or hemodialysis for oliguric renal failure
• Usually needed only short-term; rapid initiation shown to reduce mortality
• Continuous venovenous hemofiltration (CVVH) preferred with multiorgan involvement or pulmonary edema

Pulmonary Hemorrhage / ARDS

• Protective ventilation: low tidal volumes (<6 mL/kg) + high PEEP
• ECMO has been used successfully for refractory respiratory failure
• Consider early intubation

Other Complications

• Cardiac monitoring for arrhythmias
• Platelet/FFP transfusion for severe coagulopathy/hemorrhage
• Avoid nephrotoxic drugs

9. Chemoprophylaxis

Note: Efficacy of doxycycline prophylaxis in endemic/epidemic settings remains unclear. Azithromycin may be preferable in some contexts.

10. Prevention

• Avoid contact with potentially contaminated water/soil (especially with broken skin)
• Personal protective equipment: boots, gloves, goggles, waterproof overalls
• Rodent control measures
• Immunization of domestic animals
• Vaccination available for humans in some countries (Cuba, China, France) - serovar-specific, limited cross-protection
• Public health: flood management, improved sanitation, rodent surveillance

Summary Flowchart

Acute febrile illness + exposure history
           ↓
Clinical suspicion: fever + headache + myalgia + conjunctival suffusion + calf tenderness
           ↓
Start empiric therapy immediately (do NOT wait for confirmation)
           ↓
Send: PCR (blood/urine) + IgM ELISA + MAT (acute & convalescent serum)
           ↓
     Mild disease?              Severe/Weil's disease?
         ↓                              ↓
  Oral doxycycline          IV Penicillin G / Ceftriaxone
  or amoxicillin            + aggressive supportive care
  (7 days)                  + dialysis if oliguric AKI
                            + protective ventilation if ARDS

• Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapter 189
• Goldman-Cecil Medicine, Chapter 298
• Comprehensive Clinical Nephrology, 7th Edition, Chapter 71
• Dengue-leptospirosis coinfection meta-analysis (BMC Infect Dis, 2025, PMID 39856559) - notes overlap in coinfection settings, reinforcing the need for dual testing in endemic regions