Leptospirosis is a globally distributed zoonotic spirochetal infection caused by pathogenic species of the genus Leptospira, transmitted through contact with water, soil, or food contaminated by the urine of infected animals (especially rodents). An estimated one million cases and ~60,000 deaths occur annually worldwide. [1-2] Most infections are mild and self-limiting (~90%), but 5–10% progress to severe multiorgan dysfunction (Weil's disease) with a case-fatality ratio of 5–15%. [3]
1. History
- Exposure history is critical: contact with floodwater, freshwater (rivers, lakes), soil, or animal urine; occupational exposure (farmers, abattoir workers, veterinarians, sewer workers); adventure tourism (kayaking, rafting, triathlons); recent flooding events [4-6]
- Incubation period: 2–30 days, typically 5–14 days after exposure [3]
- Symptom characterization: abrupt onset of high fever, severe headache (often with photophobia and retro-orbital pain), calf and lower back myalgia, chills, nausea/vomiting, diarrhea, abdominal pain, cough [3][7]
- Biphasic illness pattern: initial septicemic phase (~7 days) → temporary defervescence → immune phase with potential complications [3]
- Important negatives: absence of rash (rash is rare in leptospirosis, unlike dengue/rickettsia); absence of lymphadenopathy [8]
2. Alarm Features
- Jaundice — suggests hepatic involvement / Weil's disease [3][7]
- Oliguria/anuria — acute kidney injury, a hallmark of severe disease [3]
- Hemoptysis / respiratory distress — pulmonary hemorrhage syndrome (case-fatality >50%) [3][9]
- Altered mental status / confusion — CNS involvement, aseptic meningitis [10]
- Hemodynamic instability / tachycardia — septic shock; tachycardia strongly associated with severity (OR 9.69) [11]
- Dyspnea — independent predictor of severe disease (OR 5.54) [11]
- Hemorrhagic manifestations — petechiae, epistaxis, GI bleeding [12]
- Poor prognostic indicators: older age, altered mental status, respiratory insufficiency, oliguria [3]
3. Medications
Treatment (initiate empirically without waiting for confirmatory testing): [3]
- Mild disease: Doxycycline 100 mg PO BID × 7 days (drug of choice); alternatives: amoxicillin, ampicillin, or azithromycin [3][13]
- Severe disease: IV penicillin G 1.5 MU q6h; alternatives: ceftriaxone 1 g IV daily or cefotaxime 1 g IV q6h [3-4]
- Network meta-analysis suggests cephalosporins, doxycycline, and penicillin significantly reduce defervescence time; azithromycin is a suitable alternative [13]
Cautions
- Jarisch-Herxheimer reaction occurs in ~9% of treated patients — acute febrile reaction within 24 hours of antibiotic initiation; rarely fatal but can cause multi-organ failure in severe cases [3][7]
- Doxycycline contraindicated in pregnancy and children <8 years
- Corticosteroids have been used in severe cases but insufficient evidence currently supports routine use [2][7]
Prophylaxis: Doxycycline 200 mg PO weekly has been used for high-risk exposures, though efficacy is unconfirmed in clinical trials [1][14]
4. Diet
- No specific dietary triggers
- Aggressive IV hydration is essential in severe disease to support renal perfusion and manage AKI [3]
- Electrolyte supplementation as guided by labs (hypokalemia and hyponatremia may occur with renal dysfunction)
- Avoid alcohol (hepatotoxicity risk in the setting of hepatic involvement)
5. Review of Systems
- Constitutional: fever, chills, rigors, malaise, anorexia
- MSK: severe myalgias (especially calves and lumbar region)
- Ophthalmologic: conjunctival suffusion (characteristic), photophobia
- GI: nausea, vomiting, diarrhea, abdominal pain
- Respiratory: cough, dyspnea, hemoptysis
- Renal: decreased urine output, dark urine, hematuria
- Hepatic: jaundice, pruritus
- Neurologic: headache, confusion, neck stiffness (meningismus)
- Cardiovascular: palpitations, chest pain
- Dermatologic: rash (rare but associated with severity when present) [11]
6. Collateral History and Family History
- Occupational exposure: farming, livestock handling, abattoir work, sewer maintenance, military, rice field workers [4-5]
- Recreational exposure: freshwater swimming, kayaking, caving, triathlons in endemic areas [5]
- Travel history: recent travel to tropical/subtropical regions; post-flood exposure [6-7]
- Animal contact: rodents, dogs, cattle, pigs, horses [2]
- Household contacts: not transmitted person-to-person (rare exceptions via sexual contact or breastfeeding) [15]
- No significant hereditary predisposition, though genetic factors may influence severity of immune response [1]
7. Risk Factors
- Environmental: flooding, heavy rainfall, contact with contaminated freshwater or soil [6-7]
- Occupational: farmers, veterinarians, abattoir workers, sewer workers, military personnel [4-5]
- Recreational: adventure tourism, water sports in endemic areas [5]
- Demographic: male predominance (~85% of confirmed cases), mean age ~37–47 years [10-11]
- Urbanization: living in urban slums with poor sanitation and rodent infestation [6]
- Comorbidities increasing severity: chronic alcohol abuse, older age, chronic kidney disease [3][10]
- Climate: tropical/subtropical regions; emergence aggravated by climate change and El Niño events [6][12]
8. Differential Diagnosis
The nonspecific presentation makes leptospirosis a clinical mimic of many tropical and non-tropical febrile illnesses: [12]
- Dengue fever — overlapping fever, myalgia, thrombocytopenia; distinguished by rash, positive NS1/IgM, absence of conjunctival suffusion [16]
- Malaria — periodic fevers, travel history; thick/thin smear or rapid diagnostic test [8]
- Rickettsioses (scrub typhus, Rocky Mountain spotted fever) — rash, eschar; doxycycline-responsive [5]
- Viral hepatitis — jaundice, transaminitis; hepatitis serologies distinguish [12]
- Hantavirus — renal syndrome, pulmonary involvement; rodent exposure overlap [5]
- Influenza — myalgia, fever, cough; lacks conjunctival suffusion and renal involvement
- Meningococcemia — meningismus, petechial rash, rapid deterioration
- Yellow fever — jaundice, hemorrhage; vaccination history and travel [12]
- Typhoid fever — prolonged fever, GI symptoms; blood cultures
- Goodpasture syndrome / vasculitis — if pulmonary hemorrhage predominates [17]
Key distinguishing feature: Conjunctival suffusion (conjunctival injection without exudate) is relatively characteristic of leptospirosis and uncommon in most mimics. [3][8][15]
9. Past Medical History
- Prior episodes of leptospirosis (reinfection with different serovars is possible)
- Chronic kidney disease (increases risk of severe AKI)
- Chronic liver disease / alcohol use disorder (worsens hepatic dysfunction, associated with higher mortality) [10]
- Immunosuppression (transplant recipients may have atypical presentations) [15]
- Splenectomy (increased susceptibility to encapsulated organisms; consider in differential)
10. Physical Exam
Vital signs: High fever (often >39°C), tachycardia, hypotension in severe cases
Key findings
- Conjunctival suffusion — bilateral, non-purulent conjunctival injection; the most characteristic physical finding [3][15]
- Scleral icterus / jaundice — suggests Weil's disease [7]
- Hepatosplenomegaly [15][18]
- Calf tenderness — disproportionate to exam; characteristic myalgia pattern [3]
- Meningismus — neck stiffness if aseptic meningitis present
- Petechiae / purpura / hemorrhagic signs [12]
- Lung crackles / decreased breath sounds — pulmonary hemorrhage or ARDS [17]
- Skin rash — rare, transient, maculopapular; when present, associated with severity [11]
- Lymphadenopathy — typically absent (helps distinguish from other infections)
11. Lab Studies
Recommended initial labs
- CBC: thrombocytopenia (80% of cases), anemia (66%), neutrophilia (neutrophil >80% associated with diagnosis) [18-19]
- BMP/CMP: elevated creatinine (AKI in up to 87–94% of severe cases), elevated BUN, electrolyte abnormalities [9][20]
- LFTs: elevated bilirubin (conjugated predominant), elevated AST/ALT (AST often > ALT), elevated alkaline phosphatase [18-19]
- CRP — markedly elevated (median 19 mg/dL in one series) [18]
- Coagulation studies: PT/INR, fibrinogen (DIC workup if hemorrhagic)
- Urinalysis: hematuria, proteinuria, pyuria [18]
- Blood cultures (low yield due to slow growth but should be sent)
- CPK — may be elevated with rhabdomyolysis from severe myalgia
Diagnostic confirmation: [12][21]
- Week 1 (early/septicemic phase): PCR (blood) — high sensitivity and specificity for early diagnosis; recommended as first-line early test
- Week 2+ (immune phase): IgM ELISA, followed by MAT (microscopic agglutination test) — the reference standard; requires paired sera for seroconversion
- Combination of PCR + serology maximizes diagnostic accuracy across disease stages [21]
Severity markers: Creatinine >1.13 mg/dL, ALT >50 IU, platelets <150,000, acute hemoglobin drop (suggests pulmonary hemorrhage) [9][20]
12. Imaging
- Chest X-ray: indicated in all patients with respiratory symptoms; bilateral alveolar infiltrates suggest pulmonary hemorrhage; may mimic viral pneumonia, ARDS, or bronchopneumonia [17]
- CT chest (HRCT): ground-glass opacities, consolidation, crazy-paving pattern — secondary to pulmonary hemorrhage; not specific but suggestive in appropriate clinical context [17]
- Abdominal ultrasound: hepatosplenomegaly, renal enlargement; useful if jaundice or AKI present [8]
- Renal ultrasound: to evaluate for obstructive causes if AKI present
- Imaging is not required for mild, uncomplicated cases
13. Special Tests
- Microscopic Agglutination Test (MAT): gold standard serologic test; requires acute and convalescent sera (≥4-fold titer rise); limited availability [12]
- IgM ELISA / rapid lateral flow tests: useful for point-of-care screening in the immune phase [12]
- PCR (real-time): recommended first-line for early diagnosis (DPO ≤10); can be performed on blood and urine [12][21]
- Metagenomic next-generation sequencing (mNGS): emerging tool for atypical or diagnostically challenging cases [22-23]
- Diagnostic scoring model (Rajapakse et al.): exposure history + creatinine >150 µmol/L + neutrophils >80% + bilirubin >30 µmol/L + platelets <85,000 → AUC 0.762 for diagnosis in resource-limited settings [19]
- Bronchoalveolar lavage: hemorrhagic return confirms DAH in pulmonary hemorrhage cases [23]
14. ECG
- ECG indicated in all hospitalized patients
- Cardiac arrhythmias: atrial fibrillation (associated with mortality in severe cases) [3][9]
- Myocarditis: ST-segment changes, T-wave inversions, conduction abnormalities; myocarditis reported in up to 33% of complicated cases [9][12]
- Troponin elevation may accompany myocardial involvement
- Continuous telemetry monitoring recommended in severe disease
15. Assessment
Severity stratification
- Mild/anicteric (~90% of clinical cases): self-limiting febrile illness with myalgia, headache; resolves in 1–2 weeks [3]
- Severe/icteric (Weil's disease) (5–10%): jaundice + AKI ± hemorrhage; CFR 5–15% [3]
- Severe pulmonary hemorrhage syndrome: DAH, ARDS; CFR >50% [3][9]
- Neurological leptospirosis: aseptic meningitis, confusion; highest organ failure scores and mortality in ICU phenotype analysis [10]
Four ICU phenotypes identified in a French multicenter study: moderately severe (21%), hepato-renal (63%), neurological (5%), and respiratory/pulmonary hemorrhage (11%). [10]
Complications: AKI (most common), hepatic failure, pulmonary hemorrhage, myocarditis, DIC, aseptic meningitis, ARDS, septic shock, multi-organ failure. [7][9][12]
16. Treatment Plan
Initial stabilization
- ABCs; IV access, fluid resuscitation (conservative strategy preferred in ICU setting) [24]
- Initiate empiric antibiotics immediately upon clinical suspicion — do not wait for confirmatory testing [3][7]
Antibiotic therapy
Supportive care for severe disease: [3][24]
- IV hydration and electrolyte supplementation (conservative fluid strategy in ICU)
- Dialysis/RRT for oliguric renal failure (traditional initiation thresholds appear adequate) [24]
- Mechanical ventilation with lung-protective strategies for ARDS/pulmonary hemorrhage
- VV-ECMO — emerging rescue therapy for refractory pulmonary hemorrhage with favorable case reports [9][23][25]
- Vasopressor support for hemodynamic instability
- Monitor for Jarisch-Herxheimer reaction within first 24 hours of antibiotics [3][7]
17. Disposition
Admission criteria
- Jaundice, AKI (elevated creatinine), oliguria
- Hemoptysis, respiratory distress, hypoxia
- Hemodynamic instability, septic shock
- Altered mental status, meningismus
- Thrombocytopenia with hemorrhagic manifestations
- Inability to tolerate oral medications/fluids
ICU admission: multi-organ dysfunction, need for vasopressors, mechanical ventilation, or RRT; pulmonary hemorrhage [4][10][24]
Discharge criteria
- Mild disease with stable vitals, tolerating oral antibiotics, adequate urine output, improving labs
- Reliable follow-up and ability to return if worsening
Specialist consultation triggers: Infectious disease (all confirmed/suspected cases); Nephrology (AKI requiring RRT); Pulmonology/Critical Care (pulmonary hemorrhage, ARDS); Cardiology (myocarditis, arrhythmias)
18. Follow Up / Return Precautions
- Follow-up: within 48–72 hours for patients discharged on oral antibiotics; repeat renal function and CBC
- Convalescent serology: paired MAT titers at 2+ weeks to confirm diagnosis [12]
- Return precautions — seek immediate care for:
- Worsening fever or recurrence of fever after initial improvement
- Decreased urine output or dark urine
- Yellowing of skin/eyes
- Coughing up blood or worsening shortness of breath
- Confusion or severe headache with neck stiffness
- Bleeding from any site
- Expected recovery: mild cases typically resolve within 1–2 weeks; severe cases may require weeks of recovery; renal function usually recovers but may take months [3]
- Counseling: educate on exposure avoidance — protective footwear, avoid wading in floodwater, rodent control measures [1]
References
1. Leptospirosis. — Rajapakse S, Fernando N, Dreyfus A, Smith C, Rodrigo C. Nature Reviews. Disease Primers. 2025.
2. Corticosteroids for Treatment of Leptospirosis. — Lee N, Han SM, Mukadi P, et al. The Cochrane Database of Systematic Reviews. 2025.
3. Leptospirosis. — Christine J. Atherstone and Robyn A. Stoddard CDC Yellow Book. 2025.
4. Leptospirosis: Report From the Task Force on Tropical Diseases by the World Federation of Societies of Intensive and Critical Care Medicine. — Jiménez JIS, Marroquin JLH, Richards GA, Amin P. Journal of Critical Care. 2018.
5. Fever of Unknown Origin. — Haidar G, Singh N. The New England Journal of Medicine. 2022.
6. Waterborne Diseases That Are Sensitive to Climate Variability and Climate Change. — Semenza JC, Ko AI. The New England Journal of Medicine. 2023.
7. Antibiotics for Treatment of Leptospirosis. — Win TZ, Han SM, Edwards T, et al. The Cochrane Database of Systematic Reviews. 2024.
8. Approach to Fever in the Returning Traveler. — Thwaites GE, Day NP. The New England Journal of Medicine. 2017.
9. Pulmonary Haemorrhage as a Frequent Cause of Death Among Patients With Severe Complicated Leptospirosis in Southern Sri Lanka. — Fonseka CL, Dahanayake NJ, Mihiran DJD, et al. PLoS Neglected Tropical Diseases. 2023.
10. Severe Leptospirosis in Non-Tropical Areas: A Nationwide, Multicentre, Retrospective Study in French ICUs. — Miailhe AF, Mercier E, Maamar A, et al. Intensive Care Medicine. 2019.
11. Demographic and Clinical Risk Factors Associated With Severity of Lab-Confirmed Human Leptospirosis in Colombia, 2015-2020. — Parra Barrera EL, Bello Piruccini S, Rodríguez K, et al. PLoS Neglected Tropical Diseases. 2023.
12. Nucleic Acid and Antigen Detection Tests for Leptospirosis. — Yang B, de Vries SG, Ahmed A, et al. The Cochrane Database of Systematic Reviews. 2019.
13. Efficacy and Safety of Antibiotics for Treatment of Leptospirosis: A Systematic Review and Network Meta-Analysis. — Ji Z, Jian M, Su X, et al. Systematic Reviews. 2024.
14. Antibiotic Prophylaxis for Leptospirosis. — Win TZ, Perinpanathan T, Mukadi P, et al. The Cochrane Database of Systematic Reviews. 2024.
15. Endemic or Regionally Limited Bacterial and Viral Infections in Haematopoietic Stem-Cell Transplantation Recipients: A Worldwide Network for Blood and Marrow Transplantation (WBMT) Review. — Muhsen IN, Galeano S, Niederwieser D, et al. The Lancet. Haematology. 2023.
16. Pathogen-Specific Leptospiral Proteins in Urine of Patients With Febrile Illness Aids in Differential Diagnosis of Leptospirosis From Dengue. — Chaurasia R, Thresiamma KC, Eapen CK, et al. European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology. 2018.
17. Clinical and Imaging Manifestations of Hemorrhagic Pulmonary Leptospirosis: A State-of-the-Art Review. — Marchiori E, Lourenço S, Setúbal S, et al. Lung. 2011.
18. Epidemiology, Clinical and Laboratory Findings of Leptospirosis in Southwestern Greece. — Gkentzi D, Lagadinou M, Bountouris P, et al. Infectious Diseases. 2020.
19. A Diagnostic Scoring Model for Leptospirosis in Resource Limited Settings. — Rajapakse S, Weeratunga P, Niloofa R, et al. PLoS Neglected Tropical Diseases. 2016.
20. Predictors of Severe Leptospirosis: A Multicentre Observational Study From Central Malaysia. — Philip N, Lung Than LT, Shah AM, et al. BMC Infectious Diseases. 2021.
21. Diagnostic Advances in Leptospirosis: A Comparative Analysis of Paraclinical Tests With a Focus on PCR. — Ciurariu E, Prodan-Barbulescu C, Mateescu DM, et al. Microorganisms. 2025.
22. Leptospirosis-Induced Diffuse Alveolar Hemorrhage: A Rare Case Report From a Non-Epidemic Area and Literature Review. — Yu Y, Hong S, Wang Z, Li S, Zhang S. Medicine. 2026.
23. Successful Management of Severe Pulmonary Form of Leptospirosis With VV-ECMO, Prone Ventilation, and Bronchoalveolar Lavage: Two Case Reports. — Chen M, Wu H, Xie L, Wu M, Lan P. Frontiers in Medicine. 2025.
24. Severe Leptospirosis in Tropical Australia: Optimising Intensive Care Unit Management to Reduce Mortality. — Smith S, Liu YH, Carter A, et al. PLoS Neglected Tropical Diseases. 2019.
25. Leptospirosis Manifested With Severe Pulmonary Hemorrhagic Syndrome Successfully Treated With Veno-Venous Extracorporeal Membrane Oxygenation: A Case Report and Literature Review. — Zhang XC, Lei XQ, Sun Y, Shan NB. Medicine. 2024.