01Approach to the Critical Patient/attcp67

Immediate threats and stabilization

›Life-threatening presentations requiring immediate action

›Pulmonary hemorrhage syndrome

›Hemoptysis with hypoxemia

›Case fatality rate >50%

›Immediate intubation with lung-protective ventilation

›Septic shock

›MAP <65 mmHg

›Vasopressor initiation with norepinephrine

›Acute respiratory failure

›SpO2 <90% on room air

›HFNC or intubation depending on trajectory

›Altered mental status with meningismus

›CNS leptospirosis or aseptic meningitis

›LP after neuroimaging if no herniation risk

›Airway and breathing priorities

›Oxygen supplementation

›Target SpO2 92-96%

›HFNC for moderate hypoxemia prior to intubation

›If hemoptysis with deteriorating gas exchange, proceed to intubation

›Low tidal volume strategy 6 ml/kg ideal body weight

›PEEP titration to oxygenation

›VV-ECMO consideration for refractory pulmonary hemorrhage

›Specialist consultation

›Favorable case reports support use

›Circulation and resuscitation

›IV access with crystalloid resuscitation

›Conservative fluid strategy in ICU setting

02History/hx82

Exposure and incubation

›Exposure history

›Contact with contaminated freshwater or floodwater

›Swimming, wading, kayaking in endemic areas

›Post-flooding exposure

›Occupational exposure

›Farmers, abattoir workers, veterinarians

›Sewer workers, rice field workers, military personnel

›Recreational exposure

›Triathlon, adventure racing, cave exploration

›Water sports in tropical or subtropical regions

›Animal contact

›Rodents, dogs, cattle, pigs, horses

›Indirect contact via contaminated soil or water

›Incubation and timeline

›Incubation period 2-30 days, typically 5-14 days

›Abrupt onset of symptoms after exposure

›Biphasic pattern in some cases

›Septicemic phase first 7 days

›Brief defervescence then immune phase with complications

Presenting symptoms

›Classic symptom complex

›High fever with abrupt onset

›Often >39 degrees Celsius

›Chills and rigors

›Severe myalgia

›Calf and lumbar region predominance

›Disproportionately severe

03Physical Exam/exam65

Vitals and general appearance

›Vital signs pattern

›Temperature

›High fever often >39 degrees Celsius

›Hypothermia as severe sepsis marker

›Heart rate

›Tachycardia strongly associated with severity (OR 9.69)

›Hemodynamic compromise indicator

›Blood pressure

›Hypotension in severe cases

›MAP <65 mmHg triggers resuscitation

›Respiratory rate

›Tachypnea in pulmonary involvement

›Rising rate as deterioration signal

›General appearance

›Severity impression

›Toxic appearance with high fever

›Jaundice visible in Weil's disease

›Mental status

›Confusion or agitation suggesting CNS involvement

›GCS documentation

Key examination findings

›Conjunctival suffusion

›Most characteristic physical finding of leptospirosis

›Bilateral non-purulent conjunctival injection

›Absent exudate distinguishes from conjunctivitis

›Helps differentiate from dengue and other febrile illnesses

›Hepatic and splenic findings

04Differential Diagnosis/ddx57

Life-threatening mimics

›Immediate threats to differentiate

›Malaria

›ICD-10 B50-B54

›Periodic fever pattern, travel history

›Thick and thin blood smear or rapid diagnostic test

›Dengue hemorrhagic fever

›ICD-10 A91

›Rash, thrombocytopenia, positive NS1 antigen or IgM

›Absent conjunctival suffusion

›Meningococcemia

›ICD-10 A39.2

›Petechial rash, rapid deterioration, purpura fulminans

›Septic shock from bacterial source

›ICD-10 A41.9

›Blood cultures identify organism

Febrile illness differential

›Tropical and travel-related infections

›Rickettsioses

›Scrub typhus, Rocky Mountain spotted fever

›Eschar, maculopapular rash, doxycycline-responsive

›ICD-10 A77-A79

›Typhoid fever

›ICD-10 A01.0

›Prolonged fever, relative bradycardia, rose spots

›Blood cultures positive in first week

›Yellow fever

›ICD-10 A95

05Laboratory Tests/lt74

Initial diagnostic workup

›Complete blood count

›Thrombocytopenia in up to 80% of cases

›Severity and hemorrhagic risk marker

›Platelets <85,000 associated with worse prognosis

›Anemia in approximately 66% of cases

›Hemolysis and hemorrhage mechanisms

›Neutrophilia

›Neutrophils >80% associated with diagnosis

›Leukocytosis common

›Renal function panel

›Creatinine elevation

›AKI in up to 87-94% of severe cases

›Creatinine >150 mmol/l associated with severity

›Electrolyte abnormalities

›Hypokalemia from tubular dysfunction

›Hyponatremia possible

›Urea elevation proportional to AKI severity

Liver function and coagulation

›Hepatic panel

›Bilirubin elevation

›Conjugated bilirubin predominant

›Elevated bilirubin >30 mmol/l in Weil's disease

›Transaminase pattern

›AST often greater than ALT

›Magnitude lower than in hepatitis

›Alkaline phosphatase elevation

›Cholestatic component

06Diagnostic Tests/dt82

Scoring Systems

›Diagnostic scoring model (Rajapakse)

›Variables

›Exposure history present

›Creatinine >150 mmol/l

›Neutrophils >80%

›Bilirubin >30 mmol/l

›Platelets <85,000

›AUC 0.762 for diagnosis in resource-limited settings

›Useful when confirmatory testing unavailable

›Severity stratification criteria

›Mild/anicteric disease (approximately 90% of clinical cases)

›Self-limiting febrile illness

›Resolves in 1-2 weeks without organ failure

›Severe/icteric (Weil's disease, 5-10%)

›Jaundice plus AKI plus or minus hemorrhage

›Case fatality rate 5-15%

›Severe pulmonary hemorrhage syndrome

›DAH and ARDS

›Case fatality rate >50%

›Predictor model for severity (Malaysian multicenter study)

›Tachycardia independently associated (OR 9.69)

›Dyspnea independently associated (OR 5.54)

›Rash when present associated with severity

MRI

›MRI brain indications

›Neurological leptospirosis evaluation

›Encephalitis pattern on FLAIR sequences

07Disposition/dispo52

Admission indications

›Ward admission criteria

›Jaundice or elevated bilirubin

›Weil's disease marker

›Elevated creatinine or oliguria

›AKI requiring monitoring and IV hydration

›Thrombocytopenia with hemorrhagic manifestations

›Platelet transfusion consideration

›Hemoptysis or respiratory symptoms

›Even mild hypoxemia warrants admission

›Altered mental status or meningismus

›Inability to tolerate oral medications or fluids

›ICU admission criteria

›Multi-organ dysfunction

›Hepato-renal failure combination

›Disseminated intravascular coagulation

›Requirement for vasopressors

›Hemodynamic instability despite resuscitation

›Mechanical ventilation requirement

›ARDS or pulmonary hemorrhage

›Renal replacement therapy requirement

›Oliguric AKI with fluid overload

›Pulmonary hemorrhage syndrome

›Case fatality >50%, highest acuity

Transfer criteria

›Transfer triggers

›VV-ECMO capability required for refractory pulmonary hemorrhage

›Transfer to ECMO-capable center

08Treatment/t85

Empiric antibiotic therapy

›Principle of empiric initiation

›Initiate antibiotics immediately upon clinical suspicion

›Do not await confirmatory PCR or serology

›Cochrane review supports early treatment

›Clinical suspicion triggers

›Compatible exposure plus febrile illness plus organ involvement

›Class I recommendation by WFSICCM task force

Mild disease regimen

›Doxycycline oral

›Drug of choice for mild leptospirosis

›Doxycycline 100 mg PO twice daily

›Duration 7 days

›Alternatives when doxycycline contraindicated

›Amoxicillin 500 mg PO three times daily for 7 days

›Azithromycin 500 mg PO once daily for 7 days

›Ampicillin 500-750 mg PO four times daily for 7 days

›Network meta-analysis 2024 supports doxycycline and cephalosporins

›Significantly reduces defervescence time

›Azithromycin suitable alternative

›Cochrane Systematic Review 2024

Severe disease regimen

›IV penicillin G first-line

›Penicillin G 1.5 million units IV every 6 hours

›Duration 7 days

›Preferred in severe/icteric disease

›Alternative IV regimens

›Ceftriaxone 1 g IV once daily for 7 days

›Cefotaxime 1 g IV every 6 hours for 7 days

›Evidence base

›Cephalosporins equivalent to penicillin in RCT data

›Network meta-analysis 2024 (Ji Z et al. Systematic Reviews)

›Jarisch-Herxheimer reaction management

›Occurs in approximately 9% of treated patients

›Acute febrile reaction within 24 hours of antibiotic initiation

›Fever, rigors, hemodynamic instability

›Management

›Supportive care, antipyretics

›Continue antibiotics

›Rarely fatal but can precipitate multi-organ failure in severe cases

Supportive care

›Fluid and electrolyte management

›IV crystalloid for AKI and hemodynamic support

›Conservative strategy in ICU to avoid volume overload

›Target urine output >=0.5 ml/kg/hour

›Electrolyte supplementation

›Potassium replacement for hypokalemia

›Sodium correction per standard protocols

›Electrolyte monitoring every 6-12 hours in severe AKI

›Renal replacement therapy

›Indications

›Oliguric renal failure with fluid overload

›Severe hyperkalemia or metabolic acidosis

›Modality

›Continuous RRT preferred in hemodynamically unstable patients

›Intermittent HD when hemodynamically stable

›Recovery

›Renal function usually recovers but may take months

›Mechanical ventilation for ARDS and pulmonary hemorrhage

›Lung-protective strategy

›Tidal volume 6 ml/kg ideal body weight

›Plateau pressure <30 cmH2O

›PEEP optimization

›Higher PEEP for pulmonary hemorrhage to tamponade bleeding

›Prone positioning consideration

›Refractory hypoxemia with pulmonary hemorrhage

›Case reports support with VV-ECMO

›VV-ECMO for refractory pulmonary hemorrhage

›Emerging rescue therapy

›Favorable outcomes in case series

›Frontiers in Medicine 2025 case reports

›Bridge to antibiotic effect and lung recovery

›Specialist ECMO center required

›Vasopressor support

›Norepinephrine first-line

›Start at 0.05-0.1 mcg/kg/minute

›Titrate to MAP >=65 mmHg

›Vasopressin adjunct for refractory shock

›0.03-0.04 units/minute fixed dose

›Corticosteroids

›Insufficient evidence to support routine use

›Cochrane Review 2025 (Lee N et al.)

›Reserve for specific indications pending further trials

›Not recommended as standard adjunct

Prophylaxis

›Post-exposure prophylaxis

›Doxycycline 200 mg PO once weekly

›Used for high-risk exposures

›Efficacy unconfirmed in clinical trials

›Cochrane Review 2024 on prophylaxis inconclusive

09Special Populations/sp72

Pregnancy

›Leptospirosis in pregnancy

›Maternal risks

›Severe AKI with volume management challenge

›Jaundice and hepatic involvement

›Higher risk of preterm labor and fetal loss

›Fetal risks

›Intrauterine infection possible

›Miscarriage and stillbirth reported

›Congenital leptospirosis rare but described

›Antibiotic selection in pregnancy

›Doxycycline contraindicated

›Affects fetal bone and tooth development

›Avoid throughout pregnancy

›Preferred alternatives

›Amoxicillin 500 mg PO three times daily for mild disease

›Ampicillin 500 mg PO four times daily for mild disease

›Severe disease in pregnancy

›IV penicillin G 1.5 million units every 6 hours

›Safe in all trimesters

›Azithromycin alternative

›500 mg PO once daily for 7 days

›Generally considered safe in pregnancy

›Monitoring considerations

›Fetal monitoring when viable gestation

›Continuous monitoring in severe maternal disease

›Obstetric consultation for all pregnant patients

›Target maternal SpO2 >=95% for fetal oxygenation

10Background/b82

Epidemiology

›Global burden

›Estimated one million cases and approximately 60,000 deaths annually worldwide

›Rajapakse S et al., Nature Reviews Disease Primers 2025

›Most infections mild and self-limiting (approximately 90%)

›5-10% progress to severe multi-organ dysfunction

›Case fatality ratio 5-15% for severe disease

›Pulmonary hemorrhage syndrome

›Case fatality rate >50%

›Leading cause of death in severe leptospirosis

›Distribution and demographics

›Tropical and subtropical regions predominant

›Asia, Africa, Latin America, Caribbean highest burden

›Expanding with climate change and El Nino events

›Male predominance approximately 85% of confirmed cases

›Occupational exposure explanation

›Mean age 37-47 years in epidemiologic studies

›Urban slum outbreaks

›Rodent population and poor sanitation

›Brazil, Bangladesh, India, and other high-density urban areas

›ICU phenotypes (French multicenter study)

›Moderately severe phenotype 21%

›Hepato-renal phenotype 63%

›Neurological phenotype 5%

›Respiratory and pulmonary hemorrhage phenotype 11%

Pathophysiology

›Organism and transmission

›Pathogenic Leptospira species

›Spirochetal bacteria

›Multiple pathogenic serovars (>200 described)

›Transmission routes

›Contact with contaminated water or soil

›Entry through skin abrasions or mucous membranes

›Ingestion of contaminated food or water

›Animal reservoir

›Rodents as primary maintenance host

›Cattle, pigs, dogs, horses as incidental hosts

›Disease mechanisms

›Septicemic phase (first 7 days)

›Bacteremia and direct organ invasion

›Endothelial damage and capillary leak

›Immune phase (after day 7)

›Antibody production and immune complex deposition

›Inflammatory organ injury

›Renal injury mechanism

›Tubulointerstitial nephritis predominant

›Tubular dysfunction leads to hypokalemia and polyuria

›Glomerular involvement less prominent

›Pulmonary hemorrhage mechanism

›Diffuse alveolar hemorrhage from endothelial injury

›Immune-mediated capillary leak

›Not coagulopathy-driven in most cases

›Hepatic injury mechanism

›Hepatocyte injury without necrosis

›Cholestasis and conjugated hyperbilirubinemia

›Bilirubin disproportionately elevated relative to transaminases

Therapeutic Considerations

›Antibiotic principles

›Early initiation critical

›Best outcomes with treatment in first week

›Benefit demonstrated even in later phases

›Duration 7 days standard for all severities

›No antibiotic resistance reported clinically

›Leptospira remains susceptible to penicillins, cephalosporins, doxycycline

›Evidence base for treatment

›Cochrane Review 2024 (Win TZ et al.)

›Antibiotics for treatment of leptospirosis

›Supports use but highlights evidence gaps

›Network meta-analysis 2024 (Ji Z et al.)

›Cephalosporins, doxycycline, penicillin reduce defervescence time

›Systematic Reviews journal

›Cochrane Review 2025 (Lee N et al.)

›Corticosteroids for leptospirosis

›Insufficient evidence to recommend routine corticosteroids

›Preventive and public health considerations

›No widely available human vaccine in most countries

›Cuba and China have limited licensed vaccines

›Animal vaccination reduces environmental contamination

›Exposure prevention

›Protective footwear in endemic areas

›Avoid wading in floodwater

›Rodent control measures

›Prophylaxis uncertainty

›Doxycycline weekly for high-risk exposure

›Cochrane Review 2024 on prophylaxis inconclusive

11Patient Discharge Instructions/pdi33

copy discharge instructions

›Leptospirosis home care instructions

›Take all antibiotic doses exactly as prescribed

›Complete the full 7-day course even if feeling better

›Doxycycline: take with a full glass of water, stay upright for 30 minutes

›Rest and hydration

›Drink plenty of fluids daily

›Avoid strenuous activity until fully recovered

›Avoid alcohol during recovery

›Alcohol worsens liver stress during leptospirosis recovery

›Return to Emergency immediately for any of these warning signs

›Yellowing of the skin or eyes (jaundice)

›New or worsening

›Decreased urine output or no urine for more than 8 hours

›Dark brown or cola-colored urine

›Coughing up blood or blood-tinged sputum

›Worsening shortness of breath or difficulty breathing at rest

›Confusion, severe headache with neck stiffness

›Bleeding from any site

›Gums, nose, skin bruising

›Fever returning after initially improving

›Persistent vomiting preventing fluid intake

›Follow-up instructions

›Return to clinic or family doctor within 48-72 hours

›Blood tests will be repeated to monitor kidneys and blood counts

›Specialist blood test at 2-3 weeks

›Confirms the diagnosis of leptospirosis

›Ophthalmology referral if eye symptoms develop weeks later

12References/r19

Guidelines and key sources

›Primary references

›Rajapakse S, Fernando N, Dreyfus A, Smith C, Rodrigo C. Leptospirosis. Nature Reviews Disease Primers. 2025. PMID 40316520

›Win TZ, Han SM, Edwards T, et al. Antibiotics for Treatment of Leptospirosis. Cochrane Database of Systematic Reviews. 2024

›Lee N, Han SM, Mukadi P, et al. Corticosteroids for Treatment of Leptospirosis. Cochrane Database of Systematic Reviews. 2025

›Ji Z, Jian M, Su X, et al. Efficacy and Safety of Antibiotics for Leptospirosis: Network Meta-Analysis. Systematic Reviews. 2024. PMID 38627798

›Critical care and ICU references

›Jimenez JIS, Marroquin JLH, Richards GA, Amin P. Leptospirosis: Report From the Task Force on Tropical Diseases by WFSICCM. Journal of Critical Care. 2018. PMID 29129539

›Miailhe AF, Mercier E, Maamar A, et al. Severe Leptospirosis in Non-Tropical Areas: French Multicenter ICU Study. Intensive Care Medicine. 2019. PMID 31654079

›Smith S, Liu YH, Carter A, et al. Severe Leptospirosis in Tropical Australia: ICU Management. PLoS Neglected Tropical Diseases. 2019. PMID 31790405

›Chen M, Wu H, Xie L, Wu M, Lan P. VV-ECMO for Severe Pulmonary Leptospirosis. Frontiers in Medicine. 2025. PMID 40520796

Epidemiology and diagnostics

›Diagnostic and epidemiologic references

›Yang B, de Vries SG, Ahmed A, et al. Nucleic Acid and Antigen Detection Tests for Leptospirosis. Cochrane Database of Systematic Reviews. 2019

›Rajapakse S, Weeratunga P, Niloofa R, et al. Diagnostic Scoring Model for Leptospirosis in Resource Limited Settings. PLoS Neglected Tropical Diseases. 2016. PMID 27333195

›Philip N, Lung Than LT, Shah AM, et al. Predictors of Severe Leptospirosis: Malaysian Multicenter Study. BMC Infectious Diseases. 2021. PMID 34666707

›Ciurariu E, Prodan-Barbulescu C, Mateescu DM, et al. Diagnostic Advances in Leptospirosis: Focus on PCR. Microorganisms. 2025. PMID 40142559

›Semenza JC, Ko AI. Waterborne Diseases Sensitive to Climate Variability. New England Journal of Medicine. 2023

›CDC Yellow Book 2025. Leptospirosis. Atherstone CJ and Stoddard RA

›Fonseka CL, et al. Pulmonary Haemorrhage in Severe Complicated Leptospirosis. PLoS Neglected Tropical Diseases. 2023. PMID 37844119

›Win TZ, Perinpanathan T, Mukadi P, et al. Antibiotic Prophylaxis for Leptospirosis. Cochrane Database of Systematic Reviews. 2024

Evidence & Review