Leptospirosis

Introduction

Leptospirosis is a widespread zoonotic disease caused by pathogenic spirochetes of the genus Leptospira. It is considered the most widespread zoonosis in the world, with significant morbidity and mortality, particularly in tropical and subtropical regions. The disease is characterized by a broad spectrum of clinical manifestations, ranging from subclinical or mild anicteric febrile illness to severe multiorgan failure known as Weil syndrome. It is often referred to as a "neglected tropical disease" and is an emerging pathogen due to increased human-animal interface and climate change events like flooding.

Etiology

The causative organism belongs to the order Spirochaetales, family Leptospiraceae, and genus Leptospira.

• Morphology: They are thin, varying from 0.1 $\mu$m in diameter and 6–20 $\mu$m in length, tightly coiled, aerobic spirochetes with hooked ends (shepherd's crook appearance). They are highly motile due to periplasmic flagella.
• Classification: Traditionally, the genus was divided into two species: L. interrogans (pathogenic) and L. biflexa (saprophytic). Current classification based on DNA relatedness identifies over 20 species and more than 300 serovars.
  • Pathogenic Species: Includes L. interrogans, L. kirschneri, L. noguchii, etc.
  • Serovars: Common pathogenic serovars include Icterohaemorrhagiae (associated with rats/severe disease), Canicola (dogs), Pomona (cattle/swine), Grippotyphosa, and Autumnalis.

Epidemiology

Reservoirs and Transmission

• Animal Reservoirs: Rodents (especially rats) are the most important maintenance hosts. Other reservoirs include dogs, cattle, swine, and wild mammals. These animals develop chronic renal infection and shed leptospires in their urine for prolonged periods (leptospiruria) without apparent illness.
• Transmission to Humans: Humans are incidental (dead-end) hosts. Infection occurs via:
  1. Direct Contact: With urine, blood, or tissues of infected animals.
  2. Indirect Contact: Exposure to water, soil, or mud contaminated with infected animal urine. The organism can survive for weeks in moist, warm environments.
  3. Portals of Entry: Mucous membranes (conjunctiva, nose, mouth) or abraded skin (cuts, scratches). Ingestion of contaminated water is another route.

Risk Factors

• Occupational: Veterinarians, sewer workers, rice field workers, abattoir workers, and farmers.
• Recreational: Swimming in fresh water, kayaking, or camping.
• Environmental: Flooding and heavy rainfall are major predictors of outbreaks, especially in urban slums with poor sanitation and rodent infestation.

Pathogenesis and Pathophysiology

Following entry through skin or mucosa, the organisms enter the bloodstream and disseminate rapidly to all parts of the body, including the central nervous system (CNS) and eyes.

Systemic Vasculitis

The hallmark of leptospirosis is extensive small-vessel vasculitis (capillary injury).

• Mechanism: Leptospires damage the endothelium of small blood vessels.
• Consequence: This leads to leakage of fluid and protein (edema), extravasation of cells (hemorrhage), and ischemic damage to end organs.

Biphasic Nature

The natural history typically follows two phases:

1. Leptospiremic (Septicemic) Phase: Lasts 4–7 days. Organisms are present in the blood and CSF. Characterized by abrupt onset of symptoms.
2. Immune (Leptospiruric) Phase: Follows the first phase (sometimes after a brief asymptomatic period). Characterized by the appearance of IgM antibodies, disappearance of organisms from blood, and localization of inflammation in tissues (kidney, liver, meninges, eye). Leptospires may be shed in urine during this phase.

Organ-Specific Pathophysiology

• Kidney: Tubulointerstitial nephritis is the primary lesion. Pathophysiology involves hypoxic/ischemic insult, direct nephrotoxicity, and immune-mediated damage. This leads to acute tubular necrosis (ATN) and acute kidney injury (AKI). Hypokalemia is often seen due to inhibition of tubular sodium-potassium transport.
• Liver: Hepatocellular necrosis and cholestasis occur but are generally less severe than the functional impairment suggests. Jaundice is caused by hepatocellular dysfunction, bilirubin overload from hemolysis, and cholestasis.
• Lungs: Pulmonary hemorrhage is a severe complication caused by toxic/immune-mediated damage to alveolar capillaries (alveolitis).
• Muscles: Direct invasion leads to vacuolization of myofibrils and focal necrosis (rhabdomyolysis), causing severe myalgia.
• Hemostatic Derangement: Thrombocytopenia is common (due to consumption and immune destruction). Coagulopathy can occur in severe cases.

Clinical Manifestations

The incubation period is usually 7–12 days (range 2–30 days). The clinical presentation is protean.

1. Anicteric Leptospirosis (90% of cases)

This is the milder and most common form. It typically presents with a biphasic course.

• Septicemic Phase:
  • Onset: Abrupt onset of high fever (remittent), chills, and rigor.
  • Headache: Severe, incapacitating frontal or retro-orbital headache.
  • Myalgia: Intense muscle pain, classically affecting the calves, lumbosacral region, and abdomen. Calf tenderness is a distinguishing feature.
  • Conjunctival Suffusion: Bilateral redness of conjunctiva without purulent discharge. This is a pathognomonic sign often appearing on days 3–4.
  • GI Symptoms: Nausea, vomiting, abdominal pain (may mimic appendicitis).
  • Rash: Transient macular, maculopapular, or petechial rash (e.g., pretibial rash in L. autumnalis).
• Immune Phase:
  • Fever may recur.
  • Aseptic Meningitis: Occurs in up to 80% of children (CSF pleocytosis) but clinical signs (neck stiffness) are present in only 50%.
  • Uveitis: Anterior uveitis (iridocyclitis) may develop weeks to months later.

2. Icteric Leptospirosis (Weil Syndrome) (5–10% of cases)

A severe, potentially fatal form characterized by the triad of jaundice, renal failure, and hemorrhage.

• Hepatic: Jaundice appears between days 4 and 9. Hepatomegaly and right upper quadrant tenderness are common. Liver failure is rare.
• Renal: Azotemia, oliguria, or anuria. Acute Renal Failure (ARF) is a major cause of mortality.
• Hemorrhagic Diathesis: Epistaxis, petechiae, purpura, melena, and hematemesis.
• Cardiovascular: Myocarditis, arrhythmias, and hypotension/shock.

3. Severe Pulmonary Hemorrhage Syndrome (SPHS)

An emerging severe form characterized by hemoptysis and respiratory failure.

• Presents with dyspnea, cough, and chest pain.
• Rapid progression to massive pulmonary hemorrhage and ARDS.
• Can occur without jaundice. High mortality rate (>50%).

Pediatric Considerations

• Clinical features in children are similar to adults but may also include acalculous cholecystitis, pancreatitis, and facial nerve palsy.
• Hypertension may occur due to renal vasculitis.
• "Kawasaki-like" presentation has been reported.

Diagnostic Investigations

Diagnosis is based on a combination of clinical suspicion and laboratory confirmation.

A. Nonspecific Laboratory Findings

• Hematology:
  • Leukocytosis with neutrophilia and shift to the left.
  • Thrombocytopenia (common predictor of severity).
  • Elevated ESR and CRP.
• Biochemistry:
  • Creatine Phosphokinase (CPK): Elevated in the first week (reflects myositis); helps differentiate from viral hepatitis.
  • Liver Function Tests: Elevated bilirubin (conjugated and unconjugated). Transaminases (AST/ALT) are elevated but usually <200–500 IU/L (in contrast to viral hepatitis where they are >1000 IU/L).
  • Renal Function: Elevated BUN and creatinine. Hypokalemia is a characteristic finding in the early stage.
• Urinalysis: Proteinuria, pyuria, microscopic hematuria, and hyaline/granular casts.
• CSF Analysis: Lymphocytic pleocytosis (10–500 cells/mm${}^3$), elevated protein, normal glucose.

B. Specific Microbiological Diagnosis

1. Microscopy:
   • Dark-field microscopy of blood/urine can visualize spirochetes but has low sensitivity and specificity (false positives with fibrin threads). Not recommended for routine diagnosis.
2. Culture:
   • Definitive diagnosis.
   • Specimens: Blood/CSF (first 7-10 days), Urine (after 10 days).
   • Media: EMJH (Ellinghausen-McCullough-Johnson-Harris) or Fletcher’s medium.
   • Drawback: Slow growth (up to 6 weeks), low sensitivity.
3. Serology (Mainstay of Diagnosis):
   • Microscopic Agglutination Test (MAT): The Gold Standard.
     • Uses live leptospiral antigens.
     • Positive Result: Four-fold rise in titer in paired sera or a single high titer ($\ge$ 1:400 or 1:800 depending on endemicity) in a clinical context.
     • Seroconversion occurs late (2nd week).
   • IgM ELISA / Rapid Diagnostic Tests (RDTs):
     • Detect IgM antibodies (e.g., Lepto-Dipstick, macroscopic agglutination).
     • Useful for early diagnosis (positive from day 5 onwards).
     • High sensitivity but lower specificity than MAT.
4. Molecular Methods:
   • PCR: Highly sensitive and specific for detecting leptospiral DNA in blood (early phase) or urine. Useful for diagnosis in the first few days before antibodies appear.

Differential Diagnosis

Leptospirosis is a great mimicker.

• Dengue Fever: Differentiated by retro-orbital pain, distinctive rash, and absence of significant renal failure or neutrophilic leukocytosis.
• Malaria: Differentiated by periodicity of fever, splenomegaly, and blood smear.
• Viral Hepatitis: Higher transaminases (>1000), absence of neutrophilia and renal failure.
• Enteric Fever: Step-ladder fever, relative bradycardia, Widal test.
• Hantavirus (HFRS): Similar renal/hemorrhagic picture; distinguished by epidemiology and serology.
• Rickettsial Diseases: Eschar, rash distribution.
• Meningitis/Encephalitis: In the immune phase.

Treatment

1. Antimicrobial Therapy

Antibiotics shorten the duration of illness and reduce shedding if started early (preferably within the first 4-5 days).

• Severe Disease (Hospitalized):
  • Penicillin G: 6–8 million units/m${}^2$/day IV in 4–6 divided doses for 7 days.
  • Ceftriaxone: 80–100 mg/kg/day IV once daily for 7 days. (Equally effective and easier administration).
  • Cefotaxime: Alternative parenteral agent.
• Mild Disease (Outpatient):
  • Doxycycline: 4 mg/kg/day PO in 2 divided doses (Max 200 mg/day) for 7 days. (Avoid in children <8 years unless benefit outweighs risk; usually safe for short courses).
  • Amoxicillin: 30–50 mg/kg/day PO in 3 divided doses for 7 days.
  • Azithromycin: 10 mg/kg on day 1, then 5 mg/kg/day for 4 days.

Jarisch-Herxheimer Reaction: A transient worsening of symptoms (fever, tachycardia, hypotension) may occur shortly after starting antibiotics due to massive release of bacterial toxins. It is generally self-limiting but requires monitoring.

2. Supportive Management

Crucial for determining outcome in severe cases.

• Fluid and Electrolyte Balance: Aggressive rehydration for hypovolemia. Correction of hypokalemia.
• Renal Failure:
  • Maintain perfusion pressure.
  • Diuretics (furosemide) may be tried to convert oliguric to non-oliguric failure.
  • Dialysis: Early initiation of Peritoneal Dialysis or Hemodialysis significantly reduces mortality in Weil syndrome.
• Liver Failure: Vitamin K for coagulopathy, nutritional support.
• Respiratory Failure: Mechanical ventilation with high PEEP for pulmonary hemorrhage/ARDS.
• Transfusion: Platelets/Fresh Frozen Plasma for severe bleeding.

Prognosis

• Anicteric: Excellent prognosis; mortality is nil.
• Severe Icteric (Weil's): Mortality ranges from 5% to 15%.
• Pulmonary Hemorrhage: High mortality (>50%).
• Poor Prognostic Factors: Altered mental status, oliguric renal failure, respiratory insufficiency, hypotension, arrhythmias, and age >60 years (though less relevant for pediatrics, severe disease in children is dangerous).

Prevention

1. General Measures

• Rodent Control: Sanitary disposal of garbage to reduce rat population.
• Avoidance: Avoid swimming or wading in potentially contaminated waters (floodwater, stagnant ponds), especially if there are skin abrasions.
• Protective Clothing: Use of boots and gloves for high-risk occupational activities.
• Wound Care: Cover cuts/abrasions with waterproof dressings.

2. Chemoprophylaxis

Indicated for individuals with short-term, high-risk exposure (e.g., soldiers, disaster relief workers in floods).

• Drug: Doxycycline 200 mg orally once weekly. (Not routinely recommended for children <8 years).
• Azithromycin may be considered for younger children or pregnant women.

3. Vaccination

• Animals: Vaccination of dogs and cattle reduces disease and shedding but provides serovar-specific immunity.
• Humans: Vaccines exist (e.g., in Cuba, China) but are serovar-specific, offer short-term immunity, and are not widely available or WHO-prequalified for global use.