Leptospirosis

Definition, Etiology, Pathogenesis

1. Etiologic agent: Spirochetes of the genus Leptospira; small, gram-negative obligate aerobes with a characteristic question-mark shape. The pathogen is widespread globally, except in polar regions (leptospirosis is considered the most common zoonosis). The genus Leptospira comprises both pathogenic (L interrogans) and nonpathogenic (L biflexa) species. Microscopic agglutination test (MAT) identifies specific serotypes within a species. L interrogans has >200 serotypes, of which L icterohaemorrhagiae, L canicola, and L australis are the most pathogenic for humans. Unlike serologic classification, the phylogenetic classification distinguishes 16 genospecies, but it is less commonly used for practical reasons. The majority of symptomatic leptospirosis cases in Europe are due to the rat-borne L interrogans serotypes L copenhageni and L icterohaemorrhagiae.

2. Pathogenesis: Leptospires enter the human body through abraded skin, mucosa, or conjunctiva, or via inhalation or oral ingestion. They are carried by bloodstream and can cross tissue barriers, including the blood-brain barrier and aqueous humor. Leptospires damage the endothelium of small vessels, leading to vasculitis and subsequent organ involvement (see below). Multiplication of leptospires in tissues occurs in week 2 of infection.

3. Reservoir and transmission: The reservoir is usually rodents and other small mammals, but domestic animals may also harbor the infection. Animals get infected at a young age, developing chronic urinary tract infection and excreting leptospires with urine continuously or intermittently for lifetime. Humans acquire infection through direct contact with animal urine or, more frequently, indirectly, through contact with contaminated water or moist soil.

4. Risk factors: Direct contact with animals, either professionally (eg, veterinarians, slaughterers, individuals working in dairy factories) or nonprofessionally (eg, hunters, breeders); or indirect contact with animals (eg, farmers, flood victims).

5. Incubation and contagious period: The incubation period ranges from 2 to 20 days (10 days on average). Humans can be the source of infection through contact with urine of an infected individual, including through sexual contact (leptospires are excreted from day 2 of infection to up to 11 months after infection). Blood-borne transmission is also possible, for example, via puncture wounds caused by a pointed object contaminated with pathogens from a person with bacteremia (up to ~10 days of onset). Vertical transmission (through the placenta) is also possible.

Epidemiology

Leptospirosis remains a significant endemic infectious disease in most countries in South and Southeast Asia, posing a major public health challenge. The actual incidence of the disease in the region is underreported, mostly due to unavailability of confirmatory diagnostic tests for Leptospira. The highest incidence of leptospirosis in South Asia has been reported in Bangladesh, India (Andaman and Nicobar Islands), and Sri Lanka. Outbreaks mostly occur in the rainy season and following floods, when the risk of exposure to water contaminated with urine from infected animals is high.

Clinical Features and Natural History

The clinical spectrum in humans ranges from asymptomatic infection (most often undiagnosed) to severe disease with multiorgan failure and high mortality rates.

The disease follows a biphasic course. Phase 1 (septic) is an acute febrile phase and lasts ~7 days; then the symptoms subside for 1 to 3 days to progress to phase 2 (immune), characterized by the production of specific antibodies and excretion of leptospires with urine. The distinction between phases 1 and 2 may be difficult, particularly in severe disease, or distinct clinical symptoms may be present only in the immune phase.

1. Acute (septic) phase: Sudden onset; intermittent fever (up to 40 degrees Celsius) that may be accompanied by chills, headache, myalgia, subconjunctival hemorrhage (conjunctival suffusion), abdominal pain, anorexia, vomiting, diarrhea, cough, and sore throat. Severe muscle pain affecting the thighs and calves as well as conjunctival suffusion are the most typical manifestations. Lymphadenopathy, hepatosplenomegaly, and short-lived rash are far less frequent. Early in the disease meningeal signs are not pronounced, but patients may have severe headache with accompanying retrobulbar pain and photophobia. The acute phase lasts 5 to 7 days.

2. Immune phase: The short afebrile period is followed by symptoms of organ involvement that last from 4 to 30 days, accompanied by a reduction in the number of leptospires in blood and cerebrospinal fluid (CSF) and by the production of IgM antibodies. Leptospires are present in almost all tissues and organs and can be excreted with urine for several weeks. The immune phase may or may not be accompanied by jaundice. Hepatosplenomegaly and symptoms of organ involvement (see below) may be present.

Weil disease develops in 5% to 15% of patients with leptospirosis and is caused mainly by L icterohaemorrhagiae. Typical manifestations include jaundice and other features of liver injury as well as renal failure resulting from interstitial nephritis or immune complex glomerulonephritis. This is often accompanied by features of other organ damage.

Meningitis develops in ~80% of patients with leptospirosis and manifests as lymphocytic meningitis. Symptoms persist for several days to weeks. Encephalitis, transverse myelitis, hemiplegia, and Guillain-Barré syndrome are rarely seen.

Hemorrhagic diathesis develops as a result of vascular endothelial injury and manifests as epistaxis, petechiae, and ecchymoses. Gastrointestinal bleeding, adrenal hemorrhage, and subarachnoid hemorrhage are rare.

Myocarditis manifests with arrhythmia; abnormal T waves are present in as many as 80% of cases.

Pulmonary involvement may be the leading manifestation of severe leptospirosis and cause of death. There is no direct correlation between the severity of jaundice and pulmonary involvement. Clinical manifestations vary from cough, dyspnea, and hemoptysis (of varying severity) to acute respiratory distress syndrome (ARDS). Severe pulmonary hemorrhagic syndrome (SPHS) may occur in both Weil disease and in leptospirosis without jaundice. Findings in most patients include blood collecting within the alveoli, although this is not necessarily accompanied by hemoptysis or overt hemorrhage; SPHS should be suspected in every patient with leptospirosis and breathing disorders. Pleural effusion may also be present. Respiratory failure is associated with a high risk of death.

Other organ-specific manifestations: Pancreatitis, massive skeletal muscle injury (rhabdomyolysis), reactive arthritis, hemolytic anemia, anterior uveitis and retinitis (conjunctival suffusion is a particularly frequent sign).

Diagnosis

Epidemiologic history is of major importance. Diagnosis is made based on serologic test results.

Diagnostic Tests

1. Identification of the etiologic agent:

1) Polymerase chain reaction (PCR): Use whole blood collected in the first week of illness (preferably in the first 4 days), urine (ideally ≥1 week after symptom onset), or CSF from patients with signs of meningitis.

2) Serology: As antibodies develop 3 to 10 days after symptom onset, negative test results in the first week do not exclude the disease. Serologic testing should be repeated 7 to 14 days after the initial test. These tests (enzyme-linked immunosorbent assay [ELISA] IgM, immunoblot, lateral flow) are screening tests and should be confirmed with a MAT or PCR.

3) MAT: Supportive criteria for a probable case of leptospirosis include a single MAT titer of ≥1:200 accompanied by a clinically compatible illness. Criteria required for a confirmed diagnosis include a MAT titer of ≥1:800 in ≥1 serum sample or a ≥4-fold increase in a MAT titer between the acute and convalescent serum samples.

2. Other tests:

1) Blood tests:

a) Leukocytosis, elevated C-reactive protein (CRP) level, accelerated erythrocyte sedimentation rate (ESR).

b) Weil disease: High bilirubin levels (usually in mild liver pathologies), returning to normal over several weeks; moderately elevated aminotransferase levels (usually <200 IU/L; helpful in differentiation from viral hepatitis) that quickly return to normal during recovery; elevated creatine kinase levels due to muscle injury; features of renal failure.

2) Urinalysis: Proteinuria, bacteriuria.

3) CSF examination: Features of nonpurulent meningitis (see Meningitis).

4) Imaging: In patients with pulmonary involvement, radiography reveals minor scattered opacities (corresponding to blood in alveoli), sometimes confluent; pleural effusion may coexist.

Differential Diagnosis

1. Acute (septic) phase: Common febrile diseases including influenza. In tropical regions: dengue, enteric fever.

2. Immune phase:

1) Other causes of jaundice: see Jaundice.

2) Other causes of diffuse alveolar hemorrhage: see Hemoptysis.

3) Other causes of acute kidney injury (AKI): see Acute Kidney Injury (AKI).

4) Other causes of meningitis: see Meningitis.

5) Acute pancreatitis.

6) Other infectious diseases including enteric fever, acute retroviral syndrome, yellow fever, dengue, mononucleosis, brucellosis, enterovirus infection, malaria, Q fever and other rickettsial diseases, viral hemorrhagic fever, trichinellosis.

Treatment

Antibacterial Treatment

1. Mild disease: Oral doxycycline 100 mg bid for 7 days or, if contraindicated, oral amoxicillin 500 mg every 6 hours for 7 days or oral azithromycin 500 mg once daily for 3 days. 

2. Severe disease: IV penicillin is the drug of choice, 1.5 million IU every 6 hours, or ceftriaxone 1 g IV once daily.

Symptomatic Treatment

Depends on the manifestations of organ involvement.

Complications

1. Patients with meningitis may have persistent periodic headaches.

2. Patients with uveitis may develop permanent visual disturbances associated with changes in lens pigmentation or synechiae formation in the anterior eye chamber.

3. A Jarisch-Herxheimer reaction may develop following antibiotic administration.

Prognosis

In mild disease the prognosis is good. Death in septic leptospirosis is very rare and usually occurs as a result of massive pulmonary hemorrhage.

Mortality in severe cases reaches 40%. Most deaths are due to renal failure, hemorrhage, or ARDS.

Prevention

Specific Prevention

1. Vaccination: A human vaccine is only licensed in some countries but not in Canada or the United States.

2. Chemoprophylaxis: The following has been used in high risk areas, although the evidence in support is very uncertain: oral doxycycline 200 mg once weekly, to be started 1 to 2 days before the travel (contraindicated in pregnancy and in children aged <8 years).

Nonspecific Prevention

1. Avoiding exposure in endemic areas: Avoiding swimming in standing waters and long stays in wet areas; wearing proper rubber-coated clothes when working in humid environments; rodent control.

2. Patient isolation: Not required.

3. Personal protective equipment (PPE): Standard.