Leptospirosis

Definition, Etiology, PathogenesisTop

1. Etiologic agent: Spirochetes of the genus Leptospira; very small, gram-negative obligate aerobes with characteristic shape resembling a question mark. The pathogen is prevalent worldwide, except for 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) allows for identification of specific serotypes within a species. L interrogans has >200 serotypes, of which L icterohaemorrhagiae, L canicola, and L australis are most pathogenic for humans. Unlike serologic classification, the phylogenetic classification distinguishes 16 genospecies. However, for practical reasons it is less commonly used. 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 the oral route. Then, they are carried by bloodstream and cross tissue barriers, including the blood-brain barrier and the aqueous humor. Damage to the endothelium of small vessels caused by leptospires leads to vasculitis and subsequent organ involvement (see below). Multiplication of leptospires in tissues occurs in week 2 of the disease.

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. They develop chronic urinary tract infection and excrete leptospires with urine continuously or intermittently for lifetime. Humans acquire infection through direct or, more frequently, indirect (contaminated water or moist soil) contact with animal urine.

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

5. Incubation and contagious period: The incubation period is 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), or through the blood-borne route, for example, a puncture wound 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.

EpidemiologyTop

Leptospirosis remains a major endemic infectious disease in most countries in South and Southeast Asia and is an important public health problem there. The actual incidence of the disease in the region is not well reported, mostly due to unavailability of confirmatory diagnostic tests for Leptospira. The highest incidence of leptospirosis in South Asia is reported in Bangladesh, India (Andaman and Nicobar Islands), and Sri Lanka. Outbreaks mostly occur in the rainy season and following flooding, when there is high risk of exposure to water contaminated with urine from infected animals.

Clinical Features and Natural HistoryTop

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

The disease is biphasic. 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 production of specific antibodies and excretion of leptospires with urine. The distinction between phases 1 and 2 may be difficult to notice, 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 and 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-lasting 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. This is accompanied by reduction in the number of leptospires in blood and cerebrospinal fluid (CSF) and by production of IgM antibodies. Leptospires are present in almost all tissues and organs. They 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 glomerulonephritis with immune complexes. 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 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).

DiagnosisTop

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

Diagnostic Tests

1. Identification of the etiologic agent:

1) Culture: Leptospires can be isolated from blood and CSF in week 1 of disease and from urine, after the first week at the earliest; however, a positive culture result is rarely obtained (leptospires are difficult to culture, as they grow slowly).

2) Serologic studies: MAT with antigens representing different serotypes specific for the given country (performed by very few reference laboratories), enzyme-linked immunosorbent assay (ELISA), passive hemagglutination assay (PHA), immunofluorescence assay, Western blot assay. Seroconversion may be delayed and may occur even after a month of disease onset, which obscures diagnosis in the septic phase. A ≥4-fold increase in specific antibody titers supports the diagnosis (hence the necessity to perform ≥2 serum samplings at ~2-week intervals), and so does high antibody titer (≥1:800) in the agglutination-lysis test.

3) Strip tests aimed at detecting the LipL32 membrane protein of leptospires (sensitivity and specificity similar to that of MAT).

4) Molecular studies: Polymerase chain reaction (PCR) aimed at identification of leptospires in bloodstream and CSF in the acute phase; available only in reference laboratories.

5) Direct microscopic specimen examination: Visualization of motile leptospires by dark-field microscopy; not recommended due to low sensitivity and specificity.

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.

TreatmentTop

Antibacterial Treatment

1. Mild disease: Oral doxycycline 100 mg bid or, if contraindicated, oral amoxicillin 500 mg tid or IV ampicillin for 7 to 14 days.

2. Severe disease: 3 million IU of IV penicillin G qid or, alternatively, 1 to 2 g of IV ceftriaxone once daily, or IV cefotaxime, or 1 g of IV ampicillin qid for 7 to 14 days.

Symptomatic Treatment

Depends on the manifestations of organ involvement.

ComplicationsTop

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.

PrognosisTop

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.

PreventionTop

Specific Prevention

1. Vaccination: Used sporadically in humans.

2. Chemoprophylaxis should be considered by travelers to endemic areas: 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.