Leptospira species

Background

Microbiology

Thin, flagellated spirochetes
Best viewed with darkfield microscopy
Species and serovars are divided into three broad categories within the genus Leptospira
- Pathogens: L. interrogans (multiple serovars, most common), L. noguchii, L. borgpetersenii, L. santarosai, L. kirschneri, L. weilii, L. alexanderi, L. alstonii, L. meyeri, L. wolffi, and L. kmetyi
- Non-pathogenic saprophytes: L. biflexa, L. wolbachii, L. vanthielii, L. terpstrae, L. yanagawae, and L. idonii
- Species of indeterminate pathogenicity: L. inadai, L. fainei, L. broomii, and L. licerasiae
Within each species, there may be multiple serovars that are defined based on lipopolysaccharide (LPS) O-antigens
- A single species may have pathogenic and non-pathogenic serovars

Epidemiology

Endemic worldwide
- More common during rainy seasons in tropical regions and late summer to fall in temperate regions
- In US, more common in Hawaii
Major reservoir is as a chronic kidney infection in animals, especially rodents
- Among livestock, may cause spontaneous abortions
Most common risk factor is exposure to water or soil contaminated with rodent urine
- Includes occupational exposures and direct contact
- High-risk occupations include farmers, slaughterhouse workers, pet traders, veterinarians, rodent catchers and sewer workers
Leptospires can survive in water or soil for months, depending on the conditions

Pathophysiology

Bacteria enter through cuts and abrasions, mucous membranes, conjunctivae, and inhalation
After entering, it disseminates hematogenously
Human TLR4 cannot bind leptospiral LPS
Virulence factors
- Sphingomyelinase and hemolysin
- Also spirochete motility
- Also hooked ends

Clinical Presentation

Spectrum of severity, from asymptomatic seroconversion (most common) to nonspecific febrile illness to severe, life-threating multiorgan failure
- Asymptomatic disease is likely frequent, given high seroprevalence in some populations
Incubation period 10 days (range 5 to 14)
Acute febrile phase
- Acute phase lasts 5 to 7 days
- Starts with high fevers, headaches, chills, rigors, and myalgias
- Conjunctival injection is an identifying feature
- Muscle tenderness, especially in the calf and lumbar areas, is also characteristic
- Can also have lymphadenopathy, splenomegaly, and hepatomegaly
- Spirochetes in blood and CSF, possibly urine
Immune phase
- Lasts 4 to 30 days
- IgM antibodies appear
- Spirochete is cleared from blood and CSF but detectable in other organs, including urine
- May develop jaundice, renal failure, arrhythmias, pulmonary symptoms, aseptic meningitis, conjunctival injection, photophobia, eye pain, muscle tenderness, adenopathy, and hepaosplenomegaly
Weil disease (liver and renal failure) may develop during or directly following the acute phase
- Liver injury is predominantly jaundice with only mild liver enzyme rise
- Renal failure
  - Nonoliguric hypokalemia with impaired sodium reabsorption and increased distal sodium delivery
  - Selective loss of ENaC channels in proximal ubule
  - Biopsy shows AIN
Severe pulmonary hemorrhage syndrome (SPHS)
- May have frank hemoptysis, but not always
- Can show up as CXR lower lobe "snowflake-like" densities
Arrhythmias, including atrial fibrillation and ventricular tachycardia
Circulatory shock
- Rarely, congestive heart failure from myocarditis
Severe disease has high mortality from 5 to 40%

Diagnosis

In general, use PCR if early in disease (<7 days) and ELISA IgM followed by confirmatory MAT if further in disease (≥7 days)

Method	Sens	Spec
Culture	5-50%	100%
Microscopic agglutination test (MAT)	90%	>90%
ELISA IgM	>90%	88-95%
Latex agglutination	92%	95%
Lateral flow assay	81%	96%
PCR	100%	93%

Microscopy

Leptospires can be seen directly under darkfield microscopy
Low sensitivity and specificity of blood and urine samples, even if spirochetes are seen (as spirochetes can also be normal flora)

Culture

Can get positive cultures from blood and CSF, ideally when collected while febrile and before antibiotics
Can inoculate one to blood drops directly into culture at bedside
Urine can be cultured after the first week of illness, but need to be processed quickly
Use Fletcher's medium (commercial version)
Not very sensitive, and cultures can take weeks

Serology

Detects IgM antibodies, which appear around day 5 to 7
Microscopic agglutination test (MAT) for antigen detection (Sn 90%, Sp 90%)
- Leptospira antigens are mixed with serum and monitored for agglutination
- Monitor for a four-fold rise in titres from acute-phase to convalescent phase (repeat 4 to 6 weeks), or a single titre of at least 1:800
- May cross-react with syphilis, relapsing fever, Lyme disease, viral hepatitis, HIV, Legionella, and autoimmune diseases
- Cross-reacts between different serogroups
IgM ELISA, needs confirmation by MAT (Sn 90%, Sp 90%)
Latex agglutination test, needs confirmation by MAT (Sn 80%, Sp 95%)
Lateral flow test, needs confirmation by MAT (Sn 80%, Sp 95%)

PCR

Loop-mediated isothermal amplification (LAMP) assays and other PCR assays exist
Unclear sensitivity and specificity, but has the potential to diagnose disease before antibodies develop
Usually done from blood, but can try in urine as well

Differential Diagnosis

Other infections, including influenza, hepatitis, dengue, Hantavirus infections or other viral haemorrhagic fevers, yellow fever, malaria, brucellosis, borreliosis, typhoid fever or other enteric diseases, and pneumonia.
- Think about measles, too, in febrile patients with conjunctivitis (can occur atypically without rash)

Management

Treat early in disease course, usually before diagnosis
Usual treatment is penicillin G 1.5 MU IV q6h, if severe, or doxycycline 100 mg po bid, if mild
- May be able to use amoxicillin, ampicillin, ceftriaxone, or azithromycin as alternatives
- May develop a Jarisch-Herxheimer reaction during treatment (only with beta-lactams)
- Duration is 5 to 7 days (except 3 days for azithromycin
Close monitor and intensive supportive therapy required for severe patient
May need hemodialysis, but usually recovers renal function
SPHS is managed as ARDS with lung-protective ventilation

Prevention

Mostly avoidance of high-risk exposures
Immunization is possible but rarely done, and covers only specific serovars
- Even if immunizing animals, it prevents disease but not asymptomatic carriage
Can do chemoprophylaxis of high risk occupations with doxycycline 200 mg PO once weekly