Leptospira

Background

Microbiology

• Thin, flagellated spirochete
• 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
  • Occasionally have a pretibial papular eruption
  • Can also have lymphadenopathy, splenomegaly, and hepatomegaly
  • Mild leukocytosis and neutrophilia, with thrombocytopenia and occasionally anemia
  • Spirochetes detectable in blood and CSF, possibly urine
• Immune phase
  • Lasts 4 to 30 days
  • Corresponds with the appearance of IgM antibodies
  • Spirochete is cleared from blood and CSF but detectable in other organs, including urine
  • May develop jaundice, renal failure, arrhythmias, pulmonary symptoms, aseptic meningitis, non-purulent 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%
Darkfield microscopy	40%	60%
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%) (this is the test in Canada)
• 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

• Early in disease, it is essentially a non-specific febrile syndrome
• Viral
  • Influenza
  • Acute HIV
  • Infectious mononucleosis (EBV/CMV)
  • Flaviviruses: dengue virus, yellow fever virus, West Nile virus
  • Alphaviruses: Chikungunya virus
  • Bunyaviruses: Hantavirus, Lassa fever virus
  • Other viral hemorrhagic fever virus
  • Viral hepatitis
  • Measles virus, with cough and conjunctivitis
• Bacterial
  • Rickettsioses, including Rocky Mountain spotted fever
  • Borreliosis
  • Brucella
  • Enteric fever
• Parasitic
  • Malaria

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