Leptospira/Leptospirosis

Leptospira is a spiral or question mark–shaped, gram-negative spirochete with hook-shaped ends. The disease, leptospirosis, is a zoonosis, infecting animals. Rodents are the most important reservoir. Bacteria shed in the urine of rodents and other animals can be transmitted to humans via contaminated water. The major clinical species is Leptospira interrogans, which causes a mild flu-like illness in a majority of cases. The manifestations are biphasic, with Leptospira found in the blood initially. In the immune phase, the bacteria disappear from the bloodstream and can be detected in the urine. In about 10% of infections, icterohemorrhagic leptospirosis develops, manifesting as hemorrhage, renal failure, and jaundice. Bacterial culture takes weeks, so other diagnostic tests such as serology and dark field microscopy are used. Treatment is primarily with penicillin.

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General Characteristics

Leptospira

  • Characteristics: 
    • A spirochete 
    • Structure: 
      • Spiral or shaped like a question mark
      • Has hook-shaped ends (differentiates Leptospira from other spirochetes)
    • Oxygen requirement: aerobic
    • Gram stain: gram-negative (stains poorly)
    • Other stain(s): silver stain
    • Microscopy: 
      • Best visualized with dark field microscopy 
      • Fluorescent microscopy 
    • Culture: special media required
  • Associated diseases (zoonosis):
    • Leptospirosis (anicteric)
    • Weil’s disease (icterohemorrhagic)

Clinically relevant species

There are pathogenic (disease-causing) and saprophytic types (free living and generally do not cause disease). The following types are all pathogenic:

  • L. interrogans (most prevalent)
  • L. kirschneri
  • L. noguchii
  • L. alexanderi
  • L. weilii
  • L. alstonii
  • L. borgpetersenii
  • L. santarosai
  • L. kmetyi
  • L. mayottensis

Epidemiology

  • 870,000 cases of leptospirosis with 48,600 deaths annually worldwide
  • Highest disease morbidity and mortality in South and Southeast Asia, Oceania, the Caribbean, Latin America, and Africa
  • Lack of testing in many areas makes it difficult to estimate the number of leptospirosis cases. 
  • United States: majority of cases in Hawaii (128/100,000 population annually)
  • Peak seasons:
    • Summer and fall in the Northern and Southern hemispheres
    • Rainy season in the tropics
Leptospira liver impression smear

Visualizing Leptospira, the spirochete seen in a liver impression smear (fluorescent antibody stain)

Image: “Leptospira bacteria in liver impression smear. FA stain.” by the CDC/Mildred Galton. License: Public domain.

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Pathogenesis

Reservoirs

  • Animals are infected and can be asymptomatic.
  • Infected animals (only mammals) shed Leptospira via urine:
    • Rodents (most important reservoir) 
    • Household pets
    • Domesticated livestock 

Transmission

  • Bacteria transmitted from: 
    • Water or soil contaminated with animal urine or blood
    • Infected animal tissue
  • Human portals of entry:
    • Abraded skin
    • Mucous membranes
    • Conjunctivae
    • Rarely, by ingestion of food contaminated with urine
    • Transplacental infection (frequency unknown)
  • Incubation period: 5–14 days (can reach up to 30 days)

Virulence and disease process

  • Bacterial factors affecting pathogenicity:
    • Lipopolysaccharide (LPS) (a major antigenic stimulus)
    • Hemolysins (lyse erythrocytes and cell membranes)
    • Complement regulators (help evade the complement system)
    • Adherence factors such as outer membrane proteins (bind the host extracellular matrix (ECM))
    • Enzymes (hydrolyze ECM and some inactivate the complement system)
  • Disease process: 
    • Leptospiremic/bacteremic phase:
      • Once in the host, the spirochetes enter the bloodstream (bacteria can be cultured from the blood).
      • Toxins released lead to breakdown of the vessel walls and fluid leakage.
      • Duration often < 10 days
    • Immune phase: 
      • At this time, organisms have escaped from the bloodstream to the tissues. 
      • Leptospires are absent in the blood, but are found in the urine. 
      • Immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies directed against the Leptospira LPS are generated by the host.
      • These antibodies are opsonins that enhance phagocytosis.
  • Effects:
    • Initially, Leptospira in the bloodstream cause flu-like symptoms.
    • From the bloodstream, bacteria establish in other areas, particularly parenchymatous organs.
    • Renal effects:
      • Renal failure (tubulo-interstitial nephritis)
      • Hypokalemia and hyponatremia due to inhibition of sodium-potassium-chloride (Na-K-Cl) cotransporter
    • Hepatic: vascular injury in hepatic capillaries and bile canalicular plugging (jaundice)
    • Pulmonary: capillary damage and alveolar hemorrhage, acute respiratory distress syndrome (ARDS)
    • Hematologic effects: 
      • Hemolysis
      • Thrombocytopenia

Host risk factors

  • Poor housing, poor sanitation (rodent-infested areas)
  • Contaminated water in floods after a rainfall 
  • Recreational activities:
    • Freshwater swimming
    • Water activities
  • Occupations involving infected animals and contaminated soil and water

Clinical Presentation

Leptospirosis

  • Mild anicteric syndrome
  • Often variable course
  • Described as a biphasic illness (leptospiremic and immune phases), but phases may overlap
  • 90% of illnesses are mild (usually resolve in < 10 days)
  • Symptoms:
    • Febrile, with flu-like symptoms
    • Myalgias (especially of the calves and back) 
    • Diarrhea, vomiting
    • Rash
    • Retro-orbital or frontal headache
    • Photophobia with conjunctival suffusion (erythema without exudate)
  • Symptom recurrence and complications are possible in the immune phase.

Weil’s syndrome/disease

  • Icterohemorrhagic leptospirosis
  • Rare but severe, systemic form
  • Occurs in 10% of cases, and has a mortality rate of up to 40% 
  • Causes a triad of:
    • Renal injury 
    • Jaundice (hepatic dysfunction, cholestasis)
    • Hemorrhage
  • Also associated with multi-organ failure:
    • Myocarditis (conduction abnormalities)
    • Rhabdomyolysis (muscle pain, renal failure)
    • ARDS (shortness of breath)
    • Pulmonary hemorrhage (hemoptysis)
Table: Comparison of diseases caused by Leptospira
CharacteristicsLeptospirosisWeil’s syndrome (icterohemorrhagic leptospirosis)
PresentationMild flu-like infectionSevere form
Population at riskPrevalent among surfers and in the tropicsDevelops in 10% of infected patients
Signs and symptoms
  • Myalgias (classically of the calves)
  • Rash
  • Photophobia with conjunctival suffusion (erythema without exudate)
  • Headache
  • Jaundice (liver dysfunction)
  • Azotemia (kidney dysfunction)
  • Hemorrhages, vascular collapse
  • Anemia
DiagnosisUrine is an excellent body fluid to identify the organisms.
Management
  • Penicillin or erythromycin
  • Doxycycline for post-exposure prevention
Conjunctival suffusion leptospirosis

Image of eye changes noted in leptospirosis: Conjunctival suffusion and jaundice are seen.

Image: “Conjunctival suffusion of the eyes due to leptospirosis” by Daniel Ostermayer. License: CC BY 4.0.

Diagnosis

Tests for Leptospira

Serology:

  • Antibody titer can be detected by the 2nd week.
  • Serologic confirmation of infection: a rise in titer by a factor of 4 
  • Test through:
    • Microscopic agglutination test (MAT) (the most specific test)
    • Enzyme-linked immunosorbent assay (ELISA)

Isolation of leptospires (blood, urine, tissue, or cerebrospinal fluid (CSF)):

  • Polymerase chain reaction (PCR): can confirm the diagnosis from blood samples early in the illness 
  • Visualization by dark field microscopy
  • Culture:
    • Ellinghausen-McCullough-Johnson-Harris (the most commonly used medium)
    • Growth takes 2 weeks to 3 months (used more for retrospective diagnosis)

Additional tests

  • Obtained in multi-organ involvement
  • Laboratory tests:
    • Complete blood count (↑ white blood cells, ↓ hemoglobin, ↓ platelets)
    • Renal function (abnormal creatinine) 
    • Liver function tests (↑ transaminases, ↑ bilirubin)
    • ↓ Potassium, ↓ sodium
    • Elevated inflammatory markers (C-reactive protein, procalcitonin, erythrocyte sedimentation rate)
    • CSF (normal glucose, lymphocytic or neutrophilic pleocytosis)
  • Chest X-ray obtained with pulmonary involvement:
    • Patchy alveolar pattern in the lower lobes (suggestive of hemorrhage)
    • May have ground-glass opacities if with ARDS

Management

Treatment

  • Severe leptospirosis: 
    • Intravenous (IV) penicillin
    • Other options: cephalosporins, macrolides, doxycycline 
  • Mild cases: 
    • Amoxicillin/doxycycline/azithromycin
  • Aggressive supportive treatment with multi-organ involvement:
    • Fluid and electrolyte resuscitation
    • Dialysis in severe renal failure
    • Mechanical ventilation in respiratory failure from ARDS or pulmonary hemorrhage

Prevention

  • Improve housing, infrastructure, and sanitation standards.
  • Rodent abatement efforts and flood mitigation projects
  • Proper use of personal protective equipment (PPE) by people who have a high risk of occupational exposure 
  • Weekly doxycycline when exposure in an endemic area is anticipated

Differential Diagnosis

  • Dengue: illness caused by dengue viruses, which spread to humans through mosquito bites (infected Aedes species). Dengue presents with fever, body aches, and rash with most patients recovering. In severe cases, dengue progresses to internal hemorrhage and shock. Specific antibodies and reverse-transcriptase-PCR detection of viral genomic sequences differentiate the viral illness. 
  • Viral hepatitis: infection from a virus causing an acute inflammatory reaction in the liver. Presents with jaundice, fever, and hepatomegaly but transaminases are usually > 1,000 in cases of viral hepatitis. Differentiation is established by detecting viral antigens and antibodies in the serum. Treatment is based on etiology. For certain hepatitis types, prevention is achieved by vaccination. 
  • Hantavirus: virus spread mainly by rodents and reaches humans commonly via an aerosolized virus that sheds in urine, feces, and saliva. The presentation can be hantavirus pulmonary syndrome (HPS) or hemorrhagic fever with renal syndrome (HFRS). Serologic tests help distinguish hantavirus from leptospirosis.

References

  1. Day, N., Calderwood, S., & Baron, E. (2019), Leptospirosis: Epidemiology, microbiology, clinical manifestations and diagnosis. UpToDate. Retrieved Dec 13, 2020, from https://www.uptodate.com/contents/leptospirosis-epidemiology-microbiology-clinical-manifestations-and-diagnosis
  2. Day, N., Calderwood, S., Edwards, M., & Baron, E. (2020). Leptospirosis: Treatment and prevention. UpToDate. Retrieved Dec 13, 2020, from https://www.uptodate.com/contents/leptospirosis-treatment-and-prevention
  3. DeBrito, T., Goncalves da Silva, A., & Abreu, P. (2018). Pathology and pathogenesis of human leptospirosis: A commented review. Revista do Instituto de Medicina Tropical de São Paulo vol.6. https://doi.org/10.1590/s1678-9946201860023
  4. Evangelista, K., & Coburn, J. (2010). Leptospira as an emerging pathogen: A review of its biology, pathogenesis and host immune responses. Future Microbiol, 5(9): 1413–1425. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037011/
  5. Fraga, T., Isaac, L., & Barbosa, A. (2016). Complement evasion by pathogenic Leptospira. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2016.00623
  6. Riedel S, Hobden J.A., Miller S, et al. (Ed.) (2019). Spirochetes: Treponema, Borrelia, and Leptospira. In Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill.
  7. Southwick, F.S. (2020). Emerging bacterial infections (including zoonotic pathogens and biological weapons). In Southwick F.S.(Ed.), Infectious Diseases: A Clinical Short Course, 4th ed. McGraw-Hill.
  8. Sun, A., Liu, X., & Yan, J. (2020). Leptospirosis is an invasive infectious and systemic inflammatory disease. Biomedical Journal 43(1): 24–31. https://doi.org/10.1016/j.bj.2019.12.002
  9. Wagenaar J.P., & Goris M.A. (2018). Leptospirosis. In Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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