Microbiology, parasitology & COVID-19

Atypical bacteria

Spirochetes

Leptospira



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Last staff update: 25 January 2023

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PubMed Search: Leptospira

Amaro Nunes Duarte-Neto, M.D., Ph.D.
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Cite this page: Duarte-Neto AN. Leptospira. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/microbiologyleptospira.html. Accessed February 5th, 2023.
Definition / general
  • Leptospirosis is caused by pathogenic species of Leptospira, a gram negative bacteria
  • Infection causes febrile disease and is mainly characterized by acute hepatic and renal damage
Essential features
  • Febrile jaundice with acute kidney injury, pulmonary hemorrhage, myositis
  • Uremia and oliguria with low levels of serum potassium
  • Histology: liver cell plate disarray, acute tubular necrosis and interstitial nephritis, intense pulmonary hemorrhage and myositis
  • Other organs: congestion, hemorrhage and secondary lesions due to hypoxic ischemic injury (Lancet Infect Dis 2003;3:757)
ICD coding
  • ICD-10:
    • A27.0 - leptospirosis icterohemorrhagica
    • A27.9 - leptospirosis, unspecified
Epidemiology
  • Leptospirosis is a neglected zoonotic disease, caused by pathogenic species of Leptospira, a spirochete gram negative bacteria; the disease occurs worldwide but it is more common in tropical or subtropical countries
  • Endemic in Latin America, Asia with periodic seasonal peak of cases
  • Seasonal period: late November, early April in South America (rainy season)
  • Infected through indirect or direct contact with contaminated water and wet soil, with urine and other fluids contaminated with Leptospira from infected reservoir animals (mainly rats but also dogs, cats and cattle); ingestion of food or water contaminated by other fluids is less common
    • Leptospira enters the host body through skin and mucosal abrasions
  • Associated with poor housing and sanitation, and is also an occupational and recreational disease (Lancet Infect Dis 2003;3:757)
  • Workers in the outdoors or in flooded areas, where infected animals excrete Leptospira in urine are at high risk of infection (e.g., farmers, mine workers, sewer workers, slaughterhouse workers, veterinarians and animal caretakers, fish workers, dairy farmers)
  • Practice of aquatic sports in lakes and rivers with contaminated water with pathogenic Leptospira increases risk (e.g., swimming, wading, kayaking, rafting)
  • Military personnel working in endemic / flooded areas are under high risk of exposure (Lancet Infect Dis 2003;3:757, PLoS Negl Trop Dis 2015;9:e0003898)
Sites
  • Liver: cholestatic acute hepatitis
  • Kidneys: acute tubular necrosis, interstitial nephritis
  • Lungs: intense acute pulmonary hemorrhage and acute lung injury with respiratory insufficiency
  • Pancreas: pancreatitis
  • Brain: perivascular hemorrhages, mild lymphocytic meningitis
  • Optic neuritis, anterior uveitis
  • Heart: acute dysfunction
  • Intestines: diarrhea
  • Muscles: intense myositis (Lancet Infect Dis 2003;3:757)
Pathophysiology
  • Direct damage by pathogenic Leptospira to hepatocytes and Kupffer cells, associated with host immune response causing hepatitis; vasculopathy and coagulopathy leading to visceral hemorrhages; multiorgan dysfunction (Rev Inst Med Trop Sao Paulo 2018;60:e23)
  • Proteins and toxins (still unknown) cause injury on cell membranes from the human host, with rupture of intercellular junctions on vasculature and epithelium
  • Epithelial (E)-cadherin and vascular endothelial (VE)-cadherin are lower expressed in some organs (liver, lungs and kidneys) during the acute phase of the disease
  • Leptospira causes tubular damage with dysfunction of Na, K ATPase
  • Complement components are involved in the pathogenesis of pulmonary hemorrhage (Clin Microbiol Infect 2010;16:593)
  • Intense lymphoid hypoplasia in the spleen in severe cases (Lancet Infect Dis 2003;3:757, Front Immunol 2019;10:920)
Etiology
  • Leptospira spp., a spirochete gram negative bacteria, classified in more than 250 pathogenic serovars; the taxonomic classification may change after molecular analysis in the near future
  • L. icterohaemorrhagiae is the most common pathogenic serotype in South America (Lancet Infect Dis 2003;3:757)
Clinical features
  • Incubation: 2 - 30 days (mean: 10 days) after exposure
  • Most cases asymptomatic / oligosymptomatic
  • Acute febrile disease: fever, headache, photophobia, nausea, vomiting, abdominal pain, diarrhea, myalgia (mainly on calves and lower back), skin hyperemia, cough
  • Approximately 10% of cases evolve to severe forms
  • Weil disease: acute kidney injury with jaundice and fever associated with Leptospira infection
  • Severe cases: jaundice, oliguria, pulmonary hemorrhage, aseptic meningitis, arrhythmias, shock
  • Diagnostic findings suggestive of leptospirosis: conjunctival suffusion, myalgia, hypokalemia, sterile pyuria, thrombocytopenia, hepatosplenomegaly
  • Rare clinical manifestations: chorioretinitis, optic neuritis, anterior uveitis (Lancet Infect Dis 2003;3:757, Am J Trop Med Hyg 2008;79:911)
Diagnosis
Laboratory
  • Anemia, leukocytosis (mild to severe)
  • Neutrophilia
  • Progressively low platelet count
  • Normal prothrombin time (PT) and normal activated partial thromboplastin time (APTT)
  • Elevated urea and creatinine
  • Low serum potassium levels at the beginning of Weil disease; elevated levels with anuric kidney failure
  • Elevated plasmatic levels of creatine phosphokinase (CPK)
  • Discrete elevated liver transaminase levels
  • Metabolic acidosis with high lactic acid
  • Hypoxemia in cases with pulmonary hemorrhage
  • Progressive and refractory hypoxemia in fatal cases (Braz J Infect Dis 2007;11:142, Lung 2011;189:1, Am J Trop Med Hyg 2008;79:911)
Radiology description
  • Abdominal ultrasound: hepatomegaly, absence of biliary lithiasis
  • Chest Xrays: bilateral alveolar / interstitial infiltrates
  • High resolution CT scans of the chest: nodular infiltrates, areas of consolidation, ground glass attenuation and crazy paving patterns (Lung 2011;189:1)
Radiology images

Contributed by Amaro Nunes Duarte-Neto, M.D., Ph.D.
Bilateral and diffuse alveolar interstitial pattern

Bilateral and diffuse alveolar interstitial pattern

Post-tracheal intubation

Post tracheal intubation

Prognostic factors
  • Markers of unfavorable prognosis: renal dysfunction, elevated potassium, pulmonary hemorrhage, severe hypoxemia, shock (Am J Trop Med Hyg 2008;79:911)
  • Complete recovery in those who survive
Case reports
  • 19 year old man with no prior comorbidities presenting with high grade fever and altered sensorium, due to leptospirosis and meningitis (BMJ Case Rep 2018;2018:bcr2018225281)
  • 26 and 37 year old men presenting asymptomatic aseptic meningitis due to neuroleptospirosis (BMC Infect Dis 2021;21:488)
  • 41 year old man with appendicitis, rectal perforation, jaundice and thrombocytopenia due to leptospirosis (Trop Doct 2021;51:427)
Treatment
  • Supportive: fluids, antipyretics, analgesics
  • Prompt antibiotic therapy: intravenous penicillin, ceftriaxone, ceftazidime, ampicillin, amoxicillin, oxacilina, tetracycline, azithromicin
  • Intensive care treatment: hemodialysis, vasoactive drugs, platelet transfusion, mechanical ventilation (Lancet Infect Dis 2003;3:757)
Gross description
  • Enlarged, congested and icteric liver
  • Fibrosis is observed if chronic liver disease coexists
  • Intense pulmonary hemorrhage
  • Enlarged and hemorrhagic spleen
  • Congestion, hemorrhage and jaundice in other organs
  • Reference: Malays J Pathol 2018;40:169
Microscopic (histologic) description
  • Liver: hepatocyte plate disarray; sinusoidal congestion; mixed inflammatory infiltrate in the portal areas; cholestasis
  • Kidneys: acute tubular necrosis and interstitial nephritis with mild and mixed inflammatory infiltrate, vascular congestion
  • Lungs: diffuse and massive pulmonary hemorrhage, alveolar edema, interstitial lymphocytic pneumonitis (Am J Trop Med Hyg 1997;56:181)
  • Brain: vascular congestion, mild lymphocytic infiltrate in meninges
  • Spleen: red pulp with hemorrhage, hyperplasia of sinusoidal cells and splenitis; white pulp with marked hypoplasia (Front Immunol 2019;10:920)
  • Muscles: foci of myositis (Rev Inst Med Trop Sao Paulo 2020;62:e85)
  • Heart: diffuse interstitial edema in the myocardium, hyaline degeneration of cardiomyocytes, foci of mild myocarditis (Trans R Soc Trop Med Hyg 2012;106:515)
Microscopic (histologic) images

Contributed by Amaro Nunes Duarte-Neto, M.D., Ph.D.
Severe leptospirosis hepatitis Severe leptospirosis hepatitis

Severe leptospirosis hepatitis

Severe leptospirosis hepatitis Severe leptospirosis hepatitis

Severe leptospirosis hepatitis

Severe leptospirosis hepatitis - IHC

Severe leptospirosis hepatitis - IHC


Lung in fatal leptospirosis Lung in fatal leptospirosis

Lung in fatal leptospirosis

Brain in fatal yellow fever

Brain in fatal yellow fever

Heart in fatal yellow fever

Heart in fatal yellow fever

Kidney in fatal yellow fever

Kidney in fatal yellow fever

Renal lesion in leptospirosis (interstitial nephritis) - IHC

Renal lesion in leptospirosis (interstitial nephritis) - IHC

Virtual slides

Images hosted on other servers:

Hepatic damage due to leptospirosis

Positive stains
  • Immunohistochemistry (IHC): positive in Kupffer cells; positive in some inflammatory cells in the portal tracts and renal interstitial inflammatory infiltrate; positive in the red / white pulp of the spleen
  • IHC may be positive even in cases with severe liver cell disarray and autolysis (Rev Inst Med Trop Sao Paulo 1986;28:170)
  • In humans, usually the IHC shows a granular and cytoplasmic pattern of positivity in inflammatory cells; it is very rare to see conserved forms of Leptospira in tissues
  • This pattern is secondary to antibiotic action on Leptospira cell walls, fragmenting the bacteria
  • Reticulin stain: preserved, without loss or proliferation
  • Perls Prussian blue: little iron deposition in hepatocytes and Kupffer cells (Rev Inst Med Trop Sao Paulo 2018;60:e23)
Negative stains
  • Negative for other etiologic agents that cause hemorrhagic fever
Electron microscopy description
Electron microscopy images

Images hosted on other servers:

Septal capillary

Sample pathology report
  • Liver, autopsy sample:
    • Leptospirosis (see comment)
    • Comment: The hepatic parenchyma shows liver plate cell disarray, without necrosis and minimal lobular inflammatory reaction. Hyperplasia of Kupffer cells. Sinusoidal congestion. Mixed inflammatory reaction in the portal areas. Regeneration and ductular reaction are not observed. The reticulin framework is preserved. Immunohistochemiscal stain is positive for Leptospira antigens in the cytoplasm of Kupffer cells and in the cytoplasm of inflammatory mononuclear cells in the portal areas.

  • Kidney, autopsy sample:
    • Leptospirosis (see comment)
    • Comment: Foci of mixed interstitial nephritis and acute tubular necrosis. Intense alveolar hemorrhage. Immunohistochemistry detects Leptospira antigens in the cytoplasm of inflammatory mononuclear cells in the renal interstitium.

  • Lungs, autopsy samples:
    • Leptospirosis (see comment)
    • Comment: Diffuse and intense alveolar edema and hemorrhage; foci of intra-alveolar hyaline membranes; mild lymphoid infiltrate in the alveolar septa. Immunohistochemistry detects Leptospira antigens in the cytoplasm of endothelial cells and mononuclear cells in the alveolar septa.

  • Skeletal muscle, autopsy samples:
    • Leptospirosis (see comment)
    • Comment: Focal myositis, with mixed inflammatory infiltrate in the skeletal muscles from thighs and calves. Immunohistochemistry detects Leptospira antigens in the cytoplasm of Kupffer cells and in the cytoplasm of inflammatory mononuclear cells in the interstitium.
Differential diagnosis
  • Dengue:
    • Serology, RT-PCR
    • Dengue virus also induces midzonal hepatitis indistinguishable from YFV
    • IHC is not a reliable method to diagnose dengue hepatitis in fatal cases, probably due to a lack of specific primary antibodies against different serotypes (BMC Infect Dis 2021;21:311)
  • Yellow fever:
    • Serology, RT-PCR
    • Midzonal hepatitis with apoptotic (Councilman bodies) and steatotic hepatocytes, minimal inflammatory reaction in the liver, mainly located in portal area, hyperplasia of Kupffer cells (PLoS Negl Trop Dis 2019;13:e0007625)
    • RT-PCR in blood: positive, collected at the beginning of symptoms (up to fifth day of disease)
    • Serology: IgM after the seventh day of disease; IgG after the tenth to fourteenth day of disease
  • Malaria:
    • Blood smear (Plasmodium trophozoites and gametocytes), antigen detection, RT-PCR
    • Detection of parasites in red blood cells in tissue samples and within Kupffer cells (BMJ Glob Health 2021;6:e005218)
  • Viral hepatitis (hepatitis A, B, C, D and E):
  • Typhoid fever:
  • Hantavirus:
    • RT-PCR, viral culture, serology
    • Centrilobular congestion, hemorrhages and necrosis due to shock, mild inflammation
    • Positive IHC in endothelial cells (mainly in the lungs and kidneys; less positive in the liver) (Am J Pathol 1995;146:552)
  • Meningococcal septicemia and gram negative sepsis:
    • Blood cultures, serology
    • Liver exhibits reactive hepatitis (congestion, inflammatory cells in the sinusoids, with neutrophils, forming microabscess, mixed inflammatory reaction in the portal areas, cholestasis, microvesicular steatosis) (Am J Clin Pathol 2004;122:754)
  • Spotted fever (rickettsial infections):
    • Serology, RT-PCR
    • Vascular lesions with endothelial tumefaction, vasculitis, ischemic necrosis and thrombosis, with ischemic damage associated in the surrounding parenchyma, in various organs
    • IHC detects antigens in the cytoplasm of endothelial cells (J Infect Dis 1999;179:1469)
  • Q fever:
  • Influenza:
  • Drug related hepatitis:
  • Alcoholic hepatitis:
    • Apoptotic bodies are randomly distributed through hepatic lobules
    • Mallory bodies and diffuse macrovesicular steatosis
    • RT-PCR and IHC negative for YFV infection (World J Gastroenterol 2014;20:16474)
  • Decompensated cirrhosis:
    • Clinical history of hepatotropic virus infection, alcohol consumption, serology, RT-PCR and IHC negative for YFV infection
    • Portal and lobular cirrhosis (Clin Mol Hepatol 2017;23:302)
Board review style question #1

A 35 year old man, a sanitation worker in the city of São Paulo, started having symptoms of fever, severe myalgia in the calves, headache, abdominal pain and mild jaundice, 4 days after contact with garbage in a flooded area of the city. Laboratory tests showed mild leukocytosis, anemia, platelet count of 100,000/μL, mild elevation of direct bilirubin, mild elevation of urea and creatinine, very high creatine phosphokinase (CPK) and normal liver enzymes. Serologies and RT-PCR for hepatotropic viruses (A, B, C, D and E), dengue fever, and Rickettsia were negative. Blood cultures for pyogenic bacteria were negative. He was hospitalized and prescribed with fluids and ceftriaxone. What are the main histological hepatic and renal pathological findings in this disease?

  1. Congestion and mild hepatocyte necrosis in the centrilobular area and acute tubular necrosis
  2. Granulomatous hepatitis and nephritis
  3. Liver cell plate disarray and interstitial nephritis
  4. Midzonal hepatitis and acute tubular necrosis
  5. Vasculitis in the liver and kidneys, with thrombi
Board review style answer #1
C. Liver cell plate disarray and interstitial nephritis, as these findings are the hallmark of leptospirosis.

Comment Here

Reference: Leptospira
Board review style question #2
What is the typical late sequela in the liver of patients who survive leptospirosis?

  1. Autoimmune hepatitis
  2. Cholangiopathy
  3. Complete recovery
  4. Portal hypertension due to portal fibrosis
  5. Vanishing bile duct syndrome
Board review style answer #2
C. Complete recovery. There is no lobular necrosis in leptospirosis.

Comment Here

Reference: Leptospira
Board review style question #3
A patient with suspected leptospirosis improved after empirical treatment with antibiotics during the hospitalization and was discharged on the 13th day of illness. The initial serology for leptospirosis (microscopic agglutination test), collected on the 4th day of disease, was negative. The PCR on whole blood, collected on the 6th day of disease, was negative. Serologies for viral hepatitis were negative and the abdominal ultrasound showed no biliary lithiasis or liver abscess. What is the diagnostic test to be requested at this time of the disease (convalescence)?

  1. Blood culture
  2. Cerebral fluid analysis
  3. Liver biopsy
  4. RT-PCR on the whole blood
  5. Serology on a second plasma sample (convalescent sample)
Board review style answer #3
E. Serology on a second plasma sample (convalescent sample). Microscopic agglutination test (MAT) is the confirmatory test. The second sample, collected on the tenth to fourteenth day of disease, shows increased titers.

Comment Here

Reference: Leptospira
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