Microbiology & infectious diseases

• 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

• Serology
  • Microscopic agglutination test (MAT) is the confirmatory test
  • 2 samples of plasma must be collected, the first on the second to fifth day of disease and the second on the tenth to fourteenth day of disease
  • 4x increase in the titers in the second sample is diagnostic (Lancet Infect Dis 2003;3:757)
• RT-PCR in blood (ideally, up to the third to fourth day of disease), urine, cerebrospinal fluid, tissues (CDC: Leptospirosis Fact Sheet for Clinicians [Accessed 18 November 2022])
• Blood culture in EMJ Fletcher / Stuart medium (Lancet Infect Dis 2003;3:757)
• Histology: samples collected at autopsy
  • Biopsy is not performed during the acute phase of the disease that is characterized by hemorrhagic fever and severe coagulopathy
• Diagnosis must be confirmed by public health authority / reference laboratories
  • In the U.S., diagnosis is confirmed by CDC (CDC: Leptospirosis Fact Sheet for Clinicians [Accessed 18 November 2022])
    • Contact CDC-INFO at (800) 232-4636
  • In São Paulo, Brazil, at Instituto Adolfo Lutz (Instituto Adolfo Lutz: Governo do Estado de São Paulo - Secretaria de Estado da Saúde [Accessed 18 November 2022])

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

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

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• 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):
  • Serology, RT-PCR
  • Panlobular necrosis with rupture of reticulin framework (Surg Pathol Clin 2018;11:251)
• Typhoid fever:
  • Serology, blood culture
  • Granulomatous hepatitis (Am J Trop Med Hyg 1997;56:490, Histopathology 2007;50:55)
• 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:
  • Serology, blood cultures
  • Doughnut granulomas at microscopy (Infection 2016;44:677)
• Influenza:
  • RT-PCR on respiratory fluids positive for influenza virus
  • Hepatic lesion is due to ischemic hypoxic injury
  • RT-PCR and IHC negative for YFV infection (Am J Respir Crit Care Med 2010;181:72)
• Drug related hepatitis:
  • Various patterns
  • Uncommon midzonal lesion
  • RT-PCR and IHC negative for YFV infection (Surg Pathol Clin 2018;11:297, Hepatology 2014;59:661)
• 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)

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

C. Liver cell plate disarray and interstitial nephritis, as these findings are the hallmark of leptospirosis.

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Reference: Leptospira

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

C. Complete recovery. There is no lobular necrosis in leptospirosis.

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Reference: Leptospira

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)

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.

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Reference: Leptospira