Microbiology, parasitology & COVID-19

Viruses

Yellow fever



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Last staff update: 20 January 2022

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PubMed Search: Yellow fever[TI] pathology "last 5 years" [DP]

Amaro Nunes Duarte-Neto, M.D., Ph.D.
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Cite this page: Duarte-Neto AN. Yellow fever. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/microbiologyyellowfever.html. Accessed December 7th, 2022.
Definition / general
  • Yellow fever (YF) is a hemorrhagic viral disease caused by an arbovirus of the Flaviviridae family, endemic in parts of central eastern Africa and South America, with recent outbreaks
  • Clinical presentation of yellow fever can range from asymptomatic disease to severe hemorrhagic fever, with fulminant hepatitis, multiple organ dysfunctions and high mortality rates (J Clin Virol 2015;64:160)
  • Yellow fever can be controlled and prevented by vaccination, before exposure (J Clin Virol 2015;64:160)
Essential features
ICD coding
  • ICD-10:
    • A95.0 - sylvatic yellow fever
    • A95.9 - yellow fever, unspecified
Epidemiology
  • Endemic in sub Saharan Africa and South America with recent outbreaks in Africa (Angola and neighboring Democratic Republic of the Congo [2015 to 2016]) and southeastern Brazil (late 2016 to early 2020)
  • Travelers visiting endemic areas without having been vaccinated or within 10 - 14 days after vaccination
  • Seasonal period: late November to early April in South America (rainy season) (J Clin Virol 2015;64:160)
Sites
  • Liver: steatotic hepatitis
  • Kidneys: acute kidney injury
  • Lungs: pulmonary hemorrhages and secondary infections
  • Pancreas: ischemic pancreatitis
  • Brain: oedema, hemorrhages
  • Heart: acute dysfunction
  • Intestines: diarrhea, ischemic colitis (PLoS Negl Trop Dis 2019;13:e0007625)
Pathophysiology
  • Direct damage by the yellow fever virus (YFV) to hepatocytes and Kupffer cells, associated with host immune response causing hepatitis; vasculopathy and coagulopathy leading to visceral hemorrhages; multiple organ dysfunction (Trans R Soc Trop Med Hyg 2007;101:161)
Etiology
  • Yellow fever is a mosquito borne disease, caused by the YFV, a member of the Flaviviridae family
  • YFV: positive sense and single stranded RNA virus, measuring 40 - 60 nm, enveloped, replicated in endoplasmic reticulum in the cytoplasm of infected cells
  • 7 major genotypes: West Africa (2), Central East Africa and Angola (3) and South America (2)
  • YFV has a single serotype and it is antigenically conserved, permitting vaccine protection against all YFV strains (J Clin Virol 2015;64:160, J Travel Med 2019;26:taz040)
Clinical features
  • Mild to no symptoms with complete recovery in the majority of infected individuals; risk of severe disease and death in a minor proportion of patients
  • Period of infection:
    • First 3 - 4 days, viremic phase, with nonspecific symptoms: high fever, prostration, headache, photophobia, back pain, intense myalgia, anorexia, nausea, vomiting, irritability, dizziness, dehydration, abdominal pain
    • Enlarged and tender liver, conjunctival injection and Faget sign (fever with relative bradycardia, reflecting dissociation of temperature and pulse)
  • Period of remission:
    • Defervescence period with improvement of symptoms; patients can either recover or evolve to the intoxication phase (about 15 - 30%)
  • Period of intoxication:
    • At this stage (third to sixth day of disease), the symptoms return, with worsening of the clinical picture
    • Fever returns, intense myalgia, severe hepatites, coagulopathy with hemorrhages and acute kidney injury with oliguria
    • Patient may develop hepatic encephalopathy with stupor, coma, seizures
    • YFV RNA (reverse transcription PCR) is positive in the first days of this phase
    • IgM antibody is positive by the seventh day of disease (J Clin Virol 2015;64:160, Lancet Infect Dis 2019;19:750, J Travel Med 2019;26:taz040)
Diagnosis
Laboratory
  • Anemia, leukopenia (mild to severe), low platelet count
  • Neutrophilia (secondary infection, intestinal translocation)
  • Elevated liver transaminase levels
  • Prolonged prothrombin time (PT), activated partial thromboplastin time (APTT)
  • Low levels of fibrinogen
  • Elevated D dimer
  • Elevated urea and creatinine
  • Metabolic acidosis (J Clin Virol 2015;64:160, J Travel Med 2019;26:taz040)
Radiology description
Radiology images

Images hosted on other servers:

Ultrasound showing hepatic steatosis

Prognostic factors
Case reports
  • 58 year old man, a kidney transplant recipient nonimmunized against yellow fever, visited the hot spot of a yellow fever outbreak in southeastern Brazil (Clin Infect Dis 2020;70:144)
  • Autopsy findings in 4 young men, ages 16 - 40 years, submitted to liver transplantation to treat yellow fever related fulminant hepatitis (Histopathology 2019;75:638)
  • Ultrasound guided minimally invasive autopsy findings of 17 patients with sylvatic yellow fever (PLoS Negl Trop Dis 2019;13:e0007625)
Treatment
  • Supportive: fluids, antipyretics, analgesics; intensive care to treat coagulopathy, hepatic coma and renal failure
  • Liver transplant is not recommended
  • No specific antiviral therapy is available yet (J Clin Virol 2015;64:160, J Travel Med 2019;26:taz040)
Gross description
  • Enlarged, congested, icteric and steatotic liver, with nutmeg pattern
    • Portal or lobular fibrosis does not occur in yellow fever, as the reticulin framework is preserved, not destroyed, during the acute phase of YF
    • Fibrosis is observed if chronic alcoholic liver disease coexists
  • Enlarged, congested, hemorrhagic spleen
  • Congestion, hemorrhages and jaundice in other organs (PLoS Negl Trop Dis 2019;13:e0007625)
Gross images

Images hosted on other servers:

Steatotic liver in YF

Yellowish color due to diffuse steatosis

Microscopic (histologic) description
  • Midzonal hepatitis (can extend to periportal area and centrilobular area in patients with severe and prolonged disease, treated in intensive care)
  • Apoptotic (Councilman bodies) and steatotic hepatocytes
  • Minimal inflammatory reaction in the liver, mainly located in portal area
  • Hyperplasia of Kupffer cells; hemophagocytosis can be seen
  • Villela bodies: bright ochre colored bodies in Kupffer cells, mainly in the midzone; these granular bodies are believed to result from disintegration of Councilman bodies and bile pigment in the cytoplasm of Kupffer cells
  • Torres bodies: eosinophilic intranuclear inclusion, rarely observed in human YF; it is a cytopathic change induced by YFV in the hepatocytes, commonly seen in Rhesus monkeys (experimental YF)
  • Regeneration and ductular reaction are not common in fatal cases
  • Preserved reticulin framework even in fulminant cases
  • Other organs: direct damage caused by the YFV (kidneys, spleen and heart); congestion and hemorrhages; lesions due to ischemic hypoxic injury and secondary infections
  • Viscerotropic disease, related to 17D / 17DD strains (vaccine), exhibits similar pathological lesions (Lancet 2001;358:91)
  • Livers in yellow fever related orthotropic liver transplantation show similar histological findings (infection of the graft), with more extensive ischemic lesions (Histopathology 2019;75:638)
  • Reference: PLoS Negl Trop Dis 2019;13:e0007625
Microscopic (histologic) images

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

Severe yellow fever hepatitis

Characteristic distribution of damage in yellow fever hepatitis

Characteristic distribution of damage in YF hepatitis

Apoptosis in yellow fever hepatitis

Apoptosis in yellow fever hepatitis

Centrilobular area in yellow fever hepatitis

Centrilobular area in yellow fever hepatitis

Hallmark diagnostic findings for yellow fever hepatitis

Hallmark diagnostic findings for YF hepatitis

Portal tract in yellow fever hepatitis

Portal tract in yellow fever hepatitis


Distribution of YFV antigens in yellow fever hepatitis

Distribution of YFV antigens in yellow fever hepatitis

Diagnostic immuno-histochemistry in YF hepatitis

Diagnostic immuno-histochemistry in YF hepatitis

Renal damage in yellow fever

Renal damage in yellow fever

Lung in fatal yellow fever

Lung in fatal yellow fever

Brain in fatal yellow fever

Brain in fatal yellow fever

Virtual slides

Images hosted on other servers:

Yellow fever liver

Positive stains
  • IHC (mouse or goat, polyclonal primary antibody anti-YFV): positive in apoptotic or steatotic hepatocytes and Kupffer cells, mainly in the midzonal lobular area; positive in some inflammatory cells in the portal tracts; positive in scattered tubular epithelial cells in the kidney; positive in the red-white pulp of the spleen and in some inflammatory cells in the heart (Histopathology 2019;75:638, PLoS Negl Trop Dis 2019;13:e0007625)
  • Reticulin stain: preserved, without loss or proliferation
  • Perls Prussian blue: little iron deposition in hepatocytes or Kupffer cells
Negative stains
  • Negative for other etiologic agents that cause hemorrhagic fever
Electron microscopy description
Molecular / cytogenetics description
  • Reverse transcription PCR detects YFV RNA in fresh frozen samples from liver, kidneys, heart, lungs and spleen, collected at autopsy (Histopathology 2019;75:638)
Sample pathology report
  • Liver biopsy (left lobe):
    • Midzonal hepatitis, characterized by numerous apoptotic (Councilman bodies) and steatotic hepatocytes, with minimal inflammatory reaction in the liver, mainly located in portal areas. Nuclear or cytoplasmic viral inclusions are not seen. Hyperplasia of Kupffer cells and figures of hemophagocytosis can be seen scattered through hepatic lobules. Regeneration and ductular reaction is variable. The reticulin framework is preserved. Immunohistochemistry reaction detects YFV antigens in apoptotic and steatotic hepatotocytes, mainly in the midzonal area, as well as in the cytoplasm of Kupffer cells and inflammatory mononuclear cells in the portal areas.
Differential diagnosis
  • Dengue:
    • Serology, reverse transcription PCR
    • Dengue virus also induces midzonal hepatitis indistinguishable from yellow fever
    • IHC is not a reliable method to diagnosis dengue hepatitis in fatal cases, probably due to a lack of specific primary antibodies against different serotypes (BMC Infect Dis 2021;21:311)
  • Malaria:
    • Blood smear, antigen detection, reverse transcription PCR
    • Detection of Plasmodium 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, reverse transcription PCR
    • Histological pattern is different from yellow fever: panlobular necrosis with rupture of reticulin framework (Surg Pathol Clin 2018;11:251)
  • Leptospirosis:
    • Serology, blood culture
    • Hepatocyte disarray and IHC positive for preserved fragmented Leptospira in the liver are typical for the diagnosis
    • IHC is usually positive in the kidneys (inflammatory cells, interstitium and tubular cells) (Rev Inst Med Trop Sao Paulo 2018;60:e23)
  • Typhoid fever:
  • Hantavirus:
    • Reverse transcription 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 and less positive in the liver) (Am J Pathol 1995;146:552)
  • Meningococcal septicaemia and gram negative sepsis:
    • Blood cultures, serology
    • Liver exhibits reactive hepatitis (congestion, inflammatory cells in the sinusoids, with neutrophils, forming micro-abscesses, mixed inflammatory reaction in the portal areas, cholestasis, microvesicular steatosis) (Am J Clin Pathol 2004;122:754)
  • Spotted fever (rickettsial infections):
    • Serology, reverse transcription PCR
    • Vascular lesions with endothelial tumefaction, vasculitis, ischemic necrosis and thrombosis, with ischemic damage involving the surrounding parenchyma, in various organs
    • IHC detects antigens in the cytoplasm of endothelial cells (J Infect Dis 1999;179:1469)
  • Q fever:
  • Influenza:
    • Reverse transcription PCR on respiratory fluids positive for influenza virus
    • Hepatic lesion is due to ischemic hypoxic injury
    • Reverse transcription PCR and IHC negative for YFV infection (Am J Respir Crit Care Med 2010;181:72)
  • Drug related hepatitis:
  • Alcoholic hepatitis:
    • Apoptotic bodies are randomly distributed through hepatic lobules
    • Mallory bodies and diffuse macrovesicular steatosis
    • Reverse transcription PCR and IHC negative for YFV infection (World J Gastroenterol 2014;20:16474)
  • Decompensated cirrhosis:
    • Clinical history of hepatotropic virus infection, alcohol consumption
    • Serology, reverse transcription PCR and IHC negative for YFV infection
    • Portal and lobular cirrhosis (Clin Mol Hepatol 2017;23:302)
Board review style question #1

A 25 year old European man traveled on vacation in southeastern Brazil, in early January, where he visited forested areas. He returned to his country of origin and within 7 days, he presented with high fever and myalgia, fulminant hepatitis, hemorrhages, coma and multiple organ dysfunction. He died on the fifth day of illness. The autopsy was performed and the histological section of the liver is shown above. Serologies and reverse transcription PCR for hepatotropic viruses (A, B, C, D and E), dengue fever, Leptospira and Rickettsia were negative. Antigen and blood smear for Plasmodium detection were also negative as well as blood cultures for pyogenic bacteria. What are the main mechanisms of liver cell damage in this disease?

  1. Granulomatous inflammatory reaction
  2. Lytic necrosis
  3. NETosis
  4. Steatosis and apoptosis
  5. Vascular damage and ischemic necrosis
Board review style answer #1
D. Steatosis and apoptosis. Apoptotic cells are so called Councilman bodies.

Comment Here

Reference: Yellow fever
Board review style question #2
What are the late repercussions on liver function in yellow fever?

  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 yellow fever. The reticulin framework is preserved.

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Reference: Yellow fever
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