Yellow Fever

Infectious Disease MONDO:0020502 Pathograph 10 Show in embeddings browser Arbovirus Infection Viral Hemorrhagic Fever

Yellow fever is a mosquito-borne viral hemorrhagic fever caused by yellow fever virus, an orthoflavivirus endemic to tropical and subtropical regions of Africa and South America and transmitted by Aedes, Haemogogus, and Sabethes mosquitoes. Following dermal inoculation, the virus infects dendritic cells, amplifies in draining lymph nodes, and disseminates via the bloodstream to the liver, where viral cytopathic replication and an unbalanced pro- and anti-inflammatory cytokine response (TNF-alpha, TGF-beta) drive hepatocyte apoptosis, lytic necrosis, steatosis, consumptive and synthetic coagulopathy, endothelial dysfunction, and in 20% to 60% of symptomatic patients a toxic phase marked by jaundice, hemorrhage, thrombocytopenia, and hepatic and renal failure.

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⚙

Pathophysiology

3
Dermal Dendritic Cell Infection, Lymphatic Amplification, and Systemic Viremia
Following inoculation of yellow fever virus from mosquito salivary glands into the dermis, virions attach via heparan sulfate glycosaminoglycans, enter cutaneous dendritic cells by clathrin-mediated endocytosis, and traffic to draining lymph nodes where viral replication amplifies and seeds systemic viremia reaching the liver, spleen, heart, and kidneys.
dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology.
viral entry into host cell GO:0046718 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral entry into host cell, annotated with symbiont entry into host cell (GO:0046718). GO:0046718 is a biological process from the Gene Ontology. viral genome replication GO:0019079 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology.
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology. lymph node UBERON:0000029 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lymph node (UBERON:0000029). UBERON:0000029 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hepatocyte Apoptosis, Lytic Necrosis, and Cytokine-Driven Hepatotoxicity Hematogenous dissemination delivers high-titer virus to the liver, where hepatocytes and Kupffer cells are infected.
Endothelial Activation and Increased Vascular Permeability High-titer viremia and pro-inflammatory mediator release act on vascular endothelial cells to induce vasculopathy and capillary leakage.
Fever Acute systemic viremia and innate cytokine release trigger the initial febrile flu-like phase.
Show evidence (2 references)
PMID:29933925 SUPPORT Other
"Current models suggest that after YFV transmission from the mosquito salivary glands to the host’s dermal environment, the virus infects DCs and circulates to the lymph nodes"
Establishes dermal dendritic cell infection and lymphatic dissemination to regional lymph nodes.
PMID:29933925 SUPPORT Other
"In this tissue, YFV amplifies and primes the cellular immune response before spreading through the peripheral blood, ultimately reaching the liver for active replication."
Documents viral amplification in lymph nodes followed by hematogenous spread to the liver.
Hepatocyte Apoptosis, Lytic Necrosis, and Cytokine-Driven Hepatotoxicity
In the liver, yellow fever virus replicates extensively in hepatocytes and Kupffer cells, inducing direct cytopathic hepatocyte apoptosis (Councilman bodies), lytic necrosis, and microvesicular steatosis, compounded by an unbalanced intrahepatic cytokine storm driven by TNF-alpha, IFN-gamma, and pro-apoptotic TGF-beta from infiltrating CD4+ T cells and activated macrophages.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hepatic failure Extensive hepatocyte apoptosis, necrosis, and steatosis cause acute hepatic failure and loss of coagulation factor synthesis.
Jaundice Hepatocellular necrosis and cholestasis produce severe hyperbilirubinemia and clinical jaundice, from which the disease takes its name.
Show evidence (2 references)
PMID:29933925 SUPPORT Human clinical
"In this main target organ, YFV induces hepatocyte apoptosis and lytic necrosis, which, combined with steatosis, results in most of the liver damage observed during infection"
Establishes hepatocyte apoptosis, lytic necrosis, and steatosis as the primary drivers of liver injury in yellow fever.
PMID:29933925 SUPPORT Human clinical
"In addition to the virus-induced cytopathic effect, several studies suggest that the immune response itself, via a systemic and unbalanced cytokine response (or cytokine storm), is a major driver of hepatotoxicity and YF disease"
Documents the systemic and intrahepatic cytokine storm as a major driver of hepatotoxicity in severe yellow fever.
Endothelial Activation and Increased Vascular Permeability
Wild-type yellow fever virus infects vascular endothelial cells and induces a prolonged pro-inflammatory cytokine response that, together with systemic cytokine storm and hepatic synthesis failure of clotting factors, disrupts endothelial barrier integrity, increases vascular permeability, and leads to vasculopathy, capillary leak, thrombocytopenia, hemorrhagic manifestations, acute kidney injury, and shock during the toxic phase.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
regulation of vascular permeability GO:0043114 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. endothelial cell activation GO:0042118 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endothelial cell activation (GO:0042118). GO:0042118 is a biological process from the Gene Ontology.
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Abnormal bleeding Endothelial barrier dysfunction, thrombocytopenia, and hepatic coagulation-factor depletion produce mucosal and gastrointestinal hemorrhage.
Thrombocytopenia Platelet consumption and bone marrow suppression during the toxic phase cause severe thrombocytopenia.
Acute kidney injury Intravascular volume depletion, vasculopathy, and direct tubular injury lead to acute renal failure in the toxic phase.
Show evidence (3 references)
PMID:29933925 SUPPORT In vitro / ex vivo
"In primary human vascular endothelial cells, Kupffer cells, MDMs and monocyte-derived dendritic cells (MoDCs), YFV-Asibi causes a greater, more prolonged pro-inflammatory response than YFV-17D"
Demonstrates that virulent wild-type YFV-Asibi directly elicits a prolonged pro-inflammatory response in primary human vascular endothelial cells.
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Links toxic-phase progression to hemorrhagic fever, thrombocytopenia, vasculopathy, and multi-organ dysfunction.
PMID:41734218 SUPPORT REVIEW SYNTHESIS Other
"Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
Places yellow fever within the shared viral hemorrhagic fever pathway of endothelial dysfunction, capillary leak, and coagulopathy.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Yellow Fever Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 2
Thrombocytopenia FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Documents thrombocytopenia in the toxic phase of yellow fever.
Abnormal bleeding FREQUENT HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Documents hemorrhagic fever manifestations in the toxic phase.
Digestive 2
Jaundice FREQUENT HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Identifies jaundice as a defining clinical feature of the toxic phase of yellow fever.
Hepatic failure FREQUENT HP:0001399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic failure (HP:0001399). HP:0001399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Identifies liver failure as a hallmark of the toxic phase.
Genitourinary 1
Acute kidney injury FREQUENT HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Identifies renal failure as a hallmark of the toxic phase of yellow fever.
Metabolism 1
Fever VERY_FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
Describes the initial febrile flu-like phase following the 3- to 6-day incubation period.
💊

Medical Actions

2
Live-Attenuated Yellow Fever 17D Vaccine (YF-VAX / Stamaril)
Action: vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Agent: Yellow Fever Vaccine NCIT:C96396 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Yellow Fever Vaccine (NCIT:C96396). NCIT:C96396 is a therapeutic agent from the NCI Thesaurus.
Platform: Vaccine
Single subcutaneous dose of live-attenuated yellow fever 17D vaccine (or a one-fifth fractional dose during emergency mass-vaccination campaigns) induces serum neutralizing antibodies within 2 weeks in most vaccinees and provides decades-long protective immunity via persistent memory B cells and polyfunctional CD8+ T cells. Rare serious adverse events include yellow fever vaccine-associated viscerotropic disease (YEL-AVD; 0.4 per 100,000 doses, CFR 63%) and vaccine-associated neurotropic disease (YEL-AND; 0.8 per 100,000 doses), which are linked to host genetic defects in innate antiviral immunity (such as type I/III IFN pathway defects).
Mechanism Target:
INHIBITS Dermal Dendritic Cell Infection, Lymphatic Amplification, and Systemic Viremia — Vaccine-elicited neutralizing IgG antibodies and memory CD8+ T cells neutralize incoming wild-type yellow fever virus and prevent systemic viremia and hepatic dissemination.
Show evidence (1 reference)
PMID:29933925 SUPPORT INDIRECT Human clinical
"Following subcutaneous injection of 17D in a cohort of human patients neither previously exposed or immunized to YFV, neutralizing antibodies were detectable in the serum of most individuals two weeks post vaccination"
Demonstrates rapid induction of serum neutralizing antibodies within two weeks after 17D vaccination.
Show evidence (3 references)
PMID:29933925 SUPPORT Human clinical
"Following subcutaneous injection of 17D in a cohort of human patients neither previously exposed or immunized to YFV, neutralizing antibodies were detectable in the serum of most individuals two weeks post vaccination"
Confirms immunogenicity of subcutaneous YFV-17D vaccination in naive human cohorts.
PMID:29933925 SUPPORT Human clinical
"A strong, antigen-specific T cell response and persistent memory B cell response seem to represent the hallmarks of long-term protective immunity, as YFV-specific memory T cells and IgG antibodies can persist for decades in patient sera"
Establishes decades-long humoral and cellular memory after YFV-17D immunization.
PMID:29933925 SUPPORT Human clinical
"As worldwide stocks of YFV-17D are experiencing a significant shortage, such campaigns use only one-fifth of the regular vaccine dose, which is still sufficient to provide immunity for at least one year"
Documents fractional-dose (one-fifth standard dose) YFV-17D vaccination providing protective immunity during vaccine shortages.
Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No licensed specific antiviral drug is available for yellow fever; clinical management of the toxic phase relies on intensive supportive care for hemorrhage, hepatic failure, and renal failure.
Show evidence (1 reference)
PMID:42076078 SUPPORT REVIEW SYNTHESIS Other
"Supportive care continues to represent the cornerstone of clinical management for most infections, while pathogen-targeted therapies are available only for a restricted number of diseases."
Confirms supportive care as the cornerstone of clinical management for viral hemorrhagic fevers lacking licensed antivirals.
🔬

Diagnosis

1
Laboratory Confirmation of Yellow Fever Virus Infection
Laboratory confirmation of yellow fever virus infection by molecular testing, serology, antigen detection, or viral culture, typically performed at specialized reference laboratories.
laboratory examination NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30021822 SUPPORT Human clinical
"A number of diagnostic methods and assays have been described for the detection of YFV infection, including viral culture, molecular testing, serology, and antigen detection. Commercial diagnostics are not widely available, and testing is generally performed at a small number of reference laboratories."
Documents the specific laboratory diagnostic modalities used to confirm yellow fever virus infection (molecular testing, serology, antigen detection, and viral culture).
PMID:29933925 SUPPORT Human clinical
"Such risk is exemplified by the 2016 report of 10 laboratory-confirmed YF cases in China imported from Angola, the first ever reported cases in Asia."
Documents laboratory confirmation as the diagnostic standard for identifying imported yellow fever cases.
📈

Progression

3
Incubation and Acute Febrile Phase (Period of Infection)
Duration: 3 to 6 days incubation followed by acute flu-like febrile phase
Following an infected mosquito bite and a 3- to 6-day incubation period, patients develop acute onset of fever and flu-like symptoms driven by primary and secondary viremia.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
Documents the 3- to 6-day incubation period and subsequent acute febrile flu-like phase.
Period of Remission
Duration: 1 to 2 days
Transient defervescence and clinical improvement lasting 1 to 2 days, after which most patients recover while 20% to 60% progress to the toxic phase.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
Documents the 1- to 2-day remission period between the acute febrile phase and the toxic phase.
Toxic Hepatorenal and Hemorrhagic Phase (Period of Intoxication)
Approximately 20% to 60% of symptomatic patients relapse into a severe toxic phase characterized by recurrence of fever, jaundice, thrombocytopenia, hemorrhagic manifestations, and hepatic and renal failure (case fatality rate 20% to 60%).
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
Characterizes the toxic phase of yellow fever that follows the remission period in 20% to 60% of patients.
📊

Prevalence

1
Global endemic regions (tropical Africa and South America)
Annual incidence
Estimated 80,000 to 200,000 yellow fever cases and 30,000 to 60,000 fatalities annually worldwide, with a case fatality rate of 20% to 60% in the toxic phase.
Show evidence (1 reference)
PMID:29933925 SUPPORT Human clinical
"Annually, there are approximately 80,000–200,000 YFV cases worldwide. The number of fatalities annually is commonly estimated as 30,000–60,000, with a case fatality rate (CFR) ranging from 20–60%"
Provides global annual case and fatality estimates and the 20% to 60% case fatality rate.
🦠

Infectious Agent

1
Yellow fever virus
Enveloped, single-stranded positive-sense RNA virus (~11 kb genome encoding three structural proteins Core, PrM, and E and seven nonstructural proteins NS1 through NS5) in the family Flaviviridae.
Yellow fever virus NCBITaxon:3046277 NCBI Taxonomy (NCBITaxon)
Show evidence (2 references)
PMID:25453327 SUPPORT Other
"Yellow fever, a mosquito-borne flavivirus disease occurs in tropical areas of South America and Africa."
Identifies yellow fever as a mosquito-borne flavivirus disease in tropical South America and Africa.
PMID:29933925 SUPPORT Other
"YFV is an enveloped virus that contains a single-stranded, positive-sense RNA genome of about 11,000 nucleotides"
Describes the genome and virion structure of yellow fever virus.
↔️

Transmission

1
Mosquito vector transmission (Haemogogus, Sabethes, and Aedes genera)
Transmitted to humans through the bite of infected mosquitoes of the Haemogogus, Sabethes, and Aedes genera across sylvatic, intermediate, and urban transmission cycles.
Show evidence (1 reference)
PMID:29933925 SUPPORT Other
"Endemic to tropical and sub-tropical regions of South America and Africa, YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes and Aedes genera."
Identifies the three mosquito genera responsible for transmitting yellow fever virus to humans.
{ }

Source YAML

click to show 
name: Yellow Fever
creation_date: '2026-10-25T20:05:00Z'
category: Infectious Disease
description: >-
  Yellow fever is a mosquito-borne viral hemorrhagic fever caused by yellow
  fever virus, an orthoflavivirus endemic to tropical and subtropical regions of
  Africa and South America and transmitted by Aedes, Haemogogus, and Sabethes
  mosquitoes. Following dermal inoculation, the virus infects dendritic cells,
  amplifies in draining lymph nodes, and disseminates via the bloodstream to the
  liver, where viral cytopathic replication and an unbalanced pro- and
  anti-inflammatory cytokine response (TNF-alpha, TGF-beta) drive hepatocyte
  apoptosis, lytic necrosis, steatosis, consumptive and synthetic coagulopathy,
  endothelial dysfunction, and in 20% to 60% of symptomatic patients a toxic
  phase marked by jaundice, hemorrhage, thrombocytopenia, and hepatic and renal
  failure.
disease_term:
  preferred_term: yellow fever
  term:
    id: MONDO:0020502
    label: yellow fever
parents:
- Arbovirus Infection
- Viral Hemorrhagic Fever
synonyms:
- Sylvan yellow fever
- Urban yellow fever
- Yellow jack
infectious_agent:
- name: Yellow fever virus
  description: >-
    Enveloped, single-stranded positive-sense RNA virus (~11 kb genome encoding
    three structural proteins Core, PrM, and E and seven nonstructural proteins
    NS1 through NS5) in the family Flaviviridae.
  infectious_agent_term:
    preferred_term: Yellow fever virus
    term:
      id: NCBITaxon:3046277
      label: Orthoflavivirus flavi
  evidence:
  - reference: PMID:25453327
    reference_title: "Yellow fever."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Yellow fever, a mosquito-borne flavivirus disease occurs in tropical areas of South America and Africa."
    explanation: Identifies yellow fever as a mosquito-borne flavivirus disease in tropical South America and Africa.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "YFV is an enveloped virus that contains a single-stranded, positive-sense RNA genome of about 11,000 nucleotides"
    explanation: Describes the genome and virion structure of yellow fever virus.
agent_life_cycle:
  description: >-
    Yellow fever virus circulates in sylvatic cycles between non-human primates
    and forest canopy mosquitoes (Haemogogus and Sabethes in South America,
    sylvatic Aedes in Africa) and in urban cycles between humans and Aedes
    aegypti mosquitoes.
  hosts:
  - preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
    role: definitive host in urban cycle
  - preferred_term: Aedes aegypti
    term:
      id: NCBITaxon:7159
      label: Aedes aegypti
    role: vector
transmission:
- name: Mosquito vector transmission (Haemogogus, Sabethes, and Aedes genera)
  description: >-
    Transmitted to humans through the bite of infected mosquitoes of the
    Haemogogus, Sabethes, and Aedes genera across sylvatic, intermediate, and
    urban transmission cycles.
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Endemic to tropical and sub-tropical regions of South America and Africa, YFV is transmitted to humans via mosquitoes of the Haemogogus, Sabethes and Aedes genera."
    explanation: Identifies the three mosquito genera responsible for transmitting yellow fever virus to humans.
prevalence:
- population: Global endemic regions (tropical Africa and South America)
  measure_type: ANNUAL_INCIDENCE
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    Estimated 80,000 to 200,000 yellow fever cases and 30,000 to 60,000
    fatalities annually worldwide, with a case fatality rate of 20% to 60% in
    the toxic phase.
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annually, there are approximately 80,000–200,000 YFV cases worldwide. The number of fatalities annually is commonly estimated as 30,000–60,000, with a case fatality rate (CFR) ranging from 20–60%"
    explanation: Provides global annual case and fatality estimates and the 20% to 60% case fatality rate.
progression:
- phase: Incubation and Acute Febrile Phase (Period of Infection)
  duration: 3 to 6 days incubation followed by acute flu-like febrile phase
  notes: >-
    Following an infected mosquito bite and a 3- to 6-day incubation period,
    patients develop acute onset of fever and flu-like symptoms driven by
    primary and secondary viremia.
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
    explanation: Documents the 3- to 6-day incubation period and subsequent acute febrile flu-like phase.
- phase: Period of Remission
  duration: 1 to 2 days
  notes: >-
    Transient defervescence and clinical improvement lasting 1 to 2 days, after
    which most patients recover while 20% to 60% progress to the toxic phase.
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
    explanation: Documents the 1- to 2-day remission period between the acute febrile phase and the toxic phase.
- phase: Toxic Hepatorenal and Hemorrhagic Phase (Period of Intoxication)
  notes: >-
    Approximately 20% to 60% of symptomatic patients relapse into a severe
    toxic phase characterized by recurrence of fever, jaundice,
    thrombocytopenia, hemorrhagic manifestations, and hepatic and renal failure
    (case fatality rate 20% to 60%).
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Characterizes the toxic phase of yellow fever that follows the remission period in 20% to 60% of patients.
pathophysiology:
- name: Dermal Dendritic Cell Infection, Lymphatic Amplification, and Systemic Viremia
  description: >-
    Following inoculation of yellow fever virus from mosquito salivary glands
    into the dermis, virions attach via heparan sulfate glycosaminoglycans,
    enter cutaneous dendritic cells by clathrin-mediated endocytosis, and
    traffic to draining lymph nodes where viral replication amplifies and seeds
    systemic viremia reaching the liver, spleen, heart, and kidneys.
  role: trigger
  biological_scale: CELLULAR
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  - preferred_term: lymph node
    term:
      id: UBERON:0000029
      label: lymph node
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: viral entry into host cell
    modifier: INCREASED
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  - preferred_term: viral genome replication
    modifier: INCREASED
    term:
      id: GO:0019079
      label: viral genome replication
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Current models suggest that after YFV transmission from the mosquito salivary glands to the host’s dermal environment, the virus infects DCs and circulates to the lymph nodes"
    explanation: Establishes dermal dendritic cell infection and lymphatic dissemination to regional lymph nodes.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In this tissue, YFV amplifies and primes the cellular immune response before spreading through the peripheral blood, ultimately reaching the liver for active replication."
    explanation: Documents viral amplification in lymph nodes followed by hematogenous spread to the liver.
  downstream:
  - target: Hepatocyte Apoptosis, Lytic Necrosis, and Cytokine-Driven Hepatotoxicity
    description: Hematogenous dissemination delivers high-titer virus to the liver, where hepatocytes and Kupffer cells are infected.
    causal_link_type: DIRECT
  - target: Endothelial Activation and Increased Vascular Permeability
    description: High-titer viremia and pro-inflammatory mediator release act on vascular endothelial cells to induce vasculopathy and capillary leakage.
    causal_link_type: DIRECT
  - target: Fever
    description: Acute systemic viremia and innate cytokine release trigger the initial febrile flu-like phase.
- name: Hepatocyte Apoptosis, Lytic Necrosis, and Cytokine-Driven Hepatotoxicity
  description: >-
    In the liver, yellow fever virus replicates extensively in hepatocytes and
    Kupffer cells, inducing direct cytopathic hepatocyte apoptosis (Councilman
    bodies), lytic necrosis, and microvesicular steatosis, compounded by an
    unbalanced intrahepatic cytokine storm driven by TNF-alpha, IFN-gamma, and
    pro-apoptotic TGF-beta from infiltrating CD4+ T cells and activated
    macrophages.
  role: amplifier
  biological_scale: TISSUE
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this main target organ, YFV induces hepatocyte apoptosis and lytic necrosis, which, combined with steatosis, results in most of the liver damage observed during infection"
    explanation: Establishes hepatocyte apoptosis, lytic necrosis, and steatosis as the primary drivers of liver injury in yellow fever.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to the virus-induced cytopathic effect, several studies suggest that the immune response itself, via a systemic and unbalanced cytokine response (or cytokine storm), is a major driver of hepatotoxicity and YF disease"
    explanation: Documents the systemic and intrahepatic cytokine storm as a major driver of hepatotoxicity in severe yellow fever.
  downstream:
  - target: Hepatic failure
    description: Extensive hepatocyte apoptosis, necrosis, and steatosis cause acute hepatic failure and loss of coagulation factor synthesis.
  - target: Jaundice
    description: Hepatocellular necrosis and cholestasis produce severe hyperbilirubinemia and clinical jaundice, from which the disease takes its name.
- name: Endothelial Activation and Increased Vascular Permeability
  conforms_to: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
  description: >-
    Wild-type yellow fever virus infects vascular endothelial cells and induces
    a prolonged pro-inflammatory cytokine response that, together with systemic
    cytokine storm and hepatic synthesis failure of clotting factors, disrupts
    endothelial barrier integrity, increases vascular permeability, and leads to
    vasculopathy, capillary leak, thrombocytopenia, hemorrhagic manifestations,
    acute kidney injury, and shock during the toxic phase.
  role: central_effector
  biological_scale: TISSUE
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: ABNORMAL
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  - preferred_term: endothelial cell activation
    modifier: INCREASED
    term:
      id: GO:0042118
      label: endothelial cell activation
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In primary human vascular endothelial cells, Kupffer cells, MDMs and monocyte-derived dendritic cells (MoDCs), YFV-Asibi causes a greater, more prolonged pro-inflammatory response than YFV-17D"
    explanation: Demonstrates that virulent wild-type YFV-Asibi directly elicits a prolonged pro-inflammatory response in primary human vascular endothelial cells.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Links toxic-phase progression to hemorrhagic fever, thrombocytopenia, vasculopathy, and multi-organ dysfunction.
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
    explanation: Places yellow fever within the shared viral hemorrhagic fever pathway of endothelial dysfunction, capillary leak, and coagulopathy.
  downstream:
  - target: Abnormal bleeding
    description: Endothelial barrier dysfunction, thrombocytopenia, and hepatic coagulation-factor depletion produce mucosal and gastrointestinal hemorrhage.
  - target: Thrombocytopenia
    description: Platelet consumption and bone marrow suppression during the toxic phase cause severe thrombocytopenia.
  - target: Acute kidney injury
    description: Intravascular volume depletion, vasculopathy, and direct tubular injury lead to acute renal failure in the toxic phase.
phenotypes:
- name: Fever
  category: Constitutional
  frequency: VERY_FREQUENT
  description: Acute onset of fever and flu-like symptoms occurs after a 3- to 6-day incubation period.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the bite of an infected mosquito, individuals typically experience an incubation period of 3 to 6 days, subsequently displaying flu-like symptoms prior to a remission period of 1 to 2 days."
    explanation: Describes the initial febrile flu-like phase following the 3- to 6-day incubation period.
- name: Jaundice
  category: Hepatic
  frequency: FREQUENT
  description: Jaundice develops in the 20% to 60% of patients who progress to the toxic hepatorenal phase.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Identifies jaundice as a defining clinical feature of the toxic phase of yellow fever.
- name: Thrombocytopenia
  category: Hematologic
  frequency: FREQUENT
  description: Marked thrombocytopenia characterizes the toxic hemorrhagic phase of yellow fever.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Documents thrombocytopenia in the toxic phase of yellow fever.
- name: Abnormal bleeding
  category: Hematologic
  frequency: FREQUENT
  description: Hemorrhagic manifestations occur in the 20% to 60% of patients who enter the toxic phase.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Documents hemorrhagic fever manifestations in the toxic phase.
- name: Hepatic failure
  category: Hepatic
  frequency: FREQUENT
  description: Acute liver failure driven by hepatocyte apoptosis, lytic necrosis, and steatosis is central to fatal yellow fever.
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Identifies liver failure as a hallmark of the toxic phase.
- name: Acute kidney injury
  category: Renal
  frequency: FREQUENT
  description: Renal failure accompanies hepatic failure during the toxic phase of yellow fever.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following remission, some patients (20–60%) progress to a more toxic phase of disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, liver and renal failure"
    explanation: Identifies renal failure as a hallmark of the toxic phase of yellow fever.
diagnosis:
- name: Laboratory Confirmation of Yellow Fever Virus Infection
  description: >-
    Laboratory confirmation of yellow fever virus infection by molecular testing,
    serology, antigen detection, or viral culture, typically performed at
    specialized reference laboratories.
  diagnosis_term:
    preferred_term: laboratory examination
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:30021822
    reference_title: "Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of diagnostic methods and assays have been described for the detection of YFV infection, including viral culture, molecular testing, serology, and antigen detection. Commercial diagnostics are not widely available, and testing is generally performed at a small number of reference laboratories."
    explanation: Documents the specific laboratory diagnostic modalities used to confirm yellow fever virus infection (molecular testing, serology, antigen detection, and viral culture).
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Such risk is exemplified by the 2016 report of 10 laboratory-confirmed YF cases in China imported from Angola, the first ever reported cases in Asia."
    explanation: Documents laboratory confirmation as the diagnostic standard for identifying imported yellow fever cases.
treatments:
- name: Live-Attenuated Yellow Fever 17D Vaccine (YF-VAX / Stamaril)
  description: >-
    Single subcutaneous dose of live-attenuated yellow fever 17D vaccine (or a
    one-fifth fractional dose during emergency mass-vaccination campaigns)
    induces serum neutralizing antibodies within 2 weeks in most vaccinees and
    provides decades-long protective immunity via persistent memory B cells and
    polyfunctional CD8+ T cells. Rare serious adverse events include yellow
    fever vaccine-associated viscerotropic disease (YEL-AVD; 0.4 per 100,000
    doses, CFR 63%) and vaccine-associated neurotropic disease (YEL-AND; 0.8 per
    100,000 doses), which are linked to host genetic defects in innate antiviral
    immunity (such as type I/III IFN pathway defects).
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
    therapeutic_agent:
    - preferred_term: Yellow Fever Vaccine
      term:
        id: NCIT:C96396
        label: Yellow Fever Vaccine
  target_mechanisms:
  - target: Dermal Dendritic Cell Infection, Lymphatic Amplification, and Systemic Viremia
    treatment_effect: INHIBITS
    description: >-
      Vaccine-elicited neutralizing IgG antibodies and memory CD8+ T cells
      neutralize incoming wild-type yellow fever virus and prevent systemic
      viremia and hepatic dissemination.
    evidence:
    - reference: PMID:29933925
      reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Following subcutaneous injection of 17D in a cohort of human patients neither previously exposed or immunized to YFV, neutralizing antibodies were detectable in the serum of most individuals two weeks post vaccination"
      explanation: Demonstrates rapid induction of serum neutralizing antibodies within two weeks after 17D vaccination.
  evidence:
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following subcutaneous injection of 17D in a cohort of human patients neither previously exposed or immunized to YFV, neutralizing antibodies were detectable in the serum of most individuals two weeks post vaccination"
    explanation: Confirms immunogenicity of subcutaneous YFV-17D vaccination in naive human cohorts.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong, antigen-specific T cell response and persistent memory B cell response seem to represent the hallmarks of long-term protective immunity, as YFV-specific memory T cells and IgG antibodies can persist for decades in patient sera"
    explanation: Establishes decades-long humoral and cellular memory after YFV-17D immunization.
  - reference: PMID:29933925
    reference_title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As worldwide stocks of YFV-17D are experiencing a significant shortage, such campaigns use only one-fifth of the regular vaccine dose, which is still sufficient to provide immunity for at least one year"
    explanation: Documents fractional-dose (one-fifth standard dose) YFV-17D vaccination providing protective immunity during vaccine shortages.
- name: Supportive Care
  description: >-
    No licensed specific antiviral drug is available for yellow fever; clinical
    management of the toxic phase relies on intensive supportive care for
    hemorrhage, hepatic failure, and renal failure.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42076078
    reference_title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Supportive care continues to represent the cornerstone of clinical management for most infections, while pathogen-targeted therapies are available only for a restricted number of diseases."
    explanation: Confirms supportive care as the cornerstone of clinical management for viral hemorrhagic fevers lacking licensed antivirals.
references:
- reference: PMID:29933925
  title: "Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe."
  findings: []
- reference: PMID:30021822
  title: "Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat."
  findings: []
- reference: PMID:25453327
  title: "Yellow fever."
  findings: []
- reference: PMID:41734218
  title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
  findings: []
- reference: PMID:42076078
  title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
  findings: []
📚

References & Deep Research

References

5
PMID:29933925
Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe.
No top-level findings curated for this source.
PMID:30021822
Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat.
No top-level findings curated for this source.
PMID:25453327
Yellow fever.
No top-level findings curated for this source.
PMID:41734218
[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations].
No top-level findings curated for this source.
PMID:42076078
Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review.
No top-level findings curated for this source.