The viral hemorrhagic fevers

name: Viral Hemorrhagic Fevers
display_name: The viral hemorrhagic fevers
creation_date: "2026-09-17T00:00:00Z"
description: >-
  The viral hemorrhagic fevers are the human diseases in which an enveloped RNA
  virus produces a shared acute vascular and hemostatic syndrome - endothelial
  dysfunction, capillary leak, coagulopathy, and in severe cases hemorrhage and
  shock. The agents come from six unrelated virus families: filoviruses (Ebola,
  Marburg), arenaviruses (Lassa), nairoviruses (Crimean-Congo), phenuiviruses
  (Rift Valley fever), flaviviruses (dengue, yellow fever) and hantaviruses.
  They share no organism, no reservoir, no vector and, with one exception, no
  therapy; what they share is the mechanism, which is curated once as
  `kb/modules/viral_hemorrhagic_fever_syndrome.yaml` and declared by each
  member through `conforms_to`. This grouping therefore carries the membership
  and the boundary, and has no pathophysiology of its own.
grouping_basis:
- SHARED_MECHANISM
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on an organism-independent final common pathway. However the virus
  arrives, severe disease converges on one lesion: high viremia presented to
  the vasculature and to mononuclear phagocytes, endothelial activation and
  damage, increased vascular permeability expressed as capillary leak, and a
  four-route hemostatic failure producing coagulopathy, thrombocytopenia and
  bleeding. "Viral hemorrhagic fever" is also a long-standing clinical and
  public-health category - it drives the same isolation, contact-tracing and
  reference-laboratory response whichever agent is suspected - so the grouping
  reflects how the field actually reasons about these diseases at the point
  where recognition matters most, before the agent is known.

  The members are kept as separate Disease entries rather than merged, and the
  axes on which they are split are the ones that decide what is done about a
  case. They differ in virus family and therefore in every molecular detail of
  entry and replication (filovirus, hantavirus and flavivirus members use
  unrelated receptors). They differ in reservoir and vector, which is what sets
  the exposure history that raises the suspicion at all: Ebola virus disease is
  acquired from an animal reservoir and then spreads person-to-person through
  infectious body fluids, hemorrhagic fever with renal syndrome from aerosolised
  rodent excreta with no person-to-person spread, and dengue from a day-biting
  Aedes mosquito. They differ in geography - dengue is pantropical and the
  commonest of the three by orders of magnitude, hemorrhagic fever with renal
  syndrome is Eurasian, Ebola virus disease is focal to sub-Saharan Africa and
  reaches elsewhere only as an imported case. They differ in the organ the
  syndrome damages most: renal for hantavirus, hepatic for Ebola. And they
  differ in specific therapy, which is the sharpest axis of all: monoclonal
  antibodies are licensed for Ebola virus disease and for no other member,
  hemorrhagic fever with renal syndrome has an intravenous ribavirin and a
  bradykinin-antagonist literature, and severe dengue has supportive fluid
  management and nothing pathogen-directed at all. Merging them would erase
  exactly the distinctions that determine how each is transmitted, prevented
  and treated, while the mechanism they genuinely share is not lost - it is
  curated once, in the module.

  The grouping is incomplete by design rather than by boundary. Four diseases
  that satisfy its criteria have no entry yet - Marburg virus disease, Lassa
  fever, yellow fever and Rift Valley fever - and each carries a `stubs/`
  record naming this grouping. They are members that have not been curated, not
  concepts argued out of the group.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018087
      label: viral hemorrhagic fever
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch rather than exactMatch, and deliberately not narrowMatch. The
      boundary this grouping intends is the MONDO class's boundary - the same
      clinical category, with the same members - so a narrowMatch, which
      asserts a stable proper-subclass relation, would be wrong. But its
      declared extension today is three curated diseases against at least eight
      in the class, because five members are still stubs, so an exactMatch
      would assert a coextension that does not hold yet. closeMatch is the
      honest reading of both facts, and it has the right consequence: under the
      MONDO coverage rule only exactMatch and narrowMatch retire a concept from
      the curation queue, so MONDO:0018087 stays in the queue until the
      stubbed members are curated. Revisit the predicate then. Note that the
      retired `Viral_Hemorrhagic_Fever` Disease entry bound this same class as
      its `disease_term`, which counted as curated coverage of the whole
      class - the change to closeMatch is what stops the group looking covered
      while most of it is not.
membership_criteria:
- description: >-
    A disease belongs to the viral hemorrhagic fevers if it is a human
    infection caused by a hemorrhagic fever virus AND its severe form runs
    through the shared vascular and hemostatic mechanism - that is, it conforms
    to the viral hemorrhagic fever syndrome module.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: OTHER
      description: >-
        Caused by a hemorrhagic fever virus - an enveloped RNA virus of the
        filovirus, arenavirus, nairovirus, phenuivirus, flavivirus or
        hantavirus groups whose human disease is conventionally counted among
        the viral hemorrhagic fevers.
    - criterion_predicate: CONFORMS_TO_MODULE
      module: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
      description: >-
        Has a pathophysiology node conforming to the module's central effector,
        the increased vascular permeability that every member funnels through.
        This is the criterion that keeps the grouping mechanistic rather than
        merely nominal: a febrile viral illness that never produces the
        vascular lesion is not a member however alarming its name.
members:
- member: Ebola Virus Disease (EVD)
  member_type: DISEASE
  display_name: Ebola virus disease
  differentiating_mechanisms:
  - description: >-
      A filovirus disease acquired from an animal reservoir and then amplified
      by person-to-person and nosocomial transmission through infectious blood
      and body fluids, which is what makes it an outbreak disease and puts
      isolation, contact tracing and healthcare-worker PPE at the centre of its
      management. It is the only member with a licensed pathogen-targeted
      therapy: monoclonal antibodies have achieved the most significant
      regulatory success of any hemorrhagic fever treatment, and they are
      specific to this agent. Hepatic involvement and multiorgan failure
      dominate the severe presentation, where the hantavirus member's is renal.
    module: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
- member: Dengue
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A flavivirus disease transmitted by day-biting Aedes mosquitoes, with no
      person-to-person spread and no non-human reservoir in the urban cycle -
      the transmission axis furthest from the other two members. It is by far
      the commonest, pantropical rather than focal, and the only member in
      which prior infection with a different serotype is itself the principal
      risk factor for severe disease. The vascular lesion is also the most
      distinctive: plasma leakage in severe dengue is abrupt, brief and
      self-limiting rather than progressive, which is what makes fluid
      management rather than any pathogen-directed drug the intervention that
      decides survival. Only the severe form manifests the hemorrhagic fever
      syndrome; uncomplicated dengue does not.
    module: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
- member: Hantavirus Hemorrhagic Fever with Renal Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A hantavirus disease acquired by inhaling aerosolised excreta of a rodent
      reservoir, with essentially no person-to-person transmission, so the
      public-health response is rodent control rather than contact tracing.
      Mechanistically it is the member whose endothelial infection is
      noncytopathic: the barrier fails through VEGF-driven VE-cadherin
      destabilisation and bradykinin release rather than through lysis of
      infected cells, which is why a bradykinin B2 receptor antagonist has been
      tried here and nowhere else in the group. It is the only member with a
      defining organ - the renal syndrome in its name - and the only one with a
      staged oliguric-then-polyuric course and a described convalescent phase.
    module: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
- member: Crimean-Congo Hemorrhagic Fever
  member_type: DISEASE
  display_name: Crimean-Congo hemorrhagic fever
  differentiating_mechanisms:
  - description: >-
      A nairovirus disease and the only member acquired by all three of the
      group's transmission modes: the bite of a Hyalomma tick (its vector and
      reservoir), contact with the blood and tissues of viraemic livestock at
      slaughter, and nosocomial person-to-person blood and body-fluid exposure.
      It is also the most widely distributed of the members, spanning Africa,
      the Balkans, the Middle East and much of Asia along the Hyalomma range.
      Severe disease converges on the shared vascular and hemostatic lesion but
      is distinguished clinically by prominent hepatocellular injury and by
      ecchymoses that are particularly pronounced compared with the other
      hemorrhagic fevers; there is no licensed vaccine or proven specific
      antiviral, and the widely used ribavirin has no demonstrated survival
      benefit.
    module: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
references:
- reference: PMID:41734218
  title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
  findings:
  - statement: >-
      The group is defined by its agents being selected enveloped RNA viruses
      drawn from several unrelated families, which is what makes it an organ
      syndrome across unrelated organisms rather than a taxonomic family of
      diseases.
    supporting_text: >-
      Viral hemorrhagic fevers are severe infections caused by selected enveloped RNA viruses from the families Filoviridae, Arenaviridae, Flaviviridae, and the order Bunyavirales.
  - statement: >-
      Transmission is the axis on which members most obviously differ, and it
      spans three broad categories across the group - arthropod vectors,
      zoonotic spread from animal reservoirs, and healthcare-associated or
      household transmission. Each member's own route is recorded on its entry.
    supporting_text: >-
      For many of these infections, transmission via vectors, zoonotic spread, or nosocomial transmission plays a significant role.
  - statement: >-
      The early clinical picture is shared and nonspecific across the group,
      which is precisely why the category is operationally useful: recognition
      turns on exposure history rather than on any feature that distinguishes
      one member from another.
    supporting_text: >-
      Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock.
  - statement: >-
      The laboratory picture is likewise shared across the group. Early
      leukopenia in particular is a cross-member finding that no individual
      member entry currently carries, and it is recorded here rather than being
      asserted as a mechanism, because the module's chain does not explain it.
    supporting_text: >-
      Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes.
  - statement: >-
      The public-health response is common to the group and is triggered before
      the agent is known - surveillance of imported cases, reference-laboratory
      access, infection control against nosocomial spread, and vigilance in a
      febrile patient with a compatible exposure. This is the practical content
      of the clinical convention that makes the grouping worth having.
    supporting_text: >-
      Continuous surveillance of imported cases, together with access to high-quality laboratory testing, effective infection control including prevention of nosocomial spread, and vigilance in febrile patients with relevant epidemiological exposure, are essential.
- reference: PMID:42076078
  title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
  findings:
  - statement: >-
      Therapy is the axis on which the members are most sharply split, and the
      asymmetry is a property of the group rather than of any member: the
      shared mechanism has no treatment directed at it, so supportive care is
      the cornerstone everywhere and pathogen-targeted therapy exists for only
      a few members. This is why the mechanism module carries no treatments
      block.
    supporting_text: >-
      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.
  - statement: >-
      Monoclonal antibody therapy is the one licensed pathogen-targeted class,
      and it belongs to a single member, Ebola virus disease. It is recorded on
      that entry and is not a group-level treatment.
    supporting_text: >-
      Monoclonal antibody-based therapies have achieved the most significant regulatory success to date, particularly for Ebola virus disease.
  - statement: >-
      Vaccination is likewise agent-specific rather than group-level. Licensed
      vaccines exist for three of the diseases in this group - two of them
      still stubs - and their existence says nothing about the other members.
    supporting_text: >-
      Vaccine development has progressed further, with licensed vaccines available for selected VHFs, including Ebola, yellow fever, and dengue, and multiple candidates based on diverse technological platforms advancing through clinical evaluation.
- reference: PMID:31668201
  title: Viral Hemorrhagic Fevers Other than Ebola and Lassa.
  findings:
  - statement: >-
      Definitive diagnosis for every member runs through specialized reference
      laboratories, which is a group-level constraint on the diagnostic
      pathway: the assay differs by suspected agent, but the containment
      requirement and the referral do not.
    supporting_text: >-
      Laboratory diagnosis takes place in highly specialized reference laboratories.
- reference: PMID:41754561
  title: CRISPR-Based Detection of Viral Hemorrhagic Fevers at the Point of Care.
  findings:
  - statement: >-
      The second group-level constraint on the diagnostic pathway, beside the
      reference-laboratory requirement above: the established molecular and
      serological tests are effective but are not point-of-care tests, which is
      what an outbreak of any member actually needs. The gap is a property of
      the group rather than of any one member - this review's scope spans Ebola
      virus, Lassa virus, dengue virus and Crimean-Congo haemorrhagic fever
      virus, four members across four virus families, two of which are still
      stubs.
    supporting_text: >-
      Current molecular and serological diagnostic tests, while efficient and effective, lack the characteristics required of a POC test (POCT) to quickly and easily respond to a VHF outbreak while maintaining a low cost.
  - statement: >-
      CRISPR-based point-of-care assays are the investigational direction
      proposed to close that gap, and the evidence base for them in these
      diseases is explicitly thin. Recorded here as an open diagnostic
      direction, not as an established alternative to the reference-laboratory
      pathway.
    supporting_text: >-
      However, studies on the development of CRISPR-based POC diagnostic tests for VHFs are limited.
- reference: PMID:41410052
  title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
  findings:
  - statement: >-
      Whether the bleeding mechanisms are the same across members is an open
      question, and it is the reason the shared module draws its four
      hemostatic routes in parallel rather than in sequence. The same question
      is recorded as a KNOWLEDGE_GAP discussion on the module.
    supporting_text: >-
      There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses.
notes: >-
  Provenance. This grouping and the `viral_hemorrhagic_fever_syndrome` module
  together replace the former `kb/disorders/Viral_Hemorrhagic_Fever.yaml`
  umbrella Disease entry, under the infectious disease granularity ladder
  (design decisions section 3e): an organ syndrome spanning unrelated organisms
  is a Grouping (R4), and where the syndrome has an organism-independent
  mechanism that mechanism is a module with `conforms_to` (R4, R24). The old
  entry listed eight one-line subtypes, three of which were full Disease
  entries with no cross-link either way, and was the one instance
  `check_granularity.py` reported as DOUBLE_MODELLED (R20). Its history records
  carry `target.superseded_by` pointing here.

  Deliberate exclusion: hantavirus pulmonary syndrome. `kb/disorders/
  Hantavirus_Pulmonary_Syndrome.yaml` exists and is caused by New World
  hantaviruses, siblings of the Old World hantaviruses that cause the
  hemorrhagic fever with renal syndrome member. It is not listed, because the
  boundary of this grouping is the hemorrhagic fever clinical category and the
  field treats the two hantavirus syndromes as separate entities: the
  cardiopulmonary syndrome presents with pulmonary oedema and cardiogenic
  shock rather than with hemorrhage or renal failure, and is not conventionally
  counted among the viral hemorrhagic fevers. That is a judgement about the
  clinical category, not about the mechanism - the capillary-leak lesion is
  plainly shared, and hantavirus pulmonary syndrome could reasonably declare
  `conforms_to` against the module without becoming a member here. Module
  conformance and grouping membership are independent, and this is a case where
  they should come apart. Anyone who disagrees with the exclusion should argue
  it on the clinical-category axis rather than the mechanistic one.

  How the advisory evaluator reads these criteria. `just check-groupings` will
  report members as `UNKNOWN` rather than `SATISFIED`, because the `OTHER` leaf
  ("caused by a hemorrhagic fever virus") is not machine-evaluable and the
  conjunction it sits in therefore cannot resolve, however complete the members
  are. The module branch it is ANDed with is satisfied by all three. The
  `OTHER` leaf is used because `CriterionPredicateEnum` has no
  infectious-agent predicate; a `HAS_INFECTIOUS_AGENT` predicate taking an
  NCBITaxon-bound `infectious_agent_term` would make this criterion checkable
  against each member's `infectious_agent` block and would generalize to every
  infectious-disease grouping. `Treponematoses` records the same gap, so this
  is now the second grouping blocked on it.

  Note also that the module anchor in the CONFORMS_TO_MODULE criterion is
  checked as a foreign key but is not used as a membership verdict: a member
  conforming to `viral_hemorrhagic_fever_syndrome` at any node satisfies the
  criterion. The anchor names the node a member is expected to declare, and
  all three do declare that node.

  No `SUFFICIENT` criteria block is provided. "Caused by a hemorrhagic fever
  virus and conforms to the module" is close to definitional, but encoding it
  as sufficient would invite the classifier to propose any entry with an
  endothelial-permeability node as a candidate, and the boundary the clinical
  category draws is narrower than that. The boundary is recorded in the
  rationale and in the exclusion above rather than as machine-checkable
  sufficiency.