Viral hemorrhagic fever

Microbiology

• All are negative-sense ssRNA viruses, except for Flaviviridae which are positive-sense ssRNA viruses

Species

• Family Arenaviridae: typically rodent-associated
  • Old World viruses
    • Lassa fever
    • Lujo virus
  • New World viruses
    • Junin virus/Argentine HF
    • Machupo virus/Bolivian HF
    • Chapare virus
    • Guanarito virus/Venezuelan HF
    • Sabia virus/Brazilian HF
• Family Bunyaviridae: typically vector-borne
  • Rift valley fever (RVF)
  • Crimean Congo hemorrhagic fever (CCHF)
• Family Filoviridae
  • Genus Marburg virus (MARV)
  • Genus Ebola virus (EBOV)
    • Bundibugyo ebolavirus (BEBOV)
    • Côte d'Ivoire ebolavirus (CIEBOV)
    • Reston ebolavirus (REBOV)
    • Sudan ebolavirus (SEBOV)
    • Reston ebolavirus (REBOV)
• Family Flaviviridae
  • Dengue virus
  • Yellow fever virus

Differential Diagnosis of Hemorrhagic Fever

• Malaria
• Enteric fever
• Bacteremia
• Typhuses, including scrub typhus

Epidemiology

• Various hemorrhagic fever viruses are present in worldwide, mostly in the tropics but also North America (Hantavirus), Siberia (Omsk virus), Northern Europe (HFRS)
• Zoonotic viruses with reservoirs that include rodents (especially Arenaviridae), livestock, primates, birds, etc.
  • Humans are generally end hosts
• Some (especially Bunyaviridae and Flaviviridae) are tick-borne, others are mosquito-borne
  • Many can be transmitted person-to-person through secretions and blood
  • A few cannot be transmitted person-to-person: dengue, yellow fever, and Rift Valley fever
• Most human infections are associated with agriculture, mining, or military activity

Pathophysiology

• Mostly replicate in monocytes, macrophages, and dendritic cells, though some like Ebola and Marburg viruses, can spread to many tissues
• Host response at least in part determines severity of disease
• Hemorrhagic disease results from inflammation causing vasodilatation and increased permeability, rather than viral infection of the endothelium

Clinical Manifestations

• Myriad, from asymptomatic to self-limited fever to fatal
• Early symptoms typically include fever, malaise, myalgias, and headache
  • Fever is typically high and unremitting
• Severe abdominal pain
• Vomiting and diarrhea, especially in Filoviridae
• Bleeding is rarely a presenting symptom
• On examination, may have diffuse blanchable erythema on the upper body from capillary dilatation, conjunctival injection with petechial hemorrhages, or an erythematous rash (early Marburg, Ebola, CCHF, and dengue)
  • Edema of face and extremities, especially in Lassa fever
• Filoviridae and Yellow fever: bradycardia
• Arenaviridae: pharyngitis, retrosternal chest pain, and proteinuria
• Mortality depends on the specific infection
• After resolution of symptoms, can still have virus present in privileged sites (eye, CNS, mammary gland, and male genitourinary tract)
  • They will still be infectious for months after resolution
  • They may have a recurrence or relapse of disease from these sites, which may be limited (e.g. uveitis or meningitis alone)

Case Definitions

CDC Case Definition

• CDC has a case definition (2011) for VHF caused by Ebola, Lassa, Lujo, or Marburg virus, a New World arenavirus, or Crimean-Congo hemorrhagic fever
  • Clinical criteria: acute onset of both of the following
    • Fever >40º C
    • One or more of:
      • Severe headache
      • Muscle pain
      • Erythematous maculopapular rash on the trunk with fine desquamation 3–4 days after rash onset
      • Vomiting
      • Diarrhea
      • Pharyngitis (arenavirus only)
      • Abdominal pain
      • Bleeding not related to injury
      • Retrosternal chest pain (arenavirus only)
      • Proteinuria (arenavirus only)
      • Thrombocytopenia
  • Laboratory criteria: one of more of the following
    • Detection of viral hemorrhagic fever (VHF) viral antigens in blood by enzyme-linked Immunosorbent Assay (ELISA) antigen detection
    • VHF viral isolation in cell culture for blood or tissues
    • Detection of VHF-specific genetic sequence by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) from blood or tissues
    • Detection of VHF viral antigens in tissues by immunohistochemistry
  • Epidemiologic linkage: one or more of the following exposures within 3 weeks of symptoms
    • Contact with blood or other body fluids of a patient with VHF
    • Residence in—or travel to—a VHF endemic area
    • Work in a laboratory that handles VHF specimens
    • Work in a laboratory that handles bats, rodents, or primates from endemic areas
    • Exposure to semen from a confirmed acute or convalescent case of VHF within the 10 weeks of that person's onset of symptoms
  • Case classification
    • Suspected: case meets clinical and epidemiologic linkage criteria
    • Confirmed: case meets clinical and laboratory criteria

Public Health Ontario Case Definition

• Case classification
  • Confirmed case: clinically compatible signs and symptoms and at least two of the hemorrhagic manifestations, and laboratory confirmation of infection
  • Probable case: clinically compatible signs and symptoms and at least one of the hemorrhagic manifestations, and a history within the last 3 weeks of fever one of the following
    • Travel in a specific area of a country where an outbreak of viral hemorrhagic fever (VHF) has recently occurred
    • An epidemiologic link with a confirmed and/or probable case of VHF
    • Direct contact with blood or other body fluids from a confirmed or probable case of VHF
    • Work in a laboratory that handles VHF virus specimens or in a facility that handles animals with VHF
• Laboratory criteria
  • Any of the following
    • Isolation and identification of virus from an appropriate clinical specimen (e.g., blood, serum, tissue, urine specimens or throat secretions) (performed at the National Microbiology Laboratory);
    • Detection of virus-specific RNA by reverse-transcriptase PCR from an appropriate clinical specimen (e.g., blood, serum, tissue) using two independent targets or two independent samples AND confirmed by the National Microbiology Laboratory by nucleic acid testing or serology;
    • Demonstration of virus antigen in tissue (e.g., skin, liver or spleen) by immunohistochemical or immunofluorescent techniques AND another test (e.g., PCR);
    • Demonstration of specific IgM AND IgG antibody by EIA, immunofluorescent assay or Western Blot by the National Microbiology Laboratory or an approved WHO collaboration centre
    • Demonstration of a fourfold rise in IgG titre by EIA, immunofluorescent assay from an acute vs. a convalescent serum sample (performed at the National Microbiology Laboratory).
  • Validated tests
    • Culture
    • NAAT (RT-PCR)
    • Antigen detection
    • IgM and IgG serology
• Clinical criteria
  • Any 2 of the following hemorrhagic manifestations (from WHO recommended surveillance standards, 1999):
    • Hemorrhagic or purpuric rash
    • Epistaxis
    • Hematemesis
    • Hemoptysis
    • Blood in stools
    • Other hemorrhagic symptom and no known predisposing host factors for hemorrhagic manifestations
  • Sign and symptoms consistent with the following: Lassa, Junin, Machupo, Sabia, Guanarito (arenaviruses); Crimean Congo, Rift Valley fever (bunyaviruses); Ebola, Marburg (filoviruses); Dengue fever, Yellow fever, Omsk hemorrhagic fever, Kyasanur Forest Disease (flaviviruses).
  • Onset may be gradual or acute depending on the type of VHF, with fever, headache, malaise, sore throat, cough, nausea, vomiting, diarrhea, myalgia and chest and abdominal pain. Fever is persistent or spikes intermittently. Inflammation and exudation of the pharynx and conjunctivae are commonly observed.

Investigations

• Rule out malaria and other routine infections
• Before collecting appropriate specimens for investigation of suspected VHF, the clinician must:
  • Consult with a Public Health Ontario Laboratory (PHOL) microbiologist available through the PHOL Customer Service Centre at 416-235-6556 or toll free at 1-877-604-4567.
  • Contact both the local public health unit/Medical Officer of Health.

Diagnosis

• Be careful; inform the Microbiologist/Biochemist before taking or sending samples
• Diagnostic testing includes culture, PCR, antigen detection, and serology
  • Usually PCR

Management

• Once a non-Flavivirus viral hemorrhagic fever is suspected, laboratory testing should be minimized
  • Most hemorrhagic fever viruses are biosafety level 3 or 4
• Management is largely supportive
  • Fluid and electrolyte management: patients often need significant volume resuscitation due to third-spacing from increased vascular permeability
  • Manage coagulopathy with cryoprecipitate, FFP, and platelets as needed
• Ribavirin may have activity against Lassa fever, New World Arenaviridae, and Rift Valley fever
• Other treatments are extremely investigative

Prevention

• Mostly focusses on good infection control, with isolation of cases
  • Enveloped viruses, so more susceptible to detergents, alcohol, etc.
  • Routine infection control practices with all patients
  • Additional precautions for Filoviridae (e.g. Ebola, Marburg) or Arenaviridae (e.g. Lassa, Machupo, Junin) families or due to Crimean-Congo hemorrhagic fever virus
    • Contact and droplet precautions with lots of PPE and a dedicated single-patient room
    • Should be kept in negative-pressure isolation with airborne precautions if any signs of respiratory disease
• Nosocomial exposures
  • Healthcare workers with a high-risk (i.e. fluid-on-membrane) exposure should be monitored for 21 days
  • Could consider Ebola (and other experimental) vaccine as post-exposure prophylaxis
• Some experimental vaccines exist

Further Reading

• Viral hemorrhagic fever (VHF). CIDRAP 2012.
• Guidance for Patients with Suspect or Confirmed Viral Haemorrhagic Fevers (VHF) in Acute Care Settings. Public Health Ontario 2016.