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
