The Topic of This Month Vol. 32, No. 7 (No. 377)

Viral hemorrhagic fevers and the preparedness in Japan
(IASR 32: 187-188, July 2011)

Viral hemorrhagic fever (VHF) is defined as viral infection associated high fever, subcutaneous mucosal or intra-organ bleeding, and multi-organ failures.  The case-fatality rate is high.  The causative agents include ebolavirus (EBOV), marburgvirus (MARV), Crimean-Congo hemorrhagic fever virus (CCHFV), Lassa virus (LASV) and South American hemorrhagic fever viruses (SAHFVs) in the narrow sense, but yellow fever virus, dengue virus, hantavirus, Rift Valley fever virus and others that cause similar symptoms can be included in the group in the broad sense.  This article mainly deals with the review of the five Category I VHFs under the Law Concerning the Prevention of Infectious Diseases and Medical Care for Patients of Infections (Infectious Diseases Control Law), which could be imported into Japan at any time, and the preparedness for the possible risk of emergence VHF outbreaks in Japan.

Infectious Diseases Control Law and VHFs
Ebola hemorrhagic fever (EHF), Marburg hemorrhagic fever (MHF), Crimean-Congo hemorrhagic fever (CCHF), Lassa fever (LF) and South American hemorrhagic fevers (SAHF), together with smallpox and plague (Yersinia pestis infections), are Category I infectious diseases under the Infectious Diseases Control Law (see p. 189′ of this issue) (SAHF was added to Category I on April 2007).  They are quarantine infectious diseases under the Quarantine Law and Class I school infectious diseases under the School Health and Safety Law whose provisions include suspension of attendance until complete recovery.  A physician having made diagnosis of Category I infectious diseases has to notify the case (including a suspected case) to a local health center immediately (  No case has been notified until now.  In principle, such patients should be treated in a hospital, preferably in a properly equipped one designated as an infectious disease hospital (

Viruses causing the five VHFs themselves are also under Infectious Diseases Control Law and classified as Group I pathogens (  The law restricts importation, possession, transportation, transfer and sterilization of these viruses (  Since the amendment of the law in October 2004, veterinarian has to notify the monkey suspected of EBOV or MARV carrier (  No case has been notified until now.  In October 2005, the law tightened the control of animal importation (prohibition of importation, notification of importation and quarantine of imported animals) (IASR 26: 196-198, 2005 & 26: 200-202, 2005 and p. 191 of this issue).

Characteristics of VHFs
1. Ebola hemorrhagic fever
The causative agent of EHF is EBOV, a member of the family Filoviridae .  EBOV genus comprises five virus species, Zaire, Sudan, Côte d'Ivoire, Bundibugyo, and Reston EBOVs.  The mortality rate was the highest for Zaire EBOV followed by Sudan EBOV, Bundibugyo EBOV and C te dfIvoire EBOV in this order.  Reston EBOV is considered non-pathogenic to humans though asymptomatic infections are known (see p. 191 of this issue).

The first outbreak of EHF occurred in southern part of Sudan followed by the second in northern part of former Zaire (Democratic Republic of Congo, DRC) at an interval of two months in 1976.  In the Sudan outbreak, 284 became ill and 151 (53%) died.  In the DRC outbreak, 318 became ill and 280 (88%) died (see p. 190 of this issue).  EBOVs isolated during these outbreaks are Sudan EBOV and Zaire EBOV.  In May 2011, one fatal case of EHF was reported in Uganda (see p. 205 of this issue and WHO WER 86: 221, 2011).

2. Marburg hemorrhagic fever
The causative agent of MHF is MARV, a member of the family Filoviridae .  MARV genus comprises a single species, Lake Victoria MARV.  MARV was discovered in 1967.  Large-scale outbreaks of MHF occurred in DRC and Angola in 1998-2000 and 2004-2005, respectively.  The case-fatality rate of MHF in Angola in 2004-2005, was extremely high at a level of approximately 90% (see p. 190 of this issue and IASR 26: 215-217, 2005), which prompted the Japanese immigration control to include MHF in the questionnaire to the immigrants (IASR 26: 217-218, 2005).

3. Crimean-Congo hemorrhagic fever
The causative agent of CCHF is CCHFV, which belongs to genus Nairovirus , family Bunyaviridae .  The reservoir/vector of CCHFV is Ixodes and Hyalomma tick species.  The virus is transmitted from these ticks to mammals, such as rabbits, rodents, sheep, goats and cattle, and from the infected animals to the ticks, establishing the CCHF infection cycle.  Humans usually get infection through tick bites as well as through direct contact with blood, body fluids or organs of viremic sheep, goats and other animals.  In Northern hemisphere, its outbreak frequently occurs from April to June when the ticks become active.  The CCHFV is prevalent in large areas covering Africa, Europe and Asia.

4. Lassa fever
The causative agent of LF is LASV, which belongs to genus Arenavirus , family Arenaviridae .  The reservoir of LASV is a species of rodent, Mastomys natalensis , inhabiting western part of Africa.  Humans are usually infected with LASV through inhalation of or direct contact to contaminated excreta from the infected rodents in the endemic regions.  Human to human transmission is not rare as a form of nosocomial infection in places where medical and sanitary condition is below the standard.  It is also transmitted through direct contact with blood or excreta of the patients or through sexual contact.  It is estimated that in the western part of Africa where LF is endemic, 100,000-300,000 peoples are infected annually and approximately 5,000 of them die.

5. South American hemorrhagic fevers
VHF caused by the arenaviruses in South America is called SAHF.  Five SAHFV species, Junin, Machupo, Guanarito, Sabia, and Chapare viruses, are known (see p. 193 of this issue).  Among them, Junin virus, a causative agent for Argentine hemorrhagic fever, is most popular.  The reservoirs for SAHFV are certain species of rodents inhabiting South America.  The clinical pictures of SAHF resemble those of LF.

Imported cases of VHFs around the world
VHF most frequently encountered outside of endemic areas is LF.  More than 20 laboratory-confirmed LF cases, infected in Western Africa and returned to home country within incubation period, have been reported.  One such Japanese case occurred in Tokyo, Japan in 1987.

Two imported cases of MHF were reported from the USA and the Netherlands in 2008 (see p. 192 of this issue).  There is only one EHF imported case; in 1996 a patient transported from Gabon to South Africa caused a nosocomial outbreak among caregivers in the hospital (IASR 17: 82-83, 1996).  Two imported cases of CCHF have been reported; one was a patient that developed symptoms after coming back from Senegal to France, and the other was a patient transported from Afghanistan to Germany for clinical care.

Diagnostic systems prepared in the National Institute of Infectious Diseases (NIID) in Japan
Department of Virology I in the NIID conducts virological diagnosis of VHFs (IASR 26: 218-221, 2005).  Immunoglobulin-G (IgG)-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay using the recombinant nucleocapsid proteins (rNPs) detect antibody with high sensitivity and specificity.  For detection of virus antigens in patientfs specimens, sandwich antigen (Ag)-capture ELISA systems are available.  RT-PCR assay systems are used for detection of viral genomes in patientfs specimens.  The available diagnostic systems for VHFs are summarized in Table 1.

Doctors, who diagnosed or suspected a patient as having VHF, are required to consult the Department of Virology I or the Infectious Diseases Surveillance Center, NIID, Tokyo, Japan for a proper management of the outbreak (Tel: 03-5285-1111, or E-mail: info[at}   Please type @ in substitution for [at]).  Information on the current situation in the endemic areas is available from quarantine stations of Ministry of Health Labour and Welfare (

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