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Dengue fever virus (DEN 1, DEN 2, DEN 3, DEN 4) - Pathogen Safety Data Sheet

SECTION I - INFECTOUS AGENT

NAME: Dengue Virus Footnote 1Footnote 2Footnote 3Footnote 4

SYNONYM OR CROSS REFERENCE: Dengue fever, break bone fever, Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS), DENV, DEN Footnote 1Footnote 2

CHARACTERISTICS:  Dengue Virus is an arbovirus of the Flaviviridae family and Flavivirus genus Footnote 1Footnote 3.  Dengue is an enveloped virus, 40-60 nm in size, with an isometric nucleocapsid of 25-30 nm and an ~10.7 kb, linear, positive-sense RNA genome Footnote 1Footnote 4.  Dengue virus exists as four serotypes (Dengue 1–4) and is genetically related to other flaviviruses such as yellow fever and tick-borne encephalitis viruses Footnote 1Footnote 4. Dengue virus may undergo 2 different cycles of transmission and amplification, sylvan and urban. In the sylvan cycle the virus undergoes rounds of infection, amplification, and re-infection between nonhuman primates and arthropod vectors Footnote 5.  It is believed that infected arthropod vectors then migrate from jungle environments and initiate the urban cycle in which the cycles of infection, amplification, and re-infection occur between humans and vector species Footnote 5.

SECTION II - HAZARD IDENTIFICATION

PATHOGENICITY/TOXICITY: Dengue virus infection can cause Dengue fever, Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS) Footnote 1. Clinical signs of Dengue fever include influenza type symptoms, fever, rash, myalgias and arthralgias, with a febrile period lasting between 2 and 10 days Footnote 6Footnote 7. Importantly, the risk of progression to hemorrhagic fever is higher after secondary infection with other dengue serotypes Footnote 6, although primary DSS can occur from a single infection especially in pediatric age groups.  Epidemiological data suggest that the serotypes differ in their ability to produce large outbreaks and severe clinical symptoms; however, all serotypes have the potential to cause severe disease Footnote 8. DHF and DSS are defined by four clinical manifestations: high fever, hemorrhagic diathesis, hepatomegaly, and shock Footnote 2. Depending on severity, relatively mild cases without shock, grades I and II, are defined as DHF, while severe cases accompanied by shock, grades III and IV are defined as DSS Footnote 2Footnote 9. If patients do not receive appropriate treatment, grade IV dengue virus can cause severe shock, in which pulse and blood pressure become undetectable, resulting in death within 12 to 36 h Footnote 9. Mortality rates for Dengue hemorrhagic fever can reach 20% Footnote 6.

EPIDEMIOLOGY: Cases are typical in tropical, developing countries worldwide Footnote 6. Dengue hemorrhagic fever cases have now been confirmed in more than 60 countries and Dengue Virus is endemic in more than 100 countries, including most of Southeast Asia, South America, Central America, and the Caribbean and South Pacific region Footnote 10. It is estimated that 50 million infections occur each year and more than 2.5 billion people are at risk of infection from dengue virus Footnote 9. Infection with any of the dengue serotypes may be asymptomatic in the majority of cases Footnote 9. In Asia the risk of developing severe disease is greater in dengue-infected children (≤15 years) than in adults Footnote 9. In contrast, in the Americas, the adult population is mainly affected, with most developing mild disease symptoms Footnote 9.

HOST RANGE: Humans, Simians, and Mosquitoes Footnote 2Footnote 11.

INFECTIOUS DOSE: Human ID50 is <10 PFU. Fewer than 10 PFU led to infection in 50% of volunteers treated with an attenuated dengue virus vaccine candidate Footnote 10.

MODE OF TRANSMISSION: Dengue virus is transmitted to humans through mosquito bites or through contaminated blood transfusion Footnote 2.  Peak mosquito biting times are 2-3 hours after dawn and several hours before dusk Footnote 7Footnote 12.

INCUBATION PERIOD: Humans have an average incubation period of 4-7 days (range of 3-15 days) Footnote 13.

COMMUNICABILITY: Virus can be communicated from human-to-human via transfusion of tainted blood Footnote 2.  Humans are infective for mosquitoes a few days before and after the febrile period and mosquitoes become infective for humans 8-12 days after infectionFootnote 7Footnote 14.

SECTION III – DISSEMINATION

RESERVOIR: Aedes aegypti and Aedes albopictus mosquitoes (transovarial transmission occurs in mosquitoes and salivary glands are highly infected), humans, and lower primates (enzootic cycles between primates and mosquitoes have been found in the forests of Africa and Asia) Footnote 1Footnote 7Footnote 12Footnote 13Footnote 15.

ZOONOSIS: Yes,via infected mosquitoes.   

VECTOR: Dengue virus is transmitted to humans by the bite of infected Aedes aegypti and Aedes albopictus mosquitoes Footnote 1Footnote 2. The eggs of A. aegypti can survive dessication for several months Footnote 16.

SECTION IV: STABILITY AND VIABILITY

DRUG SUSCEPTIBILITY/RESISTANCE: AlthoughDengue Virus is sensitive to ribavirin in vitro Footnote 5, clinical studies with ribavirin have been disappointing. Anti-Dengue Virus drugs are currently under development Footnote 13. Drug resistance has not been evaluated.

SUSCEPTIBILITY/RESISTANCE TO DISINFECTANTS: Dengue Virus is susceptible to phenol-guanidine isothiocyanate (TRIzol® LS) and chaotropic salt (AVL Buffer) Footnote 17. Viruses are sensitive to 1% sodium hypochlorite, 2% gluteraldehyde, 2% peracetic acid, 70 % ethanol, iodophors, phenolic compounds, and 3-6% hydrogen peroxide Footnote 18Footnote 19.  

PHYSICAL INACTIVATION: Viruses are sensitive to moist heat (121°C for at least 15 min), dry heat (160-170°C for at least 1 hour), and low temperature sterilization (i.e. Ethylene oxide or plasma sterilization) Footnote 20-23. The virus is also inactivated at a pH of 3 Footnote 24.

SURVIVAL OUTSIDE HOST: The virus is stable in dried blood for up to 9 weeks at room temperature Footnote 25.

SECTION V - FIRST AID / MEDICAL

SURVEILLANCE: Monitor for symptoms. Realtime PCR assay can be used to quantitatively measure RNA number as an indicator of viral load in infection Footnote 6. Dengue induced seroconversion can be detected using ELISA Footnote 5. Detection of circulating secondary antibodies directed against proteins such as NS1, NS2, NS3 and NS5 in patient samples, indicative of prior dengue exposure, can aid in evaluating risk of DHF development Footnote 5. RT-PCR can be used for direct virus detection Footnote 2.

Note: All diagnostic methods are not necessarily available in all countries.

FIRST AID TREATMENT: Monitor patient’s vital signs closely and transfuse plasma fluid and/or blood in cases of severe hemorrhagic fever Footnote 2Footnote 5. Solutions with dextran 70 have been used to treat hemorrhagic shock Footnote 2.

IMMUNIZATION: No vaccine is presently licensed for the prevention of Dengue Virus infection; however, numerous candidates are in various stages of pre-clinical and clinical development Footnote 10Footnote 26.

PROPHYLAXIS: None

SECTION VI - LABORATORY HAZARDS

LABORATORY ACQUIRED INFECTIONS: There have been 14 reported cases of laboratory acquired infections with no deaths Footnote 8.

SOURCES / SPECIMENS: Infected human blood, human liver, lung, and kidney tissue; nonhuman primate kidney cell lines, CSF, spleen and lymph nodes Footnote 2Footnote 27Footnote 28.Aedes aegypti and Aedes albopictus mosquitoes, and environmental samples from mosquito habitats are also sources of infection Footnote 1Footnote 13.

PRIMARY HAZARDS: Parenteral inoculation or bites from experimentally infected mosquito can be potentially infectious Footnote 1Footnote 2.

SPECIAL HAZARDS: None

SECTION VII - EXPOSURE CONTROLS / PERSONAL PROTECTION

RISK GROUP CLASSIFICATION: Risk Group 2.

CONTAINMENT REQUIREMENTS: Containment Level 2 facilities, equipment, and operational practices for work involving infectious or potentially infectious materials, animals, or cultures.

PROTECTIVE CLOTHING: Lab coat. Gloves when direct skin contact with infected materials or animals is unavoidable. Eye protection must be used where there is a known or potential risk of exposure to splashes Footnote 29.

OTHER PRECAUTIONS: All procedures that may produce aerosols, or involve high concentrations or large volumes should be conducted in a biological safety cabinet (BSC). The use of needles, syringes, and other sharp objects should be strictly limited. Additional precautions should be considered with work involving animals or large scale activities Footnote 29.

SECTION VIII - HANDLING AND STORAGE

SPILLS: Allow aerosols to settle and, wearing protective clothing, gently cover spill with paper towels and apply an appropriate disinfectant, starting at the perimeter and working towards the center.  Allow sufficient contact time before clean up Footnote 29.

DISPOSAL: Decontaminate all wastes that contain or have come in contact with the infectious organism by autoclave, chemical disinfection, gamma irradiation, or incineration before disposing Footnote 29.

STORAGE: The infectious agent should be stored in leak-proof containers that are appropriately labelled Footnote 29.

SECTION IX – REGULATORY AND OTHER INFORMATION

REGULATORY INFORMATION: The import, transport, and use of pathogens in Canada is regulated under many regulatory bodies, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment Canada, and Transport Canada. Users are responsible for ensuring they are compliant with all relevant acts, regulations, guidelines, and standards.

UPDATED: December 2011

PREPARED BY: Pathogen Regulation Directorate, Public Health Agency of Canada
Although the information, opinions and recommendations contained in this Pathogen Safety Data Sheet are compiled from sources believed to be reliable, we accept no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information. Newly discovered hazards are frequent and this information may not be completely up to date.

Copyright © Public Health Agency of Canada, 2011

REFERENCES

Footnote 1
Paranjape, S. M., & Harris, E. (2010). Control of dengue virus translation and replication. Current Topics in Microbiology and Immunology, 338, 15-34.
Footnote 2
Krauss, H., Weber, A., Appel, M., Enders, B., Isenberg, H. D., Schiefer, H. G., Slenczka, H. G., Graevenitz, A. V., & Zahner, H. (2003). Viral zoonoses. Zoonoses: Infectious diseases transmissible from Animals to Humans (3rd ed., pp. 57-61). Washington, USA: ASM press.
Footnote 3
Ray, G. C. (2004). Arthropod-Borne and other zoonotic viruses. In K. J. Ryan, & C. G. Ray (Eds.), Sherris: Medical Microbiology An introduction to infectious diseases (4th ed., pp. 585-596). USA: McgrawHill.
Footnote 4
Dimmock, N. J., Easton, A. J., & Leppard, K. N. (2007). Appendix: survey of virus properties. Introduction to modern virology (6th ed., pp. 444-453, 479). MA, USA: Blackwell Publishing.
Footnote 5
Burke, D. S., & Monath, T. P. (2001). Flaviviruses. In D. M. Knipe, P. M. Howley, D. E. Griffin, M. A. Martin, R. A. Lamb & B. Roizman (Eds.), Fields Virology (4th ed., pp. 1043-1126). PA, USA: Lippincott Williams and Wilkins.
Footnote 6
Rico-Hesse, R. (2009). Dengue virus markers of virulence and pathogenicity. Future Virology, 4(6), 581-589.
Footnote 7
Gubler, D. J. (1998). Dengue and dengue hemorrhagic fever. Clinical Microbiology Reviews, 11(3), 480-496.
Footnote 8
Paragas, J., & Endy, P. T. (2006). Viral Agents of human disease: Biosafety concerns. In D. O. Fleming, & D. L. Hunt (Eds.), Biological Safety: principles and practices (4th ed., pp. 179-207). Washinton, DC: ASM press.
Footnote 9
Martina, B. E. E., Koraka, P., & Osterhaus, A. D. M. E. (2009). Dengue virus pathogenesis: An integrated view. Clinical Microbiology Reviews, 22(4), 564-581.
Footnote 10
Blaney Jr., J. E., Durbin, A. P., Murphy, B. R., & Whitehead, S. S. (2010). Targeted mutagenesis as a rational approach to dengue virus vaccine development. Current Topics in Microbiology and Immunology, 338, 145-158.
Footnote 11
Carver, S., Bestall, A., Jardine, A., & Ostfeld, R. S. (2009). Influence of hosts on the ecology of arboviral transmission: Potential mechanisms influencing dengue, Murray Valley encephalitis, and Ross River virus in Australia. Vector-Borne and Zoonotic Diseases, 9(1), 51-64.
Footnote 12
Gurugama, P., Garg, P., Perera, J., Wijewickrama, A., & Seneviratne, S. L. (2010). Dengue viral infections. Indian Journal of Dermatology, 55(1), 68-78. doi:10.4103/0019-5154.60357
Footnote 13
Scott, T. W., & Morrison, A. C. (2010). Vector dynamics and transmission of dengue virus: implications for dengue surveillance and prevention strategies: vector dynamics and dengue prevention. Current Topics in Microbiology and Immunology, 338, 115-128.
Footnote 14
Esler, D. (2009). Dengue - Clinical and public health ramifications. Australian Family Physician, 38(11), 876-879.
Footnote 15
Platt, K. B., Linthicum, K. J., Myint, K. S., Innis, B. L., Lerdthusnee, K., & Vaughn, D. W. (1997). Impact of dengue virus infection on feeding behavior of Aedes aegypti. The American Journal of Tropical Medicine and Hygiene, 57(2), 119-125.
Footnote 16
Hopp, M. J., & Foley, J. A. (2001). Global-Scale Relationships between Climate and the Dengue Fever Vector, Aedes Aegypti. Climatic Change, 48, 441-463.
Footnote 17
Blow, J. A., Dohm, D. J., Negley, D. L., & Mores, C. N. (2004). Virus inactivation by nucleic acid extraction reagents. Journal of Virological Methods, 119(2), 195-198.
Footnote 18
Collins, C. H., & Kennedy, D. A. (1999). Laboratory acquired infections. Laboratory acquired infections: History, incidence, causes and prevention (4th ed., pp. 1-37). Woburn, MA: BH.
Footnote 19
Rutala, W. A. (1996). APIC guideline for selection and use of disinfectants. American Journal of Infection Control, 24(4), 313-342.
Footnote 20
Burnett, L. A. C., Lunn, G., & Coico, R. (2009). Biosafety: Guidelines for working with pathogenic and infectious microorganisms. Current Protocols in Microbiology, (SUPPL. 13), 1A.1.1-1A.1.14.
Footnote 21
Moisan, M., Barbeau, J., Crevier, M. -., Pelletier, J., Philip, N., & Saoudi, B. (2002). Plasma sterilization. Methods and mechanisms. Pure and Applied Chemistry, 74(3), 349-358.
Footnote 22
Richmond, J. Y., & Mckinney, R. W. (1999). Fungal agents. In R. Y. Jonathan, & M. Robert (Eds.), Biosafety in microbial and biomedical laboratories (4th ed., pp. 118-119). Washington, USA: U.S government printing office.
Footnote 23
Wood, M. (1974). Ethylene oxide sterilization. RESP.THER., 4(1), 43-47+75.
Footnote 24
Jindadamrongwech, S., Thepparit, C., & Smith, D. R. (2004). Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Archives of Virology, 149(5), 915-927. doi:10.1007/s00705-003-0263-x
Footnote 25
Prado, I., Rosario, D., Bernardo, L., Alvarez, M., Rodriguez, R., Vazquez, S., & Guzman, M. G. (2005). PCR detection of dengue virus using dried whole blood spotted on filter paper. Journal of Virological Methods, 125(1), 75-81. doi:10.1016/j.jviromet.2005.01.001
Footnote 26
Guy, B., Guirakhoo, F., Barban, V., Higgs, S., Monath, T. P., & Lang, J. (2010). Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine, 28(3), 632-649.
Footnote 27
Cam, B. V., Fonsmark, L., Hue, N. B., Phuong, N. T., Poulsen, A., & Heegaard, E. D. (2001). Prospective case-control study of encephalopathy in children with dengue hemorrhagic fever. The American Journal of Tropical Medicine and Hygiene, 65(6), 848-851.
Footnote 28
Rico-Hesse, R. (2010). Dengue virus virulence and transmission determinants. Current Topics in Microbiology and Immunology, 338, 45-55.
Footnote 29
Public Health Agency of Canada. (2004). In Best M., Graham M. L., Leitner R., Ouellette M. and Ugwu K. (Eds.), Laboratory Biosafety Guidelines (3rd ed.). Canada: Public Health Agency of Canada.