Snowy Owl
Retired in 2010, In Memoriam
Gratitude to Florida1, Director and President of Flu Trackers
The Lancet 1999; 354:1401-1402
DOI:10.1016/S0140-6736(99)00236-6
Variation in virulence of dengue virus
Nicholas J White http://www.thelancet.com/journals/lancet/article/PIIS0140673699040155/fulltext
There is a global pandemic of dengue infection in the tropics. It is related to poor vector control, urbanisation, and increases in population and migration.1 Dengue fever and its more serious manifestation, dengue haemorrhagic fever (DHF), are caused by RNA viruses of the Flavivirus genus, which are transmitted by several species of Aedes mosquitoes.
DHF and the dengue shock syndrome (DSS) are characterised by a haemorrhagic diathesis and a sudden increase in systemic vascular permeability that coincides with defervescence. DHF/DSS is now a leading cause of paediatric admission to hospital in many Asian countries. Case-fatality rates from DHF/DSS are generally below 2% in places where there are good facilities for intravenous resuscitation, but the mortality is much higher where such facilities are lacking or when the diagnosis is not made.2 In the 1996 epidemic, which took Delhi unawares, the mortality was 4?2% among the 8900 reported cases.3
There are four antigenically related dengue virus serotypes (DEN1?4), any one of which may cause severe disease. DHF has generally been thought to result from a second infection, with a virus different in serotype to that which caused the primary infection.4 Cross-reacting enhancing antibodies augment cell-surface binding and internalisation and increase intracellular virus multiplication.5 There has been some progress in the understanding of the pathogenesis of dengue fever6,7 but the cause of the sudden, potentially lethal, and reversible vascular leak remains elusive.
Epidemiologists have long puzzled over why severe epidemic DHF/DSS seems to have emerged in southeast Asia only in the past 50 years, despite descriptions of ?dengue-fever-like? syndromes from many parts of the world going back to antiquity.1 In addition, the more severe forms of dengue have been common in some epidemics but rare or absent in others.
A consistent feature of the recent emergence of epidemic DHF/DSS in the Pacific and the Caribbean has been the introduction of dengue viruses of Asian origin on a background of preceding dengue transmission coinciding with increased spread and mosquito densities of the main vector Aedes aegypti.1 The well-documented Cuban epidemic of 1981, in which there were an estimated 10 000 cases of DHF/DSS, was caused by a new strain of DEN-2 virus, thought to be of Vietnamese origin.8 The same strain may have caused the Venezuelan epidemic of 1989?90 (6000 DHF/DSS cases). DEN-3 virus, probably of Indian or Sri Lankan origin, caused a major epidemic of DHF/DSS in Nicaragua in 1994. A different DEN-3, but also probably of Asian origin, caused the 1990 DHF/DSS epidemic in Tahiti, whereas previous epidemics of dengue 1, 2, and 3 had been considerably less severe.9
In today's Lancet, Douglas Watts and colleagues present the results of a prospective epidemiological study from Iquitos in Amazonian Peru that provide strong evidence of significant differences in disease severity between secondary dengue infections of American and Asian origin. In anticipation of the southern spread of dengue from Venezuela and adjacent countries, the researchers mounted a surveillance study in the late 1980s. DEN-1 duly arrived in 1990 and then an epidemic of DEN-2 followed in 1995. The results were compared with the prospective Rayong study, conducted in Thailand in 1980, in which DHF/DSS developed in a fifth of schoolchildren with acute DEN-2 infections following upon previous DEN-1.10 In sharp contrast, not a single case of severe dengue was reported in Iquitos among an estimated 50000 infected schoolchildren. The Iquitos DEN-2 certainly seems to be much less virulent than its Asian counterparts. Host genetic factors and the pattern of previous infections undoubtedly contribute to the risk of severe dengue infection, but these data suggest that viruses originating from Asia possess a virulence determinant that is absent from viruses originating elsewhere.
There is 60?80% homology in the structural and non-structural proteins between the four dengue serotypes. The serotype is determined largely from the antigenicity of the virus envelope (E) glycoprotein, and within each serotype there is also substantial heterogeneity. Sequence data indicate that the dengue viruses are evolving, and diverging rapidly.11 The widespread intraserotype recombination among dengue viruses12 could well lead to a proliferation in the number of antigenic types in the near future. Within this variety must lie the key to virulence. A comparison of gene sequences from viruses such as the Iquitos DEN-2 and those DEN-2 viruses that caused the serious epidemics in southeast Asia, Cuba, and Delhi will surely yield clues to the answer. Effective vaccines may soon become available,13 but these will produce considerable selective pressures on the dengue virus population. Greater understanding of the molecular basis of virulence and the pathogenetic mechanisms involved in DHF/DSS will be needed to ensure that vaccine development stays ahead of viral evolution.
<!--start simple-tail=-->References
1. Gubler DJ. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford: CAB International, 1997: 1-22.
2. Nimmannitya S. Clinical spectrum and management of dengue haemorrhagic fever. SE Asian J Trop Med Publ Health 1987; 20: 325-330.
3. Dar L, Broor S, Sengupta S, Xess I, Seth P. The first major outbreak of dengue hemorrhagic fever in Delhi, India. Emerg Infect Dis 1999; 5: 589-590.
4. Halstead SB, Nimmanitya S, Cohen SN. Observations related to pathogenesis of dengue haemorrhagic fever: I, relation of disease severity to antibody response and virus recovered. Yale J Biol Med 1970; 42: 311-328. MEDLINE
5. Halstead SB, O'Rourke EJ. Antibody enhanced dengue virus infection in primate leukocytes. Nature 1977; 265: 739-741. MEDLINE | CrossRef
6. Falconar AK. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol 1997; 142: 897-916. CrossRef
7. Leitmeyer KC, Vaughn DW, Watts DM, et al. Dengue virus structural differences that correlate with pathogenesis. J Virol 1999; 73: 4738-4747.
8. Kouri GP, Guzman MG, Bravo JR, Triana C. Dengue haemorrhagic fever/dengue shock syndrome: lessons learned from the Cuban epidemic. Bull World Health Organ 1989; 67: 375-380. MEDLINE
9. Chungue E, Deubel V, Cassar O, Laille M, Martin PMV. Molecular epidemiology of dengue 3 virus and genetic relatedness among dengue 3 strains isolated from patients with mild or severe forms of dengue fever in French Polynesia. J Gen Virol 1993; 74: 1765-1770.
10. Sangkawibha N, Rojanasuphot Ahandrik S, et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. Am J Epidemiol 1984; 120: 653-659. MEDLINE
11. Trent DW, Manske CL, Fox GE, Chu MC, Kliks SC, Monath TP. The molecular epidemiology of dengue viruses: genetic variation and microevolution. Applied Virol Res 1990; 2: 293-315.
12. Worobey M, Rambaut A, Holmes EC. Widespread intraserotype recombination in natural populations of dengue virus. Proc Natl Acad Sci USA 1999; 96: 7352-7357. CrossRef
13. Bhamarapravati N, Yoksan S. Live attenuated tetravalent dengue vaccine In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford: CAB International, 1997: 367-377.
The Lancet 1999; 354:1401-1402
DOI:10.1016/S0140-6736(99)00236-6
Variation in virulence of dengue virus
Nicholas J White http://www.thelancet.com/journals/lancet/article/PIIS0140673699040155/fulltext
There is a global pandemic of dengue infection in the tropics. It is related to poor vector control, urbanisation, and increases in population and migration.1 Dengue fever and its more serious manifestation, dengue haemorrhagic fever (DHF), are caused by RNA viruses of the Flavivirus genus, which are transmitted by several species of Aedes mosquitoes.
DHF and the dengue shock syndrome (DSS) are characterised by a haemorrhagic diathesis and a sudden increase in systemic vascular permeability that coincides with defervescence. DHF/DSS is now a leading cause of paediatric admission to hospital in many Asian countries. Case-fatality rates from DHF/DSS are generally below 2% in places where there are good facilities for intravenous resuscitation, but the mortality is much higher where such facilities are lacking or when the diagnosis is not made.2 In the 1996 epidemic, which took Delhi unawares, the mortality was 4?2% among the 8900 reported cases.3
There are four antigenically related dengue virus serotypes (DEN1?4), any one of which may cause severe disease. DHF has generally been thought to result from a second infection, with a virus different in serotype to that which caused the primary infection.4 Cross-reacting enhancing antibodies augment cell-surface binding and internalisation and increase intracellular virus multiplication.5 There has been some progress in the understanding of the pathogenesis of dengue fever6,7 but the cause of the sudden, potentially lethal, and reversible vascular leak remains elusive.
Epidemiologists have long puzzled over why severe epidemic DHF/DSS seems to have emerged in southeast Asia only in the past 50 years, despite descriptions of ?dengue-fever-like? syndromes from many parts of the world going back to antiquity.1 In addition, the more severe forms of dengue have been common in some epidemics but rare or absent in others.
A consistent feature of the recent emergence of epidemic DHF/DSS in the Pacific and the Caribbean has been the introduction of dengue viruses of Asian origin on a background of preceding dengue transmission coinciding with increased spread and mosquito densities of the main vector Aedes aegypti.1 The well-documented Cuban epidemic of 1981, in which there were an estimated 10 000 cases of DHF/DSS, was caused by a new strain of DEN-2 virus, thought to be of Vietnamese origin.8 The same strain may have caused the Venezuelan epidemic of 1989?90 (6000 DHF/DSS cases). DEN-3 virus, probably of Indian or Sri Lankan origin, caused a major epidemic of DHF/DSS in Nicaragua in 1994. A different DEN-3, but also probably of Asian origin, caused the 1990 DHF/DSS epidemic in Tahiti, whereas previous epidemics of dengue 1, 2, and 3 had been considerably less severe.9
In today's Lancet, Douglas Watts and colleagues present the results of a prospective epidemiological study from Iquitos in Amazonian Peru that provide strong evidence of significant differences in disease severity between secondary dengue infections of American and Asian origin. In anticipation of the southern spread of dengue from Venezuela and adjacent countries, the researchers mounted a surveillance study in the late 1980s. DEN-1 duly arrived in 1990 and then an epidemic of DEN-2 followed in 1995. The results were compared with the prospective Rayong study, conducted in Thailand in 1980, in which DHF/DSS developed in a fifth of schoolchildren with acute DEN-2 infections following upon previous DEN-1.10 In sharp contrast, not a single case of severe dengue was reported in Iquitos among an estimated 50000 infected schoolchildren. The Iquitos DEN-2 certainly seems to be much less virulent than its Asian counterparts. Host genetic factors and the pattern of previous infections undoubtedly contribute to the risk of severe dengue infection, but these data suggest that viruses originating from Asia possess a virulence determinant that is absent from viruses originating elsewhere.
There is 60?80% homology in the structural and non-structural proteins between the four dengue serotypes. The serotype is determined largely from the antigenicity of the virus envelope (E) glycoprotein, and within each serotype there is also substantial heterogeneity. Sequence data indicate that the dengue viruses are evolving, and diverging rapidly.11 The widespread intraserotype recombination among dengue viruses12 could well lead to a proliferation in the number of antigenic types in the near future. Within this variety must lie the key to virulence. A comparison of gene sequences from viruses such as the Iquitos DEN-2 and those DEN-2 viruses that caused the serious epidemics in southeast Asia, Cuba, and Delhi will surely yield clues to the answer. Effective vaccines may soon become available,13 but these will produce considerable selective pressures on the dengue virus population. Greater understanding of the molecular basis of virulence and the pathogenetic mechanisms involved in DHF/DSS will be needed to ensure that vaccine development stays ahead of viral evolution.
<!--start simple-tail=-->References
1. Gubler DJ. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford: CAB International, 1997: 1-22.
2. Nimmannitya S. Clinical spectrum and management of dengue haemorrhagic fever. SE Asian J Trop Med Publ Health 1987; 20: 325-330.
3. Dar L, Broor S, Sengupta S, Xess I, Seth P. The first major outbreak of dengue hemorrhagic fever in Delhi, India. Emerg Infect Dis 1999; 5: 589-590.
4. Halstead SB, Nimmanitya S, Cohen SN. Observations related to pathogenesis of dengue haemorrhagic fever: I, relation of disease severity to antibody response and virus recovered. Yale J Biol Med 1970; 42: 311-328. MEDLINE
5. Halstead SB, O'Rourke EJ. Antibody enhanced dengue virus infection in primate leukocytes. Nature 1977; 265: 739-741. MEDLINE | CrossRef
6. Falconar AK. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol 1997; 142: 897-916. CrossRef
7. Leitmeyer KC, Vaughn DW, Watts DM, et al. Dengue virus structural differences that correlate with pathogenesis. J Virol 1999; 73: 4738-4747.
8. Kouri GP, Guzman MG, Bravo JR, Triana C. Dengue haemorrhagic fever/dengue shock syndrome: lessons learned from the Cuban epidemic. Bull World Health Organ 1989; 67: 375-380. MEDLINE
9. Chungue E, Deubel V, Cassar O, Laille M, Martin PMV. Molecular epidemiology of dengue 3 virus and genetic relatedness among dengue 3 strains isolated from patients with mild or severe forms of dengue fever in French Polynesia. J Gen Virol 1993; 74: 1765-1770.
10. Sangkawibha N, Rojanasuphot Ahandrik S, et al. Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. Am J Epidemiol 1984; 120: 653-659. MEDLINE
11. Trent DW, Manske CL, Fox GE, Chu MC, Kliks SC, Monath TP. The molecular epidemiology of dengue viruses: genetic variation and microevolution. Applied Virol Res 1990; 2: 293-315.
12. Worobey M, Rambaut A, Holmes EC. Widespread intraserotype recombination in natural populations of dengue virus. Proc Natl Acad Sci USA 1999; 96: 7352-7357. CrossRef
13. Bhamarapravati N, Yoksan S. Live attenuated tetravalent dengue vaccine In: Gubler DJ, Kuno G, eds. Dengue and dengue hemorrhagic fever. Wallingford: CAB International, 1997: 367-377.