Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection


Today, dengue viruses are the most prevalent arthropod-borne viruses in the world. Since the 1960s, numerous reports have identified a second heterologous dengue virus (DENV) infection as a principal risk factor for severe dengue disease (dengue hemorrhagic fever/dengue shock syndrome, DHF/DSS). Modifiers of dengue disease response include the specific sequence of two DENV infections, the interval between infections, and contributions from the human host, such as age, ethnicity, chronic illnesses and genetic background. Antibody-dependent enhancement (ADE) of dengue virus infection has been proposed as the early mechanism underlying DHF/DSS. Dengue cross-reactive antibodies raised following a first dengue infection combine with a second infecting virus to form infectious immune complexes that enter Fc-receptor-bearing cells. This results in an increased number of infected cells and increased viral output per cell. At the late illness stage, high levels of cytokines, possibly the result of T cell elimination of infected cells, result in vascular permeability, leading to shock and death. This review is focused on the etiological role of secondary infections (SI) and mechanisms of ADE.

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  1. 1.

    Adams B, Holmes EC, Zhang C, Mammen MP Jr, Nimmannitya S, Kalayanarooj S, Boots M (2006) Cross-protective immunity can account for the alternating epidemic pattern of dengue virus serotypes circulating in Bangkok. Proc Natl Acad Sci USA 103:14234–14239

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Alvarez M, Rodriguez-Roche R, Bernardo L, Vazquez S, Morier L, Gonzalez D, Castro O, Kouri G, Halstead SB, Guzman MG (2006) Dengue hemorrhagic Fever caused by sequential dengue 1–3 virus infections over a long time interval: Havana epidemic, 2001–2002. Am J Trop Med Hyg 75:1113–1117

    PubMed  Google Scholar 

  3. 3.

    Anantapreecha S, Chanama S, An A, Naemkhunthot S, Sa-Ngasang A, Sawanpanyalert P, Kurane I (2005) Serological and virological features of dengue fever and dengue haemorrhagic fever in Thailand from 1999 to 2002. Epidemiol Infect 133:503–507

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Armstrong PM, Rico-Hesse R (2001) Differential susceptibility of Aedes aegypti to infection by the American and Southeast Asian genotypes of dengue type 2 virus. Vector Borne Zoonotic Dis 1:159–168

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Armstrong PM, Rico-Hesse R (2003) Efficiency of dengue serotype 2 virus strains to infect and disseminate in Aedes aegypti. Am J Trop Med Hyg 68:539–544

    PubMed  Google Scholar 

  6. 6.

    Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL, Mehlhop E, Johnson S, Diamond MS, Beatty PR, Harris E (2010) Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6:e1000790

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Beaslet DWC, Barrett A (2008) Dengue. In: Halstead SB (ed) The Infectious agent Tropical Medicine. Science and Practice, pp 29–73

  8. 8.

    Beatty ME, Stone A, Fitzsimons DW, Hanna JN, Lam SK, Vong S, Guzman MG, Mendez-Galvan JF, Halstead SB, Letson GW, Kuritsky J, Mahoney R, Margolis HS (2010) Best practices in dengue surveillance: a report from the Asia-Pacific and Americas Dengue Prevention Boards. PLoS Negl Trop Dis 4:e890

    PubMed  Article  Google Scholar 

  9. 9.

    Becquart P, Wauquier N, Nkoghe D, Ndjoyi-Mbiguino A, Padilla C, Souris M, Leroy EM (2010) Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC Infect Dis 10:356

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Bethell DB, Gamble J, Loc PP, Dung NM, Chau H, Loan HT, Thuy TTN, Tam DTH, Gartside IB, White NJ, Day NPJ (2001) Noninvasive measurement of microvascular leakage in patients with dengue hemorrhagic fever. CID 32:243–253

    CAS  Article  Google Scholar 

  11. 11.

    Boonnak K, Slike BM, Burgess TH, Mason RM, Wu SJ, Sun P, Porter K, Rudiman IF, Yuwono D, Puthavathana P, Marovich MA (2008) Role of Dendritic Cells in antibody dependent enhancement of dengue infection. J Virol 82(8):3939–3951

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Brady OJGP, Bhatt S, Messina JP, Brownstein JS, Hoen AG, Moyes CL, Farlow AW, Scott TW, Hay SI (2012) Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis 6:e1760

    PubMed  Article  Google Scholar 

  13. 13.

    Burke DS, Nisalak A, Johnson DE, Scott RM (1988) A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 38:172–180

    PubMed  CAS  Google Scholar 

  14. 14.

    Burton DR, Saphire EO, Parren PW (2001) A model for neutralization of viruses based on antibody coating of the virion surface. Curr Top Microbiol Immunol 260:109–143

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Cantelar de Francisco N, Fernandez A, Albert Molina L, Perez Balbis E (1981) Survey of dengue in Cuba. 1978–1979. Rev Cubana Med Trop 33:72–78

    PubMed  CAS  Google Scholar 

  16. 16.

    Cohen SN, Halstead SB (1966) Shock associated with dengue infection. I. Clinical and physiologic manifestations of dengue hemorrhagic fever in Thailand, 1964. J Pediatr 68:448–456

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Cologna R, Rico-Hesse R (2003) American genotype structures decrease dengue virus output from human monocytes and dendritic cells. J Virol 77:3929–3938

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Cologna R, Armstrong PM, Rico-Hesse R (2005) Selection for virulent dengue viruses occurs in humans and mosquitoes. J Virol 79:853–859

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Cummings DA, Schwartz IB, Billings L, Shaw LB, Burke DS (2005) Dynamic effects of antibody-dependent enhancement on the fitness of viruses. Proc Natl Acad Sci USA 102:15259–15264

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Cummings DA, Iamsirithaworn S, Lessler JT, McDermott A, Prasanthong R, Nisalak A, Jarman RG, Burke DS, Gibbons RV (2009) The impact of the demographic transition on dengue in Thailand: insights from a statistical analysis and mathematical modeling. PLoS Med 6:e1000139

    PubMed  Article  Google Scholar 

  21. 21.

    Chareonsirisuthigul T, Kalayanarooj S, Ubol S (2007) Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells. J Gen Virol 88:365–375

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Chau TN, Quyen NT, Thuy TT, Tuan NM, Hoang DM, Dung NT, le Lien B, Quy NT, Hieu NT, Hieu LT, Hien TT, Hung NT, Farrar J, Simmons CP (2008) Dengue in Vietnamese infants–results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity. J Infect Dis 198:516–524

    PubMed  Article  Google Scholar 

  23. 23.

    Chau TN, Anders KL, le Lien B, Hung NT, Hieu LT, Tuan NM, Thuy TT, le Phuong T, Tham NT, Lanh MN, Farrar JJ, Whitehead SS, Simmons CP (2010) Clinical and virological features of Dengue in Vietnamese infants. PLoS Negl Trop Dis 4:e657

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Chen JP, Lu HL, Lai SL, Campanella GS, Sung JM, Lu MY, Wu-Hsieh BA, Lin YL, Lane TE, Luster AD, Liao F (2006) Dengue virus induces expression of CXC chemokine ligand 10/IFN-gamma-inducible protein 10, which competitively inhibits viral binding to cell surface heparan sulfate. J Immunol 177:3185–3192

    PubMed  CAS  Google Scholar 

  25. 25.

    Chen RF, Yeh WT, Yang MY, Yang KD (2001) A model of the real-time correlation of viral titers with immune reactions in antibody-dependent enhancement of dengue-2 infections. FEMS Immunol Med Microbiol 30:1–7

    PubMed  Article  Google Scholar 

  26. 26.

    Cherian T, Ponnuraj E, Kuruvilla T, Kirubakaran C, John TJ, Raghupathy P (1994) An epidemic of dengue haemorrhagic fever & dengue shock syndrome in & around Vellore. Indian J Med Res 100:51–56

    PubMed  CAS  Google Scholar 

  27. 27.

    Chungue E, Spiegel A, Roux J, Laudon F, Cardines R (1990) Dengue-3 in French Polynesia: preliminary data. Med J Aust 152:557–558

    PubMed  CAS  Google Scholar 

  28. 28.

    de Araujo JM, de Filippis AM, Schatzmayr HG, de Araujo ES, Britto C, Cardoso MA, Camacho LA, Nogueira RM (2009) Quantification of dengue virus type 3 RNA in fatal and non-fatal cases in Brazil, 2002. Trans R Soc Trop Med Hyg 103(9):952–954

    Article  CAS  Google Scholar 

  29. 29.

    de Araujo JM, Schatzmayr HG, de Filippis AM, Dos Santos FB, Cardoso MA, Britto C, Coelho JM, Nogueira RM (2009) A retrospective survey of dengue virus infection in fatal cases from an epidemic in Brazil. J Virol Methods 155:34–38

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    De Carvalho Bittencourt M, Martial J, Cabié A, Thomas L, Césaire R (2012) Decreased peripheral dendritic cell numbers in dengue virus infection. J Clin Immunol 32:161–172

    Article  Google Scholar 

  31. 31.

    Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G (2010) Cross-reacting antibodies enhance dengue virus infection in humans. Science 328:745–748

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Della-Porta AJ, Westaway EG (1978) A multi-hit model for the neutralization of animal viruses. J Gen Virol 38:1–19

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Diaz A, Kouri G, Guzman MG, Lobaina L, Bravo J, Ruiz A, Ramos A, Martinez R (1988) Description of the clinical picture of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in adults. Bull Pan Am Health Organ 22:133–144

    PubMed  CAS  Google Scholar 

  34. 34.

    Duraisamy RGG (1981) Bleeding manifestations of dengue haemorrhagic fever in Malaysia. Acta Trop 38:71–78

    PubMed  Google Scholar 

  35. 35.

    Endy TP, Nisalak A, Chunsuttitwat S, Vaughn DW, Green S, Ennis FA, Rothman AL, Libraty DH (2004) The relationship of preexisting dengue virus (DV) neutralizing antibody levels to viremia and severity of disease in a prospective cohort study of DV infection in Thailand. J Infect Dis 189:990–1000

    PubMed  Article  Google Scholar 

  36. 36.

    Fagundes CT, Costa VV, Cisalpino D, Amaral FA, Souza PR, Souza RS, Ryffel B, Vieira LQ, Silva TA, Atrasheuskaya A, Ignatyev G, Sousa LP, Souza DG, Teixeira MM (2011) IFN-gamma production depends on IL-12 and IL-18 combined action and mediates host resistance to dengue virus infection in a nitric oxide-dependent manner. PLoS Negl Trop Dis 5:e1449

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Ferguson NM, Donnelly CA, Anderson RM (1999) Transmission dynamics and epidemiology of dengue: insights from age-stratified sero-prevalence surveys. Philos Trans R Soc Lond B Biol Sci 354:757–768

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Fried JR, Gibbons RV, Kalayanarooj S, Thomas SJ, Srikiatkhachorn A, Yoon IK, Jarman RG, Green S, Rothman AL, Cummings DA (2010) Serotype-specific differences in the risk of dengue hemorrhagic Fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006. PLoS Negl Trop Dis 4:e617

    PubMed  Article  Google Scholar 

  39. 39.

    Gamble J, Bethell D, Day NP, Loc PP, Phu NH, Gartside IB, Farrar JF, White NJ (2000) Age-related changes in microvascular permeability: a significant factor in the susceptibility of children to shock? Clin Sci (Lond) 98:211–216

    CAS  Article  Google Scholar 

  40. 40.

    Gibbons RV, Kalanarooj S, Jarman RG, Nisalak A, Vaughn DW, Endy TP, Mammen MP Jr, Srikiatkhachorn A (2007) Analysis of repeat hospital admissions for dengue to estimate the frequency of third or fourth dengue infections resulting in admissions and dengue hemorrhagic fever, and serotype sequences. Am J Trop Med Hyg 77:910–913

    PubMed  Google Scholar 

  41. 41.

    Goh KT (1997) Dengue–a re-emerging infectious disease in Singapore. Ann Acad Med Singapore 26:664–670

    PubMed  CAS  Google Scholar 

  42. 42.

    Gollins SW, Porterfield JS (1985) Flavivirus infection enhancement in macrophages: an electron microscopic study of viral cellular entry. J Gen Virol 66:1969–1982

    PubMed  Article  Google Scholar 

  43. 43.

    Goncalvez A, Engle R, St Claire M, Purcell R, Lai C (2007) Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies and perspectives for prevention. Proc Nat Acad Sci USA 104:9422–9427

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Gonzalez D, Castro OE, Kouri G, Perez J, Martinez E, Vazquez S, Rosario D, Cancio R, Guzman MG (2005) Classical dengue hemorrhagic fever resulting from two dengue infections spaced 20 years or more apart: Havana, Dengue 3 epidemic, 2001-2002. Int J Infect Dis 9(5):280–285

    Google Scholar 

  45. 45.

    Graham RR, Juffrie M, Tan R, Hayes CG, Laksono I, Ma’roef C, Erlin, Sutaryo, Porter KR, Halstead SB (1999) A prospective seroepidemiologic study on dengue in children four to nine years of age in Yogyakarta, Indonesia I. studies in 1995–1996. Am J Trop Med Hyg 61:412–419

    PubMed  CAS  Google Scholar 

  46. 46.

    Gubler DJ, Suharyono W, Lubis I, Eram S, Sulianti Saroso J (1979) Epidemic dengue hemorrhagic fever in rural Indonesia. I. Virological and epidemiological studies. Am J Trop Med Hyg 28:701–710

    PubMed  CAS  Google Scholar 

  47. 47.

    Guilarde AO, Turchi MD, Siqueira JB Jr, Feres VC, Rocha B, Levi JE, Souza VA, Boas LS, Pannuti CS, Martelli CM (2008) Dengue and dengue hemorrhagic fever among adults: clinical outcomes related to viremia, serotypes, and antibody response. J Infect Dis 197:817–824

    PubMed  Article  Google Scholar 

  48. 48.

    Guzman MG, Kouri G, Morier L, Soler M, Fernandez A (1984) A study of fatal hemorrhagic dengue cases in Cuba, 1981. Bull Pan Am Health Organ 18:213–220

    PubMed  CAS  Google Scholar 

  49. 49.

    Guzman MG, Kouri G, Martinez E, Bravo J, Riveron R, Soler M, Vazquez S, Morier L (1987) Clinical and serologic study of Cuban children with dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Bull Pan Am Health Organ 21:270–279

    PubMed  CAS  Google Scholar 

  50. 50.

    Guzman MG, Alvarez M, Rodriguez R, Rosario D, Vazquez S, Valdes L, Cabrera MV, Kouri G (1999) Fatal dengue hemorrhagic fever in Cuba, 1997. Int J Infect Dis 3:130–135

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Guzman MG, Kouri G, Halstead SB (2000) Do escape mutants explain rapid increases in dengue case-fatality rates within epidemics? Lancet 355:1902–1903

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Guzman MG, Kouri G, Valdes L, Bravo J, Alvarez M, Vazques S, Delgado I, Halstead SB (2000) Epidemiologic studies on Dengue in Santiago de Cuba, 1997. Am J Epidemiol 152:793–799

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Guzman MG, Kouri G, Bravo J, Valdes L, Vazquez S, Halstead SB (2002) Effect of age on outcome of secondary dengue 2 infections. Int J Infect Dis 6:118–124

    PubMed  Article  Google Scholar 

  54. 54.

    Guzman MG, Kouri G, Valdes L, Bravo J, Vazquez S, Halstead SB (2002) Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Rev Panam Salud Publica 11:223–227

    PubMed  Article  Google Scholar 

  55. 55.

    Guzman MG, Pelaez O, Kouri G, Quintana I, Vazquez S, Penton M, Avila LC (2006) Final characterization of and lessons learned from the dengue 3 epidemic in Cuba, 2001–2002. Rev Panam Salud Publica 19:282–289

    PubMed  Article  Google Scholar 

  56. 56.

    Guzman MG, Alvarez M, Rodriguez-Roche R, Bernardo L, Montes T, Vazquez S, Morier L, Alvarez A, Gould EA, Kouri G, Halstead SB (2007) Neutralizing antibodies after infection with dengue 1 virus. Emerg Infect Dis 13:282–286

    PubMed  Article  Google Scholar 

  57. 57.

    Guzman MG, Kouri G (2008) Dengue haemorrhagic fever integral hypothesis: confirming observations, 1987–2007. Trans R Soc Trop Med Hyg 102:522–523

    PubMed  Article  Google Scholar 

  58. 58.

    Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martinez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW (2010) Dengue: a continuing global threat. Nat Rev Microbiol 8:S7–S16

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Guzman MG, Vazquez S (2010) The complexity of antibody-dependent enhancement of dengue virus infection. Viruses 2:2649–2662

    PubMed  Article  Google Scholar 

  60. 60.

    Guzman MG, Alvarez A, Vazquez S, Alvarez M, Rosario D, Pelaez O, Cruz G, Rodriguez R, Pavon A, Gonzalez A, Morier L, Ruiz D, Kouri G, Halstead SB (2012) Epidemiological studies on dengue virus type 3 in Playa municipality, Havana, Cuba, 2001–2002. Int J Infect Dis 16(3):e198–e203

    PubMed  Article  Google Scholar 

  61. 61.

    Halstead S (2008) Dengue hemorrhagic fever is caused by autoimmune phenomena triggered by a dengue viral infection. In: Halstead SB (ed) dengue. Series editors G Pasvol and SL Hoffman. Imperial College Press, London, pp 472–474

  62. 62.

    Halstead S (1993) Pathophysiology and pathogenesis of dengue hemorrhagic fever. In: Organization WH, Thongcharoen P (eds) SEARO No. 22, Regional Publication, pp 80–103

  63. 63.

    Halstead S (2008) Dengue hemorrhagic fever is caused by an abnormal or accelerated T cell response to infection. In: Halstead SB (ed) dengue. Series editors G Pasvol and SL Hoffman. Imperial College Press, London, pp 465–468

  64. 64.

    Halstead S (2008) Dengue: overview and history. In: Halstead SB (ed) dengue. Series editors G Pasvol and SL Hoffman. Imperial College Press, London, pp 1–28

  65. 65.

    Halstead S (2012) Controversies in dengue pathogenesis. Paediatr Int Child Health 32:5–9

    PubMed  Article  Google Scholar 

  66. 66.

    Halstead SB, Nimmannitya S, Yamarat C, Russell PK (1967) Hemorrhagic fever in Thailand; recent knowledge regarding etiology. Jpn J Med Sci Biol 20:96–103

    PubMed  Google Scholar 

  67. 67.

    Halstead SB (1970) Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med 42:350–362

    PubMed  CAS  Google Scholar 

  68. 68.

    Halstead SB, Nimmannitya S, Cohen SN (1970) Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med 42:311–328

    PubMed  CAS  Google Scholar 

  69. 69.

    Halstead SB (1981) The Alexander D. Langmuir Lecture. The pathogenesis of dengue. Molecular epidemiology in infectious disease. Am J Epidemiol 114:632–648

    PubMed  CAS  Google Scholar 

  70. 70.

    Halstead SB (1982) Immune enhancement of viral infection. Prog Allergy 31:301–364

    CAS  PubMed  Google Scholar 

  71. 71.

    Halstead SB, Lan NT, Myint TT, Shwe TN, Nisalak A, Kalyanarooj S, Nimmannitya S, Soegijanto S, Vaughn DW, Endy TP (2002) Dengue hemorrhagic fever in infants: research opportunities ignored. Emerg Infect Dis 8:1474–1479

    PubMed  Article  Google Scholar 

  72. 72.

    Halstead SB (2006) Dengue in the Americas and Southeast Asia: do they differ? Rev Panam Salud Publica 20:407–415

    PubMed  Article  Google Scholar 

  73. 73.

    Halstead SB (2008) Pathogenesis: risk factors prior to infection. In: Halstead SB (ed) Dengue. Imperial College Press, London, pp 219–256

  74. 74.

    Halstead SB (2009) Antibodies determine virulence in dengue. Ann N Y Acad Sci 1171(Suppl 1):E48–E56

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Halstead SB, Mahalingam S, Marovich MA, Ubol S, Mosser DM (2010) Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 10:712–722

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Halstead SB, Scanlon JE, Umpaivit P, Udomsakdi S (1969) Dengue and chikungunya virus infection in man in Thailand. IV. Epidemiological studies in the Bangkok metropolitan area. Am J Trop Med Hyg 18:997–1021

    PubMed  CAS  Google Scholar 

  77. 77.

    Halstead SBYC (1965) Recent epidemics of hemorrhagic fever in Thailand. Observations related to pathogenesis of a “new” dengue disease. J Am Pub Health Assoc 55:1386–1395

    CAS  Article  Google Scholar 

  78. 78.

    Hammond SN, Balmaseda A, Perez L, Tellez Y, Saborio SI, Mercado JC, Videa E, Rodriguez Y, Perez MA, Cuadra R, Solano S, Rocha J, Idiaquez W, Gonzalez A, Harris E (2005) Differences in Dengue severity in infants, children, and adults in a 3-year hospital-based study in Nicaragua. Am J Trop Med Hyg 73:1063–1070

    PubMed  Google Scholar 

  79. 79.

    Harris E, Videa E, Perez L, Sandoval E, Tellez Y, Perez ML, Cuadra R, Rocha J, Idiaquez W, Alonso RE, Delgado MA, Campo LA, Acevedo F, Gonzalez A, Amador JJ, Balmaseda A (2000) Clinical, epidemiologic, and virologic features of dengue in the 1998 epidemic in Nicaragua. Am J Trop Med Hyg 63:5–11

    PubMed  CAS  Google Scholar 

  80. 80.

    Hung NT, Lan NL, Lei HY, Lien LB, Huang KJ, lin CF, Ha DQ, Huong VTQ, My LT, Yeh TM, Huang JH, Liu CC, Halstead SB (2005) Association between sex, nutritional status, severity of dengue hemorrhagic fever and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg 72:370–374

    CAS  Google Scholar 

  81. 81.

    Jain A, Chaturvedi UC (2010) Dengue in infants: an overview. FEMS Immunol Med Microbiol 59:119–130

    PubMed  CAS  Google Scholar 

  82. 82.

    Jatanasen S, Skuntanaga P, Dhanasiri C (1962) Some aspects of epidemiology of Thai haemorrhagic fever 1958–1961. In: Symposium on hemorrhagic fever. SEATO medical research monograph, No 2 Bangkok, pp 6–21

  83. 83.

    Kliks S (1990) Antibody-enhanced infection of monocytes as the pathogenetic mechanism for severe dengue illness. AIDS Res Hum Retroviruses 6:993–998

    PubMed  CAS  Google Scholar 

  84. 84.

    Kliks SC, Nimmanitya S, Nisalak A, Burke DS (1988) Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 38:411–419

    PubMed  CAS  Google Scholar 

  85. 85.

    Kliks SC, Nisalak A, Brandt WE, Wahl L, Burke DS (1989) Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever. Am J Trop Med Hyg 40:444–451

    PubMed  CAS  Google Scholar 

  86. 86.

    Kochel TJ, Watts DM, Halstead SB, Hayes CG, Espinoza A, Felices V, Caceda R, Bautista CT, Montoya Y, Douglas S, Russell KL (2002) Effect of dengue-1 antibodies on American dengue-2 viral infection and dengue haemorrhagic fever. Lancet 360:310–312

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Kou Z, Quinn M, Chen H, Rodrigo WW, Rose RC, Schlesinger JJ, Jin X (2008) Monocytes, but not T or B cells, are the principal target cells for dengue virus (DV) infection among human peripheral blood mononuclear cells. J Med Virol 80:134–146

    PubMed  Article  Google Scholar 

  88. 88.

    Kouri G, Guzman MG, Bravo J (1986) Hemorrhagic dengue in Cuba: history of an epidemic. Bull Pan Am Health Organ 20:24–30

    PubMed  CAS  Google Scholar 

  89. 89.

    Kouri G, Guzman MG, Valdes L, Carbonel I, del Rosario D, Vazquez S, Laferte J, Delgado J, Cabrera MV (1998) Reemergence of dengue in Cuba: a 1997 epidemic in Santiago de Cuba. Emerg Infect Dis 4:89–92

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Kouri GP, Guzman MG, Bravo JR (1987) Why dengue haemorrhagic fever in Cuba? 2. An integral analysis. Trans R Soc Trop Med Hyg 81:821–823

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Kouri GP, Guzman MG, Bravo JR, Triana C (1989) Dengue haemorrhagic fever/dengue shock syndrome: lessons from the Cuban epidemic, 1981. Bull World Health Organ 67:375–380

    PubMed  CAS  Google Scholar 

  92. 92.

    Leitmeyer KC, Vaughn DW, Watts DM, Salas R, Villalobos I, de C, Ramos C, Rico-Hesse R (1999) Dengue virus structural differences that correlate with pathogenesis. J Virol 73:4738–4747

    PubMed  CAS  Google Scholar 

  93. 93.

    Libraty DH, Acosta LP, Tallo V, Segubre-Mercado E, Bautista A, Potts JA, Jarman RG, Yoon IK, Gibbons RV, Brion JD, Capeding RZ (2009) A prospective nested case-control study of Dengue in infants: rethinking and refining the antibody-dependent enhancement dengue hemorrhagic fever model. PLoS Med 6:e1000171

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Littaua R, Kurane I, Ennis FA (1990) Human IgG Fc receptor II mediates antibody-dependent enhancement of dengue virus infection. J Immunol 144:3183–3186

    PubMed  CAS  Google Scholar 

  95. 95.

    Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ, Sukupolvi-Petty S, Sedlak D, Fremont DH, Chipman PR, Roehrig JT, Diamond MS, Kuhn RJ, Rossmann MG (2008) Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Nat Struct Mol Biol 15:312–317

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Malavige GN, Ranatunga PK, Velathanthiri VG, Fernando S, Karunatilaka DH, Aaskov J, Seneviratne SL (2006) Patterns of disease in Sri Lankan dengue patients. Arch Dis Child 91:396–400

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Malik A, Earhart K, Mohareb E, Saad M, Saeed M, Ageep A, Soliman A (2011) Dengue hemorrhagic fever outbreak in children in Port Sudan. J Infect Public Health 4:1–6

    PubMed  Article  Google Scholar 

  98. 98.

    Mas Lago P (1979) Dengue fever in Cuba in 1977: some laboratory aspects. PAHO Scientific Publication 375:40–43

    Google Scholar 

  99. 99.

    Mathew A, Rothman AL (2008) Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol Rev 225:300–313

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Modhiran N, Kalayanarooj S, Ubol S (2010) Subversion of innate defenses by the interplay between DENV and pre-existing enhancing antibodies: TLRs signaling collapse. PLoS Negl Trop Dis 4:e924

    PubMed  CAS  Article  Google Scholar 

  101. 101.

    Moi ML, Lim CK, Kotaki A, Takasaki T, Kurane I (2011) Detection of higher levels of dengue Viremia using Fc{gamma}R-expressing BHK-21 cells than Fc{gamma}R-negative cells in secondary infection but not in primary infection. J Inf Dis 203:1405–1414

    CAS  Article  Google Scholar 

  102. 102.

    Moi ML, Lim CK, Takasaki T, Kurane I (2010) Involvement of the Fc gamma receptor IIA cytoplasmic domain in antibody-dependent enhancement of dengue virus infection. J Gen Virol 91:103–111

    PubMed  CAS  Article  Google Scholar 

  103. 103.

    Morens DM, Larsen LK, Halstead SB (1987) Study of the distribution of antibody-dependent enhancement determinants on dengue 2 isolates using dengue 2-derived monoclonal antibodies. J Med Virol 22:163–167

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Mukhopadhyay S, Kuhn RJ, Rossmann MG (2005) A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3:13–22

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Murgue B, Deparis X, Chungue E, Cassar O, Roche C (1999) Dengue: an evaluation of dengue severity in French Polynesia based on an analysis of 403 laboratory-confirmed cases. Trop Med Int Health 4:765–773

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Nagao Y, Koelle K (2008) Decreases in dengue transmission may act to increase the incidence of dengue hemorrhagic fever. Proc Natl Acad Sci USA 105(6):2238–2243

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Nguyen TH, Lei HY, Nguyen TL, Lin YS, Huang KJ, Le BL, Lin CF, Yeh TM, Do QH, Vu TQ, Chen LC, Huang JH, Lam TM, Liu CC, Halstead SB (2004) Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J Infect Dis 189:221–232

    PubMed  Article  Google Scholar 

  108. 108.

    Nogueira RM, de Araujo JM, Schatzmayr HG (2007) Dengue viruses in Brazil, 1986–2006. Rev Panam Salud Publica 22:358–363

    PubMed  Article  Google Scholar 

  109. 109.

    Ocasionez R, Cortes FM, Villar LA, Gomez SY (2006) Temporal distribution of dengue virus serotypes in Colombian endemic area and dengue incidence. Re-introduction of dengue-3 associated to mild febrile illness and primary infection. Mem Inst Oswaldo Cruz 101:725–731

    Google Scholar 

  110. 110.

    Ohainle M, Balmaseda A, Macalalad AR, Tellez Y, Zody MC, Saborio S, Nunez A, Lennon NJ, Birren BW, Gordon A, Henn MR, Harris E (2011) Dynamics of dengue disease severity determined by the interplay between viral genetics and serotype-specific immunity. Sci Transl Med 3: 114ra128

  111. 111.

    Ong A, Sandar M, Chen MI, Sin LY (2007) Fatal dengue hemorrhagic fever in adults during a dengue epidemic in Singapore. Int J Infect Dis 11:263–267

    PubMed  Article  Google Scholar 

  112. 112.

    Ooi EE, Goh KT, Chee Wang DN (2003) Effect of increasing age on the trend of dengue and dengue hemorrhagic fever in Singapore. Int J Infect Dis 7:231–232

    PubMed  Article  Google Scholar 

  113. 113.

    OPS (2006) Brote de dengue en Cuba, 2006. EEER noticias: enfermedades infecciosas emergentes y reemergentes. Región de las Américas, vol 3, p 24

  114. 114.

    PAHO (1990) Dengue hemorrhagic fever in Venezuela. Epidemiol Bull 11:7–9

    Google Scholar 

  115. 115.

    PAHO (1994) Dengue and dengue hemorrhagic fever in the Americas: guidelines for prevention and control. Scientific publication no. 548. PAHO, Washington

  116. 116.

    Pancharoen C, Mekmullica J, Thisyakorn U (2001) Primary dengue infection: what are the clinical distinctions from secondary infection? Southeast Asian J Trop Med Public Health 32:476–480

    PubMed  CAS  Google Scholar 

  117. 117.

    Pelaez O, Guzman MG, Kouri G, Perez R, San Martin JL, Vazquez S, Rosario D, Mora R, Quintana I, Bisset J, Cancio R, Masa AM, Castro O, Gonzalez D, Avila LC, Rodriguez R, Alvarez M, Pelegrino JL, Bernardo L, Prado I (2004) Dengue 3 epidemic, Havana, 2001. Emerg Infect Dis 10:719–722

    PubMed  Article  Google Scholar 

  118. 118.

    Perez AB, Garcia G, Sierra B, Alvarez M, Vazquez S, Cabrera MV, Rodriguez R, Rosario D, Martinez E, Denny T, Guzman MG (2004) IL-10 levels in Dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J Med Virol 73:230–234

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Pierson TC, Diamond MS (2008) Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection. Expert Rev Mol Med 10:e12

    PubMed  Article  Google Scholar 

  120. 120.

    Pongpanich B, Kumponpant S (1973) Studies of dengue hemorrhagic fever. V. Hemodynamic studies of clinical shock associated with dengue hemorrhagic fever. J Pediatr 83:1073–1077

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Pongpanich B, Ayuthya PI, Varavithya W, Preeyasombat C, Phanichyakarn P (1975) Management of shock associated with Dengue haemorrhagic fever based on pathophysiological findings. Southeast Asian J Trop Med Public Health 6:115–119

    PubMed  CAS  Google Scholar 

  122. 122.

    Porter KR, Beckett CG, Kosasih H, Tan RI, Alisjahbana B, Rudiman PI, Widjaja S, Listiyaningsih E, Ma’roef CN, McArdle JL, Parwati I, Sudjana P, Jusuf H, Yuwono D, Wuryadi S (2005) Epidemiology of dengue and dengue hemorrhagic fever in a cohort of adults living in Bandung, West Java, Indonesia. Am J Trop Med Hyg 72:60–66

    PubMed  Google Scholar 

  123. 123.

    Porterfield JS (1985) Antibody enhanced viral growth in macrophages. Immunol Lett 11:213–217

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Porterfield JS (1986) Antibody-dependent enhancement of viral infectivity. Adv Virus Res 31:335–355

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Pryor MJ, Carr JM, Hocking H, Davidson AD, Li P, Wright PJ (2001) Replication of dengue virus type 2 in human monocyte-derived macrophages: comparisons of isolates and recombinant viruses with substitutions at amino acid 390 in the envelope glycoprotein. Am J Trop Med Hyg 65:427–434

    PubMed  CAS  Google Scholar 

  126. 126.

    Quintos FN, lim L, Juliano L, Reyes A, Lacson P (1954) Hemorrhagic fever observed among children in the Philippines. Philippine J Pediatr 3:1–19

    Google Scholar 

  127. 127.

    Recker M, Blyuss KB, Simmons CP, Hien TT, Wills B, Farrar J, Gupta S (2009) Immunological serotype interactions and their effect on the epidemiological pattern of dengue. Proc Biol Sci 276:2541–2548

    PubMed  Article  Google Scholar 

  128. 128.

    Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C, Boshell J, de Mesa MT, Nogueira RM, da Rosa AT (1997) Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 230:244–251

    PubMed  CAS  Article  Google Scholar 

  129. 129.

    Rico-Hesse R, Harrison LM, Nisalak A, Vaughn DW, Kalayanarooj S, Green S, Rothman AL, Ennis FA (1998) Molecular evolution of dengue type 2 virus in Thailand. Am J Trop Med Hyg 58:96–101

    PubMed  CAS  Google Scholar 

  130. 130.

    Rigau-Perez JG, Vorndam AV, Clark GG (2001) The dengue and dengue hemorrhagic fever epidemic in Puerto Rico, 1994–1995. Am J Trop Med Hyg 64:67–74

    PubMed  CAS  Google Scholar 

  131. 131.

    Rodenhuis-Zybert IA, Moesker B, da Silva Voorham JM, van der Ende-Metselaar H, Diamond MS, Wilschut J, Smit JM (2011) A fusion-loop antibody enhances the infectious properties of immature flavivirus particles. J Virol 85:11800–11808

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Rodenhuis-Zybert IA, Wilschut J, Smit JM (2011) Partial maturation: an immune-evasion strategy of dengue virus? Trends Microbiol 19(5):248–254

    PubMed  CAS  Article  Google Scholar 

  133. 133.

    Rodrigo WW, Jin X, Blackley SD, Rose RC, Schlesinger JJ (2006) Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32). J Virol 80:10128–10138

    PubMed  CAS  Article  Google Scholar 

  134. 134.

    Rodrigo WW, Alcena DC, Kou Z, Kochel TJ, Porter KR, Comach G, Rose RC, Jin X, Schlesinger JJ (2009) Difference between the abilities of human Fcgamma receptor-expressing CV-1 cells to neutralize American and Asian genotypes of dengue virus 2. Clin Vaccine Immunol 16:285–287

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Rodrigo WW, Block OK, Lane C, Sukupolvi-Petty S, Goncalvez AP, Johnson S, Diamond MS, Lai CJ, Rose RC, Jin X, Schlesinger JJ (2009) Dengue virus neutralization is modulated by IgG antibody subclass and Fc gamma receptor subtype. Virology 394:175–182

    PubMed  CAS  Article  Google Scholar 

  136. 136.

    Rodriguez-Barraquer I, Cordeiro MT, Braga C, de Souza WV, Marques ET, Cummings DA (2011) From re-emergence to hyperendemicity: the natural history of the dengue epidemic in Brazil. PLoS Negl Trop Dis 5:e935

    PubMed  Article  Google Scholar 

  137. 137.

    Rodriguez-Roche R, Alvarez M, Gritsun T, Halstead S, Kouri G, Gould EA, Guzman MG (2005) Virus evolution during a severe dengue epidemic in Cuba, 1997. Virology 334:154–159

    PubMed  CAS  Article  Google Scholar 

  138. 138.

    Rodriguez-Roche R, Alvarez M, Gritsun T, Rosario D, Halstead S, Kouri G, Gould EA, Guzman MG (2005) Dengue virus type 2 in Cuba, 1997: conservation of E gene sequence in isolates obtained at different times during the epidemic. Arch Virol 150:415–425

    PubMed  CAS  Article  Google Scholar 

  139. 139.

    Rodriguez-Roche R, Sanchez L, Burgher Y, Rosario D, Alvarez M, Kouri G, Halstead SB, Gould EA, Guzman MG (2011) Virus role during intraepidemic increase in dengue disease severity. Vector Borne Zoonotic Dis 11:675–681

    PubMed  Article  Google Scholar 

  140. 140.

    Rothman AL (2011) Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11:532–543

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Russell PK, Yuill TM, Nisalak A, Udomsakdi S, Gould DJ, Winter PE (1968) An insular outbreak of dengue hemorrhagic fever. II. Virologic and serologic studies. Am J Trop Med Hyg 17:600–608

    PubMed  CAS  Google Scholar 

  142. 142.

    Sabin AB (1952) Research on dengue during World War II. Am J Trop Med Hyg 1:30–50

    PubMed  CAS  Google Scholar 

  143. 143.

    San Martin JL, Brathwaite O, Zambrano B, Solorzano JO, Bouckenooghe A, Dayan GH, Guzman MG (2010) The epidemiology of dengue in the americas over the last three decades: a worrisome reality. Am J Trop Med Hyg 82:128–135

    PubMed  Article  Google Scholar 

  144. 144.

    Sangkawibha N, Rojanasuphot S, Ahandrik S, Viriyapongse S, Jatanasen S, Salitul V, Phanthumachinda B, Halstead SB (1984) Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol 120:653–669

    PubMed  CAS  Google Scholar 

  145. 145.

    Shresta S, Sharar KL, Prigozhin DM, Snider HM, Beatty PR, Harris E (2005) Critical roles for both STAT1-dependent and STAT1-independent pathways in the control of primary dengue virus infection in mice. J Immunol 175:3946–3954

    PubMed  CAS  Google Scholar 

  146. 146.

    Simmons CP, Chau TN, Thuy TT, Tuan NM, Hoang DM, Thien NT, le Lien B, Quy NT, Hieu NT, Hien TT, McElnea C, Young P, Whitehead S, Hung NT, Farrar J (2007) Maternal antibody and viral factors in the pathogenesis of dengue virus in infants. J Infect Dis 196:416–424

    PubMed  Article  Google Scholar 

  147. 147.

    Siqueira JB Jr, Martelli CM, Coelho GE, Simplicio AC, Hatch DL (2005) Dengue and dengue hemorrhagic fever, Brazil, 1981–2002. Emerg Infect Dis 11:48–53

    PubMed  Article  Google Scholar 

  148. 148.

    Smith SA, Zhou Y, Olivarez NP, Broadwater AH, de Silva AM, Crowe JE (2012) Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J Virol 86:2665–2675

    PubMed  CAS  Article  Google Scholar 

  149. 149.

    Tantracheewathorn T, Tantracheewathorn S (2007) Risk factors of dengue shock syndrome in children. J Med Assoc Thai 90:272–277

    PubMed  Google Scholar 

  150. 150.

    Teixeira MG, Costa MC, Coelho G, Barreto ML (2008) Recent shift in age pattern of dengue hemorrhagic fever. Brazil. Emerg Infect Dis 14:1663

    Article  Google Scholar 

  151. 151.

    Teixeira MG, Costa Mda C, Barreto F, Barreto ML (2009) Dengue: twenty-five years since reemergence in Brazil. Cad Saude Publica 25(Suppl 1):S7–18

    PubMed  Google Scholar 

  152. 152.

    Thai KT, Nishiura H, Hoang PL, Tran NT, Phan GT, Le HQ, Tran BQ, Nguyen NV, de Vries PJ (2011) Age-specificity of clinical dengue during primary and secondary infections. PLoS Negl Trop Dis 5:e1180

    PubMed  Article  Google Scholar 

  153. 153.

    Thammapalo S, Nagao Y, Sakamoto W, Saengtharatip S, Tsujitani M, Nakamura Y, Coleman PG, Davies C (2008) Relationship between transmission intensity and incidence of dengue hemorrhagic fever in Thailand. PLoS Negl Trop Dis 2:e263

    PubMed  Article  Google Scholar 

  154. 154.

    Thomas L, Verlaeten O, Cabie A, Kaidomar S, Moravie V, Martial J, Najioullah F, Plumelle Y, Fonteau C, Dussart P, Cesaire R (2008) Influence of the dengue serotype, previous dengue infection, and plasma viral load on clinical presentation and outcome during a dengue-2 and dengue-4 co-epidemic. Am J Trop Med Hyg 78:990–998

    PubMed  Google Scholar 

  155. 155.

    Thongcharoen PJS (1993) Epidemiology of dengue and dengue hemorrhagic fever. Chapter in Monograph on dengue/dengue hemorrhagic fever. Regional Publication SEARO 22:1–8

    Google Scholar 

  156. 156.

    Ubol S, Halstead SB (2010) How innate immune mechanisms contribute to antibody-enhanced viral infections. Clin Vaccine Immunol 17:1829–1835

    PubMed  CAS  Article  Google Scholar 

  157. 157.

    Ubol S, Phuklia W, Kalayanarooj S, Modhiran N (2010) Mechanisms of immune evasion induced by a complex of dengue virus and preexisting enhancing antibodies. J Infect Dis 201:923–935

    PubMed  CAS  Article  Google Scholar 

  158. 158.

    Valdes L, Guzman MG, Kouri G, Delgado J, Carbonell I, Cabrera MV, Rosario D, Vazquez S (1999) La epidemiologia del dengue y del dengue hemorragico en Santiago de Cuba, 1997. (Epidemiology of dengue and hemorrhagic dengue in Santiago, Cuba 1997). Rev Panam Salud Publica 6:16–25

    PubMed  CAS  Article  Google Scholar 

  159. 159.

    Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA, Nisalak A (2000) Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181:2–9

    PubMed  CAS  Article  Google Scholar 

  160. 160.

    Voorham JMS, Rodenhuis-Zybert IA, Ayala NV, Colpitts TM, Ende-Metselaar H, van der Fikrig E, Diamond MS, Wilschut J, Smit JM (2012) Antibodies against the envelope glycoprotein promote infectivity of immature dengue virus serotype 2. PLOS one 7:1–10

    Google Scholar 

  161. 161.

    Wang WK, Chen HL, Yang CF, Hsieh SC, Juan CC, Chang SM, Yu CC, Lin LH, Huang JH, King CC (2006) Slower rates of clearance of viral load and virus-containing immune complexes in patients with dengue hemorrhagic fever. Clin Infect Dis 43:1023–1030

    PubMed  CAS  Article  Google Scholar 

  162. 162.

    Wearing HJ, Rohani P (2006) Ecological and immunological determinants of dengue epidemics. Proc Natl Acad Sci USA 103:11802–11807

    PubMed  CAS  Article  Google Scholar 

  163. 163.

    WHO (1965) Report of the WHO seminar on mosquito-borne haemorrhagic fevers in the Southeast Asia and Western Pacific region, Bangkok, 19–26 October 1964, New Delhi

  164. 164.

    WHO (1975) Technical guides for diagnosis, treatment, surveillance, prevention and control of dengue haemorrhagic fever. World Health Organization, Geneva, p 1975

    Google Scholar 

  165. 165.

    WHO (1986) Dengue haemorrhagic fever: diagnosis, treatment and control. World Health Organization, Geneva, p 58

  166. 166.

    WHO (1997) Dengue haemorrhagic fever: diagnosis, treatment, prevention and control, 2nd edn. WHO, Geneva

    Google Scholar 

  167. 167.

    WHO/TDR (2009) Dengue guidelines for diagnosis, treatment, prevention and control. New Edition. WHO Press, Geneva

  168. 168.

    Wikramaratna PS, Simmons CP, Gupta S, Recker M (2010) The effects of tertiary and quaternary infections on the epidemiology of dengue. PLoS ONE 5:e12347

    PubMed  Article  CAS  Google Scholar 

  169. 169.

    Wilder-Smith A, Yoksan S, Earnest A, Subramaniam R, Paton NI (2005) Serological evidence for the co-circulation of multiple dengue virus serotypes in Singapore. Epidemiol Infect 133:667–671

    PubMed  Article  Google Scholar 

  170. 170.

    Yeh WT, Chen RF, Wang L, Liu JW, Shaio MF, Yang KD (2006) Implications of previous subclinical dengue infection but not virus load in dengue hemorrhagic fever. FEMS Immunol Med Microbiol 48:84–90

    PubMed  CAS  Article  Google Scholar 

  171. 171.

    Zompi S, Montoya M, Pohl MO, Balmaseda A, Harris E (2012) Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. PLoS Negl Trop Dis 6:1–14

    Article  CAS  Google Scholar 

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We thank Dr. Daniel Limonta from the Pedro Kourí Institute, Havana, Cuba, for his useful comments and suggestions.

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Correspondence to Maria G. Guzman.

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Guzman, M.G., Alvarez, M. & Halstead, S.B. Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol 158, 1445–1459 (2013).

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  • Dengue Virus
  • Secondary Infection
  • Dengue Fever
  • Dengue Infection
  • DENV Infection