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The History of Dengue Research before 1950 A Forgotten History ?

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Presentation on theme: "The History of Dengue Research before 1950 A Forgotten History ?"— Presentation transcript:

1 The History of Dengue Research before 1950 A Forgotten History ?

2 Early Dengue Investigation in the Shadow of Yellow Fever Research

3 Reminder “Dengue”=dengue or dengue- like illness Period covered: 1890-1950

4 Important Events: 1897-98 1. “Filterable agent” [=virus] 2. Vector-borne transmission 3. Extrinsic incubation period 4. Controversy on etiology of YF 5. Dengue outbreaks in Texas 6. Spanish-American War

5 George Miller Sternberg (Source: U.S. Army Archive)


7 Walter Reed (Source: U.S. Army Archive)

8 Farewell Clara…. Clara was buried in Havana, Cuba and later reburied in New Jersey at Fairmount Cemetery.

9 Charles Franklin Craig (Source: Am. J. Trop. Med., 1951)

10 Vector-Borne Transmission of Human Diseases: Historical Events before Dengue Research

11 Patrick Manson (Source: U.S. Army Archives)

12 Ronald Ross (Source: U.S. Army Archive)

13 Carlos Juan Finlay (Source: Univ. Virginia Claude Moore Health Science Library)

14 Photo Henry Rose Carter (Source: Am. J. Publ. Hlth. 15:994; 1926)

15 Etiologic Investigation: Transmission Mechanism

16 Experimental Design for Dengue Transmission Studies 1.Source of “infectious agent” 2. Location for human experiment

17 Special Considerations for Human Experiment 1.Informed Consent 2.Monetary Reward

18 Dengue Transmission Mechanism: Early Researchers

19 Harris Graham (Source: American University of Beirut, Lebanon)

20 Dengue Studies in Cuba by the Former Members of the Walter Reed Commission : Left—Aristides Agramonte; Right– Juan Guiteras (Source of photos: Wikipedia Commons)

21 T.L. Bancroft (Source: Courtesy of Australian Nat. Univ.)

22 Percy M. Ashburn (Source: U.S. Army Archive)

23 Makoto Koizumi (Source: The 50-year history (1929-79) of parasitologic research in Japan. Japanese Society of Parasitologists, 1981)

24 J. Burton Cleland (Source: Courtesy: Australian National University)

25 Joseph Franklin Siler (Source: U.S. Army Archive)

26 James S. Simmons (Source: U.S. Army Archive)

27 Emilius Paulus Snijders (Source: Academic Medical Centre, University of Amsterdam, The Netherlands)

28 Dutch group portrait by Lizzy Ansingh (1933): From left to right- van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)

29 Etiologic Investigation: Virus Isolation

30 Susumu Hotta (Source: Kobe University School of Medicine, Kobe, Japan)

31 Mrs. Mochizuki (Source: S. Hotta-- Uirusu, 51:106; 2001)

32 Albert B. Sabin (Courtesy: U.S. Army )

33 Sabin visiting Hotta at Kobe University, 1961 (Source: Kobe University, Kobe, Japan)

34 Cornelius Becker Philip (Source: J. Parasitol. 73:678)

35 Laboratory-identified Dengue Viruses Year Location Serotype 1943 Nagasaki, Japan DENV-1 1943-44 Hawaii DENV-1 1944 New Guinea DENV-1 and DENV-2

36 Serologically-identified Viruses 1924-25 Philippines DENV-4 1925-26 QLD, Australia DENV-1 1927 South Africa DENV-1 1929-30 Philippines DENV-1 1942 QLD, Australia DENV-2/DENV-1 1943 Singapore DENV-1 1944-45 Guam DENV-2(DENV-1?) 1945 Calcutta, India DENV-1 1942-44 Japan DENV-1(DENV-2?)

37 Clinical Definition of “Dengue”- a Source of Constant Controversy 1.Variation depending on physicians, year, location, and unknown human conditions 2. “Typical” vs “atypical” symptoms 3. Syndrome in human experiment as ‘standard” 4. Confusion with other etiologies

38 Atypical Clinical Symptoms or Syndromes: Extensive Hemorrhage and/or Shock with Fatal Outcome

39 F. E. Hare ( Source: J. Aaskov, Austr. Defense Force Health 4:66;2003 )

40 Hemorrhagic Manifestations and Fatality Diagnosis: Rumpell-Leede test (=Tourniquet test) Borbely’s vascular resistance test Study: Correlations among increased vascular permeability, thrombocytopenia, and hemorrhage

41 (Source:

42 Selected Records of Fatal Cases 1895-1926 Australia 816 1897 QLD, Australia 97 1904-05 Australia 201 1926 Australia 93 1907-09 Vietnam 4 1931 Okinawa, Japan 508 1932 Taiwan 26 1943-44 Philippines 7 1944 Taiwan 5

43 Fatal Non-Fatal [A] 1897 - 1902 [B] 1926 - 1931 [C] 1940 - 1944

44 Other “Unusual” Syndromes 1. CNS syndrome 2. Pulmonary syndrome

45 3. Ophthalmologic Dysfunctions ( Source:Yuguchi, Kai-Gun-Ikai-Shi 32:627;1943)

46 Medical Care 1.Antipyretics 2.Salicylates (Aspirin- contraindicant) 3.Immunotherapy 4.Blood transfusion

47 Pandemic Pattern of Dengue Spread and Human Movement

48 The Importance of Human Movement by Ships and the Critical Roles played by the Physicians on board for unraveling Dengue Transmission




52 Investigating the Patterns of Dengue Spread in Urban Areas

53 Mapping New Cases in Chronologic Order (Source: Miyao,T. Kaigun-Gun-Ikai-Zasshi 20:564;1931)

54 Recognition of dengue as an urban disease (Source: Barraud, P.J. Indian J. Med. Res. 16:377; 1928)

55 Investigating the Mechanism of Transmission in Living Quarter

56 Transmission in a Military Barrack (Source: Kennedy, R.S. Indian Med. Gaz. 46:436; 1912)

57 Dengue Attack Difference—Indoor vs Outdoor ( Source: Clayton,F.H.A. J. Roy. Army Med. Corps 14:171;1910 )

58 Epidemiologic Reporting Dengue as a reportable disease 1.Western Australia—1912 2.International Sanitary Convention--1934

59 Cyclic Pattern of Epidemic in Dengue Endemic Area (Seasonality)

60 Seasonality in Endemic Area ( Source: Simmons, J.S., et al. Philippine J. Sci. 44:1;1931 )

61 Multiple Dengue Infection 1. Occurrence 2. Interpretation a. Dengue-multiple etiologies b. Opposition to vaccine development 3. Emergence of the concept of “multiple immunotype” 4. Existence of 4 serotypes

62 Antibody Responses to Dengue Infection: Primary vs Secondary Infection

63 Antibody response profiles—primary (lower curve) vs re-infection (upper curve) ( Source: Hotta, S & Kimura, R. Nisshin Igaku 36:470;1949)

64 Development of Serologic Tests A. Complement Fixation Test (CF) Earlier application for YF since 1929 Application to dengue by Sabin- 1948 B. Neutralization (in vivo) Test (NT) Development for YF since 1929 Sawyer and Lloyd—1931 Application to dengue in the 1940s

65 Animal Model Vertebrates other than primates Unique breed of Swiss (albino) mouse “dba” =dilute brown non-agouti Subhuman primates Macaca fasciatus Macaca philippinensis

66 Vector Identification and Biology Vectors: Aedes aegypti -- T. Bancroft Ae. albopictus– M. Koizumi Ae. scutellaris – R.H. Daggy Breeding technique: Ae. aegypti – J. Siler

67 Geographic Distribution of Vectors Aedes aegypti and Ae. albopictus H. Kumm – 1931 Clara Ludlow

68 Clara S. Ludlow (Source: George Washington University Photographic Collection)

69 Venereal and Vertical Transmission in Mosquitoes Venereal Transmission Simmons, et al. (1931) Vertical Transmission Impacts of earlier YF studies by Simond and Marchoux For dengue Legendre (1911) and Siler, et al. (1925)

70 Jean-Paul Simond (Courtesy: Thomas P. Monath)

71 Emile Marchoux (Courtesy: Thomas P. Monath)

72 Vector Competence

73 Vector Control: Biological Control: 1.Predatory mosquitoes (Toxorhynchites spp.) 2. Fishes

74 Toxorhynchites Larva (Source: New South Wales Arbovirus Surveillance and Vector Monitoring Programme, Australia)

75 Kill fish (Oryzias latipes) (Source:

76 Vector Control Applications of Insecticides Including Indoor Residual Spray of DDT

77 Vector Control Source reduction Community participation Public education and organized campaign

78 Dengue Prevention other than Vector Control Unusual people’s reaction to fear International Convention League of Nations Legislation of Law

79 Vaccine Development- attenuation or inactivation methods Cleland (1917-19) – human passage Blanc & Caminopetros (1931)– bovine bile St. John & Holt (1931) – killed vaccine Holt, et al. (1931) – X-ray irradiation Simmons, et al. (1929-31) – mosquito passage + antiserum + desiccation Hotta & Kimura (1943-49) – formalin Sabin & Schlesinger (1944-49) –attenuation in suckling mice

80 Economic Cost

81 Economic Cost Estimate [reproduced with minor modifications] ( Source: Hamlyn-Smith, R. Ann. Trop. Med. Parasitol. 25:21;1931 ) Occupation Loss in wage (pound/ % Sick Workers Category shilling/d) 1 438/4/8 65.6 2 569/2/7 23.8 3 213/17/4 17.0 4 200/0/0 20.0 5 220/0/0 20.0 6 303/0/0 26.0 7 500/0/0 35.0 8 130/0/0 24.0 9 1451/0/0 15.3

82 Completing the full Circle of YF and Dengue Research History Interaction: Grave Sites of Walter Reed and Albert Sabin (Arlington National Cemetery, Virginia) (Source: U.S. National Archives)

83 Acknowledgments Yuki Eshita- Oita University School of Medicine, Oita, Japan David Hill – U.S. Army, Silver Spring, Maryland, USA Eva Lee – Australian National University, Canberra, ACT, Australia Jennifer Lehman – CDC, Fort Collins, Colorado, USA Mathieu Mazarin – CDC, Fort Collins, Colorado, USA Thomas P. Monath – Kleisner Perkins Caufield & Byers, Menlo Park, California, USA J.F. Wendte – Medical Centre, University of Amsterdam, the Netherlands

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