the history of dengue research before 1950 a forgotten history ?
TRANSCRIPT
The History of Dengue Research before 1950
A Forgotten History ?
Early Dengue Investigationin the Shadow of Yellow Fever
Research
Reminder
“Dengue”=dengue or dengue-like illness
Period covered: 1890-1950
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
George Miller Sternberg(Source: U.S. Army Archive)
Walter Reed
(Source: U.S. Army Archive)
Farewell Clara….Clara was buried in Havana, Cuba and later reburied in
New Jersey at Fairmount Cemetery
.
Charles Franklin Craig (Source: Am. J. Trop. Med., 1951)
Vector-Borne Transmission of
Human Diseases:Historical Events before
Dengue Research
Patrick Manson(Source: U.S. Army Archives)
Ronald Ross(Source: U.S. Army Archive)
Carlos Juan Finlay(Source: Univ. Virginia Claude Moore Health Science
Library)
Photo
Henry Rose Carter(Source: Am. J. Publ. Hlth. 15:994; 1926)
Etiologic Investigation:Transmission Mechanism
Experimental Design for Dengue Transmission
Studies
1. Source of
“infectious agent”
2. Location for human
experiment
Special Considerations for Human Experiment
1. Informed Consent
2. Monetary Reward
Dengue Transmission Mechanism:
Early Researchers
Harris Graham(Source: American University of Beirut, Lebanon)
Dengue Studies in Cubaby the Former Members of the Walter Reed Commission: Left—Aristides Agramonte; Right– Juan
Guiteras (Source of photos: Wikipedia Commons)
T.L. Bancroft(Source: Courtesy of Australian Nat. Univ.)
Percy M. Ashburn(Source: U.S. Army Archive)
Makoto Koizumi(Source: The 50-year history (1929-79) of parasitologic research in
Japan. Japanese Society of Parasitologists, 1981)
J. Burton Cleland(Source: Courtesy: Australian National University)
Joseph Franklin Siler(Source: U.S. Army Archive)
James S. Simmons (Source: U.S. Army Archive)
Emilius Paulus Snijders(Source: Academic Medical Centre, University of
Amsterdam, The Netherlands)
Dutch group portrait by Lizzy Ansingh (1933): From left to right-van Loghem, Kuenen, Schueffner, Swellengrebel, Snijders (Source: Univ. Museum Amsterdam)
Etiologic Investigation:
Virus Isolation
Susumu Hotta (Source: Kobe University School of Medicine,
Kobe, Japan)
Mrs. Mochizuki (Source: S. Hotta-- Uirusu, 51:106; 2001)
Albert B. Sabin
(Courtesy: U.S. Army )
Sabin visiting Hotta at Kobe University, 1961 (Source: Kobe University, Kobe, Japan)
Cornelius Becker Philip
(Source: J. Parasitol. 73:678)
Laboratory-identified DengueViruses
Year Location Serotype
1943 Nagasaki, Japan DENV-1
1943-44 Hawaii DENV-1
1944 New Guinea DENV-1 and
DENV-2
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?)
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
Atypical Clinical Symptoms or Syndromes:
Extensive Hemorrhage and/or Shock with Fatal
Outcome
F. E. Hare
(Source: J. Aaskov, Austr. Defense Force Health 4:66;2003)
Hemorrhagic Manifestations and Fatality
Diagnosis:
Rumpell-Leede test (=Tourniquet test)
Borbely’s vascular resistance test
Study:
Correlations among increased vascular permeability, thrombocytopenia, and hemorrhage
(Source: www.historyplace.com)
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
FatalNon-Fatal[A] 1897 - 1902
[B] 1926 - 1931
[C] 1940 - 1944
Other “Unusual” Syndromes
1. CNS syndrome2. Pulmonary syndrome
3. Ophthalmologic Dysfunctions(Source:Yuguchi, Kai-Gun-Ikai-Shi 32:627;1943)
Medical Care
1. Antipyretics
2. Salicylates (Aspirin-contraindicant)
3. Immunotherapy
4. Blood transfusion
Pandemic Pattern of Dengue Spread and Human
Movement
The Importance of Human Movement by Ships
andthe Critical Roles played by the Physicians on board for
unraveling Dengue Transmission
Investigating the Patterns of Dengue
Spread in Urban Areas
Mapping New Cases in Chronologic Order (Source: Miyao,T. Kaigun-Gun-Ikai-Zasshi 20:564;1931)
Recognition of dengue as an urban disease (Source: Barraud, P.J. Indian J. Med. Res. 16:377; 1928)
Investigating the Mechanism of
Transmission in Living Quarter
Transmission in a Military Barrack (Source: Kennedy, R.S. Indian Med. Gaz. 46:436; 1912)
Dengue Attack Difference—Indoor vs Outdoor(Source: Clayton,F.H.A. J. Roy. Army Med. Corps 14:171;1910)
Epidemiologic Reporting
Dengue as a reportable disease
1. Western Australia—1912
2. International Sanitary
Convention--1934
Cyclic Pattern of Epidemic in Dengue
Endemic Area (Seasonality)
Seasonality in Endemic Area (Source: Simmons, J.S., et al. Philippine J. Sci. 44:1;1931)
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
Antibody Responses to Dengue Infection:Primary vs Secondary
Infection
Antibody response profiles—primary (lower curve) vs re-infection (upper curve)
(Source: Hotta, S & Kimura, R. Nisshin Igaku 36:470;1949)
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
Animal Model
Vertebrates other than primates
Unique breed of Swiss (albino) mouse
“dba” =dilute brown non-agouti
Subhuman primates
Macaca fasciatus
Macaca philippinensis
Vector Identification and Biology
Vectors:
Aedes aegypti -- T. Bancroft
Ae. albopictus– M. Koizumi
Ae. scutellaris – R.H. Daggy
Breeding technique:
Ae. aegypti – J. Siler
Geographic Distribution of Vectors
Aedes aegypti and Ae. albopictus
H. Kumm – 1931
Clara Ludlow
Clara S. Ludlow (Source: George Washington University Photographic Collection)
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)
Jean-Paul Simond
(Courtesy: Thomas P. Monath)
Emile Marchoux (Courtesy: Thomas P. Monath)
Vector Competence
Vector Control:Biological Control:
1. Predatory mosquitoes
(Toxorhynchites spp.)
2. Fishes
Toxorhynchites Larva(Source: New South Wales Arbovirus Surveillance and
Vector Monitoring Programme, Australia)
Kill fish (Oryzias latipes) (Source: http://biol1.bio.nagoya-
u.ac.jp:8000/9808/8.html)
Vector Control
Applications of Insecticides
Including Indoor Residual Spray of DDT
Vector Control
• Source reduction
• Community participation
• Public education and organized campaign
Dengue Prevention other than Vector Control
Unusual people’s reaction to fear
International Convention
League of Nations
Legislation of Law
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
Economic Cost
Economic Cost Estimate [reproduced with minor modifications]
(Source: Hamlyn-Smith, R. Ann. Trop. Med. Parasitol.
25:21;1931)
Occupation Loss in wage (pound/ % Sick WorkersCategory 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
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)
AcknowledgmentsYuki Eshita- Oita University School of Medicine, Oita,
JapanDavid Hill – U.S. Army, Silver Spring, Maryland, USAEva Lee – Australian National University, Canberra,
ACT, AustraliaJennifer Lehman – CDC, Fort Collins, Colorado, USAMathieu Mazarin – CDC, Fort Collins, Colorado, USAThomas P. Monath – Kleisner Perkins Caufield & Byers,
Menlo Park, California, USAJ.F. Wendte – Medical Centre, University of
Amsterdam, the Netherlands