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