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HISTORY OF THE OFFICE OF MEDICAL HISTORY
Richard B. Capps, M.D.
Dengue is an acute febrile illness caused by a filterable virus transmitted by mosquitoes. It was first described by David Bylon in 1779 under the name of joint fever.1 Since then, the disease has come to be recognized as common in many parts of the world, and a number of extensive epidemics have been described.2 Bancroft,3 in 1906, was the first to suggest that transmission might be due to Aedes aegypti. This was conclusively established by Cleland, Bradley, and McDonald in 1916 and 1919,4 Siler, Hall, and Hitchens5 in 1926, and Simmons, St. John, and Reynolds in 1931.6 Subsequently, it was demonstrated that Aedes albopictus, Aedes scutellaris, and Aedes hebrideus7 can also serve as insect vectors. That the etiological agent was a filterable virus was first proved by Ashburn and Craig in 1907.8 In 1929, Blanc, Caminopétros, Dumas, and Saenz9 found that certain species of monkeys could be infected with the virus and could thus serve as a natural reservoir. This was confirmed by Simmons, St. John, and Reynolds in 1931.
Although dengue is a nonfatal disease, it may assume considerable military importance because of its tendency to occur in massive outbreaks resulting in incapacity of large numbers of men. This type of epidemic is favored by the introduction of nonimmunes into an endemic area as so often occurred
1Pepper, O. H. Perry: A Note on David Bylon and Dengue. Ann. M.
363-368, September 1941.
during World War II. Since prophylactic measures were limited to mosquito control and since this was difficult to accomplish during combat, the disease was a definite military hazard throughout World War II in practically all areas of the Pacific and Asiatic theaters.
The incidence of dengue in the U.S. Army during World War II, by theaters of operations, is shown in table 3. It is evident that the disease was largely restricted to the Pacific and Asiatic theaters, although scattered cases were reported from each of the other theaters. The lack of a specific diagnostic test raises a question as to the validity of the diagnosis, especially where sporadic cases were reported. On the other hand, many cases were undoubtedly not recognized and were reported under the diagnosis of "fever of undetermined origin." It seems probable that the actual cases exceeded those reported. Finally, it should be noted that the incidence remained low throughout 1945. This was presumably due to improved mosquito control measures, although in certain areas an increased percentage of immunes may have also been a factor.
[Rate expressed as number of cases per annum per 1,000 average strength]
1Troops present in the area; no cases reported.
In March, April, and May of 1942, an extension epidemic of dengue occurred among U.S. Army troops stationed in Northern Territory and Queens-
FIGURE 2.-Capt. Thomas G. Graham, MC, Medical Inspector, Motor Transport Command No. 1, and Lt. Col. George H. Rohrbacher, MC, Surgeon, Motor Transport Command No. 1, in right foreground, inspect water for mosquito breeding patches, Breakaway Creek, Mt. Isa, Queensland, Australia, October 1942.
land (fig. 2). Approximately 80 percent of all U.S. personnel in this area were attacked within a period of about 3 months.10 Epidemics were reported during January, February, and March of 1943 at Rockhampton and in the Brisbane area. Four hundred and sixty-three cases occurred among U.S. military personnel in the former outbreak.11 A survey of Rockhampton during this period showed that 80 percent of more than 6,000 dwellings examined were breeding dengue-carrying mosquitoes. U.S. Army personnel required for mosquito control varied from 15 to 55 men; oil was supplied by the Rockhampton City Council (fig. 3).12 The vector in Australia was A. aegypti.13
10Letter, Chief Surgeon, U.S. Army, Services of Supply, Southwest Pacific
Area, to The Surgeon General, 15 Dec. 1942, subject: Medical Service in
Australia, Section I: Sanitation and Vital Statistics.
New Hebrides and New Caledonia
An extensive epidemic of dengue occurred at Espíritu Santo between February and August 1943. Over 5,000 cases were reported in military personnel, representing approximately 25 percent of the base strength (table 4).14 For several months prior to the onset of the epidemic, there had been widespread dumping of tin cans over the base without regard to sanitary regulations. This had resulted in heavy breeding of A. aegypti and Aedes scutellaris hebrideus. In June, with the epidemic still continuing, a complete mosquito survey of all camp areas and all territory within 500 yards of camp was instituted. All possible water containers, including tin can dumps, stored tires, oil drums, machinery, and tarpaulins were spotted on maps. A cleanup campaign was started employing approximately 300 men, 40 trucks, and other heavy equipment, and by August the epidemic was under control. It is noteworthy that very few cases occurred at this base during the succeeding rainy season in 1944.
14(1) Malaria News Letter No. 3, Headquarters, Malaria and Epidemic Control, South Pacific Area, September 1943. (2) Stevens, Frank W.: Medicine-South Pacific Area. [official record.]
[Rate expressed as number of cases per annum per 1,000 average strength]
A less severe epidemic occurred at New Caledonia in 1943, as shown in table 4. The wide distribution of breeding places for A. aegypti and the lack of preventive measures by the resident population contributed to the persistence of the outbreak. The incidence of infection in military personnel would undoubtedly have been much higher if it had not been for intensive mosquito control measures carried out by the base malaria control unit. An epidemic was avoided, although cases developed during the 1944 rainy season.
In 1943, dengue appeared in Honolulu, T.H., in epidemic form for the first time in over 30 years. The evidence suggested that the disease was imported from Suva, Fiji Islands, where an epidemic was in progress. Two commercial airline pilots were hospitalized with dengue in Honolulu early in July 1943, shortly after arrival from Suva. One of the pilots was ill upon arrival whereas the other did not develop symptoms for several days and was not isolated by hospitalization until he had passed through the infectious period.15 Three weeks later, two civilian cases appeared in the Waikiki Beach area of Honolulu, and, 12 days later, two cases occurred in Army personnel in the same section.16 Measures were taken immediately to prevent an explosive outbreak, consisting chiefly of an extensive program of mosquito control. Also, proper screening of patients in hospitals and in homes was made mandatory, and large areas of the City of Honolulu were placed off limits to troops. Although 1,355 civilian cases were reported through 31 December 1943, only 56 cases occurred in military personnel.
15Gilbertson, W. E.: Sanitary Aspects of the Control of
the 1943-1944 Epidemic of Dengue Fever in Honolulu. Am. J. Pub. Health 35: 261-270,
In order to render effective measures for control of mosquitoes in military areas, it was necessary to have adequate control in the surrounding civilian areas. Toward this end, the Army gave all possible assistance to civilian agencies. A medical officer was attached to the territorial board of health to make an epidemiological study of all new cases. Fifty enlisted men were assigned to spray the buildings and to eliminate breeding places of mosquitoes in homes where there were cases of dengue. Trucks, ladders, and spraying equipment were made available for use by civilian agencies. In September 1943, it became necessary to extend the program for mosquito control to include the entire City of Honolulu. The program was supervised by the U.S. Public Health Service, and labor was provided by a medical service company. Honolulu was divided into 3 districts and subdivided into 77 inspection zones, each of such size that one man could thoroughly cover his zone every 10 days.
Aedes mosquitoes were found breeding in all varieties of containers that could hold water, such as tin cans, bottles, barrels, jars, flower vases and cups, tanks, tubs, tires, storm drains, catch basins, unstocked fishponds, abandoned cesspools, and cisterns. Breeding places were also encountered in waterholding plants, such as spider lilies, pineapple lilies, and ape plants and in rotted-out holes and crotches in poinciana, algarroba, haole koa and guava trees, bamboo and banana stumps, and the larger water-holding pockets in traveler's palms. Other unusual breeding places were in fallen palm fronds and the holes of lava-formed rocks and pockets in emerged formations of coral reef. It is striking that in over one million inspections, on only four occasions were ground pools found to be breeding places for Aedes mosquitoes. Since both A. aegypti and A. albopictus have short flight ranges (up to 200 yards), it was only necessary to extend control operations to the fringes of the inhabited areas.
The effectiveness of these measures is shown in table 5. It will be noted that the breeding indices of Aedes mosquitoes were satisfactorily reduced. It
1Percentage of premises inspected in which Aedes larvae were found.
is interesting that the critical index or threshold of importance for dengue was 3.0 or less, which is considerably lower than the value of 5.0 which is generally accepted as the critical point for yellow fever.17
New Guinea and the Philippine Islands
From the onset of operations in New Guinea and adjacent islands, dengue was an important cause of noneffectiveness of troops.18 Table 6 shows the case rates for the years 1944 and 1945; separate rates for this area are not available for the year 1943. It will be noted that the incidence was highest during January and February, which are the months of heavy rainfall. During the first 6 months of 1944, the case rates for dengue exceeded those for
[Rate expressed as number of cases per annum per 1,000 average strength]
17Soper, F. L., and Wilson,
D. B.: Species Eradication; A Practical Goal of Species Reduction in the
Control of Mosquito-borne Disease. J. Nat. Malaria Soc. 1 (No. 1): 5-25, 1945.
malaria. It will be noted that in 1945 the rates remained low, even during the rainy season. This presumably was due to improved mosquito control and to an increased percentage of immunes among military personnel. As occurred elsewhere, striking outbreaks appeared in certain units, notably in the Hollandia and Biak areas. In the Biak area, the ratio of dengue to malaria was 4:1.19
In New Guinea, the vector appeared to be A. scutellaris.20 A. aegypti are rare in this area. This increased the problem of mosquito control because of the greater variety of breeding places employed by A. scutellaris (fig. 4). In addition, the day-biting habits of this species made individual protective measures necessary at all hours, especially in shaded jungle areas.
The situation in the Philippines is of particular interest because it illustrates the effectiveness of measures for controlling mosquitoes. Prior to World War II, dengue had always been a problem among Army forces stationed in the Philippines. Replacements frequently contracted the disease within a few months after arrival. Consequently, with the opening of the campaign for reoccupation, a serious situation was anticipated, especially
19Quarterly Report, Surgeon, I Corps, Southwest Pacific Area, 1 Apr.
1944-30 June 1944.
during the rainy season in areas of dense population. However, in spite of the presence of large numbers of nonimmunes and the appearance of cases throughout the Philippine Islands, no real epidemic outbreaks developed. The case rates are shown in table 7.
[Rate expressed as number of cases per annum per 1,000 average strength]
Effective mosquito control was achieved by attaching malaria units to all forces operating in the Philippines. In addition to the usual control measures which were carried out on an intensive scale, area spraying with DDT (dichlorodiphenyltrichloroethane) from airplanes was carried out extensively over Manila (fig. 5) and other populated centers on Luzon Island during the early months of 1945.21 The houses of natives adjacent to concentrations of troops were also sprayed with DDT.
It is of interest that reports from this area indicated considerable variation in the clinical picture. Thus, many cases showed only a single peak in temperature, and in many instances the disease was quite mild. The difficulties in diagnosis, particularly during the first few days of illness, were
21Essential Technical Medical Data, U.S. Army Forces in the Far East, for March and April 1945, Inclosure 13, subject: DDT Spraying in Luzon.
repeatedly pointed out. The disease was most commonly confused with malaria, acute infectious hepatitis, and scrub typhus.
Perhaps the most extensive outbreak of dengue during World War II occurred in the Marianas Islands in the late summer of 1944. Relatively complete records are available only for Saipan. Shortly after the assault on this island, on 15 June 1944, dengue made its appearance among the troops. At first, the incidence was low, probably because the rainy season did not begin until the first of August and mosquitoes were not abundant. However, by 11 August, mosquitoes had become plentiful and the dengue rate had reached 300. The incidence continued to rise rapidly, and by 8 September the rate had reached approximately 3,500 per 1,000 per annum.22
This outbreak was obviously caused by the presence of large numbers of mosquitoes and the ineffectiveness of ordinary measures of control. Thus, there were innumerable breeding places provided by "an unbelievable amount
22Essential Technical Medical Data, U.S. Army Forces, Pacific Ocean Areas, for September 1944. Inclosure 4 thereto.
of rubble resulting from the total destruction of villages and scattered dwellings, a multitude of wells, cisterns, vats, troughs and rainwater-collection facilities as well as an immense quantity of tins, shell cases, et cetera." The difficulties encountered in controlling mosquitoes during and immediately following the assault phase of a campaign are sufficiently great under ordinary circumstances, but in this instance they proved to be insurmountable. This is illustrated by counts made of the number of mosquitoes found biting a single human during 10-minute periods. Thus, between 16 August and 10 September 1944, counts made in the late afternoon near the vicinity of towns or villages showed from 5 to 36 specimens of A. aegypti and from 2 to 16 specimens of A. albopictus as well as 1 to 7 specimens of other species. Counts made at night showed as many as 42 specimens of still other species.
Effective control of mosquitoes only became possible when a supply of DDT arrived on 3 September 1944. Area control was employed by spraying 5 percent DDT and kerosene from airplanes. It was found that small planes were inadequate and that it was necessary to use C-47's because of the size of the area involved. Between 12 and 22 September, 8,600 gallons of the mixture was sprayed over a total of approximately 15,000 acres, an average of approximately two-tenths of a pound of DDT per acre. In addition, DDT residual spray was used in all tents and living quarters of hospitals.23 This was accomplished with a truck-mounted power spray unit for chemical decontamination provided by the Chemical Warfare Service.
The effectiveness of these measures is shown in table 8. The number of new cases began to decrease significantly about 1 week after the aerial spraying of DDT was started. After the first of October, the number of new cases was less than 10 percent of the number which occurred at the height of the epidemic. Although the preliminary summary reports show only 10,834 cases of dengue for the entire Pacific Ocean Area during August, September, and October, 1944, it is reliably estimated that there were 20,000 cases on Saipan alone.24 This discrepancy was probably due to a high percentage of cases that were cared for in quarters and were not officially reported.
The effectiveness of these measures in controlling the mosquito population was clearly demonstrated by observations on the "biting rate" per minute. Thus, surveys made before and after spraying by airplane indicated a decrease up to 98 percent. In addition, it was generally agreed by troops that there had been a tremendous reduction in the mosquito population. This was further substantiated by surveys of breeding places of mosquitoes made before and after DDT spraying. Finally, the effectiveness of these measures is indicated by the marked decrease in new cases of dengue which occurred before the end of the rainy season and at a time when susceptible troops were still arriving on the island.
23Letter, Deputy Surgeon, Headquarters, U.S. Army
Forces, Pacific Ocean Areas, to Surgeon, Pacific Ocean Areas, 30 Sept. 1944,
subject: Measures Used for Control of Dengue Fever on Saipan.
Although dengue was endemic in most of the China-Burma-India theater, the majority of cases among U.S. troops occurred in the region of Calcutta, India. The highest incidence appeared between July and October with the peak varying according to the dates of the monsoon.25 During 1942, 1943, and 1944, the dengue rates were approximately the same; namely, 25 per 1,000 per annum. However, in 1945, the rate dropped to less than half. Although the explanation for this is not entirely clear, it is felt that the improvement was largely due to the work of malaria control detachments whose measures were directed towards Aedes mosquitoes as well as the Anopheles mosquitoes. In addition, antimosquito supplies and equipment were more readily available in 1945 and individual protective measures were better enforced (fig. 6).
One small but sharp outbreak of dengue which occurred in the China theater illustrates the military importance of this disease as follows: During September 1945, after V-J Day, an epidemic was reported in Hankow, China, which was said to have affected 80 percent of the population of the city. When American forces occupied the airport, 40 of the first 48 men to arrive contracted dengue within 5 to 10 days.26 Because of this situation, it was first recommended that operations from Hankow be suspended. Subsequently, however, they were considered essential. Intensive measures for
25Van Auken, H. A. : A
History of Preventive Medicine in the
United States Army Forces of the India-Burma Theater, 1942 to 1945, p. 317.
FIGURE 6.-A train medical officer (holding box) distributes enough mosquito repellent to car commanders for them to issue one bottle per man in their cars. Immediate distribution is made to insure each man having adequate antimalarial protection prior to departure of train from port at Bombay, India, March 1945.
mosquito control were undertaken, the city of Hankow was declared out of bounds, and personal protective measures were rigorously enforced. The effectiveness of these steps was indicated by an absence of further cases among U.S. military personnel.
Variations in the character and severity of dengue have long been recognized as dependent upon differences in particular outbreaks and upon inherent and acquired degrees of individual resistance.27 The variabilities of this disease in civilian populations have been discussed in detail elsewhere28
27Lumley, G. F.: Dengue. Service Publication No. 3, Commonwealth of Australia. Department
of Health, 1943.
and provide a comprehensive background for the military cases described in different parts of the Pacific area. These were likewise of varying severity and symptomatology,29 and in some instances, because of lack of specific laboratory tests, the diagnosis could be only denguelike fever30 based on symptomatology and epidemiological considerations.
Characteristically, the onset of dengue was sudden, accompanied by fever and sometimes by a chill. The fever was of two types-saddleback and single phase. Patients were usually admitted to the hospital within a few hours of onset of the disease, with a temperature ranging from 99° to 104° F. which persisted for at least 2 or 3 days.31 Over half the patients then had a remission in which both the fever and symptoms practically disappeared. This remission lasted 1 or 2 days and was followed by a second rise in temperature and return of symptoms. These, in turn, subsided rapidly on the fifth to seventh day of illness. In patients who did not exhibit this saddleback type of fever, symptoms and fever were largely the same but persisted for several days, regressing gradually from the third to the eighth day of illness.
Dizziness, prostration, and extreme weakness in the legs were frequent presenting symptoms. Frontal or occipital headache, generalized aching especially in the back and joints, and pain in and around the eyes developed early. Anorexia was common and was often accompanied by nausea and sometimes by vomiting. Occasionally, mild abdominal pain was noted. Many patients complained of insomnia and restlessness, and these symptoms frequently persisted into convalescence.
Flushing of the face and neck and scleral injection were common. Two types of rash were observed. One, an enanthem, appeared within the first 12 hours, if at all, and consisted of pinpoint-sized, discrete, glistening vesicles on the posterior half of the soft palate. Star-shaped redness developed beneath these within 24 hours. This rash was morbilliform; it faded during the period of remission and did not recur with the second rise in temperature. The other type of rash was an exanthem (fig. 7). Seventy-nine percent of the patients in one group had this rash on admission to hospital. It could be mild (a few discrete, light pink, morbilliform spots on the sides of the thorax, inner surfaces of the upper arms, and in the lumbar region) or severe when it presented unbroken, erythematous areas covering the face below the forehead, neck, shoulders, and thorax. The morbilliform charac-
29(1) Diasio, J.S., and Richardson, F.
M.: Clinical Observations on Dengue Fever; Report of 100 Cases. Mil. Surgeon 94:
365-369, June 1944. (2) Kisner, P., and Lisansky, E. T.: Analysis of an Epidemic
of Dengue Fever. Ann. Int. Med. 20: 41-51, January 1944.
ter became apparent at the edges of the confluent areas, notably the lower half of the upper arm, upper part of the abdomen, and thoracic extensions of the axillary spaces. This rash also faded during remission but recurred, usually in less intense form, with recrudescence of fever. When it extended to the palms of the hands and soles of the feet, it was frequently followed by itching.
The incidence of adenopathy was highly variable and, when present, it most commonly involved the cervical nodes,32 persisting through the second phase of fever and subsiding gradually during convalescence. Bradycardia was usually present and first appeared after the second day of illness, sometimes lasting into convalescence. Leukopenia was present early, with an average reduction in number of white blood cells to 5,450 per cubic millimeter. By the fifth day of illness, the average count numbered 3,500 cells per cubic millimeter, with a relative lymphocytosis. Atypical lymphocytes with vacuolated cytoplasm and coarse granular inclusions were commonly seen. The symptoms and signs of disease in two groups of patients in the U.S. Army are recorded in table 9.
32See footnote 29, p. 72.
1Of those with adenopathy; 16 percent of the total group (318 cases).
The disease ran its course in 6 to 10 days (average hospital stay 7½ to 9 days) with complete recovery. In general, symptoms tended to abate with the fever, but during convalescence some degree of neurasthenia manifested by muscular weakness, lack of ambition, mental depression, insomnia, and anorexia was almost invariable. These usually disappeared in 7 to 14 days, but sometimes lasted much longer.33 Recurrences were rare and could probably be explained as re-infections.
Occasional complications of dengue were observed, including hemorrhagic nephritis, trismus of the jaw, arthritis of hip, suppuration of glands, persistent bradycardia, and purpuric manifestations.34 Urogenital complications were also occasionally observed. Dull testicular pain and impotence were not infrequent during convalescence, and the latter was attributed to generalized weakness.35 In one group of 141 patients, 8 men
33(1) See footnotes 29, p. 72; and 31 (2), p. 72. (2)
Hyman, A. S.: The Heart in Dengue; Some Observations Made Among Navy and
Marine Combat Units in the South Pacific. War Med. 4: 497-501, November 1943.
(5.7 percent) had late involvement of the urogenital tract, including orchitis, with subsequent atrophy of the testis and repeated bloody seminal emissions. Rare neurological complications following dengue were described by Kaplan and Lindgren36 who reported palsy of the facial, palatine, long thoracic, ulnar, peroneal, and sciatic nerves.
Dengue may be confused with rubella because of the rash and because of the type of cervical adenopathy observed. Other diseases frequently considered in differential diagnosis included scarlet fever, infectious mononucleosis, malaria, viral pneumonia, influenza, and occasionally meningitis. A knowledge of the epidemiology of dengue and its clinical course was helpful in early diagnosis.
Sufficient discrepancies in signs and symptoms existed in certain outbreaks of denguelike fever to question the diagnosis. In 32 cases from Panama,37 the symptoms and course of the disease were similar to dengue except that the typical rash was not seen, bradycardia did not occur, and the incidence of lymphadenopathy was low. Definite diagnosis was impossible because of lack of laboratory methods. Many of the patients observed in Okinawa in 1945 likewise had most of the diagnostic signs of dengue.38 The clinical picture presented by these cases was remarkably uniform. Specifically noted was the sudden onset, with chilly sensations, rapid rise in temperature, headache, pain on movement of the eye, postorbital pain, photophobia, generalized aching, periarticular soreness, conjunctivitis, lymphadenopathy, bradycardia, and hematological changes. However, it was pointed out that the short duration, relative infrequency of recrudescence of fever and symptoms, and the absence of rash in these patients were against the diagnosis of dengue. Later, Sabin,39 on the basis of failure to produce dengue in four human volunteers inoculated with serum from five of these patients, suggested that this outbreak may have been leptospiral meningitis.
The treatment of dengue was symptomatic. Codeine (½ to 1 gr.) and acetylsalicylic acid (10 gr.) usually sufficed for relief of pain,40 and phenobarbital (1½ gr.) was employed for insomnia and restlessness. Morphine was rarely required.
The military importance of dengue became evident early in World War II. As a result, the Commission on Neurotropic Virus Diseases, Army Epidemiological Board (Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army), became interested in
36Kaplan, A., and Lindgren, A. J.: Neurologic Complications Following Dengue. U.S.
Nav. M. Bull. 45: 506-510, September 1945.
promoting research in this field with the specific objectives of producing a protective vaccine and, if possible, of developing a specific diagnostic procedure. Neither of these was available before World War II, for up to that time the virus had not yet been definitely propagated in animals or in tissue culture. Lt. Col. Albert B. Sabin, MC, was the central figure in the series of studies which provided pertinent key information. Detailed reports of his findings are available elsewhere.41 The following summarizes those findings especially pertinent to military medicine:
1. Proof of the existence of multiple immunological types. Seven strains of dengue virus were isolated from patients who contracted their illness in Hawaii, New Guinea, and India. Serum obtained during the first 48 hours of the disease was shipped to the United States under refrigeration and inoculated into volunteers who had never resided in areas where dengue is endemic. Subsequently, studies of transmission by mosquitoes were conducted with A. aegypti. The existence of separate strains was demonstrated both by studies of cross-immunity and through virus neutralization tests using immune serum. At least two immunologically distinct types of virus were identified. It was shown that the Hawaiian strain, one of the four New Guinea strains, and the two Indian strains were identical. Thus, two separate strains were detected in New Guinea.
2. The long persistence of immunity to homologous types of virus. It was found that homologous immunity persisted for at least 18 months under conditions which precluded reinforcement of immunity by subclinical reinfection. Heterologous immunity was observed but persisted for only about 2 months.
3. The modifications of the clinical manifestations of the disease which result from reinfection with a heterologous type of virus at various periods after the primary attack. It was shown that a superimposed heterologous infection produced marked variations in the course of the disease depending upon the time which lapsed from the primary infection. A short febrile illness of 2 days' duration with or without rash, lymphadenopathy, or other characteristic manifestations occurred under these circumstances. In these experimental cases, the virus, recovered from the blood showed conclusively that the observed disease actually was dengue. This knowledge readily explained the many cases reported of the transitory acute illnesses which could not be specifically identified, particularly from New Guinea. This explanation is confirmed further by the fact that two of the New Guinea samples of serum from individuals with this type of illness produced the
41(1) See footnotes 2, p. 50; and 39, p. 76. (2) Sabin, A. B., and Schlesinger, R. W.: Experimental Studies on Human and Mouse Adapted Dengue Virus. Paper presented at joint meeting of American Society for Experimental Pathology and American Association of Immunologists, Atlantic City, N.J., 13 Mar. 1946. (3) Letter, Maj. Albert B. Sabin, MC, to Preventive Medicine Service, Office of the Surgeon General, 3 Aug. 1944, subject: Isolation of Several Strains of Dengue Virus From Serum of Patients With Various Types of Fevers in New Guinea. (4) Sabin, A. B., and Schlesinger, R. W.: Production of Immunity to Dengue With Virus Modified by Propagation in Mice. Science 101: 640-642, 22 June 1945.
classical picture of dengue when inoculated into nonimmune volunteers in the United States.
4. The demonstration that type-specific immunity to dengue is associated with neutralizing antibodies for the virus. It was shown that the demonstration of neutralizing antibodies can be employed for diagnostic and epidemiological survey purposes. They should prove to be of great value in the future.
5. The propagation of dengue virus in mice. Sabin finally succeeded in propagating the virus in mice. In the course of a number of passages, the virus underwent a mutation since it lost its capacity to produce severe illness in man but retained its capacity to produce a rash. A mousebrain extract of this modified virus was found to afford complete protection against the naturally acquired disease. A single mousebrain was shown to contain at least 10,000 immunizing doses which led to the preparation of an effective lyophilized vaccine. Unfortunately, large-scale field trials were not undertaken because the opportunities for testing the vaccine ceased with the ending of the war.
6. Investigations of dengue, conducted by Colonel Sabin in Panama, showed clearly that dengue has occurred there since 1941 and suggested that the interior of Panama may be an endemic focus of the disease.
In conclusion, it should be pointed out that the history of dengue during World War II reflects great credit on the U.S. Army Medical Department. Like some other virus diseases, dengue was promoted to the category of an illness diagnosable by laboratory means and preventable.