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Chapter 5

Chapter 5

Group B Arboviruses

Colonel Philip K. Russell, MC, USA, and Brigadier General Andre J. Ognibene, MC, USA

Section I. Dengue and Dengue Shock Syndrome

Colonel Philip K. Russell, MC, USA

HISTORY

Epidemics of an illness clinically resembling dengue fever have been recognized in tropical and subtropical areas of the world since the 17th century. A disease now thought by many to have been dengue was reported from the West Indies in 1635. In the latter part of the 18th century, epidemics were described in Java, Egypt, India, Spain, and the United States. In the 19th century, four widespread epidemics occurred in the Americas, mainly in the Caribbean region. Dengue epidemics of major proportion were also reported in Southeast Asia in the 19th century; however, in Indochina and the Philippines the disease was more frequently noted among foreigners than among the local populations. In this century, very large epidemics have occurred in the United States, Greece, Australia, Japan, and the Caribbean region.

Dengue has long been recognized as a major threat to nonindigenous troops operating in endemic areas. Before World War II, it frequently occurred among U.S. military personnel in the Philippines and was the subject of intensive research there under the auspices of the Army Medical Research Board. Early in the century, the viral etiology of dengue was proven and the presence of infectious virus in the blood was demonstrated in volunteers by Ashburn and Craig (1907). Siler and coworkers (1926) conclusively demonstrated that Aedes aegypti is a vector of dengue, confirming earlier work done by Cleland and associates (1919) in Australia. Simmons and associates (1931) proved that Aedes albopictus is also capable of biological transmission.

During World War II, epidemics of dengue assumed considerable military importance. For example, 24,079 cases were reported among U.S. troops in New Guinea in 1944, and more than 20,000 cases were reported among Army, Navy, and Marine Corps personnel on Saipan in June through October of the same year (MD-PM7, pp. 29-62). Epidemics during World War II often were related to combat operations, which complicated mosquito control measures. The continuous transportation of men and materiel associated with military operations may


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have been related to the outbreaks of dengue which occurred in Japan, Hawaii, and Australia, as well as on many of the Pacific islands. The disease was also a problem for U.S. troops in China, Burma, and India. Extensive research on dengue was carried on by the U.S. Army during the war; of particular importance was the work of Sabin (1952), which resulted in the isolation of dengue viruses by intracerebral inoculation of mice and the demonstration of the existence of separate serotypes, dengue-1 and dengue-2, by experiments in volunteers.

DHF (dengue hemorrhagic fever) and DSS (dengue shock syndrome) were first recognized among children in the Philippines in 1954 and subsequently assumed importance throughout Southeast Asia. From 1960 to 1973, major DHF epidemics occurred in Bangkok, Manila, Singapore, Calcutta, Phnom Penh, Rangoon, Saigon, Hanoi, and Djakarta, as well as in many smaller cities; in several large cities, such as Bangkok, epidemics occurred annually during the rainy season. The dengue virus etiology of DHF was established by Hammon in 1958, and the existence of the dengue-3 and dengue-4 serotypes was discovered (Hammon, Rudnick, and Sather 1960).

EPIDEMIOLOGY

The transmission of dengue viruses is dependent on mosquitoes of the subgenus Stegomyia. The domestic mosquito, Aedes aegypti, is the principal vector throughout the world; other species, such as A. albopictus, A. scutellaris, and A. polynesiensis, have also been incriminated, usually as secondary vectors. Mosquitoes become infected by feeding on a viremic man and transmit the virus by bite after a short (5 to 7 days) extrinsic incubation period. No vertebrate hosts other than man are of major epidemiological importance. Monkeys can become infected, however, and a jungle cycle involving wild monkeys and forestbreeding Aedes mosquitoes may exist in Southeast Asia.

Four serotypes of dengue virus are now recognized, each of which has been associated with both dengue fever and DHF. These serotypes, although antigenically related, do not cross protect; infection with one confers homologous but not heterologous immunity. This fact accounts for closely spaced epidemics and the sequential reinfection of children in some endemic areas.

The three basic epidemiological patterns of dengue virus transmission are intermittent epidemic, endemic, and hyperendemic. The intermittent epidemic pattern usually involves a single serotype and occurs in areas where transmission is interrupted, often for long periods, by climate, vector control, or high levels of acquired immunity in a small population. Recurrence of disease requires reintroduction of a dengue virus when conditions are suitable for transmission. The classical epidemic is manifested by high clinical attack rates in nonimmune populations with all age groups being affected. Examples of this pattern are the epidemics which have occurred recently in island populations in Puerto Rico, Tahiti, New Caledonia, and Samoa.

The endemic pattern occurs when at least one dengue serotype is continuously present in a population and transmission continues uninterrupted over


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a period of years. Clinical attack rates usually appear low since infections occur mainly in children and dengue infections in children most commonly result in mild undifferentiated febrile illnesses which are difficult to diagnose. A high level of acquired immunity protects the adult population from clinical illness. In endemic areas, dengue is frequently unrecognized. Nigeria, where dengue-1 and dengue-2 viruses are endemic, is a good example of the endemic pattern, as was most of Southeast Asia before the 1950's.

The hyperendemic pattern is manifested by the continued presence of multiple serotypes of dengue virus. In several hyperendemic areas of Southeast Asia, all four serotypes are present and continuous transmission occurs throughout the year with peaks during the rainy season. The most important clinical manifestations are DHF and DSS, which occur mainly in indigenous children. Hemorrhagic fever in hyperendemic areas is associated with second dengue infections. It is the hyperendemic pattern which allows multiple exposure and successive infection with heterologous serotypes among children. Clinical attack rates may be high, and case fatality rates for DHF may reach 5 to 15 percent. During U.S. Army involvement in Vietnam, hyperendemic dengue existed in Burma, Thailand, Cambodia, Vietnam, the Philippines, Indonesia, and India.

ETIOLOGY

Dengue viruses form a subgroup of the group B arboviruses (flaviviruses). These small (50 nm) RNA viruses are composed of a nucleocapsid with cubical symmetry surrounded by a lipoprotein envelope. The virion contains three virus-specific proteins, a large (mw 52,000) envelope glycoprotein, a very small (mw 8,000) envelope protein, and a single internal protein (mw 14,000). The envelope glycoprotein is associated with viral hemagglutinin activity and constitutes the major surface antigen. At least two nonvirion proteins specified by the viral genome and synthesized during infection are also known to evoke an antibody response during infection.

The four serotypes are designated dengue-1, -2, -3, and -4; in addition, a distinct subtype of dengue-3 exists. Serotypes are differentiated on the basis of neutralization tests and cross protection. Shared or cross-reactive antigenic determinants are located on the surface of the virion and on the nonstructural antigens and can be demonstrated by HI (hemagglutination inhibition) and CF (complement fixation) tests, which are commonly used for diagnosis. Dengue viruses also exhibit serologic cross-reaction with other group B arboviruses such as yellow fever and Japanese B encephalitis. Dengue viruses are infectious for man, several species of primates, and mosquitoes. In the laboratory, they can be adapted to grow in intracerebrally infected mice, and they replicate in several types of mammalian and insect cells in culture.

PATHOGENESIS

The deposition of virus by the bite of an infected mosquito is followed by an


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incubation period of 3 to 15 days. In an experimentally infected monkey, the virus replicates in the skin at the site of infection and in local lymphatic tissues. Virus replication is thought to occur in lymphocytes. After the onset of symptoms a viremia occurs, which in man lasts 3 to 5 days. In plasma the virus may reach a concentration of 105 infectious units per ml. Since dengue fever very rarely is fatal, histopathologic observations in proven cases have been based solely on skin biopsies taken at the site of maculopapular and petechial eruptions. Nonspecific changes consist of endothelial swelling, perivascular edema, and, in petechiae, extravasation of blood. Mononuclear cell infiltration was observed by Sabin (1952, p. 36) in biopsies taken at the site of injection of virus in volunteers.

DHF and DSS result from an immunopathologic process in which complement activation and the formation of C3a and C5a anaphylatoxins play a major role (WHO). An anamnestic antibody response results when second heterologous dengue infections occur; this causes rapid formation of IgG antibody while virus and viral antigens are present in the blood. Complement is activated through C1 and by the alternate pathway through C3 activator. Plasma C3 levels fall abruptly, concomitant with a marked increase in vascular permeability which in turn results in hypovolemia and shock. Thrombocytopenia and varying degrees of diffuse intravascular coagulation occur, which contribute to a hemorrhagic diathesis. Autopsy of fatal cases of DHF reveals pleural and peritoneal effusions and widespread hemorrhagic lesions and petechiae. Paracentral hepatic necrosis is a common finding.

CLINICAL FEATURES

Dengue Fever

The onset of dengue in adults is usually accompanied by headache, backache, anorexia, chilliness, and malaise. Prodromal symptoms may precede the onset of fever by up to 12 hours or the onset may be abrupt, with severe headache, backache, myalgia, and ocular pain accompanying fever and chills. Nausea, vomiting, sore throat, and arthralgias may occur. Fever of 101 to 104F persists for 3 to 6 days, usually without remitting; a diphasic "saddleback" temperature curve sometimes occurs.

Early in the febrile period, a transient erythematous flush may be present over the face, neck, and upper trunk. In many cases, a distinct skin rash, usually macular or occasionally maculopapular, appears; it is more prominent on the trunk but can involve the face and extremities. It usually occurs between the third and fifth day of illness, lasting 1 to 3 days. Petechiae may be present in some patients, most commonly occurring on the lower extremities and usually appearing near the end of the febrile period. Generalized and frequently tender lymphadenopathy is a common physical finding early in the disease. The spleen is rarely enlarged. The conjunctivae are often injected and the eyes may be tender to pressure.


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Leukopenia ( < 5,000 per mm3) is present in most cases, total leukocyte counts sometimes dropping as low as 1,500 per mm3. Thrombocytopenia may also occur. Hematocrit, erythrocyte sedimentation rates, SGOT (serum glutamic oxaloacetic transaminase), and BUN (blood urea nitrogen) usually remain within normal limits (table 15).

TABLE 15. - Summary of clinical signs and laboratory findings in 55 dengue patients in Bangkok hospitals, 1971

Complications from a primary infection rarely occur in dengue fever. Epistaxis and menorragia have been reported, as has gastrointestinal bleeding, which is usually concomitant with a gastrointestinal disorder such as peptic ulcer. Prolonged convalescence with asthenia has been noted in some epidemics.

Dengue Shock Syndrome

Dengue hemorrhagic fever with shock or dengue shock syndrome is a distinct clinical entity which differs significantly from dengue fever. It occurs most frequently in children, rarely affecting adults. DHF and DSS occur in association with a second dengue infection. An initial febrile period lasting 2 to 5 days is characterized by headache, anorexia, vomiting, respiratory symptoms, and a maculopapular or petechial rash. Abdominal pain and marked lethargy in the first phase are poor prognostic signs presaging the onset of shock.

The shock phase may begin abruptly with lassitude, diaphoresis, and physical collapse. Patients appear severely ill with clammy extremities and peripheral vascular congestion. Cyanosis may be present, and petechiae and ecchymoses are common. The tourniquet test is usually positive. Pulse pressure is


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narrowed and systolic and diastolic blood pressures may drop to undetectable levels, with a concomitant tachyeardia. The liver is usually enlarged.

Untreated shock may result in coma, metabolic acidosis, and death. Bleeding may be marked, with epistaxis, hematemesis, or melena. Severe bleeding generally occurs after the onset of shock but sometimes happens during recovery from the hypotensive phase.

Marked hemoconcentration occurs as a result of increased capillary permeability; the hematocrit rises with the onset of shock. Leukocytosis occurs, in contrast to the leukopenia seen in primary dengue, and thrombocytopenia may be profound. The most marked depression of platelets occurs with the onset of shock. Serum albumin levels are low, as are serum sodium and bicarbonate, and terminal elevation of serum potassium levels has been noted in fatal cases. SCOT and SGPT (serum glutamic pyruvic transaminase) are elevated and parallel the severity of illness. The BUN is usually elevated. Serum C3 levels are markedly depressed, and the other early complement components are also low. Plasma fibrinogen levels are often low, and fibrin split products are present.

LABORATORY DIAGNOSIS

Conclusive diagnosis of a dengue infection requires isolation and serotypic identification of the virus. Virus usually can be recovered from the blood during the first 3 to 5 days of illness; success of isolation is highest on the first day. Fresh or frozen serum or plasma and cell culture systems such as LLC-MK 2 or A. albopictus cells are needed.

The HI, CF, and VN (virus neutralization) tests, using dengue antigens, can be of diagnostic value; however, antigenic sharing between group B arboviruses and the occurrence of broad cross-reactions with anamnestic antibody responses often make virus-specific diagnosis impossible by serology alone. The VN test is the most specific, the HI test the least. In some circumstances, separation of the IgM antibody for serologic testing may aid in providing a specific diagnosis.

In patients with primary dengue who have had no previous antigenic experience with a group B arbovirus, serum antibody becomes detectable on the fifth to eighth day, and titers rise for the next 2 to 4 weeks. The VN and CF tests may demonstrate type-specific antibody. Where previous exposure to a group B agent (including yellow fever vaccine) has occurred, antibody rises rapidly, as early as the fourth day. Titers in secondary antibody responses rise to very high levels, often within a few days, and extensive cross-reactions are seen, precluding a virus-specific diagnosis.

Demonstration of a significant (usually fourfold) rise in titer is necessary to serologically establish a recent infection; therefore, serum specimens collected early (day 1 to 4) and late (day 14 or later) are necessary.

PREVENTION AND TREATMENT

As of this writing, prevention of dengue depends on controlling or preventing exposure to mosquitoes; no dengue vaccine has been approved for use. A.


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aegypti has been successfully eradicated from large areas of Central and South America, but vector control is ineffective or nonexistent in many tropical regions where dengue is endemic or hyperendemic.

A. aegypti breeds in and near human habitation, depositing its eggs in water storage vessels, ant traps, discarded tires, cans, and similar containers. Environmental cleanup and larvicide application can reduce vector populations. Insecticides such as malathion, delivered by fog or ultra-low-volume spray, are useful for short term control in limited areas, but residual spray techniques are no longer effective because of vector resistance. A. aegypti prefers to bite indoors during daylight; bed nets are therefore of little value. Screening of homes and billets effectively reduces exposure.

Treatment of dengue fever is entirely symptomatic as no effective antiviral therapy exists. DSS requires careful clinical observation and intravenous fluid therapy to maintain a satisfactory intravascular volume; patients may be dehy drated from vomiting and poor fluid intake before the shock phase. Plasma or plasma expanders can be lifesaving when shock occurs. A rising hematocrit is an indication for plasma replacement; whole blood transfusion may be required if bleeding is severe. Correction of acidosis is frequently required. There is no evidence that adrenocortical steroids, vasoactive agents, or antibiotics are of therapeutic value.

NEW ADVANCES

The Army Medical Department, as a result of U.S. involvement in the Vietnam war, made major contributions to the understanding of dengue in Southeast Asia in the areas of epidemiology, medical entomology, virology, immunology, and medicine. A research program on dengue and dengue hemorrhagic fever was initiated by the U.S. Army Medical Component, SEATO (Southeast Asia Treaty Organization), in 1962. Studies were carried out by the U.S. Army Medical Research Team, Vietnam, and by medical officers in several hospitals, including the 93d Evacuation Hospital at Long Binh, the 8th Field Hospital at Nha Trang, and the 3d Field Hospital at Saigon, in collaboration with the SEATO Laboratory in Bangkok, Thailand, the basic research facility (Deller and Russell 1967; Reiley and Russell 1969). Collaborative studies were also done in conjunction with 1'Institut Pasteur in Vietnam.

Major epidemics of dengue fever did not occur among U.S. forces in Vietnam, undoubtedly because of the high level of environmental sanitation and the resulting absence of A. aegypti on most U.S. Army bases in Vietnam. Sporadic cases of dengue fever did occur and the disease was a significant cause of FUO (fever of undetermined origin); the FUO studies detailed in chapter 4 show that dengue was the cause of disease in 3.4 to 28 percent of patients hospitalized with FUO. Dengue was contracted mainly by support troops who had contact with civilian populations, as most mosquito transmission occurred in local communities. All dengue seen among U.S. military personnel was clinical dengue fever or mild undifferentiated febrile illness; although dengue hemorrhagic fever was not seen, epidemics did occur among Vietnamese children.


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The first well-documented study of DHF in Vietnam, by Halstead and associates (1965), showed dengue-2 virus to be an etiologic agent; serologic tests demonstrated secondary antibody responses to the virus in eight patients (table 16). Epidemiological surveillance by Dr. Nguyen-Thi-Kim Thoa of 1'Institut Pasteur indicated that annual epidemics of DHF occurred during the rainy season in the Saigon area from 1965 through 1973, and that DHF occurred occasionally in Vinh Long, Can Tho, Nha Trang, Qui Nhon, and Da Nang. A study of vector mosquitoes by Russell and associates (1969) showed that all four dengue virus serotypes were present in the Saigon area and confirmed A. aegypti as the major vector. An important observation in this study was that dengue in U.S. troops occurred at the same time as did epidemics of DHF in Vietnamese children; all four dengue serotypes were found to cause both dengue fever and DHF.

TABLE 16. - Clinical and serologic findings in eight patients' with clinically diagnosed hemorrhagic fever, Saigon, 1963


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Section II. Japanese B Encephalitis

Brigadier General Andre J. Ognibene, MC, USA

Following the U.S. troop buildup in Vietnam in 1965-66, a number of cases of encephalitis occurred yearly between April and September (USARV-MC). During these months in 1969, 57 cases were evaluated by the U.S. Army. Most patients had acquired their disease in the Saigon-Long Binh area, although sporadic cases occurred in the coastal areas to the north. Diagnosis of JBE (Japanese B encephalitis) was definitively established by serologic study or viral isolation in 10; the available information on the remaining 47 was not as detailed as desired. The difficulties of conducting a study during wartime made a more comprehensive investigation impractical. A significant number of patients never came to the attention of the reviewers. However, the extent of the yearly epidemic and the possible future impact of mild or subclinical infections on U.S. troops in endemic areas direct that the available data be reported.

Twenty-four cases of JBE among U.S. personnel in I Corps were identified by the Naval Medical Research Team No. 2 in 1967 in a study of 295 febrile patients (Berman, Irving, and Kundin 1968). The seasonal period of occurrence was clearly demonstrated. Average rainfall and temperature in relation to identified cases are depicted on chart 3.

MATERIALS AND METHODS

During the 1969 season, 57 patients with encephalitic manifestations were transferred to the neurology center at the 93d Evacuation Hospital in Long Binh for evaluation and therapy. They came primarily from the III and IV Corps areas, which included the Saigon-Long Binh complex. Nine patients with classical clinical signs were confirmed as having JBE by acute and convalescent serologic studies-CF, HI, and PRNT (plaque red neutralization test)-and an additional patient by virus isolation and identification from postmortem brain tissue at the SEATO Laboratory in Bangkok (table 17). A presumptive diagnosis was made in four others based on clinical observation and HI titers of 1:80 plus a fourfold titer rise in the convalescent specimen (table 18). In 43 patients, classical clinical encephalitis and abnormal C.S.F. (cerebrospinal fluid) were present and a probable diagnosis of JBE was made. Unfortunately, neither acute nor convalescent titers were available in this group, primarily because specimens were lost in the insecure and low priority transport system.

CLINICAL DATA

All of the 57 patients evaluated in this epidemic were males between 18 and 55 years of age, the majority under 25 years. Twenty-six were assigned to fixed

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This section of the chapter is a revised version of an article by W. B. Ketel and A. J. Ognibene entitled "Japanese B encephalitis in Vietnam," originally published in Am. J. M. Sc. 261: 271-79,1971.


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CHART 3. - Seasonal occurrence of meningoencephalitis and group B arbovirus infections in Vietnam, 1967

installations engaged in support activities; 12 of these had not left the confines of the large Long Binh military complex. Of the total group, 20 returned to duty in Vietnam after an illness not exceeding 2 weeks. Mental and neurological residuals warranting medical evacuation were noted in 36 patients; all were evacuated after the acute phase of the illness, and none returned to duty in Vietnam. Patients evacuated to Japan and then to the United States were lost to followup.

When initially examined, 86 percent of the patients were alert. They complained of several days of headache, fever, chills, vomiting, stiff neck, and photophobia or eye pain. The onset of fever heralded the most severe phase of the illness. Temperatures reached 104° to 106° F, rectally, remaining elevated from 3 to 6 days, then falling to normal within a few hours or over a 24-hour period. Changes in sensorium were most severe during the febrile period; many patients were extremely confused and combative. A semicomatose or comatose state occurred in 12 percent (chart 4).

Mental and neurological residua were not present at the time of discharge in the 20 patients returned to duty in Vietnam. During the acute phase in this group, alterations of consciousness were minor in degree, manifested primarily by lethargy, hypersomnolence, or confusion of time, place, or person. Otherwise, findings from neurological examinations were normal. Among evacuated patients, neurological residua varied from mild confusion to severe organic brain


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TABLE 17. - Clinical and laboratory data of ten confirmed Japanese B encephalitis patients in Vietnam, 1969

syndrome with alterations in intellect, orientation, judgment, and memory. Abnormal neurological signs, such as reflex changes, positive Babinski signs, ataxia, weakness, and tremor, were noted infrequently, and two patients demonstrated an expressive aphasia.

Headache, a constant feature of the disease, was present in all patients and was usually described as frontal and bitemporal at the onset, becoming generalized. The pain markedly increased in severity with movement or walking and remained 48 to 72 hours beyond lysis of fever.

The severity of the nuchal rigidity which was present in 94 percent of the patients evaluated appeared to correlate with the severity of the clinical course. In most patients, nuchal rigidity was present on admission or developed within the first 48 hours. When it was moderate or severe, Kernig and Brudzinski signs were usually present.

Eye pain or sensitivity to light was a frequent initial complaint, noted in 45 percent of the patients. Increasing periorbital pain with exposure to light was characteristic; some patients stated that the light increased their frontal headache.

In 86 percent of the patients, mental status in the febrile period following admission deteriorated in varying degrees. In some patients, the symptoms were mild, consisting of a short period of confusion, poor orientation to surround-


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TABLE 18. - Clinical and laboratory data of four suspected Japanese B encephalitis patients in Vietnam, 1969

CHART 4. - Mental status of Japanese B encephalitis patients in Vietnam, 19691


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FIGURE 38. - Patient with Japanese B encephalitis under therapy at the 93d Evacuation Hospital with controlled hypothermia. Control of fever during the acute phase of illness was consistently practiced in the support of patients with Japanese B encephalitis in Vietnam.

ings, and lethargy. The remaining patients demonstrated moderate to marked mental status changes, which persisted in 32 (see chart 4). Severe disorientation to time, place, person, or surroundings, with confusion, hyperirritability, and belligerent behavior, occurred during the febrile period. Deterioration of mental functions generally appeared by the third or fourth day of illness. Coma or a semicomatose state on admission was indicative of severe morbidity and a slow recovery. Fifteen patients remained severely demented at the time of medical evacuation.

Paresis of the extremities occurred frequently during the acute phase but always resolved rapidly in the convalescent period despite persistence of mental changes. Ocular palsies and nystagmus occurred in three patients and rapidly cleared. Aphasia occurred in two and persisted as an expressive type. Mild alterations in coordination, clumsiness of gait, and mild tremor were frequently noted. Increased tone, hyperreflexia, spasticity, and positive Babinski signs were uncommon except in those patients who had a major motor seizure. The one patient who died was lethargic and aphasic and had spontaneous choreoathetoid movements of the right extremities and left hemiparesis on admission. He rapidly lapsed into deep coma with decorticate posturing which persisted through 9 hospital days.

Seizures have been reported infrequently in adults with JBE, although they are common in children (Lincoln and Sivertson 1952; Sabin 1947; Hullinghorst et


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al. 1951; Clarke and Casals 1965). Six patients in this study experienced seizures during the febrile phase of their illness (fig. 38). These were always generalized and major motor in type, and occurred during the first febrile day in five patients; one patient experienced a seizure on the third hospital day. Seizures were significantly correlated with persistent mental status abnormalities, reflex asymmetries, hemiparesis, or aphasia. This association has not been previously emphasized and may be explained by more extensive cortical inflammation and edema. Electroencephalograms were available for two patients and revealed diffuse slowing with predominant frequencies of 4 to 6 cycles per second. Epileptiform discharges were not noted. In five of the six patients, only a single seizure occurred.

The one death which occurred in this series represents a much lower mortality rate than those reported previously. In Korea, mortality as high as 53 percent occurred among local civilians during the epidemic of 1949 (Hullinghorst et al. 1951), and a rate of 8.5 percent was recorded in the epidemic involving American personnel in 1950 (Lincoln and Sivertson 1952). The low mortality in the present series may reflect the effect of more modern nursing and supportive care available to the patients. Vigorous efforts to reduce highly elevated temperatures, including controlled hypothermia, were made, and fluid balance was carefully monitored. Improvements appeared unrelated to the use of steroids or antibiotics.

The major persisting abnormality was in mental status. Present in 95 percent of evacuees, it usually took the form of any of a wide spectrum of persistent memory defects, poor orientation or attention span, or gross dementia. Abnormal neurological signs were not clinically prominent in this group; the most common neurological dysfunctions during the convalescent period were tremulousness and mild incoordination of the extremities or mildly ataxic gait.

Persistent alteration of mental status and ataxia correlate with microscopic findings. Throughout the cortex and cerebellum, cellular inflammatory nodules are present, consisting of increased numbers of oligodendroglia, microglia, and macrophages. Loss of neurons occurs in the cerebral cortex and in the Purkinje cells of the cerebellum (Greenfield 1963). It is therefore surprising that spasticity or other long tract signs were not observed.

The average white blood cell count in this series was 13,000/mm3 and varied from 5,500 to 18,000. A "shift to the left" was frequent.

A lumbar puncture was performed on all patients with clinical encephalitis. Opening pressure was generally mildly elevated. Only one patient had a pressure below 160 mm H2O; 22 values above 200 mm H2O were recorded. The cerebrospinal fluid was clear in those lumbar punctures performed at the neurology center. Cell counts ranged from 5 to 2,500/cm3. The predominate cell type was lymphocyte in all but four patients. C.S.F. glucose values were normal, cultures sterile, and Gram's stains negative in all patients. C.S.F. protein values were abnormal (above 45 mg percent) at the time of the initial lumbar puncture in 46 patients. Values ranged from 30 to 200 mg percent. There was no relationship between the number or types of cells or protein concentration in the spinal fluid and the clinical severity of the disease.


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DISCUSSION

The typical patient presented with a symptom complex consisting of severe headache, fever, malaise, myalgia, nausea, vomiting, photophobia, and nuchal rigidity or pain. Confusion, disorientation, and combativeness dominated the febrile period.

A large percentage of patients infected with JBE do not develop clinical encephalitis (Halstead and Grosz 1962; Halstead and Sudie 1962; Scherer et al. 1959). Principal manifestations of the abortive form of the disease are mild head ache, fever, and malaise of a few days' duration. The true incidence of low-grade or subclinical infections is difficult to assess; estimates have varied from 500 to 1,000 inapparent infections for each case of clinically apparent disease in one study (Southam 1956) to a ratio of 25 subclinical infections to 1 overt case of encephalitis during the Korean epidemic of 1958 (Halstead and Grosz 1962).

Serologic studies were performed on paired serum specimens (collected 1 year apart) from Australian soldiers deployed in Vietnam in 1966-67 (Russell et al. 1967). A significant serologic conversion establishing exposure to JBE virus occurred in 20.9 percent of those tested. These patients had been symptomfree. Only two cases of overt JBE had occurred among Australian troops during that same period; a ratio of subclinical to clinical infections of 210:1 was recorded. It can be estimated from this figure that during the epidemic of 1969 at least 11,970 American troops in Vietnam may have been infected with JBE virus and developed mild or subacute infections that did not come to the attention of medical personnel. Available information indicates that 61 clinical cases of encephalitis occurred among U.S. personnel in Vietnam in 1970, with two reported deaths (Edgett).

Considering the variable onset and often mild course of the abortive form of the disease, it is not surprising that the diagnosis is not established clinically. Therefore, it is strongly recommended that during an epidemic period lumbar punctures be performed on all persons with a suggestive history and symptoms of fever and headache. Serologic studies, when feasible, are mandatory. This recommendation is applicable to epidemics of other forms of encephalitis confined to the continental United States. It would surely have been of value to U.S. physicians in Vietnam, who were constantly challenged by patients with "fever of undetermined origin," for which lumbar punctures were not a routine procedure.

Incidence of late morbidity, such as personality changes, persistent memory loss, early dementia, Parkinsonism, and dyskinesias, in clinically overt cases of JBE is approximately 10 percent (Edgett 1971). Information concerning late morbidity in the much larger group with subclinical infection is not available. Minimal loss of intelligence and dexterity may accompany infections when both the functional loss and the infection itself remain entirely unrecognized. The continuing yearly epidemics in Vietnam and the still unresolved problem of late sequelae in subclinical infection (Weaver et al. 1958) warrant serious consideration of the development of protective immunization for individuals assigned to


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endemic areas; this would be a realistic approach to recurring epidemics worldwide.

REFERENCES

Ashburn, P. M., and Craig, C. F. 1907. Experimental investigations regarding the etiology of dengue fever. J. Infect. Dis. 4: 440-75.

Berman, S. J.; Irving, G.; and Kundin, W. D. 1968. Infectious disease survey of U.S. personnel in I Corps, South Vietnam. U.S. Naval Medical Research Unit No. 2, Taipai, Taiwan, Mar. 68.
Clarke, D. H., and Casals, J. 1965. Japanese encephalitis virus. In Viral and rickettsial infections of man, eds. F. L. Horsfall and I. Tamm, 4th ed., pp. 626-31. Philadelphia: J. B. Lippincott Co.
Cleland, J. B.; Bradley, B.; and McDonald, W. 1919. Further experiments in the aetiology of dengue fever. J. Hyg. 18: 217-54.

Communicable disease: Arthropodborne diseases other than malaria, Preventive Medicine in World War II. See MD-PM7.

Deller, J. J., and Russell, P. K. 1967. An analysis of fevers of unknown origin in American soldiers in Vietnam. Ann. Int. Med. 66: 1129-43.

Edgett, Lt. Col. Joseph W., Jr., MC, USARV medical consultant. 1970 yearly admissions tabulations. Report, undated.

______1971. Monthly report to USARV surgeon, Jan. 71.

Greenfield, J. G. 1963. Infectious diseases of the central nervous system. In Neuropathology, 2d ed., pp. 201-3. Baltimore: Williams & Wilkins.

Halstead, S. B., and Grosz, C. R. 1962. Subclinical Japanese encephalitis. I. Infection of Americans with limited residence in Korea. Am. J. Hyg. 75: 190-201.

Halstead, S. B., and Sudie, B. R. 1962. Subclinical Japanese encephalitis. II. Antibody responses of Americans to single exposure to JE virus. Am. J. Hyg. 75: 202-11.

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