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Chapter 5, Part 3
NEUROTROPIC VIRAL DISEASES IN THE FAR EAST DURING THE KOREAN WAR*
WILLIAM L. POND, PH. D., AND JOSEPH E. SMADEL, M. D.
When one speaks of neurotropic viruses he generally has in mind the arthropod-borne encephalitides, poliomyelitis, and rabies. However, the neurotropic virus group is generally extended to include many other viruses which affect the central nervous system, for example, agents of lymphocytic choriomeningitis, mumps, the Coxsackie group, and the agents from mosquitoes and patients of the equatorial areas of Africa and South America; this last group has, in our patois, come to be known as the "tropical group" of viruses.
It should be mentioned at once that the two neurotropic virus diseases of importance in the Korean conflict were Japanese encephalitis and poliomyelitis. The total numbers of cases occurring in American troops in Korea during the years 1950-1953 were not great, 402 of encephalitis and 120 of paralytic poliomyelitis.
At the beginning of World War II the subject of Japanese encephalitis was one which caused much worry to those concerned with maintaining the health of American troops in case they should enter the areas where this disease was endemic. One had only to recall the great epidemics in Japan and the complete susceptibility of Americans to this virus which does not exist in the Western Hemisphere to understand the reasons for such worry. The theme of this report is to de-emphasize to some extent the military importance of Japanese encephalitis. However, it should be pointed out at once that the basis for de-emphasis has developed since the end of World War II. Moreover, we should continue to respect the judgment and admire the work of those who contributed so much to our knowledge and preparedness in this field during World War II.
Incidence of Japanese Encephalitis
The number of cases of encephalitis in civilian populations of Japan, Korea, and Okinawa in certain years since 1924 are indicated in table 1. Epidemic encephalitis has been recognized as a clinical entity in Japan at least since 1924 (1). Subsequently, epidemics were recognized in
*Presented 28 April
1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical
Service Graduate School, Walter Reed Army Medical Center, Washington,
Table 1. Number of Cases of Encephalitis in Civilian Populations of Okinawa, Korea, and Japan from 1924-52
*Designates data not known.
this population yearly with incidences ranging from 150 cases up to over 7,000 cases (1-3). The disease was recognized in Korea at least in 1949 (4); however, the mass movement of civilian residents has precluded any reliable data during the years of the Korean conflict except that the incidence of encephalitis in Korea, 1951, was considered rare (2). Encephalitis on Okinawa has been studied extensively by American personnel, yielding data (2, 5, 6) more reliable than the other data presented, since most statistical data are compilations made through native public health organizations.
The actual experience of the American troops with encephalitis is epitomized in table 2 which summarizes the annual incidence of encephalitis in American personnel in the Far East (5-8) and also
Table 2. Number of Cases of Encephalitis in Military Forces, Their Dependents, and Department of the Army Civilians in Various Areas of the FECOM
indicates the number of cases which were proved to be caused by Japanese encephalitis virus. Such proof was obtained at the 406th Medical General Laboratory and consisted of isolation of the virus from autopsy or clinical materials or demonstration of specific antibodies in the sera of convalescent patients.
The figures for 1950 are of particular importance since they include the outbreak during the late summer and early fall in our troops who were then compressed into the Pusan perimeter (6). Colonel Long will report the details of this episode later in this symposium, hence no more will be said about it now. It is worth pointing out that, during 1950, when the vast majority of cases of encephalitis in the Far East Command consisted of cases from the Korean epidemic, about two-thirds of the patients were proved to have been infected with the virus of Japanese encephalitis. Since then a progressively smaller proportion of the cases with a clinical diagnosis of encephalitis have been caused by Japanese virus. This matter cannot be explained on the basis of inadequate laboratory methods since the armamentarium of technics has been constantly improving in recent years. It is suggested that this change is connected with such factors as the increasing awareness of clinicians regarding the diagnosis of central nervous system infections and their tendency at times to include patients with aseptic meningitis in the group of encephalitides. Many of the paired sera have been tested in the usual battery of diagnostic procedures employed at the 406th Medical General Laboratory and the Army Medical Service Graduate School (3) without throwing light on the etiology.
Japanese Encephalitis Vaccine
An important decision regarding vaccination against Japanese encephalitis was made during the Korean conflict. Therefore, it is appropriate to review the background for the decision and to estimate its effects.
Vaccination against Japanese encephalitis had been practiced by the Russians since 1941 (9), and in the United States a formalinized mouse brain vaccine was developed by Sabin and others for trials in the U. S. Army (10). This mouse brain vaccine was safe and potent as judged by laboratory tests (10). Inoculation of over 250,000 persons on Okinawa with this type of vaccine in 1945 and 1946 (11) did not provide sufficient data to draw a firm conclusion as to its efficacy in engendering immunity to Japanese encephalitis. Dr. Sabin claimed that no case of demyelinating encephalitis occurred in these vaccinated troops. However, he noted three cases of polyneuritis (one fatal) in this vaccinated group but also pointed out that patients with the same signs were present during this period in non-vaccinated troops.
In 1945 and 1946, commercially prepared mouse brain vaccine was used in the Far Eastern Theater (12). The new chick-embryo-type Japanese encephalitis vaccine was introduced into the Far East in 1946 (12), when, in this year and in 1947, the Army Medical Service Graduate School supplied over 800,000 ml. of mouse brain vaccine. These vaccines were effective in protecting mice against challenge with Japanese encephalitis virus and in eliciting neutralizing antibodies in 60 percent of human volunteers inoculated under controlled conditions. Routine immunization of all troops in the Far East Command with the chick embryo vaccine was adopted in 1948 and continued until the fall of 1951.
Of 11,338 persons inoculated with Japanese encephalitis chick embryo vaccine, on whom observations were made in the Far East and the records forwarded to The Surgeon General's Office, eight developed reactions of an allergic nature. Three of these were classed as severe and anaphylactic in nature with onset varying from 20 minutes to 24 hours after administration of vaccine. The other five had moderate reactions characterized by fever and urticaria. There were no fatalities (13).
Trials of the vaccine were also made in civilians and those trials in Okayama, Japan, offered the most complete results (6). In 1946 over 14,000 children in Okayama received three inoculations of commercially prepared mouse brain vaccine and in 1948 and 1949 almost 40,000 additional children were vaccinated in the same manner with the standard Army chick embryo vaccine. After the initial series of inoculations each child was revaccinated yearly until 1950 with one stimulating dose of the chick embryo vaccine. Thus, during the period 1946-1949, over 50,000 children between 5 and 10 years of age were vaccinated, leaving other children unvaccinated.
This population was observed yearly and the results (quoted from Dr. Sabin's report to the Virus and Rickettsial Commission, Armed Forces Epidemiological Board) (14) were as follows: ". . . the incidence of the disease in the unvaccinated group turned out to be much less than was anticipated. The evaluation of the results is further less than was anticipated. The evaluation of the results is further complicated by the fact that only a varying and sometimes small proportion of the clinically diagnosed cases were studied serologically. Nevertheless, during the years of 1948 and 1949, when chick embryo vaccine was administered and a sufficient number of clinically diagnosed cases occurred in the group under investigation, the incidence was 7.6 and 9.2 times higher in the unvaccinated than in the vaccinated group. While the data are not statistically significant for any one year, they do achieve such significance when the results for the years 1947 to 1949 are combined. Even in 1950, when no vaccine was admin-
istered but a residual effect from the previous years might still have been in operation the incidence was 4.6 times greater in the unvaccinated group. It should be noted that cases, not all confirmed, occurred among the vaccinated, but the incidence was at all times greater among the unvaccinated. However, these results cannot be completely transposed to individuals of Army age, since it has been found that the same dosage of vaccine gives rise to a higher incidence of neutralizing antibodies in children than in adults . . . ."
The value of the vaccine in protecting U. S. troops was more difficult to judge. This was due to the lack of control of unvaccinated troops, their rapid movements, and the lack of complete individual immunization records. Using those data available, however, a reconsideration of the value of this vaccine was made by certain members of the Virus and Rickettsial Disease Commission, Armed Forces Epidemiological Board, in the fall of 1951. Briefly, the considered opinion (15) was:
There is some evidence that the annual administration of this vaccine to Japanese children has lowered the incidence of clinically reported cases in Okayama prefecture (in Japan).
The evidence so far fails to indicate that vaccination of the U. S. troops in Japan and Korea has been effective as a prophylactic measure. No controlled studies have been made in American troops and the data collected have not proved conclusively that the vaccine is worthless. It appears, however, that the vaccine is of dubious value as a prophylactic measure for the protection of troops.
On the basis of these recommendations, the commercial production of Japanese encephalitis vaccine was stopped and the Adjutant General ordered that, "effective with the 1952 season," routine vaccination of personnel in the Far East Command with Japanese encephalitis vaccine cease (16).
The failure of the vaccine has been attributed by some to low potency and lack of stability. At the present time no vaccine is available for routine vaccination of military personnel against Japanese encephalitis but a search is still being carried out at the Army Medical Service Graduate School for a safe, potent and stable immunizing material to be used against this disease. To achieve this, various procedures have been attempted without yielding any preparation with advantages over formalinized mouse brain vaccine, already used in the field. The procedures have included investigations of various methods of inactivation of Japanese encephalitis virus such as the use of ethylene oxide, acetone, high-speed cathode rays, ultraviolet light, ultrasonic vibration, and various levels of formaldehyde (17); various methods of purification using protamine sulfate, norite, cellite, or
attaclay (17); attempts to obtain higher titers of virus to use in a vaccine (17); and attempts to attenuate the infectivity of the virus for use as a live virus vaccine (17). At the present time a satisfactory immunizing agent against Japanese encephalitis is considered highly desirable.
Recent Research on Japanese Encephalitis
Most of the recent advances concerning Japanese encephalitis have been in its ecology and this approach has been most fruitfully pursued at the 406th Medical General Laboratory in Tokyo (2, 3, 6). It had already been found by them that Japanese encephalitis epidemics occurred at the same time as the Culex tritaenorrhynchus mosquito population peak; moreover, without this peak, epidemics did not occur. Even with this information it was not known how the mosquito became infected and potentiated the virus during inter-epidemic seasons. Investigations on the ecology of this disease in Japan revealed that certain migrating fowl also experienced infection with Japanese encephalitis virus and the mosquitoes associated with them were found to contain active virus but at approximately the same time that epidemics occurred in man. This does not indicate that the fowl is a reservoir of infection but indicates that it may be vitally concerned in the potentiation of the epidemic, once started. It should be mentioned that viral infections had previously been diagnosed in animals in Japan (18) when no visible epidemic was occurring in human beings in the same locality.
The use of hemagglutination-inhibition procedures for demonstration of antibodies to Japanese encephalitis as well as to certain other arthropod-borne viral diseases has been described in the literature (19, 20) and offers hope as an additional diagnostic tool. Although much experience needs to be obtained with any new diagnostic tool in order for it to be of value and to establish suitable criteria for its use as a routine diagnostic aid, this procedure is being evaluated at the present time in Japan (3). In conjunction with the complement-fixation test and neutralization test it may form part of a widely varied armamentarium of available diagnostic tests.
At the time of the Korean conflict, studies on Japanese encephalitis were proceeding in other geographical locations: in 1951, a U. S. Army Medical Research Team, in conjunction with British scientists, isolated a virus from a fatal case of encephalitis in Malaya which was later identified as Japanese encephalitis virus (21). Subsequently other isolations of this same virus were made by British investigators in Malaya (22, 23).
Serological studies carried out by the Japanese in World War II (24) and by the U. S. Army Medical Research Team in 1951 (25) indicated that 75 percent of the Malayan indigenous population tested had evidence of past infection with Japanese encephalitis virus. Also most pigs, bovines, equines, and dogs showed evidence of past infection. This is in no way different from serological studies carried out in Japan (18, 26) but epidemic encephalitis has been reported very rarely in Southeast Asia (25). The lack of outbreaks is thought to be due to the possible presence of arthropod vectors throughout the year in this tropical region but this does not explain the quantitative lack of clinical cases one would expect in a population where Japanese encephalitis virus is continually present. A semi-permanent U. S. Army laboratory was established in 1953 at the Institute for Medical Research, Kuala Lumpur, Malaya, and there further studies on the ecology of Japanese encephalitis as well as other arthropod-borne viral diseases are being carried out.
Using published results in which neutralizing antibodies to Japanese encephalitis in man and animals have been described, Japanese encephalitis virus has been isolated and identified, or cases of Japanese encephalitis have been proved, a chart of the probable distribution of Japanese encephalitis in the world has been constructed as figure 1. Although the zones of Japanese encephalitis incidence appear dispersed, as exemplified by serological survey results in the cities of Kirin, Tientsin and others, it would seem logical from the data to consider Japanese encephalitis present, not as foci, but as a broad endemic band in all of Eastern Asia (4, 7, 9, 21, 22, 24, 25, 27, 32), at least as far north as the Maritime District of Siberia and extending south well into the East Indies, possibly even into New Guinea and Australia. This band would include the islands off the coast of Asia; of Japan (1, 26), Okinawa (5, 11, 28), Formosa (24, 33), Guam (34), the Philippine Islands (24, 35, 36), and Borneo (25). Moreover, it is believed on the basis of serological surveys that the disease extends to the westward in Southern Asia at least as far as India (37); antibodies to this virus were even reported at one time in the sera of African residents (38). However, in certain of these areas, notably Africa, where serological surveys indicate that West Nile virus is present, such data must now be interpreted with some caution; since an antigenic relationship is known to exist between West Nile and Japanese virus, and may exist between other "tropical viruses" and the Japanese encephalitis virus (39).
In 1951 an epidemic of encephalitis occurred in Australia and from this outbreak an infective agent was isolated (40) and identified as a newly recognized arthropod-borne virus called Murray Valley encephalitis virus, closely related antigenically to Japanese encepha-
litis virus (41). Its distribution and importance outside Australia are not known. However, because of its very close antigenic relationship to Japanese encephalitis virus it could logically be considered a variant of Japanese encephalitis virus in the same way as influenza A´ is a variant of influenza A. Interesting speculations have been published that this newly discovered virus disease is a recurrence of Australian X disease last seen in Australia in 1925 (42). Its distribution in Australia, and possibly in New Guinea (43), is indicated also in figure 1 in lighter shading. It should be pointed out that the limits of the endemic Japanese encephalitis areas, as represented on this map, are delineated not by evidence of the lack of disease but by our ignorance.
Russian Spring-Summer Encephalitis
Russian spring-summer encephalitis (RSSE), a tick-borne disease, was not observed in any American troops in the Far East nor has
any report been received of RSSE in our troops in Korea. Louping ill (LI), serologically similar (44) and even indistinguishable (45) from RSSE, is a cause of epizootics in sheep in the British Islands but the relationship of these epizootics to the epidemics of RSSE is not clearly understood. The probable geographic distribution of RSSE and LI is indicated in figure 2.
It is unfortunate that we do not have more accurate data on the distribution of this important disease. However, language barriers as well as the lack of published experimental data require us to form only general conclusions as to the location of those zones in the Soviet Union where RSSE has existed and may now exist. RSSE is predominantly a disease of the U. S. S. R. (1) extending from the steppes of Russia in East Siberia to continental Europe where the disease has been recognized in West Russia. Outbreaks have been reported recently from Central Europe; in Czechoslovakia (46), as well as in Austria and Slovenia. (47). Here it is termed by some workers as Central European encephalitis. Louping ill exists predominantly in the British Islands where it has been endemic for over a century and only a few cases of human infection under natural conditions have been reported from the area representing the LI distribution (48-50).
Neutralizing antibodies to RSSE virus were found in the sera of a few inhabitants of India (37) but as yet such antibodies have not been reported in Southeast Asia, Japan or Korea (24). Its presence in Khabarovsk, in the eastern Maritime Province of Siberia, was dangerously close to the area of combat during the Korean conflict. This severe neurotropic virus disease, as judged by morbidity, case fatality rate and presence of residual signs, has not yet been recognized in Korea nor have neutralizing antibodies to this virus been demonstrated in small numbers of sera tested from Japanese nationals (17) and Okinawan natives (5).
Russian spring-summer encephalitis mouse brain vaccine used for vaccinating laboratory personnel working with this virus has been satisfactory for eliciting neutralizing antibody responses in these individuals and for protecting mice against subsequent challenge with RSSE viruses. In the hands of the Russians, the vaccine was reported to decrease the rate of infection in Siberian residents (1). It appears, however, that this vaccine cannot be lyophilized without losing large amounts of antigenicity (17). Therefore, it must be left in the wet state under refrigeration and under these conditions it becomes antigenically unsatisfactory within 60 to 90 days (17, 27).
Other Arthropod-borne Virus Diseases, Rabies and Poliomyelitis
In the years preceding and during the Korean conflict, St. Louis encephalitis, Western equine encephalomyelitis and Venezuelan equine
encephalomyelitis were reported only in the Western Hemisphere. However, Eastern equine encephalomyelitis, another disease of the Americas, was recognized in the Philippine Islands (51).
Although rabies never became a serious problem in the Far East Command and only one human case was recorded in U. S. troops (6), nevertheless, laboratory facilities were frequently employed in the Far East on diagnostic work on specimens submitted from animals suspected of having rabies. During this period, ideas regarding prophylaxis against this disease in exposed human beings, guided by the recommendations of investigators in this field (52), swung toward administration of immune serum coupled with fewer doses of the standard rabies vaccine. As yet, the use of this method in the Army is reserved for those persons experiencing possible accidental infection with rabies in the laboratory. Although there are other worth-while recent advances in the prophylaxis against this disease, such as the World Health Organization sponsored field use of the avian adapted Flury vaccine in dogs (53), these had little or no effect on the practice of medicine in Japan and Korea during the period of the Korean conflict.
Table 3. Number of Cases of Paralytic Poliomyelitis in Military Forces, Their Dependents, and Department of the Army Civilians in Various Areas of the FECOM During the Korean Conflict
Clinically diagnosed paralytic poliomyelitis accounted for about one-fourth as many cases of central nervous system infection (3, 8) during this period as did infectious encephalitis (table 3). The technical difficulties in laboratory diagnosis of poliomyelitis are only now being resolved; hence, little has been done among troops in the Far East regarding laboratory proof of inapparent infection and non-paralytic disease caused by the three antigenic types of poliomyelitis virus. Nevertheless, these forms of the infection undoubtedly are fairly common in such personnel as they are in any group with a high proportion of susceptibles that live in contact with relatively unsanitary populations in which poliomyelitis virus circulates freely. In one group of 18 soldiers in Japan who were diagnosed clinically in
1946 as having aseptic meningitis, 2 were shown by laboratory studies to have suffered an infection with poliomyelitis virus (54).
No isolation of Coxsackie agents was reported from the military forces in the Far East Command during the Korean War. However, the members of this ubiquitous group have become so numerous and their identification so cumbersome that routine diagnosis is usually avoided.
Lymphocytic choriomeningitis was not reported as a cause of disease in the Far East Command during or just preceeding the Korean conflict. Moreover, materials from 47 cases of aseptic meningitis from this theater were studied in the laboratory for evidence of infection with the agent, with negative results (3). However, with the wide geographic distribution of lymphocytic choriomeningitis virus in mice, it would be presumptuous to conclude that this disease has never occurred in troops of the Far East Command.
We should not close this discussion without mentioning that group of heterogeneous agents conveniently called the "tropical viruses." These viruses, isolated in Africa or South America, sometimes from man but usually from mosquitoes, produce a fulminating encephalitis in mice when inoculated intracerebrally, but the nature of most of the diseases caused by these viruses under natural conditions is yet unknown. They are, no doubt, arthropod-borne viruses but whether in man most of them are neurotropic in character remains to be determined. Much effort is being expanded currently by groups from the Rockefeller Foundation and the Army Medical Service Graduate School to determine the distribution of these viruses in the world and their importance as causes of diseases in man. These agents include: Semliki (55), Uganda S (56), Ntaya (57), Anopheles A (58), Anopheles B (58), Wyeomyia (58), Zika (59), Ilheus (60), West Nile (61), Bunyamwera (62), Mengo (63), and Bwamba, (64).
No discussion of neurotropic viruses in Northeast Asia could neglect to mention at this time (April 1954) the additional available information on the occurrence of arthropod-borne viral agents in Southeast Asia, particularly Indochina. Recent, and as yet unpublished, serological surveys undertaken in our laboratory in collaboration with other groups of workers, as well as other recently published results (65) indicate that infections with Zika, Ntaya, Ilheus, and Dengue I and II viruses are almost as frequent in the population of Malaya as is that with Japanese encephalitis virus. Furthermore, Semliki Forest and Uganda S agents have left a few antibody trails in this area but Anopheles A and B, Bunyamwera, Bwamba and Wyeomyia have not. Little is known about the occurrence of these agents in the more northerly parts of Southeast Asia; however, the flora and fauna of much of this general region are similar and one would anticipate that
the viruses of Malaya spread beyond its geographic boundaries. Japanese encephalitis virus, at least, is found in Indochina and Burma; during World War II Japanese investigators found antibodies against this agent in 44 percent of the native peoples of Hanoi and in 52 percent of the horses in Burma (24).
What new things have we learned about the neurotropic viruses as military problems from the Korean experience? The following statements answer the question in part at least.
1. Japanese encephalitis has not yet been brought under adequate control in armies in the field by either immunization or mosquito control measures. Additional work is indicated in preventive measures.
2. Despite this, Japanese encephalitis has not turned out to be the awe-inspiring epidemic disease which the Americans in 1942 thought it might prove to be, when susceptible populations were brought into endemic areas. Four hundred and two cases of encephalitis occurred in American military forces in Korea during the years 1950 to 1953 and about half of these were proved to be caused by Japanese encephalitis virus.
3. Paralytic poliomyelitis was the second most important neurotropic virus disease among troops in Korea with 120 cases occurring over the period 1950-53. With the increasing numbers of susceptibles (no neutralizing antibodies against one or more of the three types of poliomyelitis virus) among young American adults, poliomyelitis can be expected to be an increasing problem among troops maintained under unsanitary conditions or in contact with foreigners with unsuitable habits.
4. Other neurotropic viral diseases were of relatively little importance during the Korean conflict. No evidence of infection with Russian spring-summer encephalitis virus has been encountered in our forces in Korea. Fifty to a hundred sporadic cases of central nervous system disease in which a viral etiology was suspected occurred in the Far East annually from 1950 to 1953, but the responsible etiological agents in most instances remained undetermined, a finding also common in other geographic areas.
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