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KOREAN HEMORRHAGIC FEVER

HO WANG LEE
The Institute for Viral Diseases, Korea University Medical College, Seoul, Korea
INTRODUCTION

Epidemic hemorrhagic fever with renal syndrome was recognized for the first time in 1951 among United Nation troops (1). Since that time it has been known as Korean hemorrhagic fever (KHF) and has remained endemic near the Demilitarized Zone (DMZ) between North and South Korea. In recent years the disease has invaded the southern parts of the Korean peninsula and 100 to 800 hospitalized cases are clinically diagnosed each year (Table 1).

KHF is an acute infectious febrile, often fatal, otherwise self-limited, illness of viral etiology characterized by severe toxemia, widespread capillary damage, hemorrhagic phenomena and renal insufficiency (2).

Similar diseases to KHF as shown in Figure 1, have been described by Japanese from Manchuria (3,4,5), from the Soviet Union (6,7), from Scandinavia (8,9,10), from several countries in Eastern Europe (11) and recently from Japan (12).

In early 1940's Japanese and Russians reproduced hemorrhagic fever by injection of urine and blood of the patients into monkeys (4) and volunteers. The injection of a suspension of Trombicula mite obtained from Apodemus agrarius into human caused hemorrhagic fever, and mites have been suspected as its reservoir(13). Many attempts have been made to isolate the causative agent of KHF and clinically similar disease.

In 1976 Lee and Lee (14) succeeded in demonstrating an antigen in the lungs of the striped field mouse, Apodemus agrarius coreae, which gave immunofluorescent reaction with sera from patients convalescent from KHF and named it as Korea antigen. In 1977 Lee and Tamura 15 reported that epidemic hemorrhagic fever in Japan is related serologically to KHF agent, if not identical. Very recently, Lee et al. (16) have reported that this antigen is the etiologic agent of KHF for the first time and convalescent sera from hemorrhagic nephrosonephritis in the Soviet Union were positive for antibodies.

This presentation is the review of KHF, recent progress of KHF research and serologic relationships between KHF agent and other hemorrhagic fevers of viral and unknown etiology.

EPIDEMIOLOGY

KHF has not been described previously in Korea before 1951, but some workers consider that its epidemicity and pathogenesis suggest the possibility of endemic disease before 1950 and it may had been missed because of lack of knowledge and its rare occurrences in rural areas due to special ecology.

After the Korean War, the disease was designated as endemic in the area of DMZ and since then has gradually spread southwesterly, Fig. 2. A conspicuous increase in the number of the civilian cases was observed in 1970's. However, most cases are still reported near the area of the DMZ where Korean soldiers are stationed. However, considering its epidemiological changing status of KHF for the past 25 years, the imported germ theory in which it originates possibly from North-Eastern part of Asia in the period of Korean War, could not be excluded (17). While a few cases usually occur throughout the year, the seasonal pattern of outbreaks marks in two peaks, small one is in June and large peak in October through December, Fig. 3. The occurrence of more than one case in the same house is extremely rare. Nor has been any information to implicate food, water, clothing in the transmission of KHF. The disease appeared to affect most frequently the age group of 21-50 years although disease cases occur in both sexes, the disease is significantly more frequent in males than in females with the ratio of two to one (18). Main victims are farmers and soldiers stationing in the field. Small numbers of patients have been reported from the surrounding towns recently. The distribution of immunofluorescent antibodies to KHF agent is 1% in city residents, 3.8% in farmers of endemic areas and 1.1% in the soldiers residing in the endemic areas. The antibodies are present some 14 years after the recovery from the disease and there is no case of reinfection yet (16).

The reservoir of KHF in the endemic areas in Korea is Apodemus agrarius coreae. There are about 7 species of field rodents in the endemic areas of KHF but only Apodemus species contained KHF agent (14,16). Three patients had occurred among the personells who dealt with naturally and experimentally infected Apodemus agrarius coreae with KHF agent in our laboratory.

The mode of transmission of the agent from infected Apodemus to normal Apodemus and to man are not clarified yet. As regards arthropod vectors, Asanuma (13) and Traub et al. (19) suggested that Trombiculla pallida was the species most closely fitted to the seasonal incidence of KHF.


Fig. 1 Map showing endemic areas of hemorrhagic fever with renal syndrome


Japan


Epidemic Hem. Fever


Bulgaria


Epidemic Hem. Fever


Korea


Korean Hem. Fever


Hungaria


Epidemic Hem. Fever


China


Epidemic Hem. Fever


Czechoslovakia


Epidemic Hem. Fever


Inner Mongolia


Mongolian Hem. Fever


Finland


Nephropatia Epidemica


USSR


Hem. Nephrosonephritis


Sweden


Endemic Benign Nephropatia


Yugoslavia


Epidemic Nephritis

   

TABLE 1
HOSPITALIZED CASES OF KOREAN HEMORRHAGIC FEVER PATIENTS


Year


US Forces


ROK army


Korean civilian


Total


1951


827

   

827


1952


833

   

833


1953


455

   

455


1954


307

 

19


326


1955


20

   

20


1956


28


26

 

54


1957


13


21

 

34


1958


15


20

 

35


1959


79


47

 

126


1960


10


185

 

195


1961


27


341

 

368


1962


29


311

 

340


1963


11


257

 

268


1964


22


205


18


245


1965


99


110


2


211


1966


36


82


11


129


1967


31


86


13


130


1968


28


102


13


143


1969


9


134


8


151


1970


13


221


85


319


1971


2


358


311


671


1972


0


203


186


389


1973


0


237


241


478


1974


0


251


170


421


1975


1


370


466


837


1976


4


304


521


829


1977


7


212


288


507


Total


2,906


4,083


2,352


9,341


Fatality


5.00%


6.50%


8.00%


6.50%

ETIOLOGIC AGENT

In early 1940's Japanese and Russians successfully reproduced hemorrhagic fever by injection of urine and sera of the patients in the acute stage into monkeys (4) and volunteers (6,7). Filtered sera of the patients were also produced clinical symptoms, so this disease has been suspected as being of viral origin. Many attempts have been made to isolate the causative agent of KHF and clinically similar diseases. A Russian report of cultivation of a virus in cell cultures from patients with hemorrhagic nephrosonephritis (20) has not been confirmed.

In 1976 Lee and Lee succeeded in demonstrating an antigen in the lungs and kidneys of the Apodemus agrarius collected in the endemic foci, which gave specific immunofluorescent reaction with convalescent sera from KHF patients (14) and named it as Korea antigen. Very recently, Lee et al. have demonstrated that this antigen is the etiologic agent of KHF and is produced by a replicating microbe (16). It passes 0.1 micro millipore filter and antibiotics are ineffective. Under the electron microscope round virus-like particles of about 50 nm in diameter can be observed in crystalline array at the cytoplasm of infected pulmonary epithelia of Apodemus as shown in Fig. 4 (21).

All attempts to establish the KHF agent in hosts other than Apodemus agrarius have been unsuccessful. Various species of laboratory animals as well as more than 20 types of cell cultures all failed to show specific immunofluorescent antibody staining after inoculation of the agent. Apodemus agrarius coreae infected either naturally or experimentally have never showed the clinical symptoms (16). When KHF agent is inoculated the agent begins to appear at lungs 10 days later. After then it can be identified at kidneys, liver and submaxillary glands. The most amount of agent can be detected toward 20 days, and then start to decline gradually. However, it was still able to be detected after day-60. The agent was serially propagated in Apodemus agrarius as shown in Table 2 and study on characteristics of the agent is in progress.

Immunofluorescent antibody responses to KHF agent after subcutaneous inoculation into rabbits were demonstrated and, the antibodies started to appear at 7 days, reached maximum at 14 days and declined slowly by 60 days.



Fig. 2 : Distribution of KHF cases in Korea



Fig.3 Cumulative prevalence of Korean Hemorrhagic Fever from 1951 to 1977.

HUMAN INFECTION
Incubation period is usually 13-22 days, varying from 9 to 42 days. The disease is an acute disease characterized by sudden onset with fever of 3 to 6 days with chills, conjunctival injection, prostration, anorexia, vomiting, hemorrhagic manifestations which begin about the third day, proteinuria about

the fourth day, and hypotension about the fifth, renal disorder for several weeks. The widespread abnormalities of blood vessels, chiefly arterioles and capillaries have been considered as main and initial defect which lead to impairment of function in a number of organs. The resulting clinical, laboratory and functional features are very diverse and there is considerable variation among patients, not only in the incidence of various manifestations of the disease but also in the severity of the illness (2). Moreover the symptoms and signs of the disease are in no way specific and in the early phases diagnosis may be difficult, particularly in respect to differentiation from other febrile illness such as infections of the upper and lower respiratory tract. Approximately 70% of cases show mild course and 30% have several complications, such as shock, bleeding, renal failure, electrolyte imbalance, pulmonary edema, and secondary bacterial infections.

The first immunoglobulin of KHF patient is IgM. This is followed by the appearance and increase of IgG At the same time the immunofluorescent and neutralizing antibodies are produced. They start to appear right after onset of the disease and their levels reach the peak at the time lapse of around 2 weeks. Thereafter they slowly decline over a certain period but (14 years after the experience the antibody continues to be produced at low level. The specific antibody has been identified from the serum of the KHF patients showing not only typical severe clinical symptoms but also mild and subclinical cases (16).

DIAGNOSIS

Due to the lack of specific tests for the etiologic agent of KHF till 1976, clinical manifestation with acute renal failure and laboratory findings such as proteinuria, leukocytosis, thrombocytopenia, and elevated blood urea nitrogen and epidemiologic findings assist in establishing the diagnosis (2,23) and in the fatal case is confirmed by the characteristic lesions (24,25).

In 1976 Lee and Lee (14) demonstrated specific antigen and antibodies of KHF for the first time, and since that time serologic diagnosis of KHF patients has been routinely employed in their laboratory. Specific serologic diagnosis of KHF can be made by demonstrating the increase of specific immunofluorescent antibodies against KHF agent with the sera collected 2 times at the interval of 1 week during course of illness.

Isolation of the agent is difficult but may be recovered from serum taken in the acute stage of the infection (16).

Infected Apodemus agrarius with KHF agent can be recognized by observing the pulmonary and renal tissues by means of FA technique (14,16). Whether it has been infected or not in the past can be realized by detecting specific antibodies from the serum.

RELATIONSHIP BETWEEN KHF AND OTHER VIRAL HEMORRHAGIC FEVERS

In 1962 Gajdusek (11) described in detail natural endemic foci of hemorrhagic fever with renal syndrome and Southern Soviet hemorrhagic fever that occurring from many parts of the world and, possibility of their close relation for the first time. However, there has been no laboratory diagnostic method to study the serologic relationship of similar hemorrhagic fevers because of lack of knowledge on the etiologic agent of the disease.

Very recently, Lee et al. reported that antisera of Lassa, Machupo, lymphocytic choriomeningitis, Pichinde and Tacaribe of the arenavirus group, Marburg and Ebola were negative to KHF agent by IFA technique. In contrast, close serologic relationships between KHF and hemorrhagic fever with renal syndrome in the Soviet Union (16) and epidemic hemorrhagic fever in Japan (15) were established, shown in Table 3.

Furthermore, relationship between KHF agent and other hemorrhagic fevers of unknown etiology that occurring in Scandinavia (9,10) and in Eastern Europe (11) remains to be solved.

TABLE 2
PROPAGATION AND NEUTRALIZATION OF KHF AGENT IN APODEMUS AGRARIUS COREAE


Passage number


Total days in Apodemus

Cumulative log of dilution of original inoculum


Infectivity for Apodemus


Clinical symptom


Titration Apodemus in ID50 /0.1 ml


Neutralization with immune serum ID50/0.1ml in Apodemus


1


20


1.0


10/16


0/16

   

4


91


4.0


7/28


0/28

   

8


171


8.0


12/12


0/12


10^5.3


< 10^1.0


11


231


21.0


21/21


0/21


10^7.2

 

16


324


38.0


15/15


0/15


10^6.7


< 10^1.0


Fig. 4 : Electron micrographs of KHF agent in lung tissues of Apodemus agrarius coreae

A. Virus-like particles showing clustering in pulmonary epithelium.
B. Virus-like particles in crystalline array, round and about 50 nm in diameter.

TABLE 3
SEROLOGIC RELATIONSHIP BETWEEN KHF AGENT AND OTHER VIRAL HEMORRHAGIC FEVERS


Antigen


Name of antiserum


Immuno-fluorescent antibody test


Lung tissue of infected Apodemus with KHF agent76/118, 6th passage



Anti-Pichinde monkey serum


-


Anti-Tacaribe monkey serum


-


Anti-Machupo human serum


-


Anti-Lassa human serum


-


Anti-LCM guinea pig serum


-


Anti-Ebola human serum


-


Anti-Marburg human serum


-


Convalescent sera of KHF


+


Convalescent sera of hemorrhagic fever with renal syndrome - Soviet Union


+


Convalescent sera of epidemic hemorrhagic fever - Japan


+

SUMMARY

Hemorrhagic fevers with renal syndrome are being reported from many parts of the world. It has been reviewed and discussed on KHF and similar diseases which occur all over the Asian and European Continents.

The number of KHF patients in not only soldiers but also civilians tend to increase every year. So it is urgent need to take some measures to prevent this disease. Recently the etiological agent of KHF was isolated, the natural reservoir was demonstrated as Apodemus agrarius coreae and the serological diagnosis also comes to be available, by means of immunofluorescent antibody technique.

The etiological agent did not react with the antisera of arenaviruses but did with convalescent sera of Japanese epidemic hemorrhagic fever and Soviet hemorrhagic nephrosonephritis patients, showing close serological relationship. The relationship between KHF and the similar diseases of unknown etiology occurring in Scandinavia and Eurasia remains to be answered.

ACKNOWLEDGEMENTS

Supported by the U.S. Army Medical Research and Development Command, Washington, D.C. 20314 under Grant Nº DAMD17-77-G-943.

REFERENCES
1. Smadel, J.E. (1951) Epidemic hemorrhagic fever, Amer. J. Pub. Health, 43: 1327-1330.
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5. Kitano, M.A. (1944) A study of epidemic hemorrhagic fever, J. Manchou Med., 40: 191-209.
6. Smorodintsev, A.A., et al. (1944) Etiology and clinics of hemorrhagic nephrosonephritis, Moscow Medgiz, 26-47.
7. Smorodintsev, A.A., et al. (1964) Virus hemorrhagic fevers, Gimiz Gosndrastvennse Izdatel'stro Meditsinskol Literatury, Leningrad, 1963, (Israel program for Scientific Translation. Jerusalem).
8. Myhrman, G. (1951) Nephropathia epidemica, a new infectious disease in northern Scandinavia, Acta. Med. Scand., 140: 52-56.
9. Lähdevirta, J. (1971) Nephropathia epidemica in Finland, Ann. Clin. Res., 3: 12-17.
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13. Asauma, K. (1952) Two new species of the blood sucking mites parasitic on the striped mouse, Apodemus agrarius from Manchuria (Acarina; Laelaptidae) Miscellaneous Report of Research Institute of Natural Resources, (Tokyo), 25: 86-92.
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15. Lee, H.W. & Tamura, M. (1977) Study on serologic relationship between Korean hemorrhagic fever and epidemic hemorrhagic fever in Japan, Abstract of The 25th Academic Meeting of the Society of Japanese Virologist, Oct. 22, Osaka, Japan, page 212.
16. Lee, H.W. et al., Isolation of the etiologic agent of Korean hemorrhagic fever, J. Infect. Dis., in press.
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20. Gavrilyuk, B. & Smorodintsev, A.A.(1971) Isolation of hemorrhagic nephrosonephritis virus in cell cultures, Archiv für die gesamte Virusforschung, 34: 171-178.
21. Lee, P.W. & Lee, H.W. (1978) Electron microscopic findings of Korean hemorrhagic fever agent, in press, J. Korean Med. Assoc.
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DISCUSSION
S.R. Pattyn : Has this material been inoculated on mycoplasma medium ?
Ho Wang Lee : It does not grow. Antibiotics are without effect on this agent.

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