International Notes Korean Hemorrhagic Fever

Fourteen cases of Korean hemorrhagic fever (KHF) were identified among 3,754 U.S. Marines who participated in a joint U.S.-Korean military training exercise in the Republic of Korea (ROK) from late September to mid-November 1986. Ten individuals were hospitalized; two of these died. Cases were confirmed by serologic testing and by postdeployment screening of serum from 2,053 of the participants.

Korean hemorrhagic fever occurs frequently among rural civilians and Korean military personnel. However, in recent years, fewer than 10 cases have been recognized annually among U.S. troops. The Marine units participating in the military exercise were from camps in Okinawa, Japan, where KHF has not been reported. In addition, KHF had not been previously reported in association with this exercise, which is held annually, even though most of the training takes place northeast of Seoul in an area where the disease is endemic. There was nothing unusual about the exercise, except that it occurred approximately 1 month earlier than those held in previous years. The weather was milder; conditions were warm, dry, and dusty until early November.

Most (1,969) of the U.S. force was quartered in tents at Uncheon Base Camp, within the perimeter of a permanent ROK Army garrison camp southwest of Uncheon. Another 1,105 Marines were at Watkins Range, about 2 km northwest of Uncheon Base Camp. The remaining 680 troops were engaged in aviation activities at various locations distant from the base camp.

The patient with the index case became ill on October 26. The other patients had onsets of illness throughout the ensuing 51 days (Figure 1). The last patient identified became ill on December 17, 38 days following his departure from Korea. The 10 hospitalized patients initially had nonspecific flu-like illnesses. The four nonhospitalized patients had a variety of symptoms. Prominent findings on admission included fever (100%), fatigue (100%), headache (90%), conjunctival injection (90%), thrombocytopenia (100%), and proteinuria (100%).

The overall attack rate was 4.6/1,000 among the total group of soldiers deployed in the Uncheon area (14/3,074) and 7.0/1,000 among the group that was screened (14/1,985). Cases occurred in several different units, but 13 of the 14 were among the 1,969 persons housed at Uncheon Base Camp. One was among the 1,105 persons housed at Watkins Range (rate ratio = 7.3; 95% confidence interval, 0.96 to 55.7). At least 10 of the patients lived in tents pitched along the periphery of the camp in an area near high grass and scrub brush. Six of the 14 patients (43%), including the two who died, were from a single engineer company of 118 men and women. All of the affected persons in this company were assigned to two of the three company platoons (attack rates, 54/1,000 and 94/1,000).

All of the soldiers who had been tested for antibody completed a questionnaire within 2 months of their return from Korea. In addition, 11 of the 12 surviving patients were interviewed. No temporal clustering by unit, field exercise area, environment, or work-related factors could be identified as risk factors for infection.

Fifteen persons with IgM antibody titers greater than 1:3,000 were identified by an enzyme- linked immunosorbent assay (ELISA) specific for hantaviruses. Thirteen were confirmed by indirect immunofluorescence assay (IFA) (greater than 1:128) and plaque-reduction neutralization (PRN) (greater than 1:20). The fourteenth case was diagnosed by IFA and PRN alone. Neutralization tests distinguished Apodemus-associated (Hantaan) virus from urban rat-associated (Seoul) virus. All sera that had been confirmed as positive yielded titers at least fourfold higher against prototype Hantaan virus than against Seoul virus.

Approximately 150 cases of KHF were reported among ROK military forces between September and December 1986. Nine cases of KHF were identified among ROK troops stationed in the Uncheon area during the time of the exercise. Two of these occurred among the approximately 1,500 ROK Marines participating with the U.S. forces. Differential neutralization revealed Apodemus-associated infection in these patients as well. Reported by: CDR E Pon, LCDR B Merrell, LCDR R Thomas, US Navy Environmental Preventive Medicine Unit #6, Pearl Harbor, Hawaii. LT A Corwin, Consolidated Preventive Medicine Svc, US Naval Hospital, Okinawa, Japan. MAJ B Diniega, MAJ K McKee, Walter Reed Army Institute of Research, Washington, DC. LTC T Ksiazek, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland. H-W Lee, Korea Univ Medical College, Seoul, Korea.* Special Pathogens Br, Div of Viral Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Hemorrhagic fever with renal syndrome (HFRS), sometimes known as Korean hemorrhagic fever, is a viral infection acquired from rodents, principally the species Apodemus agrarius, Rattus rattus, and Clethrionomys glariolus. Human infections are widespread, particularly in Asia north of the Himalayas. For example, in the People's Republic of China, HFRS is responsible for over 100,000 reported cases annually, with the reported incidence increasing rapidly in the last few years (1). This increase may be the result of recent changes in agricultural practices, which may have altered rodent populations. The disease is undoubtedly ancient, but was first recognized independently and reported in the 1930s in Scandinavia and in Manchuria during the Japanese campaign (2). Most of the early recognized outbreaks were associated with military maneuvers, especially where troops had bivouacked in the open or had been involved in trench warfare. During the Korean conflict, at least 3,000 United Nations troops were affected (3,4). The prototype virus was isolated in 1978 and named after the Hantaan river in Korea (5).

The group of closely related viruses causing HFRS have recently been classified as the genus Hantavirus, forming a subgroup of the family Bunyaviridae (6). The virus is usually acquired directly from rodents, in which it establishes a silent but persistent infection. In these rodents, the virus is detected primarily in the lung and kidney, where it is able to persist in the presence of serum antibodies. Large quantities of virus are excreted throughout life. Humans may become infected through minor cuts and abrasions contaminated with rodent urine or feces, but evidence also suggests that aerosol infection may occur where virus contamination is heavy. Infections have also been reported among laboratory personnel in the Soviet Union, Japan, Scandinavia, and Belgium. Most of these have been associated with handling of infected wild or laboratory rodents (2,7).

Both the epidemiologic characteristics of outbreaks of human disease and the severity of the infection may be determined by the rodent host. A. agrarius, the major host in Asia, is found mainly in rural areas, particularly in the eastern Soviet Union, mainland China, and Korea, where its habits are increasingly peridomestic. The Apodemus-associated hantaviruses probably cause the most severe human disease, with mortality rates currently reported between 3% and 7% (1). Rattus-associated disease is apparently less severe, and asymptomatic infections may be more common than with Apodemus-associated disease (8). Human infections from R. rattus are reported from some inner cities in Asia and probably occur also in rural areas where infestation with both R. rattus and A. agrarius is common. Although infected rats have been detected in Western cities, associated human disease has yet to be described (9). Nephropathia epidemica, which was first described in Scandinavia, is now known to be due to infection with a strain of Hantavirus that infects voles (Clethrionomys species) (10). It has become apparent recently that infected voles and human disease occur throughout Western Europe (11). Nephropathia epidemica is typically the least severe disease and causes very few deaths, although some patients may require dialysis. Some severe cases with hemorrhagic tendency have occurred in some European countries, particularly France (12). A severe disease caused by the local Apodemus species has been recently reported from Greece (13).

Hemorrhagic fever with renal syndrome has classically been divided into five stages: febrile, shock, oliguric, polyuric, and convalescent (2). In practice these stages frequently overlap, particularly the shock and oliguric phases. The initial symptoms are usually fever, flushed face, periorbital edema, and palatal and axillary petechiae. Conjunctivitis, headache, eye pain, lumbar pain, and tenderness are also common. Principal laboratory findings are proteinuria, hemoconcentration, and thrombocytopenia. Most patients recover spontaneously from this stage. A few progress to a phase of oliguria or anuria that is short and usually self-limiting. Shock can be managed by careful fluid replacement; the greatest danger to the patient is inadvertent fluid overload. Although petechiae, thrombocytopenia, and platelet functional abnormalities are very common, overt bleeding is not. In hospitals in some endemic areas of the People's Republic of China, the infection is most often self-limiting and without a severe phase, and the few deaths are usually due to intracranial hemorrhage or generalized uncontrollable bleeding.

The outbreak being reported is typical of endemic Apodemus-associated HFRS in Asia. There were no asymptomatic seropositives among those at risk for the disease. There was no evidence for a point source. The cases occurred sporadically during the fall season and were localized in an area presumably infested with infected A. agrarius. The experience mirrors those of the Japanese during their occupation of China and of the United Nations forces during the Korean conflict. The attack rate of the outbreak in this report is higher than that usually reported in civilian populations and probably reflects the relatively intense exposure to the virus encountered during the military operation.

References

1. Chen H-X, Qiu F-X, Dong B-J, et al. Epidemiological studies on hemorrhagic fever with renal syndrome in China. J Infect Dis 1986;154:394-8.

2. Fisher-Hoch SP, McCormick JB. Haemorrhagic fever with renal syndrome: a review. Abstracts on Hygiene and Communicable Diseases 1985;60:R1-20.

3. Earle DP. Analysis of sequential physiologic derangements in epidemic hemorrhagic fever. Am J Med 1954;16:690-709.

4. Sheedy JA, Froeb HF, Batson HA, et al. The clinical course of epidemic hemorrhagic fever. Am J Med 1954;16:619-28.

5. Lee HW, Lee PW, Johnson KM. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978;137:298-308.

6. Schmaljohn CS, Hasty SE, Dalrymple JM, et al. Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome. Science 1985;227:1041-4.

7. Desmyter J, LeDuc JW, Johnson KM, Brasseur F, Deckers C, van Ypersele de Strihou C. Laboratory rat associated outbreak of haemorrhagic fever with renal syndrome due to Hantaan-like virus in Belgium. Lancet 1983;2:1445-8.

8. Tsai TF, Bauer SP, Sasso DR, et al. Serological and virological evidence of a Hantaan virus-related enzootic in the United States. J Infect Dis 1985;152:126-36.

9. Lee HW, Baek LJ, Johnson KM. Isolation of Hantaan virus, the etiologic agent of Korean hemorrhagic fever, from wild urban rats. J Infect Dis 1982;146:638-44.

10. Lahdevirta J. Nephropathia epidemica in Finland: a clinical histological and epidemiological study. Ann Clin Res 1971;3:1-54.

11. Centers for Disease Control. Hemorrhagic fever with renal syndrome--France. MMWR 1984;33:228,233-4.

12. Dournon E, Girard P, Moriniere B, Brion N. (Hemorrhagic fever with renal syndrome. Epidemiologic data (Letter).) Presse Med 1985;14:1101.

13. Antoniadis A, Pyrpasopoulos M, Sion M, Daniel S, Peters CJ. Two cases of hemorrhagic fever with renal syndrome in Northern Greece. J Infect Dis 1984;149:1011-3. *The views of the authors do not purport to reflect the position of the U.S. Department of the Army or the U.S. Department of Defense.

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