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Hemorrhagic Fever with Renal Syndrome

In Korea, hemorrhagic fever with renal syndrome (HFRS) was first reported in a United Nations (UN) soldier stationed in the central front, also known as the “Iron Triangle”. In 1976, professor Ho Wang Lee discovered an antigen in the lung and kidney tissues of Apodemus agrarius. In 1980, this novel virus was named Hantaan virus after the Hantaan river. The Old World Hantaviruses, which are usually found in East Asia and Europe, are generally transmitted to humans via the respiratory pathway during dry seasons, usually in late spring and fall. Currently, 300 – 600 cases per year are reported in Korea with a mortality rate of 1 – 2%. The typical clinical course of HFRS is classified into five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. And treatment for HFRS is mostly conservative. A vaccine for the Hantaan virus was developed in 1988 and marketed in 1990. Because HFRS outbreaks mostly occur in regions near the truce line in Korea, vaccination is virtually the only protection against the virus among military personnel working in such regions and local residents. Therefore, proving the effectiveness of the HFRS vaccine and devising efficient vaccination plans have been considered a major task for Korea's health authorities.

In 1976, professor Ho Wang Lee and his research team discovered an antigen in the lung and kidney tissues of Apodemus agrarius (Fig. 1) captured in Songnae-dong, Dongducheon-si, and Gyeonggi-do, regions marked with high incidence of hemorrhagic fever. Using an indirect immunofluorescence technique, the antigen was found to specifically react to sera taken from patients with Korean hemorrhagic fever during the recovery period. The team named it the Korean-type antigen and went on to isolate it from blood samples of hemorrhagic fever patients in 1978 and successfully proliferate the virus in A549 cells [5]. In 1980, this novel virus was named Hantaan virus after the Hantaan river ( Fig. 2) [6]. With the development of a serologic diagnostic technique using the Hantaan virus as the antigen, it has been confirmed that the Hantaan virus or similar viruses are responsible for the Korean hemorrhagic fever occurring in Korea, the hemorrhagic nephrosonephritis occurring in Russia, epidemic hemorrhagic fever in China and Japan, and nephropathia epidemica in Scandinavia. In the spring of 1982, the World Health Organization (WHO) launched a meeting with the Working Group on Hemorrhagic Fever with Renal Syndrome in Tokyo, Japan. During this meeting, various diseases showing clinical symptoms similar to those of the Korean hemorrhagic fever were collectively termed hemorrhagic fever with renal syndrome. In 1984, a new genus, Hantavirus, was discovered under which all pathogens of HFRS are included.

TYPES OF VIRUS
Hantaviruses are known as rodent-transmitted viruses, and each species of this family is associated with a unique wild rodent as a carrier. These viruses are generally found in East Asia and Europe, but New World Hantaviruses have also been discovered in North and South America. The latter are distinguished from the Old World Hantavirus that causes HFRS by their substantially higher mortality (40 -50%). Recently, novel Hantaviruses, such as Imjin virus, were discovered in shrews (Insectivora) and bats (Chiroptera) worldwide, including Korea (

INCIDENCE AND EPIDEMIOLOGY
The Old World Hantaviruses, which are usually found in East Asia and Europe, are generally transmitted to humans via the respiratory pathway during dry seasons, usually in late spring and fall. However, in recent years, an increased incidence of Hantavirus infection in Korea has been reported in late fall and early winter. During the Korean war, the Hantavirus affected Korean soldiers and civilians in the region along the truce line and subsequently spread to the entire nation with the exception of a few island regions. More than 1,000 infections were reported in one year, with mortality ranging from 5% to 7%. Currently, 12,000 -20,000 cases of HFRS are reported every year in China, while approximately 300-600 cases per year are reported in Korea ( Fig. 3) with a mortality rate of 1 -2% [7].

DISEASE CHARACTERISTICS A. Symptoms
During the Korean War, an HFRS outbreak occurred, culminating in 1,000 US military soldiers developing fever and bleeding tendency in 1951. Numerous foreign countries have reported the characteristics of this disease; the major symptoms include fever, headache, and chills, generally accompanied by loss of appetite, vomiting, bleeding tendency and renal failure. The patients' oral temperature ranged from 38.8°C to 40°C and persisted for 4 -5 days. The latent period was believed to be about 2 -3 weeks. At the time, it was difficult to diagnose HFRS because the causative pathogen was not identified and no screening method was available. HFRS was suspected if the patient had been exposed to an epidemic region; developed symptoms such as fever, chills, malaise, headache, and low back pain; experienced hot flushes; had mucosal or conjunctival congestion. A typical patient showed albuminuria on day 4 of onset, with albuminuria being considered definitive evidence for HFRS.  1951 1954 1957 1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999

B. Clinical course
The typical clinical course of HFRS is classified into five phases: febrile, hypotensive, oliguric, diuretic, and convalescent [8]. The febrile phase persists for about 4 -6 days and petechial bleeding usually occurs in the palate, axilla and chest on the third day of fever onset. The hypotensive phase persists from a few hours to 3 days and may be absent in patients with mild HFRS. Patients with severe HFRS may experience shock. The oliguric phase persists for 3 -6 days. This phase is characterized by relief of symptoms that had developed in the febrile phase and elevation or restoration of normal blood pressure, but symptoms of renal failure may begin to manifest. The diuretic phase is marked by an increase in urine output for several days to several weeks, then most patients begin to show improvements and return of appetite (convalescence).
A recent report suggests that in 74% of patients definitively diagnosed with HFRS, the disease was not suspected as the cause of acute renal failure until a few days after admission, because the patient did not exhibit the typical five-phase course as documented in the past. Whereas most HFRS patients experience the febrile and diuretic phases, the incidence of hypotensive and oliguric phases was relatively low. Approximately 48 -86% of patients with HFRS had abdominal pain, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea were common. As a result, fever, renal failure, and gastrointestinal symptoms were proposed as the clinical characteristics of HFRS [9].
HFRS can be classified into four clinical types according to its clinical course: 1) oliguric type, marked by a typical clinical course and is the most severe form; 2) non-oliguric type, which lacks the oliguric phase and has better prognosis; 3) non-typical type, which lacks the hypotensive and oliguric phases and is characterized by the presence of proteinuria during the initial febrile phase and its resolution after the febrile phase; and 4) asymptomatic type.
The fatality rate differs according to the patient and period. Smadel reported a fatality rate of <5% in about 500 UN soldiers who were treated at the US 8,228th Mobile Army Surgical Hospital, and most deaths occurred at the end of the first week or early second week after onset [1]. In a previous study that analyzed admissions to the Hemorrhagic Fever Hospital from April to December 1952, 46 out of 828 patients died, with a fatality rate of 5.6%; most died from shock, while only a few died following hemorrhagic complications [10]. Among 9,409 patients with HFRS in Korea from 1951 to 1978, the mortality rate was 6.5% [11]. The fatality rate of HFRS in Korean civilians was high, exceeding 25% in the 1960s, after which it began to decline by 1985; it had substantially decreased to 1% [12].
Hypoalbuminemia in the acute phase has been associated with the severity of HFRS. A study on military patients with HFRS from 2000 to 2004 reported that leukocytosis, an elevation of aspartate aminotransferase, and microscopic hematuria in early days of onset are associated with renal failure with oliguria [13]. Compared with patients with HFRS caused by the Hantaan virus, patients with urban HFRS caused by the Seoul virus showed less bleeding and renal damage but more severe hepatic dysfunction [14].

C. Pathological findings
In a pathology report on a case of death by HFRS in late 1951, bleeding in the renal medulla, right atrium, and submucosa of gastrointestinal tract; necrosis in the renal medulla, anterior pituitary lobe, and adrenal gland; and monocyte infiltration in the myocardium, pancreas, spleen, and liver were reported as characteristic findings [15]. There were prominent vascular changes, such as capillary congestion, diapedesis of red blood cells, bleeding, and increased capillary permeability; interstitial edema and retroperitoneal edema were believed to occur as a result of increased capillary permeability [16]. Particularly, retroperitoneal edema was observed in 75% of patients who died in the hypotensive phase but was rarely observed in patients who died in the oliguric or diuretic phase.

A. Prior to the discovery of the Hantaan virus
Epidemic hemorrhagic fever in Korea was first officially reported in the medical community in 1951. However, there have been opinions that it existed as an endemic before 1951 based on verbal statements that there had been Korean people with similar symptoms in the past and on various epidemiological observations. The reason for the low awareness in the medical community despite being an endemic was speculated to be due to the lack of knowledge, disinterest in the disease, and the absence of a large epidemic [17]. However, there are several opinions regarding the origin of the disease. Lee et al. suggested the possibility of an accidental introduction of HFRS through the Chinese army during the Korean War, following an outbreak in the Amur valley and Vladivostok in the early 20th century and its introduction in Manchuria during the Manchurian incident [12].
Until it was confirmed as a separate disease called epidemic hemorrhagic fever by the US military in 1953, HFRS was commonly mistaken as leptospirosis and no preventive measures had been established. As a result of continuous HFRS epidemics and increases in the mortality rate, diverse academic studies were collated and findings were shared. In 1944, Smorodinsef of the Soviet Union speculated that the pathogen for HFRS is a virus, and Kitano et al. in Japan argued that A. agrarius is the major reservoir. The US military founded a hemorrhagic fever center in Seoul in 1952 for research but failed to isolate the pathogen.
In the Korea Armed Forces, a hemorrhagic fever research unit was launched in 1960 and operated until the 1970s, but the unit also failed to identify the pathogen. However, given that HFRS is a viral disease and that infection is mediated by A. agrarius became well known, preventive measures such as alerting the farming population and soldiers to avoid contact with rats and exterminating rats, were actively enforced. Furthermore, to treat acute renal failure caused by HFRS, hemodialysis, a very advanced treatment at the time, was introduced in Korea by the US military in 1952, and a hemodialysis unit was first launched in 1965 in the Capital Armed Forces General Hospital.

B. After the development of a vaccine for the Hantaan virus
A vaccine for the Hantaan virus (Hantavax™, Green Cross Corporation, Yongin, Korea) was developed in 1988 and marketed in 1990. It is prepared by inoculating the Hantaan virus isolated from patient's blood to Vero E6 cells, culturing it in the brain of a mouse and inactivating it with formalin. Hantavax™ vaccination was administered through local health centers and the Korea Armed Forces from 1992. Currently, it is generally administered to residents in high-risk regions and military personnel. Vaccination was performed widely between 2005 and 2010, with about 100,000 military personnel vaccinated each year (Fig. 4). As of 2017, however, the Korea Armed Forces performs vaccination under limited conditions. In the last 3 years, the vaccine has only been administered to units with a confirmed case of HFRS.

C. Preventive measures for and management of HFRS since the 2000s
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1) Promotion of effective vaccination and development of a new vaccine
Because HFRS outbreaks mostly occur in regions near the truce line in Korea, vaccination is virtually the only protection against the virus among military personnel working in such regions and local residents-particularly farmers. Therefore, proving the effects of the HFRS vaccine and devising efficient vaccination plans have been considered a major task for Korea's health authorities and Ministry of Defense.
In a 2016 study that aimed to prove the long-term immunogenicity of the vaccine, the neutralizing antibody conversion rate was founds to be 1.4% one year after the first and second doses of vaccination and 40.6% one year after the third dose. This finding suggests that the existing three-dose vaccination schedule should be modified to increase the number of doses or adjust the interval between doses [18]. Furthermore, the conversion rate of the vaccine in a recent study conducted by the Ministry of Defense was 58.9%. These findings suggest that the HFRS vaccine does have effects but they are small. Therefore, a novel vaccine must be developed or the vaccination schedule for the existing vaccine must be modified to effectively manage patients with HFRS.

(3) Diagnosis and surveillance of HFRS
Korea designated HFRS as group 3 communicable disease and is monitoring its incidence in line with the Infectious Disease Control and Prevention Act. Furthermore, since the 2000s, the government has developed and distributed a quick diagnostic kit for HFRS. Currently, a quick diagnostic kit that can concurrently test for three Korean-type febrile diseases in the fall, namely, scrub typhus, leptospirosis, and HFRS, is widely used. For patients definitively diagnosed with HFRS, local health centers collect their data in an epidemiology report.

(4) HFRS research using molecular genetic technology and utilization of research findings
Since 2015, Korea University and the Agency for Defense Development have been conducting joint research on Hantaviruses with the US Department of Defense using a novel molecular genetics technology. Genetic information for hantaviruses is acquired from the HFRS vectors that have been accumulated over the past 40 years and are stored in a geographic information system. These data are compared with the genetic information for hantaviruses extracted from patients with HFRS to approximate the location of infection. This has been used to perform an in-depth molecular epidemiological investigation of HFRS since 2016. The process involves the acquisition of genetic information about the hantavirus from the HFRS patient's blood sample and its comparison with genetic information extracted from a vector captured from the suspected location of infection. Based on this investigation, the approximate region of infection is obtained, which the Korea Armed Forces uses to identify hazardous regions, provide vaccinations to military personnel training and working in those regions, and restrict access to those regions (Fig. 5).