CLINICAL REVIEW
The Protean Manifestations of Hemorrhagic Fever with
Renal Syndrome
A Retrospective Review of 26 Cases from Korea
Philip Bruno, DO; L. Harrison Hassell, MD; Joel Brown, MD; William Tanner, MD;
and Alan Lau, MD
Twenty-six cases of hemorrhagic fever with renal syndrome from
1981 to 1986 were retrospectively reviewed to determine the scope
of clinical presentation and the unique complications of the illness.
The diagnosis was confirmed by detection of Hantaan virus anti-
body in 25 cases and by characteristic autopsy findings in 1 case.
The illness could be classified into three distinct clinical subgroups.
Fever was universally present. Two patients presented with intrac-
table shock and diffuse hemorrhage and died within 6 days from
multi-organ system failure, mimicking the clinical picture of over-
whelming sepsis. Eighteen patients presented with acute renal
failure with an illness lasting a mean of 21 days (range, 10 to 36
days). Resolution of thrombocytopenia heralded recovery of renal
function. At discharge, the serum creatinine level was normal in 13
patients; 5 patients had evidence of minimal renal dysfunction.
Acute pulmonary edema requiring hemodialysis and retroperito-
neal hemorrhage were the major complications in this subgroup.
Six patients had an undifferentiated febrile illness with normal
renal function. Fever, thrombocytopenia, abnormal urinalysis,
hypertransaminasemia, and a benign clinical course characterized
the third clinical pattern. The recent availability of serodiagnostic
methods to detect Hantavirus group antibody facilitates the diag-
nosis of hemorrhagic fever with renal syndrome. Application of this
test in the described clinical settings will identify unsuspected cases,
broaden the knowledge of the geographic distribution of Hantavirus
infection, and increase physician awareness of its protean manifes-
tations.
Annals of Internal Medicine. 1990;113:385-391.
From Tripler Army Medical Center, Tripler AMC, Hawaii, the
121st U.S. Army Evacuation Hospital, Yongson, Korea; and
the 13th Air Force Medical Center, Clark Air Base, Republic
of the Philippines. For current author addresses, see end of
text.
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During the Korean War, U.S. military physicians en-
countered an enigmatic acute illness that afflicted thou-
sands of United Nations troops. Fever, renal failure,
thrombocytopenia, and hemorrhages were its cardinal
manifestations. On the basis of clinical observation, the
illness was arbitrarily divided into five sequential
stages: febrile, hypotensive, oliguric, diuretic, and con-
valescent phases (1). This disease became known as
Korean hemorrhagic fever.
The cause remained obscure until 1976 when a ro-
dent-borne RNA virus, known as the Hantaan virus,
was discovered to cause the disease (2, 3). Viruses
antigenically related to Hantaan virus have been found
to cause similar febrile illnesses in other countries. Han-
taan and related viruses form the genus Hantavirus
within the Bunyaviridae family (4-6). Diseases caused
by Hantavirus infection are now collectively referred to
as hemorrhagic fever with renal syndrome (7).
In rodents, Hantavirus infection is an asymptomatic
carrier state (8). Transmission to humans occurs by
direct contact or inhalation of rodent excrement (9).
Three Hantavirus types are known to cause disease in
humans. In rural northern Asia, hemorrhagic fever with
renal syndrome is caused by the Hantaan virus; it is
transmitted to humans from the field mouse, Apodemus
agrarius. In Scandinavia, the Puumala virus is transmit-
ted to humans from the bank vole, Clethrionomys glar-
eolus, and causes a mild form of the syndrome called
nephropathia epidemica (6, 8, 10). Seoul virus is respon-
sible for urban cases of the syndrome in Asia and lab-
oratory-acquired cases in Asia and Europe; it is trans-
mitted by wild urban or laboratory rats (11-14).
Prospect Hill virus, another Hantavirus, has been iso-
lated from rodents in North America but has not been
associated with human disease. However, some North
American mammologists have serologic evidence of
asymptomatic infection with this Hantavirus species
(15).
When the Hantaan virus was isolated, development
of serodiagnostic tests for hemorrhagic fever with renal
syndrome became possible. Rising titers of IgG anti-
body to Hantaan virus during 1 week can be detected
by the indirect immunofluorescent assay technique (2,
3). Specific IgM antibodies to Hantaan virus in human
serum can also be found by enzyme-linked immunosor-
bent assay (ELISA). Both of these methods are simple,
rapid, and sensitive for identifying Hantavirus group
antibodies. Distinguishing specific Hantavirus types re-
quires more expensive, cumbersome immunologic tests
that are not as readily available. Detection of serum
385
 IgM Hantavirus antibodies by ELISA is currently the
diagnostic method of choice (16, 17).
Although the geographic distribution of hemorrhagic
fever with renal syndrome includes northern Asia, the
Soviet Union, Scandinavia, and Europe, serosurveys
indicate that rodent populations are infected with Han-
tavirus species worldwide. Although hemorrhagic fever
with renal syndrome has not been described in North
America, serosurveys of human populations suggest
that asymptomatic or unrecognized human Hantavirus
infections occur in the United States (15-22).
Because several patients with hemorrhagic fever with
renal syndrome were referred to Tripler Army Medical
Center from Korea, we decided to review the recent
U.S. military experience with this infection. The study
is a retrospective review describing the scope of clinical
presentation and the complications of recognized cases
of Hantavirus infection occurring among U.S. military
personnel stationed within the Republic of Korea from
1981 to 1986.
Patients and Methods
The available medical records of patients with a discharge
diagnosis of hemorrhagic fever with renal syndrome from three
Pacific basin U.S. military hospitals from 1981 through 1986
were retrospectively reviewed. The three hospitals included
the 121st U.S. Army Evacuation Hospital in Yongson, Korea;
the 13th Air Force Medical Center at Clark Air Base in the
Republic of the Philippines; and Tripler Army Medical Center
in Honolulu, Hawaii.
All patients included in the study had an acute febrile illness
with either a diagnostic serologic test for Hantaan virus anti-
body or characteristic autopsy findings of Korean hemorrhagic
fever (23). The serologic diagnosis was made in 19 cases by
indirect immunofluorescent antibody tests (2, 3) at the Institute
for Viral Disease, Korea University, Seoul, Korea; 6 cases
were confirmed by identifying serum IgM antibody to Hantaan
virus using the ELISA technique at the U.S. Army Medical
Research Institute of Infectious Disease, Fort Detrick, Mary-
land (17).
Medical records were reviewed for the following informa-
tion: location at onset of the illness, history of rodent expo-
sure, initial diagnosis, clinical manifestations at the time of
hospital admission, complications, treatment, duration of ill-
ness, final outcome, and autopsy results.
The following admission laboratory tests were compiled for
all patients: complete blood count, urinalysis, prothrombin
time, partial thromboplastin time, blood urea nitrogen, serum
creatinine, serum calcium, serum alanine aminotransferase,
and serum aspartate aminotransferase. Thrombocytopenia was
defined as a platelet count less than 150 x 109/L; leukocytosis
as a leukocyte count greater than 10.8 x 109/L; hemoconcen-
tration as a hemoglobin concentration greater than 180 g/L for
men and greater than 160 g/L for women; azotemia as a blood
urea nitrogen greater than 8.9 mmol/L. The serum creatinine
level was determined to be elevated if greater than 130
/xmol/L, the alanine aminotransferase if greater than 0.67
/xkat/L, and the aspartate aminotransferase if greater than 0.67
/ikat/L. Hypocalcemia was present if the serum calcium was
less than 2.12 mmol/L. Proteinuria was detected by sulfasali-
cylic acid protein precipitation, and graded on a scale from 0
to 4+. Hematuria and pyuria were present on urinalysis if
there were more than five erythrocytes or five leukocytes per
high power field, respectively. Prothrombin and partial throm-
boplastin times were prolonged if greater than 14 seconds and
45 seconds, respectively.
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Results
Patient Characteristics
Twenty-six patients were identified; their epidemio-
logic features are listed in Table 1. The mean age was
26.2 years (range, 19 to 44 years). Officers and enlisted
personnel were affected. All occurred during the recog-
nized epidemic seasons of late fall or early spring.
Twenty-five military personnel were men; one female
civilian was treated. All had been in Korea shortly
before the onset of their illness. Seventeen had field
duty within 30 days of the illness and 18 developed
symptoms in Korea. Eight presented with symptoms at
their permanent duty station in Okinawa, Japan, soon
after returning from field training maneuvers in Korea.
Twenty-five patients were seropositive for Hantavirus
antibody. A mean of 2.5 clinic visits per person (range,
1 to 6) occurred before the diagnosis was suspected.
Most initial correct diagnoses in this series were made
after recognition of an index case in 1986 among a
group of U.S. Marines. Seven cases were correctly
diagnosed on the first clinic visit. The other 19 patients
had initial diagnoses of viral syndrome, glomerulone-
phritis, aseptic meningitis, streptococcal pharyngitis,
acute abdomen, appendicitis, nephrolithiasis, renal vein
thrombosis, leptospirosis, scrub typhus, or volume de-
pletion.
Clinical Findings
The number and combination of clinical findings in
individual cases varied considerably (Tables 2 and 3).
Fever, fatigue, malaise, and weakness were universal.
Pain was common, manifested by headache, abdominal
discomfort, myalgia, backache, and sore throat. Vomit-
ing, rigors, diminished urine output, dizziness, and
blurred vision were also major symptoms. Physical
signs included conjunctival injection or hemorrhage, ab-
dominal tenderness, orthostatic hypotension, pharyngi-
tis, petechial rash, facial flushing, palatal petechiae, cer-
vical adenopathy, periorbital edema, and ecchymoses.
Two patients had shock. Thrombocytopenia, protein-
uria, azotemia, hematuria, leukocytosis, hypertransam-
inasemia, hypocalcemia, and prolonged prothrombin
and partial thromboplastin times were the most signifi-
cant abnormalities in laboratory tests.
The patients presented initially with one of three clin-
ical patterns. Two had shock with multi-organ system
failure; 18 had acute renal failure; and 6 had a mild,
undifferentiated febrile illness without renal failure.
The Shock Syndrome
The two patients with shock had a fulminant course.
They had the classic picture of hemorrhagic fever with
renal syndrome: high fever, flushed face, delirium, pe-
riorbital edema, dyspnea, hypotension, and oliguria.
Hemorrhagic manifestations included conjunctival hem-
orrhage, petechial and purpuric rash, hematuria, diffuse
bleeding from venipuncture sites, and gastrointestinal
hemorrhage.
The complete blood count showed hemoconcentra-
tion, leukocytosis, and thrombocytopenia. Urinalysis
 Table 1. Characteristics of 26 Patients with Hemorrhagic Fever Who Had Renal Syndrome
Patient Sex, Age Recent Rodent Date of Duration Clinic Initial Diagnosis
Field Exposure Illness of Illness Visits
Duty

y moly d n

The shock syndrome

l*t M, 20 Yes Yes 11/86 4 3 Viral syndrome
2*t M, 35 Yes Yes 11/86 6 1 Korean hemorrhagic fever
Acute renal failure
3*1 M, 19 No No 6/81 12 3 Streptococcal pharyngitis
4 M, 34 Yes No 10/83 22 3 Volume depletion
5* M, 22 Yes Yes 11/83 16 3 Acute abdomen
6* M, 28 No No 12/83 22 4 Streptococcal pharyngitis
7 M, 26 No No 12/84 10 5 Viral syndrome
8 M, 20 No No 5/85 14 1 Viral syndrome
9 M, 23 No No 11/85 23 6 Renal vein thrombosis
10 M, 20 Yes Yes 4/86 10 4 Poststreptococcal glomerulonephritis
11 M, 37 Yes No 11/86 30 3 Viral syndrome
12 M, 24 Yes No 11/86 2 Korean hemorrhagic fever
13 M, 29 No No 11/86 25 2 Viral syndrome
14* M, 26 Yes No 12/86 25 1 Korean hemorrhagic fever
15 M, 26 Yes No 11/86 23 5 Glomerulonephritis
16t M, 25 Yes No 11/86 32 4 Nephrolithiasis
17t M, 31 Yes No 12/86 22 2 Korean hemorrhagic fever
18t M, 20 Yes Yes 12/86 36 2 Appendicitis
19t M, 44 Yes Yes 12/86 19 1 Korean hemorrhagic fever
20t M, 25 Yes Yes 12/86 17 1 Korean hemorrhagic fever
Undifferentiated
febrile illness
21 M, 21 No No 4/85 10 2 Glomerulonephritis
22 M, 20 No No 11/85 10 1 Aseptic meningitis
23 F, 32 No No 8/86 10 2 Aseptic meningitis
24 M, 32 Yes No 9/86 10 1 Scrub typhus
25t M, 19 Yes Yes 11/86 22 1 Korean hemorrhagic fever
26t M, 22 Yes Yes 12/86 16 2 Viral syndrome

* Patient died.
t Patient was described briefly in an epidemiologic analysis (33) in 1988.
* Patient required hemodialysis.
§ Patient was described in a single case report (34) in 1984.

revealed proteinuria, pyuria, and hematuria. Pulmonary
edema, renal failure, disseminated intravascular coagu-
lation, and significant elevations of aspartate ami-
notransferase, alanine aminotransferase, lactate dehy-
drogenase, and creatine kinase enzymes also occurred.
One of the two patients had a positive serologic test for
Hantavirus antibody. Cardiac tamponade caused by he-
mopericardium complicated one case and was relieved
by pericardiocentesis. Both patients with shock died
within 6 days from multi-organ system failure. Autop-
sies revealed generalized edema and petechial hemor-
rhage of several organs, including the right atrium,
lungs, anterior pituitary gland, and renal medulla. Hem-
orrhagic mucosal ulcerations were found throughout the
gastrointestinal tract.
Acute Renal Failure
Eighteen patients presented with fever and oliguric
acute renal failure. This clinical pattern had a subacute
course with a mean duration of illness of 21 days
(range, 10 to 36 days). Most patients recovered. Fever,
abdominal pain, azotemia, and thrombocytopenia were
the major clinical findings. The illness began with a
febrile phase that overlapped the onset of oliguria.
Shock was notably absent. The mean duration of the
febrile phase was 6.9 days (range, 4 to 9 days). Initial
symptoms of fever, chills, headache, myalgias, and sore
throat were gradually replaced by vomiting, abdominal
pain, and oliguria. Urinalyses showed proteinuria and
hematuria. Moderate elevations (three to nine times
normal) of serum aspartate and alanine aminotrans-
ferases were common.
Sixteen patients had oliguria (urine output < 400
mL/d) on the day of hospitalization. Two patients had
normal renal function at admission but developed olig-
uric renal failure within 72 hours. The mean duration of
the oliguric phase was 8 days (range, 3 to 17 days). The
median admission serum creatinine level was 880
/imol/L (range, 97 to 1010 /rniol/L), and peaked at a
median value of 690 /miol/L (range, 260 to 1410 //,mol/
L). The median admission blood urea nitrogen was 17.9
mmol/L urea (range, 3.9 to 56.8 mmol/L urea), and
peaked at a median value of 27.5 mmol/L urea (range,
13.9 to 56.8 mmol/L urea). The abrupt onset of polyuria
(urine output > 3 L/d) marked the end of the oliguric
phase. Polyuria lasted a mean of 6.4 days (range, 2 to
12 days).
All patients had thrombocytopenia. The mean dura-
tion was 9 days (range, 4 to 16 days). Resolution of
thrombocytopenia heralded improvement in renal func-
tion.
The convalescent phase extended from the end of the

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 diuretic phase to hospital discharge. Mild residual back
or flank discomfort and headache were occasionally re-
ported by a few patients during this period; however,
most felt well. One patient remained hypertensive but
all other patients' physical signs had returned to nor-
mal. Seven patients had a normochromic, normocytic
anemia at discharge. Thirteen patients had a normal
serum creatinine level at discharge; and 5 had serum
creatinine values ranging from 140 to 200 /x,mol/L.
New or progressive symptoms or signs after the first
week of illness signaled the presence of a complication;
most were due to volume overload. Hypertension oc-
curred in ten patients. Six patients developed acute
pulmonary edema; the occurrence was unpredictable.
Four patients with acute pulmonary edema required
hemodialysis. Two patients with milder cases of pulmo-
nary edema were successfully managed with salt restric-
tion and diuretics. Two patients developed acute pul-
monary edema during air transport. One patient's death
was directly related to acute pulmonary edema sus-
tained during aeromedical evacuation.
Retroperitoneal hemorrhage complicated one case.
The patient (Patient 6) developed increased abdominal
pain, hypotension, and anemia on the tenth day of ill-
ness. Abdominal computed tomography confirmed the
diagnosis (Figure 1). Successful conservative manage-
ment included blood transfusions and analgesics. This
hemorrhagic episode occurred after the resolution of
thrombocytopenia; the patient recovered fully.
Conservative supportive medical management was
successful in 14 of 18 cases. Meticulous attention was
directed toward fluid and electrolyte balance, nutrition,
and prevention of infection. Hemodialysis was neces-
sary in 4 of 18 patients to treat pulmonary edema. The
need for hemodialysis was unpredictable. Transfusion
of blood products was required in 7 of 18 patients.
Failure to recognize hemorrhagic fever with renal
syndrome resulted in the treatment of one patient with
cyclophosphamide and corticosteroids for presumed
rapidly progressive glomerulonephritis. Another patient
received heparin for treatment of suspected renal vein
thrombosis before the correct diagnosis was made. Mis-
diagnosis also resulted in the unnecessary overseas aer-
omedical evacuation of several patients in this sub-
group.
Undifferentiated Febrile Illness
Six patients had a milder febrile illness without renal
failure. All had thrombocytopenia. Four had increased
(three to nine times normal) serum aspartate and alanine
aminotransferase values; alkaline phosphatase and bili-
rubin values were normal. Three had abnormal urinal-
yses showing proteinuria; two had hematuria; and one
had pyuria. Two had hypocalcemia despite normal renal
function and normal serum albumin concentrations.
Blood urea nitrogen and serum creatinine values re-
mained normal in all patients. The mean duration of
illness in this subgroup was 13 days (range, 4 to 22
days), and recovery was complete and uncomplicated.
Aseptic meningitis was suspected in two of these pa-
tients, but cerebrospinal fluid examinations were nor-
mal.
Discussion
These confirmed cases demonstrate the protean clin-
ical manifestations of hemorrhagic fever with renal syn-

Table 2. Percentages of Symptoms and Signs of Korean Hemorrhagic Fever at Admission

Symptoms and Current Series Powell (32) Sheedy et al. (1)
Signs 1981 to 1986 1951 1952
(n = 26) (n = 300) (n = 264)

< %(95%CI) >

Fever 100 100 100

Malaise or weakness 100 Not reported 49(43 to 55)
Headache 69(51 to 87) 86(82 to 90) 46(40 to 52)
Abdominal pain 65(47 to 83) 71(66 to 76) 30(24 to 36)
Vomiting 59(40 to 78) 82(78 to 86) 24(19 to 29)
Myalgias 54(35 to 73) 55(49 to 61) 28(23 to 33)
Chills 54(35 to 73) 90(87 to 93) 42(36 to 48)
Conjunctival injection 46(27 to 65) 69(64 to 74) 39(33 to 45)
Oliguria 42(23 to 61) 81(77 to 85) Not reported
Abdominal tenderness 42(23 to 61) 75(70 to 80) 22(17 to 27)
Conjunctival hemorrhage 39(20 to 58) 38(32 to 44) Rare
Dizziness 39(20 to 58) Not reported 25(20 to 30)
Back or flank pain 35(17 to 53) 78(73 to 83) 44(38 to 50)
Orthostatic hypotension 35(17 to 53) Not reported Not reported
Other eye symptoms 31(13 to 49) 41(35 to 47) Not reported
Pharyngeal injection 31(13 to 49) 55(49 to 61) Not reported
Diarrhea 27(10 to 44) 11(7 to 15) Not reported
Petechial rash 27(10 to 44) 32(27 to 37) 33(27 to 39)
Flushing 27(10 to 44) 48(42 to 54) 27(22 to 32)
Palatal petechiae 27( 10 to 44) 36(31 to 41) Not reported
Adenopathy 23(7 to 39) 38(32 to 44) 11(7 to 15)
Flank tenderness 23(7 to 39) 73(68 to 78) 19(14 to 24)
Sore throat 19(4 to 34) 19(15 to 23) Not reported
Periorbital edema 19(4 to 34) 21(16 to 26) 24(19 to 29)
Cough 15(1 to 29) 40(34 to 46) Not reported

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 Table 3. Median Values and Ranges for Abnormalities in Admission Laboratory Tests
Laboratory Test All Patients The Shock Syndrome Acute Renal Failure Undifferentiated
(n = 26) (* = 2) (n = 18) Febrile Illness (n = 6)

in (rai k
n medic 'ige)
Thrombocytopenia,
x 109IL 26 59(5 to 145) 2 51(33 to 68) 18 49(5 to 145) 6 77(46 to 126)
Qualitative proteinuria 22 3 +(1 + to 4 +) 1 4+* 18 3 +(3 + to 4 + ) 3 3 +(3 + to 4 +)
Azotemia, mmollL urea 19 16.4(10.4 to 56.8) 2 11.1(10.4 to 11.8) 17 17.9(10.4 to 56.8) 0
Increased serum creat-
inine, ixmollL 20 370(140 to 390) 2 290(220 to 350) 18 380(140 to 1010) 0
Leukocytosis, x 109IL 19 18(11 to 51) 2 38(31 to 45) 16 18(11 to 51) 1 12*
Hematuria 19 1 16 2
Elevated aspartate amino-
transferase, /jJcat/L 17 2.22(1.00 to 28.34) 2 14.92(1.50 to 28.34) 11 2.22(1.03 to 14.00) 4 1.53(1.00 to 7.54)
Hypocalcemia, mmollL 16 1.77(1.37 to 2.00) 2 1.50(1.50) 12 1.77(1.37 to 2.00) 2 1.90(1.82 to 1.95)
Elevated alanine amino-
transferase \ikatlL 16 1.40(0.67 to 13.44) 1 13.44* 13 1.40(0.67 to 5.82) 3 1.10(0.73 to 5.65)
Prolonged partial thrombo-
plastin time, s 7 66(46 to 200) 2 126(52 to 200) 4 69(46 to 77) 1 66*
Pyuria 6 1 4 1
Prolonged prothrombin
time, s 5 16.3(14 to 45) 1 45* 3 14.9(14 to 17) 1 18.5*
Hemoconcentration gIL 4 192(181 to 210) 0 4 192(181 to 210) 0

* Single value is reported.

drome. The severity of illness and constellation of Six patients presented with an undifferentiated febrile
symptoms and physical signs varied considerably illness. The clinical course was benign with few positive
among patients. Such diversity made initial diagnosis of signs on physical examination. Renal failure and hypo-
the syndrome difficult. The classic, fulminant form, oc- tension did not occur. All had thrombocytopenia. Hy-
curring within an endemic area and evolving through pertransaminasemia, proteinuria, and hematuria were
the five recognized phases of fever, hypotension, olig- common findings, but three patients had normal urinal-
uria, diuresis, and convalescence, would be relatively yses at admission. Thirty percent of patients with Han-
easy to identify. Many patients in this series, however, tavirus infection in Korea have a similar mild illness
did not show the classic evolution of these phases. (16). These cases could be mistaken for influenza, viral
Often phases overlapped or did not occur. Many pa- hepatitis, or streptococcal pharyngitis.
tients presented to physicians unfamiliar with Hantavi- The clinical findings in this review are in agreement
rus infection. In 19 cases, a correct initial diagnosis was with previous studies (Table 2). Fever and thrombocy-
not made. This finding is in agreement with a study by topenia were the most important clinical clues to the
Lee (16) showing that a correct clinical diagnosis was diagnosis. Physical signs that also were diagnostically
made in only 50% of patients with a serologically con- helpful included conjunctival hemorrhages, pharyngeal
firmed diagnosis of Hantavirus infection. We believe erythema, palatal petechiae, periorbital edema, facial
that recognition of Hantavirus infection could be im- flushing, and petechial skin rash. Jaundice did not occur
proved by emphasizing the three described clinical pre-
sentations a physician might encounter during initial
patient evaluation.
Two patients presented with a fulminant infection
with shock, multi-organ system failure, and diffuse hem-
orrhages. Despite intensive medical management, both
patients died within 6 days. This clinical pattern resem-
bles septic shock or nonbacteremic clinical sepsis of
unknown cause (24). Twenty percent of patients with
Korean hemorrhagic fever have severe disease, and 5%
to 10% of all patients die from shock and renal failure
(16).
Eighteen patients presented with fever, acute renal
failure, and mild hemorrhagic manifestations. These pa-
tients all had thrombocytopenia. Seventeen patients
gradually recovered, but one died from pulmonary
edema. Fifty percent of patients with Hantavirus infec-
tions in Korea have such a moderate course (16). Hem-
orrhagic fever with renal syndrome should be included
in the differential diagnosis of acute renal failure with
Figure 1. Abdominal computed tomographic scan in Patient 6
thrombocytopenia, particularly in patients having expo- showing intrarenal hemorrhage (A) with retroperitoneal exten-
sure in known endemic areas. sion (B).

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 and its absence may be a useful clue to help differen-
tiate Hantavirus infection from leptospirosis, viral hep-
atitis, or bacterial sepsis. Maculopapular rash was ab-
sent and may also be helpful in discriminating between
Hantavirus infection and leptospirosis, dengue fever, or
scrub typhus.
The major complications noted in this study included
pulmonary edema, hemorrhages, and death. Pulmonary
edema commonly appeared during the oliguric phase of
acute renal failure and was the main indication for he-
modialysis in four patients. The occurrence of pulmo-
nary edema was unpredictable. This complication de-
veloped in two patients during aeromedical evacuation.
Emergency landing of the aircraft and hemodialysis
were required in both instances. One of these patients
died. Because development of pulmonary edema is un-
predictable and may be precipitated by air travel, aer-
omedical evacuation of these patients is not advised.
One patient developed intrarenal hemorrhage with
retroperitoneal extension. Although medullary hemor-
rhage is a common gross pathologic finding at autopsy
in Korean hemorrhagic fever, extension through the
renal capsule into surrounding tissues is rare (23, 25,
26). This hemorrhagic event occurred after resolution of
thrombocytopenia. The two patients who died from
shock had thrombocytopenia, disseminated intravascu-
lar coagulopathy, and diffuse hemorrhages into the gas-
trointestinal system, right atrium, renal medulla, lungs,
and anterior pituitary gland. Such hemorrhages are
common findings at autopsy (23).
The pathogenesis of these hemorrhagic phenomena is
not completely understood. Vascular endothelial cells
appear to be the primary site of Hantaan virus multi-
plication. Virus-induced vascular injury may then play
a role in causing diffuse hemorrhage and edema by
increasing vascular permeability, vascular fragility,
thrombocytopenia, and disseminated intravascular coag-
ulation; by activating the fibrinolytic, complement, and
kinin systems; and by inducing the formation of circu-
lating immune complexes (27).
American physicians need to become more aware of
Hantavirus infection syndromes. The recognized en-
demic areas for hemorrhagic fever with renal syndrome
have recently expanded from Korea, Japan, China, the
Soviet Union, and Scandinavia to include Belgium,
France, Scotland, Italy, central Europe, Bulgaria, Yu-
goslavia, Romania, and Greece (28-31). Given modern
worldwide air travel along with the incubation period
for Hantavirus infection syndromes of 4 to 42 days, the
potential exists for travelers returning from endemic
areas to present with this illness to unsuspecting U.S.
physicians. Furthermore, seroepidemiologic evidence
suggests that asymptomatic or unrecognized human
Hantavirus infections do occur in Canada and the
United States (18-22).
Conclusions
We present the clinical findings of 26 cases that show
the protean manifestations of hemorrhagic fever with
renal syndrome. The differential diagnosis of any per-
plexing case of septic shock, nonbacteremic clinical
sepsis, acute renal failure with thrombocytopenia, or
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undifferentiated febrile illness should include Hantavi-
rus infection. The diagnosis can then be confirmed by a
positive serologic test for IgM antibody to Hantavirus
by ELISA or by a rising titer of IgG antibody to Han-
tavirus using the indirect immunofluorescent assay tech-
nique (2, 3, 16). Application of these tests in the de-
scribed clinical settings will identify unsuspected cases,
broaden the knowledge of the geographic distribution of
Hantavirus infection, and increase physician awareness
of the disease.
The opinions expressed in this article are those of the authors, and are
not to be construed as those of the U.S. Army, U.S. Air Force, or the
Department of Defense.
Acknowledgments: The authors thank Ms. Marian Kawano and Mr.
Gilden Thomas, Visual Information Branch, Photography Section, for
their assistance in preparation of the manuscript.
Requests for Reprints: Philip Bruno, DO, LTC, MC, Infectious Disease
Service, Tripler Army Medical Center, Tripler AMC, HI 96859-5000.
Current Author Addresses: Drs. Bruno, LTC, MC; Brown, COL, MC;
and Hassell, LTC, MC: Tripler Army Medical Center, Tripler AMC, HI
96859-5000.
Dr. Tanner: 11701 Livingston Road, No. 101, Fort Washington, MD
20744.
Dr. Lau, MAJ, MC: PSC 3 Box 16215 APO San Francisco, CA 96432-
0006.
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