Hemorrhagic Fever with

Renal Syndrome (HFRS)

You-Peng Chen, Prof. Dr.

Dept. of Infectious Diseases ，

The first affiliated hospital of Jinan university

E-mail: youpeng.chen@163.com
2018 年 4 月 9 日
Hemorrhagic Fever With Renal Syndrome

• What is the cause of HFRS?

• What is the epidemiology of HFRS?
• What are the clinical manifestations ?
• How can we diagnose HFRS?
• How can we prevent HFRS?

2
 Contents
• Definition
• Etiology
• Epidemiology
• Pathogenesis
• Clinical Manifestations
• Laboratory tests
• Treatment
• Prevention
• Case report
 Definition
 HFRS, also called epidemic hemorrhagic fever,
Korean hemorrhage fever.
Infectious diseases with natural source
 Caused by Hantaviruses
 Characterized by fever, hemorrhage,
proteinuria, shock and acute renal
failure.
 Five phases in the typical cases
Febrile phase, Hypotensive (shock) phase,
Oliguric phase, Diuretic phase, Convalescent phase
4
Epidemic Hemorrhagic Fever ( EHF)

Suggested name by WHO in 1982:

Hemorrhagic Fever with Renal Syndrome
(HFRS)

5
 Etiology
Hantaviruses belong to the family
Bunyaviridae
Spherical enveloped viruses with about 80-
120nm in diameter
are enveloped RNA viruses with a negative-
sense, tri-segmented genome which consists of
three single-stranded RNA segments.
 S (small): encodes neucleocapsid protein

 M (medium): encodes envelope glycoproteins (Gn and Gc)

 L (large): encodes viral RNA-dependent-RNA polymerase

 Etiology
• The genus Hantavirus is roughly composed of two main groups:
Old World and New World hantaviruses.
• HFRS in humans is caused by pathogenic Old World hantaviruses
that include:
Hantaan (type I, HTNV)
Seoul (type II, SEOV)
Puumala (type III, PUUV)
Prospect hill (type IV)
Dobrava-belgrade

7
 Etiology

• HFRS caused by Hantaan and Dobrava viruses is

usually more severe than that caused by Seoul
and Puumala viruses.
• The epidemic serotypes in China are Hantaan
and Seoul viruses.
• Hantavirus pulmonary syndrome (HPS) is
caused by New World hantaviruses (those
present mainly in North and South America)
that include Sinnombre virus, Andes and so on.
8
Resistance of virus
Low resistance:
Inactivated by acid (<pH 5.0), ethanol,
ether, chloroform.
by heating to 60℃ for 30min or 100℃
for 1min.
Be sensitive to alcohol and
ultraviolet ray

9
 Epidemiology
History of HFRS
• While Hantavirus pulmonary syndrome (HPS)
has only been identified since 1993, HFRS has
a much longer and complex history.
• HFRS may have been recognized in China as
early as 1000 years ago.
• HFRS described in 1913 Russian records.

10
 Epidemiology
Recent HFRS Cases
• HFRS is endemic in a belt from Norway in the
west, through Sweden, Finland, the Soviet
Union, China, Korea to Japan in the east.
• China is one of the most seriously affected
countries in the world.
• About 50 000 to 100 000 cases occurred
annually from 1980-2000, 20 000 to 40 000 cases
occurred annually after 2001.
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Geographical distribution of pathogenic hantaviruses and principal associated
pathologies in humans. HCPS = hantavirus cardiopulmonary syndrome; HFRS = haemorrhagic
12
fever with renal syndrome; NE = nephropathia epidemica
Geographical distribution of hantaviruses

Chandy S, Mathai D. Globally emerging hantaviruses: An overview.

Indian J Med Microbiol. 2017;35(2):165-175. doi:
13
10.4103/ijmm.IJMM_16_429.
Geographic distribution of HFRS incidence in China from 2006 to 2012.

Zhang S, Wang S, Yin W, et al. BMC Infect Dis. 2014;14:384.

14
Demographic characteristics of HFRS in China, 2006-2012.
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Basic factors for epidemic communicable
disease

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 Source of infection
• Animals: more than 170 species of animal found
carrying hantavirus.
• Rodent animals such as mice are mainly the source of
infection.
• Other animals: dogs, cats and rabbits.
• Those pathogenic species hosted by moles( 鼹鼠 ),
shrews( 象鼩 ) and bats are of doubtful pathogenicity.
• Patients: Humans are considered dead-end hosts.

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 Source of infection
• Striped field mouse (Apodemus agrarius, 黑线姬鼠 ) and Mus
norvegicus (Rattus norvegicus, 褐家鼠 ) are mainly
indentified in China.
• Apodemus sylvaticus( 大林姬鼠 ) are observed
mainly in regions of forest.

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Striped field mouse
Apodemus sylvaticus 19
 Routes of transmission: Five
1>Airborne spread: inhaling aerosols of rodent
excreta.

2> Faeco-oral spread: ingesting food contaminated

by rodent excreta.

3>Contact transmission: direct contact of wound

to rodent excreta or being bitten by rodents
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21
 Routes of transmission
4>Bitten by the vector rodent mite.
Gamasida ( 革 螨 亚 目 ), Trombidium ( 恙 螨 属 )
mites
-confirmed

5>Vertical transmission
mother to baby, very rare

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 Susceptible People
• All of the people are susceptible.
• The disease appears to most frequently affected
persons of 20 to 50 years old.
• Although the disease occurs in both sexes, the
figures accumulated show a higher prevalence in
males.
• Low incidence rate of covert infection (3.5-4.3%).
• Stable and persistent immunity after infection.
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 Pathogenesis
• The pathogenesis of HFRS is unclear yet.
incompletely understood!
▲ Virus is the initiator
▲ Immune responses, humoral immunity
and cellular immunity responses, both
involves in the pathogenesis.

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 Pathogenesis
1.Direct damage by Hantan virus
Virus infection---replication in infected cells,
especially in microvascular endothelial cells
(endotheliocytes) of small blood vessels---
damage on cells.
2. Immune-mediated damage
Type III,I,II, and IV hypersensitivity reactions;
CTL reaction-mediated damage;
Cytokine-mediated cells damage
25
1>Type III hypersensitivity reaction
Hantan virus infection—induce specific
antibodies—immune complex-activating
complements-accumulation of immune
complex in small blood vessels,
basement of glomeruli and renal tubules---
damage

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2> Other hypersensitivity reaction

Type I-- IgE mediated damage.

Type II-- linear IgG dependent

immune response
complex–accumulation, ↓ platelet and
basement membranes of renal tubules.

Type IV--

CD8+ cells mediated immune damage. 27

3>.Cellular immune response:

Hantan virus infection –activation of CD8+

T cells--CTL response–release lymphokines ---

damage

4>.Hantan virus—lymphocyte and

macrophage—cytokins:

such as interleukin-1 (IL-1), IFN-γ, tumor

necrosis factor(TNF)—damage
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 Pathophysiology

1. Shock

Primary shock and secondary shock

2. Hemorrhage

3. Acute renal failure

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Pathophysiology: shock
Immune mediated
vascular endothelial injury
Increased capillary
permeability
Plasma extravasation
Insufficient blood volume
Primary shock
occurs before oliguric stage
Massive hemorrhage
or
Secondary infection
or
Insufficient
water-electrolyte supply
during polyuric stage
Insufficient blood volume
Secondary shock
occurs after oliguric stage
Pathophysiology: hemorrhage
tendency
• Damage of the blood vessel wall
• Thrombocytopenia
• Uremic bleeding defects
• Increase of heparin–like substances
• DIC
Pathophysiology : acute renal failure
Reasons: Six
1>.Exudation of plasma, blood volume
---low blood flow and vascular perfusion in
kidney
glomerular filtrate rate (GFR)
2>.Immune-mediated kidney damage
small vessel and renal tubule
3>.Renal interstitial hemorrhage and edema
crush renal tubules
4>. Renal tissue necrosis

5>. Activation of renin-angiotensin2 system

---renal arterial contract---renal cortex blood
flow ---

GFR (glomerular filtrate rate)

6>. Renal tubule was blocked

by proteins and casts

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 Pathology
1. Organ of pathological damage

▲Small blood vessel and kidney

▲Other organs
Such as heart, liver and
brains, so on.

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2. Pathological features

 pathological changes
Endotheliocytes of small blood vessel
congestion, edema,
hemorrhage, necrosis.
pathognomonic lesion of HFRS in kidneys.

 Similar pathological changes in various organs.

 without significant inflammatory reaction

Pathognomonic [pəˌθɒgnə'mɒnɪk] adj. 特殊（病征）的，特定的，（病征）能确定诊断的

35
 *
Histologic changes in kidney (medulla)
Most prominent change in the medulla is well–defined
necrotic lesion (asterisk)
Intracranial hemorrhage in HFRS patient
 Clinical Manifestations
 Incubation period: 4 days to 46 days, usually
1 to 2 weeks
 The hallmark of HFRS is the triad of fever,
hemorrhage, and renal insufficiency
 5 progressive stages: Febrile Phase →
Hypotensive Phase → Oliguric Phase →
Diuretic Phase → Convalescent Phase
 Some patients may present with overlapping
(febrile, hypotensive, and oliguric stages) in
atypical or severe patients, and/or bypass
phases in atypical or mild patients.
38
 HFRS: Febrile Phase
• lasts 3-7 days, seldom over 10 days.
• Sudden onset of high fever(40℃)and chills
• Systemic toxic symptoms(nausea, vomiting,
abdominal pain, diarrhea and so on)
• It often appears headache, lumbar pain and pain
on ocular movement.( 三痛 : pains of three sites)
• Flushing over Face, the V area of the neck
(drunken face), and upper chest area ( 三红 :
blushes of three sites) and the conjunctival
congestion and edema.
lumber [ˈlʌmbə(r)] 39
 HFRS: Febrile Phase
• Hemorrhagic tendency
• Petechiae are also seen in the face, neck, soft
palate, axillary folds, and anterior chest wall.
• Ecchymosis in severe cases
• Visceral bleeding
Epistaxis, bloody stool, hemoptysis, and so on
鼻衄 咯血

40
 HFRS: Febrile Phase
Kidney damage signs
Proteinuria, sometimes with casts, blood
cells and membrane-shaped substance
consisting of protein, blood cells and
mucosal epithelia.

41
 HFRS: Febrile Phase
• It often has severe abdominal pain because of
the extensive mesentery congestion and
edema. It is often misdiagnosed “acute
abdomen”.
• When the body temperature drops, the
condition deteriorates AND the disease goes
progress (“ 热退病进” ).
It differs from other infectious disease.

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Drunken face
Subconjunctival hemorrhage Chemosis
[ke‘məʊsɪs] 结膜水肿
Petechiae on the soft palate
Petechiae on axilla
Ecchymosis in severe case
 HFRS: Hypotensive phase
• Lasts for several hours or days
• Blood pressure decrease, hypovolemia,
shock (primary shock)
• Worsening of bleeding manifestations:
petechiae, epistaxis, gastrointestinal and
intracranial bleeding
• Levels of urea and creatinine in blood rise,
proteinuria, leukocytosis, thrombocytopenia.
33% of all HFRS deaths are linked to multi-organ
hypoperfusion at this stage
 HFRS: Oliguric Phase

• Lasts 3-7 days

Oliguria: urine output <400 ml /d
Anuria: urine output <50 ml/d
• Hemorrhagic symptoms continue:
Epistaxis, conjunctival hemorrhage, cerebral
hemorrhage, gastrointestinal bleeding and
extensive purpura.

49
 HFRS: Oliguric Phase
• Onset of renal failure
 Symptoms associated with uremia

 Water-sodium retention

Hypertension; pulmonary edema; ascites

 Acidosis, fluid and electrolyte imbalance, BUN

↑ ， Cr ↑
• Severe complications: cardiac failure,
pulmonary edema, and cerebral bleeding.
50% of the fatality during this phase
50
 HFRS: Diuretic Phase
• Lasts a few days to a few weeks.
• Characterized by diuresis and hyposthenuria
• migratory stage: 400-2000 ml/d, although the
urine output increases, blood urea and
creatinine still rise.
• earlier polyuric stage: more than 2000 ml/d,
azotemia does not improve, the symptoms
are still severe.
• later polyuric stage: more than 3000 ml/d, the
urine output increases per day, the azotemia
improve.
hyposthenuria [haɪpɒsθɪ'njʊərɪə] 低渗尿
51
azotemia[æzə'ti:mɪə] 氮质血症
 HFRS: Diuretic Phase

• Clinical recovery begins

• Urine output : 3-6 liters / day.

• Dehydration, electrolyte imbalance, or infection

will occur.
Fluid replacement is inadequate → secondary
shock
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 HFRS: Convalescent Phase

• Lasts 2-3 months.

• The urine output: less than 2000 ml/d.

• Unusual complication, such as neurologic

sequela, hypopituitarism or chronic renal
failure was rarely experienced.
[ˌhaɪpəʊpɪ'tju:ɪtəˌrɪzəm] 垂体机能减退
53
 Clinical Types
Five types:
1. Mild type
2. Moderate
3. Severe
4. Very serious
5. Atypical type

54
1. Mild type:
T< 39℃, mild intoxication
symptoms without oliguria
and shock

55
2. Moderate:
T>39℃ , severe intoxicating
symptoms, drunkenness,
conjunctiva edema,
hemorrhage, hypotension,
oliguria and marked proteinuria.

56
3. Severe:
T>40℃, more severe intoxicating
symptoms, shock, bleeding,
oliguria for less than 5 days or
anuria for less than 2 days.

57
4. Very serious:
The symptoms and signs in
severe type with one of following
six signs:
1>. hard-corrective Shock
2>. Bleeding in main organ
3>. Acute renal failure
4>. Cardiac failure
pulmonary edema
5>. Complication in central nervous system
6>. Serious secondary infection
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5. Atypical

T<38℃, atypical symptoms

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 Laboratory test
• Blood Routine: a normal or slightly decreased WBC
count in some patients
 leukocytosis, 15-50x 109/L in a few instances
 neutrophils dominated in early stage,
lymphocytes in late stage.
Atypical lymphocytes 10%~15%
 hematocrit value and hemoglobin rise
 thrombocytopenia
Q: Viral infections causing leukocytosis

HFRS , Infectious mononucleosis, Japanese

encephalitis, Rabies

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 Laboratory test

• Urine tests :
 Proteinuria (abnormally high amounts of
protein in the urine. )
 Hematuria
 Casts ( 管型 )
may be found in 2 days of diseases course
62
Massive protein and shedded epithelial cells in
urine form Membrane-like substance
 Laboratory test

• Biochemical assay
 Elevated PT/APTT or prolonged bleeding time.
 Elevated liver enzymes, blood urea nitrogen
(BUN), and serum creatinine
 Electrolyte abnormalities

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 Laboratory test
 Etiological diagnosis
 Enzyme-linked immunosorbent assay (ELISA)

①Anti-hantaviral specific IgM ＞ 1:20(+)

Early diagnostic value
②Anti-hantaviral specific IgG ＞ 1:40(+)
Fourfold or greater rise in IgG titer can also
confirm suspected cases
 Isolation of virus

 RT-PCR: identify viral RNA

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 Diagnosis
• Epidemiology:
a history of exposure in an endemic area.
• Clinical manifestations: 5 stages, atypical cases
have overlapping or bypass stages.
• 三痛 : pains of three body sites, e.g. headache, lumbar
pain and pain on ocular movement. 三红 :
blushes of three body sites, e.g. flushing over
face, the V area of the neck (drunken face) and
upper chest area.
• When the body temperature drops, the condition
deteriorates (“ 热退病进” ).
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 Laboratory findings
• Progressive thrombocytopenia, left-shifted
leukocytosis, presence of abnormal lymphocyte,
abnormal renal function, positive urine protein
 Etiological diagnosis

 ①Anti-hantaviral specific antibody IgM ＞ 1:20(+)

Early diagnostic value

②Anti-hantaviral specific IgG ＞ 1:40(+)
Fourfold or greater rise in IgG titer can also
confirm suspected cases
 RT-PCR: viral RNA fragment

67
 Complications
• Neurological complications: encephalitis,
cerebral hemorrhage, etc.
• Pulmonary edema
• Rupture of kidney
• chronic renal failure

68
 Differential diagnosis
1. In febrile phase

with influenza, typhoid fever, dengue, Septicemia.

2. In Hypotensive phase

with other infection shock

3. Pyrexia, intracrania hemorrhage and cerebral

edema with meningococcal meningitis    

69
4. Oliguria and renal failure with acute nephritis
5. Pyrexia and hemorrhage with Leptospirosis
6. Marked hemorrhage with:
thrombocytopenic purpura,
gastrointestinal bleeding caused by gastric ulcer

70
 Prognosis
Fatality is related to clinical type, whether being
treated earlier.
mortality 1%~5%.
major reasons for death:
renal failure, cerebrohernia
secondary infection/septicemia
massive bleeding.
mortality higher in patients with type I (Hantann)
virus infection.
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 Treatment

No specific treatment !
So the management of the patient must be
supportive and based on an understanding of the
pathophysiologic characteristics of the disease, and
an evaluation of clinical and/or laboratory findings.
Early diagnosis and hospitalization are most
important.

72
 Treatment in febrile phase

• Bed rest , strict maintenance of fluid balance

• check blood pressures, record the urine output
• Ribavirin has shown to be effective during the
first 5 days of the HFRS illness.
 To relieve the permeability of blood vessel:

Rutosids and vitamin C

芦丁

73
 Treatment in febrile phase

 Management of the fever and toxic symptoms

 Physical cooling
 Antipyretic can be used carefully.
 Short course dexamethasone

74
 Treatment in hypotensive phase
Principle of treatment:
►Supplement blood volume
► Correct acidosis

1>.Supplement blood volume

A. Principle:
early rapidly adequate
75
B: kinds of fluids:
Crystalloid fluids and Colloid fluids containing
suitable glucose, electrolytes and
vitamins:
Ringer’s Solution
Normal saline solution
Dextran, albumin
Plasma, Artificial plasma

76
2>Correct metabolic acidosis

5% sodium bicarbonate (NaHCO₃) solution

3>.Blood vessel activating (vasoactive) drugs

for hypotension and shock:

dopamine, norepinephrine, anisodamine (654-2)

77
 Treatment in oliguric phase
 Maintenance of internal environment homeostasis
 Restrict the volume of infusion
Daily urine volume + 500-700ml
 Control the azotemia
Supply sufficient carbohydrate to reduce the protein
degradation
 Maintaining electrolyte balance
Treatment of Hyperkalemia
 Correction of acidosis
5% Sodium Bicarbonate Injection

78
 Treatment in oliguric phase
 Diuretics: furosemide [fjʊə‘rəʊsəmaɪd] 速尿
• Consider hemodialysis in following conditions:
 Severe azotemia

 Fluid overload that cannot be managed with

diuretics
 Hyperkalemia refractory to medical therapy

 Severe acid-base disturbances

79
 Treatment in Diuretic phase

• Adequate replacement of fluid and

electrolytes
• Prevent secondary infection
Antibiotics with nephrotoxic potential should
be avoided

80
Treatment in Convalescent phase

• intensive nutrition and have a good rest.

• Examination renal function, blood pressure,

pituitary function at regular interval

81
 Prevention
• Control source of infectin: Rodent control
• Cut off the route of transmission:
Avoid contact with rodent urine, droppings,
saliva, and nesting materials
• Protect susceptible people: inject specific
vaccine.
Inactivated hantavirus vaccine (IHV), DNA
vaccine.
Jung J, Ko SJ, Oh HS, et al. Protective effectiveness of inactivated hantavirus vaccine against
hemorrhagic fever with renal syndrome. J Infect Dis. 2018 Jan 24. doi: 10.1093/infdis/jiy037. 82
 Summary
• 汉坦老鼠欧亚流
热血休克肾脏损
热退病进系统累
三红三痛五期过
白游板少尿蛋白
病急对症预防重

83
 Home work
1. The main reason for early shock in HFRS is
A. Infection.
B. Blood plasma-losing
C. Hypervolemia
D. Hemorrhage
E. Vomiting .

84
 Home work
2. The patient had fever, lumbago, headache for
three days. Physical examination: drunken face,
petechiae in axillary folds, chemosis. Blood
routine test: WBC 19×109 /L ， N 83%, PLT
20×109 /L. Urine protein (+++), RBC 3-5/HP .The
diagnosis may be
A.Typhoid fever
B.Typhus
C.Acute glumerulonephritis
D.Epidemic hemorrhagic fever
85
 Home work
3. Typical hemorrhagic fever with renal
syndrome caused by Hantaan virus evolve in
five identifiable stages:______, ______,
______, ______ and ______.
4. Give a introduction about the management
principle of the oliguric phase of the
hemorrhagic fever with renal syndrome

86
 Case report
Male, 30 years old, farmer. he was admitted because of
fever, headache and lumbar pain for 4 days. he was in good
health in the past. PE: T 39℃, BP 110/70mmHg, flushing
on the face, conjunctival congestion, petechiae are
observed in the axillary folds. Both of lung were clear, and
the heart rate was normal. The abdomen was flat and soft ,
the liver and the spleen couldn’t be palpable, lightly
percussion pain in renal region, shifting dullness negative.
Laboratory findings:
Blood routine: WBC: 15×109/L, PLT: 70×109/L
Urine routine: protein ＋ , BUN: 20mmol/L.CR:
433umol/L.
 Case

• 1. What is the most possible diagnosis do you

think? and what is the proof of diagnosis?
• 2. What do you do to make diagnosis clear?

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