Hemorrhagic Fever with Renal Syndrome

Duan Zhongping MDBeijing Youan Hospital

Capital Medical University

Worldwide distributions of HFRS

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Definition and Introduction

Febrile phase; Hypotensive phase; Oliguric phase;

Diuretic phase; Convalescent phase

Infectious diseases with natural source Caused by Hantan virus Characterized by fever, hemorrhage,

proteinuria, shock and acute renal failure Five phases in the typical cases

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Hantan virus Member of the family of Bunyaviridae Feature of virus Single-strand negative RNA virus Circular or oval in shape 90~210 nm in diameter Envelope

proteins:glycoprotein1(G1)

glycoprotein2(G2)

Etiology of HFRS

Surface and Core Structure of Hantaviruse

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Human HFRS

caused by four type of virus: Hantaan virus (type I, HTNV) Seoul virus(type II, SEOV) Puumala virus (type III,PUUV) Dobrava-belgrade virus(DEOV) In China: Hantaan virus and Seoul virus

hantaan virus and DEOV show stronger pathogenecity than type II and III virus

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Resistance of Hantavirus

Low resistance:

Inactivated by acid, ethanol, ether, chloroform

heat in 56ºC for 30min or 100ºC for 1min

Be sensitive to alcohol

Viruses survive<1week in indoor environments

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Epidemiology

1. Sources of infection Infected rodents, most of them are rats Apodemus agrarius Mus norvegicus Apodemus sylvaticus Citellus undulatus Laboratory Rats Other animals: cats/dogs/rabbits Patients: unimportant

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Apodemus agrarius Mus norvegicus

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2. Modes of transmission: Five

Air-borne transmission

via inhale aerosol contaminated with virus-

containing excretion or secretion of rats Food-borne transmission via oral and esophageal mucosa (eat food contaminated with virus-containing excretion or secretion of rats)

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Infection via contact

Be bitten by rats or wound is contaminated

with virus-containing excretions or

secretions of ratsVertical transmission: mother to baby, very rare

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3. Epidemic features

District localization mainly in Asia.Less in Europe and Africa, America

In China: higher incidence except for Qinghai/Xinjiang

Seasonality May occur all the year, however seasonality

▶March to May transmitted by house rats

▶November to January and May to July

transmitted by Apodemus agrarius

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Epidemic form

three kinds of epidemic form:

sporadic, endemic, seldom epidemic Occupation and age

▶ Residents in countryside

▶ urban and rural worker

Most victims are young adults!

Male adults, rodent control workers, farmers, forestry workers be at higher risk of infection

Chin J Pest Control, 2009, l12 （ 5 ） :350-352

Male adults, rodent control workers, farmers, forestry workers be at higher risk of infection

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Pathogenesis

Pathogenesis of HFRS is not so clear Virus is the initiator Immune responses, humoral and

cellular immune response,both

involves in the pathogenesis

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Pathophysiology

1.Shock Primary shock and secondary shock

2.Hemorrhage

3.Acute renal failure

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1. shock Virus and immune response--- small blood

vessel damage---permeability of vessel ---

plasma exudation---blood volume ---blood

concentrate, viscosity of blood ---DIC---blood

flow ---blood volume ---hypotension shock

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2. Hemorrhage Pete’chia, ecchy’mosis in skin and mucosas,

visceral bleeding

Reasons: Capillary damage

Platelet decrease and dysfunction

DIC; increased Heparin-like substance; anuria

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3. Acute renal failure

Six Main Reasons Exudation of plasma, blood volume

blood concentrate---blood flow in kidney

glomerular filtrate rate (GFR) Immune-mediated kidney damage small vessel and

renal tubule Renal interstitial hemorrhage and edema ---crush renal

tubule

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Renal tissue necrosis Activation of renin

angiotensin II—renal arterial

contract---renal cortex blood flow

GFR (glomerular filtrate rate) Renal tubule was blocked

by proteins and casts

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Clinical Manifestations

Incubation period: 1-2 weeks Three major manifestations: 1> pyrexia, intoxication 2> hyperemia and hemorrhage 3> hypotension and renal malfunction Five typical phases

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Five typical phase 1. Febrile phase

2. Hypotensive (shock) phase

3. Oliguric phase

4. Diuretic phase

5. Convalescent phase

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1. Febrile phase Pyrexia

Intoxication symptoms

Capillary damage signs

Kidney damage signs

Clinical Manifestations

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1. Febrile phase

(1) Pyrexia

acute onset, 39oC- 40oC,

lasts 3-7 days

Feature of pyrexia:

Sustained fever or remittent fever

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2. Intoxication symptoms

a. Three ache

headache

because of small vessel expansion

lumbar backache , orbital pain.

because of hyperemia and edema in tissue.

b. Gastrointestinal symptoms

hiccup, vomiting

abdominal pain and diarrhea

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3. Capillary damage signs

a. hyperemia Flush over face, neck and chest skin (three flush) drunkenness

b. Hemorrhage For most cases, petechia, ecchymosis, or stripe-shaped bleeding in chest and back skin, conjunctiva bleeding. For a partial cases, hematuria, DIC

c. Exudative edema mainly conjunctiva edema. face edema

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4. Kidney damage signs

Proteinuria, sometimes with casts, blood cells and membrane-shaped substance consisting of protein, blood cells and mucosal epithelia.

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Summary in febrile phase

Pyrexia, three flush, three ache,

hemorrhage and conjunctiva edema,

proteinuria, sometimes with casts, blood

cells and membrane-shaped substance

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Patient with HFRS: hemorrhage and conjunctiva edema

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Patient with HFRS: petechia, ecchymosis

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2.Hypotensive(shock) phase

1> Occur during defever scence in 4 to 5 days

of diseases course, lasts 1 to 3 days.

2>. Main signs: Hypotension or shock

3>. nausea, vomiting, abdominal pain.

Platelet, hematocrit value

proteinuria, leukocytosis,

atypical lymphocytes >10%

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3. Oliguric phase

Oliguria or anuria

Uremia

Metabolic acidosis and imbalance of

fluids and electrolyte

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3. Oliguric phase Occur during or soon after hypotensive phase,

in 5 to 8 days of diseases course

Lasts 2-5 days.

With uremia,metabolic acidosis and

imbalance of fluids and electrolyte

Oliguria or anuria Oliguria: urine volume< 500ml/24h

Anuria: urine volume< 50ml/24h

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4. Diuretic phase

▲ Urine >3000ml/24h Occur in 9 to 14 days of diseases course, last for 1 day or several days ▲ Three phase According to urine volume and azotemia signs ►Transition phase ► Early stage of diuretic phase ► Late stage of diuretic phase

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5. Convalescent phase

urine return to 1000-2000ml/24h normal appetite taking 1-3 months for recovering

Five phase be not seen in every case. hypotension and /or oliguria phase may be absent in atypical cases

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Laboratory Finding

1. Blood routine

leukocytosis, 15-50 x 109/L

neutrophils dominated in early stage,

but lymphocytes in late stage.

With atypical lymphocytes10%~15%

hematocrit value and hemoglobin rise,

thrombocytopenia

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2. Urine routine Proteinuria, sometimes with casts, blood

cells and membrane-shaped substance, consisting of protein, blood cells and mucosal epithelia.

May be found in 2 days of diseases course

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3. Blood biochemical examination

BUN and Cr increased

CO2-CP decreased

hyperkalemia in oliguric phase.

hypokalemia in diuretic phase

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4. Serological tests Hantan virus antigen and specific antibody

test by ELISA, RIA or WB. Antibody against

nuclear protein is useful for diagnosis.

1> IgM antibody

2> IgG antibody

5. Molecular biological tests

Viral RNA by RT-PCR

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Complications

1.Visceral bleeding 2.Complication in CNS Encephalitis and meningitis,Intracrania hemorrhage and cerebral edema

3.Pneumon edema

4.Others Secondary infection with bacterials. Spontaneous rupture of the kidneys Hepatitis, myocarditis, pericarditis

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Diagnosis

Epidemiologic data Clinical symptoms Clinical signs Laboratory examinations

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1. Epidemiologic data

place, season,

history of contacting rats or excretion and secretions of rats

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2. Clinical features

three manifestations in early stage and the course of five phase in typical case ►Pyrexia, “three aches”,intoxicating symptoms ► “Three flush”: face, neck and chest skin. ► conjunctiva congestion and edema. ► hemorrhage ► Oliguria, renal region pain on percussion ► Five phase in typical case

Five phase is not observed in every case. Hypotension and /or oliguria phase may be absent in atypical cases

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3. Laboratory data 1. Blood Leukocytosis atypical lymphocytes>10% thrombocytopenia. 2.Urine: proteinuria. membrane- shaped substance in urine. 3.Virus antigen and antibody Viral RNA by RT-PCR

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Differential diagnosis

1. In febrile phase

with common cold, influenza, Septicemia.

2. In Hypotensive phase

with other infection shock

3. Pyrexia, intracranal hemorrhage and cerebral

edema with meningococcal meningitis    

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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.

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Prognosis

Fatality is related to clinical type, whether being treated earlier.

Mortality 1%~5%.

Major reasons for death:

renal failure

secondary septicemia

massive bleeding.

Mortality higher in infection with type I virus.

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Treatment

Principle of treatment Diagnosis, rest and treatment in early Treatment in near hospital

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1. Supportive treatment

bed rest

easy digestive food

vitamins

Intravenous fluids containing

suitable glucose, electrolytes

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2. Treatment in febrile phase

Principle of treatment

a. Anti-virus therapy

b. Reduce exudation of plasma

c. Reduce intoxicating symptoms

d. Preventing from DIC

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3.Treatment in Hypotensive phase

Principle of treatment: ►Supplement blood volume

► Correct acidosis

Supplement blood volume Attention: early rapidly adequate

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Correct metabolic acidosis

5% sodium bicarbonate solution. The amount

calculated according to CO2CP value

Blood vessel activating drugs

for hypotension and shock:

aramine, dopamine, 654-2

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4.Treatment in oliguric phase

Principle of treatment :

►Balance intra-environment

►Diuretic therapy

►Catharsis therapy for preventing

from hypervolemia

►Dialysis therapy

Pharmacological manipulation,hemodialysis and kidney transplantation had maken the beginning of a new era in the treatment of patients with renal failure

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Marker of giving Dialysis therapy Oliguria lasts for 4 days or anuria lasts

for 24 hours with one of following five signs: a>.Seral BUN >28.56mmol/L; b>.BUN increasing more than 7.14mmol/L every day; C>.Blood potassium > 6mmol/L; d>.hypervolemia or/and pulmonary edema; e>.being terrible fretful or cerebral edema.

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5. Treatment in Diuretic phase

a. Keeping balance of fluid and electrolytes

b.Preventing and treatment secondary

infection: antibiotics

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6.Convalescent phase

Supplement nutrition food Examination renal function, blood pressure,

pituitary function at regular interval

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Prophylaxis

1. Exterminate field rats, house rats.

2. Wipe out mites: Drugs:

Derivatives of pyrethrin

Organic phosphoric compounds

Preventing from biting.

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3.Vaccine Two Kinds of vaccines can be available:

►Against Hantan virus type I ►Against Hantan virus type II Antibody production: 88%-94%, and last for 3~6 months

Inoculation of the vaccine is carried out one month earlier than epidemic, and a bloost injection should be given one year later.

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SUMMARY

1. HFRS is an acute infectious diseases caused HV2. Major sources of infection are: Infected field rats, house rats,et al.3. Pathological damage and feature major in small blood vessel and kidney. congestion, edema, hemorrhage, necrosis4. Pathophysiology: Shock Hemorrhage Acute renal failure

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5.Clinical feature Five phase in typical : Febrile,

hypotensive phase, oliguric, diuretic and convalescent phase

6. Diagnosis Combination of epidemiologic data,

clinical feature and laboratory examinations data

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7. Treatment 1. Supportive treatment

2. Anti-viral therapy

3. Symptomatic treatment

8. Prevention 1. Exterminate field rats, house rats 2. Vaccines ►Against Hantan virus type I ►Against Hantan virus type II

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CASE STUDY

A 30-year-old male presented with fever and oliguria in Apr.1, 2008.

5 days ago, he developed chill and high fever, with the highest temperature 39C°, which

was accompanied with headache, generalized muscular pain. He received penicillin

and infusion at local clinic with no improvement. He was referred to county hospital

after he fainted 1 day ago. On arrival, PE showed that BP 70/50mmHg, blood routine

test revealed WBC 22×109/L, N 0.9, L 0.1, PLT 80×109/L. The aminoglycosides was

given to him. The fever was gone but oliguria developed.

He is a forestry worker in Gansu province. His past history is not remarkable.

PE on admission ： T 37.1C, P 96 bpm, R 20 bpm, BP 120/80mmHg, with remarkable

conjunctiva congestion, several petechia on upper chest and at injection sites.

Lab findings ： WBC 26×109/L ， N 0.79 ， L 0.18 ， atypical lymphocytes

6% ， HGB 128g/L ， PLT50×109/L. Urinalysis ： PRO(++++) ， RBC(+) Fecal

occult blood (+)

Questions ： What’s the most probable diagnosis ？ What’s your diagnostic criteria? What’s the further lab tests for conformed diagnosis?

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Questions and Answers

1. Q: What are the major sources of HFRS?

A: Infected field rats, house rats, cats, et al.

2. Q: What is the main transmission route of HFRS?

A: Air or aerosol, contaminated food or water, contact transmission, vertical transmission.

3. Q: How many phases does a typical HFRS case have?

A: Five typical phases: febrile, hypotensive, oliguric,

diuretic and convalescent phase.