Hemorrhagic Fever with Renal SyndromeDepartment of Infectious Diseases Third Affiliated Hospital of Sun Yat-sen University Lin Yang

Definition 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 Febrile phase, Hypotensive (shock) phase,Oliguric phase, Diuretic phase, Convalescent phase

Epidemic Hemorrhagic Fever ( EHF)

Suggested name by WHO in 1982:Hemorrhagic Fever with Renal Syndrome (HFRS)

Hantan virus Member of the family of Bunyaviridae Feature of virus Single-strand negative RNA virus Circular or oval in shape 78~210 nm in diameter Envelope proteins:glycoprotein1(G1) glycoprotein2(G2) Viral genomeRNA: L M S gene Etiology

Viral proteins L--- Polymerase M---Envelope protein G1 and G2 the membrane antigen G2: contain neutrolization antigen (vaccine antigen) S---Nucleocapsid protein: strong antigenicity and immunogenicity, and containing complement binding antigen.

Serologic type of Hantan virus Over twenty serologic types hantaan virus (type I, HTNV) seoul virus(type II, SEOV) puumala virus (type III,PUUV) prospect hill virus(type IV,PHV) dobrava-belgrade virus (DEOV)

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) China: Hantaan virus Seoul virushantaan virus and DEOV show stronger pathogenecity than type II and III virus

Resistance of virus Low resistance: Inactivated by acid (

Epidemiology 1.Sources of infection In our country: Apodemus agrarius Mus norvegicus Apodemus sylvaticus Citellus undulatus Laboratory Rats Other animals: cats dogs rabbits Patients:unimportantInfected field rats, house rats

Apodemus agrariusMus norvegicus

2. Modes of transmission: Five 1>.Air-borne transmission via inhale aerosol contaminated with virus- containing excretion or secretion of rats 2>.Food-borne transmission via oral and esophageal mucosa (eat food contaminated with virus-containing excretion or secretion of rats)

3>. Infection via contact Be bitten by rats or wound is contaminated with virus-containing excretions or secretions of rats4>. Vertical transmission: mother to baby, very rare5>. Arthropod-borne: rats mite, red mite, harvest mite may carry Hantan virus. need to be confirmed

3. Epidemic features 1>. District localization: mainly in Asia. Europe and Africa, America In China: higher incidence except for Qinghai and Xizhang provinces 2>.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 agrariusEpidemic peak : three

3>. Epidemic form three kinds of epidemic form: sporadic, endemic, seldom epidemic 4>. Occupation and age Residents in countryside urban and rural worker Most victims are young adults.

4. Susceptibility Susceptibility is universal Low rate of covert infection (3.5.-4.3%). Stable immunity obtain from illness IgG against type I virus: last for 1-30 years IgG aganst type II virus: last less 2 years

Pathogenesis Pathogenesis of HFRS is not so clear. Virus is the initiator Immune responses, humoral and cellular immune response,both involves in the pathogenesis

1.Direct damage by Hantan virus Virus infection---replication in infected cells, especially in 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

1>Type III hypersensitivity reaction Hantan virus infectioninduce specific antibodiesimmune complex-activating complements-accumulation of immune complex in small blood vessels, basement of glomerulus and renal tubule--- damage

2> Other hypersensitivity reaction Type I--IgE mediated damage. Type II-- linear IgG immune complexaccumulation in platelet and basement membranes of renal tubule Type IV CD8+ cell mediated immune damage.

3>.Cellular immune response: Hantan virus infection activation of CD8+ T cellsCTL responserelease lymphokines damage 4>.Hantan viruslymphocyte and macrophagecytokins: such as interleukin1(IL-1), IFNr, tumor necrosis factor(TNF)damage

Pathophysiology 1.Shock Primary shock and secondary shock 2.Hemorrhage 3.Acute renal failure

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

Secondary shock: Occur in diuretic phase Reasons: Severe hemorrhage Secondary infection Imbalance of fluid, electrolytes

2. Hemorrhage Petechia, ecchymosis in skin and mucosas, visceral bleeding Reasons: Capillary damage; Platelet decrease and dysfunction; DIC; increased Heparin-like substance; anuria

3. Acute renal failure Reasons: Six 1>.Exudation of plasma, blood volume blood concentrate---blood flow in kidney glomerular filtrate rate (GFR) 2>.Immune-mediated kidney damage small vessel and renal tubule 3>.Renal interstitial hemorrhage and edema --- crush renal tubule

4>. Renal tissue necrosis5>. Activation of renin angiotensin IIrenal arterial contract---renal cortex blood flow GFR (glomerular filtrate rate) 6>. Renal tubule was blocked by proteins and casts

Pathology 1. Organ of pathological damage Small blood vessel and kidney Other organs Such as heart, liver and brains, so on.

2. Pathological feature 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

Clinical Manifestations Incubation period: 1-2 weeks Three major manifestations: 1> pyrexia, intoxication 2> hyperemia and hemorrhage 3> hypotension and renal malfunction Five typical phase. Five clinic types

A:Five typical phase 1.Febrile phase 2.Hypotensive (shock) phase 3.Oliguric phase 4.Diuretic phase 5.Convalescent phase

1.Febrile phase Pyrexia Intoxication symptoms Capillary damage signs Kidney damage signs Clinical Manifestations

1.Febrile phase 1>. Pyrexia acute onset, 39oC- 40oC, lasts 3-7 days Feature of pyrexia: Sustained fever or remittent fever. For most cases, going to more serious with pyrexia gradually disappeared

2>.Intoxication symptoms a. Three ache headache because of small vessel expansion lumbago, orbital pain. because of hyperemia and edema in tissue. b.Gastrointestinal symptoms hiccup vomiting abdominal pain and diarrhea

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 babular conjunctiva edema. palpebra edema and face edema 4>. Kidney damage signs Proteinuria, sometimes with casts, blood cells and membrane-shaped substance consisting of protein, blood cells and mucosal epithelia.

Summary in febrile phase Pyrexia, three flush, three ache, hemorrhage and conjunctiva edema, malaise, proteinuria, sometimes with casts, blood cells and membrane-shaped substance

Patient with HFRS

Patient with HFRS:petechia, ecchymosis

2.Hypotensive(shock) phase 1> Occur during defeverscence 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% Clinical Manifestations

3. Oliguric phase Oliguria or anuria Uremia Metabolic acidosis and imbalance of fluids and electrolyte Clinical Manifestations

3. Oliguric phase Occur during or soon after hypotensive phase, in 5 to 8 days of diseases course, lasts 2-5 days. 1>. Oliguria or anuria Oliguria: urine volume< 500ml/24h Anuria: urine volume< 50ml/24h

2>.Uremia a. gastrointestinal symptoms hiccup, vomiting, abdominal pain, diarrhea b. Aggravating hemorrhage hemoptysis, hematemesis, hematuria or melena c. Nervous system symptoms

3>.Metabolic acidosis and imbalance of fluids and electrolyte Metabolic acidosis fatal hyperkalemia hypervolemic syndrome edema and restlessness high blood pressure engorged neck veins.

4 Diuretic phase Urine >3000ml/24h Occur in 9 to 14 days of diseases course, last for 1 day or several months Three phase according to urine volume and azotemia signs Transition phase Early stage of diuretic phase Late stage of diuretic phase Clinical Manifestations

1>. Transition phase a.Urine from 500ml to 2000ml/24h b. BUN and Cr persistently c. State of patient may change to more serious.more serious although urine increasehigh mortality

2>. Early stage of diuretic phase urine volume > 2000ml/24h no marked decrease in azotemia3>. Late stage of diuretic phase a. urine volume > 3000ml/24h in most of cases: 4000 to 8000/24h, 15000ml/24h b. azotemia improving, BUN falling down c. Secondary shock, dehydration hypokalemia, hyponatremia

5. Convalescent phase urine return to 1000-2000ml/24h normal appetite taking 1-3 months for recoveringFive phase be not seen in every case. hypotension and /or oliguria phase may be absent in atypical cases Clinical Manifestations

B:Five clinic types 1. Mild type 2. Moderate 3. Severe 4. Very serious 5. Atypical type

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

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

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

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

5. Atypical T

Laboratory Finding 1. Blood routine leukocytosis, 15-50x 109/L, neutrophils dominated in early stage, lymphocytes in late stage. Atypical lymphocytes10%~15% hematocrit value and hemoglobin rise, thrombocytopenia

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

3. Blood biochemical examination BUN and Cr increased. CO2-CP decreased. hyperkalemia in oliguric phase. hypokalemia in diuretic phase.

4. Blood coagulating function examination thrombocytopenia, platelet prolongated PT Fibrinogen decreased secondary fibrin lysis

5. Serological tests Hantan virus antigen and specific antibody test by IFAT, ELISA, RIA or WB. Antibody against nuclear protein is useful for diagnosis. 1> IgM antibody 1:20 positive: diagnosis marker 2> IgG antibody: > 4 times/week useful for diagnosis. Anti-G2--- estimate prognosis. 6. Molecular biological tests Viral RNA by RT-PCR

Complications 1.Visceral bleeding Intracrania hemorrhage hemoptysis, hematemesis, hematuria, cerebral hemorrhage

2. Complication in central nervous system Encephalitis and meningitis Intracrania hemorrhage and cerebral edema

3.Pneumon edema commonly occur in hypotensive phase and oliguric phase. ARDS: Mortality ~ 67%) (Adult respiratory distress syndrome) Reasons: increasing permeability of the pulmonary capillarries, and decreasing in alveolar surface activating substances

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

Diagnosis Epidemiologic data Clinical feature Laboratory examinations

1. Epidemiologic data place, season, history of contacting rats or excretion and secretions of rats

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

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

Differential diagnosis 1. In febrile phase with common cold, influenza, Septicemia. 2. In Hypotensive phase with other infection shock 3. Pyrexia, intracrania hemorrhage and cerebral edema with meningococcal meningitis

4.Oliguria and renal failure with acute nephritis 5.Pyrexia and hemorrhage with Leptospirosis6.Marked hemorrhage with: thrombocytopenic purpura, gastrointestinal bleeding caused by gastric ulcer.

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

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

Treatment Supportive treatment Anti-viral therapy Symptomatic treatment

1. Supportive treatment bed rest easy digestive food vitamins Intravenous fluids containing suitable glucose, electrolytes

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

1>.Anti-viral therapy: important giving anti-virus drug in early stage. (Ribavirin(virazole) 1.0g iv drip with 10%GS qd for 3-5 days 2>.Reduce permeability of small vessel and exudation Lutin and Vitamin C

3>.Reduce intoxicating symptoms a>For hyperpyrexia Physical measures to decrease temperature. For example: putting ice-bag on head, neck or big vessel location. Avoiding using heavy antipyretics b>.Corticosteroids for hyperpyrexia and heavy intoxicating symptoms Dexamethasone 5-10mg iv. Drip c> c>.Anti-vomiting: 20mg of Paspertin im p.r.n

4>.Prevention from DIC a>. Reduce the blood viscosity Danshen solution, Dextran 40 b>. anti-coagulation therapy Heparin should be given once the CT is less than 3 min or APTT less than 34 seconds.

3.Treatment in Hypotensive phase Principle of treatment: Supplement blood volume Correct acidosis 1>.Supplement blood volume A.Principle: early rapidly adequate

1>.Supplement blood volume A.Principle: early rapidly adequate B:kinds of fluids: Crystalloid fluids and Colloid fluids containing suitable glucose, electrolytes and vitamins: Ringers Solution Normal saline solution Dextran, 20% Mannitol Plasma, albumin, Artificial plasma.

2>Correct metabolic acidosis 5% sodium bicarbonate solution. The amount calculated according to CO2CP value. 3>.Blood vessel activating drugs for hypotension and shock: aramine, dopamine, 654-2

4>.Corticosteroids Reduce severe toxemia, Reduce permeation of small vessel Improving microcirculation of tissue.

10~20mg of Dexamethason is given by intravenous drip.

4.Treatment in oliguric phase Principle of treatment : Balance intra-environment Diuretic therapy Catharsis therapy for preventing from hypervolemia Dialysis therapy

1>.Balance intra-environment a>.Correct imbalance of fluid electrolytes, acid- base Closely observe and record urine volume. Examine blood biochemical parameter and renal function adjusting amount of fluid and electrolytes

b>. Reducing protein degradation and control of azotemia. Food containing high vitamins high carbohydrate, low protein. For the serious patient: Supplement glucose 200~300g every day by intravenous drip 20-25% GS with insulin.

2>.Diuretic for oliguria 20%Mannitol solution. lasix (furosemide) 3>Catharsis therapy for hypervolemia inducing diarrhea to take out fluids by intestinal. 50% Magnesium Sulfate solution 20%Mannitol solution

Reducing blood volume therapy

For hypervolemia with cardiac failure and pulmonary edema, taking out 300ml ~400ml blood may be useful.used rare now

4>.Dialysis therapy for serious azotemia

very important, save life Hemodialysis or Peritoneal dialysis

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.

5. Treatment in Diuretic phase a. Keeping balance of fluid and electrolytes. b.Preventing and treatment secondary infection: antibiotics

6.Convalescent phase a:Supplement nutrition food. b:Examination renal function, blood pressure, pituitary function at regular interval.

7.Complications treatment 1>. Hemostatics therapy for heavy bleeding such as gastrointestinal hemorrhage treatment of DIC: according to different phase of DIC, giving EACA, protamine ,respectively.

2>.Treatment ARDS a: Control of amount of intravenous infusion. b: Giving oxygen, or mechanical ventilation: positive end expiratory pressure. c.Corticosteroids: 20 to 30mg of dexamethasone d. Cedilanid for cardiac failure.

3>.Treatment of central nervous system complications a> Diazepam for tics b>.Cerebral edema and high intracranial pressure: 20% of mannitol or/and lasix dripped intravenously.

4>. Prevention and treatment of secondary infections: Antibiotics 5>. Spontaneous rupture of the kidneys Surgery therapy

Prophylaxis 1. Exterminate field rats, house rats. 2.Wipe out mites: Drugs: Derivatives of pyrethrin Organic phosphoric compounds Preventing from biting.

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.

SUMMARY 1.HFRS:Infectious diseases caused by Hantan virus 2. Major sources of infection: Infected field rats, house rats, 3. Epidemic features: three epidemic peaks: March to May: by house rats November to January, May to July: by Apodemus agrarius

4. Pathogenesis Viral direct damage of Hantanvirus. Immune-mediated damage5. Pathological damage and feature major in small blood vessel and kidney. congestion, edema, hemorrhage, necrosis.6.Pathophysiology: Shock Hemorrhage Acute renal failure Without significant inflammatory reaction

7.Clinical feature Fever, three flush, three ache, exudative edema, hemorrhage, proteinuria, shock and acute renal failure. Five phase in typical cases. 8. Diagnosis Combination of epidemiologic data, clinical feature and laboratory examinations data.9.Principle of treatment: diagnosis, rest and treatment early Treatment in near hospital10. Principle of treatment for each phase ??

11. Treatment 1>. Supportive treatment 2>.Anti-viral therapy 3>.Symptomatic treatment12. Prevention 1>.Exterminate field rats, house rats 2>. vaccines Against Hantan virus type I Against Hantan virus type II