5 Hemorrhagic Fever With Renal Syndrome

• 1. Hemorrhagic Fever with Renal Syndrome Department of Infectious DiseasesThird Affiliated Hospital of Sun Yat-sen University LinYang

2.

• Definition

• Infectious diseases with natural source

• Caused by Hantan virus

• Characterized by fever,hemorrhage,

• proteinuria, shock and acute renal

• failure.

• Five phasesin the typical cases

Febrile phase, Hypotensive (shock) phase, Oliguric phase, Diuretic phase, Convalescent phase 3. Epidemic Hemorrhagic Fever ( EHF) Suggested name by WHO in 1982: Hemorrhagic Fever with Renal Syndrome (HFRS) 4. Hantan virus Member of the familyof Bunyaviridae Feature of virus Single-strand negative RNA virusCircular or oval in shape 78~210 nm in diameter Envelope proteins:glycoprotein1(G1) glycoprotein2(G2) Viral genomeRNA :LMS geneEtiology 5.

• 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.

6. 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) 7. 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 virusSeoul virus hantaan virusand DEOV show strongerpathogenecity than type II and III virus 8. Resistance of virus Low resistance: Inactivated by acid (.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 withvirus-containing excretion or secretion of rats)

12.

• 3>. Infection via contact

• Be bitten by ratsor wound is contaminated

• with virus-containing excretions or

• secretions of rats

• 4>. Vertical transmission:

• mother to baby,very rare

• 5>. Arthropod-borne :

• rats mite,red mite, harvest mite may carry Hantan virus.need to be confirmed

13.

• 3. Epidemic features

• 1>. District localization: mainly in Asia.

• Europeand Africa, America

• In China: higher incidence

• except for Qinghai and Xizhang provinces

• 2>.Seasonality

• May occur all the year, howeverseasonality

• March to Maytransmitted by house rats

• November to JanuaryandMay to July

• transmitted byApodemus agrarius

Epidemic peak : three 14.

• 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 .

15.

• 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 less2 years

16. Pathogenesis Pathogenesis of HFRS is not so clear. Virus is theinitiator Immune responses, humoral andcellular immune response,bothinvolves in the pathogenesis 17. 1.Direct damage by Hantan virus Virusinfection---replication in infected cells,especially inendotheliocytesof small bloodvessels---damage oncells. 2. Immune-mediated damage Type III,I,II, and IV hypersensitivity reactions; CTL reaction-mediated damage;Cytokine-mediated cells damage 18. 1>Type III hypersensitivity reaction Hantan virus infectioninduce specificantibodiesimmune complex-activatingcomplements-accumulation of immunecomplexin small bloodvessels,basement of glomerulus and renal tubule---damage 19. 2> Other hypersensitivity reaction Type I--IgE mediated damage. Type II-- linear IgG immunecomplexaccumulation in platelet andbasement membranes of renal tubule Type IV CD8+ cell mediatedimmunedamage. 20. 3>.Cellular immune response: Hantan virus infection activation of CD8 + T cellsCTL responserelease lymphokines damage 4>. Hantan viruslymphocyte andmacrophagecytokins: such as interleukin1(IL-1), IFNr, tumornecrosis factor(TNF)damage 21.

• Pathophysiology

• 1.Shock

• Primary shock and secondary shock

• 2.Hemorrhage

• 3.Acute renal failure

22.

• 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

23.

• Secondary shock:

• Occur in diuretic phase

• Reasons:

• Severe hemorrhage

• Secondary infection

• Imbalance of fluid,electrolytes

24.

• 2. Hemorrhage

• Petechia, ecchymosis in skin and mucosas,

• visceral bleeding

• Reasons:

• Capillary damage;

• Platelet decrease and dysfunction;

• DIC;increased Heparin-like substance;anuria

25.

• 3. Acute renal failure

• Reasons: Six

• 1>.Exudation of plasma, bloodvolume

• blood concentrate---blood flowin kidney

• glomerular filtrate rate (GFR)

• 2>.Immune-mediated kidney damage

• small vessel and renal tubule

• 3>.Renal interstitial hemorrhage and edema ---

• crushrenal tubule

26.

• 4>. Renal tissue necrosis

• 5>. Activation of renin

• angiotensin IIrenal arterial

• contract---renal cortex blood flow

• GFR(glomerular filtrate rate)

• 6>. Renal tubule was blocked

• by proteins and casts

27.

• Pathology

• 1. Organ of pathological damage

• Small blood vessel and kidney

• Other organs

• Such as heart,liver and

• brains, so on.

28.

• 2. Pathological feature

• pathological changes

• Endotheliocytes ofsmall blood vessel

• congestion, edema,

• hemorrhage, necrosis.

• pathognomonic lesion of HFRS in kidneys.

• Similar pathological changes in various organs .

• without significant inflammatory reaction

29.

• 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

30.

• A:Five typical phase

• 1.Febrile phase

• 2.Hypotensive (shock) phase

• 3.Oliguric phase

• 4.Diuretic phase

• 5.Convalescent phase

31.

• 1.Febrile phase

• Pyrexia

• Intoxication symptoms

• Capillary damage signs

• Kidney damage signs

Clinical Manifestations 32.

• 1.Febrile phase

• 1>. Pyrexia

• acute onset, 39 o C- 40 o C,

• lasts 3-7 days

• Feature of pyrexia:

• Sustained fever or remittent fever.

For most cases, going to more serious with pyrexia gradually disappeared 33.

• 2>.Intoxication symptoms

• a. Three ache

• headache

• because of small vesselexpansion

• lumbago,orbital pain .

• because of hyperemia and edema in tissue.

• b.Gastrointestinal symptoms

• hiccupvomiting

• abdominal pain and diarrhea

34.

• 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

35.

• c.Exudative edema

• mainly babular conjunctiva edema.

• palpebra edema and face edema

• 4>. Kidneydamage signs

• Proteinuria, sometimes with casts,blood

• cells and membrane-shapedsubstance

• consisting of protein, blood cells and

• mucosal epithelia.

36.

• Summary in febrile phase

• Pyrexia, three flush, three ache,

• hemorrhage and conjunctiva edema ,

• malaise,

• proteinuria , sometimes with casts,blood

• cells and membrane-shapedsubstance

37. 38. Patient with HFRS 39. Patient with HFRS: petechia, ecchymosis 40.

• 2.Hypotensive(shock) phase

• 1> Occur during defeverscence in 4 to 5 days

• ofdiseases 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 41.

• 3. Oliguric phase

• Oliguria or anuria

• Uremia

• Metabolic acidosis and imbalance of

• fluids and electrolyte

Clinical Manifestations 42.

• 3. Oliguric phase

• Occur during orsoon after hypotensive

• phase, in 5 to 8 days ofdiseases course,

• lasts 2-5 days.

• 1>. Oliguria or anuria

• Oliguria: urine volume < 500ml/24h

• Anuria: urine volume < 50ml/24h

43.

• 2>.Uremia

• a. gastrointestinal symptoms

• hiccup, vomiting, abdominal pain,

• diarrhea

• b. Aggravating hemorrhage

• hemoptysis, hematemesis,

• hematuria or melena

• c. Nervous system symptoms

44.

• 3>. Metabolic acidosis and imbalance of

• fluids and electrolyte

• Metabolic acidosis

• fatalhyperkalemia

• hypervolemic syndrome

• edema andrestlessness

• high blood pressure

• engorgedneck veins

• .

45.

• 4 Diuretic phase

• Urine >3000ml/24h

• Occur in 9 to 14 days ofdiseases course,

• last for 1 day or several months

• Three phase

• according to urine volume and azotemiasigns

• Transition phase

• Early stage of diuretic phase

• Late stage of diuretic phase

Clinical Manifestations 46.

• 1>. Transition phase

• a.Urinefrom 500ml to 2000ml/24h

• b. BUNand Crpersistently

• c. State of patient may change to more

• serious.

more serious although urine increase high mortality 47. 2>. Early stage of diuretic phase u rinevolume > 2000ml/24h no marked decrease in azotemia 3>. 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 downc. Secondary shock,dehydrationhypokalemia,hyponatremia 48.

• 5. Convalescent phase

• urine return to 1000-2000ml/24h

• normal appetite

• taking 1-3months for recovering

Five phase be not seen in every case.hypotension and /or oliguria phase may be absent in atypical cases Clinical Manifestations 49.

• B:Five clinic types

• 1. Mild type

• 2. Moderate

• 3. Severe

• 4. Very serious

• 5. Atypical type

50.

• 1. Mild type:

• T< 39 o C ,mild intoxication

• symptoms without oliguria

• and shock

51.

• 2.Moderate:

• T>39 o C , severe intoxicating

• symptoms,drunkenness,

• conjunctiva edema,

• hemorrhage,hypotension,

• oliguria andmarked proteinuria .

52.

• 3.Severe:

• T>40 C , more severe intoxicating

• symptoms, shock, bleeding,

• oliguria for less than 5days or

• anuria for less than 2days.

53.

• 4.Very serious:

• The symptoms and signsin

• severe typewith 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

54.

• 5. Atypical

• T IgM antibody

• 1:20 positive:diagnosis marker

• 2> IgG antibody:

• >4 times/weekuseful for diagnosis.

• Anti-G2--- estimate prognosis .

• 6. Molecular biological tests

• Viral RNA by RT-PCR

60.

• Complications

• 1.Visceral bleeding

• Intracrania hemorrhage

• hemoptysis, hematemesis,

• hematuria, cerebral hemorrhage

61. 2. Complication in central nervoussystem Encephalitis and meningitisIntracrania hemorrhage and cerebral edema 62.

• 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

63.

• 4.Others

• Secondary infection with bacterials

• Spontaneous rupture of the kidneys

• Hepatitis,myocarditis, pericarditis

64.

• Diagnosis

• Epidemiologic data

• Clinical feature

• Laboratory examinations

65.

• 1. Epidemiologic data

• place,season,

• history ofcontacting rats or excretion

• and secretions of rats

66.

• 2. Clinical features

• three manifestations in early stage and the

• course of five phasein 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 phasein typical case

Five phase is not observed in every case.hypotension and /or oliguria phase may be absent in atypical cases 67.

• 3.Laboratory data

• 1>.Blood

• Leukocytosis

• atypicallymphocytes>10%

• thrombocytopenia.

• 2>. Urine :

• proteinuria .

• membrane- shaped substance in urine.

• 3>. Virus antigen and antibody

• Viral RNA by RT-PCR

68. Differential diagnosis 1. In febrile phasewithcommon cold, influenza,Septicemia .2. InHypotensive phasewithother infection shock 3. P yrexia, intracrania hemorrhage and cerebraledema withmeningococcal meningitis 69. 4.Oliguria and renal failure withacute nephritis 5.Pyrexia and hemorrhage withLeptospirosis 6. Marked hemorrhage with:thrombocytopenic purpura,gastrointestinal bleeding caused by gastric ulcer . 70.

• Prognosis

• Fatality is related to clinical type, whether being

• treated earlier.

• mortality1%~5%.

• major reasons for death :

• renal failure,cerebrohernia

• secondary septicemia

• massive bleeding.

• mortality higher in infection with type I virus.

71.

• Treatment

• Principle of treatment

• Diagnosis, rest and treatmentin early

• Treatmentin near hospital

72. Treatment Supportive treatment Anti-viral therapy Symptomatic treatment 73.

• 1. Supportive treatment

• bed rest

• easy digestive food

• vitamins

• Intravenous fluids containing

• suitable glucose, electrolytes

74. 2. Treatment in febrile phase Principle of treatment a>.Anti-virus therapy b>.Reduce exudation ofplasma c>.Reduce intoxicating symptomsd>.Preventing from DIC 75. 1 >.Anti-viral therapy:important giving anti-virus drug in early stage. (Ribavirin(virazole) 1.0g iv drip with 10%GS qdfor 3-5 days 2>.Reduce permeability of smallvessel and exudation Lutin and Vitamin C 76.

• 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>.Corticosteroidsfor hyperpyrexia and heavy

• intoxicating symptoms

• Dexamethasone 5-10mg iv. Drip

• c>c>.Anti-vomiting:

• 20mg of Paspertinim p.r.n

77. 4>.Prevention from DIC a>. Reduce the blood viscosity Danshen solution, Dextran 40 b>. anti-coagulation therapy Heparin should be given once the CT isless than 3 min or APTTless than34seconds. 78. 3.Treatment in Hypotensive phase Principle of treatment: Supplement blood volume Correct acidosis1>.Supplement blood volume A.Principle:earlyrapidlyadequate 79. 1>.Supplement blood volume A.Principle:earlyrapidlyadequate B:kinds of fluids: Crystalloid fluids and Colloid fluidscontaining suitable glucose, electrolytes and vitamins:Ringers Solution Normal saline solution Dextran, 20% Mannitol Plasma, albumin, Artificial plasma. 80. 2>Correct metabolic acidosis 5% sodium bicarbonate solution. The amountcalculated according to CO 2 CPvalue. 3>.Blood vessel activating drugs for hypotension and shock: aramine,dopamine, 654-2 81. 4>.Corticosteroids Reduce severe toxemia,Reduce permeation of smallvesselImproving microcirculation of tissue. 10~20mg ofDexamethasonisgivenby intravenous drip. 82. 4.Treatment in oliguric phase Principle of treatment: Balance intra-environment Diuretic therapy Catharsis therapy for preventingfrom hypervolemia Dialysis therapy 83. 1>.Balance intra-environment a>.Correct imbalance of fluid electrolytes,acid- baseClosely observeand record urine volume.Examine bloodbiochemical parameterand renal function adjusting amount of fluid and electrolytes 84. b>. Reducing protein degradationand control of azotemia. Foodcontaining high vitaminshigh carbohydrate, low protein.For theserious patient : Supplementglucose 200~300g every daybyintravenous drip 20-25% GS with insulin. 85. 2>.Diureticfor oliguria 20%Mannitol solution. lasix (furosemide)3>Catharsis therapy forhypervolemia inducing diarrhea to take out fluids byintestinal. 50% Magnesium Sulfate solution20%Mannitol solution 86. Reducing blood volume therapy For hypervolemia with cardiac failure andpulmonary edema, taking out 300ml ~400ml blood may be useful. used rare now 87.

• 4>.Dialysis therapy

• for serious azotemia

• very important,save life

• Hemodialysis or Peritoneal dialysis

88.

• Marker of giving Dialysistherapy :

• Oliguria lasts for4 daysoranuria lasts

• for24 hourswith oneof 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.

89. 5 . Treatment in Diuretic phase a. Keeping balance of fluid and electrolytes. b.Preventing and treatment secondary infection: antibiotics 90. 6.Convalescent phase a:Supplement nutrition food. b:Examination renal function, blood pressure, pituitary function at regular interval. 91. 7.Complications treatment 1>. Hemostatics therapy for heavy bleeding such asgastrointestinal hemorrhage treatment of DIC: according to different phase of DIC,giving EACA, protamine ,respectively. 92. 2>.Treatment ARDS a: Control of amount of intravenous infusion. b: Giving oxygen, or mechanicalventilation: positive end expiratorypressure. c.Corticosteroids:20 to 30mg of dexamethasone d. Cedilanid for cardiac failure. 93. 3>.Treatment of central nervoussystem complications a> Diazepam for ticsb>.Cerebral edema andhigh intracranial pressure: 20% of mannitol or/and lasix drippedintravenously. 94. 4>. Prevention and treatment ofsecondaryinfections: Antibiotics 5>. Spontaneous rupture of thekidneys Surgery therapy 95.

• Prophylaxis

• 1. Exterminate field rats, house rats.

• 2.Wipe out mites:

• Drugs:

• Derivatives of pyrethrin

• Organic phosphoric compounds

• Preventing from biting .

96.

• 3.Vaccine

• Two Kinds of vaccines can be available:

• Against Hantan virus type I

• Against Hantan virus type II

• A ntibody production:

• 88%-94%, and last for 3~6 months

• Inoculation of the vaccine is carried outone

• month earlier than epidemic , and a bloost

• injection should be given one year later.

97. THANKS!!! 98.

• SUMMARY

• 1.HFRS:Infectious diseases caused by Hantan virus

• 2. Major sources of infection:

• Infected field rats,house rats,

• 3. Epidemic features:

• threeepidemic peaks:

• March to May: by house rats

• November to January, May to July: by Apodemus agrarius

99.

• 4. Pathogenesis

• V iral direct damage of Hantanvirus.

• Immune-mediated damage

• 5. Pathological damage and feature

• major in small blood vessel and kidney.

• congestion, edema, hemorrhage, necrosis.

• 6. Pathophysiology:

• Shock HemorrhageAcute renal failure

Without significant inflammatory reaction 100.

• 7.Clinical feature

• Fever, three flush, three ache, exudative edema, hemorrhage, proteinuria,shockand acute renal failure.Five phase in typical cases.

• 8. Diagnosis

• Combination ofepidemiologic data, clinical featureand laboratory examinations data.

9.Principle of treatment: diagnosis, rest and treatment earlyTreatmentin near hospital 10. Principle of treatment for each phase ?? 101.

• 11. Treatment

• 1>. Supportive treatment

• 2>. Anti-viral therapy

• 3>.Symptomatic treatment

12. Prevention 1>. Exterminate field rats, house rats 2>. vaccines Against Hantan virus type I Against Hantan virus type II 102. THANKS!!!