H F R S Hemorrhagic Fever with Renal Syndrome (Epidemic Hemorrhagic Fever)

2 summarization 1. HFRS is a natural focal disease 2. Caused by epidemic hemorrhagic fever virus (EHFV) 3. Rats are the main source of infection 4. Multi-route transmitted 5.pathology:Extensive small vessel injury

3 summarization Three main clinical manifestations: fever and shock hyperemia hemorrhage and exudation renal damage Five phases: febrile phase hypotensive phase oliguric phase diuretic phase convalescent phase

4 summarization WHO supposed to be named as hemorrhagic fever with renal syndrome.

5 ETIOLOGY EHFV: belongs to Bunyaviridae, Hantavirus

6 ETIOLOGY Hantavirus can be divided into at least 11 serotypes: Type 1: Hantaan virus (wild mouse Type 2: Seoul virus (house mouse) Type 3: Puumala virus Type 4: Prospect hill virus (field mouse) These 4 types had been cognized by WHO hantavirus center.

7 ETIOLOGY Resistance: 1.The resistance of EHFV is not very strong. 2.sensitive to majority disinfector,such as aether,ethanol, iodine, ultraviolet radiation. 3.Be inactivated in boiling water for 1 minute.

8 EPIDEMIOLOGY Source of infection:170 kind rodent, especially mice(Apodemus agrarius, Mus norvegicus, Apodemus sylvaticus etc.) Human is not main source of infection

9 EPIDEMIOLOGY Transmission route: 1. Respiratory tract: Aerosol formed of infected mouse excretion(urine, feces, saliva) maybe responsible for the sporadic cases through respiratory tract.

10 EPIDEMIOLOGY Transmission route: 2. Digestive tract: 3. Contact: bitten by mice; blood contact 4. Mother to baby: 5. Entomophily

11 EPIDEMIOLOGY Susceptible All people is susceptible. In prevalent region,people subclinical infection rate is 3.5—4.3%

12 EPIDEMIOLOGY Epidemic features regional feature seasonal and cyclicity feature crowed distribution

13 EPIDEMIOLOGY Epidemiologic feature Regional feature: Asia,Europe – Africa,Americas Epidemic situation in china is more serious than other countries. Epidemic area:

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15 EPIDEMIOLOGY

16 EPIDEMIOLOGY Epidemiologic feature Seasonal and cyclicity: Apodemus agrarius: 11~ 1 ， 5~ 7 Mus norvegicus : 3~ 5 Apodemus sylvaticus: summer season

17 EPIDEMIOLOGY Crowed distribution: Affect most frequently persons 20 to 50 years old Cases under 10 years old are rare Significantly in males Long-last immunity can be got after infection

18 PATHOGENESIS Lesions in multiple organs （ pantropic virus ） The injury caused by ： direct injury immune effect effect of kinds of cellular factors and medium 泛嗜性病毒

19 PATHOGENESIS Damaged by the virus directly : Based on ： 1.Toxic symptoms during viremia period 2.The degree of the clinical manifestation related to the different type of virus 3. Ag of EHFV can be detected from different organs,especially in vessel endothelial cell. 4. Culture in vitro of bone marrow cells and endothelial cells of blood vessel: EHFV can cause cellular damage without the factors of cellular and body fluid immunity

20 PATHOGENESIS By immune reaction: immune complex (type Ⅲ allergy) other immune response (type ⅠⅡⅣ allergy) effect of different kinds of cellerlar factors and medium (IL-1 TNF PGI2/TXA2)

21 PATHOGENESIS Mechanism of shock hemorrhage acute renal failure

22 PATHOGENESIS shock Primary shock:blood vessel permeability increase →blood plasma exude Secondary shock: infection hemorrhage water and electrolyte imbalance

23 PATHOGENESIS Hemorrhage: injury of blood vessel wall Decrease of platelet Increase of heparin material DIC

24 PATHOGENESIS Acute renal failure Renal blood stream hindrance Glomerular and renal tubule immune injury Renal tissue hyperemia and edema Glomerular microthrombus form ischemic necrosis renal tubule block by protein and cast

25 PATHOLOGY The basic changes of EHRS is cellular swelling, degeneration and necrosis of endothelial cells in small vessels. Exudation and Edema (due to the increased capillary permeability) Hemorrhage

26 CLINICAL MANIFESTATIONS Three main clinical manifestations Five phases Some patients may present with overlapping or overleaping phase Incubation period for HFRS is usually 2 weeks, varying from 4 to 46 days.

27 CLINICAL MANIFESTATIONS 30% to 40% of patients have mild courses. 40% to 50% of all cases exhibit a moderate course. 10% to 20% of patients exhibit severe courses of shock, serious hemorrhage, marked electrolyte imbalance, renal failure, and pulmonary edema

28 CLINICAL MANIFESTATIONS According to its characteristic clinical, laboratory and pathophysiologic features, HFRS can be divided into five phases: Febrile phase Hypotensive phase Oliguric phase Diuretic phase Convalescent phase

29 CLINICAL MANIFESTATIONS Febrile Phase: mainly manifested by High fever General toxic symptoms Injury of capillary(hyperemia hemorrhage and exudation) Renal damage

30 CLINICAL MANIFESTATIONS Febrile Phase: high fever Lasts 3 to 7 days Sudden onset with the high fever( sustained or remittent fever) of 39~40 ℃. The higher temperature and longer lasted fever promote a more severe case. When high fever relieve,disease become serious

31 CLINICAL MANIFESTATIONS Febrile Phase : toxic symptoms Three pain: headache due to dilation of brain blood vessels waist pain due to edema of the tissue around the kidney orbit pain due to edema of the tissue around the eyeballs

32 CLINICAL MANIFESTATIONS Febrile Phase : toxic symptoms Gastrointestinal tract symptoms such as nausea, vomit, abdominal pain and diarrhea etc. CNS symptoms can be seen in severe cases.

33 CLINICAL MANIFESTATIONS Febrile Phase : capillary injury result in hyperemia, hemorrhage, exudation and edema. Three red: flushing over the face, neck and anterior chest ( Drunk facies) Hyperemia and bleeding of conjunctival, soft palate, pharynx. nose bleeding, hemoptysis and so on petechiae can be observed in the axillary folds, face, neck and anterior chest wall. exudation and edema:bulbar conjunctiva edema

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36 CLINICAL MANIFESTATIONS Febrile Phase :renal damage Protein and cast can be found in the urine.

37 CLINICAL MANIFESTATIONS Hypotensive Phase: 4 ~6d in course of disease Symptoms become more severe after the temperature decrease to normal. The hypotensive phase develops abruptly and can last from several hours to 3 days. In sever cases it can reach more than one week. Primary shock happen at the same time or after the withdraw of the fever

38 CLINICAL MANIFESTATIONS Hypotensive Phase: The classical signs of shock can be noted, including tachycardia, narrowed pulse pressure, hypotension, cold and clammy skin. CNS symptoms can be seen in this stage due to inadequate brain blood flow.

39 CLINICAL MANIFESTATIONS Hypotensive Phase: Capillary hemorrhages are most prominent at this time. Oliguria may appear during the late shock phase and then blood urea and creatinine begin to rise.

40 CLINICAL MANIFESTATIONS Oliguric Phase: The oliguric phase usually happen at 5th~8th day and lasts from 2 to 5 days. Blood pressure begins to return to normal and then up to 60% become hypertensive due to their relative hypervolemia state. Facial flushing and petechiae begin to diminish.

41 CLINICAL MANIFESTATIONS Oliguric Phase: uremia Patients may have severe nausea and vomiting associated with persistent oliguria. The tendency to bleed becomes more marked and various includes cerebral hemorrhage, gastrointestinal bleeding and extensive purpura et.

42 CLINICAL MANIFESTATIONS Oliguric Phase: acidosis Mainly expressed by fast respiratory, Kussmaul respiratory.

43 CLINICAL MANIFESTATIONS Oliguric Phase: imbalance of water and electrolytes severe edema which can result in ascites hypervolemia syndrome include dilation of vein, magnificent pulse, heart rate increase, pulse pressure increase. imbalance of electrolyte such as hyponatremia and hyperkalemia

44 CLINICAL MANIFESTATIONS Oliguric Phase: Symptoms of central nervous system and pulmonary edema occur in severe cases. About 50% of the fatal cases occur during the oliguric phase.

45 CLINICAL MANIFESTATIONS Diuretic Phase: Mechanism: renal tissue resume result in the increase of GFR, but the reabsorb function of renal tubule do not recovery completely.

46 CLINICAL MANIFESTATIONS Diuretic Phase: Diuretic phase can be divided into 3 periods: Migratory period: the amount of urine: 500~2000ml per day Early diuretic period: the amount of urine: more than 2000ml Late diuretic period: the amount of urine: more than 3000ml

47 CLINICAL MANIFESTATIONS Diuretic Phase: In migratory period, though the urine begin to increase, but the BUN and Cr are still very high and the symptoms are still severe, complications may happen in this period.

48 CLINICAL MANIFESTATIONS Diuretic Phase: In late diuretic period, azotaemia begin to disappear, but secondary shock may be found in this period due to secondary infection or inadequate complement of water and electrolyte.

49 CLINICAL MANIFESTATIONS Convalescent Phase: Amount of urine resume Symptoms disappear gradually Physical force and appetite resume

50 CLINICAL MANIFESTATIONS based on the symptoms, the disease can be divided into light, moderate, severe and critical types.

51 LABORATORY TESTS Blood routine test: WBC increase to (15~30) x10 9 /L, even (50~100)x10 9 /L from the 3th day neutrocytosis in early period lymphocytosis in late period Plt decrease from the 2nd day, heterotype lymphocytosis and Plt can be seen

52 LABORATORY TESTS Urine routine test: Proteinuria +++~++++ at 4th~6th day membranoid substance formed by protein and epithelial cells can be seen cast and RBC can be seen

53 LABORATORY TESTS Biochemical examinations: Blood urea, Creatinine blood gas analysis electrolyte examination

54 LABORATORY TESTS Blood coagulation function PLT decrease Blood coagulation time prolong

55 LABORATORY TESTS Immunology test: Specific Ag can be found in serum, neutrophilic granulocytes and monocytes Specific Ab: IgM (1:20)and IgG(1:40)

56 LABORATORY TESTS Other tests: Liver function :50% ALT ↑ ECG ： bradycardia ， conduction block ； Hyperkalemia T wave ， Hypokalemia u wave

57 complication Cavity hemorrhage Complications of CNS Pulmonary edema others

58 complication Cavity hemorrhage hematemesis ， hemafecia nose blooding ， abdominal cavity blooding ， vagina blooding

59 complication Complications of CNS Virus direct violate CNS lead to encephalitis and meningitis Brain edema Hypertension cerebrosis encephalic hemorrhage

60 complication Pulmonary edema 1.ARDS: pulmonary capillary vessel injury lead to permeability increase→pulmonary interstitial numerous exude →ARDS 2.Cardiac pulmonary edema ： pulmonary alveoli numerous exude hypervolemia cardiac muscle injury

61 CLINICAL DIAGNOSIS 1.EpidemiologyEpidemiology 2.HistoryHistory symptoms signs 3.TestsTests

62 CLINICAL DIAGNOSIS Epidemiology A history of exposure in an endemic area, particularly during an epidemic season

63 CLINICAL DIAGNOSIS Symptoms and signs Three main clinical manifestations. Typical 5 phases process

64 CLINICAL DIAGNOSIS Tests mainly depend on routine examinations Specific Ab appear during the first week of symptoms, reach it ’ s peak at the end of the second week, and persist for several years.

65 DIFFERENTIAL DIAGNOSIS Differential diagnosis should be considered due to different phases febrile phases shock phases oliguria phases hemorrhage abdominal pain

66 PROGNOSIS Mortality rate: decrease from 10 ﹪ to 3~5 ﹪ in resent years

67 TREATMENT rule: early discover early rest early treatment nearby treatment different phases possess it ’ s own treatment rules

68 TREATMENT Febrile phase: Control infection Decrease extrudation Amend toxic symptoms Prevent DIC

69 TREATMENT hypotensive phase supply blood volume Correct acidosis Improve microcirculation

70 TREATMENT oliguric phase Stablize internal enviroment Diuresis Catharsis dialysis

71 TREATMENT Diuretic phase The treatment rule in migratory and early diuretic period is the same with oliguric phase Late diuretic period : keep the balance of water and electrolyte, prevent secondary infection

72 TREATMENT Convalescent phase Good nutrition and rest

73 PREVENTION Administration of the epidemic situation Kill the rats Hygiene Vaccine

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