流行性腦脊髓膜炎的鑑別診 斷、治療、處置及感染管制 衛福部 疾病管制署 中區傳染病防治醫療網 王任賢 指揮官.

Presentation on theme: "流行性腦脊髓膜炎的鑑別診 斷、治療、處置及感染管制 衛福部 疾病管制署 中區傳染病防治醫療網 王任賢 指揮官."— Presentation transcript:

1 流行性腦脊髓膜炎的鑑別診 斷、治療、處置及感染管制 衛福部 疾病管制署 中區傳染病防治醫療網 王任賢 指揮官

2 課程大綱 1. 腦脊髓膜炎之鑑別診斷 2. 腦脊髓膜炎之治療 3. 腦脊髓膜炎之感染管制 4. 結論 2

3 1. 腦脊髓膜炎之鑑別診斷

4 病例報告 (1/2) 陳先生，大專提前入伍生，新兵訓練中心在雲 林縣 陳先生，大專提前入伍生，新兵訓練中心在雲 林縣 入伍一星期，前日下午已感不適，今日勉強出 操，但仍出現高燒、答非所問，緊急送往醫務 室休息 入伍一星期，前日下午已感不適，今日勉強出 操，但仍出現高燒、答非所問，緊急送往醫務 室休息 到醫務室已神智不清，立即外送就醫，但在到 醫前病患已往生 到醫務室已神智不清，立即外送就醫，但在到 醫前病患已往生 4

5 病例報告 (2/2) 由於到院前死亡，醫院不願開具死診；也由於 離營前仍未往生，軍方醫務室也不願意開立死 診 由於到院前死亡，醫院不願開具死診；也由於 離營前仍未往生，軍方醫務室也不願意開立死 診 病患大體就暫時冰存於殯儀館，無法安葬 病患大體就暫時冰存於殯儀館，無法安葬 雲林縣衛生局申請驗屍，看見大體表面呈現一 些出血斑，由此抽血做培養長出腦膜炎雙球菌 雲林縣衛生局申請驗屍，看見大體表面呈現一 些出血斑，由此抽血做培養長出腦膜炎雙球菌 5

6 病例剖析 疾病風險因子 疾病風險因子  入伍新兵 臨床進程 臨床進程  快速進行性腦膜炎  休克 死亡原因 死亡原因  休克 6

7 Neisseria Meningitidis Exclusively human Exclusively human Gram(-), bean-shaped diplococci Gram(-), bean-shaped diplococci Surface structure － Outer membrane: lipid proteins (OMPs) lipopolysaccharides － Polysaccharide capsule Surface structure － Outer membrane: lipid proteins (OMPs) lipopolysaccharides － Polysaccharide capsule 7

8 Typing of Neisseria Meningitidis Identify capsule antigens 13 serogroups Identify capsule antigens 13 serogroups Identify class 2/3 OMP antigens 20 serotypes Identify class 2/3 OMP antigens 20 serotypes Identify class 1 OMP antigens 10 subtypes Identify class 1 OMP antigens 10 subtypes Identify lipopolysaccharide (LOS) L1-13 immunotypes Identify lipopolysaccharide (LOS) L1-13 immunotypes Identify IgA1 protease and pili Identify IgA1 protease and pili 8

9 Molecular Typing of Neisseria Meningitidis For identify clonal expansion － multilocus enzyme electrophoresis － DNA fingerprinting － PCR For identify clonal expansion － multilocus enzyme electrophoresis － DNA fingerprinting － PCR 9

10 Conditions for Invasive Disease Exposure to meningococci Exposure to meningococci Colonization of the naso-oropharyngeal mucosa Colonization of the naso-oropharyngeal mucosa Invasion or penetration of the naso-oropharyngeal mucosa Invasion or penetration of the naso-oropharyngeal mucosa Survival of the meningococci in the bloodstream Survival of the meningococci in the bloodstream 10

11 Age-related Nasopharyngeal Meningococcal Carriage in 1238 Asymptomatic Montreal Children asymptomatic carrier (%) Age AM J Epidemiol 1979;109:563-71 11

12 Prevalence of Initial Colonization and Duration of Carriage: 104 Contacts of 29 ill Index Cases Age (years)No. positive/Mean duration of No. tested (%) carriage in wks (range) < 3 1/8 (12.5)20 (20) 3-10 6/26 (23.1)13.5 (1-24) 11-18 4/19 (21.1)20 (4-52) > 18 4/51 (7.8)11.8 (1-20) Total 15/104 (14)15.2 AM J Epidemiol 1979;109:563-71 12

13 Nasopharyngeal Carriage of N. meningitidis in Australian Aboriginal Children Occupants per dwellingPercentage% dwellings with at and serogroupcarriageleast 1 group C carrier 1-5 people C/non C, non-typable2.0/3.97.1 6-10 people C/non C, non-typable2.3/4.716.7 >10 people C/non C, non-typable4.0/5.057.1 Population mean C/non C, non-typable4.0/5.057.1 Lancet 1995;346:20-3 13

14 Factors Favor Meningococcal Naso- Oropharyngeal Colonization Damage to ciliated epithelium Damage to ciliated epithelium Pili of bacteria (as adhesin of CD46) Pili of bacteria (as adhesin of CD46) Class 5 OMPs(Opa & Opc) － enhance engulfment by epithelial cell Class 5 OMPs(Opa & Opc) － enhance engulfment by epithelial cell No capsule, no sialylated LOS No capsule, no sialylated LOS 14

15 Factors Favor Meningococcal Naso- Oropharyngeal Penetration ProB (a class 2/3 OMP) － affect maturation of phagosome ProB (a class 2/3 OMP) － affect maturation of phagosome IgA1 proteases (OMPs) IgA1 proteases (OMPs) Virus or Mycoplasma infection Virus or Mycoplasma infection 15

16 Factors Favor Meningococcal Survival in the Bloodstream Polysaccharide capsule Polysaccharide capsule Class 1 OMPs － impede ingestion by neutrophil Class 1 OMPs － impede ingestion by neutrophil IgA1 protease － break IgA1 in the hinge region IgA1 protease － break IgA1 in the hinge region 16

17 Clinical Presentations of Invasive Meningococcal Disease Bacteremia without shock Bacteremia without shock Septic shock without meningitis Septic shock without meningitis Septic shock with meningitis Septic shock with meningitis Meningitis alone Meningitis alone Metastatic infection (rare) arthritis, pericarditis, cellulitis, endophthalmitis Metastatic infection (rare) arthritis, pericarditis, cellulitis, endophthalmitis Chronic benign meningococcemia Chronic benign meningococcemia 17

18 Epidemiological Trends: Endemic Industrialized countries － serogroups B and C － incidence: 1-3/100,000 Industrialized countries － serogroups B and C － incidence: 1-3/100,000 Third-world countries － serogroup A and C (less) － incidence: 10-25/100,000 Third-world countries － serogroup A and C (less) － incidence: 10-25/100,000 18

19 Cases of Meningococcal Disease in New England, 1993-1998 State (No.)MedianB/C/Y (%)Die (%) age (yrs) Connecticut (231) 1818/39/3719 (8) Maine (80) 1330/49/13 6 (8) Massachusetts (394) 1729/40/2835 (9) New Hampshire (81) 1828/45/25 9 (11) Rhode island (77) 1530/45/2316 (21) Vermont (36) 1732/27/27 3 (8) New England (899) 1726/41/2988 (10) MMWR 1999;48:629-33 19

20 Age Distribution of Cases of Meningococcal Disease in Quebec, Canada,1990-1994 Age group (y)Serogroup B (No, %) Serogroup C (No, %) < 1 72 (43.1)26 (8.6) 1-4 32 (19.1)57 (18.8) 5-9 7 (4.2)32 (10.5) 10-19 16 (9.6) 101 (33.2) 20-59 30 (18.0)74 (24.3) 60 10 (6.0)14 (4.6) Total 167 (100) 304 (100) Average (median) age 13.5 (2) 17.6 (14) CID 1998;26:1159-64 20

21 Diagnostic Classification of Meningococcal Disease, Quebec, Canada, 1990-1994 ClassificationNo. (%) of cases Serogroup BSerogroup C Septicemia only 62 (38.8)109 (37.4) Meningitis only 28 (17.5) 24 (8.2) Septicemia + meningitis 65 (40.6)149 (51.0) Other 5 (3.1) 10 (3.4) Total160 (100)292 (100) CID 1998;26:1159-64 21

22 Sequelae Among Survivors of Meningococcal Dsease in Quebec, Canada, 1990-1994 Category of sequelaeNo. (%) of survivors Serogroup BSerogroup C Scars 2 (1.2) 30 (11.5) Amputation 1 (0.6) 12 (4.6) Hearing loss 3 (1.9) 5 (1.9) Renal failure 0 3 (1.1) Others 4 (2.5) 9 (3.3) Any sequelae 5 (3.2) 40 (15.3) CID 1998;26:1159-64 22

23 Epidemiological Trends: Epidemic Meningitis belt in Sub-Saharan Africa Meningitis belt in Sub-Saharan Africa Epidemic in Nepal & intercontinental spread Epidemic in Nepal & intercontinental spread Epidemic in industrialized countries Epidemic in industrialized countries 23

24 Meningitis Belt in Sub-Saharan Africa First described by Lapeyssonnie in 1963 First described by Lapeyssonnie in 1963 Comprised Burkina Faso, Ghana, Togo, Benin, Niger, Chad, Nigeria, Cameroon, Sudan, Central African, Ethiopia, Mali, Guinea, Senegal, Gambia Comprised Burkina Faso, Ghana, Togo, Benin, Niger, Chad, Nigeria, Cameroon, Sudan, Central African, Ethiopia, Mali, Guinea, Senegal, Gambia Serogroup A occur in yearly recurrent wave － rise at the end of dry season － decline rapidly after the onset of rainy season － peak incidence: 1,000/100,000 Serogroup A occur in yearly recurrent wave － rise at the end of dry season － decline rapidly after the onset of rainy season － peak incidence: 1,000/100,000 24

25 Average Annual Incidence (per 1,000) of Meningococcal Disease in Meningitis Belt Benin*0.9 Benin*0.9 Burkina Faso5.6 Burkina Faso5.6 Cameroon*1.9 Cameroon*1.9 Central Africa0.3 Central Africa0.3 Chad2.2 Chad2.2 Ethiopia2.8 Ethiopia2.8 Ghana*1.7 Ghana*1.7 Guinea0.2 Guinea0.2 Ivory Coast0.2 Mali1.7 Mauritania0.1 Niger6.1 Nigeria*14.2 Senegal0.7 Sudan6.0 Togo*0.8 *only area in meningitis belt was considered Pediatr Infect Dis J 1999;18:1051-9 25

26 Epidemic in Nepal, 1983-1984 Come from Tibet, serogroup A (subgroup III) Come from Tibet, serogroup A (subgroup III) 1985: India, Pakistan 1985: India, Pakistan 1987: Moslem pilgrimage to Mecca 1987: Moslem pilgrimage to Mecca 1988: Chad, Sudan, Ethiopia, Kenya, Uganda 1988: Chad, Sudan, Ethiopia, Kenya, Uganda 1990s: Nigeria, South Africa (1996) 1990s: Nigeria, South Africa (1996) No epidemics in USA, Europe No epidemics in USA, Europe 26

27 Epidemic in Industrialized Countries: Lineage III (ET-5), Serogroup B mid-1970s: Norway, Iceland, UK, Netherlands attack rate: 4-50/100,000 mid-1970s: Norway, Iceland, UK, Netherlands attack rate: 4-50/100,000 1974: China, Japan, Thailand, Spain, Cuba, Chile 1974: China, Japan, Thailand, Spain, Cuba, Chile 1980s: Brazil 1980s: Brazil 1990s: North Africa, Israel, Australia, Oregon 1990s: North Africa, Israel, Australia, Oregon 27

28 Epidemic in Industrialized Countries: ET-37 (Serogroup C, or B, W-135, Y) Since 1917, Worldwide distribution Since 1917, Worldwide distribution 1960s: USA military outbreak 1960s: USA military outbreak 1970s: Brasil (serogroup C), China (serogroup B) South Africa (serogroup B) 1970s: Brasil (serogroup C), China (serogroup B) South Africa (serogroup B) 1980s: most serogroup C isolated in USA, Europe 1980s: most serogroup C isolated in USA, Europe 28

29 Epidemic in Industrialized Countries: Lineage III (ET-24, 25), Serogroup B 1980: Netherlands 1980: Netherlands 1990s: Finland, Norway, Iceland (a few cases) New Zealand (a sharp rise) United kingdom, Belgium, Chile 1990s: Finland, Norway, Iceland (a few cases) New Zealand (a sharp rise) United kingdom, Belgium, Chile 29

30 Epidemic in Industrialized Countries: ET-15 (Variant of ET-37) 1980s: North America School-based, jail-based cluster 1980s: North America School-based, jail-based cluster 1990s: Israel, Czech Republic, Australia, England, Canada 1990s: Israel, Czech Republic, Australia, England, Canada 30

31 Epidemic in Industrialized Countries: ET-508 (Serogroup Y, C, B) mid-1990s: United States endemic case clusters: 2/3 Y, 1/3 C mid-1990s: United States endemic case clusters: 2/3 Y, 1/3 C ET-508, serogroup Y in Europe: exclusively in patients with terminal complement deficiencies in USA: high incidence, in immunocompetent ET-508, serogroup Y in Europe: exclusively in patients with terminal complement deficiencies in USA: high incidence, in immunocompetent 31

32 Age Distribution of Sporadic & Community- Outbreak-associated Cases of Serogroup C Meningococcal Disease, 1980-1993, USA Case number Age (yr) JAMA 1995;273:383-9 32

33 Clues of Meningococcal Epidemic A shift in age distribution A shift in age distribution Clonality of strains isolated Clonality of strains isolated JAMA 1995;273:383-9 33

34 Age Specific Attack Rates & Case Fatality Rates: Meningococcal Outbreak in Sudanese Refugee Camp in Northern Uganda 1994 Age groupPopulationAttack rate (%) Case-fatality rate (%) <1 3874 0.4616.7 1-4 14045 0.17 0 5-9 13948 0.1211.8 10-14 11623 0.22 7.7 15-19 9880 0.3917.9 20-29 15498 0.23 5.7 30-44 15110 0.1723.1 >45 12882 0.1121.4 Total 96860 0.3014.4 Epidemiol Infect 2000;124:75-81 34

35 Attack Rates & Case Fatality Rates by Residence for Refugees Only: Meningococcal Outbreak in Sudanese Refugee Camp in Uganda 1994 ResidencePopulationAttack rate (%) Case-fatality rate (%) Pachara 2000 0.8511.7 Transit 58762 0.2511.5 Settlements 38098 0.19 6.8 Unknown 33.3 Total 96860 0.3014.4 Epidemiol Infect 2000;124:75-81 35

36 2. 腦脊髓膜炎之治療

37 Meningitis Treatment Treatment –Emergent empirical antimicrobial therapy Based on age and underlying disease status Based on age and underlying disease status –Empiric antibiotic regimines Neonates (<3 months) Neonates (<3 months) –Ampicillin plus a third generation cephalosporin Children Children –Third generation cephalosporin ( alternative -ampicillin and chloramphenicol) Young adults Young adults –Third generation cephalosporin (Ceftriaxone) + Vancomycin 37

38 Meningitis Treatment Treatment –Empiric Antibiotic Regimines Older adults Older adults –Ampicillin in combination with third generation ceph Postneurosurgical Pt’s Postneurosurgical Pt’s –Vancomycin plus ceftazidime until cultures are available 38

39 Meningitis Treatment Treatment –N. Meningitidis High dose Pen G High dose Pen G –S. pneumoniae Ceftriaxone Ceftriaxone For areas with high level resistance For areas with high level resistance –Vancomycin plus third generation cephalosporin or rifampin 39

40 Meningitis Treatment Treatment –Duration of Treatment Dependent on infecting organism Dependent on infecting organism –Average of 10-14 days –Gm (-) bacilli for 3 weeks 40

41 3. 腦脊髓膜炎之感染管制

42 Isolation Meningococcal infection Meningococcal infection –24 hours respiratory isolation –Person with close contact Chemoprophylaxis to eradicate meningococcal carriage Chemoprophylaxis to eradicate meningococcal carriage Pneumococcal infection Pneumococcal infection –Otitis, pneumonia –No Isolation 42

43 Prevention of Meningococcal Disease Antibiotics prophylaxis Antibiotics prophylaxis Vaccination Vaccination 43

44 Meningococcal (group C) Carrier Rate in Household Contact < 1 year:37.8% (14/37) < 1 year:37.8% (14/37) 1-14 years:17.5% (43/246) 1-14 years:17.5% (43/246) > 15 years:6.9% (6/87) > 15 years:6.9% (6/87) J Pediatr 1981;98:485 44

45 Secondary Attack Rate of Meningococcal Meningitis Norton & Gordon (1929): 4.4% (30/724) Norton & Gordon (1929): 4.4% (30/724) (data from outbreak in Detroit) Pizzi (1944): 3.9% ( 15 y/o) 2.5% (all ages) Pizzi (1944): 3.9% ( 15 y/o) 2.5% (all ages) (data from outbreak in Santiago, Chile) Jacobson, et al (1976): do not increase risk among classmate contact Jacobson, et al (1976): do not increase risk among classmate contact (data from Brazilian epidemic) 45

46 Eradication Rates of Meningococcus and HIB Following Treatment of Carrier Meningococcus HIB Agent tested % eradicationAgent tested% eradication Oxytetracycline 5%Placebo 26% Erythromycin 0%Cefaclor 18% Pen G 25-33%EM/SMX 20% Procaine PC 49%TMP/SMX 58% Ampicillin 62%mpicillinA 70% Minocycline 83%Rifampin 71% Rifampin 93% (10 mg/kg/dose) Minocycline 100%Rifampin 96% /Rifampin (20 mg/kg/dose) Ped Infect Dis 1982;1:140 & NEJM 1969;281:641 46

47 Prophylactic Agents for Bacterial Meningitis For meningococcus For meningococcus － rifampin:adult 600 mg bid for 2 days < 12 y/o 10 mg/kg bid for 2 days < 1 m/o 5 mg/kg bid for 2 days － rifampin:adult 600 mg bid for 2 days < 12 y/o 10 mg/kg bid for 2 days < 1 m/o 5 mg/kg bid for 2 days ciprofloxacin500 mg PO single dose ceftriaxone250 mg, adult, IM single dose 125 mg, children, IM single dose ciprofloxacin500 mg PO single dose ceftriaxone250 mg, adult, IM single dose 125 mg, children, IM single dose For HIB For HIB － rifampin:20 mg/kg qd for 4 days － rifampin:20 mg/kg qd for 4 days 47

48 Prophylaxis of Meningococcus Indicated for chemoprophylaxis Indicated for chemoprophylaxis － all household contacts － all household contacts － nursery school contacts － nursery school contacts － mouth-to-mouth resuscitation － mouth-to-mouth resuscitation － index case － index case Not indicated for chemoprophylaxis Not indicated for chemoprophylaxis － school-age contacts － school-age contacts － medical personnel － medical personnel 48

49 Mass Antibiotics Prophylaxis to Control a Prolonged Outbreak of Meningococcal Disease in an Israeli Village Eur J Clin Microbiol Infect Dis 1998;17:749-53

50 背景資料 以色列北部長期遭 meningococcus B 的肆虐， 疾病年平均發生率為 37.4/10 萬，死亡率 11% 以色列北部長期遭 meningococcus B 的肆虐， 疾病年平均發生率為 37.4/10 萬，死亡率 11% 其中有兩村落 Deir el-Asad 與 B‘ine ，總人口數 11,600 ，環境衛生很差，死亡率 23% 其中有兩村落 Deir el-Asad 與 B‘ine ，總人口數 11,600 ，環境衛生很差，死亡率 23% 由於此兩村落的居民相當恐慌，當地衛生單位 便對此二地於 Jan 15-18, 1994 實施全面抗生素 預防性投藥 (ceftriaxone 125 mg IM stat or ciprofloxacin 500 mg PO stat) 由於此兩村落的居民相當恐慌，當地衛生單位 便對此二地於 Jan 15-18, 1994 實施全面抗生素 預防性投藥 (ceftriaxone 125 mg IM stat or ciprofloxacin 500 mg PO stat) Eur J Clin Microbiol Infect Dis 1998;17:749-53 50

51 Neisseria Meningitidis Isolated from Pharyngeal Carriers* before vs after Prophylaxis Age (yrs)No. of Total isolate (%) subjectsBeforeAfter 024919 (7.6)3 (1.2) 1-911818 (15.3)1 (0.8) 10-1912916 (12.4)2 (1.5) 20-29141 3 (2.1)3 (2.7) 30-39128 7 (5.5)1 (0.8) >4027115 (5.5)4 (1.4) Total103686 (8.3)14 (1.3) *in control an prolonged outbreak in northern Israel Eur J Clin Microb Infect Dis 1998;17:749-53 51

52 Incidence of Meningococcal Disease before & after Mass Antibiotic Prophylaxis YearAnnual incidence/100,000 (no. of cases)Relative VillagesDistrictTotalrisk* 199125.9 (3)1.3 (4)2.1 (7)20.7 1992 8.7 (1)1.6 (5)1.8 (6) 5.4 199377.6 (9)2.8 (9)5.4 (18)27.7 1991-9337.4 (13)1.9 (18)3.1 (31)19.6 199443.1 (5)1.2 (4)2.7 (9)34.5 199543.1 (5)0.9 (3)2.4 (8)45.8 199617.2 (2)3.1 (10)3.6 (12) 5.5 1994-9634.5 (12)1.8 (17)2.9 (29)19.2 *Reference group is the Akko district without villages Eur J Clin Microb Infect Dis 1998;17:749-53 52

53 Types of Meningococcal Vaccination Routine vaccination model Routine vaccination model Outbreak response model (campaign model) Outbreak response model (campaign model) 53

54 Controlled Field Trials to Estimate Efficacy of Serogroup C Meningococcal Vaccine SourceStudy population Vaccine efficacy % (95% CI) ArtensteinUS Army recruits90 (24-99) Gold US Army recruits88 (13-98) BiselliItalian military recruits91 (30-99) TaunayBrazilian children 2-3y67 (8-89) DeWalsQuebec residents79 (53-91) aged 6 m-20 y JAMA 1998;279:435-9 54

55 Meningococcal Vaccination: Estimated Wastage Rates Routine vaccination model － around 40% Routine vaccination model － around 40% Outbreak response model － around 15% Outbreak response model － around 15% 55

56 Effect of Vaccination (A+C) on the Incidence of Meningococcal Disease in Nigeria Villages Weeks before vaccination Weeks after vaccination V Number of cases Lancet 1980;8171:729-32 56

57 Moore’s Threshold for Meningococcal Epidemic 15 cases/100,000 population/week averaged over 2 weeks Int J Epidemiol 1992;21:155-62

58 Sensitivity Analysis of Campaign Response Model: Cost Per Life Saved vs Threshold Incidence for Emergency Response Base Case Effectiveness Cost per life saved $2400 $1950 $1450 $1000 Threshold incidence (per 100,000) Pediatr Infect Dis J 1999;18:1051-9 58

59 Sensitivity Analysis of Campaign Response Model: Effectiveness vs Weeks of Delay for Protective Response Base Case Effectiveness Cost per life saved $1800 $1400 $1000 Weeks Delay Pediatr Infect Dis J 1999;18:1051-9 59

60 Sensitivity Analysis of Campaign Response Model: Effectiveness vs Vaccination Coverage Base Case Effectiveness Vaccination coverage Pediatr Infect Dis J 1999;18:1051-9 60

61 4. 結論

62 結論 流行性腦脊髓膜炎好發於新兵、大學新鮮人、 新入監所者、住校生 流行性腦脊髓膜炎好發於新兵、大學新鮮人、 新入監所者、住校生 腦膜炎進行快速，常伴隨休克及全身擴散 腦膜炎進行快速，常伴隨休克及全身擴散 依腦膜炎治療準則治療可快速痊癒，但治療必 須及時 依腦膜炎治療準則治療可快速痊癒，但治療必 須及時 只有親密接觸者與個案本身才須預防性投藥 只有親密接觸者與個案本身才須預防性投藥 疫苗應在爆發流行時，針對流行型號施打 疫苗應在爆發流行時，針對流行型號施打 62

63 課程結束