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Meningococcal Disease

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1 Meningococcal Disease
Neisseria meningitidis Meningococcal Disease MKT4734 1/1/99

2 Neisseria meningitidis
Etiology Gram negative diplococcus with polysaccharide capsule 13 serogroups classed by capsular specificity (A/B/C/Y/W-135 & others) T-independent capsular antigen (no memory response) Other classifications - outer membrane proteins & lipopolysaccharide (LPS) 1. Apicella MA, Chapter 189: Neisseria meningitidis. In: Principles and Practice of Infectious Diseases, 4th ed. Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995,

3 Antigens & Virulence Factors
Etiology Porin* (PorA or PorB) Polysaccharide Capsule Opacity* Associated Protein (Opa) Pili LPS * outer membrane proteins 10. Poolman JT, Development of a meningococcal vaccine, Infectious Agents and Disease, 4:1, 1995, 21

4 Neisseria meningitidis
Epidemiology Incubation - 2 to 10 days; often 3 to 42 Transmission2 - respiratory route direct contact Reservoir - humans only10 Carrier prevalence - 5% to 10%10, 14 2. WHO Information Fact Sheets, Meningococcal meningitis-Update: 10. Poolman JT, Development of a meningococcal vaccine, Infectious Agents and Disease, 4:1, 1995, 13 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33

5 Global Epidemiology Group A epidemics: Epidemiology
Senegal, Gambia, Guinea-Bissau, Guinea, Sierra Leone, Ivory Coast, Burkina Faso, Ghana, Togo, Benin, Nigeria, Cameroon, Chad, Niger, Mali, Cen. African Republic, Sudan, Uganda, Kenya, Ethiopia 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 4

6 Global Epidemiology Meningitis belt - peaks in dry season
Epidemics occasionally occur in: Saudi Arabia Kenya & Tanzania Burundi & Mongolia CDC travelers information (404) 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 4

7 U. S. Epidemiology Epidemiology
Serogroup Distribution cases ( ) and deaths ( ) annually23 Highest total disease incidence in children 3 to 12 mos. of age4 Leading cause of bacterial meningitis in ages 2 to 18 yrs.5 Peaks late winter/early spring4 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 1 5. Schuchat A, et al, Bacterial meningitis in the United States in 1995, The New England Journal of Medicine, 337:1997, 970 23. CDC. Summary of notifiable diseases, United States, MMWR 45:53, 1996,74, 76, 80

8 U.S. Total Disease Incidence < 5 to > 59 yrs. - 1989 -1991
Epidemiology Incidence (cases/100,000) <5 5 - 10 Age (years) >59 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 2, with actual data points supplied by CDC

9 U.S. Total Disease Incidence < 1 to 23 mos. - 1989 -1991
Epidemiology U.S. Incidence of Meningococcal Disease < 1 to 23 Months (cases/100,000) Incidence 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 2, with actual data points supplied by CDC

10 Bacterial Meningitis Incidence Major Causes
Epidemiology Age (months) 5. Schuchat A, et al, Bacterial meningitis in the United States in 1995, The New England Journal of Medicine, 337:1997, 972

11 Meningococcal Disease United States
Epidemiology Case-fatality rate 13% for meningitic disease (isolated in CSF)4 11.5% when isolated from blood4 case-fatality rate even higher with severe meningococcemia1 case-fatality rate consistent in spite of antibiotic use4 1. Apicella MA, Chapter 189: Neisseria meningitidis. In: Principles and Practice of Infectious Diseases, 4th ed. Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995, 1899 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 1

12 U.S.A.- Changing Serogroup Prevalence - 1990’s
Epidemiology Group C common cause of outbreaks since early 1990’s6 Group Y disease also increasing4 Overall invasive disease incidence constant 1.3/100,000 (since 1986)5 Meningitis incidence decreased 0.9 to 0.6/100,000 (since 1986)5 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 1 5. Schuchat A, et al, Bacterial meningitis in the United States in 1995, The New England Journal of Medicine, 337, 1997, 972 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 13

13 Serogroup C Outbreaks - United States - 1980 - 1993
Epidemiology 21 outbreaks6 8 school outbreaks8 3 institutional outbreaks8 10 community outbreaks (no known contact)8 Affect school-aged children & young adults 8 High frequency and severity of sequelae17 Most attack rates > 10 cases/100,000 (20 X higher than endemic rate)6 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 13 8. Jackson LA, et al, Serogroup C meningococcal outbreaks in the United States, an emerging threat, JAMA, 273:5, 1995, 384, 386 17. Erickson L, et al, Complications and sequelae of meningococcal disease in Quebec, Canada, , Clin Infect Dis, 26, 1998, 1163

14 Serogroup Y Disease - United States
Epidemiology Increasing proportion of disease since 19917 More frequently associated with meningococcal pneumonia7 Median age 21.8 yrs.7 7. CDC, Serogroup Y meningococcal disease - Illinois, Connecticut, and selected areas, United States, , MMWR, 45:46, 1996, 9. Quick uptakes meningitis patterns shift, JAMA, 279:16, 1998, 1249

15 Clinical Syndromes 19955 Epidemiology
5. Schuchat A, et al, Bacterial meningitis in the United States in 1995, The New England Journal of Medicine, 337, 1997, 973

16 Risk Groups Persons with terminal complement deficiencies
Epidemiology Persons with terminal complement deficiencies Persons with anatomic or functional asplenia Persons with immunosuppression Industrial or laboratory personnel routinely exposed to organism Residents or travelers to hyperendemic or epidemic areas 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 3 & 4

17 Stages of Pathogenesis
Organism Enters Nose or Mouth11 Mucosal Barrier Cleared11 Intravascular Space Invaded11 Host Response12 (Cytokines, PAF*, Arachidonic Metabolites) * Platelet activation factor 11. Quagliarello V, et al, Bacterial meningitis: pathogenesis, pathophysiology, and progress, The New England Journal of Medicine, 327:12, 1992, 865 12. Saez-Llorens X, et al, Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications, The Journal of Pediatrics, 116:5, 1990, 672, 673, 675, 677

18 Disease Manifested Host Response12 Blood Brain Barrier
Pathogenesis Host Response12 Blood Brain Barrier Breached Effective Immune Response 1,12 13,26 1,13, 26 Meningitis with or without Meningococcemia Bacteremia without Sepsis Vascular Damage, DIC*, Tissue Damage, Shock 1,12 13,26 Meningococcemia without Meningitis * Disseminated Intravascular Coagulation 1. Apicella MA, Chapter 189: Neisseria meningitidis. In: Principles and Practice of Infectious Diseases, 4th ed. Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995, Saez-Llorens X, et al, Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications, The Journal of Pediatrics, 116:5, 1990, 672, 673, Young LS, Chapter 56: Sepsis syndrome. In: Principles and Practice of Infectious Diseases, 4th ed., Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995, Glode MP, Smith AL, Meningococcal disease. In: Textbook of Pediatric Infectious Diseases. Eds. Feigin RD, et al. W. B. Saunders Company, Phila., 1981,

19 Meningococcemia without Meningitis
Clinical Manifestations Malaise, weakness, nausea, myalgia, arthralgia15 Significant fever & chills15 Macular, erythematous rash usually on extremities15 Petechiae/purpura on extremities14,15 Hypotension14 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33 15. Howe WB, Meningococcemia heading off a killer, The Physician and Sportsmedicine, 24:2, 1996, 2

20 Meningococcemia without Meningitis (cont’d.)
Clinical Manifestations Disseminated intravascular coagulation (DIC)14 Multiorgan failure14 Laboratory abnormalities15 leukocytosis with left shift leukopenia coagulopathy blood positive for N. meningitidis 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33 15. Howe WB, Meningococcemia heading off a killer, The Physician and Sportsmedicine, 24:2, 1996, 2

21 Meningococcemia Complications
Clinical Manifestations Waterhouse-Friderichsen syndrome (10%)15 Pneumonia1 Endocarditis, myocarditis, pericarditis15 Pleurisy15 Peritonitis15 Arthritis15 1. Apicella MA, Chapter 189: Neisseria meningitidis. In: Principles and Practice of Infectious Diseases, 4th ed. Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995, 1902 15. Howe WB, Meningococcemia heading off a killer, The Physician and Sportsmedicine, 24:2, 1996, 2

22 Expressions of Waterhouse-Friderichsen Syndrome
Clinical Manifestations Fulminant septicemia Shock Purpura fulminans DIC Congestive heart failure Bilateral adrenal hemorrhage Progressive, irreversible collapse 15. Howe WB, Meningococcemia heading off a killer, The Physician and Sportsmedicine, 24:2, 1996, 2 25. DeLellis RA, Chapter 26: The endocrine system. In: Robbins Pathologic Basis of Disease 4th ed. Eds. Cotran RS, et al. W. B. Saunders Company, Phila., 1989, 1253

23 Meningitis with/without Meningococcemia
Clinical Manifestations Fever Headache Nuchal rigidity CSF > WBCs < glucose > Protein levels + for N. meningitidis 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33

24 Meningitis with/without Meningococcemia
Clinical Manifestations Outcomes Death Long-term neurologic sequelae deafness cranial nerve palsy retardation 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33

25 Pathogenesis - Meningitis
Clinical Manifestations Skull Dura mater Capillary in arachnoid Space Brain

26 Pathogenesis - Meningitis
Clinical Manifestations Blood Brain Barrier (Tight Junctions) Meningococci

27 Pathogenesis - Meningitis
Clinical Manifestations 4. Neutrophils summoned; attach to endothelium 1. Meningococci release endotoxins 2. Cytokines summoned; endothelial cell inflamed 3. Blood Brain Barrier disrupted 5. Neutrophils enter brain; secrete inflammatory factors; further BBB disruption 11. Quagliarello V, et al, Bacterial meningitis: pathogenesis, pathophysiology, and progress, N Eng Jour Med, 327:12, 1992, 12. Saez-Llorens X, et al, Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications, Journ Pediatrics, 116:5, 1990, 672, 673,

28 Diagnostic Features (Adults & Children)
Diagnosis Upper respiratory symptoms Headache Petechiae/purpura (significant finding) Fever Extreme vomiting Photophobia Nuchal rigidity 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33

29 Diagnostic Features (Infants)
Diagnosis Irritability Full fontanel Poor feeding Elevated or subnormal temperature Vomiting Lethargy Altered consciousness levels Increased intracranial pressure (ICP) Kernig’s & Brudzinski’s signs present 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 33

30 Case Definitions Confirmed case Presumptive case Probable case
Diagnosis Confirmed case isolation N. meningitidis from blood, CSF, petechiae or purpuric lesions, synovial fluid, pleural fluid, pericardial fluid Presumptive case Gram negative diplococci in any of above normally sterile fluids Probable case + antigen test for organism in blood or CSF with illness profile for meningococcal disease 3. American Academy of Pediatrics, Meningococcal disease prevention and control strategies for practice-based physicians, Pediatrics, 97:3, 1996, 405

31 Laboratory Findings Meningococcemia Diagnosis
isolation of N. meningitidis15 left shift leukocytosis 14, 15 leukopenia (overwhelming disease)14 coagulopathy15 metabolic acidosis14 proteinuria14 increased urine specific gravity14, 15 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 34 15. Howe WB, Meningococcemia heading off a killer, The Physician and Sportsmedicine, 24:2, 1996, 2

32 Laboratory Findings Meningitis - CSF Diagnosis + for N. meningitidis
Normal in early or overwhelming infection WBCs - >90% segmented neutrophils > protein levels < glucose levels (< 60 mg/dL) 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 34

33 Definitions Treatment Primary case - occurs in the absence of previously known close contact with another case Secondary case - occurs among close contacts of a primary case > 24 hours after onset of illness in primary case Coprimary case - two or more cases occur among group of close contacts with illness onsets separated by < 24 hours 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 15

34 Treatment - Primary Cases
Appropriate antibiotics Penicillin G1,14 Cefotaxime1 Ceftriaxone1,14 Chloramphenicol (for penicillin-resistant)14 1. Apicella MA, Chapter 189: Neisseria meningitidis. In: Principles and Practice of Infectious Diseases, 4th ed. Eds. Mandell GL, et al. Churchill Livingstone, New York, 1995, 1903 14. Herf C, et al, Meningococcal disease: recognition, treatment, and prevention, The Nurse Practitioner, 23:8, 1998, 36

35 Definitions Close contacts - Organization-based outbreak - Control
household members day care center contacts persons directly exposed to the patient’s oral secretions (e.g. through mouth-to-mouth resuscitation or kissing) Organization-based outbreak - three or more confirmed or probable cases during period < 3 mos. in persons with common affiliation, but no close contact primary disease attack rate of >10 cases/100,000 includes schools, universities, correctional facilities 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 15

36 Definitions Community-based outbreak -
Control Community-based outbreak - three or more confirmed or probable cases during period < 3 months among residents in same area with no close contact and not sharing common affiliation primary attack rate of >10 cases/100,000 includes towns, cities, counties Population at risk - group of persons, who, in addition to close contacts, are considered to be at increased risk for disease, when compared with historical patterns of disease risk in the same population 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 15, 16

37 Ten Steps to Control Establish diagnosis
Administer chemoprophylaxis to contacts Enhance surveillance, save isolates, review historical data Investigate links between cases Consider subtyping 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 20

38 Ten Steps to Control Exclude secondary & co-primary cases
Determine if suspected outbreak is organization- or community-based Define population at risk and determine size Calculate attack rate Select target group for vaccination Refer to MMWR reference below for information 6. CDC, Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 13-22

39 Chemoprophylaxis - Contact Cases
Control Rifampin Ciprofloxacin Ceftriaxone 4. CDC, Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR, 46:RR-5, 1997, 6

40 Menomune® - A/C/Y/W-135 Vaccination Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined16 Dose 0.5 ml, subcutaneously16 Protective antibody levels may be achieved 7 to 10 days post-vaccination16 Revaccination may be indicated for persons remaining at high risk16 Refractoriness to group C polysaccharide may limit secondary response24 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494 24. Granoff DM, et al, Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination, J Infec Dis, 178:1998, 874 

41 Indications Active immunization against serogroups A, C, Y, W-135
Vaccination Active immunization against serogroups A, C, Y, W-135 May be used to prevent & control outbreaks of serogroup C Does not protect against other serogroups or etiologic agents Not for < 2 years of age except as short-term protection of infants >3 mos. against group A 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494

42 Efficacy Group A & C - 85% to 100% in children > 4 yrs. & adults16
Vaccination Group A & C - 85% to 100% in children > 4 yrs. & adults16 Group A/C/Y/W % in 2 to 29 yr. olds in controlling group C outbreaks18 Group A/C/Y/W % in preschoolers 2 to 5 yrs. in controlling group C outbreaks18 Group A/C/Y/W > 4-fold increase increased bactericidal antibody; 90% subjects16 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494 18. Rosenstein N, et al, Efficacy of meningococcal vaccine and barriers to vaccination, JAMA, 279:6, 1998, 435, 437

43 Vaccine Use Routine vaccination recommended for high risk groups:
deficiencies in late complement components (C3, C5-C9) functional or actual asplenia persons with laboratory or industrial exposure to N. meningitidis aerosols travelers to, and residents of, hyperendemic areas such as sub-Saharan Africa 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494

44 Vaccine Use Consider vaccination for Vaccination
college students to reduce risk as recommended by the American College Health Association (ACHA)16 household or institutional contacts16 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494 

45 Contraindications, Warnings
Vaccination Contraindications defer during any acute illness known sensitivity to thimerosal, or any other vaccine component Warnings contains latex rubber in stopper expected response may not be obtained in immunosuppressed persons do not give concurrently with whole-cell pertussis or whole-cell typhoid vaccines As with any vaccine, vaccination does not protect 100% of all susceptible individuals 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494

46 Precautions Precautions Vaccination
health care worker to assure safe and effective use of vaccine epinephrine (1:1000) to be immediately available review patient’s history and current health use separate, sterile syringe and needle for each patient avoid intradermal, intramuscular, intravenous injections 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494

47 Adverse Reactions Vaccination Mild, consisting mainly of pain & redness at injection site for 1 to 2 days Transient fever in < 2% of young children No significant systemic reactions reported in 150 adults observed Other reactions - mild to moderate headaches, malaise, mild chills and fever 16. Pasteur Mérieux Connaught Meningococcal Polysaccharide Vaccine Groups A, C, Y and W-135 Combined, Menomune ® - A/C/Y/W-135 package insert, June 1998, Copy serial 2494

48 PCR Testing New Developments PCR (polymerase chain reaction) testing peripheral blood (buffy coat) used in research laboratories:19 100% specificity rapid & sensitive sensitivity unaffected by antibiotic treatment serotype can be identified May also be used on normally sterile fluids such as CSF 19. Newcombe J, et al, PCR of peripheral blood for diagnosis of meningococcal disease, Journal of Clinical Microbiology, 34:7, 1996, 1637

49 Treatments New Developments Additional data required to establish efficacy of dexamethasone therapy to control inflammation20,21 Rare, intermediate penicillin-resistant isolates in Europe, South Africa, North Carolina20 Chloramphenicol-resistant serogroup B strains in Vietnam & France22 20. Quagliarello VJ, Scheld WM, Treatment of bacterial meningitis, N Engl J Med, 336:10, 1997, 710, 713 21. Schaad UB, et al, Steroid therapy for bacterial meningitis, Clin Infect Dis, 20, 1995, 689 22. Galimand M, et al, High-level Chloramphenicol resistance in Neisseria meningitidis. N Engl J Med,339:13, 1998, 868

50 Vaccines in Development
New Developments Conjugate vaccines Single strain, outer membrane protein (OMP) vaccines Recombinant multivalent serosubtype vaccines Lipopolysaccharide (LPS) vaccines 10. Poolman JT, Development of a meningococcal vaccine, Infectious Agents and Disease, 4:1, 1995, 24


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