Rabeen Lutchman

John, an eight year old boy, presents to you with a one day history of severe headache and fever. He has vomited once. On examination there are signs of meningeal irritation, a decreased level of consciousness as well as a few petechiae on his conjunctivae. You suspect meningococcal meningitis. 1) Give a brief description of the causative organism. 2) Describe the pathogenesis of the disease. 3) Which Serogroups commonly cause disease in South Africa? 4) During which time of the year do you expect to find an increase in cases in South Africa? 5) Which laboratory investigations will you request and what results do you expect? 6) Discuss the initial management of the patient John, an eight year old boy, presents to you with a one day history of severe headache and fever. He has vomited once. On examination there are signs of meningeal irritation, a decreased level of consciousness as well as a few petechiae on his conjunctivae. You suspect meningococcal meningitis. 1) Give a brief description of the causative organism. 2) Describe the pathogenesis of the disease. 3) Which Serogroups commonly cause disease in South Africa? 4) During which time of the year do you expect to find an increase in cases in South Africa? 5) Which laboratory investigations will you request and what results do you expect? 6) Discuss the initial management of the patient

John’s pregnant mother is concerned about herself and her younger daughter of 4 years old and enquires about chemoprophylaxis 1) To whom should chemoprophylaxis be given? 2) For how long after the index case identification will chemoprophylaxis still be beneficial 3) Which drugs can be used for chemoprophylaxis for the contacts in this case 4) Should John receive antibiotics to eradicate meningococcal carriage? John’s pregnant mother is concerned about herself and her younger daughter of 4 years old and enquires about chemoprophylaxis 1) To whom should chemoprophylaxis be given? 2) For how long after the index case identification will chemoprophylaxis still be beneficial 3) Which drugs can be used for chemoprophylaxis for the contacts in this case 4) Should John receive antibiotics to eradicate meningococcal carriage?

The infection sister asks you whether contacts can be immunized to prevent disease 1) Discuss the use of immunization to prevent disease in contacts 2) Which different types of vaccines are available against meningococcal disease? 3) Against which common Serogroup is a vaccine not commercially available? The infection sister asks you whether contacts can be immunized to prevent disease 1) Discuss the use of immunization to prevent disease in contacts 2) Which different types of vaccines are available against meningococcal disease? 3) Against which common Serogroup is a vaccine not commercially available?

 Neisseria meningitidis is a gram-negative diplococcus.  Kidney-shaped pairs  Humans only natural reservoir  Commensal colonizers of the nasopharynx  The meningococcal cell : lipid A–containing lipo-oligosaccharides (LOS), including endotoxin, which is covered by a polysaccharide capsule  13 Serogroups  Serogroups A, B, C, W135, and Y

 Droplet spread or intimate contact with nasopharyngeal secretions.  Nasopharyngeal colonization  Asymptomatic carriage of meningococcus is an immunising event and serum antibodies develops about 14 days after acquisition  Invasive disease - the organisms in the nasopharynx invade the epithelium and evade the immune system and result in septiceamia and dissemination  Type IV pili.  Pili attach to CD46 proteins that serve as receptors for C3b, C4b, measles, and other viruses on the epithelial cell surface.  Endocytosis  Serum antibodies  Polysaccharide capsule - resist phagocytic killing.  The virulence of meningococcus is related to the release of lipopolysaccharide (endotoxin)

Risk Factors for acquiring invasive disease :  The Agent - Certain strains are associated with invasive disease and have acquired virulence factors  The Host - Medical conditions : Complement deficiency / Immune deficiency, Functional or anatomical asplenia - Underlying chronic diseases,  The Environment - Nature and duration of contact - Household contacts have fold increase risk - Overcrowding (Hostel/Barracks/Millitry) - Coexisting viral infection (especially Influenza) - Exposure to tobacco (passive and active) - Low socioeconomic status are associated with higher risk

 The meningococcal cell wall has lipid A– containing lipo-oligosaccharides (LOS), including endotoxin, which is covered by a polysaccharide capsule.  6 Serogroups A, B, C, W135, X and Y  These 6 Serogroups have geographic and time differences in distribution

Number Of laboratory-confirmed meningococcal disease cases reported until the end of week 9, 2012 and 2013, by province Province Eastern Cape89 Free State03 Gauteng2210 KwaZulu-Natal88 Limpopo11 Mpumalanga11 Northern Cape01 North West21 Western Cape1312 Total5546

Serogroup data available for 25/46 (54%) Western Cape - Serogroup B predominance Gauteng / North West – Serogroup W135 Predominance

 Occurs throughout the year but the incidence is highest in the late winter and early spring  Follows behind the Influenza season  Numbers are expected to increase during June and July, and to peak during the months of August to October

 Try and add slide from medscape

 ?Clinical signs : Raised Intracranial Pressure  A Lumbar Puncture is NOT indicated in a child with meningococcaemia even if Meningism is found  A lumber puncture should never be done if there is any suggestion of impaired level of consciousness  A blood culture and urgent treatment based on clinical assessment

Non Culture Diagnostic Tests :  Polysaccharide antigen testing  PCR  Skin Scrapings  Post mortem specimens – in cases with undiagnosed infection. Spleen/Heart blood cultures or post mortem CSF cultures

Medical Emergency and Treatment should not be delayed Early recognition : Nonspecific symptoms  The classical, rapidly evolving purpuric rash associated with MD and neck pain, or stiffness, usually develops after 12 h. Early recognition of shock:  signs of hypoperfusion such as poor peripheral perfusion, impaired level of consciousness, and reduced urine output should be evident. Fluid resuscitation:  Initial emergency fluid resuscitation should include repeated boluses of 20 mL/kg of isotonic crystalloid or colloids until shock has resolved.  May require even mL/kg of fluid resuscitation (mostly those that need ventilatory support  There is a 94% rate of survival when shock is reversed within 75 minutes of presentation.  Fluid resuscitation more carefully if a child presents with signs of shock and hepatosplenomegaly or rales - myocardial dysfunction may be present.

Antibiotics:  Antibiotic therapy - cornerstone of treatment.  Should be initiated early  Should not be delayed because of clinical investigation.  Choice determined by ability to penetrate CSF and susceptibility of organism  Recommended First line drug of choice for proven meningococcal septicaemia or meningitis is IV benzyl penicillin for 5-7days  However Ceftriaxone or Cefotaxime should be used for emperic therapy for suspected meningitis  Those with a Beta-lactam allergy should receive Chloramphenicol.

Public Health Responsibility:  IMMEDIATE telephonic notification followed by written notification to the Department of Health  Isolation  Identification of close contacts for all confirmed and probable cases  Provision of required post exposure prophlaxis to close contacts  Rapid investigation of the case  Identification of other cases in the same institute or community that may suggest a cluster

John’s pregnant mother is concerned about herself and her younger daughter of 4 years old and enquires about chemoprophylaxis To whom should chemoprophylaxis be given? = All CLOSE CONTACTS irrespective of vaccination status  Living/sleeping in the same household  Pupils/students/military living in the same dormitory  Sharing a kitchen or same bathroom  Any person who has been exposed to large droplets or secretions from the respiratory tract- applies to health care staff/ambulance/emergency personnel

Where prophylaxis is NOT indicated:  ALL the pupils in the classroom/creche  ALL work/ school colleagues  ALL Residents of the Hostel  All individuals attending same social function  All passengers travelling in the same plane, train, bus or car

 Prophylaxis should be given as early as possible (preferrable within 24hours)  It may still be effective if given up to 0 days after the presentation of the index case if delays are unavoidable  Overnight visitors to the home of the index case within 7 days before onset of illness should also receive prophylaxis

*Close contacts who are pregnant should receive Ceftriaxone 250mg IM NameDose (adults) Dose (children) RouteDuration Ciprofloxacin 500mg10mg/kgPOSingle dose Ceftriaxone250mg(<12years) 125mg IMSingle Dose Rifampicin10mg/kg bdPO2 days

 About 5-10 % people carry meningococci in the nasopharynx and very few will become ill depending on the risk factors previously mentioned  Carriage rates increase from about 2% in children about 5 to 25% in the late teens  Asymptomatic carriage is an immunising event and serum antibodies develops about 14 days after the acquisition of the meningococcus – it lasts for about 3 – 4 months and generates herd immunity  In households and closed populations the carriage rate is significantly higher  Nasopharyngeal carriers rather than patients with meningococcal disease are generally the source of new infections

The infection sister asks you whether contacts can be immunized to prevent disease Discuss the use of immunization to prevent disease in contacts (i.e post exposure vaccination)  Close contacts that HAVE BEEN GIVEN prophylaxis can LATER be offered the appropriate vaccine once the serotype has been confirmed  This extends period of protection  Can be given up to 4 weeks after exposure and is not an urgent procedure  Use of the vaccine does NOT replace the immediate need for prophylaxis (as the Serogroup is not known)

3 Types of Vaccines available: Polysaccharide Vaccines Protein Conjugate Vaccines Outer Membrane Vesicle(OMV) Vaccine

Polysaccharide Vaccine  Quadrivalent Vaccine available in SA (Serogroup A,C, W135, Y)  Bivalent Vaccine (A and C) also available  Effective in controlling outbreaks  Limitations: - Short duration of immune response (protection for about days after vaccination) - Serogroup A component is effective from 3 months of age and last about 3 years but poorer protection for C, W135 and Y - Low immunogenicity in children <2 - Diminishes antibody responses after repeated vaccinations against Serogroup C (hyporesponsiveness)

Protein Conjugate Vaccines:  Tetanus Toxoid and CRM 197 carrier proteins  Immunogenic in all ages from > 2 months  Available for single serotypes (C –MEN C, A)  Induce immunologic memory - booster response  Prevent acquisition of carriage (MEN C used in adolescent programs in Europe, Canada, Australia - decreased the incidence of MD)  Offers longer duration of protection than polysaccharide vaccines  Direct protection and herd immunity

OMV Vaccines :  Serogroup B vaccine  Have been effective in controlling outbreaks or epidemics (Cuba/New Zealand/ Normandy)  Short duration of protection  VERY strain specific – no cross protection against strains that are not contained in the vaccine  Lack immunogenicity for infants

Pre exposure vaccination:  Protect individuals at risk - Travellers to African Belt - Pilgrims to Saudi Arabia (at least 10 days prior to arrival) - Persons with functional or anatomical asplenia - Complement deficiencies - Lab staff in reference Labs routinely working with the organism - ?1 st year students moving into university residences

 The development of Vaccines against Serogroup B has many challenges  Serogroup B polysaccharide is poorly immunogenic (lacks immunogenicity) even when conjugated to a protein carrier  Outer membrane vaccines show some promise – but strain specific differences in the Outer membrane proteins suggest that these vaccines may still not provide protection against all Serogroup B meningococci

New Vaccines for Meningococcal Serogroup B disease:  Main problem is capsule not immunogenic and is associated with autoimmunity( similar to some embryonic neural tissue)  Therefore must use subcapsular antigens : OMV  New protein recombinant vaccines are under trial using ALL the subcapsular antigens, not only the OMV  2 vaccines are currently in phase 3 clinical trials  One 4 component antigen vaccine has now being licensed in the European Union – broader cover against different Serogroup B strains  Watch this space…

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