Meningitis Flashcards
Define meningitis
Infection of the meninges (protective membranes) that surround the brain and spinal cord.
Infection can cause the meninges to become inflamed and damage the brain.
What are the three pathogens that cause bacterial meningitis?
- Streptococcus pneumonia
- Neisseria meningitidis
- Haemophilus influenzae type b (Hib)
Describe the bacteriology of Neisseria meningitidis
- exclusively human pathogen
- commonly part of the respiratory microbiota in healthy individuals which makes it hard to eliminate
- gram-negative, diplococcus bacteria
- encapsulated - provides basis for serotyping
- obligate aerobe
- can undergo horizontal gene transfer
Describe the different serotypes of N. meningitidis
12 serogroups have been identified based on their antigenic polysaccharides.
o A, B, C, Y, and W135 are most important serotypes for disease.
o The serotypes differ in their geographical distribution. Groups B and C are most common in the US and Europe.
o Meningitis belt in Africa is mainly due to A, however C and W135 are also seen
Describe mechanism of pathogenesis for N.meningitidis
Infection is by aspiration of infective bacteria, which attach to epithelial cells via pili of the nasopharynx and they colonise these cells.
The bacteria enter the bloodstream and circulate through the body. They can damage skin capillaries, causing the petechiae/skin rash often seen in MD.
Lysing bacteria in the blood can release endotoxins and can trigger septic shock.
Bacteria can then enter the central nervous system and cause meningitis by triggering inflammation of the meninges.
The inflammatory response will cause obstruction of normal flow of the CSF – causing increased pressure which impairs brain function. Damage to the motor nerves will cause paralysis.
What is meningococcal disease?
Diseases caused by bacterium N.meningitidis
Describe meningococcal disease
It can present itself as meningitis (similar symptoms as the meningitis caused by other bacteria) and/or septicaemia which can lead to septic shock.
Ranges from transient bacteraemia illness characterized by a fever and malaise; symptoms resolve spontaneously in 1 to 2 days to a fulminant disease that likely results in death – most patients die within 24 hours.
The onset may be abrupt or insidious but the illness often progresses quickly (within hours)
Sequelae in survivors include amputations, brain damage, seizures and deafness.
Describe epidemiology of MD
It’s the number one killer of children aged 1-5 years. Overall fatality is 2-10%.
Babies and young children are more at risk because their immunological defences are not fully developed.
A risk factor for teenagers and young adults is increased social interaction; this increases the number of carriers to around 30%.
Likewise, people who live in overcrowded premises are also at increased risk of MD.
22% of MD cases are associated with passive smoking, especially in children - exposure to tobacco smoke increases risk of acquiring MD. This may be due to bacteria being able to adhere to nasopharynx better, since tobacco smoke adversely affects immune response.
Invasive MD was recently shown to have increased rates in MSM in NYC – all were of the serogroup C and with a high mortality.
o MSM have shown to have high carriage of N. meningitidis in oropharynx, rectum and urethra in epidemiological studies.
o HIV has been shown to increase risk of invasive MD – though only half men in study were infected.
What is treatment for MD
If treated in time, meningitis can be cured with penicillin/ceftriaxone and patients recover without permanent nervous system damage.
Rifampicin is given to those exposed.
Describe susceptibility to MD
Systemic infections only occur in individuals who lack bacterial antibodies directed against the capsular antigens of N. meningitidis.
The elderly population have low numbers of these antibodies which is why meningitis is high amongst this population. And in young children the antibodies haven’t developed yet.
Efficacy of vaccine against meningitis is dependent on induction of these antibodies.
If they have the antibodies, they are protected as re-infection is very rare.
Integrity of pharyngeal and respiratory epithelium also important in protection from invasive disease. Irritation, damage to these epithelial cells is predisposing factor.
What are the host susceptibility factors to MD
Plasminogen activator inhibitor 1 - patients with the 4G/4G polymorphism were more likely to develop vascular complications and die from MD - tissue damage
Mannose binding lectin – polymorphism in the MBL2 increases severity of MD - complement deficiency
Factor V Leiden - a mutation exacerbates purpura fulminans (thrombosis) in MD due to increase in blood clotting.
Toll receptor 4 (TLR4) - mutants are associated with increased susceptibility to MD due to defect in recognition.
A GWAS for host susceptibility to MD found that complement factor H (CFH) was an important determinant.
- N. meningitidis evades complement-mediated killing by the binding of host CFH to the meningococcal factor H-binding protein (fHbp).
- The study suggests that host genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive disease versus asymptomatic colonization by this pathogen.
Describe the two MD vaccines available today
Purified capsular polysaccharide vaccine -
o Response is age dependent (not effective on children <2 years of age)
o T-cell independent - only short-term protection and no immunological memory.
o Ab levels not increased after a second dose of the vaccine.
o A, C, Y and W135 (NOT B)
Conjugate polysaccharide vaccine
o Research began in 1980s, they found that attaching a carrier protein to polysaccharide capsule made the vaccine much more effective.
o T cell dependent response with memory.
o Good response in children – in the UK, the vaccine is given 2, 3 and 4 months of age.
o Serogroups A, C, Y and W-135.
Outline recent developments in vaccines for MD
We need a vaccine for serotype B
- There is still a lot of cases.
- Serogroup B has little or no immune response to CPS
- Capsule shares compounds with host cells (e.g. NCM - neural cell adhesion molecule, which is present in a lot of tissues around the body)
- Immune response believed to involve outer membrane proteins - OMPs
- Need a vaccine that gives cross-protection against multiple strains (particularly in the UK)
Outer membrane vesicle (OMV) vaccines
o The vesicles bleb off the bacteria and take some of the periplasm. They can be extracted and used in vaccines as they have a lot of outer membrane material.
Meningitis belt vaccine: Highest incidence of MD worldwide occurs in the meningitis belt which extends between Senegal and Ethiopia in sub-Saharan Africa.
- MenAfriVac®—the meningococcal A conjugate vaccine has been developed for use in the belt. While it’s been successful so far (a million people have been vaccinated), emergence of W-135 strain means a new vaccine will soon need to be developed.
Describe OMV vaccines
o Three OMV vaccines have been used in Cuba, Norway and New Zealand.
o Protection has been largely strain specific
o Useful in single strain epidemic
PorA OMV based vaccines:
- PorA is the major immunogen and component of the outer membrane.
- A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results.
- This vaccine contains six different PorA OMPs each representing a different serosubtype.
- However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes - we have to mix and match depending on local region
Bexsero - first broad coverage serotype B vaccine
- consists of fHBp, NadA and NHBA with PorA OMV (all from serotype B) and was shown to have good tolerability in children in phase III trials. 73% coverage in the UK.
- However there are concerns regarding strain coverage, antibody persistence from the vaccine, its effect on carriage, escape mutants/resistance, cost-effectiveness.
- The department of health concluded that the Bexsero vaccine wouldn’t be cost-effective in the UK in children but that an evaluation would be required for adolescents.
