Cause
Viral meningitis infections are generally mild in patients with no immune deficiency and recovery is usually spontaneous – sufferers recover fully within a few days with no lasting effects.
Bacterial meningitis infections can be serious, and the species responsible for acute meningitis vary according to age. In newborn infants (the first 28 days), group B streptococci Escherichia coli and Listeria monocytogenes are the most feared bacteria. In young children up to five, Haemophilus influenzae, Neisseria meningitidis (meningococcal infections) and Streptococcus pneumoniae (pneumococcal infections) are the main species responsible. After the age of five, the two most frequently encountered bacterial species are Neisseria meningitidis and Streptococcus pneumoniae. Childhood immunization against H. influenza type b has practically eliminated this meningitis agent. Meningitis and septicemia infections due to Haemophilus influenzae or Streptococcus pneumoniae also occur in the elderly. Finally, two bacterial species can be found in immunosuppressed individuals at all stages of life: Listeria monocytogenes and Mycobacterium tuberculosis, the causative agent of tuberculosis.
The human nasopharynx is the natural habitat of bacterial species most often responsible for acute meningitis (H. influenzae, N. meningitidis, and S. pneumoniae). Following a local, respiratory or ENT infection (tonsillitis, ear infection, sinusitis, etc.), bacteria can be found in the blood and may even cross the blood-brain barrier to infect the cerebrospinal fluid, leading to swelling and inflammation of the meninges.
Fungal meningitis infections are less common but very serious. In France, they are monitored by the National Reference Center for Invasive Mycoses & Antifungals at the Institut Pasteur. Cryptococcus neoformans is the main fungus responsible for meningitis and pigeon droppings are a reservoir. This yeast causes opportunistic infections, particularly in AIDS patients. Other fungi can also cause meningitis – Candida spp. during disseminated infections in immunosuppressed individuals or newborns, and, more rarely in mainland France as it is not an endemic country, fungi such as Histoplasma capsulatum or Coccidioides immitis.
Symptoms
Viral meningitis infections are generally mild in patients with no immune deficiency and recovery is usually spontaneous – sufferers recover fully within a few days with no lasting effects.
Bacterial meningitis infections can be serious, and the species responsible for acute meningitis vary according to age. In newborn infants (the first 28 days), group B streptococci Escherichia coli and Listeria monocytogenes are the most feared bacteria. In young children up to five, Haemophilus influenzae, Neisseria meningitidis (meningococcal infections) and Streptococcus pneumoniae (pneumococcal infections) are the main species responsible. After the age of five, the two most frequently encountered bacterial species are Neisseria meningitidis and Streptococcus pneumoniae. Childhood immunization against H. influenza type b has practically eliminated this meningitis agent. Meningitis and septicemia infections due to Haemophilus influenzae or Streptococcus pneumoniae also occur in the elderly. Finally, two bacterial species can be found in immunosuppressed individuals at all stages of life: Listeria monocytogenes and Mycobacterium tuberculosis, the causative agent of tuberculosis.
The human nasopharynx is the natural habitat of bacterial species most often responsible for acute meningitis (H. influenzae, N. meningitidis, and S. pneumoniae). Following a local, respiratory or ENT infection (tonsillitis, ear infection, sinusitis, etc.), bacteria can be found in the blood and may even cross the blood-brain barrier to infect the cerebrospinal fluid, leading to swelling and inflammation of the meninges.
Fungal meningitis infections are less common but very serious. In France, they are monitored by the National Reference Center for Invasive Mycoses & Antifungals at the Institut Pasteur. Cryptococcus neoformans is the main fungus responsible for meningitis and pigeon droppings are a reservoir. This yeast causes opportunistic infections, particularly in AIDS patients. Other fungi can also cause meningitis – Candida spp. during disseminated infections in immunosuppressed individuals or newborns, and, more rarely in mainland France as it is not an endemic country, fungi such as Histoplasma capsulatum or Coccidioides immitis.
Epidemiology
Meningococcal bacteria are spread by direct, prolonged (over an hour) and close (less than a meter) contact with nasopharyngeal secretions. Meningococcal infections are endemic worldwide (500,000 cases a year according to WHO). The annual incidence of meningococcal infections, with seasonal peaks in winter and spring, is 1 to 3 cases per 100,000 people in industrialized countries. Meningococci are the only bacterial species able to cause outbreaks of meningitis.
Twelve Neisseria meningitidis serogroups have been identified according to bacterial capsule composition. But serogroups A, B, C, W, X and Y are responsible for almost all cases of invasive infection. During outbreaks, it is the same strain that spreads; transmission is clonal. Invasive meningococcal infections occur in the form of periodic outbreaks in the "African meningitis belt", a region stretching from Ethiopia to Senegal where infections arise during the dry season marked by its dusty trade wind (harmattan).
- Serogroup A, which was responsible for these outbreaks in the belt, has practically disappeared since the conjugate vaccine against this serogroup was introduced in 2010. However, other serogroups (C, W and X) have recently emerged in Sub-Saharan Africa.
- Serogroup B, which is usually responsible for sporadic cases, is prevalent in Europe and America.
- Serogroup C causes small flash outbreaks, not just in America and Europe but also in Asia and Sub-Saharan Africa.
- And serogroup W has been on the rise globally since 2015.
According to data from the National Reference Center, of the 416 cases with a known serogroup in France in 2018, 51% were serogroup B, 13% serogroup C, 21% serogroup W, 13% serogroup Y and 2% were strains that were rare and had not been serogrouped. In 2020, important changes are observed since the emergence of SARS-Cov-2 and under conditions of social and physical containment and distancing.
Other invasive meningococcal infections
Clinical presentations may correspond to a severe form of meningococcal infection. Acute meningococcemia, in particular, causes sudden onset septicemia associated with a widespread vascular skin purpura, or rash. Purpura is characterized by bruises and small skin hemorrhages (that do not disappear on diascopy - glass test used in dermatology), as the endotoxins released during bacterial lysis cause tissue necrosis. Septic shock causes intravascular coagulation and is often life threatening. Fatal purpura fulminans occurs in 30% of cases.
Less common symptoms of meningococcal infection may also be observed – abdominal syndromes, septic arthritis, pericarditis, and acute pulmonary diseases (that most often affect immunosuppressed individuals and patients over 70 years of age) revealed by the bacteremia.
Treatment
The severity and risk of rapid progression of meningococcal infections mean antibiotic treatment must be prescribed as quickly as possible. Treatment is administered intravenously, usually for a period of 4 to 7 days. In industrialized countries, first-line third-generation cephalosporins (cefotaxime, ceftriaxone) are used.
The use of a single dose of ceftriaxone has been suggested for treating meningococcal meningitis in Africa during outbreaks.
Surveillance of antibiotic resistance is therefore vital as it would be a huge blow in the fight against outbreaks in the "meningitis belt".
Vaccination
Conjugate vaccines, combining bacterial capsular polysaccharides with a protein carrier, confer protection even in infants over two months of age. These conjugate vaccines represent a major step forward compared with unconjugated (polysaccharide only) vaccines.
There are two types of anticapsular conjugate vaccine:
- monovalent conjugate vaccines (conjugate vaccines against serogroup C and the conjugate vaccine against serogroup A used in Sub-Saharan Africa).
- tetravalent conjugate vaccines against serogroups A, C, W and Y.
Capsule B is poorly immunogenic as it is similar to a self-antigen and this prevents its use as a vaccine. Major scientific breakthroughs have led to a new generation serogroup B meningococcal vaccine. In this case it is not the capsule that is targeted by the immune response induced by these vaccines but bacterial proteins beneath the capsule and in the outer bacterial membrane. Two vaccines have obtained marketing authorization:
- the first vaccine primarily contains four proteins: a variant (variant 1) of the human factor H binding protein (fHbp), a variant of the Neisserial Heparin Binding Antigen (NHBA) and Neisseria adhesin A (NadA), and an OMV component (MeNZB) containing the PorA P1.4 protein. This vaccine obtained marketing authorization in 2013 (and can be used from 2 months up),
- the second vaccine contains two variants of the same protein (fHbp). It obtained marketing authorization in 2017 (and can be used from 10 years up).
The following meningococcal vaccine strategy is currently in place in France
Meningitis C
- Compulsory vaccination at 5 months followed by a booster at 12 months.
- One catch-up dose for all individuals between 2 and 24 years old.
Meningitis ACWY
- Vaccination of people in contact with a patient, other individuals at risk (travelers to endemic regions; research laboratory staff working specifically on meningococci; people with a complement terminal fraction deficiency or a properdin deficiency; people with functional or anatomic asplenia; people who have had a hematopoietic stem cell transplant) or in specific situations (clustered cases and outbreaks).
- If there is a long-term risk, a booster is required every 5 years.
Meningitis B
- Vaccination of individuals at risk and in specific situations (clustered cases and outbreaks).
Prophylaxis for those in close contact with the patient in France
A circular from the French General Directorate of Health of July 27, 2018 sets out prevention measures for close contacts: Directive No. DGS/SP/2018/163 of July 27, 2018 relating to prophylaxis for invasive meningococcal infections.
- In all cases of meningococcal infections, antibiotic prophylaxis is recommended for anyone in close contact with the patient to prevent transmission between individuals – rifampicin must be administered for 2 days. But there are contraindications (hypersensitivity, pregnancy, severe liver disease, alcoholism, porphyria, etc.), and rifampicin resistance has been reported for rare meningococcal strains. Prevention is then based on ceftriaxone administered by injection or ciprofloxacine taken orally, in a single dose.
- In the case of serogroup A, C, Y or W meningococcal meningitis, prevention through vaccination completes the antibiotic prophylaxis established to protect individuals who have come into close and repeated contact with a patient (generally those living at the same address) and young children living in crowded group settings.
New weapons to fight bacteria
At the Institut Pasteur
The Invasive Bacterial Infections Unit, led by Muhamed-Kheir Taha, and the Pathogenesis of Vascular Infections Unit, led by Guillaume Dumenil, focus their research on these bacteria, and on understanding their pathogenesis and interaction with humans.
The Invasive Bacterial Infections Unit is also home to the National Reference Center (CNR) for Meningococci and Haemophilus influenzae and the WHO Collaborating Center for Bacterial Meningitis.
The CNR notably boasts expertise in strains isolated in France in terms of their antigenic typing (serogroup, serotype, etc.) and their sensitivity to antibiotics, and also monitors potential genotypic relations between isolated strains within the same human community (molecular sequencing, study of genetic polymorphisms, etc.). The CNR is actively involved in establishing vaccine strategies against invasive meningococcal infections in France.
The Institut Pasteur teams working on the topic
Research units
Invasive Bacterial Infections Unit, led by Muhamed-Kheir Taha
Pathogenesis of Vascular Infections Unit, led by Guillaume Dumenil
Surveillance and public health : National Reference Center for Meningococci and Haemophilus influenzae
At international level
The WHO Collaborating Center and meningitis projects conducted with and in the Pasteur Network
September 2020
