A male baby, age 7 days, presented to the Emergency Department with an 11 hour history of reduced feeding. He was afebrile but had a petechial rash, lethargy and poor perfusion. He was born by uncomplicated, term vaginal delivery and went home at 5 days of age with his parents and a fully immunised 2-year-old sister. There were no reports of contacts with unwell persons, and there was no household overcrowding. The number of visitors to the baby in the preceding days was not recorded.
The neonate was resuscitated with intravenous fluids. Cefotaxime, penicillin and gentamicin were administered. He improved somewhat following fluid administration and proceeded to a full septic screen when stable.
Investigations revealed a normal full blood count, coagulation profile, electrolytes and c-reactive protein. Urine showed a high specific gravity (>1.03) indicative of dehydration, with the final negative culture. Cerebrospinal fluid contained 1×106/L leucocytes, 371 × 106/L erythrocytes, protein 1.06 g/L and glucose 2.2 mmol/L (blood glucose 3.2 mmol/L). Nasopharyngeal aspirate was negative, and the chest x-ray was normal.
Due to the infant’s state on presentation, the paediatric team decided to arrange early transfer to a tertiary centre for likely intensive care management. However, while awaiting the arrival of the transfer team, the baby developed irregular breathing, prolonged apnoeas and finally, cardiorespiratory arrest. The presence of disseminated intravascular coagulation complicated intubation and ventilation. The baby died despite prolonged cardiopulmonary resuscitation. Cerebrospinal fluid and blood cultures both grew Neisseria meningitides serogroup B.
Who gets meningococcal disease?
Meningococcal disease is a rare yet rapidly progressing and highly fatal infection caused by the gram-negative aerobic bacterium Neisseria meningitidis. There are 13 known serogroups but A, B, C, W135 and Y are the most common to cause disease.
Neisseria menigitidis may cause endemic and epidemic infections – the vast majority of the latter occur in low- and middle-income settings where disease control is complicated by poor health infrastructure. The most recent epidemic in the ‘meningitis belt’ of sub-Saharan Africa occurred in 2009 and resulted in the deaths of over 4,000 children due to serotype A disease.
It is spread by aerosolised particles and colonises the nasopharynx of a significant proportion of the population. Carriage rates vary by age, from 5% of infants to a peak of 24% in 19 year olds before diminishing to 8% in older adults. The bacteria attach to the mucosal surfaces of tonsils and adenoids via adhesion proteins. A tiny proportion of these will cross the mucosal barrier to cause invasive meningococcal disease (IMD), which presents as septicaemia and/or meningitis. There are two small peaks in IMD incidence across the age range, which occur in children <5 years and adolescents aged 15-19 years (in whom carriage rates are highest).
While most people will carry Neisseria asymptomatically, a tiny proportion proceeds to invasive infection. Factors associated with an increased risk of progressing to IMD include:
- Complement deficiency, due to either a congenital deficiency in a single terminal protein (which will almost always be undiagnosed) or a complement-depleting underlying illness
- Recent or concurrent viral respiratory tract infection, particularly influenza virus
- Living in close confines
- Intimate kissing
- Exposure to either active or passive cigarette smoke (in one study, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children)
- History of preterm birth
How does IMD present?
The clinical presentation of IMD is non-specific with features including sudden-onset fever, a rash (which may be petechial, purpuric or maculopapular); altered LOC, cool peripheries, nausea and vomiting; and photophobia and neck stiffness (with meningitis). The mortality risk is high (between 5 to 10% even with appropriate antibiotic therapy), and of those who survive up to 1 in 3 will suffer long-term consequences (predominantly limb deformities, sensorineural hearing loss and neurological deficits). This high mortality and morbidity burden is secondary to endotoxin-induced vascular collapse induced by N.menigitidis.
Despite media reports often marred by an element of hysteria, IMD remains extremely rare with 1.1 per 100,000 people diagnosed in Australia in 2016 (compare this to the incidence of influenza which occurs in close to 500 per 100,000 Australian children each season, necessitating ICU admission in 6 per 100,000). IMD has seasonal and temporal variations, with peaks seen in Spring each year and multi-year cycles resulting in variable prevalence rates for different serotypes each year. The natural fluctuation in the predominant serogroup over time is only partially attributable to vaccination – a significant decline in the prevalence of serogroup B disease had already begun to occur prior to the current surge in private immunisation rates.
A recent increase in serogroup W135 disease (responsible for 45% of cases in 2016) has boosted interest in immunisation against this serotype. There were 110 cases of W135 in 2016, surpassing serogroup B for the first time since 2002. Concurrently, a small increase in serogroup Y disease (41 cases [16%] in 2016) occurred. Despite causing the highest burden from a global perspective serotype A remains rare in Australia, while serogroup C has dropped from 225 (2002) to 3 notified cases per year (2016; a 99% decline following the national immunisation programme roll-out in 2003).
Part of the concern regarding the increase in W135 disease is that many of these cases have belonged to the hypervirulent ST11 clonal complex, which is associated with an atypical clinical presentation and a higher case fatality rate (8%).
Should we be immunising everyone?
Vaccination for meningococcal is aimed at stopping the transmission between asymptomatic colonised people and those who are susceptible and non-colonised. In light of the recent increase in W135 and Y serotype illness, targeted state-based immunisation programmes were introduced in 2017 for adolescents (targeting 15 – 19 year olds) to protect the age bracket with the highest rates of nasopharyngeal colonisation. For other age groups, the quadrivalent meningococcal vaccine may be provided through private prescription. Vaccination should be recommended for:
- People at increased risk of IMD – those with known complement disorders, functional or anatomical asplenia, and other immunocompromising conditions
- Children in age groups with increased incidence of IMD or high carriage rates of meningitidis – particularly those aged <2 years and adolescents, or those living in close quarters such as boarding school or college accommodation
- Travellers – in particular to the ‘meningitis belt’ of Africa. Proof of immunisation with the 4vMenCV is also a requisite for pilgrims attending the annual Hajj in Mecca.
The only vaccine on the current Australian Immunisation Schedule is the serotype C conjugate vaccine, given at 12 months of age. A quadrivalent vaccine covering serotypes A, C, W123 and Y is available and recommended for some high-risk groups (such as overseas travellers), but immune responses are limited in young children.
The meningococcal B vaccine was slow in development because the capsule of the bacterium has protein marker similarities with human antigen neural-cell adhesion molecules. After many years of research, a meningococcal B vaccine is now available in Australia for private purchase only.
Which should I prescribe? Are they all the same?
There are two types of quadrivalent meningococcal vaccination – polysaccharide and conjugate vaccines. However, as of early 2017, the polysaccharide vaccines (MPSV4; Mencevax and Menomune) have been discontinued in Australia due to their poorer immunogenicity potential. The available conjugate vaccines (4vMenCV) work by conjugating the antigens of four serogroups (A, C, W135 and Y) to a carrier protein. All are safe and immunogenic. Available 4vMenCV in Australia include:
- Menactra (Sanofi Pasteur)
- Menveo (GSK)
- Nimenrix (Pfizer)
The brand and dosing regimen depends upon the age group you are prescribing for, but for healthy children:
|Age at presentation to commence immunisation course||Recommended brand||Number of doses required||Interval between doses|
|≤ 6 months*||Menveo||3 doses||8 weeks|
|7 – 11 months||Menveo||2 doses||12 weeks|
|12 – 23 months||Menveo Or Nimenrix||2 doses 1 dose||12 weeks –|
|≥2 years||Any||1 dose||–|
*Immunisation is not indicated in children <2/12
A simple rule is to prescribe Menveo for younger age groups opening to broader possibilities with increased age, and the younger the child, the more doses that will be required. Booster doses will be needed in adolescence and travellers. The vaccines are not interchangeable, and commencing a course with one brand involves completing the course with that brand.
A little more on Bexsero
Bexsero is a 4-component, protein-based vaccine (4CMen B) – which means the vaccine contains four antigenic meningococcal B components (identified after whole-genome sequencing of the bacterium).
The Therapeutic Goods Authority approved it in August 2013. It can be used in persons over two months of age (although the first dose may be given as early as six weeks to suit the current vaccination schedule). It is recommended for children under five, adolescents aged 15-19, and immunocompromised/asplenic children and adults.
As per laboratory tests, just under 80% of meningococcal B strains are covered by the vaccine. For infants under six months, three doses of the vaccine plus a booster at 12 months are the current recommendation. Older children and adults need fewer doses. One month after the third dose in infants, 84-100% of patients in clinical trials had achieved an adequate immunological response – following the booster dose; this increased to 95-100%.
Local and systemic reactions are very common – particularly fever (77% of infants, compared to 45% post routine vaccinations). A very small rate of febrile seizures have been attributed to the vaccine. Therefore paracetamol should be given prophylactically prior to and in the 12-24 hours following administration. Some cases of Kawasaki disease were seen in the original cohort, but this has not been replicated in surveillance following Bexsero’s general release. In order to lessen the risk of fever, many infants are being given their vaccines at 3, 5, and 7 months, off-setting with the usual vaccine schedule.
The current cost is AU$140-150 per vaccine.
So, should parents fork out the cash?
The public health ethics in this situation are a little tough to take – it’s so expensive that the vaccine is out of reach for many families. Invasive meningococcal disease is rare, but the outcome can easily be devastating. Given the relatively reassuring safety profile of the vaccine so far, it would appear to be a straightforward choice (if not for the financial implications) for most families. Having seen the tragedy of meningococcal B, I won’t hesitate to vaccinate my own children. It hardly seems fair that families struggling to make ends meet won’t be able to offer the same to their children, at least for now.
Why isn’t it funded yet?
The Pharmaceutical Benefits Advisory Committee has so far rejected inclusion of Bexsero in the immunisation schedule due to essentially a limited cost-benefit ratio. They noted that “approximately 272,224 individuals would need to be fully vaccinated to avoid one death”.
Essentially, Bexsero is still yet to prove itself. Lab evidence is one thing, but a measurable reduction in actual cases is what the Committee wants to see.
Other countries, like the UK, are currently funding it on their routine vaccination schedules, but since the vaccine remains in its own infancy, its large-scale impact on morbidity and mortality remains yet to be proven.
The Committee has a fair point. The vaccine does need to prove itself, but whilst an apparently safe vaccine exists, with at least a theoretical 80% protectiveness against a truly horrific disease, it’s going to be very hard to explain to affected families why they have to suffer the consequences of the Committee’s decision.
ED attendance following vaccination
In September 2015, the UK introduced the 4Conjugate Meningococcal B vaccine to the routine immunisation schedule, to be given at 2 and 4 months. Those who’ve witnessed the devastating effects of meningococcal sepsis welcomed this warmly. There was, however, a tiny catch. It was recognised that one of the effects of the vaccination was to produce a fever in the recipient shortly after administration, and parents were advised to give paracetamol.
This of course posed a dilemma to the ED physician met with a febrile infant post immunisation. Was the fever solely vaccine related or was it the presentation of a serious bacterial infection? Somewhat unhelpfully there was no, and still is no, national guidance on what to do. Do we assume all fevers are vaccine related and risk missing a septic infant, or do we assume all are possibly septic and risk over-treating?
Several teams in the UK are currently auditing their practices and publishing their findings. The first group to do so was in Northern Ireland – publishing their findings in the Archives of Disease in Childhood. This is an important start to collecting data to allow us to come up with some guidance and to this end I have summarised the paper in the following infographic.
I’ll never forget the throbbing, pounding headache that heralded the onset of meningococcal meningitis and septicaemia as a 14-year-old girl, overwhelmed by the horrifying physical sensation of sepsis. Within two hours, I was unconscious – but thanks to a vocal family member advocating their concern for how sick I was, a NETS retrieval to a tertiary unit was swiftly arranged, where I was diagnosed with serotype C strain meningococcal disease. I was incredibly fortunate to receive excellent care and survive unscathed.
Recently, a surge in (serogroup W135) meningococcal disease has resulted in increased attention towards the quadrivalent vaccine. Many parents are questioning if they should immunise their babies or toddlers and, in a similar vein to the MenB vaccine (another post in itself), why isn’t it part of the National Immunisation Programme for this age group?
The bottom line
Up to one quarter of children carry Neisseria meningitidis in their nasopharynx. Risk factors for progression to invasive disease include exposure to cigarette smoke, a recent or concurrent viral illness, living in close confines or immunodeficiency (particularly within the complement pathway)
Serotype W135 is currently the most common strain causing invasive meningococcal disease in Australia, although disease incidence remains extremely rare
Vaccination should be encouraged for children in age groups with increased incidence of IMD or high carriage rates of meningitidis, particularly children aged <2 years and adolescents, and those living in close quarters such as boarding school or college accommodation
Adolescents (aged 15 – 19 years) are currently eligible to receive the quadrivalent vaccine under the national immunisation programme administered via state-based programmes
Children >2 months can be immunised on a private prescription using one of 3 available conjugate quadrivalent vaccines which require increasing doses when the course is commenced at a younger age. The available vaccines are not interchangeable and a course needs to be completed with the brand in which it was commenced.
The World Health Organisation; Global Health Observatory Data: Number of suspected meningitis cases and deaths reported (2010); Available: https://www.who.int/gho/epidemic_diseases/meningitis/suspected_cases_deaths_text/en/
Christensen, H. et al. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infectious Diseases (2010); 10(12) 853-61.
Ellison, R. et al. Prevalence of congenital or acquired complement deficiency in patients with sporadic meningococcal disease. NEJM(1983),308(16), 913.
Fischer, M. et al. Tobacco smoke as a risk factor for meningococcal disease. Paediatric Infectious Disease Journal; 1997; 16(10); 979.
Australian Government Department of Health. Invasive meningococcal disease national surveillance report, with a focus on MenW. 9 January 2017. Available from: ntent/ohp-meningococcal-W.htm (Accessed February 2017)
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Australian Government Department of Health Invasive Meningococcal Disease National Surveillance Report; 12 December 2016
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Vesikari T, Esposito S, Prymula R, Ypma E, Kohl I, Toneatto D et al. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. The Lancet. 2013;381(9869):825-835.