Invasive meningococcal disease in older adults in North America and Europe: is this the time for action? A review of the literature

Neisseria meningitidis is an encapsulated Gram-negative diplococcus that asymptomatically colonises the upper respiratory tract in up to 25% of the population (mainly adolescents and young adults). Twelve different serogroups cause invasive meningococcal disease (IMD)[1] of which six serogroups (A, B, C, W, X, and Y) are responsible for most infections [2]. Neisseria meningitidis is one of the leading causes of bacterial meningitis and sepsis globally [3]; less common presentations include pneumonia and a number of other manifestations [3, 4]. The case fatality rate of meningococcal disease remains high (5–15%) despite treatment [5‐7] and survivors can have significant sequelae, with around 20% suffering long-term disability [8]. IMD causes a substantial financial burden, often associated with hospitalisation or ongoing treatment of long-term sequaelae [9‐15], as well as negatively impacting the quality of life of patients, their families, caregivers and their extended networks [16, 17].

Vaccination remains the best strategy to prevent IMD [2], and antibiotics are recommended for post-exposure prophylaxis and treatment [18]. IMD is easily misdiagnosed [18‐20], because the severity of illness is often obscured by non-specific symptoms [21], and presentation is similar to that of many self-limiting viral infections [22], or there are extra-meningeal foci of infections, including pneumonia, pericarditis, epiglotitis and conjunctivitis [23‐25]. There is also a lack of confirmatory testing available in many healthcare settings. Although first-line antibiotics such as third generation cepholosporins are still effective in the treatment of IMD, the emergence of antibiotic-resistant strains have made IMD management more complex. As a result, morbidity and mortality rates have essentially remained unchanged over the last two decades [24, 26‐29].

The epidemiology of IMD varies markedly by region and over time but there are an estimated 500,000 newly diagnosed cases per annum [30]. The highest incidences of IMD are found in countries in the African ‘meningitis belt’ region, with the lowest incidences found in parts of Europe and the Americas [3]. A recent systematic review showed that serogroup B was responsible for the highest proportion of N. meningitidis IMD cases worldwide; nevertheless, the predominant serogroup varies by region, country, age group and over time [31]. Vaccination against IMD has also contributed to the shift in the predominant serogroups. For example, data from Italy [32], Canada [33] and Germany [34] showed that following the introduction of paediatric meningococcal C vaccination, serogroup C cases in children declined, whilst the median age of those affected by serogroup C increased. For example, in Canada, the median age of cases increased from 16 years in 2003 to 42 years in 2006 [33]. There was also an increased proportion of IMD cases caused by serogroup Y (Germany and Canada) [33, 34] and serogroup B and Y (Italy) [32]. Studies in Australia have also suggested that following the introduction of childhood vaccination against serogroup C, the proportion of notified cases in those aged > 65 years increased [35], whilst studies in the European Union (EU)/European Economic Area (EEA) [36] and Italy [37] also suggested that cases in older adults have increased. Taken together, this would suggest a need to utilise multivalent vaccines and increase vaccine coverage beyond paediatric age groups to counteract these trends.

These epidemiological shifts to older adults have also highlighted the need for further investigation and extension of active surveillance systems (e.g. to include a broader age population than those who are currently covered by national immunisation programs) to accurately assess the changing epidemiology of IMD, and to inform priorities for national health care systems and any associated future vaccination programmes [36‐39]. There is an acknowledgement that such data are currently lacking [40].

To date, limited attention has been given to older adults. As such, there is a lack of awareness of the disease in this age group among healthcare professionals, and older adults are not generally considered for immunisation against meningitis. The objective of our review was to assess the published data on the epidemiology of IMD in older adults (generally those aged ≥ 56 years) in North America and Europe to examine how this has changed over time, the impact it has had in terms of clinical burden and mortality, and the extent of currently available data. Such information would assist recommending bodies at national and international levels in developing future public health programmes for preventing IMD.

A search was undertaken on 11 August 2020 across three databases: EMBASE, Medline and BIOSIS. The search used MeSH, EMTREE and free text terms as applicable to the databases. Citations were limited to those in English language, in human subjects and published since 1 January 2009. A simplified version of the search strategy is shown in Supplementary Table S1. Papers were included if they met the following criteria: full paper written in the English language (not just the abstract); included patients aged ≥ 56 years; was published after 1 January 2009 but before 11 August 2020; and included patients with either suspected or confirmed IMD or infection with N. meningitidis in North America or Europe. Case studies/reports/series were eligible for inclusion if they included persons in the age range of interest. Animal studies, non-English language articles and letters to editors were excluded. Review papers were checked to see if they reported primary data or included studies not captured by the database searches, in which case the original papers were ordered and considered for inclusion.

Three authors (KE, SG and PO) assessed the studies independently and discussed any papers for which there were disagreements as to their potential inclusion or exclusion. Data from studies which met the inclusion criteria were then entered into Microsoft Excel. Because the potential studies did not involve standardised study designs and the interventions and comparators were not relevant, only participant data and outcomes data were entered. Because the studies covered a wide range of countries and time periods and used various different methods to determine levels of IMD infection, it was felt that any attempt to combine studies in a formal meta-analysis would not be appropriate; therefore, the data extracted from the studies are discussed in a narrative format.

Additionally, the websites of the following international and national organisations and societies were also searched for relevant data on IMD in the age groups of interest: World Health Organization (WHO); European Centre for Disease Prevention and Control (ECDC); US Centers for Disease Control and Prevention (CDC); Active Bacterial Core Surveillance (ABCs); Emerging Infections Program Network; MenAfriNet; National Foundation for Infectious Diseases; Health Protection Scotland (HPS); Public Health England (PHE); National Institute for Health and Care Excellence (NICE); Institut Pasteur; Robert Koch Institut; Meningitis Research Foundation (MRF) & Meningitis Progress Tracker; Confederation of Meningitis Organisations (CoMO); Meningitis Now; Global Meningitis Genome Library; Infectious Diseases Society of America (IDSA); European Society of Clinical Microbiology and Infectious Diseases (ESCMID); International Society for Infectious Diseases (ISID); American Society for Microbiology (ASM); and European Society for Paediatric Infectious Diseases (ESPID).

There were 5,351 citations identified. Following initial review, 505 papers (9% of the original search) plus 13 identified by searching the reference lists of these papers were obtained for full assessment. Following discussion among the authors, a total of 76 papers were included in this review. The reasons for exclusion are summarized in Fig. 1. Data extracted from each study/website was categorised within three headings, as containing data on epidemiology, atypical presentation or clinical burden of IMD (some contained data in multiple categories). Summary information on the published studies included (not including data taken from websites) can be found in Table 1. Publications we identified, which reported data from national or international organisations (e.g. CDC or ECDC), were not included in Table 1 if the organisation’s website provided more recent data which we have then presented below.

This comprehensive literature review found evidence that IMD in older adults (those aged ≥ 55 years of age) is mainly caused by serogroups W and Y, which are generally not the predominant circulating strains in any given country or region, and older adults generally have higher CFRs than other age groups (likely linked to underlying comorbidities). Older adults also appear to be more likely to present with atypical symptoms. In addition, there appears to be a shift in IMD prevalence from younger to older people, attributed in part to the success of vaccination programmes against meningitis C in infants and adolescents, but this may also be linked to other factors such as waning immunity amongst those previously vaccinated or immune senescence as a result of aging. Our results are consistent with previous studies which have shown similar trends over time in the epidemiology and clinical presentation of IMD; for example, the link between atypical clinical presentation and higher CFRs [23, 47, 59, 78, 89]. A recent meta analysis of the CFR for laboratory-confirmed IMD cases reported a CFR of 9.0% in infants, which gradually decreased to 7.0% in 7-year olds, subsequently increased to 15.0% in young adults (aged < 28 years), stabilised between 15 and 20% in mid-aged adults and reached a high in older adults [90]. Similar links between age and higher mortality have also previously been reported [4].

There is likely considerable underreporting of IMD cases worldwide. The MRF [83] noted that because meningitis deaths are based on national death registration rather than national surveillance estimates and that because 97% of cases occur in countries with either no or low quality data recording systems, the number of deaths would be substantially underestimated (although it should be noted this comment applies to meningitis in general and not that caused solely by Neisseria menigitidis). Improved surveillance systems could help improve disease monitoring. The Global Burden of Disease Study showed that six of the ten countries with the highest number of meningitis deaths (all-causes) are in the African meningitis belt region; though data for older adults from these countries are lacking, suggesting a potential underreporting of cases in older adults in this region [41, 91, 92]. Since we restricted our search to English langauge papers only we decided to exclude date from outside North American and Europe but it is interesting to note that we identified only eleven English language published studies of IMD in older adults from countries outside Europe or North America, which appers to be consistent with previous research highlighting the lack of regional data, particularly from South-East Asia and the Eastern Mediterranean [3] in non-native languages. It is also interesting to note that some of the data from these studies was consistent with the findings from Europe and North America with respect to serology and the shift in the incidence to older age groups [93, 94]. In addition, many of the publications identified in this review, despite having patients in the age group of interest, did not present data on clinical presentation and/or serogroups by age (and indeed when they did present these data, they tended to focus specifically on younger adults) or they presented all meningitis cases together without distinction by pathogenic cause [51, 95‐100].

There is evidence to suggest that some risk groups are underrepresented in this review. It is worth noting that IMD cases in MSM are reported as a specific category within the CDC data, and multiple studies in this group have previously been published [101, 102]. There is evidence that younger men are more willing to be vaccinated than older men[103]. However, only a single study in this group was identified in the literature review and only one patient fell within the age range of interest, suggesting the predominant focus is possibly on younger men [45]. It also surprising that, with the exception of two case reports [77], there were no studies examining older adults living in nursing or residential care homes, where one might suspect that close contact between individuals could potentially lead to an increase in transmission of infectious diseases such as IMD.

Of note, the high CFRs observed in older adults in studies included in this review, up to 34% [104], are consistent with those reported in a recent meta-analysis of laboratory-confirmed IMD. In addition, the meta-analysis also showed that CFRs generally increased with age and were highest in the oldest age groups [90]. As such, older adults represent an unmet need for meningococcal vaccination because, as noted by Trezikowski de Lima et al. [105] “given the increasing proportion of older people in the population and the high CFR of meningococcal disease in the elderly, it would be interesting to evaluate the insertion of these vaccines in the immunization programs for this age group…also, vaccines can generate other benefits, e.g. lower overall cost of healthcare”.

The strengths of this study were that it included a comprehensive literature review and grey literature search to supplement the data derived from publications. However, there was relatively little information on IMD in older adults, and the difficulties of interpreting the results were compounded by the inconsistent reporting by age group, or where demographic breakdown of a study population was presented in detail the subsequent results (e.g. epidemiology, clinical presentations) were only presented for the cohort as a whole. The issue is further complicated by the lack of standardised case definitions, changes to national immunisation programmes over time and the varying surveillance and laboratory techniques employed worldwide, as commonly acknowledged [106, 107]. As such, there remains the need for more specific age-related studies and improvements in consistency of reporting across all age groups, including older adults [108, 109].

It should also be noted that the data presented here predate the severe acute respiratory syndrome coronavirus 2 pandemic and the introduction of coronavirus disease 2019 (COVID-19) control measures; social distancing and shielding appear to have led to a decrease in recorded cases of IMD in some countries [110]. However, IMD cases that were associated with respiratory presentations of which some corresponded to suspected COVID-19 appeared to increase in 2020 compared with 2018 (P = 0.029) and 2019 (P = 0.002) and involved the elderly and with unusual isolates [111]. Moreover, IMD concomitant with COVID-19 may be associated with poorer outcomes in the elderly, because the prognosis of either disease is usually worse in this age group, though definitive data are lacking. Nonetheless, IMD burden would likely return to previous levels once on-going COVID-19 measures are relaxed, and as such continued surveillance for meningococcal and invasive bacterial infections will also be important as the pandemic progresses. The authors of the latter study [111] concluded that surveillance of IMD should be improved and vaccination against meningococcal disease in older adults should be considered (currently only Italy suggests adopting a lifelong approach to vaccination, with regular immunisation being offered to adults in the future) [112].

This comprehensive literature review, supplemented by data from national organisations, institutions and societies provides evidence that older adults (those aged ≥ 55 years) with IMD are mainly affected by serogroups W and Y, which are generally not the predominant strains in circulation in any country. Older adults have the highest CFRs, probably linked to underlying comorbidities and more atypical presentations hindering appropriate timely diagnosis and management. In addition, there has been a shift in the incidence of IMD from younger to older adults, which may be attributed to the success of meningococcal vaccination programmes, although the exact scale of this shift is difficult to quantify. Future research should evaluate the alternative options of either implementating adolescent vaccination programmes with conjugate vaccines in some countries that may lead to indirect protection in older adults or te use of meningococcal vaccines that include coverage against serogroups W and Y in immunization programs for older adults to help inform health authorities’ decisions of the benefits of vaccination and the utility of expanding national immunization programmes to extend protection to older adults.