Systematic review of invasive meningococcal disease epidemiology in the Eastern Mediterranean and North Africa region

Background Invasive meningococcal disease (IMD) represents a global health burden. However, its epidemiology in the Eastern Mediterranean (EM) and North Africa (NA) regions is currently not well understood. This review had four key objectives: to describe asymptomatic meningococcal carriage, IMD epidemiology (e.g. serogroup prevalence, case-fatality rates [CFRs]), IMD presentation and management (e.g. clinical diagnosis, antibiotic treatments) and economic impact and evaluation (including health technology assessment [HTA] recommendations) in EM and NA. Methods A systematic literature search (MEDLINE and EMBASE) was conducted (January 2000 to February 2021). Search strings included meningococcal disease and the regions/countries of interest. Identified publications were screened sequentially by title/abstract, followed by screening of the full-text article; articles were also assessed on methodological quality. Literature reviews, genetic sequencing or diagnostic accuracy studies, or other non-pertinent publication type were excluded. An additional grey literature search (non-peer-reviewed sources; start date January 2000) was conducted to the end of April 2019. Results Of the 1745 publications identified, 79 were eligible for the final analysis (n = 61 for EM and n = 19 for NA; one study was relevant to both). Asymptomatic meningococcal carriage rates were 0–33% in risk groups (e.g. military personnel, pilgrims) in EM (no data in NA). In terms of epidemiology, serogroups A, B and W were most prevalent in EM compared with serogroups B and C in NA. IMD incidence was 0–20.5/100,000 in EM and 0.1–3.75/100,000 in NA (reported by 7/15 countries in EM and 3/5 countries in NA). CFRs were heterogenous across the EM, ranging from 0 to 57.9%, but were generally lower than 50%. Limited NA data showed a CFR of 0–50%. Data were also limited in terms of IMD presentation and management, particularly relating to clinical diagnosis/antibiotic treatment. No economic evaluation or HTA studies were found. Conclusions High-risk groups remain a significant reservoir of asymptomatic meningococcal carriage. It is probable that inadequacies in national surveillance systems have contributed to the gaps identified. There is consequently a pressing need to improve national surveillance systems in order to estimate the true burden of IMD and guide appropriate prevention and control programmes in these regions. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-021-06781-6.

Dogu et al. BMC Infect Dis (2021) 21:1088 Background Neisseria meningitidis, a bacterium found exclusively in humans, poses a global health risk [1]. Infection with N. meningitidis usually results in asymptomatic carriage, in which the bacteria colonise the naso-oropharyngeal mucosa [2][3][4]. Globally, carriage prevalence varies both by region and age group [2,5]. International estimates indicate that carriage prevalence ranges from 4.5% in infants to 7.7% in children aged 10 years, peaking at 23.7% in adolescents (19 years) and decreasing to 7.8% by the age of 50 years [2,5]. It should be noted, however, that individual regions may have different carriage agedistributions [5,6]. Although the majority of N. meningitidis carriages are cleared spontaneously (i.e. without treatment), in some cases the pathogen may pass through the naso-oropharyngeal mucosa, entering the bloodstream. Persistence of N. meningitidis in the bloodstream may subsequently result in invasive meningococcal disease (IMD) [2,4].
IMD is the most severe type of meningococcal infection, with common clinical manifestations including meningitis and meningococcaemia [1]. Approximately 1.2 million IMD cases occur annually worldwide, and it is associated with a case-fatality rate (CFR) of approximately 10% [1,7]. However, the CFR may increase significantly in cases of inadequate or delayed diagnosis and treatment, and varies according to serogroup [8,9]. Atypical clinical presentation has been observed for various serogroups (e.g. acute gastrointestinal symptoms for serogroup W, primary pneumonia for serogroup Y, septic arthritis for serogroups C and W); such cases may be misdiagnosed, potentially leading to a high CFR [1,[8][9][10]. The incidence of IMD, which may occur as sporadic, endemic or epidemic infection, is influenced by various factors. These include microbial factors (e.g. virulence), host susceptibility factors (e.g. age, medical conditions) and environmental factors such as geographical location (including travel to endemic/epidemic areas), seasonal variations, and mass gatherings [1,7,[11][12][13][14]. Globally, the incidence of IMD is highest in infants and young children, with over 75% of all cases of meningococcal meningitis and meningococcaemia occurring in children aged < 5 years. However, a second, smaller peak of incidence has been observed in adolescents and young adults [1,15]. In addition, the CFR is age dependant, and is highest in older adults (aged ≥ 65 years) [16,17].
The majority of cases of IMD are caused by serogroups A, B, C, W and Y [1,7,11]. Given the unpredictability of IMD, proactive vaccination strategies are considered the best method to ensure population-wide protection [18]. Currently available vaccines provide coverage for serogroups A, B, C, W and Y; quadrivalent vaccines cover the serogroups A, C, W and Y, while mono-/bivalent vaccines are available for prevention of disease caused by serogroups A, B and C [18]. Two pentavalent vaccines (ABCWY and ACYWX) are also currently in development [19,20].
IMD is often associated with situations in which a high degree of crowding occurs, which includes events such as the Umrah and Hajj, which are mass gatherings of Muslim pilgrims in Saudi Arabia [11,14,21]. Attendance at the Hajj in particular may exceed 1 million non-resident attendees [22]. These gatherings have previously been associated with local and international outbreaks of IMD, as many pilgrims who attend Umrah/Hajj travel to Saudi Arabia from the African meningitis belt [13]. The latter is a geographical region stretching from Senegal to Ethiopia that has the highest burden of IMD in the world [6,23]. It is thought that this mass movement of pilgrims may influence the epidemiology of IMD in the Eastern Mediterranean (EM) and North Africa (NA) regions (referred to collectively as the EMNA region), allowing different serogroups to spread between regions and potentially resulting in local outbreaks of disease [24]. Despite these concerns, however, data on IMD are sparse or lacking in the EMNA region as a whole. Various surveillance systems (ranging from developed to suboptimal) are present in the African meningitis belt, Algeria, Morocco and Turkey, but few other countries in the region have established this type of infrastructure [25].
The aim of this systematic review is to describe asymptomatic meningococcal carriage, IMD epidemiology, IMD presentation and management, and economic impact and evaluation in the EMNA region.

Objectives
The key objectives of this study were to review the following in the EMNA region: (1) asymptomatic meningococcal carriage; (2) IMD epidemiology (serogroup distribution, incidence, CFRs and complications and sequelae); (3) IMD presentation and management (clinical presentation, hospitalisation, antibiotic treatment and prophylaxis/vaccination); (4) and economic impact and evaluation (including health technology assessment [HTA] recommendations).

Systematic literature search
A systematic review of the literature was performed following the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [26]. A literature search of the MEDLINE and EMBASE databases was completed with date limits of 1 January 2000 to February 2021. The search strings included English-language terms for meningococcal disease, and the regions and countries of interest.
Full details of the PRISMA checklist and the systematic review search strategy (including formulation of review questions, literature searches, selection procedure, data extraction and quality control) are included in Additional file 1. Unless otherwise specified, dates and date ranges stated in the Results section indicate the time period during which the data contained in individual publications were collected, and not the year of publication.
The original search was conducted in the Asia, Middle East and Eurasia (AMEE) region. Given the importance of meningitis in the EMNA region, we have chosen to focus solely on studies relevant to that region in this manuscript. As mass gatherings of Muslim pilgrims are a regular occurrence in the EMNA region, Eurasian countries proximal to the Middle East with a majority Muslim population (i.e. Pakistan, Turkey) were also included in the EM region. For the purposes of this review, the EMNA region was divided into two sections (EM and NA). The EM region was defined as Bahrain, Iran, Iraq, Jordan, Kuwait, Lebanon, Oman, Pakistan, Palestinian Territories, Qatar, Saudi Arabia, Syria, Turkey, United Arab Emirates, and Yemen. The NA region was defined as Algeria, Egypt, Libya, Morocco, and Tunisia.

Study screening
Details of the search strategy can be found in Additional file 1. Selection was not limited by language of the publication. Publications identified by the search were screened sequentially by title and abstract, followed by screening of the full-text article. Literature reviews, genetic sequencing or diagnostic accuracy studies, or other non-pertinent publication type were excluded. As most studies were not of a classical design suited to appraisal using existing standardised checklists, such as surveillance studies or cross-sectional studies, no checklists were used to assess the quality of the articles or to calculate a total quality score. Nevertheless, articles were assessed on their methodological quality without standardised checklists and one article was excluded because of major limitations in their design. To fill the gaps from the peer-reviewed literature, a grey literature search (i.e. hand search) was conducted in April 2019. Key websites (listed in Additional file 1) were searched using English search terms for relevant grey literature documents, conference abstracts and other data sources (including other websites) dating from January 2000 to April 2019.

Data extraction
Data on the key objectives were extracted and stratified by age group (children only [defined per study; variable age range], adults only, and children and adults), serogroup and population (general population, military, students, pilgrims, and household contacts of individuals with IMD) using a standard Excel spreadsheet. No formal assessment of publication bias was performed.

Results
The literature search identified a total of 1745 publications, of which 563 were duplicates (Fig. 1).
A total of 955 publications were excluded as they did not include data relevant to the objectives of this study, leaving 227 articles for full-text screening. An additional 48 articles were identified by hand search, and 16 articles were excluded as they were not found in full text. Following full-text screening of the remaining 259 articles, 164 articles were excluded as they did not meet the inclusion criteria (further details can be found in Fig. 1). A total of 95 articles were then considered for inclusion (i.e. included in qualitative synthesis) in the systematic literature review. Of these, 79 were relevant to the EM and NA regions; (n = 61 and n = 19 respectively, with one study spanning both regions).
Data were unavailable for objective 4 (economic impact and evaluation). Data for objectives 1-3 (asymptomatic meningococcal carriage, IMD epidemiology and IMD presentation and management, respectively) were not always available for all countries, and overall, there were fewer relevant publications identified in the NA versus the EM region (Additional file 1: Fig. S1).

Objective 1: asymptomatic meningococcal carriage
Here, we report the asymptomatic meningococcal carriage by age group (children, adults, and adults or children) in the general population or by risk group (household contact, military, pilgrim or student) in the EMNA region. Data were only available in the EM region (Table 1).
For the NA region, studies included incidence data collected between 1967 and 2018, all in the general population. IMD incidence in children only (aged between 0 and 18 years) was reported at 1.5/100,000 [64] in one study in Tunisia in 2014. Data for children and adults was available from two Egyptian studies and one Moroccan study, with incidence ranging from 0.1/100,000 [61] to 3.75/100,000 [63]. Data from the grey literature included a report from the Ministry of Health of the Kingdom of Saudi Arabia. This source reported an overall incidence of 0.02-0.03/100,000 persons in 2017, rising very slightly from 0.01 in 2013 [65]. A World Health Organization (WHO) consultation from 2001 also reported on the number of meningococcal disease cases in Saudi Arabia over time, with the number of annual cases rising from < 20 in 1995 to 253 in 2000 [66].
Four studies in the EM region provided data on CFRs in risk groups (military n = 1 [50] and pilgrims n = 3 [54,55,71]). CFR data from the military population (based in Iran) ranged from 0 to 50.0% between 2000 and 2004, [50] while data from the pilgrim population (all studies in Saudi Arabia) showed a CFR range from 0.0% [55,71] to 57.9% [71]. Data from the previously-mentioned WHO consultation reported a CFR of 27.7% among IMD cases in Saudi Arabia in 2001, with a CFR of 32.1% observed in the subset of cases associated with the Hajj [66].

Hospitalisation
Six studies in the EM region (Kuwait n = 1 [94]; Pakistan n = 1 [105]; Saudi Arabia n = 2 [53,54]; and Turkey n = 2 [97,101]) and two studies in the NA region (Egypt n = 2 [62,78]) included data on hospitalisation. In the EM region studies in children, the mean/median length of hospital stay (LOS) ranged from 9.8 [101] to 21.9 [97] days. Intensive care unit (ICU) admission was required for 30.0% of cases in Kuwait [94] and 5.4% of cases in Saudi Arabia [53], and mean ICU LOS ranged from 5.0 [53] to 7.8 days [97]. In children and adults in Saudi Arabia, 24.1% required ICU admission, with 64.7% of this group requiring ICU care for more than 1 day [54]. Studies from Egypt (in children and adults) reported that LOS was generally lower than 15 days (median LOS 10 days [78], mean LOS 14.7 days [62]).

Symptoms, complications and sequelae
Data were collected on acute symptoms, admission and acute complications, and post-discharge complications and sequelae; full information is provided in Table 3. Since outcomes were not well defined in the majority of included articles, it was not possible to provide a list of definitions for these outcomes.
Six studies from the EM region (Iran n = 2 [91,106]; Qatar n = 1 [69]; Saudi Arabia n = 1 [71]; and Turkey n = 2 [97,107]) and two studies from the NA region (Egypt n = 1 [78] and Morocco n = 1 [104]) included information on acute symptoms of meningococcal disease. Commonly observed symptoms across both regions included rash, seizure, headache, stiff neck and fever. No particular pattern was observed for symptoms or age groups. Serogroup was infrequently reported in these studies and so it was not possible to correlate serogroups with symptoms. Data on complications at admission and acute complications were available from three studies (all in children), of which two were in the EM region (Iran n = 1 [91]; Turkey n = 1 [97]), and one in the NA region (Morocco n = 1 [104]). Septic shock was reported in approximately 40% of patients in the studies from the EM region, while hemodynamic disorder/sepsis were reported in over half of patients in the study from the NA region. Data on post-discharge complications and sequelae were available from eight EM region studies (Kuwait n = 2 [93,94]; Qatar n = 2 [52,69]; Saudi Arabia n = 2 [53,71]; and Turkey n = 2 [98,99]) and two NA region studies (Egypt n = 1 [78] and Tunisia n = 1 [89]). The majority of studies in the EM region reported non-specified sequelae; there was little overlap across studies in terms of specific reported events for either region.

Antibiotic treatment
Three studies in Turkey and one in Qatar had data on antibiotic treatment; no studies were retrieved from the NA region. The Turkish studies focused on antibiotic use in children only [74,97,100], while the Qatari study included data from a mixed population of children and adults aged 0-80 years [69]. Ceftriaxone monotherapy was prescribed to 53.8 [97]-100% [100] of patients in all studies in Turkey, and in combination with vancomycin in one study (40.0% of cases) [74]. Penicillin was used by 9.8% of patients in another study [97]. In the Qatari study, ceftriaxone was prescribed in 80.0%, and penicillin in 20.0% of cases [69].

Prophylaxis or vaccination of persons in close contact
No studies in the EM or NA region reported on prophylaxis or vaccination of persons in close contact with a known case of meningococcal infection.

Discussion
This systematic review identified that high-risk groups such as military personnel, pilgrims and students remain a significant reservoir of asymptomatic meningococcal carriage in the EMNA region, with few studies specifying    [123] asymptomatic carriage by age group. In general, more studies were retrieved from the EM region compared with the NA region. Incidence of IMD in the EMNA region was poorly defined, with data only available for 7/15 countries in the EM region and 3/5 countries in the NA region. CFRs associated with IMD were heterogenous, and few data were available on CFRs in key risk groups (including household contacts, military personnel, pilgrims and students). Data were also heterogenous for complications and sequelae. Approximately one-third of patients were admitted to the ICU, and LOS was generally below 3 weeks (in hospital or in the ICU). Relatively few studies reported data on antibiotic treatment, which were reported in the EM region only. In studies that did provide data on antibiotic use, ceftriaxone was commonly used. Information on antibiotic resistance was not captured in this study. Furthermore, no studies in the EMNA region reported on prophylaxis or vaccination of persons in contact with known cases of infection, or on economic impact and evaluation. These data gaps indicate a pressing need for more studies from the region, ideally focusing on similar study outcomes for ease of comparison.
Results from a recent meta-analysis (spanning 2012-2017) indicate that N. meningitidis accounts for 9% and 36% of all bacterial meningitis cases in Eastern Mediterranean and African regions, respectively [108]. Furthermore, the burden of IMD in the Eastern Mediterranean Regional Office (EMRO) region is second highest after the African meningitis belt (bacterial meningitis is also second highest in the EMRO region compared with the African region), with several countries (where data exists) reporting moderate/high endemic rates [45,109,110]. In our review, the most comprehensive IMD incidence data were available for Saudi Arabia. There were no EM regional IMD incidence data from Bahrain, Iraq, Jordan, Lebanon, Oman, Palestinian Territories, Syria, Turkey, and the United Arab Emirates.
It is interesting to compare our findings with those from other regions. Data from various sources showed that the overall incidence of IMD was 0.  [111][112][113][114]. Incidence in the EM region in the current study ranged from 0 to 20.5/100,000 persons (based on data from seven countries). In contrast, incidence in the NA region ranged from 0.1 to 3.75/100000 persons (based on data from Egypt, Morocco and Tunisia). The incidence of IMD was highest in infants and young children in several regions (e.g. Europe, USA/Canada, Latin America) which is similar to data from EMNA presented here [112].
IMD CFRs are often high in the EMNA region with rates up to 50% reported, and many studies reporting rates between 5 and 25%. It is possible that the high CFRs observed in the EMNA region could potentially reflect inadequate or delayed treatment [1]. CFRs elsewhere vary, both by region and by age group. For example, overall CFR was 10% in Europe in 2017 and increased to 18% in cases in people aged 65 [111,114].
Globally, the IMD CFR can be higher in infants than older children, but is highest in those ≥ 65 years of age [15]. Although data on CFRs in children and adults were identified in the EM and NA regions, it is difficult to make comparisons between age groups, especially when considering heterogeneity in study design. Furthermore, given the importance of age for the epidemiology of IMD, it is notable that patients were not routinely separated by age in the studies included here.
In our study, serogroups A, B and W were common in the EM region, and the B and C serogroups were common in the NA region. This is in line with findings from a recent systematic review, which reported that N. meningitidis serogroup B is the predominant cause of IMD in various parts of Europe, North America, Latin America and the Western Pacific, while serogroups C and W were responsible for a substantial proportion of IMD cases in large parts of Africa and Latin America. It should also be noted that serogroups W, A and X were reported as causes of IMD in many countries in the African meningitis belt [115,116].
The WHO has also identified the need for awareness of meningococcal disease burden and development of surveillance systems to characterise national epidemiology in all countries [14,117]. In particular, the WHO global roadmap for defeating meningitis by 2030 recommends that all countries should design and implement a surveillance system which allows integration of public/ private healthcare and also covers key components such as epidemiology, laboratory and data management [109]. Evaluation of mass vaccine programmes in countries in the African meningitis belt is also recommended [117]. Introduction of vaccines specific to particular serogroups has previously led to a reduction in the burden associated with those serogroups in the African meningitis belt and Europe [17,112,118], illustrating that vaccination programmes may change the burden and molecular epidemiology of IMD. However, migration dynamics may also influence IMD burden and epidemiology in the EMNA region, due to the increased risk of IMD transmission during the Umrah and Hajj pilgrimages [11,13,14,20]. These dynamics render the regional situation even more complex, and provide at least a partial explanation as to why the WHO goals of increased awareness/improved surveillance systems are still far from being met in the EMNA region.
It has long been known that vaccination has important benefits in terms of protecting individuals against IMD, lowering the carriage rates of N. meningitidis in the community and providing herd protection for non-vaccinated individuals [119]. Since the 2000s, these Hajj-related outbreaks have been reduced through local vaccination programmes for pilgrims with the quadrivalent meningococcal vaccine in Saudi Arabia [13]. Saudi Arabia also now demands proof of recent meningococcal vaccination (specifying a quadrivalent vaccine [ACYW]) as a visa requirement for international pilgrims travelling to these gatherings [11,120]. However, IMD burden in the region remains high and so further action is needed.
These data highlight gaps in our current understanding of the epidemiology and disease burden of IMD in the EMNA region [24]. This situation contrasts with the much stronger IMD surveillance data available for areas such as Europe [17] and the African meningitis belt [24], and may be linked to lack of systems or resources for disease surveillance within the EMNA region. It should be noted that the general lack of effective surveillance in the EMNA region occurs even though, as in Europe, IMD is a notifiable disease. To improve surveillance in this region, the WHO has funded the Invasive Bacterial Vaccine Preventable Diseases Laboratory Network, including a regional reference laboratory in Egypt and a site laboratory in Yemen; however, other EMNA countries in this study do not appear to have laboratories associated with this network [121]. In addition, despite some EMNA countries having national surveillance networks and laboratories with the ability to serogroup IMD samples [24,115], there is still a general lack of published epidemiological studies from these countries. These findings suggest the need for a standardised global approach to IMD reporting to improve the epidemiological evidence base and address the high disease burden.
The strengths of this systematic literature review include that it was based on broad search terms and included articles in all languages and reports on data amassed over an 18-year period. Limitations include the lack of consistent data availability. In addition, the heterogeneity of the design/methodology of the selected studies and the resulting data means that it is difficult to compare outcomes across studies. As a result, the findings from this search may not reflect the true disease burden and serogroup distribution; therefore, further data on the epidemiology and disease burden of IMD in the EMNA region are needed.
In conclusion, our systematic review identifies the crucial need to increase national surveillance systems and laboratory capacity in this region in order to improve the quality of data and reporting. There is also a pressing requirement for conducting further research on the consequences and burden of meningitis and meningococcaemia. This will allow us to better understand their epidemiology and design health policies to reduce the subsequent burden on regional healthcare systems.