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Evidence review for risk factors associated with meningococcal disease
Evidence review A4
NICE Guideline, No. 240
Risk factors associated with meningococcal disease
Review question
What factors are associated with an increased risk of meningococcal disease?
Introduction
Meningococcal disease (meningococcal sepsis with or without an associated meningitis) is a rare but serious infection, which can occur in any age group. Meningococcal disease is a life-threatening medical emergency, which may progress with devastating speed. Early recognition of the condition requires a high index of suspicion.
The diagnosis of meningococcal disease is frequently hindered by the non-specific nature of the early symptoms and signs, which may mimic those found in other serious conditions or milder viral illnesses.
The aim of this review is to evaluate the factors that are associated with an increased risk of meningococcal disease, which healthcare professionals may take into consideration when initially assessing a patient.
Summary of the protocol
See Table 1 for a summary of the Population, Prognostic factors, Comparison and Outcome characteristics of this review.
For further details see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
Prognostic evidence
Included studies
Although there are population-level factors that may be associated with meningococcal disease (for example, socioeconomic factors, age, winter season), this review focuses on risk factors that might be associated with an increased risk of meningococcal disease at an individual level.
Four studies were included for this review, 1 prospective cross-sectional study (Waterfield 2021), 1 prospective matched cohort study (Tully 2006), and 2 retrospective cohort studies (Mandal 2017, Yusuf 1999). Limited prospective studies and multivariate analyses were identified, so retrospective studies and univariate analyses were included.
The included studies for the prognostic evidence review are summarised in Table 2.
Two studies included babies and children (Yusuf 1999, Waterfield 2021), 1 study included adolescents aged between 15 and 19 years (Tully 2006), 1 study included adults aged 18 to 19 years (Mandal 2017).
Risk factors for meningococcal disease reported by the papers could be categorised as: demographic (Mandal 2017, Tully 2006), biological/clinical (Tully 2006, Waterfield 2021, Yusuf 1999), maternal and perinatal (Tully 2006, Yusuf 1999), and health behaviour and social (Tully 2006). All studies compared these risk factors for meningococcal disease relative to a no meningococcal disease control group (without further specification).
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
Studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.
Summary of included studies
Summaries of the studies that were included in this review are presented in Table 2.
See the full evidence tables in appendix D. No meta-analysis was conducted (and so there are no forest plots in appendix E).
Summary of the evidence
This section is a narrative summary of the findings of the review, as presented in the GRADE tables in appendix F. For details of the committee's confidence in the evidence and how this affected recommendations, see The committee’s discussion and interpretation of the evidence.
The evidence was assessed as being very low quality due to high or moderate risk of bias across several domains (for example, bias arising from the reliance on self-report and recall for some risk factors, a lack of clear specification of methods of measurement for the risk factors, and no or limited control for confounding factors), and imprecision due to a very low number of events. See the GRADE tables in appendix F for the certainty of the evidence for each individual outcome.
No meta-analyses were conducted for any of the risk factors due to insufficient evidence after stratifying for age. It was not possible to stratify by the population that did not receive a diagnosis of meningococcal disease (the control group), as all studies compared risk factors for meningococcal disease relative to a no meningococcal disease control group (without further specification).
Risk factors for meningococcal disease in babies and children
There was no evidence of an increased risk of meningococcal disease in babies and children in the evidence reviewed, due to missing vaccines (vaccines not up to date for age, did not receive the meningococcal B vaccine, or did not receive the meningococcal C vaccine), any abnormal condition as a newborn, low birth weight, or pre-term birth. However, as the findings were seriously or very seriously imprecise for all these risk factors, they should not be taken as definitive evidence of a lack of association.
There was some evidence showing a strong association between maternal smoking during pregnancy and a diagnosis of meningococcal disease in babies and children (estimate adjusted for mother's age, ethnicity, receipt of medicaid, marital status, and education).
Risk factors for meningococcal disease in adolescents (15-19 years)
There was no evidence of an increased risk of meningococcal disease in adolescents in the evidence reviewed, due to being a university student, recent infection with Epstein-Barr virus, deficiency in mannose-binding lectin, infection with influenza A H3N2 or H1N1 subtype or influenza B during the past year, being a regular smoker, passive smoke exposure, the consumption of any alcohol in the 2 weeks prior to diagnosis or interview, or living in dormitory accommodation. However, as the findings were seriously or very seriously imprecise for all these risk factors, they should not be taken as definitive evidence of a lack of association.
There was some evidence showing a strong association between preceding/prodromal illness in the 2 weeks before diagnosis or interview and a diagnosis of meningococcal disease in adolescents (estimate adjusted for socioeconomic status and seasonality of meningococcal disease).
There was some evidence that receiving the meningococcal serogroup C vaccine reduced the risk of a diagnosis of meningococcal disease in adolescents (estimate adjusted for socioeconomic status and seasonality of meningococcal disease).
Pre-term birth showed a strong association with a diagnosis of meningococcal disease in adolescents (estimate adjusted for socioeconomic status and seasonality of meningococcal disease).
There was some evidence showing a moderate association between regular consumption of illegal drugs and a diagnosis of meningococcal disease in adolescents. The association between attending a bar or party (in the 2 weeks prior to diagnosis or interview) and a diagnosis of meningococcal disease was not statistically significant but only just crossed the line of no effect.
There was some evidence showing a strong association between multiple intimate kissing contacts and a diagnosis of meningococcal disease in adolescents (estimate adjusted for socioeconomic status and seasonality of meningococcal disease), and a moderate association for sharing a bedroom.
Risk factors for meningococcal disease in adults (18-19 years)
There was some evidence showing a strong association between being a university student and a diagnosis of meningococcal disease in adults (aged 18 to 19 years).
See appendix F for full GRADE tables.
Economic evidence
Included studies
A single economic search was undertaken for all topics included in the scope of this guideline, but no economic studies were identified which were applicable to this review question.
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation. This was because this review does not involve a comparison of competing courses of action.
The committee’s discussion and interpretation of the evidence
The outcomes that matter most
As the objective of this review was to identify factors that are associated with an increased risk of meningococcal disease to aid recognition, diagnosis of meningococcal disease was the only outcome included for this review.
The quality of the evidence
The quality of the evidence was assessed using GRADE methodology. The evidence was very low quality and the reasons for downgrading were risk of bias (arising from issues with measurement of the prognostic factor and failure to adjust for confounding factors) and imprecision due to a very low number of events.
Evidence was found for demographic, biological/clinical, maternal and perinatal, and health behaviour and social risk factors.
Benefits and harms
The committee acknowledged that the evidence was limited and very low quality. The committee discussed the evidence identified for this review and made recommendations based on this evidence and on their clinical knowledge and experience.
There was evidence showing that receiving the meningococcal serogroup C vaccine reduced the risk of a diagnosis of meningococcal disease in adolescents. The committee noted that in the evidence reviewed, missing vaccines was not significantly associated with an increased risk of meningococcal disease for babies and children. However, the findings were seriously imprecise with very low numbers of babies and children who had not received relevant vaccinations (around 1% event rates), and this should not be taken as definitive evidence of absence of association. The committee agreed that although the evidence reviewed for vaccinations was limited, drawing on their clinical knowledge and experience, it was important to consider receipt of meningococcal vaccinations as part of assessing the risk of meningococcal disease and included this in the recommendation.
There was evidence showing a strong association between being a university student and a diagnosis of meningococcal disease in adults (aged 18 to 19 years). Increased risk of meningococcal disease was also associated with multiple kissing contacts, sharing a bedroom, and regular consumption of illegal drugs. The committee agreed that it was important that healthcare professionals be on heightened alert to the possibility of meningococcal disease in people who are students in further or higher education particularly those in halls of residence or other large shared accommodations. The committee noted that risk would also increase for those in close contact with people with meningococcal disease outside of the educational setting, and included in the recommendation that healthcare professionals should ascertain whether close contact with an infected person or presence in an area with an outbreak of meningococcal disease had occurred and factor this into the assessment.
Based on their clinical knowledge and experience, the committee agreed that there are certain groups of people, particularly those that have complement deficiency or inhibition, or splenectomy or splenic dysfunction, who might be more at risk of developing meningococcal disease. The committee discussed family history of meningococcal disease as a potential indicator of immune deficiency given that most deficiency syndromes (including complement deficiency) are inherited. The committee also highlighted that a previous episode of meningococcal disease may suggest potential immunodeficiency and make people more susceptible to another episode. Based on clinical consensus, the committee recommended that healthcare professionals should be on heightened alert to the possibility of meningococcal disease in people with these risk factors. The recommendations also direct people who have had a previous episode of meningococcal disease to consider risk factors for recurrent meningococcal disease (based on Evidence review J2).
Evidence showed an association between preceding/prodromal illness in the 2 weeks before diagnosis or interview and a diagnosis of meningococcal disease in adolescents. The committee noted that this risk factor was not clearly specified and could include heterogeneous conditions and symptoms. The committee agreed not to include this in the recommendations about risk factors for meningococcal disease but noted that early signs or symptoms should be captured by Evidence review A3 (signs and symptoms of meningococcal disease).
The committee discussed evidence showing an increased risk of meningococcal disease associated with pre-term birth and maternal smoking during pregnancy, but agreed not to include these risk factors as they are not specific to meningococcal disease, and they did not want to detract attention from risk factors that may be more useful in terms of aiding recognition.
Cost effectiveness and resource use
This review question did not consider decisions between competing alternatives and therefore is not directly relevant to the tools of economic evaluation. The recommendations primarily provide advice to health care professionals on the recognition and diagnosis of meningococcal disease rather than specific courses of action. However, the committee considered that early and correct identification of meningococcal disease was a prerequisite of cost-effective management. They also reflected that the recommendations largely reinforce current best practice and knowledge and therefore they did not believe they would have a significant resource impact.
Recommendations supported by this evidence review
This evidence review supports recommendation 1.1.14 and 1.1.15.
References - included studies
Mandal 2017
Mandal S., Campbell H., Ribeiro S., Gray S., Carr T., White J., Ladhani S. N., Ramsay M. E., Risk of invasive meningococcal disease in university students in England and optimal strategies for protection using MenACWY vaccine, Vaccine, 35, 5814–5818, 2017 [PubMed: 28928076]Tully 2006
Tully J., Viner R. M., Coen P.G., Stuart J. M., Zambon M., Peckham C., Booth C., Klein N., Kaczmarski E., Booy R., Risk and protective factors for meningococcal disease in adolescents: matched cohort study, BMJ, 332, 445–450, 2006 [PMC free article: PMC1382533] [PubMed: 16473859]Waterfield 2021
Waterfield T., Maney J. A., Fairley D., Lyttle M. D., McKenna J. P., Roland D., Corr M., McFetridge L., Mitchell H., Woolfall K., Lynn F., Patenall B., Shields M. D., Validating clinical practice guidelines for the management of children with non-blanching rashes in the UK (PiC): a prospective, multicentre cohort study, The Lancet Infectious Diseases, 21, 569–577, 2021 [PubMed: 33186517]Yusuf 1999
Yusuf H. R., Rochat R. W., Baughman W. S., Gargiullo P. M., Perkins B. A., Brantley M. D., Stephens D. S., Maternal cigarette smoking and invasive meningococcal disease: a cohort study among young children in Metropolitan Atlanta, 1989–1996, American Journal of Public Health, 89, 712–717, 1999 [PMC free article: PMC1508714] [PubMed: 10224983]
Prognostic
Economic
No studies were identified which were applicable to this review question.
Appendices
Appendix A. Review protocols
Appendix B. Literature search strategies
Appendix C. Prognostic evidence study selection
Appendix D. Evidence tables
Appendix E. Forest plots
Forest plots for review question: What factors are associated with an increased risk of meningococcal disease?
No meta-analysis was conducted for this review question and so there are no forest plots.
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Study selection for: What factors are associated with an increased risk of meningococcal disease? (PDF, 71K)
Appendix H. Economic evidence tables
Economic evidence tables for review question: What factors are associated with an increased risk of meningococcal disease?
No evidence was identified which was applicable to this review question.
Appendix I. Economic model
Economic model for review question: What factors are associated with an increased risk of meningococcal disease?
No economic analysis was conducted for this review question.
Appendix J. Excluded studies
Excluded studies for review question: What factors are associated with an increased risk of meningococcal disease?
Excluded prognostic studies
Table 8Excluded studies and reasons for their exclusion
| Study | Reason |
|---|---|
| Cao S, Yang C, Gan Y et al (2015) The Health Effects of Passive Smoking: An Overview of Systematic Reviews Based on Observational Epidemiological Evidence. PLoS ONE 10(10): e0139907 [PMC free article: PMC4595077] [PubMed: 26440943] |
- Study design not of interest for review An overview of systematic reviews |
| Close R.M, Ejidokun O.O, Verlander N.Q et al (2011) Early diagnosis model for meningitis supports public health decision making. Journal of Infection 63(1): 32–38 [PubMed: 21652009] |
- Outcomes not of interest for review Data only available on age, sex, and winter season (population-level risk factors) |
| Domingo P, Muniz-Diaz E, Baraldes M. A et al (2002) Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease. American journal of medicine 112(1): 19–25 [PubMed: 11812402] |
- Study design not of interest for review Case-control study |
| Dubey Himanshu, Oster Philipp, Fazeli Mir Sohail et al (2022) Risk Factors for Contracting Invasive Meningococcal Disease and Related Mortality: A Systematic Literature Review and Meta-analysis. International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 119: 1–9 [PubMed: 35339714] | - Systematic review - included studies failed to meet inclusion criteria |
| Harrison L. H, Kreiner C. J, Shutt K. A et al (2008) Risk factors for meningococcal disease in students in grades 9–12. Pediatric Infectious Disease Journal 27(3): 193–199 [PubMed: 18277925] |
- Study design not of interest for review Case series |
| Honish L, Soskolne C.L, Senthilselvan A et al (2008) Modifiable risk factors for invasive meningococcal disease during an Edmonton, Alberta outbreak, 1999–2002. Canadian Journal of Public Health 99(1): 46–51 [PMC free article: PMC6976143] [PubMed: 18435391] |
- Study design not of interest for review Case-control study |
| Murray R. L; Britton J; Leonardi-Bee J. (2012) Second hand smoke exposure and the risk of invasive meningococcal disease in children: systematic review and meta-analysis. BMC Public Health 12: 1062 [PMC free article: PMC3534009] [PubMed: 23228219] |
- Study design not of interest for review Case-control and cohort studies included in the systematic review. Studies included in this review were assessed for potential inclusion |
| Nelson S. J, Charlett A, Orr H. J et al (2001) Risk factors for meningococcal disease in university halls of residence. Epidemiology and Infection 126(2): 211–217 [PMC free article: PMC2869685] [PubMed: 11349971] |
- Study design not of interest for review Retrospective ecological study |
| Nielsen H.E, Andersen E.A, Andersen J et al (2001) Diagnostic assessment of haemorrhagic rash and fever. Archives of Disease in Childhood 85(2): 160–165 [PMC free article: PMC1718873] [PubMed: 11466193] |
- Outcomes not of interest for review Signs and symptoms rather than risk factors for diagnosis |
| Norheim G, Sadarangani M, Omar O et al (2014) Association between population prevalence of smoking and incidence of meningococcal disease in Norway, Sweden, Denmark and the Netherlands between 1975 and 2009: a population-based time series analysis. BMJ Open 4(2): e003312 [PMC free article: PMC3927814] [PubMed: 24513866] |
- Study design not of interest for review Population based time series |
| Olcen P, Kjellander J, Danielsson D et al (1981) Epidemiology of Neisseria meningitidis: Prevalence and symptoms from the upper respiratory tract in family members to patients with meningococcal disease. Scandinavian Journal of Infectious Diseases 13(2): 105–109 [PubMed: 6797052] |
- Study design not of interest for review Neisseria meningitidis carrier rate |
| Smith I, Bjoornevik A.T, Augland I.M. B et al (2006) Variations in case fatality and fatality risk factors of meningococcal disease in Western Norway, 1985–2002. Epidemiology and Infection 134(1): 103–110 [PMC free article: PMC2870352] [PubMed: 16409656] |
- Outcomes not of interest for review Risk factors for death or sequelae with meningococcal disease |
| Spyromitrou-Xioufi P; Tsirigotaki M; Ladomenou F. (2020) Risk factors for meningococcal disease in children and adolescents: a systematic review and META-analysis. European Journal of Pediatrics 179(7): 1017–1027 [PubMed: 32405695] |
- Study design not of interest for review Majority of studies case-control. Studies included in this review were assessed for potential inclusion |
| Stephens D. S, Hajjeh R. A, Baughman W. S et al (1995) Sporadic meningococcal disease in adults: Results of a 5-year population- based study. Annals of Internal Medicine 123(12): 937–940 [PubMed: 7486489] |
- Comparison not of interest for review Comparison signs and symptoms of different serogroups |
Excluded economic studies
No studies were identified which were applicable to this review question.
Appendix K. Research recommendations - full details
Research recommendations for review question: What factors are associated with an increased risk of meningococcal disease?
No research recommendations were made for this review question.
Tables
Table 1Summary of the protocol
| Population | All adults, young people, children and babies (excluding neonates defined as aged 28 days old and younger) with suspected or confirmed meningococcal disease (excluding meningococcal meningitis alone, as this is included in the reviews on bacterial meningitis). |
| Prognostic factors | Any risk factors, alone or in combination |
| Comparator | Absence of risk factor(s) |
| Outcome |
Critical
Important None * Diagnosis of meningococcal disease must be made based on any diagnostic laboratory test for N. meningitidis. |
N. meningitidis: Neisseria meningitidis.
Table 2Summary of included studies
| Study | Population | Risk factor | Outcomes | Comments |
|---|---|---|---|---|
|
Retrospective cohort study UK |
N=1,315,630 Cases of meningococcal disease in university students were identified from HPZone (a national, web-based case management tool capturing all meningococcal cases reported to Public Health England) and matched with laboratory-confirmed cases in the national surveillance dataset for 2014/15.Student MD cases compared against non-students with denominators calculated based on English population estimates. Characteristics not reported for the included sample |
| Diagnosis of meningococcal disease |
2014/2015 epidemiological year was selected as it was prior to the emergency introduction of the MenACWY immunisation programme in August 2015. Meningococcal disease diagnosed based on positive PCR test. Only unadjusted data available. Some control for age as restricted inclusion to 2013 and 2014 school leavers |
|
Prospective matched cohort study UK |
N=288 Adolescents aged 15–19 who were admitted to the hospital with primary clinical diagnosis of meningococcal disease (including meningococcal meningitis alone) and their matched controls (recruited from GP and matched by sex and closest date of birth). Meningococcal disease (n=144): Age in years (median): 17.6 Sex: male: 74 (51%); female 70 (49%) Serogroup: n=66 (58%) serogroup B, n=43 (38%) serogroup C, n=1 (0.9%) serogroup W135, n=1 (0.9%) serogroup Y, n=3 ungroupable No meningococcal disease (n=144): Age in years (median): 17.7 Sex: male: 74 (51%); female 70 (49%) |
| Diagnosis of meningococcal disease |
Diagnosis of meningococcal disease based on culture, or detection by PCR of N. meningitidis from a normally sterile site or serodiagnosis. n=114 (79%) confirmed microbiologically by culture, PCR or serology test. No significant differences in symptoms or intensive case admission between microbiologically proved and unproved cases. Adjusted data available for factors where the difference between MD and no MD groups had a significance level of p < 0.2 in univariate analyses (having received a vaccine against serogroup C meningococci, preceding illness, intimate kissing, being a student and preterm birth). Factors adjusted for in multivariate model included socioeconomic status (defined as household ownership of car and home and based on occupation) and seasonality of MD (high season defined as ≥70 MD cases/week). Data not extracted for population-level risk factors. |
|
Prospective cross-sectional study UK |
N=1329 Children (aged under 18 years) presenting to a participating paediatric emergency department; fever (≥38°C); new-onset non-blanching rash or features suggestive of meningococcal infection Meningococcal disease (n=19): Age in months (median; interquartile range (IQR) in parentheses): 37 (9–58) Sex: male: 16 (84%); female: 3 (16%) Serogroup of N. meningitidis: B N=17 (89%); C N=1 (5%); W N=1 (5%) No meningococcal disease (n=1310): Age in months (median; interquartile range (IQR) in parentheses): 24 (12–48) Sex: male: 765 (58%); female: 545 (42%) No further details provided for those negative for meningococcal disease |
| Diagnosis of meningococcal disease |
Diagnosis based on a positive culture or PCR test for N. meningitidis or other bacterial pathogen from a sterile body site (for example, blood or CSF). No consideration of confounding factors reported. Data not extracted for population-level risk factors. |
|
Retrospective cohort study USA |
N=283291 Children 3 years or younger who were born in the Atlanta metropolitan area and identified in Georgia’s birth certificate database. Meningococcal disease (n=47): Age in years: median/mean not reported (0–3 years) Sex: male: 28 (60%); female 19 (40%) Serogroup B n=17 (36%); serogroup C n=10 (21%), serogroup Y n=5 (11%); serogroup W135 n=1 (2%); serogroup information not available for n=14 No meningococcal disease (n=283244): Age in years: median/mean not reported (0–3 years) Sex: male: 144896 (51%); female 138348 (49%) |
| Diagnosis of meningococcal disease |
Diagnosis was confirmed by the isolation of N. meningitidis in blood or CSF. Of the risk factors of interest, adjusted data only available for maternal smoking during pregnancy (estimate adjusted for mother’s age, ethnicity, receipt of medicaid, marital status, and education). No adjustment for potential confounding factors for other risk factors. Data not extracted for population-level risk factors. |
CSF: cerebrospinal fluid; GP: general practitioner; IQR: interquartile range; MD: meningococcal disease; N. meningitidis: Neisseria Meningitidis; PCR: positive polymerase chain reaction
Final
Evidence review underpinning recommendation 1.1.14 and 1.1.15 in the NICE guideline
This evidence review was developed by NICE
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.