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Evidence review for factors associated with recurrent meningococcal disease
Evidence review J2
NICE Guideline, No. 240
Factors associated with an increased risk of recurrent meningococcal disease
Review question
What factors (individually or in combination) are associated with an increased risk of recurrent 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. Recurrent meningococcal disease is exceptionally rare but may indicate an underlying disorder predisposing to the infection.
The aim of this review is to determine what additional investigations should be performed in people who develop recurrent meningococcal disease.
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
Two studies were included for this review (D’Amelio 1992, Zimran 1987); both retrospective cohort studies reporting on complement deficiency as a prognostic factor for recurrent meningococcal disease in babies, children and adults combined.
The included studies are summarised in Table 2.
Studies with univariate analyses were included as no studies with multivariate analyses were identified.
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 and the forest plot 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 in some of the domains of the QUIPs checklist and imprecision due to a very low number of events.
It was not possible to stratify the evidence by the groups outlined in the protocol.
The evidence showed that the presence of complement deficiency was strongly associated with an increased risk of recurrent meningococcal disease in babies, children and adults combined.
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. See the literature search strategy in appendix B and economic study selection flow chart in appendix G.
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 topic was an epidemiological review which does not involve a comparison of competing courses of action.
The committee’s discussion and interpretation of the evidence
The outcomes that matter most
This review aimed to identify risk factors for recurrent meningococcal disease; therefore, risk ratios and odds ratios for recurrence of meningococcal disease were selected as the critical outcomes. No other outcomes were included.
The quality of the evidence
The quality of the evidence was assessed using GRADE methodology. The evidence for the outcome identified in this review was rated as very low quality and the reasons for downgrading the evidence were risk of bias (arising from study participation, measurement of the outcome, and failure to adjust for confounding factors) and imprecision due to a very low number of events.
Evidence was found for 1 prognostic factor only, complement deficiency.
Benefits and harms
The committee considered the evidence for factors associated with an increased risk of recurrent meningococcal disease and noted that evidence was only identified for a single prognostic factor and the quality of the evidence was very low. The committee made recommendations based on the best available evidence and their clinical knowledge and experience. Because meningococcal disease is very rare in neonates the protocol for this evidence review did not include neonates. However, based on their clinical knowledge and experience, the committee agreed that the recommendations about recurrent meningococcal disease that applied to babies (aged 28 days to 1 year) would also apply to neonates.
The evidence reviewed showed a strong association between presence of complement deficiency and an increased risk of recurrent meningococcal disease in babies, children and adults combined. Based on this evidence, and their clinical knowledge and experience, the committee recommended that congenital complement deficiency or acquired inhibition should be considered as a risk factor for recurrent meningococcal disease. Based on their experience, the committee also agreed that other reasons for primary or secondary immunodeficiency, such as HIV and splenectomy or splenic dysfunction, would increase susceptibility to infection more broadly and would therefore also be associated with an increased risk of recurrent meningococcal disease.
Based on the evidence reviewed that showed that an increased risk of recurrent meningococcal disease was associated with complement deficiency, and the consensus clinical opinion of the committee, it was recommended that a detailed drug history should be taken, because immunomodulatory drugs such as eculizumab may suppress the immune system and increase susceptibility to infections caused by Neisseria meningitidis (Joint Formulary Committee 2022).
The committee acknowledged the limited evidence base identified for this review and made recommendations based on their clinical knowledge and experience. The committee discussed including a recommendation for further research given that evidence was only identified for 1 prognostic factor. However, they agreed that this was not appropriate because the prognostic factors of interest and recurrent meningococcal disease are both sufficiently rare that very large sample sizes would be required to give reliable results, and it would be difficult to recruit large numbers as people with known immunodeficiency would receive interventions to prevent recurrent infections such that future episodes rarely occur.
The committee agreed it was important to make recommendations about the actions that should be taken following both a first episode and a recurrent episode of meningococcal disease. The committee agreed that it was necessary to recommend actions that should be taken after a first episode to identify people at risk of a future episode so that interventions can be initiated early with the aim of preventing future episodes, rather than waiting for a second, potentially preventable, episode to occur. However, there were some differences in the actions recommended following first and recurrent episodes, as they agreed that the likelihood of factors that increase susceptibility to infection being present would be greater in those that have already had a recurrent episode compared with those who have had a single episode.
People with a first episode of meningococcal disease
The committee were aware, based on their knowledge and experience that the risk of infections is higher in people with HIV. For example, they were aware of evidence that the risk of invasive meningococcal disease (Simmons 2015) is higher in people with HIV compared with people who are HIV negative. The committee discussed that it is common practice to offer a HIV test to adults with a serious infection, so recommended this should be done following a first episode of meningococcal disease. However, the committee agreed they would be less likely to suspect HIV in babies and children due, in part, to behaviours that increase risk of HIV being uncommon in these age groups. Therefore, routine HIV testing in babies and children with a first episode of meningococcal disease was not recommended, but the committee agreed it should be considered where there are signs of immunodeficiency and risk factors for HIV, such as being from a country with a high rate of HIV infection (NICE 2016). The committee agreed that signs of immunodeficiency alone would be more likely to indicate primary immunodeficiency than presence of HIV in babies and children. The committee did not include neonates in this recommendation as they were not aware of any link between HIV and neonatal meningococcal disease.
The committee recommended that in addition to a drug history (discussed above), an immunisation history should be taken. They agreed taking an immunisation history was important to identify both people who have not had routine vaccinations for Neisseria meningitidis, in which vaccination uptake may help prevent future occurrences, and people who may have not responded to vaccination, indicating possible immunodeficiency as discussed above.
People with a recurrent episode of meningococcal disease
The committee agreed that people with recurrent meningococcal disease should be reviewed by appropriate immunology and infection specialists (paediatric immunology and infectious disease specialist for babies and children, and adult infection specialist or immunologist for adults) to seek advice on treating the current episode and to identify what action is needed to reduce the risk of further recurrence. They could not make recommendations about what further investigations or interventions would be needed as the accuracy of investigations for identifying immunodeficiency, or the effectiveness of interventions to reduce recurrence, were not reviewed as part of this guideline. However, they discussed that the further action would be guided by the specialist and would likely involve investigations for primary and secondary immunodeficiency, and consideration of vaccinations and other interventions to manage the risk associated with any identified immunodeficiency. They agreed it was necessary to specify the roles involved based on their experience that sometimes people are incorrectly referred to immunological laboratories which can cause delays.
Several of the recommendations the committee made regarding recurrent meningococcal disease were the same as or similar to those made following a single episode. The committee agreed that a detailed immunisation and drug history should be taken, and adults should be offered a HIV test, as per the recommendations above. However, they agreed that a HIV test should also be offered to babies and children with recurrent meningococcal disease, in the absence of additional risk factors for HIV due to the increased likelihood of there being an underlying immunodeficiency in people with recurrent meningococcal disease discussed above.
Cost effectiveness and resource use
This review question was not prioritised for economic analysis and therefore the committee made a qualitative assessment of the likely cost-effectiveness of their recommendations. The committee noted that recurrent meningococcal disease was rare. Further, the recommendations do not fundamentally change current practice and no significant resource impact to the NHS is anticipated.
The committee considered that highlighting risk factors associated with recurrent meningococcal disease would promote awareness which in turn would facilitate more timely, appropriate, and cost-effective management. The committee considered that their management recommendations for recurrent meningococcal disease were generally low cost and likely to be cost-effective given the anticipated benefits of such measures.
Recommendations supported by this evidence review
This evidence review supports recommendations 1.10.1 to 1.10.2, 1.10.5, 1.14.2 to 1.14.4 and 1.14.7. Other evidence supporting these recommendations can be found in the evidence review on factors associated with recurrent bacterial meningitis (see evidence review J1).
References – included studies
D’Amelio 1992
D’Amelio, R, Agostoni, A, Biselli, R, Brai, M, Caruso, G, Cicardi, M, et al. Complement deficiency and antibody profile in survivors of meningococcal meningitis due to common serogroups in Italy. Scandinavian Journal of Immunology 35(5):589–95 1992 [PubMed: 1579859]Zimran 1987
Zimran, A, Rudensky, B, Kramer, M. R, Tedesco, F, Ehrenfeld, M, Raz, et al. Hereditary complement deficiency in survivors of meningococcal disease: high prevalence of C7/C8 deficiency in Sephardic (Moroccan) Jews. Quarterly Journal of Medicine 63(240):349–58, 1987 [PubMed: 3685247]Joint Formulary Committee 2022
Joint Formulary Committee. British National Formulary (online). London: BMJ Group and Pharmaceutical Press. Available at: http://www.medicinescomplete.com [Accessed 04/04/2022] NICE 2016
National Institute for Health and Care Excellence (2016). HIV testing: increasing uptake among people who may have undiagnosed HIV. Available at: https://www.nice.org.uk/guidance/ng60 [Accessed 08/08/2022] Simmons 2015
Simmons RD, Kirwan P, Beebeejaun K, Riordan A, Borrow R, Ramsay ME, Delpech V, Lattimore S, Ladhani S. Risk of invasive meningococcal disease in children and adults with HIV in England: a population-based cohort study. BMC Medicine 13:1–9, 2015 [PMC free article: PMC4674945] [PubMed: 26654248]
Prognostic
Economic
No studies were identified which were applicable to this review question.
Other
Appendices
Appendix A. Review protocol
Appendix B. Literature search strategies
Appendix C. Prognostic evidence study selection
Appendix D. Evidence tables
Appendix E. Forest plots
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Appendix H. Economic evidence tables
Economic evidence tables for review question: What factors (individually or in combination) are associated with an increased risk of recurrent meningococcal disease?
No evidence was identified which was applicable to this review question.
Appendix I. Economic model
Economic model for review question: What factors (individually or in combination) are associated with an increased risk of recurrent meningococcal disease?
No economic analysis was conducted for this review question.
Appendix J. Excluded studies
Excluded studies for review question: What factors (individually or in combination) are associated with an increased risk of recurrent meningococcal disease?
Excluded prognostic studies
The excluded studies table only lists the studies that were considered and then excluded at the full-text stage for this review (N=8) and not studies (N=94) that were considered and then excluded from the search at the full-text stage as per the PRISMA diagram in Appendix C for the other review question in the same search.
Table 6Excluded studies and reasons for their exclusion
| Study | Reason for exclusion |
|---|---|
| Cabellos, C, Pelegrin, I, Benavent, E et al. (2019) Impact of pre-hospital antibiotic therapy on mortality in invasive meningococcal disease: a propensity score study. European Journal of Clinical Microbiology and Infectious Diseases 38(9): 1671–1676 [PubMed: 31140070] | No outcomes of interest for review |
| Cooke, R. P. D; Zafar, M; Haeney, M. R. (1987) Recurrent meningococcal meningitis associated with deficiencies of C8 and anti-meningococcal antibody. Journal of Clinical and Laboratory Immunology 23(1): 53–56 [PubMed: 3112405] | Study design not of interest for review [case report] |
| Hongeng, S, Wilimas, J. A, Harris, S et al. (1997) Recurrent Streptococcus pneumoniae sepsis in children with sickle cell disease. Journal of Pediatrics 130(5): 814–6 [PubMed: 9152293] | No outcomes of interest for review |
| Krone, M, Lam, T. T, Claus, H et al. (2020) Recurrent invasive meningococcal infections - quantifying the risk, Germany, 2002 to 2018. Euro Surveillance: Bulletin Europeen sur les Maladies Transmissibles = European Communicable Disease BulletinEuro Surveill 25(25): 6 [PMC free article: PMC7331141] [PubMed: 32613936] | No outcomes of interest for review |
| Kuijpers, T. W, Nguyen, M, Hopman, C. T et al. (2010) Complement factor 7 gene mutations in relation to meningococcal infection and clinical recurrence of meningococcal disease. Molecular Immunology 47(4): 671–7 [PubMed: 19931914] | No outcomes of interest for review |
| Platonov, A. E, Kuijper, E. J, Vershinina, I. V et al. (1998) Meningococcal disease and polymorphism of FcgammaRIIa (CD32) in late complement component-deficient individuals. Clinical & Experimental ImmunologyClin Exp Immunol 111(1): 97–101 [PMC free article: PMC1904866] [PubMed: 9472667] | Comparison not of interest for review [compares the distributions of IIa-R131 and IIa-H131 allotypes in participants with late complement component-deficiency and meningococcal disease] |
| Retchless, A. C, Kretz, C. B, Rodriguez-Rivera, L. D et al. (2020) Oropharyngeal microbiome of a college population following a meningococcal disease outbreak. Scientific ReportsSci 10(1): 632 [PMC free article: PMC6971049] [PubMed: 31959912] | Study design not of interest for review [cross-sectional] |
| Ronne, T., Lind, I., Buhl, L.H (1986) Recurrent localized outbreaks of group C meningococcal disease and selective vaccination programmes. International Journal of General and Molecular Microbiology; vol. 52 (no. 3); 221–222 | Study design not of interest for review [a short description of 3 group C meningococcal disease outbreaks in the Randers area, The Netherlands] |
Excluded economic studies
No economic evidence was identified for this review.
Appendix K. Research recommendations – full details
Research recommendations for review question: What factors (individually or in combination) are associated with an increased risk of recurrent meningococcal disease?
No research recommendation was made for this review.
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 recurrent 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 |
| Comparison | Absence of risk factor(s) |
| Outcome |
Critical
Important None |
Table 2Summary of included studies
| Study | Population | Prognostic factor | Outcomes | Comments |
|---|---|---|---|---|
|
Retrospective cohort study Italy |
N=59, n=6 with recurrent meningococcal disease Individuals with =>1 episode of meningococcal infection(s) Those with normal complement activity (n=49):
|
|
| No multivariate analysis |
|
Retrospective cohort study Israel |
N=110, n=8 with recurrent meningococcal disease Patients with meningococcal meningitis or bacteraemia Those with complement deficiency (n=10):
|
|
| No multivariate analysis |
Final
Evidence review underpinning recommendations 1.10.1 to 1.10.2, 1.10.5, 1.14.2 to 1.14.4 and 1.14.7 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.