Evidence review for investigating and diagnosing suspected bacterial meningitis with blood and urine investigations

Evidence review for investigating and diagnosing suspected bacterial meningitis with blood and urine investigations

Meningitis (bacterial) and meningococcal disease: recognition, diagnosis and management

Evidence review B1

NICE Guideline, No. 240

London: National Institute for Health and Care Excellence (NICE); 2024 Mar.

ISBN-13: 978-1-4731-5755-2

Investigating and diagnosing suspected bacterial meningitis with blood and urine investigations

Review question

What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis?

Introduction

Bacterial meningitis is a rare but serious infection, which can occur in any age group. Early recognition of the condition requires a high index of suspicion.

Accurately diagnosing bacterial meningitis in a timely manner ensures that appropriate antibiotic therapy can be initiated, and subsequently adjusted according to the bacterial aetiology and antibiotic sensitivity results. There are a number of tests that may be used to assist in the diagnosis of bacterial meningitis. It is therefore important to determine which tests are the most accurate and cost-effective for use in clinical practice.

The aim of this review (B1) is to evaluate these tests and determine which are the most effective for the diagnosis of bacterial meningitis.

Summary of the protocol

See Table 1 for a summary of the Population, Index tests, Reference standard and Target condition characteristics of this review.

Table 1

Summary of the protocol.

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.

Diagnostic evidence

Included studies

Twenty five studies were included in this review, 15 single-gate cross-sectional diagnostic accuracy (DTA) studies (Benjamin 1984, Bonsu 2003, Borchsenius 1991, Hansson 1993, Knudsen 2007, Lembo 1991a, Lembo 1991b, Morales Casado 2016, Peltola 1982, Ray 2007, Roine 1991, Santotoribo 2018, Schwarz 2000, Tzanakaki 2015, Viallon 2011), 3 single-gate retrospective DTA studies (De Cauwer 2007, Dubos 2008, Morrissey 2017), and 7 two-gate cross-sectional DTA studies (Dagan 1998, Dubos 2006, Jereb 2001, Paradowski 1995, Park 2011, Sormunen 1999, Tatara 2000). No evidence from test and treat randomised controlled trials were identified.

The included studies are summarised in Table 2.

Two studies included babies only (Bonsu 2003, Morrissey 2017); 11 studies included babies and children (Benjamin 1984, Dagan 1998, De Cauwer 2007, Dubos 2006, Dubos 2008, Lembo 1991a, Lembo 1991b, Peltola 1982, Roine 1999, Sormunen 1999, Tatara 2000); 4 studies included children and adults (Hansson 1993, Knudsen 2007, Morales Casado 2016, Santotoribo 2018); 6 studies included adults (Jereb 2001, Paradowski 1995, Park 2017, Ray 2007, Schwarz 2000, Viallon 2011); and 2 studies did not define the age range of participants (Borchsenius 1991, Tzanakaki 2005).

Seven studies looked at the DTA of white cell count (WCC; Bonsu 2003, Borchsenius 1991, Dubos 2006, Dubos 2008, Lembo 1991a, Lembo 1991b, Sormunen 1999); 2 studies looked at the DTA for neutrophil count (Dubos 2006, Dubos 2008); 19 studies looked at the DTA of C-reactive protein (CRP; Benjamin 1984, Borchsenius 1991, De Cauwer 2007, Dubos 2006, Dubos 2008, Hansson 1993, Jereb 2001, Knudsen 2007, Lembo 1991b, Morales Casado 2016, Paradowski 1995, Peltola 1982, Ray 2007, Roine 1991, Santotoribo 2018, Schwarz 2000, Sormunen 1999, Tatara 2000, Viallon 2011); 10 studies looked at the DTA of procalcitonin (PCT; Dubos 2006, Dubos 2008, Jereb 2001, Knudsen 2007, Morales Casado 2016, Park 2017, Ray 2007, Santotoribo 2018, Schwarz 2000, Viallon 2011); and 3 studies looked at molecular diagnosis for bacterial pathogens, specifically the DTA of polymerase chain reaction (PCR) for Neisseria meningitides (Tzanakaki 2005), Streptococcus pneumonia (Dagan 1998, Tzanakaki 2005), Group B streptococcus (Morrissey 2017) and Haemophilus influenza (Tzanakaki 2005). There was no evidence identified for antigen detection for bacterial pathogens in urine, blood culture of bacterial pathogens or any molecular diagnosis techniques apart from PCR.

Six studies used cerebrospinal fluid (CSF) culture as the reference standard (Benjamin 1984, Bonsu 2003, Morrissey 2017, Sormunen 1999, Tatara 2000, Viallon 2011); 2 studies used CSF culture and/or antigen for bacterial pathogens (Hansson 1993, Morales Casado 2016); 6 studies used CSF culture and/or CSF antigen for bacterial pathogens and/or other reference standard not listed in protocol including other CSF findings (Knudsen 2007, Lembo 1991a, Lembo 1991b, Paradowski 1995, Park 2017, Santotoribo 2018); 2 studies used CSF culture and/or CSF antigen and/or blood culture (Dubos 2006, Dubos 2008); 1 study used CSF cultures and/or CSF antigen and/or blood culture and/or other CSF findings (Ray 2007); 4 studies used CSF culture and/or blood culture (Dagan 1998, Peltola 1982, Roine 1991, Tzanakaki 2005); and 4 studies used CSF culture and/or blood culture and/or other reference standard not listed in protocol including other CSF findings as the reference standard (Borchsenius 1991, De Cauwer 2007, Jereb 2001, Schwarz 2000).

Seventeen studies compared people with bacterial meningitis to those with viral meningitis (De Cauwer 2007, Dubos 2006, Dubos 2008, Hansson 1993, Jereb 2001, Morales Casado 2016, Paradowski 1995, Park 2017, Peltola 1982, Ray 2007, Roine 1991, Santotoribo 2018, Schwarz 2000, Sormunen 1999, Tatara 2000, Tzanakaki 2005, Viallon 2011). For 5 studies, the comparison was between those with bacterial meningitis and a mixed comparison group including both those without meningitis and those with other types of meningitis (Benjamin 1984, Borchsenius 1991, Knudsen 2007, Lembo 1991a, Lembo 1991b). One study compared a bacterial meningitis group to a mixed comparison group including those with non-meningitis illnesses and healthy controls (Dagan 1998). For 2 studies the comparison was between people with bacterial meningitis and an undefined non-bacterial meningitis control group (Bonsu 2003, Morrissey 2017).

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.

Table 2

Summary of included studies.

See the full evidence tables in appendix D and the 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.

No meta-analyses were conducted for any of the index tests because of the high level of heterogeneity between studies in terms of study design, population, threshold, and reference standard. The evidence was stratified by age, different thresholds for the index test and infective organism diagnosed as a result of testing polymerase chain reaction (PCR).

The evidence was assessed as being high to very low quality. Downgrading of the evidence was commonly due to risk of bias and imprecision (95% confidence intervals crossing decision making thresholds). See the GRADE tables in appendix F for the certainty of the evidence for each individual outcome.

For interpreting the sensitivity and specificity estimates, the following rules of thumb were used (as outlined in the review protocol in Appendix A): sensitivity/specificity estimates of at least 90% were considered as very sensitive/specific; at least 50% as moderately sensitive/specific; and less than 50% as not sensitive/specific.

White cell count (WCC)

In babies and children, there was evidence that white cell count (WCC) at a threshold of 15000 cells/μl was moderately specific for a diagnosis of bacterial meningitis, although estimates of sensitivity varied they were also largely moderately sensitive.

There was also some evidence showing WCC to be moderately specific (but not sensitive) for a diagnosis of bacterial meningitis in babies at a threshold of 15000 cells/μl.

One study from an undefined age range showed that WCC outside of the normal range (less than 4000 or more than 11000 cells/μl) was moderately sensitive but not specific for a diagnosis of meningococcal meningitis. No evidence was available for the accuracy of WCC in adults.

Neutrophil count

Neutrophil count was moderately sensitive and moderately specific for a diagnosis of bacterial meningitis in babies and children at thresholds of 10,000 cells/μl. No evidence was available for the accuracy of neutrophil count in adults.

C-reactive protein (CRP)

Overall, c-reactive protein (CRP) was both moderately to highly sensitive and specific for a diagnosis of bacterial meningitis in babies and children at thresholds of 2mg/l, 10mg/l and 20mg/l.

In children and adults, CRP was also largely both moderately to highly sensitive and specific for a diagnosis of bacterial meningitis at thresholds of 14mg/l, 40mg/l, 50mg/l and 90mg/l.

CRP was both moderately to highly sensitive and specific for a diagnosis of bacterial meningitis in adults at thresholds of 8mg/l, 22mg/l, 37mg/l, 40mg/l, and 50mg/l.

There was also some evidence showing CRP to be very sensitive and moderately specific for a diagnosis of bacterial meningitis, at a threshold of 20mg/l, in an undefined age range.

Procalcitonin (PCT)

Overall, procalcitonin (PCT) was very sensitive and very specific for a diagnosis of bacterial meningitis in babies and children, children and adults, and adults. Thresholds ranged from 0.12 ng/ml to 2.13 ng/ml, with the majority of studies using a threshold of 0.5ng/ml.

Polymerase chain reaction (PCR)

Overall, polymerase chain reaction (PCR) for N. meningitides, S. pneumonia, and H. influenzae was highly specific and moderately to highly sensitive in an undefined age. PCR for S. pneumonia in babies and children was very sensitive and moderately specific. PCR for group B streptococcus in babies was both very sensitive and very specific.

No evidence was available for urine detection of bacterial pathogens, blood culture of bacterial pathogens or any molecular diagnosis techniques apart from PCR.

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.

Excluded studies

Economic studies not included in this review are listed, and reasons for their exclusion are provided in Appendix J.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

The committee's discussion and interpretation of the evidence

The outcomes that matter most

The committee agreed that they would prioritise sensitivity over specificity for this diagnostic test accuracy review. They considered the impact of true positives (correctly identifying bacterial meningitis and starting the appropriate management), true negatives (reassuring patients and carers that the person does not have bacterial meningitis), false positives (potentially promoting further investigations that are unnecessary, such as lumbar puncture, or starting unnecessary treatments) and false negatives (failing to identify people that require further interventions and intensive management) and noted that false negatives could be particularly impactful as they could lead to treatment being delayed until condition worsens, which would likely result in worse outcomes for the person affected – hence a particular need to focus on the sensitivity of tests. The committee considered the positive and negative predictive values as additional information alongside sensitivity and specificity to allow them to understand what the impact of a system that recommended a certain action for all positive or negative test results would have.

The quality of the evidence

The quality of the evidence was assessed with GRADE and was rated as high to very low. Generally, evidence was downgraded due to imprecision of effect estimates (95% confidence intervals crossing decision making thresholds) and risk of bias (for example, non-consecutive patient selection, lack of details on population, two-gate study design, lack of information about whether thresholds for index tests were pre-specified, and differences between the reference standard used and the gold standard specified in the protocol). Despite there being a significant body of evidence, meta-analyses could not be conducted because of heterogeneity between studies (for example, different populations included in the studies and different criteria for diagnosing bacterial meningitis).

The committee noted that no evidence was available for urine detection of bacterial pathogens, blood culture of bacterial pathogens or any molecular diagnosis techniques apart from PCR.

Benefits and harms

The committee noted that all the evidence was based on individual blood tests and agreed that none of these blood tests alone would be sufficient to make a diagnosis of bacterial meningitis, nor should any of these tests be used to rule out bacterial meningitis. However, the committee agreed that blood tests can be an important tool when used alongside clinical features and lumbar puncture results, and these tests are simple, cheap, and widely used in current practice. The committee considered the evidence on sensitivity and specificity, together with their clinical knowledge and experience, to recommend blood tests that might support a diagnosis of bacterial meningitis.

The evidence showed that, overall, procalcitonin (PCT) was very sensitive and very specific for diagnosing bacterial meningitis in babies, children, and adults. C-reactive protein (CRP) was largely both moderately to highly sensitive and specific for a diagnosis of bacterial meningitis in babies, children, and adults. The committee discussed the higher costs associated with PCT and agreed that the difference in diagnostic accuracy was not sufficient to warrant recommending PCT over CRP. The committee therefore recommended that CRP, or PCT if CRP is not available, should be included in the blood tests performed for people with suspected bacterial meningitis.

The evidence showed that white cell count (WCC) at a threshold of greater than or equal to 15000 cells/μl was moderately specific for diagnosing bacterial meningitis in babies and children, although estimates of sensitivity varied they were also largely moderately sensitive. There was also some evidence from an undefined age range that abnormal WCC (either below 4000 or above 11000 cells/μl) was moderately sensitive (but not specific) for diagnosing meningococcal meningitis. Neutrophil count was shown to be both moderately sensitive and moderately specific for a diagnosis of bacterial meningitis in babies and children. The committee agreed that white blood cell count (including neutrophils) may be valuable to treatment decisions when considered alongside clinical presentation and could guide healthcare professionals in deciding if further investigations are required, and on this basis the committee recommended that this test should be performed.

There was limited evidence on the accuracy of polymerase chain reaction (PCR), mainly from an undefined age range. However, the evidence that was available showed that, overall, PCR for N. meningitidis, S. pneumoniae, and H. influenzae were both moderately to highly sensitive and specific for diagnosing bacterial meningitis. PCR for group B streptococcus in babies was both very sensitive and very specific. Based on the evidence, and their clinical knowledge and experience, the committee recommended that whole-blood diagnostic PCR should be included in the battery of blood tests performed. The committee agreed to give examples of PCR for meningococcal and pneumococcal as these are the more widely available tests in clinical practice, however, they did not want to restrict the recommendation to these tests as this is an area of active research and development.

There was no evidence available on the accuracy of blood culture for diagnosing bacterial meningitis. The committee agreed that it was important to specify that this should be performed as the absence of blood culture from the recommended list of tests could have the unintended consequence that this test would no longer be performed, and the committee agreed the test is important and part of routine practice. Additionally, the committee acknowledged that it is standard practice to take blood sugar and agreed to include blood glucose test to avoid situations where this test could be missed.

The committee were aware of the Guidance for public health management of meningococcal disease in the UK, and that meningococcal meningitis (without septicaemia) is included in this review. The committee agreed to reflect this guidance and recommend that a bacterial throat swab for meningococcal culture should be performed for people with suspected bacterial meningitis. The committee also noted that this should preferably be performed before starting antibiotics as antibiotics can affect the likelihood of obtaining a positive culture result, and that the request form should be explicit that this is specifically for meningococcal culture.

The committee also agreed that a HIV test should be performed in adults with suspected bacterial meningitis because HIV is a risk factor for serious infections. This is also in line with current practice.

No evidence was identified for urine detection of bacterial pathogens, and the committee agreed that it was not appropriate to make recommendations in this area.

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 did not think the clinical evidence was sufficiently strong to conclude that the additional costs of PCT would represent a cost-effective use of NHS resources. Therefore, they only recommended its use when CRP was not available (for example, if a local decision was made to prefer PCT over CRP, this would be acceptable, and it would not be necessary to perform both tests). The committee believed that their recommendations for investigating and diagnosing suspected meningitis are low cost and reflect current NHS practice. Therefore, the committee did not anticipate that their recommendations would result in a significant resource impact to the NHS.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.4.2 to 1.4.5.

References - included studies

Diagnostic

Benjamin 1984
Benjamin D. R., Opheim K. E., Brewer L., Is C-reactive protein useful in the management of children with suspected bacterial meningitis?, American Journal of Clinical Pathology, 81, 779–782, 1984 [PubMed: 6731357]
Bonsu 2003
Bonsu B. K., Harper M. B., Utility of the peripheral blood white blood cell count for identifying sick young infants who need lumbar puncture, Annals of emergency medicine, 41, 206–214, 2003 [PubMed: 12548270]
Borchsenius 1991
Borchsenius F., Bruun J. N., Tonjum T. Systemic meningococcal disease: the diagnosis on admission to hospital, NIPH annals, 11–22, 1991 [PubMed: 1881574]
Dagan 1998
Dagan R., Shriker O., Hazan I., Leibovitz E., Greenberg D., Schlaeffer F., Levy R., Prospective study to determine clinical relevance of detection of pneumococcal DNA in sera of children by PCR, Journal of clinical microbiology, 36, 669–73, 1998 [PMC free article: PMC104606] [PubMed: 9508293]
De Cauwer 2007
De Cauwer H. G., Eykens L., Hellinckx J., Mortelmans L. J. M., Differential diagnosis between viral and bacterial meningitis in children, European Journal of Emergency Medicine, 14, 343–347, 2007 [PubMed: 17968200]
Dubos 2006
Dubos F., Moulin F., Gajdos V., De Suremain N., Biscardi S., Lebon P., Raymond J., Breart G., Gendrel D., Chalumeau M., Serum procalcitonin and other biologic markers to distinguish between bacterial and aseptic meningitis, Journal of pediatrics, 149, 72–76, 2006 [PubMed: 16860131]
Dubos 2008
Dubos F., Korczowski B., Aygun D.A., Martinot A., Prat C., Galetto-Lacour A., Casado-Flores J., Taskin E., Leclerc F., Rodrigo C., Gervaix A., Leroy S., Gendrel D., Breart G., Chalumeau M., Serum procalcitonin level and other biological markers to distinguish between bacterial and aseptic meningitis in children: A European multicenter case cohort study, Archives of Pediatrics and Adolescent Medicine, 162, 1157–1163, 2008 [PubMed: 19047543]
Hansson 1993
Hansson L. O., Axelsson G., Linne T., Aurelius E., Lindquist L., Serum C-reactive protein in the differential diagnosis of acute meningitis, Scandinavian Journal of Infectious Diseases, 25, 625–630, 1993 [PubMed: 8284648]
Jereb 2001
Jereb M., Muzlovic I., Hojker S., Strle F., Predictive value of serum and cerebrospinal fluid procalcitonin levels for the diagnosis of bacterial meningitis, Infection, 29, 209–212, 2001 [PubMed: 11545482]
Knudsen 2007
Knudsen T.B., Larsen K., Kristiansen T.B., Moller H.J., Tvede M., Eugen-Olsen J., Kronborg G., Diagnostic value of soluble CD163 serum levels in patients suspected of meningitis: comparison with CRP and procalcitonin, Scandinavian Journal of Infectious Diseases, 542–553, 2007 [PubMed: 17577816]
Lembo 1991a
Lembo R. M., Rubin D. H., Krowchuk D. P., McCarthy P. L., Peripheral white blood cell counts and bacterial meningitis: Implications regarding diagnostic efficacy in febrile children, Pediatric Emergency Care, 7, 4–11, 1991 [PubMed: 2027812]
Lembo 1991b
Lembo R.M., Marchant C.D., Acute phase reactants and risk of bacterial meningitis among febrile infants and children, Annals of Emergency Medicine, 20, 36–40, 1991 [PubMed: 1984725]
Morales Casado 2016
Morales Casado M. I., Moreno Alonso F., Juarez Belaunde A. L., Heredero Galvez E., Talavera Encinas O., Julian-Jimenez A., Ability of procalcitonin to predict bacterial meningitis in the emergency department, Neurologia, 31, 9–17, 2016 [PubMed: 25288535]
Morrissey 2017
Morrissey S. M., Nielsen M., Ryan L., Al Dhanhani H., Meehan M., McDermott S., Doyle M., Gavin P., O'Sullivan N., Cunney R., Drew R. J. Group B streptococcal PCR testing in comparison to culture for diagnosis of late onset bacteraemia and meningitis in infants aged 7–90 days: a multi-centre diagnostic accuracy study, European Journal of Clinical Microbiology and Infectious Diseases, 1317–1324, 2017 [PubMed: 28247153]
Paradowski 1995
Paradowski M., Lobos M., Kuydowicz J., Krakowiak M., Kubasiewicz-Ujma B., Acute phase proteins in serum and cerebrospinal fluid in the course of bacterial meningitis, Clinical Biochemistry, 28, 459–466, 1995 [PubMed: 8521602]
Park 2017
Park B. S., Park S. H., Kim J., Shin K. J., Ha S. Y., Park J., Kim S. E., Lee B. I., Park K. M., Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis, Journal of Clinical Neuroscience, 36, 129–133, 2017 [PubMed: 28341167]
Peltola 1982
Peltola H. O., C-reactive protein for rapid monitoring of infections of the central nervous system, Lancet, 1, 980–2, 1982 [PubMed: 6122844]
Ray 2007
Ray P., Badarou-Acossi G., Viallon A., Boutoille D., Arthaud M., Trystram D., Riou B., Accuracy of the cerebrospinal fluid results to differentiate bacterial from non bacterial meningitis, in case of negative gram-stained smear, American journal of emergency medicine, 25, 179–184, 2007 [PubMed: 17276808]
Roine 1991
Roine I., Banfi A., Bosch P., Ledermann W., Contreras C., Peltola H., Serum C-reactive protein in childhood meningitis in countries with limited laboratory resources: a Chilean experience, Pediatric infectious disease journal, 10, 923–8, 1991 [PubMed: 1766708]
Santotoribo 2018
Santotoribio J. D., Cuadros-Munoz J. F., Garcia-Casares N., Comparison of C reactive protein and procalcitonin levels in cerebrospinal fluid and serum to differentiate bacterial from viral meningitis, Annals of Clinical and Laboratory Science, 48, 506–510, 2018 [PubMed: 30143494]
Schwarz 2000
Schwarz S., Bertram M., Schwab S., Andrassy K., Hacke W., Serum procalcitonin levels in bacterial and abacterial meningitis, Critical care medicine, 28, 1828–1832, 2000 [PubMed: 10890628]
Sormunen 1999
Sormunen P., Kallio M. J. T., Kilpi T., Peltola H., C-reactive protein is useful in distinguishing Gram stain-negative bacterial meningitis from viral meningitis in children, Journal of paediatrics, 725–729, 1999 [PubMed: 10356141]
Tatara 2000
Tatara R., Imai H., Serum C-reactive protein in the differential diagnosis of childhood meningitis, Pediatrics International, 241–246, 2000 [PubMed: 11059546]
Tzanakaki 2005
Tzanakaki G., Tsophanomichalou M., Kesanopoulos K., Matzourani R., Sioumala M., Tabaki A., Kremastinou J., Simultaneous single-tube PCR assay for the detection of Neisseria meningitidis, Haemophilus influenzae type b and Streptococcus pneumoniae, Clinical Microbiology and Infection, 11, 386–390, 2005 [PubMed: 15819865]
Viallon 2011
Viallon A., Desseigne N., Marjollet O., Birynczyk A., Belin M., Guyomarch S., Borg J., Pozetto B., Bertrand J. C., Zeni F., Meningitis in adult patients with a negative direct cerebrospinal fluid examination: Value of cytochemical markers for differential diagnosis, Critical Care, 15 (3) (no pagination), 2011 [PMC free article: PMC3219005] [PubMed: 21645387]

Appendix A. Review protocols

Review protocol for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 290K)

Appendix B. Literature search strategies

Literature search strategies for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 255K)

Appendix C. Diagnostic evidence study selection

Study selection for: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 173K)

Appendix D. Evidence tables

Evidence tables for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 594K)

Appendix E. Forest plots

Forest plots for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 213K)

Appendix F. GRADE tables

GRADE tables for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 402K)

Appendix G. Economic evidence study selection

Study selection for: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis? (PDF, 98K)

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis?

No evidence was identified which was applicable to this review question.

Appendix I. Economic model

Economic model for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis?

No economic analysis was conducted for this review question.

Appendix J. Excluded studies

Excluded studies for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis?

Although there was a combined search to cover both this review (evidence review B1) and evidence review B2, the excluded studies list only reflects those excluded from the current review (B1).

Diagnostic studies

Table 21

Excluded studies and reasons for their exclusion.

Excluded economic studies

Table 22

Excluded studies and reasons for their exclusion.

Appendix K. Research recommendations - full details

Research recommendations for review question: What is the accuracy and effectiveness of blood and urine investigations in diagnosing bacterial meningitis?

No research recommendation was made for this review.

Final

Evidence review underpinning recommendations 1.4.2 to 1.4.5 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.

Bookshelf ID: NBK604179PMID: 38843364

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 bacterial meningitis
Index tests	Use of the following investigations, individually or in combination: Blood white cell count neutrophil count C-reactive protein (CRP) procalcitonin molecular diagnosis for bacterial pathogens blood culture for bacterial pathogens Urine Antigen detection for bacterial pathogens
Reference standard	Either of the following, alone or in combination: Cerebrospinal fluid (CSF) bacterial culture Molecular diagnosis in the CSF for bacterial pathogens
Target condition	Bacterial meningitis (including meningococcal meningitis alone)

: CRP: c-reactive protein; CSF: cerebrospinal fluid

Table 2Summary of included studies

Study

Population

Index test(s)

Reference standard(s)

Outcomes

Comments

Benjamin 1984

Single-gate cross-sectional DTA study

USA

N=79

CSF samples submitted to laboratory during study period, including all cases of bacterial and viral meningitis

Bacterial meningitis n=21:

Age/sex not reported by arm

Viral meningitis (n=8)/no meningitis (n=50) n=58:

Age/sex not reported by arm

Whole sample (N=79):

Age (range): 1 week-18 years (mean/median not reported)

CRP

Elevated threshold defined as >1mg/dL (converted to mg/l for consistency with other studies)

CSF bacterial culture

Sensitivity

Specificity

Causative organisms: n=14 H. influenzae type b, n=2 S. pneumoniae, n=3 N. meningitidis, n=1 M. tuberculosis, n=1 Salmonella species

n=40 with leukaemia excluded from the analysis

Bonsu 2003

Single-gate cross-sectional DTA study

USA

N=5353

Babies evaluated for serious bacterial infection in the ED (presenting with a temperature ≥38°C)

Bacterial meningitis (n=22):

Age and sex not reported for BM group

Non-bacterial meningitis (5331):

No further details reported for control group

Whole sample (N=5353):

Age in days (range): 3–89 (mean/median not reported)

WCC

Elevated threshold defined as ≥15000 cells/mm³ (converted to cells/μl for consistency with other studies)

CSF bacterial culture

Sensitivity

Specificity

Causative organisms: n= 11 E. coli, n=9 group B streptococcus, n=1 S. pneumoniae, n=1 C. koseri

Data also reported for WCC thresholds of <5000, ≥10000, ≥20000, ≥25000, <5000 or ≥15000, and <5000 or ≥20000 cells/mm3, but data only extracted for the ≥15000 threshold as this is most consistent with other studies

Borchsenius 1991

Single-gate cross-sectional DTA study

Norway

N=92

People with suspected systemic meningococcal disease admitted to hospital (those with meningitis only are included in this review, and those with septicaemia or meningitis and septicaemia are included in the review on blood and urine investigations for meningococcal disease)

Meningococcal meningitis (n=56):

Age: Reported for whole sample only (including those with meningococcal disease); Mean/median not reported; 50% aged < 12

years No meningococcal or bacterial infection (n=36):

Age: Reported for whole sample only (including control participants not included in this review; Mean/median not reported; 79% aged < 12 years

CRP

Elevated threshold defined as ≥20 mg/l

WCC

Threshold defined as <4,000 or ≥11,000 cells/mm³ (converted to cells/μl for consistency with other studies)

CSF and/or blood culture, clinical picture, meningococcal antigen in CSF, or growth of N. meningitidis in pharyngeal swab specimens

Sensitivity

Specificity

Study includes patients without bacteriological proof (N=44, 38% of the full sample that includes those with meningococcal disease)

Dagan1998

Two-gate cross-sectional DTA study

Israel

N=281

Babies and children with meningitis and other conditions recruited from the ED. Healthy controls recruited from Maternal Child Health Centres (primary care)

Pneumococcal meningitis n= 4:

Age/sex not reported by arm

No meningitis (n=75)/ healthy controls (n=202) n=277:

Age/sex not reported by arm

Whole sample (N=281):

Age (range): 10 months to 16 years

Molecular diagnosis

Specific PCR for S. pneumoniae

CSF and serum culture for pneumococcal isolates

Sensitivity

Specificity

De Cauwer 2007

Single-gate retrospective DTA study

Belgium

N=92

Children (0–15 years old) admitted to the paediatric ward for clinical observations of meningitis, and final diagnosis of viral or bacterial meningitis

Bacterial meningitis (n=21):

Age in years (mean; range in parentheses): 3.9 (0–13)

Sex: male 12 (57%); female: 9 (43%)

Viral meningitis (n=71):

Age in years (mean; range in parentheses): 6.1 (0–15)

Sex: male 46 (65%); female: 25 (35%)

CRP

Elevated threshold defined as ≥2mg/L

CSF culture or pleocytosis in the CSF and a positive blood culture for a bacterial disease

Sensitivity

Specificity

Bacterial aetiology: Meningococcal meningitis (n=16; 76%); pneumococcal meningitis (n=5; 24%)

CSF cultures were positive in 14/21 and negative in 7/21

Dubos 2006

Two-gate cross-sectional DTA study

France

N=167

Children (aged 28 days to 16 years) admitted to hospital with a diagnosis of acute meningitis

Children with BM admitted to hospital 1995–2004 compared to children admitted to hospital with VM 2000–2004

Bacterial meningitis n=21:

Age/sex not reported by arm

Viral meningitis n=146:

Age/sex not reported by arm

Whole sample (N=167):

Age in years (median; range in parentheses): 4.6 (0.2–14.9)

Sex: male: 117 (70%); female: 50 (30%)

PCT

Elevated threshold defined as ≥0.5 ng/ml

CRP

Elevated threshold defined as ≥20mg/L

WCC

Elevated threshold defined as ≥15000/mm³ (converted to cells/μl for consistency with other studies)

Neutrophils

Elevated threshold defined as ≥10000/mm³ (converted to cells/μl for consistency with other studies)

Bacterial infection in CSF (direct examination, culture, latex agglutination, or PCR) or blood culture

Sensitivity

Specificity

Causative organism: n=10 S. pneumonia, n=9 N. meningitidis, n=1 H. influenzae b, n=1 Streptococcus group B

Dubos 2008

Single-gate retrospective DTA study

5 European countries (France, Spain, Switzerland, Turkey, & Poland)

N=198

People aged 29 days to 18 years who were admitted for bacterial or viral meningitis and had measurements of the main inflammatory markers (including PCT) in blood and CSF taken in the ED

Bacterial meningitis n=96:

Age in years (mean; range in parentheses): 3.2 (0.1–14)

Viral meningitis n=102:

Age not reported for this arm separately

Whole sample (N=198):

Age in years (mean; range in parentheses): 4.8 (0.1–15.9)

WCC

Elevated threshold defined as ≥15000/mm³ (converted to cells/μl for consistency with other studies)

Neutrophils

Elevated threshold defined as ≥10000/mm³ (converted to cells/μl for consistency with other studies)

CRP

Elevated threshold defined as ≥20 mg/l

PCT

Elevated threshold defined as ≥0.5 ng/ml

Bacterial infection in CSF (direct examination, culture, latex agglutination, or PCR) or blood culture

Sensitivity

Specificity

Causative organisms: n=45 N. meningitidis, n=32 S. pneumoniae, n=7 H. influenzae, n=4 S. agalactiae

76/96 (79%) diagnosed on the basis of positive CSF culture

Hansson 1993

Single-gate cross-sectional DTA study

Sweden

N=206

Children and adults undergoing lumbar puncture due to suspected CNS infection

Bacterial meningitis n=60:

Age/sex not available

Viral meningitis n=146:

Age/sex not available

CRP

Elevated threshold defined as ≥50 mg/l

CSF culture or bacterial antigen in CSF

Sensitivity

Specificity

Causative organisms: not reported

Total of 235 patients enrolled but 2×2 table can only be calculated based on those with bacterial meningitis (n=60) and those with viral meningitis (n=146) due to insufficient presentation of results

Jereb 2001

Two-gate cross-sectional DTA study

Slovenia

N=45

Adults admitted to hospital with bacterial meningitis compared to adults admitted with viral meningitis (tick-borne encephalitis)

Bacterial meningitis n=20:

Age in years (median; range in parentheses): 55 (16–77)

Sex: male: 9 (45%); female: 11 (55%)

Viral meningitis (tick-borne encephalitis) n=25:

Age in years (median; range in parentheses): 49 (22–66)

Sex: male: 13 (52%); female: 12 (48%)

CRP

Elevated threshold defined as ≥50mg/L

PCT

Elevated threshold defined as ≥0.5 ng/ml

CSF and/or blood culture or CSF gram-stained smear

Sensitivity

Specificity

Causative organisms: n=9 S. pneumonia, n=4 Staphylococcus aureus, n=2 Listeria monocytogenes, n=2 N. meningitides, n=1 H. influenzae b, n=1 Clostridium perfringens, n=1 CSF and blood cultures negative but positive Gram smear (gram positive cocci)

Knudsen 2007

Single-gate cross-sectional DTA study

Denmark

N=52

People suspected of meningitis on admission to hospital, who received a lumbar puncture

Bacterial meningitis n=10:

Age/sex not reported by arm

Viral meningitis (n=12)/no meningitis (n=30) n=42:

Age/sex not reported by arm

Whole sample (N=52):

Age in years (median; range in parentheses): 36.1 (12.8–92.3)

Sex: male: 25 (48%); female: 27 (52%)

CRP

Elevated threshold defined as ≥40 mg/l

PCT

Elevated threshold defined as ≥0.25 ng/ml

>800 leukocytes/l of which >80% are neutrophilic granulocytes in CSF and/or CSF culture or bacterial antigens in CSF

Sensitivity

Specificity

Causative organism: n=5 pneumococci; n=3 meningococci; n=1 E.coli; n=1 unknown

n=21 had antibiotic treatment before LP (median time for initiation of antibiotic treatment prior to LP: 1 day, range 0–6 day)

Lembo 1991a

Single-gate cross-sectional DTA study

USA

N=232 (included in analysis)

Babies and children with suspected meningitis who had lumbar puncture

Bacterial meningitis n=46:

Age in months (median; range in parentheses): 11 (0–157)

Sex: male: 28 (61%); female: 18 (39%)

Viral meningitis/no meningitis n=186:

Viral meningitis n=130:

Age in months (median; range in parentheses): 2 (0–219)

Sex: male: 69 (53%); female: 61 (47%)

No meningitis n=56:

Age in months (median; range in parentheses): 6.5 (0–79)

Sex: male: 25 (45%); female: 31 (55%)

WCC

Elevated threshold defined as ≥ 15,000/mm³ (converted to cells/μl for consistency with other studies)

CSF culture or bacterial antigen in CSF or urine in combination with CSF pleocytosis and a positive gram strain of CSF

Sensitivity

Specificity

Causative organism: n=29 H. influenza type b; n=6 S. pneumoniae; n=3 N. meningitidis; n=3 streptococcus group b; n=2 streptococcus group a; n=1 listeria monocytogenes; n=1 E. coli; n=1 P. mirabilis

Lembo 1991b

Single-gate cross-sectional DTA study

USA

N=160

Babies and children presenting with an acute febrile episode who had a lumbar puncture

Bacterial meningitis n=10:

Age/sex not reported by arm

Viral meningitis/no meningitis n=150:

Viral meningitis n=14; other bacterial infection n=10; other illnesses n=126

Age/sex not reported by arm

Whole sample (N=160):

Age in months (median; no measure of variance reported): 60

Sex: male: 84 (52.5%); female: 76 (47.5%)

WCC

Elevated threshold defined as ≥15,000/mm³ (converted to cells/μl for consistency with other studies)

CRP

Elevated threshold defined as >1mg/dl (converted to mg/l for consistency with other studies)

CSF culture or bacterial antigen in combination with a positive gram strain of CSF

Sensitivity

Specificity

Causative organism: n=5 H. influenza type b, n=3 S. pneumoniae, n=1 group A streptococci, n=1 listeria monocytogenes

Morales Casado 2016

Single-gate cross-sectional DTA study

Spain

N=71

People aged >15 years old with acute meningitis who underwent lumbar punctures, blood culture tests, CRP and PCT

Bacterial meningitis n=38:

Age in years (mean; SD in parentheses): 56 (22)

Sex: male: 28 (74%); female: 10 (26%)

Viral meningitis n=33:

Age in years (mean; SD in parentheses): 38 (16)

Sex: male: 20 (61%); female 13 (39%)

CRP

Elevated threshold defined as ≥90 mg/l

PCT

Elevated threshold defined as ≥0.74 ng/ml

CSF culture or bacterial antigen in CSF

Sensitivity

Specificity

AUC

Causative organism: n=18 S. pneumoniae; n=7 N. meningitidis; n=7 L. monocytogenes; n=4 H. influenzae; n=2 E. coli

Data for n=27 not included in analysis: n=15 probable VM with negative results from cultures; n=12 presumptively diagnosed partially-treated acute meningitis (history of antibiotic treatment and negative results from cultures)

Immunosuppression: 5/38 (13%) in BM group; 1/33 (3%) in VM group

Antibiotic use in previous 72 hours: 4/38 (11%) in BM group; 4/33 (12%) in VM group

Morrissey 2017

Single-gate retrospective DTA study

Ireland

N=827 (data only included for those with CSF samples)

Babies (aged 7–90 days) that had a blood or CSF sample tested by GBS PCR

Bacterial meningitis n=5:

Age/sex not reported by arm

Non-GBS group n=822:

No further details reported

Whole sample (N=827):

Age in days (median; IQR in parentheses): 35 (20.75–57)

Sex: male: 478 (58%); female: 340 (41%)

Molecular diagnosis

Specific PCR for group B streptococcus

CSF culture

Sensitivity

Specificity

Causative organism: n=5 late onset group B streptococcal (GBS) disease

Paradowski 1995

Two-gate cross-sectional DTA study

Poland

N=60

Adults hospitalised with acute meningitis

Bacterial meningitis n=30:

Age in years (mean; range in parentheses): 49 (19–82)

Sex: male: 22 (73%); female: 8 (27%)

Viral meningitis n=30:

Age in years (mean; range in parentheses): 38 (23–75)

Sex: male: 16 (53%); female: 14 (47%)

CRP

Elevated threshold defined as >40 mg/l

CSF culture, bacterial antigen in CSF, or clinical picture

Sensitivity

Specificity

Causative organism: n=10 N. meningitidis; n=7 S. pneumoniae; n=4 H. influenzae; n=3 Streptococcus group B; n=3 Streptococcus aureus; n=1 Pseudomonas aeruginosa; n=2 bacteria not identified

Study also included healthy controls but data is not extractable for this group

The majority of BM cases (93%) were confirmed through microbiological techniques

Park 2017

Two-gate cross-sectional DTA study

Korea

N=138

Adults admitted to hospital with a clinical suspicion of bacterial meningitis compared to those admitted with viral meningitis during a similar time period

Bacterial meningitis n=80

Age in years (median; IQR in parentheses): 66 (16–91)

Sex: male: 49 (61%); female: 31 (39%)

Viral meningitis n=58

Age in years (median; IQR in parentheses): 37 (15–81)

Sex: male: 30 (52%); female: 28 (48%)

PCT

Elevated threshold defined as >0.12 ng/ml

CSF culture, smear, or PCR for bacterial pathogens or good specific response to antibacterial therapy, clinical features, or other positive CSF findings

Sensitivity

Specificity

Causative organism identified (n=47): n=24 streptococcus species; n=8 staphylococcus species; n=6 klebsiella species; n=5 listeria species; n=4 other species

47/80 (59%) had positive CSF culture, smear, or PCR for bacterial pathogens

Peltola 1982

Single-gate cross-sectional DTA study

Finland

N=31

Babies and children diagnosed with bacterial meningitis, viral meningitis, or meningoencephalitis

Bacterial meningitis n=16:

Age in years (mean; standard deviation in parentheses): 1.69 (1.97)

Sex not reported

Viral illness n=15:

n=14 viral meningitis or meningoencephalitis; n=1 encephalitis

Age in years (mean; standard deviation in parentheses): 8.24 (14.01)

Sex not reported

CRP

Elevated threshold defined as ≥10mg/l

CSF culture and/or blood culture

Sensitivity

Specificity

Causative organism: n=11 H. influenzae; n=2 meningococci; n=2 pneumococci; n=1 β-haemolytic streptococcus

n=2 adults in viral illness group but study categorised as babies and children as all other participants aged 0.04–9 years

Ray 2007

Single-gate cross-sectional DTA study

France

N=151

Adults (aged at least 16 years) presenting to the emergency department and hospitalised with acute meningitis, with initial gram staining negative for bacteria

Bacterial meningitis n=18:

Age in years (mean; SD in parentheses): 52 (20)

Sex: male: 9 (50%); female: 9 (50%)

Viral meningitis n=133:

Age in years (mean; SD in parentheses): 33 (13)

Sex: male: 66 (50%); female: 67 (50%)

PCT

Elevated threshold defined as ≥2.13 ng/ml

CRP

Elevated threshold defined as ≥22 mg/l

CSF culture, CSF antigen test or blood culture, or CSF pleocytosis

Sensitivity

Specificity

AUC

Causative organism: n=4 Streptococcus species other than pneumonia; n=2 S. pneumoniae; n=2 N. meningitidis; n=1 Fusobacterium; n=1 Klebsiella pneumoniae; n=1 Mycobacterium tuberculosis; n=7 unknown

61% of diagnoses made on a positive CSF culture, antigen test or blood culture

n=2 HIV positive, and n=2 daily steroid treatment

Previous antibiotics: 4/18 (23%) in BM group; 8/133 (6%) in VM group

Roine 1991

Single-gate cross-sectional DTA study

Chile

N=83

Babies and children diagnosed with bacterial or viral meningitis

Bacterial meningitis n=67:

Age in months (mean; SD in parentheses): 23 (34)

Sex not reported

Viral meningitis n=16:

Age in months (mean; SD in parentheses): 24 (32)

Sex not reported

CRP

Elevated threshold defined as ≥20 mg/l

CSF culture or blood culture

Sensitivity

Specificity

Causative organism: n=31 H. influenzae type b; n=18 S. pneumoniae; n=10 N. meningitidis; n=4 beta haemolytic streptococcus B; n=1 enterococcus; n=1 staphylococcus aureus; n=1 klebsiella pneumonia

Diagnosis made on basis of CSF culture for 60/67 (90%)

Santotoribo 2018

Single-gate cross-sectional DTA study

Spain

N=30

Children and adults diagnosed with bacterial or viral meningitis

Bacterial meningitis

n=18

Age/sex not reported by arm

Viral meningitis n=12

Age/sex not reported by arm

Whole sample (N=30):

Age in years (median; range in parentheses): 52 (6–86)

Sex: male: 24 (80%); female: 6 (20%)

CRP

Elevated threshold defined as ≥14mg/l

PCT

Elevated threshold defined as ≥0.18 ng/ml

CSF culture, or signs/symptoms of acute infectious meningitis together with CSF showing intense PMN pleocytosis, elevated total protein and a marked glucose consumption

Sensitivity

Specificity

AUC

Causative organism (identified for 10/18): n=3 S. pneumoniae; n=2 N. meningitidis; n=2 Klebsiella pneumoniae; n=2 Staphylococcus aureus; n=1 Staphylococcus hominis

Diagnosis made on basis of CSF culture for 10/18 (56%)

Schwarz 2000

Single-gate cross-sectional DTA study

Germany

N=30

Adults (aged at least 16 years) hospitalised with acute meningitis

Bacterial meningitis n=16

Age in years (mean; range in parentheses): 61 (16–87)

Sex not reported

Viral meningitis n=14

Age in years (mean; range in parentheses): 42 (19–48)

Sex not reported

PCT

Elevated threshold defined as >0.5ng/ml

CRP

Elevated threshold defined as >8mg/l

Microscopy of CSF, CSF culture, or blood culture

Sensitivity

Specificity

Causative organism (identified in 11/16): n=6 S. pneumoniae; n=1 H. influenzae; n=1 Staphylococcus aureus; n=1 mycobacterium tuberculosis; n=1 borrelia burgdorferi; n=1 klebsiella pneumonia

Diagnosis made on basis of CSF culture for 11/16 (69%)

Sormunen 1999

Two-gate cross-sectional DTA study

Finland

N=237

Babies and children with bacterial meningitis with initial gram staining negative for bacteria, compared to children diagnosed with viral meningitis during a similar time period (hospital charts reviewed)

Bacterial meningitis n=55 (gram stain negative):

Age/sex not available for those included in the analysis

Viral meningitis n=182:

Age/sex not available

WCC

Elevated threshold defined as >15,0000 cells/mm³ (converted to cells/μl for consistency with other studies)

CRP

Elevated threshold defined as >20 mg/l

CSF culture

Sensitivity

Specificity

Causative organism: n=26 N. meningitidis; n=23 H. influenzae type b; n=3 S. pneumoniae; n=1 Listeria monocytogenes; n=1 E. coli; n=1 S. agalactiae

Paper also reports WCC thresholds of >20,000 and >25,000 cells/mm³, but data only extracted for the >15,0000 threshold as this is consistent with other studies

Paper also reports CRP for threshold >40mg/l, but data only extracted for the >20 mg/l threshold, as this is most consistent with other studies

Tatara 2000

Two-gate cross-sectional DTA study

Japan

N=192

Babies and children (aged 1 month to 15 years) with a diagnosis of acute meningitis. Babies and children with BM compared to those with VM

Bacterial meningitis n=66:

Age in years (mean; SD in parentheses): 1.6 (1.8)

Sex not reported

Viral meningitis n=126:

Age in years (mean; SD in parentheses): 3.8 (3.4)

Sex not reported

CRP

Elevated threshold defined as ≥2 mg/dL (converted to mg/l for consistency with other studies)

CSF culture

Sensitivity

Specificity

Causative organism: n=45 H. influenzae; n=13 S. pneumoniae; n=3 group B streptococcus; n=3 E. coli; n=2 Listeria monocytogeneous; n=1 N. meningitidis

Tzanakaki 2005

Single-gate cross-sectional DTA study

Greece

N=217

People diagnosed with bacterial or viral meningitis based on blood and/or CSF samples submitted to laboratory

N. meningitidis n=33:

No further details reported

S. pneumoniae n=26:

No further details reported

H. influenzae type B n=8:

No further details reported

Viral meningitis n=150:

No further details reported

Molecular diagnosis

Specific PCR for N. meningitidis

Specific PCR for S. pneumoniae

Specific PCR for H. influenzae

CSF culture and/or blood culture

Sensitivity

Specificity

Data not extracted for n=54 suspected bacterial meningitis (clinically suspected cases of bacterial meningitis, but with culture and other tests yielding negative results)

Viallon 2011

Single-gate cross-sectional DTA study

France

N=253

Adults admitted to the ED with acute meningitis and a negative direct CSF examination

Bacterial meningitis n=35 (negative direct CSF examination):

Age in years (mean; SD in parentheses): 55 (20)

Sex: male: 17 (49%); female: 18 (51%)

Viral meningitis n=218:

Age in years (mean; SD in parentheses): 35 (18)

Sex: male: 116 (53%); female: 102 47%)

CRP

Elevated threshold defined as ≥37mg/l

PCT

Elevated threshold defined as ≥0.28 ng/ml

CSF culture (but only those with negative direct CSF examination included)

Sensitivity

Specificity

AUC

Causative organism: n=14 S. pneumoniae; n=6 Listeria monocytogenes; n=5 N. meningitidis; n=4 Streptococcus species; n=2 H. influenzae; n=2 Staphylococcus aureus; n=2 other species

: AUC: area under the curve; BM: bacterial meningitis; C. koseri: citrobacter koseri; CNS: central nervous system; CRP: c-reactive protein; CSF: cerebrospinal fluid; DTA: diagnostic test accuracy; E.coli: escherichia coli; ED: emergency department; GBS: group B streptococcal; H. influenza: haemophilus influenza; IQR: interquartile range; L. monocytogenes: listeria monocytogenes; LP: lumbar puncture; M. tuberculosis: mycobacterium tuberculosis; N. meningitidis: Neisseria meningitides; P. mirabilis: proteus mirabilis; PCR: polymerase chain reaction; PCT: procalcitonin; PMN: polymorphonuclear; S. agalactiae: streptococcus agalactiae; S. pneumoniae; streptococcus pneumonia; SD: standard deviation; VM: viral meningitis; WCC: white cell count

Table 21Excluded studies and reasons for their exclusion

Study	Reason for Exclusion
Abdeldaim G. M. K, Stralin K, Korsgaard J et al (2010) Multiplex quantitative PCR for detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. BMC Microbiology 10 (no pagination) [PMC free article: PMC3016321] [PubMed: 21129171]	- Index test not of interest for review PCR on CSF
Abelian A and Pritchard I. (2011) Neonatal bacterial meningitis: Has time come for polymerase chain reaction?. Journal of Pediatric Infectious Diseases 6(3): 227–229	- Index test not of interest for review Only CSF samples tested
Aksoy F, Yilmaz G, Nur Aydin N et al (2017) Are new biomarkers useful in the diagnosis of meningitis in adults?. Open Forum Infectious Diseases 4 (Supplement 1): 303	- Study design not of interest for review Conference abstract
Albuquerque R. C, Moreno A. C. R, Dos Santos S. R et al (2019) Multiplex-PCR for diagnosis of bacterial meningitis. Brazilian journal of microbiology: [publication of the Brazilian Society for Microbiology] 50(2): 435–443 [PMC free article: PMC6863191] [PubMed: 30796713]	- Index test not of interest for review Only CSF samples tested
Alkholi U. M, Abd Al-Monem N, Abd El-Azim A. A et al (2011) Serum procalcitonin in viral and bacterial meningitis. Journal of Global Infectious Diseases 3(1): 14–18 [PMC free article: PMC3068572] [PubMed: 21572603]	- Country not of interest for review Not a high-income OECD country
Alons I. M, Verheul R. J, Kuipers I et al (2016) Procalcitonin in cerebrospinal fluid in meningitis: a prospective diagnostic study. Brain and Behavior 6(11): e00545 [PMC free article: PMC5102643] [PubMed: 27843698]	- Insufficient presentation of results Cannot calculate 2×2 table for plasma PCT (data reported for CSF PCT only)
Altun O, Athlin S, Almuhayawi M et al (2016) Rapid identification of Streptococcus pneumoniae in blood cultures by using the ImmuLex, Slidex and Wellcogen latex agglutination tests and the BinaxNOW antigen test. European Journal of Clinical Microbiology and Infectious Diseases 35(4): 579–585 [PubMed: 26796552]	- Population does not meet inclusion criteria Streptococcus pneumoniae in blood culture (diagnosis not reported)
Ansong A. K, Smith P. B, Benjamin D. K et al (2009) Group B streptococcal meningitis: cerebrospinal fluid parameters in the era of intrapartum antibiotic prophylaxis. Early human development 85(10suppl): S5–7 [PMC free article: PMC2783609] [PubMed: 19767158]	- Population does not meet inclusion criteria Neonates
Anttila M and Peltola H. (1992) Serum C-reactive protein in the course of Haemophilus influenzae type b meningitis. Journal of infectious diseases 165(suppl1): S36–S37 [PubMed: 1588173]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Ao D, Wei L, Hui-Hui G et al (2014) Rapid diagnosis and discrimination of bacterial meningitis in children using gram probe real-time polymerase chain reaction. Clinical pediatrics 53(9): 839–844 [PubMed: 24790023]	- Index test not of interest for review Only CSF samples tested
Ascher D. P; Wilson S; Fischer G. W. (1991) Comparison of commercially available group B streptococcal latex agglutination assays. Journal of clinical microbiology 29(12): 2895–6 [PMC free article: PMC270458] [PubMed: 1757570]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Athlin S, Altun O, Eriksen H. B et al (2015) The Uni-GoldTM Streptococcus pneumoniae urinary antigen test: an interassay comparison with the BinaxNOW Streptococcus pneumoniae test on consecutive urine samples and evaluation on patients with bacteremia. European Journal of Clinical Microbiology and Infectious Diseases 34(8): 1583–1588 [PubMed: 25926305]	- Population does not meet inclusion criteria Streptococcus pneumoniae positive bacteraemia (diagnosis not reported)
Athlin S; Iversen A; Ozenci V. (2017) Comparison of the ImmuView and the BinaxNOW antigen tests in detection of Streptococcus pneumoniae and Legionella pneumophila in urine. European journal of clinical microbiology & infectious diseases 36(10): 1933–1938 [PMC free article: PMC5602076] [PubMed: 28589425]	- Population does not meet inclusion criteria Streptococcus pneumoniae positive bacteraemia (diagnosis not reported)
Avni T, Mansur N, Leibovici L et al (2010) PCR using blood for diagnosis of invasive pneumococcal disease: systematic review and meta-analysis. Journal of clinical microbiology 48(2): 489–496 [PMC free article: PMC2815606] [PubMed: 20007385]	- Population does not meet inclusion criteria Checked included studies for inclusion.
Aygun F, Durak C, Varol F et al (2020) Evaluation of complete blood count parameters for diagnosis in children with sepsis in the pediatric intensive care unit. Cocuk Enfeksiyon Dergisi 14(2): e55–e62	- Population does not meet inclusion criteria Sepsis (only 11% were CNS in origin)
Azzari C, Moriondo M, Indolfi G et al (2008) Molecular detection methods and serotyping performed directly on clinical samples improve diagnostic sensitivity and reveal increased incidence of invasive disease by Streptococcus pneumoniae in Italian children. Journal of Medical Microbiology 57(10): 1205–1212 [PMC free article: PMC2884936] [PubMed: 18809546]	- Index test not of interest for review PCR and culture used as reference standard
Backman A, Lantz P. G, Radstrom P et al Evaluation of an extended diagnostic PCR assay for detection and verification of the common causes of bacterial meningitis in CSF and other biological samples. Molecular and Cellular Probes 13(1): 49–60 [PubMed: 10024433]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Baker C. J and Rench M. A. (1983) Commercial latex agglutination for detection of group B streptococcal antigen in body fluids. Journal of pediatrics 102(3): 393–395 [PubMed: 6338186]	- Index test not of interest for review Latex agglutination
Ballard T. L; Roe M. H; Wheeler R. C. (1987) Comparison of three latex agglutination kits and counterimmunoelectrophoresis for the detection of bacterial antigens in a pediatric population. Pediatric infectious disease journal 6(7): 630–634 [PubMed: 2441346]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Ben R. J, Kung S, Chang F. Y et al (2008) Rapid diagnosis of bacterial meningitis using a microarray. Journal of the Formosan Medical Association 107(6): 448–453 [PubMed: 18583215]	- Reference standard not of interest for review CSF pleocytosis (> 5 leukocytes/μL of CSF)
Bilavsky E, Yarden-Bilavsky H, Ashkenazi S et al (2009) C-reactive protein as a marker of serious bacterial infections in hospitalized febrile infants. Acta Paediatrica 98(11): 1776–1780 [PubMed: 19664100]	- Population does not meet inclusion criteria 10% with bacterial meningitis
Borrow R, Claus H, Chaudhry U et al (1998) siaD PCR ELISA for confirmation and identification of serogroup Y and W135 meningococcal infections. FEMS Microbiology Letters 159(2): 209–14 [PubMed: 9503614]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Borschsenius F, Bruun J. N, Michaelsen T. E et al (1986) Serum C-reactive protein in systemic infections due to Neisseria meningitidis. NIPH annals 9(1): 15–21 [PubMed: 3092149]	- Insufficient presentation of results Same data as reported in Borschsenius 1991
Boudet A, Pantel A, Carles M. J et al (2019) A review of a 13-month period of FilmArray Meningitis/Encephalitis panel implementation as a first-line diagnosis tool at a university hospital. 14(10): e0223887 [PMC free article: PMC6812749] [PubMed: 31647847]	- Index test not of interest for review Only CSF samples tested
Brouwer M. C; Tunkel A. R; Van De Beek D. (2010) Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clinical Microbiology Reviews 23(3): 467–492 [PMC free article: PMC2901656] [PubMed: 20610819]	- Study design not of interest for review Discussion paper
Bryant P. A, Li H. Y, Zaia A et al (2004) Prospective study of a real-time PCR that is highly sensitive, specific, and clinically useful for diagnosis of meningococcal disease in children. Journal of clinical microbiology 42(7): 2919–2925 [PMC free article: PMC446275] [PubMed: 15243039]	- Index test/reference standard not of interest for review Index tests: blood culture and lab-based PCR; reference standard includes clinical criteria
Carrol E. D, Newland P, Thomson A. P. J et al (2005) Prognostic value of procalcitonin in children with meningococcal sepsis. Critical care medicine 33(1): 224–225 [PubMed: 15644674]	- Study design and outcomes not of interest for review PCT as a prognostic marker in people with meningococcal sepsis
Carrol E.D, Newland P, Riordan F.A. I et al (2002) Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash. Archives of Disease in Childhood 86(4): 282–285 [PMC free article: PMC1719162] [PubMed: 11919107]	- Population not of interest for review Meningococcal disease
Carrol E.D, Thomson A.P. J, Shears P et al (2000) Performance characteristics of the polymerase chain reaction assay to confirm clinical meningococcal disease. Archives of Disease in Childhood 83(3): 271–273 [PMC free article: PMC1718454] [PubMed: 10952654]	- Index test not of interest for review Lab-based PCR (meningococcal disease)
Clarke D and Cost K. (1983) Use of serum C-reactive protein in differentiating septic from aseptic meningitis in children. Journal of pediatrics 102(5): 718–720 [PubMed: 6842329]	- Insufficient presentation of results Insufficient information to calculate 2×2 tables
Coant P.N, Kornberg A.E, Duffy L.C et al (1992) Blood culture results as determinants in the organism identification of bacterial meningitis. Pediatric Emergency Care 8(4): 200–205 [PubMed: 1381091]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Cocquerelle V, Fossard C, Souply L et al (2009) Evaluation of three diagnosis models for differentiating bacterial from viral meningitis. Clinical Microbiology and Infection 15 (S4): S224–S225	- Study design not of interest for review Conference Abstract
Drakopoulou Z, Kesanopoulos K, Sioumala M et al (2008) Simultaneous single-tube PCR-based assay for the direct identification of the five most common meningococcal serogroups from clinical samples. FEMS Immunology and Medical Microbiology 53(2): 178–182 [PubMed: 18623625]	- Population does not meet inclusion criteria All patients confirmed as having meningococcal serogroups, diagnostic accuracy data on identification of individual serogroups in confirmed meningococcal isolates
Drew R. J, Maoldomhnaigh C O., Gavin P. J, O' Sullivan N, Butler K. M et al (2012) The impact of meningococcal polymerase chain reaction testing on laboratory confirmation of invasive meningococcal disease. Pediatric infectious disease journal 31(3): 316–8 [PubMed: 22173139]	- Reference standard not of interest for review Unclear if culture of CSF done for comparator group of BSI
Dubos F, Korczowski B, Aygun D.A et al (2010) Distinguishing between bacterial and aseptic meningitis in children: European comparison of two clinical decision rules. Archives of Disease in Childhood 95(12): 963–967 [PubMed: 20660523]	- Index test not of interest for review Combination of index tests not of interest (includes clinical presentation and CSF parameters)
Edelstein P. H; Jorgensen C. S; Wolf L. A. (2020) Performance of the ImmuView and BinaxNOW assays for the detection of urine and cerebrospinal fluid Streptococcus pneumoniae and Legionella pneumophila serogroup 1 antigen in patients with Legionnaires' disease or pneumococcal pneumonia and meningitis. PloS one 15 (8 August) [PMC free article: PMC7458278] [PubMed: 32866217]	- Population does not meet inclusion criteria Legionnaires disease or pneumonia
El Bashir H; Laundy M; Booy R. (2003) Diagnosis and treatment of bacterial meningitis. Archives of Disease in Childhood 88(7): 615–620 [PMC free article: PMC1763168] [PubMed: 12818910]	- Study design not of interest for review Discussion paper
El shorbagy H. H, Barseem N. F, Abdelghani W. E et al (2018) The value of serum procalcitonin in acute meningitis in children. Journal of Clinical Neuroscience 56: 28–33 [PubMed: 30143413]	- Country not of interest for review Not a high-income OECD country
Emiroglu M; Kesli R; Kilicaslan M. (2020) Diagnostic Value of Clinical and Laboratory Findings in Childhood Meningitis. Journal of Pediatric Infectious Diseases 15(2): 79–85	- Population does not meet inclusion criteria Meningitis (predominantly viral meningitis)
Failace L, Wagner M, Chesky M et al (2005) Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae and Streptococcus sp. by polymerase chain reaction for the diagnosis of bacterial meningitis. Arquivos de neuro-psiquiatria 63(4): 920–924 [PubMed: 16400405]	- Country not of interest for review Not a high-income OECD country
Fan S. J, Tan H. K, Xu Y. C et al (2020) A pooled analysis of the LAMP assay for the detection of Neisseria meningitidis. BMC Infectious Diseases 20 (1) [PMC free article: PMC7372874] [PubMed: 32689953]	- Study design not of interest for review All studies in the meta-analysis don’t meet the inclusion criteria for the review. Studies that meet the inclusion criteria (McKenna 2011; Bourke 2015; Higgins 2018) extracted from primary paper
Farahani H, Ghaznavi-Rad E, Mondanizadeh M et al (2016) Specific detection of common pathogens of acute bacterial meningitis using an internally controlled tetraplex-PCR assay. Molecular & Cellular ProbesMol Cell Probes 30(4): 261–265 [PubMed: 27401970]	- Country not of interest for review Not a high-income OECD country
Favaro M, Savini V, Favalli C et al (2013) A multi-target real-time PCR assay for rapid identification of meningitis-associated microorganisms. Molecular BiotechnologyMol Biotechnol 53(1): 74–9 [PubMed: 22450734]	- Index test not of interest for review Only CSF samples tested
Feigin R. D, Wong M, Shackelford P. G et al (1976) Countercurrent immunoelectrophoresis of urine as well as of CSF and blood for diagnosis of bacterial meningitis. Journal of pediatrics 89(5): 773–775 [PubMed: 978326]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Fraisier C, Stor R, Tenebray B et al (2009) Use of a new single multiplex PCR-based assay for direct simultaneous characterization of six Neisseria meningitidis serogroups. Journal of Clinical MicrobiologyJ Clin Microbiol 47(8): 2662–6 [PMC free article: PMC2725692] [PubMed: 19553584]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Gendrel D, Raymond J, Coste J et al (1999) Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. Pediatric Infectious Disease Journal 18(10): 875–881 [PubMed: 10530583]	- Insufficient presentation of results Not enough data to construct 2 × 2 tables for review
Gerdes L. U, Jorgensen P. E, Nexo E et al (1998) C-reactive protein and bacterial meningitis: a meta-analysis. Scandinavian Journal of Clinical & Laboratory InvestigationScand J Clin Lab Invest 58(5): 383–93 [PubMed: 9819187]	- Insufficient presentation of results Insufficient info to construct 2 × 2 tables. Reference list checked for studies
Guiducci S, Moriondo M, Nieddu F et al (2019) Culture and Real-time Polymerase Chain reaction sensitivity in the diagnosis of invasive meningococcal disease: Does culture miss less severe cases?. PLoS ONE [Electronic Resource] 14(3): e0212922 [PMC free article: PMC6415896] [PubMed: 30865671]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Hackett S. J, Carrol E. D, Guiver M et al (2002) Improved case confirmation in meningococcal disease with whole blood Taqman PCR. Archives of disease in childhood 86(6): 449–452 [PMC free article: PMC1762989] [PubMed: 12023187]	- Index test not of interest for review Lab-based PCR (meningococcal disease)
Henry B. M, Roy J, Ramakrishnan P. K et al (2016) Procalcitonin as a Serum Biomarker for Differentiation of Bacterial Meningitis from Viral Meningitis in Children:Evidence from a Meta-Analysis. Clinical pediatrics 55(8): 749–764 [PubMed: 26378091]	- Study design not of interest for review All studies in the meta-analysis don’t meet the inclusion criteria for the review (includes studies that are not from a high-income OECD country). Studies that meet the inclusion criteria extracted from primary papers
Higa F. T, Fukasawa L. O, Goncalves M. G et al (2013) Use of sodC versus ctrA for real-time polymerase chain reaction-based detection of Neisseria meningitidis in sterile body fluids. Memorias do Instituto Oswaldo Cruz 108(2): 246–247 [PMC free article: PMC3970655] [PubMed: 23579808]	- Country not of interest for review Not a high-income OECD country
Higgins O, Clancy E, Cormican M et al (2018) Evaluation of an Internally Controlled Multiplex Tth Endonuclease Cleavage Loop-Mediated Isothermal Amplification (TEC-LAMP) Assay for the Detection of Bacterial Meningitis Pathogens. International Journal of Molecular SciencesInt 19(2): 9 [PMC free article: PMC5855746] [PubMed: 29425124]	- Index test not of interest for review PCR in various clinical samples (blood, CSF, pleural fluid, knee fluid)
Higgins O, Clancy E, Forrest M. S et al (2018) Duplex recombinase polymerase amplification assays incorporating competitive internal controls for bacterial meningitis detection. Analytical Biochemistry 546: Oct-16 [PubMed: 29378166]	- Index test not of interest for review PCR in various clinical samples (blood, CSF, pleural fluid, knee fluid)
Hu R; Gong Y; Wang Y. (2015) Relationship of serum procalcitonin levels to severity and prognosis in pediatric bacterial meningitis. Clinical pediatrics 54(12): 1141–1144 [PubMed: 25652198]	- Country not of interest for review Not a high-income OECD country
Huy N. T, Hang le T. T, Boamah D et al Development of a single-tube loop-mediated isothermal amplification assay for detection of four pathogens of bacterial meningitis. FEMS Microbiology Letters 337(1): 25–30 [PubMed: 22946506]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Jenkins P; Barnes R. A; Coakley W. T. (1997) Detection of meningitis antigens in buffer and body fluids by ultrasound-enhanced particle agglutination. Journal of Immunological Methods 205(2): 191–200 [PubMed: 9294601]	- Study design not of interest for review Not enough data to construct 2 × 2 tables for review
Jing-Zi P, Zheng-Xin H, Wei-Jun C et al (2018) Detection of bacterial meningitis pathogens by PCR-mass spectrometry in cerebrospinal fluid. Clinical Laboratory 64(6): 1013–1019 [PubMed: 29945321]	- Country not of interest for review Not a high-income OECD country
Julian-Jimenez A and Morales-Casado M. I. (2019) Usefulness of blood and cerebrospinal fluid laboratory testing to predict bacterial meningitis in the emergency department. NeurologiaNeurologia 34(2): 105–113 [PubMed: 27469578]	- Non-English language article Article in Spanish
Kaldor J; Asznowicz R; Buist D. G. P. (1977) Latex agglutination in diagnosis of bacterial infections, with special reference to patients with meningitis and septicemia. American Journal of Clinical Pathology 68(2): 284–289 [PubMed: 879103]	- Population does not meet inclusion criteria Purulent meningitis or septicaemia (no proportions reported)
Kesanopoulos K, Tzanakaki G, Levidiotou S et al (2005) Evaluation of touch-down real-time PCR based on SYBR Green I fluorescent dye for the detection of Neisseria meningitidis in clinical samples. FEMS Immunology and Medical Microbiology 43(3): 419–424 [PubMed: 15708317]	- Index test not of interest for review Lab-based PCR
Korczowski B; Bijoś A; Rybak A. (2000) Procalcitonin in diagnosis of purulent and aseptic meningitis in children. Polski merkuriusz lekarski 9(53): 755–757 [PubMed: 11204322]	- Non-English language article Article in Polish
La Scolea L. J Jr and Dryja D. (1984) Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. Journal of clinical microbiology 19(2): 187–190 [PMC free article: PMC271014] [PubMed: 6365957]	- Index test not of interest for review Only CSF samples tested
Lansac N, Picard F. J, Menard C et al (2000) Novel genus-specific PCR-based assays for rapid identification of Neisseria species and Neisseria meningitidis. European journal of clinical microbiology & infectious diseases 19(6): 443–51 [PubMed: 10947220]	- Study design/index test not of interest for review Development of PCR assays for neisseria species
Lee C. T, Hsiao K. M, Chen J. C et al (2015) Multiplex polymerase chain reaction assay developed to diagnose adult bacterial meningitis in Taiwan. Apmis 123(11): 945–50 [PubMed: 26332098]	- Country not of interest for review Not a high-income OECD country
Leitner E, Hoenigl M, Wagner B et al (2016) Performance of the FilmArray Blood culture identification panel in positive blood culture bottles and cerebrospinal fluid for the diagnosis of sepsis and meningitis. GMS Infectious DiseasesGMS Infect Dis 4: doc06 [PMC free article: PMC6301725] [PubMed: 30671320]	- Study design not of interest for review PCR applied to positive cultures only
Mace S. E. (2008) Acute Bacterial Meningitis. Emergency Medicine Clinics of North America 26(2): 281–317 [PubMed: 18406976]	- Study design not of interest for review Discussion paper
Makoo Z. B, Soltani H. R, Hasani A et al (2010) Diagnostic value of serum and Cerebrospinal fluid procalcitonin in differentiation bacterial from Aseptic meningitis. American Journal of Infectious Diseases 6(4): 93–97	- Country not of interest for review Not a high-income OECD country
Manzano S, Bailey B, Gervaix A et al. (2011) Markers for bacterial infection in children with fever without source. Archives of Disease in Childhood 96(5): 440–446 [PubMed: 21278424]	- Insufficient presentation of results Outcome is detection of serious bacterial infection and results not presented separately for meningitis or meningococcal disease
Maor Y, Avnon T, Schindler Y et al (2012) The significance of PCR in the diagnosis of post surgical meningitis. Clinical Microbiology and Infection 3: 356	- Study design not of interest for review Conference Abstract
Metrou M and Crain E. F. (1991) The complete blood count differential ratio in the assessment of febrile infants with meningitis. Pediatric infectious disease journal 10(4): 334–335 [PubMed: 2062632]	- Study design not of interest for review Not diagnostic accuracy study
Michael B. D, Sidhu M, Stoeter D et al (2010) Acute central nervous system infections in adults-a retrospective cohort study in the NHS North West region. Qjm 103(10): 749–758 [PubMed: 20657024]	- Index test not of interest for review Only CSF samples tested
Moayedi A. R, Nejatizadeh A, Mohammadian M et al (2015) Accuracy of universal polymerase chain reaction (PCR) for detection of bacterial meningitis among suspected patients. Electronic Physician [Electronic Resource]Electron Physician 7(8): 1609–12 [PMC free article: PMC4725414] [PubMed: 26816587]	- Country not of interest for review Not a high-income OECD country
Mohamed H. B, Alif H. A, Awadalla A. A et al (2012) Detection and significance of blood neutrophil CD64 expression as a diagnostic marker in bacterial meningitis in children. The Egyptian journal of immunology / Egyptian Association of Immunologists 19(2): 35–40 [PubMed: 23885405]	- Country not of interest for review Not a high-income OECD country
Mohammadi S. F, Patil A. B, Nadagir S. D et al (2013) Diagnostic value of latex agglutination test in diagnosis of acute bacterial meningitis. Annals of Indian Academy of Neurology 16(4): 645–649 [PMC free article: PMC3841619] [PubMed: 24339598]	- Country not of interest for review Not a high-income OECD country
Nacro B, Konate S, Gaudreault S et al (2008) Use of polymerase chain reaction in the diagnosis of acute bacterial meningitis in children. Journal of Pediatric Infectious Diseases 3(2): 119–124	- Country not of interest for review Not a high-income OECD country
Nolte F. S, Rogers B. B, Tang Y. W et al (2011) Evaluation of a rapid and completely automated real-time reverse transcriptase PCR assay for diagnosis of enteroviral meningitis. Journal of Clinical MicrobiologyJ Clin Microbiol 49(2): 528–33 [PMC free article: PMC3043510] [PubMed: 21159942]	- Index test not of interest for review Only CSF samples tested
Onal H, Onal Z, Ozdil M et al (2008) A new parameter in the differential diagnosis of bacterial and viral meningitis. Neurosciences 13(1): 91–92 [PubMed: 21063298]	- Country not of interest for review Not a high-income OECD country
Orvelid P; Backman A; Olcen P. (1999) PCR identification of the group A Neisseria meningitidis gene in cerebrospinal fluid. Scandinavian Journal of Infectious Diseases 31(5): 481–483 [PubMed: 10576127]	- Index test not of interest for review Only CSF samples tested
Papavasileiou K, Papavasileiou E, Tzanakaki G et al (2011) Acute bacterial meningitis cases diagnosed by culture and PCR in a children's hospital throughout a 9-year period (2000–2008) in Athens, Greece. Molecular Diagnosis and Therapy 15(2): 109–113 [PubMed: 21452905]	- Study design not of interest for review Descriptive study (no DTA data)
Poplin V; Boulware D. R; Bahr N. C. (2020) Methods for rapid diagnosis of meningitis etiology in adults. Biomarkers in MedicineBiomark 14(6): 459–479 [PMC free article: PMC7248681] [PubMed: 32270693]	- Study design not of interest for review Discussion paper
Poppert S, Essig A, Stoehr B et al (2005) Rapid diagnosis of bacterial meningitis by real-time PCR and fluorescence in situ hybridization. Journal of clinical microbiology 43(7): 3390–7 [PMC free article: PMC1169125] [PubMed: 16000464]	- Index test not of interest for review Only CSF samples tested
Porritt R. J; Mercer J. L; Munro R. (2000) Detection and serogroup determination of Neisseria meningitidis in CSF by polymerase chain reaction (PCR). Pathology 32(1): 42–45 [PubMed: 10740805]	- Index test not of interest for review Only CSF samples tested
Porritt R. J; Mercer J. L; Munro R. (2003) Ultrasound-enhanced latex immunoagglutination test (USELAT) for detection of capsular polysaccharide antigen of Neisseria meningitidis from CSF and plasma. Pathology 35(1): 61–4 [PubMed: 12701687]	- Index test not of interest for review Latex agglutination
Prasad P. L; Nair M. N. G; Kalghatgi A. T. (2005) Childhood bacterial meningitis and usefulness of C-reactive protein. Medical Journal Armed Forces India 61(1): 13–15 [PMC free article: PMC4923348] [PubMed: 27407696]	- Country not of interest for review Not a high-income OECD country
Prat C, Dominguez J, Rodrigo C et al (2004) Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. European Journal of Clinical Microbiology and Infectious Diseases 23(2): 136–138 [PubMed: 14689316]	- Population not of interest for review Groups those with sepsis and/or meningitis
Requejo H. I; Nascimento C. M; Fahrat C. K. (1992) Comparison of counterimmunoelectrophoresis, latex agglutination and bacterial culture for the diagnosis of bacterial meningitis using urine, serum and cerebrospinal fluid samples. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica .. etal25(4): 357–367 [PubMed: 1342212]	- Country not of interest for review Not a high-income OECD country
Sakushima K, Hayashino Y, Kawaguchi T et al (2011) Diagnostic accuracy of O cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. Journal of InfectionJ Infect 62(4): 255–62 [PubMed: 21382412]	- Index test not of interest for review Only CSF samples tested
Saravolatz L. D, Manzor O, VanderVelde N et al (2003) Broad-range bacterial O polymerase chain reaction for early detection of bacterial meningitis. Clinical infectious diseases 36(1): 40–5 [PubMed: 12491200]	- Index test not of interest for review Only CSF samples tested
Schaad U.B. (1997) Diagnosis and treatment of bacterial meningitis. Annales D Nestle 55(3): 103–110	- Study design not of interest for review Discussion paper
Seward R. J and Towner K. J. (2000) Evaluation of a PCR-immunoassay N technique for detection of Neisseria meningitidis in cerebrospinal fluid and peripheral blood. Journal of Medical Microbiology 49(5): 451–456 [PubMed: 10798558]	- Index test not of interest for review No index test of interest
Sippel J. E, Girgis N. I, Kilpatrick M. et al (1991) Laboratory diagnosis of bacterial D meningitis. Transactions of the royal society of tropical medicine and hygiene 85(suppl1): 06-Aug [PubMed: 1803698]	- Study design not of interest for review Discussion paper
Soetiono S; Sunartini, Machfudz S; Setyawati P. S. (1989) Cerebrospinal fluid N C-reactive protein in the diagnosis of meningitis in children. Paediatrica Indonesiana 29(01feb): 20–27 [PubMed: 2797840]	- Country not of interest for review Not a high-income OECD country
Srifuengfung S and Chokephaibulkit K. (2010) Detection of bacterial antigen in D cerebrospinal fluid in patients with bacterial meningitis: a literature review. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 93suppl5: S71–75 [PubMed: 21298833]	- Study design not of interest for review Discussion paper
Srinivasan L, Pisapia J. M, Shah S. S et al (2012) Can broad-range 16S ribosomal P ribonucleic acid gene polymerase chain reactions improve the diagnosis of bacterial meningitis? A systematic review and meta-analysis. Annals of Emergency MedicineAnn Emerg Med 60(5): 609620.e2 [PubMed: 22883680]	- Index test not of interest for review PCR tested in CSF
Taveras J and Villalobos-Fry T. (2018) The use of multiplex PCR panel in the diagnosis of meningitis in children. Open Forum Infectious Diseases 5 (Supplement 1): 135	- Study design not of interest for review Conference Abstract
Ure R, Lindsay D, Edwards G et al (2012) Evaluation of the FTD bacterial meninigitis kit in comparison to in-house assays for the direct detection of N. meningitidis, S. pneumoniae and H. influenzae in clinical specimens. Clinical Microbiology and Infection 3: 403	- Study design not of interest for review Conference Abstract
Van Gastel E, Bruynseels P, Verstrepen W et al (2007) Evaluation of a real-time polymerase chain reaction assay for the diagnosis of pneumococcal and meningococcal meningitis in a tertiary care hospital. European Journal of Clinical Microbiology and Infectious Diseases 26(9): 651–653 [PubMed: 17610095]	- Insufficient presentation of results Data cannot be extracted as control group includes those with other types of bacterial meningitis
Velissaris D, Pintea M, Pantzaris N et al (2018) The Role of Procalcitonin in the Diagnosis of Meningitis: A Literature Review. Journal of Clinical MedicineJ 7(6): 11 [PMC free article: PMC6025317] [PubMed: 29891780]	- Study design not of interest for review Non-systematic review
Viallon A, Zeni F, Lambert C et al (1999) High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis. Clinical infectious diseases 28(6): 1313–1316 [PubMed: 10451174]	- Insufficient presentation of results Insufficient information to calculate 2×2 table or precision around the estimates
Vikse J, Henry B. M, Roy J et al (2015) The role of serum procalcitonin in the diagnosis of bacterial meningitis in adults: a systematic review and meta-analysis. International Journal of Infectious DiseasesInt J Infect Dis 38: 68–76 [PubMed: 26188130]	- Reference standard not of interest for review No comparator of interest
Vuong J, Collard J. M, Whaley M. J et al (2016) Development of real-time PCR methods for the detection of bacterial meningitis pathogens without DNA extraction. PloS one 11 (2) [PMC free article: PMC4735509] [PubMed: 26829233]	- Index test not of interest for review PCR on CSF
Wang X, Theodore M. J, Mair R et al (2012) Clinical validation of multiplex realtime PCR assays for detection of bacterial meningitis pathogens. Journal of Clinical MicrobiologyJ Clin Microbiol 50(3): 702–8 [PMC free article: PMC3295090] [PubMed: 22170919]	- Index test/country not of interest for review PCR on nasal washes and/or throat swabs for Lakeland (USA) cohort and other cohorts not from a high-income OECD country
Wei T. T, Hu Z. D, Qin B. D et al (2016) Diagnostic Accuracy of Procalcitonin in Bacterial Meningitis Versus Nonbacterial Meningitis: A Systematic Review and Meta-Analysis. MedicineMedicine (Baltimore) 95(11): e3079 [PMC free article: PMC4839921] [PubMed: 26986140]	- Study design not of interest for review Studies that meet inclusion criteria for review extracted from primary papers
Zhang L, Ma L, Zhou X et al (2019) Diagnostic Value of Procalcitonin for Bacterial Meningitis in Children: A Comparison Analysis Between Serum and Cerebrospinal Fluid Procalcitonin Levels. Clinical pediatrics 58(2): 159–165 [PubMed: 30371098]	- Country not of interest for review Not a high-income OECD country

: CSF: cerebrospinal fluid; LAMP: Loop-mediated isothermal amplification; PCR: polymerase chain reaction; PCT: procalcitonin; OECD: Organisation for Economic Co-operation and Development; RCT: randomised controlled trial

Table 22Excluded studies and reasons for their exclusion

Study	Reason for Exclusion
Duff, S., Hasbun, R., Balada-Llasat, J. M., Zimmer, L., Bozzette, S. A., Ginocchio, C. C., Economic analysis of rapid multiplex polymerase chain reaction testing for meningitis/encephalitis in adult patients, Infection, 20, 20, 2019 [PubMed: 31111325]	Excluded as rated not applicable. US resource use and costs and judged unlikely to be applicable to current UK NHS context.
Duff, S., Hasbun, R., Ginocchio, C. C., Balada-Llasat, J. M., Zimmer, L., Bozzette, S. A., Economic analysis of rapid multiplex polymerase chain reaction testing for meningitis/encephalitis in pediatric patients, Future Microbiology, 13, 617–629, 2018 [PubMed: 29316801]	Excluded as rated not applicable. US resource use and costs and judged unlikely to be applicable to current UK NHS context.