Journal of Infection 88 (2024) 106111

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Journal of Infection
journal homepage: www.elsevier.com/locate/jinf

Review

Distinguishing community-acquired bacterial and viral meningitis:

Microbes and biomarkers ]]
]]]]]]
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⁎
Lauri Ivaska a,b, Jethro Herberg c, Manish Sadarangani d,e,
a
Department of Paediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Savitehtaankatu 5, 20521 Turku, Finland
b
InFLAMES Research Flagship Center, University of Turku, Kiinanmyllynkatu 10, 20520 Turku, Finland
c
Section of Paediatric Infectious Disease, Faculty of Medicine, Imperial College London, Norfolk Place, London, United Kingdom
d
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
e
Vaccine Evaluation Center, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada

a r t i cl e i nfo s umma r y

Article history: Diagnostic tools to differentiate between community-acquired bacterial and viral meningitis are essential to
Accepted 22 January 2024 target the potentially lifesaving antibiotic treatment to those at greatest risk and concurrently spare pa­
Available online 1 February 2024 tients with viral meningitis from the disadvantages of antibiotics. In addition, excluding bacterial meningitis
and thus decreasing antibiotic consumption would be important to help reduce antimicrobial resistance
Keywords:
and healthcare expenses. The available diagnostic laboratory tests for differentiating bacterial and viral
Meningitis
meningitis can be divided microbiological pathogen-focussed methods and biomarkers of the host re­
Bacterial
Viral sponse. Bacterial culture-independent microbiological methods, such as highly multiplexed nucleic acid
Aseptic amplification tests, are rapidly making their way into the clinical practice. At the same time, more con­
Meningitis panel ventional host protein biomarkers, such as procalcitonin and C-reactive protein, are supplemented by
Biomarker newer proteomic and transcriptomic signatures. This review aims to summarise the current state and the
recent advances in diagnostic methods to differentiate bacterial from viral meningitis.
© 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction S. pneumoniae, N. meningitidis, or Hib are now the causative agents in

only 3.5% of children aged under 5 years with suspected meningitis
Bacterial meningitis is a devastating disease with 5–30% case- in the World Health Organisation (WHO) African region.19 There is
fatality despite of antimicrobial treatment and considerable risk of still great geographical variation in the incidence of bacterial me­
long-term sequelae, including hearing loss, developmental delay, ningitis, with highest yearly incidences in sub-Saharan Africa and
and motor deficits.1,2 Rapid initiation of antibiotics is recommended lowest in high-income countries.20 Vaccination programmes have
to improve post-infection outcomes.3–8 Conversely, rapid diagnosis significantly decreased the incidence of mumps meningitis.21 On the
of viral meningitis can help to reduce hospitalisation rates, length of other hand, emerging use of nucleic acid amplification tests (NAATs)
hospital stay, costs, and detrimental effects of unnecessary anti­ has increased the detection rate of some neurotropic viruses, such as
biotics on antimicrobial resistance and for the host microbiome.9–14 enteroviruses.22 The dramatic reduction in cases of bacterial me­
Early differentiation between bacterial and viral causes of meningitis ningitis has lowered the probability that a fully vaccinated child with
is therefore crucial. clinical features suggestive of meningitis actually has a bacterial
The incidence of community-acquired bacterial meningitis has cause and thus makes a high level of accuracy essential for a diag­
declined steadily following introduction of protein-polysaccharide nostic test to be useful.
conjugate vaccines against Haemophilus influenzae type b (Hib), and Current guidelines for bacterial meningitis state that the diag­
serotype/capsular group specific vaccines against Streptococcus nosis of meningitis should be based on CSF analysis.5–7 Clinical
pneumoniae and Neisseria meningitidis in the past few decades.15–18 prediction rules that include simple laboratory parameters from
blood and cerebrospinal fluid (CSF) samples are able to reliably ex­
clude bacterial meningitis in some children with a raised CSF white
⁎
Correspondence to: Vaccine Evaluation Center, BC Children’s Hospital Research blood cell (WBC) count (CSF pleocytosis).23,24 The most widely stu­
Institute, 950 West 28th Ave, Vancouver, British Columbia V5Z 4H4, Canada. died clinical scoring system, the Bacterial Meningitis Score, was
E-mail addresses: [email protected] (L. Ivaska), designed to exclude a bacterial aetiology in children with suspected
[email protected] (J. Herberg), [email protected] (M. Sadarangani).

https://doi.org/10.1016/j.jinf.2024.01.010
0163-4453/© 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

Fig. 1. Diagnostic tests for meningitis.

meningitis. A meta-analysis reported a negative predictive value of studies. Based on authors’ assessment, the most relevant papers for this
99.6% and a positive predictive value of 28% for the Bacterial Me­ review were cited. Only papers written in English were included.
ningitis Score in a pooled cohort of patients with suspected me­
ningitis and a high prevalence (25%) of bacterial meningitis.25 A Current microbiological diagnostic methods
recent cohort study included adults with bacterial or viral central
nervous system (CNS) infection, negative CSF Gram stain, and CSF The increasing use of NAATs is changing microbiological diag­
WBC count > 10/mm3. In this cohort, a clinical score comprising of nostics of meningitis. Conventional methods, such as direct ex­
routinely collected clinical and CSF parameters (body temperature, amination with Gram stain and bacterial CSF culture, are still an
serum WBC count, CSF WBC count, CSF granulocyte count, CSF essential part of the routine diagnostic work-up but are increasingly
glucose level, CSF protein concentration) was promising in excluding supplemented by molecular techniques. Highly multiplexed NAATs
bacterial meningitis.26 However, clinical prediction rules are not and sequencing based metagenomic assays enable a sensitive diag­
validated in children receiving antibiotics before the lumbar punc­ nostic approach based on the clinical syndrome that does not rely on
ture (LP), and only a third of children have a timely LP prior to an­ detection of a small, restricted number of pre-specified target pa­
tibiotic treatment.27 Ideally, biomarkers detectable early from blood thogens. However, the high sensitivity of NAATs might complicate
and/or CSF in patients pre-treated with antibiotics could overcome the interpretation of the results. Application of multiplex PCR NAAT
these issues (Fig. 1). There have been numerous studies to identify diagnostics to blood and respiratory secretions of children with fever
improved biomarkers for differentiation of invasive bacterial infec­ found that for most common bacterial and viral pathogens, a posi­
tions from other causes of fever. Novel diagnostic approaches are tive detection was insufficient to assign aetiology, as positive viral
based on quantitating one or more mRNA transcripts or proteins and bacterial results were not restricted to patients judged to have a
simultaneously in a blood sample comprising a signature char­ viral or bacterial cause of illness, and many pathogens were detected
acteristic for bacterial or viral aetiology.28–39 at high frequency in healthy controls.41
The WHO driven campaign, ’Defeating bacterial meningitis by Antigen detection tests have a limited role in the current mi­
2030’, calls for improved diagnostic methods.40 Rapid diagnostic crobiological diagnosis of meningitis. However, a recent meta-ana­
tests would expedite aetiological diagnosis, and thus identify pa­ lysis suggested that pneumococcal antigen detection tests in CSF
tients who will most likely benefit from the early treatment with could be useful in excluding pneumococcal meningitis.42
effective antibiotics. Point-of-care tests operated independently
without the immediate support of a central laboratory could be Pathogen-specific NAATs
useful also in helping to reach the microbiological diagnosis of Enteroviruses are the commonest cause of viral meningitis.
meningitis in a greater proportion of patients than before, especially Detection of enteroviruses from CSF reduces use of additional di­
in remote and low-resource settings, and thereby simplify epide­ agnostic tests, doses of antibiotics administered, and length of hos­
miological surveillance. This review aims to summarise the existing pital stay.9–12 Currently, NAATs are the mainstay of enterovirus
data on the diagnostic tests for distinguishing between community- diagnosis because of their significantly higher clinical sensitivity and
acquired bacterial and viral meningitis. shorter turn-around time than viral culture.43,44 For children under 2
years of age, enterovirus polymerase chain reaction (PCR) testing
Search strategy and selection criteria from blood has been recommended in addition to CSF testing be­
cause of higher diagnostic yield.45 Stool PCR improves the detection
We searched PubMed for articles published from August 1980 to rate of enteroviruses in adults with culture-negative meningitis,
September 2023, by use of the. terms: ’meningitis’ AND ’aseptic’ OR especially if symptoms have lasted longer than 2 days.44 PCR is the
’viral’ AND ’bacterial’ AND ’diagnostics’, and reference lists of identified method of choice also for diagnosing parechovirus infections and

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L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

should be performed in the target population of infants 12 months of 25 (2%) were positive for HHV6, with only 5/25 (20%) receiving a
age and younger with suspected meningitis.46 It is important to note clinical diagnosis of HHV6 meningitis/meningoencephalitis.79 In the
that viral loads in CSF are often low, and some commercial assays same study, chromosomally integrated HHV6 was identified in 3/18
have insufficient sensitivity to detect the low copy numbers of en­ (20%) children. Concerns over the interpretation of HHV6 positive
teroviruses, including enterovirus D68, and parechoviruses.47 CSF samples have been raised in adult patients as well. In a case
For bacteria, it has been shown that use of NAATs, in addition to series of 12 adult patients with CSF sample positive for HHV6 by the
blood and CSF bacterial culture, can increase the detection rate of the Filmarray Meningitis/Encephalitis panel, the majority of the patients
most common pathogenic bacteria.48–50 In infants 7–90 days of age had an alternative explanation for their symptoms.80
with suspected meningitis, PCR for Streptococcus agalactiae was Clinical data describing the diagnostic performance of the
positive in the CSF of 22/2495 (0.9%) infants in comparison bacterial Filmarray Meningitis/Encephalitis panel, especially in paediatric
culture that was positive in 5/2495 (0.2%).51 Culture-independent patients, are limited. Prospective large-scale studies with adequate
tests also aid detection of N. meningitidis in patients treated with numbers of bacterial meningitis cases are needed to allow statistical
antibiotics prior to LP for several days after starting the treat­ evaluation of each individual target.81 In many clinical settings, the
ment.52,53 Despite the advantages offered by NAATs, their use in the low pre-test probability of bacterial meningitis affects the usefulness
clinical setting is not universal.27 of diagnostic tests. This is demonstrated by another recent meta-
analysis on the Filmarray Meningitis/Encephalitis panel that re­
Multiplexed NAATs for infections in the central nervous system ported that when the prevalence of bacterial meningitis is 2%, the
Recently, a novel NAAT to detect the three pathogens (S. pneu­ positive predictive value of a positive bacterial finding in the panel
moniae, N. meningitidis, Hib) directly from samples without nucleic for bacterial meningitis ranges from 42% to 68%, depending on the
acid extraction has been developed, allowing simplified specimen reference method.82
processing.54 More comprehensive syndromic tests for CNS infec­ Novel diagnostic tests should become part of the daily clinical
tions are being increasingly developed and implemented. These as­ practice when their safety and test parameters have been evaluated
says are based on nucleic acid amplification and simultaneously and are deemed acceptable, and in addition post-implementation
detect multiple important bacterial, viral, and fungal pathogens from impact should be assessed regarding treatment decisions/outcomes,
CSF. The most widely studied assay, the Biofire Filmarray Meningitis/ safety, and cost-effectiveness. In Greece, a randomised controlled
Encephalitis panel, targets 14 pathogens and delivers results in ap­ trial was performed with 142 children randomised 1:1 for inter­
proximately one hour: six bacteria (Escherichia coli K1, Hib, Listeria ventional and control arms. The aim was to assess the impact of the
monocytogenes, N. meningitidis, S. agalactiae, S. pneumoniae), seven Filmarray Meningitis/Encephalitis panel as part of the diagnostic
viruses (cytomegalovirus, enteroviruses, herpes simplex virus 1 workup of children with suspected CNS infection and CSF pleocy­
(HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 tosis (CSF WBC count > 15/mm3).83 The detection rate of pathogens
(HHV6), human parechovirus, varicella-zoster virus), and one fungus was increased (37/71, 52% versus 16/71, 23%) and length of hospital
(Cryptococcus neoformans/gattii). Most studies have found the assay stay in patients with non-bacterial meningitis (5 versus 8 days),
to be sensitive and specific compared with bacterial culture and duration of antimicrobial use (4 versus 7 days), and hospitalisation
virus PCR.55–62 In comparison with culture-based methodologies, an costs (1042€ versus 1552€) were decreased in cases compared with
enhanced detection rate of bacterial pathogens has been reported in controls.
antibiotic pre-treated patients.57,63,64 The assay seems less useful for In addition to Filmarray Meningitis/Encephalitis panel, other
diagnosing cryptococcal meningitis in settings where CSF crypto­ syndrome based diagnostic tools for CNS infections or combination
coccal antigen tests are in use: in comparison with antigen testing, of viral and bacterial multiplex assays are available, but not widely
the sensitivity of the Filmarray Meningitis/Encephalitis panel for validated in different clinical settings.84–89 It has been suggested that
Cryptococcus has varied between 52% and 84%.55,65,66 Several retro­ a multiplex NAAT originally designed for detecting bacteria in posi­
spective studies have found that introducing the Filmarray Me­ tive blood culture could expedite the detection of bacteria in CSF of
ningitis/Encephalitis panel in clinical practice has shortened the patients with suspected nosocomial meningitis.90
duration of antiviral treatment against HSV infections.67–70 A retro­
spective study in children > 60 days of age showed that im­ Sequencing based methods to detect pathogens
plementation of the Filmarray Meningitis/Encephalitis panel Nucleic acid sequencing of the bacterial 16S rRNA gene can be
doubled the amount of testing for HSV in the CSF, had no impact on used to detect bacterial pathogens directly from CSF, which may be
the amount of acyclovir initiation, and decreased the duration of the useful especially in patients pre-treated with antibiotics.91–94 A
acyclovir treatment from a median of five to two doses.71 In con­ meta-analysis reported a sensitivity of 92% and specificity of 94% for
sidering whether the Filmarray Meningitis/Encephalitis panel is detection of bacteria compared with culture. In patients with pre­
suitable for excluding HSV meningoencephalitis as a standalone test, sumed bacterial meningitis who were CSF culture-negative, 16S
a recent meta-analysis reported pooled sensitivity of 84% for HSV-1% rRNA PCR identified a potential cause in 30% of the cases.95 However,
and 93% for HSV-2 in comparison with HSV PCR.72 16S gene sequencing does not always allow identification of bacteria
Occasional false positive and negative results have been reported to the species level, there is still lack of available reference sequence
with the Filmarray Meningitis/Encephalitis panel, an observation data in gene libraries, and potential contamination of the reagents/
which emphasises the need for caution when novel tests are in­ samples impair the diagnostic performance of 16S approaches.96
troduced in clinical practice, especially if used without backup Metagenomic approaches to diagnosis rely on sequencing of
methods.60,73–76 In addition to false positive results, pathogens can nucleic acids in a sample and, in context of microbiological diag­
be detected without certainty of clinical relevance, for example nostics, removal of the host DNA and RNA reads. Reads from the
HHV6. When CSF from 262 paediatric patients were tested with the remaining genomic material are then compared with libraries of
Filmarray Meningitis/Encephalitis panel, HHV6 was the second most known bacterial and viral sequences. Few preliminary studies de­
frequently detected pathogen (in 9/262 (3%) samples), surpassed scribe the use of metagenomic sequencing as a diagnostic tool in
only by enteroviruses (in 20/262 (8%) samples). In the age group of meningitis patients.97–100 A recent study compared the additional
1–12 months, 6/55 (11%) CSF samples were HHV6 positive.77 De­ information provided by the CSF metagenomic sequencing in com­
tection of HHV6 in the CSF of young infants does not always require parison with routine clinical testing in children and adults with
antiviral treatment.78 In a study of 1005 children who were tested suspected meningitis and/or encephalitis of unknown origin. In this
with Filmarray Meningitis/Encephalitis panel in their CSF samples, study, 58 infective agents could be diagnosed in 57/204 (28%)

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L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

patients; 13/58 (22%) infections were diagnosed solely by metage­ infection. The signature was combined with a gene expression sig­
nomic sequencing and the findings were thought to have clinical nature for viral infection and validated in a prospective cohort of
relevance in 8/13 cases. Interpretation of sequencing data is not al­ febrile ED patients. The combined signature had sensitivity of 94%
ways straightforward and in this study, treating physicians received and specificity of 93% for bacterial infection and receiver operating
support from experts in infectious diseases, microbiology, bioinfor­ characteristic area under the curve of 0.95.117 Before novel tests can
matics, and sequencing techniques.101 Sequencing of clinical sam­ be helpful in a larger scale or prove their impact at the point-of-care,
ples does not need to be slow. A novel rapid metagenomic next useable and affordable platforms must be developed.118,119 Gene
generation sequencing method was able to deliver results in only six expression profiling of multiple biomarkers simultaneously holds
hours.100 Novel metagenomic applications focus on detecting mi­ potential to diagnose a wide range of causes of fever (bacterial, viral,
crobial cell-free DNA from liquid samples but their clinical utility is inflammatory) simultaneously in a single multiclass test.120
not well established yet.102,103 Another approach for the same objective is to combine blood
levels of protein biomarkers. Oved et al. screened potential host
Host-based blood biomarkers response biomarkers in blood and developed a combination of three
proteins.32 In an external validation study in young children with
Clinical guidelines do not recommend meningitis diagnosis to be lower respiratory tract infection or with fever without a source,
based only on blood test results due to the absence of high quality of proteome based host signature discriminated bacterial from viral
evidence to reliably exclude bacterial meningitis.5–7 CSF testing en­ infection with sensitivity of 87% and specificity of 91%.31 At the
ables distinguishing bacterial meningitis from other invasive bac­ present time, results from studies focusing specifically on differ­
terial infections more accurately, increases specific microbiological entiating bacterial and viral meningitis are lacking but studies in
diagnosis, and allows antibiotic susceptibility testing for cultured both children and adults imminent.121,122
isolates and epidemiological surveillance.
Host-based CSF biomarkers
Procalcitonin, C-reactive protein (CRP)
Good availability and short turn-around-time make blood-based, Elevated CSF WBC count and protein concentration, and de­
non-specific biomarkers of inflammation, such as procalcitonin or creased CSF glucose all support the diagnosis of bacterial meningitis.
CRP, attractive diagnostic options for supporting the diagnosis of In a prospective study in adults with bacterial meningitis at least one
bacterial meningitis in situations where an LP is not possible, for of these laboratory findings was present in 88% of the patients.123 In
example when it is contraindicated. In small studies, blood pro­ a study of 9111 LPs in neonates, cut off of 21 WBCs/mm3 in the CSF
calcitonin has shown potential for distinguishing between bacterial had sensitivity of 79% and specificity of 81% for bacterial me­
and viral meningitis. A French study enrolled 254 adult meningitis ningitis.124 In a retrospective study in US paediatric EDs among
patients with CSF WBC count > 5/mm3 and negative CSF Gram stain children with CSF pleocytosis (CSF WBC count ≥10/mm3) not re­
in the emergency department (ED) setting.104 Patients pre-treated quiring immediate admission and not pre-treated with antibiotics,
with more than two doses of antibiotics were excluded. A cut-off of only 121/3295 (3.7%) children had bacterial meningitis.23 In the
0.28 ng/mL for blood procalcitonin resulted in sensitivity of 95% and current post-vaccine era, conventional CSF tests are not sufficient as
specificity of 100% for bacterial meningitis. In two paediatric ED the only rationale for clinical decision making.
studies, 167 and 50 children with suspected meningitis were re­
cruited.105,106 Serum procalcitonin concentration of 0.5 ng/mL was Defensin and lactoferrin, lactate dehydrogenase (LDH), lactate, soluble
used as the cut-off for bacterial meningitis in both studies and re­ triggering receptor expressed on myeloid cells-1 (sTREM-1)
sulted in sensitivities of 89% and 95%, and specificities of 89% and Antimicrobial peptides such as defensin and lactoferrin, enzymes
85%, respectively. Young infants are at risk for invasive bacterial including LDH, and metabolic products including lactate have all
infections including meningitis and sometimes appear without focal been studied. Defensin and lactoferrin are secreted mainly by neu­
signs of CNS involvement. In a recent study of 1821 febrile infants 60 trophils, and are elevated in blood and in CSF during the in­
days and younger, a clinical prediction rule including serum pro­ flammatory response to bacterial infection.125,126 As a catalyst of
calcitonin level identified patients with low risk for serious bacterial lactate metabolism, LDH is elevated in various CNS pathologies in­
infection (negative predictive value 99.6%) without missing any of cluding bacterial meningitis.127 CSF lactate concentration is con­
the ten infants with bacterial meningitis.107 Blood CRP performance sidered to increase as a result of anaerobic metabolic conditions
is inferior to procalcitonin in some studies but may be useful induced by bacterial meningitis. For defensin, lactoferrin, and LDH
(Table 1).108–116 It was proven helpful in differentiating bacterial there are only few reports and no well-designed clinical studies on
meningitis (n = 55) from viral meningitis (n = 182) in children with a their diagnostic performance.127–130 In contrast to CSF glucose con­
negative CSF Gram stain.109 With the cut-off of 20 mg/L, the mea­ centration that is proportional to blood glucose concentration, CSF
surement had a negative predictive value of 99% for bacterial me­ lactate concentration seems not to be a direct consequence of the
ningitis. blood lactate concentration.131,132 Results from the earlier studies on
the diagnostic utility of CSF lactate concentration in meningitis are
Blood RNA transcriptome and proteome controversial (Table 1).133–138 Pretreatment with antibiotics com­
Blood transcriptome profiles in the host are increasingly studied plicates the interpretation of CSF lactate results in the diagnosis of
to identify gene expression signatures that are specific for either meningitis: 2 meta-analyses and one more recent adult study re­
bacterial or viral infections. Recently, an international research ported sensitivities of 94–96% for CSF lactate for differentiating
consortium reported 100% sensitivity and 96% specificity for distin­ bacterial from culture-negative meningitis in non-pretreated pa­
guishing bacterial (including bacterial-viral co-infections) from viral tients.104,139,140 However, in studies that did not exclude antibiotic
infections in febrile children by using a two transcript RNA signature pretreated patients, the sensitivity of CSF lactate to detect bacterial
of the host.30 Another study on RNA signature profiles in febrile meningitis was only 49%.139 The optimal cut off value for CSF lactate
infants 60 days or younger reported 87% sensitivity and 89% speci­ concentration derived from the meta-analysis was 3.5 mg/L or
ficity for distinguishing between bacterial non-bacterial aetiolo­ 3.9 mmol/L.139 CSF lactate is not a perfect biomarker for differ­
gies.29 A separate analysis combined transcriptional expression entiation between bacterial and viral meningitis: it requires CSF
datasets from 8 published studies and used computational machine sampling and cannot give the exact microbiological diagnosis.
learning methods to create a ‘rule-out’ signature of bacterial However, it is readily available, relatively inexpensive, and performs

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L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

Table 1
Main biomarkers to distinguish bacterial meningitis from other aetiologies.

Study setting and population Pretreatment with antibiotics Number of bacterial Main results (cut-off,
and viral meningitis sensitivity, specificity for
cases, n (%) bacterial meningitis)

Blood PCT
Children
Kuppermann et al.107 Prospective study in infants < 60 Excluded if pretreatment with Bacterial meningitis: Cut-off 1.71 ng/mL (as part of
(n = 1821, of whom LP in days evaluated for serious bacterial antibiotics in < 48 hours n = 10 (0.7%) a clinical prediction rule)
n = 1399) infection Viral: not reported Sensitivity 100%
Dubos et al.105 (n = 167) Retrospective study in children Excluded if pretreatment with Bacterial: n = 21 (12.6%) Cut-off 0.5 ng/mL
hospitalised with meningitis antibiotics in < 48 hours Viral: n = 146 (87.4%) Sensitivity 89%
Specificity 89%
Adults
Viallon et al.104 (n = 254) Prospective study in adults at the Patients with > 2 preceding doses of Bacterial: n = 35 (13.8%) Cut-off 0.28 ng/mL
ED with meningitis and negative antibiotics were excluded Viral: n = 181 (71.3%) Sensitivity 95%
direct CSF examination Specificity 100%

Blood CRP
Children
Sormunen et al.109 (n = 237) Prospective study in children with Excluded if pretreatment with Bacterial: n = 55 (23.2%) Cut-off 20 mg/L
bacterial meningitis and negative antibiotics Viral: n = 182 (76.8%) Sensitivity 96%
direct CSF examination. Specificity 93%
Retrospective cohort of children
with viral meningitis
Roine et al.110 (n = 83) Retrospective study in children with Not reported Bacterial: n = 67 (80.7%) Cut-off 20 mg/L
meningitis Viral: n = 16 (19.3%) Sensitivity 96%
Specificity 88%.
Children and adults
Hansson et al.113 (n = 235) Retrospective study in both children 8/60 (13.3%) of the patients Bacterial: n = 60 (25.5%) Cut-off 50 mg/L
and adults with suspected CNS categorised as bacterial meningitis Viral: n = 146 (62.1%) Sensitivity 88%
infection (culture-negative) pretreated with
antibiotics

CSF lactate
Children
Ruuskanen et al.135 (n = 447, Retrospective study in children with Not reported Bacterial: n = 32 (7.2%) Cut-off 3.0 mmol/L
of whom n = 104 with CSF lactate results available Culture-negative Sensitivity 94%
meningitis) meningitis: n = 72 Specificity 92%
(16.1%)
Rutledge et al.138 (n = 185, of Retrospective study in children with Pretreatment with antibiotics in 8/29 Bacterial: n = 29 (15.7%) Cut-off 3.0 mmol/L
whom n = 116 with CSF available for lactate (27.6%) of those with bacterial Culture-negative Sensitivity 93%
meningitis) measurement meningitis meningitis: n = 87 Specificity 84%
(47.0%)
Adults
Viallon et al.104 (n = 254) Prospective study in adults at the Patients with > 2 preceding doses of Bacterial: n = 35 (13.8%) Cut-off 3.8 mmol/L
ED with meningitis and negative antibiotics were excluded Viral: n = 181 (71.3%) Sensitivity 94%
direct CSF examination Specificity 97%

CSF IL-6
Children
Srinivasan et al.150 (n = 684) Prospective study in infants Pretreatment with antibiotics in 522/ Bacterial: n = 11 (1.6%) Cut-off 790 pg/mL
younger than 180 days receiving LP 684 (76.3%) Viral: n = 3 (0.4%) Sensitivity 82%
Specificity 99%
Adults
Takahashi et al.151 (n = 70) Retrospective study in critically ill Not reported Bacterial: n = 13 (18.6%) Cut-off 644 pg/mL
adults admitted in the ICU with Viral: n = 6 (8.6%) Sensitivity 92%
suspected bacterial meningitis Specificity 90%

PCT = procalcitonin; LP = lumbar puncture; ED = emergency department; CSF = cerebrospinal fluid; CNS = central nervous system; ICU = intensive care unit.

moderately well, with the prerequisite of usage only in patients bacterial meningitis was shown in a study with adults with either
without prior antibiotic treatment (Fig. 2). bacterial meningitis or tick-borne encephalitis.143 A threshold of
The expression of sTREM-1 is upregulated in phagocytes fol­ 0.5 µg/L for serum and CSF procalcitonin concentrations had sensi­
lowing exposure to microbial products. In addition to other bacterial tivities of 90% and 55% and specificities of 100% for bacterial me­
infections, sTREM-1 concentration in CSF has been studied as a ningitis, respectively. In a prospective study in 120 adults in the ED
biomarker for bacterial meningitis.141,142 In a retrospective study with suspected meningitis without antibiotic pre-treatment, a CSF
with 92 adults with community-acquired meningitis a cut-off level procalcitonin cut-off of 0.74 µg/L had sensitivity of 69% and specifi­
of 20 pg/mL had the sensitivity of 73% and specificity of 77% for city of 100%, and a serum procalcitonin cut-off of 0.88 µg/L had
bacterial meningitis. It was also noted that among patient with sensitivity of 87% and specificity of 100% for detecting bacterial
bacterial meningitis, higher levels of sTREM-1 were associated with meningitis.144 A systematic review and meta-analysis included 2058
higher mortality.141 study subjects in 22 different studies and reported overall sensitiv­
ities and specificities of 86% and 80% for CSF procalcitonin and 97%
Procalcitonin in CSF and 95% for blood procalcitonin for diagnosing bacterial meningitis,
Measuring the procalcitonin level in the CSF has not been shown respectively.145 A more recent report from a neurological tertiary
to offer an advantage over serum measurement. The superiority of unit reported better discriminatory value for procalcitonin in CSF
serum procalcitonin over CSF procalcitonin as a biomarker for than in blood between adult patients with bacterial meningitis in

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L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

Fig. 2. An approximation of the effect of antibiotic pretreatment on the capability of diagnostic tests to detect bacterial meningitis.

comparison with tuberculous meningitis, viral meningitis, auto­ host-based biomarker results could point out the right direction. It can
immune meningitis/encephalitis, or non-inflammatory conditions. It be hypothesised that a combination of the two above mentioned ap­
is of note that 89% of the patients, including all the patients in the proaches, the host-based and the molecular microbiology based, could
bacterial meningitis group, had received pre-treatment with anti­ overcome the major diagnostic obstacles, e.g. decreased sensitivity of
biotics for a median of 8 days. The results suggest that in patients host-based biomarkers very early in the disease and the low diagnostic
with bacterial meningitis pre-treated with antibiotics, procalcitonin yield of microbiological assays in antibiotic pretreated patients. There is
concentration in CSF might normalise later than in blood.146 CSF no perfect diagnostic test with 100% sensitivity and specificity. As more
procalcitonin has also been suggested to be useful in differential tests enter use that have multiple parallel host or pathogen targets, then
diagnosis of neonates with suspected meningitis and traumatic LP147 interpretation of the results will require careful consideration of the pre-
and in the diagnosis of post-neurosurgical bacterial meningitis.148 In test probabilities, potentially through integration of clinical data with
a prospective study with 50 children with suspected meningitis and test results, in order to avoid over-calling of false-positive results.
CSF pleocytosis, CSF or serum procalcitonin levels were not found to As stated in WHO ’Defeating bacterial meningitis by 2030’ cam­
be useful in differentiating bacterial and viral meningitis.149 In an ED paign, rapid molecular microbiology assays hold promise of identi­
setting, CSF procalcitonin seems to be of limited diagnostic value. fying pathogens in emerging outbreaks early. In this respect, it is
reassuring that the most widely used NAAT assay, the Filmarray
CSF cytokines Meningitis/Encephalitis panel, was successfully implemented for
Other biomarkers in the CSF have also been investigated to dif­ diagnostic use in an Ethiopian centre without previous experience of
ferentiate bacterial and non-bacterial meningitis. A study of 684 molecular microbiological assays164 and could improve the detection
infants < 6 months of age who had an LP investigated the diagnostic rate of pathogenic bacteria and viruses in children with suspected
accuracy of six different cytokines to predict culture positive bac­ meningitis as demonstrated by a retrospective study from Nigeria.165
terial meningitis.150 Definite bacterial meningitis was diagnosed in The costs of rapid molecular assays still restrict their use but in­
11/684 (2%) infants of whom 9/11 (82%) were antibiotic pre-treated. creasing competition in the market, and the emergence of platforms
A pro-inflammatory cytokine interleukin 6 (IL-6) and an anti-in­ based on new technologies, could improve the price trajectory and
flammatory cytokine IL-10 had the best discriminatory power be­ thus enable wider adoption.
tween culture-proven and antibiotic non-pretreated, culture-
negative cases. Elevated levels of IL-6 in the CSF have been asso­ Limitations
ciated with bacterial meningitis in other studies (Table 1).151–153
Additionally, several biomarkers in the CSF have been investigated to Bacterial meningitis can co-exist with bacteraemia or other forms of
assist in the diagnosis of Lyme neuroborreliosis.154,155 The most invasive bacterial infection. For completeness of the data, we have in­
promising and widely studied is C-X-C Motif Chemokine Ligand 13 cluded some studies in this review that did not focus solely on me­
(CXCL13). An elevated level of CXCL13 in the CSF is closely related to ningitis. Also, the definition of meningitis that was used in different
intrathecal production of Borrelia burgdorferi antibodies and is studies was highly variable reflecting real world differences of managing
therefore helpful for diagnosing neuroborreliosis.154,156–160 Also patients with suspected meningitis. The clinical utility of diagnostic tests
neurosyphilis can cause elevation of CXCL13 level in the CSF.161 depends on their sensitivity, specificity, and the pretest probability of the
target condition. Screening tests typically require a high sensitivity,
Future perspectives whilst targeted diagnostics require high specificity. For conditions that
are rare, or for populations with a low pretest probability, the devel­
Microbiological aetiology remains unclear in approximately half of opment and introduction of tests requires careful consideration of the
the patients with a clinical diagnosis of meningitis. Some reports have population that is suitable for testing, to avoid unacceptably high rates of
suggested that additional methods could facilitate more rapid identifi­ false positive tests. With discovery pipelines delivering potential bio­
cation of causative bacteria including direct CSF examination by matrix- markers for a wide range of sometimes rare conditions, there is a need
assisted laser desorption/ionisation time-of-flight mass spectrometry in for new strategies, for instance using artificial intelligence approaches,
smear positive patients or by microarrays that target multiple pathogens that can define and identify the subset of patients with a higher pre-test
simultaneously.162,163 In terms of treatment decisions, the exact micro­ probability based on their clinical characteristics - ie those patients
biological aetiology might not always be required immediately and suitable for testing in clinical use.

6
L. Ivaska, J. Herberg and M. Sadarangani Journal of Infection 88 (2024) 106111

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MS has been an investigator on projects funded by 17. Hsu HE, Shutt KA, Moore MR, Beall BW, Bennett NM, Craig AS, et al. Effect of
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GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, 2009;360:244–56. https://doi.org/10.1056/NEJMoa0800836
Symvivo and VBI Vaccines. All funds have been paid to his institute, 18. Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for
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population-based observational study. Lancet Infect Dis 2014;14:397–405. https://
although no tests are commercially available. Other authors have no doi.org/10.1016/S1473-3099(14)70027-1
competing interests to declare. 19. Mwenda JM, Soda E, Weldegebriel G, Katsande R, Biey JNM, Traore T, et al. Pediatric
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