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Three Part Question

In [adults undergoing lumbar punctures for possible meningitis] what are [the sensitivity and specificity of CSF lactate] for [diagnosing acute community-acquired bacterial meningitis]?

Clinical Scenario

You are evaluating a patient in the emergency department in whom you are considering the diagnosis of acute community-acquired bacterial meningitis. You perform a lumbar puncture and when ordering CSF studies wonder if sending a CSF lactate would help distinguish acute bacterial meningitis (ABM) from acute viral meningitis (AVM).

Search Strategy

PubMed
((("bacteria"[mesh] OR "bacterial infections"[mesh]) AND ("meningitis"[mesh:noexp])) OR "meningitis, bacterial"[mesh] OR (mening*[tw] AND (bacteria*[tw] OR escherichia[tw] OR haemophilus[tw] OR listeria[tw] OR meningococc*[tw] OR neisseria[tw] OR pneumococc*[tw] OR streptococc*[tw]))
AND (“cerebrospinal fluid”[mesh] OR “cerebrospinal fluid”[subheading] OR “cerebrospinal fluid”[tw] OR “CSF”[tw]) AND (“lactates”[mesh] OR lacta*[tw] OR lacti*[tw]))
AND english[lang]

EMBASE
(((‘bacterium’/exp OR ‘bacterial infection’/exp) AND ‘meningitis’/exp) OR (mening*:ab,ti,kw AND (bacteria*:ab,ti,kw OR ‘escherichia’:ab,ti,kw OR ‘haemophilus’:ab,ti,kw OR listeria:ab,ti,kw OR meningococc*:ab,ti,kw OR ‘neisseria’:ab,ti,kw OR pneumococc*:ab,ti,kw OR streptococc*:ab,ti,kw)))
AND ((‘cerebrospinal fluid'/exp OR ‘cerebrospinal fluid’:ab,ti,kw OR ‘CSF’:ab,ti,kw) AND (‘lactic acid'/exp OR lact*:ab,ti,kw))
AND [english]/lim

Search Outcome

PubMed -- 506 results
EMBASE -- 643 results
Total -- 742 unique results

106 full text articles were reviewed after screening titles/abstracts from which 33 original articles and two systematic reviews were ultimately selected for inclusion. One of the 33 articles (Schwarz et al.) was initially screened out but ultimately included after reviewing the two systematic reviews and the full text of the article. For completeness, the original articles included in the two systematic reviews are listed below as there appear to be several minor discrepancies in the data abstracted in the systematic reviews.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Abro et al. 2009 UAE	Single hospital Mean 34±12y, 84% male n=53 ABM, n=42 AVM	Cohort Lactate cutoff 3.8mM	Sensitivity	98.1%	Excluded ABM without organism identified Significant overlap in patients with Abro et al. 2008
			Specificity	100%
			LR+	Infinity
			LR-	0.019
Abro et al. 2008 UAE	Single hospital Mean 34±12y, 87% male n=86 ABM, n=48 AVM	Cohort Lactate cutoff 3.8mM	Sensitivity	98.8% (?erroneously reported as 98.3% by authors)	Significant overlap in patients with Abro et al. 2009
			Specificity	100%
			LR+	Infinity
			LR-	0.012
Berg et. al 1982 Sweden	Multicenter Mean 30 vs. 21y ABM vs. AVM n=18 ABM, n=121 AVM	Cohort Lactate cutoff 3.0mM	Sensitivity	88.9%	Excluded ABM without organism identified
			Specificity	92.6%
			LR+	12.0
			LR-	0.120
Briem et al. 1983 Sweden	Single hospital Mean 44 vs. 29y ABM vs. AVM, 52% male n=45 ABM, n=102 AVM	Cohort Lactate cutoff 3.5mM	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	96.1%
			LR+	25.5
			LR-	0
Brook et al. 1978 USA	Single hospital 54% adults n=25 ABM, n=26 AVM	Cohort Lactate cutoff 3.9mM using chromatographic method	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0
Buch et al. 2018 Denmark	Multicenter Median 64 vs. 41y ABM vs. AVM, 51% male n=51 ABM, n=125 AVM	Cohort Lactate cutoff 3.5/4.5mM using Radiometer analyzer	Sensitivity	96.1%/92.2%
			Specificity	84.8%/94.4%
			LR+	6.32/16.5
			LR-	0.046/0.083
Chen et al. 2012 China	Single hospital Mean 43±15 vs. 32±17y, 45% vs. 67% male ABM vs. AVM n=21 ABM, n=30 AVM	Cohort Lactate cutoff 3.3mM	Sensitivity	71.4%	Included patients pretreated with antibiotics/steroids
			Specificity	100%
			LR+	Infinity
			LR-	0.286
Curtis et al. 1981 UK	Two hospitals Unknown demographics n=10 ABM, n=12 AVM	Cohort Lactate cutoff 2.8mM	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0
D'Souza et al. 1978 UK	Two hospitals Unknown demographics n=5 ABM, n=26 AVM	Cohort Lactate cutoff 4.3mM	Sensitivity	100%	Unclear definition of ABM
			Specificity	100%
			LR+	Infinity
			LR-	0
Ellis and Oei 1979 USA	Single hospital Unknown demographics n=10 ABM, n=12 "CNS inflammation" including AVM	Cohort Lactate cutoff 5.0mM	Sensitivity	100%	Excluded ABM without organism identified "CNS inflammation" group included not only AVM but also leukemia, ICH, MS, and "hypoxic seizures"
			Specificity	100%
			LR+	Infinity
			LR-	0
Ferguson and Tearle 1977 UK	Single hospital Unknown demographics n=8 ABM, n=15 AVM	Cohort Lactate cutoff 5.6mM using chromatographic method	Sensitivity	100%	Unclear definition of ABM Included patients pretreated with antibiotics
			Specificity	100%
			LR+	Infinity
			LR-	0
Gastrin et al. 1979 Sweden	Single hospital Median 33 vs. 54 vs. 24y ABM vs. presumed ABM vs. AVM n=38 ABM, n=5 presumed ABM, n=17 AVM	Cohort Lactate cutoff 3.5mM using chromatographic method	Sensitivity	96%	Included patients pretreated with antibiotics
			Specificity	82.4%
			LR+	5.40
			LR-	0.056
Genton and Berger 1990 Switzerland	Single hospital Median 35/33y M/F, 46% male n=25 ABM, n=28 AVM	Cohort Lactate cutoff 4.2 using Hoffman-La Roche analyzer	Sensitivity	96%	Included patients pretreated with antibiotics Excluded ABM without organism identified
			Specificity	96.4% (erroneously reported as 100% by authors)
			LR+	26.9
			LR-	0.041
Giulieri et al. 2015 Switzerland	Multicenter Median 53 vs. 35y, 50% vs. 56% male ABM vs. AVM n=18 ABM, n=27 AVM	Cohort Lactate cutoff 3.5mM	Sensitivity	100%	Excluded ABM without organism identified Excluded AVM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0
Gould et al. 1980 UK	Single hospital Unknown demographics n=6 ABM, n=26 AVM	Cohort Lactate cutoff 3.4mM using chromatographic method	Sensitivity	83.3%	ABM group included TB meningitis
			Specificity	100%
			LR+	Infinity
			LR-	0.167
Herold et al. 1981 USA	Single hospital Unknown demographics n=9 ABM, n=2 AVM	Cohort Lactate cutoff 9mM	Sensitivity	100%	Unclear definition of ABM n=2 AVM makes the specificity extraordinarily fragile
			Specificity	100%
			LR+	Infinity
			LR-	0
Hurd et al. 1978 USA	Single affiliated adult/children hospital 77% adult n=11 ABM, n=80 comparator group including AVM	Cohort Lactate cutoff 3.4mM using chromatographic method	Sensitivity	100%	Excluded ABM without organism identified Comparator group included not only AVM but also ICH, cancer, and post-neurosurgical patients
			Specificity	97.5%
			LR+	40.0
			LR-	0
Jordan et al. 1983 USA	Single hospital Unknown demographics n=7 ABM, n=3 AVM	Cohort Lactate cutoff 3.0mM	Sensitivity	100%	Excluded ABM without organism identified n=3 AVM makes the specificity extraordinarily fragile
			Specificity	66.7%
			LR+	3.00
			LR-	0
Kleine et al. 2003 Germany	Single hospital Mean 49.5 vs. 43.1y, 58% vs. 54% male ABM vs. AVM n=40 ABM, n=46 AVM	Cohort Lactate cutoff 3.5mM	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	100% (?erroneously reported as 99.6% by authors)
			LR+	Infinity
			LR-	0
Komorowski et al. 1978 USA	Single hospital Unknown demographics n=21 "CNS infections", n=3 AVM	Cohort Lactate cutoff 3.4mM using chromatographic method	Sensitivity	100%	Unclear definition of ABM "CNS infections" included not only ABM but also fungal meningitis and CNS syphilis n=3 AVM makes the specificity extraordinarily fragile
			Specificity	100%
			LR+	Infinity
			LR-	0
Komorowski et al. 1986 USA	Single hospital Unknown demographics n=28 ABM, n=5 AVM	Cohort Lactate cutoff 3.0mM	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0
Lagi et al. 2016 Italy	Single ED 51% male n=24 ABM, n=641 comparator group including AVM	Cohort Lactate cutoff 3.9mM	Sensitivity	100%	Data not published -- personal communication from author Excluded ABM without organism identified and cases with organisms thought to represent contamination Comparator group included not only AVM but all patients undergoing lumbar puncture to evaluate for meningitis and ultimately deemed to not have ABM
			Specificity	97%
			LR+	33.7
			LR-	0
Landaas and Von Der Lippe 1985 Norway	Single hospital 47% vs. 52% male ABM vs. AVM n=19 ABM, n=24 AVM	Cohort Lactate cutoff 6.0mM	Sensitivity	84.2%	Included patients pretreated with antibiotics Excluded ABM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0.158
Lannigan et al. 1980 Canada	Single hospital 58% male n=14 ABM, n=14 AVM	Cohort Lactate cutoff 3.9mM	Sensitivity	92.9%	Excluded ABM without organism identified
			Specificity	78.6%
			LR+	4.33
			LR-	0.091
Lauwers 1978 Belgium	Single hospital Unknown demographics n=35 ABM, n=20 AVM	Cohort Lactate cutoff 3.9mM using chromatographic method	Sensitivity	100%	Excluded ABM without organism identified
			Specificity	100%
			LR+	Infinity
			LR-	0
Lester et al. 1985 Denmark	Multicenter Unknown demographics n=16 ABM, n=15 AVM	Cohort Lactate cutoff 3.5mM	Sensitivity	93.8%	Included patients pretreated with antibiotics
			Specificity	86.7%
			LR+	7.03
			LR-	0.072
Lindquist et al. 1988 Sweden	Multicenter Unknown demographics n=63 ABM, n=616 comparator group including AVM	Cohort Lactate cutoff 3.5mM	Sensitivity	88.9%	ABM group included TB meningitis Comparator group included not only AVM but also "unclassified meningitis", other infectious CNS conditions, seizures, and strokes
			Specificity	96.4%
			LR+	24.9
			LR-	0.115
Mandal et al. 1983 UK	Single hospital Unknown demographics n=20 ABM, n=59 AVM	Cohort Lactate cutoff 4.3mM	Sensitivity	100%
			Specificity	98.3%
			LR+	59.0
			LR-	0
Patterson et al. 2013 Uganda	Single hospital Mean 31±13y, 50% male, 81% HIV+ n=17 ABM, n=128 comparator group including AVM	Cohort Lactate cutoff 7.7mM using Accutrend POC analyzer	Sensitivity	88.2%	Comparator group included not only AVM but also fungal and TB meningitis
			Specificity	89.8%
			LR+	8.69
			LR-	0.131
Ponka et al. 1983 Finland	Single hospital Unknown demographics n=11 ABM, n=27 AVM	Cohort Lactate cutoff 3.0mM	Sensitivity	90.9%	Excluded ABM without organism identified
			Specificity	96.3%
			LR+	24.5
			LR-	0.094
Schwarz et al. 2000 Germany	Single hospital Mean 52y, 43% male n=16 ABM, n=14 AVM	Cohort Lactate cutoff 2.1mM using unknown method	Sensitivity	93.8%	No mention of lactate assay method (main focus of study was procalcitonin) Used lower cutoff of 2.1mM based on normal reference range
			Specificity	42.9%
			LR+	1.64
			LR-	0.146
Viallon et al. 2011 France	Single ED Mean 55±20 vs. 35±18y, 48% vs. 53% male ABM vs. AVM n=35 ABM, n=218 AVM	Cohort Lactate cutoff 3.8mM using i-STAT POC analyzer	Sensitivity	94.3%	Excluded ABM with initially positive gram stain/antigen detection Excluded ABM with concurrent alternative infection (e.g. pneumonia) Excluded culture-negative ABM
			Specificity	96.8%
			LR+	29.4
			LR-	0.059
de Almeida et al. 2009 Brazil	Single hospital Mean 21±20y, 53% male n=20 ABM, n=41 AVM	Cohort Lactate cutoff 3.5mM using Date Behring analyzer	Sensitivity	80%
			Specificity	97.6%
			LR+	32.8
			LR-	0.205
Huy et al. 2010 N/A	25 studies included (both adults and children) n=783 ABM, n=909 AVM	Systematic review and meta-analysis	AUC CSF lactate	0.984	Excluded non-English studies No gray literature Excluded studies with n<8 for either ABM or AVM Excluded studies with comparator groups including but not exclusively comprised of AVM
			AUC CSF WBC	0.948
			AUC CSF glucose	0.881
			AUC CSF/plasma glucose	0.952
			AUC CSF protein	0.862
Sakushima et al. 2011 N/A	33 studies included (both adults and children) n=934 ABM, n=951 AVM	Systematic review and meta-analysis	Sensitivity	93%	Excluded non-English studies No gray literature Excluded studies with comparator groups including but not exclusively comprised of AVM
			Specificity	96%
			LR+	22.9
			LR-	0.07

Comment(s)

Distinguishing acute bacterial meningitis from acute viral meningitis can be challenging. While a strategy of treating all possible cases of ABM with broad spectrum antibiotics until CSF cultures result is commonly employed, this strategy may lead to antibiotic resistance and unnecessary hospitalization. A combination of CSF white blood cell count/differential, CSF glucose, and CSF protein is commonly used to distinguish ABM from AVM. Unfortunately these tests all suffer from suboptimal sensitivity and specificity. The ideal test would be maximally sensitive and specific, rapidly available, and cheap. Despite not being commonly used, CSF lactate has been widely studied and appears to satisfy all three domains. The median cutoff used in the included studies was 3.5mM (~31mg/dL), with the majority of studies using enzymatic assays. As with most CSF tests including the gold-standard culture, CSF lactate's utility is somewhat limited in patients pretreated with antibiotics. In such cases, a lower cutoff should be used to maintain sufficient sensitivity.

Clinical Bottom Line

CSF lactate at a cutoff of 3.5mM appears to be both a sensitive and specific test for distinguishing acute bacterial meningitis from acute viral meningitis. With over 30 studies supporting its use over the past 40 years, it appears ready for routine use.

References

1. Abro et al. CSF lactate level: a useful diagnostic tool to differentiate acute bacterial and viral meningitis. J Pak Med Assoc 2009; 508-511
2. Abro et al. Cerebrospinal fluid analysis: acute bacterial versus viral meningitis Pak J Med Sci 2008; 645-650
3. Berg et al. Cerebrospinal fluid lactate in the diagnosis of meningitis. Diagnostic value compared to standard biochemical methods. Scand J Infect Dis 1982; 111-115
4. Briem et al. Comparison between cerebrospinal fluid concentrations of glucose, total protein, chloride, lactate, and total amino acids for the differential diagnosis of patients with meningitis. Scand J Infect Dis 1983; 277-284
5. Brook et al. Measurement of lactic acid in cerebrospinal fluid of patients with infections of the central nervous system. J Infect Dis 1978; 384-390
6. Buch et al. Cerebrospinal fluid lactate as a marker to differentiate between community-acquired acute bacterial meningitis and aseptic meningitis/encephalitis in adults: a Danish prospective observational cohort Infectious Diseases 2018; 1-8
7. Chen et al. The clinical diagnostic significance of cerebrospinal fluid d-lactate for bacterial meningitis Clinica Chimica Acta 2012; 1512-1515
8. Curtis et al. Cerebrospinal fluid lactate and the diagnosis of meningitis. J Infect 1981; 159-165
9. D'Souza et al. Lactic-acid concentration in cerebrospinal fluid and differential diagnosis of meningitis. Lancet 1978; 579-580
10. Ellis and Oei Cerebrospinal fluid lactic acid: a valuable aid in the of diagnosis septic meningitis. J Indiana State Med Assoc 1979; 530-531
11. Ferguson and Tearle Gas liquid chromatography in the rapid diagnosis of meningitis. J Clin Pathol 1977; 1163-1167
12. Gastrin et al. Rapid diagnosis of meningitis with use of selected clinical data and gas-liquid chromatographic determination of lactate concentration in cerebrospinal fluid. J Infect Dis 1979; 529-533
13. Genton and Berger Cerebrospinal fluid lactate in 78 cases of adult meningitis. Intensive Care Med 1990; 196-200
14. Giulieri et al. CSF lactate for accurate diagnosis of community-acquired bacterial meningitis Eur J Clin Microbiol Infect Dis 2015; 2049-2055
15. Gould et al. The use of cerebrospinal fluid lactate determination in the diagnosis of meningitis. Scand J Infect Dis 1980; 185-188
16. Herold et al. Lactic acid in cerebrospinal fluid: evaluation and application of an automated enzymatic assay. Ann Clin Lab Sci 1981; 416-421
17. Hurd et al. Use of cerebrospinal fluid lactate levels in the diagnosis of bacterial meningitis. Am J Med Technol 1978; 11-13
18. Jordan et al. CSF lactate in diseases of the CNS. Arch Intern Med 1983; 85-87
19. Kleine et al. New and old diagnostic markers of meningitis in cerebrospinal fluid (CSF). Brain Res Bull 2003; 287-297
20. Komorowski et al. Cerebrospinal fluid lactic acid in diagnosis of meningitis. J Clin Microbiol 1978; 89-92
21. Komorowski et al. Comparison of cerebrospinal fluid C-reactive protein and lactate for diagnosis of meningitis. J Clin Microbiol 1986; 982-985
22. Lagi et al. Proposal for a New Score-Based Approach To Improve Efficiency of Diagnostic Laboratory Workflow for Acute Bacterial Meningitis in Adults J Clin Microbiol 2016; 1851-1854
23. Landaas and Von Der Lippe Chemical analyses for early differential diagnosis between bacterial and viral meningitis. Scand J Clin Lab Invest 1985; 525-529
24. Lannigan et al. Evaluation of cerebrospinal fluid lactic acid levels as an aid in differential diagnosis of bacterial and viral meningitis in adults. J Clin Microbiol 1980; 324-327
25. Lauwers Lactic-acid concentration in cerebrospinal fluid and differential diagnosis of meningitis. Lancet 1978; 163
26. Lester et al. Value of CSF lactate in the differential diagnosis between bacterial meningitis and other diseases with meningeal involvement. Acta Pathol Microbiol Immunol Scand B 1985; 21-25
27. Lindquist et al. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis 1988; 374-380
28. Mandal et al. How useful is cerebrospinal fluid lactate estimation in differential diagnosis of meningitis? J Infect 1983; 231-237
29. Patterson et al. Handheld Point-of-Care Cerebrospinal Fluid Lactate Testing Predicts Bacterial Meningitis in Uganda Am J Trop Med Hyg 2013; 127-131
30. Ponka et al. The differential diagnosis of bacterial and aseptic meningitis using cerebrospinal fluid laboratory tests. Infection 1983; 129-131
31. Schwarz et al. Serum procalcitonin levels in bacterial and abacterial meningitis. Crit Care Med 2000; 1828-1832
32. Viallon et al. Meningitis in adult patients with a negative direct cerebrospinal fluid examination: value of cytochemical markers for differential diagnosis Crit Care 2011; R136
33. de Almeida et al. Quantitation of cerebrospinal fluid lactic acid in infectious and non-infectious neurological diseases Clin Chem Lab Med 2009; 755-761
34. Huy et al. Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: a systemic review and meta-analysis Crit Care 2010; R240
35. Sakushima et al. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: A meta-analysis J Infect 2011; 255-262