Significance of cerebrospinal fluid inflammatory markers for diagnosing external ventricular drain–associated ventriculitis in patients with severe traumatic brain injury

Lenski, Markus; Biczok, Annamaria; Neufischer, Katrin; Tonn, Jörg‐Christian; Briegel, Josef; Thon, Niklas

doi:10.3171/2019.8.focus19407

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…Important common complications associated with traumatic brain injury and critical care such as EVD-associated ventriculitis and sepsis were also under-reported. For example, only two cases of ventriculitis were reported in our review of 699 patients, compared to typical rates of 5–15% reported in the wider literature [ 60 – 62 ]. Such complications have previously been shown to significantly impact IL-6 concentrations in bodily fluids and therefore represent important confounders [ 60 , 63 ].…”

Section: Discussioncontrasting

confidence: 62%

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

et al. 2022

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Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200

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Section: Discussioncontrasting

confidence: 62%

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

et al. 2022

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“…Elevated CSF levels of IL-6 have been well described in studies of community-acquired bacterial meningitis ( Prasad et al , 2014 ; García-Hernández et al , 2016 ; Srinivasan et al , 2016 ; Lepennetier et al , 2019 ; Liba et al , 2019 ), but not in all ( Asano et al , 2010 ), and IL-6 is also raised in encephalitis ( Morichi et al , 2018 ). Elevated IL-6 levels in CSF have not only been reported in nosocomial infections in patients with shunts and EVDs ( Asi-Bautista et al , 1997 ; Schoch et al , 2008 ; Lenski et al , 2019 , Skar et al , 2019 b ) but also in inflammation and vasospasm after subarachnoid haemorrhage ( Lenski et al , 2017 ), all combining to make it a poor differentiator between nosocomial infection and sterile neuroinflammation. EN-RAGE is produced by macrophages in response to IL-6 in vitro ( Hasegawa et al , 2003 ), and both EN-RAGE and IL-6 ( Chiaretti et al , 2008 ) have previously been noted as increased in serum or CSF, respectively, in response to cerebral trauma and during paediatric CNS infection when compared to controls ( Prasad et al , 2014 ; García-Hernández et al , 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor linked cytokine profiles in cerebrospinal fluid discriminate neurological infection from sterile inflammation

Cuff

Merola

Twohig

et al. 2020

Brain Communications

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Rapid determination of an infective aetiology causing neurological inflammation in the cerebrospinal fluid can be challenging in clinical practice. Post-surgical nosocomial infection is difficult to diagnose accurately, as it occurs on a background of altered cerebrospinal fluid composition due to the underlying pathologies and surgical procedures involved. There is additional diagnostic difficulty after external ventricular drain or ventriculoperitoneal shunt surgery, as infection is often caused by pathogens growing as biofilms, which may fail to elicit a significant inflammatory response and are challenging to identify by microbiological culture. Despite much research effort, a single sensitive and specific cerebrospinal fluid biomarker has yet to be defined which reliably distinguishes infective from non-infective inflammation. As a result, many patients with suspected infection are treated empirically with broad-spectrum antibiotics in the absence of definitive diagnostic criteria. To begin to address these issues, we examined cerebrospinal fluid taken at the point of clinical equipoise to diagnose cerebrospinal fluid infection in 14 consecutive neurosurgical patients showing signs of inflammatory complications. Using the guidelines of the Infectious Diseases Society of America, six cases were subsequently characterized as infected and eight as sterile inflammation. Twenty-four contemporaneous patients with idiopathic intracranial hypertension or normal pressure hydrocephalus were included as non-inflamed controls. We measured 182 immune and neurological biomarkers in each sample and used pathway analysis to elucidate the biological underpinnings of any biomarker changes. Increased levels of the inflammatory cytokine interleukin-6 and interleukin-6-related mediators such as oncostatin M were excellent indicators of inflammation. However, interleukin-6 levels alone could not distinguish between bacterially infected and uninfected patients. Within the patient cohort with neurological inflammation, a pattern of raised interleukin-17, interleukin-12p40/p70 and interleukin-23 levels delineated nosocomial bacteriological infection from background neuroinflammation. Pathway analysis showed that the observed immune signatures could be explained through a common generic inflammatory response marked by interleukin-6 in both nosocomial and non-infectious inflammation, overlaid with a toll-like receptor-associated and bacterial peptidoglycan-triggered interleukin-17 pathway response that occurred exclusively during infection. This is the first demonstration of a pathway dependent cerebrospinal fluid biomarker differentiation distinguishing nosocomial infection from background neuroinflammation. It is especially relevant to the commonly encountered pathologies in clinical practice, such as subarachnoid haemorrhage and post-cranial neurosurgery. While requiring confirmation in a larger cohort, the current data indicate the potential utility of cerebrospinal fluid biomarker strategies to identify differential initiation of a common downstream interleukin-6 pathway to diagnose nosocomial infection in this challenging clinical cohort.

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“…In another study [ 32 ], the level of IL-6 in the CSF of patients with a diagnosis of purulent bacterial meningitis with a more severe course reached 392 ± 199 pg/mL. Retrospective data [ 33 ] from patients with traumatic brain injury ( n = 40) and external ventricular drain-associated ventriculitis showed that the CSF IL-6 levels higher than the threshold of 4064 pg/mL were significantly associated with the probability of ventriculitis. In another prospective study [ 29 ], all patients with proven bacterial meningitis had CSF IL-6 more than 500 pg/mL.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxyphenyllactic Acid in Cerebrospinal Fluid as a Possible Marker of Post-Neurosurgical Meningitis: Retrospective Study

Pautova

Meglei

Chernevskaya

et al. 2022

JPM

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The search for new potential biomarkers for the diagnostics of post-neurosurgical bacterial meningitis is required because of the difficulties in its early verification using results of the routine laboratory and biochemical analyses of the cerebrospinal fluid (CSF). The goal of the study was to determine the contents of the aromatic metabolites and biomarkers in the CSF samples of the post-neurosurgical patients (n = 82) and their potential diagnostical significance for the evaluation of the risk of post-neurosurgical meningitis. Patients with signs of post-neurosurgical meningitis (n = 30) had lower median values of glucose and higher values of cell count, neutrophils, lactate, protein, 3-(4-hydroxyphenyl)lactic acid (p-HPhLA), and interleukin-6 (IL-6) than patients without signs of post-neurosurgical meningitis (n = 52). ROC analysis for IL-6 and p-HPhLA resulted in 0.785 and 0.734 values of the area under the ROC curve, with sensitivity 96.30 and 66.67%; specificity 54.17 and 82.69%, respectively. IL-6 should be considered as a non-specific biomarker, in contrast to the microbial metabolite p-HPhLA. If the concentration of p-HPhLA was more or equal to 0.9 µmol/L, the risk of bacterial complications was 9.6 times higher. p-HPhLA is a promising marker for the prognosis of post-neurosurgical meningitis, and its determination on a larger group of post-neurosurgical patients can subsequently prove its diagnostic significance for the verification of CNS infections.

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Significance of cerebrospinal fluid inflammatory markers for diagnosing external ventricular drain–associated ventriculitis in patients with severe traumatic brain injury

Cited by 15 publications

References 36 publications

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

Toll-like receptor linked cytokine profiles in cerebrospinal fluid discriminate neurological infection from sterile inflammation

4-Hydroxyphenyllactic Acid in Cerebrospinal Fluid as a Possible Marker of Post-Neurosurgical Meningitis: Retrospective Study

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