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

Cuff, Simone M., Merola, Joseph P., Twohig, Jason P., Eberl, Matthias and Gray, William P. 2020. Toll-like receptor linked cytokine profiles in cerebrospinal fluid discriminate neurological infection from sterile inflammation. Brain Communications 2 (2) , fcaa218. 10.1093/braincomms/fcaa218

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Abstract

Rapid determination of an infective aetiology causing neurological inflammation in the cerebrospinal fluid (CSF) can be challenging in clinical practice. Post-surgical nosocomial infection is difficult to diagnose accurately, as it occurs on a background of altered CSF 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 CSF 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 CSF taken at the point of clinical equipoise to diagnose CSF infection in 14 consecutive neurosurgical patients showing signs of inflammatory complications. Using the guidelines of the Infectious Diseases Society of America, 6 cases were subsequently characterised as infected, and 8 as sterile inflammation. 24 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 (IL)-6 and IL-6 related mediators such as oncostatin M were excellent indicators of inflammation. However, IL-6 levels alone could not distinguish between bacterially infected and uninfected patients. Within the patient cohort with neurological inflammation, a pattern of raised IL-17, IL-12p40/p70 and IL-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 IL-6 in both nosocomial and non-infectious inflammation, overlaid with a Toll-like receptor associated and bacterial peptidoglycan-triggered IL-17 pathway response that occurred exclusively during infection. This is the first demonstration of a pathway dependent CSF 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 CSF biomarker strategies to identify differential initiation of a common downstream IL-6 pathway to diagnose nosocomial infection in this challenging clinical cohort.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher: Oxford University Press
ISSN: 2632-1297
Funders: Wellcome Trust, MRC
Date of First Compliant Deposit: 4 December 2020
Date of Acceptance: 12 November 2020
Last Modified: 31 Jan 2021 08:15
URI: http://orca.cardiff.ac.uk/id/eprint/136808

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