Word counts: Abstract: 245, text: 2760 2 7 Keywords: Meningitis, central nervous system infections, mass-spectrometry, lipocalin 2, 2 8 biomarkers 2 9Running title: Diagnostic biomarker discovery in central nervous system infected patients 3 0 ABSTRACT 1 Background: Central nervous system (CNS) infections are common causes of morbidity and 2 mortality worldwide. Rapid, accurate identification of the likely cause is essential for clinical 3 management and the early initiation of antimicrobial therapy, which potentially improves clinical 4 outcome.
5Methods: We applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal 6 fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential 7 diagnostic protein biomarkers. We then validated the diagnostic performance of a selected 8 biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS 9 infections admitted to a referral hospital in southern Vietnam.
0Results: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of 1 1 bacterial meningitis. The analysis of the validation cohort showed that LCN2 could discriminate 1 2 bacterial meningitis from other CNS infections, including tuberculous meningitis, cryptococcal 1 3 meningitis and viral/antibody-mediated encephalitis (sensitivity: 0.88 (95% confident interval 1 4 (CI): 0.77-0.94), specificity: 0.91 (95%CI: 0.88-0.94) and diagnostic odd ratio: 73.8 (95%CI: 1 5 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) 1 6 commonly used in routine care worldwide. The combination of LCN2 and these four routine 1 7 CSF markers resulted in the highest diagnostic performance for bacterial meningitis (area under 1 8 receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99).1 9Conclusions: Our results suggest that LCN2 is a sensitive and specific biomarker for 2 0 discriminating bacterial meningitis from a broad spectrum of CNS infections. A prospective 2 1 study is needed to further assess the diagnostic utility of LCN2 in the diagnosis and management 2 2 of CNS infections. 2 3 1 Central nervous system (CNS) infections cause significant mortality and morbidity worldwide, 2 but especially in low-and middle-income countries (1). Common CNS infections include 3 bacterial meningitis (BM), viral encephalitis, tuberculous meningitis (TBM) and cryptococcal 4 meningitis (2), but there are >100 documented infectious causes of CNS infections (3). 5 Additionally, over the last decade, antibody-mediated causes of encephalitis (e.g. anti-N-methyl-6 D-aspartate receptor (anti-NMDAR) encephalitis) have been recognized (4), which further 7 challenges routine diagnostics. 8 Clinical features are often insufficient to discriminate the likely cause and standard laboratory 9 investigations identify the causative agent in <60% of cases (5, 6). Critically, the clinical We thank Le 1 logistic support, and Dr Nguyen Thi Hoang Mai for her help with material collection. We are 2 indebted to patients for the...