Serum levels of neurofilament light chain and glial fibrillary acidic protein correlate with disease severity in patients with West Nile virus infection

Abstract

West Nile virus (WNV) is a neurotropic mosquito-borne orthoflavivirus, representing a relevant public health threat. Identification of biomarkers that would predict the course of WNV infection is of interest for the early identification of patients at risk and for supporting decisions on therapeutic interventions. In this study, serum levels of glial fibrillary acidic protein (sGFAP) and neurofilament light chain (sNfL), which are markers of brain tissue damage and inflammation, were analysed in 103 subjects with laboratory-confirmed WNV infection, comprising 13 asymptomatic blood donors, 23 with WN fever (WNF), 50 with encephalitis/meningoencephalitis (E/ME) and 17 with acute flaccid paralysis (AFP). In addition, 55 WNV-negative subjects with fever, encephalitis or healthy asymptomatic were included as controls. Age-adjusted levels of both sNfL and sGFAP were significantly higher in patients with neuroinvasive disease than in those with fever or asymptomatic (both WNV-positive and WNV-negative), suggesting a broad association of these biomarkers with systemic inflammation and brain injury resulting from infection. In WNV patients, the combined analysis of sNfL and sGFAP early after symptom onset allowed discrimination between neuroinvasive disease and fever with 67.2% sensitivity and 91.3% specificity, but not between E/ME and AFP. Furthermore, high levels of sNfL and sGFAP were significantly associated with prolonged hospital stay, intensive care unit admission and the occurrence of death or severe sequelae. Detection of WNV RNA in CSF was associated with increased sGFAP. In conclusion, our study indicates the potential utility of sNfL and sGFAP as biomarkers of WNV disease severity and adverse outcome.

Keywords: West Nile virus; acute flaccid paralysis; encephalitis; glial fibrillary acidic protein; neurofilament light chain.

Figure 1.

Association between age-adjusted sGFAP and sNfL levels and severity of disease in WNV-infected patients (a,b). Comparisons between groups were done by Mann–Whitney test. WNND: West Nile neuroinvasive disease; WNF: West Nile fever; AFP: Acute flaccid paralysis; E/ME: encephalitis/meningoencephalitis. (c) Multiple logistic regression analysis of the performance of composite sGFAP and sNfL (with cut-offs of 344.0 and 55.5 pg/mL, respectively) in prognosticating WNND vs WNF. ****p < 0.0001; ns: p not significant.

Figure 2.

Association between age-adjusted sGFAP and sNfL levels and outcome parameters in patients with WNV infection. Comparisons between groups were done by Mann–Whitney test. ICU: intensive care unit. ****p < 0.0001.

Figure 3.

Serum levels of age-adjusted GFAP and NfL according to the lineage of the infecting WNV in all the patients with WNV infection and in the subgroups of patients with neuroinvasive disease (WNND). Comparisons between groups were done by Mann–Whitney test. WNV-1: WNV lineage 1; WNV-2: WNV lineage 2. ns: p not significant.

Figure 4.

Serum levels of age-adjusted GFAP and NfL in WNV patients according to the detection of WNV RNA in blood and CSF. Comparisons between groups were done by Mann–Whitney test. CSF: cerebrospinal fluid. *p < 0.05; ns: p not significant.

Figure 5.

Serum levels of age-adjusted GFAP and NfL in all study subjects grouped according to WNV infection and clinical presentation. Comparisons between groups were done by Mann–Whitney test. AFP: Acute flaccid paralysis; E/ME: encephalitis/meningoencephalitis; WNF: West Nile fever; Asympt: asymptomatic. ns: p not significant.