The Role of Viral Load in COVID-19-Induced Encephalitis

<b>Introduction:</b> Acute encephalitis is a severe neurological complication whose association with SARS-CoV-2 infection is increasingly recognized. However, the precise pathophysiological mechanisms remain incompletely understood. Understanding the factors contributing to central nervous system involvement in COVID-19 is crucial for guiding clinical management and improving patient outcomes. <b>Methods:</b> This single-center, retrospective cohort study analyzed data from 450 adult critically ill patients with RT-qPCR-confirmed SARS-CoV-2 infection admitted to our ICU between May 2021 and March 2023. All SARS-CoV-2-positive patients with suspected CNS involvement were included and categorized into encephalitis-positive (E+, <i>n</i> = 38) and encephalitis-negative (E-, <i>n</i> = 58) groups according to neurological examination, imaging, and lumbar puncture findings during ventilator weaning. Key patient characteristics, laboratory parameters at ICU admission (including SARS-CoV-2 Ct values and D-dimer levels), and clinical outcomes were analyzed with appropriate statistical methods, including ROC curve analysis and Cox regression. <b>Results:</b> Patients in the E+ group, compared with the E- group, were significantly older (mean 69 ± 15 vs. 61 ± 12 years, <i>p</i> = 0.006) and exhibited significantly lower median SARS-CoV-2 Ct values (23.7 vs. 27.0, <i>p</i> < 0.001) indicative of higher viral loads. The median D-dimer levels were also significantly elevated in the E+ group (4.6 vs. 1.1, <i>p</i> < 0.001). Other baseline characteristics and inflammatory markers were comparable between groups. Patients with encephalitis experienced significantly longer mechanical ventilation durations (median 19 vs. 14 days, <i>p</i> = 0.006) and ICU stays (median 21 vs. 15 days, <i>p</i> = 0.009) compared to those without encephalitis. No significant difference was observed in overall mortality between the groups (50.0% vs. 56.9%, <i>p</i> = 0.507). Multivariate analysis identified lower Ct values (HR: 1.9, <i>p</i> = 0.032) and higher D-dimer levels (HR: 2.9, <i>p</i> < 0.010) at ICU admission as independent risk factors for encephalitis development. <b>Conclusions:</b> Our findings indicated that higher SARS-CoV-2 viral loads (lower Ct values), older age, and higher D-dimer levels were significantly associated with a greater risk of COVID-19-associated encephalitis in critically ill patients. These markers might aid in identifying patients at high risk of neurological complications, thereby facilitating earlier monitoring and potentially improving patient management. Further prospective studies are warranted to fully elucidate the pathophysiological mechanisms underlying this association.