Unique proteome signatures in ICU patients with COVID-19 and delirium: an observational study

BackgroundDelirium is common in COVID-19 intensive care unit (ICU) patients. Biomarkers for prediction, detection, and monitoring are missing. Unbiased omics analyses are warranted to gain a systems biology view on pathophysiology. MethodsThis prospective observational satellite study aims to investigate the proteome signatures of COVID-19 ICU patients, comparing those with delirium to those without. This study was conducted in ICUs of a university hospital between March 2020 and September 2021. ICU patients of legal age with a positive SARS-CoV-2 test were screened daily for oversedation and delirium. Blood samples were taken thrice a week. 457 samples were analyzed using data-in-dependent acquisition mass spectrometry to determine protein levels. A mixed-effects regression model was developed to identify proteins significantly influenced by delirium, accounting for sex and age as confounders. This model also aimed to determine proteins that were either up- or downregulated in association with delirium. Additionally, an enrichment analysis was conducted to examine the biological pathways linked to these delirium-associated proteins. ResultsOut of 360 ICU patients, 69 were analyzed for protein profiling. Out of these 69 patients, 42 patients (60.9%) had delirium on ICU admission, and 27 (39.1%) did not. Based on the multivariate model, the analysis of 204 proteins unfolded 125 (61.3%) to be differentially expressed. In total, 80.8% (n=101) of these 125 proteins were associated with delirium. Of these, 10 proteins were uniquely associated with delirium and were not significant in the multivariate model (SERPING1, SERPINA7, HP, TGFBI, CD5L, IGHV3-7, IGHV1-46, IGHV3-15, IGHV3-23, and "IGHV4-34;IGHV4-38-2"). In the univariate model for delirium, six out of 111 significant proteins showed increased expression with a log2FC > 0.5: PIGR, MST1, LBP, CRP, SAA1, and "SAA1;SAA2"; while three showed decreased expression with a log2FC < - 0.5: HP, PPBP, and "HP;HPR". The enrichment analysis of delirium-influenced proteins revealed three significant pathways: "Network map of SARS-CoV-2 signaling" (M42569/WP5115), "Acute inflammatory response" (M10617), and "Regulation of defense response" (M15277). ConclusionWe identified a unique proteomic signature in COVID-19 ICU patients with delirium, including up- and downregulated proteins. These findings may provide potential biomarker candidates for the assessment of delirium risk and its underlying causes. These findings could be a further step towards the development of personalized, causative treatments for delirium and its monitoring in the ICU. Trial registrationThe study was retrospectively registered in the German Clinical Trials Register on May 13, 2020 (DRKS00021688).