Persistent Depletion of Neuroprotective Factors Accompanies Neuroinflammatory, Neurodegenerative, and Vascular Remodeling Spectra in Serum Three Months after Non-Emergent Cardiac Surgery.

We hypothesized that the persistent depletion of neuroprotective markers accompanies neuroinflammation and neurodegeneration in patients after cardiac surgery. A total of 158 patients underwent elective heart surgery with their blood collected before surgery (tbaseline) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-surgery. The patients' serum was measured for markers of neurodegeneration (τau, τaup181-183, amyloid ß1-40/ß2-42, and S100), atypical neurodegeneration (KLK6 and NRGN), neuro-injury (neurofilament light/heavy, UC-HL, and GFAP), neuroinflammation (YKL-40 and TDP-43), peripheral nerve damage (NCAM-1), neuroprotection (apoE4, BDNF, fetuin, and clusterin), and vascular smoldering inflammation (C-reactive protein, CCL-28 IL-6, and IL-8). The mortality at 28 days, incidence of cerebrovascular accidents (CVA), and functional status were followed for three months. The levels of amyloid ß1-40/ß1-42 and NF-L were significantly elevated at all time points. The levels of τau, S100, KLK6, NRGN, and NCAM-1 were significantly elevated at 24 h. A cluster analysis demonstrated groupings around amyloids, KLK6, and NCAM-1. YKL-40, but not TDP-43, was significantly elevated across all time points. BDNF, apoE4, fetuin, and clusterin levels were significantly diminished long-term. IL-6 and IL-8 levles returned to baseline at t3m. The levels of CRP, CCL-28, and Hsp-70 remained elevated. At 3 months, 8.2% of the patients experienced a stroke, with transfusion volume being a significant variable. Cardiac-surgery patients exhibited persistent peripheral and neuronal inflammation, blood vessel remodeling, and the depletion of neuroprotective factors 3 months post-procedure.

A disturbed balance between blood complement protective factors (FH, ApoE) and common pathway effectors (C5a, TCC) in acute COVID-19 and during convalesce.

A complement effect on homeostasis during infection is determined by both cytotoxic (activate complement component 5 (C5a) terminal cytotoxic complex (TCC)), and cytoprotective elements (complement factor H (FH), as well as apolipoprotein E (ApoE)). Here, we investigated the gap in knowledge in their blood milieu during SARS-CoV-2 infection with respect to the viral burden, level of tissue necrosis, and immunological response. 101 patients hospitalized with a PCR-confirmed diagnosis of COVID-19 had blood collected at H1 (48 h), H2 (3-4 Days), H3 (5-7 days), H4 (more than 7 days up to 93 days). Pre-existing conditions, treatment, the incidence of cerebrovascular events (CVA), a history of deep venous thrombosis (DVT) and pulmonary embolism (PE), and mortality was collected using electronic medical records. Plasma C5a, TCC, FH, and ApoE were considered as a complement milieu. Tissue necrosis (HMGB1, RAGE), non-specific inflammatory responses (IL-6, C-reactive protein), overall viral burden (SARS-CoV-2 spike protein), and specific immune responses (IgG, IgA, IgM directed αS- & N-proteins) were assessed simultaneously. C5a remained elevated across all time points, with the peak at 5-7 days. Studied elements of complement coalesced around three clusters: #0 (↑↑↑C5a, ↑↑TCC, ↓↓ApoE), #1 ↑C5a, ↑TCC, ↑↑↑FH); #2 (↑C5a, ↑TCC, ↑FH, ↑↑↑ApoE). The decline in FH and ApoE was a predictor of death, while TCC and C5a correlated with patient length of stay, APACHE, and CRP. Increased levels of C5a (Δ = 122.64; p = 0.0294; data not shown) and diminished levels of FH (Δ = 836,969; p = 0.0285; data not shown) co-existed with CVA incidence. C5a correlated storngly with blood RAGE and HMGB1, but not with viral load and immunological responsiveness. Remdesivir positively affected FH preservation, while convalescent plasma treatment elevated C5a levels. Three clusters of complement activation demonstrated a various milieu of ApoE & FH vs C5a & TCC in COVID-19 patients. Complement activation is linked to increased necrosis markers but not to viral burden or immune system response.

A decline of protective apolipoprotein J and complement factor H concomitant with increase in C5a 3 months after cardiac surgery-Evidence of long-term complement perturbations.

Background: Heart surgery results in complement activation with the potential for collateral end-organ damage, especially if the protective elements (complement factor H, Apolipoprotein J) are inadequate. Here, we have investigated if peri-operative stress results in an imbalance between complement activation and its protective mechanisms up to 3 months after heart surgery. Methods: 101 patients scheduled for non-emergent cardiac surgery donated blood before the procedure (tbaseline), and 24 h (t24h ), 7 days (t7d ) and 3 months (t3m ) after. Complement activation was measured as a serum level of soluble activated component 5 (sC5a) and soluble terminal complement complex (sTCC). Simultaneously, protective complement factor H (CfH), and apolipoprotein J (ApoJ) were measured. Inflammatory responses were quantified using C-reactive protein (CRP) and interleukin-6 (IL-6). Details regarding anesthesia, intensive care unit (ICU) stay, pre-existing conditions, the incidence of postoperative complications, and mortality were collected from medical records. Results: C5a declined at t24h to rebound at t7d and t3m . sTCC was significantly depressed at t24h and returned to baseline at later time points. In contrast, CfH and ApoJ were depressed at t3m . Milieu of complement factors aligned along two longitudinal patterns:cluster#1 (C5a/sTTC continuously increasing and CfH/ApoJ preserved at tbaseline) and cluster#2 (transient sC5a/sTTC increase and progressive decline of CfH). Most patients belonged to cluster #1 at t24h (68%), t7d (74%) and t3m (72%). sTCC correlated with APACHE1h (r 2 =-0.25; p < 0.031) and APACHE24h (r 2 = 0.27; p < 0.049). IL-6 correlated with C5a (r 2 =-0.28; p < 0.042) and sTTC (r 2 =-0.28; p < 0.015). Peri-operative administration of acetaminophen and aspirin altered the complement elements. Prolonged hospital stay correlated with elevated C5a [t (78) = 2.03; p = 0.048] and sTTC serum levels [U (73) = 2.07; p = 0.037]. Patients with stroke had a decreased serum level of C5a at t7d and t3m. Conclusion: There is a significant decrease in complement protective factors 3 months after cardiac surgery, while C5a seems to be slightly elevated, suggesting that cardiac surgery affects complement milieu long into recovery.

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes.

The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2's neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid ß42, TDP43, NF-L, and KLK6 serum levels declined 2-3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3-7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-ß40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure.

Kidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney's critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.

Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics.

Identification of novel immune biomarkers to gauge the underlying pathology and severity of COVID-19 has been difficult due to the lack of longitudinal studies. Here, we analyzed serum collected upon COVID-19 admission (t1), 48 hours (t2), and seven days later (t3) using Olink proteomics and correlated to clinical, demographics, and therapeutic data. Older age positively correlated with decorin, pleiotrophin, and TNFRS21 but inversely correlated with chemokine (both C-C and C-X-C type) ligands, monocyte attractant proteins (MCP) and TNFRS14. The burden of pre-existing conditions was positively correlated with MCP-4, CAIX, TWEAK, TNFRS12A, and PD-L2 levels. Individuals with COVID-19 demonstrated increased expression of several chemokines, most notably from the C-C and C-X-C family, as well as MCP-1 and MCP-3 early in the course of the disease. Similarly, deceased individuals had elevated MCP-1 and MCP-3 as well as Gal-9 serum levels. LAMP3, GZMB, and LAG3 at admission correlated with mortality. Only CX3CL13 and MCP-4 correlated positively with APACHE score and length of stay, while decorin, MUC-16 and TNFRSF21 with being admitted to the ICU. We also identified several organ-failure-specific immunological markers, including those for respiratory (IL-18, IL-15, Gal-9) or kidney failure (CD28, VEGF). Treatment with hydroxychloroquine, remdesivir, convalescent plasma, and steroids had a very limited effect on the serum variation of biomarkers. Our study identified several potential targets related to COVID-19 heterogeneity (MCP-1, MCP-3, MCP-4, TNFR superfamily members, and programmed death-ligand), suggesting a potential role of these molecules in the pathology of COVID-19.