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1.
Sci Rep ; 11(1): 19675, 2021 10 04.
Article in English | MEDLINE | ID: covidwho-1450292

ABSTRACT

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.


Subject(s)
Acute Kidney Injury/pathology , Biomarkers/urine , COVID-19/immunology , Renal Insufficiency, Chronic/pathology , Acute Kidney Injury/complications , Adult , Aged , Antigens, CD/urine , Biomarkers/blood , CA-125 Antigen/urine , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Chemokines, CC/blood , Cross-Sectional Studies , Female , Humans , Interleukin-12/urine , Interleukin-6/blood , Male , Membrane Proteins/urine , Middle Aged , Procalcitonin/blood , Renal Insufficiency, Chronic/complications , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Spike Glycoprotein, Coronavirus/blood
2.
Front Immunol ; 12: 650465, 2021.
Article in English | MEDLINE | ID: covidwho-1285288

ABSTRACT

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.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Chemokines, CC/blood , Monocyte Chemoattractant Proteins/blood , SARS-CoV-2/physiology , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , Female , Humans , Immune Sera , Immune System , Male , Middle Aged , Socioeconomic Factors , United States/epidemiology , Young Adult
3.
Thromb Res ; 204: 88-94, 2021 08.
Article in English | MEDLINE | ID: covidwho-1260871

ABSTRACT

PURPOSE: A derangement of the coagulation process and thromboinflammatory events has emerged as pathologic characteristics of severe COVID-19, characterized by severe respiratory failure. CC motive chemokine ligand 2 (CCL2), a chemokine originally described as a chemotactic agent for monocytes, is involved in inflammation, coagulation activation and neoangiogenesis. We investigated the association of CCL2 levels with coagulation derangement and respiratory impairment in patients with COVID-19. METHODS: We retrospectively evaluated 281 patients admitted to two hospitals in Italy with COVID-19. Among them, CCL2 values were compared in different groups (identified according to D-dimer levels and the lowest PaO2/FiO2 recorded during hospital stay, P/Fnadir) by Jonckheere-Terpstra tests; linear regression analysis was used to analyse the relationship between CCL2 and P/Fnadir. We performed Mann-Whitney test and Kaplan-Meier curves to investigate the role of CCL2 according to different clinical outcomes (survival and endotracheal intubation [ETI]). RESULTS: CCL2 levels were progressively higher in patients with increasing D-dimer levels and with worse gas exchange impairment; there was a statistically significant linear correlation between log CCL2 and log P/Fnadir. CCL2 levels were significantly higher in patients with unfavourable clinical outcomes; Kaplan-Meier curves for the composite outcome death and/or need for ETI showed a significantly worse prognosis for patients with higher (> median) CCL2 levels. CONCLUSIONS: CCL2 correlates with both indices of activation of the coagulation cascade and respiratory impairment severity, which are likely closely related in COVID-19 pathology, thus suggesting that CCL2 could be involved in the thromboinflammatory events characterizing this disease.


Subject(s)
COVID-19 , Thrombosis , Chemokine CCL2 , Chemokines, CC , Humans , Inflammation , Italy , Ligands , Retrospective Studies , SARS-CoV-2
4.
J Intern Med ; 289(4): 523-531, 2021 04.
Article in English | MEDLINE | ID: covidwho-796040

ABSTRACT

BACKGROUND: A high proportion of COVID-19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 and the renin-angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID-19 patients. METHODS: Plasma levels of a gut leakage marker (LPS-binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL-1ß, IL-18 and their regulatory proteins) were measured at three time points (day 1, 3-5 and 7-10) in 39 hospitalized COVID-19 patients and related to cardiac involvement. RESULTS: Compared to controls, COVID-19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT-pro-BNP levels, whereas IL-18, IL-18BP and IL-1Ra were associated with higher troponin levels. CONCLUSION: Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut-heart axis in COVID-19.


Subject(s)
COVID-19 , Chemokines, CC/metabolism , Gastrointestinal Microbiome/immunology , Heart Diseases , Inflammasomes/metabolism , Intestinal Mucosa , SARS-CoV-2 , Acute-Phase Proteins/metabolism , COVID-19/complications , COVID-19/immunology , Carrier Proteins/metabolism , Correlation of Data , Heart Diseases/immunology , Heart Diseases/virology , Humans , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/physiopathology , Membrane Glycoproteins/metabolism , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Troponin/blood
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