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1.
Crit Care Explor ; 4(1): e0620, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1621690

ABSTRACT

We investigated the effect of prone ventilation on right ventricular (RV) function of intubated patients with COVID-19-associated acute respiratory distress syndrome by measuring both conventional RV functional variables (namely, tricuspid annular peak systolic velocity, tricuspid annular plane systolic excursion, and fractional area change) and right ventricular free wall strain (RVFWS) using transthoracic speckle-tracking echocardiography at baseline (before prone positioning), 18 hours after prone positioning, and 1 hour after supine repositioning. We found that transthoracic echocardiography was feasible in a considerable proportion (nine patients, 75% of our cohort) of patients undergoing prone ventilation. Also, abnormal as opposed to normal RVFWS values (in the absence of conventional variables of RV dysfunction) at baseline were associated with higher mortality (100% vs 20%; p = 0.048). Finally, we found that, among patients without acute cor pulmonale or conventional markers of RV dysfunction, one session of prone ventilation may not affect right myocardial strain.

2.
Nutrients ; 14(1)2021 Dec 29.
Article in English | MEDLINE | ID: covidwho-1580548

ABSTRACT

The outbreak of the new coronavirus strain SARS-CoV-2 (COVID-19) highlighted the need for appropriate feeding practices among critically ill patients admitted to the intensive care unit (ICU). This study aimed to describe feeding practices of intubated COVID-19 patients during their second week of hospitalization in the First Department of Critical Care Medicine, Evaggelismos General Hospital, and evaluate potential associations with all cause 30-day mortality, length of hospital stay, and duration of mechanical ventilation. We enrolled adult intubated COVID-19 patients admitted to the ICU between September 2020 and July 2021 and prospectively monitored until their hospital discharge. Of the 162 patients analyzed (52.8% men, 51.6% overweight/obese, mean age 63.2 ± 11.9 years), 27.2% of patients used parenteral nutrition, while the rest were fed enterally. By 30 days, 34.2% of the patients in the parenteral group had died compared to 32.7% of the patients in the enteral group (relative risk (RR) for the group receiving enteral nutrition = 0.97, 95% confidence interval = 0.88-1.06, p = 0.120). Those in the enteral group demonstrated a lower duration of hospital stay (RR = 0.91, 95% CI = 0.85-0.97, p = 0.036) as well as mechanical ventilation support (RR = 0.94, 95% CI = 0.89-0.99, p = 0.043). Enteral feeding during second week of ICU hospitalization may be associated with a shorter duration of hospitalization and stay in mechanical ventilation support among critically ill intubated patients with COVID-19.

3.
Crit Care Med ; 49(12): 2131-2136, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1522360

ABSTRACT

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.


Subject(s)
COVID-19/physiopathology , Hydrocortisone/blood , Leucine Zippers/physiology , Receptors, Glucocorticoid/biosynthesis , Academic Medical Centers , Adult , Aged , Comorbidity , Critical Illness , Female , Greece , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Severity of Illness Index
4.
Diagnostics (Basel) ; 11(7)2021 Jul 13.
Article in English | MEDLINE | ID: covidwho-1526808

ABSTRACT

Endothelial dysfunction, coagulation and inflammation biomarkers are increasingly emerging as prognostic markers of poor outcomes and mortality in severe and critical COVID-19. However, the effect of dexamethasone has not been investigated on these biomarkers. Hence, we studied potential prognostic biomarkers of mortality in critically ill COVID-19 patients who had either received or not dexamethasone. Biomarker serum levels were measured on intensive care unit (ICU) admission (within 24 h) in 37 dexamethasone-free and 29 COVID-19 patients who had received the first dose (6 mg) of dexamethasone. Receiver operating characteristic (ROC) curves were generated to assess their value in ICU mortality prediction, while Kaplan-Meier analysis was used to explore associations between biomarkers and survival. In the dexamethasone-free COVID-19 ICU patients, non-survivors had considerably higher levels of various endothelial, immunothrombotic and inflammatory biomarkers. In the cohort who had received one dexamethasone dose, non-survivors had higher ICU admission levels of only soluble (s) vascular cell adhesion molecule-1 (VCAM-1), soluble urokinase-type plasminogen activator receptor (suPAR) and presepsin. As determined from the generated ROC curves, sVCAM-1, suPAR and presepsin could still be reliable prognostic ICU mortality biomarkers, following dexamethasone administration (0.7 < AUC < 0.9). Moreover, the Kaplan-Meier survival analysis showed that patients with higher than the median values for sVCAM-1 or suPAR exhibited a greater mortality risk than patients with lower values (Log-Rank test, p < 0.01). In our single-center study, sVCAM-1, suPAR and presepsin appear to be valuable prognostic biomarkers in assessing ICU mortality risk in COVID-19 patients, even following dexamethasone administration.

5.
Preprint in English | EuropePMC | ID: ppcovidwho-292295

ABSTRACT

Aim: Arterial involvement has been implicated in the coronavirus disease of 2019 (COVID-19). 18F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is a valuable tool for the assessment of disease severity in different types of vasculitis and is a predictor of outcome. We sought to prospectively assess the presence of aortic inflammation and its time-dependent trend by measuring the 18-FDG uptake in PET/CT in patients with severe or critical COVID-19. Methods: In this pilot case control study, we recruited 20 patients, who were admitted with severe or critical COVID-19 illness. Patients underwent imaging between 20 to 120 days after hospital admission. Ten age- and sex-matched individuals with prior history of malignancy but free of active disease served as the control group. Arterial inflammation was assessed by measuring 18-FDG uptake in PET/CT and calculating aortic target to blood ratio (TBR). Results: There was a significant correlation between aortic TBR values and time distance from diagnosis to 18F-FDG PET/CT scan (-rho- =0.547, p=0.015) even after adjustment for confounders (p=0.002). Patients who were scanned less than 60 days (median) from diagnosis had significantly higher TBR values compared to patients examined more than 60 days post-diagnosis (1.55 [1.47-1.61] vs 1.40 [1.33-1.45], respectively, p=0.013). Conclusion: This is the first study suggesting that 18 FDG PET/CT imaging could be used for assessment of arterial inflammation in patients with severe/critical COVID-19. These findings may have important implications for the understanding of the pathophysiology and the course of the disease and for improving our preventive and therapeutic strategies.

6.
J Pers Med ; 11(11)2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1488659

ABSTRACT

The COVID-19 disease can cause hypoxemic respiratory failure due to ARDS, requiring invasive mechanical ventilation. Although early studies reported that COVID-19-associated ARDS has distinctive features from ARDS of other causes, recent observational studies have demonstrated that ARDS related to COVID-19 shares common clinical characteristics and respiratory system mechanics with ARDS of other origins. Therefore, mechanical ventilation in these patients should be based on strategies aiming to mitigate ventilator-induced lung injury. Assisted mechanical ventilation should be applied early in the course of mechanical ventilation by considering evaluation and minimizing factors associated with patient-inflicted lung injury. Extracorporeal membrane oxygenation should be considered in selected patients with refractory hypoxia not responding to conventional ventilation strategies. This review highlights the current and evolving practice in managing mechanically ventilated patients with ARDS related to COVID-19.

7.
In Vivo ; 35(6): 3305-3313, 2021.
Article in English | MEDLINE | ID: covidwho-1485627

ABSTRACT

BACKGROUND: The study provides a novel prediction model for COVID-19 progression and outcome by the combination of the CD8+: B-cells ratio with neutrophil-to-lymphocyte ratio (NLR). PATIENTS AND METHODS: Immune phenotyping was performed in 120 COVID-19 patients. RESULTS: A decrease in CD8+:B-cell (p<0.0001) and in lymphocyte-to-CRP (LCR) ratio (p<0.0001) was observed in intubated patients versus non-intubated with an increase for CD4+:CD8+ (p<0.01), NLR (p<0.0001) and CRP: Albumin (p<0.001). Receiving operating curve (ROC) analysis predicting requirement for mechanical ventilation revealed the highest AUC for CD8+:B-cells, (AUC=0.795, p<0.001) versus NLR (AUC=0.783, p<0.001), LCR (AUC=0.779, p<0.001), Albumin:CRP (AUC=0.750, p<0.001) and CD4+:CD8+ (AUC=0.779, p<0.001). Combination of the CD8+: B-cell ratio with the NLR increased the AUC (AUC=0.845, p<0.001). The combined ratios correlated with outcome defined as duration of hospital (r=0.435, p<0.001) or ICU stay (r=0.596, p<0.001). CONCLUSION: Combination of the CD8+: B-cell ratio and NLR serves as a useful prognostic tool for COVID-19 patient progression.


Subject(s)
COVID-19 , Neutrophils , B-Lymphocytes , CD8-Positive T-Lymphocytes , Humans , Intubation, Intratracheal , Lymphocytes , Prognosis , ROC Curve , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
8.
Int J Mol Sci ; 22(21)2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1480799

ABSTRACT

The hypothalamus-pituitary-adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).


Subject(s)
COVID-19/metabolism , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/virology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/virology , Receptors, Glucocorticoid/metabolism , Critical Illness , Glucocorticoids/metabolism , Humans , Stress, Physiological
9.
Crit Care Explor ; 3(10): e531, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1467421

ABSTRACT

Since changes in pharmacological treatments for severely ill patients with coronavirus disease 2019 have been incorporated into clinical practice, both by their use (corticosteroids and remdesivir) and by stopping them (e.g., hydroxychloroquine), we sought to compare the rate of intubation and mortality of intubated patients in our ICUs between the first and second waves of the pandemic. DESIGN: Single-center, observational. SETTING: Four coronavirus disease 2019 designated ICUs at an urban Greek teaching hospital. PATIENTS: All adult patients with coronavirus disease 2019 consecutively admitted to ICU during the first (n = 50) and second (n = 212) waves of the pandemic. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The percentage of intubated ICU patients dropped from 82% during the first wave to 66% during the second wave (p = 0.042). However, the absolute number of intubated ICU patients was lower during the first than the second wave (41 vs 140 patients). ICU or hospital mortality of intubated patients increased from 39% during the first wave to 60% during the second wave (p = 0.028). The binary logistic regression for hospital mortality as the dependent variable in intubated patients and covariates the age, Acute Physiology and Chronic Health Evaluation II score, cardiovascular comorbidity, lactate, positive end-expiratory pressure, Sequential Organ Failure Assessment score, and wave, distinguished only Acute Physiology and Chronic Health Evaluation II (odds ratio, 1.40 with 95% CI, 1.14-1.72; p = 0.001) as the sole independent predictor of hospital mortality. CONCLUSIONS: Pharmacological adaptations and other measures may have led to fewer intubations over time. However, these changes do not seem to be translated into improved outcomes of intubated patients. Perhaps the same change in the use of drugs and protocols that could cause fewer intubations of ICU patients might be a reason of increased mortality in those patients who are eventually intubated. Furthermore, the relative staff inexperience and overall increase in patients' comorbidities during the second wave could have contributed to increased Acute Physiology and Chronic Health Evaluation II score and mortality of intubated patients.

10.
Microbiol Spectr ; 9(2): e0126021, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1455683

ABSTRACT

Severe COVID-19 pneumonia has been associated with the development of intense inflammatory responses during the course of infections with SARS-CoV-2. Given that human endogenous retroviruses (HERVs) are known to be activated during and participate in inflammatory processes, we examined whether HERV dysregulation signatures are present in COVID-19 patients. By comparing transcriptomes of bronchoalveolar lavage fluid (BALF) of COVID-19 patients and healthy controls, and peripheral blood monocytes (PBMCs) from patients and controls, we have shown that HERVs are intensely dysregulated in BALF of COVID-19 patients compared to those in BALF of healthy control patients but not in PBMCs. In particular, upregulation in the expression of specific HERV families was detected in BALF samples of COVID-19 patients, with HERV-FRD being the most highly upregulated family among the families analyzed. In addition, we compared the expression of HERVs in human bronchial epithelial cells (HBECs) without and after senescence induction in an oncogene-induced senescence model in order to quantitatively measure changes in the expression of HERVs in bronchial cells during the process of cellular senescence. This apparent difference of HERV dysregulation between PBMCs and BALF warrants further studies in the involvement of HERVs in inflammatory pathogenetic mechanisms as well as exploration of HERVs as potential biomarkers for disease progression. Furthermore, the increase in the expression of HERVs in senescent HBECs in comparison to that in noninduced HBECs provides a potential link for increased COVID-19 severity and mortality in aged populations. IMPORTANCE SARS-CoV-2 emerged in late 2019 in China, causing a global pandemic. Severe COVID-19 is characterized by intensive inflammatory responses, and older age is an important risk factor for unfavorable outcomes. HERVs are remnants of ancient infections whose expression is upregulated in multiple conditions, including cancer and inflammation, and their expression is increased with increasing age. The significance of this work is that we were able to recognize dysregulated expression of endogenous retroviral elements in BALF samples but not in PBMCs of COVID-19 patients. At the same time, we were able to identify upregulated expression of multiple HERV families in senescence-induced HBECs in comparison to that in noninduced HBECs, a fact that could possibly explain the differences in disease severity among age groups. These results indicate that HERV expression might play a pathophysiological role in local inflammatory pathways in lungs afflicted by SARS-CoV-2 and their expression could be a potential therapeutic target.


Subject(s)
Bronchioles/virology , Bronchoalveolar Lavage Fluid/virology , COVID-19/pathology , Endogenous Retroviruses/growth & development , Respiratory Mucosa/virology , Bronchioles/cytology , Endogenous Retroviruses/isolation & purification , Epithelial Cells/virology , Humans , Inflammation/virology , Leukocytes, Mononuclear/virology , Respiratory Mucosa/cytology , SARS-CoV-2 , Transcriptome/genetics , Up-Regulation
11.
J Epidemiol Glob Health ; 11(4): 338-343, 2021 12.
Article in English | MEDLINE | ID: covidwho-1446308

ABSTRACT

INTRODUCTION: Immunoglobulins (Igs) comprise a critical part of the immune response. Little information exists on Ig serum levels in COVID-19 patients. We, therefore, investigated whether hospital admission Igs in patients with mild-to-critical disease are associated with clinical outcome. MATERIALS AND METHODS: This prospective, observational, single-center, cross-sectional study included 126 consecutive non-critically ill and critically ill and COVID-19 patients, in whom IgG, IgM, and IgA were measured on hospital admission. RESULTS: The cohort was divided in survivors and non-survivors, based on in-hospital mortality. Median IgG levels of survivors were significantly higher than non-survivors (p < 0.01). The cohort was subsequently divided in IgG deficient (< 690 mg/dl) and sufficient (≥ 690 mg/dl) patients. IgG-deficient patients had a higher mortality rate (p < 0.01). The multivariate logistic regression model showed that subnormal IgG was significantly associated with increased mortality risk (p < 0.01). CONCLUSION: In our COVID-19 cohort, admission subnormal IgG levels might be independently associated with reduced survival.

12.
Vaccines (Basel) ; 9(9)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1438752

ABSTRACT

BNT162b2 has proven to be highly effective, but there is a paucity of data regarding immunogenicity factors and comparison between response to vaccination and natural infection. This study included 871 vaccinated healthcare workers (HCW) and 181 patients with natural infection. Immunogenicity was assessed by measuring anti-SARS-CoV-2 against the RBD domain of the spike protein (anti-RBD). Samples were collected 1-2 weeks after vaccination or 15-59 days post-onset of symptoms. Post-vaccine anti-RBD concentrations were associated with age, gender, vaccination side-effects (VSE) and prior infection (Pr-CoV). Anti-RBD median levels (95%CI) were lower by 2466 (651-5583), 6228 (3254-9203) and 7651 (4479-10,823) AU/mL in 35-44, 45-54, 55-70 yrs, respectively, compared with the 18-34 yrs group. In females, the median levels were higher by 2823 (859-4787), 5024 (3122-6926) in individuals with VSE, and 9971 (5158-14,783) AU/mL in HCWs with Pr-CoV. The ratio of anti-RBD in vaccinated individuals versus those with natural infection varied from 1.0 to 19.4. The high immunogenicity of BNT162b2 is verified, although its sustainability has yet to be elucidated. The use of comparative data from natural infection serological panels, expressing the clinical heterogeneity of natural infection, may facilitate early decisions for candidate vaccines to be evaluated in clinical trials.

13.
Life (Basel) ; 11(10)2021 Sep 27.
Article in English | MEDLINE | ID: covidwho-1438659

ABSTRACT

The present cross-sectional study consists of a comprehensive analysis of epidemiological, laboratory, and clinical characteristics of COVID-19 patients in relation to their immunogenetic profiles. We studied 125 COVID-19 patients comprising different stages of disease severity; non-hospitalized (mild n = 69) and hospitalized (n = 56). Analysis of disease characteristics revealed no major differences between males and females of each group of patients while hospitalized patients were older and presented with comorbidities. A positive allele association was observed for HLA-DRB1*01 in total COVID-19 patients versus healthy controls. Subgrouping of COVID-19 patients in mild and hospitalized further identified a statistically significant increase in HLA-DRB1*01 in mild COVID-19 patients versus controls. The frequency of A*11, A*23, and DRB1*09 alleles was higher, while the frequency of C*12 was lower, in hospitalized patients versus healthy controls albeit with uncorrected statistical significance. The identification of specific allele associations may provide useful future markers for disease susceptibility in order to allow successful clinical management of COVID-19 patients.

14.
Minerva Endocrinol (Torino) ; 2021 Sep 21.
Article in English | MEDLINE | ID: covidwho-1431239

ABSTRACT

BACKGROUND: Low Testosterone (mainly total testosterone; TTe) has been noted in patients with COVID-19. Calculated free testosterone (FTe) and bioavailable testosterone (BavTe) may reflect more accurately this hormone's levels. In this study, we sought to assess TTe, FTe as well as BavTe in male patients with COVID-19. SUBJECTS/METHODS: Sera were collected upon admission from 65 men (10 in the intensive care units [ICU] and 55 in the wards) with polymerase chain reaction - proven COVID-19. A group of age-matched COVID-19-negative men (n=29) hospitalized in general medical wards served as controls. Age, body mass index (BMI) and 28-day mortality were noted. Measurements included TTe, sex-hormone binding globulin, albumin (the latter two for calculating FTe and BavTe) and laboratory markers of inflammation (white blood cell count [WBC], D-Dimers [D-D], lactate dehydrogenease [LDH], ferritin [Fer] and C-reactive protein [CRP]). RESULTS: Profoundly low TTe, FTe and BavTe were noted in most patients, and were associated with disease severity/outcome (being the lowest in COVID-19 patients in the ICU and overall being lower in non-survivors; analysis of covariance p<0.05). Pearson's correlations for logTe, logFTe or logBavTe versus WBC, D-D, LDH, Ferr or CRP were negative, ranging from -0.403 to -0.293 (p=0.009 to 0.014). CONCLUSIONS: TTe, FTe and BavTe are prone to be low in patients with COVID-19, are negatively associated with disease severity and may be considered to have prognostic value.

15.
J Pers Med ; 11(9)2021 Sep 07.
Article in English | MEDLINE | ID: covidwho-1417166

ABSTRACT

Studies have hypothesized a potential role of the interleukin (IL)-23/17 axis in coronavirus disease 2019 (COVID-19). However, to date, levels of IL-23 and 17 have not been compared between critically ill COVID-19 patients and critically ill non-COVID-19 patients. IL-23 and 17 were measured on admission to the intensive care unit (ICU) in critically ill COVID-19 (N = 38) and critically ill non-COVID-19 (N = 34) patients with an equal critical illness severity. Critically ill non-COVID-19 patients did not have sepsis or septic shock on ICU admission. None of the enrolled patients had previously received corticosteroids. In our study, circulating IL-17 levels were higher in the COVID-19 patients. More specifically, critically ill COVID-19 patients had levels of 0.78 (0.05-1.8) pg/mL compared to 0.11 (0.05-0.9) pg/mL in the critically ill non-COVID-19 patients (p = 0.04). In contrast, IL-23 levels were comparable between groups. A group of patients hospitalized in the specialized COVID-19 clinic (N = 16) was also used to evaluate IL-17 and IL-23 levels with respect to COVID-19 severity. Non-critically ill COVID-19 patients had undetectable levels of both cytokines. Our results support the notion of inhibiting IL-17 in critical COVID-19 infection.

16.
Viruses ; 13(9)2021 09 15.
Article in English | MEDLINE | ID: covidwho-1411088

ABSTRACT

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Nucleocapsid/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Load , Aged , Aged, 80 and over , Antibody Formation/immunology , COVID-19/therapy , Female , Host-Pathogen Interactions , Humans , Immunization, Passive , Kinetics , Male , Middle Aged
17.
Int J Mol Sci ; 22(18)2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1409704

ABSTRACT

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.


Subject(s)
COVID-19/diagnosis , Dendritic Cells/immunology , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/blood , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/therapy , Cohort Studies , Datasets as Topic , Dendritic Cells/drug effects , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Female , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Male , Middle Aged , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , RNA-Seq , Respiration, Artificial , SARS-CoV-2/isolation & purification , Severity of Illness Index , Signal Transduction/drug effects , Signal Transduction/immunology , Single-Cell Analysis
18.
Blood ; 136(Supplement 1):1-2, 2020.
Article in English | PMC | ID: covidwho-1338965

ABSTRACT

Introduction: Convalescent plasma is a promising therapeutic option for corona virus disease 2019 (COVID-19). A recent study in 34 COVID-19 patients showed a reduction of recovered patients antibodies within 3 months of infection. The aim on this analysis was to evaluate the antibody titers and explore possible correlations with disease characteristics in volunteer donors, who participated in a phase 2 study for the use of convalescent plasma for the treatment of severe COVID-19 infection.Patients and Methods: This in an ongoing phase 2 study (NCT04408209) for the use of convalescent plasma for severe COVID-19. This analysis reports the results of the first part of the study, regarding the presence of anti-SARS-CoV-2 antibodies in volunteer plasma donors and their correlation with disease characteristics. The main Inclusion criteria for plasma donors included: (i) confirmed SARS-CoV-2 infection by PCR of the nasal/pharyngeal swab;(ii) interval of at least 14 days after complete recovery from COVID-19;(iii) presence of anti-SARS-CoV-2 antibodies;(iv) two negative SARS-CoV-2 PCR results (the second at least 7 days prior to plasmapheresis). For the detection of anti-SARS-CoV-2 antibodies we used two commercially developed assays: one ELISA assay (Euroimmun Medizinische Labordiagnostika AG, Lubeck, Germany), which detects antibodies against the recombinant Spike protein of the virus (S1 domain) and a multiplex assay (ProtATonce Ltd, Athens, Greece) based on the Luminex® xMAP™ technology that detects total antibodies (IgG/IgM/IgA) and individual antibody isotypes IgG, IgM and IgA against 3 SARS-CoV-2 antigens (S1, basic nucleocapsid (N) protein and receptor-binding domain (RBD).Results: To-date, 260 (137M/123F) possible plasma donors were tested for the presence of anti-SARS-CoV-2 antibodies. At the time of their COVID-19 diagnosis, 20 (7.7%) were asymptomatic, 157 (60.3%) were symptomatic but did not need hospitalization and 83 (32%) were hospitalized. Median time from the day of their first symptom or PCR+ (for asymptomatic patients) till the day of screening was 62 (range: 14-104) days. Anti-SARS-CoV-2 antibodies were detected in 229 (88%) donors with the Euroimmun assay and in 238 (91.5%) with the multiplex assay (including the 229 who had antibodies with the Euroimmun method). Univariate analysis showed that donors who had asymptomatic COVID-19 had lower antibody titer compared to those who had symptomatic disease but did not need hospitalization or those who hospitalized (Fig. A-D). Donors <50 years had lower antibody titer compared with older patients [for Euroimmun method, median (IQR): 3.94 (5.10) vs. 7.34 (6.16);p<0.0001], while patients who were tested within 60 days from the first day of symptom or PCR+ (for asymptomatic patients) had higher antibody titer [6.09 (6.52) vs. 4.68 (6.12);p=0.024]. The multivariate analysis showed that age ≥50 years (OR 2.88, 95% CI:1.60-5.18;p<0.001) and need for hospitalization (OR 4.11, 95% CI:2.13-7.90;p<0.001) correlated with higher antibody titers, while asymptomatic phase (OR 0.10, 95% CI:0,01-0.82;p<0.001) and testing within ≥60 days post symptoms onset (OR 0.36, 95% CI:0.20-0.66;p=0.001) correlated with lower antibody titers. In the multivariate logistic regression analysis examining associations between individual symptoms and antibody levels, there was strong correlation between anti-SARS-CoV-2 antibodies and anosmia (OR 11.14, 95% CI:3.92-31.67;p<0.001), loss of taste (OR 5.50, 95% CI:2.23-13.56;p<0.001), fever (OR 4.25, 95% CI:1.90-9.51;p<0.001), and headache (OR 2.34, 95% CI:1.09-5.03;p=0.029). To-date, plasmapheresis was performed in 74 patients with anti-SARS-CoV-2 antibodies, within a median time of 12 (8-19) days after screening;the respective median time (range) from the first day of symptoms or PCR+ was 52 (14-84) days. Interestingly, there was a significant reduction in the antibody titers between the day of screening and the day of plasmapheresis [Fig. E].Conclusion: Lower anti-SARS-CoV-2 antibody titers, against all studied epitopes, are found in asymptomatic patients, in patients <50 years and in those who were tested ≥60 days post onset of first symptoms. The rapid reduction of anti-SARS-CoV-2 antibodies in our cohort reveals a time pattern of reduction, although we do not know if neutralizing antibodies share the same trend or if this reduction affects the host immunity against SARS-CoV-2.

19.
Pharmaceuticals (Basel) ; 14(7)2021 Jul 19.
Article in English | MEDLINE | ID: covidwho-1323319

ABSTRACT

A damaged endothelium is an underlying condition of the many complications of COVID-19 patients. The increased mortality risk associated with diseases that have underlying endothelial dysfunction, such as acute respiratory distress syndrome (ARDS), suggests that endothelial (e) nitric oxide synthase (NOS)-derived nitric oxide could be an important defense mechanism. Additionally, intravenous recombinant angiotensin converting enzyme 2 (ACE2) was recently reported as an effective therapy in severe COVID-19, by blocking viral entry, and thus reducing lung injury. Very few studies exist on the prognostic value of endothelium-related protective molecules in severe COVID-19 disease. To this end, serum levels of eNOS, inducible (i) NOS, adrenomedullin (ADM), soluble (s) ACE2 levels, and serum (s) ACE activity were measured on hospital admission in 89 COVID-19 patients, hospitalized either in a ward or ICU, of whom 68 had ARDS, while 21 did not. In our cohort, the COVID-19-ARDS patients had considerably lower eNOS levels compared to the COVID-19 non-ARDS patients. On the other hand, sACE2 was significantly higher in the ARDS patients. iNOS, ADM and sACE activity did not differ. Our results might support the notion of two distinct defense mechanisms in COVID-19-derived ARDS; eNOS-derived nitric oxide could be one of them, while the dramatic rise in sACE2 may also represent an endogenous mechanism involved in severe COVID-19 complications, such as ARDS. These results could provide insight to therapeutical applications in COVID-19.

20.
Endocr Connect ; 10(6): 646-655, 2021 Jun 17.
Article in English | MEDLINE | ID: covidwho-1304497

ABSTRACT

Objective: Following the evolution of COVID-19 pandemic, reports pointed on a high prevalence of thyroiditis-related thyrotoxicosis. Interpretation of thyroid tests during illness, however, is hampered by changes occurring in the context of non-thyroidal illness syndrome (NTIS). In order to elucidate these findings, we studied thyroid function in carefully selected cohorts of COVID-19 positive and negative patients. Design: Cohort observational study. Methods: We measured TSH, FT4, T3 within 24 h of admission in 196 patients without thyroid disease and/or confounding medications. In this study, 102 patients were SARS-CoV-2 positive; 41 admitted in the ICU, 46 in the ward and 15 outpatients. Controls consisted of 94 SARS-CoV-2 negative patients; 39 in the ICU and 55 in the ward. We designated the thyroid hormone patterns as consistent with NTIS, thyrotoxicosis and hypothyroidism. Results: A NTIS pattern was encountered in 60% of ICU and 36% of ward patients, with similar frequencies between SARS-CoV-2 positive and negative patients (46.0% vs 46.8%, P = NS). A thyrotoxicosis pattern was observed in 14.6% SARS-CoV-2 ICU patients vs 7.7% in ICU negative (P = NS) and, overall in 8.8% of SARS-CoV-2 positive vs 7.4% of negative patients. In these patients, thyroglobulin levels were similar to those with normal thyroid function or NTIS. The hypothyroidism pattern was rare. Conclusions: NTIS pattern is common and relates to the severity of disease rather than SARS-CoV-2 infection. A thyrotoxicosis pattern is less frequently observed with similar frequency between patients with and without COVID-19. It is suggested that thyroid hormone monitoring in COVID-19 should not differ from other critically ill patients.

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