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1.
Cells ; 10(12)2021 11 30.
Article in English | MEDLINE | ID: covidwho-1613627

ABSTRACT

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2.


Subject(s)
Aging/pathology , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Monocytes/pathology , Acute Disease , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/metabolism , Humans , Longitudinal Studies , Middle Aged , Neutrophils/metabolism , Prospective Studies , SARS-CoV-2 , Young Adult
2.
Crit Care ; 26(1): 9, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1606943

ABSTRACT

ClinicalTrials.gov identifier (NCT number): NCT03852537 , Registered February 25, 2019.


Subject(s)
COVID-19 , Steroids , Biomarkers , COVID-19/drug therapy , Humans , Pilot Projects , Steroids/administration & dosage , Treatment Outcome
3.
BMC Infect Dis ; 22(1): 27, 2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1603460

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a highly transmittable virus which causes the novel coronavirus disease (COVID-19). Monocyte distribution width (MDW) is an in-vitro hematological parameter which describes the changes in monocyte size distribution and can indicate progression from localized infection to systemic infection. In this study we evaluated the correlation between the laboratory parameters and available clinical data in different quartiles of MDW to predict the progression and severity of COVID-19 infection. METHODS: A retrospective analysis of clinical data collected in the Emergency Department of Rashid Hospital Trauma Center-DHA from adult individuals tested for SARS-CoV-2 between January and June 2020. The patients (n = 2454) were assigned into quartiles based on their MDW value on admission. The four groups were analyzed to determine if MDW was an indicator to identify patients who are at increased risk for progression to sepsis. RESULTS: Our data showed a significant positive correlation between MDW and various laboratory parameters associated with SARS-CoV-2 infection. The study also revealed that MDW ≥ 24.685 has a strong correlation with poor prognosis of COVID-19. CONCLUSIONS: Monitoring of monocytes provides a window into the systemic inflammation caused by infection and can aid in evaluating the progression and severity of COVID-19 infection.


Subject(s)
COVID-19 , Sepsis , Adult , Biomarkers , Humans , Monocytes , Retrospective Studies , SARS-CoV-2 , Sepsis/diagnosis
4.
Iran Biomed J ; 25(6): 381-9, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1599259

ABSTRACT

Background: Lung injury is common in coronavirus disease 2019 (COVID-19) patients. The severity of lung injury appears to be reflected in serum Krebs von den Lungen-6 (KL-6), a glycoprotein expressed on type II alveolar epithelium. This study aims to assess the role of serum KL-6 in reflecting the severity of lung injury in COVID-19 patients. Methods: A systematic search was conducted in Scopus, PubMed, Wiley Online Library, and ProQuest. Articles were screened based on several eligibility criteria and assessed for study quality using Newcastle-Ottawa Scale. Results: This systematic review included four studies involving a total of 151 adult COVID-19 patients. Pooled analysis revealed that serum KL-6 was significantly higher in severe patients (SMD = 1.16; 95% CI = 0.69­1.63) with moderately high pooled sensitivity (79%; 95% CI = 61­91%) and specificity (86%; 95% CI = 72­95%). Conclusion: High serum KL-6 may depict more severe lung injury in COVID-19 patients with moderately high sensitivity and specificity.


Subject(s)
COVID-19/complications , Lung Injury/diagnosis , Lung Injury/virology , Mucin-1/blood , Severity of Illness Index , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , Humans , Lung Injury/blood , Sensitivity and Specificity
5.
J Coll Physicians Surg Pak ; 32(1): 37-41, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1599461

ABSTRACT

OBJECTIVE: To determine the efficacy and cut-off values of C-reactive protein (CRP), lactate dehydrogenase (LDH), serum ferritin, and D-dimer for predicting mortality of COVID-19 infection. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Medicine, Jinnah Hospital, Lahore from January to May 2021. METHODOLOGY: Serum CRP, LDH, ferritin, and D-dimer were measured in patients with moderate to severe COVID-19 infection at admission. Patients were followed for in-hospital disease outcome. ROC curve was used to determine area under curve (AUC) and cut-off values of biomarkers, followed by multi-variate analysis by logistic regression. RESULTS: In 386 patients, male to female ratio was 1.47/1 (230/156); and mean age was 54.03 ± 16.2 years. Disease was fatal in 135 (35%) patients. AUC for mortality was 0.730 for LDH, 0.737 for CRP, 0.747 for ferritin and 0.758 for D-dimer. Mortality was higher with LDH ≥400 U/ml, Odds Ratio (OR) 5.37 (95% CI 3.01-9.57: p = 0.001), CRP ≥30 ng/L, OR 4.30 (95% CI 2.11-8.74: p = <0.001), serum ferritin ≥200 ng/ml, OR 4.13 (95% CI 1.05-16.2: p = 0.02), and D-dimer ≥400 ng/ml, OR 2.72 (95% CI 1.06-7.01: p = 0.03) with 2 log likelihood of 131.54 for predicting disease outcome with 71.7% accuracy in multi-variate analysis. CONCLUSION: Elevated serum CRP, LDH, ferritin and D-dimer are associated with higher mortality in patients of COVID-19 infection. Serum CRP ≥30ng/ml, LDH ≥400 U/L, ferritin ≥200 ng/ml and D-dimer ≥400 ng/ml can predict fatal outcome in COVID-19 patients. Key Words: C-reactive protein (CRP), COVID-19 infection, D-dimer, Ferritin, Lactate dehydrogenase (LDH), Mortality.


Subject(s)
Biomarkers/blood , COVID-19 , Adult , Aged , C-Reactive Protein/analysis , COVID-19/mortality , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Humans , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Prognosis , ROC Curve , Retrospective Studies
6.
Cells ; 10(12)2021 11 28.
Article in English | MEDLINE | ID: covidwho-1598211

ABSTRACT

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.


Subject(s)
Autophagy , Cardiac Glycosides/pharmacology , Animals , Apoptosis/drug effects , Autophagy/drug effects , Biomarkers/metabolism , Humans , Models, Biological , Sodium-Potassium-Exchanging ATPase/metabolism
7.
J Coll Physicians Surg Pak ; 32(1): 2-3, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1596110
8.
Dis Markers ; 2021: 7686374, 2021.
Article in English | MEDLINE | ID: covidwho-1595046

ABSTRACT

Objective: S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are indicators of global transmethylation and may play an important role as markers of severity of COVID-19. Methods: The levels of plasma SAM and SAH were determined in patients admitted with COVID-19 (n = 56, mean age = 61). Lung injury was identified by computed tomography (CT) in accordance with the CT0-4 classification. Results: SAM was found to be a potential marker of lung damage risk in COVID-19 patients (SAM > 80 nM; CT3,4 vs. CT 0-2: relative ratio (RR) was 3.0; p = 0.0029). SAM/SAH > 6.0 was also found to be a marker of lung injury (CT2-4 vs. CT0,1: RR = 3.47, p = 0.0004). There was a negative association between SAM and glutathione level (ρ = -0.343, p = 0.011). Interleukin-6 (IL-6) levels were associated with SAM (ρ = 0.44, p = 0.01) and SAH (ρ = 0.534, p = 0.001) levels. Conclusions: A high SAM level and high methylation index are associated with the risk of lung injury in patients with COVID-19. The association of SAM with IL-6 and glutathione indicates an important role of transmethylation in the development of cytokine imbalance and oxidative stress in patients with COVID-19.


Subject(s)
COVID-19/complications , Lung Injury/blood , S-Adenosylhomocysteine/blood , S-Adenosylmethionine/blood , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Atherosclerosis/epidemiology , Biomarkers , COVID-19/epidemiology , Comorbidity , Diabetes Mellitus/epidemiology , Female , Glutathione/blood , Humans , Hypertension/epidemiology , Interleukin-6/blood , Lung Injury/diagnostic imaging , Lung Injury/etiology , Male , Methylation , Middle Aged , Military Personnel , Risk , Tomography, X-Ray Computed , Young Adult
9.
Cell Metab ; 33(10): 1911-1925, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1588059

ABSTRACT

High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.


Subject(s)
Atherosclerosis/metabolism , COVID-19/metabolism , Cholesterol/metabolism , Hypercholesterolemia/metabolism , Animals , Anticholesteremic Agents/therapeutic use , Atherosclerosis/diagnosis , Atherosclerosis/drug therapy , Atherosclerosis/epidemiology , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , Humans , Hypercholesterolemia/diagnosis , Hypercholesterolemia/drug therapy , Hypercholesterolemia/epidemiology , Prognosis , Risk Factors
10.
Metabolomics ; 18(1): 6, 2021 12 20.
Article in English | MEDLINE | ID: covidwho-1588749

ABSTRACT

INTRODUCTION: The diagnosis of COVID-19 is normally based on the qualitative detection of viral nucleic acid sequences. Properties of the host response are not measured but are key in determining outcome. Although metabolic profiles are well suited to capture host state, most metabolomics studies are either underpowered, measure only a restricted subset of metabolites, compare infected individuals against uninfected control cohorts that are not suitably matched, or do not provide a compact predictive model. OBJECTIVES: Here we provide a well-powered, untargeted metabolomics assessment of 120 COVID-19 patient samples acquired at hospital admission. The study aims to predict the patient's infection severity (i.e., mild or severe) and potential outcome (i.e., discharged or deceased). METHODS: High resolution untargeted UHPLC-MS/MS analysis was performed on patient serum using both positive and negative ionization modes. A subset of 20 intermediary metabolites predictive of severity or outcome were selected based on univariate statistical significance and a multiple predictor Bayesian logistic regression model was created. RESULTS: The predictors were selected for their relevant biological function and include deoxycytidine and ureidopropionate (indirectly reflecting viral load), kynurenine (reflecting host inflammatory response), and multiple short chain acylcarnitines (energy metabolism) among others. Currently, this approach predicts outcome and severity with a Monte Carlo cross validated area under the ROC curve of 0.792 (SD 0.09) and 0.793 (SD 0.08), respectively. A blind validation study on an additional 90 patients predicted outcome and severity at ROC AUC of 0.83 (CI 0.74-0.91) and 0.76 (CI 0.67-0.86). CONCLUSION: Prognostic tests based on the markers discussed in this paper could allow improvement in the planning of COVID-19 patient treatment.


Subject(s)
COVID-19/blood , Chromatography, Liquid/methods , Metabolomics/methods , Tandem Mass Spectrometry/methods , Aged , Biomarkers/blood , Female , Humans , Male , Middle Aged , Prognosis , SARS-CoV-2 , Severity of Illness Index
11.
Signal Transduct Target Ther ; 6(1): 427, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1585887

ABSTRACT

Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.


Subject(s)
COVID-19/blood , Hyperglycemia/blood , Insulin Resistance , Lipid Metabolism , Lipids/blood , SARS-CoV-2/metabolism , Adult , Aged , Biomarkers/blood , COVID-19/complications , Female , Humans , Hyperglycemia/etiology , Male , Middle Aged , Retrospective Studies
12.
Blood Cancer J ; 11(12): 202, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585877

ABSTRACT

There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.


Subject(s)
Biomarkers/blood , COVID-19 Vaccines , COVID-19/immunology , Hematologic Neoplasms/complications , Immunocompromised Host/immunology , Adult , Aged , Aged, 80 and over , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , SARS-CoV-2
13.
Open Heart ; 8(2)2021 12.
Article in English | MEDLINE | ID: covidwho-1582998

ABSTRACT

OBJECTIVE: Soluble ST2 (sST2) reflects inflammation, endothelial dysfunction and myocardial fibrosis, is produced in the lungs and is an established biomarker in heart failure. We sought to determine the role of sST2 in COVID-19 by assessing pathophysiological correlates and its association to in-hospital outcomes. METHODS: We enrolled 123 consecutive, hospitalised patients with COVID-19 in the prospective, observational COVID-19 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The key exposure variable was sST2, and the outcome was ICU treatment with mechanical ventilation or in-hospital death. RESULTS: Concentrations of sST2 at baseline was median 48 (IQR 37-67) ng/mL, and 74% had elevated concentrations (>37.9 ng/mL). Higher baseline sST2 concentrations were associated with older age, male sex, white race, smoking, diabetes, hypertension and chronic kidney disease. Baseline sST2 also associated with the presence of SARS-CoV-2 viraemia, lower oxygen saturation, higher respiratory rate and increasing concentrations of biomarkers reflecting inflammation, thrombosis and cardiovascular disease. During the hospitalisation, 8 (7%) patients died and 27 (22%) survivors received intensive care unit (ICU) treatment. Baseline sST2 concentrations demonstrated a graded association with disease severity (median, IQR): medical ward 43 (36-59) ng/mL; ICU 67 (39-104) ng/mL and non-survivors 107 (72-116) ng/mL (p<0.001 for all comparisons). These associations persisted at day 3 and day 9 . CONCLUSIONS: sST2 concentrations associate with SARS-CoV-2 viraemia, hypoxaemia and concentrations of inflammatory and cardiovascular biomarkers. There was a robust association between baseline sST2 and disease severity that was independent of, and superior to, established risk factors. sST2 reflects key pathophysiology and may be a promising biomarker in COVID-19. TRIAL REGISTRATION NUMBER: NCT04314232.


Subject(s)
COVID-19 , Hypoxia , Interleukin-1 Receptor-Like 1 Protein/analysis , SARS-CoV-2/isolation & purification , Viremia , Aged , Biomarkers/analysis , COVID-19/blood , COVID-19/mortality , COVID-19/physiopathology , Comorbidity , Correlation of Data , Female , Hospital Mortality , Humans , Hypoxia/diagnosis , Hypoxia/etiology , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Norway/epidemiology , Prognosis , Risk Factors , Severity of Illness Index , Smoking/epidemiology , Viremia/diagnosis , Viremia/etiology
14.
Clin Appl Thromb Hemost ; 27: 10760296211010973, 2021.
Article in English | MEDLINE | ID: covidwho-1582642

ABSTRACT

SARS-CoV-2 in COVID-19 triggers abnormalities in coagulation parameters that can contribute to thrombosis. The goals of this research were to determine the levels of fibrinogen, D-dimer and FDP in COVID-19 patients. Following a systematic study, among 1198 articles, 35 studies were included in the meta-analysis of fibrinogen levels in both severe and non-severe groups. The funnel plot, Egger's regression asymmetry test, and Begg's test used to measure the bias of publications. All meta-analysis performed by comprehensive meta-analysis version 2 (CMA2). The pooled findings of fibrinogen levels revealed a significant rise in fibrinogen levels in severe COVID-19 than non-severe patients with COVID-19. The D-dimer and FDP levels were significantly higher in severe patients than non-severe patients with COVID-19 were. The levels of fibrinogen, D-dimer, and FDP have increased significantly in ICU patients compared to non-ICU patients. Although, levels of clotting parameters do not always correlate with the severity of disease, these findings showed the diagnostic importance for fibrinogen, D-dimer, and FDP in COVID-19. The presence of a continuous rise in serial measurements of fibrinogen, D-dimer, and FDP may predict that patients with COVID-19 may become critically ill.


Subject(s)
COVID-19/blood , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Hemostasis , SARS-CoV-2 , Biomarkers , COVID-19/complications , Critical Illness , Humans , Prognosis , Severity of Illness Index , Thrombophilia/blood , Thrombophilia/etiology
15.
Int J Immunopathol Pharmacol ; 35: 20587384211059675, 2021.
Article in English | MEDLINE | ID: covidwho-1582485

ABSTRACT

INTRODUCTION: The fully-human monoclonal anti-interleukin (IL)-1ß antibody canakinumab may inhibit the production of inflammatory mediators in patients with coronavirus disease 2019 (COVID-19) and the hyperinflammatory response potentially leading to acute respiratory distress syndrome. OBJECTIVES: The goal of our retrospective, observational analysis was to evaluate the safety and efficacy of subcutaneous (s.c.) canakinumab in combination with our standard of care (SOC) treatment of selected patients with COVID-19 with respiratory failure and elevated reactive pro-inflammatory markers. METHODS: Eight participants received two doses of s.c. canakinumab 150 mg (or 2 mg/kg for participants weighing ≤40 kg) in addition to SOC. 12 patients received only SOC treatment. RESULTS: Canakinumab treatment reduced the need for mechanical ventilation and reduced proinflammatory markers, resulting in an amelioration of the final outcome, with respect to the control group who received SOC alone. The treatment was safe and well tolerated; no adverse events were reported. CONCLUSION: The use of canakinumab (300 mg, s.c.) in the early stage of COVID-19 with mild-to-moderate respiratory failure was superior to SOC at preventing clinical deterioration and may warrant further investigation as a treatment option for patients with COVID-19 who experience a hyperinflammatory response in the early stage of the disease.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Interleukin-1beta , Respiration, Artificial , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/immunology , Biomarkers/blood , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , COVID-19/therapy , Dose-Response Relationship, Drug , Female , Humans , Inflammation Mediators/blood , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/immunology , Italy/epidemiology , Male , Middle Aged , Monitoring, Immunologic/methods , Outcome and Process Assessment, Health Care , Patient Selection , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2 , Time-to-Treatment
17.
Front Immunol ; 12: 707159, 2021.
Article in English | MEDLINE | ID: covidwho-1581347

ABSTRACT

Coronavirus disease-2019 (COVID-19) was declared as a pandemic by WHO in March 2020. SARS-CoV-2 causes a wide range of illness from asymptomatic to life-threatening. There is an essential need to identify biomarkers to predict disease severity and mortality during the earlier stages of the disease, aiding treatment and allocation of resources to improve survival. The aim of this study was to identify at the time of SARS-COV-2 infection patients at high risk of developing severe disease associated with low survival using blood parameters, including inflammation and coagulation mediators, vital signs, and pre-existing comorbidities. This cohort included 89 multi-ethnic COVID-19 patients recruited between July 14th and October 20th 2020 in Doha, Qatar. According to clinical severity, patients were grouped into severe (n=33), mild (n=33) and asymptomatic (n=23). Common routine tests such as complete blood count (CBC), glucose, electrolytes, liver and kidney function parameters and markers of inflammation, thrombosis and endothelial dysfunction including complement component split product C5a, Interleukin-6, ferritin and C-reactive protein were measured at the time COVID-19 infection was confirmed. Correlation tests suggest that C5a is a predictive marker of disease severity and mortality, in addition to 40 biological and physiological parameters that were found statistically significant between survivors and non-survivors. Survival analysis showed that high C5a levels, hypoalbuminemia, lymphopenia, elevated procalcitonin, neutrophilic leukocytosis, acute anemia along with increased acute kidney and hepatocellular injury markers were associated with a higher risk of death in COVID-19 patients. Altogether, we created a prognostic classification model, the CAL model (C5a, Albumin, and Lymphocyte count) to predict severity with significant accuracy. Stratification of patients using the CAL model could help in the identification of patients likely to develop severe symptoms in advance so that treatments can be targeted accordingly.


Subject(s)
Biomarkers/blood , COVID-19/blood , COVID-19/mortality , Complement C5a/analysis , Patient Acuity , Adult , Aged , COVID-19/complications , Cohort Studies , Female , Humans , Hypoalbuminemia/mortality , Hypoalbuminemia/virology , Lymphocyte Count , Lymphopenia/mortality , Lymphopenia/virology , Male , Middle Aged , Prognosis , Prospective Studies , Qatar , SARS-CoV-2
18.
Front Immunol ; 12: 760249, 2021.
Article in English | MEDLINE | ID: covidwho-1581341

ABSTRACT

Background: The humoral and cellular immune responses to SARS-COV-2 vaccination remain to be elucidated in hemodialysis (HD) patients and kidney transplant recipients (KTRs), considering their baseline immunosuppressed status. The aim of our study was to assess the associations of vaccine-induced antibody responses with circulating lymphocytes sub-populations and their respective patterns of alterations in maintenance HD patients and KTRs. Materials and Methods: We included 34 HD patients and 54 KTRs who received two doses of the mRNA-vaccine BNT162b2. Lymphocyte subpopulations were analyzed by flow cytometry before vaccination (T0), before the second vaccine dose (T1) and 2 weeks after the second dose (T2). The anti-SARS-CoV2 antibody response was assessed at T1 and at T2. Results: 31 HD patients (91.8%) and 16 KTRs (29.6%) became seropositive at T2. HD patients who became seropositive following the first dose displayed higher CD19+ B lymphocytes compared to their seronegative HD counterparts. A positive correlation was established between CD19+ B cells counts and antibody titers at all time-points in both groups (p < 0.001). KTRs showed higher naïve CD4+CD45RA+ T helper cells compared to HD patients at baseline and T2 whereas HD patients displayed higher memory CD45RO+ T cells compared to KTRs at T2. The naïve CD4+CD45RA to memory CD4+CD45RO+ T helper cells fraction was negatively associated with antibody production in both groups. Conclusions: Our study provides a potential conceptual framework for monitoring vaccination efficacy in HD patients and KTRs considering the correlation established between CD19+ B cells, generation of memory CD4+ T helper cells and anti SARS-CoV2 antibody response to vaccination.


Subject(s)
Antibody Formation/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Immunity, Humoral , Immunocompromised Host , Immunologic Memory , B-Lymphocytes/metabolism , Biomarkers , CD4-Positive T-Lymphocytes/metabolism , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , Female , Humans , Immunophenotyping , Kidney Transplantation , Lymphocyte Count , Male , Renal Dialysis , SARS-CoV-2/immunology
19.
Front Immunol ; 12: 763292, 2021.
Article in English | MEDLINE | ID: covidwho-1581338

ABSTRACT

The cytokine release syndrome has been proposed as the driver of inflammation in coronavirus disease 2019 (COVID-19). However, studies on longitudinal cytokine profiles in patients across the whole severity spectrum of COVID-19 are lacking. In this prospective observational study on adult COVID-19 patients admitted to two Hong Kong public hospitals, cytokine profiling was performed on blood samples taken during early phase (within 7 days of symptom onset) and late phase (8 to 12 days of symptom onset). The primary objective was to evaluate the difference in early and late cytokine profiles among patient groups with different disease severity. The secondary objective was to assess the associations between cytokines and clinical endpoints in critically ill patients. A total of 40 adult patients (mild = 8, moderate = 15, severe/critical = 17) hospitalized with COVID-19 were included in this study. We found 22 cytokines which were correlated with disease severity, as proinflammatory Th1-related cytokines (interleukin (IL)-18, interferon-induced protein-10 (IP-10), monokine-induced by gamma interferon (MIG), and IL-10) and ARDS-associated cytokines (IL-6, monocyte chemoattractant protein-1 (MCP-1), interleukin-1 receptor antagonist (IL-1RA), and IL-8) were progressively elevated with increasing disease severity. Furthermore, 11 cytokines were consistently different in both early and late phases, including seven (growth-regulated oncogene-alpha (GRO-α), IL-1RA, IL-6, IL-8, IL-10, IP-10, and MIG) that increased and four (FGF-2, IL-5, macrophage-derived chemokine (MDC), and MIP-1α) that decreased from mild to severe/critical patients. IL-8, followed by IP-10 and MDC were the best performing early biomarkers to predict disease severity. Among critically ill patients, MCP-1 predicted the duration of mechanical ventilation, highest norepinephrine dose administered, and length of intensive care stay.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Cytokines/blood , Adult , Aged , COVID-19/blood , Cytokines/immunology , Female , Hong Kong , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Severity of Illness Index
20.
Front Immunol ; 12: 784028, 2021.
Article in English | MEDLINE | ID: covidwho-1581324

ABSTRACT

Background: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. Methods: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. Results: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, padjusted<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, padjusted=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. Conclusion: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Extracellular Vesicles/immunology , MicroRNAs/immunology , Aged , Aged, 80 and over , COVID-19/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Pneumonia/immunology , Pneumonia/pathology , SARS-CoV-2 , Signal Transduction/immunology
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