NOTCH and tumor necrosis factor-alpha converting enzyme levels could be used in COVID-19 for risk stratification

Background: Novel coronavirus disease-2019 (COVID-19) has become a public emergency that is characterized by a dysregulated immune response and hypercoagulable state. The purpose of the present study was to evaluate NOTCH and tumor necrosis factor-alpha converting enzyme (TACE) levels in COVID-19-infected patients and assess their predictive value on the severity of the disease. Methods: A total of 116 severe-critical COVID-19 patients who were interned intensive care were included in the study. The severity of the disease was evaluated according to the WHO classification system. Patients were divided into two groups according to their cTroponin T (cTnT) levels. Patients who had cTnT levels at least five times the upper limit of normal constituted Group 1 (n = 58);patients who had normal cTnT levels constituted Group 2 (n = 58). Besides, 62 age- and sex-matched healthy controls, who applied to cardiology outward clinic were taken as a control group (Group 3). All patients underwent echocardiographic examination. NOTCH and TACE levels were assessed using enzyme-linked immunosorbent assay. Results: The average age of the patients was 59.96 +/- 15.46 years, 92 (51.7%) were female and 86 (48.3%) were male. The mean length of hospital stay was 16.35 +/- 10.97 days. NOTCH levels were significantly higher in Group 1 patients compared to Group 2 and control group of patients P = 0.001). NOTCH levels of Group 2 were significantly higher compared to the control group (P = 0.002). Similarly, the TACE levels of Group 1 were significantly higher than that of Group 2 and the control group (P = 0.001). Mortality and length of hospital stay were significantly higher in Group 1 patients compared to Group 2 patients (P = 0.002 and P = 0.004, respectively). TACE levels of deceased patients were significantly higher than that of live patients (P = 0.004). There was a positive relationship between the length of hospital stay and NOTCH levels in Group 1 patients (r = 0.527, P = 0.003). TACE and NOTCH levels were positively correlated with troponin levels (r = 0.627 and r = 0.671, respectively P < 0.001 for both). NOTCH value of 0.34 nmol/L and TACE value of 6.53 mu g/mL predicted inhospital mortality with a sensitivity of 90.30% and 63.6% and specificity of 91.5% and 78.6%, respectively. Conclusion: Measurement of NOTCH and TACE levels during severe acute respiratory syndrome coronavirus infection could be helpful for risk stratification.

ANTIPHOSPHOLIPID ANTIBODY (aPL) PRESENCE IN COVID-19 PATIENTS

Objective: In our study, we aimed to show whether there is a relationship between antiphospholipid antibody (aPL) positivity and complications of COVID-19. Material and Methods: Eighty-three patients who were diagnosed with COVID-19 infection and hospitalized in the intensive care unit (ICU) of Bakirkoy Dr. Sadi Konuk Research and Training Hospital were included in our study as the case group and 79 healthy volunteers as the control group. Only patients with a positive polymerase chain reaction (PCR) test were included in the case group. Serum antiphospholipid antibodies (aPL IgM/G), C-Reactive Protein (CRP), ferritin, procalcitonin (PCT), plasma D-Dimer levels, prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) were analyzed by routine laboratory methods. Results: Both groups were found statistically similar in terms of gender (chi(2) test, p=0.236). The mean age of the case group and control group was 60.54 +/- 16.86 and 51.47 +/- 14.64 years, respectively. When aPL positivity was evaluated between the case and control groups, a statistically remarkable difference was found between the groups (p=0.046). The case group showed an aPL positivity of 7.5% and the control group 1%. The correlation between D-Dimer, PT, INR, aPTT levels, and aPL IgM/G positivity in the case group was significant. Conclusion: Our results revealed that aPL positivity in patients with COVID-19 infection relate to the severity of the disease, in-dependent from age and gender. To confirm the result of this study further studies with participation of larger patient groups from national and international hospitals are required.

Serum presepsin levels among patients with COVID-19

Background: Presepsin provides information about prognosis of various inflammatory diseases and helps guide therapy. The present study was aimed to evaluate presepsin levels in COVID-19 patients and assess its predictive value on severity and mortality of the disease. Materials and Methods: A total of 259 patients were divided into two groups according to severity of the disease. Patients with mild-moderate illness constituted group 0 and those with severe-critical illness constituted group 1. Biochemical parameters including hemogram, coagulation tests, C-reactive protein (CRP), procalcitonin, creatine kinase, troponin, D-dimer, presepsin, and liver and kidney function tests were assessed for each patient. Results: Group 1 patients were older and had a higher length of hospital stay and mortality compared to group 0 patients. Blood levels of urea, creatinine, lactate dehydrogenase (LDH), aspartate aminotransferase, ferritin, procalcitonin, CRP, activated partial thromboplastin time, troponin, and presepsin were statistically significantly higher and lymphocyte and albumin levels were significantly lower in group 1 patients than that of group 0 patients. Presepsin had a weak positive correlation with LDH (r = 0.147, P = 0.018) and troponin levels (r = 0.141, P = 0.024), and had a weak negative correlation with albumin level (r = -0.134, 0.031). According to multivariate logistic regression analysis, only lymphocyte count was an independent predictor of hospital mortality. Presepsin with a cutoff value of 42.79 pg/ml predicted severe-critical infection with 64.4% sensitivity and 52.5% specificity. It had a lower diagnostic value for prediction of disease severity compared to procalcitonin and CRP. Conclusion: Presepsin might be used in risk stratification of COVID-19 disease. Further studies are needed to delineate its prognostic value for survival.

Adrenocortical System Hormones in Non-Critically Ill COVID-19 Patients.

CONTEXT: The effects of COVID-19 on the adrenocortical system and its hormones are not well known. OBJECTIVES: We studied serum cortisol, serum adrenocorticotropic hormone (ACTH), and their ratio in hospitalized non-critically ill COVID-19 patients. DESIGN: A prospective case-control study. METHODS: The study participants were divided into 2 groups. Group 1 consisted of 74 COVID-19 patients. The second group consisted of 33 healthy persons. Early admission above hormones levels was determined and compared between the study groups. Besides that, COVID-19 patients were grouped according to their Glasgow Coma Score (GCS), CURB-65 score, and intensive care unit (ICU) requirement, and further sub-analyses were performed. RESULTS: There were no significant differences in the mean age or gender distribution in both groups. In the patients' group, the serum ACTH concentration was lower than in the healthy group (p<0.05). On the other hand, the serum cortisol levels and cortisol/ACTH ratio of the patients' group were significantly higher than of the healthy controls (p<0.05, all). Further analyses showed that, although serum cortisol and ACTH levels were not high, the cortisol/ACTH ratio was higher in COVID-19 patients with low GCS (<15) than patients with normal GCS (=15) (p<0.05). In COVID-19 in patients with different CURB-65 scores, the cortisol/ACTH ratio was significantly different (p<0.05), while serum cortisol and ACTH were not different in groups (p>0.05). Serum cortisol levels and cortisol/ACTH ratio were higher but ACTH level was lower in the ICU needed COVID-19 patients than in patients who do not need ICU (p<0.05). CONCLUSION: Our pilot study results showed that the cortisol/ACTH ratio would be more useful than serum cortisol and/or ACTH levels alone in evaluating the adrenocortical system of COVID-19 patients. Still, further detailed studies are needed to confirm these.

The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial.

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-ß, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Mesenchymal stem cells treatment in COVID-19 patient with multi-organ involvement.

The aim of this study is to evaluate the therapeutic effect of mesenchymal stem cells (MSCs) in a severe case of brain and multiple organ involvement in a patient with COVID-19. Here, a 51-year-old male patient with multi-organ involvement due to COVID-19 infection and developing cardiac arrest is presented. MSCs were transplanted to the patient four times systematically and once intrathecally. As a result, the application of MSCs has been found to have a healing effect on organs in this patient with severe COVID-19 infection. In addition, transplantation of MSCs both systematically and intrathecally is considered to be effective in the treatment of the central nervous system (Tab. 2, Fig. 2, Ref. 24). Keywords: mesenchymal stem cell, COVID-19, organ involvement.