Association of genetic variations in ACE2, TIRAP and factor X with outcomes in COVID-19

Background Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. Methods We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. Results Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55–75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. Conclusion This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.

A More Important Role of Diabetes Mellitus in Mortality in Elderly Critical COVID-19 Patients: a Single-center Retrospective Study

BackgroundCOVID-19 has been circulating worldwide since December 2019. However, its independent risk factors of mortality need further insights in elderly critical COVID-19 patients.MethodsTotally 48 elderly and critically ill COVID-19 patients with clear end point were enrolled when the data were collected, with 16 discharged and 32 died. Kaplan-Meier analysis and Cox regression were performed to identify the risk factors of mortality in elderly critical COVID-19 patients. Survival curve was conducted to present the impact of Diabetes Mellitus on mortality. Mann-Whitney U and t tests were used to 39 clinical variates between the survivor and non-survivor groups.ResultsAs Kaplan-Meier analysis confirmed, only three variates Diabetes Mellitus, chronic obstructive pulmonary disease and family aggregation showed significant difference between the survivor and non-survivor groups. However, only variate Diabetes Mellitus presented significance in Cox regression. Higher C-reaction protein, interleukin-2 (IL-2), IL-8 and creatinine were detected in survivor group than non-survivor group, which was reverse to estimated glomerular filtration rate. The other laboratory finding showed no significant difference between survivor and non-survivor groups.ConclusionsDiabetes Mellitus, chronic obstructive pulmonary disease and family aggregation can contribute to mortality by COVID-19 while Diabetes Mellitus also reduces the survival time of elderly and critically ill COVID-19 patients, highlighting the more important role of Diabetes Mellitus. Laboratory findings could not serve as good predictors of death for elderly and critically ill COVID-19 patients.

Prognostic factors in children with acute fulminant myocarditis receiving venoarterial extracorporeal membrane oxygenation

BackgroundPediatric acute fulminant myocarditis (AFM) is a very dangerous disease that may lead to acute heart failure or even sudden death. Previous reports have identified some prognostic factors in adult AFM; however, there is no such research on children with AFM on venoarterial extracorporeal membrane oxygenation (VA-ECMO). This study aimed to find relevant prognostic factors for predicting adverse clinical outcomes.MethodsA retrospective analysis was performed in an affiliated university children’s hospital with consecutive patients receiving VA-ECMO for AFM from July 2010 to November 2020. These children were classified into a survivor group (n=33) and a non-survivor group (n=8). Patient demographics, clinical events, laboratory findings, and electrocardiographic and echocardiographic parameters were analyzed.ResultsPeak serum creatinine (SCr) and peak creatine kinase isoenzyme MB during ECMO had joint predictive value for in-hospital mortality (p=0.011, AUC=0.962). Based on multivariable logistic regression analysis, peak SCr level during ECMO support was an independent predictor of in-hospital mortality (OR=1.035, 95% CI 1.006 to 1.064, p=0.017, AUC=0.936, with optimal cut-off value of 78 μmol/L).ConclusionTissue hypoperfusion and consequent end-organ damage ultimately hampered the outcomes. The need for left atrial decompression indicated a sicker patient on ECMO and introduced additional risk for complications. Earlier and more cautious deployment would likely be associated with decreased risk of complications and mortality.

Efficacy of Tocilizumab in COVID-19: Single-Center Experience

Background. Cytokine release syndrome can be observed during the course of COVID-19. Tocilizumab is used for treating this highly fatal syndrome. We think that the starting time of tocilizumab is important. In this article, we aimed to discuss the efficacy of tocilizumab and to review the necessity of starting it in the early period and the laboratory values that guide us in determining the time of this early period. Methods. This retrospective study includes a total of 308 patients with a diagnosis of COVID-19 who were treated with tocilizumab, who were hospitalized in the University of Health Sciences, Gazi Yaşargil Training and Research Hospital between July 2020 and December 2020. The data of the patients were recorded on the day of hospitalization, the day of taking tocilizumab (day 0), and the 1st day, 3rd day, 7th day, and 14th day after taking tocilizumab. Data included age, gender, underlying diseases, where the patient was followed, duration of symptoms before admission to the hospital, duration of oxygen demand before tocilizumab, fever, saturation, and laboratory values. Patients were divided into the mortality group (group 1) and the survival group (group 2), and all data were compared. Results. The study consisted of 308 COVID-19 patients divided into two groups: the mortality group (group 1, n = 135 ) and the survival group (group 2, n = 173 ). The median age of the patients was 60 (min–max: 50-70) years, 75.3% ( n = 232 ) were male, and 56.8% had at least one comorbidity. While 88.9% of group 1 was in the intensive care unit, 26.6% of group 2 received tocilizumab while in the intensive care unit, and there was a statistically significant difference. Median SpO2 values and lymphocyte counts were significantly lower in group 1 than in group 2, both on the day of hospitalization and on the day of the first dose of tocilizumab treatment ( p < 0.001 for both). C-reactive protein, d-dimer, and alanine aminotransferase values were higher in the mortal group on the first day of hospitalization, and this was significant ( p = 0.021 , p = 0.001 , and p = 0.036 , respectively). In our study, d-dimer was 766.5 ng/mL in the survivor group and 988.5 ng/mL in the mortal group. In our patient group, the mean lymphocyte count was 700 × 10 3 / m m 3 in the group that survived the first day of TCZ and 500 × 10 3 / m m 3 in the mortal group. In addition, the CRP value was 135.5 mg/L in the survivor group and 169 mg/L in the mortal group. There was no difference between ferritin values. Conclusions. Tocilizumab is still among the COVID-19 treatment options and appears to be effective. But the start time is important. In order to increase its effectiveness, it may be important to know a cut-off value of the laboratory findings required for the diagnosis of cytokine release syndrome. Further studies are needed for this.

Clinical Characteristics and Prognostic Risk Factors of Patients With Proven Invasive Pulmonary Aspergillosis: A Single-Institution Retrospective Study

Background: The mortality and burden of medical costs associated with invasive pulmonary aspergillosis (IPA) is very high. Currently, the clinical features and prognostic factors of patients with proven IPA are not very clear, especially in the Chinese population. In this retrospective analysis, we aimed to identify the clinical features and prognostic factors of patients with proven IPA.Methods: The diagnostic criteria for proven IPA were based on the international consensus of the EORTC/MSG. Data of patients with proven IPA at the West China Hospital of Sichuan University between January 2012 and December 2018 were collected. The optimal cut-off value of continuous variables was determined by Receiver Operating Characteristic curve and maximum Youden's index. Finally, using the Cox regression analysis to identify correlations between the clinical parameters associated with morbidity.Results: A total of 117 patients with proven IPA were included in the study, and 32 (27.4%) patients died during the follow-up period. Compared with the survivor group, elderly, patients with comorbidities, and patients undergoing chemotherapy and the level of inflammatory biomarkers [erythrocyte sedimentation rate, platelet count, interleukin-6, C-reactive protein (CRP)] in the non-survivor group were higher, while the albumin level was lower (P = 0.018). The imaging features were consolidation, nodules, cavities, pleural effusion, ground-glass shadows, and halo signs in order. Overall, 41.0% patients had mixed imaging features. The results suggested the most appropriate cut-off value of age and CRP were 60 years and 14.1 mg/L, respectively. The multivariate Cox regression analysis suggested that advanced age (&gt;60 years) [hazard ratio (HR): 10.7, confidence interval (CI): 2.5–44.9, P &lt; 0.001), undergoing chemotherapy (HR: 9.5, CI: 2.7–32.9, P &lt; 0.001), presence of pleural effusion (HR: 5.74, CI: 1.6–20.8, P = 0.008), and increased CRP levels (&gt;14.1 mg/L) (HR: 6.3, CI: 1.2–34.3, P = 0.033) were risk factors for all-cause mortality in patients with proven aspergillosis.Conclusions: This study showed that the prognosis of proven IPA is poor, and the age &gt;60 years, undergoing chemotherapy, pleural effusion on CT image, and CRP levels &gt;14.1 mg/L may be as risk factors for mortality in patients with proven IPA. large samples and real-world studies are needed to confirm these results in the future.

Correlation of Nitrite Oxide with Severity and Survival Rate of Sepsis Patients

The objective of this research was to determine the correlation between Nitric Oxide (NO) levels with the severity ofsepsis, to describe the kinetics of NO levels, and to evaluate it in predicting mortality. This research was a longitudinal cohortobservational analytical study. The variables were serum NO levels and SOFA scores, which were serially evaluated. Thecorrelation test and difference test were used for statistical analysis. The survivor and the non-survivor group consisted of 14(41.18%) and 20 (58.82%) patients, respectively. There was a correlation between serum NO levels and the SOFA score at the24-hour observation (r=0.403; p=0.041). Non-parametric Mann-Whitney test showed that there was no kinetics of NOth levels at 0, 24, 72, and 144-hour observation (p-values =0.897 and 0.703, respectively). NO levels > 111,16 μmol/L at the 24hour could predict the risk of death with hazard ratio 4.7 compared to NO levels < 111,16 μmol/L. The survival rate ofpatients with serum NO levels <111,16 μmol/L and > 111,16 μmol/L was 83.3% and 37.5%, respectively. There was acorrelation between serum NO levels and SOFA scores at the 24-hour observation. However, there was no kinetics of NOlevels at serial evaluations. Nitric oxide levels with a cut-off of 111,16 μmol/L at 24 hours could predict the survival of septicth patients. Utilization of serum NO level at 24 hour can be used to evaluate the severity of septic patients and aggressivemanagement if there is an increase in serum NO levels > 111,16 μmol/L at 24 hours.

Therapeutic Effects of Mutian® Xraphconn on 141 Client-Owned Cats with Feline Infectious Peritonitis Predicted by Total Bilirubin Levels

Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus or its variant, referred to as the FIP virus. Recently, favorable treatment outcomes of the anti-viral drug Mutian® Xraphconn (Mutian X) were noted in cats with FIP. Thus, the therapeutic efficacy of Mutian X in cats with FIP must be explored, although the predictors of therapeutic success remain unknown. In the present study, we administered Mutian X to 141 pet cats with effusive FIP following initial veterinarian examinations. Of these, 116 cats survived but the remaining 25 died during treatment. Pre-treatment signalment, viral gene expression, and representative laboratory parameters for routine FIP diagnosis (i.e., hematocrit, albumin-to-globulin ratio, total bilirubin, serum amyloid-A, and α1-acid glycoprotein) were statistically compared between the survivor and non-survivor groups. The majority of these parameters, including hematocrit, albumin-to-globulin ratio, serum amyloid-A, α1-acid glycoprotein, and viral gene expression, were comparable between the two groups. Interestingly, however, total bilirubin levels in the survivor group were significantly lower than those in the non-survivor group (p < 0.0001). Furthermore, in almost all surviving cats with effusive FIP (96.6%, 28/29), the pre-treatment total bilirubin levels were below 0.5 mg/dL; however, the survival rate decreased drastically (14.3%, 1/7) when the pre-treatment total bilirubin levels exceeded 4.0 mg/dL. Thus, circulating total bilirubin levels may act as a prognostic risk factor for severe FIP and may serve as the predictor of the therapeutic efficacy of Mutian X against this fatal disease.

Analysis of factors associated with early neonatal deaths through linkage between SIM and SINASC, in Sergipe, Brazil

In Brazil, more than 70% of neonatal deaths are concentrated in the early neonatal period, with about 41.2% of them occurring in the first 24 hours of life. Thus, the objective of this study was to carry out an analysis of factors associated with early neonatal deaths that occurred in Sergipe, Brazil, through the linkage of records in the information systems: Live Birth Information System (SINASC) and Mortality Information System (SIM). This study was carried out in Sergipe, Brazil, in which an analysis was made of secondary data on children born and early neonatal deaths in Sergipe between 2006 and 2019 registered in the SINASC and in the SIM. A linkage was carried out between the databases, identifying 484,629 live births, 480,784 survivors and 3,845 who died with less than 7 days of life, with a low percentage of ignored data or absent. Maternal age was similar between groups. However, the newborns who died had lower weight, gestational age and Apgar in the first and fifth minutes than the survivor group. Regarding the newborn, there were more deaths in males and in congenital malformations. As for information about the mother and pregnancy, there were more deaths in single women, multiple pregnancies, lower gestational ages and vaginal delivery. There was an association between neonatal deaths and lower Apgar in the first and fifth minutes, lower weights, lower gestational ages, male gender, congenital malformations, women with multiple pregnancies, vaginal births and single mothers.

Serial measurement of cytokines strongly predict COVID-19 outcome

Purpose Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. Methods In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. Results At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). Conclusion Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.

Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19

Background We investigated the feasibility of two biomarkers of endothelial damage (Syndecan-1 and thrombomodulin) in coronavirus disease 2019 (COVID-19), and their association with inflammation, coagulopathy, and mortality. Methods The records of 49 COVID-19 patients who were admitted to an intensive care unit (ICU) in Wuhan, China between February and April 2020 were examined. Demographic, clinical, and laboratory data, and outcomes were compared between survivors and non-survivors COVID-19 patients, and between patients with high and low serum Syndecan-1 levels. The dynamics of serum Syndecan-1 levels were also analyzed. Results The levels of Syndecan-1 were significantly higher in non-survivor group compared with survivor group (median 1031.4 versus 504.0 ng/mL, P = 0.002), and the levels of thrombomodulin were not significantly different between these two groups (median 4534.0 versus 3780.0 ng/mL, P = 0.070). Kaplan–Meier survival analysis showed that the group with high Syndecan-1 levels had worse overall survival (log-rank test: P = 0.023). Patients with high Syndecan-1 levels also had significantly higher levels of thrombomodulin, interleukin-6, and tumor necrosis factor-α. Data on the dynamics of Syndecan-1 levels indicated much greater variations in non-survivors than survivors. Conclusions COVID-19 patients with high levels of Syndecan-1 develop more serious endothelial damage and inflammatory reactions, and have increased mortality. Syndecan-1 has potential for use as a marker for progression or severity of COVID-19. Protecting the glycocalyx from destruction is a potential treatment for COVID-19.