Severe Coronavirus Disease 2019 Patients Research Articles

Freeze-dried plasma: From damage control resuscitation to coronavirus disease 2019 therapy.

Freeze-dried plasma (FDP) is a promising blood component for prehospital resuscitation given its logistic advantages over fresh frozen plasma (FFP). COVID-19 convalescent (CC) plasma has been used to treat coronavirus disease 2019 (COVID-19) patients, and its corresponding FDP has potential use during future pandemics. Therefore, we conducted the study to determine if the hemostatic and immunological properties of plasma can be retained after lyophilization. Hemostatic tests were conducted with Rotational Thromboelastometry (ROTEM) and a Stago analyzer. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG (Immunoglobulin G) and neutralizing activity were analyzed using Meso Scale Diagnostics immunoassay kits. There were no differences in ROTEM parameters and Stago measurements for prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D-dimer concentrations, and antithrombin, factor V, VIII, and protein S activities between FFP and FDP for either pre-COVID-19 or CC samples. Differences were observed in INTEM clotting time and PT and PTT when comparing reconstituted FDP stored at 4°C for 24 h or room temperature for 4 h to healthy control. Both CC-FFP and CC-FDP showed two orders of magnitude higher concentrations of IgG antibodies against SARS-CoV-2 antigens than pre-COVID-19-FFP and pre-COVID-19-FDP and healthy control. Similarly, the CC samples showed approximately 4-fold higher %-inhibition of receptor binding than the pre-COVID-19 samples. There were no differences in either the antibody levels or neutralization activity between CC-FFP and CC-FDP. We demonstrated that FDP and CC-FDP retained the same hemostatic and antibody functional activities relative to their initial plasma sources, supporting clinical evaluation of their benefits in severe trauma and COVID-19 patients.

Neuropathological findings in fatal COVID-19 and their associated neurological clinical manifestations

Severe cases of Coronavirus Disease 2019 (COVID-19) can present with multiple neurological symptoms. The available neuropathological studies have described different lesions; the most frequent was the presence of neuroinflammation and vascular-related lesions. The objective of this study was to report the neuropathological studies performed in a medical institution, with abundant long intensive care unit stays, and their associated clinical manifestations. This is a retrospective monocentric case series study based on the neuropathological reports of 13 autopsies with a wide range of illness duration (13–108 days). A neuroinflammatory score was calculated based on the quantification of CD8- and CD68-positive cells in representative areas of the central nervous system. This score was correlated afterwards with illness duration and parameters related to systemic inflammation. Widespread microglial and cytotoxic T-cell activation was found in all patients. There was no correlation between the neuroinflammatory score and the duration of the illness; nor with parameters of systemic inflammation such as the peak of IL-6 or the HScore (a parameter of systemic macrophage activation syndrome). Two patients had global hypoxic ischaemic damage and five patients had subacute infarcts. One patient had many more brain vascular microthrombi compared to the others and multiple subacute pituitary infarcts. SARS-CoV-2 RNA was not detected with qRT-PCR. The proportion of brain lesions in severe COVID-19 patients could be related to illness duration. In our series, with abundant long hospitalisation stays, neuroinflammation was present in all patients and was more prominent between day 34 and day 45 after onset of symptoms. Clinical correlation showed that two patients with the highest neuroinflammatory scores had severe encephalopathies that were not attributable to any other cause. The second most frequent lesions were related to vascular pathology.

The Effect of Exercise-Based Pulmonary Rehabilitation on Quality of Life in Recovered COVID-19 Patients; a Quasi-Experimental Study

Introduction:The coronavirus disease 2019 (COVID-19) is associated with a variety of physical and emotional disorders, and subsequently lower Quality of Life (QOL). This study aimed to investigate the effect of a 2-week exercise-based pulmonary rehabilitation on clinical characteristics and QOL of severe COVID-19 patients after discharge from intensive care unit (ICU).Methods:In this quasi-experimental study, eligible severe COVID-19 cases, who had survived and were discharged from ICU were selected using convenience sampling method. O2 saturation (SpO2), pulse rate, dyspnea, and QOL were evaluated and compared before and after two weeks of exercise-based pulmonary rehabilitation (PR).Results:35 cases with the mean age of 57.86 ± 11.73 (18-75) years were studied (51.4% female). The mean SpO2 increased from 90.41 ± 3.97 to 95.11 ± 1.96% after two weeks of pulmonary rehabilitation (p<0.0001). In addition, the mean pulse rate (98.97±16.23 to 88.91±14.03 pulse/minute; p<0.001) and the mean dyspnea severity (5.6±1.97 to 3.45±1.97; p<0.0001) decreased after two weeks of intervention. Besides, the mean total QOL and its dimensions, including general health (p<0.0001), physical status (p<0.0001), emotional status (p = 0.036), and social function (p<0.0001) of patients, had significantly increased after intervention. Conclusion: Based on the findings of this study, it seems that two-week exercise-based pulmonary rehabilitation could be effective in increasing the SpO2, decreasing dyspnea and pulse rate, and improving the QOL of patients with severe COVID-19 after discharge from ICU.

Therapeutic anticoagulation using heparin in early phase severe coronavirus disease 2019: A retrospective study

BackgroundAlthough several reports recommend the use of systemic anticoagulation therapy in patients with severe coronavirus disease 2019 (COVID-19) pneumonia, appropriate target population and timing of administration are unknown. We assessed association between therapeutic anticoagulation administration with unfractionated heparin and outcomes in patients with severe COVID-19 pneumonia, assuming that anticoagulant administration effects are influenced by therapy timing. MethodsThis retrospective observational study included severe COVID-19 patients requiring mechanical ventilation in a tertiary emergency critical care hospital intensive care unit (ICU) in Japan from May 1, 2020 to September 30, 2021. All included patients were divided into early and late-phase administration groups based on therapeutic anticoagulant administration timing (≤5 and >5 days, respectively, after commencing oxygen therapy). Primary outcomes (in-hospital mortality and adverse events related to anticoagulation therapy) and secondary outcomes [veno-venous extracorporeal membrane oxygenation (ECMO), ventilator-free days (VFD), and ICU-free days] were compared between groups using univariate and multivariate models. ResultsOf 198 included patients 104 (52.5%) and 94 (47.5%) were in early-phase and late-phase administration groups, respectively. Although background characteristics were similar between the groups, the early-phase administration group had a significantly lower in-hospital mortality rate (3.8% vs. 27.7%; p < 0.001), lower adverse event rates (1.9% vs. 12.8%; p < 0.001), significantly longer VFD and ICU-free days, and lower ECMO rates, than the late-phase administration group, in the multivariate model. ConclusionsLate administration of therapeutic-dose anticoagulation in patients with severe COVID-19 pneumonia was significantly associated with worse outcomes than early administration.

Anti-SARS-CoV-2 Titers Predict the Severity of COVID-19.

Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 is associated with a wide spectrum of disease, ranging from asymptomatic infection to acute respiratory distress syndrome. Some biomarkers may predict disease severity. Among them, the anti-SARS-CoV-2 antibody response has been related to severe disease. The aim of this study was to assess the correlation between the anti-SARS-CoV-2 serological response and COVID-19 outcome. Demographic, clinical, and biological data from nasopharyngeal-PCR confirmed COVID-19 hospitalized patients were prospectively collected between April and August 2020 at our institution. All patients had serial weekly serology testing for a maximum of three blood samples or until discharge. Two different serological assays were used: a chemiluminescent assay and an in-house developed Luminex immunoassay. Kinetics of the serological response and correlation between the antibody titers and outcome were assessed. Among the 70 patients enrolled in the study, 22 required invasive ventilation, 29 required non-invasive ventilation or oxygen supplementation, and 19 did not require any oxygen supplementation. Median duration of symptoms upon admission for the three groups were 13, 8, and 9 days, respectively. Antibody titers gradually increased for up to 3 weeks since the onset of symptoms for patients requiring oxygen supplementation with significantly higher antibody titers for patients requiring invasive ventilation. Antibody titers on admission were also significantly higher in severely ill patients and serology performed well in predicting the necessity of invasive ventilation (AUC: 0.79, 95% CI: 0.67–0.9). Serology testing at admission may be a good indicator to identify severe COVID-19 patients who will require invasive mechanical ventilation.

Inflammatory Markers as Early Predictors of Disease Severity in COVID-19 Patients Admitted to Intensive Care Units: A Retrospective Observational Analysis

BackgroundIn pandemic situations, it is essential that the limited resources are used judiciously to achieve most benefits. Prediction of the disease severity at the earliest will help in better allocation, thus, positively affecting prognosis and treatment.Aim and objectiveTo investigate patient characteristics and specific biomarkers as possible early predictors of disease severity of SARS-COV-2 infection.Materials and methodsRetrospective single-centric observational study conducted at 70-bedded intensive care unit of tertiary care hospital at Haryana, India. 100 consecutive RT-PCR positive coronavirus disease-2019 (COVID-19) adult patients. Demographics, acute physiology and chronic health evaluation II (Apache-II) score, and Inflammatory markers were compared with respect to oxygenation defect (PaO2/FiO2 ratio: <300 or ≥300 mm Hg), need of invasive ventilation, ICU length of stay and 28-day mortality.FindingsMean age was significantly more in lower PF ratio group (58.01 ± 15.33 vs 50.97 ± 13.78, p = 0.023) whereas sex ratio was comparable among patients in two groups. Significantly, higher APACHE-II score (p ≤0.001) and presence of hypertension (43.54% vs 23.68%; p = 0·045) in low PF ratio group along with higher C-reactive protein (171.78 ± 124.45 vs 101.52 ± 88.70), IL-6 (173.51 vs 53.18) and ferritin (1677.60 ± 2271.13 vs 643.54 ± 718.68) levels. Procalcitonin, lactate dehydrogenase, and creatine phosphokinase (CPK) levels were not significant.InterpretationAge and APACHE II score and among laboratory parameters CRP, ferritin, and IL-6 levels were significantly higher in low PF ratio group, patients requiring invasive ventilation and in mortality group. Use of this triad (CRP, ferritin, and IL-6 levels) at admission may predict the disease severity early in the course. Addition of APACHE-II may further improve the accuracy of the score.How to cite this articleGupta D, Jain A, Chauhan M, Dewan S. Inflammatory Markers as Early Predictors of Disease Severity in COVID-19 Patients Admitted to Intensive Care Units: A Retrospective Observational Analysis. Indian J Crit Care Med 2022;26(4):482–486.

Immune-Related Protein Interaction Network in Severe COVID-19 Patients toward the Identification of Key Proteins and Drug Repurposing.

Coronavirus disease 2019 (COVID-19) is still an active global public health issue. Although vaccines and therapeutic options are available, some patients experience severe conditions and need critical care support. Hence, identifying key genes or proteins involved in immune-related severe COVID-19 is necessary to find or develop the targeted therapies. This study proposed a novel construction of an immune-related protein interaction network (IPIN) in severe cases with the use of a network diffusion technique on a human interactome network and transcriptomic data. Enrichment analysis revealed that the IPIN was mainly associated with antiviral, innate immune, apoptosis, cell division, and cell cycle regulation signaling pathways. Twenty-three proteins were identified as key proteins to find associated drugs. Finally, poly (I:C), mitomycin C, decitabine, gemcitabine, hydroxyurea, tamoxifen, and curcumin were the potential drugs interacting with the key proteins to heal severe COVID-19. In conclusion, IPIN can be a good representative network for the immune system that integrates the protein interaction network and transcriptomic data. Thus, the key proteins and target drugs in IPIN help to find a new treatment with the use of existing drugs to treat the disease apart from vaccination and conventional antiviral therapy.

Effects of Renin-Angiotensin System Inhibitors on Mortality and Disease Severity of COVID-19 Patients: A Meta-analysis of Randomized Controlled Trials.

There is controversy over the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on the prognosis in patients with coronavirus disease 2019 (COVID-19), therefore, we aim to further explore the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19-associated disease severity and mortality. We systematically searched PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv from inception to 6 September 2021. The primary outcome was all-cause mortality. Secondary outcome was severe disease which was defined as admission to the intensive care unit, the use of noninvasive or invasive mechanical ventilation, or death. A total of 7 randomized controlled trials involving 1,321 COVID-19 patients were included. Fixed-effects meta-analysis demonstrated that the use of ACEI/ARB was not associated with higher risk of mortality (risk ratio [RR] = 0.84, 95% confidence interval [CI] 0.57-1.22, P = 0.10, I2 = 43%) and disease severity (RR = 0.86, 95% CI 0.71-1.05, P = 0.11, I2 = 47%). However, the subgroup analysis showed that compared with no ACEI/ARB use, the use of ARB was associated with a significant reduction of mortality (RR = 0.23, CI 0.09-0.60, P = 0.55, I2 = 0%) and disease severity (RR = 0.38, CI 0.19-0.77, P = 0.007). In conclusion, based on the available data, ACEI/ARB is not associated with the risk of mortality and disease severity in COVID-19 patients. And ACEI/ARB medications, especially ARB, should not be discontinued for patients with COVID-19.

Effectiveness of corticosteroids to treat coronavirus disease 2019 symptoms: A meta-analysis

ObjectiveCurrently, corticosteroids are widely used to treat coronavirus disease 2019 (COVID-19) symptoms. However, the therapeutic role of corticosteroids remains highly controversial. To that end, we aimed to assess the efficacy of corticosteroids in treating COVID-19 patients. MethodWe searched PubMed, Embase, and Cochrane Library to select suitable studies. Our primary study endpoint was all-cause mortality. The secondary study endpoint was the length of hospital stay. ResultsA total of 9 randomized controlled trials (RCTs) with 7907 patients were assessed. The pooled result indicated that corticosteroids treatment could significantly reduce all-cause mortality in patients with COVID-19 (RR=0.88, 95% CI [0.82, 0.95], P=0.002). When subgroup analyses were performed, we found that corticosteroids were associated with decreased all-cause mortality in severe COVID-19 patients (RR=0.77, 95% CI [0.68, 0.88], P<0.0001), however no obvious difference was observed in all-cause mortality of non-severe COVID-19 patients between the corticosteroid and control group (RR=0.96, 95% CI [0.86, 1.06], P=0.41), meanwhile, a low dose (RR=0.89, 95% CI [0.82, 0.97], P=0.007) of dexamethasone (RR=0.9, 95% CI [0.83, 0.98], P=0.01) with a long treatment course (RR=0.89, 95% CI [0.82, 0.98], P=0.02) was beneficial for all-cause mortality in COVID-19 patients. Additionally, we found that corticosteroids might be associated with a longer length of hospital stay in non-severe COVID-19 patients (MD=3.83, 95% CI [1.11, 6.56], P=0.006). ConclusionOur results showed that corticosteroid therapy was related to a reduction in all-cause mortality in severe COVID-19 patients. However, in patients with non-severe COVID-19, the use of corticosteroids did not decrease all-cause mortality and may prolong the duration of hospital stay. In addition, we revealed that a low dose of dexamethasone with a long treatment course could reduce all-cause mortality in COVID-19 patients.

MO113: Estimation of Hypocalcaemia, Hypoalbuminemia and Hypomagnesaemia Prevalence in Patients with COVID-19 and its Relationship with Clinical Manifestations and Disease Progression

Abstract BACKGROUND AND AIMS Electrolyte abnormalities are common among patients with coronavirus disease 2019 (COVID-19). This study aims to investigate the electrolyte changes in severe and non-severe COVID-19 patients. Hypocalcaemia, hypomagnesaemia and hypoalbuminemia and their relationship with the severity of symptoms and prognosis will also be determined. METHOD We enrolled 270 COVID-19 patients. Serum tests were taken from each patient on the day of admission to check the level of variables. Thereon, calcium, magnesium and phosphorus levels were measured twice a week and albumin levels were measured once a week. Variables such as PTH and 25 (OH) D were measured once at the beginning of the study. Other laboratory results like complete blood count, C-reactive protein and clinical data such as arterial blood oxygen levels, length of stay in the ICU and the treatment regimen were extracted from patients' medical records and history. Finally, patients were categorized as mild, moderate, severe and critical group based on the severity of the disease. The data analyses were carried out via SPSS software (version 21.0). RESULTS Of 270 patients, 135 people (50%) were men. The mean age of patients was 46.7 years. Based on the severity of the disease, 91 patients had mild disease, 90 patients presented with moderate disease, 54 patients were in severe condition and 35 patients were critical. Hypocalcaemia (Ca 2+ ≤8.6 mg/dL) was detected in 49 patients (18.1%) on admission. The mean of serum magnesium, phosphorus and albumin levels on admission was 2.2 ± 0.22 mEq/L, 3.39 ± 0.79 mg/dL and 4.49 ± 0.66g/dL, respectively. Phosphorus level was lower than 2.63 mg/dL in 11 patients (4.07%) and 43 patients (15.92%) had hypoalbuminemia. The mean 25(OH) D level was 32.92 ± 10.29 μg/L; therefore, 182 patients (67.40%) fall within the normal range (&amp;gt;30 μg/L). CONCLUSION Patients with mild and moderate disease tend to develop hypocalcaemia, hypoalbuminemia and hypomagnesaemia more often than severe and critical COVID-19 patients during treatment. 25(OH) D deficiency rate was higher in the moderate group. Patients with hypocalcaemia during treatment had higher mortality than other patients. We recommend electrolytes be measured at initial presentation and serially monitored during hospitalization in order to establish timely and appropriate corrective actions and prevent the serious complications of the disease.

Critical coronavirus disease 2019 complicated with heparin resistance in 2 patients

To explore the diagnosis process and treatment experience of severe coronavirus disease 2019 (COVID-19) patients with heparin resistance (HR). The medical team of the First People's Hospital of Lianyungang admitted 2 severe COVID-19 patients with HR in intensive care unit (ICU) during their support to the designated hospital for the treatment of COVID-19 patients in Lianyungang City in November 2021. The clinical features, laboratory examinations, imaging features, treatment and prognosis of the two patients were analyzed. Both severe COVID-19 patients received mechanical ventilation, 1 patient was treated with extracorporeal membrane oxygenation (ECMO) support. Both patients were complicated with lower extremity deep venous thrombosis and HR phenomenon under routine dose anticoagulant therapy. The maximum daily dose of unfractionated heparin exceeded 35 000 U (up to 43 200 U), the 2 patients failed to meet the standard of anticoagulation treatment, and the course of disease was prolonged. After that, argatroban was given 0.4 μg×kg-1×min-1 combined with anticoagulant therapy, the activated partial thromboplastin time (APTT) of patients undergoing ECMO could be maintained at 55-60 seconds and the activated coagulation time (ACT) of them could be maintained at 180-200 seconds. After ECMO support or later sequential mechanical ventilation, both patients recovered and were discharged, and deep venous thrombosis was also effectively controlled. HR phenomenon often occurs during the treatment of severe COVID-19 patients, the anticoagulation regimen should be adjusted in time, and the anticoagulation effect combined with argatroban is clear.

IgG targeting distinct seasonal coronavirus- conserved SARS-CoV-2 spike subdomains correlates with differential COVID-19 disease outcomes.

Despite SARS-CoV-2 being a “novel” virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (β-CoVs), and FcγR activation. Analysis of IgG targeting β-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2′FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2′FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2′FP ratios. These findings suggest that HR2/S2′FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.

Value of red blood cell distribution width in evaluating the severity of illness of novel coronavirus Delta variant

To explore the value of red blood cell distribution width (RDW) in evaluating the severity of patients infected with novel coronavirus Delta variant. A total of 28 patients infected with novel coronavirus Delta variant in designated hospital treated by the First Affiliated Hospital of Xi'an Jiaotong University medical team from December 2021 to January 2022 were enrolled (23 cases of common type, 4 severe and 1 critical cases). The detailed clinical data of patients was collected. Then, Pearson's correlation analysis was used to identify the blood examination indexes which affected the arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2). According to the median standard deviation of red blood cell distribution width (RDW-SD, 42.5 fL), 28 patients were divided into low RDW-SD group (≤ 42.5 fL, 16 cases) and high RDW-SD group (> 42.5 fL, 12 cases), and the immune related indexes of the two groups were compared. Receiver operator characteristic curve (ROC) was drawn to evaluate the predictive value of RDW-SD on the severity of illness of coronavirus disease 2019 (COVID-19). Correlation analysis showed that RDW-SD was the only index related to PaO2 and PaCO2 on the first day of admission, which was negative correlation with PaO2 (r = -0.379, P = 0.047) and positive correlation with PaCO2 (r = 0.509, P = 0.006). The results of effects of different clinical characteristics on RDW-SD level showed that there was no statistically significant difference in RDW-SD between groups with different clinical characteristics (including male/female, ≥ 65 years old/< 65 years old, having/without hypertension, having/without diabetes, smoking/not smoking, having/without hyperpyrexia, with/without fever for 3 days, with/without respiratory symptoms, with/without digestive symptoms). It was suggested that RDW-SD be relatively stable and not affected by the patient's baseline level. The percentage of B cells in low RDW-SD group was higher than that in high RDW-SD group (23.01±3.01 vs. 15.34±5.34, P < 0.05), immunoglobulin G (IgG) level in low RDW-SD group was lower than that in high RDW-SD group (g/L: 11.43±3.20 vs. 15.42±1.54, P < 0.05). The area under ROC curve (AUC) of RDW-SD in evaluating severe cases was 0.83 [95% confidence interval (95%CI) was 0.59-1.06], which was close to multilobularinltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hyper-tension and age (MuL BSTA score; AUC = 0.82, 95%CI was 0.51-1.12) and better than British Thoracic Society's modified pneumonia score (CURB-65 score; AUC = 0.70, 95%CI was 0.50-0.91). RDW-SD has significant evaluative effect on the severity of COVID-19 patients with Delta variants.

Relationship between blood electrolytes and prognosis of patients with severe coronavirus disease 2019

To analyze the relationship between blood electrolytes and the prognosis of patients with severe coronavirus disease 2019 (COVID-19) and to provide assistance for clinical decision-making. The clinical data of patients with severe COVID-19 admitted to intensive care unit (ICU) of the Wuhan Third Hospital by the Shanghai aid-Hubei medical team from January 21 to March 4, 2020 were collected. Excluding ineligible patients, 110 patients were finally enrolled. The patients' gender, age, temperature, heart rate, systolic and diastolic blood pressure, clinical symptoms at admission, time of symptom onset, duration of fever, and relevant indicators at admission to ICU (including blood potassium, chloride, sodium, calcium, phosphorus, and magnesium, etc.) and prognosis were analyzed. The patients were grouped by blood potassium or calcium levels or blood potassium/calcium ratio. The Kaplan-Meier survival curves were used to analyze the survival of patients in each group. The relationship between the potassium/calcium ratio and the prognosis was analyzed using restricted cubic spline plots. The relationship between each index in the different models and the prognosis was analyzed using Cox regression models. Among 110 severe COVID-19 patients, 78 cases survived, and 32 cases died. Compared with the surviving group, patients in the death group had higher blood potassium levels [mmol/L: 4.25 (3.80, 4.65) vs. 3.90 (3.60, 4.20), P < 0.05] and lower blood calcium levels (mmol/L: 2.00±0.14 vs. 2.19±0.18, P < 0.05). The Kaplan-Meier survival curves showed that patients in the potassium > 4.2 mmol/L group had a worse prognosis than the potassium < 3.8 mmol/L group and the potassium 3.8-4.2 mmol/L group (P = 0.011), patients in the calcium > 2.23 mmol/L group had a better prognosis than the calcium < 2.03 mmol/L group and the calcium 2.03-2.23 mmol/L group, and the lower calcium group had a worse prognosis (P = 0.000 15). Cox regression analysis showed that the hazard ratio (HR) of blood potassium and calcium were 2.08 and 0.01, respectively, in model 1 (single blood potassium or calcium) and in model 2 (model 1 plus age and gender), the HR of blood potassium and calcium were 1.98 and 0.01 respectively, which were significantly associated with patient prognosis (all P < 0.05). Patients in the group with the potassium/calcium ratio > 1.9 had higher blood potassium levels and a higher proportion of mechanical ventilation, lower calcium levels and lower proportion of survival, and longer time of ICU admission compared with the groups with the potassium/calcium ratio < 1.7 and 1.7-1.9. The Kaplan-Meier survival curves showed that the survival rate of the potassium/calcium ratio > 1.9 group was the lowest (P < 0.000 1), and there was no statistically significant difference in survival between the potassium/calcium ratio < 1.7 group and the potassium/calcium ratio 1.7-1.9 group. A restricted cubic spline plot corrected for age and gender showed that patients in the potassium/calcium ratio > 1.8 group had HR values > 1. Cox regression analysis corrected for other indicators showed that the potassium/calcium ratio was still associated with patient prognosis (HR = 4.85, P = 0.033). Blood potassium, calcium, and the potassium/calcium ratio at ICU admission are related to the prognosis of patients with severe COVID-19, and the potassium/calcium ratio is an independent risk factor for the death of patients. The higher the potassium/calcium ratio, the worse the prognosis of patients.

PcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury.

Background and ObjectivesThe novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS).MethodsOn Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed.ResultsNone of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray’s lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy.Conclusionpc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

Remdesivir plus Dexamethasone in COVID-19: A cohort study of severe patients requiring high flow oxygen therapy or non-invasive ventilation.

IntroductionRemdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown.Materials and methodsProspective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality.ResultsWe included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, p<0.01). Although the end-of-treatment clinical improvement was larger among Rem-Dexa group (69.7% vs 51.5%, p = 0.05), the 28-day and 90-day mortalities were similar (4.5% and 10.6% vs. 15.2% and 16.7%; p = 0.08 and p = 0.45, respectively). The logistic regression and Cox-regression models showed that concomitant Rem-Dexa therapy was associated with a reduction of 28-day intubation rate (OR 0.22, CI95% 0.05–0.94, p = 0.04), in absence of laboratory abnormalities and clinical complications (p = ns).ConclusionsIn COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.

Evaluating The Utility of Interleukin-6, C -Reactive Protein (CRP) and Procalcitonin in Predicting Disease Severity and Prognosis in Hospitalized SARS-CoV-2 Patients: A North Indian Retrospective Study

Background: Coronavirus disease 2019 (COVID-19) associated inflammatory cytokine storm that worsens COVID-19, relies heavily on the inflammatory response. IL-6, a TH1 cytokine, PCT and CRP have been linked to serious illness and a higher mortality rate. We further tried to evaluate the role of these indicators and their association with clinical severity in COVID-19 patients. Material and Methods: Eighty-three consecutive patients with age ≥18 years with RT-PCR test positive for SARS-CoV-2 were included in the study. Demographic characteristics (age and sex), underlying co-morbidities, symptoms, physical findings, and laboratory tests of the patients were recorded. All patients were categorized as having mild, moderate, and severe COVID-19 disease, according to the Indian Council of Medical Research (ICMR). The levels of IL-6 and PCT were estimated by electrochemiluminescence immunoassay (ECLIA) using Cobas-e411 Immunoassay System, and Quantitative CRP was done by Unicorn-230 automated biochemistry analyzer to find out their correlation with disease severity and outcome. Multiple Regression was performed to find out factors associated with the adverse outcome of the disease. Result: Mean age of patients was 51 years. IL-6, CRP, and PCT levels increased in 73 %, 68.0 %, and 8.2 % patients on admission, respectively. The most common co-morbidity associated with the disease was hypertension (25%), followed by diabetes (24%) and respiratory disease (15%). Increased IL-6, CRP, and PCT levels were found in 77 percent, 79 percent, and 20 percent of patients, respectively. We found that IL-6 (P≤0.05), CRP (P≤0.05), and PCT (P≤0.05) were significantly raised in COVID-19 patients with increasing severity of the disease. The Area under the receiver operating characteristic (AUROC) of these parameters ranged between 0.65 and 0.8 (IL-6, 0.828; CRP, 0.809; and PCT, 0.658), indicating a reliable biomarker to assess clinical severity. Conclusion: Sequential measurement of blood levels of IL-6, CRP, and PCT levels is useful in determining the severity and predicting the outcome of the patients with severe disease. IL-6 and CRP have an independent prognostic value. On the other hand, the importance of normal PCT concentrations in patients with viral pneumonia needs to be studied further.

Platelet activation by SARS-CoV-2 implicates the release of active tissue factor by infected cells

AbstractPlatelets are hyperactivated in coronavirus disease 2019 (COVID-19). However, the mechanisms promoting platelet activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not well understood. This may be due to inherent challenges in discriminating the contribution of viral vs host components produced by infected cells. This is particularly true for enveloped viruses and extracellular vesicles (EVs), as they are concomitantly released during infection and share biophysical properties. To study this, we evaluated whether SARS-CoV-2 itself or components derived from SARS-CoV-2-infected human lung epithelial cells could activate isolated platelets from healthy donors. Activation was measured by the surface expression of P-selectin and the activated conformation of integrin αIIbβ3, degranulation, aggregation under flow conditions, and the release of EVs. We find that neither SARS-CoV-2 nor purified spike activates platelets. In contrast, tissue factor (TF) produced by infected cells was highly potent at activating platelets. This required trace amounts of plasma containing the coagulation factors FX, FII, and FVII. Robust platelet activation involved thrombin and the activation of protease-activated receptor (PAR)-1 and -4 expressed by platelets. Virions and EVs were identified by electron microscopy. Through size-exclusion chromatography, TF activity was found to be associated with a virus or EVs, which were indistinguishable. Increased TF messenger RNA (mRNA) expression and activity were also found in lungs in a murine model of COVID-19 and plasma of severe COVID-19 patients, respectively. In summary, TF activity from SARS-CoV-2–infected cells activates thrombin, which signals to PARs on platelets. Blockade of molecules in this pathway may interfere with platelet activation and the coagulation characteristic of COVID-19.

Assessing clinical applicability of COVID-19 detection in chest radiography with deep learning

The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems across the world. Chest radiography (CXR) can be used as a complementary method for diagnosing/following COVID-19 patients. However, experience level and workload of technicians and radiologists may affect the decision process. Recent studies suggest that deep learning can be used to assess CXRs, providing an important second opinion for radiologists and technicians in the decision process, and super-human performance in detection of COVID-19 has been reported in multiple studies. In this study, the clinical applicability of deep learning systems for COVID-19 screening was assessed by testing the performance of deep learning systems for the detection of COVID-19. Specifically, four datasets were used: (1) a collection of multiple public datasets (284.793 CXRs); (2) BIMCV dataset (16.631 CXRs); (3) COVIDGR (852 CXRs) and 4) a private dataset (6.361 CXRs). All datasets were collected retrospectively and consist of only frontal CXR views. A ResNet-18 was trained on each of the datasets for the detection of COVID-19. It is shown that a high dataset bias was present, leading to high performance in intradataset train-test scenarios (area under the curve 0.55–0.84 on the collection of public datasets). Significantly lower performances were obtained in interdataset train-test scenarios however (area under the curve > 0.98). A subset of the data was then assessed by radiologists for comparison to the automatic systems. Finetuning with radiologist annotations significantly increased performance across datasets (area under the curve 0.61–0.88) and improved the attention on clinical findings in positive COVID-19 CXRs. Nevertheless, tests on CXRs from different hospital services indicate that the screening performance of CXR and automatic systems is limited (area under the curve < 0.6 on emergency service CXRs). However, COVID-19 manifestations can be accurately detected when present, motivating the use of these tools for evaluating disease progression on mild to severe COVID-19 patients.

Coronavirus Disease 2019-Related Alterations of Total and Anti-Spike IgG Glycosylation in Relation to Age and Anti-Spike IgG Titer.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been affecting the world since January 2020 and has caused millions of deaths. To gain a better insight into molecular changes underlying the COVID-19 disease, we investigated here the N-glycosylation of three immunoglobulin G (IgG) fractions isolated from plasma of 35 severe COVID-19 patients, namely total IgG1, total IgG2, and anti-Spike IgG, by means of MALDI-TOF-MS. All analyses were performed at the glycopeptide level to assure subclass- and site-specific information. For each COVID-19 patient, the analyses included three blood withdrawals at different time-points of hospitalization, which allowed profiling longitudinal alterations in IgG glycosylation. The COVID-19 patients presented altered IgG N-glycosylation profiles in all investigated IgG fractions. The most pronounced COVID-19-related changes were observed in the glycosylation profiles of antigen-specific anti-Spike IgG1. Anti-Spike IgG1 fucosylation and galactosylation showed the strongest variation during the disease course, with the difference in anti-Spike IgG1 fucosylation being significantly correlated with patients’ age. Decreases in anti-Spike IgG1 galactosylation and sialylation in the course of the disease were found to be significantly correlated with the difference in anti-Spike IgG plasma concentration. The present findings suggest that patients’ age and anti-S IgG abundance might influence IgG N-glycosylation alterations occurring in COVID-19.