Effect of therapeutic versus prophylactic anticoagulation therapy on clinical outcomes in COVID-19 patients: a systematic review with an updated meta-analysis (preprint)

Background: Previous studies demonstrate a reduced risk of thrombosis and mortality with anticoagulant treatment in patients with COVID-19 than those without anticoagulation treatment. However, an open question regarding the efficacy and safety of therapeutic anticoagulation (T-AC) versus a lower dose, prophylaxis anticoagulation (P-AC) in COVID-19 patients is still controversial. Methods: We systematically reviewed currently available randomized clinical trials (RCTs) and observational studies (OBs) from January 8, 2019, to January 8, 2022, and compared prophylactic and therapeutic anticoagulant treatment in COVID-19 patients. The primary outcomes were risk of mortality, major bleeding, and the secondary outcomes included venous and arterial thromboembolism. Subgroup analysis was also performed between critically ill and non-critically ill patients with COVID-19 and between patients with higher and lower levels of D-dimer. Sensitive analysis was performed to decrease the bias and the impact of population heterogeneity.Results: We identified 11 RCTs and 17 OBs fulfilling our inclusion criteria. In the RCTs analyses, there was no statistically significant difference in the relative risk of mortality between COVID-19 patients with T-AC treatment and those treated with P-AC (RR 0.95, 95% CI, 0.78–1.16, P = 0.61). Similar results were also found in the OBs analyses (RR 1.21, 95% CI, 0.98-1.49, P = 0.08). The pooling meta-analysis using a random-effects model combined with effect sizes showed that in the RCTs and OBs analyses, patients with COVID-19 who received T-AC treatment had a significantly higher relative risk of the major bleeding event than those with P-AC treatment in COVID-19 patients (RCTs: RR 1.76, 95% CI, 1.19-2.62, P = 0.005; OBs: RR 2.39, 95% CI, 1.56-3.68, P < 0.0001). Compared with P-AC treatment in COVID-19 patients, patients with T-AC treatment significantly reduced the incidence of venous thromboembolism (RR 0.51, 95%, 0.39-0.67, P＜0.00001), but it is not associated with arterial thrombosis events (RR 0.97, 95%, 0.66-1.42, P = 0.88). The subgroup analysis of OBs shows that the mortality risk significantly reduces in critically ill COVID-19 patients treated with T-AC compared with those with P-AC treatment (RR 0.58, 95% CI, 0.39-0.86, P = 0.007), while the mortality risk significantly increases in non-critically ill COVID-19 patients treated with T-AC (RR 1.56, 95% CI, 1.34-1.80, P < 0.00001). In addition, T-AC treatment does not reduce the risk of mortality in COVID-19 patients with high d-dimer levels in RCTs. Finally, the overall sensitivity analysis after excluding two RCTs studies remains consistent with the previous results.Conclusions: A comprehensive meta-analysis of OBs demonstrated that T-AC treatment in critically ill patients with COVID-19 significantly increased survival compared with those treated with P-AC, which was not found in the RCTs analyses. Meanwhile, P-AC treatment showed survival superiority in non-critically ill patients with COVID-19. In both RCTs and OBs, T-AC treatment in COVID-19 patients significantly reduced the incidence of venous thromboembolism but showed a higher risk of bleeding than those with P-AC treatment. Protocol registration: PROSPERO (CRD42021293294). Registered 24 November 2021.

Antinuclear Autoimmunity Potentially Makes the Middle-aged and Female with COVID-19 Prone to Severe Progression: A Case-control Study (preprint)

Background: Elderliness is known risk factor for severe progression of COVID-19 due to compromised immunity, however aberrant hyperactive immune response including autoimmunity might be responsible for younger patients. Methods: 162 patients tested with autoimmunological detections were enrolled, and study of “Severe” cases and “Non-severe” controls was retrospectively analyzed. Results: Multivariable analysis involving antinuclear autoimmunity manifests correlation of disease severity with middle age and attenuates the risk of age older than 65. Middle age (45≤age≤65) and female turn out to be the risk factors after hierarchical cluster analysis, before which however sex was not correlated. We find antinuclear autoimmunity to be strongly correlated with severity for the middle-aged (OR= 21.000, 95% CI 4.893- 90.126, p< 0.001) and female (OR= 16.044, 95% CI 4.717- 54.568, p< 0.001), especially for the middle-aged female (Pearson R= 0.770, p< 0.001). Incidence of symptoms fever and chest distress, and complication myocardial injury are statistically more frequent in patients with positive antinuclear antibody, compared with those negative. Severe patients with positive antinuclear antibody possess significantly shorter onset of symptoms to severity time (p= 0.021), indicating quicker progression, and interestingly, present more incidence (21%) of post-remission aggravation, compared with those negative (6%). Conclusions: The presence of antinuclear autoimmunity potentially makes COVID-19 prone to severe progression, especially for the middle-aged and female, probably even quicker.

Safety and Feasibility of Umbilical Cord Mesenchymal Stem Cells in Patients with COVID-19 Pneumonia: A Pilot Study (preprint)

Background: We aim to explore the safety and feasibility of umbilical cord mesenchymal stem cells (UC-MSCs) transplantation in severe and critically severe type Coronavirus disease 2019 (COVID-19) patients.Methods: In addition to normal therapy, we performed four times transplantation of UC-MSCs in 16 severe and critically severe type COVID-19 patients. We observed adverse events from enrollment to D28. We evaluated the oxygenation index, inflammatory biomarkers, chest imaging, lymphocyte subsets count et al on the 7th day (D7±1 day), the 14th day (D14±1 day) and the 28th day (D28±3 days).Results: There were no infusion-related or allergic reactions. The oxygenation index was improved after transplantation. The mortality of enrolled patients was 6.25%. The level of cytokines estimated was varied in normal range, the chest imaging was improved, the lymphocyte count and lymphocyte subsets count were recovered after transplantation.Conclusions: Intravenous transplantation of UC-MSCs was safe and feasible for treatment in patients with COVID-19 pneumonia.Trial registration: Clinical Trial, NCT04269525. Registered 7 February 2020. https://clinicaltrials.gov/ct2/show/NCT04269525

Differential effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on COVID-19 (preprint)

BackgroundThe effect of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB) on the COVID-19 remains controversial from clinic evidence. MethodsThis is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. ResultsAmong 198 patients, 58 (29.3%) and 16 (8.1%) were on were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and ARDS when compared with patients treated with ACEI alone or not receiving and RAAS blocker (P＜0.05). The Kaplan-Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend towards a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27; 95% CI, 0.07-1.02; P = 0.054). The Cox-regression analysis to compared ACEI vs. ARB groups showed a significantly lower mortality rate in the ARB group (adjusted hazard ratio, 0.03; 95% CI, 0.00-0.58; P = 0.02). ConclusionsUsing of ARB was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19.

Scoring Systems for Predicting Mortality for Severe Patients with COVID-19 (preprint)

Background: Coronavirus disease 2019 (COVID-19) has been widely spread and caused tens of thousands of deaths, mainly in patients with severe COVID-19.Methods: Patients with COVID-19 were retrospectively analyzed. Clinical characteristics were compared, and LASSO regression as well as multivariate analysis were used to screen variables and establish prediction model. Findings: A total of 2529 patients with COVID-19 was retrospectively analyzed, and 452 eligible severe COVID-19 were used for finally analysis. In training cohort, the median age was 66·0 years while it was 73·0 years in non-survivors. Patients aged 60-75 years accounted for the largest proportion of infected populations and mortality toll. Anti-SARS-CoV-2 antibodies were monitored up to 54 days, and IgG levels reached the highest during 20-30 days. About 60.2% of severe patients had complications. Acute myocardial injury was the earliest injured organ, whereas the time from acute kidney injury to death was the shortest. Age, diabetes, coronary heart disease (CHD), percentage of lymphocytes (LYM%), procalcitonin (PCT), serum urea, C reactive protein and D-dimer (DD), were identified associated with mortality by LASSO binary logistic regression. Then multivariate analysis was performed to conclude that old age, CHD, LYM%, PCT and DD remained independent risk factors for mortality. Based on the above variables, a scoring system of COVID-19 (CSS) was established and divided into low-risk and high-risk groups. This model displayed good discrimination (AUC=0·919) and calibration (P =0·264). The complications in low-risk and high-risk groups were significantly different. We also found that the use of corticosteroids in low-risk groups increased hospital stays by 4·5 days (P =0·036) and durations of disease by 7·5 days (P =0 · 012) compared with no corticosteroids.Interpretation: Old age, CHD, LYM%, PCT and DD were independently related to mortality. CSS was useful for predicting in-hospital mortality and complications, and it could help clinicians to identify high-risk patients with poor prognosis.Funding Statement: This work was supported by the Key Project for Anti-2019 novel Coronavirus Pneumonia from the Ministry of Science and Technology, China (grant number 2020YFC0845500). Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study was conducted according to the principles of Helsinki and approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No.2020063).

Clinical Features of Pregnant Women and Neonates with COVID-19 in Wuhan: a paired comparison study (preprint)

Background Our study aimed to find symptoms unique in pregnancy and to help the early diagnosis in pregnant women and to evaluate the impact of COVID-19 in postpartum women and their newborns.Methods Clinical data were reviewed and collected for 11 pregnant women with laboratory-confirmed COVID-19 who were consecutively admitted to Zhongnan Hospital of Wuhan University and Women and Children’s Hospital of Hubei Province, from Jan 26 to Feb 26, 2020.Results All the confirmed women didn’t have any exposure history and their early symptoms were mildly elevated temperate and fatigue. The chest CT scans of confirmed women can be atypical manifestations, such as bilateral pleural effusions and slightly increased densities. Eight of eleven confirmed women did not feel anything unusual until abnormalities were found on chest CT scans on admission screening test. All three groups had elevated white blood cell count, neutrophil count and lactate dehydrogenase, and reduced total protein.The infection did not increase the risk for premature delivery, premature rupture of membrane, or comorbidities in pregnancy.Conclusions Pregnant women were often asymptomatic and accidentally detected abnormalities on chest CT scan on admission which emphasize the importance of CT scan in prevalent areas of the COVID-19. Even after the laboratory confirmation, the manifestation of the CT scan could be atypical, which alerted the necessity of protection for healthcare workers. The COVID-19 did not increase the risk of complications in pregnant women and their neonates.Trial registration: This case series was approved by the institutional ethics board of Zhongnan Hospital of Wuhan University (No. 2020020) and Women and Children’s Hospital of Hubei Province(NO. LW035).

Clinical outcomes of 402 patients with COVID-2019 from a single center in Wuhan, China (preprint)

The SARS-CoV-2 outbreak is causing widespread infections and significant mortality. Previous studies describing clinical characteristics of the disease contained small cohorts from individual centers or larger series consisting of mixed cases from different hospitals. We report analyses of mortality and disease severity among 402 patients from a single hospital. The cohort included 297 patients with confirmed and 105 with suspected diagnosis. The latter group met the criteria for clinical diagnosis but nucleic acid tests results were initially interpreted as suspicious. Data were compared between genders and among different age groups. The overall case fatality is 5.2%. However, patients 70 years of age or older suffered a significantly higher mortality (17.8%), associated with more patients having severe or critical illness (57.5%). Patients 50 years of age or older had a mortality of 8.0%, and those younger than 50 years, 1.2%. Male patients had a mortality of 7.6% versus 2.9% in females.

Clinical features and outcomes of 221 patients with COVID-19 in Wuhan, China (preprint)

Rationale: In late December 2019, an outbreak of acute respiratory illness, now officially named as COVID-19, or coronavirus disease 2019, emerged in Wuhan, China, now spreading across the whole country and world. More data were needed to understand the clinical characteristics of the disease. Objectives: To study the epidemiology, clinical features and outcomes of patients with COVID-19. Methods: we performed a single center, retrospective case series study in 221 patients with laboratory confirmed SARS-CoV-2 pneumonia at a university hospital. Measurements and Main Results: The median age was 55.0 years and 48.9% were male and only 8 (3.6%) patients had a history of exposure to the Huanan Seafood Market. Compared to the non-severe pneumonia patients, the median age of the severe patients was significantly older, and they were more likely to have chronic comorbidities. Most common symptoms in severe patients were high fever, anorexia and dyspnea. On admission, 33.0% patients showed leukopenia and 73.8% showed lymphopenia. In addition, the severe patients suffered a higher rate of co-infections with bacteria or fungus and they were more likely to developing complications. As of February 15, 2020, 19.0% patients had been discharged and 5.4% patients died. 80% of severe cases received ICU care, and 52.3% of them transferred to the general wards due to relieved symptoms, and the mortality rate of severe patients in ICU was 20.5%. Conclusions: The COVID-19 epidemic spreads rapidly by human-to-human transmission. Patients with elder age, chronic comorbidities, blood leukocyte/lymphocyte count, procalcitonin level, co-infection and severe complications might increase the risk of poor clinical outcomes. Keywords: coronavirus disease 2019; clinical features; outcomes; severe patients

Clinical features of critically ill patients with COVID-19 infection in China (preprint)

Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections outbreak in China is now a global issue. There is only a limited understanding of the clinical characteristics of patients with SARS-CoV-2 infections is available.Objective:To describe the characteristics, management strategies, and outcomes of critically ill patients with SARS-CoV-2 infection.Design, Setting, and Patients: This is aretrospective, multi-center case series of 50 critically ill patients with confirmed SARS-CoV-2 infection who were admitted at Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital in Wuhan, China, from January 8 to February 9, 2020.Exposures:Documented Corona Virus Disease, 2019 (COVID-19).Main Outcome Measures: Demographic, clinical, laboratory, imaging data were collected along with management strategies, complications and outcomes of enrolled individuals. Results Fifty critically ill patients with SARS-CoV-2 infections were enrolled. Their median age was 62 (range, 29-92) [IQR,49.5-69.0] years, 68% were male, and 28 (56%) patients had comorbidities, the most common being hypertension. In this cohort, 20(40%) patients survived ,16(32%) patients died, and the rest remained hospitalized. The invasive mechanical ventilator was used in 36(72%) patients with 15(30%) of them requiring prone positioning, and 17(34%) switched to ECMO. The compliance scores of lungs (Cstat)on the day of ICU admission among survivors were higher than those in non-survivors [42.0(18.0-47.0), vs. 19.5(14.0-24.2), p=0.038].The blood IL-6 levels and neutrophils counts at the first day of ICU admission were significantly higher in non-survivors compared to survivors [123.7(85.3-228.8), vs. 20.2(6.8-67.2) ng/ml, p=0.025 for IL-6, and 20.2(6.8-67.2) vs. 4.01(1.99-7.05) × 10⁹/L, p=0.02 for neutrophils counts].The heart rates, PaCO2, lung injury scale (LIS), and positive end-expiratory pressure levels were constantly higher for 10 days in non-survivors than those who survived (p<0.05). The frequency of vasopressor uses and neuromuscular blockers was higher in non-survivors from day 1 to day 10 compared to survivors (p<0.05). In the whole cohort, the most common complications were ARDS (97%), shock (44%), arrhythmia (38%), acute cardiac injury (26%), and acute kidney injury (22%). A secondary bacterial infection was noted in 17(34%) patients. Univariate analysis indicated that lower lung complianceand higher neutrophil counts at the day of ICU admission were related to higher mortality (p-0.03, and 0.04, respectively)ConclusionWe demonstrated that SARS-CoV-2 infection-related critical illness predominantly affected old individuals with comorbidities and characterized by severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies. Low lung compliance and persistently elevated PaCO2 indicated poor outcomes.

Umbilical Cord(UC)-Derived Mesenchymal Stem Cells(MSCs) Treatment for the 2019-novel Coronavirus(nCOV) Pneumonia

Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia