Neuraminidase inhibitor treatment is associated with decreased mortality in COVID-19 patients: a retrospective analysis.

AIMS: The aim of this study was to investigate the effects of Neuraminidase inhibitors (NI) on COVID-19 in a retrospective study. METHODS AND RESULTS: The study included an overall COVID-19 patients (n = 3267) and a 1:1 propensity score-matched patients (n = 972). The levels of plasma N-acetylneuraminic acid and neuraminidase expression were further evaluated in a panel of hospitalized and 1-month post-infection recovered COVID-19 subjects. The mortality rate in the overall patients was 9.6% (313/3267) and 9.2% (89/972) in the propensity-score matched patients. The NI treatment lowered the mortality rate (5.7% vs. 10.3%) and the critically ill conversion rate (14.1% vs. 19.7%) compare to those in the non-NI group in the overall patients and evaluated in the propensity score-matched patients when applying the multivariate Cox model for adjusting imbalanced confounding factors. Furthermore, NI treatment was associated with attenuated cytokine storm levels and acute heart injury but not liver or kidney injuries. Further analysis in a small panel of patients found the levels of N-acetylneuraminic acid and neuraminidase (dominantly the NEU3 isoform) were elevated in the hospitalized COVID-19 subjects and recovered at the 1-month post-infection stage, suggesting increasing desialylation in COVID-19 patients. CONCLUSION: These results suggest that NI treatment is associated with decreased mortality in COVID-19 subjects, especially for those subjects with acute heart injury.

Cardiovascular Involvement in Patients with 2019 Novel Coronavirus Disease.

2019 novel coronavirus disease (COVID-19) is caused by the infection of severe acute respiratory syndrome novel coronavirus (SARS-CoV-2). It is characterized by substantial respiratory symptoms and complicated with widespread other organ injuries. Cardiovascular impairment is one of the notable extrapulmonary manifestations, in terms of the deterioration of pre-existing cardiovascular diseases and newly onset acute events. We hereby review the high-quality reports about cardiovascular involvement in COVID-19 and summarize the main clinical characteristics of cardiac relevance for the all the first line clinical physicians. Additionally, the possible underlying mechanisms and the rationale for the application of specific medications, such as renin-angiotensin-aldosterone system inhibitors and hydroxychloroquine are also discussed.

Cardiac Involvement in Recovered Patients From COVID-19: A Preliminary 6-Month Follow-Up Study.

Background: Accumulating evidence has revealed that coronavirus disease 2019 (COVID-19) patients may be complicated with myocardial injury during hospitalization. However, data regarding persistent cardiac involvement in patients who recovered from COVID-19 are limited. Our goal is to further explore the sustained impact of COVID-19 during follow-up, focusing on the cardiac involvement in the recovered patients. Methods: In this prospective observational follow-up study, we enrolled a total of 40 COVID-19 patients (20 with and 20 without cardiac injury during hospitalization) who were discharged from Zhongnan Hospital of Wuhan University for more than 6 months, and 27 patients (13 with and 14 without cardiac injury during hospitalization) were finally included in the analysis. Clinical information including self-reported symptoms, medications, laboratory findings, Short Form 36-item scores, 6-min walk test, clinical events, electrocardiogram assessment, echocardiography measurement, and cardiac magnetic resonance imaging was collected and analyzed. Results: Among 27 patients finally included, none of patients reported any obvious cardiopulmonary symptoms at the 6-month follow-up. There were no statistically significant differences in terms of the quality of life and exercise capacity between the patients with and without cardiac injury. No significant abnormalities were detected in electrocardiogram manifestations in both groups, except for nonspecific ST-T changes, premature beats, sinus tachycardia/bradycardia, PR interval prolongation, and bundle-branch block. All patients showed normal cardiac structure and function, without any statistical differences between patients with and without cardiac injury by echocardiography. Compared with patients without cardiac injury, patients with cardiac injury exhibited a significantly higher positive proportion in late gadolinium enhancement sequences [7/13 (53.8%) vs. 1/14 (7.1%), p = 0.013], accompanied by the elevation of circulating ST2 level [median (interquartile range) = 16.6 (12.1, 22.5) vs. 12.5 (9.5, 16.7); p = 0.044]. Patients with cardiac injury presented higher levels of aspartate aminotransferase, creatinine, high-sensitivity troponin I, lactate dehydrogenase, and N-terminal pro-B-type natriuretic peptide than those without cardiac injury, although these indexes were within the normal range for all recovered patients at the 6-month follow-up. Among patients with cardiac injury, patients with positive late gadolinium enhancement presented higher cardiac biomarker (high-sensitivity troponin I) and inflammatory factor (high-sensitivity C-reactive protein) on admission than the late gadolinium enhancement-negative subgroup. Conclusions: Our preliminary 6-month follow-up study with a limited number of patients revealed persistent cardiac involvement in 29.6% (8/27) of recovered patients from COVID-19 after discharge. Patients with cardiac injury during hospitalization were more prone to develop cardiac fibrosis during their recovery. Among patients with cardiac injury, those with relatively higher cardiac biomarkers and inflammatory factors on admission appeared more likely to have cardiac involvement in the convalescence phase.

The SARS-CoV-2 induced targeted amino acid profiling in patients at hospitalized and convalescent stage.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has induced an ongoing global health crisis. Here we utilized a combination of targeted amino acids (AAs) and clinical biochemical profiling to analyze the plasma of coronavirus disease 2019 (COVID-19) subjects at the hospitalization stage and 1-month post-infection convalescent stage, respectively, to investigate the systematic injury during COVID-19 disease progress. We found the virus-induced inflammatory status and reduced liver synthesis capacity in hospitalized patients, which manifested with increased branched-chain AAs (BCAAs), aromatic AAs (AAAs), one-carbon related metabolites, and decreased methionine. Most of these disturbances during infection recover except for the increased levels of medium-chain acylcarnitines (ACs) in the convalescent subjects, implying the existence of incomplete fatty acids oxidation during recovery periods. Our results suggested that the imbalance of the AA profiling in COVID-19 patients. The majority of disturbed AAs recovered in 1 month. The incomplete fatty acid oxidation products suggested it might take longer time for convalescent patients to get complete recovery.

Widespread myocardial dysfunction in COVID-19 patients detected by myocardial strain imaging using 2-D speckle-tracking echocardiography.

COVID-19 is a multiorgan systemic inflammatory disease caused by SARS-CoV-2 virus. Patients with COVID-19 often exhibit cardiac dysfunction and myocardial injury, but imaging evidence is lacking. In the study we detected and evaluated the severity of myocardial dysfunction in COVID-19 patient population using two-dimensional speckle-tracking echocardiography (2-D STE). A total of 218 consecutive patients with confirmed diagnosis of COVID-19 who had no underlying cardiovascular diseases were enrolled and underwent transthoracic echocardiography. This study cohort included 52 (23.8%) critically ill and 166 noncritically ill patients. Global longitudinal strains (GLSs) and layer-specific longitudinal strains (LSLSs) were obtained using 2-D STE. Changes in GLS were correlated with the clinical parameters. We showed that GLS was reduced (<-21.0%) in about 83% of the patients. GLS reduction was more common in critically sick patients (98% vs. 78.3%, P < 0.001), and the mean GLS was significantly lower in the critically sick patients than those noncritical (-13.7% ± 3.4% vs. -17.4% ± 3.2%, P < 0.001). The alteration of GLS was more prominent in the subepicardium than in the subendocardium (P < 0.001). GLS was correlated to mean serum pulse oxygen saturation (SpO2, RR = 0.42, P < 0.0001), high-sensitive C-reactive protein (hsCRP, R = -0.20, P = 0.006) and inflammatory cytokines, particularly IL-6 (R = -0.21, P = 0.003). In conclusions, our results demonstrate that myocardial dysfunction is common in COVID-19 patients, particularly those who are critically sick. Changes in indices of myocardial strain were associated with indices of inflammatory markers and hypoxia, suggesting partly secondary nature of myocardial dysfunction.

Association of Statin Use With the In-Hospital Outcomes of 2019-Coronavirus Disease Patients: A Retrospective Study.

Background: Statins have multiple protective effects on inflammation, immunity and coagulation, and may help alleviate pneumonia. However, there was no report focusing on the association of statin use with in-hospital outcomes of patients with coronavirus disease 2019 (COVID-19). We investigated the association between the use of statins and in-hospital outcomes of patients with COVID-19. Methods: In this retrospective case series, consecutive COVID-19 patients admitted at 2 hospitals in Wuhan, China, from March 12, 2020 to April 14, 2020 were analyzed. A 1:1 matched cohort was created by propensity score-matched analysis. Demographic data, laboratory findings, comorbidities, treatments and in-hospital outcomes were collected and compared between COVID-19 patients taking and not taking statins. Result: A total of 2,147 patients with COVID-19 were enrolled in this study. Of which, 250 patients were on statin therapy. The mortality was 2.4% (6/250) for patients taking statins while 3.7% (70/1,897) for those not taking statins. In the multivariate Cox model, after adjusting for age, gender, admitted hospital, comorbidities, in-hospital medications and blood lipids, the risk was lower for mortality (adjusted HR, 0.428; 95% CI, 0.169-0.907; P = 0.029), acute respiratory distress syndrome (ARDS) (adjusted HR, 0.371; 95% CI, 0.180-0.772; P = 0.008) or intensive care unit (ICU) care (adjusted HR, 0.319; 95% CI, 0.270-0.945; P = 0.032) in the statin group vs. the non-statin group. After propensity score-matched analysis based on 18 potential confounders, a 1:1 matched cohort (206:206) was created. In the matched cohort, the Kaplan-Meier survival curves showed that the use of statins was associated with better survival (P = 0.025). In a Cox regression model, the use of statins was associated with lower risk of mortality (unadjusted HR, 0.254; 95% CI, 0.070-0.926; P = 0.038), development of ARDS (unadjusted HR, 0.240; 95% CI, 0.087-0.657; P = 0.006), and admission of ICU (unadjusted HR, 0.349; 95% CI, 0.150-0.813; P = 0.015). The results remained consistent when being adjusted for age, gender, total cholesterol, triglyceride, low density lipoprotein cholesterol, procalcitonin, and brain natriuretic peptide. The favorable outcomes in statin users remained statistically significant in the first sensitivity analysis with comorbid diabetes being excluded in matching and in the second sensitivity analysis with chronic obstructive pulmonary disease being added in matching. Conclusion: In this retrospective analysis, the use of statins in COVID-19 patients was associated with better clinical outcomes and is recommended to be continued in patients with COVID-19.

Insulin Treatment Is Associated with Increased Mortality in Patients with COVID-19 and Type 2 Diabetes.

COVID-19 caused by SARS-COV-2 infection can lead to multi-organ injuries and significant mortality in severe and critical patients, especially among those individuals with type 2 diabetes (T2D) as a comorbidity. While attenuated mortality was observed with aggressive glucose control, it was unclear whether therapeutic regimens including insulin treatment were beneficial for patients with COVID-19 and T2D. This retrospective study investigated 689 patients with COVID-19 and T2D from a cohort of 3,305 cases from Wuhan, China. Unexpectedly, we found that insulin treatment for patients with COVID-19 and T2D was associated with a significant increase in mortality (27.2% versus 3.5%; adjusted HR, 5.38 [2.75-10.54]). Further analysis showed that insulin treatment was associated with enhanced systemic inflammation and aggravated injuries of vital organs. Therefore, insulin treatment for patients with COVID-19 and T2D should be used with caution.

Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.

BACKGROUND: Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome. METHODS: We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors. RESULTS: Median age was 63 years (first to third quartile 51-70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p < 0.001), with increased mortality during hospitalization (38.4% vs. 0%, p < 0.001). Among critically ill patients, non-survivors (N = 183) had a continuous increase in hs-cTnI levels during hospitalization, while survivors (N = 293) showed a decrease in hs-cTnI level between day 4 and 7 after admission. Specifically, cardiac injury is an independent marker of mortality among critically ill patients at admission, day 4-7 and 8-14. Consistent positive correlations between hs-cTnI and interleukin (IL)-6 on admission (r = 0.59), day 4-7 (r = 0.66) and day 8-14 (r = 0.61; all p < 0.001) and d-dimer (at the same timepoints r = 0.54; 0.65; 0.61, all p < 0.001) were observed. A similar behavior was observed between hs-cTnI and most of other biomarkers of inflammation and coagulation. CONCLUSIONS: Cardiac injury commonly occurs in critically ill COVID-19 patients, with increased levels of hs-cTnI beyond day 3 since admission portending a poor prognosis. A consistent positive correlation of hs-cTnI with IL-6 and d-dimer at several timepoints along hospitalization could suggest nonspecific cytokine-mediated cardiotoxicity.

Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

Erratum to: Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19.

1. In the abstract, we missed a piece of information. The correct sentence should be "In this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation (63.5%) and oxygen therapy (35.6%) in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020." 2. We mistakenly put an approval number from Tongji Hospital ethics committee in the paper (IRBID: TJ-C20200113). The correct number should be TJ-IRB20200229. 3. We mistakenly filled some data in Table 1 and the correct Table 1 (the corrected data are in boldface) should be as follows.

Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases.

Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups-non-critically ill, critically ill, and death groups-in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52-71). Among the patients enrolled in the study, 2,008 (76.6%) were diagnosed as non-critically ill and 615 (23.4%) were critically ill patients, including 383 (14.6%) critically ill survivors and 232 (8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients.