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1.
Cells ; 11(8)2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1785542

ABSTRACT

Salvia miltiorrhiza Bunge, commonly called danshen, is widely used in traditional Chinese medicine for its cardiovascular and neuroprotective effects, which include antioxidative, anti-inflammatory, and antifibrotic properties. The purpose of this study was to evaluate the preclinical potential of S. miltiorrhiza extracts for the treatment of COVID-19. First, the impact of the extract on the binding between SARS-CoV-2 and the cellular ACE2 receptors was assessed using atomic force microscopy (AFM), showing a significant reduction in binding by the extract at concentrations in the µg/mL range. Second, the interference of this extract with the inflammatory response of blood mononuclear cells (PBMCs) was determined, demonstrating potent inhibitory properties in the same concentration range on pro-inflammatory cytokine release and interference with the activation of NFκB signaling. Together, these in vitro data demonstrate the potential of S. miltiorrhiza against COVID-19, consisting first of the blockade of the binding of SARS-CoV-2 to the ACE2 receptor and the mitigation of the inflammatory response from leukocytes by interfering with NFκB signaling. This dataset prompts the launch of a clinical trial to address in vivo the clinical benefits of this promising agent.


Subject(s)
COVID-19 , Salvia miltiorrhiza , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , Medicine, Chinese Traditional , NF-kappa B , SARS-CoV-2 , Salvia miltiorrhiza/chemistry
2.
ERJ Open Res ; 8(1)2022 Jan.
Article in English | MEDLINE | ID: covidwho-1724402

ABSTRACT

BACKGROUND AND OBJECTIVES: Azithromycin was rapidly adopted as a repurposed drug to treat coronavirus disease 2019 (COVID-19) early in the pandemic. We aimed to evaluate its efficacy in patients hospitalised for COVID-19. METHODS: In a series of randomised, open-label, phase 2 proof-of-concept, multicentre clinical trials (Direct Antivirals Working against the novel coronavirus (DAWn)), several treatments were compared with standard of care. In 15 Belgian hospitals, patients hospitalised with moderate to severe COVID-19 were allocated 2:1 to receive standard of care plus azithromycin or standard of care alone. The primary outcome was time to live discharge or sustained clinical improvement, defined as a two-point improvement on the World Health Organization (WHO) ordinal scale sustained for at least 3 days. RESULTS: Patients were included between April 22 and December 17, 2020. When 15-day follow-up data were available for 160 patients (56% of preset cohort), an interim analysis was performed at request of the independent Data Safety and Monitoring Board. Subsequently, DAWn-AZITHRO was stopped for futility. In total, 121 patients were allocated to the treatment arm and 64 patients to the standard-of-care arm. We found no effect of azithromycin on the primary outcome with a hazard ratio of 1.044 (95% CI 0.772-1.413; p=0.7798). None of the predefined subgroups showed significant interaction as covariates in the Fine-Gray regression analysis. No benefit of azithromycin was found on any of the short- and longer-term secondary outcomes. CONCLUSION: Time to clinical improvement is not influenced by azithromycin in patients hospitalised with moderate to severe COVID-19.

3.
ERJ open research ; 2022.
Article in English | EuropePMC | ID: covidwho-1661114

ABSTRACT

Background and objectives Azithromycin was rapidly adopted as a repurposed drug to treat COVID-19 early in the pandemic. We aimed to evaluate its efficacy in patients hospitalised for COVID-19. Methods In a series of randomised, open-label, phase 2 proof-of-concept, multicenter clinical trials (Direct Antivirals Working against the novel Coronavirus [DAWn]), several treatments were compared with standard of care. In 15 Belgian hospitals, patients hospitalised with moderate to severe COVID-19 patients were allocated 2:1 to receive standard of care plus azithromycin or standard of care alone. The primary outcome was time to live discharge or sustained clinical improvement, defined as a two-point improvement on the WHO ordinal scale sustained for at least 3 days. Results Patients were included between April 22 and December 17, 2020. When 15-day follow-up data were available for 160 patients (56% of preset cohort), an interim analysis was performed at request of the independent Data Safety and Monitoring Board. Subsequently, DAWn-AZITHRO was stopped for futility. In total, 121 patients were allocated to the treatment arm and 64 patients to the standard of care arm. We found no effect of azithromycin on the primary outcome with Hazard ratio of 1.044 (95% confidence interval, 0.772–1.413;p=0.7798). None of the predefined subgroups showed significant interaction as covariates in the Fine-Gray regression analysis. No benefit of azithromycin was found on any of the short- and longer-term secondary outcomes. Conclusion Time to clinical improvement is not influenced by azithromycin in patients hospitalised with moderate to severe COVID-19.

4.
Am J Respir Crit Care Med ; 204(9): 1024-1034, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1495777

ABSTRACT

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Immunohistochemistry , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Retrospective Studies , Severity of Illness Index , Up-Regulation
5.
J Med Virol ; 93(9): 5416-5424, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363679

ABSTRACT

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Immunocompromised Host , Immunoglobulin G/blood , Respiratory Insufficiency/immunology , SARS-CoV-2/immunology , Adrenal Cortex Hormones/therapeutic use , Aged , Body Mass Index , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19 Serological Testing , Convalescence , Female , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Respiratory Insufficiency/blood , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/drug therapy , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index , Time Factors
6.
Respir Med ; 183: 106438, 2021 07.
Article in English | MEDLINE | ID: covidwho-1219627

ABSTRACT

BACKGROUND: The impact of the COVID-19 pandemic on functional exercise capacity seemed quickly clinically evident. The objective of this study was to assess the functional exercise capacity of patients with severe COVID-19 and to evaluate the effect of a telerehabilitation program in the specific context of the COVID-19 pandemic. METHOD: Patients hospitalized for severe or critical COVID-19 were recruited. The functional exercise capacity (1-min sit-to-stand test (STST)) was prospectively quantified at discharge. A telerehabilitation program was then proposed. A control group was composed with the patients refusing the program. RESULTS: At discharge, none of the 48 recruited patients had a STST higher than the 50th percentile and 77% of them were below the 2.5th percentile. SpO2 was 92.6 ± 3.0% after STST and 15 patients had oxygen desaturation. After 3-months of follow-up, the number of repetitions during STST significantly increased either in telerehabilitation (n = 14) (p < 0.001) or in control groups (n = 13) (p = 0.002) but only one patient had a result higher than the 50th percentile (in Telerehabilitation group) and 37% of them were still under the 2.5th percentile for this result. The improvement was significantly and clinically greater after the telerehabilitation program (p = 0.005). No adverse events were reported by the patients during the program. CONCLUSIONS: Patients hospitalized for COVID-19 have a low functional exercise capacity at discharge and the recovery after three months is poor. The feasibility and the effect of a simple telerehabilitation program were verified, this program being able to substantially improve the functional recovery after three months.


Subject(s)
COVID-19/rehabilitation , Exercise Therapy/methods , Exercise Tolerance/physiology , Pandemics , Recovery of Function , Telerehabilitation/methods , Aged , Belgium/epidemiology , COVID-19/epidemiology , COVID-19/physiopathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2
7.
Respir Med ; 181: 106383, 2021 05.
Article in English | MEDLINE | ID: covidwho-1174487

ABSTRACT

BACKGROUND: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected. RESEARCH QUESTION: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging. STUDY DESIGN: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT. RESULTS: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea. INTERPRETATION: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/physiopathology , Lung/diagnostic imaging , Lung/physiopathology , Aged , COVID-19/complications , Cohort Studies , Dyspnea/etiology , Fatigue/etiology , Female , Follow-Up Studies , Humans , Linear Models , Male , Middle Aged , Positron-Emission Tomography , Radiographic Image Enhancement , Respiratory Function Tests , Severity of Illness Index , Tomography, X-Ray Computed
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