Intravenous Injection of Coronavirus Disease 2019 (COVID-19) mRNA Vaccine Can Induce Acute Myopericarditis in Mouse Model.

BACKGROUND: Post-vaccination myopericarditis is reported after immunization with coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines. The effect of inadvertent intravenous injection of this vaccine on the heart is unknown. METHODS: We compared the clinical manifestations, histopathological changes, tissue mRNA expression, and serum levels of cytokine/chemokine and troponin in Balb/c mice at different time points after intravenous (IV) or intramuscular (IM) vaccine injection with normal saline (NS) control. RESULTS: Although significant weight loss and higher serum cytokine/chemokine levels were found in IM group at 1-2 days post-injection (dpi), only IV group developed histopathological changes of myopericarditis as evidenced by cardiomyocyte degeneration, apoptosis, and necrosis with adjacent inflammatory cell infiltration and calcific deposits on visceral pericardium, although evidence of coronary artery or other cardiac pathologies was absent. Serum troponin level was significantly higher in IV group. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen expression by immunostaining was occasionally found in infiltrating immune cells of the heart or injection site, in cardiomyocytes and intracardiac vascular endothelial cells, but not skeletal myocytes. The histological changes of myopericarditis after the first IV-priming dose persisted for 2 weeks and were markedly aggravated by a second IM- or IV-booster dose. Cardiac tissue mRNA expression of interleukin (IL)-1ß, interferon (IFN)-ß, IL-6, and tumor necrosis factor (TNF)-α increased significantly from 1 dpi to 2 dpi in the IV group but not the IM group, compatible with presence of myopericarditis in the IV group. Ballooning degeneration of hepatocytes was consistently found in the IV group. All other organs appeared normal. CONCLUSIONS: This study provided in vivo evidence that inadvertent intravenous injection of COVID-19 mRNA vaccines may induce myopericarditis. Brief withdrawal of syringe plunger to exclude blood aspiration may be one possible way to reduce such risk.

Metoprolol in Critically Ill Patients With COVID-19.

BACKGROUND: Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. OBJECTIVES: The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19-associated ARDS. METHODS: A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. RESULTS: Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). CONCLUSIONS: In this pilot trial, intravenous metoprolol administration to patients with COVID-19-associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19-associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.

Oral administration of methylprednisolone powder for intravenous injection dissolved in water to treat MS and NMOSD relapses during COVID-19 pandemic in a real-world setting.

BACKGROUND: Upon the COVID-19 pandemic emergence, safety concerns and logistic drawbacks stimulated the search for alternatives to pulse therapy at infusion centres to treat multiple sclerosis relapses. OBJECTIVE: To describe our experience treating multiple sclerosis relapses with a dilute injectable methylprednisolone powder orally administered, in a safe home-based environment and with totally virtual assessment and follow up via telemedicine. METHODS: Descriptive observational, retrospective, single-centre, open label, study in the real-world setting. RESULTS: Between August 2020 and March 2021, ten multiple sclerosis patients and one neuromyelitis optica spectrum disease patient, regularly assisted at our multiple sclerosis centre in Argentina, experienced twelve disease relapses (nine moderate/severe relapses and three mild relapses) and were treated with the oral dilute of injectable methylprednisolone powder pulses with good efficacy as well as adequate tolerance and safety profile. CONCLUSIONS: The oral pulse therapy based on the methylprednisolone powder dilution we describe is simple and comfortable to administer and can be an option in countries like Argentina, where the oral methylprednisolone formulation is not marketed. In these pandemic times, a home based and virtually monitored pulse therapy could represent a safe and effective alternative to manage relapses while minimizing the patient's risk of exposure to SARS-CoV-2.

Nanoparticle-mediated surfactant therapy in patients with severe COVID-19: a perspective.

Coronavirus disease 2019 (COVID-19) is an RNA virus-based disease that can be deadly. For critically ill patients, mechanical ventilation is an important life-saving treatment. However, mechanical ventilation shows a trade-off between supporting respiratory function and ventilator-induced lung injury (VILI). Surfactant therapy is a medical administration of exogenous surfactant to supplement or replace deficient or dysfunctional endogenous surfactant. Surfactant therapy can be used to postpone or shorten the use of mechanical ventilation to minimize or avoid VILI, because surfactants can reduce surface tension, improve lung compliance, and enhance oxygenation. In addition, nanotechnology can be applied to improve the therapeutic effect and reduce the adverse effects of surfactants. In this perspective, we discussed how nanoparticles deliver surfactants through intravenous injection and inhalation to the expected lung disease regions where surfactants are mostly needed, and discussed the prospects of nanoparticle-mediated surfactant therapy in the treatment of patients with severe COVID-19.

Combating hypoxemia in COVID-19 patients with a natural oxygen carrier, HEMO2Life® (M101).

BACKGROUND: Infection with SARS-CoV-2 is responsible for the COVID-19 crisis affecting the whole world. This virus can provoke acute respiratory distress syndrome (ARDS) leading to overcrowed the intensive care unit (ICU). Over the last months, worldwide experience demonstrated that the ARDS in COVID-19 patients are in many ways "atypical". The mortality rate in ventilated patients is high despite the application of the gold standard treatment (protective ventilation, curare, prone position, inhaled NO). Several studies suggested that the SARS-CoV-2 could interact negatively on red blood cell homeostasis. Furthermore, SarsCov2 creates Reactive Oxygen Species (ROS), which are toxic and generate endothelial dysfunction. Hypothesis/objective(s) We hypothesis that HEMO2Life® administrated intravenously is safe and could help symptomatically the patient condition. It would increase arterial oxygen content despite lung failure and allow better tissue oxygenation control. The use of HEMO2Life® is also interesting due to its anti-oxidative effect preventing cytokine storm induced by the SARS-CoV-2. Evaluation of the hypothesis: Hemarina is based on the properties of the hemoglobin of the Arenicola marina sea-worm (HEMO2Life®). This extracellular hemoglobin has an oxygen capacity 40 times greater than the hemoglobin of vertebrates. Furthermore, the size of this molecule is 250 times smaller than a human red blood cell, allowing it to diffuse in all areas of the microcirculation, without diffusing outside the vascular sector. It possesses an antioxidative property du a Superoxide Dismutase Activity. This technology has been the subject of numerous publications and HEMO2Life® was found to be well-tolerated and did not induce toxicity. It was administered intravenously to hamsters and rats, and showed no acute effect on heart rate and blood pressure and did not cause microvascular vasoconstriction. In preclinical in vivo models (mice, rats, and dogs), HEMO2Life® has enabled better tissue oxygenation, especially in the brain. This molecule has already been used in humans in organ preservation solutions and the patients showed no abnormal clinical signs. CONSEQUENCES OF THE HYPOTHESIS: The expected benefits of HEMO2Life® for COVID-19 patients are improved survival, avoidance of tracheal intubation, shorter oxygen supplementation, and the possibility of treating a larger number of patients as molecular respirator without to use an invasive machine.

A pilot double-blind safety and feasibility randomized controlled trial of high-dose intravenous zinc in hospitalized COVID-19 patients.

Zinc inhibits replication of the SARS-CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high-dose intravenous zinc (HDIVZn) to patients with COVID-19. We performed a Phase IIa double-blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID-19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p < .001) on Day 6. Our study did not reach its target enrollment because stringent public health measures markedly reduced patient hospitalizations. Hospitalized COVID-19 patients demonstrated zinc deficiency. This can be corrected with HDIVZn. Such treatment appears safe, feasible, and only associated with minimal peripheral infusion site irritation. This pilot study justifies further investigation of this treatment in COVID-19 patients.

Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue.

Fatigue is common not only in cancer patients but also after viral and other infections. Effective treatment options are still very rare. Therefore, the present knowledge on the pathophysiology of fatigue and the potential positive impact of treatment with vitamin C is illustrated. Additionally, the effectiveness of high-dose IV vitamin C in fatigue resulting from various diseases was assessed by a systematic literature review in order to assess the feasibility of vitamin C in post-viral, especially in long COVID, fatigue. Nine clinical studies with 720 participants were identified. Three of the four controlled trials observed a significant decrease in fatigue scores in the vitamin C group compared to the control group. Four of the five observational or before-and-after studies observed a significant reduction in pre-post levels of fatigue. Attendant symptoms of fatigue such as sleep disturbances, lack of concentration, depression, and pain were also frequently alleviated. Oxidative stress, inflammation, and circulatory disorders, which are important contributors to fatigue, are also discussed in long COVID fatigue. Thus, the antioxidant, anti-inflammatory, endothelial-restoring, and immunomodulatory effects of high-dose IV vitamin C might be a suitable treatment option.

Identification of the absorbed ingredients and metabolites in rats after an intravenous administration of Tanreqing injection using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

The metabolic profiles of Tanreqing injection, which is a traditional Chinese medicine recommended for complementary administration to treat a novel coronavirus, have remained unclear, which inhibit the understanding of the effective chemical compounds of Tanreqing injection. In this study, a sensitive high-performance liquid chromatography quadrupole time-of-flight mass spectrometry method was used to identify the compounds and metabolites in various biosamples, including plasma, bile, liver, lung, kidney, urine, and feces, following the intravenous administration of Tanreqing injection in rats. A total of 89 compounds were characterized in the biosamples of Tanreqing injection-treated rats including 25 precursor constituents and 64 metabolites. Nine flavonoid compounds, twelve phenolic acids, and four iridoid glycosides were identified in the rats. Their metabolites were mainly produced by glucuronidation, deglucuronidation, glycosylation, deglycosylation, methylation, demethylation, N-heterocyclisation, sulphation, dehydroxylation, decarboxylation, dehydration, hydroxylation, and corresponding recombination reactions. This study was the first to comprehensively investigate the metabolic profile of Tanreqing injection and provides a scientific basis to further elucidate the pharmacodynamic material basis and therapeutic mechanism of Tanreqing injection.

Efficacy of early anti-inflammatory treatment with high doses of intravenous anakinra with or without glucocorticoids in patients with severe COVID-19 pneumonia.

BACKGROUND: IL-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes. OBJECTIVE: Our aim was to analyze the efficacy and safety of early anti-inflammatory treatment (AIT) with intravenous anakinra with or without glucocorticoids in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: We performed a retrospective single-center cohort study of patients admitted for COVID-19 pneumonia from February 26 to April 29, 2020, to assess the efficacy of early AIT with intravenous anakinra (100 mg every 8 hours for 3 days, with tapering) alone or in combination with a glucocorticoid (intravenous methylprednisolone, 1-2 mg/kg daily, with tapering). The standard of care (SOC) treatment was hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on overall survival was assessed by a propensity score-adjusted Cox model. RESULTS: A total of 128 patients were analyzed; 63 patients received early AIT (30 received anakinra alone and 33 received anakinra plus a glucocorticoid) at admission, and 65 patients did not receive early AIT and were used as controls; of the latter 65 patients, 44 received the SOC treatment alone and 21 received the SOC treatment plus late rescue AIT. After adjustment for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted hazard ratio [HR] = 0.26; P < .001). The effect was similar in patients receiving anakinra alone (adjusted HR = 0.28; P = .04) and anakinra plus a glucocorticoid (adjusted HR = 0.33; P = .07). Late rescue treatment did not show a significant advantage over SOC treatment alone (adjusted HR = 0.82; P = .70). CONCLUSIONS: This study suggests, on a larger series of patients with COVID-19 pneumonia, the potential efficacy and safety of the early use of high doses of intravenous anakinra with or without glucocorticoids.

Dexamethasone in Hospitalized Patients with Covid-19.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial.

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

Recombinant human C1 esterase inhibitor (conestat alfa) in the prevention of severe SARS-CoV-2 infection in hospitalized patients with COVID-19: A structured summary of a study protocol for a randomized, parallel-group, open-label, multi-center pilot trial (PROTECT-COVID-19).

OBJECTIVES: Conestat alfa, a recombinant human C1 esterase inhibitor, is a multi-target inhibitor of inflammatory cascades including the complement, the kinin-kallikrein and the contact activation system. The study objective is to investigate the efficacy and safety of conestat alfa in improving disease severity and short-term outcome in COVID-19 patients with pulmonary disease. TRIAL DESIGN: This study is an investigator-initiated, randomized (2:1 ratio), open-label, parallel-group, controlled, multi-center, phase 2a clinical trial. PARTICIPANTS: This trial is conducted in 3 hospitals in Switzerland, 1 hospital in Brazil and 1 hospital in Mexico (academic and non-academic). All patients with confirmed SARS-CoV-2 infection requiring hospitalization for at least 3 calendar days for severe COVID-19 will be screened for study eligibility. INCLUSION CRITERIA: - Signed informed consent - Age 18-85 years - Evidence of pulmonary involvement on CT scan or X-ray of the chest - Duration of symptoms associated with COVID-19 ≤ 10 days - At least one of the following risk factors for progression to mechanical ventilation on the day of enrolment: 1) Arterial hypertension 2) ≥ 50 years 3) Obesity (BMI ≥ 30 kg/m2) 4) History of cardiovascular disease 5) Chronic pulmonary disease 6) Chronic renal disease 7) C-reactive protein > 35mg/L 8) Oxygen saturation at rest of ≤ 94% when breathing ambient air Exclusion criteria: - Incapacity or inability to provide informed consent - Contraindications to the class of drugs under investigation (C1 esterase inhibitor) - Treatment with tocilizumab or another IL-6R or IL-6 inhibitor before enrolment - History or suspicion of allergy to rabbits - Pregnancy or breast feeding - Active or anticipated treatment with any other complement inhibitor - Liver cirrhosis (any Child-Pugh score) - Admission to an ICU on the day or anticipated within the next 24 hours of enrolment - Invasive or non-invasive ventilation - Participation in another study with any investigational drug within the 30 days prior to enrolment - Enrolment of the study investigators, their family members, employees and other closely related or dependent persons INTERVENTION AND COMPARATOR: Patients randomized to the experimental arm will receive conestat alfa in addition to standard of care (SOC). Conestat alfa (8400 U followed by 4200 U every 8 hours) will be administered as a slow intravenous injection (5-10 minutes) over a 72-hour period (i.e. 9 administrations in total). The first conestat alfa treatment will be administered on the day of enrolment. The control group will receive SOC only. SOC treatment will be administered according to local institutional guidelines, including supplemental oxygen, antibiotics, corticosteroids, remdesivir, and anticoagulation. MAIN OUTCOMES: The primary endpoint of this trial is disease severity on day 7 after enrolment assessed by an adapted WHO Ordinal Scale for Clinical Improvement (score 0 will be omitted and score 6 and 7 will be combined) from 1 (no limitation of activities) to 7 (death). Secondary outcomes include (i) the time to clinical improvement (time from randomization to an improvement of two points on the WHO ordinal scale or discharge from hospital) within 14 days after enrolment, (ii) the proportion of participants alive and not having required invasive or non-invasive ventilation at 14 days after enrolment and (iii) the proportion of subjects without an acute lung injury (defined by PaO2/FiO2 ratio of ≤300mmHg) within 14 days after enrolment. Exploratory outcomes include virological clearance, C1 esterase inhibitor pharmacokinetics and changes in routine laboratory parameters and inflammatory proteins. RANDOMISATION: Subjects will be randomised in a 2:1 ratio to treatment with conestat alfa in addition to SOC or SOC only. Randomization is performed via an interactive web response system (SecuTrial®). BLINDING (MASKING): In this open-label trial, participants, caregivers and outcome assessors are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We will randomise approximately 120 individuals (80 in the active treatment arm, 40 in the SOC group). Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels αp = 0.0221. The results of the interim analysis will allow adjustment of the sample size (Lehmacher, Wassmer, 1999). TRIAL STATUS: PROTECT-COVID-19 protocol version 3.0 (July 07 2020). Participant recruitment started on July 30 2020 in one center (Basel, Switzerland, first participant included on August 06 2020). In four of five study centers patients are actively recruited. Participation of the fifth study center (Mexico) is anticipated by mid December 2020. Completion of trial recruitment depends on the development of the SARS-CoV-2 pandemic. TRIAL REGISTRATION: Clinicaltrials.gov, number: NCT04414631 , registered on 4 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Impacts of the COVID-19 outbreak on visits and treatments for patients with ureteral stones in a general hospital emergency department.

BACKGROUND: The COVID-19 is a challenge for both patients and physicians in emergency department (ED). This study was aimed to report the impacts of the COVID-19 outbreak on visits and treatments for patients with ureteral stones in a general hospital ED. METHODS: The patients with ureteral stones were collected from 24 January to 24 March 2020 during the COVID-19 outbreak in Beijing. Two periods were divided for study: 24 January to 24 February (Period 1) and 25 February to 24 March (Period 2). Data on patients' characteristics, attendance, visual analog scale (VAS) scores, stone features, and final treatment choices were retrieved from the computer and compared with the data in the same periods in 2019. RESULTS: The study included 376 patients with ureteral stones during the COVID-19 outbreak periods in 2020 and 343 patients during the same periods in 2019. Compared with the same periods in 2019, the number of patients with ureteral stones was less in Period 1 (137 vs 163) but had a rebound phenomenon in Period 2 (239 vs 180). The visit frequency was significantly reduced (2.6 ± 0.4 vs 3.6 ± 0.8, p < 0.01) and the VAS scores and the onset time increased (7.7 ± 1.3 vs 5.5 ± 1.6, p < 0.01; 7.4 ± 1.8 vs 8.2 ± 1.5, p < 0.01, respectively) in Period 1. More patients chose oral analgesics medication to release from renal colic in the COVID-19 outbreak period instead of ESWL and intravenous analgesics medication (Period 1, 54.0% vs 20.2%, p < 0.01; Period 2, 20.9% vs 13.3%, p = 0.044; respectively). However, the percentage of patients underwent endoscopy surgery in outbreak period showed no significant difference compared with that in 2019. CONCLUSION: These results showed that the COVID-19 outbreak can directly affect the visits and final treatment choices for patients with ureteral stones.

Helmet mask and tocilizumab for a patient with hemophagocytic lymphohistiocytosis syndrome and COVID-19: a case report.

The management of acute hypoxemic respiratory failure and the effect of antiviral drugs in patients with severe COVID-19 have been debated. This case presents the management of a 64-year-old man COVID-19 patient admitted to the Intensive Care Unit with fever, fatigue, shortness of breath and hemophagocytic lymphohistiocytosis syndrome. Helmet mask was successfully used to treat his hypoxemic respiratory failure without any aerosol problems. Tocilizumab, an antagonist interleukin-6, was intravenously infused as an alternative drug. After administration, the high level of IL-6, CRP, ferritin, D-dimer, triglyceride, and H-scores decreased, and the patient observed good clinical and laboratory improvements. In this case report, we describe the effect of noninvasive ventilation delivered by helmet mask and antiviral drugs, and the intravenous administration of tocilizumab in a patient with hemophagocytic lymphohistiocytosis syndrome and COVID-19.

Learning from past failures: Challenges with monoclonal antibody therapies for COVID-19.

COVID-19, the disease caused by infection with SARS-CoV-2, requires urgent development of therapeutic interventions. Due to their safety, specificity, and potential for rapid advancement into the clinic, monoclonal antibodies (mAbs) represent a highly promising class of antiviral or anti-inflammatory agents. Herein, by analyzing prior efforts to advance antiviral mAbs for other acute respiratory infections (ARIs), we highlight the challenges faced by mAb-based immunotherapies for COVID-19. We present evidence supporting early intervention immediately following a positive diagnosis via inhaled delivery of mAbs with vibrating mesh nebulizers as a promising approach for the treatment of COVID-19.