Informing emergency care for COVID‐19 patients: The COVID‐19 Emergency Department Quality Improvement Project protocol

Objectives: There is an urgency to support Australian ED clinicians with real‐time tools as the COVID‐19 pandemic evolves. The COVID‐19 Emergency Department (COVED) Quality Improvement Project has commenced and will provide flexible and responsive clinical tools to determine the predictors of key ED‐relevant clinical outcomes. Methods: The COVED Project includes all adult patients presenting to a participating ED and meeting contemporary testing criteria for COVID‐19. The dataset has been embedded in the electronic medical record and the COVED Registry has been developed. Results: Outcomes measured include being COVID‐19 positive and requiring intensive respiratory support. Regression methodology will be used to generate clinical prediction tools. Conclusion: This project will support EDs during this pandemic.     

Coagulopathy in COVID‐19

The COVID‐19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)‐like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID‐19. The clinical presentation of COVID‐19‐associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D‐dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial‐sepsis‐associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID‐19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID‐19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain.     

Electronic medical record platform enhancements during COVID‐19 to support identify‐isolate‐inform strategy for initial detection and management of patients

Singapore was one of the earliest countries affected by COVID‐19, outside China. EDs in Singapore faced a surge of confirmed cases of COVID‐19 patients, which stretched their resources. Here we describe how we adopted strategic changes using the identify‐isolate‐inform tool to improve the evaluation, treatment and management of COVID‐19 patients. During this pandemic, information technology integration, modifications to the electronic medical record and essential enhancements to the dashboard were implemented in a timely manner to match the clinical needs. Considerations for an isolation facility within an ED are especially important for future outbreaks.     

The protective rather than prothrombotic fibrinogen in COVID‐19 and other inflammatory states

Hypercoagulability has been recognized as a common complication of COVID‐19. Exact mechanisms for this extreme coagulation activation have not yet been elucidated. However, one of the consistent laboratory finding is the increase in fibrinogen, in some cases, marked elevation. High circulating levels of fibrinogen have been linked to thrombosis for years and for this reason, hyperfibrinogenemia is considered one of the mechanisms for COVID‐19 coagulopathy. In this forum article, instead of the prothrombotic role, a protective function for fibrinogen is discussed. Fibrinogen, like the other well‐known acute phase reactants, is increased in COVID‐19 possibly to protect the host.     

COVID‐19 and acute coagulopathy in pregnancy

We present a putative link between maternal COVID‐19 infection in the peripartum period and rapid maternal deterioration with early organ dysfunction and coagulopathy. The current pandemic with SARS‐CoV‐2 has already resulted in high numbers of critically ill patients and deaths in the non‐pregnant population, mainly due to respiratory failure. During viral outbreaks, pregnancy poses a uniquely increased risk to women due to changes to immune function, alongside physiological adaptive alterations, such as increased oxygen consumption and edema of the respiratory tract. The laboratory derangements may be reminiscent of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, and thus knowledge of the COVID‐19 relationship is paramount for appropriate diagnosis and management. In addition to routine measurements of D‐dimers, prothrombin time, and platelet count in all patients presenting with COVID‐19 as per International Society on Thrombosis and Haemostasis (ISTH) guidance, monitoring of activated partial thromboplastin time (APTT) and fibrinogen levels should be considered in pregnancy, as highlighted in this report. These investigations in SARS‐CoV‐2‐positive pregnant women are vital, as their derangement may signal a more severe COVID‐19 infection, and may warrant pre‐emptive admission and consideration of delivery to achieve maternal stabilization.     

ISTH DIC subcommittee communication on anticoagulation in COVID‐19

Hypercoagulability is an increasingly recognized complication of SARS‐CoV‐2 infection. As such, anticoagulation has become part and parcel of comprehensive COVID‐19 management. However, several uncertainties exist in this area, including the appropriate type and dose of heparin. In addition, special patient populations, including those with high body mass index and renal impairment, require special consideration. Although the current evidence is still insufficient, we provide a pragmatic approach to anticoagulation in COVID‐19, but stress the need for further trials in this area.     

A qualitative analysis of nursing students' tweets during the COVID‐19 pandemic

The COVID‐19 outbreak has profoundly changed daily life and the ways in which students learn and interact. This study explores the nature and content of tweets posted by students enrolled in nursing programs (hereafter nursing students) in the United Kingdom, the United States, and South Korea during the COVID‐19 pandemic between March 4 and April 7, 2020. A total of 8856 tweets from the Twitter accounts of 95 self‐identified nursing students were included in our qualitative analysis. The findings revealed five categories of tweet content: (i) reactions to COVID‐19; (ii) everyday life; (iii) role as a student; (iv) social connections; and (v) sociopolitical issues. Students shared concerns about the impact of COVID‐19 on their education, discussed their experiences as nursing students, tweeted details of their daily lives, and sought social connections for support as well as for information sharing. The findings of this study can inform nurse educators to better understand their students' responses to and sentiments about the COVID‐19 pandemic. Nurse educators should incorporate this understanding into curricula for pandemic preparedness and response efforts.     

A Large‐Scale Survey on Trauma,Burnout, and Posttraumatic Growth among Nurses during the COVID‐19 Pandemic

A large‐scale survey study was conducted to assess trauma, burnout, posttraumatic growth, and associated factors for nurses in the COVID‐19 pandemic. The Trauma Screening Questionnaire, Maslach Burnout Inventory, and Posttraumatic Growth Inventory‐Short Form were utilized. Factors associated with trauma, burnout, and posttraumatic growth were analysed using logistic and multiple regressions. In total, 12 596 completed the survey, and 52.3% worked in COVID‐19 designated hospitals. At the survey’s conclusion in April, 13.3% reported trauma (Trauma ≥ 6), there were moderate degrees of emotional exhaustion, and 4,949 (39.3%) experienced posttraumatic growth. Traumatic response and emotional exhaustion were greater among (i) women (odds ratio [OR]: 1.48, 95% CI 1.12–1.97 P = 0.006; emotional exhaustion OR: 1.30, 95% CI 1.09–1.54, P = 0.003), (ii) critical care units (OR: 1.20, 95% CI 1.06–1.35, P = 0.004; emotional exhaustion OR: 1.23, 95% CI 1.12–1.33, P < 0.001) (iii) COVID‐19 designated hospital (OR: 1.24, 95% CI 1.11–1.38; P < 0.001; emotional exhaustion OR: 1.26, 95% CI 1.17–1.36; P < 0.001) and (iv) COVID‐19‐related departments (OR: 1.16, 95% CI 1.04–1.29, P = 0.006, emotional exhaustion only). To date, this is the first large‐scale study to report the rates of trauma and burnout for nurses during the COVID‐19 pandemic. The study indicates that nurses who identified as women, working in ICUs, COVID‐19 designated hospitals, and departments involved with treating COVID‐19 patients had higher scores in mental health outcomes. Future research can focus on the factors the study has identified that could lead to more effective prevention and treatment strategies for adverse health outcomes and better use of resources to promote positive outcomes.     

CLUE: COVID‐19 lung ultrasound in emergency department

Lung ultrasound (LUS) plays a critical role in the SARS‐CoV‐2 pandemic. Evidence is mounting on its utility to diagnose, assess the severity and as a triage tool in the ED. Sonographic features correlate well to computed tomography (CT) chest findings and a bedside LUS performed by a trained clinician along with clinical examination, could be an alternative to chest X‐ray and CT chest in these highly infectious patients. In this article, we have described a step‐by‐step approach to LUS in COVID patients and the CLUE (COVID‐19 LUS in the ED) protocol, which involves an anatomical parameter, the severity of lung changes, objectively scored using the validated LUS scoring system and a physiological parameter, oxygen requirement. We believe this CLUE protocol can help risk‐stratify patients presenting to ED with suspected COVID‐19 and aid clinicians in making appropriate disposition decisions.     

COVID‐19: A collision of complement,coagulation and inflammatory pathways

COVID‐19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical acute respiratory distress syndrome (ARDS) seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical hemolytic uremic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID‐19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5, respectively. C5a is a potent cell signalling protein that activates a cytokine storm—a hyper‐inflammatory phenomenon—within hours of infection and the innate immune response. However, excess C5a can result in a pro‐inflammatory environment orchestrated through a plethora of mechanisms that propagate lung injury, lymphocyte exhaustion, and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro‐coagulant state in the microvasculature of critical organs. Fatal COVID‐19 has been associated with a systemic inflammatory response accompanied by a pro‐coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID‐19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID‐19.     

The principle of salvage in the context of COVID‐19

The prioritisation of scarce resources has a particular urgency within the context of the COVID‐19 pandemic crisis. This paper sets out a hypothetical case of Patient X (who is a nurse) and Patient Y (who is a non‐health care worker). They are both in need of a ventilator due to COVID‐19 with the same clinical situation and expected outcomes. However, there is only one ventilator available. In addressing the question of who should get priority, the proposal is made that the answer may lie in how the pandemic is metaphorically described using military terms. If nursing is understood to take place at the ‘frontline’ in the ‘battle’ against COVID‐19, a principle of military medical ethics—namely the principle of salvage—can offer guidance on how to prioritise access to a life‐saving resource in such a situation. This principle of salvage purports a moral direction to return wounded soldiers back to duty on the battlefield. Applying this principle to the hypothetical case, this paper proposes that Patient X (who is a nurse) should get priority of access to the ventilator so that he/she can return to the ‘frontline’ in the fight against COVID‐19.     

Macrothrombosis and stroke in patients with mild Covid‐19 infection

Coronavirus disease 2019 (COVID‐19) is a pandemic disease currently affecting millions of people worldwide. Its neurological implications are poorly understood, and further study is urgently required. A hypercoagulable state has been reported in patients with severe COVID‐19, but nothing is known about coagulopathy in patients with milder disease. We describe cases of patients in New York City presenting with stroke secondary to large vessel thrombosis without occlusion, incidentally found to have COVID‐19 with only mild respiratory symptoms. This is in contrast to the venous thrombosis and microangiopathy that has been reported in patients with severe COVID‐19. Our cases suggest that even in the absence of severe disease, patients with COVID‐19 may be at increased risk of thrombus formation leading to stroke, perhaps resulting from viral involvement of the endothelium. Further systematic study is needed because this may have implications for primary and secondary stroke prevention in patients with COVID‐19.     

Fibrinolysis and COVID‐19: A plasmin paradox

The COVID‐19 pandemic has provided many challenges in the field of thrombosis and hemostasis. Among these is a novel form of coagulopathy that includes exceptionally high levels of D‐dimer. D‐dimer is a marker of poor prognosis, but does this also imply a causal relationship? These spectacularly raised D‐dimer levels may actually signify the failing attempt of the fibrinolytic system to remove fibrin and necrotic tissue from the lung parenchyma, being consumed or overwhelmed in the process. Indeed, recent studies suggest that increasing fibrinolytic activity might offer hope for patients with critical disease and severe respiratory failure. However, the fibrinolytic system can also be harnessed by coronavirus to promote infectivity and where antifibrinolytic measures would also seem appropriate. Hence, there is a clinical paradox where plasmin formation can be either deleterious or beneficial in COVID‐19, but not at the same time. Hence, it all comes down to timing.     

Outcome of patients hospitalized for COVID‐19 and exposure to angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers in France: results of the ACE‐CoV study

Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID‐19 with hypertension/cardiovascular disease, particularly in Europe. The ACE‐CoV study was designed to assess this question. The study was conducted in the Covid‐Clinic‐Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS‐CoV‐2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid‐Clinic‐Toul included 263 patients. Among them, 111 were included in the ACE‐CoV study population. In OW‐PS‐adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73–3.33). It was 0.99 (95% CI: 0.68–1.45) for ACEIs and 1.64 (95% CI: 0.77–3.50) for ARBs. Analyses with weighting by the IPTW‐PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE‐CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID‐19 with a history of cardiovascular disease/arterial hypertension.     

COVID‐19 drug repurposing: A review of computational screening methods,clinical trials,and protein interaction assays

The situation of coronavirus disease 2019 (COVID‐19) pandemic is rapidly evolving, and medical researchers around the globe are dedicated to finding cures for the disease. Drug repurposing, as an efficient way for drug development, has received a lot of attention. However, the huge amount of studies makes it challenging to keep up to date with the literature on COVID‐19 therapeutic development. This review addresses this challenge by grouping the COVID‐19 drug repurposing research into three large groups, including clinical trials, computational research, and in vitro protein‐binding experiments. Particularly, to facilitate future drug discovery and the creation of effective drug combinations, drugs are organized by their mechanisms of action and reviewed by their efficacy measured by clinical trials. Providing this subtyping information, we hope this review would serve the scientists, clinicians, and the pharmaceutical industry who are looking at the new therapeutics for COVID‐19 treatment.     

The De Ritis ratio as prognostic biomarker of in‐hospital mortality in COVID‐19 patients

Increased concentrations of serum aspartate transaminase (AST) and alanine transaminase (ALT) are common in COVID‐19 patients. However, their capacity to predict mortality, particularly the AST/ALT ratio, commonly referred to as the De Ritis ratio, is unknown. We investigated the association between the De Ritis ratio on admission and in‐hospital mortality in 105 consecutive patients with coronavirus disease of 2019 (COVID‐19) admitted to three COVID‐19 referral centres in Sardinia, Italy. The De Ritis ratio was significantly lower in survivors than nonsurvivors (median: 1.25; IQR: 0.91‐1.64 vs 1.67; IQR: 1.38‐1.97, P = .002) whilst there were no significant between‐group differences in ALT and AST concentrations. In ROC curve analysis, the AUC value of the De Ritis ratio was 0.701 (95% CI 0.603‐0.787, P = .0006) with sensitivity and specificity of 74% and 70%, respectively. Kaplan‐Meier survival curves showed a significant association between the De Ritis ratio and mortality (logrank test P = .014). By contrast, no associations were observed between the ALT and AST concentrations and mortality (logrank test P = .83 and P = .62, respectively). In multivariate Cox regression analysis, the HR in patients with De Ritis ratios ≥1.63 (upper tertile of this parameter) remained significant after adjusting for age, gender, smoking status, cardiovascular disease, intensity of care, diabetes, respiratory diseases, malignancies and kidney disease (HR: 2.46, 95% CI 1.05‐5.73, P = .037). Therefore, the De Ritis ratio on admission was significantly associated with in‐hospital mortality in COVID‐19 patients. Larger studies are required to confirm the capacity of this parameter to independently predict mortality in this group.     

Tissue plasminogen activator (tPA) treatment for COVID‐19 associated acute respiratory distress syndrome (ARDS): A case series

A prothrombotic coagulopathy is commonly found in critically ill COVID‐19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID‐19 respiratory failure is a relatively preserved lung compliance and high Alveolar‐arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low‐compliance in ARDS. The COVID‐19 pandemic is overwhelming the world’s medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID‐19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.     

Pharmacological agents under investigation in the treatment of coronavirus disease 2019 and the importance of melatonin

Coronavirus disease 2019 (COVID‐19) is a life‐threatening infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 pandemic causing morbidities and even deaths worldwide revealed that there is urgent need to find pharmacological agents or vaccines. Although there are a lot of agents under investigation, there is no approved agent for the prevention or treatment of the COVID‐19 yet. Treatment of patients remains mainly supportive as well as compassionate use of the agents under investigation. It is well established that excessive inflammatory and immune response and oxidative injury play a critical role in the pathogenesis of COVID‐19. In this review, we aimed to update knowledge about pathogenesis, clinical features, and pharmacological treatment of COVID‐19 and review the potential beneficial effects of ancient antioxidant, anti‐inflammatory, and immunomodulatory molecule melatonin for prevention and treatment of COVID‐19.