Role of monoclonal antibody drugs in the treatment of COVID-19

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.     

Extracorporeal blood purification treatment options for COVID-19: The role of immunoadsorption

The activation of the innate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

The use of corticosteroids in severe sepsis and acute respiratory distress syndrome

During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. Relative adrenal insufficiency and peripheral glucocorticoid resistance syndrome are the two main features of the inappropriate hormonal response and provide the grounds for cortisol replacement in these diseases. In practice, a high dose of corticosteroids (i.e. one to four boluses of 30 mg/kg of methylprednisolone, or equivalent) had no effects on survival in severe sepsis or acute respiratory distress syndrome. There are at least seven randomised controlled trials reporting the benefits and risks of low dose corticosteroids (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) given for a prolonged period in severe sepsis or in the late phase of acute respiratory distress syndrome. These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.     

COVID-19 and the heart

An outbreak of coronavirus disease 2019 (COVID-19) occurred in December 2019 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a strain of SARS-CoV. Patients infected with the virus present a wide spectrum of manifestations ranging from mild flu-like symptoms, cough, fever and fatigue to severe lung injury, appearing as bilateral interstitial pneumonia or acute respiratory failure. Although SARS-CoV-2 infection predominantly offends the respiratory system, it has been associated with several cardiovascular complications as well. For example, patients with COVID-19 may either develop type 2 myocardial infarction due to myocardial oxygen demand and supply imbalance or acute coronary syndrome resulting from excessive inflammatory response to the primary infection. The incidence of COVID-19 related myocarditis is estimated to be accountable for an average of 7% of all COVID-19 related fatal cases, whereas heart failure (HF) may develop due to infiltration of the heart by inflammatory cells, destructive action of pro-inflammatory cytokines, micro-thrombosis and new onset or aggravated endothelial and respiratory failure. Lastly, SARS-CoV-2 can engender arrhythmias through direct myocardial damage causing acute myocarditis or through HF decompensation or secondary, through respiratory failure or severe respiratory distress syndrome. In this comprehensive review we summarize the COVID-19 related cardiovascular complications (acute coronary syndromes, myocarditis, HF, arrhythmias) and discuss the main underlying pathophysiological mechanisms.     

One disease,many faces-typical and atypical presentations of SARS-CoV-2 infection-related COVID-19 disease

Since the appearance of the novel coronavirus (severe acute respiratory syndrome-coronavirus-2) and related coronavirus disease 2019 (COVID-19) in China in December 2019, a very high number of small and large patient series have been published in literature from around the world. Even though the classical presentation of COVID-19 is one with respiratory symptoms with or without pneumonia that can be self-limiting or evolve into severe respiratory distress syndrome with multiple organ failure, and secondary bacterial sepsis, a large body of evidence suggests a plethora of other types of clinical presentation. In this exhaustive review, we reviewed all of the published literature on COVID-19 to identify different types of clinical presentations affecting various organ systems, to provide an in-depth analysis that may prove useful for clinicians and health-workers on the frontline, battling the severe pandemic.     

Challenges in hyperglycemia management in critically ill patients with COVID-19

Hyperglycemia is commonly associated with adverse outcomes especially in patients requiring intensive care unit stay. Data from the corona virus disease 2019 (COVID-19) pandemic indicates that individuals with diabetes appear to be at similar risk for COVID-19 infection to those without diabetes but are more likely to experience increased morbidity and mortality. The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglycemia (stress- induced hyperglycemia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction. Diabetic patients are more likely to have severe hyperglycemic complications including diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of hyperglycemia in COVID-19 is often complicated by use of steroids, prolonged total parenteral or enteral nutrition, frequent acute hyperglycemic events, and restrictions with fluid management due to acute respiratory distress syndrome. While managing hyperglycemia special attention should be paid to mode of insulin delivery, frequency of glucose monitoring based on patient and caregiver safety thereby minimizing exposure and conserving personal protective equipment. In this article we describe the pathophysiology of hyperglycemia, challenges encountered in managing hyperglycemia, and review some potential solutions to address them.     

The role of mesenchymal stem/stromal cells in the acute clinical setting

IntroductionAccumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU).ObjectiveThis article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU.DiscussionAll clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies.ConclusionMSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED.     

Stem cell therapy: A promising treatment for COVID-19

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. COVID-19 can lead to a cytokine storm and patients usually have early respiratory signs and further secondary infections, which can be fatal. COVID-19 has entered an emergency phase, but there are still no specific effective drugs for this disease. Mesenchymal stem cells (MSCs) are multipotent stromal cells, which cause antiapoptosis and can repair damaged epithelial cells. Many clinical trials have proved that MSC therapy could be a potential feasible therapy for COVID-19 patients, especially those with acute respiratory distress syndrome, without serious adverse events or toxicities. However, more studies are needed in the future, in order to confirm the effect of this therapy.     

Venous thromboembolism in patients with COVID-19. A prevalent and a preventable complication of the pandemic

Coronavirus disease 2019 or most commonly known as COVID-19 is a trending global infectious disease which a few months ago was affirmed as a global health emergency or a pandemic by the WHO Emergency Committee. The common symptoms manifested in this pandemic disease are high grade fever, cough, fatigue, shortness of breath and flu like symptom which can evolve into severe respiratory disorders such as pneumonia, acute respiratory distress syndrome (ARDS) and/or end-organ failure. Factors that contribute to the severity or high mortality rate in COVID-19 include old age, comorbidities like hypertension, diabetes, hyperlipidaemia, neutrophilia, and organ and coagulation dysfunction. Disseminated intravascular coagulation and other various coagulopathies including Venous thromboembolism have known to become a major contributing factor to high mortality rate. Venous thromboembolism is a disease which is a combination of deep vein thrombosis and pulmonary embolism. Prophylactic anticoagulation in patients prone to or with a pre-existing history of venous thromboembolism is associated with decreased mortality in severe COVID-19 pneumonia. This review article focuses upon COVID-19 and increased incidence of venous thromboembolism in patients infected by COVID-19 along with the role it has in high mortality rate in COVID-19 patients.     

A Critical Appraisal of the Effects of Anesthetics on Immune-system Modulation in Critically Ill Patients With COVID-19

PurposeThe aim of the present article was to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19.MethodsThe PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies.FindingsThe novel coronavirus causes a wide spectrum of clinical manifestations, with a large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune-system modulation may vary and includes both pro-inflammatory and anti-inflammatory effects.ImplicationsInhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in patients with COVID-19.     

Clinical features and potential mechanism of coronavirus disease 2019-associated liver injury

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has posed a serious threat to global public health security. With the increase in the number of confirmed cases globally, the World Health Organization has declared the outbreak of COVID-19 an international public health emergency. Despite atypical pneumonia as the primary symptom, liver dysfunction has also been observed in many clinical cases and is associated with the mortality risk in patients with COVID-19, like severe acute respiratory syndrome and Middle East respiratory syndrome. Here we will provide a schematic overview of the clinical characteristics and the possible mechanisms of liver injury caused by severe acute respiratory syndrome coronavirus 2 infection, which may provide help for optimizing the management of liver injury and reducing mortality in COVID-19 patients.     

Apheresis and COVID-19 in intensive care unit (ICU)

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease has since spread worldwide, and on March 2020 the World Health Organization (WHO) declared it as pandemic, causing a public health crisis. Symptoms of COVID-19 are variable, ranging from mild symptoms like fever, cough, and fatigue to severe illness. Elderly patients and those with comorbidities like cardiovascular disease, diabetes, chronic respiratory disease, or cancer are more likely to develop severe forms of the disease. Asymptomatic infections have been well documented. Accumulating evidence suggests that the severity of COVID-19 is due to high levels of circulating inflammatory mediators including cytokines and chemokines leading to cytokine storm syndrome (CSS). Patients are admitted in ICU with severe respiratory failure, but can also develop acute renal failure and multi organ failure. Advances in science and technology have permitted the development of more sophisticated therapies such as extracorporeal organ support (ECOS) therapies that includes renal replacement therapies (RRTs), venoarterial (VA) or veno-venous (VV) extracorporeal membrane Oxygenation (ECMO), extracorporeal CO2 removal (ECCO2R), liver support systems, hemoperfusion, and various blood purification devices, for the treatment of ARDS and septic shock.     

Extracorporeal membrane oxygenation for coronavirus disease 2019-associated acute respiratory distress syndrome: Report of two cases and review of the literature

BACKGROUNDCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is a worldwide pandemic. Some COVID-19 patients develop severe acute respiratory distress syndrome and progress to respiratory failure. In such cases, extracorporeal membrane oxygenation (ECMO) treatment is a necessary life-saving procedure.CASE SUMMARYTwo special COVID-19 cases—one full-term pregnant woman and one elderly (72-year-old) man—were treated by veno-venous (VV)-ECMO in the Second People’s Hospital of Zhongshan, Zhongshan City, Guangdong Province, China. Both patients had developed refractory hypoxemia shortly after hospital admission, despite conventional support, and were therefore managed by VV-ECMO. Although both experienced multiple ECMO-related complications on top of the COVID-19 disease, their conditions improved gradually. Both patients were weaned successfully from the ECMO therapy. At the time of writing of this report, the woman has recovered completely and been discharged from hospital to home; the man remains on mechanical ventilation, due to respiratory muscle weakness and suspected lung fibrosis. As ECMO itself is associated with various complications, it is very important to understand and treat these complications to achieve optimal outcome.CONCLUSIONVV-ECMO can provide sufficient gas exchange for COVID-19 patients with acute respiratory distress syndrome. However, it is crucial to understand and treat ECMO-related complications.     

From bench to bedside: bacterial growth and cytokines

The recognition that neutrophils, macrophages, and other components of the inflammatory cascade participate in the generation and progression of acute lung injury/acute respiratory distress syndrome has resulted in the use of anti-inflammatory agents in an attempt to attenuate this inflammatory response and to prevent further progression of the acute lung injury. The recent finding that cytokines, in part mediators of this ''overwhelming'' inflammatory reaction, may also stimulate bacterial growth, impair bacterial clearance, and promote the subsequent development of nosocomial infections may have important implications to the management of the acute lung injury/acute respiratory distress syndrome patient.     

Contemporary use of cardiac imaging for COVID-19 patients: a three center experience defining a potential role for cardiac MRI

The pandemic of coronavirus disease 2019 (COVID-19) secondary to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has bestowed an unprecedented challenge upon us, resulting in an international public health emergency. COVID-19 has already resulted in >?1,600,000 deaths worldwide and the fear of a global economic collapse. SARS-CoV-2 is notorious for causing acute respiratory distress syndrome, however emerging literature suggests various dreaded cardiac manifestations associated with high mortality. The mechanism of myocardial damage in COVID-19 is unclear but thought to be multifactorial and mainly driven by the host’s immune response (cytokine storm), hypoxemia and direct myocardial injury by the virus. Cardiac manifestations from COVID-19 include but are not limited to, acute myocardial injury, cardiac arrhythmias, congestive heart failure and acute coronary syndrome. Cardiac imaging is paramount to appropriately diagnose and manage the cardiac manifestations of COVID-19. Herein, we present cardiac imaging findings of COVID-19 patients with biomarker and imaging confirmed myocarditis to provide insight regarding the variable manifestations of COVID-19 myocarditis via Cardiac MRI (CMR) coupled with CMR-edema education along with recommendations on how to incorporate advanced CMR into the clinicians’ COVID-19 armamentarium.

     

Red blood cell exchange to avoid intubating a COVID-19 positive patient with sickle cell disease?

As the COVID-19 pandemic continues to claim lives across the globe, insufficient data exists regarding the optimal treatment. It is well known that patients 55 years of age or older and patients with certain chronic diseases are at higher risk of severe illness, including acute respiratory distress syndrome and death. A potentially fatal pulmonary complication of sickle cell disease, acute chest syndrome, can be precipitated by acute infections, including respiratory viruses. We report the case of a patient with sickle cell disease (HbSC) who developed COVID-19 pneumonia and acute chest syndrome who was treated with emergent red blood cell exchange in order to avoid endotracheal intubation.     

Complexities of diagnosis and management of COVID-19 in autoimmune diseases: Potential benefits and detriments of immunosuppression

Recent advances in our understanding of coronavirus disease 2019 (COVID-19) and the associated acute respiratory distress syndrome might approximate the cytokine release syndrome of severe immune-mediated disease. Importantly, this presumption provides the rationale for utilization of therapy, until recently reserved mostly for autoimmune diseases (ADs), in the management of COVID-19 hyperinflammation condition and has led to an extensive discussion for the potential benefits and detriments of immunosuppression. Our paper intends to examine the available recommendations, complexities in diagnosis and management when dealing with patients with ADs amidst the COVID-19 crisis. Mimicking a flare of an underlying AD, overlapping pathological lung patterns, probability of higher rates of false-positive antibody test, and lack of concrete data are only a part of the detrimental and specific characteristics of COVID-19 outbreak among the population with ADs. The administration of pharmaceutical therapy should not undermine the physical and psychological status of the patient with the maximum utilization of telemedicine. Researchers and clinicians should be vigilant for upcoming research for insight and perspective to fine-tune the clinical guidelines and practice and to weigh the potential benefits and detrimental effects of the applied immunomodulating therapy.     

COVID-19 in patients with cancer: Risks and precautions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronavirus family, which causes coronavirus disease 2019 (COVID-19). The phenotype of the disease varies from asymptomatic, to a mild phenotype, through to the severe form of acute respiratory distress syndrome (ARDS), which often leads to death, especially in those with underlying diseases. It has been reported that those who suffer from cancer (especially lung cancer and hematological malignancies) are at higher risk of serious complications and death from COVID-19. Some cancer treatments such as CAR T cell therapy can produce a cytokine storm, which is also a hallmark of severe COVID-19. Therefore, patients receiving CAR T cells are at higher risk if they become infected with COVID-19, and could be treated with anti-cytokine approaches.     

What have anatomic and pathologic studies taught us about acute lung injury and acute respiratory distress syndrome?

PURPOSE OF REVIEW: Acute lung injury and acute respiratory distress syndrome are defined as morphologic and functional manifestations of pulmonary injury of various causes. Acute lung injury and acute respiratory distress syndrome may result from direct effects on epithelial lung cells or from indirect effects on endothelial lung cells, reflecting lung involvement as part of a more distant systemic inflammatory response. This review addresses anatomic/pathologic differences between acute lung injury and acute respiratory distress syndrome lungs. RECENT FINDINGS: It is well established that acute lung injury and acute respiratory distress syndrome are characterized by local and intense inflammatory responses, with accumulation of several types of cells and soluble mediators. There are parallel anti-inflammatory response and lung remodeling, with deposition of collagen. Patient outcome will depend on resolution of the initial event and on the balance between the inflammatory and remodeling responses. Several trials have attempted to modify both responses, but all have yielded negative results. SUMMARY: An appreciation of the acute respiratory distress syndrome must take into account anatomic/pathologic characteristics, which depend upon the initial cause. Consideration of each pathologic mechanism will permit more precise clinical management and probably improved outcomes.