Neutrophil activation and neutrophil extracellular traps (NETs) in COVID-19 ARDS and immunothrombosis

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by triggering the formation of neutrophil extracellular traps (NETs), producing cytokines including interleukin-8 (CXCL8), and mediating the recruitment of other immune cells to regulate processes such as acute and chronic inflammation, which can lead to ARDS. CXCL8 is involved in the recruitment, activation, and degranulation of neutrophils, and therefore contributes to inflammation amplification and severity of disease. Furthermore, activation of neutrophils also supports a prothrombotic phenotype, which may explain the development of immunothrombosis observed in COVID-19 ARDS. This review aims to describe hyperinflammatory ARDS due to SARS-CoV-2 infection. In addition, we address the critical role of polymorphonuclear neutrophils, inflammatory cytokines, and the potential targeting of CXCL8 in treating the hyperinflammatory ARDS population.     

A compendium answering 150 questions on COVID-19 and SARS-CoV-2

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome–related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date, it has resulted in ~9 million confirmed cases and caused almost 500 000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19–related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.     

The role of IL-1 family of cytokines and receptors in pathogenesis of COVID-19

A global pandemic has erupted as a result of the new brand coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic has been consociated with widespread mortality worldwide. The antiviral immune response is an imperative factor in confronting the recent coronavirus disease 2019 (COVID-19) infections. Meantime, cytokines recognize as crucial components in guiding the appropriate immune pathways in the restraining and eradication of the virus. Moreover, SARS-CoV-2 can induce uncontrolled inflammatory responses characterized by hyper-inflammatory cytokine production, which causes cytokine storm and acute respiratory distress syndrome (ARDS). As excessive inflammatory responses are contributed to the severe stage of the COVID-19 disease, therefore, the pro-inflammatory cytokines are regarded as the Achilles heel during COVID-19 infection. Among these cytokines, interleukin (IL-) 1 family cytokines (IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38) appear to have a strong inflammatory role in severe COVID-19. Hence, understanding the underlying inflammatory mechanism of these cytokines during infection is critical for reducing the symptoms and severity of the disease. Here, the possible mechanisms and pathways involved in inflammatory immune responses are discussed.

     

Roles of Type I and III Interferons in COVID-19

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I and III interferon (IFN) responses act as the first line of defense against viral infection and are activated by the recognition of viruses by infected cells and innate immune cells. Dysregulation of host IFN responses has been known to be associated with severe disease progression in COVID-19 patients. However, the reported results are controversial and the roles of IFN responses in COVID-19 need to be investigated further. In the absence of a highly efficacious antiviral drug, clinical studies have evaluated recombinant type I and III IFNs, as they have been successfully used for the treatment of infections caused by two other epidemic coronaviruses, SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV. In this review, we describe the strategies by which SARS-CoV-2 evades IFN responses and the dysregulation of host IFN responses in COVID-19 patients. In addition, we discuss the therapeutic potential of type I and III IFNs in COVID-19.     

Impaired innate antiviral defenses in COVID-19: Causes,consequences and therapeutic opportunities

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogen that has caused coronavirus disease 2019 (COVID-19), the worst pandemic of our times leading to tremendous loss of human life and unprecedented measures of social distancing. COVID-19 symptom manifestations range from asymptomatic disease to severe and lethal outcomes. Lack of previous exposure and immunity to SARS-CoV-2, and high infectivity of the virus have contributed to its broad spread across the globe. In the absence of specific adaptive immunity, innate immune mechanisms are crucial for efficient antiviral defenses and control of the infection. Accumulating evidence now suggests that the remarkable heterogeneity in COVID-19 disease manifestations is due to variable degrees of impairment of innate immune mechanisms. In this review, we summarize recent findings describing both viral and host intrinsic factors that have been linked to defective innate immune responses and account for severe COVID-19. We also discuss emerging therapeutic opportunities for targeting innate immunity for the treatment of COVID-19.     

Are nucleotide inhibitors,already used for treating hepatitis C virus infection,a potential option for the treatment of COVID-19 compared with standard of care? A literature review

Coronavirus disease 2019 (COVID-19) is global pandemic with various clinical presentations, ranging from cold to sometimes unrecoverable acute respiratory distress syndrome. Although urgently needed, currently there are no specific treatments for COVID-19. Repurposing existing pharmaceuticals to treat COVID-19 is crucial to control the pandemic. In silico and in vitro studies suggest that a nucleotide inhibitor called Sofosbuvir, has also antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from suppressing other positive-strand ribonucleic Acid viruses with conserved polymerase (hepatitis C virus). The aim of this study was to assess if Sofosbuvir improves clinical outcomes in patients with moderate or severe COVID-19. A compre-hensive overview of scientific literature has been made. Terms searched in PubMed were: COVID-19, SARS-CoV-2, nucleotide inhibitors, pandemic, Sofosbuvir. Results clinical trials conducted among adults with moderate or severe COVID-19 were analyzed. Patients were divided in treatment and control arms, receiving Sofosbuvir plus standard care and standard care alone respectively. The addition of Sofosbuvir to standard care significantly reduced the duration of hospital stay compared with standard care alone in clinical trials examined. If efficacy of these repurposed, cheap and easily available drug against SARS-CoV-2 is further demonstrated, it could be essential to refine the treatment of COVID-19.     

COVID-19: A pluralistic and integrated approach for efficient management of the pandemic

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which triggered the ongoing pandemic, was first discovered in China in late 2019. SARS-CoV-2 is a respiratory virus responsible for coronavirus disease 2019 (COVID-19) that often manifests as a pneumonic syndrome. In the context of the pandemic, there are mixed views on the data provided by epidemiologists and the information collected by hospital clinicians about their patients. In addition, the literature reports a large proportion of patients free of pneumonia vs a small percentage of patients with severe pneumonia among confirmed COVID-19 cases. This raises the issue of the complexity of the work required to control or contain the pandemic. We believe that an integrative and pluralistic approach will help to put the analyses into perspective and reinforce collaboration and creativity in the fight against this major scourge. This paper proposes a comprehensive and integrative approach to COVID-19 research, prevention, control, and treatment to better address the pandemic. Thus, this literature review applies a pluralistic approach to fight the pandemic.     

Pharmacological approach for the reduction of inflammatory and prothrombotic hyperactive state in COVID-19 positive patients by acting on complement cascade

The novel Coronavirus SARS-CoV-2 is the viral pathogen responsible for the ongoing global pandemic, COVID-19 (Coronavirus disease 2019). To date, the data recorded indicate 1.62 Mln deaths and 72.8 Mln people infected (WHO situation report Dec 2020). On December 27, the first anti-COVID-19 vaccinations started in Europe. There are no direct antivirals against SARS-CoV-2. Understanding the pathophysiological and inflammatory/immunological processes of SARS-CoV-2 infection is essential to identify new drug therapies. In the most severe COVID-19 cases, an unregulated immunological/inflammatory system results in organ injury that can be fatal to the host in some cases. Pharmacologic approaches to normalize the unregulated inflammatory/immunologic response is an important therapeutic solution. Evidence associates a non-regulation of the “complement system” as one of the causes of generalized inflammation causing multi-organ dysfunction. Serum levels of a complement cascade mediator, factor “C5a”, have been found in high concentrations in the blood of COVID-19 patients with severe disease. In this article we discuss the correlation between complement system and COVID-19 infection and pharmacological solutions directed to regulate.     

Risk factors for severe and critically ill COVID-19 patients: A review

The pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and high numbers of deaths. Many risk factors have been identified in the progression of COVID-19 into a severe and critical stage, including old age, male gender, underlying comorbidities such as hypertension, diabetes, obesity, chronic lung diseases, heart, liver and kidney diseases, tumors, clinically apparent immunodeficiencies, local immunodeficiencies, such as early type I interferon secretion capacity, and pregnancy. Possible complications include acute kidney injury, coagulation disorders, thoromboembolism. The development of lymphopenia and eosinopenia are laboratory indicators of COVID-19. Laboratory parameters to monitor disease progression include lactate dehydrogenase, procalcitonin, high-sensitivity C-reactive protein, proinflammatory cytokines such as interleukin (IL)-6, IL-1β, Krebs von den Lungen-6 (KL-6), and ferritin. The development of a cytokine storm and extensive chest computed tomography imaging patterns are indicators of a severe disease. In addition, socioeconomic status, diet, lifestyle, geographical differences, ethnicity, exposed viral load, day of initiation of treatment, and quality of health care have been reported to influence individual outcomes. In this review, we highlight the scientific evidence on the risk factors of severity of COVID-19.     

Gaucher disease and SARS-CoV-2 infection: Experience from 181 patients in New York

SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid β-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients.     

Impact of COVID-19 on liver disease: From the experimental to the clinic perspective

Coronavirus disease 2019 (COVID-19) has caused a global pandemic unprecedented in over a century. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a predominantly respiratory infection, various degrees of liver function abnormalities have been reported. Pre-existing liver disease in patients with SARS-CoV-2 infection has not been comprehensively evaluated in most studies, but it can critically compromise survival and trigger hepatic decompensation. The collapse of the healthcare services has negatively impacted the diagnosis, monitoring, and treatment of liver diseases in non-COVID-19 patients. In this review, we aim to discuss the impact of COVID-19 on liver disease from the experimental to the clinic perspective.     

Humoral immune mechanisms involved in protective and pathological immunity during COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is associated with excessive inflammation, as a main reason for severe condition and death. Increased inflammatory cytokines and humoral response to SARS-CoV-2 correlate with COVID-19 immunity and pathogenesis. Importantly, the levels of pro-inflammatory cytokines that increase profoundly in systemic circulation appear as part of the clinical pictures of two overlapping conditions, sepsis and the hemophagocytic syndromes. Both conditions can develop lethal inflammatory responses that lead to tissue damage, however, in many patients hemophagocytic lymphohistiocytosis (HLH) can be differentiated from sepsis. This is a key issue because the life-saving aggressive immunosuppressive treatment, required in the HLH therapy, is absent in sepsis guidelines. This paper aims to describe the pathophysiology and clinical relevance of these distinct entities in the course of COVID-19 that resemble sepsis and further highlights two effector arms of the humoral immune response (inflammatory cytokine and immunoglobulin production) during COVID-19 infection.     

COVID-19 and Obesity: Overlapping of Two Pandemics

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has recently led to worldwide research efforts to identify subjects at greater risk of developing more severe illness: overall obesity displayed a strong correlation with critical illness and major severity of COVID-19 manifestations.SummaryObesity and metabolic disorders are closely linked to chronic systemic inflammation. The adipose tissue constitutes a source of cytokines, which configure a low-grade inflammation and a hypercoagulation status; in addition, diagnosis and care of obese patients are often complicated by excess weight and ventilation difficulties.Key MessagesThis review aims to examine the intersection between obesity and adverse outcomes of COVID-19, in order to investigate its preventive and/or therapeutic potential in the management of obesity-related COVID-19 complications.     

Characteristics of patients with coronavirus disease (COVID-19) confirmed using an IgM-IgG antibody test

Coronavirus disease (COVID-19), caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly developed into a pandemic since it was first reported in December 2019. Nucleic acid testing is the standard method for the diagnosis of viral infections. However, this method reportedly has a low positivity rate. To increase the sensitivity of COVID-19 diagnoses, we developed an IgM-IgG combined assay and tested it in patients with suspected SARS-CoV-2 infection. In total, 56 patients were enrolled in this study and SARS-CoV-2 was detected by using both IgM-IgG antibody and nucleic acid tests. Clinical and laboratory data were collected and analyzed. Our findings suggest that patients who develop severe illness might experience longer virus exposure times and develop a more severe inflammatory response. The IgM-IgG test is an accurate and sensitive diagnostic method. A combination of nucleic acid and IgM-IgG testing is a more sensitive and accurate approach for diagnosis and early treatment of COVID-19.     

Angiotensin-converting enzyme 2 receptors,chronic liver diseases,common medications,and clinical outcomes in coronavirus disease 2019 patients

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), enters affected cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in type II alveolar cells, enterocytes, and cholangiocytes. SARS-CoV-2 infection causes fever, dry cough, and breathing difficulty, which can progress to respiratory distress due to interstitial pneumonia, and hepatobiliary injury due to COVID-19 is increasingly recognized. The hepatobiliary injury may be evident at presentation of the disease or develop during the disease progression. The development of more severe clinical outcomes in patients with chronic liver diseases (CLD) with or without cirrhosis infected with SARS-CoV-2 has not been elucidated. Moreover, there is limited data related to common medications that affect the disease severity of COVID-19 patients. Additionally, ACE2 receptor expression of hepatobiliary tissue related to the disease severity also have not been clarified. This review summarized the current situation regarding the clinical outcomes of COVID-19 patients with chronic liver diseases who were treated with common medications. Furthermore, the association between ACE2 receptor expression and disease severity in these patients is discussed.     

A Case Report for Using Methylprednisolone for Severe ARDS Caused by SARS-CoV-2 Delta Variant in a Pediatric Patient With Lennox-Gastaut Syndrome

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 can result in fatal comorbidities, including acute respiratory distress syndrome (ARDS). Several reports suggest that children have milder illness, though severe cases have still been reported. We report a 9-year-old boy with ARDS caused by the SARS-CoV-2 delta (B.1.617.2) variant. He was admitted to our hospital and carefully observed due to underlying Lennox-Gastaut syndrome. He developed intractable seizures with a high fever. Although the seizures were controlled, his respiratory condition deteriorated to severe ARDS. High-dose methylprednisolone was administered with high positive end-expiratory pressure and low tidal volume. After ARDS treatment, oxygenation improved sufficiently to permit extubation. This case suggests that close observation is required in pediatric patients with neurologic comorbidities because of an increased risk for severe COVID-19.     

TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib

COVID-19 emerges as a pandemic disease with high mortality. Development of effective prevention and treatment is an urgent need. We reviewed TH17 responses in patients with SARS-CoV-2 and proposed an FDA approved JAK2 inhibitor Fedratinib for reducing mortality of patients with TH17 type immune profiles.     

IL-6, IL-10, sFas,granulysin and indicators of intestinal permeability as early biomarkers for a fatal outcome in COVID-19

The clinical presentation of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranges between mild respiratory symptoms and a severe disease that shares many of the features of sepsis. Sepsis is a deregulated response to infection that causes life-threatening organ failure. During sepsis, the intestinal epithelial cells are affected, causing an increase in intestinal permeability and allowing microbial translocation from the intestine to the circulation, which exacerbates the inflammatory response. Here we studied patients with moderate, severe and critical COVID-19 by measuring a panel of molecules representative of the innate and adaptive immune responses to SARS-CoV-2, which also reflect the presence of systemic inflammation and the state of the intestinal barrier. We found that non-surviving COVID-19 patients had higher levels of low-affinity anti-RBD IgA antibodies than surviving patients, which may be a response to increased microbial translocation. We identified sFas and granulysin, in addition to IL-6 and IL-10, as possible early biomarkers with high sensitivity (>73 %) and specificity (>51 %) to discriminate between surviving and non-surviving COVID-19 patients. Finally, we found that the microbial metabolite d-lactate and the tight junction regulator zonulin were increased in the serum of patients with severe COVID-19 and in COVID-19 patients with secondary infections, suggesting that increased intestinal permeability may be a source of secondary infections in these patients. COVID-19 patients with secondary infections had higher disease severity and mortality than patients without these infections, indicating that intestinal permeability markers could provide complementary information to the serum cytokines for the early identification of COVID-19 patients with a high risk of a fatal outcome.     

COVID-19 in dialysis units: A comprehensive review

The coronavirus disease 2019 (COVID-19) pandemic has been challenging for healthcare professionals worldwide. One of the populations affected by the pandemic are patients on renal replacement therapy, as kidney disease is an independent risk factor for severe COVID-19 and maintenance dialysis (a life-sustaining therapy) cannot be interrupted in the vast majority of cases. Over the past months, several authors and medical societies have published recommendations and guidelines on the management of this population. This article is a comprehensive review regarding the measures to prevent, contain and deal with a COVID-19 pandemic in the dialysis setting. We recapitulate the epidemiology and pathophysiology of COVID-19 in kidney dysfunction and present the main recommendations concerning the screening of healthcare personnel, dialysis patients and visitors as well as measures to improve the safety of the dialysis facilities’ environments. In addition to preventive measures, this article briefly describes actions directed towards management of an outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a dialysis facility, the management of complications in dialysis patients with COVID-19 and overall data regarding the management of children with kidney disease.