Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducte...

/pdf/remdesivir-for-the-treatment-of-covid-19-final-report-19ndo8n619.pdf

Remdesivir for the Treatment of Covid-19 - Final Report.

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

/pdf/pathophysiology-transmission-diagnosis-and-treatment-of-2o6dok06xg.pdf

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail. In this Review, Shi and colleagues summarize the exceptional amount of research that has characterized acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) since this virus has swept around the globe. They discuss what we know so far about the emergence and virology of SARS-CoV-2 and the pathogenesis and treatment of COVID-19.

/pdf/characteristics-of-sars-cov-2-and-covid-19-eeqnaghpho.pdf

Characteristics of SARS-CoV-2 and COVID-19

Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involvin...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2001282?articleTools=true

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

To date, only minimal attention has been paid to assessment of immunity state in patients with post-COVID syndrome. Influence of the SARS-CoV-2 virus on various systems in the body, including the immune system, may contribute to the development of disorders causing different diseases. At the same time, the patients suffering from the COVID-19 complications, including hospitalization and isolation from their family members, experience severe psychological and social stress. In almost every fourth case, these factors lead to development of the s.c. post-COVID syndrome. The aim of the present study was to evaluate the numbers of NK cells, levels of cortisol and characteristics of immune system disorders in the patients who underwent SARS-CoV-2 infection. 
78 patients were examined 6 months after suffering COVID-19. We have assessed 25 parameters of the blood system (general blood test), 50 parameters of immune system, i.e., counts of T lymphocytes, B lymphocytes and their functional markers, NK, T-NK cell subsets, phagocytic components of immune system, as well as factors of humoral immunity, including total and specific immunoglobulins and complement fragments. 
Our studies showed a sharp, three-fold decrease in the number of natural killers in more than 1/3 of the examined individuals. This decrease is accompanied by higher relative contents of T lymphocytes and T helper cells. The latter finding may be associated with a compensatory increase in T lymphocytes and dysregulation of the T cell link of immune system, thus requiring a more detailed study and, most likely, evaluation of the cytokine profile in such patients. Moreover, in some post-COVID patients, high levels of cortisol still persist, thus suggesting maintenance of chronic stress in these patients. Some changes in platelet counts are also important (increased levels of blood platelets and thrombocytocrit), which may promote later disorders of blood clotting system and development of thrombosis.

/pdf/impairment-of-natural-killer-populations-in-the-patients-3eua91r1.pdf

Impairment of natural killer populations in the patients recovered from COVID-19

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of a diverse array of autoantibodies and the dysfunctional activation of the complement system. The specific association between the complement component C3a (C3a) protein and antibodies specific for double-stranded DNA (anti-dsDNA), however, has not been studied in detail to date. This study was thus designed to more fully explore circulating C3a levels in SLE patients. In total, 13 SLE patients were enrolled in this study after having been diagnosed in accordance with the SLICC classification criteria, with 7 and 6 patients respectively exhibiting positivity for anti-dsDNA and anti-Sm autoantibodies. Serum complement component C1q (C1q) and C3a levels in samples from these patients were detected via Western blotting, while other serological, biochemical, and clinical parkers associated with disease activity were detected using standard laboratory techniques. The levels of serum C3a in anti-dsDNA+ patients were significantly elevated as compared to those in anti-Sm+ patients (P < 0.01), and a positive correlation between serum C3a levels and SLE Disease Activity Index scores was detected (P < 0.05, r = 0.6134). C3a levels are correlated with the degree of SLE disease activity and other clinically relevant readouts in SLE patients. C3a levels may also enable the differentiation between inactive and active SLE, while also offering value as an advantageous biomarker for thrombophilia monitoring in SLE patients. 

/pdf/brief-report-on-the-relation-between-complement-c3a-and-anti-mbhnc57d.pdf

Brief report on the relation between complement C3a and anti dsDNA antibody in systemic lupus erythematosus

Assessment of the state of the cells of the immune system in post-COVID patients currently remains little studied. The consequences of the influence of the virus itself, as well as drugs received by patients in the treatment of infection, on various body systems, including the immune system, contribute to disorders leading to post-COVID syndrome. The aim of the study was to study the level of cytotoxic T cells and features of immune system disorders in patients who had undergone SARS-CoV-2 infection. Materials and methods of research: 78 patients were examined 6 months after suffering COVID-19; studied 25 parameters of the blood system (general blood test), 50 parameters of the immune system, including T-lymphocytes, B-lymphocytes and their functional markers, NK, TNK cells, phagocytic part of the immune system, and humoral factors, including general and specific immunoglobulins and complement fragments. Results and discussion: when analyzing the results obtained, it was found that 44.8% of the examined individuals had a 1.7-fold decrease in the number of cytotoxic T-cells. This phenomenon was accompanied by a decrease in the level of T-lymphocytes in general, TNK-lymphocytes, some growth of T-helpers, an increase in the ratio of CD4/CD8 cells, levels of B-lymphocytes, due to B-total and B1, B2-lymphocytes of non-memory cells related to plasma cells (or otherwise the most actively producing immunoglobulins B cells). All these data indicate that in such patients, an immune response is formed to a greater extent according to the TH2 type (increased production of antibodies), and not according to the TH1 type (formation of cellular immune responses). In addition, in such patients, a violation of the TH1 response is observed and the likelihood of developing pathological processes associated with an inadequate response to viral antigens (including re-infection with the SARS-CoV-2 virus, exacerbations of chronic infections) increases. It is possible that the disorders we have identified in such patients may contribute to the occurrence or exacerbation of allergic and autoimmune processes in case of impaired functioning (hyperactivation) of the B-cell link of the immune system. All this requires further more detailed research, both in terms of further clinical observations of these patients, and the development of methods for correcting the identified disorders of the immune system.

Shanshan Luo

Papers

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

Impairment of natural killer populations in the patients recovered from COVID-19

Brief report on the relation between complement C3a and anti dsDNA antibody in systemic lupus erythematosus

Аsessment of relationships of cytotoxic Т-lymphocyte disturbances with other compartments of the immune system in post-COVID patients