Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19.

There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.

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Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

OBJECTIVE: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. DATA SOURCES: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). STUDY SELECTION: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. DATA EXTRACTION: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. DATA SYNTHESIS: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications.

Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis.

In December 2019, the first cases of infection with a novel human microorganism, now officially defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were reported in Wuhan, China.1 On April 1, 2020, as we write, more than 800,000 cases of the novel coronavirus disease 2019 (COVID-19) have been reported worldwide, with more than 40,000 COVID-19–related deaths.2 Studies have reported disturbed coagulation in COVID-19 patients, including prolonged prothrombin time,3,4 decreased antithrombin,3 and increased fibrin degradation products such as D-dimer.3–7 This implies increased risk of thromboembolic disease, as well as bleeding and, for the most serious cases, development of disseminated intravascular coagulation (DIC),which, inonecase series,was reported inasmanyas71% of nonsurvivors of COVID-19.5 This commentary explores the potential role of platelets in COVID-19, including the link between thrombocytopenia and disease severity and the considerations for the potential role for platelet function and/or platelet activation testing in COVID-19 patients.

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Platelets in Coronavirus Disease 2019.

SARS-CoV-2 (COVID-19), viral load and clinical outcomes; lessons learned one year into the pandemic: A systematic review

SARS-CoV-2 (COVID-19), viral load and clinical outcomes;lessons learned one year into the pandemic: A systematic review

INTRODUCTION: Coronavirus disease-2019 (COVID-19) outbreak has spread around the world. However, the dynamic course of critically ill COVID-19 has not been described thoroughly. PATIENTS AND METHODS: We retrospectively analyzed 195 critically ill COVID-19 patients in Hubei province, China, between January 5, 2020 and April 3, 2020. Epidemiologic data, clinical features, treatments, and outcomes were collected and analyzed. RESULTS: Most critically ill patients were older with higher Acute Physiology and Chronic Health Evaluation II scores. After critical illness onset, a total of 181 (92.8%) patients received ventilation support, of which 84 (43.1%) received noninvasive and 97 (49.7%) received invasive mechanic ventilation (IMV). Among the 97 patients with IMV, 28 (28.9%) received prone ventilation, 57 (58.8%) received neuromuscular blocked therapy, and 22 (11.3%) received tracheostomy due to prolonged ventilator use. Early hypoxemia, subsequent hypercapnia, pulmonary hypertension, and finally pulmonary fibrosis were notable in the clinical course of acute respiratory distress syndrome (ARDS). Eighty-nine (45.6%) patients presented with shock. Acute kidney injury (29.7%) and secondary infection (28.2%) were also notable. The overall mortality of critically ill patients at day 28 was 42.1%. Intensive care unit (ICU) mortality was around 33%, as 16 patients died prior to ICU admission. A low PaO2/FiO2 ratio was an independent risk factor for death. High viral load was observed in most non-survivors. CONCLUSION: ARDS and shock were notable in the critical illness of COVID-19. Ventilation support and hemodynamic support were the cornerstones for critical care. High viral load was associated with death of critically ill COVID-19 patients.

Clinical Course of 195 Critically Ill COVID-19 Patients: A Retrospective Multicenter Study.


 Background In December 2019, Coronavirus Disease 2019 (COVID-19) outbreak was reported from Wuhan, China. Information on the clinical progress and prognosis of COVID-19 was not thoroughly described. We described the clinical courses and prognosis in COVID-19 patients. Methods Retrospective case series of COVID-19 patients from Zhongnan Hospital of Wuhan University in Wuhan, and Xi-shui Hospital, Hubei Province, China, up to February 10, 2020. Epidemiological, demographic and clinical data were collected. Clinical progress of survivors and non-survivors were compared. Risk factors for death were analyzed. Results A total of 107 discharged patients with COVID-19 were enrolled. The clinical progression of COVID-19 presented as a tri-phasic pattern. Week 1 after illness onset was characterized by fever, cough, dyspnea, lymphopenia and radiological multilobar pulmonary infiltrates. In severe cases, thrombocytopenia, acute kidney injury, acute myocardial injury or adult respiratory distress syndrome were observed. During week 2, in mild cases, fever, cough and systemic symptoms began to resolve and platelet count rose to normal range, but lymphopenia persisted. In severe cases, leukocytosis, neutrophilia and deteriorating multi-organ dysfunction were dominant. By week 3, mild cases had clinically resolved except for lymphopenia. However, severe cases showed persistent lymphopenia, severe acute respiratory dyspnea syndrome , refractory shock, anuric acute kidney injury, coagulopathy, thrombocytopenia and death. Older age and male sex were independent risk factors for poor outcome of the illness. Conclusions A period of 7–13 days after illness onset is the critical stage in COVID-19 progression. Age and male gender were independent risk factors for death of COVID-19.

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Clinical course and outcome of novel coronavirus COVID-19 infection in 107 patients discharged from the Wuhan hospital

Background There is a need to assess the long-term outcomes of survivors from critically ill COVID-19. Methods Ninety-two critically ill survivors of COVID-19 from four hospitals in Hubei province, China participated in this prospective cohort study. Multiple characteristics including lung function (lung volumes, diffusing capacity of lung for carbon monoxide, chest CT scores and walking capacity), immune status (SARS-COV-2 neutralizing antibody and all sub-types of IgG against SARS-CoV-2, immune cells in response to ex-vivo antigen peptide stimuli, lymphocyte count and its sub-type), liver, coagulation and kidney function, quality of life, cognitive function and mental status were assessed after 3, 6 and 12-months of follow-up. Results Among the 92 enrolled survivors, 72 (78%) patients required mechanical ventilation. At 12 months, the predicted percentage diffusing capacity of lung for carbon monoxide was 82% (IQR, 76%-97%) with a residual volume of 77% (64%-88%). Other lung function parameters and the 6-minute walk test improved gradually over time and were almost back to normal by 12 months. The titers of IgG and neutralizing antibody to COVID-19 remained high at 12 months compared to non-COVID-19 infected controls, although IgG titers decreased significantly from 33.96 AU/ml (IQR, 23.79-74.30) to 14.98 AU/ml (5.75-24.30) (P Conclusions Critically ill COVID-19 survivors show some persistent long-term impairments in lung function, however the majority of these tests are normal by 12 months. These patients still have detectable levels of neutralising antibodies against SARS-COV-2 and all types of IgG at 12 months, but the levels had declined over this time period.

Xingguo Zhang

Papers

Clinical Course of 195 Critically Ill COVID-19 Patients: A Retrospective Multicenter Study.

Clinical course and outcome of novel coronavirus COVID-19 infection in 107 patients discharged from the Wuhan hospital

Prognosis and antibody profiles in survivors of critical illness from COVID-19: a prospective, multi-centre, cohort study