SARS-CoV-2 N Protein Triggers Acute Lung Injury via Modulating Macrophage Activation and Infiltration in in vitro and in vivo.

Background: SARS-CoV-2-induced acute lung injury but its nucleocapsid (N) and/or Spike (S) protein involvements in the disease pathology remain elusive. Methods: In vitro, the cultured THP-1 macrophages were stimulated with alive SARS-CoV-2 virus at different loading dose, N protein or S protein with/without TICAM2-siRNA, TIRAP-siRNA or MyD88-siRNA. The TICAM2, TIRAP and MyD88 expression in the THP-1 cells after N protein stimulation were determined. In vivo, naïve mice or mice with depletion macrophages were injected with N protein or dead SARS-CoV-2. The macrophages in the lung were analyzed with flow cytometry, and lung sections were stained with H&E or immunohistochemistry. Culture supernatants and serum were harvested for cytokines measurements with cytometric bead array. Results: Alive SARS-CoV-2 virus or N protein but not S protein induced high cytokine releases from macrophages in a time or virus loading dependent manner. MyD88 and TIRAP but not TICAM2 were highly involved in macrophage activation triggered by N protein whilst both inhibited with siRNA decreased inflammatory responses. Moreover, N protein and dead SARS-CoV-2 caused systemic inflammation, macrophage accumulation and acute lung injury in mice. Macrophage depletion in mice decreased cytokines in response to N protein. Conclusion: SARS-CoV-2 and its N protein but not S protein induced acute lung injury and systemic inflammation, which was closely related to macrophage activation, infiltration and release cytokines.

The potential impact of COVID-19 disease caused multi-organ injuries on patients' surgical outcomes

Purpose To provide an expert commentary on the impact of prior COVID-19 infection on patient's surgical outcomes and postoperative recovery. To highlight the need for greater focus on peri-operative care of patients who have recovered from COVID-19. Methods A narrative review of the literature was conducted by searching Pubmed and EMBASE for relevant articles using keywords such as "COVID-19”, "Coronavirus”, "surgery” and "peri-operative infection”. Results Post-COVID-19 condition also known as long COVID has an estimated incidence of between 3.0 to 11.7%. COVID-19 has been shown to cause a series of short and long-term sequelae including cardiopulmonary complications, renal impairment, chronic fatigue and muscular deconditioning. Peri-operative infection with COVID-19 is associated with increased peri-operative mortality. Elective surgery patients who developed COVID-19 were 26 times more likely to die whilst in hospital compared to controls without COVID-19 infection, and for emergency surgery patients with COVID-19 infection were six times more likely to die. A large international prospective cohort study identified that patients who had surgery delayed over 7 weeks from the date of COVID-19 infection had no increased 30-day postoperative mortality, except those with ongoing symptoms. Conclusions COVID-19 infection and its complications have been shown to adversely affect surgical outcomes. Further research is required to better characterise long COVID and the long-term sequelae that develop, which should be used to guide comprehensive peri-operative assessment of patients. Graphical Abstract

Prognosis and antibody profiles in survivors of critical illness from COVID-19: a prospective multicentre cohort study.

BACKGROUND: There is a need to assess the long-term outcomes of survivors of critical illness from COVID-19. METHODS: Ninety-two survivors of critical illness from COVID-19 from four hospitals in Hubei Province, China participated in this prospective cohort study. Multiple characteristics, including lung function (lung volumes, diffusing capacity for carbon monoxide, chest computed tomography scores, and walking capacity); immune status (SARS-CoV-2-neutralising antibody and all subtypes of immunoglobulin (Ig) G against SARS-CoV-2, immune cells in response to ex vivo antigen peptide stimuli, and lymphocyte count and its subtypes); liver, coagulation, and kidney functions; quality of life; cognitive function; and mental status, were assessed after 3, 6, and 12 months of follow-up. RESULTS: Amongst 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% (inter-quartile range [IQR]: 76-97%) with a residual volume of 77 (64-88)%. Other lung function parameters and the 6-min walk test improved gradually over time and were almost back to normal by 12 months. The titres of IgG and neutralising antibody to COVID-19 remained high at 12 months compared with those of controls who were not infected with COVID-19, although IgG titres decreased significantly from 34.0 (IQR: 23.8-74.3) to 15.0 (5.8-24.3) AU ml-1 (P<0.001), whereas neutralising antibodies decreased from 29.99 (IQR: 19.43-53.93) AU ml-1 at 6 months to 19.75 (13.1-29.8) AU ml-1 (P<0.001) at 12 months. In general, liver, kidney, physical, and mental functions also improved over time. CONCLUSIONS: Survivors of critical illness from COVID-19 show some persistent long-term impairments in lung function. However, a majority of these tests were normal by 12 months. These patients still had 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. CLINICAL TRIAL REGISTRATION: None.

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

BACKGROUND: Coronavirus 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 SUMMARY: Two 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. CONCLUSION: VV-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.

Gastrointestinal Symptoms Associated With Unfavorable Prognosis of COVID-19 Patients: A Retrospective Study.

Background and Aim: The global pandemic of COVID-19 has posed an enormous threat to the economy and people's lives across various countries. Patients with COVID-19 most commonly present with respiratory symptoms. However, gastrointestinal (GI) symptoms can also occur. We aimed to study the relationship between GI symptoms and disease prognosis in patients with COVID-19. Methods: In a single-center and retrospective cohort study, the outcomes in COVID-19 patients with or without GI symptoms were compared. The propensity score is a conditional probability of having a particular exposure (COVID-19 patients with GI symptoms vs. without GI symptoms) given a set of baseline measured covariates. Survival was estimated using the Kaplan-Meier method, and any differences in survival were evaluated with a stratified log-rank-test. To explore the GI symptoms associated with ARDS, non-invasive ventilator treatment, tracheal intubation, tracheotomy, and CRRT, univariable and multivariable COX regression models were used. Results: Among 1,113 eligible patients, 359 patients with GI symptoms and 718 without GI symptoms had similar propensity scores and were included in the analyses. Patients with GI symptoms, as compared with those without GI symptoms, were associated with a similar risk of death, but with higher risks of ARDS, non-invasive mechanical ventilation in COVID-19 patients, respectively. Conclusions: The presence of GI symptoms was associated with a high risk of ARDS, non-invasive mechanical ventilation and tracheal intubation in patients with COVID-19 but not mortality.

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications.

The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.