The first case of acute necrotizing encephalopathy associated with coronavirus disease in a child in Asia: a case report and literature review (preprint)

Background Acute necrotic encephalopathy（ANE） in children is a very rare complication of Severe Acute Respiratory Syndrome Coronavirus 2（SARS-CoV-2） infection, which has rarely been reported worldwide. Case presentation A 45-day-old girl was admitted to our hospital with fever and listlessness. A nose swab tested positive for novel coronavirus nucleic acid, and her cerebrospinal fluid was positive for SARS-CoV-2. An early head magnetic resonance imaging (MRI) scan indicated multiple abnormal signals in her bilateral cerebral hemispheres, and encephalitis was diagnosed. Twenty-three days after hospitalization, bilateral cerebral atrophy-like changes were observed by MRI, with multiple softening lesions in the bilateral cerebral hemispheres, accompanied by convulsions. She was admitted to hospital for mechanically-assisted ventilation, and her condition improved after treatment of her symptoms, including anti-epileptic medication, anti-infection drugs, glucocorticoids, and immunoglobulins. Conclusions Acute necrotic encephalopathy associated with novel coronavirus infection in children should be detected and treated as early as possible. Satisfactory short-term efficacy can be obtained, but long-term neurological sequelae often linger.

Transferrin receptor is another receptor for SARS-CoV-2 entry (preprint)

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

Transferrin receptor is another receptor for SARS-CoV-2 entry (preprint)

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ∼16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

Computed Tomography Features of COVID-19 in Children: A Systematic Review and Meta-analysis (preprint)

Objectives: To systematically analyze the chest CT imaging features of children with COVID-19 and provide references for clinical practice. Methods: We searched PubMed, Web of Science, and Embase; data published by Johns Hopkins University; and Chinese databases CNKI, Wanfang, and Chongqing Weipu. Reports on chest CT imaging features of children with COVID-19 from January 1, 2020, to August 10, 2020, were analyzed retrospectively and a meta-analysis carried out using Stata12.0 software. Results: Thirty-seven articles (1747 children) were included in this study. The overall rate of abnormal lung CT findings was 63.2% (95% confidence interval [CI]: 55.8-70.6%), with a rate of 61.0% (95% CI: 50.8-71.2%) in China and 67.8% (95% CI: 57.1-78.4%) in the rest of the world in the subgroup analysis. The incidence of ground-glass opacities was 39.5% (95% CI: 30.7-48.3%), multiple lung lobe lesions 65.1% (95% CI: 55.1-67.9%), and bilateral lung lesions 61.5% (95% CI: 58.8-72.2%). Other imaging features included nodules (25.7%), patchy shadows (36.8%), halo sign (24.8%), consolidation (24.1%), air bronchogram signs (11.2%), cord-like shadows (9.7%), crazy-paving pattern (6.1%), and pleural effusion (9.1%). Two articles reported three cases of white lung, another reported two cases of pneumothorax, and another one case of bullae. CONCLUSION: The lung CT results of children with COVID-19 are usually normal or slightly atypica, with a low sensitivity and specificity compared with that in adults. The lung lesions of COVID-19 pediatric patients mostly involve both lungs or multiple lobes, and the common manifestations are patchy shadows, ground-glass opacities, consolidation, partial air bronchogram signs, nodules, and halo signs; white lung, pleural effusion, and paving stone signs are rare. CLINICAL IMPACT: Therefore, chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool.

Predication of Inflection Point and Outbreak Size of COVID-19 in New Epicentres (preprint)

The coronavirus disease 2019 (COVID-19) had caused more that 8 million infections as of middle June 2020. Recently, Brazil has become a new epicentre of COVID-19, while India and African region are potential epicentres. This study aims to predict the inflection point and outbreak size of these new/potential epicentres at the early phase of the epidemics by borrowing information from more `mature' curves from other countries. We modeled the cumulative cases to the well-known sigmoid growth curves to describe the epidemic trends under the mixed-effect models and using the four-parameter logistic model after power transformations. African region is predicted to have the largest total outbreak size of 3.9 million cases (2.2 to 6 million), and the inflection will come around September 13, 2020. Brazil and India are predicted to have a similar final outbreak size of around 2.5 million cases (1.1 to 4.3 million), with the inflection points arriving June 23 and July 26, respectively. We conclude in Brazil, India, and African the epidemics of COVI19 have not yet passed the inflection points; these regions potentially can take over USA in terms of outbreak size

Gastrointestinal symptoms and fecal nucleic acid testing of children with 2019 coronavirus disease: a systematic review and meta-analysis (preprint)

In order to understand the clinical manifestations and incidence of gastrointestinal symptoms of coronavirus disease (COVID-19) in children and discuss the importance of fecal nucleic acid testing.We retrospectively analyzed studies on gastrointestinal symptoms and fecal nucleic acid detection in pediatric COVID-19 patients from January 1, 2020 to August 10, 2020, including prospective clinical studies and case reports. The results of fecal nucleic acid detection were analyzed systematically. Stata12.0 software was used for meta-analysis.The results showed that the most common gastrointestinal symptoms in children with COVID-19 were vomiting and diarrhea, with a total incidence of 17.7% (95% Cl: 13.9%-21.5%). However, the prevalence of gastrointestinal symptoms in other countries (21.1%, 95% CI: 16.5%-25.7%) was higher compared to China (12.9%, 95% CI: 8%-17.7%). In Wuhan, the pooled prevalence was much higher (41.3%, 95 % CI: 3.2%-79.4%) compared to areas outside Wuhan in China (7.1%, 95 % CI: 4.0%-10.3%).The positive rate of fecal nucleic acid testing in COVID-19 children was relatively high at 85.8% (91/106). Additionally, 71.2% (52/73) were still positive for fecal nucleic acid after respiratory tract specimens turned negative. One and two weeks after the respiratory tract specimens turned nucleic acid-negative, 45.2% (33/73) and 34.2% (25/73) patients, respectively, remained fecal nucleic acid-positive. The longest interval between the respiratory tract specimens turning negative and fecal specimens turning negative exceeded 70 days.Conclusions and Relevance:Gastrointestinal symptoms in pediatric COVID-19 are relatively common. Attention should be paid to the detection of fecal nucleic acids in children. Fecal nucleic acid-negative status should be considered as one of the desegregation standards.

Spike protein up-regulates inflammatory axis of both thromboinflammation and leukotriene in severe COVID-19 (preprint)

Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that fibrinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent inflammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identified as a fibrinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the first endogenous inhibitor of LTA4H, a pro-inflammatory enzyme catalyzing final and rating limited step in biosynthesis of leukotriene-B4 that is an extremely inflammatory mediator and a target to design superior anti-inflammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and fibrinogen expression in vivo. Collectively, these findings identify the imbalance between inflammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior anti-inflammatory function because it specifically targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H’s aminopeptidase activity.