Single-cell RNA-seq analysis identifies distinct myeloid cells in a case with encephalitis temporally associated with COVID-19 vaccination

Recently accumulating evidence has highlighted the rare occurrence of COVID-19 vaccination-induced inflammation in the central nervous system. However, the precise information on immune dysregulation related to the COVID-19 vaccination-associated autoimmunity remains elusive. Here we report a case of encephalitis temporally associated with COVID-19 vaccination, where single-cell RNA sequencing (scRNA-seq) analysis was applied to elucidate the distinct immune signature in the peripheral immune system. Peripheral blood mononuclear cells (PBMCs) were analyzed using scRNA-seq to clarify the cellular components of the patients in the acute and remission phases of the disease. The data obtained were compared to those acquired from a healthy cohort. The scRNA-seq analysis identified a distinct myeloid cell population in PBMCs during the acute phase of encephalitis. This specific myeloid population was detected neither in the remission phase of the disease nor in the healthy cohort. Our findings illustrate induction of a unique myeloid subset in encephalitis temporally associated with COVID-19 vaccination. Further research into the dysregulated immune signature of COVID-19 vaccination-associated autoimmunity including the cerebrospinal fluid (CSF) cells of central nervous system (CNS) is warranted to clarify the pathogenic role of the myeloid subset observed in our study.

Single-cell RNA-seq analysis identifies distinct myeloid cells in a case with encephalitis temporally associated with COVID-19 vaccination.

Recently accumulating evidence has highlighted the rare occurrence of COVID-19 vaccination-induced inflammation in the central nervous system. However, the precise information on immune dysregulation related to the COVID-19 vaccination-associated autoimmunity remains elusive. Here we report a case of encephalitis temporally associated with COVID-19 vaccination, where single-cell RNA sequencing (scRNA-seq) analysis was applied to elucidate the distinct immune signature in the peripheral immune system. Peripheral blood mononuclear cells (PBMCs) were analyzed using scRNA-seq to clarify the cellular components of the patients in the acute and remission phases of the disease. The data obtained were compared to those acquired from a healthy cohort. The scRNA-seq analysis identified a distinct myeloid cell population in PBMCs during the acute phase of encephalitis. This specific myeloid population was detected neither in the remission phase of the disease nor in the healthy cohort. Our findings illustrate induction of a unique myeloid subset in encephalitis temporally associated with COVID-19 vaccination. Further research into the dysregulated immune signature of COVID-19 vaccination-associated autoimmunity including the cerebrospinal fluid (CSF) cells of central nervous system (CNS) is warranted to clarify the pathogenic role of the myeloid subset observed in our study.

Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients.

BACKGROUND: COVID-19 is now a common disease, but its pathogenesis remains unknown. Blood circulating proteins reflect host defenses against COVID-19. We investigated whether evaluation of longitudinal blood proteomics for COVID-19 and merging with clinical information would allow elucidation of its pathogenesis and develop a useful clinical phenotype. METHODS: To achieve the first goal (determining key proteins), we derived plasma proteins related to disease severity by using a first discovery cohort. We then assessed the association of the derived proteins with clinical outcome in a second discovery cohort. Finally, the candidates were validated by enzyme-linked immunosorbent assay in a validation cohort to determine key proteins. For the second goal (understanding the associations of the clinical phenotypes with 28-day mortality and clinical outcome), we assessed the associations between clinical phenotypes derived by latent cluster analysis with the key proteins and 28-day mortality and clinical outcome. RESULTS: We identified four key proteins (WFDC2, GDF15, CHI3L1, and KRT19) involved in critical pathogenesis from the three different cohorts. These key proteins were related to the function of cell adhesion and not immune response. Considering the multicollinearity, three clinical phenotypes based on WFDC2, CHI3L1, and KRT19 were identified that were associated with mortality and clinical outcome. CONCLUSION: The use of these easily measured key proteins offered new insight into the pathogenesis of COVID-19 and could be useful in a potential clinical application.

Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19.

Introduction: Resistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis. Materials and Methods: First, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis. Results: In the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules. Conclusion: Resistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Transcriptional differences between coronavirus disease 2019 and bacterial sepsis.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has led to major public health crises worldwide. Several studies have reported the comprehensive mRNA expression analysis of immune-related genes in patients with COVID-19, using blood samples, to understand its pathogenesis; however, the characteristics of RNA expression in COVID-19 and bacterial sepsis have not been compared. The current study aimed to address this gap. METHODS: RNA-sequencing and bioinformatics analyses were used to compare the transcriptome expression of whole blood samples from patients with COVID-19 and patients with sepsis who were admitted to the intensive care unit of Osaka University Graduate School of Medicine. RESULTS: The COVID-19 and sepsis cohorts showed upregulation of mitochondrial- and neutrophil-related transcripts, respectively. Compared with that in the control cohort, neutrophil-related transcripts were upregulated in both the COVID-19 and sepsis cohorts. In contrast, mitochondrial-related transcripts were upregulated in the COVID-19 cohort and downregulated in the sepsis cohort, compared to those in the control cohort. Moreover, transcript levels of the pro-apoptotic genes BAK1, CYCS, BBC3, CASP7, and CASP8 were upregulated in the COVID-19 cohort, whereas those of anti-apoptotic genes, such as BCL2L11 and BCL2L1, were upregulated in the sepsis cohort. CONCLUSIONS: This study clarified the differential expression of transcripts related to neutrophils and mitochondria in sepsis and COVID-19 conditions. Mitochondrial-related transcripts were downregulated in sepsis than in COVID-19 conditions, and our results indicated suboptimal intrinsic apoptotic features in sepsis samples compared with that in COVID-19 samples. This study is expected to contribute to the development of specific treatments for COVID-19.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (July 2022).

Background: Coronavirus disease (COVID-19), an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese Rapid/Living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. Methods: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of recommendations. The first edition of this guideline was released on September 9, 2020, and this is the revised edition (version 5.0; released on July 15, 2022). Clinical questions (CQs) were set for the following 10 drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), casirivimab/imdevimab (CQ9-1), sotrovimab (CQ9-2), molnupiravir (CQ10), and nirmatrelvir/ritonavir (CQ11). Recommendations: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with mild COVID-19 who do not require oxygen, and patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (both GRADE 2B). Corticosteroids are recommended for moderate and severe COVID-19 (GRADE 1B, 1A). However, their administration is not recommended for mild COVID-19 (GRADE 1B). Tocilizumab is suggested for moderate and severe COVID-19 (GRADE 2B, 2C). Anticoagulant administration is recommended for moderate and severe COVID-19 (Good Practice Statement). Baricitinib is suggested for moderate and severe COVID-19 (both GRADE 2C). Casirivimab/imdevimab and sotrovimab are recommended for mild COVID-19 (both GRADE 2C). Molnupiravir and nirmatrelvir/ritonavir are recommended for mild COVID-19 (both GRADE 2C). SARS-CoV-2 mutant strains emerge occasionally, and each time, the treatment policy at clinics is forced to change drastically. We ask health-care professionals in the field to refer to the recommendations in these guidelines and use these to keep up to date with COVID-19 epidemiological information.

A case of massive refractory diarrhea in a patient with COVID‐19

Background The new coronavirus disease (COVID‐19) causes gastrointestinal symptoms as well as respiratory symptoms. Case Presentation A 60‐year‐old man was transferred with respiratory difficulty. He was diagnosed as having COVID‐19 and was intubated and placed on mechanical ventilation. He suffered from diarrhea from day 12 and produced a maximum of approximately 6,384 mL/day of watery diarrhea on day 21. He required massive transfusion. Adsorbents and pectin‐containing oligomeric formulas were administered, which decreased the amount of diarrhea. Fecal metagenomic analysis showed the proportions of the genera Enterococcus and Staphylococcus were the most dominate at the genus level. The proportion of Bacteroidetes was <1%. Thereafter, his diarrhea decreased to several times, and he was transferred to another ward on day 104. Conclusion Therapy for intestinal complications as well as that for pneumonia might be important in treating COVID‐19. Fecal Gram stain shows that simplified bacteria cover the field instead of normal bacteria. (Upper left) Healthy control. (Upper right) Enterococcus. (Lower left) Fungi. (Lower right) Klebsiella pneumoniae.

A case of massive refractory diarrhea in a patient with COVID-19.

Background: The new coronavirus disease (COVID-19) causes gastrointestinal symptoms as well as respiratory symptoms. Case Presentation: A 60-year-old man was transferred with respiratory difficulty. He was diagnosed as having COVID-19 and was intubated and placed on mechanical ventilation. He suffered from diarrhea from day 12 and produced a maximum of approximately 6,384 mL/day of watery diarrhea on day 21. He required massive transfusion. Adsorbents and pectin-containing oligomeric formulas were administered, which decreased the amount of diarrhea. Fecal metagenomic analysis showed the proportions of the genera Enterococcus and Staphylococcus were the most dominate at the genus level. The proportion of Bacteroidetes was <1%. Thereafter, his diarrhea decreased to several times, and he was transferred to another ward on day 104. Conclusion: Therapy for intestinal complications as well as that for pneumonia might be important in treating COVID-19.

Survival following an out-of-hospital cardiac arrest in Japan in 2020 versus 2019 according to the cause.

Aim: The coronavirus disease (COVID-19) pandemic has led to an increase in out-of-hospital cardiac arrests (OHCAs) and mortality. However, there has been no reports in Japan using nationwide registry data. We compared survival among patients with OHCAs and detailed information on the cause during the COVID-19 pandemic (2020), and during the pre-pandemic period (2019). Methods: Using a Japanese population-based retrospective cohort study design, we analyzed registry data on 39,324 and 39,170 patients with OHCAs in 2019 and 2020, respectively. We compared patient outcomes in 2019 and 2020 using univariable and multivariable logistic regression analyses. Results: The proportion of OHCAs of cardiac origin increased significantly from 61.6% in 2019 to 62.7% in 2020 (P = 0.001). The use of bystander CPR (6.9% versus 5.7%, P < 0.001) and publicaccess automated external defibrillator pads (3.7% versus 3.0%, P < 0.001) decreased significantly from 2019 to 2020. The 1-month survival for OHCA of cardiac origin (12.1% versus 10.7%; adjusted odds ratio [OR] 0.93, 95% confidence interval [CI] 0.87-1.00), asphyxia (10.9% versus 8.8%; adjusted OR 0.80, 95% CI 0.70-0.92), and external causes (adjusted OR 0.66; 95% CI 0.46-0.96), also decreased significantly from 2019 to 2020. Conclusions: In Japan, the 1-month survival after OHCA of cardiac origin, or due to asphyxia or external causes, decreased significantly during the COVID-19 pandemic period.

Significance of interferon signaling based on mRNA-microRNA integration and plasma protein analyses in critically ill COVID-19 patients.

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-ß, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-ß plasma level was elevated in line with increased severity compared with HCs, as were IFN-ß downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-ß (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression.

Resistin Associated With Cytokines and Endothelial Cell Adhesion Molecules Is Related to Worse Outcome in COVID-19

Introduction Resistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis. Materials and Methods First, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis. Results In the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules. Conclusion Resistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

Hour-1 bundle adherence was associated with reduction of in-hospital mortality among patients with sepsis in Japan.

BACKGROUND: The updated Surviving Sepsis Campaign guidelines recommend a 1-hour window for completion of a sepsis care bundle; however, the effectiveness of the hour-1 bundle has not been fully evaluated. The present study aimed to evaluate the impact of hour-1 bundle completion on clinical outcomes in sepsis patients. METHODS: This was a multicenter, prospective, observational study conducted in 17 intensive care units in tertiary hospitals in Japan. We included all adult patients who were diagnosed as having sepsis by Sepsis-3 and admitted to intensive care units from July 2019 to August 2020. Impacts of hour-1 bundle adherence and delay of adherence on risk-adjusted in-hospital mortality were estimated by multivariable logistic regression analyses. RESULTS: The final study cohort included 178 patients with sepsis. Among them, 89 received bundle-adherent care. Completion rates of each component (measure lactate level, obtain blood cultures, administer broad-spectrum antibiotics, administer crystalloid, apply vasopressors) within 1 hour were 98.9%, 86.2%, 51.1%, 94.9%, and 69.1%, respectively. Completion rate of all components within 1 hour was 50%. In-hospital mortality was 18.0% in the patients with and 30.3% in the patients without bundle-adherent care (p = 0.054). The adjusted odds ratio of non-bundle-adherent versus bundle-adherent care for in-hospital mortality was 2.32 (95% CI 1.09-4.95) using propensity scoring. Non-adherence to obtaining blood cultures and administering broad-spectrum antibiotics within 1 hour was related to in-hospital mortality (2.65 [95% CI 1.25-5.62] and 4.81 [95% CI 1.38-16.72], respectively). The adjusted odds ratio for 1-hour delay in achieving hour-1 bundle components for in-hospital mortality was 1.28 (95% CI 1.04-1.57) by logistic regression analysis. CONCLUSION: Completion of the hour-1 bundle was associated with lower in-hospital mortality. Obtaining blood cultures and administering antibiotics within 1 hour may have been the components most contributing to decreased in-hospital mortality.

Cytokine Elevation in Severe COVID-19 From Longitudinal Proteomics Analysis: Comparison With Sepsis

Introduction Coronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called “cytokine storm” is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis. Materials and Methods In a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19. Results IL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382–0.789]). The GDF-15 level at ICU admission predicted late recovery. Conclusion GDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.

Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis.

INTRODUCTION: COVID-19 patients have been reported to have digestive symptoms with poor outcome. Ivermectin, an antiparasitic drug, has been used in COVID-19 patients. The objective of this study was to evaluate whether ivermectin has effects on gastrointestinal complications and ventilator-free days in ventilated patients with COVID-19. METHODS: COVID-19 patients who were mechanically ventilated in the ICU were included in this study. The ventilated patients who received ivermectin within 3 days after admission were assigned to the Ivermectin group, and the others were assigned to the Control group. Patients in the Ivermectin group received ivermectin 200 µg/kg via nasal tube. The incidence of gastrointestinal complications and ventilator-free days within 4 weeks from admission were evaluated as clinical outcomes using a propensity score with the inverse probability weighting method. RESULTS: We included 88 patients in this study, of whom 39 patients were classified into the Ivermectin group, and 49 patients were classified into the Control group. The hazard ratio for gastrointestinal complications in the Ivermectin group as compared with the Control group was 0.221 (95% confidence interval [CI], 0.057 to 0.855; p = 0.029) in a Cox proportional-hazard regression model. The odds ratio for ventilator-free days as compared with the Control group was 1.920 (95% CI, 1.076 to 3.425; p = 0.027) in a proportional odds logistic regression model. CONCLUSIONS: Ivermectin improved gastrointestinal complications and the number of ventilator-free days in severe COVID-19 patients undergoing mechanical ventilation. Prevention of gastrointestinal symptoms by SARS-Cov-2 might be associated with COVID-19 outcome.

Japanese rapid/living recommendations on drug management for COVID-19: updated guidelines (September 2021).

BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCG. METHODS: The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on September 9, 2020, and this document is the revised edition (version 4.0; released on September 9, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), corticosteroids (CQ4), tocilizumab (CQ5), anticoagulants (CQ7), baricitinib (CQ8), and casirivimab/imdevimab (CQ9). Two CQs (hydroxychloroquine [CQ3] and ciclesonide [CQ6]) were retrieved in this updated version. RECOMMENDATIONS: Favipiravir is not suggested for all patients with COVID-19 (GRADE 2C). Remdesivir is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Corticosteroids are recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 1B) and for patients with severe COVID-19 requiring mechanical ventilation/intensive care (GRADE 1A); however, their administration is not recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). Tocilizumab is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant administration is recommended for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization and patients with severe COVID-19 requiring mechanical ventilation/intensive care (good practice statement). Baricitinib is suggested for patients with moderate COVID-19 requiring supplemental oxygen/hospitalization (GRADE 2C). Casirivimab/imdevimab is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 1B). We hope that these updated clinical practice guidelines will help medical professionals involved in the care of patients with COVID-19.

Japanese rapid/living recommendations on drug management for COVID-19.

The coronavirus disease (COVID-19) has spread worldwide since early 2020, and there are still no signs of resolution. The Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock (J-SSCG) 2020 Special Committee created the Japanese rapid/living recommendations on drug management for COVID-19 using the experience of creating the J-SSCGs. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to determine the certainty of the evidence and strength of the recommendations. The first edition of this guideline was released on 9 September, 2020, and this document is the revised edition (version 3.1) (released 30 March, 2021). Clinical questions (CQs) were set for the following seven drugs: favipiravir (CQ1), remdesivir (CQ2), hydroxychloroquine (CQ3), corticosteroids (CQ4), tocilizumab (CQ5), ciclesonide (CQ6), and anticoagulants (CQ7). Favipiravir is recommended for patients with mild COVID-19 not requiring supplemental oxygen (GRADE 2C); remdesivir for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Hydroxychloroquine is not recommended for all COVID-19 patients (GRADE 1B). Corticosteroids are recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 1B) and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 1A); however, their use is not recommended for mild COVID-19 patients not requiring supplemental oxygen (GRADE 1B). Tocilizumab is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization (GRADE 2B). Anticoagulant therapy is recommended for moderate COVID-19 patients requiring supplemental oxygen/hospitalization and severe COVID-19 patients requiring ventilator management/intensive care (GRADE 2C). We hope that these clinical practice guidelines will aid medical professionals involved in the care of COVID-19 patients.

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.