Risk Factors Associated with Mortality among Mechanically Ventilated Patients with Coronavirus Disease 2019 Pneumonia: A Multicenter Cohort Study in Japan (J-RECOVER Study).

Objective Mortality analyses of patients with coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation in Japan are limited. The present study therefore determined the risk factors for mortality in patients with COVID-19 requiring invasive mechanical ventilation. Methods This retrospective cohort study used the dataset from the Japanese multicenter research of COVID-19 by assembling real-word data (J-RECOVER) study that was conducted between January 1 and September 31, 2020. Independent risk factors associated with in-hospital mortality were evaluated using a multivariate logistic regression analysis. Kaplan-Meier estimates of the survival were calculated for different age groups. A subgroup analysis was performed to assess differences in survival rates according to additional risk factors, including an older age and chronic pulmonary disease. Patients A total of 561 patients were eligible. The median age was 67 (interquartile range: 56-75) years old, 442 (78.8%) were men, and 151 (26.9%) died in the hospital. Results Age, chronic pulmonary disease, and renal disease were significantly associated with in-hospital mortality. Compared with patients 18-54 years old, the adjusted odds ratios of patients 55-64, 65-74, and 75-94 years old were 3.34 (95% CI, 1.34-8.31), 7.07 (95% CI, 3.05-16.40), and 18.43 (95% CI, 7.94-42.78), respectively. Conclusion Age, chronic pulmonary disease, and renal disease were independently associated with mortality in patients with COVID-19 requiring invasive mechanical ventilation, and age was the most decisive indicator of a poor prognosis. Our results may aid in formulating treatment strategies and allocating healthcare resources.

PaO2 / FiO2 ratio responsiveness to prone positioning in intubated patients with severe COVID-19: a retrospective observational study.

Aim: Prone positioning of coronavirus disease 2019 (COVID-19) patients could improve oxygenation. However, clinical data on prone positioning of intubated COVID-19 patients are limited. We investigated trends of PaO2 / FiO2 ratio values in patients during prone positioning to identify a predictive factor for early detection of patients requiring advanced therapeutic intervention such as extracorporeal membrane oxygenation (ECMO). Methods: This retrospective, observational cohort study was undertaken between April 2020 and May 2021 in a tertiary referral hospital for COVID-19 in Osaka, Japan. We included intubated adult COVID-19 patients treated with prone positioning within the first 72 h of admission to the intensive care unit and followed them until hospital discharge or death. Primary outcomes were in-hospital mortality and escalation of care to ECMO. We used unsupervised k-means clustering modeling to categorize COVID-19 patients by PaO2 / FiO2 ratio responsiveness to prone positioning. Results: The final study cohort comprised 54 of 155 consecutive severe COVID-19 patients. Three clusters were generated according to trends in PaO2 / FiO2 ratios during prone positioning (cluster A, n = 16; cluster B, n = 24; cluster C, n = 14). Baseline characteristics of all clusters were almost similar. Cluster A (no increase in PaO2 / FiO2 ratio during prone positioning) had a significantly higher proportion of patients placed on ECMO or who died (6/16, 37.5%). Numbers of patients with ECMO and with in-hospital death were significantly different between the three groups (p = 0.017). Conclusion: In Japanese patients intubated due to COVID-19, clinicians should consider earlier escalation of treatment, such as facility transfer or ECMO, if the PaO2 / FiO2 ratio does not increase during initial prone positioning.

Relationship between institutional intensive care volume prior to the COVID-19 pandemic and in-hospital death in ventilated patients with severe COVID-19.

We aimed to evaluate the association between ICU patient volume before the COVID-19 pandemic and the outcomes of ventilated COVID-19 patients. We analyzed ventilated patients with COVID-19 aged > 17 years and enrolled in the J-RECOVER study, a retrospective multicenter observational study conducted in Japan between January and September 2020. Based on the number of patients admitted to the ICU between January and December 2019, the top third institutions were defined as high-volume centers, the middle third ones as middle-volume centers, and the bottom third ones as low-volume centers. The primary outcome measure was in-hospital mortality. Multivariate logistic regression analysis for in-hospital mortality and ICU patient volume was performed after adjusting for multiple propensity scores. Among 461 patients, 158, 158, and 145 patients were admitted to low-volume (20 institutions), middle-volume (14 institutions), and high-volume (13 institutions) centers, respectively. Admission to middle- and high-volume centers was not significantly associated with in-hospital death compared with admission to low-volume centers (adjusted odds ratio, 1.11 [95% confidence interval (CI): 0.55-2.25] and adjusted odds ratio, 0.81 [95% CI: 0.31-1.94], respectively). In conclusion, institutional intensive care patient volume prior to the COVID-19 pandemic was not significantly associated with in-hospital death in ventilated COVID-19 patients.

Residual persistence of cytotoxicity lymphocytes and regulatory T cells in patients with severe coronavirus disease 2019 over a 1-year recovery process.

Aim: To clarify the immune cellular changes in critically ill patients recovering from coronavirus disease 2019 (COVID-19). Methods: The immune response of peripheral blood mononuclear cells from patients with severe COVID-19 in different stages of recovery (3, 6, and 12 months from hospitalization) was evaluated by single-cell mass cytometry. Immunological changes in patients were compared with those in age-matched healthy donors. Results: Three patients with severe COVID-19 were compared with four healthy donors. In the patients, there was an increase in the cell density of CD4- and CD8-positive T lymphocytes, and B cells, over the course of the recovery period. CD4- and CD8-positive T lymphocytes expressing T-bet and granzyme B (Gzm B) in patients were abundant during all recovery periods. The level of regulatory T cells remained high throughout the year. The levels of natural killer (NK) cells in patients were higher than in those in the healthy donors, and the frequency of CD16+ NK cells expressing Gzm B increased throughout the year. Conclusion: Patients recovering from severe COVID-19 showed persistence of cytotoxic lymphocytes, NK cells, and regulatory T cells throughout the posthospitalization year of recovery.

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.

Prevalence and Risk Factor Analysis of Post-Intensive Care Syndrome in Patients with COVID-19 Requiring Mechanical Ventilation: A Multicenter Prospective Observational Study.

INTRODUCTION: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. METHODS: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. RESULTS: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. CONCLUSION: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Early intubation and decreased in-hospital mortality in patients with coronavirus disease 2019.

BACKGROUND: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. METHODS: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. RESULTS: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27-0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19-0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission. CONCLUSIONS: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation. Trial Registration None.

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.

Special Issue on "Disseminated Intravascular Coagulation: Current Understanding and Future Perspectives".

Disseminated intravascular coagulation (DIC) is characterized by the systemic activation of blood coagulation that generates and deposits fibrin that causes microvascular thrombi to develop in various organs, which contributes to multiple organ dysfunction [...].

Relation between nutrition therapy in the acute phase and outcomes of ventilated patients with COVID-19 infection: a multicenter prospective observational study.

BACKGROUND: Optimal nutrition therapy has not yet been established for the acute phase of severe coronavirus disease 2019 (COVID-19) infection. OBJECTIVES: We aimed to examine the effects of nutrition delivery in the acute phase on mortality and the long-term outcomes of post-intensive care syndrome (PICS). METHODS: A multicenter prospective study was conducted on adult patients with COVID-19 infection requiring mechanical ventilation during an intensive care unit (ICU) stay. Daily total energy (kcal/kg) and protein (g/kg) deliveries in the first week of the ICU stay were calculated. The questionnaire for PICS evaluation was mailed within a median of 6 mo after hospital discharge. The primary outcome was in-hospital mortality, and secondary outcomes were the PICS components of physical impairment, cognitive dysfunction, and mental illness. RESULTS: Among 414 eligible patients, 297 who received mechanical ventilation for 7 d or longer were examined. PICS was evaluated in 175 patients among them. High protein delivery on days 4-7 correlated with a low in-hospital mortality rate. In contrast, high protein delivery on days 1-3 correlated with physical impairment. A multivariate logistic regression analysis adjusted for age, sex, BMI, and severity revealed that average energy and protein deliveries on days 4-7 correlated with decreased in-hospital mortality (OR: 0.94; 95% CI: 0.89, 0.99; P = 0.013 and OR: 0.40; 95% CI: 0.17, 0.93; P = 0.031, respectively). Nutrition delivery did not correlate with PICS outcomes after adjustments. In the multivariate regression using a restricted cubic spline model, in-hospital mortality monotonically decreased with increases in average nutrition delivery on days 4-7. CONCLUSIONS: In patents with COVID-19 on mechanical ventilation for ≥7 d, nutrition delivery in the late period of the acute phase was monotonically associated with a decrease in in-hospital mortality. Adequate protein delivery is needed on days 4-7.This trial was registered at https://www.umin.ac.jp as UMIN000041276.

Prolonged enhancement of cytotoxic T lymphocytes in the post-recovery state of severe COVID-19.

We evaluated the peripheral blood immune responses of lymphocytes in severe Coronavirus disease 2019 (COVID-19) patients in different stages of recovery using single-cell mass cytometry. The patients with prolonged hospitalization did not show recovery of B lymphocyte counts and CD4-positive T lymphocyte counts but did show abundant CD8-positive T lymphocytes. CD4 and CD8 T cells expressing high levels of T-bet and Granzyme B were more abundant in post-recovery patients. This study showed that cytotoxic Th1 and CD8 T cells are recruited to the peripheral blood long after recovery from COVID-19.

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.

Efficacy and safety of nintedanib for pulmonary fibrosis in severe pneumonia induced by COVID-19: An interventional study.

OBJECTIVES: One of the most significant features of poor prognosis in COVID-19 is pulmonary fibrosis. Nintedanib is a new antifibrotic agent that interferes with processes of pulmonary fibrosis. This study aimed to investigate the efficacy and safety of nintedanib in COVID-19. METHODS: This was an interventional study in which adult patients with COVID-19 requiring mechanical ventilation were consecutively enrolled. The primary endpoint was 28-day mortality after the initiation of mechanical ventilation. The secondary endpoints were length of mechanical ventilation, volume of lung injury, and the incidence of gastrointestinal adverse events and acute liver failure. RESULTS: Thirty patients with COVID-19 underwent nintedanib therapy. We included 30 patients not receiving nintedanib as the historical control group. There were no significant differences in 28-day mortality between the groups (23.3% vs 20%, P = 0.834). Lengths of mechanical ventilation were significantly shorter in the nintedanib group (P = 0.046). Computed tomography volumetry showed that the percentages of high-attenuation areas were significantly lower in the nintedanib group at liberation from mechanical ventilation (38.7% vs 25.7%, P = 0.027). There were no significant differences in the adverse events. CONCLUSIONS: The administration of nintedanib may offer potential benefits for minimizing lung injury in 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.

Hematological Phenotype of COVID-19-Induced Coagulopathy: Far from Typical Sepsis-Induced Coagulopathy.

BACKGROUND: Blood coagulation disorders commonly occur with severe coronavirus disease 2019 (COVID-19). However, there is only limited evidence on differentiating the pattern of the hemostatic parameters from those of typical sepsis-induced coagulopathy (SIC). METHODS: To elucidate the specific pattern of coagulopathy induced by COVID-19 pneumonia, this retrospective, observational study targeted consecutive adult patients with COVID-19-induced acute respiratory distress syndrome (ARDS) and compared hemostatic biomarkers with non-COVID-19-induced septic ARDS. Multilevel mixed-effects regression analysis was performed and Kaplan-Meier failure curves were constructed. RESULTS: We enrolled 24 patients with COVID-19-induced ARDS and 200 patients with non-COVID-19-induced ARDS. Platelet count, antithrombin activity, and prothrombin time in the COVID-19 group were almost within normal range and time series alterations of these markers were significantly milder than the non-COVID-19 group (p = 0.052, 0.037, and 0.005, respectively). However, fibrin/fibrinogen degradation product and D-dimer were significantly higher in the COVID-19 group (p = 0.001, 0.002, respectively). COVID-19 patients had moderately high levels of thrombin-antithrombin complex and plasmin-alpha2-plasmin inhibitor complex but normal plasminogen activator inhibitor-1 level. CONCLUSIONS: The hematological phenotype of COVID-19-induced coagulopathy is quite different from that in typical SIC characterized by systemic hypercoagulation and suppressed fibrinolysis. Instead, local thrombus formation might be promoted in severe COVID-19.