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.

Impact of COVID-19 pandemic on the care of severe burns in Japan: Repeated survey of specialized burn care facilities.

BACKGROUND: The spread of coronavirus disease 2019 (COVID-19), which began in 2020, has had a major impact on healthcare systems. The spread of COVID-19 has been reported to have affected the readiness to treat patients with burns worldwide. However, the existing reports have evaluated burn care status within a limited time period during the pandemic, and no report clarifies the change in the impact of infection status on burn care from the beginning of the pandemic to the present. METHODS: Japanese Society for Burn Injuries-accredited burn care facilities were surveyed using questionnaires on April 9-23, 2020; June 23-July 6, 2020; July 9-21, 2021; and January 21-31, 2022. Differences between groups were evaluated using Friedman's test or Bonferroni's multiple comparison test, as appropriate. RESULTS: From the 103 facilities included in the study, we received 85, 55, 56, and 58 responses in the first, second, third, and fourth surveys, respectively. We could continuously observe 34 facilities. The rate of acceptance of patients with severe burns improved significantly over time (P < 0.05). However, in the second and third surveys, there was an increase in the number of respondents who did not accept patients with burns irrespective of COVID-19 status. CONCLUSIONS: The number of facilities treating patients with burns who have COVID-19 is increasing; however, COVID-19 care may negatively impact routine burn care. It is necessary to continuously examine medical resource allocation through methods such as information sharing by academic societies.

Intensive Care Unit versus High-Dependency Care Unit for COVID-19 Patients with Invasive Mechanical Ventilation.

RATIONALE: High-dependency care units (HDUs), also termed "intermediate care units," "step-down units," or "respiratory high-dependency units" are areas where patient care levels and costs are between those of the intensive care unit (ICU) and the general ward. In general, patients requiring mechanical ventilation are treated in the ICU rather than in the HDU, except for the use of HDU beds as surge capacity beds during a massive strain; however, the HDU as well as ICU are used as the standard care units for mechanically ventilated patients with coronavirus disease 2019 (COVID-19) in Japan. OBJECTIVES: To assess the outcomes of COVID-19 patients with invasive mechanical ventilation treated in the HDU versus those treated in the ICU. METHODS: In this retrospective cohort study, we used a multicenter inpatient database in Japan to identify mechanically ventilated patients with COVID-19 in the ICU or HDU on the start day of invasive mechanical ventilation from February 10, 2020 to November 30, 2021. The primary outcome was in-hospital mortality within 30 days from the start of the first invasive mechanical ventilation. Propensity score matching was performed to compare the outcomes of patients treated in the ICU with those treated in the HDU. RESULTS: Of 1,985 eligible COVID-19 patients with invasive mechanical ventilation, 1,303 (66%) were treated in the ICU and 682 (34%) were treated in the HDU on the start day of invasive mechanical ventilation. After propensity score matching, patients treated in the ICU had significantly lower in-hospital mortality within 30 days than those treated in the HDU (18.3% vs. 24.2%; risk difference, -5.8%; 95% confidence interval, -10.9% to -0.8%). CONCLUSIONS: This multicenter observational study in Japan suggests that care for mechanically ventilated COVID-19 patients in the ICU may significantly reduce in-hospital mortality within 30 days compared with care in the HDU. Establishing a critical care system that would allow COVID-19 patients requiring ventilators to be treated in the ICU is desirable. Because this study was an observational study, our finding represents an association, not a causation. Further studies of different critical care systems are warranted to confirm our findings.

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.

Trends in survival during the pandemic in patients with critical COVID-19 receiving mechanical ventilation with or without ECMO: analysis of the Japanese national registry data.

BACKGROUND: The survival rate of patients with critical coronavirus disease-19 (COVID-19) over time is inconsistent in different settings. In Japan, a national database was organized to monitor and share the patient generation across the country in an immediate response to the COVID-19 pandemic. This study aimed to evaluate changes in survival over time and the prognostic factors in critical COVID-19 patients receiving mechanical ventilation with/without extracorporeal membrane oxygenation (ECMO) using the largest database in Japan. METHODS: This is a prospective observational cohort study of patients admitted to intensive care units in Japan with fatal COVID-19 pneumonia receiving mechanical ventilation and/or ECMO. We developed a prospective nationwide registry covering > 80% of intensive care units in Japan, and analyzed the association between patients' backgrounds, institutional ECMO experience, and timing of treatment initiation and prognosis between February 2020 and November 2021. Prognostic factors were evaluated by Kaplan-Meier analysis and Cox proportional hazards analysis. RESULTS: A total of 9418 patients were ventilated, of whom 1214 (13%) received ECMO. The overall survival rate for ventilated patients was 79%, 65% for those receiving ECMO. There have been five outbreaks in Japan to date. The survival rate of ventilated patients increased from 76% in the first outbreak to 84% in the fifth outbreak (p < 0.001). The survival rate of ECMO patients remained unchanged at 60-68% from the first to fifth outbreaks (p = 0.084). Age of ≥ 59 (hazard ratio [HR] 2.17; 95% confidence interval [CI] 1.76-2.68), ventilator days of ≥ 3 before starting ECMO (HR 1.91; 95% CI 1.57-2.32), and institutional ECMO experiences of ≥ 11 (HR 0.70; 95% CI 0.58-0.85) were independent prognostic factors for ECMO. CONCLUSIONS: During five COVID-19 outbreaks in Japan, the survival rate of ventilated patients tended to have gradually improved, and that of ECMO patients did not deteriorate. Older age, longer ventilator days before starting ECMO, and fewer institutional ECMO experiences may be independent prognostic factors for critical COVID-19 patients receiving ECMO.

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.

Antibody titers against SARS-CoV-2 decline, but do not disappear for several months.

BACKGROUND: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients. METHODS: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay. FINDINGS: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort. INTERPRETATION: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection. FUNDING: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.

Safety and harms of bronchoalveolar lavage for acute respiratory failure: A systematic review and meta-analysis.

BACKGROUND: This review aimed to investigate whether bronchoalveolar lavage (BAL) is safe in patients with severe acute respiratory failure (ARF). METHODS: We searched the MEDLINE, CENTRAL, and other databases up to June 2, 2021 for studies that examined BAL for severe ARF. We included all cohort studies and randomized or non-randomized trials, while we excluded case-control studies, case reports, and case series. We evaluated the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: We included 17 studies (1085 patients) in the meta-analysis. The integrated frequency of death was 0.000% (95% confidence interval [CI]: 0.000-0.045%, I2 = 0.0%). The pooled risk of severe complications of respiratory system, cardiovascular system, and major bleeding was 1.32% (95% CI: 0.000-4.41%, I2 = 84.8%), 0.040% (95% CI: 0.000-0.71%, I2 = 9.3%), and 0.000% (95% CI: 0.000-0.27%, I2 = 0.0%), respectively. In the subgroup analysis with mechanical ventilation during BAL, there were few severe complications of the respiratory system (3/717 patients in 13 studies) and almost no heterogeneity (I2 = 0.0%). CONCLUSIONS: Our study suggests that severe complications of BAL for severe ARF are probably rare, particularly in patients receiving mechanical ventilation. After considering the risks and benefits, it would be worthwhile to consider performing BAL in patients with severe ARF of unknown etiology to pursue its cause. TRIAL REGISTRATION: The protocol was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000040600).

Establishment of a Disaster Management-like System for COVID-19 Patients Requiring Veno-Venous Extracorporeal Membrane Oxygenation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic has increased the number of patients who require extracorporeal membrane oxygenation (ECMO). To manage the demand for ECMO, Japan ECMOnet for COVID-19 was developed as a "disaster management-like system", utilizing the Cross ICU Searchable Information System (CRISIS) database. This study investigated the effect of the establishment of this disaster management-like system in Japan. This was a nationwide retrospective observational study conducted from 1 February to 31 July in 2020. A total of 187 patients with COVID-19 who received ECMO were included. The median age was 60 years (interquartile range, 53-68), the median length of ventilatory support before ECMO was 3 days (1-5), and the median PaO2 to FiO2 ratio at ECMO initiation was 86 (71.3-101.5). During the study period, 165 telephone consultations were conducted, including general questions about ECMO. Among them, 44 concerned patients who were already on ECMO or who ultimately received ECMO. Further coordination, including transport and ECMO physician dispatch, was provided for 23 cases. Overall, 125/187 (66.8%) patients were successfully weaned from ECMO. This study demonstrated that Japan has achieved favorable survival outcomes for patients with COVID-19 who received ECMO with a disaster management-like system. Further research on the causes of these outcomes is needed.

Characterization of a new SARS-CoV-2 variant that emerged in Brazil.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a key role in viral infectivity. It is also the major antigen stimulating the host's protective immune response, specifically, the production of neutralizing antibodies. Recently, a new variant of SARS-CoV-2 possessing multiple mutations in the S protein, designated P.1, emerged in Brazil. Here, we characterized a P.1 variant isolated in Japan by using Syrian hamsters, a well-established small animal model for the study of SARS-CoV-2 disease (COVID-19). In hamsters, the variant showed replicative abilities and pathogenicity similar to those of early and contemporary strains (i.e., SARS-CoV-2 bearing aspartic acid [D] or glycine [G] at position 614 of the S protein). Sera and/or plasma from convalescent patients and BNT162b2 messenger RNA vaccinees showed comparable neutralization titers across the P.1 variant, S-614D, and S-614G strains. In contrast, the S-614D and S-614G strains were less well recognized than the P.1 variant by serum from a P.1-infected patient. Prior infection with S-614D or S-614G strains efficiently prevented the replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. In addition, passive transfer of neutralizing antibodies to hamsters infected with the P.1 variant or the S-614G strain led to reduced virus replication in the lower respiratory tract. However, the effect was less pronounced against the P.1 variant than the S-614G strain. These findings suggest that the P.1 variant may be somewhat antigenically different from the early and contemporary strains of SARS-CoV-2.

Longitudinal antibody repertoire in "mild" versus "severe" COVID-19 patients reveals immune markers associated with disease severity and resolution.

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.

Comparison of Rapid Antigen Tests for COVID-19.

Reverse transcription-quantitative PCR (RT-qPCR)-based tests are widely used to diagnose coronavirus disease 2019 (COVID-19). As a result that these tests cannot be done in local clinics where RT-qPCR testing capability is lacking, rapid antigen tests (RATs) for COVID-19 based on lateral flow immunoassays are used for rapid diagnosis. However, their sensitivity compared with each other and with RT-qPCR and infectious virus isolation has not been examined. Here, we compared the sensitivity among four RATs by using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates and several types of COVID-19 patient specimens and compared their sensitivity with that of RT-qPCR and infectious virus isolation. Although the RATs read the samples containing large amounts of virus as positive, even the most sensitive RAT read the samples containing small amounts of virus as negative. Moreover, all RATs tested failed to detect viral antigens in several specimens from which the virus was isolated. The current RATs will likely miss some COVID-19 patients who are shedding infectious SARS-CoV-2.