Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis.

BACKGROUND: Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model. METHOD: We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study. RESULTS: We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I2 values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I2 value 55%). CONCLUSIONS: Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).

Urine Output and Development of Acute Kidney Injury in Sepsis: A Multicenter Observational Study.

BACKGROUND: Acute kidney injury (AKI) is common in sepsis and a urine output <0.5 mL/kg/h associated with increased mortality is incorporated into AKI diagnosis. We aimed to identify the urine-output threshold associated with increased AKI incidence and hypothesized that a higher urine output than a specified threshold, which differs from the predominantly used 0.5 mL/kg/h threshold, would be associated with an increased AKI incidence. METHODS: This was a post-hoc analysis of a nationwide prospective observational study. This study included adult patients newly diagnosed with sepsis and requiring intensive care. Urine output on the day of sepsis diagnosis was categorized as low, moderate, or high (<0.5, 0.5-1.0, and >1.0 mL/kg/h, respectively), and we compared AKI incidence, renal replacement therapy (RRT) requirement, and 28-day survival by category. Estimated probabilities for these outcomes were also compared after adjusting for patient background and hourly fluid administration. RESULTS: Among 172 eligible patients, AKI occurred in 46.3%, 48.3%, and 53.1% of those with high, moderate, and low urine output, respectively. The probability of AKI was lower in patients with high urine output than in those with low output (43.6% vs 56.5%; P = .028), whereas RRT requirement was lower in patients with high and moderate urine output (11.7% and 12.8% vs 49.1%; P < .001). Patients with low urine output demonstrated significantly lower survival (87.7% vs 82.8% and 67.8%; P = .018). Cubic spline curves for AKI, RRT, and survival prediction indicated different urine-output thresholds, including <1.2 to 1.3 mL/kg/h for AKI and <0.6 to 0.8 mL/kg/h for RRT and mortality risk. CONCLUSIONS: Urine output >1.0 mL/kg/h on the day of sepsis diagnosis was associated with lower AKI incidence. The urine-output threshold was higher for developing AKI than for RRT requirement or mortality.

Relationship between critical care nutrition and post-intensive care syndrome in surviving ventilated patients with COVID-19: a multicenter prospective observational study.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12-0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16-1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

Understanding the pathophysiology of acute critical illness: translational lessons from zebrafish models.

The models used to investigate the pathophysiological mechanisms of acute critical illness are not limited to mammalian species. The zebrafish (Danio rerio) is a popular model organism for studying diseases due to its transparency and rapid development. The genes and signaling pathways involved in acute critical illness appear highly conserved among zebrafish and humans. Forward genetics such as random mutagenesis by a chemical mutagen or reverse genetics methods represented by CRISPR/Cas9 allowed researchers to reveal multiple novel aspects of pathological processes in areas including infection, immunity, and regeneration. As a model of sepsis, transgenic zebrafish allowed the visualization of lipopolysaccharide (LPS)-induced vascular leakage in vivo and the demonstration of changes in the expression of cellular junction proteins. Other transgenic zebrafish visualizing the extravascular migration of neutrophils and macrophages have demonstrated a decrease in neutrophil numbers and an increased expression of an inflammatory gene, which replicates a phenomenon observed in humans in clinically encountered sepsis. The regenerative potential and the visibility of zebrafish organs also enabled clarification of important mechanisms in wound healing, angiogenesis, and neurogenesis. After spinal cord injury (SCI), a marker gene expressed in glial bridging was discovered. Furthermore, localized epithelial-to-mesenchymal transition (EMT) and molecular mechanisms leading to spinal cord repair were revealed. These translational studies using zebrafish show the potential of the model system for the treatment of acute critical illnesses such as sepsis, organ failure, and trauma.

Efficacy of unfractionated heparin in patients with moderate sepsis-induced coagulopathy: An observational study.

INTRODUCTION: The 2021 Surviving Sepsis Campaign guidelines recommend low-molecular-weight heparin for the prevention of venous thromboembolism in sepsis. However, observational studies suggest that anticoagulants as a whole may benefit severely ill sepsis patients with coagulopathy, but the optimal targets of unfractionated heparin remain unclear. This study investigated which sepsis patients could most benefit from unfractionated heparin. MATERIALS AND METHODS: In this retrospective observational study, we identified adult sepsis patients requiring urgent hospitalization from 2006 to 2019 using a large-scale Japanese medical database. Patients were divided into two groups: those receiving unfractionated heparin within 72 h of admission and those who did not. We compared in-hospital mortality, major bleeding complications, and thromboembolic events between these groups using a multivariate logistic regression model adjusted for patient and treatment variables. Additionally, we assessed the association between heparin administration and in-hospital mortality across various subgroups. RESULTS: Among 30,342 sepsis patients, 2520 received early heparin administration, and 27,822 did not. Multivariate logistic regression revealed a significant association between heparin and reduced in-hospital mortality (adjusted OR: 0.735, 95 % CI: 0.596-0.903) but no significant association with major bleeding and thromboembolic risk (adjusted OR: 1.137, 1.243; 95 % CI: 0.926-1.391, 0.853-1.788, respectively). Subgroup analyses suggested significant survival benefits associated with heparin only in the sepsis patients with moderate coagulopathy and sepsis-induced coagulopathy scores of 3 or 4 (adjusted OR: 0.452, 0.625; 95 % CI: 0.265-0.751, 0.410-0.940, respectively). CONCLUSIONS: Early heparin administration upon admission is associated with lower in-hospital mortality, especially in moderate sepsis-induced coagulopathy, and no significant increase in complications.

A systematic review and meta-analysis of recombinant human soluble thrombomodulin for the treatment of DIC associated with hematological malignancies.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies. METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS). RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients). CONCLUSION: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

Current Clinical Practice of Laboratory Testing of the Hemostasis and Coagulation System in Patients with Sepsis: A Nationwide Observational Study in Japan.

Introduction: The clinical benefit of hemostasis molecular indicators such as thrombin-antithrombin complex (TAT), soluble fibrin (SF), and prothrombin fragment 1 + 2 (F1+2) for the diagnosis of disseminated intravascular coagulation (DIC) is reported. Recently, novel DIC diagnostic criteria that adopt them were proposed in Japan. Despite the theoretical understanding of their function, the practical use of these markers remains unclear. The present study aimed to provide a descriptive overview of current clinical practice regarding the measurement of hemostasis markers in sepsis management in Japan. Methods: This retrospective observational analysis used the Japanese Diagnosis Procedure Combination inpatient database containing data from more than 1500 acute-care hospitals in Japan. We identified adult patients hospitalized for sepsis between April 2018 and March 2021. Descriptive statistics for measuring several hemostasis laboratory markers were summarized using patient disease characteristics, hospital characteristic, and geographical location. Results: This study included 153,474 adult sepsis patients. Crude in-hospital mortality was 30.0%. Frequency of measurement of fibrinogen, fibrin degradation products (FDP), and D-dimer in sepsis patients on admission was 43.2%, 36.1%, and 46.4%, respectively. Novel and specific hemostasis molecular markers such as TAT, SF, and F1+2 were seldom measured (1.9%, 1.7%, and 0.02%, respectively). Hemostasis molecular markers were more frequently measured with progression of thrombocytopenia. Measurement of these clinically favorite hemostasis markers was influenced not only by disease characteristics but also hospital characteristic or geographical location. Conclusions: Hemostasis molecular markers such as TAT, SF, and F1+2 were rarely measured in clinical settings. Although adopted by several DIC scoring systems, neither fibrinogen, FDP, nor D-dimer was routinely measured.

Determining prognostic indicator for anticoagulant therapy in sepsis-induced disseminated intravascular coagulation.

BACKGROUND: There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment. METHODS: The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan's nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan-Meier analysis. RESULTS: In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22-0.45, P < 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36-0.50, P < 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score-Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71. CONCLUSION: CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.

Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for trauma and its performance in Japan over the past 18 years: a nationwide descriptive study.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been used to control massive hemorrhages. Although there is no consensus on the efficacy of REBOA, it remains an option as a bridging therapy in non-trauma centers where trauma surgeons are not available. To better understand the current landscape of REBOA application, we examined changes in its usage, target population, and treatment outcomes in Japan, where immediate hemostasis procedures sometimes cannot be performed. METHODS: This retrospective observational study used the Japan Trauma Data Bank data. All cases in which REBOA was performed between January 2004 and December 2021 were included. The primary outcome was the in-hospital mortality rate. We analyzed mortality trends over time according to the number of cases, number of centers, severity of injury, and overall and subgroup mortality associated with REBOA usage. We performed a logistic analysis of mortality trends over time, adjusting for probability of survival based on the trauma and injury severity score. RESULTS: Overall, 2557 patients were treated with REBOA and were deemed eligible for inclusion. The median age of the participants was 55 years, and male patients constituted 65.3% of the study population. Blunt trauma accounted for approximately 93.0% of the cases. The number of cases and facilities that used REBOA increased until 2019. While the injury severity score and revised trauma score did not change throughout the observation period, the hospital mortality rate decreased from 91.3 to 50.9%. The REBOA group without severe head or spine injuries showed greater improvement in mortality than the all-patient group using REBOA and all-trauma patient group. The greatest improvement in mortality was observed in patients with systolic blood pressure ≥ 80 mmHg. The adjusted odds ratios for hospital mortality steadily declined, even after adjusting for the probability of survival. CONCLUSIONS: While there was no significant change in patient severity, mortality of patients treated with REBOA decreased over time. Further research is required to determine the reasons for these improvements in trauma care.

A meta-analysis and trial sequential analysis of randomised controlled trials comparing nonoperative and operative management of chest trauma with multiple rib fractures.

BACKGROUND: Operative treatment of traumatic rib fractures for better outcomes remains under debate. Surgical stabilization of rib fractures has dramatically increased in the last decade. This study aimed to perform a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the effectiveness and safety of operative treatment compared to conservative treatment in adult patients with traumatic multiple rib fractures. METHODS: A systematic literature review was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines. We searched MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials and used the Cochrane Risk-of-Bias 2 tool to evaluate methodological quality. Relative risks with 95% confidence interval (CI) were calculated for outcomes: all-cause mortality, pneumonia incidence, and number of mechanical ventilation days. Overall certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, with trial sequential analysis performed to establish implications for further research. RESULTS: From 719 records, we included nine RCTs, which recruited 862 patients. Patients were assigned to the operative group (received surgical stabilization of chest wall injury, n = 423) or control group (n = 439). All-cause mortality was not significantly different (RR = 0.53; 95% CI 0.21 to 1.38, P = 0.35, I2 = 11%) between the two groups. However, in the operative group, duration of mechanical ventilation (mean difference -4.62; 95% CI -7.64 to -1.60, P < 0.00001, I2 = 94%) and length of intensive care unit stay (mean difference -3.05; 95% CI -5.87 to -0.22; P < 0.00001, I2 = 96%) were significantly shorter, and pneumonia incidence (RR = 0.57; 95% CI 0.35 to 0.92; P = 0.02, I2 = 57%) was significantly lower. Trial sequential analysis for mortality indicated insufficient sample size for a definitive judgment. GRADE showed this meta-analysis to have very low to low confidence. CONCLUSION: Meta-analysis of large-scale trials showed that surgical stabilization of multiple rib fractures shortened the duration of mechanical ventilation and reduced the incidence of pneumonia but lacked clear evidence for improvement of mortality compared to conservative treatment. Trial sequential analysis suggested the need for more cases, and GRADE highlighted low certainty, emphasizing the necessity for further targeted RCTs, especially in mechanically ventilated patients. SYSTEMATIC REVIEW REGISTRATION: UMIN Clinical Trials Registry UMIN000049365.

Efficacy of antithrombin administration for patients with sepsis: A systematic review, meta-analysis, and meta-regression.

Aims: There have been inconsistent reports regarding the effect of antithrombin on sepsis; furthermore, there are limited reports on how dosage affects therapeutic efficacy. Thus, we aimed to perform a systematic review and meta-analysis of the use of antithrombin for sepsis and a meta-regression analysis of antithrombin dosage. Methods: We included randomized controlled trials (RCTs) and observational studies of adult patients with sepsis who received antithrombin. Outcomes included all-cause mortality and serious bleeding complications. Statistical analyses and data synthesis were performed using a random-effects model; further, meta-regression and funnel plots were used to explore heterogeneity and biases. Results: Seven RCTs and six observational studies were included. Most patients in the RCTs and observational studies had severe sepsis and septic-disseminated intravascular coagulation (DIC), respectively. A meta-analysis using RCTs showed no significant differences in mortality between the antithrombin and control groups. However, the meta-analysis of observational studies indicated a trend of decreasing mortality rates with antithrombin administration (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.68-0.92; p = 0.002). Bleeding complications were significantly higher in the antithrombin group than in the control group in both study types (OR, 1.90; 95% CI, 1.52-2.37; p < 0.01). The meta-regression analysis showed no correlation between antithrombin dosage and mortality. Conclusion: A meta-analysis of RCTs confirmed no survival benefit of antithrombin, whereas that of observational studies, which mostly focused on septic DIC, showed a significant beneficial effect on improving outcomes. Indications of antithrombin should be considered based on its beneficial and harmful effects.

Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

External Validation of Updated Prediction Models for Neurological Outcomes at 90 Days in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: Few prediction models for individuals with early-stage out-of-hospital cardiac arrest (OHCA) have undergone external validation. This study aimed to externally validate updated prediction models for OHCA outcomes using a large nationwide dataset. METHODS AND RESULTS: We performed a secondary analysis of the JAAM-OHCA (Comprehensive Registry of In-Hospital Intensive Care for Out-of-Hospital Cardiac Arrest Survival and the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest) registry. Previously developed prediction models for patients with cardiac arrest who achieved the return of spontaneous circulation were updated. External validation was conducted using data from 56 institutions from the JAAM-OHCA registry. The primary outcome was a dichotomized 90-day cerebral performance category score. Two models were updated using the derivation set (n=3337). Model 1 included patient demographics, prehospital information, and the initial rhythm upon hospital admission; Model 2 included information obtained in the hospital immediately after the return of spontaneous circulation. In the validation set (n=4250), Models 1 and 2 exhibited a C-statistic of 0.945 (95% CI, 0.935-0.955) and 0.958 (95% CI, 0.951-0.960), respectively. Both models were well-calibrated to the observed outcomes. The decision curve analysis showed that Model 2 demonstrated higher net benefits at all risk thresholds than Model 1. A web-based calculator was developed to estimate the probability of poor outcomes (https://pcas-prediction.shinyapps.io/90d_lasso/). CONCLUSIONS: The updated models offer valuable information to medical professionals in the prediction of long-term neurological outcomes for patients with OHCA, potentially playing a vital role in clinical decision-making processes.

Hyperoxia for sepsis and development of acute lung injury with increased mortality.

BACKGROUND: Supraphysiological oxygen administration causes unfavourable clinical outcomes in various diseases. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with severe infection. METHODS: A post-hoc analysis of a nationwide multicentre prospective observational study on sepsis (SPICE Study) was conducted, including adult patients admitted to the intensive care unit with available arterial partial pressure of oxygen (PaO2) at the treatment initiation for severe infection. Hyperoxia was defined as a PaO2 level of ≥300 mm Hg and in-hospital mortality was compared between patients with and without hyperoxia. RESULTS: Of the 563 patients eligible for the study, 49 had hyperoxia at treatment initiation for severe infection. The in-hospital all-cause mortality rates of patients with and without hyperoxia were 14 (29.2%) and 90 (17.6%), respectively. Inverse probability weighting analyses with propensity scores revealed the association between hyperoxia and increased in-hospital mortality rate (28.8% vs 18.8%; adjusted OR 1.75 (1.03 to 2.97); p=0.038), adjusting for patient demographics, comorbidities, site of infection, severity of infection, haemodynamic and respiratory status, laboratory data and location of patient at infection development. Acute lung injury developed more frequently in patients with hyperoxia on the following days after infection treatment, whereas sepsis-related mortality was comparable regardless of hyperoxia exposure. CONCLUSION: Hyperoxia with PaO2 ≥300 mm Hg at treatment initiation of severe infection was associated with an increased in-hospital mortality rate in patients requiring intensive care. The amount of oxygen to administer to patients with severe infection should be carefully determined. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry (UMIN000027452).

Japanese Multicenter Research of COVID-19 by Assembling Real-world Data: A Study Protocol.

BACKGROUND: Data on the evaluation of the clinical course of coronavirus disease 2019 (COVID-19) and the efficacy of treatments after hospitalization in Japan are limited. OBJECTIVE: This study aimed to construct a database of confirmed COVID-19 cases in Japan and promptly address unresolved research issues. METHODS: This multicenter observational study included patients who had a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and were discharged from each participating institution between January 1 and September 31, 2020. We called for participating facilities and research proposals until the end of September 2020. The research steering committee members provided advice to co-investigators on refining their research proposals and analyses. After developing the research proposal, we collected clinical information, facility information, and laboratory data from each participating institution. Clinical information was also obtained from the Diagnosis Procedure Combination (DPC) data using a dedicated software called DPC hash application. ANALYSIS: We planned to conduct an analysis based on the research proposal. Overall, 66 institutions from Japan announced their participation, and 102 research proposals were selected for the analyses. Research areas from the proposals included epidemiology, pathophysiology, therapeutic agents, ventilator settings, cost-benefit analyses, and prognosis prediction for COVID-19. CONTRIBUTION AND SIGNIFICANCE TO THE FIELD: We have established an efficient data collection system and clinical research team for COVID-19 infection studies. The results of this study may be utilized in future response strategies for COVID-19.