Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 × 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Computed tomography (CT) embedded in the emergency room has gained importance in the early diagnostic phase of trauma care. In 2011, we implemented a new trauma workflow concept with a sliding CT scanner system with interventional radiology features (IVR-CT) that allows CT examination and emergency therapeutic intervention without relocating the patient, which we call the Hybrid emergency room (Hybrid ER). In the Hybrid ER, all life-saving procedures, CT examination, damage control surgery, and transcatheter arterial embolisation can be performed on the same table. Although the trauma workflow realized in the Hybrid ER may improve mortality in severe trauma, the Hybrid ER can potentially affect the efficacy of other in/outpatient diagnostic workflow because one room is occupied by one severely injured patient undergoing both emergency trauma care and CT scanning for long periods. In July 2017, we implemented a new trauma workflow concept with a dual-room sliding CT scanner system with interventional radiology features (dual-room IVR-CT) to increase patient throughput. When we perform emergency surgery or interventional radiology for a severely injured or ill patient in the Hybrid ER, the sliding CT scanner moves to the adjacent CT suite, and we can perform CT scanning of another in/outpatient. We believe that dual-room IVR-CT can contribute to the improvement of both the survival of severely injured or ill patients and patient throughput.

Background We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

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.

Background Serum Krebs von den Lungen 6 (KL-6), which reflects alveolar epithelial injury, was reported to be useful to predict the progression of pneumonitis induced by COVID-19 in the early phase. This study aimed to evaluate the peak value of serum KL-6 during hospitalization for COVID-19 to discover a more useful biomarker for predicting prognosis in COVID-19 patients. Methods In this retrospective, single-center, observational study, we analyzed the data of 147 hospitalized patients who required supplemental oxygen, high-flow oxygen therapy, or invasive mechanical ventilation for respiratory failure due to COVID-19 from March 2020 to February 2021. We extracted data on patient sex, age, comorbidities, treatment, and biomarkers including the initial and peak values of KL-6. Inclusion criteria were examination of the studied biomarkers at least once within 3 days of admission, then at least once a week, and at a minimum, at least twice during the entire hospitalization. Area under the receiver operating curve (AUC) was analyzed to determine the accuracy of several biomarkers including KL-6 and LDH for predicting poor prognosis defined as survivors requiring invasive mechanical ventilation for over 28 days or non-survivors of COVID-19. Univariable and multivariate logistic regression analyses were performed to investigate the prognostic value of the baseline characteristics and biomarkers. Results Among the 147 patients, 108 (73.5%) had a good prognosis and 39 (26.5%) had a poor prognosis. The AUC analysis indicated that peak KL-6 showed precise accuracy in the discrimination of patients with poor prognosis (AUC 0.89, p < 0.001). The best cut-off value for KL-6 concentration was 966 U/mL (sensitivity 81.6%, specificity84.3%). After adjustment, increasing peak values of KL-6 or LDH were associated with a high risk of poor prognosis, with an adjusted odds ratio of 1.35 for peak value of KL-6, per 100 U/mL increase (95% CI 1.17–1.57, p < 0.001) and 2.16 for peak value of LDH, per 100 U/L increase (95% CI 1.46–3.20, p < 0.001). Conclusions Peak values of KL-6 and LDH measured during hospitalization might help to identify COVID-19 patients with respiratory failure who are at higher risk for a poor prognosis.

Because prolonged viral replication of SARS-CoV-2 is increasingly being recognized among immunocompromised patients, subacute or chronic COVID-19 pneumonia can cause persistent lung damage and may lead to viral escape phenomena. Highly efficacious antiviral therapies in immunosuppressed hosts with COVID-19 are urgently needed. From February 2022, we introduced novel treatment combining antiviral therapies and neutralizing antibodies with frequent monitoring of spike-specific antibody and RT-PCR cycle threshold (Ct) values as indicators of viral load for immunocompromised patients with persistent COVID-19 infection. We applied this treatment to 10 immunosuppressed patients with COVID-19, and all completed treatment without relapse of infection. This may be a potentially successful treatment strategy that enables us to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation in immunocompromised patients with persistent COVID-19.

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.