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.

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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.

Background/Aim: The present study aimed to prospectively examine the usefulness of interferon-gamma (IFNγ) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx). Patients and Methods: IGR was measured using enzymelinked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8±3 (T2), 22±7 (T3), and 43±7 (T4) days after ICI-Tx. Results: Twenty-nine patients were divided into three groups based on IFN-γ levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-γ levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-γ levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes. Conclusion: IFN-γ levels could be a biomarker for ICI-Tx. After the programmed cell death-1 (PD-1) gene was cloned (1), an anti-PD-1 antibody (2) was rapidly developed as an immune checkpoint inhibitor (ICI). ICIs have since become very important anticancer agents (3-5). However, there is currently no other biomarker for non-small-cell lung cancer (NSCLC) than programmed deathligand 1 (PD-L1) (6). Recently, we have reported on NSCLC patients who developed pulmonary Mycobacterium tuberculosis (MTB) infection while receiving nivolumab (7). We have shown that the development of this paradoxical response closely resembles that of pseudo progression after ICI treatment. Furthermore, several studies (8-10) have indicated that the PD-1/PD-L1 axis and interferon-gamma (IFN-γ) are very important for cellular immunity to MTB. The interferon-gamma release assay (IGRA) is widely used as a diagnostic method for latent MTB infection (11). The QuantiFERON ®-TB Test is an IGRA that can measure IFN-γ released from T lymphocytes by whole bloodbased enzyme-linked immunosorbent assay (ELISA). We hypothesized that changes in the PD-1/PD-L1 axis by ICI treatment affect IFN-γ release by T lymphocytes. Thus, the aim of the present prospective observational study was to verify our hypothesis and to examine the usefulness of monitoring IFNγ as a biomarker in patients with NSCLC who are receiving ICI treatment. Patients and Methods Ethics. This study was approved by our institutional review board (approval no.: 884). All patients who participated in this study were enrolled after providing their written informed consent. Furthermore, this study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031881).