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.

BackgroundAnti-glycyl-tRNA synthetase (anti-EJ) antibody is occasionally positive in patients with interstitial lung disease (ILD). We aimed to define the clinical, radiological and pathological features of patients with anti-EJ antibody-positive ILD (EJ-ILD).MethodsWe retrospectively analyzed the medical records of 12 consecutive patients with EJ-ILD who underwent surgical lung biopsy.ResultsThe median follow-up time was 74 months (range, 17–115 months). The median age was 62 years (range, 47–75 years). Seven of 12 patients were female. Eight patients presented with acute onset. Six patients eventually developed polymyositis/dermatomyositis. On high-resolution computed tomography, consolidation and volume loss were predominantly observed in the middle or lower lung zone. Nine patients presented pathologically nonspecific interstitial pneumonia with organizing pneumonia, alveolar epithelial injury and prominent interstitial cellular infiltrations whereas the other three patients were diagnosed with unclassifiable interstitial pneumonia. Although all patients but one improved with the initial immunosuppressive therapy, five patients relapsed. When ILD relapsed, four of the five patients were treated with corticosteroid monotherapy. Four of the six patients without relapse have been continuously treated with combination therapy of corticosteroid and immunosuppressant.ConclusionsPatients with EJ-ILD often had acute onset of ILD with lower lung-predominant shadows and pathologically nonspecific interstitial pneumonia or unclassifiable interstitial pneumonia with acute inflammatory findings. Although the disease responded well to the initial treatment, relapse was frequent. Because of the diversity of the clinical courses, combination therapy of corticosteroid and immunosuppressant should be on the list of options to prevent relapse of EJ-ILD.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread worldwide and coronavirus disease 2019 remains a top health concern. Several SARS-CoV-2 vaccines have been produced and are playing great roles in the prevention of infection and worsening to a severe state, and in improving mortality [1]. However, some concerns about adverse effects related to SARS-CoV-2 vaccination have been raised. Recently, various adverse effects have been reported, but there is little data on adverse effects on the lungs [2].

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.

BackgroundA better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME.MethodsWhole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score (tumor proliferation), I-score (antitumor immunity) and S-score (immunosuppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy.ResultsThe representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in Thi (G5-8) than Tlo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in Thi and was dampened in Thi/Ilo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. Thi/Ilo/Shi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group Tlo/Ihi/Slo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma.ConclusionThe TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.

Aim Diabetes mellitus (DM) is a known risk factor for severe coronavirus disease 2019 (COVID‐19), but the clinical impact of undiagnosed diabetes and prediabetes in COVID‐19 are unclear particularly in Japan. We clarify the difference in clinical characteristics, including age, sex, body mass index and co‐morbidities, laboratory findings and critical outcomes, in a large Japanese COVID‐19 cohort without diabetes, with prediabetes, undiagnosed diabetes and diagnosed diabetes, and to identify associated risk factors. Materials and Methods This multicentre, retrospective cohort study used the Japan COVID‐19 Task Force database, which included data on 2430 hospitalized COVID‐19 patients from over 70 hospitals from February 2020 to October 2021. The prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes were estimated based on HbA1c levels or a clinical diabetes history. Critical outcomes were defined as the use of high‐flow oxygen, invasive positive‐pressure ventilation or extracorporeal membrane oxygenation, or death during hospitalization. Results Prediabetes, undiagnosed diabetes and diagnosed diabetes were observed in 40.9%, 10.0% and 23.0%, respectively. Similar to diagnosed diabetes, prediabetes and undiagnosed diabetes were risk factors for critical COVID‐19 outcomes (adjusted odds ratio [aOR] [95% CI]: 2.13 [1.31‐3.48] and 4.00 [2.19‐7.28], respectively). HbA1c was associated with COVID‐19 severity in prediabetes patients (aOR [95% CI]: 11.2 [3.49‐36.3]), but not other groups. Conclusions We documented the clinical characteristics and outcomes of Japanese COVID‐19 patients according to HbA1c levels or diabetes co‐morbidity. As well as undiagnosed and diagnosed diabetes, physicians should be aware of prediabetes related to COVID‐19 severity.