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.

Systemic corticosteroid therapy is frequently used to treat coronavirus disease 2019 . However, its maximum duration without secondary infections remains unclear. We aimed to evaluate the utility of monitoring cytomegalovirus (CMV) infection in patients with COVID-19 and estimate the maximum duration of systemic corticosteroid therapy without secondary infections. We included 59 patients with severe COVID-19 without CMV infection on admission to the intensive care unit (ICU). All patients received systemic corticosteroid therapy under invasive mechanical ventilation, with examination for plasma CMV-deoxyribonucleic acid (DNA) levels during the ICU stay. We analyzed the correlations among patient characteristics, CMV infection, diseases, and patient mortality. CMV infections were newly identified in 15 (25.4%) patients; moreover, anti-CMV treatment was administered to six (10.2%) patients during the ICU stay. Four (6.8%) patients had secondary infection-related mortality. The cumulative incidences of CMV infection and anti-CMV treatment during the ICU stay were 26.8% (95% confidence interval [CI], 15.8%-39.0%) and 12.3% (95% CI, 4.8%-23.4%), respectively. Furthermore, the median duration of systemic corticosteroid therapy without CMV infection was 15 days (95% CI, 13-16 days). The presence of CMV infection was associated with mortality during the ICU stay (p = 0.003). Monitoring plasma CMV-DNA levels could facilitate the detection of secondary CMV infection due to prolonged systemic corticosteroid therapy. The duration of systemic corticosteroid therapy for COVID-19 should be limited.

mRNA vaccines that protect against coronavirus disease (COVID-19) are widely used in many countries due to their high efficacy and safety profiles. Recently, some severe adverse events, such as anaphylaxis and myocarditis, were reported in healthy individuals. The safety of mRNA COVID-19 vaccines has not been adequately studied in patients with interstitial lung disease. We report two cases of acute exacerbation of pre-existing interstitial pneumonia associated with mRNA COVID-19 vaccination. In both cases, lung disease was stable prior to the vaccination. Initial responses to steroid therapy were unfavorable, and intravenous cyclophosphamide was administered in both cases. Both patients were diagnosed with vaccine-related exacerbation of interstitial pneumonia, based on laboratory results, radiological features, and the observed clinical course, which lacked other causative events. We suggest that clinicians should note the possibility of acute exacerbation of pneumonia after mRNA COVID-19 vaccination, and carefully monitor patients with interstitial lung disease.

Background: Docetaxel (DOC) plus ramucirumab (RAM) has been recommended as an optimal therapy for previously treated patients with non-small cell lung cancer (NSCLC). In a clinical setting, there are few reports about DOC plus RAM, therefore its effect on factors such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic sites is still unknown. Methods:We recruited NSCLC patients who received DOC plus RAM in four medical facilities in Japan from June 2016 to March 2020. We retrospectively investigated the overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of DOC plus RAM and conducted univariate and multivariate analyses using PFS as a dependent factor. Patients were followed up until June 30, 2020.

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Undifferentiated pleomorphic sarcoma (UPS) is a new disease in the World Health Organization's classification of tumors of soft tissue and bone published in 2013. Primary mediastinal UPS is rare, especially with pleural effusion. Herein, we describe the pathological findings of pleural effusion followed by mediastinal UPS, which was initially misdiagnosed as epithelial malignant pleural mesothelioma (MPM). The cytopathological findings of the pleural effusion cell block often contribute to the diagnosis of various malignant tumors. However, these findings may lead to misdiagnosis of highly invasive mediastinal tumors such as UPS. A biopsy for primary mediastinal lesions should be performed because MPM rarely mimics mediastinal tumors with pleural effusion.

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.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.