The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.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

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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

Effectiveness of Corticosteroid Therapy for Non-Severe COVID-19 in Patients Not Requiring Supplemental Oxygen Who Have Risk Factors for Severe Disease

journal articl

Pulmonary embolism and deep vein thrombosis in eosinophilic granulomatosis with polyangiitis successfully treated with rivaroxaban

A 41-year-old woman presented complaining of cough and purpura for one month. On her first visit, a blood test demonstrated peripheral blood eosinophilia, but chest radiography showed no abnormalities. However, 2 days after the first visit, she went to the emergency room because of fever and right-sided chest pain. Contrast-enhanced computed tomography of the chest showed pulmonary embolism and air space consolidation. Thrombosis was present in the popliteal vein. Bronchoscopy revealed alveolar hemorrhage and increased eosinophils in the bronchoalveolar lavage fluid, and a skin biopsy demonstrated a perivascular eosinophilic infiltrate. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). We started steroid therapy and low-molecular-weight heparin (LMWH). The chest pain and fever disappeared, and the peripheral eosinophil count normalized. However, the thrombosis in the leg worsened. It was dramatically improved by changing from LMWH to oral rivaroxaban. The thrombogenic risk of eosinophilia should be recognized. This case suggests that oral rivaroxaban is useful when thrombosis is uncontrolled by LMWH in a patient with EGPA

Spontaneous pulmonary hematoma with diffuse pulmonary ossification requiring emergency treatment: a case report

Abstract Background Pulmonary hematoma is most often caused by thoracic trauma. However, rare cases of pulmonary hematoma without any obvious cause are sometimes reported, when the condition is referred to as spontaneous or idiopathic pulmonary hematoma. Herein, we report a very rare case—to the best of our knowledge, this is the first case of pulmonary hematoma associated with diffuse pulmonary ossification requiring emergency treatment reported in the English literature. Case presentation Our patient was a 44-year-old man with a history of IgA nephropathy and had no history of trauma or anticoagulant use. He presented with the chief complaint of bloody sputum and was referred to our hospital for detailed examination. Chest computed tomography showed a right pleural effusion and a large round mass in the right lower lobe. We performed chest tube drainage of the right thorax and confirmed bloody pleural effusion. Although bronchial artery embolization was performed, the patient’s anemia worsened, and we performed right lower lobectomy. Histopathological examination of the resected specimen showed a hematoma with diffuse pulmonary ossification, although the relationship between the two was unclear. There was no evidence of malignancy or angiitis. Therefore, we made the diagnosis of spontaneous pulmonary hematoma in this case. The postoperative course was uneventful. The patient is currently under observation as an outpatient, and a recent chest X-ray showed no evidence of recurrence. Conclusion We report a case of spontaneous pulmonary hematoma with diffuse pulmonary ossification. Although the relationship between the two remains unclear, considering the possibility of appearance of new lesions/recurrence, we believe that careful follow-up is necessary for this patient

Kikuchi-Fujimoto disease can present as delayed lymphadenopathy after COVID-19 vaccination

Following COVID-19 vaccination, ipsilateral axillary and cervical lymphadenopathy may occur, called vaccine-related hypermetabolic lymphadenopathy, which is considered reactive lymphadenopathy. We report here a case of Kikuchi-Fujimoto disease, which occurred three months after vaccination with COVID-19 vaccine. The patient had cervical and axillary lymph node enlargement and a short-term fever that resolved spontaneously after the first and second vaccines. On the 90th day after the first vaccination, the patient developed a high fever and pathologically diagnosed necrotizing lymphadenitis in the axilla, which was diagnosed as Kikuchi-Fujimoto disease. Gallium scintigraphy showed localized swelling and strong uptake in the ipsilateral axilla. It implies the possibility of Kikuchi-Fujimoto Disease in axillary drainage lymph nodes in association with COVID-19 vaccine. Although only a few cases have been reported so far, this case is novel because of its later onset and diagnosis based on pathological and gallium scintigraphy imaging findings