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.

Rationale: Levels of pleural fluid adenosine deaminase (ADA), a useful marker for the diagnosis of tuberculous pleurisy, are elevated in some reports of immunoglobulin G4 (IgG4)-related pleural effusion. We describe a patient with IgG4-related pleural effusion who exhibited a high concentration of ADA. Furthermore, we reviewed the literature to compare patients with IgG4-related pleural effusion and tuberculous pleurisy. Patient concerns: A 75-year-old male patient had dyspnea for 1 month with a left pleural effusion that was exudative, lymphocyte dominant. The pleural fluid test results revealed a total protein (TP) concentration of 6.60 g/dl, a lactate dehydrogenase (LDH) level of 383 IU/dl, and an ADA concentration of 54.5 U/L. An interferon gamma release assay showed a negative result. Diagnoses: Histological analysis of the thoracoscopic pleural biopsy revealed lymphoplasmacytic infiltration, with 80 IgG4-positive plasma cells/high-power field, and an IgG4/IgG ratio of approximately 40% to 50%. Other diseases were ruled out based on symptoms, negative autoimmune antigen results, and histopathologic findings. Thus, he was diagnosed with IgG4-related pleural effusion. Interventions: He received 15 mg of prednisolone as therapy. Outcomes: His pleural effusion and symptoms improved gradually within several months, and prednisolone was tapered to 6 mg daily. Lessons: It is important to distinguish between IgG4-related pleural effusion and tuberculous pleurisy. Therefore, we compared 22 patients with IgG4-related pleural effusion from PubMed and the Japan Medical Abstracts Society to 40 patients with tuberculous pleurisy at Fukujuji Hospital from January 2017 to May 2019. According to thoracentesis findings, 14 of 18 patients with IgG4-related pleural effusion had high ADA more than 40 U/L. The pleural effusion of patients with IgG4-related pleural effusion showed higher TP levels (P < .001) and lower LDH (P < .001) and ADA levels (P = .002) than those with tuberculous pleurisy. Moreover, the pleural fluid ADA/TP ratio was a good predictor for differentiating IgG4-related pleural effusion and tuberculous pleurisy (area under the receiver operating characteristic curve of 0.909; 95% confidence level: 0.824–0.994).

Humidifier lung is a phenotype of hypersensitivity pneumonitis (HP) caused by the inhalation of humidifier vapours. A recent study comparing humidifier lung with summer-type HP reported several distinct features, including lower serum Krebs von den Lungen-6 (KL-6) levels, less common centrilobular ground-glass nodules on computed tomography scan and a higher ratio of CD4 + to CD8 + cells in bronchoalveolar lavage. 1 However, the features and mechanisms of humidifier lung are not well characterized. Indicators for discrimination of humidifier lung from other phenotypes of HP are uncertain. Here, we report more characteristics of histopathological findings and a diagnostic predictor for humidifier lung compared to summer-type HP, which is the most common phenotype of HP in Japan. 1,2 Among 82 adult patients hospitalized for HP at Fukujuji Hospital from April 1999 to March 2018, 7 patients with humidifier lung (18.3%) and 26 patients with summer-type HP (43.3%) were † Humidifier lung n = 6, summer-type HP n = 22. ‡ Humidifier lung n = 7, summer-type HP n = 22. § Humidifier lung n = 7, summer-type HP n = 7. ¶ Humidifier lung n = 10, summer-type HP n = 23. † † Humidifier lung n = 5, summer-type HP n = 16. CD4/8 ratio, ratio of CD4 + to CD8 + cells; CRP, C-reactive protein; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; IQR, interquartile range; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; WBC, white blood cell.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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.

A 51-year-old man was transferred to our hospital due to acute respiratory failure that had progressed over four days. A chest X-ray and thoracic computed tomography scan showed multiple faint micronodules randomly distributed throughout both lungs with ground glass opacity, suggesting miliary tuberculosis or Pneumocystis jirovecii pneumonia with acute respiratory distress syndrome. Six hours after admission, the patient died of septic shock. Later, the cryptococcal antigen titer was found to be markedly elevated (1/65,536), with a positive result for anti-human immunodeficiency virus and a low CD4 cell count (12/μL). The present case is reminder that disseminated cryptococcosis with HIV infection can be misdiagnosed as miliary tuberculosis based on radiological findings.

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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.