Effect of a mobile app chatbot and an interactive small-group webinar on COVID-19 vaccine intention and confidence in Japan: a randomised controlled trial.

INTRODUCTION: We investigated the effect of social media-based interventions on COVID-19 vaccine intention (VI) and confidence in Japan. METHODS: We conducted a three-arm randomised controlled trial between 5 November 2021 and 9 January 2022 during a low incidence (<1000/day) of COVID-19 in Japan in the midst of the second and the third waves. Japanese citizens aged ≥20 who had not received any COVID-19 vaccine and did not intend to be vaccinated were randomly assigned to one of the following three groups: (1) a control group, (2) a group using a mobile app chatbot providing information on COVID-19 vaccines and (3) a group using interactive webinars with health professionals. VI and predefined Vaccine Confidence Index (VCI) measuring confidence in the importance, safety and effectiveness were compared before and after the interventions under intention-to-treat principle. Logistic regression models were used to investigate the effect of each intervention on postintervention VI and changes of VCI compared with control. RESULTS: Among 386 participants in each group, 359 (93.0%), 231 (59.8%) and 207 (53.6%) completed the postsurvey for the control, chatbot and webinar groups, respectively. The average duration between the intervention and the postsurvey was 32 days in chatbot group and 27 days in webinar group. VI increased from 0% to 18.5% (95% CI 14.5%, 22.5%) in control group, 15.4% (95% CI 10.8%, 20.1%) in chatbot group and 19.7% (95% CI 14.5%, 24.9%) in webinar group without significant difference (OR for improvement=0.8 (95% CI 0.5, 1.3), p=0.33 between chatbot and control, OR=1.1 (95% CI 0.7, 1.6), p=0.73 between webinar and control). VCI change tended to be larger in chatbot group compared with control group without significant difference (3.3% vs -2.5% in importance, OR for improvement=1.3 (95% CI 0.9, 2.0), p=0.18; 2.5% vs 1.9% in safety, OR=1.1 (95% CI 0.7, 1.9), p=0.62; -2.4% vs -7.6% in effectiveness, OR=1.4 (95% CI 0.9, 2.1), p=0.09). Improvement in VCI was larger in webinar group compared with control group for importance (7.8% vs -2.5%, OR=1.8 (95% CI 1.2, 2.8), p<0.01), effectiveness (6.4% vs -7.6%, OR=2.2 (95% CI 1.4, 3.4), p<0.01) and safety (6.0% vs 1.9%, OR=1.6 (95% CI 1.0, 2.6), p=0.08). CONCLUSION: This study demonstrated that neither the chatbot nor the webinar changed VI importantly compared with control. Interactive webinars could be an effective tool to change vaccine confidence. Further study is needed to identify risk factors associated with decreased vaccine confidence and investigate what intervention can increase VI and vaccine confidence for COVID-19 vaccines. TRIAL REGISTRATION NUMBER: UMIN000045747.

Clinical prediction rule for bacterial arthritis: Chi-squared automatic interaction detector decision tree analysis model.

Objectives: Differences in demographic factors, symptoms, and laboratory data between bacterial and non-bacterial arthritis have not been defined. We aimed to identify predictors of bacterial arthritis, excluding synovial testing. Methods: This retrospective cross-sectional survey was performed at a university hospital. All patients included received arthrocentesis from January 1, 2010, to December 31, 2020. Clinical information was gathered from medical charts from the time of synovial fluid sample collection. Factors potentially predictive of bacterial arthritis were analyzed using the Student's t-test or chi-squared test, and the chi-squared automatic interaction detector decision tree analysis. The resulting subgroups were divided into three groups according to the risk of bacterial arthritis: low-risk, intermediate-risk, or high-risk groups. Results: A total of 460 patients (male/female = 229/231; mean ± standard deviation age, 70.26 ± 17.66 years) were included, of whom 68 patients (14.8%) had bacterial arthritis. The chi-squared automatic interaction detector decision tree analysis revealed that patients with C-reactive protein > 21.09 mg/dL (incidence of septic arthritis: 48.7%) and C-reactive protein ⩽ 21.09 mg/dL plus 27.70 < platelet count ⩽ 30.70 × 104/µL (incidence: 36.1%) were high-risk groups. Conclusions: Our results emphasize that patients categorized as high risk of bacterial arthritis, and appropriate treatment could be initiated as soon as possible.

Subcutaneous panniculitis-like T-cell lymphoma post-mRNA-1273 COVID-19 vaccination.

This is a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) was diagnosed by skin biopsy in a patient who presented with fever and erythema nodosum in the umbilicum following mRNA-1273 COVID-19 vaccination. COVID-19 vaccines may cause SPTCL and skin biopsy may help in the diagnosis of erythema nodosum.

Concurrent hypereosinophilic syndrome and deep vein thrombosis after Pfizer-BioNTech COVID-19 vaccination: A case report.

Herein, we report a case of eosinophilia syndrome and deep vein thrombosis presenting concurrently after the administration of the BNT162b2 mRNA-based coronavirus disease 2019 (COVID-19) vaccine. It is extremely rare to have both hypereosinophilic syndrome and deep vein thrombosis simultaneously. Both are serious diseases and should be treated with caution.

SARS-CoV-2 evolution among patients with immunosuppression in a nosocomial cluster of a Japanese medical center during the Delta (AY.29 sublineage) surge.

Background: Previous studies have shown that patients with immunosuppression tend to have longer-lasting SARS-CoV-2 infections and a number of mutations were observed during the infection period. However, these studies were, in general, conducted longitudinally. Mutation evolution among groups of patients with immunosuppression have not been well studied, especially among Asian populations. Methods: Our study targeted a nosocomial cluster of SARS-CoV-2 infection in a Japanese medical center during Delta surge (AY.29 sublineage), involving ward nurses and inpatients. Whole-genome sequencing analyses were performed to examine mutation changes. Haplotype and minor variant analyses were furtherly performed to detect the mutations on the viral genomes in detail. In addition, sequences of the first wild-type strain hCoV-19/Wuhan/WIV04/2019 and AY.29 wild-type strain hCoV-19/Japan/TKYK15779/2021 were used as references to assess the phylogenetical development of this cluster. Results: A total of 6 nurses and 14 inpatients were identified as a nosocomial cluster from September 14 through 28, 2021. All were Delta variant (AY.29 sublineage) positive. 92.9% of infected patients (13 out of 14) were either cancer patients and/or receiving immunosuppressive or steroid treatments. Compared to AY.29 wild type, a total of 12 mutations were found in the 20 cases. Haplotype analysis found one index group of eight cases with F274F (N) mutation and 10 other haplotypes with one to three additional mutations. Furthermore, we found that cases with more than three minor variants were all cancer patients under immunosuppressive treatments. The phylogenetical tree analysis, including 20 nosocomial cluster-associated viral genomes, the first wild-type strain and the AY.29 wild-type strain as references, indicated the mutation development of the AY.29 virus in this cluster. Conclusion: Our study of a nosocomial SARS-CoV-2 cluster highlights mutation acquisition during transmission. More importantly, it provided new evidence emphasizing the need to further improve infection control measures to prevent nosocomial infection among immunosuppressed patients.

Increased SARS-CoV-2 seroprevalence and spread of infection without awareness among healthcare workers through 2020-2022 in a Japanese medical center.

Despite Japan's high vaccination coverage, daily numbers of new COVID-19 cases have been high. However, studies on the seroprevalence among Japanese people and the causative factors for rapid spread have remained limited. In this study, we aimed to examine the seroprevalence and associated factors in healthcare workers (HCWs) of a medical center in Tokyo using blood samples drawn at annual check-ups from 2020 to 2022. We found that of the 3,788 HCWs in 2022 (by mid-June), 669 were seropositive for N-specific antibodies (tested by Roche Elecsys Anti-SARS-CoV-2 assay); the seroprevalence surged from 0.3% in 2020 and 1.6% in 2021 to 17.7% in 2022. Notably, our study found 325 (48.6%; 325/669) cases were infected without awareness. Among those with a previously PCR-confirmed SARS-CoV-2 infection during the past three years, 79.0% (282/357) were found after January 2022, after the Omicron variant was first detected in Tokyo at the end of 2021. This study indicates the fast spread of the SARS-CoV-2 among HCWs during the Omicron surge in Japan. The high percentage of infection without awareness may be a key driving factor causing rapid person-to-person transmission, as shown in this medical center with high vaccination coverage and strict infection control measures.

Dietary Intake in Older Patients with Dementia Prior to and After the Onset of Coronavirus Disease 2019.

This was an observational study of hospitalized patients with dementia who developed COVID-19. The disease course, dietary intake, and disease severity (mild/severe) were evaluated. Twenty-nine patients with a median age of 84 years, with both mild (18) and severe conditions, (11) were evaluated. Mild group had decreased food intake from the day of symptom onset. In the severe group, the decline began the day before symptom onset. On day 30 of the disease, the median food intake of the mild group returned to levels observed prior to symptom onset, in contrast to those in the severe group.

Mortality Prediction of COVID-19 in Hospitalized Patients Using the 2020 Diagnosis Procedure Combination Administrative Database of Japan.

Objectives Numerous people have died from coronavirus disease 2019 (COVID-19) infection. Identifying crucial predictive biomarkers of disease mortality is critical to support decision-making and logistic planning in healthcare systems. This study investigated the association between mortality and medical factors and prescription records in 2020 in Japan, where COVID-19 prevalence and mortality remain relatively low. Methods This retrospective cohort study analyzed anonymous administrative data from the Diagnosis Procedure Combination (DPC) database in Japan. Results A total of 22,795 patients were treated in DPC hospitals in 2020 in Japan, and of these, 5,980 patients over 50 years old were hospitalized, with 299 (5.0%) dying. There were 2,399 severe patients among 11,440 total hospitalized patients (all ages). The results of a logistic model analysis revealed that an older age, male sex, Parkinson's disease, cerebrovascular diseases, and chronic kidney diseases were risk factors for mortality. A machine learning analysis identified an older age, male sex (mortality), pneumonia, drugs for acid-related disorders, analgesics, anesthesia, upper respiratory tract disease, drugs for functional gastrointestinal disorders, drugs for obstructive airway diseases, topical products for joint and muscular pain, diabetes, lipid-modifying agents, calcium channel blockers, drugs for diabetes, and agents acting on the renin-angiotensin system as risk factors for a severe status. Conclusions This COVID-19 mortality risk tool is a well-calibrated and accurate model for predicting mortality risk among hospitalized patients with COVID-19 in Japan, which is characterized by a relatively low COVID-19 prevalence, aging society, and high population density. This COVID-19 mortality prediction model can assist in resource utilization and patient and caregiver education and be useful as a risk stratification instrument for future research trials.

Performance evaluation of the Ortho VITROS SARS-CoV-2 Spike-Specific Quantitative IgG test by comparison with the surrogate virus neutralizing antibody test and clinical assessment.

BACKGROUND: Despite the worldwide campaigns of COVID-19 vaccinations, the pandemic is still a major medical and social problem. The Ortho VITROS SARS-CoV-2 spike-specific quantitative IgG (VITROS S-IgG) assay has been developed to assess neutralizing antibody (NT antibody) against SARS-CoV-2 spike (S) antibodies. However, it has not been evaluated in Japan, where the total cases and death toll are lower than the rest of the world. METHODS: The clinical performance of VITROS S-IgG was evaluated by comparing with the NT antibody levels measured by the surrogate virus neutralizing antibody test (sVNT). A total of 332 serum samples from 188 individuals were used. Of these, 219 samples were from 75 COVID-19 patients: 96 samples from 20 severe/critical cases (Group S), and 123 samples from 55 mild/moderate cases (Group M). The remaining 113 samples were from 113 healthcare workers who had received 2 doses of the BNT162b2 vaccine. RESULTS: VITROS S-IgG showed good correlation with the cPass sVNT assay (Spearman rho = 0.91). Both VITROS S-IgG and cPass sVNT showed significantly higher plateau levels of antibodies in Group S compared to Group M. Regarding the humoral immune responses after BNT162b2 vaccination, individuals who were negative for SARS-CoV-2 nucleocapsid (N)-specific antibodies had statistically lower titers of both S-IgG and sVNT compared to individuals with a history of COVID-19 and individuals who were positive for N-specific antibodies without history of COVID-19. In individuals who were positive for N-specific antibodies, S-IgG and sVNT titers were similar to individuals with a history of COVID-19. CONCLUSIONS: Although the automated quantitative immunoassay VITROS S-IgG showed a reasonable correlation with sVNT antibodies, there is some discrepancy between Vitros S-IgG and cPass sVNT in milder cases. Thus, VITROS S-IgG can be a useful diagnostic tool in assessing the immune responses to vaccination and herd immunity. However, careful analysis is necessary to interpret the results.

Performance evaluation of the Roche Elecsys® Anti-SARS-CoV-2 immunoassays by comparison with neutralizing antibodies and clinical assessment.

Quantitative measurement of SARS-CoV-2 neutralizing antibodies is highly expected to evaluate immune status, vaccine response, and antiviral therapy. The Elecsys® Anti-SARS-CoV-2 S (Elecsys® anti-S) was developed to measure anti-SARS-CoV-2 S proteins. We sought to investigate whether Elecsys® anti-S can be used to predict neutralizing activities in patients' serums using an authentic virus neutralization assay. One hundred forty-six serum samples were obtained from 59 patients with COVID-19 at multiple time points. Of the 59 patients, 44 cases were included in Group M (mild 23, moderate 21) and produced 84 samples (mild 35, moderate 49), while 15 cases were included in Group S (severe 11, critical 4) and produced 62 samples (severe 43, critical 19). The neutralization assay detected 73% positive cases, and Elecsys® anti-S and Elecsys® Anti-SARS-CoV-2 (Elecsys® anti-N) showed 72% and 66% positive cases, respectively. A linear correlation between the Elecsys® anti-S assay and the neutralization assay were highly correlated (r = 0.7253, r2 = 0.5261) than a linear correlation between the Elecsys® anti-N and neutralization assay (r = 0.5824, r2 = 0.3392). The levels of Elecsys® anti-S antibody and neutralizing activities were significantly higher in Group S than in Group M after 6 weeks from onset of symptoms (p < 0.05). Conversely, the levels of Elecsys® anti-N were comparable in both groups. Three immunosuppressed patients, including cancer patients, showed low levels of anti-S and anti-N antibodies and neutralizing activities throughout the measurement period, indicating the need for careful follow-up. Our data indicate that Elecsys® anti-S can predict the neutralization antibodies in COVID-19.

Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations.

To develop preventive and therapeutic measures against coronavirus disease 2019, the complete characterization of immune response and sustained immune activation following viral infection and vaccination are critical. However, the mechanisms controlling intrapersonal variation in antibody titers against SARS-CoV-2 antigens remain unclear. To gain further insights, we performed a robust molecular and cellular investigation of immune responses in infected, recovered, and vaccinated individuals. We evaluated the serum levels of 29 cytokines and their correlation with neutralizing antibody titer. We investigated memory B-cell response in patients infected with the original SARS-CoV-2 strain or other variants, and in vaccinated individuals. Longitudinal correlation analyses revealed that post-vaccination neutralizing potential was more strongly associated with various serum cytokine levels in recovered patients than in naïve individuals. We found that IL-10, CCL2, CXCL10, and IL-12p40 are candidate biomarkers of serum-neutralizing antibody titer after the vaccination of recovered individuals. We found a similar distribution of virus-specific antibody gene families in triple-vaccinated individuals and a patient with COVID-19 pneumonia for 1 year. Thus, distinct immune responses occur depending on the viral strain and clinical history, suggesting that therapeutic options should be selected on a case-by-case basis. Candidate biomarkers that correlate with repeated vaccination may support the efficacy and safety evaluation systems of mRNA vaccines and lead to the development of novel vaccine strategies.

Th1 cytokine endotype discriminates and predicts severe complications in COVID-19

Treatment of severe and critical cases of coronavirus disease 2019 (COVID-19) is still a top priority in public health. Previously, we reported distinct Th1 cytokines related to the pathophysiology of severe COVID-19 condition. In the present study, we investigated the association of Th1 and Th2 cytokine/chemokine endotypes with cell-mediated immunity via multiplex immunophenotyping, single-cell RNA-Seq analysis of peripheral blood mononuclear cells, and analysis of the clinical features of COVID-19 patients. Based on serum cytokine and systemic inflammatory markers, COVID-19 cases were classified into four clusters of increasing (I-IV) severity. Two prominent clusters were of interest and could be used as prognostic reference for a targeted treatment of severe COVID-19 cases. Cluster III reflected severe/critical pathology and was characterized by decreased in CCL17 levels and increase in IL-6, C-reactive protein CXCL9, IL-18, and IL-10 levels. The second cluster (Cluster II) showed mild to moderate pathology and was characterized by predominated CXCL9 and IL-18 levels, levels of IL-6 and CRP were relatively low. Cluster II patients received anti-inflammatory treatment in early-stage, which may have led prevent disease prognosis which is accompanied to IL-6 and CRP induction. In Cluster III, a decrease in the proportion of effector T cells with signs of T cell exhaustion was observed. This study highlights the mechanisms of endotype clustering based on specific inflammatory markers in related the clinical outcome of COVID-19.

COVID-19 Severity and Thrombo-Inflammatory Response Linked to Ethnicity.

Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients' disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany.

Circulating tumor necrosis factor receptors are associated with mortality and disease severity in COVID-19 patients.

BACKGROUND: Although hyperinflammatory response influences the severity of coronavirus disease 2019 (COVID-19), little has been reported about the utility of tumor necrosis factor (TNF)-related biomarkers in reflecting the prognosis. We examined whether TNF receptors (TNFRs: TNFR1, TNFR2) and progranulin (PGRN) levels, in addition to interleukin 6 (IL-6) and C-reactive protein (CRP), are associated with mortality or disease severity in COVID-19 patients. METHODS: This retrospective study was conducted at Juntendo University Hospital. Eighty hospitalized patients with various severities of COVID-19 were enrolled. Furthermore, serum levels of TNF-related biomarkers were measured using enzyme-linked immunosorbent assay. RESULTS: Twenty-five patients died during hospitalization, and 55 were discharged. The median (25th and 75th percentiles) age of the study patients was 70 (61-76) years, 44 (55.0%) patients were males, and 26 (32.5%) patients had chronic kidney disease (CKD). When comparing with patients who received and did not receive treatment at the intensive care unit (ICU), the former had a higher tendency of being male and have diabetes, hypertension, and CKD; had higher levels of white blood cells, D-dimer, and lactate dehydrogenase; and had lower body mass index, estimated glomerular filtration rate, and lymphocyte counts. Significant differences were observed in TNFR, PGRN, IL-6, and CRP levels between each severity (mild-severe) group. Furthermore, the serum levels of TNFR, IL-6, and CRP, but not PGRN, in ICU patients were significantly higher than in the patients who were not admitted to the ICU. Multivariate logistic regression analysis demonstrated that high levels of TNFR2 were only associated with mortality in patients with COVID-19 even after adjustment for relevant clinical parameters. CONCLUSIONS: High TNFR2 level might be helpful for predicting mortality or disease severity in patients with COVID-19.

Activation of SARS-CoV-2 neutralizing antibody is slower than elevation of spike-specific IgG, IgM, and nucleocapsid-specific IgG antibodies.

COVID-19 antibody testing has been developed to investigate humoral immune response in SARS-CoV-2 infection. To assess the serological dynamics and neutralizing potency following SARS-CoV-2 infection, we investigated the neutralizing (NT) antibody, anti-spike, and anti-nucleocapsid antibodies responses using a total of 168 samples obtained from 68 SARS-CoV-2 infected patients. Antibodies were measured using an authentic virus neutralization assay, the high-throughput laboratory measurements of the Abbott Alinity quantitative anti-spike receptor-binding domain IgG (S-IgG), semiquantitative anti-spike IgM (S-IgM), and anti-nucleocapsid IgG (N-IgG) assays. The quantitative measurement of S-IgG antibodies was well correlated with the neutralizing activity detected by the neutralization assay (r = 0.8943, p < 0.0001). However, the kinetics of the SARS-CoV-2 NT antibody in severe cases were slower than that of anti-S and anti-N specific antibodies. These findings indicate a limitation of using the S-IgG antibody titer, detected by the chemiluminescent immunoassay, as a direct quantitative marker of neutralizing activity capacity. Antibody testing should be carefully interpreted when utilized as a marker for serological responses to facilitate diagnostic, therapeutic, and prophylactic interventions.

The impact of the COVID-19 pandemic on other infections differs by their route of transmission: A retrospective, observational study in Japan.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) pandemic and people's subsequent behavioral changes have decreased the cases of respiratory infection worldwide. However, research on infectious diseases with other transmission modes is insufficient. The aim was to assess the impact of the COVID-19 pandemic on non-respiratory infectious diseases: infectious enterocolitis, sexually transmitted diseases such as human immunodeficiency virus (HIV) infection and syphilis, and tick-borne diseases. METHODS: This retrospective, cohort study used comprehensive surveillance data from the National Institute of Infectious Diseases in Japan from January 1, 2018, to December 31, 2021. The number of cases of infectious diseases before the COVID-19 pandemic (2018-2019) was compared with that during the COVID-19 pandemic (2020-2021). Reduction rates were calculated as the number of disease cases during the COVID-19 pandemic in 2020 and 2021, respectively, divided by the mean number of disease cases in 2018 and 2019. RESULTS: The total numbers of cases of infectious enterocolitis, sexually transmitted diseases, and tick-borne diseases during the study period were 2,507,304 cases, 24,972 cases, and 3012 cases, respectively. The number of cases decreased for infectious enterocolitis and sexually transmitted diseases during the COVID-19 pandemic compared with before the COVID-19 pandemic, with an approximately 40-50% decrease in enterocolitis and 30-55% decreases in sexually transmitted diseases. However, cases of tick-borne diseases changed little, with a 0.2% increase in 2020 and a 6% increase in 2021. CONCLUSION: The COVID-19 pandemic had a different impact on the number of cases of infectious diseases depending on their mode of transmission.

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

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.

Molecular characterization of SARS-CoV-2 detected in Tokyo, Japan during five waves: Identification of the amino acid substitutions associated with transmissibility and severity

Many variants of SARS-CoV-2 have emerged around the world. It is therefore important to understand its global viral evolution and the corresponding mutations associated with transmissibility and severity. In this study, we analyzed 112 whole genome sequences of SARS-CoV-2 collected from patients at Juntendo University Hospital in Tokyo and the genome data from entire Japan deposited in Global Initiative on Sharing Avian Influenza Data (GISAID) to examine the relationship of amino acid changes with the transmissibility and the severity of each strain/lineage. We identified 12 lineages, including B.1.1.284, B.1.1.214, R.1, AY.29, and AY.29.1, which were prevalent specifically in Japan. B.1.1.284 was most frequently detected in the second wave, but B.1.1.214 became the predominant lineage in the third wave, indicating that B.1.1.214 has a higher transmissibility than B.1.1.284. The most prevalent lineage during the fourth and fifth wave was B.1.1.7 and AY.29, respectively. In regard to the severity of identified lineages, B.1.1.214 was significantly lower than the reference lineage, B.1.1.284. Analysis of the genome sequence and other traits of each lineage/strain revealed the mutations in S, N, and NSPs that increase the transmissibility and/or severity. These mutations include S: M153T, N: P151L, NSP3: S543P, NSP5: P108S, and NSP12: A423V in B.1.1.284;S: W152L and E484K in R.1;S: H69del, V70del, and N501Y in the Alpha strain;S: L452R, T478K, and P681R in the Delta strain. Furthermore, it is suggested that the transmissibility of B.1.1.214 could be enhanced by the mutations N: M234I, NSP14: P43L, and NSP16: R287I. To address the issue of the virus evolution, it is necessary to continuously monitor the genomes of SARS-CoV-2 and analyze the effects of mutations for developing vaccines and antiviral drugs effective against SARS-CoV-2 variants.

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

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.