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1.
J Infect Chemother ; 28(7): 1015-1017, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1768315

ABSTRACT

By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19 Vaccines , Humans , RNA, Viral , Vaccines, Synthetic
2.
Pharmacoepidemiol Drug Saf ; 31(6): 680-688, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1756631

ABSTRACT

PURPOSE: The coagulation activation leads to thrombotic complications such as venous thromboembolism (VTE) in patients with coronavirus disease-2019 (COVID-19). Prophylactic anticoagulation therapy has been recommended for hospitalized COVID-19 patients in clinical guidelines. This retrospective cohort study aimed to examine the association between pre-admission anticoagulation treatment and three outcomes: in-hospital death, VTE, and major bleeding among hospitalized COVID-19 patients in Japan. METHODS: Using a large-scale claims database built by the Medical Data Vision Co. in Japan, we identified patients hospitalized for COVID-19 who had outpatient prescription data at least once within 3 months before being hospitalized. Exposure was set as pre-admission anticoagulation treatment (direct oral anticoagulant or vitamin K antagonist), and outcomes were in-hospital death, VTE, and major bleeding. We conducted multivariable logistic regression analyses, adjusting for a single summarized score (a propensity score of receiving pre-admission anticoagulation) for VTE and major bleeding, due to the small number of outcomes. RESULTS: Among the 2612 analytic patients, 179 (6.9%) had pre-admission anticoagulation. Crude incidence proportions were 13.4% versus 8.5% for in-hospital death, 0.56% versus 0.58% for VTE, and 2.2% versus 1.1% for major bleeding among patients with and without pre-admission anticoagulation, respectively. Adjusted odds ratios (95% confidence intervals) were 1.25 (0.75-2.08) for in-hospital death, 0.21 (0.02-1.97) for VTE, and 2.63 (0.80-8.65) for major bleeding. Several sensitivity analyses did not change the results. CONCLUSIONS: We found no evidence that pre-admission anticoagulation treatment was associated with in-hospital death. However, a larger sample size may be needed to conclude its effect on VTE and major bleeding.


Subject(s)
COVID-19 , Venous Thromboembolism , Anticoagulants , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Hospital Mortality , Humans , Japan/epidemiology , Retrospective Studies , Risk Factors , Venous Thromboembolism/drug therapy , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology
3.
Microbiol Spectr ; 10(2): e0168921, 2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1731262

ABSTRACT

The role of the intestinal microbiota in coronavirus disease 2019 (COVID-19) is being elucidated. Here, we analyzed the temporal changes in microbiota composition and the correlation between inflammation biomarkers/cytokines and microbiota in hospitalized COVID-19 patients. We obtained stool specimens, blood samples, and patient records from 22 hospitalized COVID-19 patients and performed 16S rRNA metagenomic analysis of stool samples over the course of disease onset compared to 40 healthy individual stool samples. We analyzed the correlation between the changes in the gut microbiota and plasma proinflammatory cytokine levels. Immediately after admission, differences in the gut microbiota were observed between COVID-19 patients and healthy subjects, mainly including enrichment of the classes Bacilli and Coriobacteriia and decrease in abundance of the class Clostridia. The bacterial profile continued to change throughout the hospitalization, with a decrease in short-chain fatty acid-producing bacteria including Faecalibacterium and an increase in the facultatively anaerobic bacteria Escherichia-Shigella. A consistent increase in Eggerthella belonging to the class Coriobacteriia was observed. The abundance of the class Clostridia was inversely correlated with interferon-γ level and that of the phylum Actinobacteria, which was enriched in COVID-19, and was positively correlated with gp130/sIL-6Rb levels. Dysbiosis was continued even after 21 days from onset. The intestines tended to be an aerobic environment in hospitalized COVID-19 patients. Because the composition of the gut microbiota correlates with the levels of proinflammatory cytokines, this finding emphasizes the need to understand how pathology is related to the temporal changes in the specific gut microbiota observed in COVID-19 patients. IMPORTANCE There is growing evidence that the commensal microbiota of the gastrointestinal and respiratory tracts regulates local and systemic inflammation (gut-lung axis). COVID-19 is primarily a respiratory disease, but the involvement of microbiota changes in the pathogenesis of this disease remains unclear. The composition of the gut microbiota of patients with COVID-19 changed over time during hospitalization, and the intestines tended to be an aerobic environment in hospitalized COVID-19 patients. These changes in gut microbiota may induce increased intestinal permeability, called leaky gut, allowing bacteria and toxins to enter the circulatory system and further aggravate the systemic inflammatory response. Since gut microbiota composition correlates with levels of proinflammatory cytokines, this finding highlights the need to understand how pathology relates to the gut environment, including the temporal changes in specific gut microbiota observed in COVID-19 patients.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Bacteria/genetics , Cytokines , Dysbiosis/microbiology , Feces/microbiology , Gastrointestinal Microbiome/physiology , Hospitalization , Humans , Inflammation , RNA, Ribosomal, 16S/genetics
4.
Br J Haematol ; 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1714140

ABSTRACT

Data on the response to the COVID-19 vaccine in patients with myeloid malignancy, who are at severe risk in case of infection, have not emerged. In a study of 69 patients with myeloid malignancies, including 46 patients with acute myeloid leukaemia (AML) and 23 patients with myelodysplastic syndrome (MDS), anti-spike SARS-CoV-2 antibody titres were measured 3 months after the second mRNA-based vaccination. Seroconversion rates for AML and MDS were 94.7% and 100% respectively, with no significant difference from healthy controls (HCs). Patients with MDS showed a significantly lower antibody titre than that in HCs or AML patients. In AML patients, the antibody titres were comparable to those in HCs when treatment was completed, but lower in patients under maintenance therapy. The response to COVID-19 vaccine appears to be related to disease and treatment status. Patients with myeloid malignancies may be more responsive to vaccines than patients with lymphoid malignancies.

7.
Lancet Reg Health West Pac ; 20: 100365, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1587056

ABSTRACT

BACKGROUND: COVID-19 has worse mortality than influenza in American and European studies, but evidence from the Western Pacific region is scarce. METHODS: Using a large-scale multicenter inpatient claims data in Japan, we identified individuals hospitalised with COVID-19 in 2020 or influenza in 2017-2020. We compared patient characteristics, supportive care, and in-hospital mortality, with multivariable logistic regression analyses for in-hospital mortality overall, by age group, and among patients with mechanical ventilation. FINDINGS: We identified 16,790 COVID-19 patients and 27,870 influenza patients, with the different age distribution (peak at 70-89 years in COVID-19 vs. bimodal peaks at 0-9 and 80-89 years in influenza). On admission, the use of mechanical ventilation was similar in both groups (1·4% vs. 1·4%) but higher in the COVID-19 group (3·3% vs. 2·5%; p<0·0001) during the entire hospitalisation. The crude in-hospital mortality was 5·1% (856/16,790) for COVID-19 and 2·8% (791/27,870) for influenza. Adjusted for potential confounders, the in-hospital mortality was higher for COVID-19 than for influenza (adjusted odds ratio [aOR] 1·83, 95% confidence interval [CI] 1·64-2·04). In age-stratified analyses, the aOR (95%CI) were 0·78 (0·56-1·08) and 2·05 (1·83-2·30) in patients aged 20-69 years and ≥70 years, respectively (p-for-interaction<0·0001). Among patients with mechanical ventilation, the aOR was 0·79 (0·59-1·05). INTERPRETATION: Patients hospitalised with COVID-19 in Japan were more likely to die than those with influenza. However, this was mainly driven by findings in older people, and there was no difference once mechanical ventilation was started. FUNDING: Ministry of Health, Labour and Welfare of Japan (21AA2007).

8.
EClinicalMedicine ; 32: 100734, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1385450

ABSTRACT

BACKGROUND: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients. METHODS: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay. FINDINGS: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort. INTERPRETATION: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection. FUNDING: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.

10.
PLoS One ; 16(6): e0253293, 2021.
Article in English | MEDLINE | ID: covidwho-1280625

ABSTRACT

BACKGROUND: Human microbiotas are communities of microorganisms living in symbiosis with humans. They play an important role in the host immune response to respiratory viral infection. However, evidence on the human microbiome and coronavirus disease (COVID-19) relationship is insufficient. The aim of this systematic literature review was to evaluate existing evidence on the association between the microbiome and COVID-19 in humans and summarize these data in the pandemic era. METHODS: We conducted a systematic literature review on the association between the microbiome and COVID-19 in humans by searching PubMed, Embase, and the Cochrane Library, CINAHL, and Web of Science databases for articles in English published up to October 31, 2020. The results were analyzed qualitatively. This study is registered with PROSPERO (CRD42020195982). RESULTS: Of the 543 articles identified by searching databases, 16 in line with the research objectives were eligible for qualitative review: eight sampled the microbiome using stool, four using nasopharyngeal or throat swab, three using bronchoalveolar lavage fluid, and one using lung tissue. Fecal microbiome dysbiosis and increased opportunistic pathogens were reported in COVID-19 patients. Several studies suggested the dysbiosis in the lung microbiome of COVID-19 patients with an abundance of opportunistic pathogens using lower respiratory tract samples. The association between COVID-19 severity and the human microbiome remains uncertain. CONCLUSION: The human fecal and respiratory tract microbiome changed in COVID-19 patients with opportunistic pathogen abundance. Further research to elucidate the effect of alternation of the human microbiome in disease pathogenesis is warranted.


Subject(s)
COVID-19/microbiology , Dysbiosis/microbiology , Microbiota , Nasopharynx/microbiology , Bronchoalveolar Lavage Fluid , Dysbiosis/virology , Feces/microbiology , Gastrointestinal Microbiome , Humans
11.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1276013

ABSTRACT

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a key role in viral infectivity. It is also the major antigen stimulating the host's protective immune response, specifically, the production of neutralizing antibodies. Recently, a new variant of SARS-CoV-2 possessing multiple mutations in the S protein, designated P.1, emerged in Brazil. Here, we characterized a P.1 variant isolated in Japan by using Syrian hamsters, a well-established small animal model for the study of SARS-CoV-2 disease (COVID-19). In hamsters, the variant showed replicative abilities and pathogenicity similar to those of early and contemporary strains (i.e., SARS-CoV-2 bearing aspartic acid [D] or glycine [G] at position 614 of the S protein). Sera and/or plasma from convalescent patients and BNT162b2 messenger RNA vaccinees showed comparable neutralization titers across the P.1 variant, S-614D, and S-614G strains. In contrast, the S-614D and S-614G strains were less well recognized than the P.1 variant by serum from a P.1-infected patient. Prior infection with S-614D or S-614G strains efficiently prevented the replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. In addition, passive transfer of neutralizing antibodies to hamsters infected with the P.1 variant or the S-614G strain led to reduced virus replication in the lower respiratory tract. However, the effect was less pronounced against the P.1 variant than the S-614G strain. These findings suggest that the P.1 variant may be somewhat antigenically different from the early and contemporary strains of SARS-CoV-2.


Subject(s)
COVID-19/virology , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Virus Replication , Animals , Antibodies, Neutralizing , COVID-19/diagnostic imaging , COVID-19/pathology , Cricetinae , Humans , Immunogenicity, Vaccine , Lung/pathology , Mesocricetus , Mice , Spike Glycoprotein, Coronavirus/genetics , X-Ray Microtomography
12.
HLA ; 98(1): 37-42, 2021 07.
Article in English | MEDLINE | ID: covidwho-1199730

ABSTRACT

HLA-A, -C, -B, and -DRB1 genotypes were analyzed in 178 Japanese COVID-19 patients to investigate the association of HLA with severe COVID-19. Analysis of 32 common HLA alleles at four loci revealed a significant association between HLA-DRB1*09:01 and severe COVID-19 (odds ratio [OR], 3.62; 95% CI, 1.57-8.35; p = 0.00251 [permutation p value = 0.0418]) when age, sex, and other common HLA alleles at the DRB1 locus were adjusted. The DRB1*09:01 allele was more significantly associated with risk for severe COVID-19 compared to preexisting medical conditions such as hypertension, diabetes, and cardiovascular diseases. These results indicate a potential role for HLA in predisposition to severe COVID-19.


Subject(s)
COVID-19 , HLA-DRB1 Chains , Alleles , COVID-19/diagnosis , COVID-19/genetics , Gene Frequency , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Humans
14.
Sci Adv ; 7(10)2021 03.
Article in English | MEDLINE | ID: covidwho-1119272

ABSTRACT

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.


Subject(s)
Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigens, Viral/immunology , Biomarkers/blood , COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Antibody Affinity/immunology , Antibody Formation/immunology , COVID-19/blood , COVID-19/virology , Cytokines/blood , HEK293 Cells , Hospitalization , Humans , Immunoglobulin Class Switching , Kinetics , Neutralization Tests , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Load
16.
Viruses ; 12(12)2020 12 10.
Article in English | MEDLINE | ID: covidwho-970091

ABSTRACT

Reverse transcription-quantitative PCR (RT-qPCR)-based tests are widely used to diagnose coronavirus disease 2019 (COVID-19). As a result that these tests cannot be done in local clinics where RT-qPCR testing capability is lacking, rapid antigen tests (RATs) for COVID-19 based on lateral flow immunoassays are used for rapid diagnosis. However, their sensitivity compared with each other and with RT-qPCR and infectious virus isolation has not been examined. Here, we compared the sensitivity among four RATs by using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates and several types of COVID-19 patient specimens and compared their sensitivity with that of RT-qPCR and infectious virus isolation. Although the RATs read the samples containing large amounts of virus as positive, even the most sensitive RAT read the samples containing small amounts of virus as negative. Moreover, all RATs tested failed to detect viral antigens in several specimens from which the virus was isolated. The current RATs will likely miss some COVID-19 patients who are shedding infectious SARS-CoV-2.


Subject(s)
Antigens, Viral/analysis , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Point-of-Care Systems , SARS-CoV-2/isolation & purification , False Negative Reactions , Humans , Immunoassay , Real-Time Polymerase Chain Reaction , SARS-CoV-2/immunology , Sensitivity and Specificity , Specimen Handling
17.
Hepatol Res ; 51(2): 227-232, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-852324

ABSTRACT

AIM: Liver dysfunction is sometimes observed in patients with coronavirus disease 2019 (COVID-19), but most studies are from China, and the frequency in other countries is unclear. In addition, previous studies suggested several mechanisms of liver damage, but precise or additional mechanisms are not clearly elucidated. Therefore, we examined COVID-19 patients to explore the proportion of patients with liver dysfunction and also the factors associated with liver dysfunction. METHODS: We retrospectively examined 60 COVID-19 patients hospitalized at the Hospital affiliated with The Institute of Medical Science, The University of Tokyo (Tokyo, Japan). Patients who presented ≥40 U/L alanine aminotransferase (ALT) levels at least once during their hospitalization were defined as high-ALT patients, and the others as normal-ALT patients. The worst values of physical and laboratory findings during hospitalization for each patient were extracted for the analyses. Univariable and multivariable logistic regression models with bootstrap (for 1000 times) were carried out. RESULTS: Among 60 patients, there were 31 (52%) high-ALT patients. The high-ALT patients were obese, and had significantly higher levels of D-dimer and fibrin/fibrinogen degradation products, as well as white blood cell count, and levels of C-reactive protein, ferritin, and fibrinogen. Multivariable analysis showed D-dimer and white blood cells as independent factors. CONCLUSIONS: Considering that higher D-dimer level and white blood cell count were independently associated with ALT elevation, liver dysfunction in COVID-19 patients might be induced by microvascular thrombosis in addition to systemic inflammation.

20.
Intern Med ; 59(19): 2443-2444, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-713918
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