Association between SARS-CoV-2 anti-spike antibody titers and the development of post-COVID conditions: A retrospective observational study

Summary The symptoms that persist after an acute coronavirus disease 2019 (COVID-19) are referred to as post- COVID conditions. Although the cause of post-COVID conditions remains unclear, the host immune response to SARS-CoV-2 may be involved. Hence, we aimed to investigate the effect of serum antibody titers against SARS-CoV-2 on the development of post-COVID conditions. We conducted a retrospective observational study of COVID-19-recovered individuals who attended the clinic at the National Center for Global Health and Medicine between January 2020 and April 2021. Serum SARS-CoV-2 anti-spike antibody titers were measured and a questionnaire survey was used to collect information on the presence of post-COVID conditions and demographic characteristics of the participants. Participants were then divided into two groups: high peak antibody titer group [≥ 0.759 OD450 value], and low peak antibody titer group [< 0.759 OD450 value] and compared their frequency of post-COVID conditions. Of 526 individuals attending the clinic, 457 (86.9%) responded to the questionnaire. We analyzed the data of 227 (49.7%) participants with measurements of serum antibody titers during the peak period. The incidence of depressed mood was significantly higher in the group with higher antibody titers (odds ratio: 2.34, 95% CI: 1.17-4.67, p = 0.016). There was no significant difference in the frequency of the remaining symptoms between the two groups. Among post-COVID conditions, the depressed mood was more frequent in the group with high serum antibody titers which suggests a difference in pathogenesis between depressive mood and other post-COVID conditions that requires further investigation.

Recent changes in the reporting of STIs in Japan during the COVID-19 pandemic.

OBJECTIVES: The COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan. METHODS: We used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020. RESULTS: Chlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021. CONCLUSIONS: The COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.

Glycemic control using intermittently scanned continuous glucose monitoring in patients with diabetes requiring methylprednisolone therapy for severe COVID-19.

In patients with severe coronavirus disease 2019 (COVID-19) with diabetes, glycemic control is essential for a better outcome, however, we face difficulty controlling hyperglycemia induced by high-dose glucocorticoids. We report five cases of severe COVID-19 patients with diabetes, whose glycemic control was managed using an intermittently scanned continuous glucose monitoring (isCGM) system during methylprednisolone therapy. Patients using isCGM showed significantly lower average blood glucose levels and significantly higher total daily insulin dose during the methylprednisolone therapy, compared to patients under regular blood glucose monitoring. The use of isCGM enables remote glucose monitoring, and this can reduce the risks of healthcare workers who have frequent contact with the patients. Thus, we suggest that using isCGM should be considered in hospitalized patients with diabetes under the COVID-19 pandemic to achieve better glycemic control and to minimize the possible risks of healthcare workers.

An Autopsy Report of a Case with Cerebral Infarction Complicated by Coronavirus Disease 2019 Infection.

We herein report a case of cerebral infarct in a patient with coronavirus disease 2019 (COVID-19) infection who died of aspiration pneumonia. The postmortem examination of the brain revealed embolic infarct with negative findings on quantitative reverse transcription polymerase chain reaction (qRT-PCR) as well as immunohistochemistry to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The systemic examination only revealed low copy numbers of SARS-CoV-2 in the bronchus. This is the first and so far only autopsy case of COVID-19 infection with pathologic and virologic findings of the postmortem brain in Japan.

Potential usage of anterior nasal sampling in clinical practice with three rapid antigen tests for SARS-CoV-2

Introduction Anterior nasal sampling (AN) might be more convenient for patients than NP sampling to diagnose coronavirus disease. This study investigated the feasibility of rapid antigen tests for AN sampling, and the factors affecting the test accuracy. Methods This single-center prospective study evaluated one qualitative (ESP) and two quantitative (LUMI and LUMI-P) rapid antigen tests using AN and NP swabs. Symptomatic patients aged 20 years or older, who were considered eligible for reverse-transcription quantitative polymerase chain reaction using NP samples within 9 days of onset were recruited. Sensitivity, specificity, and positive and negative concordance rates between AN and NP samples were assessed for the rapid antigen tests. We investigated the characteristics that affected the concordance between AN and NP sampling results. Results A total of 128 cases were recruited, including 28 positive samples and 100 negative samples. The sensitivity and specificity of AN samples using ESP were 0.81 and 1.00, while those of NP samples were 0.94 and 1.00. The sensitivity of AN and NP samples was 0.91 and 0.97, respectively, and specificity was 1.00, for both LUMI and LUMI-P. The positive concordance rates of AN to NP sampling were 0.87, 0.94, and 0.85 for ESP, LUMI, and LUMI-P, respectively. No factor had a significant effect on the concordance between the sampling methods. Conclusions ESP, LUMI, and LUMI-P showed practical diagnostic accuracy for AN sampling compared to NP sampling. There was no significant factor affecting the concordance between AN and NP sampling for these rapid antigen tests.

Impact of long-COVID on health-related quality of life in Japanese COVID-19 patients.

BACKGROUND: The empirical basis for a quantitative assessment of the disease burden imposed by long-COVID is currently scant. We aimed to inform the disease burden caused by long-COVID in Japan. METHODS: We conducted a cross sectional self-report questionnaire survey. The questionnaire was mailed to 526 eligible patients, who were recovered from acute COVID-19 in April 2021. Answers were classified into two groups; participants who have no symptom and those who have any ongoing prolonged symptoms that lasted longer than four weeks at the time of the survey. We estimated the average treatment effect (ATE) of ongoing prolonged symptoms on EQ-VAS and EQ-5D-3L questionnaire using inverse probability weighting. In addition to symptom prolongation, we investigated whether other factors (including demography, lifestyle, and acute severity) were associated with low EQ-VAS and EQ-5D-3L values, by multivariable linear regression. RESULTS: 349 participants reported no symptoms and 108 reported any symptoms at the time of the survey. The participants who reported any symptoms showed a lower average value on the EQ-VAS (69.9 vs 82.8, respectively) and on the EQ-5D-3L (0.85 vs 0.96, respectively) than those reporting no symptoms considering the ATE of ongoing prolonged symptoms. The ATE of ongoing prolonged symptoms on EQ-VAS was - 12.9 [95% CI - 15.9 to - 9.8], and on the EQ-5D-3L it was - 0.11 [95% CI - 0.13 to - 0.09], implying prolonged symptoms have a negative impact on patients' EQ-VAS and EQ-5D-3L score. In multivariable linear regression, only having prolonged symptoms was associated with lower scores (- 11.7 [95% CI - 15.0 to - 8.5] for EQ-VAS and - 0.10 [95% CI - 0.13 to - 0.08] for EQ-5D-3L). CONCLUSIONS: Due to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life.

A Fatal Breakthrough COVID-19 Case Following Bendamustine-Rituximab Therapy.

Although messenger ribonucleic acid vaccines are substantially effective toward SARS-CoV-2 infection, patients with hematologic malignancies are still prone to the virus. Herein, we report a fatal case of breakthrough SARS-CoV-2 Delta variant infection in a patient with mucosa-associated lymphoid tissue lymphoma with remission by bendamustine-rituximab (BR) therapy completed a year ago. The serologic study revealed impaired responsiveness toward vaccines and prolonged high viral load after infection. BR therapy seemingly induced an immune escape. Prevention and treatment strategies for such vulnerable patients should be clarified immediately.

Factors associated with development and persistence of post-COVID conditions: A cross-sectional study.

INTRODUCTION: The post-COVID condition has become a social concern. Although the patient characteristics associated with the development of this condition are partially known, those associated with its persistence have not been identified. METHODS: We conducted a cross-sectional questionnaire-based survey among patients who had recovered from COVID-19 and visited the National Center for Global Health and Medicine between February 2021 and March 2021. Demographic and clinical data, and data regarding the presence and duration of post-COVID conditions were obtained. We identified factors associated with the development and persistence of post-COVID conditions using multivariate logistic and linear regression analyses, respectively. RESULTS: We analyzed 457 of 526 responses (response rate, 86.9%). The median patient age was 47 years. Of these, 378 patients (84.4%) had mild disease in the acute phase. The number of patients with symptoms at 6 and 12 months after onset or diagnosis was 120 (26.3%) and 40 (8.8%), respectively. Women were at risk of developing fatigue (odds ratio [OR]: 2.03, 95% confidence interval [CI]: 1.31-3.14), dysosmia (OR: 1.91, 95%CI: 1.24-2.93), dysgeusia (OR: 1.56, 95%CI: 1.02-2.39), hair loss (OR: 3.00, 95%CI: 1.77-5.09), and persistence of any symptoms (coefficient: 38.0, 95%CI: 13.3-62.8). Younger age and low body mass index were factors for developing dysosmia (OR: 0.96, 95%CI: 0.94-0.98 and OR: 0.94, 95%CI: 0.89-0.99, respectively) and dysgeusia (OR: 0.98, 95%CI: 0.96-1.00 and OR: 0.93, 95%CI: 0.88-0.98, respectively). CONCLUSION: We identified factors involved in the development and persistence of post-COVID conditions. Many patients, even those with mild conditions, experience long-term residual symptoms.

Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19.

Management of COVID-19 patients with humoral immunodeficiency is challenging. We describe a woman with COVID-19 with multiple relapses due to anti-CD20 monoclonal antibody treatment. She was successfully treated with casirivimab/imdevimab and confirmed to have neutralizing antibodies. This case suggests that monoclonal antibodies have therapeutic and prophylactic value in patients with humoral immunodeficiency.

Genetic association of IL17 and the importance of ABO blood group antigens in saliva to COVID-19.

The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, and the number of patients presenting with respiratory failure is rapidly increasing in Japan. An international meta-analysis has been conducted to identify genetic factors associated with the onset and severity of COVID-19, but these factors have yet to be fully clarified. Here, we carried out genomic analysis based on a genome-wide association study (GWAS) in Japanese COVID-19 patients to determine whether genetic factors reported to be associated with the onset or severity of COVID-19 in the international meta-GWAS are replicated in the Japanese population, and whether new genetic factors exist. Although no significant genome-wide association was detected in the Japanese GWAS, an integrated analysis with the international meta-GWAS identified for the first time the involvement of the IL17A/IL17F gene in the severity of COVID-19. Among nine genes reported in the international meta-GWAS as genes involved in the onset of COVID-19, the association of FOXP4-AS1, ABO, and IFNAR2 genes was replicated in the Japanese population. Moreover, combined analysis of ABO and FUT2 genotypes revealed that the presence of oral AB antigens was significantly associated with the onset of COVID-19. FOXP4-AS1 and IFNAR2 were also significantly associated in the integrated analysis of the Japanese GWAS and international meta-GWAS when compared with severe COVID-19 cases and the general population. This made it clear that these two genes were also involved in not only the onset but also the severity of COVID-19. In particular, FOXP4-AS1 was not found to be associated with the severity of COVID-19 in the international meta-GWAS, but an integrated analysis with the Japanese GWAS revealed an association with severity. Individuals with the SNP risk allele found between IL17A and IL17F had significantly lower mRNA expression levels of IL17F, suggesting that activation of the innate immune response by IL17F may play an important role in the severity of SARS-CoV-2 infection.

Impact of newly diagnosed diabetes on coronavirus disease 2019 severity and hyperglycemia.

AIMS/INTRODUCTION: Diabetes is associated with poor clinical outcomes of coronavirus disease 2019 (COVID-19). However, the impact of newly diagnosed diabetes on prognosis has not been clarified. The objective of this study was to show the features and outcome of COVID-19 patients with newly diagnosed diabetes in Japan. MATERIALS AND METHODS: We retrospectively analyzed 62 patients with diabetes hospitalized for COVID-19 between 1 April and 18 August 2021 at the National Center for Global Health and Medicine in Tokyo, Japan. We evaluated the worst severity of COVID-19 and plasma blood glucose levels in patients with newly diagnosed diabetes or pre-existing diabetes. RESULTS: This study included 62 confirmed COVID-19 patients with diabetes, including 19 (30.6%) patients with newly diagnosed diabetes and 43 (69.4%) patients with pre-existing diabetes. Patients with newly diagnosed diabetes significantly progressed to a critical condition more frequently during hospitalization than patients with pre-existing diabetes (52.6% vs 20.9%, P = 0.018). In addition, patients with newly diagnosed diabetes had significantly higher average plasma blood glucose levels for the first 3 days after admission than those with pre-existing diabetes. CONCLUSIONS: Our study suggests that the proportion of COVID-19 patients who are newly diagnosed with diabetes is high, and they have an increased risk of developing severe disease than those with pre-existing diabetes. It might be advisable that at the point of COVID-19 diagnosis, blood glucose and glycated hemoglobin levels be assessed in all patients.

Multisystem Inflammatory Syndrome in Adult after First Dose of mRNA Vaccine.

A 32-year-old man in Japan experienced respiratory failure after receiving the first dose of coronavirus disease (COVID-19) vaccine. He was treated with noninvasive ventilation and corticosteroids. Serologic test results suggested previous COVID-19; therefore, he received a diagnosis of multisystem inflammatory syndrome. COVID-19 vaccination could be a trigger for this condition.

Fatty liver on computed tomography scan on admission is a risk factor for severe coronavirus disease.

OBJECTIVES: To alleviate the overflow of coronavirus disease 2019 (COVID-19) patients in hospitals, less invasive and simple criteria are required to triage the patients. We evaluated the relationship between COVID-19 severity and fatty liver on plain computed tomography (CT) scan performed on admission. METHODS: In this retrospective cohort study, we considered all COVID-19 patients at a large tertiary care hospital between January 31 and August 31, 2020. COVID-19 severity was categorized into severe (moderate and severe) and non-severe (asymptomatic and mild) groups, based on the Japanese National COVID-19 guidelines. Fatty liver was detected on plain CT scan. Multivariate logistic regression analysis was performed to evaluate factors associated with severe COVID-19. RESULTS: Of 222 patients (median age: 52 years), 3.2%, 58.1%, 20.7%, and 18.0% presented with asymptomatic, mild, moderate, and severe COVID-19, respectively. Although 59.9% had no fatty liver on plain CT, mild, moderate, and severe fatty liver occurred in 13.1%, 18.9%, and 8.1%, respectively. Age and presence of fatty liver were significantly associated with severe COVID-19. CONCLUSION: Our study showed that fatty liver on plain CT scan on admission can become a risk factor for severe COVID-19. This finding may help clinicians to easily triage COVID-19 patients.

Extracorporeal membrane oxygenation may decrease the plasma concentration of remdesivir in a patient with severe coronavirus disease 2019.

Remdesivir is an antiviral drug that results in clinical improvement after five days of treatment and accelerates recovery by 31%. No studies have discussed the pharmacokinetic analysis of remdesivir in patients with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO). A 63-year-old American man who underwent mechanical ventilation and ECMO for severe COVID-19 was administered remdesivir for ten days. The loading dosage was 200 mg at 7 PM on day 12 and 100 mg daily at 0:00 PM from day 13-21, administered within 1 h. The pharmacokinetic analysis was performed. The serum creatinine concentration was within the normal range of 0.5-0.7 mg/dL during treatment. According to the pharmacokinetic analysis, the plasma concentrations of remdesivir and GS-441524 4 h after administration (C4) were 662 ng/mL and 58 ng/mL, respectively, and the concentrations 18 h after administration (C18) were 32 ng/mL and 44 ng/mL, respectively. Therefore, the half-life of remdesivir and GS-441524 was 3.2 and 35.1 h, respectively. Monitoring the plasma concentrations of remdesivir and GS-441524 in patients undergoing ECMO may be necessary.

Factors associated with high antibody titer following coronavirus disease among 581 convalescent plasma donors: A single-center cross-sectional study in Japan.

INTRODUCTION: The ability to predict which patients with a history of coronavirus disease (COVID-19) will exhibit a high antibody titer is necessary for more efficient screening of potential convalescent plasma donors. We aimed to identify factors associated with a high immunoglobulin G (IgG) titer in Japanese convalescent plasma donors after COVID-19. METHODS: This cross-sectional study included volunteers undergoing screening for convalescent plasma donation after COVID-19. Serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-protein IgG antibodies were measured using a high-sensitivity chemiluminescence enzyme immunoassay. RESULTS: IgG antibodies were measured in 581 patients, 534 of whom had full information of selected independent variables. Multiple linear regression analysis revealed that increasing age (1.037 [1,025, 1.048]), days from symptom onset to sampling (0.997 [0.995, 0.998]), fever (1.664 [1.226, 2.259]), systemic corticosteroid use during SARS-CoV-2 infection (2.382 [1.576, 3.601]), and blood type AB (1.478 [1.032, 2.117]) predict antibody titer. CONCLUSION: Older participants, those who experienced fever during infection, those treated with systemic corticosteroids during infection, those from whom samples were obtained earlier after symptom onset, and those with blood type AB are the best candidates for convalescent plasma donation. Therefore, these factors should be incorporated into the screening criteria for convalescent plasma donation after SARS-CoV-2 infection.

Antibody titers against SARS-CoV-2 decline, but do not disappear for several months.

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.

Characterization of a new SARS-CoV-2 variant that emerged in Brazil.

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.

How we secured a COVID-19 convalescent plasma procurement scheme in Japan.

BACKGROUND: In order to tackle the COVID-19 pandemic, a COVID-19 convalescent plasma (CCP) procurement program was initiated in Japan in April 2020. The program was a collaboration between a government-managed national hospital, an infectious disease research institute, and a blood banking organization. Each party assumed different responsibilities: recruitment, SARS-CoV-2 antibody profiling, and plasmapheresis; conduction of screening tests; and SARS-CoV-2 blood testing, respectively. METHODS: We adopted a two-point screening approach before the collected CCP was labeled as a CCP product for investigational use, for which we mainly tested anti-SARS-CoV-2 antibody eligibility and blood product eligibility. Anti-SARS-CoV-2 spike protein titer was measured using enzyme-linked immunosorbent assay, and the IC50 value was denoted as the neutralizing activity. Blood donor eligibility was extended beyond the normal blood donation guidelines to include a broader range of participants. After both eligibility criteria were confirmed, participants were asked to revisit the hospital for blood donation, which is a unique aspect of the Japanese CCP program, as most donations are taking place in normal blood donation venues in other countries. Some donors were re-scheduled for repeat plasma donations. As public interest in anti-SARS-CoV-2 antibodies increased, test results were given to the participants. RESULTS: As of September 17, 2020, our collection of CCP products was sufficient to treat more than 100 patients. As a result, projects for administration and distribution are also being conducted. CONCLUSIONS: We successfully implemented a CCP procurement scheme with the goal to expand to other parts of the country to improve treatment options for COVID-19.