Persistent differences in the immunogenicity of the two COVID-19 primary vaccines series, modulated by booster mRNA vaccination and breakthrough infection.

INTRODUCTION: The long-term impact of initial immunogenicity induced by different primary COVID-19 vaccine series remains unclear. METHODS: A prospective cohort study was conducted at 10 tertiary hospitals in Korea from March 2021 to September 2022. Immunogenicity assessments included anti-spike protein antibody (Sab), SARS-CoV-2-specific interferon-gamma releasing assay (IGRA), and multiplex cytokine assays for spike protein-stimulated plasma. Spike proteins derived from wild-type SARS-CoV-2 and alpha variant (Spike1) and beta and gamma variant (Spike2) were utilized. RESULTS: A total of 235 healthcare workers who had received a two-dose primary vaccine series of either ChAdOx1 or BNT162b2, followed by a third booster dose of BNT162b2 (166 in the ChAdOx1/ChAdOx1/BNT162b2 (CCB) group and 69 in the BNT162b2/BNT162b2/BNT162b2 (BBB) group, based on the vaccine series) were included. Following the primary vaccine series, the BBB group exhibited significantly higher increases in Sab levels, IGRA responses, and multiple cytokines (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1ß, interleukin (IL)-1ra, IFN-γ, IL-2, IL-4, and IL-10) compared to the CCB group (all P < 0.05). One month after the third BNT162b2 booster, the CCB group showed Sab levels comparable to those of the BBB group, and both groups exhibited lower levels after six months without breakthrough infections (BIs). However, among those who experienced BA.1/2 BIs after the third booster, Sab levels increased significantly more in the BBB group than in the CCB group (P < 0.001). IGRA responses to both Spike1 and Spike2 proteins were significantly stronger in the BBB group than the CCB group after the third booster, while only the Spike2 response were higher after BIs (P = 0.007). The BBB group exhibited stronger enhancement of T-cell cytokines (IL-2, IL-4, and IL-17A) after BIs than in the CCB group (P < 0.05). CONCLUSION: Differences in immunogenicity induced by the two primary vaccine series persisted, modulated by subsequent booster vaccinations and BIs.

Physical Activity and the incidence of sepsis: A 10-year observational study among 4 million adults.

BACKGROUND: As the group at high risk for sepsis is increasing with the aging of the population, physical activity (PA), which has beneficial effects on various diseases, needs to be considered as a personalized prevention strategy for sepsis without direct anti-sepsis drug. PURPOSE: To examine the association between the amount of PA (based on intensity, duration, and frequency) and the incidence rates of sepsis and mortality after sepsis. METHODS: This was a large-scale, retrospective, longitudinal cohort study using data from the Korean National Health Insurance Service and the biennial general health screening program. The amount of PA self-reported at the time of the health screening was categorized as non-PA, mild (<500 metabolic equivalents [METs]-Min/Week), moderate (500-1000), severe (1000-1500), and extreme (≥1500). The multivariable regression model was adjusted for age, sex, income, body mass index, smoking, alcohol consumption, diabetes, hypertension, dyslipidemia, and chronic diseases. RESULTS: From 4,234,415 individuals who underwent a health screening in 2009, 3,929,165 subjects were selected after exclusion for wash-out period and a 1-year lag period, and then observed for the event of sepsis or all-cause death until December 2020. During a median 10.3 years of follow-up, 83,011 incidents of sepsis were detected. The moderate-PA group showed the lowest incidence (1.56/1000 person-years) and risk for sepsis, with an adjusted hazard ratio (aHR) of 0.73 (95% CI, 0.72-0.75, P < 0.001) compared with the non-PA group. The occurrence of sepsis among people aged ≥65 years and ex-smokers were significantly lower in the moderate-PA group (aHR; 0.77, 95% CI; 0.74-0.79; and 0.68, 0.64-0.71, respectively, Ps < 0.001). The long-term all-cause mortality after sepsis was significantly lower in the PA group than in the non-PA group (overall P = 0.003). CONCLUSIONS: Physical activity is associated with a lower risk of sepsis, especially in elderly people who have the highest incidence of sepsis. The protective effects of aerobic PA on sepsis might need to be incorporated with other interventions in sepsis guidelines through the accumulation of future studies.

The Relation Between Cigarette Smoking and Development of Sepsis: A 10-Year Follow-Up Study of Four Million Adults from the National Health Screening Program.

BACKGROUND: Sepsis remains a growing global health concern with soaring mortality and no direct anti-sepsis drug. Although smoking has distinct deleterious effects on chronic inflammatory illnesses and can impair immune function, a comprehensive analysis of the connection between sepsis and smoking is lacking. METHODS: This large-scale longitudinal cohort study retrospectively assessed adults aged ≥ 20 years who underwent national health checkups under the Korean National Health Insurance Service between January and December 2009 (N = 4,234,415) and were followed up for 10 years. Sepsis was identified based on the International Classification of Diseases, 10th Revision codes, and smoking status, including accumulated amount, was collected through a self-administered questionnaire. The Cox proportional hazard regression model was used, adjusting for age, sex, household income, body mass index, drinking, exercise, diabetes, hypertension, dyslipidemia, and chronic renal disease. RESULTS: After excluding cases with sepsis occurring before follow-up or after ≤ 1 year of follow-up, 3,881,958 participants, including non-smokers (N = 2,342,841), former smokers (N = 539,850), and active smokers (N = 999,267), were included. Compared to non-smokers, all active smokers (adjust hazard ratio: 1.41, 95% confidence interval 1.38-1.44) and former smokers (1.10, 1.07-1.14) with ≥ 20 pack-years exhibited a significantly higher risk of sepsis (p < 0.001). Smoking of ≥ 30 pack-years in former and active smokers groups significantly increased sepsis incidence (adjust hazard ratio [95% confidence interval] 1.34 [1.31-1.38], p < 0.001). CONCLUSIONS: Smoking is closely associated with the incidence of sepsis. Smoking cessation may help in the primary prevention of sepsis.

Clinical utility of quantitative immunoassays and surrogate virus neutralization tests for predicting neutralizing activity against the SARS-CoV-2 Omicron BA.1 and BA.5 variants.

Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.

Prevalence of carbapenemase producing Enterobacterales colonization and risk factor of clinical infection.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are global concerns in infection control, and the number of CPE outbreaks in hospitals is increasing despite the strengthening of contact precautions. This study aimed to confirm the prevalence and transition rate of CPE infection from stool surveillance culture and to identify the acquisition pathway of CPE. METHODS: This is a longitudinal review of patients with stool surveillance cultures at a tertiary center in Seoul, South Korea, from July 2018 to June 2020. Pulsed-field gel electrophoresis, multi-locus sequence typing, and whole genome sequencing were performed for carbapenemase-producing Klebsiella pneumoniae and Escherichia coli strains. RESULTS: Among 1620 patients who had undergone stool CPE surveillance cultures, only 7.1% of active surveillance at the Emergency Room (ER) and 4.4% of universal surveillance in the Intensive Care Unit (ICU) were stool CPE positive. The transition rates from stool carriers to clinical CPE infections were 29.4% in the ER and 31.3% in the ICU. However, it was significantly high (55.0%) in the initial stool CPE-negative ICU patients. Among the initial stool CPE-positive patients, hypertension (61% vs. 92.3%, P = 0.004), malignancy (28.8% vs. 53.8%, P = 0.027), and mechanical ventilation (25.4% vs. 53.8%, P = 0.011) were significant risk factors for clinical CPE infection. Molecular typing revealed that sequence type (ST) 307 and ST 395 were dominant in K. pneumoniae, and ST 410 was dominant in E. coli isolates. CONCLUSIONS: Active surveillance showed a higher detection rate than universal stool CPE screening, and one-third of positive stool CPE specimens ultimately developed subsquent clinical CPE infection. According to the molecular typing of the identified CPE strains, in-hospital spread prevailed over external inflow, and the transition rate to clinical CPE was particularly high in the ICU. Therefore, in order to control CPE propagation, not only active surveillance to block inflow from outside, but also continuous ICU monitoring within the hospital is necessary.

Differences of clinical characteristics and outcome in proven invasive Trichosporon infections caused by asahii and non-asahii species.

BACKGROUND: Trichosporon is an emerging yeast that causes invasive infections in immunocompromised patients experiencing prolonged hospitalisation, indwelling venous catheters and neutropenia. METHODS: This retrospective observational cohort study analysed invasive Trichosporon infections (ITIs) occurring between January 2005 and December 2022 at three tertiary hospitals and compared the clinical characteristics and prognostic factors of ITIs caused by Trichosporon asahii and non-T. asahii spp. After evaluating 1067 clinical isolates, we identified 46 patients with proven ITIs, defined as cases in which Trichosporon was isolated from blood, cerebrospinal fluid, or sterile tissues. RESULTS: The patients were separated into T. asahii and non-T. asahii groups containing 25 and 21 patients, respectively, all of which except one were immunocompromised. During this period, both the number of clinical isolates and patients with ITIs (mainly T. asahii) increased; whereas, cases involving non-T. asahii spp. decreased. Compared with the non-T. asahii group, the T. asahii group had more patients with multiple catheters (84% vs. 33%, p = .001) and those receiving renal replacement therapy (48% vs. 14%, p = .005). The all-cause 28-day mortality rate after ITI in the T. asahii group (44%) was significantly higher than in the non-T. asahii group (10%, Log-rank p = .014). The multivariate Cox regression model revealed that T. asahii (reference, non-T. asahii spp.; aHR = 4.3; 95% CI = 1.2-15.2, p = .024) and neutropenia for 5 days or more (aHR = 2.2, 95% CI = 1.5-3.6, p = .035) were independent factors in the 28-day mortality after ITI. CONCLUSION: The proven ITIs due to T. asahii produced more unfavourable outcomes compared with ITIs caused by non-T. asahii spp.

Immune Response Kinetics Following a Third Heterologous BNT162b2 Booster Dose After Primary 2-Dose ChAdOx1 Vaccination in Relation to Omicron Breakthrough Infection: A Prospective Nationwide Cohort Study in South Korea.

Background: Immune responses to each vaccine must be investigated to establish effective vaccination strategies for the ongoing coronavirus disease (COVID-19) pandemic. We investigated the long-term kinetics of immune responses after heterologous booster vaccination in relation to Omicron breakthrough infection (BI). Methods: Our study included 373 healthcare workers who received primary ChAdOx1 vaccine doses and a third BNT162b2 vaccine dose. BIs that occurred after the third vaccine were investigated. Blood specimens were collected before and 3 months after the booster dose from participants without BI and 1, 4, and 6 months after BI from participants who experienced BI. Spike-specific binding and neutralizing antibody levels against the wild-type virus, Omicron BA.1, and Omicron BA.5, as well as cellular responses, were analyzed. Results: A total of 346 participants (82 in the no BI group; 192 in the BI group during the BA.1/BA.2 period; 72 in the BI group during the BA.5 period) were included in the analysis. Participants without BI exhibited the highest binding and neutralizing antibody concentrations and greatest cellular response 1 month after the third vaccination, which reached a nadir by the ninth month. Antibody and cellular responses in participants who experienced BI substantially increased postinfection. Neutralizing antibody titers in individuals who experienced BI during the BA.1/BA.2 period showed more robust increase against wild-type virus than against BA.1 and BA.5. Conclusions: Our findings provide evidence of antigenic imprinting in participants who received a heterologous booster vaccination, thereby serving as a foundation for further studies on the impact of BIs on immune responses.

Potential causal effect of contact precautions and isolation on Clostridioides difficile infection in the hyperendemic setting: Interrupted time-series analyses before and after implementation.

BACKGROUND: Recent studies disputed the effectiveness of efforts to comply with contact precautions and isolation (CPI) considering relatively low intra-hospital transmission rate of healthcare facility-associated Clostridioides difficile infection (HCFA-CDI). We evaluated the potential causal effect of CPI on HCFA-CDI occurrence by comparing the incidence rate (IR) for different time periods with and without CPI implementation. METHODS: Long-term observational time-series data were separated into three periods (pre-CPI: January 2012-March 2016, CPI: April 2016-April 2021, post-CPI: May 2021-December 2022). CPI was suspended owing to the restriction of isolation rooms during the COVID-19 pandemic. We inferred potential causal outcomes by comparing predicted and observed IRs of HCFA-CDI using interrupted time-series analyses, including the Bayesian structural time-series or autoregressive integrated moving average (ARIMA) model in the R-language or SAS software. RESULTS: The monthly observed IR (44.9/100,000 inpatient-days) during the CPI period was significantly lower than the predicted IR (90.8) (-50.6% relative effect, P = 0.001). However, the observed IR (52.3) during the post-CPI period was significantly higher than the predicted IR (39.1) (33.6%, P = 0.001). The HCFA-CDI IR decreased during CPI (-14.3, P < 0.001) and increased post-CPI (5.4, P < 0.001) in the multivariable ARIMA model, which controlled for antibiotic usage, handwashing with soap and water, and number of toxin tests. CONCLUSIONS: Various time-series models revealed that CPI implementation had a potential causal effect on the reduction of HCFA-CDI incidence.

Changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia and the impact of their antimicrobial resistance patterns on clinical outcomes: A propensity-score-matched study.

BACKGROUND: This study aimed to evaluate changes in the prevalence of pathogens causing hospital-acquired bacterial pneumonia (HABP) and their antimicrobial resistance patterns in recent years, and to identify risk factors for 28-day all-cause mortality (ACM) in patients with HABP. METHODS: A propensity-score-matched study was performed by randomly allocating patients with ventilator-associated and non-ventilator-associated bacterial pneumonia admitted to two university hospitals between 2011 and 2021. RESULTS: In total, 17,250 patients with HABP were enrolled. The annual incidence of Staphylococcus aureus HABP decreased during the study period, while that of Klebsiella pneumoniae HABP increased significantly each year. Over the same period, the resistance rate of S. aureus to methicillin decreased from 88.4% to 64.4%, while the non-susceptibility rate of K. pneumoniae to carbapenems increased from 0% to 38%. HABP caused by A. baumannii [adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 1.25-1.79], K. pneumoniae (aOR 1.28, 95% CI 1.16-1.40) and Stenotrophomonas maltophilia (aOR 1.32, 95% CI 1.05-1.66) was a risk factor for 28-day ACM. Patients with HABP caused by methicillin-resistant S. aureus and carbapenem-non-susceptible A. baumannii or K. pneumoniae had a significantly lower probability of survival. HABP with preceding coronavirus disease 2019 (COVID-19) was associated with high 28-day ACM (aOR 5.40, 955 CI 3.03-9.64) and high incidence of bacteraemic pneumonia (aOR 40.55, 95% CI 5.26-312.79). CONCLUSIONS: This study showed shifting trends in HABP-causing pathogens in terms of annual incidence and resistance rates to major therapeutic antimicrobial agents. HABP-causing bacterial pathogens, their antimicrobial resistance phenotypes, and preceding COVID-19 were significantly associated with progression of HABP to bloodstream infection and 28-day ACM in infected patients.

Immunogenicity and Safety of Vaccines against Coronavirus Disease in Actively Treated Patients with Solid Tumors: A Prospective Cohort Study.

PURPOSE: We aimed to assess the humoral response to and reactogenicity of coronavirus disease 2019 (COVID-19) vaccination according to the vaccine type and to analyze factors associated with immunogenicity in actively treated solid cancer patients (CPs). Materials and Methods: Prospective cohorts of CPs, undergoing anticancer treatment, and healthcare workers (HCWs) were established. The participants had no history of previous COVID-19 and received either mRNA-based or adenovirus vector-based (AdV) vaccines as the primary series. Blood samples were collected before the first vaccination and after 2 weeks for each dose vaccination. Spike-specific binding antibodies (bAbs) in all participants and neutralizing antibodies (nAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type, Delta, and Omicron variants in CPs were analyzed and presented as the geometric mean titer. RESULTS: Age-matched 20 HCWs and 118 CPs were included in the analysis. The bAb seroconversion rate and antibody concentrations after the first vaccination were significantly lower in CPs than in HCWs. After the third vaccination, antibody levels in CPs with a primary series of AdV were comparable to those in HCWs, but nAb titers against the Omicron variant did not quantitatively increase in CPs with AdV vaccine as the primary series. The incidence and severity of adverse reactions post-vaccination were similar between CPs and HCWs. CONCLUSION: CPs displayed delayed humoral immune response after SARS-CoV-2 vaccination. The booster dose elicited comparable bAb concentrations between CPs and HCWs, regardless of the primary vaccine type. Neutralization against the Omicron variant was not robustly elicited following the booster dose in some CPs, implying the need for additional interventions to protect them from COVID-19.

Discrepancy of C-Reactive Protein, Procalcitonin and Interleukin-6 at Hospitalization: Infection in Patients with Normal C-Reactive Protein, Procalcitonin and High Interleukin-6 Values.

C-reactive protein (CRP) or procalcitonin (PCT) alone has limitations in the early detection of infection or inflammation due to shortcomings in specificity and varied cut-off values. Recently, interleukin (IL)-6 has been assessed, but it is not known to what extent the three values are homogeneous in reality. This retrospective study was conducted with two large datasets (discrepancy set with results within 24 h of admission [7149 patients] and follow-up set until 2 weeks of hospital stay [5261 tests]) consisting of simultaneous examinations of CRP, PCT, and IL-6 between January 2015 and August 2021. The specific discrepant group (n = 102, 1.4%) with normal CRP (<10 mg/L) and PCT (<0.1 ng/mL) and high IL-6 (≥100 pg/mL) values was extracted from the discrepancy set. Dimensionality reduction and visualization were performed using Python. The three markers were not clearly clustered after t-distributed stochastic neighbor embedding. Pearson's correlation coefficients between two markers were substantially low (0.23−0.55). Among the high normalized IL-6 levels (≥0.5) (n = 349), 17.8% and 38.7% of CRP and PCT levels were very low (≤0.01). 9.2% and 13.4% of normal CRP (n = 1522) had high PCT (≥0.5 ng/mL) and IL-6 (≥100 pg/mL) values, respectively. Infection and bacteremia among 102 patients occurred in 36 (35.3%) and 9 (8.8%) patients, respectively. In patients with bacteremia, IL-6 was the first to increase, followed by PCT and CRP. Our study revealed that CRP, PCT, and IL-6 levels were considerably discrepant, which could be misinterpreted if only CRP tests are performed.

Reactogenicity and Immunogenicity of the ChAdOx1 nCOV-19 Coronavirus Disease 2019 Vaccine in South Korean Healthcare Workers.

PURPOSE: The association between reactogenicity and immunogenicity of the ChAdOx1 nCOV-19 is controversial. We aimed to evaluate this association among South Korean healthcare workers (HCWs). MATERIALS AND METHODS: Participants received two doses of the ChAdOx1vaccine 12 weeks apart. Blood samples were tested for anti-severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) spike protein receptor binding domain antibodies about 2 months after the first and second doses using the Elecsys Anti-SARS-CoV-2 S assay kits. Adverse events were noted using an online self-reporting questionnaire. RESULTS: Among the 232 HCWs, pain (85.78% after the first dose vs. 58.62% after the second dose, p<0.001) was the most prominent local reaction, and myalgia or fatigue (84.05% vs. 53.02%, p<0.001) was the most prominent systemic reaction. The frequency of all adverse events was significantly reduced after the second dose. After the first dose, the anti-SARS-CoV-2 S showed significantly higher titer in the group with swelling, itching, fever, and nausea. Also, the anti-SARS-CoV-2 S titer significantly increased as the grade of fever (p=0.007) and duration of fever (p=0.026) increased; however, there was no significant correlation between immunogenicity and adverse event after the second dose. The group with pain after the first dose showed a greater increase in the anti-SARS-CoV-2 S difference between the second and first doses compared to the group without pain (542.2 U/mL vs. 363.8 U/mL, p=0.037). CONCLUSION: The frequency of adverse events occurring after the first dose of the ChAdOx1 was significantly reduced after the second dose. Interestingly, the elevation of anti-SARS-CoV-2 S titer was significantly increased in the group with pain after the first dose.

Kinetics of vaccine-induced neutralizing antibody titers and estimated protective immunity against wild-type SARS-CoV-2 and the Delta variant: A prospective nationwide cohort study comparing three COVID-19 vaccination protocols in South Korea.

Introduction: Despite vaccine development, the COVID-19 pandemic is ongoing due to immunity-escaping variants of concern (VOCs). Estimations of vaccine-induced protective immunity against VOCs are essential for setting proper COVID-19 vaccination policy. Methods: We performed plaque-reduction neutralizing tests (PRNTs) using sera from healthcare workers (HCWs) collected from baseline to six months after COVID-19 vaccination and from convalescent COVID-19 patients. The 20.2% of the mean PRNT titer of convalescent sera was used as 50% protective value, and the percentage of HCWs with protective immunity for each week (percent-week) was compared among vaccination groups. A correlation equation was deduced between a PRNT 50% neutralizing dose (ND50) against wild type (WT) SARS-CoV-2 and that of the Delta variant. Results: We conducted PRNTs on 1,287 serum samples from 297 HCWs (99 HCWs who received homologous ChAdOx1 vaccination (ChAd), 99 from HCWs who received homologous BNT162b2 (BNT), and 99 from HCWs who received heterologous ChAd followed by BNT (ChAd-BNT)). Using 365 serum samples from 116 convalescent COVID-19 patients, PRNT ND50 of 118.25 was derived as 50% protective value. The 6-month cumulative percentage of HCWs with protective immunity against WT SARS-CoV-2 was highest in the BNT group (2297.0 percent-week), followed by the ChAd-BNT (1576.8) and ChAd (1403.0) groups. In the inter-group comparison, protective percentage of the BNT group (median 96.0%, IQR 91.2-99.2%) was comparable to the ChAd-BNT group (median 85.4%, IQR 15.7-100%; P =0.117) and significantly higher than the ChAd group (median 60.1%, IQR 20.0-87.1%; P <0.001). When Delta PRNT was estimated using the correlation equation, protective immunity at the 6-month waning point was markedly decreased (28.3% for ChAd group, 52.5% for BNT, and 66.7% for ChAd-BNT). Conclusion: Decreased vaccine-induced protective immunity at the 6-month waning point and lesser response against the Delta variant may explain the Delta-dominated outbreak of late 2021. Follow-up studies for newly-emerging VOCs would also be needed.

Estimation of SARS-CoV-2 Neutralizing Activity and Protective Immunity in Different Vaccine Types Using Three Surrogate Virus Neutralization Test Assays and Two Semiquantitative Binding Assays Targeting the Receptor-Binding Domain.

Estimating neutralizing activity in vaccinees is crucial for predicting the protective effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As the plaque reduction neutralization test (PRNT) requires a biosafety level 3 facility, it would be advantageous if surrogate virus neutralization test (sVNT) assays and binding assays could predict neutralizing activity. Here, five different assays were evaluated with respect to the PRNT in vaccinees: three sVNT assays from GenScript, Boditech Med, and SD Biosensor and two semiquantitative binding assays from Roche and Abbott. The vaccinees were subjected to three vaccination protocols: homologous ChAdOx1, homologous BNT162b2, and heterologous administration. The ability to predict a 50% neutralizing dose (ND50) of ≥20 largely varied among the assays, with the binding assays showing substantial agreement (kappa, ~0.90) and the sVNT assays showing relatively poor performance, especially in the ChAdOx1 group (kappa, 0.33 to 0.97). The ability to predict an ND50 value of ≥118.25, indicating a protective effect, was comparable among different assays. Applying optimal cutoffs based on Youden's index, the kappa agreements were greater than 0.60 for all assays in the total group. Overall, relatively poor performance was demonstrated in the ChAdOx1 group, owing to low antibody titers. Although there were intra-assay differences related to the vaccination protocols, as well as interassay differences, all assays demonstrated fair performance in predicting the protective effect using the new cutoffs. This study demonstrates the need for a different cutoff for each assay to appropriately determine a higher neutralizing titer and suggests the clinical feasibility of using various assays for estimation of the protective effect. IMPORTANCE The coronavirus disease 2019 (COVID-19) pandemic continues to last, despite high COVID-19 vaccination rates. As many people experience breakthrough infection after prior infection and/or vaccination, estimating the neutralization activity and predicting the protective effect are major issues of concern. However, since standard neutralization tests are not available in most clinical laboratories, it would be beneficial if commercial assays could predict these aspects. In this study, we evaluated the performance of three sVNT assays and two semiquantitative binding assays targeting the receptor-binding domain with respect to the PRNT. Our results suggest that these assays could be used for predicting the protective effect by adjusting the cutoffs.

Association of cytomegalovirus diseases with newly developed myocardial infarction and congestive heart failure: data from a national population-based cohort.

Introduction: Anti-cytomegalovirus (CMV) IgG seropositive and/or titer are associated with a higher risk of cardiovascular diseases (CVD). However, it is not clear whether CMV end-organ disease may have a relation with development of CVD or chronic heart diseases. Material and methods: In matched cohort study, the National Health Insurance Database covering 50 million people was used to identify 667 patients with CMV diseases and aged ≥ 20 years between 2010 and 2014. 6,670 control subjects without CMV diseases were matched by age, sex, type 2 diabetes mellitus (DM), hypertension, dyslipidemia, and cohort entry year. Data on CMV disease and heart disease events of myocardial infarction (MI), congestive heart failure (CHF), and atrial fibrillation (AF) were retrieved. Previous events before CMV disease or cohort entry were excluded until January 2006. Subjects were followed until December 2015 in subjects without events and until date of events in subjects with events. Results: The multivariate regression model adjusted by age, sex, low-income status, type 2 DM, hypertension, dyslipidemia, solid organ transplantation, and hematopoietic stem cell transplantation showed a significantly higher incidence rate of MI (odds ratio (OR) = 2.1, 95% confidence intervals (CI): 1.0-4.5) and CHF (OR = 3.8, 95% CI: 2.1-6.8) but not AF (OR = 1.9, 95% CI: 0.9-4.0) in patients with CMV disease. The age group of 40-64 years with CMV disease had the highest risk for new-onset CHF in this regression model (OR = 9.4, 95% CI: 4.12-21.44, p = 0.029). Conclusions: Symptomatic CMV tissue-invasive diseases were associated with a higher risk of new-onset MI and CHF.

Clinical Implication of Candida Score in Multidrug-Resistant Pneumonia with Airway Candida Colonization.

BACKGROUND: The growth of Candida in respiratory secretions is usually considered colonization, and antifungal therapy is rarely required. The role of Candida colonization in the progression of bacterial pneumonia remains controversial. The aim of this study was to identify the clinical implication of Candida score by analyzinge the relationship with multidrug-resistant (MDR) pneumonia and prognosis in patients with airway Candida colonization. MATERIALS AND METHODS: This study was a retrospective review of patients with airway Candida colonization by bronchial washing or bronchoalveolar lavage. The Candida score was calculated according to the four factors (severe sepsis, surgery at baseline, total parenteral nutrition, and multifocal Candida colonization). Pneumonia related mortality or hopeless discharge expecting death was defined as a poor outcome. RESULTS: A total of 148 patients were enrolled in the study. In a multivariate analysis model, Candida score was identified as an independent predictor of poor outcomes (odds ratio 2.23; 95% confidential interval 1.57 - 3.17; P <0.001) in pneumonia patients with airway Candida colonization. With a Candida score of three or higher compared with low score group, it was associated with bacterial pneumonia, especially methicillin-resistant Staphylococcus aureus (MRSA) infection (0.0% vs. 15.2%, P = 0.004). In addition, patients with a high Candida score had a longer hospital stay (13 vs. 38 days, P <0.001), longer duration of intensive care (7 vs. 18 days, P <0.001), and higher pneumonia-related mortality (0.0% vs. 45.5%, P <0.001) as compared to the low Candida score group. The Candida score showed a positive correlation with other pneumonia severity scales such as CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure, and age ≥65 years) (r = 0.461, P <0.001), Pneumonia Severity Index (r = 0.397, P <0.001), and predisposition, insult, response, and organ dysfunction (PIRO) score (r = 0.425, P <0.001). CONCLUSION: This study revealed that Candida is no longer a bystander of airway colonization, and that it affects the progression of bacterial pneumonia, including multidrug-resistant pathogens, particularly MRSA infection. Also Candida score can be used to predict the prognosis of patients with pneumonia.

Real-World Analysis of Rapid-Acting Insulin Analog Use and Its Blood Glucose Lowering Effect in Patients with Type 2 Diabetes Mellitus: Results from PASSION Disease Registry in Korea.

Purpose: Although rapid-acting insulins (RAIs) are used frequently in Korean clinical settings, evidence on their use is limited. This study explores the pattern and clinical effectiveness of the use of RAIs in Korean patients with type 2 diabetes mellitus (T2DM). Patients and Methods: This non-interventional, observational study enrolled patients (aged >18 years) with T2DM who were prescribed RAIs. The pattern of use and effectiveness of RAI analogs were evaluated over 6 months. Results: A total of 299/451 patients were analyzed. Approximately 90% (n/N=270/299) of the patients received insulin glulisine, which significantly reduced their levels of glycated hemoglobin (HbA1c: n=270, mean± standard deviation [SD]; -1.16±6.02%, p=0.0017), fasting plasma glucose (n=40; mean±SD: -54.9±90.89 mg/dl, p=0.0005), and post prandial blood glucose (n=35, mean±SD: -89.46± 105.68 mg/dl, p<0.0001) at 6 months, with a corresponding increase in body weight (BW) (n=197, mean±SD:1.45±3.64 kg, p<0.0001). At 6 months, more patients receiving an intensive regimen (basal insulin+≥2 RAI injections/day) had HbA1c <7% than those receiving a non-intensive regimen (basal insulin+1 RAI injection/day) (20.69% vs 7.46%; p=0.0333); the corresponding reduction in HbA1c was also higher in patients receiving the intensive regimen (p<0.0001). About one-fourth patients (n/N=22/95) were switched to the intensive regimen (from 1 to ≥2 RAI injections/day), and only 4.41% (n/N=9/204) of the patients were switched to 1 RAI injection/day. The patients receiving the intensive regimen showed higher levels of HbA1c reductions (mean±SD: -1.27±1.96%) compared with the maintenance group-1 RAI injection/day (mean±SD: -0.72±1.66%) (p=0.0459), without a significant increase in BW and body mass index. Conclusion: The insulin glulisine intensification regimen showed glycemic target achievement and can be considered a therapeutic tool in the management of T2DM patients.

Heterologous ChAdOx1 and Bnt162b2 vaccination induces strong neutralizing antibody responses against SARS-CoV-2 including delta variant with tolerable reactogenicity.

OBJECTIVES: We assessed humoral responses and reactogenicity following the heterologous vaccination compared to the homologous vaccination groups. METHODS: We enrolled healthcare workers (HCWs) who were either vaccinated with ChAdOx1 followed by BNT162b2 (heterologous group) or 2 doses of ChAdOx1 (ChAdOx1 group) or BNT162b2 (BNT162b2 group). Immunogenicity was assessed by measuring antibody titers against receptor-binding domain (RBD) of SARS-CoV-2 spike protein in all participants and neutralizing antibody titer in 100 participants per group. Reactogenicity was evaluated by a questionnaire-based survey. RESULTS: We enrolled 499 HCWs (ChAdOx1, n = 199; BNT162b2, n = 200; heterologous ChAdOx1/BNT162b2, n = 100). The geometric mean titer of anti-receptor-binding domain antibody at 14 days after the booster dose was significantly higher in the heterologous group (11 780.55 binding antibody unit (BAU)/mL [95% CI, 10 891.52-12 742.14]) than in the ChAdOx1 (1561.51 [95% CI, 1415.03-1723.15]) or BNT162b2 (2895.90 [95% CI, 2664.01-3147.98]) groups (both p < 0.001). The neutralizing antibody titer of the heterologous group (geometric mean ND50, 2367.74 [95% CI, 1970.03-2845.74]) was comparable to that of the BNT162b2 group (2118.63 [95% CI, 1755.88-2556.32]; p > 0.05) but higher than that of the ChAdOx1 group (391.77 [95% CI, 326.16-470.59]; p < 0.001). Compared with those against wild-type SARS-CoV-2, the geometric mean neutralizing antibody titers against the Delta variant at 14 days after the boosting were reduced by 3.0-fold in the heterologous group (geometric mean ND50, 872.01 [95% CI, 685.33-1109.54]), 4.0-fold in the BNT162b2 group (337.93 [95% CI, 262.78-434.57]), and 3.2-fold in the ChAdOx1 group (206.61 [95% CI, 144.05-296.34]). The local or systemic reactogenicity after the booster dose in the heterologous group was higher than that of the ChAdOx1 group but comparable to that of the BNT162b2 group. DISCUSSION: Heterologous ChAdOx1 followed by BNT162b2 vaccination with a 12-week interval induced a robust humoral immune response against SARS-CoV-2, including the Delta variant, that was comparable to the homologous BNT162b2 vaccination and stronger than the homologous ChAdOx1 vaccination, with a tolerable reactogenicity profile.

Use of antimicrobial agents in actively dying inpatients after suspension of life-sustaining treatments: Suggestion for antimicrobial stewardship.

BACKGROUND: The role of antimicrobial treatment in end-of-life care has been controversial, whether antibiotics have beneficial effects on comfort and prolonged survival or long-term harmful effects on increasing antimicrobial resistance. We assessed the use of antimicrobial agents and factors associated with de-escalation in inpatients who suspended life-sustaining treatments (SLST) and immediately died. METHODS: We included 1296 (74.7%) inpatients who died within 7 days after SLST out of 1734 patients who consented to SLST on their own or family's initiative following a decision by two physicians, observing the "Life-sustaining Treatment Decision Act" between January 2020 and December 2020 at two teaching hospitals. De-escalation was defined as changing to narrower spectrum anti-bacterial drugs or stopping ≥ one antibiotic of combined treatment. RESULTS: 90.6% of total patients received anti-bacterial agents, particularly a combination treatment in 60.1% and use of ≥ three drugs in 18.2% of them. Antifungal and antiviral drugs were administered to 12.6% and 3.3% of the patients on SLST, respectively. Antibacterial and antifungal agents were withdrawn in only 8.3% and 1.3% of the patients after SLST, respectively. Anti-bacterial de-escalation was performed in 17.0% of patients, but 43.6% of them received more or broad-spectrum antibiotics after SLST. In multivariate regression, longer hospital stays before SLST, initiation of SLST in the intensive care unit, and cardiovascular diseases were independently associated with anti-bacterial de-escalation after SLST. CONCLUSIONS: The intervention for substantial antibiotic use in patients on SLST should be carefully considered as antimicrobial stewardship after decision by the will of the patient and proxy.