Development and Validation of an Enzyme-Linked Immunosorbent Assay-Based Protocol for Evaluation of Respiratory Syncytial Virus Vaccines.

Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (pre-F) antigen were approved in the United States. We aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based protocol for the practical and large-scale evaluation of RSV vaccines. Two modified pre-F proteins (DS-Cav1 and SC-TM) were produced by genetic recombination and replication using an adenoviral vector. The protocol was established by optimizing the concentrations of the coating antigen (pre-F proteins), secondary antibodies, and blocking buffer. To validate the protocol, we examined its accuracy, precision, and specificity using serum samples from 150 participants across various age groups and the standard serum provided by the National Institute of Health. In the linear correlation analysis, coating concentrations of 5 and 2.5 µg/mL of DS-Cav1 and SC-TM showed high coefficients of determination (r > 0.90), respectively. Concentrations of secondary antibodies (alkaline phosphatase-conjugated anti-human immunoglobulin G, diluted 1:2000) and blocking reagents (5% skim milk/PBS-T) were optimized to minimize non-specific reactions. High accuracy was observed for DS-Cav1 (r = 0.90) and SC-TM (r = 0.86). Further, both antigens showed high precision (coefficient of variation < 15%). Inhibition ELISA revealed cross-reactivity of antibodies against DS-Cav1 and SC-TM, but not with the attachment (G) protein.

Comparative safety analysis of mRNA and adenoviral vector COVID-19 vaccines: a nationwide cohort study using an emulated target trial approach.

OBJECTIVE: This nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines. METHODS: A targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18-85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated. RESULTS: A total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10-1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14-4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24-1.71) in mRNA vaccinees. The incidence of Guillain-Barré syndrome (IRR, 0.20; 95% CI, 0.06-0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62-0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41-0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70-0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees. DISCUSSION: A remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain-Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms.

Herpes Zoster Reactivation After mRNA and Adenovirus-Vectored Coronavirus Disease 2019 Vaccination: Analysis of National Health Insurance Database.

BACKGROUND: Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored vaccine [ChAdOx1 nCoV-19]). METHODS: This retrospective study analyzed herpes zoster cases diagnosed between 26 February 2021 and 30 June 2021 and registered in the National Health Insurance Service database. A matched case-control study with a 1:3 matching ratio and a propensity score matching (PSM) study with a 1:1 ratio of vaccinated and unvaccinated individuals were performed. RESULTS: In the matched case control analysis, BNT162b2 was associated with an increased risk of herpes zoster reactivation (first dose adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 1.06-1.15; second dose aOR, 1.17; 95% CI, 1.12-1.23). PSM analysis revealed a statistically significant increase in risk within 18 days following any vaccination (adjusted hazard ratio [aHR], 1.09; 95% CI, 1.02-1.16). BNT162b2 was associated with an increased risk at 18 days postvaccination (aHR, 1.65; 95% CI, 1.35-2.02) and second dose (aHR, 1.10; 95% CI, 1.02-1.19). However, the risk did not increase in both analyses of ChAdOx1 vaccination. CONCLUSIONS: mRNA COVID-19 vaccination possibly increases the risk of herpes zoster reactivation, and thus close follow-up for herpes zoster reactivation is required.

Concurrent Subacute Thyroiditis and Graves' Disease After COVID-19: A Case Report.

There are many reports of subacute thyroiditis (SAT) that occurred after the coronavirus disease 2019 (COVID-19), but no such case has been reported in Korea. Moreover, the simultaneous occurrence of SAT and Graves' disease (GD) is rare. Here, we describe a patient who developed SAT and GD after the second episode of COVID-19. A 27-year-old woman with no known history of thyroid disease presented with fever, upper respiratory tract symptoms, and painful neck swelling. Thyroid function tests revealed thyrotoxicosis, and thyroid ultrasound showed heterogeneous echogenicity of enlarged thyroid glands. Her initial clinical presentation was consistent with SAT after viral infection, with typical neck tenderness and spontaneous improvement of thyrotoxicosis without antithyroid drug use. However, this case had some atypical features, such as an elevated thyroid-stimulating immunoglobulin level, relapse of thyrotoxicosis in short-term follow-up, and increased Tc-99m pertechnetate uptake, suggesting the coexistence of GD. About two months after methimazole (15 mg/day) was prescribed, she was lost to follow up again. We report the first case of unusual co-occurrence of SAT and GD following COVID-19.

Predictive and prognostic factors associated with unliquefied pyogenic liver abscesses.

INTRODUCTION: Poor liquefaction of pyogenic liver abscesses, which makes drainage impossible at the time of diagnosis, is not infrequent. The impact of poor liquefaction and subsequent drainage failure on clinical outcomes is unknown. METHODS: We conducted a retrospective study with all patients diagnosed with liver abscesses from July 2017 through June 2020. Late drainage (LD) was defined as drainage performed ≥48 h after diagnosis due to poor liquefaction. Logistic regression was performed to identify the factors associated with late or non-drainage (LD/ND). The Cox proportional hazard model was used to identify the variables related to abscess recurrence by 90 days after diagnosis. RESULTS: A total of 153 patients were included. Thirty (19.6%) patients underwent LD and 54 (35.3%) did not undergo drainage. Other than non-cystic appearance, LD/ND was associated with smaller size (adjusted odds ratio [aOR] 0.85, 95% confidence interval [CI] 0.73-0.98, p = 0.031) and culture-negativity (aOR 2.69, 95% CI 1.14-6.67, p = 0.027). Current hepatopancreaticobiliary malignancy was the only significant predictor of 90-day recurrence. Neither LD/ND (OR, 0.56; 95% CI, 0.13-2.41; p = 0.426) nor LD (OR, 1.26; 95% CI, 0.23-5.55; p = 0.719) was associated with recurrence by 90 days. The incidence of late complications was reduced by drainage, without a reduction in the duration of hospitalization. CONCLUSION: Several clinical features were associated with undrainable liver abscesses. Neither LD/ND nor ND had an adverse impact on clinical outcomes.

COVID-19 Vaccination in Korea: Past, Present, and the Way Forward.

Since its first emergence in late 2019, severe acute respiratory syndrome coronavirus-2 has claimed more than 6.5 million lives worldwide and continues to infect hundreds of thousands of people daily. To combat this once-in-a-century disaster, several vaccines have been developed at unprecedented speeds. Novel vaccine platforms (messenger ribonucleic acid vaccines and adenoviral vector vaccines) have played a major role in the current pandemic. In Korea, six vaccines, including a domestically developed recombinant vaccine, have been approved. As in other countries, vaccines have been proven to be safe and highly effective in Korea. However, rare serious adverse events and breakthrough infections have undermined public trust in the vaccines, even while the benefits of vaccination far outweigh the risks. The rise of the omicron variant and the subsequent increase in excess mortality demonstrated that while vaccines are a key component of the pandemic response, it alone can fail without non-pharmaceutical interventions like masking and social distancing. The pandemic of coronavirus disease has revealed both the strengths and weaknesses of our healthcare system and pandemic preparedness. When the next pandemic arrives, improved risk communication and vaccine development should be prioritized. To enable timely vaccine development, it is essential to make strategic and sufficient investments in vaccine research and development.

COVID-19 Vaccination Rates in Patients With Chronic Medical Conditions: A Nationwide Cross-Sectional Study.

As most individuals acquire immunity to severe acute respiratory syndrome coronavirus 2, South Korea declared a return to normalcy a few months ago. However, epidemic waves continue because of endlessly emerging variants and waning immunity. Health authorities are focusing on those at high risk of severe coronavirus disease 2019 to minimize damage to public health and the economy. In this regard, we investigated the vaccination rates in patients with various chronic medical conditions by examining the national health insurance claims data and the national immunization registry. We found that patients with chronic medical conditions, especially those of higher severity, such as malignancy, had vaccination rates approximately 10-20% lower than those of the general population. Public health authorities and healthcare providers should try to vaccinate these patients to avoid preventable morbidity and mortality.

Prognostic factors of 30-day mortality in patients with COVID-19 pneumonia under standard remdesivir and dexamethasone treatment.

Although some studies have reported prognostic factors for coronavirus disease 2019 (COVID-19), they were conducted before standard treatment with remdesivir and dexamethasone was implemented. This retrospective, observational study was conducted to evaluate various prognostic factors in patients with COVID-19 pneumonia receiving standard treatment with remdesivir and dexamethasone. Of 99 patients with COVID-19 pneumonia, 68 (68.7%) died within 30 days of hospitalization. The mean age was 71.3 years. Remdesivir and dexamethasone were administered to 80 (80.8%) and 84 (84.8%) patients, respectively. Early antibiotic treatment was administered to 70 patients (70.7%) within 5 days of hospitalization. Dexamethasone (79.4% vs 96.8%, P = .033) was more frequently administered in the survived group, whereas early antibiotics (60.3% vs 93.5%, P = .001) were less frequently administered. In the multivariate analysis, a high National Early Warning Score (NEWS; odds ratio [OR] 1.272), high Charlson Comorbidity Index (CCI; OR 1.441), and dyspnea (OR 4.033) were independent risk factors for 30-day mortality. There was no significant difference in age, sex, and vaccination doses between the survived and fatal groups. Lymphopenia, monocytopenia and high levels of C-reactive protein (CRP)/lactate dehydrogenase (LDH) reflected poor prognosis. NEWS, CCI, and dyspnea were predictors of 30-day mortality in patients with COVID-19 pneumonia. Early antibiotic use did not lower the 30-day mortality risk.

Pharmacokinetic/pharmacodynamic parameters of vancomycin for predicting clinical outcome of enterococcal bacteremia.

PURPOSE: To find pharmacokinetic/pharmacodynamic parameters of vancomycin associated with the optimal outcome of severe infection due to Enterococcus species. METHODS: We retrospectively reviewed enterococcal bacteremia cases treated with vancomycin from January 2015 to December 2020. The primary outcome was 30-day mortality. We calculated cutoff values of the ratio of vancomycin area under the concentration-time curve over 24 h to the minimum inhibitory concentration (AUC24/MIC) and trough concentration (Ctrough) during the initial 72 h of treatment. The optimal cutoff value was determined using the Youden index. Binary variables created based on these cutoffs were further assessed using multivariable analysis. RESULTS: A total of 65 patients were included. The majority (87.7%) had solid or hematologic malignancies. Thirty-day mortality and nephrotoxicity occurred in nine (13.4%) and 14 (21.5%) patients, respectively. Both vancomycin AUC24/MIC and Ctrough showed fair performance in predicting 30-day mortality (AUC of receiver-operator curve for AUC24/MIC, 0.712; 95% confidence interval [CI] 0.539-0.886; AUC for Ctrough, 0.760; 95% CI 0.627-0.892; pairwise AUC comparison: p = 0.570). Ctrough ≥ 13.94 µg/mL, but not AUC24/MIC ≥ 504, had a significant association with 30-day mortality after adjusting for confounders (odds ratio, 8.40; 95% CI 1.60-86.62; p = 0.010). CONCLUSION: Mean Ctrough ≥ 13.94 µg/mL during the initial 72 h was associated with higher 30-day mortality in enterococcal bacteremia. Further studies are warranted to elucidate optimal pharmacokinetic targets for enterococcal bacteremia.

Immunogenicity and Reactogenicity of Ad26.COV2.S in Korean Adults: A Prospective Cohort Study.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) pandemic continues, there are concerns regarding waning immunity and the emergence of viral variants. The immunogenicity of Ad26.COV2.S against wild-type (WT) and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs to be evaluated. METHOD: This prospective cohort study was conducted between June 2021 and January 2022 at two university hospitals in South Korea. Healthy adults who were scheduled to be vaccinated with Ad26.COV2.S were enrolled in this study. The main outcomes included anti-spike (S) IgG antibody and neutralizing antibody responses, S-specific T-cell responses (interferon-γ enzyme-linked immunospot assay), solicited adverse events (AEs), and serious AEs. RESULTS: Fifty participants aged ≥ 19 years were included in the study. Geometric mean titers (GMTs) of anti-S IgG were 0.4 U/mL at baseline, 5.2 ± 3.0 U/mL at 3-4 weeks, 55.7 ± 2.4 U/mL at 5-8 weeks, and 81.3 ± 2.5 U/mL at 10-12 weeks after vaccination. GMTs of 50% neutralizing dilution (ND50) against WT SARS-CoV-2 were 164.6 ± 4.6 at 3-4 weeks, 313.9 ± 3.6 at 5-8 weeks, and 124.4 ± 2.6 at 10-12 weeks after vaccination. As for the S-specific T-cell responses, the median number of spot-forming units/106 peripheral blood mononuclear cell was 25.0 (5.0-29.2) at baseline, 60.0 (23.3-178.3) at 5-8 weeks, and 35.0 (13.3-71.7) at 10-12 weeks after vaccination. Compared to WT SARS-CoV-2, ND50 against Delta and Omicron variants was attenuated by 3.6-fold and 8.2-fold, respectively. The most frequent AE was injection site pain (82%), followed by myalgia (80%), fatigue (70%), and fever (50%). Most AEs were grade 1-2, and resolved within two days. CONCLUSION: Single-dose Ad26.COV2.S was safe and immunogenic. NAb titer and S-specific T-cell immunity peak at 5-8 weeks and rather decrease at 10-12 weeks after vaccination. Cross-reactive neutralizing activity against the Omicron variant was negligible.

Vaccination Rates of Hospitalized Patients at High Risk of Severe COVID-19: A Single-Center Cross-Sectional Study.

We investigated coronavirus disease 2019 (COVID-19) vaccination rate in patients admitted to chronic pulmonary disease, cardiovascular disease, chronic kidney disease, and cancer wards in the third week of April 2022 to determine the immunity level of these vulnerable groups. Compared to the general population, our study subjects had lower vaccination rates, except for higher percentages of boosted individuals in patients with chronic pulmonary disease and cardiovascular disease. This tendency was most pronounced in cancer patients, less than half of whom were boosted. Patients with cancer should be encouraged to complete their COVID-19 vaccination.

Characteristics and Clinical Outcomes of Extended-Spectrum beta-lactamase-producing Klebsiella pneumoniae Bacteremia in Cancer Patients.

BACKGROUND: Cancer patients can be at a higher risk of infection due to drug-resistant bacteria than the general population for various reasons. We performed a retrospective study to evaluate possible risk factors and outcomes of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) bacteremia in cancer patients. MATERIALS AND METHODS: Cases were divided into two groups based on whether or not the isolated strain produced ESBL and multivariable regressions were done to identify possible risk factors of ESBL-KP bacteremia and mortality. For ESBL-producing strain, additional molecular analysis was done. RESULTS: 278 cases with KP bacteremia were identified between 2010 and 2012, of which ESBL-producers were 50 (18%). The presence of percutaneous drainage catheter [odds ratio (OR) 4.99, P <0.001] and prior exposure to certain classes of antibiotics including third-generation cephalosporin (OR 2.14, P = 0.03) had significant associations with ESBL-KP bacteremia. Individuals who died within 14 days after the onset of KP bacteremia were more likely to have higher mean Pitt bacteremia score (1.56 in survival group vs. 3.43 in mortality group, P <0.001), hemodialysis (OR 17.03, P = 0.01) and chronic liver disease (OR 5.57, P = 0.01). Although 14-day mortality was higher with ESBL production (OR 2.76, P = 0.04), no significant differences in 30-day mortality (OR 1.67, P = 0.20) and other morbidity indices were observed. 49 ESBL-KP isolates, 65.4% of them produced CTX-M-14 and CTX-M-15 enzymes, and ST711 was the most common. CONCLUSION: There were several differences in clinical characteristics between ESBL-KP and non-ESBL-KP bacteremia in cancer patients, similar to previous reports including non-cancer patients.

Severe Thrombocytopenia in a Patient with COVID-19.

Coronavirus disease 2019 (COVID-19) outbreak is spreading rapidly all over the world, being a major threat to public health. Since clinical feature of COVID-19 has not been fully evaluated yet, empirical antibacterial agents are frequently combined for the treatment of COVID-19 in addition to antiviral agents, concerning co-existing bacterial pathogens. We experienced a case of severe thrombocytopenia with epistaxis and petechiae, while treating a COVID-19 patient with ceftriaxone, levofloxacin, and lopinavir/ritonavir. The platelet count decreased to 2,000/mm³ and recovered after discontinuation of the three suspected drugs. In treating a potentially fatal emerging infectious disease, empirical and/or experimental approach would be unavoidable. However, the present case suggests that the possibility of adverse effects caused by polypharmacy should also be carefully considered.

Bronchiectasis and Recurrent Respiratory Infections with a De Novo STAT1 Gain-of-Function Variant: First Case in Korea.

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.