Rise in broadly cross-reactive adaptive immunity against human ß-coronaviruses in MERS-recovered patients during the COVID-19 pandemic.

To develop a universal coronavirus (CoV) vaccine, long-term immunity against multiple CoVs, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, Middle East respiratory syndrome (MERS)-CoV, and future CoV strains, is crucial. Following the 2015 Korean MERS outbreak, we conducted a long-term follow-up study and found that although neutralizing antibodies and memory T cells against MERS-CoV declined over 5 years, some recovered patients exhibited increased antibody levels during the COVID-19 pandemic. This likely resulted from cross-reactive immunity induced by SARS-CoV-2 vaccines or infections. A significant correlation in antibody responses across various CoVs indicates shared immunogenic epitopes. Two epitopes-the spike protein's stem helix and intracellular domain-were highly immunogenic after MERS-CoV infection and after SARS-CoV-2 vaccination or infection. In addition, memory T cell responses, especially polyfunctional CD4+ T cells, were enhanced during the pandemic, correlating significantly with MERS-CoV spike-specific antibodies and neutralizing activity. Therefore, incorporating these cross-reactive and immunogenic epitopes into pan-CoV vaccine formulations may facilitate effective vaccine development.

Clinical Characteristics and Risk Factors for Mortality in Critical Coronavirus Disease 2019 Patients 50 Years of Age or Younger During the Delta Wave: Comparison With Patients > 50 Years in Korea.

BACKGROUND: Numerous patients around the globe are dying from coronavirus disease 2019 (COVID-19). While age is a known risk factor, risk analysis in the young generation is lacking. The present study aimed to evaluate the clinical features and mortality risk factors in younger patients (≤ 50 years) with a critical case of COVID-19 in comparison with those among older patients (> 50 years) in Korea. METHODS: We analyzed the data of adult patients only in critical condition (requiring high flow nasal cannula oxygen therapy or higher respiratory support) hospitalized with PCR-confirmed COVID-19 at 11 hospitals in Korea from July 1, 2021 to November 30, 2021 when the delta variant was a dominant strain. Patients' electronic medical records were reviewed to identify clinical characteristics. RESULTS: During the study period, 448 patients were enrolled. One hundred and forty-two were aged 50 years or younger (the younger group), while 306 were above 50 years of age (the older group). The most common pre-existing conditions in the younger group were diabetes mellitus and hypertension, and 69.7% of the patients had a body mass index (BMI) > 25 kg/m². Of 142 younger patients, 31 of 142 patients (21.8%, 19 women) did not have these pre-existing conditions. The overall case fatality rate among severity cases was 21.0%, and it differed according to age: 5.6% (n = 8/142) in the younger group, 28.1% in the older group, and 38% in the ≥ 65 years group. Age (odds ratio [OR], 7.902; 95% confidence interval [CI], 2.754-18.181), mechanical ventilation therapy (OR, 17.233; 95% CI, 8.439-35.192), highest creatinine > 1.5 mg/dL (OR, 17.631; 95% CI, 8.321-37.357), and combined blood stream infection (OR, 7.092; 95% CI, 1.061-18.181) were identified as independent predictors of mortality in total patients. Similar patterns were observed in age-specific analyses, but most results were statistically insignificant in multivariate analysis due to the low number of deaths in the younger group. The full vaccination rate was very low among study population (13.6%), and only three patients were fully vaccinated, with none of the patients who died having been fully vaccinated in the younger group. Seven of eight patients who died had a pre-existing condition or were obese (BMI > 25 kg/m²), and the one remaining patient died from a secondary infection. CONCLUSION: About 22% of the patients in the young critical group did not have an underlying disease or obesity, but the rate of obesity (BMI > 25 kg/m²) was high, with a fatality rate of 5.6%. The full vaccination rate was extremely low compared to the general population of the same age group, showing that non-vaccination has a grave impact on the progression of COVID-19 to a critical condition. The findings of this study highlight the need for measures to prevent critical progression of COVID-19, such as vaccinations and targeting young adults especially having risk factors.

Longevity of seropositivity and neutralizing antibodies in recovered MERS patients: a 5-year follow-up study.

OBJECTIVES: We aimed to assess the longevity of spike-specific antibody responses and neutralizing activity in the plasma of recovered Middle East respiratory syndrome (MERS) patients. METHODS: We traced the antibody responses and neutralizing activity against MERS coronavirus (MERS-CoV) in peripheral blood samples collected from 70 recovered MERS patients for 5 years after the 2015 MERS outbreak in South Korea. We also measured the half-life of neutralizing antibody titres in the longitudinal specimens. RESULTS: The seropositivity rate persisted for up to 4 years (50.7-56.1%), especially in MERS patients who suffered from severe pneumonia, and then decreased (35.9%) in the fifth year. Although the spike-specific antibody responses decreased gradually, the neutralizing antibody titres decreased more rapidly (half-life: 20 months) in 19 participants without showing negative seroconversion during the study period. Only five (26.3%) participants had neutralizing antibody titres greater than 1/1000 of PRNT50, and a high neutralizing antibody titre over 1/5000 was not detected in the participants at five years after infection. DISCUSSION: The seropositivity rate of the recovered MERS patients persisted up to 4 years after infection and significantly dropped in the fifth year, whereas the neutralizing antibody titres against MERS-CoV decreased more rapidly and were significantly reduced at 4 years after infection.

Sustained Responses of Neutralizing Antibodies Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Recovered Patients and Their Therapeutic Applicability.

BACKGROUND: Zoonotic coronaviruses have emerged as a global threat by causing fatal respiratory infections. Given the lack of specific antiviral therapies, application of human convalescent plasma retaining neutralizing activity could be a viable therapeutic option that can bridges this gap. METHODS: We traced antibody responses and memory B cells in peripheral blood collected from 70 recovered Middle East respiratory syndrome coronavirus (MERS-CoV) patients for 3 years after the 2015 outbreak in South Korea. We also used a mouse infection model to examine whether the neutralizing activity of collected sera could provide therapeutic benefit in vivo upon lethal MERS-CoV challenge. RESULTS: Anti-spike-specific IgG responses, including neutralizing activity and antibody-secreting memory B cells, persisted for up to 3 years, especially in MERS patients who suffered from severe pneumonia. Mean antibody titers gradually decreased annually by less than 2-fold. Levels of antibody responses were significantly correlated with fever duration, viral shedding periods, and maximum viral loads observed during infection periods. In a transgenic mice model challenged with lethal doses of MERS-CoV, a significant reduction in viral loads and enhanced survival was observed when therapeutically treated with human plasma retaining a high neutralizing titer (> 1/5000). However, this failed to reduce pulmonary pathogenesis, as revealed by pathological changes in lungs and initial weight loss. CONCLUSIONS: High titers of neutralizing activity are required for suppressive effect on the viral replication but may not be sufficient to reduce inflammatory lesions upon fatal infection. Therefore, immune sera with high neutralizing activity must be carefully selected for plasma therapy of zoonotic coronavirus infection.

Viral kinetics of SARS-CoV-2 over the preclinical, clinical, and postclinical period.

BACKGROUND: It is necessary to know the viral kinetics and conduct epidemiological investigations of confirmers to prevent the spread of the new infectious disease COVID-19 to the community. To date, no study has been published on viral kinetics during the preclinical and clinical periods of SARS-CoV-2. METHODS: A confirmed case was defined as a patient with positive results by real-time reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2. Both specimen types were collected over the whole clinical course in all patients. Asymptomatic patients who had been screened for COVID-19 due to a strong epidemiological link were also enrolled. The study population included 54 hospitalized patients with confirmed COVID-19. RESULTS: COVID-19 shows a very high viral load on the day of symptom development, which then decreases overall. Rapid viral proliferation was observed 0-5 days before symptoms developed. Cycle threshold (Ct) value was the lowest in the clinical course from 5 days before symptoms to 10 days after symptoms occurred (Ct < 30). The rRT-PCR results were negative approximately 3 weeks after the onset of symptoms. However, there was a continuous pattern that was negative and positive for up to 6 weeks and more. CONCLUSION: Considering the characteristic that COVID-19 has a high viral load before symptoms appear, it is necessary to consider to expand the scope of epidemiological investigations. As there is a very low possibility of transmission after 10 days of symptom occurrence, it may be considered to release isolation after 10 days of symptom occurrence in limited resource situations. This study allows for the planning of epidemiological investigations, patient's ward supply, and follow-up of patients through sequential changes in viral loads over the entire clinical course. In addition, it is possible to estimate the clinical time at which the patient is present.

Cluster of Coronavirus Disease Associated with Fitness Dance Classes, South Korea.

During 24 days in Cheonan, South Korea, 112 persons were infected with severe acute respiratory syndrome coronavirus 2 associated with fitness dance classes at 12 sports facilities. Intense physical exercise in densely populated sports facilities could increase risk for infection. Vigorous exercise in confined spaces should be minimized during outbreaks.

A Practical Approach to Condition Assessment of Asphalt-Covered Concrete Bridge Decks on Korean Expressways by Dielectric Constant Measurements Using Air-Coupled GPR.

The main objectives of this study are to investigate the variations of the dielectric constant of concrete on Korean expressways by using a 1 GHz air-coupled Ground Penetrating Radar (GPR) system and to develop a practical approach to the condition assessment of concrete bridge decks with asphalt overlay on Korean expressways by dielectric constant measurements. A total of 684 GPR investigations of 601 actual concrete bridge decks, which are in service between 2 and 43 years, were carried out during the period between 1999 and 2013. Statistical analysis revealed that the dielectric constant of asphalt-covered concrete bridge decks reduced with service age and this trend continued until service age of over 40 years. As a result, this study provides a practical dielectric constant curve that could be used for condition evaluation of top concrete in asphalt-covered bridge decks with consideration of concrete age. Based on regression analyses of the GPR field survey data and experiences through the field survey, a double cut-off dielectric constant criterion was proposed for condition assessment of asphalt-covered concrete bridge decks on Korean expressways. In addition, a GPR field survey was performed at an actual bridge on the Yeongdong expressway in Korea to test the proposed GPR signal interpretation method. The field survey results provide fundamental data to better understand the variation of the dielectric constant of concrete in actual bridges with asphalt overlay and to develop a practical approach to condition assessment of asphalt-covered concrete bridge decks on Korean expressways by dielectric constant measurements using air-coupled GPR.

Three cases of treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen therapy.

No effective treatment for COVID-19 has been well established yet. Nafamostat, known as anticoagulant, has potential anti-inflammatory and anti-viral activities against COVID-19. We report three cases of COVID-19 pneumonia who progressed while using antiviral drugs and needed supplementary oxygen therapy, improved after treatment with nafamostat. These preliminary findings show the possibility that Nafamostat can be considered to be used in elderly patients with COVID-19 pneumonia who need oxygen therapy. The effectiveness of nafamostat should be evaluated in further studies.

Sequential Emergence and Wide Spread of Neutralization Escape Middle East Respiratory Syndrome Coronavirus Mutants, South Korea, 2015.

The unexpectedly large outbreak of Middle East respiratory syndrome in South Korea in 2015 was initiated by an infected traveler and amplified by several "superspreading" events. Previously, we reported the emergence and spread of mutant Middle East respiratory syndrome coronavirus bearing spike mutations (I529T or D510G) with reduced affinity to human receptor CD26 during the outbreak. To assess the potential association of spike mutations with superspreading events, we collected virus genetic information reported during the outbreak and systemically analyzed the relationship of spike sequences and epidemiology. We found sequential emergence of the spike mutations in 2 superspreaders. In vivo virulence of the mutant viruses seems to decline in human patients, as assessed by fever duration in affected persons. In addition, neutralizing activity against these 2 mutant viruses in serum samples from mice immunized with wild-type spike antigen were gradually reduced, suggesting emergence and wide spread of neutralization escapers during the outbreak.

Capecitabine Plus Oxaliplatin Combination Therapy for Basal Cell Carcinoma.

No effective systemic chemotherapy is well-established in basal cell carcinoma. We report a case with three simultaneous malignancies: colon cancer, basal cell carcinoma, and smoldering multiple myeloma. The patient was treated with capecitabine and oxaliplatin after surgery for colon cancer. Surprisingly, he achieved a complete response for basal cell carcinoma. This is the first report of this chemotherapy regimen in basal cell carcinoma. This finding suggests that combination capecitabine and oxaliplatin can be a treatment option for patients unable to receive local therapy.

Correlation between Pneumonia Severity and Pulmonary Complications in Middle East Respiratory Syndrome.

This nationwide, prospective cohort study evaluated pulmonary function and radiological sequelae according to infection severity in 73 survivors from the 2015 Middle East respiratory syndrome (MERS) outbreak in Korea. Patients with severe pneumonia in MERS-coronavirus infection had more impaired pulmonary function than those with no or mild pneumonia at the 1-year follow-up, which was compatible with the radiological sequelae. Severe pneumonia significantly impairs pulmonary function and makes long radiological sequelae in MERS.

Predictors of mortality in Middle East respiratory syndrome (MERS).

We evaluated the clinical characteristics, cytokine/chemokine concentrations, viral shedding and antibody kinetics in 30 patients with Middle East respiratory syndrome (MERS), including 6 non-survivors admitted to 3 MERS-designated hospitals. Old age, low albumin, altered mentality and high pneumonia severity index score at admission were risk factors for mortality. In addition, severe signs of inflammation at initial presentation (at hospital days 1-4), such as high inducible protein-10 (p=0.0013), monocyte chemoattractant protein-1 (p=0.0007) and interleukin 6 (p=0.0007) concentrations, and poor viral control (high viral load at hospital days 5-10, p<0.001) without adequate antibody titres (low antibody titre at hospital days 11-16, p=0.07) during the course of disease, were associated with mortality.

Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations for estimating glomerular filtration rates in cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Although the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has been recommended for accurate estimates of glomerular filtration rate (eGFR), there is little information regarding differences in GFR estimates obtained using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) equations in East Asian cancer patients. We investigated discrepancies in GFR and toxicities in patients treated with cisplatin-based chemotherapy using three equations equations. METHODS: A total of 229 patients were retrospectively recruited. We calculated eGFR using the three equations and separated patients into three categories based on GFR < 10 (group A), 10-50 (group B), and > 50 (group C) mL/min/1.73m2. We analyzed chemotherapy toxicities. RESULTS: The mean eGFR calculated using the CG was the lowest of the values derived using the three equations. Estimates using the MDRD and CKD-EPI equations resulted in reclassifying 32 (71.1%) and 33 (73.3%) of 45 patients, originally placed in group B using the CG into group C. However, only 1 (7.7%) of 13 patients placed in group B using the MDRD were reclassified into group C using the CKD-EPI. Twenty-eight of 45 patients classified into group B using the CG equation were treated with reduced doses of cisplatin. However, these patients did not show significant differences in toxicities compared with other patients taking full doses of cisplatin. CONCLUSION: The CG equations underestimated GFR compared to the MDRD and CKD-EPI equations. Therefore, when GFR is estimated using CG equations, East Asian cancer patients may receive insufficient doses of chemotherapeutic agents, including cisplatin.

Imipenem-resistant Gram-negative bacterial isolates carried by persons upon medical examination in Korea.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) have emerged and disseminated worldwide, become a great concern worldwide including Korea. The prevalence of fecal carriage of imipenem-resistant Gram-negative bacteria (IR-GNB) in persons in Korea was investigated. Stool samples were collected from 300 persons upon medical examination. Samples were screened for IR-GNB by using MacConkey agar with 2 µl/ml imipenem. Species were identified by 16S rRNA gene sequence analysis, and antimicrobial susceptibility was determined by the broth microdilution method. In total, 82 IR-GNB bacterial isolates were obtained from 79 (26.3%) out of 300 healthy persons. Multilocus sequence typing analysis showed very high diversity among IR P. aeruginosa, S. maltophilia, and E. cloacae isolates, and pulsed-field gel electrophoresis revealed five main pulsotypes of IR P. mirabilis. As for the presence of metallo-ß-lactamases (MBLs), only one IMP-25-producing S. marcescens isolate was identified. Although only one carbapenemase-producing isolate was identified, the high colonization rates with IR-GNB isolates in this study is notable because carriers may be a reservoir for the dissemination of resistant pathogens within the community as well as in health care institutions.

Colistin resistance in Pseudomonas aeruginosa that is not linked to arnB.

PURPOSE: It is known that the arnB (or pmrH) gene encoding uridine 5'-(beta-1-threo-pentapyranosyl-4-ulose diphosphate) aminotransferase plays a critical role in colistin resistance in Pseudomonas aeruginosa through the addition of 4-amino-4-deoxy-l-arabinose (l-Ara4N) to lipid A. In this study, we attempted to obtain a colistin-resistant mutant from an arnB-deleted mutant through exposure to colistin. METHODOLOGY: We constructed an arnB deletion mutant (P5ΔarnB :: nptIII) from a colistin-susceptible strain (P5) by allelic replacement mutagenesis, and colistin-resistant mutants were selected in vitro using P5 and P5ΔarnB :: nptIII. The growth rate, lipid A structure, biofilm-forming activity and cell viability in diverse stressful conditions (osmotic, oxidative, acidic and heat stress) were investigated. Expression of phoP, pmrA, parR, and cprR was evaluated by qRT-PCR. RESULTS: An arnB deletion mutant was shown to develop colistin resistance through the addition of l-Ara4N to lipid A, despite a low survival rate (over 1000-fold lower than that of the wild-type strain) in the media with colistin. Two colistin-resistant mutants showed higher survival rates than colistin-susceptible strains against 5 % NaCl. In the presence of acidic and heat stress, P5ΔarnB :: nptIII-CstR exhibited higher survival rates during conditions of 1 % HCl and 42 °C than the other strains. Both phoP and pmrA genes were overexpressed significantly in both colistin-resistant mutants, but parR and cprR genes were not. CONCLUSION: We revealed that colistin resistance could be developed despite arnB deletion in P. aeruginosa through the addition of l-Ara4N to lipid A, which was accompanied by diverse physiological changes.

Stage IV advanced diffuse large B-cell lymphoma in human immunodeficiency virus infection with achieving cure by using highly active antiretroviral therapy alone: a case report.

After the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of lymphoma among the HIV-infected population and also significantly improved survival rates. We describe a remarkable case of an HIV-infected patient with advanced stage IV diffuse large B-cell lymphoma (DLBCL), completely regressed with the use of HAART alone. He remained disease-free for 6 years and he achieved cure without chemotherapy. Although several cases of low-grade lymphoma with complete regression were reported, we could not find any case of stage IV high-grade malignant lymphoma with HAART alone in complete remission for over 5 years from our review of the literature. This unique case shows the importance of HAART in improving survival and achieving cure in HIV-high-grade malignant lymphoma.

CA19-9 or CEA Decline after the First Cycle of Treatment Predicts Survival in Advanced Biliary Tract Cancer Patients Treated with S-1 and Cisplatin Chemotherapy.

PURPOSE: While tumor markers (carbohydrate antigen 19-9 [CA 19-9] and carcinoembryonic antigen [CEA]) can aid in the diagnosis of biliary tract cancer, their prognostic role has not been clearly elucidated. Therefore, this study was conducted to evaluate the prognostic role of tumor markers and tumor marker change in patients with advanced biliary tract cancer. MATERIALS AND METHODS: Patients with pathologically proven metastatic or relapsed biliary tract cancer who were treated in a phase II trial of first-line S-1 and cisplatin chemotherapy were enrolled. Serum tumor markers were measured at baseline and after the first cycle of chemotherapy. RESULTS: Among a total of 104 patients, 80 (77%) had elevated baseline tumor markers (69 with CA 19-9 elevation and 40 with CEA). A decline ≥ 30% of the elevated tumor marker level after the first cycle of chemotherapy conferred an improved time to progression (TTP), overall survival (OS), and better chemotherapy response. Multivariate analysis revealed tumor marker decline as an independent positive prognostic factor of TTP (adjusted hazard ratio [HR], 0.44; p=0.003) and OS (adjusted HR, 0.37; p < 0.001). Subgroup analysis revealed similar results in each group of patients with CA 19-9 elevation and CEA elevation. In addition, elevated baseline CEA was associated with poor survival in both univariate and multivariate analysis. CONCLUSION: Tumor marker decline was associated with improved survival in biliary tract cancer. Measuring tumor marker after the first cycle of chemotherapy can be used as an early assessment of treatment outcome.

Predictive risk factors for Listeria monocytogenes meningitis compared to pneumococcal meningitis: a multicenter case-control study.

PURPOSE: Various immunocompromised conditions increase the risk of meningitis caused by Listeria monocytogenes. However, the relative importance of these risk factors has not been well established. We determined the risk factors that predict meningitis due to L. monocytogenes compared to that caused by Streptococcus pneumoniae. METHODS: A nationwide multicenter case-control study was conducted in Korea. Cases of meningitis caused by L. monocytogenes between 1998 and 2013 were included. Patients with pneumococcal meningitis were included as controls. Multivariate logistic regression analysis was used to predict the risk factors of Listeria meningitis. RESULTS: A total of 36 cases and 113 controls were enrolled. The most significant predictive risk factor of Listeria meningitis was a prior history of receiving immunosuppressive therapy (odds ratio 8.12, 95 % CI 2.47-26.69). Chronic liver disease was the second most important predictive risk factor (OR 5.03, 95 % CI 1.56-16.22). Delaying appropriate antibiotic therapy by more than 6 h (hazard ratio 2.78) and fatal underlying disease (hazard ratio 2.88) were associated with increased mortality. CONCLUSIONS: Patients with a prior history of receiving immunosuppressive therapy within 1 month and chronic liver disease have 8.1-fold and 5-fold increased risk of meningitis by L. monocytogenes compared to S. pneumoniae, respectively.

Developing a model to estimate the probability of bacteremia in women with community-onset febrile urinary tract infection.

INTRODUCTION: Among patients with urinary tract infection (UTI), bacteremic cases show higher mortality rates than do nonbacteremic cases. Early identification of bacteremic cases is crucial for severity assessment of patients with febrile UTI. This study aimed to identify predictors associated with bacteremia in women with community-onset febrile UTI and to develop a prediction model to estimate the probability of bacteremic cases. METHODOLOGY: This cross-sectional study included women consecutively hospitalized with community-onset febrile UTI at 10 hospitals in Korea. Multiple logistic regression identified predictors associated with bacteremia among candidate variables chosen from univariate analysis. A prediction model was developed using all predictors weighted by their regression coefficients. RESULTS: From July to September 2014, 383 women with febrile UTI were included: 115 (30.0%) bacteremic and 268 (70.0%) nonbacteremic cases. A prediction model consisted of diabetes mellitus (1 point), urinary tract obstruction by stone (2), costovertebral angle tenderness (2), a fraction of segmented neutrophils of > 90% (2), thrombocytopenia (2), azotemia (2), and the fulfillment of all criteria for systemic inflammatory response syndrome (2). The c statistic for the model was 0.807 (95% confidence interval [CI], 0.757-0.856). At a cutoff value of ≥ 3, the model had a sensitivity of 86.1% (95% CI, 78.1-91.6%) and a specificity of 54.9% (95% CI, 48.7-91.6%). CONCLUSIONS: Our model showed a good discriminatory power for early identification of bacteremic cases in women with community-onset febrile UTI. In addition, our model can be used to identify patients at low risk for bacteremia because of its relatively high sensitivity.