Longitudinal Analysis of Memory T-Cell Responses in Survivors of Middle East Respiratory Syndrome.

BACKGROUND: Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a zoonotic betacoronavirus. The development of effective vaccines and control measures requires a thorough understanding of the immune response to this viral infection. METHODS: We investigated cellular immune responses up to 5 years after infection in a cohort of 59 MERS survivors by performing enzyme-linked immunospot assay and intracellular cytokine staining after stimulation of peripheral blood mononuclear cells with synthetic viral peptides. RESULTS: Memory T-cell responses were detected in 82%, 75%, 69%, 64%, and 64% of MERS survivors from 1-5 years post-infection, respectively. Although the frequency of virus-specific interferon gamma (IFN-γ)-secreting T cells tended to be higher in moderately/severely ill patients than in mildly ill patients during the early period of follow-up, there was no significant difference among the different clinical severity groups across all time points. While both CD4+ and CD8+ T cells were involved in memory T-cell responses, CD4+ T cells persisted slightly longer than CD8+ T cells. Both memory CD4+ and CD8+ T cells recognized the E/M/N proteins better than the S protein and maintained their polyfunctionality throughout the period examined. Memory T-cell responses correlated positively with antibody responses during the initial 3-4 years but not with maximum viral loads at any time point. CONCLUSIONS: These findings advance our understanding of the dynamics of virus-specific memory T-cell immunity after MERS-coronavirus infection, which is relevant to the development of effective T cell-based vaccines.

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.

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.

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.

Risk Factors for Mortality and Respiratory Support in Elderly Patients Hospitalized with COVID-19 in Korea.

BACKGROUND: The mortality risk of coronavirus disease 2019 (COVID-19) is higher in patients with older age, and many elderly patients are reported to require advanced respiratory support. METHODS: We reviewed medical records of 98 patients aged ≥ 65 years who were hospitalized with COVID-19 during a regional outbreak in Daegu/Gyeongsangbuk-do province of Korea. The outcome measures were in-hospital mortality and the treatment with mechanical ventilation (MV) or high-flow nasal cannula (HFNC). RESULTS: The median age of the patients was 72 years; 55.1% were female. Most (74.5%) had at least one underlying condition. Overall case fatality rate (CFR) was 20.4%, and median time to death after admission was 8 days. The CFR was 6.1% among patients aged 65-69 years, 22.7% among those aged 70-79 years, and 38.1% among those aged ≥ 80 years. The CFR among patients who required MV was 43.8%, and the proportion of patients received MV/HFNC was 28.6%. Nosocomial acquisition, diabetes, chronic lung diseases, and chronic neurologic diseases were significant risk factors for both death and MV/HFNC. Hypotension, hypoxia, and altered mental status on admission were also associated with poor outcome. CRP > 8.0 mg/dL was strongly associated with MV/HFNC (odds ratio, 26.31; 95% confidence interval, 7.78-88.92; P < 0.001), and showed better diagnostic characteristics compared to commonly used clinical scores. CONCLUSION: Patients aged ≥ 80 years had a high risk of requiring MV/HFNC, and mortality among those severe patients was very high. Severe initial presentation and laboratory abnormalities, especially high CRP, were identified as risk factors for mortality and severe hospital course.

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.

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.

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.

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.

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.

Health care-associated acute pyelonephritis is associated with inappropriate empiric antibiotic therapy in the ED.

BACKGROUND: Acute pyelonephritis (APN) is one of the most common bacterial infections. Because health care-associated (HCA) infections in the community setting have similar characteristics to hospital-acquired infections, HCA infections should be distinguished from community-acquired (CA) infections. However, the impact of HCA-APN on treatment outcomes has not been clearly defined. This study aimed to analyze the impact of HCA-APN on the appropriateness of empiric antibiotic therapy and outcomes in community-onset APN. METHODS: We prospectively identified women older than 18years who were hospitalized with APN via the emergency department and whose urine culture grew bacteria at 10 acute care hospitals in South Korea. RESULTS: Of the 388 APN episodes that were included, 99 (25.5%) were HCA-APN and 289 (74.5%) were CA-APN. Compared with patients with CA-APN, patients with HCA-APN had comorbid conditions and septic shock more frequently. Health care-associated APN was caused by resistant uropathogens more often. Patients with HCA-APN had poorer outcomes (ie, early/final clinical and microbiologic failures); however, this was not statistically significant. Patients with HCA-APN had significantly longer hospital stays than did patients with CA-APN. In the multivariable logistic regression analysis for inappropriate empiric therapy, HCA-APN (odds ratio, 1.96; 95% confidence interval, 1.07-3.57; P=.03) and being bed-ridden (odds ratio, 3.04; 95% confidence interval, 1.31-7.07; P=.01) were significant. CONCLUSIONS: Health care-associated APN was associated with inappropriate empiric antibiotic therapy, which might lead to worse outcomes. These HCA factors should be considered when prescribing empiric antibiotic therapy in patients with community-onset APN.

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.

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.

The fifth outbreak of trichinosis in Korea.

Trichinosis is a food-borne zoonotic disease caused by the nematode, Trichinella spp., and had been reported several times in Korea. Recently, there was an additional outbreak, involving 5 patients, the findings from which are reported herein. On 30 November 2010, 8 persons ate sashimi of the meat of a wild boar. Then, 2-3 weeks later, they complained of myalgia and fever. Unfortunately, muscle biopsy was not performed, but ELISA was performed using their sera. Two people among 8 were positive for Trichinella on the 34th day post-infection (PI), and 3 patients who initially revealed negative ELISA were additionally proved to be positive for trichinosis on the 42nd day PI. Hence, the confirmed patients of trichinosis were 5 in total in the present outbreak. They were treated with albendazole and discharged uneventfully. This was the fifth outbreak of trichinosis in Korea.

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.

Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation.

Heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses. Therefore, HSP70-hom gene polymorphisms may act as important factors in predicting the prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the role of HSP70-hom gene polymorphisms in the prognosis of patients receiving sibling human leukocyte antigen (HLA)-matched allogeneic HSCT, the HSP70-hom polymorphisms, T2437C and G2763A, were genotyped in 147 patients receiving sibling HLA-matched allogeneic HSCT. Individual diplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. Patients with the 2763GG or GA genotype showed longer overall survival compared with those with the 2763AA genotype, and patients with a TG haplotype (TG/TA, TG/TG or TG/CG) also showed longer overall survival compared with those with a non-TG haplotype (TA/TA or TA/CG) (both G2763A genotype and diplotype, p<0.01). Moreover, the 2437TT genotype was found to be protective for treatment-related death compared with the 2437TC genotype, and a TG haplotype was found to be very protective for treatment-related death compared with a non-TG haplotype (T2437C genotype, p=0.04; and diplotype, p=0.02). Therefore, our results suggest that HSP70-hom polymorphisms play an important role in the prognosis of patients receiving sibling HLA-matched allogeneic HSCT.

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.

Imported malaria in Korea: a 13-year experience in a single center.

The incidence of imported malaria has been increasing in Korea. We reviewed data retrospectively to evaluate the epidemiology, clinical features, and outcomes of imported malaria from 1995 to 2007 in a university hospital. All patients diagnosed with imported malaria were included. Imported malaria was defined as a positive smear for malaria that was acquired in a foreign country. A total of 49 patients (mean age, 35.7 year; M : F = 38 : 11) were enrolled. The predominant malarial species was Plasmodium falciparum (73.5%), and the most frequent area of acquisition was Africa (55.1%), followed by Southeast Asia (22.4%) and South Asia (18.4%). Fourteen-patients (30.6%) suffered from severe malaria caused by P. falciparum and 1 patient (2.0%) died of multiorgan failure. Most of the patients were treated with mefloquine (79.2%) or quinine (10.2%); other antimalarial agents had to be given in 13.2% treated with mefloquine and 44.4% with quinine due to adverse drug events (ADEs). P. falciparum was the most common cause of imported malaria, with the majority of cases acquired from Africa, and a significant number of patients had severe malaria. Alternative antimalarial agents with lower rates of ADEs might be considered for effective treatment instead of mefloquine and quinine.