A Double-Blind, Randomized, Placebo-Controlled, Phase II Clinical Study To Evaluate the Efficacy and Safety of Camostat Mesylate (DWJ1248) in Adult Patients with Mild to Moderate COVID-19.

Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).

Nosocomial Outbreak of COVID-19 from a Kidney Transplant Patient: Necessity of a Longer Isolation Period in Immunocompromised Patients.

BACKGROUND: Determination of the release from isolation for coronavirus disease 2019 (COVID-19) in immunocompromised patients who need additional hospitalization for treatment of non-COVID-19 related disease is important to prevent nosocomial transmission. However, there is insufficient evidence for an extended isolation period. MATERIALS AND METHODS: In September 2021, when the Delta variant was dominant, a nosocomial outbreak of COVID-19 occurred in the nephrology ward of a tertiary hospital in Gwangju, Korea. We conducted epidemiological investigations and whole-genome sequencing (WGS) of this virus. RESULTS: A man who underwent kidney transplantation was admitted to our hospital for the treatment of acute kidney injury. He was diagnosed with asymptomatic COVID-19 infection during a pre-admission screening test on September 1, 2021 and underwent isolation. After 10 days of isolation in the COVID-19-designated ward, he was transferred to the general nephrology ward. He underwent steroid pulse therapy (September 17 to September 23, >60 mg/day prednisolone) due to acute T-cell rejection. On September 28, 2021, the first patient with COVID-19 was identified in the nephrology ward, and a rapid-response team was activated to identify additional patients with COVID-19 and prevent the spread of COVID-19. Epidemiological investigations revealed that 12 patients, two caregivers, and three healthcare workers from the nephrology ward were diagnosed with COVID-19. The WGS of specimens from 14 nosocomial outbreak samples and released an index patient exhibited the same Delta variant originating from the B.1.617.2 lineage. This hospital-acquired COVID-19 outbreak in the nephrology ward resulted in two (11.7%) deaths in patients who underwent kidney transplantation. CONCLUSION: We demonstrated that an immunocompromised patient can cause a nosocomial outbreak due to the prolonged shedding of infectious viruses. Prolonged isolation in patients under active immunosuppressive therapy may be necessary to prevent transmission, especially in the hospital setting.

In vivo imaging of invasive aspergillosis with 18F-fluorodeoxysorbitol positron emission tomography.

Invasive aspergillosis is a critical complication in immunocompromised patients with hematologic malignancies or with viral pneumonia caused by influenza virus or SARS­CoV­2. Although early and accurate diagnosis of invasive aspergillosis can maximize clinical outcomes, current diagnostic methods are time-consuming and poorly sensitive. Here, we assess the ability of 2-deoxy-2-18F-fluorosorbitol (18F-FDS) positron emission tomography (PET) to specifically and noninvasively detect Aspergillus infections. We show that 18F-FDS PET can be used to visualize Aspergillus fumigatus infection of the lungs, brain, and muscles in mouse models. In particular, 18F-FDS can distinguish pulmonary aspergillosis from Staphylococcus aureus infection, both of which induce pulmonary infiltrates in immunocompromised patients. Thus, our results indicate that the combination of 18F-FDS PET and appropriate clinical information may be useful in the differential diagnosis and localization of invasive aspergillosis.

Performance of Severe Acute Respiratory Syndrome Coronavirus 2 Serological Diagnostic Tests and Antibody Kinetics in Coronavirus Disease 2019 Patients.

Serological testing is recommended to support the detection of undiagnosed coronavirus disease 2019 (COVID-19) cases. However, the performance of serological assays has not been sufficiently evaluated. Hence, the performance of six severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding antibody assays [three chemiluminescence (CLIAs) and three lateral flow immunoassays (LFIAs)] and a surrogate virus neutralization test (sVNT) was analyzed in a total of 988 serum samples comprising 389 COVID-19-positives and 599 COVID-19-negatives. The overall diagnostic sensitivities of CLIAs and LFIAs ranged from 54.2 to 56.6% and from 56.3 to 64.3%, respectively. The overall diagnostic specificities of CLIAs and LFIAs ranged from 98.2 to 99.8% and from 97.3 to 99.0%, respectively. In the symptomatic group (n = 321), the positivity rate increased by over 80% in all assays > 14 days after symptom onset. In the asymptomatic group (n = 68), the positivity rate increased by over 80% in all assays > 21 days after initial RT-PCR detection. In LFIAs, negatively interpreted trace bands accounted for the changes in test performance. Most false-positive results were weak or trace reactions and showed negative results in additional sVNT. For six binding antibody assays, the overall agreement percentages ranged from 91.0 to 97.8%. The median inhibition activity of sVNT was significantly higher in the symptomatic group than in the asymptomatic group (50.0% vs. 29.2%; p < 0.0001). The median times to seropositivity in the symptomatic group were 9.7 days for CLIA-IgG, 9.2 and 9.8 days for two CLIAs-Total (IgM + IgG), 7.7 days for LFIA-IgM, 9.2 days for LFIA-IgG, and 8.8 days for sVNT-IgG, respectively. There was a strong positive correlation between the quantitative results of the four binding antibody assays and sVNT with Spearman ρ-values ranging from 0.746 to 0.854. In particular, when using LFIAs, we recommend using more objective interpretable assays or establishing a band interpretation system for each laboratory, accompanied by observer training. We also anticipate that sVNT will play an essential role in SARS-CoV-2 antibody testing and become the practical routine neutralizing antibody assay.

Associations Between COVID-19 Symptoms and Psychological Distress.

Background: Hospital isolation for COVID-19 may cause significant psychological stress. The association between COVID-19 symptoms and psychological symptoms has not been systematically studied. We investigated the effects of telephonic intervention on the relationship between psychological symptoms and COVID-19 symptoms at the time of hospitalization and 1 week later. Method: We screened 461 patients with COVID-19 for psychiatric symptoms from February 29, 2020, to January 3, 2021. In total, 461 patients were evaluated 2 days after admission, and 322 (69.8%) were followed 1 week later. To assess anxiety and depressive symptoms, the Hospital Anxiety and Depression Scale (HADS) was administered to patients once per week. The Insomnia Severity Index (ISI) and item 9 of the Beck Depression Inventory (BDI-9) were used weekly to assess insomnia and suicidal ideation. Results: Of 461 enrolled patients, we observed clinically meaningful psychological anxiety symptoms (in 75/16.3% of patients), depression (122/26.5%), insomnia (154/33.4%), and suicidal ideation (54/11.7%). Commonly reported COVID-19 symptoms are cough/sputum/sneezing (244, 52.9%), headache/dizziness (98, 21.3%), myalgia (113, 24.5%), and sore throat (89, 19.3%). Compared to baseline, significant improvements were found in anxiety, depression, and suicidal ideation at 1 week. No significant group differences in ISI score were observed. Conclusions: COVID-19 symptoms at baseline had a significant and persistent negative impact on anxiety and depression at admission and at 1 week after hospitalization. Early intervention is essential to improve the outcomes of patients with mental illness.

Successful control of COVID-19 outbreak through tracing, testing, and isolation: Lessons learned from the outbreak control efforts made in a metropolitan city of South Korea.

The first surge of coronavirus disease 2019 (COVID-19) cases began on June 27, 2020 in Gwangju metropolitan city, located in the southwestern part of South Korea, with a population of 1,501,000. Local governments and the Korean Center for Disease Control and Prevention immediately started an epidemiologic investigation and traced the contacts of patients using a wide variety of data sources, including location data from mobile devices, credit card transaction, and closed-circuit television footage. Until July 16, 2020, 138 community transmission cases and 10 infection clusters were identified across the city. Through contact tracing, epidemiologic relatedness was found in 136 (98.6%) of 138 cases. Our investigation showed how the extensive and meticulous contact tracing suppressed COVID-19 outbreak in a populated city.

Source Analysis and Effective Control of a COVID-19 Outbreak in a University Teaching Hospital during a Period of Increasing Community Prevalence of COVID-19.

BACKGROUND: South Korea has been experiencing a third wave of coronavirus disease 2019 (COVID-19) since mid-November 2020. Our hospital in Gwangju metropolitan city experienced a healthcare-associated COVID-19 outbreak early in the third wave. The first confirmed COVID-19 patient was a symptomatic neurosurgery resident with high mobility throughout the hospital. We analyzed the transmission routes of nosocomial COVID-19 and discussed infection control strategies. METHODS: We retrospectively analyzed the severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction (RT-PCR) testing results according to time point and evaluated transmission routes. RESULTS: Since COVID-19 was first confirmed in a healthcare worker (HCW) on 11/13/2020, we performed RT-PCR tests for all patients and caregivers and four complete enumeration surveys for all HCWs. We detected three clusters of nosocomial spread and several sporadic cases. The first cluster originated from the community outbreak spot, where an asymptomatic HCW visited, which led to a total of 22 cases. The second cluster, which included patient-to-patient transmission, originated from a COVID-19 positive caregiver before diagnosis and the third cluster involved a radiologist and a banker. We took measures to isolate Building 1 of the hospital for 17 days and controlled the outbreak during a period of increasing community COVID-19 prevalence. Universal screening of all inpatients upon admission and resident caregivers was made mandatory and hospital-related employees are now screened monthly. CONCLUSION: Infection control strategies to prevent the nosocomial transmission of emerging infectious diseases must correspond with community disease prevalence. Our data reinforce the importance of multi-time point surveillance of asymptomatic HCWs and routine surveillance of patients and caregivers during an epidemic.

Risk Factors and a Scoring System to Predict ARDS in Patients with COVID-19 Pneumonia in Korea: A Multicenter Cohort Study.

Predictive studies of acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19) are limited. In this study, the predictors of ARDS were investigated and a score that can predict progression to ARDS in patients with COVID-19 pneumonia was developed. All patients who were diagnosed with COVID-19 pneumonia between February 1, 2020, and May 15, 2020, at five university hospitals in Korea were enrolled. Their demographic, clinical, and epidemiological characteristics and the outcomes were collected using the World Health Organization COVID-19 Case Report Form. A logistic regression analysis was performed to determine the predictors for ARDS. The receiver operating characteristic (ROC) curves were constructed for the scoring model. Of the 166 patients with COVID-19 pneumonia, 37 (22.3%) patients developed ARDS. The areas under the curves for the infiltration on a chest X-ray, C-reactive protein, neutrophil/lymphocyte ratio, and age, for prediction of ARDS were 0.91, 0.90, 0.87, and 0.80, respectively (all P < 0.001). The COVID-19 ARDS Prediction Score (CAPS) was constructed using age (≥60 years old), C-reactive protein (≥5 mg/dL), and the infiltration on a chest X-ray (≥22%), with each predictor allocated 1 point. The area under the curve of COVID-19 ARDS prediction score (CAPS) for prediction of ARDS was 0.90 (95% CI 0.86-0.95; P < 0.001). It provided 100% sensitivity and 75% specificity when the CAPS score cutoff value was 2 points. CAPS, which consists of age, C-reactive protein, and the area of infiltration on a chest X-ray, was predictive of the development of ARDS in patients with COVID-19 pneumonia.

Clinical and Virologic Effectiveness of Remdesivir Treatment for Severe Coronavirus Disease 2019 (COVID-19) in Korea: a Nationwide Multicenter Retrospective Cohort Study.

BACKGROUND: Remdesivir is widely used for the treatment of coronavirus disease 2019 (COVID-19), but controversies regarding its efficacy still remain. METHODS: A retrospective cohort study was conducted to evaluate the effect of remdesivir on clinical and virologic outcomes of severe COVID-19 patients from June to July 2020. Primary clinical endpoints included clinical recovery, additional mechanical ventilator (MV) support, and duration of oxygen or MV support. Viral load reduction by hospital day (HD) 15 was evaluated by calculating changes in cycle threshold (Ct) values. RESULTS: A total of 86 severe COVID-19 patients were evaluated including 48 remdesivir-treated patients. Baseline characteristics were not significantly different between the two groups. Remdesivir was administered an average of 7.42 days from symptom onset. The proportions of clinical recovery of the remdesivir and supportive care group at HD 14 (56.3% and 39.5%) and HD 28 (87.5% and 78.9%) were not statistically different. The proportion of patients requiring MV support by HD 28 was significantly lower in the remdesivir group than in the supportive care group (22.9% vs. 44.7%, P = 0.032), and MV duration was significantly shorter in the remdesivir group (average, 1.97 vs. 5.37 days; P = 0.017). Analysis of upper respiratory tract specimens demonstrated that increases of Ct value from HD 1-5 to 11-15 were significantly greater in the remdesivir group than the supportive care group (average, 10.19 vs. 5.36; P = 0.007), and the slope of the Ct value increase was also significantly steeper in the remdesivir group (average, 5.10 vs. 2.68; P = 0.007). CONCLUSION: The remdesivir group showed clinical and virologic benefit in terms of MV requirement and viral load reduction, supporting remdesivir treatment for severe COVID-19.

Serologic Evaluation of Healthcare Workers Caring for COVID-19 Patients in the Republic of Korea.

The safety of healthcare workers (HCWs) against severe acute respiratory syndrome virus 2 (SARS-CoV-2) transmission is an important aspect of managing the coronavirus disease 2019 (COVID-19) pandemic. In the South Korea, highly stringent infection prevention and control (IPC) guidelines are implemented, and reports of healthcare-associated SARS-CoV-2 transmission among HCWs are limited. However, subclinical infections may have been missed by the current symptom-based screening strategy. To evaluate the risk of undetected SARS-CoV-2 transmissions from COVID-19 patients to HCWs, we conducted a multicenter seroprevalence study after the first surge of the COVID-19 outbreak. A total of 432 HCWs were evaluated, comprising 309 HCWs designated to laboratory-confirmed COVID-19 patient care and 123 non-designated HCWs. Designated HCWs wore personal protective equipment including an N95 respirator, eye protection, hooded overalls, shoe covers, and inner and outer gloves. Use of a powered air-purifying respirator was recommended for aerosol-generating procedures or long-duration care activities. A high-sensitivity (99.1%) fluorescence immunoassay immunoglobulin G (IgG) kit was used as the initial screening test, and two enzyme-linked immunosorbent assay kits for total and IgG antibodies were used to confirm the test results. A microneutralization test was additionally performed to evaluate the neutralizing activity of positive specimens. Among the evaluated HCWs, none of the non-designated HCWs had a positive result, while one of the HCWs designated for COVID-19 patient care (1/309, 0.3%) was seropositive for SARS-CoV-2 with confirmed neutralizing activity (1:40). This finding suggests that subclinical seroconversion may occur among HCWs caring for COVID-19 patients, although the risk is low under strict IPC guidance.

Age-Related Morbidity and Mortality among Patients with COVID-19.

On March 11, 2020, the World Health Organization declared coronavirus disease (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. During the COVID-19 pandemic, an age-associated vulnerability in the burden of disease has been uncovered. Understanding the spectrum of illness and the pathogenic mechanism of the disease in a vulnerable population is critical, especially during the pandemic. Herein, we reviewed published COVID-19 epidemiology data from several countries to identify any consistent trends in the relationship between age and COVID-19-associated morbidity or mortality. We also reviewed the literature for studies explaining the difference in the host response to SARS-CoV-2 infection according to age. The insights from these data will be useful in determining the treatment policies and preventive measures of COVID-19.

Telephone based Interventions for Psychological Problems in Hospital Isolated Patients with COVID-19.

OBJECTIVE: : The COVID-19 is overwhelming health care systems globally. Hospital isolation may generate considerable psychological stress. However, there has been scarce evidence on psychological interventions for these patients due to maintain staff safety. We investigated the feasibility and effectiveness of telephone based interventions for psychological problems in hospital isolated patients with COVID-19. METHODS: Psychiatrists visited the ward where the patients were hospitalized and interventions were given by using a ward telephone for 30 minutes. All patients were approached to receive a two-week psychological intervention program and/or pharmacotherapy whenever needed. Psychological problems were assessed at baseline, one, and two weeks. For the assessment of anxiety and depressive symptoms, the Hospital Anxiety and Depression Scale was administered to patients once a week. Insomnia severity index and Beck Depression Inventory 9 item were checked weekly to assess insomnia and suicide idea. RESULTS: Of 33 enrolled, clinically meaningful psychological symptoms were found in 6 (18%) patients for anxiety; 13 (39%) for depression; 10 (30%) for insomnia; and 3 (9%) for suicidal ideation. In 9 patients (27%), psychotropic medications were prescribed to manage anxiety, agitation, depressed mood, insomnia, impulsivity, and suicide idea. Compared to baseline, significant improvements were found in anxiety, depression, and suicidal ideation at one week. There were no statistical differences between the values evaluated at baseline and at two weeks. CONCLUSION: Our report at least indicates potential usefulness of telephone based interventions in hospital isolated patients with COVID-19, and will hopefully form the basis for future randomized clinical trials.

Viral Load Kinetics of SARS-CoV-2 Infection in Saliva in Korean Patients: a Prospective Multi-center Comparative Study.

BACKGROUND: This study was performed to compare the viral load and kinetics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in saliva with those in standard nasopharyngeal/oropharyngeal (NP/OP) swabs. METHODS: Fifteen patients with SARS-CoV-2 infection from four hospitals were prospectively enrolled and matched samples of nasopharyngeal/oropharyngeal swabs and saliva were collected at Day 1 of admission and every other day till consequently negative for two times. Real-time reverse transcription polymerase chain reaction (rRT-PCR) was performed to detect the envelope (E) and RNA-dependent RNA polymerase (RdRP) genes. RESULTS: The cycle threshold values of saliva were comparable to those of NP/OP swabs overall (P = 0.720, Mann-Whitney U test). However, the overall sensitivity of rRT-PCR using saliva was 64% (34/53), which is lower than the 77% (41/53) using NP/OP swabs. The sensitivity of rRT-PCR using saliva was especially lower in early stage of symptom onset (1-5 days; 8/15; 53%) and in patients who did not have sputum (12/22; 55%). CONCLUSION: Saliva sample itself is not appropriate for initial diagnosis of coronavirus disease 2019 (COVID-19) to replace NP/OP swabs, especially for the person who does not produce sputum. COVID-19 cannot be excluded when the test using saliva is negative, and it is necessary to retest using NP/OP swabs.

COVID-19 Pneumonia Diagnosis Using a Simple 2D Deep Learning Framework With a Single Chest CT Image: Model Development and Validation.

BACKGROUND: Coronavirus disease (COVID-19) has spread explosively worldwide since the beginning of 2020. According to a multinational consensus statement from the Fleischner Society, computed tomography (CT) is a relevant screening tool due to its higher sensitivity for detecting early pneumonic changes. However, physicians are extremely occupied fighting COVID-19 in this era of worldwide crisis. Thus, it is crucial to accelerate the development of an artificial intelligence (AI) diagnostic tool to support physicians. OBJECTIVE: We aimed to rapidly develop an AI technique to diagnose COVID-19 pneumonia in CT images and differentiate it from non-COVID-19 pneumonia and nonpneumonia diseases. METHODS: A simple 2D deep learning framework, named the fast-track COVID-19 classification network (FCONet), was developed to diagnose COVID-19 pneumonia based on a single chest CT image. FCONet was developed by transfer learning using one of four state-of-the-art pretrained deep learning models (VGG16, ResNet-50, Inception-v3, or Xception) as a backbone. For training and testing of FCONet, we collected 3993 chest CT images of patients with COVID-19 pneumonia, other pneumonia, and nonpneumonia diseases from Wonkwang University Hospital, Chonnam National University Hospital, and the Italian Society of Medical and Interventional Radiology public database. These CT images were split into a training set and a testing set at a ratio of 8:2. For the testing data set, the diagnostic performance of the four pretrained FCONet models to diagnose COVID-19 pneumonia was compared. In addition, we tested the FCONet models on an external testing data set extracted from embedded low-quality chest CT images of COVID-19 pneumonia in recently published papers. RESULTS: Among the four pretrained models of FCONet, ResNet-50 showed excellent diagnostic performance (sensitivity 99.58%, specificity 100.00%, and accuracy 99.87%) and outperformed the other three pretrained models in the testing data set. In the additional external testing data set using low-quality CT images, the detection accuracy of the ResNet-50 model was the highest (96.97%), followed by Xception, Inception-v3, and VGG16 (90.71%, 89.38%, and 87.12%, respectively). CONCLUSIONS: FCONet, a simple 2D deep learning framework based on a single chest CT image, provides excellent diagnostic performance in detecting COVID-19 pneumonia. Based on our testing data set, the FCONet model based on ResNet-50 appears to be the best model, as it outperformed other FCONet models based on VGG16, Xception, and Inception-v3.

Age Related Morbidity and Mortality among Patients with COVID-19

On March 11, 2020, the World Health Organization declared coronavirus disease (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. During the COVID-19 pandemic, an age-associated vulnerability in the burden of disease has been uncovered. Understanding the spectrum of illness and the pathogenic mechanism of the disease in a vulnerable population is critical, especially during the pandemic. Herein, we reviewed published COVID-19 epidemiology data from several countries to identify any consistent trends in the relationship between age and COVID-19-associated morbidity or mortality. We also reviewed the literature for studies explaining the difference in the host response to SARS-CoV-2 infection according to age. The insights from these data will be useful in determining the treatment policies and preventive measures of COVID-19.