Prognostic Factors for Pulmonary Fibrosis Following Pneumonia in Patients with COVID-19: A Prospective Study.

The frequency and clinical manifestation of lung fibrosis accompanied by coronavirus disease (COVID-19) are not well-established. We aimed to identify the factors attributed to post-COVID-19 fibrosis. This single-center prospective study included patients diagnosed with COVID-19 pneumonia from 12 April to 22 October 2021 in the Republic of Korea. The primary outcome was the presence of pulmonary fibrosis on a CT scan 3 months after discharge; the fibrosis risk was estimated by a multiple logistic regression. The mean patient age was 55.03 ± 12.32 (range 27-85) years; 65 (66.3%) were men and 33 (33.7%) were women. The age, Charlson Comorbidity Index, lactate dehydrogenase level, aspartate aminotransferase level, and Krebs von den Lungen-6 level were significantly higher and the albumin level and the saturation of the peripheral oxygen/fraction of inspired oxygen (SpO2/FiO2) ratio were significantly lower in the fibrosis group than in the non-fibrosis group; the need for initial oxygen support was also greater in the fibrosis group. An older age (adjusted odds ratio (AOR) 1.12; 95% confidence interval (CI) 1.03-1.21) and a lower initial SpO2/FiO2 ratio (AOR 7.17; 95% CI 1.72-29.91) were significant independent risk factors for pulmonary fibrosis after COVID-19 pneumonia. An older age and a low initial SpO2/FiO2 ratio were crucial in predicting pulmonary fibrosis after COVID-19 pneumonia.

Enhanced antibody responses in fully vaccinated individuals against pan-SARS-CoV-2 variants following Omicron breakthrough infection.

Omicron has become the globally dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, creating additional challenges due to its ability to evade neutralization. Here, we report that neutralizing antibodies against Omicron variants are undetected following COVID-19 infection with ancestral or past SARS-CoV-2 variant viruses or after two-dose mRNA vaccination. Compared with two-dose vaccination, a three-dose vaccination course induces broad neutralizing antibody responses with improved durability against different SARS-CoV-2 variants, although neutralizing antibody titers against Omicron remain low. Intriguingly, among individuals with three-dose vaccination, Omicron breakthrough infection substantially augments serum neutralizing activity against a broad spectrum of SARS-CoV-2 variants, including Omicron variants BA.1, BA.2, and BA.5. Additionally, after Omicron breakthrough infection, memory T cells respond to the spike proteins of both ancestral and Omicron SARS-CoV-2 by producing cytokines with polyfunctionality. These results suggest that Omicron breakthrough infection following three-dose mRNA vaccination induces pan-SARS-CoV-2 immunity that may protect against emerging SARS-CoV-2 variants of concern.

Leveraging a Preexisting Global Infectious Disease Network for Local Decision Making During a Pandemic.

Emerging infectious disease epidemics require a rapid response from health systems; however, evidence-based consensus guidelines are generally absent early in the course of events. Formed in 2017 by 5 high-level isolation units spanning 3 continents, the experience of the Global Infectious Disease Preparedness Network (GIDPN) early in the course of coronavirus disease 2019 (COVID-19) provides a model for accelerating best practice development and improving decision-making in health emergencies. The network served as a platform for real-time, open and transparent information-sharing during unknowns of an active outbreak by clinicians caring for patients, by researchers conducting clinical trials and transmission and infection prevention studies, and by teams advising local and national policy makers. Shared knowledge led to earlier adoption of some treatment modalities as compared to most peer institutions and to implementation of protocols prior to incorporation into national guidelines. GIDPN and similar networks are integral in enhancing preparedness for and response to future epidemics/pandemics.

Predication of oxygen requirement in COVID-19 patients using dynamic change of inflammatory markers: CRP, hypertension, age, neutrophil and lymphocyte (CHANeL).

The objective of the study was to develop and validate a prediction model that identifies COVID-19 patients at risk of requiring oxygen support based on five parameters: C-reactive protein (CRP), hypertension, age, and neutrophil and lymphocyte counts (CHANeL). This retrospective cohort study included 221 consecutive COVID-19 patients and the patients were randomly assigned randomly to a training set and a test set in a ratio of 1:1. Logistic regression, logistic LASSO regression, Random Forest, Support Vector Machine, and XGBoost analyses were performed based on age, hypertension status, serial CRP, and neutrophil and lymphocyte counts during the first 3 days of hospitalization. The ability of the model to predict oxygen requirement during hospitalization was tested. During hospitalization, 45 (41.8%) patients in the training set (n = 110) and 41 (36.9%) in the test set (n = 111) required supplementary oxygen support. The logistic LASSO regression model exhibited the highest AUC for the test set, with a sensitivity of 0.927 and a specificity of 0.814. An online risk calculator for oxygen requirement using CHANeL predictors was developed. "CHANeL" prediction models based on serial CRP, neutrophil, and lymphocyte counts during the first 3 days of hospitalization, along with age and hypertension status, provide a reliable estimate of the risk of supplement oxygen requirement among patients hospitalized with COVID-19.

Pattern of inflammatory immune response determines the clinical course and outcome of COVID-19: unbiased clustering analysis.

The objective of the study was to identify distinct patterns in inflammatory immune responses of COVID-19 patients and to investigate their association with clinical course and outcome. Data from hospitalized COVID-19 patients were retrieved from electronic medical record. Supervised k-means clustering of serial C-reactive protein levels (CRP), absolute neutrophil counts (ANC), and absolute lymphocyte counts (ALC) was used to assign immune responses to one of three groups. Then, relationships between patterns of inflammatory responses and clinical course and outcome of COVID-19 were assessed in a discovery and validation cohort. Unbiased clustering analysis grouped 105 patients of a discovery cohort into three distinct clusters. Cluster 1 (hyper-inflammatory immune response) was characterized by high CRP levels, high ANC, and low ALC, whereas Cluster 3 (hypo-inflammatory immune response) was associated with low CRP levels and normal ANC and ALC. Cluster 2 showed an intermediate pattern. All patients in Cluster 1 required oxygen support whilst 61% patients in Cluster 2 and no patient in Cluster 3 required supplementary oxygen. Two (13.3%) patients in Cluster 1 died, whereas no patient in Clusters 2 and 3 died. The results were confirmed in an independent validation cohort of 116 patients. We identified three different patterns of inflammatory immune response to COVID-19. Hyper-inflammatory immune responses with elevated CRP, neutrophilia, and lymphopenia are associated with a severe disease and a worse outcome. Therefore, targeting the hyper-inflammatory response might improve the clinical outcome of COVID-19.

Viral Load Kinetics of SARS-CoV-2 Infection in First Two Patients in Korea.

As of February 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak started in China in December 2019 has been spreading in many countries in the world. With the numbers of confirmed cases are increasing, information on the epidemiologic investigation and clinical manifestation have been accumulated. However, data on viral load kinetics in confirmed cases are lacking. Here, we present the viral load kinetics of the first two confirmed patients with mild to moderate illnesses in Korea in whom distinct viral load kinetics are shown. This report suggests that viral load kinetics of SARS-CoV-2 may be different from that of previously reported other coronavirus infections such as SARS-CoV.

Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection After Recovery from Mild Coronavirus Disease 2019.

BACKGROUND: Positive results from real-time reverse-transcription polymerase chain reaction (rRT-PCR) in recovered patients raise concern that patients who recover from coronavirus disease 2019 (COVID-19) may be at risk of reinfection. Currently, however, evidence that supports reinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reported. METHODS: We conducted whole-genome sequencing of the viral RNA from clinical specimens at the initial infection and at the positive retest from 6 patients who recovered from COVID-19 and retested positive for SARS-CoV-2 via rRT-PCR after recovery. A total of 13 viral RNAs from the patients' respiratory specimens were consecutively obtained, which enabled us to characterize the difference in viral genomes between initial infection and positive retest. RESULTS: At the time of the positive retest, we were able to acquire a complete genome sequence from patient 1, a 21-year-old previously healthy woman. In this patient, through the phylogenetic analysis, we confirmed that the viral RNA of positive retest was clustered into a subgroup distinct from that of the initial infection, suggesting that there was a reinfection of SARS-CoV-2 with a subtype that was different from that of the primary strain. The spike protein D614G substitution that defines the clade "G" emerged in reinfection, while mutations that characterize the clade "V" (ie, nsp6 L37F and ORF3a G251V) were present at initial infection. CONCLUSIONS: Reinfection with a genetically distinct SARS-CoV-2 strain may occur in an immunocompetent patient shortly after recovery from mild COVID-19. SARS-CoV-2 infection may not confer immunity against a different SARS-CoV-2 strain.

Recommendations for the Management of Patients With Systemic Rheumatic Diseases During the Coronavirus Disease Pandemic

Patients with systemic rheumatic diseases (SRD) are vulnerable for coronavirus disease (COVID-19). The Korean College of Rheumatology recognized the urgent need to develop recommendations for rheumatologists and other physicians to manage patients with SRD during the COVID-19 pandemic. The working group was organized and was responsible for selecting key health questions, searching and reviewing the available literature, and formulating statements. The appropriateness of the statements was evaluated by voting panels using the modified Delphi method. Four general principles and thirteen individual recommendations were finalized through expert consensus based on the available evidence. The recommendations included preventive measures against COVID-19, medicinal treatment for stable or active SRD patients without COVID-19, medicinal treatment for SRD patients with COVID-19, and patient evaluation and monitoring. Medicinal treatments were categorized according to the status with respect to both COVID-19 and SRD. These recommendations should serve as a reference for individualized treatment for patients with SRD. As new evidence is emerging, an immediate update will be required.

Detection and Isolation of SARS-CoV-2 in Serum, Urine, and Stool Specimens of COVID-19 Patients from the Republic of Korea.

OBJECTIVES: Coronavirus Disease-19 (COVID-19) is a respiratory infection characterized by the main symptoms of pneumonia and fever. It is caused by the novel coronavirus severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), which is known to spread via respiratory droplets. We aimed to determine the rate and likelihood of SARS-CoV-2 transmission from COVID-19 patients through non-respiratory routes. METHODS: Serum, urine, and stool samples were collected from 74 hospitalized patients diagnosed with COVID-19 based on the detection of SARS-CoV-2 in respiratory samples. The SARS-CoV-2 RNA genome was extracted from each specimen and real-time reverse transcription polymerase chain reaction performed. CaCo-2 cells were inoculated with the specimens containing the SARS-COV-2 genome, and subcultured for virus isolation. After culturing, viral replication in the cell supernatant was assessed. RESULTS: Of the samples collected from 74 COVID-19 patients, SARS-CoV-2 was detected in 15 serum, urine, or stool samples. The virus detection rate in the serum, urine, and stool samples were 2.8% (9/323), 0.8% (2/247), and 10.1% (13/129), and the mean viral load was 1,210 ± 1,861, 79 ± 30, and 3,176 ± 7,208 copy/µL, respectively. However, the SARS-CoV-2 was not isolated by the culture method from the samples that tested positive for the SARS-CoV-2 gene. CONCLUSION: While the virus remained detectable in the respiratory samples of COVID-19 patients for several days after hospitalization, its detection in the serum, urine, and stool samples was intermittent. Since the virus could not be isolated from the SARS-COV-2-positive samples, the risk of viral transmission via stool and urine is expected to be low.

Recommendations for the management of patients with systemic rheumatic diseases during the coronavirus disease pandemic.

Patients with systemic rheumatic diseases (SRD) are vulnerable for coronavirus disease (COVID-19). The Korean College of Rheumatology recognized the urgent need to develop recommendations for rheumatologists and other physicians to manage patients with SRD during the COVID-19 pandemic. The working group was organized and was responsible for selecting key health questions, searching and reviewing the available literature, and formulating statements. The appropriateness of the statements was evaluated by voting panels using the modified Delphi method. Four general principles and thirteen individual recommendations were finalized through expert consensus based on the available evidence. The recommendations included preventive measures against COVID-19, medicinal treatment for stable or active SRD patients without COVID-19, medicinal treatment for SRD patients with COVID-19, and patient evaluation and monitoring. Medicinal treatments were categorized according to the status with respect to both COVID-19 and SRD. These recommendations should serve as a reference for individualized treatment for patients with SRD. As new evidence is emerging, an immediate update will be required.

Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2.

The previous outbreaks of SARS-CoV and MERS-CoV have led researchers to study the role of diagnostics in impediment of further spread and transmission. With the recent emergence of the novel SARS-CoV-2, the availability of rapid, sensitive, and reliable diagnostic methods is essential for disease control. Hence, we have developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the specific detection of SARS-CoV-2. The primer sets for RT-LAMP assay were designed to target the nucleocapsid gene of the viral RNA, and displayed a detection limit of 102 RNA copies close to that of qRT-PCR. Notably, the assay has exhibited a rapid detection span of 30 min combined with the colorimetric visualization. This test can detect specifically viral RNAs of the SARS-CoV-2 with no cross-reactivity to related coronaviruses, such as HCoV-229E, HCoV-NL63, HCoV-OC43, and MERS-CoV as well as human infectious influenza viruses (type B, H1N1pdm, H3N2, H5N1, H5N6, H5N8, and H7N9), and other respiratory disease-causing viruses (RSVA, RSVB, ADV, PIV, MPV, and HRV). Furthermore, the developed RT-LAMP assay has been evaluated using specimens collected from COVID-19 patients that exhibited high agreement to the qRT-PCR. Our RT-LAMP assay is simple to perform, less expensive, time-efficient, and can be used in clinical laboratories for preliminary detection of SARS-CoV-2 in suspected patients. In addition to the high sensitivity and specificity, this isothermal amplification conjugated with a single-tube colorimetric detection method may contribute to the public health responses and disease control, especially in the areas with limited laboratory capacities.

Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 not yet has established its treatment, but convalescent plasma has been expected to increase survival rates as in the case with other emerging viral infections. We describe two cases of COVID-19 treated with convalescent plasma infusion. Both patients presented severe pneumonia with acute respiratory distress syndrome and showed a favorable outcome after the use of convalescent plasma in addition to systemic corticosteroid. To our knowledge, this is the first report of the use of convalescent plasma therapy for COVID-19 in Korea.

Infection and Rapid Transmission of SARS-CoV-2 in Ferrets.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.

Clinical Course and Outcomes of Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection: a Preliminary Report of the First 28 Patients from the Korean Cohort Study on COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pneumonia emerged in Wuhan, China in December 2019. In this retrospective multicenter study, we investigated the clinical course and outcomes of novel coronavirus disease 2019 (COVID-19) from early cases in Republic of Korea. METHODS: All of the cases confirmed by real time polymerase chain reaction were enrolled from the 1st to the 28th patient nationwide. Clinical data were collected and analyzed for changes in clinical severity including laboratory, radiological, and virologic dynamics during the progression of illness. RESULTS: The median age was 40 years (range, 20-73 years) and 15 (53.6%) patients were male. The most common symptoms were cough (28.6%) and sore throat (28.6%), followed by fever (25.0%). Diarrhea was not common (10.7%). Two patients had no symptoms. Initial chest X-ray (CXR) showed infiltration in 46.4% of the patients, but computed tomography scan confirmed pneumonia in 88.9% (16/18) of the patients. Six patients (21.4%) required supplemental oxygen therapy, but no one needed mechanical ventilation. Lymphopenia was more common in severe cases. Higher level of C-reactive protein and worsening of chest radiographic score was observed during the 5-7 day period after symptom onset. Viral shedding was high from day 1 of illness, especially from the upper respiratory tract (URT). CONCLUSION: The prodromal symptoms of COVID-19 were mild and most patients did not have limitations of daily activity. Viral shedding from URT was high from the prodromal phase. Radiological pneumonia was common from the early days of illness, but it was frequently not evident in simple CXR. These findings could be plausible explanations for the easy and rapid spread of SARS-CoV-2 in the community.