Clinical significance of antinuclear antibody positivity in patients with severe coronavirus disease 2019.

BACKGROUND/AIMS: This study aimed to investigate the clinical characteristics and outcomes of fluorescent antinuclear antibody (FANA)-positive patients admitted for coronavirus disease 2019 (COVID-19) and identify FANA as a prognostic factor of mortality. METHODS: This retrospective study was conducted at a university-affiliated hospital with 1,048 beds from September 2020 to March 2022. The participants were consecutive patients who required oxygenation through a high-flow nasal cannula, non-invasive or mechanical ventilation, or extracorporeal membrane oxygenation, and conducted the FANA test within 48 hours of admission. RESULTS: A total of 132 patients with severe COVID-19 were included in this study, of which 77 (58.3%) had FANA-positive findings (≥ 1:80). FANA-positive patients were older and had higher inflammatory markers and 28-day mortality than FANA- negative patients. In the multivariate Cox proportional hazard regression analysis, FANA-positive findings (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.04-6.74), age (per 1-year; HR, 1.05; 95% CI, 1.01-1.10), underlying pulmonary disease (HR, 3.16; 95% CI, 0.97-10.26), underlying hypertension (HR, 2.97; 95% CI, 1.28-6.87), and blood urea nitrogen > 20 mg/dL (HR, 3.72; 95% CI, 1.09-12.64) were independent predictors of 28-day mortality. Remdesivir (HR, 0.34; 95% CI, 0.15-0.74) was found to be an independent predictor that reduced mortality. CONCLUSION: Our findings revealed an autoimmune phenomenon in patients with severe COVID-19, which provides an ancillary rationale for strategies to optimize immunosuppressive therapy. In particular, this study suggests the potential of FANA to predict the outcomes of COVID-19.

Model-based cost-effectiveness analysis of oral antivirals against SARS-CoV-2 in Korea.

OBJECTIVES: Many countries have authorized the emergency use of oral antiviral agents for patients with mild-to-moderate cases of coronavirus disease 2019 (COVID-19). We assessed the cost-effectiveness of these agents for reducing the number of severe COVID-19 cases and the burden on Korea's medical system. METHODS: Using an existing model, we estimated the number of people who would require hospital/intensive care unit (ICU) admission in Korea in 2022. The treatment scenarios included (1) all adult patients, (2) elderly patients only, and (3) adult patients with underlying diseases only, compared to standard care. Based on the current health system capacity, we calculated the incremental costs per severe case averted and hospital admission for each scenario. RESULTS: We estimated that 236,510 COVID-19 patients would require hospital/ICU admission in 2022 with standard care only. Nirmatrelvir/ritonavir (87% efficacy) was predicted to reduce this number by 80%, 24%, and 17% when targeting all adults, adults with underlying diseases, and elderly patients (25, 8, and 4%, respectively, for molnupiravir, with 30% efficacy). Nirmatrelvir/ritonavir use is likely to be cost-effective, with predicted costs of US$8,878, US$8,964, and US$1,454, per severe patient averted for the target groups listed above, respectively, while molnupiravir is likely to be less cost-effective, with costs of US$28,492, US$29,575, and US$7,915, respectively. CONCLUSIONS: In Korea, oral treatment using nirmatrelvir/ritonavir for symptomatic COVID-19 patients targeting elderly patients would be highly cost-effective and would substantially reduce the demand for hospital admission to below the capacity of the health system if targeted to all adult patients instead of standard care.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea.

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

Correlation Between Third Dose of COVID-19 Vaccines and Regional Case Fatality Rates During the Omicron Wave in Korea.

This study seeks to find the correlation between case fatality rates (CFRs) and third-dose vaccination coverage in 244 counties (si/gun/gu) of South Korea during the omicron variant wave. Multivariate regression analyses report that the higher third-dose vaccination rates were correlated with lower regional CFRs, when controlling for age structure. If the third-dose vaccination rate of a county is higher by 10%, it would have a CFR lower by 0.05% (95% confidence interval, 0.03-0.08%). As the number of cumulative confirmed cases in South Korea was 16,353,495 as of April 20, 2022, a lower CFR by 0.03-0.08% is equivalent to 4,394-12,448 lives (8.6-24.4 per 100,000) spared. County-specific characteristics, such as age structure, intensive care unit availability, and the level of non-pharmaceutical interventions may also affect the extent of this correlation. The conclusion implicates the potential role of coronavirus disease 2019 vaccines in reducing the pressure on the regional healthcare capacity.

Development and Roll-Out of A Coronavirus Disease 2019 Clinical Pathway for Standardized Qualified Care in Public Hospitals in Korea.

Despite the coronavirus disease 2019 (COVID-19) vaccination roll-out, variant-related outbreaks have occurred repeatedly in Korea. Although public hospitals played a major role in COVID-19 patients' care, difficulty incorporating evolving COVID-19 treatment guidelines called for a clinical pathway (CP). Eighteen public hospitals volunteered, and a professional review board was created. CPs were formulated containing inclusion/exclusion criteria, application flow charts, and standardized order sets. After CP roll-out, key parameters improved, such as increased patient/staff five-point satisfaction scores (0.41/0.57) and decreased hospital stays (1.78 days)/medical expenses (17.5%). The CPs were updated consistently after roll-out as new therapeutics drugs were introduced and quarantine policies changed.

Humoral and Cellular Immune Responses to Vector, Mix-and-Match, or mRNA Vaccines against SARS-CoV-2 and the Relationship between the Two Immune Responses.

We investigated how differences in age, sex, or vaccine type can affect humoral and cellular immune responses after vaccination with vector (ChAdOx1 nCoV-19), mix-and-match (first, ChAdOx1 nCoV-19, and second, BNT162b2), or mRNA (BNT162b2 or mRNA-1273) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Venous blood was collected from 573 subjects (vector, 396; mix-and-match, 96; and mRNA, 81) before the first vaccination (T0), 7 to 8 weeks (vector) or 3 to 4 weeks (mRNA) after the first vaccination (T1), and 3 to 4 weeks after the second vaccination (T2). The humoral and cellular immune responses were evaluated using Elecsys anti-SARS-CoV-2 (Roche), Alinity SARS-CoV-2 IgG II Quant (Abbott), cPass SARS-CoV-2 neutralization antibody detection (GenScript), and QuantiFERON SARS-CoV-2 (Qiagen) kits. At T1, the levels of the receptor-binding domain antibodies (RBD Ab) and neutralizing antibodies (NAb) decreased with aging, but interferon gamma release (IGR) levels increased. The RBD Ab, NAb, and IGR levels were higher in females than in males at T1 and T2. The NAb levels were higher in the mix-and-match and mRNA vaccine groups than in the vector vaccine group at T2. The RBD Ab and IGR levels were higher in the mRNA vaccine group than in the vector or mix-and-match vaccine groups at T2. The optimal cutoffs for RBD Ab and NAb, which were used to determine the presence of T cell responses, were 5.7 binding antibody units per milliliter (BAU mL-1) and 12.0 IU mL-1, respectively. Age, sex, and vaccine type affected the humoral and cellular immune responses, and T cell responses could be estimated from RBD Ab and NAb levels. IMPORTANCE There have been few studies that comprehensively evaluated factors affecting immune responses and the correlation between humoral and cellular immune responses after vector, mix-and-match, and mRNA vaccines against SARS-CoV-2. Therefore, we analyzed the effects of age, sex, and the different vaccine regimens on the immune responses to vaccination against SARS-CoV-2. The correlation between humoral and cellular immune responses and the cutoffs were derived for RBD antibodies and neutralizing antibodies to predict the presence of the cellular immune responses. In this comprehensive study, we demonstrated that there were differences in the immune responses induced after vaccination depending on the age and sex of an individual. Among the three vaccine regimens, the mix-and-match and mRNA vaccines induced the most robust immune responses. Finally, the proposed optimal cutoffs for RBD and neutralizing antibodies may be useful for predicting cellular immune responses when assays for cellular immune responses are not available.

Korean Society of Infectious Diseases/National Evidence-based Healthcare Collaborating Agency Recommendations for Anti-SARS-CoV-2 Monoclonal Antibody Treatment of Patients with COVID-19.

Neutralizing antibodies targeted at the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been developed and now under evaluation in clinical trials. The US Food and Drug Administration currently issued emergency use authorizations for neutralizing monoclonal antibodies in non-hospitalized patients with mild to moderate coronavirus disease 2019 (COVID-19) who are at high risk for progressing to severe disease and/or hospitalization. In terms of this situation, there is an urgent need to investigate the clinical aspects and to develop strategies to deploy them effectively in clinical practice. Here we provide guidance for the use of anti-SARS-CoV-2 monoclonal antibodies for the treatment of COVID-19 based on the latest evidence.

No Change of Pneumocystis jirovecii Pneumonia after the COVID-19 Pandemic: Multicenter Time-Series Analyses.

Consolidated infection control measures imposed by the government and hospitals during COVID-19 pandemic resulted in a sharp decline of respiratory viruses. Based on the issue of whether Pneumocystis jirovecii could be transmitted by airborne and acquired from the environment, we assessed changes in P. jirovecii pneumonia (PCP) cases in a hospital setting before and after COVID-19. We retrospectively collected data of PCP-confirmed inpatients aged ≥18 years (N = 2922) in four university-affiliated hospitals between January 2015 and June 2021. The index and intervention dates were defined as the first time of P. jirovecii diagnosis and January 2020, respectively. We predicted PCP cases for post-COVID-19 and obtained the difference (residuals) between forecasted and observed cases using the autoregressive integrated moving average (ARIMA) and the Bayesian structural time-series (BSTS) models. Overall, the average of observed PCP cases per month in each year were 36.1 and 47.3 for pre- and post-COVID-19, respectively. The estimate for residuals in the ARIMA model was not significantly different in the total PCP-confirmed inpatients (7.4%, p = 0.765). The forecasted PCP cases by the BSTS model were not significantly different from the observed cases in the post-COVID-19 (-0.6%, 95% credible interval; -9.6~9.1%, p = 0.450). The unprecedented strict non-pharmacological interventions did not affect PCP cases.

Revised Korean Society of Infectious Diseases/National Evidence-based Healthcarea Collaborating Agency Guidelines on the Treatment of Patients with COVID-19.

Despite the global effort to mitigate the spread, coronavirus disease 2019 (COVID-19) has become a pandemic that took more than 2 million lives. There are numerous ongoing clinical studies aiming to find treatment options and many are being published daily. Some effective treatment options, albeit of variable efficacy, have been discovered. Therefore, it is necessary to develop an evidence-based methodology, to continuously check for new evidence, and to update recommendations accordingly. Here we provide guidelines on pharmaceutical treatment for COVID-19 based on the latest evidence.

COVID-19 infection with asymptomatic or mild disease severity in young patients: Clinical course and association between prevalence of pneumonia and viral load.

Few studies have focused on clinical courses or viral loads in young asymptomatic or mild patients with COVID-19 infection. We sought to better understand the clinical course and association between viral load and prevalence of pneumonia in young COVID-19 patients with asymptomatic or mild disease severity. In this retrospective study, 106 COVID-19 young patients with asymptomatic or mild disease severity were analyzed for clinical characteristics, clinical course, prevalence of radiologically proven pneumonia and viral load. The cut-off value of viral load for presence of pneumonia was also investigated. The mean age was 28.0±9.3 years. Eleven patients (10.4%) experienced viral remission within one week of diagnosis, but one (0.9%) transferred to the hospital due to aggravation of pneumonia. Patients with pneumonia had significantly higher viral load than those without, and the cut-off value of the Ct value for presence of pneumonia were 31.38. The patients with pneumonia had significantly slower recovery times than those without. Diarrhea was significantly more common in patients with pneumonia than patients without pneumonia. In conclusion, most young asymptomatic and mildly symptomatic patients showed stable clinical course. There were significant differences in viral load and recovery times between patients with and without pneumonia.

Strategical Preparedness and Response Actions in the Healthcare System Against Coronavirus Disease 2019 according to Transmission Scenario in Korea.

The dynamic nature of coronavirus disease 2019 (COVID-19) pandemic requires us to be efficient and flexible in resource utilization. The strategical preparedness and response actions of the healthcare system are the key component to contain COVID-19 and to decrease its case fatality ratio. Depending on the epidemiological situation, each medical institution should systematically share the responsibility for patient screening, disposition and treatment according to clinical severity. To overcome fast-paced COVID-19 pandemic, the government should be rapidly ready and primed for action according to the specific transmission scenario.

Interim Guidelines on Antiviral Therapy for COVID-19.

Since the first case was reported in Wuhan, Hubei Province, China on December 12, 2019, Coronavirus disease 2019 (COVID-19) has spread widely to other countries since January 2020. As of April 16, 2020, 10635 confirmed cases have been reported, with 230 deaths in Korea. COVID-19 patients may be asymptomatic or show various clinical manifestations, including acute symptoms such as fever, fatigue, sore throat; pneumonia presenting as acute respiratory distress syndrome; and multiple organ failure. As COVID-19 has such varied clinical manifestations and case fatality rates, no standard antiviral therapy regimen has been established other than supportive therapy. In the present guideline, we aim to introduce potentially helpful antiviral and other drug therapies based on in vivo and in vitro research and clinical experiences from many countries.

Strategical Preparedness and Response Actions in the Healthcare System Against Coronavirus Disease 2019 according to Transmission Scenario in Korea

The dynamic nature of coronavirus disease 2019 (COVID-19) pandemic requires us to be efficient and flexible in resource utilization. The strategical preparedness and response actions of the healthcare system are the key component to contain COVID-19 and to decrease its case fatality ratio. Depending on the epidemiological situation, each medical institution should systematically share the responsibility for patient screening, disposition and treatment according to clinical severity. To overcome fast-paced COVID-19 pandemic, the government should be rapidly ready and primed for action according to the specific transmission scenario.