Immune Responses After Vaccination With Primary 2-Dose ChAdOx1 Plus a Booster of BNT162b2 or Vaccination With Primary 2-Dose BNT162b2 Plus a Booster of BNT162b2 and the Occurrence of Omicron Breakthrough Infection.

BACKGROUND: Before the omicron era, health care workers were usually vaccinated with either the primary 2-dose ChAdOx1 nCoV-19 (Oxford-AstraZeneca) series plus a booster dose of BNT162b2 (Pfizer-BioNTech) (CCB group) or the primary 2-dose BNT162b2 series plus a booster dose of BNT162b2 (BBB group) in Korea. METHODS: The two groups were compared using quantification of the surrogate virus neutralization test for wild type severe acute respiratory syndrome coronavirus 2 (SVNT-WT), the omicron variant (SVNT-O), spike-specific IgG, and interferon-gamma (IFN-γ), as well as the omicron breakthrough infection cases. RESULTS: There were 113 participants enrolled in the CCB group and 51 enrolled in the BBB group. Before and after booster vaccination, the median SVNT-WT and SVNT-O values were lower in the CCB (SVNT-WT [before-after]: 72.02-97.61%, SVNT-O: 15.18-42.29%) group than in the BBB group (SVNT-WT: 89.19-98.11%, SVNT-O: 23.58-68.56%; all P < 0.001). Although the median IgG concentrations were different between the CCB and BBB groups after the primary series (2.677 vs. 4.700 AU/mL, respectively, P < 0.001), they were not different between the two groups after the booster vaccination (7.246 vs. 7.979 AU/mL, respectively, P = 0.108). In addition, the median IFN-γ concentration was higher in the BBB group than in the CCB group (550.5 and 387.5 mIU/mL, respectively, P = 0.014). There was also a difference in the cumulative incidence curves over time (CCB group 50.0% vs. BBB group 41.8%; P = 0.045), indicating that breakthrough infection occurred faster in the CCB group. CONCLUSION: The cellular and humoral immune responses were low in the CCB group so that the breakthrough infection occurred faster in the CCB group than in the BBB group.

A study on changes in lung function, neutralizing antibodies, and symptoms of adult patients hospitalized with COVID-19.

Background/Aims: To identify changes in symptoms and pulmonary sequelae in patients with coronavirus disease 2019 (COVID-19). Methods: Patients with COVID-19 hospitalized at seven university hospitals in Korea between February 2020 and February 2021 were enrolled, provided they had ≥ 1 outpatient follow-up visit. Between January 11 and March 9, 2021 (study period), residual symptom investigations, chest computed tomography (CT) scans, pulmonary function tests (PFT), and neutralizing antibody tests (NAb) were performed at the outpatient visit (cross-sectional design). Additionally, data from patients who already had follow-up outpatient visits before the study period were collected retrospectively. Results: Investigation of residual symptoms, chest CT scans, PFT, and NAb were performed in 84, 35, 31, and 27 patients, respectively. After 6 months, chest discomfort and dyspnea persisted in 26.7% (4/15) and 33.3% (5/15) patients, respectively, and 40.0% (6/15) and 26.7% (4/15) patients experienced financial loss and emotional distress, respectively. When the ratio of later CT score to previous ones was calculated for each patient between three different time intervals (1-14, 15-60, and 61-365 days), the median values were 0.65 (the second interval to the first), 0.39 (the third to the second), and 0.20 (the third to the first), indicating that CT score decreases with time. In the high-severity group, the ratio was lower than in the low-severity group. Conclusions: In COVID-19 survivors, chest CT score recovers over time, but recovery is slower in severely ill patients. Subjects complained of various ongoing symptoms and socioeconomic problems for several months after recovery.

Immune Responses against the Omicron Variant of SARS-CoV-2 after a Third Dose of COVID-19 Vaccine in Patients Living with Human Immunodeficiency Virus (PLWH): Comparison with Healthcare Workers.

We compared immune responses against the omicron variant of SARS-CoV-2 after a third dose of the coronavirus disease 2019 (COVID-19) vaccine between people living with human immunodeficiency (PLWH) and healthcare workers (HCWs). In this prospective observational study, PLWH and HCWs vaccinated with at least two doses of vaccine were enrolled. We analyzed neutralizing responses using the GenScript SARS-CoV-2 surrogate virus neutralization test kit. Twenty-nine PLWH and 114 HCWs were included to analyze immune responses after the third vaccination. Most PLWH (86.2%) had fully suppressed viral loads and CD4 T cell counts were well-controlled (median 670.0 cells/µL). The neutralizing responses against the omicron variant in PLWH were not significantly different from those in HCWs (43.94% vs. 51.77%, p = 0.42). However, neutralizing responses against the omicron variant were significantly impaired by about 50% compared with wild type SARS-CoV-2 in PLWH (43.94% vs. 97.46%, p < 0.001) and HCWs (51.77% vs. 97.74%, p < 0.001). Although neutralizing responses against the omicron variant in well-controlled PLWH were comparable to those of HCWs, the responses were much lower than those against wild type in both PLWH and HCWs. Therefore, the risk of breakthrough SARS-CoV-2 infection due to the currently circulating omicron variant is still high despite three doses of vaccine in PLWH and will not differ from HCWs.

Immunogenicity against the Omicron Variant after mRNA-Based COVID-19 Booster Vaccination in Medical Students Who Received Two Primary Doses of the mRNA-1273 Vaccine.

We evaluated the immune response against the Omicron variant after mRNA-based COVID-19 booster vaccination in medical students. We prospectively enrolled medical students who received two primary doses of the mRNA-1273 vaccine. The neutralizing response and the SARS-CoV-2-specific T-cell response was evaluated. A total of 56 serum samples were obtained before booster vaccination. Nineteen students (33.9%) developed COVID-19 two months after booster vaccination. Of 56 students, 35 students (12 infected and 23 uninfected) were available for blood sampling four months after booster vaccination. In comparison with uninfected students, infected students showed a significantly higher level of SARS-CoV-2-specific IgG (5.23 AU/mL vs. 5.12 AU/mL, p < 0.001) and rate of neutralizing response (96.22% vs. 27.18%, p < 0.001) four months after booster vaccination. There was no significant difference in the SARS-CoV-2-specific T-cell response. Among 23 infection-naive students, the neutralizing response was significantly higher in those who received the mRNA-1273 booster than in those who received the BNT162b2 booster (69.07% vs. 26.43%, p = 0.02). In our study, booster vaccination with mRNA-1273 instead of BNT162b2 was significantly associated with a higher neutralizing response.

SARS-CoV-2 Omicron escapes mRNA vaccine booster-induced antibody neutralisation in patients with autoimmune rheumatic diseases: an observational cohort study.

OBJECTIVES: This study investigates whether COVID-19 vaccines can elicit cross-reactive antibody responses against the Omicron variant in patients with autoimmune rheumatic diseases (ARDs). METHODS: This observational cohort study comprised 149 patients with ARDs and 94 healthcare workers (HCWs). Blood samples were obtained at enrolment, a median of 15 weeks after the second vaccine dose or 8 weeks after the third dose. The functional cross-neutralisation capacity of sera was measured using the Omicron variant receptor-binding domain-ACE2 binding inhibition assay. We assessed the incidence of breakthrough infections and the potential correlation with neutralising responses in participants after receiving third doses. The association of time-from-vaccine and neutralising responses in sera was predicted using linear regression analysis. RESULTS: The mean cross-neutralising responses against the Omicron variant developed after the second dose was 11.5% in patients with ARDs and 18.1% in HCWs (p=0.007). These responses were significantly lower in patients with ARDs than in HCWs after the third dose (26.8% vs 50.3%, p<0.0001). Only 39.2% of the patient sera showed functional neutralisation capacity to the Omicron variant and cross-neutralising responses were shown to be poorly correlated with anti-spike immunoglobulin G titres. Within 6 weeks of immunological assessments, significantly lower Omicron-neutralising responses were detected in sera from patients with ARDs who developed breakthrough infections compared with those who did not (p=0.018). Additionally, a relative decline was implied in neutralising responses against the Omicron variant as a reference to the wild-type virus during 120 days since the third vaccination, with a predicted decay rate of -0.351%/day (95% CI, -0.559 to -0.144, p=0.001). CONCLUSIONS: Striking antibody evasion manifested by the Omicron variant in patients with ARDs and current vaccine-induced immunity may not confer broad protection from Omicron breakthrough infection, highlighting the need for further research on vaccine effectiveness in patients with immune dysfunctions.

Relationship between SARS-CoV-2 antibody titer and the severity of COVID-19.

BACKGROUND: It remains unclear whether high titers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies aggravate clinical manifestations in patients or whether severe clinical manifestations result in high antibody titers. Thus, we investigated the cause-effect relationship between SARS-CoV-2 antibody titers and disease severity. METHODS: We prospectively enrolled patients admitted with the diagnosis of coronavirus disease-19 (COVID-19) from February 2020 to August 2020. We measured SARS-CoV-2 antibody titers, namely anti-receptor-binding domain (RBD) antibody and neutralizing antibody (NAb), from blood samples and calculated the chest radiograph (CXR) scores of the patients to evaluate the severity of COVID-19. RESULTS: Overall, 40 patients with COVID-19 were enrolled. Pneumonia was observed in more than half of the patients (25/40, 60%). SARS-CoV-2 antibody titers were higher in patients who were aged >60 years (anti-RBD antibodies, P = 0.003 and NAb, P = 0.009), presented with pneumonia (P = 0.006 and 0.007, respectively), and required oxygen therapy (P = 0.003 and 0.004, respectively) than in those who were not. CXR scores peaked (at 15-21 days after the onset of symptoms) statistically significantly earlier than SARS-CoV-2 antibody titers (at 22-30 days for NAb and at 31-70 days for anti-RBD antibody). There was a close correlation between the maximum CXR score and the maximum SAR-CoV-2 antibody titer. CONCLUSIONS: Based on the comparison of the peak time of SARS-CoV-2 antibody titers with the CXR score after symptom onset, we suggest that severe clinical manifestations result in high titers of SARS-CoV-2 antibodies.

Hip Fracture Management during the COVID-19 Pandemic in South Korea.

BACKGROUND: The purpose of this study was to introduce a screening system for coronavirus disease 2019 (COVID-19), to evaluate the overall orthopedic management in hip fracture patients during the COVID-19 pandemic in South Korea, and to compare the surgical results in hip fracture patients during the COVID-19 pandemic with those of the previous year. METHODS: Hip fracture patients who visited emergency rooms were screened at the screening clinics before admission. The medical management was carried out with the medical staff wearing surgical masks, meticulous hand hygiene observed, and a minimum distance of 2 m between patients maintained. The demographics, operative parameters, and surgical results of patients treated during the pandemic were compared with those from the previous year. RESULTS: From January 2020 to July 21, 2020, 119 patients with hip fractures (33 men and 86 women) were admitted to our institution for surgical treatment. Five patients showed symptoms of pneumonia, but no patient was positive for COVID-19. The mortality rate during the study period was 4.2%, and none of the patients died due to COVID-19. The interval between admission and surgery and the length of hospital stay were significantly shorter (p = 0.008, p = 0.002) and the proportion of spinal anesthesia was greater in hip fracture patients during the COVID-19 pandemic compared to those from the previous year (p = 0.011). CONCLUSIONS: The COVID-19 screening system for hip fracture patients has proven to be effective in preventing intrahospital spread of the disease. Hip fracture surgery performed during the COVID-19 pandemic has shown comparable results without any COVID-19 infection and COVID-19-related mortality.

SARS-CoV-2-Specific Antibody and T Cell Response Kinetics According to Symptom Severity.

Data on the longevity of humoral and cell-mediated immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19) are limited. We evaluated the detailed kinetics of antibody and T-cell responses at the acute, convalescent, and post-convalescent phases in COVID-19 patients with a wide range of severity. We enrolled patients with COVID-19 prospectively from four hospitals and one community treatment center between February 2020 and January 2021. symptom severity was classified as mild, moderate, or severe/critical. Patient blood samples were collected at 1 week (acute), 1 month (convalescent), and 2 months after symptom onset (post-convalescent). Human SARS-CoV-2 IgG and IgM antibodies were measured using in-house-developed ELISA. The SARS-CoV-2-specific T-cell responses against overlapping peptides of spike proteins and nucleoprotein were measured by interferon-γ enzyme-linked immunospot assays. Twenty-five COVID-19 patients were analyzed (mild, n = 5; moderate, n = 9; severe/critical, n = 11). IgM and IgG antibody responses peaked at 1 month after symptom onset and decreased at 2 months. IgG response levels were significantly greater in the severe/critical group compared with other groups. Interferon-γ-producing T-cell responses increased between 1 week and 1 month after symptom onset, and had a trend toward decreasing at 2 months, but did not show significant differences according to severity. Our data indicate that SARS-CoV-2-specific antibody responses were greater in those with severe symptoms and waned after reaching a peak around 1 month after symptom onset. However, SARS-CoV-2-specific T-cell responses were not significantly different according to symptom severity, and decreased slowly during the post-convalescent phase.

Systemic Adverse Events and Use of Antipyretics Predict the Neutralizing Antibody Positivity Early after the First Dose of ChAdOx1 Coronavirus Disease Vaccine.

Vaccination is considered crucial for the eradication of the coronavirus disease (COVID-19). In our medical center in Korea, most health care workers (HCWs) were vaccinated with the ChAdOx1 COVID-19 vaccine. After vaccination, many HCWs complained of adverse events (AEs). However, it remains unclear whether the production of neutralizing antibodies (NAb) was affected. Therefore, here, we aimed to evaluate AEs and early NAb production in relatively healthy Asians who received the ChAdOx1 vaccine and determine the effect of AEs and antipyretics on early NAb production against COVID-19. Of the 182 Korean HCWs who received the first dose of ChAdOx1 vaccine, 172 (94.5%) experienced ≥1 adverse events and 148 (81.3%) tested positive for NAb 33-40 days after the vaccination. NAb-positive vaccine recipients reported systemic AEs and consumed acetaminophen more frequently than NAb-negative recipients. We identified an association between antibody response and COVID-19 vaccine-related AEs. In conclusion, most ChAdOx1 vaccine recipients reported AEs in our medical center.

Impact of social distancing on the spread of common respiratory viruses during the coronavirus disease outbreak.

During the coronavirus disease (COVID-19) pandemic, social distancing was effective in controlling disease spread across South Korea. The impact of national social distancing on the spread of common respiratory virus infections has rarely been investigated. We evaluated the weekly proportion of negative respiratory virus polymerase chain reaction (PCR) test results and weekly positive rates of each respiratory virus during the social distancing period (10th-41st weeks of 2020) and the corresponding period in different years, utilizing the national respiratory virus surveillance dataset reported by the Korean Center for Disease Control and Prevention. The proportions of negative respiratory virus PCR test results increased up to 87.8% and 86.1% during level 3 and level 2 of the social distancing period, respectively. The higher the level of social distancing, the higher the proportion of negative respiratory virus PCR test results. During the social distancing period, the mean weekly positive rates for parainfluenza virus, influenza virus, human coronavirus, and human metapneumovirus were significantly lower than those during the same period in 2015-2019 (0.1% vs. 9.3%, P <0.001; 0.1% vs. 7.2%, P <0.001; 0.4% vs. 2.3%, P <0.001; and 0.2% vs. 5.3%, P <0.001, respectively). The mean positive rate for rhinovirus/enterovirus during level 3 social distancing was lower than that in the same period in 2015-2019 (8.5% vs. 19.0%, P <0.001), but the rate during level 1 social distancing was higher than that in the same period in 2015-2019 (38.3% vs. 19.4%, P <0.001). The national application of social distancing reduced the spread of common respiratory virus infections during the COVID-19 pandemic.

Evaluation of rapid SARS-CoV-2 antigen tests, AFIAS COVID-19 Ag and ichroma COVID-19 Ag, with serial nasopharyngeal specimens from COVID-19 patients.

We evaluated the diagnostic accuracy of two newly developed, point-of-care, rapid antigen tests (RATs) for detecting SARS-CoV-2, the AFIAS COVID-19 Ag and the ichromaTM COVID-19 Ag, and investigated antigen kinetics. A total of 200 serially collected nasopharyngeal (NP) specimens from 38 COVID-19 patients and 122 specimens from negative controls were analyzed. Diagnostic sensitivity and specificity were assessed in comparison to molecular test results and subdivided according to targeted genes (E, RdRP, and N) and days post-symptom onset (PSO). For the kinetics evaluation, cut-off-indices from serial NP specimens were used according to the number of days PSO. Both RATs showed sensitivity of 91.3‒100% for specimens with cycle threshold (Ct) < 25. The specificity of AFIAS was 98.7‒98.9% and that of ichromaTM was 100.0%. The kappa values of AFIAS and ichromaTM for the molecular testing of specimens with Ct < 25 (RdRP) were 0.97 and 1.00, respectively. The sensitivity of AFIAS and ichromaTM for all genes was lower for specimens collected at 8‒14 PSO than for those collected before 7-days PSO. The kinetics profiles showed that antigen levels gradually decreased from ≤ 7-days PSO to > 22-days PSO. Both RATs showed excellent specificity and acceptable sensitivity for NP specimens with higher viral loads and for specimens collected within 7-days PSO. Hence, they have the potential to become useful tools for the early detection of SARS-CoV-2. However, because of concerns about false negativity, RATs should be used in conjunction with molecular tests.

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.

Clinical and radiological findings of adult hospitalized patients with community-acquired pneumonia from SARS-CoV-2 and endemic human coronaviruses.

Endemic human coronaviruses (HCoVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are members of the family Coronaviridae. Comparing the findings of the infections caused by these viruses would help reveal the novel characteristics of SARS-CoV-2 and provide insight into the unique pathogenesis of SARS-CoV-2 infection. This study aimed to compare the clinical and radiological characteristics of SARS-CoV-2 and endemic HCoVs infection in adult hospitalized patients with community-acquired pneumonia (CAP). This study was performed at a university-affiliated tertiary hospital in the Republic of Korea, between January 1, 2015, and July 31, 2020. A total of 109 consecutive patients who were over 18 years of age with confirmed SARS-CoV-2 and endemic HCoVs were enrolled. Finally, 19 patients with SARS-CoV-2 CAP were compared to 40 patients with endemic HCoV CAP. Flu-like symptoms such as cough, sore throat, headache, myalgia, and prolonged fever were more common in SARS-CoV-2 CAP, whereas clinical findings suggestive of bacterial pneumonia such as dyspnea, leukocytosis with left shift, and increased C-reactive protein were more common in endemic HCoV CAP. Bilateral peripherally distributed ground-glass opacities (GGOs) were typical radiologic findings in SARS-CoV-2 CAP, whereas mixed patterns of GGOs, consolidations, micronodules, and pleural effusion were observed in endemic HCoV CAP. Coinfection was not observed in patients with SARS-CoV-2 CAP, but was observed in more than half of the patients with endemic HCoV CAP. There were distinctive differences in the clinical and radiologic findings between SARS-CoV-2 and endemic HCoV CAP. Further investigations are required to elucidate the mechanism underlying this difference. Follow-up observations are needed to determine if the presentation of SARS-CoV-2 CAP changes with repeated infection.

Clinical Pathway for Emergency Brain Surgery during COVID-19 Pandemic and Its Impact on Clinical Outcomes.

BACKGROUND: One of the challenges neurosurgeons are facing in the global public health crisis caused by the coronavirus disease 2019 (COVID-19) pandemic is to balance COVID-19 screening with timely surgery. We described a clinical pathway for patients who needed emergency brain surgery and determined whether differences in the surgery preparation process caused by COVID-19 screening affected clinical outcomes. METHODS: During the COVID-19 period, patients in need of emergency brain surgery in our institution were managed using a novel standardized pathway designed for COVID-19 screening. We conducted a retrospective review of patients who were hospitalized through the emergency room and underwent emergency brain surgery. A total of 32 patients who underwent emergency brain surgery from February 1 to June 30, 2020 were included in the COVID-19 group, and 65 patients who underwent surgery from February 1 to June 30, 2019 were included in the pre-COVID-19 group. The baseline characteristics, disease severity indicators, time intervals of emergency processes, and clinical outcomes of the two groups were compared. Subgroup analysis was performed between the immediate surgery group and the semi-elective surgery group during the COVID-19 period. RESULTS: There were no significant differences in baseline characteristics and severity indicators between the pre-COVID-19 group and COVID-19 group. The time interval to skin incision was significantly increased in the COVID-19 group (P = 0.027). However, there were no significant differences in the clinical outcomes between the two groups. In subgroup comparison, the time interval to skin incision was shorter in the immediate surgery group during the COVID-19 period compared with the pre-COVID-19 group (P = 0.040). The screening process did not significantly increase the time interval to classification and admission for immediate surgery. The time interval to surgery initiation was longer in the COVID-19 period due to the increased time interval in the semi-elective surgery group (P < 0.001). CONCLUSION: We proposed a clinical pathway for the preoperative screening of COVID-19 in patients requiring emergency brain surgery. No significant differences were observed in the clinical outcomes before and after the COVID-19 pandemic. The protocol we described showed acceptable results during this pandemic.

Effect of hydroxychloroquine pre-exposure on infection with SARS-CoV-2 in rheumatic disease patients: a population-based cohort study.

OBJECTIVES: Early in vitro studies have suggested that hydroxychloroquine (HCQ) is a potentially useful drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. This study was conducted to determine whether HCQ had a preventive effect on coronavirus disease 2019 (COVID-19) in rheumatic disease patients who were taking HCQ. METHODS: We conducted a population-based retrospective cohort study using the records of the Korean Health Insurance Review and Assessment (HIRA) claim records. The clinical data of patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) who were tested for SARS-CoV-2 were investigated. We compared the attack rate of COVID-19 between those who underwent HCQ therapy within 14 days before the test for SARS-CoV-2 (HCQ users) and HCQ non-users. Data were analysed using logistic regression models, χ2, and Student's t-tests. RESULTS: As of 15th May 2020, 2066 patients with RA or SLE were tested for COVID-19. Among them, 31.4% (649/2066) were treated with HCQ. Most HCQ users (93.7%, 608/649) were taking 200-400 mg/day recommended for the treatment of rheumatic diseases. The attack rate of COVID-19 in the HCQ users (2.3%, 15/649) did not differ from that in the HCQ non-users (2.2%, 31/1417) (p 0.86). CONCLUSIONS: HCQ prophylactic use at a usual dose did not prevent COVID-19 in patients with rheumatic disease.