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Journal of Infection and Chemotherapy ; 2022.
Article in English | ScienceDirect | ID: covidwho-1799832


The Omicron variant of severe acute respiratory syndrome coronavirus 2 has amino acid mutations in its spike proteins, which may allow it to evade immunity elicited by vaccination. We examined the neutralising activity and S1-IgG titres in patients with breakthrough infections caused by the Omicron variant after two doses of vaccination. We found that neutralising activity was significantly lower for the Omicron variant than for the Wuhan strain. Two doses of vaccination might not induce sufficient neutralising activity for the Omicron variant.

Preprint in English | medRxiv | ID: ppmedrxiv-22273418


BackgroundTherapeutic effects of steroids on acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (MV) have been reported. However, predictive indicators of early weaning from MV post-treatment have not yet been defined, making treating established ARDS challenging. Interleukin (IL)-6 has been associated with the pathogenesis of ARDS. ObjectiveOur aim was to clarify clinical utility of IL-6 level in ventilated patients with established ARDS. MethodsClinical, treatment, and outcome data were evaluated in 119 invasively ventilated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated ARDS. Plasma levels of IL-6 and C-reactive protein (CRP) were measured on days 1, 4, and 7 after intubation. ResultsFifty-two patients were treated with dexamethasone (steroid group), while the remaining 67 patients were not (non-steroid group). Duration of MV use was significantly shorter in the steroid group compared to non-steroid group (11.5{+/-}0.6 vs. 16.1{+/-}1.0 days, P = 0.0005, respectively) along with significantly decreased levels of IL-6 and CRP. Even when restricted to the steroid group, among variables post-MV, IL-6 level on day 7 was most closely correlated with duration of MV use (Spearmans rank correlation coefficient [{rho}] = 0.73, P < 0.0001), followed by CRP level on day 7 and the percentage change in IL-6 or CRP levels between day 1 and day 7. Moreover, among these variables, IL-6 levels on day 7 showed the highest accuracy for withdrawal from MV within 11 days (AUC: 0.88), with optimal cutoff value of 20.6 pg/mL. Consistently, the rate of MV weaning increased significantly earlier in patients with low IL-6 ([≤] 20.6 pg/mL) than in those with high IL-6 (> 20.6 pg/mL) (log-rank test P < 0.0001). ConclusionsIn invasively ventilated patients with established ARDS due to SARS-CoV-2, plasma IL-6 levels served as a predictor of early withdrawal from MV after dexamethasone administration.

Preprint in English | medRxiv | ID: ppmedrxiv-22269723


RationaleAcute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after passing the peak of viral load. However, the underlying mechanisms remain unclear. ObjectivesHere, we assess whether alveolar epithelial cell necrosis and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravate ARDS with COVID-19 MethodsIn patients with COVID-19 with and without ARDS and healthy adults, serum levels of the following were quantified: an epithelial total cell death marker, cytokeratin18-M65; an epithelial apoptosis marker, CK18-M30; HMGB-1; and alveolar epithelial and endothelial injury markers, sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of HMGB-1 neutralization on alveolar tissue injury were assessed using a mouse model of COVID-19-induced ARDS. Measurements and main resultsThe levels of CK18-M65, CK18-M30, and alveolar tissue injury markers were elevated in early stages of ARDS. The median M30/M65 ratio, an epithelial apoptosis indicator, was 31.50% in patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Serum levels of HMGB-1, one of DAMPs released from necrotic cells, were also significantly elevated in ARDS versus non-ARDS patients. In a COVID-19-induced ARDS mouse model, alveolar epithelial cell necrosis involved two forms of programmed necrosis, necroptosis and pyroptosis. Finally, neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. ConclusionsNecrosis, including necroptosis and pyroptosis, seems to be the primary form of alveolar epithelial cell death, and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS. The impact of this researchAlveolar tissue injury in acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after passing the peak of viral load. Our analysis of serum samples from COVID-19 patients and an animal model revealed that alveolar epithelial necrosis, including necroptosis and pyroptosis, occurs at the early disease stage of COVID-19-induced ARDS. Moreover, our data indicated that damage-associated molecular patterns released from necrotic alveolar epithelial cells are promising therapeutic targets to prevent the COVID-19 aggravation.

Preprint in English | medRxiv | ID: ppmedrxiv-21252061


Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

Preprint in English | medRxiv | ID: ppmedrxiv-20158410


SARS-CoV-2 neutralizing antibodies confer protective immunity against reinfection. We have developed a rapid test for screening SARS-CoV-2 neutralization antibodies using genome-free virus-like particles incorporated with a small luciferase peptide, HiBiT. Their entry into LgBiT-expressing target cells reconstitutes NanoLuc luciferase readily detected by a luminometer. This newly developed HiBiT-tagged Virus-like particle-based Neutralization Test (hiVNT) can readily quantify SARS-CoV-2 neutralizing antibodies within three hours with a high-throughput in a low biosafety setting. Moreover, the neutralizing activity obtained from hiVNT was highly consistent with that measured by the conventional neutralization test using authentic SARS-CoV-2. Furthermore, antibody responses to both viral spike and nucleocapsid proteins correlated with the neutralization activity assessed by hiVNT. Our newly-developed hiVNT could be instrumental to survey individuals for the presence of functional neutralizing antibody against SARS-CoV-2.