COVID-19 Vaccination as a Trigger of IgA Vasculitis: Truth or Illusion?

We read with great interest the recent article by Ramdani and colleagues in The Journal of Rheumatology on a nationwide multicenter, retrospective study conducted in France describing the status of the occurrence of IgA vasculitis (IgAV) after coronavirus disease 2019 (COVID-19) vaccination.1 We support and appreciate the authors' work and agree with their conclusions that IgA vasculitis following COVID-19 vaccination is usually benign and that a fortuitous link cannot be ruled out and now requires a worldwide pharmacovigilance study, but there are some concerns about some of the details in the article.

Single-injection COVID-19 subunit vaccine elicits potent immune responses.

Current vaccination schedules, including COVID-19 vaccines, require multiple doses to be administered. Single injection vaccines eliciting equivalent immune response are highly desirable. Unfortunately because unconventional release kinetics are difficult to achieve it still remains a huge challenge. Herein a single-injection COVID-19 vaccine was designed using a highly programmable release system based on dynamic layer-by-layer (LBL) films. The antigen, S1 subunit of SARS-CoV-2 spike protein, was loaded in CaCO₃ microspheres, which were further coated with tannic acid (TA)/polyethylene glycol (PEG) LBL films. The single-injection vaccine was obtained by mixing the microspheres coated with different thickness of TA/PEG films. Because of the unique constant-rate erosion behavior of the TA/PEG coatings, this system allows for distinct multiple pulsatile release of antigen, closely mimicking the release profile of antigen in conventional multiple dose vaccines. Immunization with the single injection vaccine induces potent and persistent S1-specific humoral and cellular immune responses in mice. The sera from the vaccinated animal exhibit robust in vitro viral neutralization ability. More importantly, the immune response and viral inhibition induced by the single injection vaccine are as strong as that induced by the corresponding multiple dose vaccine, because they share the same antigen release profile. STATEMENT OF SIGNIFICANCE: Vaccines are the most powerful and cost-effective weapons against infectious diseases such as COVID-19. However, current vaccination schedules, including the COVID-19 vaccines, require multiple doses to be administered. Herein a single-injection COVID-19 vaccine is designed using a highly programmable release system. This vaccine releases antigens in a pulsatile manner, closely mimicking the release pattern of antigens in conventional multiple dose vaccines. As a result, one single injection of the new vaccine induces an immune response and viral inhibition similar to that induced by the corresponding multiple-dose vaccine approach.

Remote clinical training practice in the neurology internship during the COVID-19 pandemic.

Background: During the current COVID-19 pandemic, offline clinical education was mandated to suspend at the neurology department of many teaching hospitals globally, yet there is insufficient evidence regarding the preferred practice and methods for online neurology intern training course.Objective: The investigation aimed to examine whether the online neurology training course based on Small Private Online Course (SPOC) and blending learning mode can achieve a good effect and cater for interns from different medical programs and whether the learning group size affects the teaching effect.Design: The subjects were 92 students enrolled in the neurology internship at the Second Xiangya Hospital of China from 9 March to 9 August 2020. After completing the online course, the final scores and evaluation results were compared among different groups of interns, and their preference to distinct contents of the course was analyzed. Statistical analysis was performed using the SPSS program (version 22.0).Results: Our online course received consistent positive recognition from the interns. Ninety-nine percent of the interns recommended incorporating the online course into the conventional offline training program after the pandemic. There was no significant difference between interns from different programs concerning the final scores and course evaluation. A smaller learning group size (<15 students) could achieve a better teaching effect than a larger group size (p < 0.05). The interns preferred interactive discussions, and course contents that they can get practice and feedback from, rather than video watching and didactic lectures.Conclusions: The online neurology intern training course based on SPOC and blending learning mode is worthy of popularization in a large student base. The teaching effect of an online intern training program may be improved by limiting the group size to less than 15 students and encouraging more interactive discussion, more practice and feedback.

Immunologic memory to SARS-CoV-2 in convalescent COVID-19 patients at 1 year postinfection.

BACKGROUND: Understanding the complexities of immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is key to gain insights into the durability of protective immunity against reinfection. OBJECTIVE: We sought to evaluate the immune memory to SARS-CoV-2 in convalescent patients with longer follow-up time. METHODS: SARS-CoV-2-specific humoral and cellular responses were assessed in convalescent patients with coronavirus disease 2019 (COVID-19) at 1 year postinfection. RESULTS: A total of 78 convalescent patients with COVID-19 (26 moderate, 43 severe, and 9 critical) were recruited after 1 year of recovery. The positive rates of both anti-receptor-binding domain and antinucleocapsid antibodies were 100%, whereas we did not observe a statistical difference in antibody levels among different severity groups. Accordingly, the prevalence of neutralizing antibodies (nAbs) reached 93.59% in convalescent patients. Although nAb titers displayed an increasing trend in convalescent patients with increased severity, the difference failed to achieve statistical significance. Notably, there was a significant correlation between nAb titers and anti-receptor-binding domain levels. Interestingly, SARS-CoV-2-specific T cells could be robustly maintained in convalescent patients, and their number was positively correlated with both nAb titers and anti-receptor-binding domain levels. Amplified SARS-CoV-2-specific CD4+ T cells mainly produced a single cytokine, accompanying with increased expression of exhaustion markers including PD-1, Tim-3, TIGIT, CTLA-4, and CD39, while the proportion of multifunctional cells was low. CONCLUSIONS: Robust SARS-CoV-2-specific humoral and cellular responses are maintained in convalescent patients with COVID-19 at 1 year postinfection. However, the dysfunction of SARS-CoV-2-specific CD4+ T cells supports the notion that vaccination is needed in convalescent patients for preventing reinfection.

The Dynamic Immunological Parameter Landscape in Coronavirus Disease 2019 Patients With Different Outcomes.

Objectives: The longitudinal and systematic evaluation of immunity in coronavirus disease 2019 (COVID-19) patients is rarely reported. Methods: Parameters involved in innate, adaptive, and humoral immunity were continuously monitored in COVID-19 patients from onset of illness until 45 days after symptom onset. Results: This study enrolled 27 mild, 47 severe, and 46 deceased COVID-19 patients. Generally, deceased patients demonstrated a gradual increase of neutrophils and IL-6 but a decrease of lymphocytes and platelets after the onset of illness. Specifically, sustained low numbers of CD8+ T cells, NK cells, and dendritic cells were noted in deceased patients, while these cells gradually restored in mild and severe patients. Furthermore, deceased patients displayed a rapid increase of HLA-DR expression on CD4+ T cells in the early phase, but with a low level of overall CD45RO and HLA-DR expressions on CD4+ and CD8+ T cells, respectively. Notably, in the early phase, deceased patients showed a lower level of plasma cells and antigen-specific IgG, but higher expansion of CD16+CD14+ proinflammatory monocytes and HLA-DR-CD14+ monocytic-myeloid-derived suppressor cells (M-MDSCs) than mild or severe patients. Among these immunological parameters, M-MDSCs showed the best performance in predicting COVID-19 mortality, when using a cutoff value of ≥10%. Cluster analysis found a typical immunological pattern in deceased patients on day 9 after onset, which was characterized as the increase of inflammatory markers (M-MDSCs, neutrophils, CD16+CD14+ monocytes, and IL-6) but a decrease of host immunity markers. Conclusions: This study systemically characterizes the kinetics of immunity of COVID-19, highlighting the importance of immunity in patient prognosis.

High Prevalence of Post-stroke Anxiety in Elderly Patients Following COVID-19 Outbreak.

Objective: Post-stroke anxiety (PSA) is a common affective disorder in patients with ischemic stroke. The elderly are more susceptible to mental health issues, however, few studies have so far focused on PSA in elderly patients, especially in the context of the COVID-19, causing psychological issues in the general population. The aim of the present study was to assess the prevalence and risk factors of PSA in elderly patients following COVID-19 outbreak. Methods: We retrospectively analyzed 206 elderly inpatients with newly diagnosed acute ischemic stroke in the First Affiliated Hospital, Sun Yat-sen University, from January 2020 to December 2020. Patients were categorized into the PSA group and the non-PSA group based on Hamilton Anxiety Scale scores at admission (within 1 week after stroke onset). Demographic and clinical data, mental state by Mini-Mental State Examination, depression by Hamilton Depression Scales (HAMD), and stroke severity and outcome by National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale were compared between the two groups. Univariate analysis and binary logistic regression analysis were used to analyze risk factors associated with PSA. We determined the cutoff scores for significant predictors of PSA using the area under the curve (AUC) and receiver operating characteristic. Results: Of the 206 stroke patients, 62 (30.1%) developed anxiety. Binary logistic regression analysis showed that female gender [adjusted odds ratio (aOR): 2.288, 95% confidence interval (CI):1.021-5.128, P = 0.044], high NIHSS scores [aOR: 1.264, 95% CI: 1.074-1.486, P = 0.005] and HAMD scores [aOR: 1.345, 95% CI: 1.215-1.490, P < 0.001] were independent risk factors for PSA. The cutoff threshold for the NIHSS scores was 3.5 points with an AUC of 0.64 and the cutoff threshold for HAMD scores was 5.5 points with an AUC of 0.89. Conclusion: Our results showed a high incidence of PSA in elderly patients after the COVID-19 outbreak. Female gender, high NIHSS and HAMD scores were the independent risk factors for PSA.

Risk factors on admission associated with hospital length of stay in patients with COVID-19: a retrospective cohort study.

Treating patients with COVID-19 is expensive, thus it is essential to identify factors on admission associated with hospital length of stay (LOS) and provide a risk assessment for clinical treatment. To address this, we conduct a retrospective study, which involved patients with laboratory-confirmed COVID-19 infection in Hefei, China and being discharged between January 20 2020 and March 16 2020. Demographic information, clinical treatment, and laboratory data for the participants were extracted from medical records. A prolonged LOS was defined as equal to or greater than the median length of hospitable stay. The median LOS for the 75 patients was 17 days (IQR 13-22). We used univariable and multivariable logistic regressions to explore the risk factors associated with a prolonged hospital LOS. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated. The median age of the 75 patients was 47 years. Approximately 75% of the patients had mild or general disease. The univariate logistic regression model showed that female sex and having a fever on admission were significantly associated with longer duration of hospitalization. The multivariate logistic regression model enhances these associations. Odds of a prolonged LOS were associated with male sex (aOR 0.19, 95% CI 0.05-0.63, p = 0.01), having fever on admission (aOR 8.27, 95% CI 1.47-72.16, p = 0.028) and pre-existing chronic kidney or liver disease (aOR 13.73 95% CI 1.95-145.4, p = 0.015) as well as each 1-unit increase in creatinine level (aOR 0.94, 95% CI 0.9-0.98, p = 0.007). We also found that a prolonged LOS was associated with increased creatinine levels in patients with chronic kidney or liver disease (p < 0.001). In conclusion, female sex, fever, chronic kidney or liver disease before admission and increasing creatinine levels were associated with prolonged LOS in patients with COVID-19.

Prediction of Sepsis in COVID-19 Using Laboratory Indicators.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has become a global public health concern. Many inpatients with COVID-19 have shown clinical symptoms related to sepsis, which will aggravate the deterioration of patients' condition. We aim to diagnose Viral Sepsis Caused by SARS-CoV-2 by analyzing laboratory test data of patients with COVID-19 and establish an early predictive model for sepsis risk among patients with COVID-19. Methods: This study retrospectively investigated laboratory test data of 2,453 patients with COVID-19 from electronic health records. Extreme gradient boosting (XGBoost) was employed to build four models with different feature subsets of a total of 69 collected indicators. Meanwhile, the explainable Shapley Additive ePlanation (SHAP) method was adopted to interpret predictive results and to analyze the feature importance of risk factors. Findings: The model for classifying COVID-19 viral sepsis with seven coagulation function indicators achieved the area under the receiver operating characteristic curve (AUC) 0.9213 (95% CI, 89.94-94.31%), sensitivity 97.17% (95% CI, 94.97-98.46%), and specificity 82.05% (95% CI, 77.24-86.06%). The model for identifying COVID-19 coagulation disorders with eight features provided an average of 3.68 (±) 4.60 days in advance for early warning prediction with 0.9298 AUC (95% CI, 86.91-99.04%), 82.22% sensitivity (95% CI, 67.41-91.49%), and 84.00% specificity (95% CI, 63.08-94.75%). Interpretation: We found that an abnormality of the coagulation function was related to the occurrence of sepsis and the other routine laboratory test represented by inflammatory factors had a moderate predictive value on coagulopathy, which indicated that early warning of sepsis in COVID-19 patients could be achieved by our established model to improve the patient's prognosis and to reduce mortality.

Quantitative assessment of SARS-CoV-2 RNAemia and outcome in patients with coronavirus disease 2019.

The disease spectrum of coronavirus disease 2019 (COVID-19) varies from asymptomatic infection to critical illness and death. Identification of prognostic markers is vital for predicting progression and clinical practice. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, known as RNAemia, has been detected in the blood. However, the potential clinical value of SARS-CoV-2 RNAemia remains unknown. We, therefore, conducted a meta-analysis using a random-effects model to estimate the pooled prevalence of SARS-CoV-2 RNAemia as well as summary strength of RNAemia in association with disease severity and unfavorable clinical outcomes. A total of 21 studies involving 2181 patients were included. SARS-CoV-2 RNAemia in COVID-19 patients varied from 9.4% to 74.1%, with a pooled estimate of 34% (95% confidene interval [CI]: 26%-43%). Overall, SARS-CoV-2 RNAemia was associated with COVID-19 severity with odds ratio (OR) of 5.43 (95% CI: 3.46-8.53). In addition, SARS-CoV-2 RNAemia was a significant risk factor for unfavorable clinical outcomes (OR = 6.54, 95% CI: 3.82-11.21). The summary OR was 4.28 (95% CI: 2.20-8.33) for intensive care unit (ICU) admission, 11.07 (95% CI: 5.60-21.88) for mortality. Furthermore, RNAemia was also a significant risk factor for invasive mechanical ventilation and multiple organ failure. SARS-CoV-2 RNAemia is associated with disease severity, ICU admission, death in COVID-19, and may serve as a clinical predictor. More prospective trials in evaluating the potential of SARS-CoV-2 RNAemia as a prognostic indicator are necessary.

Prealbumin as a Predictor of Prognosis in Patients With Coronavirus Disease 2019.

Background: The predictive value of prealbumin for the prognosis of coronavirus disease 2019 (COVID-19) has not been extensively investigated. Methods: A total of 1,115 patients with laboratory-confirmed COVID-19 were enrolled at Tongji hospital from February to April 2020 and classified into fatal (n = 129) and recovered (n = 986) groups according to the patient's outcome. Prealbumin and other routine laboratory indicators were measured simultaneously. Results: The level of prealbumin on admission was significantly lower in fatal patients than in recovered patients. For predicting the prognosis of COVID-19, the performance of prealbumin was better than most routine laboratory indicators, such as albumin, lymphocyte count, neutrophil count, hypersensitive C-reactive protein, d-dimer, lactate dehydrogenase, creatinine, and hypersensitive cardiac troponin I. When a threshold of 126 mg/L was used to discriminate between fatal and recovered patients, the sensitivity and specificity of prealbumin were, respectively, 78.29 and 90.06%. Furthermore, a model based on the combination of nine indexes showed an improved performance in predicting the death of patients with COVID-19. Using a cut-off value of 0.19, the prediction model was able to distinguish between fatal and recovered individuals with a sensitivity of 86.82% and a specificity of 90.37%. Conclusions: A lower level of prealbumin on admission may indicate a worse outcome of COVID-19. Immune and nutritional status may be vital factors for predicting disease progression in the early stage of COVID-19.

Prediction Model Based on the Combination of Cytokines and Lymphocyte Subsets for Prognosis of SARS-CoV-2 Infection.

BACKGROUND: There are currently rare satisfactory markers for predicting the death of patients with coronavirus disease 2019 (COVID-19). The aim of this study is to establish a model based on the combination of serum cytokines and lymphocyte subsets for predicting the prognosis of the disease. METHODS: A total of 739 participants with COVID-19 were enrolled at Tongji Hospital from February to April 2020 and classified into fatal (n = 51) and survived (n = 688) groups according to the patient's outcome. Cytokine profile and lymphocyte subset analysis was performed simultaneously. RESULTS: The fatal patients exhibited a significant lower number of lymphocytes including B cells, CD4+ T cells, CD8+ T cells, and NK cells and remarkably higher concentrations of cytokines including interleukin-2 receptor, interleukin-6, interleukin-8, and tumor necrosis factor-α on admission compared with the survived subjects. A model based on the combination of interleukin-8 and the numbers of CD4+ T cells and NK cells showed a good performance in predicting the death of patients with COVID-19. When the threshold of 0.075 was used, the sensitivity and specificity of the prediction model were 90.20% and 90.26%, respectively. Meanwhile, interleukin-8 was found to have a potential value in predicting the length of hospital stay until death. CONCLUSIONS: Significant increase of cytokines and decrease of lymphocyte subsets are found positively correlated with in-hospital death. A model based on the combination of three markers provides an attractive approach to predict the prognosis of COVID-19.

Establishing a model for predicting the outcome of COVID-19 based on combination of laboratory tests.

INTRODUCTION: There are currently no satisfactory methods for predicting the outcome of Coronavirus Disease-2019 (COVID-19). The aim of this study is to establish a model for predicting the prognosis of the disease. METHODS: The laboratory results were collected from 54 deceased COVID-19 patients on admission and before death. Another 54 recovered COVID-19 patients were enrolled as control cases. RESULTS: Many laboratory indicators, such as neutrophils, AST, γ-GT, ALP, LDH, NT-proBNP, Hs-cTnT, PT, APTT, D-dimer, IL-2R, IL-6, IL-8, IL-10, TNF-α, CRP, ferritin and procalcitonin, were all significantly increased in deceased patients compared with recovered patients on admission. In contrast, other indicators such as lymphocytes, platelets, total protein and albumin were significantly decreased in deceased patients on admission. Some indicators such as neutrophils and procalcitonin, others such as lymphocytes and platelets, continuously increased or decreased from admission to death in deceased patients respectively. Using these indicators alone had moderate performance in differentiating between recovered and deceased COVID-19 patients. A model based on combination of four indicators (P = 1/[1 + e-(-2.658+0.587×neutrophils - 2.087×lymphocytes - 0.01×platelets+0.004×IL-2R)]) showed good performance in predicting the death of COVID-19 patients. When cutoff value of 0.572 was used, the sensitivity and specificity of the prediction model were 90.74% and 94.44%, respectively. CONCLUSIONS: Using the current indicators alone is of modest value in differentiating between recovered and deceased COVID-19 patients. A prediction model based on combination of neutrophils, lymphocytes, platelets and IL-2R shows good performance in predicting the outcome of COVID-19.

Detection of IgM and IgG antibodies in patients with coronavirus disease 2019.

OBJECTIVES: This study aimed to determine the IgM and IgG responses against severe acute respiratory syndrome coronavirus (SARS-CoV)-2 in coronavirus disease 2019 (COVID-19) patients with varying illness severities. METHODS: IgM and IgG antibody levels were assessed via chemiluminescence immunoassay in 338 COVID-19 patients. RESULTS: IgM levels increased during the first week after SARS-CoV-2 infection, peaked 2 weeks and then reduced to near-background levels in most patients. IgG was detectable after 1 week and was maintained at a high level for a long period. The positive rates of IgM and/or IgG antibody detections were not significantly different among the mild, severe and critical disease groups. Severe and critical cases had higher IgM levels than mild cases, whereas the IgG level in critical cases was lower than those in both mild and severe cases. This might be because of the high disease activity and/or a compromised immune response in critical cases. The IgM antibody levels were slightly higher in deceased patients than recovered patients, but IgG levels in these groups did not significantly differ. A longitudinal detection of antibodies revealed that IgM levels decreased rapidly in recovered patients, whereas in deceased cases, either IgM levels remained high or both IgM and IgG were undetectable during the disease course. CONCLUSION: Quantitative detection of IgM and IgG antibodies against SARS-CoV-2 quantitatively has potential significance for evaluating the severity and prognosis of COVID-19.

Using a diagnostic model based on routine laboratory tests to distinguish patients infected with SARS-CoV-2 from those infected with influenza virus.

BACKGROUND: The differential diagnosis between novel coronavirus pneumonia patients (NCPP) and influenza patients (IP) remains a challenge in clinical practice. METHODS: Between January 2018 and March 2020, 1,027 NCPP and 1,140 IP were recruited from Tongji hospital. Routine blood examination, biochemical indicators and coagulation function analysis were simultaneously performed in all participants. RESULTS: There was no sex predominance in NCPP. The NCPP were frequently encountered in the sixth and seventh decades of life. The mean age of NCPP (56±16 years) was higher than IP (47±17 years), but without statistical difference. Although most results of routine laboratory tests between NCPP and IP had no significant differences, some laboratory tests showed an obvious change in NCPP. It was observed that NCPP had significantly decreased white blood cells, alkaline phosphatase and d-dimer compared with IP. However, the results of lactate dehydrogenase, erythrocyte sedimentation rate and fibrinogen were significantly increased in NCPP compared with IP. The diagnostic model based on a combination of 18 routine laboratory indicators showed an area under the curve of 0.796 (95% CI, 0.777-0.814), with a sensitivity of 46.93% and specificity of 90.09% when using a cut-off value of 0.598. CONCLUSIONS: Some routine laboratory results had statistical difference between NCPP and IP. A diagnostic model based on a combination of routine laboratory results provided an adjunct approach in the differential diagnosis between NCPP and IP.

The laboratory tests and host immunity of COVID-19 patients with different severity of illness.

BACKGROUNDThe coronavirus disease 2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak throughout the world. The host immunity of COVID-19 patients is unknown.METHODSThe routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission.RESULTSA total of 65 SARS-CoV-2-positive patients were classified as having mild (n = 30), severe (n = 20), and extremely severe (n = 15) illness. Many routine laboratory tests, such as ferritin, lactate dehydrogenase, and D-dimer, were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells, and B cells were gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The costimulatory molecule CD28 had opposite results. The percentage of natural Tregs was decreased in extremely severe patients. The percentage of IFN-γ-producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ-producing CD4+ T cells was increased in extremely severe patients. IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients.CONCLUSIONThe number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.FUNDINGThis work was funded by the National Mega Project on Major Infectious Disease Prevention (2017ZX10103005-007) and the Fundamental Research Funds for the Central Universities (2019kfyRCPY098).