Non-severe Coronavirus Disease 2019 Research Articles

Comprehensive analysis of immunogenic cell death-related gene and construction of prediction model based on WGCNA and multiple machine learning in severe COVID-19

The death of coronavirus disease 2019 (COVID-19) is primarily due to from critically ill patients, especially from ARDS complications caused by SARS-CoV-2. Therefore, it is essential to contribute an in-depth understanding of the pathogenesis of the disease and to identify biomarkers for predicting critically ill patients at the molecular level. Immunogenic cell death (ICD), as a specific variant of regulatory cell death driven by stress, can induce adaptive immune responses against cell death antigens in the host. Studies have confirmed that both innate and adaptive immune pathways are involved in the pathogenesis of SARS-CoV-2 infection. However, the role of ICD in the pathogenesis of severe COVID-19 has rarely been explored. In this study, we systematically evaluated the role of ICD-related genes in COVID-19. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis based on ICD differentially expressed genes. The results showed that immune infiltration characteristics were altered in severe and non-severe COVID-19. In addition, we used multiple machine learning methods to screen for five risk genes (KLF5, NSUN7, APH1B, GRB10 and CD4), which are used to predict COVID-19 severity. Finally, we constructed a nomogram to predict the risk of severe COVID-19 based on the classification and recognition model, and validated the model with external data sets. This study provides a valuable direction for the exploration of the pathogenesis and progress of COVID-19, and helps in the early identification of severe cases of COVID-19 to reduce mortality.

The role of C-reactive protein, procalcitonin, interleukin-6 and neutrophil / lymphocyte ratio as a laboratory biomarker in COVID-19

Biomarkers such as Interleukin-6 (IL-6), Procalcitonin (PCT), C-reactive protein (CRP) and Neutrophil-Lymphocyte Ratio (NLR) have a role in the pathogenesis of severe coronavirus disease 2019 (COVID-19). The aim of this study was to explore the differences between serum levels of such biomarkers in severe and non-severe COVID-19 cases and compare them with normal people and to evaluate the sociodemographic variables and chronic diseases effect on the severity of COVID-19. The study included 160 subjects, divided into two groups, a case group of 80 patients, and a control group of 80 normal persons. The case group was divided into two subgroups: 40 severe COVID-19 patients and 40 patients with non-severe disease. Blood IL-6 was assessed by an enzyme-linked immunosorbent assay (ELISA), PCT by an immunoassay, CRP by an immunoturbidimetric assay and NLR from CBC. The levels of IL-6, PCT, CRP, and NLR were significantly higher in the case group than in control group (p= 0.001, for all). However, there was no difference between these biomarkers level in the non-severe COVID-19 subgroup and the control group (p>0.05 for all). The proportion of severe COVID-19 was significantly higher in patients aged >50 years, and in patients with chronic diseases (p=0.046 and p=0.001, respectively). We also found a strong correlation between such biomarkers and old age, and chronic diseases with the disease severity. There was a significant difference in the level of the three biomarkers (IL-6, PCT, CRP, and NLR) between patients’ subgroups and the control group. In conclusion, since the levels of these biomarkers are correlated with the severity of the COVID-19 disease, and there was a difference in the levels between the groups with severe and non-severe symptoms, we suggest a role of these biomarkers in predicting the severity COVID-19 disease and its poor prognosis.

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study

BackgroundCadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19).MethodsWe performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed.ResultsA total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060–2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 μg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118–25.580], p = 0.036).ConclusionsUrine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

Long-Term Impacts of COVID-19 on Severe Exacerbation and Mortality in Adult Asthma: A Nationwide Population-Based Cohort Study

BackgroundIn adults with asthma, the long-term impact of previous coronavirus disease 2019 (COVID-19) on severe exacerbations and mortality is unclear. ObjectiveWe evaluated the long-term risk of severe exacerbation and mortality in adults with asthma who recovered from COVID-19. MethodsUsing the Korean National Health Insurance claim-based database, we compared the risk of severe exacerbations (emergency room visits or hospitalization) and mortality in adults with asthma aged >20 years recovered from COVID-19 between October 8, 2020, and December 16, 2021 (COVID-19 cohort, n=10,739) with 1:1 propensity score-matched controls (n=10,739). ResultsDuring a median follow-up of 87 (range, 15–448) days, the incidence rate of severe exacerbation in the COVID-19 cohort and matched cohort was 187.3 and 119.3 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of severe exacerbation compared to the matched cohort (hazard ratio=1.57; 95% confidence interval [CI]=1.06–2.32). During a median follow-up of 360 (range, 15–721) days, the incidence rate of death in the COVID-19 and matched cohort was 128.3 and 73.5 per 10,000 person-years, respectively. The COVID-19 cohort had a higher risk of death (hazard ratio=1.76; 95% CI=1.33–2.30) compared to the matched cohort. When further analyzed by COVID-19 severity, severe COVID-19 was associated with a 5.12-fold (95% CI=3.27–8.01) and 7.31-fold (95% CI=5.41–9.88) increased risk of severe exacerbation and death, respectively, but non-severe COVID-19 was not. ConclusionOur study heightens that severe COVID-19 is associated with increased long-term risk of severe exacerbation and mortality among individuals with asthma.

Elevated level of circulating calprotectin correlates with severity and high mortality in patients with COVID-19.

Patients with coronavirus disease-2019 (COVID-19) are characterized by hyperinflammation. Calprotectin (S100A8/S100A9) is a calcium- and zinc-binding protein mainly secreted by neutrophilic granulocytes or macrophages and has been suggested to be correlated with the severity and prognosis of COVID-19. To thoroughly evaluate the diagnostic and prognostic utility of calprotectin in patients with COVID-19 by analyzing relevant studies. PubMed, Web of Science, and Cochrane Library were comprehensively searched from inception to August 1, 2023 to retrieve studies about the application of calprotectin in COVID-19. Useful data such as the level of calprotectin in different groups and the diagnostic efficacy of this biomarker for severe COVID-19 were extracted and aggregated by using Stata 16.0 software. Fifteenstudies were brought into this meta-analysis. First, the pooled standardized mean differences (SMDs) were used to estimate the differences in the levels of circulating calprotectin between patients with severe and non-severe COVID-19. The results showed an overall estimate of 1.84 (95% confidence interval [CI]: 1.09-2.60). Diagnostic information was extracted from 11 studies, and the pooled sensitivity and specificity of calprotectin for diagnosing severe COVID-19 were 0.75 (95%CI: 0.64-0.84) and 0.88 (95%CI: 0.79-0.94), respectively. The AUC was 0.89 and the pooled DOR was 18.44 (95%CI: 9.07-37.51). Furthermore, there was a strong correlation between elevated levels of circulating calprotectin and a higher risk of mortality outcomes in COVID-19 patients (odds ratio: 8.60, 95%CI: 2.17-34.12; p < 0.1). This meta-analysis showed that calprotectin was elevated in patients with severe COVID-19, and this atypical inflammatory cytokine might serve as a useful biomarker to distinguish the severity of COVID-19 and predict the prognosis.

Correlation between Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio with the severity of Covid-19 patients in Dr. Hasan Sadikin Central Public Hospital

Coronavirus Disease 2019 (COVID-19) has a clinical spectrum that varies from asymptomatic to death. Cytokine storms cause neutrophilia, lymphopenia, and thrombocytopenia at various levels of COVID-19 severity. These three parameters can be studied as markers of inflammation in the form of ratios. This study aims to discover the correlation between NLR &amp; PLR inflammatory markers in determining the severity of COVID-19.An analytical cross-sectional study was carried out on secondary data from 274 subjects collected from the subject's hematological parameters from first day of admission to Hasan Sadikin Hospital from May-December 2020. The statistical analysis with Spearman test using the SPSS 17.0 program. There are 274 subjectswith non-severe and severe COVID-19 were NLR (3,44 vs 7,17), PLR (182,4 vs 254,4). The r coefficient of NLR and PLR reached 0.308 and 0.198, p-value of &lt; 0.001.In the next phase, days 7-14, lymphocytes decrease significantly. This study found a weak correlation because neutrophilia occurred on the third-seventh day of treatment, while the assessment was performed at first day of admission with clinical symptoms on day 1-3. PLR and NLR have a weak positive correlation with the severity of COVID-19. Therefore, it cannot be utilized independently in determining the severity of COVID-19.

Evaluation of the Relationship Between Serum miR-200b-3p and miR-214-3p Expression Levels with Soluble ACE2 and TMPRSS2 in COVID-19 Patients.

The emergence and rapid global spread of the coronavirus disease 2019 (COVID-19) has presented a significant global health challenge. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human host cells through the interaction of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which serve as main regulators for viral entry. Specifically, ACE2 and TMPRSS2 genes are influenced by two microRNAs: miR-200b-3p and miR-214-3p, respectively. The objective of this study was to explore the association between the serum levels of miR-200b-3p and miR-214-3p and the presence of circulating ACE2 and TMPRSS2 in severe and non-severe cases of COVID-19. This study sought to examine the potential utility of microRNAs as biomarkers for assessing disease severity and progression. Additionally, the study aimed to elucidate the interplay between microRNAs and the ACE2 and TMPRSS2 proteins, which play crucial roles in facilitating SARS-CoV-2 viral entry and infection. This practical-foundational study involved the collection of samples from 61 hospitalized patients with confirmed COVID-19 and 31 healthy individuals. Subsequently, the enzyme-linked immunosorbent assay (ELISA) technique was utilized to measure the concentrations of ACE2 and TMPRSS2 in the blood samples. Additionally, the expression levels of serum miR-200b-3p and miR-214-3p were analyzed using real-time polymerase chain reaction (PCR). The statistical analysis of the data was conducted using GraphPad Prism software (version 8.02) and SPSS software (version 19.0), ensuring the accurate interpretation of results. The findings revealed significant increases in the peripheral blood concentrations of ACE2 and TMPRSS2 in patients with non-severe COVID-19, compared to healthy individuals (P < 0.001 and P < 0.01, respectively). Similarly, patients with severe COVID-19 exhibited higher serum levels of ACE2 and TMPRSS2 than healthy subjects (P < 0.0001). Additionally, the serum levels of miR-200b-3p and miR-214-3p were decreased in both non-severe and severe COVID-19 patients, compared to healthy individuals (P < 0.01 and P < 0.0001, respectively). Moreover, a decrease in the serum levels of both miR-200b-3p and miR-214-3p was observed in patients with severe COVID-19, compared to those with non-severe cases (P < 0.001). Furthermore, this study identified a negative correlation between miR-200b-3p and ACE2 serum levels and between miR-214-3p and TMPRSS2 peripheral blood levels. The above-mentioned findings suggest that miR-200b-3p and miR-214-3p might be potential biomarkers for disease severity and prognosis in COVID-19 patients.

Analysis of Leukocyte Subpopulations by Flow Cytometry during Hospitalization Depending on the Severity of COVID-19 Course.

The mechanisms underlying the immune response to coronavirus disease 2019 (COVID-19) and the recovery process have not been fully elucidated. The aim of the study was to analyze leukocyte subpopulations in patients at significant time points (at diagnosis, and 3 and 6 months after infection) selected according to the analysis of changes in the lungs by the CT classification system, considering the severity of the disease. The study groups consisted of severe and non-severe COVID-19 patients. There was a significant decrease in CD8+ T cells, NK and eosinophils, with an increasing percentage of neutrophils during hospitalization. We noticed lower levels of CD4 and CD8 T lymphocytes, eosinophils, basophils, and CD16+ monocytes and elevated neutrophil levels in severe patients relative to non-severe patients. Three months after infection, we observed higher levels of basophils, and after 6 months, higher CD4/CD8 ratios and T cell levels in the severe compared to non-severe group. Non-severe patients showed significant changes in the leukocyte populations studied at time of hospitalization and both within 3 months and 6 months of onset. The CT CSS classification with parameters of the flow cytometry method used for COVID-19 patients determined changes that proved useful in the initial evaluation of patients.

Effects of renin-angiotensin system blockers on outcomes from COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Randomized controlled trials (RCTs) have assessed the effects of renin-angiotensin system (RAS) blockers in adults with coronavirus disease 2019 (COVID-19). This meta-analysis provides estimates of the safety and efficacy of treatment with (vs. without) RAS blockers from these trials. PubMed, Web of Science, and ClinicalTrials.gov were searched (1 March-12 April 2023). Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment with no treatment, for the outcomes: intensive care unit (ICU) admission, mechanical ventilation, vasopressor use, acute kidney injury (AKI), renal replacement therapy (RRT), acute myocardial infarction, stroke/transient ischaemic attack, heart failure, thromboembolic events, and all-cause death. Fixed-effects meta-analysis estimates were pooled. Sixteen RCTs including 3492 patients were analysed. Compared with discontinuation of RAS blockers, continuation was not associated with increased risk of ICU [risk ratio (RR) 0.96, 0.66-1.41], ventilation (RR 0.77, 0.55-1.09), vasopressors (RR 0.92, 0.58-1.44), AKI (RR 1.01, 0.40-2.56), RRT (RR 1.01, 0.46-2.21), or thromboembolic events (RR 1.07, 0.36-3.19). RAS blocker initiation was not associated with increased risk of ICU (RR 0.71, 0.47-1.08), ventilation (RR 1.12, 0.91-1.38), AKI (RR 1.28, 0.89-1.86), RRT (RR 1.66, 0.89-3.12), or thromboembolic events (RR 1.20, 0.06-23.70), although vasopressor use increased (RR 1.27, 1.02-1.57). The RR for all-cause death in the continuation/discontinuation trials was 1.24 (0.80-1.92), and 1.22 (0.96-1.55) in the initiation trials. In patients with severe/critical COVID-19, RAS blocker initiation increased the risk of all-cause death (RR 1.31, 1.01-1.72). ACE inhibitors and ARBs may be continued in non-severe COVID-19 infection, where indicated. Conversely, initiation of RAS blockers may be harmful in critically ill patients.PROSPERO registration number: CRD42023408926.

Increased blood pressure after nonsevere COVID-19.

Various sequelae have been described after nonsevere coronavirus disease 2019 (COVID-19), but knowledge on postacute effects on blood pressure is limited. This is a cross-sectional analysis of blood pressure profiles in individuals after nonsevere COVID-19 compared with matched population-based individuals without prior COVID-19. Data were derived from the ongoing and prospective Hamburg City Health Study, a population-based study in Hamburg, Germany, and its associated COVID-19 program, which included individuals at least 4 months after COVID-19. Matching was performed by age, sex, education, and preexisting hypertension in a 1 : 4 ratio. Four hundred and thirty-two individuals after COVID-19 (mean age 56.1 years) were matched to 1728 controls without prior COVID-19 (56.2 years). About 92.8% of COVID-19 courses were mild or moderate, only 7.2% were hospitalized, and no individual had been treated on an intensive care unit. Even after adjustment for relevant competing risk factors, DBP [+4.7 mmHg, 95% confidence interval (95% CI) 3.97-5.7, P < 0.001] was significantly higher in individuals after COVID-19. For SBP, a trend towards increased values was observed (+1.4 mmHg, 95% CI -0.4 to 3.2, P = 0.120). Hypertensive blood pressures at least 130/80 mmHg (according to the ACC/AHA guideline) and at least 140/90 mmHg (ESC/ESH guideline) occurred significantly more often in individuals after COVID-19 than matched controls (odds ratio 2.0, 95% CI 1.5-2.7, P < 0.001 and odds ratio 1.6, 95% CI 1.3-2.0, P < 0.001, respectively), mainly driven by changes in DBP. Blood pressure is higher in individuals after nonsevere COVID-19 compared with uninfected individuals suggesting a significant hypertensive sequela.

Risk Factors for Severe-Critical COVID-19 in Pregnant Women.

Risk factors associated with severe-critical COVID-19 (coronavirus disease 2019) are based on findings in the general population. Pregnant women are at increased risk of severe-critical infection, and few reports are based on these women. A multicentric case-control study was conducted at the Mexican Institute of Social Security, State of Mexico, during the COVID-19 pandemic. We included pregnant women who were consecutively admitted to respiratory care units and were followed until 30 days after the resolution of pregnancy. A total of 758 pregnant women with a positive RT-PCR test for SARS-CoV-2 were enrolled from June 2020 to July 2021. We defined groups using the World Health Organization Severity Classification; cases were pregnant women with severe-critical COVID-19 (n = 123), and controls were subjects with non-severe COVID-19 (n = 635). Data was gathered from clinical files. A multivariate logistic regression analysis was used to adjust odds ratios and their 95% confidence intervals of factors associated with severe-critical COVID-19. Risk factors associated with severe-critical COVID-19 in pregnancy were non-vaccination (OR 10.18), blood type other than O (OR 6.29), maternal age > 35 years (OR 5.76), history of chronic hypertension (OR 5.12), gestational age at infection ≥ 31 weeks (OR 3.28), and multiparity (OR 2.80).

Clinical use of antiviral, antibiotic and immunomodulatory drugs in hospitalized COVID-19 patients: a retrospective study in Bandung, Indonesia

Background: Evidence of highly effective repurposed drugs for coronavirus disease 2019 (COVID-19) is insufficient. However, empirical therapy using antiviral, antibiotic and immunomodulatory drugs is massive. This study aimed to evaluate the clinical use of these drugs and the outcome of hospitalization in COVID-19 patients. Methods: We performed a retrospective study using medical records of hospitalized COVID-19 patients from July 2020 to March 2021 in Bandung, Indonesia. Data were collected at relevant timelines: age, sex, comorbid condition, peripheral oxygen saturation (SpO 2), and hematology at admission; antiviral, antibiotic, and immunomodulator treatment during hospitalization; length of stay hospitalization (LOS) and death at discharge. Clinical use of the drug regimens included dose, frequency, and duration of therapy. The main outcome of hospitalization was LOS and death. Results: Out of 249 patients, 43.3% had a comorbid condition, 74.7% had non-severe COVID-19 (SpO 2 ≥ 90%), and almost all received antiviral or antibiotic agents. Patients receiving a combination of remdesivir and favipiravir had lower SpO 2 compared to those receiving oseltamivir alone (p=0.01). Remdesivir alone and combination of favipiravir and oseltamivir had shorter LOS compared to the other antivirals (p=0.03 and p=0.01 respectively). Immunomodulatory drugs (methylprednisolone, dexamethasone, tocilizumab) were prescribed in patients with lower baseline SpO 2 (p=0.001) and resulted ini longer LOS (p=0.0043) compared to those with no immunomodulators. The increased risk of death in patients treated with the combination of remdesivir and favipiravir (OR 4.1;95%CI 1.4-12.2), and immunomodulatory drugs (OR 6.2; 95%CI 1.7-23.3) was confounded by the baseline characteristics of older age, comorbid condition, SpO 2 level, and low lymphocyte number. Conclusions: Some treatment regimens were associated with short LOS, but there were drug regimens which might increase the risk of death. Further study should control the clinical conditions of COVID-19 patients at admission to confirm the outcome of death following drug therapy.

Traditional Vietnamese Medicine Containing Garlic Extract for Patients With Non-severe COVID-19: A Phase-II, Double-Blind, Randomized Controlled Trial.

Background Coronavirus disease 2019 (COVID-19) is still ongoing with the omicron variant. Low-cost, effective treatments are still needed, particularly in low-to-middle-income countries. This study assessed the safety and efficacy of TD0068, an herbal medicine developed from mainly garlic, for patients with non-severe COVID-19. Methods This is a phase-II, double-blind, randomized controlled trial to compare oral capsule TD0068 and placebo in adults aged 18-65 years with non-severe COVID-19 between September and October 2021. The efficacy outcomes measured included daily cycle threshold (Ct) value from the time of the initial reverse transcription-polymerase chain reaction (RT-PCR) test, time to viral clearance, daily symptom severity score from 15 symptoms of interest, time to symptom resolution, and progression to severe/critical COVID-19. Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). Results Sixty patients were randomized (31 received TD0068, and 29 received a placebo). The two groups were balanced in baseline characteristics: mean age was 39 years, and female was predominant (66%). Daily Ct value (median on days 3, 5, 7, and 9 was 25.7, 30.8, 35.4, and 37.6 in the TD0068 group, and 26.4, 31.2, 36.0, and 37.4 in the placebo group, respectively) and time to viral clearance (median: 10 vs. 11 days in TD0068 and placebo groups) were similar between groups. Daily symptom severity score (median on days 3, 5, 7, and 9 was 2, 2, 1, and 0 in the TD0068 group, and 3, 2, 1, and 1 in the placebo group), and time to symptom resolution (median: seven vs. nine days, respectively) were also comparable between groups. No SAE occurred in the study. Conclusions TD0068 is safe but does not show an effect for non-severe COVID-19 patients. Further research is needed to explore the potential benefits of garlic in other forms or dosages for the treatment of COVID-19.

Associations between IL-17A G/A-rs2275913 and IL 23R A/G-rs11209026 gene polymorphisms and severe coronavirus disease 2019 (COVID-19)

Severe COVID-19 disease was linked to a severe proinflammatory response and cytokine storm interleukin 17 (IL-17) is one of these cytokines, was associated with severe acute lung injury and multiorgan dysfunction. Single nucleotide polymorphisms (SNPs) in genes coding IL-17 can affect level of IL-17 hence its role in diseases. Also, SNPs in IL-23 R which control IL-23 is the main activator of IL-17 production. This study aimed to determine whether the IL-17A (G/A-rs2275913), IL-23R (A/G rs11209026) SNPs and serum levels of IL-17 were related to the risk of severe COVID-19. This case-control study included 120 confirmed COVID-19 patients, divided into two categories according to the severity of the disease and 74 normal subjects as controls. COVID-19 patients were SARS-CoV-2 positive by a reverse transcription-polymerase chain reaction and subjected to full clinical examinations, routine laboratory tests, and radiographic evaluations. The IL-17 levels were assessed using ELISA method, and genotyping of IL-17A (197 A/G; rs2275913) and IL-23R rs11209026 (A/G) was performed by the TaqMan Genotyping Assay. There were no differences in the distribution of IL-17A or IL-23R genotypes between COVID-19 groups and the control group (p=0.93 and p=0.84, respectively). Severe COVID-19 patients had significantly higher IL-17 serum levels than non-severe COVID-19 (p=0.0001). The GG genotypes of IL-17A were significantly higher in severe COVID-19 patients (p=0.004). Multivariate logistic regression analysis revealed that AG, GG genotypes of IL-17 and IL-17A were independent predictors of COVID-19 disease severity (p < 0.0001, p=0.06 and p=0.04, respectively). ROC curve analysis for IL-17, as predictor of severe COVID-19 disease revealed a sensitivity of 87.9% and specificity of 66.1% at a cutoff point of 114 pg/ml with AUC = 0.799. In conclusion, these findings indicated that IL-17 may be considered a marker of severe COVID-19. IL-17A SNPs may have a role in COVID-19 severity. IL-23R SNPs had no role in COVID-19.

Predicting the negative conversion time of nonsevere COVID-19 patients using machine learning methods.

Based on the patient's clinical characteristics and laboratory indicators, different machine-learning methods were used to develop models for predicting the negative conversion time of nonsevere coronavirus disease 2019 (COVID-19) patients. A retrospective analysis was performed on 376 nonsevere COVID-19 patients admitted to Wuxi Fifth People's Hospital from May 2, 2022, to May 14, 2022. The patients were divided into training set (n = 309) and test set (n = 67). The clinical features and laboratory parameters of the patients were collected. In the training set, the least absolute shrinkage and selection operator (LASSO) was used to select predictive features and train six machine learning models: multiple linear regression (MLR), K-Nearest Neighbors Regression (KNNR), random forest regression (RFR), support vector machine regression (SVR), XGBoost regression (XGBR), and multilayer perceptron regression (MLPR). Seven best predictive features selected by LASSO included: age, gender, vaccination status, IgG, lymphocyte ratio, monocyte ratio, and lymphocyte count. The predictive performance of the models in the test set was MLPR > SVR > MLR > KNNR > XGBR > RFR, and MLPR had the strongest generalization performance, which is significantly better than SVR and MLR. In the MLPR model, vaccination status, IgG, lymphocyte count, and lymphocyte ratio were protective factors for negative conversion time; male gender, age, and monocyte ratio were risk factors. The top three features with the highest weights were vaccination status, gender, and IgG. Machine learning methods (especially MLPR) can effectively predict the negative conversion time of non-severe COVID-19 patients. It can help to rationally allocate limited medical resources and prevent disease transmission, especially during the Omicron pandemic.

Low humoral and cellular immune responses early after breakthrough infection may contribute to severe COVID-19.

Little is known about the immune determinants for severe coronavirus disease 2019 (COVID-19) in individuals vaccinated against severe acute respiratory syndrome coronavirus 2. We therefore attempted to identify differences in humoral and cellular immune responses between patients with non-severe and severe breakthrough COVID-19. We prospectively enrolled hospitalized patients with breakthrough COVID-19 (severe and non-severe groups) and uninfected individuals who were vaccinated at a similar time (control group). Severe cases were defined as those who required oxygen therapy while hospitalized. Enzyme-linked immunosorbent assays and flow cytometry were used to evaluate humoral and cellular immune responses, respectively. Anti-S1 IgG titers were significantly lower in the severe group than in the non-severe group within 1 week of symptom onset and higher in the non-severe group than in the control group. Compared with the control group, the cellular immune response tended to be diminished in breakthrough cases, particularly in the severe group. In multivariate analysis, advanced age and low anti-S1 IgG titer were associated with severe breakthrough COVID-19. Severe breakthrough COVID-19 might be attributed by low humoral and cellular immune responses early after infection. In the vaccinated population, delayed humoral and cellular immune responses may contribute to severe breakthrough COVID-19.

The Impact of Smoking on COVID-19 Severity: A Multi-Analysis Study

&#x0D; &#x0D; &#x0D; &#x0D; Background: Smoking is considered to be one of the main risk factors that may affect the severity of coronavirus disease 2019 (COVID-19). Previously, several meta-analyses with a limited or small sample size and insufficient methodology have been conducted investigating the impact of smoking on disease severity. Here, we use a more accurate method to identify the effect of smoking on COVID-19 disease severity.&#x0D; &#x0D; &#x0D; &#x0D; &#x0D; Methods: BMC, PubMed, Science Direct, Wiley, Springer, and Google Scholar websites were used to search for and select reliable articles to be included in the current analysis. Research articles that mentioned the relationship between smoking and COVID-19 severity were included.&#x0D; Results: Twenty-six research articles detailing 15,713 confirmed COVID-19 cases comprising patients who smoke were selected to be included in this analysis. The analysis showed a relationship between smoking, severe COVID-19, and non-severe COVID-19 (OR=0:11; 95%CI: 0.10–0.11; p&lt;0.00001). Only 15% (2407) of the smokers suffered severe COVID-19, with the other 85% (13306) of smokers experiencing non-severe COVID-19.&#x0D; Conclusion: The current analysis found that only 15% of severe COVID-19 cases were smokers. Therefore, smoking is not significantly correlated with severe covid19.

Inflammation Related to Association of Low Uric Acid and Progression to Severe Disease in Patients Hospitalized for Non-Severe Coronavirus Disease 2019

Uric acid has antioxidant properties. To examine whether a low uric acid level is associated with severe coronavirus disease 2019 (COVID-19) progression via inflammation, alveolar damage, and/or coagulation abnormality, a retrospective observational study of 488 patients with non-severe COVID-19 and serum uric acid level ≤7 mg/dL at admission was conducted. Serum C-reactive protein (CRP), serum Krebs von den Lungen 6 (KL-6), and plasma D-dimer levels were also measured as markers of inflammation, alveolar damage, and coagulation abnormality, respectively. Median values for uric acid, CRP, KL-6, and D-dimer at admission were 4.4 mg/dL, 3.33 mg/dL, 252.0 U/mL, and 0.8 µg/mL, respectively. Among the total cohort, 95 (19.5%) progressed to severe COVID-19 with a median (interquartile range) time of 7 (4-14) days. Multivariable Cox proportional hazards regression analysis showed that low uric acid level was associated with a higher rate of severe COVID-19 progression. However, uric acid level was inversely associated with CRP level, and the association between the level of uric acid and severe COVID-19 progression was significantly different with and without CRP level inclusion. In contrast, no such association was found for KL-6 or D-dimer level. Low uric acid may contribute to severe COVID-19 progression via increased inflammation in subjects without hyperuricemia.

The detectable anti-interferon-γ autoantibodies in COVID-19 patients may be associated with disease severity

BackgroundNeutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections.MethodsTo explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform.ResultsA higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2–78.0%) compared with serum from HC (median,106.7%, IQR 100.0–117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5–116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity.ConclusionOur results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19.

Elevated monocyte distribution width in patients with active adult-onset Still's disease: a novel activity indicator.

Monocyte distribution width (MDW) correlates with volume modifications of circulating monocytes upon activation. Given the crucial role of monocyte activation in the pathogenesis of adult-onset Still's disease (AOSD), we aimed to examine the associations between MDW and disease activity or inflammatory parameters in this disease. In 58 AOSD patients and 95 other patients with coronavirus disease 2019 (COVID-19) as disease control, MDW and complete blood count were determined using a UniCel DxH800 analyser. C-reactive protein (CRP) levels were measured by nephelometry, and ferritin levels by chemiluminescent immunoassay. AOSD activity was assessed using a modified Pouchot score. MDW was significantly higher in active AOSD patients (median 28.3, interquartile range [IQR] 23.3-32.1) compared with inactive AOSD (19.2, IQR 18.0-20.6, p<0.001) or non-severe COVID-19 patients (23.2, IQR 21.0-25.2, p<0.01). MDW was positively correlated with AOSD activity scores, CRP, and ferritin levels (all p<0.001). Longitudinal follow-up evaluation revealed that median MDW significantly declined (28.3 versus 18.5, p<0.001) along with disease activity, paralleling a decrease in CRP and ferritin levels. Severe COVID-19 and sepsis patients had elevated MDW, which were not different from active AOSD patients. Multivariate analysis revealed MDW as a significant predictor of active AOSD, and MDW threshold at 21.7 could predict an active status with a high sensitivity of 91.3% and specificity of 94.3%. Elevated MDW and its positive correlation with inflammatory parameters in AOSD patients indicate MDW as a novel activity indicator, with a high MDW value above 21.7 linked to a high probability of active AOSD.