COVID-19 Disease Severity Research Articles

Longitudinal soluble marker profiles reveal strong association between cytokine storms resulting from macrophage activation and disease severity in COVID-19 disease

SARS-CoV2 infection results in a range of disease severities, but the underlying differential pathogenesis is still not completely understood. At presentation it remains difficult to estimate and predict severity, in particular, identify individuals at greatest risk of progression towards the most severe disease-states. Here we used advanced models with circulating serum analytes as variables in combination with daily assessment of disease severity using the SCODA-score, not only at single time points but also during the course of disease, to correlate analyte levels and disease severity. We identified a remarkably strong pro-inflammatory cytokine/chemokine profile with high levels for sCD163, CCL20, HGF, CHintinase3like1 and Pentraxin3 in serum which correlated with COVID-19 disease severity and overall outcome. Although precise analyte levels differed, resulting biomarker profiles were highly similar at early and late disease stages, and even during convalescence similar biomarkers were elevated and further included CXCL3, CXCL6 and Osteopontin. Taken together, strong pro-inflammatory marker profiles were identified in patients with COVID-19 disease which correlated with overall outcome and disease severity.

Vaccination status and disease severity of COVID-19 in different phases of the pandemic

ABSTRACT This study aimed to explore the clinical profile and the impact of vaccination status on various health outcomes among COVID-19 patients diagnosed in different phases of the pandemic, during which several variants of concern (VOCs) circulated in South Carolina (SC). The current study included 861,526 adult COVID-19 patients diagnosed between January 2021 and April 2022. We extracted their information about demographic characteristics, vaccination, and clinical outcomes from a statewide electronic health record database. Multiple logistic regression models were used to compare clinical outcomes by vaccination status in different pandemic phases, accounting for key covariates (e.g. historical comorbidities). A reduction in mortality was observed among COVID-19 patients during the whole study period, although there were fluctuations during the Delta and Omicron dominant periods. Compared to non-vaccinated patients, full-vaccinated COVID-19 patients had lower mortality in all dominant variants, including Pre-alpha (adjusted odds ratio [aOR]: 0.33; 95%CI: 0.15–0.72), Alpha (aOR: 0.58; 95%CI: 0.42–0.82), Delta (aOR: 0.28; 95%CI: 0.25–0.31), and Omicron (aOR: 0.29; 95%CI: 0.26–0.33) phases. Regarding hospitalization, full-vaccinated parties showed lower risk of hospitalization than non-vaccinated patients in Delta (aOR: 0.44; 95%CI: 0.41–0.47) and Omicron (aOR: 0.53; 95%CI: 0.50–0.57) dominant periods. The findings demonstrated the protection effect of the COVID-19 vaccines against all VOCs, although some of the full-vaccinated population still have symptoms to varying degrees from COVID-19 disease at different phases of the pandemic.

Safety outcomes of remdesivir for treatment of COVID-19 hospitalised patients in Indonesia

Background: Remdesivir has been granted emergency use authorisation for hospitalised COVID-19 patients. However, the available evidence in Indonesia is limited to related liver and kidney injuries. Objective: This study aims to assess the safety of remdesivir based on liver and kidney function and its association with comorbidity and disease severity. Method: This retrospective study evaluated remdesivir's efficacy in hospitalised COVID-19 patients of varying severity by collecting baseline and follow-up data on aspartate aminotransferase (AST), alanine aminotransferase (ALT), Glomerular filtration rate (GFR) and Blood urea nitrogen (BUN). Result: In this study, 189 patients with elevated transaminase enzyme levels were given hepatoprotection therapy. Patients who did not receive the treatment experienced a significant rise in ALT levels (p < 0.001), while BUN levels increased significantly (p = 0.001) but within the normal range. There was no worsening of GFR value (p < 0.001), and no significant association was found between AST and ALT levels with comorbidity and disease severity (p < 0.001; OR 50.202). Conclusion: Remdesivir demonstrated good tolerability despite increased ALT and BUN without correlating to comorbidity or disease severity in COVID-19.

Relation of myocardial dysfunction to biomarkers, COVID-19 severity and all-cause mortality.

The COVID-19 infection has been described as affecting myocardial injury. However, the relation between left ventricular global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), disease severity and all-cause mortality in COVID-19 is unclear. The study consisted of 220 patients with COVID-19, including 127 (57.5%) with mild, 43 (19.5%) with moderate and 50 (22.7%) with severe/critical conditions. Myocardial dysfunction was analysed by GLS, GCS and GRS using two-dimensional speckle-tracking echocardiography. Hazard ratios and Kaplan-Meier curves were produced to assess the association between strains and cardiac biomarker indices with a composite outcome of all-cause mortality. With an average follow-up period of 11days, 19 patients reached the endpoint (death). Significant associations were found for the three strain parameters and the levels of blood urea nitrogen (BUN) (r=0.206, 0.221 and 0.355, respectively). Cardiac troponin I (cTnI) was closely related to the GLS and GCS (r=0.240 and 0.324, respectively). In multivariable Cox regression, GCS>-21.6% was associated with all-cause death {hazard ratio, 4.007 [95% confidence interval (CI), 11.347-11.919]}. GLS, GCS and GRS are significantly related to myocardial dysfunction in patients with COVID-19. Worsening GCS poses an increased risk of death in COVID-19.

Initial COVID-19 severity influenced by SARS-CoV-2-specific T cells imprints T-cell memory and inversely affects reinfection

The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8+ T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

Cell free DNA as a new prognostic biomarker for COVID-19, A prospective cohort study

Predicting the need of hospitalization and intensive care in COVID-19 patients has been challenging with current diagnostic tests since the beginning of the pandemic. We aimed to test cell free DNA (cfDNA) as a novel biomarker for COVID-19 disease severity and mortality. cfDNA concentration was quantified by RT-PCR based test. One hundred and sixty-eight patients(85 outpatients, 61 inpatients,22 ICU) included the study. Mean initial plasma cfDNA levels were significantly different (p < 0.01) in outpatients (1.190,66 ng/ml), inpatients (8.258,10 ng/ml) and ICU patients (84.806,87 ng/ml). ROC analysis showed with 95 % specificity that patients with initial cfDNA concentrations ≥6.389 ng/ml need to be hospitalized and those ≥26.104 ng/ml require ICU referral. cfDNA concentration was correlated with neutrophil/lymphocyte ratio, lymphocyte level, CRP, AST, LDH, CK, fibrinogen, ferritin and D-dimer. Plasma cfDNA levels on admission, well correlating with disease severity and mortality in COVID-19 that found as a useful biomarker.

Cytokine and chemokine profiles in the sera of COVID-19 patients with different stages of severity

IntroductionCOVID-19 is a viral infection that disturbs the host's immune system and causes an overproduction of cytokines leading to a cytokine storm. The present study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with COVID-19 disease severity. MethodsThe serum levels of 89 patients with different degrees of COVID-19 disease severity [asymptomatic (n = 14), moderate (n = 14), severe (n = 30), and critical (n = 31)] and 14 healthy individuals were tested for a panel of 27 cytokines and chemokines using Luminex assay (27 Bio‑Plex Pro Human Cytokine, Bio-rad™). ResultsIL-12, IL-2 and IL-13, as well as IL-17 and GM-CSF were clearly undetectable in asymptomatic patients. IL-8 levels were higher in asymptomatic compared with other groups. Very high levels of IL-6, IL-10 and the chemokines MIP-1α, MCP-1 and IP10 were associated with disease progression, while IL-4 tends to decrease with disease severity. ConclusionOur study provides more evidence that excessive cytokine synthesis is linked to the disease progression.

Cardioprotective effects of vaccination in hospitalized patients with COVID-19

COVID-19 vaccination has been shown to prevent and reduce the severity of COVID-19 disease. The aim of this study was to explore the cardioprotective effect of COVID-19 vaccination in hospitalized COVID-19 patients. In this retrospective, single-center cohort study, we included hospitalized COVID-19 patients with confirmed vaccination status from July 2021 to February 2022. We assessed outcomes such as acute cardiac events and cardiac biomarker levels through clinical and laboratory data. Our analysis covered 167 patients (69% male, mean age 58 years, 42% being fully vaccinated). After adjustment for confounders, vaccinated hospitalized COVID-19 patients displayed a reduced relative risk for acute cardiac events (RR: 0.33, 95% CI [0.07; 0.75]) and showed diminished troponin T levels (Cohen’s d: − 0.52, 95% CI [− 1.01; − 0.14]), compared to their non-vaccinated peers. Type 2 diabetes (OR: 2.99, 95% CI [1.22; 7.35]) and existing cardiac diseases (OR: 4.31, 95% CI [1.83; 10.74]) were identified as significant risk factors for the emergence of acute cardiac events. Our findings suggest that COVID-19 vaccination may confer both direct and indirect cardioprotective effects in hospitalized COVID-19 patients.

Gene expression profiles in COVID-19-associated tracheal stenosis indicate persistent anti-viral response and dysregulated retinol metabolism

IntroductionCoronavirus disease 2019 (COVID-19)-associated tracheal stenosis (COATS) may occur as a result of prolonged intubation during COVID-19 infection. We aimed to investigate patterns of gene expression in the tracheal granulation tissue of patients with COATS, leverage gene expression data to identify dysregulated cellular pathways and processes, and discuss potential therapeutic options based on the identified gene expression profiles.MethodsAdult patients (age ≥ 18 years) presenting to clinics for management of severe, recalcitrant COATS were included in this study. RNA sequencing and differential gene expression analysis was performed with transcriptomic data for normal tracheal tissue being used as a control. The top ten most highly upregulated and downregulated genes were identified. For each of these pathologically dysregulated genes, we identified key cellular pathways and processes they are involved in using Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) applied via Database for Annotation, Visualization, and Integrated Discovery (DAVID).ResultsTwo women, aged 36 years and 37 years, were included. The profile of dysregulated genes indicated a cellular response consistent with viral infection (CXCL11, PI15, CCL8, DEFB103A, IFI6, ACOD1, and DEFB4A) and hyperproliferation/hypergranulation (MMP3, CASP14 and HAS1), while downregulated pathways included retinol metabolism (ALDH1A2, RBP1, RBP4, CRABP1 and CRABP2).ConclusionGene expression changes consistent with persistent viral infection and dysregulated retinol metabolism may promote tracheal hypergranulation and hyperproliferation leading to COATS. Given the presence of existing literature highlighting retinoic acid’s ability to favorably regulate these genes, improve cell-cell adhesion, and decrease overall disease severity in COVID-19, future studies must evaluate its utility for adjunctive management of COATS in animal models and clinical settings.

Plasma Proteins Associated with COVID-19 Severity in Puerto Rico.

Viral strains, age, and host factors are associated with variable immune responses against SARS-CoV-2 and disease severity. Puerto Ricans have a genetic mixture of races: European, African, and Native American. We hypothesized that unique host proteins/pathways are associated with COVID-19 disease severity in Puerto Rico. Following IRB approval, a total of 95 unvaccinated men and women aged 21-71 years old were recruited in Puerto Rico from 2020-2021. Plasma samples were collected from COVID-19-positive subjects (n = 39) and COVID-19-negative individuals (n = 56) during acute disease. COVID-19-positive individuals were stratified based on symptomatology as follows: mild (n = 18), moderate (n = 13), and severe (n = 8). Quantitative proteomics was performed in plasma samples using tandem mass tag (TMT) labeling. Labeled peptides were subjected to LC/MS/MS and analyzed by Proteome Discoverer (version 2.5), Limma software (version 3.41.15), and Ingenuity Pathways Analysis (IPA, version 22.0.2). Cytokines were quantified using a human cytokine array. Proteomics analyses of severely affected COVID-19-positive individuals revealed 58 differentially expressed proteins. Cadherin-13, which participates in synaptogenesis, was downregulated in severe patients and validated by ELISA. Cytokine immunoassay showed that TNF-α levels decreased with disease severity. This study uncovers potential host predictors of COVID-19 severity and new avenues for treatment in Puerto Ricans.

S100A9: The Unusual Suspect Connecting Viral Infection and Inflammation.

The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.

Serum Adiponectin Predicts COVID-19 Severity.

Adiponectin is primarily known for its protective role in metabolic diseases, and it also possesses immunoregulatory properties. Elevated levels of adiponectin have been observed in various inflammatory diseases. However, studies investigating adiponectin levels in the serum of COVID-19 patients have yielded conflicting results. This study aimed to assess serum adiponectin levels in 26 healthy controls, as well as in 64 patients with moderate and 60 patients with severe COVID-19, to determine a potential association between serum adiponectin and the severity of COVID-19. Serum adiponectin levels in severe COVID-19 patients were significantly lower than in those with moderate disease and healthy controls, who exhibited similar serum adiponectin levels. Among patients with moderate disease, positive correlations were observed between serum adiponectin and C-reactive protein levels. Of note, serum adiponectin levels of severe COVID-19 cases were comparable between patients with and without dialysis or vasopressor therapy. Superinfection with bacteria did not exert a notable influence on serum adiponectin levels in patients with severe disease. Patients who were diagnosed with severe COVID-19 and vancomycin-resistant enterococci bacteremia showed a significant reduction in their serum adiponectin levels. An analysis conducted on the entire cohort, including both moderate and severe COVID-19 patients, showed that individuals who did not survive had lower serum adiponectin levels when compared to those who survived. In summary, this study highlights a decrease in serum adiponectin levels in severe COVID-19 cases, indicating the potential utility of adiponectin as an additional biomarker for monitoring disease severity in COVID-19 or critical illnesses in general.

Relation between ABO and RhD and prevalence and severity of COVID-19 disease

&lt;p class="MsoNormal"&gt;&lt;strong&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Backgrounds:&lt;/span&gt;&lt;/strong&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;This study aims to determine the relation between &lt;/span&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi; mso-bidi-language: AR-EG;"&gt;ABO and RhD and the prevalence and severity of COVID-19 disease.&lt;/span&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;strong&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Methods: &lt;/span&gt;&lt;/strong&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Data of 495 SARS-CoV-2 infected patients admitted to hospitals were collected. The &lt;/span&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi; mso-bidi-language: AR-EG;"&gt;ABO and RhD were determined for each patient to detect any possible relation between the prevalence of &lt;/span&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;SARS-CoV-2 infection&lt;/span&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi; mso-bidi-language: AR-EG;"&gt; and each blood group. The patients were followed up to determine oxygen saturation and surveillance outcome (died or improved) to detect any possible relation between the severity of COVID-19 disease and each blood group.&lt;/span&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;strong&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Results: &lt;/span&gt;&lt;/strong&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;A+ blood group was found to have a percentage of 32.3%, O+ to have a percentage of 30.3%, B+ to have a percentage of 21.2%, and AB+ to have a percentage of 10.1%. 19% of all the patients died. 20% of the dead patients were with O+ blood group, 60.5% were with A+ blood group, 10% with B+ blood group and 5% were with O- blood group.&lt;/span&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;The mean &amp;plusmn; SD oxygen saturation on hospital admission was 94.2 &amp;plusmn; 6.2% for the patients with O+ blood group, 91.06 &amp;plusmn; 7.5% for the patients with A+ blood group, 92.8 &amp;plusmn; 6.9% for the patients with B+ blood group, 93.4 &amp;plusmn; 3.5% for the patients with AB+ blood group, and 94.5 &amp;plusmn; 5.9% for the patients with O- blood group.&lt;/span&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;strong&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Conclusion: &lt;/span&gt;&lt;/strong&gt;&lt;/p&gt; &lt;p class="MsoNormal"&gt;&lt;span style="font-size: 10.0pt; font-family: 'Arial',sans-serif; mso-ascii-theme-font: minor-bidi; mso-hansi-theme-font: minor-bidi; mso-bidi-theme-font: minor-bidi;"&gt;Blood group A+ was the most common in the COVID-19 patients followed by O+ then B+ then AB+. Patients with blood group A+ had the worst oxygen saturation at hospital admission and had a higher mortality rate.&lt;/span&gt;&lt;/p&gt;

FURIN, IFNL4, and TLR2 gene polymorphisms in relation to COVID-19 severity: a case-control study in Egyptian patients.

A wide range of clinical manifestations and outcomes, including liver injury, have been reported in COVID-19 patients. We investigated the association of three substantial gene polymorphisms (FURIN, IFNL4, and TLR2) with COVID-19 disease susceptibility and severity to help predict prognosis. 150 adult COVID-19-assured cases were categorized as follows: 78 patients with a non-severe presentation, 39 patients with severe disease, and 33 critically ill patients. In addition, 74 healthy controls were included. Clinical and laboratory evaluations were carried out, including complete and differential blood counts, D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, ferritin, interleukin-6 (Il-6), and liver and kidney functions. FURIN (rs6226), IFNL4 (rs12979860), and TLR2 (rs3804099) genotyping allelic discrimination assays were conducted using real-time PCR. The FURIN, IFNL4, and TLR2 genotypes and their alleles differed significantly between COVID-19 patients and controls, as well as between patients with severe or critical illness and those with a non-severe presentation. According to a multivariable regression analysis, FURIN (C/T + T/T) and TLR2 (T/C + C/C) mutants were associated with COVID-19 susceptibility, with odds ratios of 3.293 and 2.839, respectively. FURIN C/C and IFNL4 T/T mutants were significantly linked to severe and critical illnesses. Multivariate regression analysis showed that FURIN (G/C + C/C) genotypes and IFNL4 T/T homozygosity were independent risk factors associated with increased mortality. FURIN, IFNL4, and TLR2 gene variants are associated with the risk of COVID-19 occurrence as well as increased severity and poor outcomes in Egyptian patients.

Decreased progenitor TCF1 + T-cells correlate with COVID-19 disease severity

COVID-19, caused by SARS-CoV-2, can lead to a severe inflammatory disease characterized by significant lymphopenia. However, the underlying cause for the depletion of T-cells in COVID-19 patients remains incompletely understood. In this study, we assessed the presence of different T-cell subsets in the progression of COVID-19 from mild to severe disease, with a focus on TCF1 expressing progenitor T-cells that are needed to replenish peripheral T-cells during infection. Our results showed a preferential decline in TCF1+ progenitor CD4 and CD8+ T-cells with disease severity. This decline was seen in various TCF1+ subsets including naive, memory and effector-memory cells, and surprisingly, was accompanied by a loss in cell division as seen by a marked decline in Ki67 expression. In addition, TCF1+ T-cells showed a reduction in pro-survival regulator, BcL2, and the appearance of a new population of TCF1 negative caspase-3 expressing cells in peripheral blood from patients with severe disease. The decline in TCF1+ T-cells was also seen in a subgroup of severe patients with vitamin D deficiency. Lastly, we found that sera from severe patients inhibited TCF1 transcription ex vivo which was attenuated by a blocking antibody against the cytokine, interleukin-12 (IL12). Collectively, our findings underscore the potential significance of TCF1+ progenitor T-cells in accounting for the loss of immunity in severe COVID-19 and outline an array of markers that could be used to identify disease progression.

Chemokine CCL19 and Its Receptors CCR7 and CCRL1 in Chronic Rhinosinusitis.

CCL19 has been shown to predict disease severity in COVID-19 and treatment response in rheumatoid arthritis. CCL19 can exert both pro- and anti-inflammatory effects and is elevated in chronic rhinosinusitis (CRS). However, its role in CRS remains unknown. This study sought to determine the transcriptional changes in CCL19, its receptors, and associated cytokines and their association with disease severity in CRS. A clinical database of control subjects and patients with CRS was examined. Lund-Kennedy, Lund-Mackay, Sinonasal Outcomes Test 22 (SNOT-22), and rhinosinusitis disability index (RSDI) scores were collected at enrollment. mRNA was extracted from sinonasal tissues and subjected to multiplex gene expression analysis. Gene transcript differences between patients with CRS and controls were compared and correlated with disease severity metrics. Immunohistochemical analyses of CCL19, CCR7, and CCRL1 were conducted to compare differences in protein expression between cohorts. A subgroup analysis was performed to compare transcriptional and protein expression difference between patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls. Thirty-eight subjects (control group, n=7; CRS group, n=31) were included in this study. CCRL1 (p=0.0093) and CCR7 (p=0.017) levels were significantly elevated in CRS compared to those in controls. CCL19 (p=0.038) and CCR7 (p=0.0097) levels were elevated in CRSwNP and CCRL1 was elevated in CRSsNP (p=0.0004). CCR7 expression was significantly elevated in sinonasal epithelial cells in CRSwNP (p=0.04). CCL19 expression was positively correlated with TNFA expression (p<0.0002). CCL19 and CCR7 expression was positively correlated with SNOT-22 and RSDI scores (p<0.05). CCL19 and CCR7 may modulate TNF-α-driven pro-inflammatory signaling and contribute to increased disease severity in CRS. Mechanistic studies are required to further elucidate the role of CCRL1 in CRS.

Defining the Subtypes of Long COVID and Risk Factors for Prolonged Disease: Population-Based Case-Crossover Study.

There have been over 772 million confirmed cases of COVID-19 worldwide. A significant portion of these infections will lead to long COVID (post-COVID-19 condition) and its attendant morbidities and costs. Numerous life-altering complications have already been associated with the development of long COVID, including chronic fatigue, brain fog, and dangerous heart rhythms. We aim to derive an actionable long COVID case definition consisting of significantly increased signs, symptoms, and diagnoses to support pandemic-related clinical, public health, research, and policy initiatives. This research employs a case-crossover population-based study using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) data generated at Veterans Affairs medical centers nationwide between January 1, 2020, and August 18, 2022. In total, 367,148 individuals with ICD-10-CM data both before and after a positive COVID-19 test were selected for analysis. We compared ICD-10-CM codes assigned 1 to 7 months following each patient's positive test with those assigned up to 6 months prior. Further, 350,315 patients had novel codes assigned during this window of time. We defined signs, symptoms, and diagnoses as being associated with long COVID if they had a novel case frequency of ≥1:1000, and they significantly increased in our entire cohort after a positive test. We present odds ratios with CIs for long COVID signs, symptoms, and diagnoses, organized by ICD-10-CM functional groups and medical specialty. We used our definition to assess long COVID risk based on a patient's demographics, Elixhauser score, vaccination status, and COVID-19 disease severity. We developed a long COVID definition consisting of 323 ICD-10-CM diagnosis codes grouped into 143 ICD-10-CM functional groups that were significantly increased in our 367,148 patient post-COVID-19 population. We defined 17 medical-specialty long COVID subtypes such as cardiology long COVID. Patients who were COVID-19-positive developed signs, symptoms, or diagnoses included in our long COVID definition at a proportion of at least 59.7% (268,320/449,450, based on a denominator of all patients who were COVID-19-positive). The long COVID cohort was 8 years older with more comorbidities (2-year Elixhauser score 7.97 in the patients with long COVID vs 4.21 in the patients with non-long COVID). Patients who had a more severe bout of COVID-19, as judged by their minimum oxygen saturation level, were also more likely to develop long COVID. An actionable, data-driven definition of long COVID can help clinicians screen for and diagnose long COVID, allowing identified patients to be admitted into appropriate monitoring and treatment programs. This long COVID definition can also support public health, research, and policy initiatives. Patients with COVID-19 who are older or have low oxygen saturation levels during their bout of COVID-19, or those who have multiple comorbidities should be preferentially watched for the development of long COVID.

HLA-B and C Expression Contributes to COVID-19 Disease Severity within a South African Cohort.

Globally, SARS-CoV-2 has negatively impacted many lives and industries due to its rapid spread, severe outcomes, and the need for the implementation of lockdown strategies across the world. SARS-CoV-2 disease severity varies among different populations. Host genetics have been associated with various diseases, and their ability to alter disease susceptibility and severity. In addition, Human Leukocyte Antigen (HLA) expression levels and alleles vary significantly among ethnic groups, which might impact the host's response to SARS-CoV-2. Our previous study highlighted that HLA-A might have an effect on COVID-19 disease severity across ethnicities. Therefore, in this study, we aim to examine the effect of HLA-B and C expression levels on COVID-19 disease severity. To achieve this, we used real-time PCR to measure the HLA mRNA expression levels of SARS-CoV-2-infected individuals from a South African cohort and compared them across ethnic groups, disease outcomes, gender, comorbidities, and age. Our results show (1) that the effect of HLA-B mRNA expression levels was associated with differences in disease severity when we compare symptomatic vs. asymptomatic (p < 0.0001). While HLA-C mRNA expression levels were not associated with COVID-19 disease severity. (2) In addition, we observed that HLA-B and HLA-C mRNA expression levels were significantly different between South African Black individuals and South African Indian individuals (p < 0.0001, p < 0.0001). HLA-B mRNA expression levels among symptomatic South African Black individuals were significantly higher than symptomatic South African Indian individuals (p < 0.0001). In addition, the HLA-B mRNA expression levels of symptomatic South African Black individuals were significantly higher than asymptomatic South African Black individuals (p > 0.0001). HLA-C mRNA expression levels among symptomatic South African Black individuals were significantly higher than among symptomatic South African Indian individuals (p = 0.0217). (3) HLA-C expression levels were significantly different between males and females (p = 0.0052). In addition, the HLA-C expression levels of asymptomatic males are higher than asymptomatic females (p = 0.0375). (4) HLA-B expression levels were significantly different between individuals with and without comorbidities (p = 0.0009). In addition, we observed a significant difference between individuals with no comorbidities and non-communicable diseases (p = 0.0034), in particular, hypertension (p = 0.0487). (5) HLA-B expression levels were significantly different between individuals between 26-35 and 56-65 years (p = 0.0380). Our work is expected to strengthen the understanding of the relationship between HLA and COVID-19 by providing insights into HLA-B and C expression levels across ethnic populations in South Africa among COVID-19-symptomatic and asymptomatic individuals. Our results highlight that HLA-B mRNA expression levels contribute to COVID-19 severity as well as variation in ethnicities associated with COVID-19. Further studies are needed to examine the effect of HLA expression levels across various ethnic groups with contributing factors.

The Association of Serum Profile of Transferrin Isoforms with COVID-19 Disease Severity.

Background/Objective: Bearing in mind the relationship of transferrin (TRF) microheterogeneity with the biological activity of its isoforms, we propose, in this study, to determine the association of the profile of TRF isoforms with COVID-19 disease severity and to compare this profile to the profiles of other diseases. Methods: The disease group consisted of 96 patients from whom blood was collected twice, upon admission to the ward and after treatment (on average on the ninth day). TRF isoforms were separated by capillary electrophoresis. The analysis included disease severity, cytokine storm, comorbidities, patient survival, oxygen therapy, and modified early warning scores (MEWSs). Results: The concentration of 5-sialoTRF was higher in patients compared to controls at the beginning and during COVID-19 treatment. The concentration of this isoform varies with the severity of disease and was higher in critical patients than those with a moderate condition. Additionally, the level of 5-sialoTRF was lower and the level of 4-sialoTRF was higher in patients with comorbidities than that in patients without them. The concentration of 5-sialoTRF was lower and the concentration of 4-sialoTRF was higher in surviving patients than in non-surviving patients. There were no statistical changes in TRF isoforms according to presence of cytokine storm, MEWS, and oxygen therapy. Conclusions: We conclude that the profile of TRF isoforms in COVID-19 patients differs from that in other diseases. An increase in the concentration of a sialic acid-rich isoform, 5-sialoTRF, may be a compensatory mechanism, the goal of which is to increase oxygen delivery to tissues and is dependent on the severity of the disease. Additionally, the concentration of 5-sialoTRF may be a prognostic marker of the survival of COVID-19 patients.

Influence of vaccination on critical COVID-19 patients with acute respiratory failure: a retrospective cohort study

BackgroundDespite vaccines’ effectiveness in reducing COVID-19 infection rates and disease severity, their impact on critical patients presenting with acute respiratory failure is elusive. The aim of this study was to further investigate the influence of vaccination on mortality rates among severely ill COVID-19 patients experiencing acute respiratory failure.MethodsThis retrospective cohort study was carried out at a tertiary medical center in Taiwan. From April to September 2022, patients who tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through reverse transcription polymerase chain reaction (RT-PCR) and subsequently experienced acute respiratory failure were included in the study. Baseline characteristics, including vaccination history, along with information regarding critical illness and clinical outcomes, were gathered and compared between patients who received the vaccine and those who did not.ResultsA total of 215 patients with COVID-19 exhibiting acute respiratory failure, as confirmed via RT‒PCR, were included in the analysis. Of this cohort, sixty-six (30.7%) patients died within 28 days. Neither administration of the vaccine nor achievement of primary series vaccination status had a significantly different effect on 28 day mortality, number of viral shedding events, acute respiratory distress syndrome (ARDS) incidence or other clinical outcomes. Patients who received the booster vaccine and completed the primary series showed a tendency of increased 28 days of ventilator-free status, though this difference was not statistically significant (p = 0.815).ConclusionsVaccination status did not significantly influence mortality rates, the occurrence of ARDS, or the viral shedding duration in COVID-19 patients with acute respiratory failure.