Development Of Severe COVID-19 Research Articles

The Impact of Antidepressants on COVID-19 and Post-Acute COVID-19 Syndrome: A Scoping-Review Update

On May 20, 2024, this systematic scoping review in PUBMED identified 1016 articles related to AD and COVID-19, Long COVID and SARS-COV-2. These included 10 retrospective "large scale" studies (> 20000 chart reviews), 8 prospective clinical trials (plus 4 regarding Long COVID), 11 placebo-controlled randomized (RCT) (plus 2 regarding Long COVID) and 15 meta-analyses. COVID-19: Retrospective studies with cohorts taking AD primarily for psychiatric comorbidities or chronic pain conditions directly prior to SARS-COV-2 infection described that this substance class (most studied: Selective Serotonin Re-Uptake Inhibitors (SSRI) and Selective Serotonin Noradrenaline Re-Uptake Inhibitors (SSNRI)) were associated with (i) significantly fewer SARS-COV-2 infections and (ii) a milder course of COVID-19 ("COVID-19 protection"). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared suitable as a prophylactic agent against severe COVID-19, taking into account its in vitro potency against the progression of intracellular sepsis cascades. Therefore, most (12 out of 15) meta-analyses also referred to fluvoxamine. They found (iii) a significant (40-70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. When this AD was used in the early stages of the disease, it was more successful than when it was given later in advanced, severe COVID-19 (e.g. severe pneumonia, final sepsis stages). A dose dependency was observed: 2x50 mg fluvoxamine over 15 days was less effective than 2x100 or even 3x100 mg with an adverse event profile still at the placebo level. Direct comparisons with drugs approved for COVID-19 do not yet exist. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: risk reduction of 95% (I2 = N/A, but only one study) or 78% (I2=0) versus 5+-5% (I2=48). However, an add-on of fluvoxamine was still significantly more efficacious than symptom-oriented standard therapy alone. Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds to AD, relaxation therapy and/or psychotherapy, has now been identified. Casuistics report positive effects of AD on fatigue, cognitive and autonomic dysfunctions. A first large prospective open-label RCT has just shown significantly more favourable courses, less viral load and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary Long COVID or fatigue. Overall, there is promising evidence of a preventive effect of AD (especially fluvoxamine) against progression to severe COVID-19 and against the development of Long COVID. It is likely, that the entire AD substance class could be effective here. This assumption is based on the results of retrospective large scale studies, but awaits verification by better controlled studies. The potential effectiveness/efficacy (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of fluvoxamine as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to pose a lasting threat to the health of those affected. We consider the evidence to date to be sufficient to be able to emphasize a possible positive effect of these substances in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other conditions - especially also against the symptoms associated with the viral disease or its consequences. In regions where neither vaccines nor antiviral agents currently approved for the prevention or treatment of COVID-19 are available, AD and in particular fluvoxamine would be a cost-effective alternative to protect against a severe course, even if this AD appears to have a smaller effect against COVID-19 than the currently approved antiviral agents, but with presumably better tolerability. A direct comparative clinical trial with approved antiviral agents is still pending and should be positive to further open the door for a guideline-based recommendation of fluvoxamine (or perhaps even AD) for COVID-19 or its aftermath.

Rapid progression of CD8 and CD4 T cells to cellular exhaustion and senescence during SARS-CoV2 infection

Abstract Risk factors for the development of severe COVID-19 include several comorbidities, but age was the most striking one since elderly people were disproportionately affected by SARS-CoV-2 infection. Among the reasons for this markedly unfavorable response in the elderly, immunosenescence and inflammaging appear as major drivers of this outcome. A finding that was also notable was that hospitalized patients with severe COVID-19 have an accumulation of senescent T cells, suggesting that immunosenescence may be aggravated by SARS-CoV-2 infection. The present work was designed to examine whether these immunosenescence changes are characteristic of COVID-19 and whether it is dependent on disease severity using cross-sectional and longitudinal studies. Our cross-sectional data show that COVID-19, but not other respiratory infections, rapidly increased cellular senescence and exhaustion in CD4 and CD8 T cells during early infection. In addition, longitudinal analyses with patients from Brazil and Portugal provided evidence of increased frequencies of senescent and exhausted T cells over a 7-d period in patients with mild/moderate and severe COVID-19. Altogether, the study suggests that accelerated immunosenescence in CD4 and especially CD8 T-cell compartments may represent a common and unique outcome of SARS-CoV2 infection.

Testosterone and estradiol reduce inflammation of human macrophages induced by anti-SARS-CoV-2 IgG.

COVID-19, the disease caused by SARS-CoV-2, particularly causes severe inflammatory disease in elderly, obese, and male patients. Since both aging and obesity are associated with decreased testosterone and estradiol expression, we hypothesized that decreased hormone levels contribute to excessive inflammation in the context of COVID-19. Previously, we and others have shown that hyperinflammation in severe COVID-19 patients is induced by the production of pathogenic anti-spike IgG antibodies that activate alveolar macrophages. Therefore, we developed an in vitro assay in which we stimulated human macrophages with viral stimuli, anti-spike IgG immune complexes, and different sex hormones. Treatment with levels of testosterone reflecting young adults led to a significant reduction in TNF and IFN-γ production by human macrophages. In addition, estradiol significantly attenuated the production of a very broad panel of cytokines, including TNF, IL-1β, IL-6, IL-10, and IFN-γ. Both testosterone and estradiol reduced the expression of Fc gamma receptors IIa and III, the two main receptors responsible for anti-spike IgG-induced inflammation. Combined, these findings indicate that sex hormones reduce the inflammatory response of human alveolar macrophages to specific COVID-19-associated stimuli, thereby providing a potential immunological mechanism for the development of severe COVID-19 in both older male and female patients.

Laboratory blood markers in COVID-19 and their connection to Viral variant

Morality rates in COVID-19 are dependent on timely diagnosis. Therefore, studying the relationship between laboratory markers and the severity of disease is important. The first wave of COVID-19 associated with the spread of the original strain of SARS-CoV-2, showed higher mortality rates caused by cytokine storm. As the viral variant changed, a change in the disease course towards a less pronounced inflammatory reaction was observed. These changes affected major players of inflammation, cytokines. However, cytokines are not the only markers in the inflammatory response. The purpose of this work was to determine the significance of laboratory markers in inflammation: WBC, C-reactive protein, ferritin, fibrinogen, and D-dimer. The study included 227 patients with acute COVID-19 in the first 5–7 days from the onset of the disease from January 2021 to March 2022. When compared with reference, all groups were characterized by reduced absolute values of lymphocytes. Correlation analysis between the absolute value of lymphocytes and plasma cytokine concentrations also revealed statistically significant strong relationships with the level of the chemokine CCL22/MDC. Given that CCL22/MDC is an important component of lymphopoiesis, its low concentrations may indicate dysregulation of this process in COVID-19. In addition, we noted a positive correlation between the level of C-reactive protein and IL-6 in peripheral blood. IL-6 is a proinflammatory cytokine, and its elevated levels have been associated with the development of severe COVID-19. One of its functions is the induction of C-reactive protein, and this trend persists regardless of which variant causes COVID-19. We also noted positive correlations between the concentrations of fibrinogen and IL-18, ferritin and IL-6, IL-18. Both of these proteins are involved in inflammation along with cytokines. The literature provides data on the significance of these markers for determining the severity of COVID-19. There is evidence of a synergistic effect of ferritin and IL-18 against viral pathogens. Of interest was the negative correlation between plasma D-dimer levels and IFNα. At the same time, data on the role of the latter in thrombus formation processes are increasingly appearing in the literature.

Early inflammatory profiles predict maximal disease severity in COVID-19: An unsupervised cluster analysis

BackgroundThe inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies. MethodsWe included individuals sampled <10 days from COVID-19 symptom onset, recruited from both inpatient and outpatient settings. We measured 61 biomarkers in plasma, including markers of innate immune and T cell activation, coagulation, tissue repair and lung injury. We used principal component analysis and hierarchical clustering to derive biomarker clusters, and ordinal logistic regression to explore associations between cluster membership and maximal disease severity, adjusting for known risk factors for severe COVID-19. ResultsIn 312 individuals, median (IQR) 7 (4–9) days from symptom onset, we found four clusters. Cluster 1 was characterised by low overall inflammation, cluster 2 was characterised by higher levels of growth factors and markers of endothelial activation (EGF, VEGF, PDGF, TGFα, PAI-1 and p-selectin). Cluster 3 and 4 both had higher overall inflammation. Cluster 4 had the highest levels of most markers including markers of innate immune activation (IL6, procalcitonin, CRP, TNFα), and coagulation (D-dimer, TPO), in contrast cluster 3 had the highest levels of alveolar epithelial injury markers (RAGE, ST2), but relative downregulation of growth factors and endothelial activation markers, suggesting a dysfunctional inflammatory pattern. In unadjusted and adjusted analysis, compared to cluster 1, cluster 3 had the highest odds of progressing to more severe disease (unadjusted OR (95%CI) 9.02 (4.53–17.96), adjusted OR (95%CI) 6.02 (2.70–13.39)). ConclusionEarly inflammatory profiles predicted subsequent maximal disease severity independent of risk factors for severe COVID-19. A cluster with downregulation of growth factors and endothelial activation markers, and early evidence of alveolar epithelial injury, had the highest risk of severe COVID-19.

Frequency and factors associated with severe COVID-19 patients.

Objective: To determine the frequency and factors leading to the development of severe COVID-19 in patients presenting at civil hospital, Karachi. Study Design: Cross-sectional study. Setting: Department of Medicine, Dr. Ruth K.M Pfau Civil Hospital, Karachi. Period: July 16, 2021 to January 15, 2022. Methods: Patients of age 20 to 80 years of either gender and presented with fever (&gt;38°C) for more than three days and diagnosed COVD-19 on PCR were included. Severity and factors of the disease were assessed and noted by researcher on pre-designed proforma. Results: The mean age was 48.5±11.07 years and most of the patients were males (56.7%) and urban residents (67%). Out of 97 COVID-19 patients, 12 had severe COVID-19 disease (12.4%), while 85 patients had mild to moderate COVID-19 disease (87.6%). In distribution of factors leading for development of severe covid-19, increasing age was noted in 8 (66.7%) patients, chronic kidney disease in 4 (33.3%), diabetes mellitus type II 3(25.0%), hypertension 6(50.0%), smoking 3 (25.0%), heart failure 2 (16.7%) while anemia was noted in 1 (8.3%) patient. Of 12 severe COVID-19 patients, 8 patients had positive family history of COVID-19. There was statistically significant association between COVID-19 severity and family history of COVID-19 (p=0.001). Conclusion: Severe covid-19 is common in patients presenting with fever while increasing age was noted as most common factor leading to development of severe covid-19 followed by hypertension and diabetes mellitus.

Impact of COVID-19 vaccination on liver transplant recipients. Experience in a reference center in Mexico.

COVID-19 vaccination has proved to be effective to prevent symptomatic infection and severe disease even in immunocompromised patients including liver transplant patients. We aim to assess the impact of COVID-19 vaccination on the mortality and development of severe and critical disease in our center. A retrospective cohort study of LT patients in a reference center between March 2020 and February 2022. Demographic data, cirrhosis etiology, time on liver transplantation, immunosuppressive therapies, and vaccination status were recorded at the time of diagnosis. Primary outcome was death due to COVID-19, and secondary outcomes included the development of severe COVID-19 and intensive care unit (ICU) requirement. 153 of 324 LT recipients developed COVID-19, in whom the main causes of cirrhosis were HCV infection and metabolic-associated fatty liver disease. The vaccines used were BNT162b2 (48.6%), ChAdOx1 nCoV-19 (21.6%), mRNA-1273 vaccine (1.4%), Sputnik V (14.9%), Ad5-nCoV-S (4.1%) and CoronaVac (9.5%). Case fatality and ICU requirement risk were similar among vaccinated and unvaccinated LT patients (adjusted relative case fatality for vaccinated versus unvaccinated of 0.68, 95% CI 0.14-3.24, p = 0.62; adjusted relative risk [aRR] for ICU requirement of 0.45, 95% CI 0.11-1.88, p = 0.27). Nonetheless, vaccination was associated with a lower risk of severe disease (aRR for severe disease of 0.32, 95% CI 0.14-0.71, p = 0.005). Vaccination reduces the risk of severe COVID-19 in LT patients, regardless of the scheme used. Vaccination should be encouraged for all.

New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications.

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice.

Effectiveness of Omega-3 Fatty Acid Supplementation in Improving the Metabolic and Inflammatory Profiles of Mexican Adults Hospitalized with COVID-19.

The development of severe COVID-19 is related to the preexistence of comorbidities and an inadequate nutritional status. The latter is a critical factor for the development of infection and the progression of the disease. Notably, optimal nutrition impacts immune system function, as malnutrition is related to high cytokine levels in the late phase of the disease, correlating with a poor prognosis. In this sense, omega-3 fatty acids (O3FAs) have anti-inflammatory properties that may reduce morbidity and mortality from COVID-19 infection. O3FAs are linked to a better prognosis in COVID-19 patients. In this randomized, double-blind clinical trial, we evaluate the administration of O3FAs to unvaccinated Mexican patients for two weeks starting after the first two hours of hospitalization. The findings support the notion that O3FAs (in a dose high enough to satisfy human physiological requirements in a short time, one capsule of 1.4 g O3FAs daily) exert a comprehensive multi-systemic modulatory influence, affecting inflammatory and metabolic pathways. Significant perturbations in biomarkers, including absolute neutrophil count, hematocrit, and platelet indices, underscore the compound's anti-inflammatory effect. Concurrently, the intervention modulates pivotal metabolic and hepatic parameters, attenuating cardiovascular risk profiles and expediting patient convalescence. These multifarious effects are likely orchestrated through intricate biochemical mechanisms and are subject to individual variations predicated on metabolic factors. The results of this trial support the notion that O3FA supplementation has beneficial effects on COVID-19 patients with moderate presentation by regulating metabolism and limiting inflammation.

Clinical and laboratory considerations: determining an antibody-based composite correlate of risk for reinfection with SARS-CoV-2 or severe COVID-19.

Much of the global population now has some level of adaptive immunity to SARS-CoV-2 induced by exposure to the virus (natural infection), vaccination, or a combination of both (hybrid immunity). Key questions that subsequently arise relate to the duration and the level of protection an individual might expect based on their infection and vaccination history. A multi-component composite correlate of risk (CoR) could inform individuals and stakeholders about protection and aid decision making. This perspective evaluates the various elements that need to be accommodated in the development of an antibody-based composite CoR for reinfection with SARS-CoV-2 or development of severe COVID-19, including variation in exposure dose, transmission route, viral genetic variation, patient factors, and vaccination status. We provide an overview of antibody dynamics to aid exploration of the specifics of SARS-CoV-2 antibody testing. We further discuss anti-SARS-CoV-2 immunoassays, sample matrices, testing formats, frequency of sampling and the optimal time point for such sampling. While the development of a composite CoR is challenging, we provide our recommendations for each of these key areas and highlight areas that require further work to be undertaken.

Clonal Hematopoiesis Is Associated with Severe COVID-19 Enhancing Inflammatory Responses in Myeloid Cells

Background Clonal hematopoiesis (CH) is prevalent among aged populations and highlighted because its association with not only hematological malignancies but various benign diseases (e.g. cardiovascular diseases). Of particular interest among these diseases is COVID-19. To date, the association between severe COVID-19 and CH-related gene mutations or mosaic chromosomal alterations (mCAs) was examined using biobank samples taken long before the pandemic and the association has not been tested in a sufficiently large cohort of patients on the basis of CH evaluated at the time of COVID-19 diagnosis. Moreover, no study examined the joint effect of gene mutations and mCAs. The mechanism of the association between severe COVID-19 and CH has not been addressed either. Methods To address these issues we enrolled a total of 4,541 patients with COVID-19, of whom 54% had a severe infection. We performed targeted-capture sequencing of 42 CH-related genes and SNP-array analysis to detect CH-related mutations and mCAs. We also performed RNA-seq (n=987) of whole blood samples and plasma proteomic analysis (n=1,200) using the Olink technology to investigate the effect of biological consequence of CH, which was applied to understand the underlying mechanism of sever COVID-19. Results We identified gene mutations and mCAs in 16.3% and 6.2% of COVID-19 patients, respectively. They coexisted in 2.4% patients. As reported in CH in normal individuals, most frequent alterations included mutations in DNMT3A (7.6%), TET2 (4.1%), ASXL1 (1.4%), PPM1D (1.7%), and mCAs such as 14qUPD, and del(20q). To evaluate the risk of severe COVID-19 conferred by CH, we compared the age-stratified frequencies of CH between severe and non-severe COVID-19 patients (Figure, a). Focusing on CH in ≧10% clonal fractions, CH was significantly enriched in severe COVID-19 in elderly patients, we detected a significant enrichment of cases with both gene mutations and mCAs and isolated gene mutations, but not that of isolated mCAs, in severe cases. Multivariable logistic regression analysis with adjustment for age and sex revealed the significant association of CH defined either CH-mutations or mCA with severe COVID-19 with an odds ratio (OR) of 1.34 [95%CI=1.03-1.84] in patients aged ≥65 years. Particularly, CH defined by combined gene mutations and mCAs conferred a remarkable increase in the risk of severe COVID-19 [OR=12.1, 95%CI=1.61-90.6], suggesting the presence of their synergistic impact on severe COVID-19. To elucidate the underlying mechanism of the observed association between severe COVID-19 and CH, we next evaluated the transcriptomic/proteomic features of severe COVID-19 and CH (Figure, b). In severe COVID-19, multiple inflammatory pathways including IFN-α/γ, TNF-α, and IL-6 responses were consistently up-regulated in both transcriptomic and proteomic analysis. Similar to these features of severe COVID-19, CH was also associated with inflammatory response and IFN-α/γ responses in RNA expression while the impact of CH on protein expression was not prominent. To further clarify the transcriptomic features of severe COVID-19 and CH, we performed deconvolution analysis of gene expression to estimate the fraction of each cell component and cell-type-specific expression profiles. Severe COVID-19 was characterized by elevated fractions of neutrophils, activated dendritic cells (DCs), and decreased fractions of several types of lymphocytes, while only a marginal increase of activated DCs was observed in CH. Cell-type-specific pathway analysis revealed up-regulations of inflammatory responses and IL-6/TNF-a signaling in neutrophils/monocytes were associated with both severe COVID-19 and CH independently, suggesting that CH might be involved in the development of severe COVID-19 through the augmentation of inflammatory responses in these myeloid cells, which are further augmented by increased neutrophils induced by COVID-19 independent of CH. Conclusion CH was significantly associated with an increased risk of severe COVID-19, particularly when the patients had both gene mutations and mCAs, where the augmented inflammatory responses by myeloid cells can be a mechanism of severe COVID-19 risk conferred by CH. Our findings highlight the link between the mechanism of severe COVID-19 and the biological effects of CH.

Morbidity and Mortality in Immunocompromised COVID-19 Patients: Which Factors Are Responsible?

Objective: The COVID-19 pandemic has caused significant morbidity and mortality and has challenged health systems worldwide. Immunosuppression is considered a risk factor for development of severe COVID-19. In this study, we aimed to determine the factors affecting morbidity and mortality in immunocompromised patients diagnosed with COVID-19. Methods: In this retrospective, cross-sectional study, laboratory findings and outcomes of 340 COVID-19 patients with secondary immunosuppression in a university hospital in Turkey from March 2020 to April 2022 were analyzed according to the 28-day clinical outcomes. Mortality-related factors were investigated in 3 patient groups with different forms of immunodeficiency: 1) malignancy (hematologic/solid), 2) organ transplantation, and 3) rheumatological diseases. Results: 172 (51%) of the patients were female, and the mean age was 61±15 years. A total of 122 (35.8%) patients died during hospitalization. The mortality rate (73.4%) in patients admitted to the intensive care unit (ICU) was significantly higher than those not admitted (p&lt;0.001). The highest laboratory median values of urea, lactate dehydrogenase (LDH), D-dimer, ferritin, C-reactive protein (CRP), and fibrinogen values were found to be significantly higher, and the first measurement lymphocyte value was found to be considerably lower compared to the surviving patients (p&lt;0.001) in the 28-day follow-up, ICU admission increased the mortality risk 13.6 (p&lt;0.001) times. Anticoagulant treatment (p=0.029) and nasal oxygen support (p&lt;0.001) led to a decrease in the risk of mortality. Conclusion: Immunocompromised patients are at risk for serious COVID-19 complications. LDH, D-dimer, CRP, and lymphocyte values can be used as markers to evaluate survival, and standard treatment is essential in immunosuppressive COVID-19 patients.

Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19.

The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein-protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe (n = 9) and non-severe COVID-19 (n = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.

Favipiravir treatment in non-severe COVID-19: promising results from multicenter propensity score-matched study (FAVICOV)

This study aimed to evaluate the efficacy of favipiravir (FPV) in preventing the development of severe COVID-19 in patients with mild-to-moderate symptoms. The study evaluated 1037 COVID-19 patients treated with FPV or standard treatment between April and September 2021, analyzed by propensity score matching. 149 patients were included in each arm after propensity score matching. The clinical outcomes showed no deterioration of the WHO clinical progression scale in the FPV group compared to the standard treatment group on day 5 (83.2% vs. 69.1%, p < 0.001). The WHO clinical progression scale also showed improvements on day 14 in the FPV group compared to the standard treatment group (66.4% vs. 46.3%, p < 0.001). The rates of oxygen supplementation and hospitalization were significantly lower in the FPV group compared to the standard treatment group (0% vs. 12.1% and 0.7% vs. 17.4%, respectively, p < 0.001 for both). There were no differences in adverse events between the two groups. The study highlights the effectiveness of FPV in preventing severe COVID-19 and hospitalization in patients with mild-to-moderate symptoms. The findings emphasize the importance of personalized treatment plans for COVID-19 patients, starting FPV treatment early, and adjusting dosages based on ethnicity and body weight.

87 Activation of complement pathways and formation of membrane attack complex contribute to the development of severe COVID-19

87 Activation of complement pathways and formation of membrane attack complex contribute to the development of severe COVID-19

Association between development of severe COVID-19 and a polymorphism in the CIAS1 gene that codes for an inflammasome component

An elevated pro-inflammatory cytokine response is associated with severe life-threatening symptoms in individuals with Coronavirus Disease-2019 (COVID). The inflammasome is an intracellular structure responsible for generation of interleukin (IL)-1β and IL-18. NALP3, a product of the CIAS1 gene, is the rate-limiting component for inflammasome activity. We evaluated if a CIAS1 42 base pair length polymorphism (rs74163773) was associated with severe COVID. DNA from 93 individuals with severe COVID, 38 with mild COVID, and 98 controls were analyzed for this polymorphism. The 12 unit repeat allele is associated with the highest inflammasome activity. Five alleles, corresponding to 6, 7, 9, 12 or 13 repeat units, divided into 12 genotypes were identified. The frequency of the 12 unit repeat allele was 45.3% in those with severe disease as opposed to 30.0% in those with mild disease and 26.0% in controls (p < 0.0001, severe vs. controls). In contrast, the 7 unit repeat allele frequency was 30.1% in controls as opposed to 14.0% and 12.5% in those with severe or mild disease, respectively (p ≤ 0.0017). We conclude that individuals positive for the CIAS1 12 allele may be at elevated risk for development of severe COVID due to an increased level of induced pro-inflammatory cytokine production.

Increased D-dimer is associated with disease progression and increased mortality in Turkish COVID-19 patients

Objective: Coagulopathy is thought to play an important role in the development of severe COVID-19. High D-dimer levels have been&#x0D; reported in Chinese cohort studies. However, ethnicity has significant implications for thrombotic risk. Our aim in this study is to&#x0D; determine the effect of D-dimer measurements on disease prognosis and mortality in Turkish patients with COVID-19.&#x0D; Patients and Methods: The study was designed retrospectively. Patients over the age of 18 who were admitted to our hospital were&#x0D; included in the study.&#x0D; Results: The study included 226 patients. According to the World Health Organization staging, 75(33.2%) patients, according to the&#x0D; staging of Siddiqi et al., 67 (29.7%) patients progressed. In the ROC analysis performed to predict mortality, AUC value for D-dimer&#x0D; was found to be 82.25% (95%CI 74.8%-89.71%). When the cut-off value for D-dimer was accepted as ≥3.25mg/L, specificity was&#x0D; 94.15%, correctly classified rate 88.5%, positive likelihood ratio as (LR):5.69, negative LR:0.71.&#x0D; Conclusion: As a result, similar to the Chinese cohorts, elevated D-dimer measurements increase disease progression and mortality&#x0D; in Turkish patients with COVID-19. D-dimer levels of 3.25 mg/L and above, strongly determine the risk of increased mortality in the&#x0D; Turkish Caucasian ethnic group.

Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion

Despite intensive research since the emergence of SARS-CoV-2, it has remained unclear precisely which components of the early immune response protect against the development of severe COVID-19. Here, we perform a comprehensive immunogenetic and virologic analysis of nasopharyngeal and peripheral blood samples obtained during the acute phase of infection with SARS-CoV-2. We find that soluble and transcriptional markers of systemic inflammation peak during the first week after symptom onset and correlate directly with upper airways viral loads (UA-VLs), whereas the contemporaneous frequencies of circulating viral nucleocapsid (NC)-specific CD4+ and CD8+ T cells correlate inversely with various inflammatory markers and UA-VLs. In addition, we show that high frequencies of activated CD4+ and CD8+ T cells are present in acutely infected nasopharyngeal tissue, many of which express genes encoding various effector molecules, such as cytotoxic proteins and IFN-γ. The presence of IFNG mRNA-expressing CD4+ and CD8+ T cells in the infected epithelium is further linked with common patterns of gene expression among virus-susceptible target cells and better local control of SARS-CoV-2. Collectively, these results identify an immune correlate of protection against SARS-CoV-2, which could inform the development of more effective vaccines to combat the acute and chronic illnesses attributable to COVID-19.

TREM2+ and interstitial-like macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

The immunopathological mechanisms driving the development of severe COVID-19 remain poorly defined. Here, we utilize a rhesus macaque model of acute SARS-CoV-2 infection to delineate perturbations in the innate immune system. SARS-CoV-2 initiates a rapid infiltration of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generate a longitudinal scRNA-Seq dataset of airway cells, and map these subsets to corresponding populations in the human lung. SARS-CoV-2 infection elicits a rapid recruitment of two macrophage subsets: CD163+MRC1-, and TREM2+ populations that are the predominant source of inflammatory cytokines. Treatment with baricitinib (Olumiant®), a JAK1/2 inhibitor is effective in eliminating the influx of non-alveolar macrophages, with a reduction of inflammatory cytokines. This study delineates the major lung macrophage subsets driving airway inflammation during SARS-CoV-2 infection.

The effects of obesity and metabolic abnormalities on severe COVID-19-related outcomes after vaccination: A population-based study

Breakthrough SARS-CoV-2 infections of vaccinated individuals are being reported globally, resulting in an increased risk of hospitalization and death among such patients. Therefore, it is crucial to identify the modifiable risk factors that may affect the protective efficacy of vaccine use against the development of severe COVID-19 and thus to initiate early medical interventions. Here, in population-based studies using the UK Biobank database and the 2021 National Health Interview Survey (NHIS), we analyzed 20,362 participants aged 50 years or older and 2,588 aged 18 years or older from both databases who tested positive for SARS-COV-2, of whom 33.1% and 67.7% received one or more doses of vaccine, respectively. In the UK Biobank, participants are followed from the vaccination date until October 18, 2021. We found that obesity and metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, and hypertension) were modifiable factors for severe COVID-19 in vaccinated patients (all p<0.05). When metabolic abnormalities were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal individuals (all p<0.05). Moreover, pharmacological interventions targeting such abnormalities (namely, antihypertensive [adjusted hazard ratio (aHR) 0.64, 95% CI 0.48-0.86; p= 0.003], glucose-lowering [aHR 0.55, 95% CI 0.36-0.83; p= 0.004], and lipid-lowering treatments [aHR 0.50, 95% CI 0.37-0.68; p<0.001]) were significantly associated with a reduced risk for this outcome. These results show that more proactive health management of patients with obesity and metabolic abnormalities is critical to reduce the incidence of severe COVID-19 after vaccination.