COVID-19 Disease Progression Research Articles

Disease progression associated cytokines in COVID-19 patients with deteriorating and recovering health conditions.

Understanding the immune response to COVID-19 is challenging due to its high variability among individuals. To identify differentially expressed cytokines between the deteriorating and recovering phases, we analyzed the Electronic Health Records (EHR) and cytokine profile data in a COVID-19 cohort of 444 infected patients and 145 non-infected healthy individuals. We categorized each patient's progression into Deterioration Phase (DP) and Recovery Phase (RP) using longitudinal neutrophil, lymphocyte and lactate dehydrogenase levels. A random forest model was built using healthy and severe patients to compute the contribution of each cytokine toward disease progression using Shapley Additive Explanations (SHAP). SHAP values were used for supervised clustering to identify DP and RP-related samples and their associated cytokines. The identified clusters effectively discriminated DP and RP samples, suggesting that the cytokine profiles differed between deteriorating and recovering health conditions. Especially, CXCL10, GDF15, PTX3, and TNFSF10 were differentially expressed between the DP and RP samples, which are involved in the JAK-STAT, NF- B, and MAPK signaling pathways contributing to the inflammatory response. Collectively, we characterized the immune response in terms of disease progression of COVID-19 with deteriorating and recovering health conditions.

Combination of the chemokine receptor type 2 (CCR2) antagonist DMX-200 and candesartan for COVID-19: a randomised controlled trial

ObjectiveTo determine whether a chemokine receptor type 2 antagonist, DMX-200 (repagermanium), in combination with an angiotensin receptor blocker, candesartan, improves clinical outcomes in people with COVID-19.DesignProspective, multicentre, double-blind, placebo-controlled trial.SettingTen...

Soluble platelet selectin and platelets in COVID-19: a multifaceted connection.

The COVID-19 pandemic has brought to light the intricate relationship between platelets, soluble platelet selectin (sP-selectin), and disease pathogenesis. Platelets, traditionally recognized for their role in hemostasis, have emerged as key contributors to the immunothrombotic complications observed in COVID-19 patients. Concurrently, elevated levels of sP-selectin, indicative of platelet activation and endothelial injury, have been consistently identified in COVID-19 patients and have shown associations with disease severity and adverse outcomes. This multifaceted connection underscores the pivotal role of platelets and sP-selectin in orchestrating thromboinflammation, vascular dysfunction, and disease progression in COVID-19. Platelet activation triggers the release of inflammatory mediators and promotes platelet-leukocyte interactions, amplifying the systemic inflammatory response and exacerbating endothelial injury. Additionally, platelet-derived factors contribute to microvascular thrombosis, further exacerbating tissue damage and organ dysfunction in severe COVID-19. Elevated sP-selectin levels serve as biomarkers for disease severity and prognostication, aiding in risk stratification and early identification of patients at higher risk of adverse outcomes. Therapeutic strategies targeting platelet dysfunction and sP-selectin-mediated pathways hold promise in mitigating thromboinflammation and improving outcomes in COVID-19 patients. Antiplatelet agents, platelet inhibitors, and anti-inflammatory therapies represent potential interventions to attenuate platelet activation, inhibit platelet-leukocyte interactions, and alleviate endothelial dysfunction. A comprehensive understanding of the multifaceted connection between platelets, sP-selectin, and COVID-19 pathogenesis offers opportunities for tailored therapeutic approaches aimed at mitigating thromboinflammation and improving patient outcomes in this complex and challenging clinical setting.

Unravelling the complex interplay of age, comorbidities, and multimorbidities in COVID-19 disease progression: Clinical implications and future perspectives

IntroductionThe COVID-19 infection as an inflammatory disease has posed significant challenges to global public health due to multi-factor risks associated with it leading to disease severity and mortality. Understanding the effect of age and comorbidities on overall disease progression is crucial to identify highly susceptible individuals and to develop effective disease management strategies in a resource limited country like Pakistan. MethodologyA retrospective study was conducted on hospitalized COVID-19 patients to assess the prevalence of various comorbidities among different age groups and their effect on disease severity and mortality rate. ResultsIn this retrospective study, a cohort of 618 hospitalized COVID-19 patients was analyzed, consisting of 387 males (62.6 %) and 231 females (37.4 %). Notably, the young age group (15–24 years), had the lowest frequency of hospitalized COVID-19 patients, while no case was observed in children (≤14 years) showing a significant association (p < 0.001) of age and disease prevalence. Comorbidities were observed in 63.9 % of COVID-19 patients including hypertension (HTN), diabetes mellitus (DM), ischemic heart diseases (IHD), asthma, chronic kidney disease (CKD) and tuberculosis (TB). The most common comorbidities were HTN (42.1 %) followed by DM (33.8 %), IHD (16.5 %), asthma (11.2 %), CKD (7.9 %) and TB (1.9 %).Furthermore, the study revealed a significant association between comorbidities, age groups, and the need for non-invasive ventilation (NIV) (p < 0.001), mechanical ventilation (MV) (p < 0.001), and intensive care unit (ICU) admission (p < 0.001). Patients with specific comorbidities and those in the older age group (≥65 years) demonstrated a higher need for these interventions. However, patients without any comorbidity consistently exhibited the highest cumulative proportion of survival at each time point, indicating better overall survival outcomes. In contrast, patients with multimorbidities of DM/HTN/IHD, HTN/IHD, and DM/HTN/CKD had comparatively lower survival rates and higher mortality rates (p < 0.001). ConclusionThis research highlights the significant impact of age, comorbidities and multimorbidities on the severity and mortality of COVID-19 patients. It highlights the importance of considering these factors in tailoring effective management strategies for patients with COVID-19 or other infectious respiratory diseases.

The Role of ACE2 Receptor and Its Polymorphisms in COVID-19 Infection and Severity and Its Association with Lipid Profile, Thrombin, and D-Dimer Levels in Iraqi Patients: A Cross-Sectional Study.

COVID-19 patients experience a complex interplay involving ACE2, thrombin, D-dimer, and lipid profile, yet its full understanding remains elusive. ACE2, a pivotal regulator of the renin-angiotensin system and the primary receptor for SARS-CoV-2 undergoes downregulation upon viral binding, potentially leading to severe cases with acute respiratory distress syndrome (ARDS). A specific ACE2 gene polymorphism (rs2285666) may be associated with COVID-19 susceptibility, with the A allele potentially increasing infection risk. COVID-19 disease progression is linked to coagulation abnormalities, but the exact connection with thrombin and D-dimer remains uncertain. A study examining coagulation parameters in COVID-19 patients admitted to Al-Diwania Educational Hospital from February to May 2022 found that thrombin and D-dimer levels were directly related to disease severity. Severe cases exhibited significantly altered coagulation function compared to mild and recovered cases, with notably higher D-dimer levels and elevated thrombin serum concentrations. Moreover, dyslipidemia, particularly low HDL cholesterol, is a prevalent comorbidity in COVID-19 patients and may be linked to worse outcomes. In conclusion, COVID-19 is associated with a prothrombotic state and dysregulation of the renin-angiotensin system due to ACE2 downregulation following viral binding. The intricate interplay between ACE2, thrombin, D-dimer, and lipid profile necessitates further investigation. The multifaceted nature of the disease demands continued research to unravel its pathogenesis and identify potential therapeutic targets.

How international guidelines recommend treating children who have severe COVID-19 or risk disease progression.

This study reviewed the current knowledge and guidelines on managing COVID-19 in children and proposed a practical approach to drug treatment. We analysed international guidelines from four prominent scientific bodies on treating COVID-19 in children. These were the UK National Institute for Health and Care Excellence, the American National Institutes of Health, the Infectious Diseases Society of America and the Australian National Clinical Evidence Taskforce COVID-19. Most paediatric patients with COVID-19 only require symptomatic treatment. There was limited evidence on treatment recommendations for children with severe COVID-19 or at risk of disease progression. However, several drugs are available for children and we have summarised the guidelines, in order to provide a concise, practical format for clinicians. All the guidelines agree that nirmatrelvir plus ritonavir or remdesivir can be used as prophylaxis for severe COVID-19 in high-risk patients. Remdesivir can also be used for severe COVID-19 cases. Glucocorticosteroids are recommended, particularly in patients requiring oxygen therapy. Tocilizumab or baricitinib should be reserved for patients with progressive disease and/or signs of systemic inflammation. The guidelines provide useful advice and a degree of consensus on specific drug treatment for children with severe COVID-19 or at risk of progression.

SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres.

Autophagy and lysosomal pathways are involved in the cell entry of SARS-CoV-2 virus. To infect the host cell, the spike protein of SARS-CoV-2 binds to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved. One possible mechanism is the endocytosis of the SARS-CoV-2-ACE2 complex and subsequent cleavage of the spike protein, mainly by the lysosomal protease cathepsin L. However, detailed molecular and dynamic insights into the role of cathepsin L in viral cell entry remain elusive. To address this, HeLa cells and iPSC-derived alveolarspheres were treated with recombinant SARS-CoV-2 spike protein, and the changes in mRNA and protein levels of cathepsins L, B, and D were monitored. Additionally, we studied the effect of cathepsin L deficiency on spike protein internalization and investigated the influence of the spike protein on cathepsin L promoters in vitro. Furthermore, we analyzed variants in the genes coding for cathepsin L, B, D, and ACE2 possibly associated with disease progression using data from Regeneron's COVID Results Browser and our own cohort of 173 patients with COVID-19, exhibiting a variant of ACE2 showing significant association with COVID-19 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS-CoV-2 spike protein in HeLa cells, accompanied by elevated mRNA levels of cathepsin B and D in alveolarspheres. Moreover, an increase in cathepsin L promoter activity was detected in vitro upon spike protein treatment. Notably, the knockout of cathepsin L resulted in reduced internalization of the spike protein. The study highlights the importance of cathepsin L and lysosomal proteases in the SARS-CoV-2 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID-19 and other viral infections.

The effect of early remdesivir administration in COVID-19 disease progression in hospitalised patients.

Antiviral drugs have become crucial in managing COVID-19, reducing complications and mortality. Remdesivir has emerged as an effective therapeutic drug for hospitalized patients at risk of disease progression, especially when alternative treatments are infeasible. While the recommended treatment duration of remdesivir extends up to 7days post-symptom onset, this study examines how early remdesivir administration impacts clinical outcomes. We conducted aretrospective analysis using clinical data from consecutively PCR confirmed SARS-CoV‑2 adult patients (≥ 18years) who received remdesivir during their hospitalization at the department of infectious diseases, Klinik Favoriten in Vienna. The data covered the period from July1, 2021, to April31, 2022. Patients were divided into two groups based on the timing of remdesivir administration: an early group (0-3days since symptom onset) and alate group (≥ 4days since symptom onset). The primary outcome was in-hospital disease progression, assessed using the WHO COVID-19 Clinical Progression Scale (≥ 1point increase). Multivariable logistic regression, adjusted for age, sex, SARS-CoV‑2 variant, and COVID-19 vaccination status, was used to assess clinical outcomes. In total 219 patients were included of whom 148 (67.6%) were in the early group and 71(32.4%) were in the late group. The average age was 66.5 (SD: 18.0) years, 68.9% of the patients were vaccinated, and 72.6% had the Omicron virus variant. Late remdesivir administration was associated with asignificantly higher probability of needing high-flow oxygen therapy (OR 2.52, 95% CI 1.40-4.52, p = 0.002) and ICU admission (OR 4.34, 95% CI 1.38-13.67, p = 0.012) after adjusting for confounders. In the late group there was atrend towards ahigher risk of clinical worsening (OR 2.13, 95% CI 0.98-4.64, p = 0.056) and need for any oxygen therapy (OR 1.85, 95% CI 0.94-3.64, p = 0.074). Compared to patients who received remdesivir within the first 3days after symptom onset, administering remdesivir after day3 in hospitalized COVID-19 patients is associated with higher risk for complications, such as the need for high-flow oxygen therapy and ICU admission.

COVID-19 Infection in Autosomal Dominant Polycystic Kidney Disease and Chronic Kidney Disease Patients: Progression of Kidney Disease.

the COVID-19 pandemic has brought to light the intricate interplay between viral infections and preexisting health conditions. In the field of kidney diseases, patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Chronic Kidney Disease (CKD) face unique challenges when exposed to the SARS-CoV-2 virus. This study aims to evaluate whether SARS-CoV-2 virus infection impacts renal function differently in patients suffering from ADPKD and CKD when compared to patients suffering only from CKD. clinical data from 103 patients were collected and retrospectively analyzed. We compared the renal function of ADPKD and CKD patients at two distinct time points: before COVID-19 infection (T0) and 1 year after the infection (T1). We studied also a subpopulation of 37 patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min and affected by ADPKD and CKD. clinical data were obtained from 59 (57.3%) ADPKD patients and 44 (42.7%) CKD patients. At T1, ADPKD patients had significantly higher serum creatinine levels compared to CKD patients, and a significantly lower eGFR was observed only in ADPKD patients with eGFR < 60 mL/min compared to CKD patients (p < 0.01, p < 0.05; respectively). Following COVID-19 infection, ADPKD-CKD patients exhibited significantly higher variation in both median serum creatinine (p < 0.001) and median eGFR (p < 0.001) compared to CKD patients. the interplay between COVID-19 and kidney disease is complex. In CKD patients, the relationship between COVID-19 and kidney disease progression is more established, while limited studies exist on the specific impact of COVID-19 on ADPKD patients. Current evidence does not suggest that ADPKD patients are at a higher risk of SARS-CoV-2 infection; however, in our study we showed a significant worsening of the renal function among ADPKD patients, particularly those with an eGFR < 60 mL/min, in comparison to patients with only CKD after a one-year follow-up from COVID-19 infection.

Safety and effectiveness of remdesivir in hospitalized patients with COVID-19 and severe renal impairment: experience at a large medical center

Background Literature on the safety of remdesivir in hospitalized COVID-19 patients with severe renal impairment is limited. We aimed to investigate the safety and effectiveness of remdesivir in this population. Methods We conducted a retrospective cohort study of adult hospitalized COVID-19 patients who received remdesivir between April 2022 and October 2022. Outcomes were compared between estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and ≥30 mL/min/1.73 m2 groups. The primary safety outcomes were acute kidney injury (AKI) and bradycardia, while the primary effectiveness outcomes included mortality in COVID-19-dedicated wards and hospital mortality. Secondary outcomes included laboratory changes, disease progression, and recovery time. Results A total of 1,343 patients were recruited, with 307 (22.9%) in the eGFR <30 group and 1,036 (77.1%) in the eGFR ≥30 group. Patients with an eGFR <30 had higher risks of AKI (adjusted hazard ratio [aHR] 2.92, 95% CI 1.93–4.44) and hospital mortality (aHR 1.47, 95% CI 1.06–2.05) but had comparable risks of bradycardia (aHR 1.15, 95% CI 0.85–1.56) and mortality in dedicated wards (aHR 1.43, 95% CI 0.90–2.28) than patients with an eGFR ≥30. Risk of disease progression was higher in the eGFR <30 group (adjusted odds ratio 1.62, 95% CI 1.16–2.26). No difference between the two groups in laboratory changes and recovery time. Conclusions Hospitalized COVID-19 patients receiving remdesivir with severe renal impairment had an increased risk of AKI, hospital mortality, and COVID-19 disease progression compared to patients without severe renal impairment.

Determinants of Disease Progression in Bangladeshi COVID-19 Patients: A Cross-sectional Survey

Background Coronavirus disease 2019 (COVID-19) shows a wide range of clinical manifestations, including asymptomatic presentation to severe pneumonia, acute respiratory distress syndrome, and respiratory failure. Although COVID-19 disease progression was studied elsewhere, it is largely unknown in Bangladesh. Methods We conducted this cross-sectional study in November 2020 to January 2021 on patients diagnosed with COVID-19 confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Pearson chi-square tests were used to assess the disease progressions across selected variables. A logistic regression model was used to assess the associated factors of COVID-19 infection for explanatory variables. All statistics were performed using the Stata software version 14.0 (Stata corporation, college station, Texas, USA). Results A total of 384 of respondents were involved in the survey. Of participants, most males (73%), unmarried (69%), aged 18 to 35 years during survey, and lived in urban community (73%). Overall, 41% of patients were in asymptotic condition, 44% were in mild condition, while 17% were moderate to severe conditions. Male patients and patients over 50 years had severe symptoms, accounting for 52% and 50%, respectively. Nearly half of business persons and office employees had severe symptoms. Almost all married patients (98%) had severe symptoms. The severity of symptoms was also higher for patients living in urban areas (79%), smoking (95%), and not physically active (52%). Patients with diabetes, asthma/COPD, and cancer were significantly associated with severe stage of COVID-19 (p≤0.05). Patient’s age, gender, smoking status, diabetics, working conditions significantly affect Covid-19 disease progression. Conclusion The study found that 7.03% of patients had severe, 9.11% had moderate and 40.36% had asymptomatic conditions. The heterogenic association between the disease progressions with age, sex, residence, marital status, smoking habits, diabetes, physical exercise, working conditions, sedentary lifestyles. Findings highlight the idea of using vulnerability ratings for each risk factor related to disease progression.

Bioinformation Analysis of Differential Expression Proteins in Different Processes of COVID-19.

COVID-19 is a highly infectious respiratory disease whose progression has been associated with multiple factors. From SARS-CoV-2 infection to death, biomarkers capable of predicting different disease processes are needed to help us further understand the molecular progression of COVID-19 disease. The aim is to find differentially expressed proteins that are associated with the progression of COVID-19 disease or can be potential biomarkers, and to provide a reference for further understanding of the molecular mechanisms of COVID-19 occurrence, progression, and treatment. Data-independent Acquisition (DIA) proteomics to obtain sample protein expression data, using R language screening differentially expressed proteins. Gene Ontology and Kyoto Encyclopedia for Genes and Genomes analysis was performed on differential proteins and protein-protein interaction (PPI) network was constructed to screen key proteins. A total of 47 differentially expressed proteins were obtained from COVID-19 incubation patients and healthy population (L/H), mainly enriched in platelet-related functions, and complement and coagulation cascade reaction pathways, such as platelet degranulation and platelet aggregation. A total of 42 differential proteins were obtained in clinical and latent phase patients (C/L), also mainly enriched in platelet-related functions and in complement and coagulation cascade reactions, platelet activation pathways. A total of 10 differential proteins were screened in recovery and clinical phase patients (R/C), mostly immune-related proteins. The differentially expressed proteins in different stages of COVID-19 are mostly closely associated with coagulation, and key differential proteins, such as FGA, FGB, FGG, ACTB, PFN1, VCL, SERPZNCL, APOC3, LTF, and DEFA1, have the potential to be used as early diagnostic markers.

Extreme γ′ fibrinogen levels in COVID-19 patients

COVID-19 disease progression can be accompanied by a “cytokine storm” that leads to secondary sequelae such as acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have high daily intra-individual variability. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (GPF) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure GPF in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression. COVID-19 patients were retrospectively enrolled between 3/16/2020 and 8/1/2020. GPF was measured using a commercial ELISA. We found that COVID-19 patients can develop extraordinarily high levels of GPF. Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of GPF ever recorded. The previous highest GPF level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. GPF levels were significantly associated with the need for ECMO and mortality. These findings have potential implications regarding prophylactic anticoagulation of COVID-19 patients.

Post-COVID fatigue: Reduced quality-of-life associated with clinically relevant fatigue in mild disease courses

ABSTRACT Fatigue is a pervasive symptom experienced by many individuals after COVID-19. Despite its widespread occurrence, fatigue remains a poorly understood and complex phenomenon. Our aim is to evaluate the subjective experience of mental fatigue after COVID-19 and to assess its significance for daily life functioning. In this online questionnaire study (N = 220), the Fatigue Severity Scale (FSS), World Health Organization Quality-of-Life assessment (WHOQoL) and a subjective severity rating of the COVID-19 disease progression were used. For our statistical analyses we utilized independent samples t-tests, one-way ANOVA with post-hoc analyses, and a multiple regression. As expected our findings revealed the COVID group reported significantly higher levels of subjective fatigue compared to the control group. Moreover, there was a significant difference between experienced fatigue across the four severity groups. Participants who had a milder course of disease also experienced severe subjective fatigue. Subjective fatigue explained 40% variance in quality-of-life. In conclusion, severe subjective fatigue appears to be associated with increased self-reported COVID-19 symptom severity and lower quality-of-life but is already observable in milder cases. This underscores, firstly, the importance of considering also less severe cases and, secondly, the need to develop rehabilitation and psychological interventions for fatigue.

Adapting transfer learning models to dataset through pruning and Avg-TopK pooling

This study focuses on efficiently adapting transfer learning models to address the challenges of creating customized deep learning models for specific datasets. Designing a model from scratch can be time-consuming and complex due to factors like model complexity, size, and dataset structure. To overcome these obstacles, a novel approach is proposed using transfer learning models. The proposed method involves identifying relevant layers in transfer learning models and removing unnecessary ones using a layer-based variance pruning technique. This results in the creation of new models with improved computational efficiency and classification performance. By streamlining the models through layer-based variance pruning, the study achieves enhanced accuracy and faster computation. Experiments were conducted using the COVID-19 dataset and well-known transfer learning models, including InceptionV3, ResNet50V2, DenseNet201, VGG16, and Xception to validate the approach. Among these models, the variance-based layer pruning technique was applied to InceptionV3 and DenseNet201, yielding the best results. When these pruned models were combined with the new pooling layer, Avg-TopK, the proposed method achieved an outstanding image classification accuracy of 99.3%. Comparisons with previous models and literature studies indicate that the proposed approach outperforms existing methods, showcasing state-of-the-art performance. This high-performance approach provides great potential for diagnosing COVID-19 and monitoring disease progression, especially on hardware-limited devices. By leveraging transfer learning models, pruning, and efficient pooling techniques, the study presents a promising strategy for tackling challenges in custom model design, leading to exceptional results in such as image classification and segmentation tasks. The proposed methodology holds the potential to yield exceptional outcomes across a spectrum of tasks, encompassing disciplines such as image classification and segmentation.

The Relationship between COVID-19 Severity and Plasma Levels of Vascular Endothelial Growth Factor (VEGF)

Background: This study aimed to assess the relationship between COVID-19 severity and the plasma levels of vascular endothelial growth factor. Methods: This cross-sectional study was conducted on 86 patients with COVID-19. A 5 ml venous blood sample was taken on the first day of hospitalization. VEGF was measured with the ELISA method using the Hangzhou East biopharm VEGF ELIZA Kit. Results: Although plasma VEGF levels were higher in the severe group than in the non-severe group, no significant relationship was found between the plasma level of VEGF and COVID-19 severity, which might be due to the small sample size. VEGF may be a valuable scientific marker, but in this study, it was not as useful as other markers in identifying COVID-19 severity. In addition, there was a direct and significant relationship between COVID-19 severity and the inflammatory markers LDH, neutrophil/lymph, and CRP. Therefore, measurement of inflammatory markers can assist in the early identification and prediction of severity and disease progression in COVID-19. Conclusion: Although plasma VEGF levels were higher in the severe group than in the non-severe group, no significant relationship was found between the plasma level of VEGF and COVID-19 severity, which might be due to the small sample size. VEGF may be a valuable scientific marker, but in this study, it was not as useful as other markers in identifying COVID-19 severity. In addition, there was a direct and significant relationship between COVID-19 severity and the inflammatory markers LDH, neutrophil/lymph, and CRP. Therefore, measurement of inflammatory markers can assist in the early identification and prediction of severity and disease progression in COVID-19.

Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab or Sotrovimab on Persistently High Viral Load in Patients with Mild-to-Moderate COVID-19: A Randomized, Phase2 BLAZE-4 Trial.

Treatment with monoclonal antibodies provides rapid, passive immunity and may stop COVID-19 disease progression. The study evaluated the effect of bamlanivimab (BAM) or BAM + etesevimab (ETE)/sotrovimab compared to placebo on SARS-CoV-2 viral load in patients with COVID-19. The phase2, randomized, single-dose study included patients aged between ≥ 18 and < 65years, not hospitalized at the time of randomization, and had ≥ 1 mild or moderate COVID-19 symptoms. Study included arms1-6 (placebo, BAM 175mg + ETE 350mg, BAM 700mg + ETE 1400mg, BAM 2800mg + ETE 2800mg, BAM 700mg alone, and BAM 350mg + ETE 700mg, respectively), BAM 700mg + ETE 700mg unintentional dosing; and arms7 and 8 (BAM 700mg + sotrovimab 500mg and placebo, respectively). The primary endpoint was proportion of patients with SARS-CoV-2 log viral load > 5.27 on day7 (persistently high viral load [PHVL]) who received BAM or BAM + (ETE or sotrovimab). A total of 725 patients, mean age 39.6years (range 18-75years), 50.2% male were randomized and infused with study drug in arms1-6; and a total 202 patients, mean age 38years (range 18-63years), 53.5% female were randomized and infused with study drug in arms7 and 8. A significantly lower proportion of patients in arms2-6 and arm 7 experienced PHVL on day7 compared to placebo. On day7, patients in arms2, 3, and 6 consistently experienced significantly greater reduction in viral load than placebo. Significant improvement was observed in time to viral load clearance and time to symptom improvement by day29 in some arms compared to placebo. No new safety concerns were observed with drug combinations. The study demonstrated that a significantly lower proportion of patients with mild-to-moderate COVID-19 treated with BAM or BAM + (ETE or sotrovimab) experienced a PHVL at day7. ClinicalTrials.gov identifier, NCT04634409.

Evaluation of outcome of disease in COVID-19 patients with Comorbidities: An experience from a Tertiary Care Center in North India

The data on the poor outcomes of COVID-19 patients pertaining to their comorbidities is scarce in Indian population. We studied 331 COVID-19 patients admitted to PGIMS, Rohtak, of which 106 were with comorbidities and 225 patients without any comorbid conditions (controls). Among 225 patients without comorbidities, the average length of stay in hospital was ~3.9 days, while patients (n=106) with comorbidities stayed for almost double time (average 7.4 days). Among 106 hospitalized patients with comorbidities, 61 (57.4%) received oxygen support, with an average intake of 6.5 L/min of oxygen, while 29 of 225 (12.8%) controls received an average 3.1 L/min of oxygen. Out 106 patients with comorbidities 49 (46.2%) required ICU admission compared to 18 (8%) of 225 controls. The mortality in patients with comorbidities was 35.8% (38/106), which was higher than patients with no comorbidities (5.7%, 13/225). The Kaplan-Meier survival curve indicated poor survival trends in COVID-19 patients with comorbidities, as compared to those without comorbidities. Overall, this study demonstrates that comorbidities, like diabetes, hypertension, chronic cardiac disease, chronic kidney disease, chronic pulmonary, thyroid disorders, etc. are associated with severe COVID-19 disease progression.

Comparison Study of the Bio-Plex and Meso Scale Multiplexed SARS-CoV-2 Serology Assays Reveals Evidence of Diminished Host Antibody Responses to SARS-CoV-2 after Monoclonal Antibody Treatment.

Assessing the breadth and duration of antigen-specific binding antibodies provides valuable information for evaluating interventions to treat or prevent SARS-CoV-2 infection. Multiplex immunoassays are a convenient method for rapid measurement of antibody responses but can sometimes provide discordant results, and antibody positive percent agreement for COVID-19 diagnosis can vary depending on assay type, disease severity, and population sampled. Therefore, we compared two assays marked for research applications, MSD and Bio-Plex Pro, to evaluate qualitative interpretation of serostatus and quantitative detection of antibodies of varying isotypes (IgG, IgM, and IgA) against receptor binding domain (RBD) and nucleocapsid (N) antigens. Specimens from ACTIV-2/A5401, a placebo-controlled clinical trial of the SARSCoV-2 monoclonal antibody (mAb) bamlanivimab to prevent COVID-19 disease progression, were used to evaluate the concordance of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 Serology Assay and the Meso Scale Discovery (MSD) V-PLEX COVID-19 Panel 1 serology assay in detecting and quantifying IgG, IgA, and IgM binding anti-SARS-CoV-2 antibody responses against the RBD and N antigens. Data were disaggregated by study arm, bamlanivimab dose, days post-enrollment, and presence of emerging resistance. We observed 90.5% (412 of 455 tests) concordance for anti-RBD IgG and 87% (396 of 455) concordance for anti-N IgG in classifying samples as negative or positive based on assay-defined cutoffs. Antibody levels converted to the WHO standard BAU/mL were significantly correlated for all isotypes (IgG, IgM, and IgA) and SARS-CoV-2 antigen targets (RBD and N) tested that were common between the two assays (Spearman r 0.65 to 0.92, P < 0.0001). Both assays uncovered evidence of diminished host-derived IgG immune responses in participants treated with bamlanivimab compared to placebo. Assessment of immune responses in the four individuals treated with the 700 mg of bamlanivimab with emerging mAb resistance demonstrated a stronger anti-N IgG response (MSD) at day 28 (median 2.18 log BAU/mL) compared to participants treated with bamlanivimab who did not develop resistance (median 1.55 log BAU/mL). These data demonstrate the utility in using multiplex immunoassays for characterizing the immune responses with and without treatment in a study population and provide evidence that monoclonal antibody treatment in acute COVID-19 may have a modest negative impact on development of host IgG responses.

Elevated CD39+T-Regulatory Cells and Reduced Levels of Adenosine Indicate a Role for Tolerogenic Signals in the Progression from Moderate to Severe COVID-19.

Viral infections trigger inflammation by controlling ATP release. CD39 ectoenzymes hydrolyze ATP/ADP to AMP, which is converted by CD73 into anti-inflammatory adenosine (ADO). ADO is an anti-inflammatory and immunosuppressant molecule which can enhance viral persistence and severity. The CD39-CD73-adenosine axis contributes to the immunosuppressive T-reg microenvironment and may affect COVID-19 disease progression. Here, we investigated the link between CD39 expression, mostly on T-regs, and levels of CD73, adenosine, and adenosine receptors with COVID-19 severity and progression. Our study included 73 hospitalized COVID-19 patients, of which 33 were moderately affected and 40 suffered from severe infection. A flow cytometric analysis was used to analyze the frequency of T-regulatory cells (T-regs), CD39+ T-regs, and CD39+CD4+ T-cells. Plasma concentrations of adenosine, IL-10, and TGF-β were quantified via an ELISA. An RT-qPCR was used to analyze the gene expression of CD73 and adenosine receptors (A1, A2A, A2B, and A3). T-reg cells were higher in COVID-19 patients compared to healthy controls (7.4 ± 0.79 vs. 2.4 ± 0.28; p < 0.0001). Patients also had a higher frequency of the CD39+ T-reg subset. In addition, patients who suffered from a severe form of the disease had higher CD39+ T-regs compared with moderately infected patients. CD39+CD4+ T cells were increased in patients compared to the control group. An analysis of serum adenosine levels showed a marked decrease in their levels in patients, particularly those suffering from severe illness. However, this was paralleled with a marked decline in the expression levels of CD73. IL-10 and TGF-β levels were higher in COVID-19; in addition, their values were also higher in the severe group. In conclusion, there are distinct immunological alterations in CD39+ lymphocyte subsets and a dysregulation in the adenosine signaling pathway in COVID-19 patients which may contribute to immune dysfunction and disease progression. Understanding these immunological alterations in the different immune cell subsets and adenosine signaling provides valuable insights into the pathogenesis of the disease and may contribute to the development of novel therapeutic approaches targeting specific immune mechanisms.