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1.
Recent Pat Biotechnol ; 15(2): 148-163, 2021 Oct 04.
Article in English | MEDLINE | ID: covidwho-1574984

ABSTRACT

BACKGROUND: Face COVID-19 pandemic, a need for accurate information on SARS-CoV-2 virus is urgent and scientific reports have been published on a daily basis to enable effective technologies to fight the disease progression. However, at the initial occurrence of Pandemic, no information on the matter was known and technologies to fight the Pandemic were not readily available. However, searches in patent databases, if strategically designed, can offer quick responses to new pandemics. OBJECTIVE: The objective of this study is aiming to provide existing information in patent documents useful for the developmentof technologies addressing COVID-19. Considering the emergency situation the world was facing and the knowledge of COVID-19 available until April, 2020, this work presents an analysis of the main characteristics of the technological information in patent documents worldwide, related to coronaviruses and the severe acute respiratory syndrome (SARS). METHODS: Regions of concentration of such technologies, the number of available documents and their technological fields are disclosed in three approaches: 1) a wide search, retrieving technologies on SARS or coronaviruses; 2) a targeted search, retrieving documents additionally referring to Angiotensin converting enzyme (ACE2), which is used by SARS- CoV-2 to enter a cell and 3) a punctual search, which retrieved patents disclosing aspects related to SARS- CoV-2 available at that time. RESULTS: Results show the high-level technology involved in these developments and a monopoly tendency of such technologies, also evidencing that it is possible to find answers to new problems in patent documents. CONCLUSION: This work, then, aims to contribute to scientific and technological development by raising the awareness of what should be considered when searching for technologies developed for other matters that could provide solutions for a new problem.


Subject(s)
COVID-19/epidemiology , Disclosure/statistics & numerical data , Patents as Topic/statistics & numerical data , Angiotensin-Converting Enzyme 2 , Betacoronavirus , Emergencies , Humans , SARS-CoV-2 , Technology
2.
J Crohns Colitis ; 15(4): 687-691, 2021 Apr 06.
Article in English | MEDLINE | ID: covidwho-1387845

ABSTRACT

Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [PIMS-TS] is a newly described condition. It has a spectrum of presentations proposed to occur as part of a post-infectious immune response. We report the first case of PIMS-TS in a child on established anti-tumour necrosis factor alpha [anti-TNFα] therapy; a 10 year-old girl with ulcerative colitis treated with infliximab. The patient had 6 weeks of daily fever with mucocutaneous, gastrointestinal, renal, and haematological involvement. Biomarkers of hyperinflammation were present including: hyperferritinaemia [up to 691 µ/L; normal 15-80 µg/L], C-reactive protein [CRP] [ >100mg/L for  >10 days, normal 0-5 mg/L], erythrocyte sedimentation rate [ESR] consistently  >100mm/h [normal 0-15 mm/h], raised white cell count with neutrophilia, elevated D-dimer and lactate dehydrogenase [LDH], anaemia and Mott cells on bone marrow analysis. Extensive investigations for alternative diagnoses for pyrexia of unknown origin [PUO] were negative. The condition was refractory to treatment with intravenous immunoglobulin [IVIG] but improved within 24 h of high-dose methylprednisolone. Infliximab treatment followed and the patient has remained well at follow-up. Polymerase chain reaction [PCR] and serology for SARS-CoV-2 were negative. Current series report such negative findings in up to half of cases. The patient experienced a milder clinical phenotype without cardiac involvement, shock, or organ failure. Accepting the wide spectrum of PIMS-TS presentations, it is possible that previous anti-TNFα therapy may have attenuated the disease course. Given the uncertainty around therapeutic strategies for PIMS-TS, this case supports the need for further investigation into continuing infliximab as a treatment option for the condition.


Subject(s)
COVID-19/diagnosis , Colitis, Ulcerative/drug therapy , Gastrointestinal Agents/therapeutic use , Infliximab/therapeutic use , Systemic Inflammatory Response Syndrome/diagnosis , COVID-19/complications , COVID-19/therapy , Child , Colitis, Ulcerative/complications , Female , Humans , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/therapy
3.
Front Immunol ; 11: 605688, 2020.
Article in English | MEDLINE | ID: covidwho-1389170

ABSTRACT

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.


Subject(s)
COVID-19 , Gene Frequency , Genetic Predisposition to Disease , HLA-DRB1 Chains , Histocompatibility Antigens Class I , SARS-CoV-2/immunology , Adult , Aged , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Female , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunogenetics , Italy , Male , Middle Aged , Severity of Illness Index
4.
Mol Cell Proteomics ; 20: 100116, 2021 Jun 17.
Article in English | MEDLINE | ID: covidwho-1271716

ABSTRACT

Immunotherapies have emerged to treat diseases by selectively modulating a patient's immune response. Although the roles of T and B cells in adaptive immunity have been well studied, it remains difficult to select targets for immunotherapeutic strategies. Because human leukocyte antigen class II (HLA-II) peptides activate CD4+ T cells and regulate B cell activation, proliferation, and differentiation, these peptide antigens represent a class of potential immunotherapy targets and biomarkers. To better understand the molecular basis of how HLA-II antigen presentation is involved in disease progression and treatment, systematic HLA-II peptidomics combined with multiomic analyses of diverse cell types in healthy and diseased states is required. For this reason, MS-based innovations that facilitate investigations into the interplay between disease pathologies and the presentation of HLA-II peptides to CD4+ T cells will aid in the development of patient-focused immunotherapies.

5.
Front Cell Infect Microbiol ; 11: 667487, 2021.
Article in English | MEDLINE | ID: covidwho-1268236

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has posed a great threat to global public health. There remains an urgent need to address the clinical significance of laboratory finding changes in predicting disease progression in COVID-19 patients. We aimed to analyze the clinical and immunological features of severe and critically severe patients with COVID-19 in comparison with non-severe patients and identify risk factors for disease severity and clinical outcome in COVID-19 patients. Methods: The consecutive records of 211 patients with COVID-19 who were admitted to Zhongnan Hospital of Wuhan University from December 2019 to February 2020 were retrospectively reviewed. Results: Of the 211 patients with COVID-19 recruited, 111 patients were classified as non-severe, 59 as severe, and 41 as critically severe cases. The median age was obviously higher in severe and critically severe cases than in non-severe cases. Severe and critically severe patients showed more underlying comorbidities than non-severe patients. Fever was the predominant presenting symptom in COVID-19 patients, and the duration of fever was longer in critically severe patients. Moreover, patients with increased levels of serum aminotransferases and creatinine (CREA) were at a higher risk for severe and critical COVID-19 presentations. The serum levels of IL-6 in severe and critically severe patients were remarkably higher than in non-severe patients. Lymphopenia was more pronounced in severe and critically severe patients compared with non-severe patients. Lymphocyte subset analysis indicated that severe and critically severe patients had significantly decreased count of lymphocyte subpopulations, such as CD4+ T cells, CD8+ T cells and B cells. A multivariate logistic analysis indicated that older age, male sex, the length of hospital stay, body temperature before admission, comorbidities, higher white blood cell (WBC) counts, lower lymphocyte counts, and increased levels of IL-6 were significantly associated with predicting the progression to severe stage of COVID-19. Conclusion: Older age, male sex, underlying illness, sustained fever status, abnormal liver and renal functions, excessive expression of IL-6, lymphopenia, and selective loss of peripheral lymphocyte subsets were related to disease deterioration and clinical outcome in COVID-19 patients. This study would provide clinicians with valuable information for risk evaluation and effective interventions for COVID-19.


Subject(s)
COVID-19 , Aged , China/epidemiology , Humans , Male , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
6.
Front Cell Infect Microbiol ; 11: 654813, 2021.
Article in English | MEDLINE | ID: covidwho-1268235

ABSTRACT

COVID-19 is a zoonotic disease with devastating economic and public health impacts globally. Being a novel disease, current research is focused on a clearer understanding of the mechanisms involved in its pathogenesis and viable therapeutic strategies. Oxidative stress and inflammation are intertwined processes that play roles in disease progression and response to therapy via interference with multiple signaling pathways. The redox status of a host cell is an important factor in viral entry due to the unique conditions required for the conformational changes that ensure the binding and entry of a virus into the host cell. Upon entry into the airways, viral replication occurs and the innate immune system responds by activating macrophage and dendritic cells which contribute to inflammation. This review examines available literature and proposes mechanisms by which oxidative stress and inflammation could contribute to COVID-19 pathogenesis. Further, certain antioxidants currently undergoing some form of trial in COVID-19 patients and the corresponding required research gaps are highlighted to show how targeting oxidative stress and inflammation could ameliorate COVID-19 severity.


Subject(s)
Antioxidants , COVID-19 , Antioxidants/therapeutic use , Humans , Oxidative Stress , SARS-CoV-2 , Virus Internalization
7.
Pulm Pharmacol Ther ; 69: 102007, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267894

ABSTRACT

BACKGROUND: In the current coronavirus health crisis, inhaled bronchodilators(IB) have been suggested as a possible treatment for patients hospitalized. Patients with evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of therapy for the disease, an indication for which this medications could be ineffective taken on account the pathophysiology and mechanisms of disease progression. OBJECTIVE: The main objective was to evaluate whether there is an association between IB use and length of stay. Primary end points were the number of days that a patient stayed in the hospital and death as a final event in a time to event analysis. Pneumonia severity, oxygen requirement, involved drugs, comorbidity, historical or current respiratory diagnoses and other drugs prescribed to treat coronavirus pneumonia were also evaluated. METHODS: A descriptive, observational, cross-sectional study was performed in this tertiary hospital in Madrid (Spain). Data were obtained regarding patients hospitalized with Covid-19, excluding those who were intubated. The primary and secondary outcomes such as duration of hospitalization and death were compared in patients who received IB with those in patients who did not. RESULTS: 327 patients were evaluated, mean age was 64.4 ± 15.8 years. Median length of hospitalization stay was 10 days. Of them 292 (89.3%) overcame the disease, the remaining 35 died. Patients who had received IB did not have less mortality rate (odds ratio 0.839; 95% CI: 0.401 to 1.752) and less hospitalization period when compared with patients who did not received IB (odds ratio 1.280; 95% CI: 0.813 to 2.027). There was no significant association between IB use and recovery or death. Hypertension and diabetes were the most common comorbidities. The prevalence of chronic respiratory disease in our cohort was low (21.1%). Anticholinergics were the IB more frequently prescribed for Covid-19 pneumonia. Better response in patients treated with inhaled corticosteroids was not observed. CONCLUSION: Off-label indication of inhaled-bronchodilators for Covid-19 patients are common in admitted patients. Taken on account our results, the use of IB for coronavirus pneumonia apparently is not associated with a significantly patient's improvement. Our study confirms the hypothesis that inhaled bronchodilators do not improve clinical outcomes or reduce the risk of Covid-19 mortality. This could be due to the fact that the virus mainly affects the lung parenchyma and the pulmonary vasculature and probably not the airway. More researches are necessary in order to fill the gap in evidence for this new indication.


Subject(s)
Bronchodilator Agents , COVID-19 , Adult , Cohort Studies , Cross-Sectional Studies , Hospitalization , Humans , Inpatients , Middle Aged , Retrospective Studies , SARS-CoV-2 , Spain/epidemiology
8.
Neurobiol Dis ; 156: 105422, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267874

ABSTRACT

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.


Subject(s)
Cerebellum/drug effects , Cerebral Cortex/drug effects , Glucocorticoids , Lung/drug effects , Pregnenediones/pharmacology , Prodrugs/pharmacology , Signal Transduction/drug effects , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/growth & development , COVID-19/drug therapy , Dexamethasone/pharmacology , Female , Mice , Mice, Inbred C57BL , Myelin Basic Protein/biosynthesis , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/drug effects
9.
Emerg Microbes Infect ; 10(1): 1320-1330, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1266083

ABSTRACT

Ebola virus (EBOV) is a negative single-stranded RNA virus within the Filoviridae family and the causative agent of Ebola virus disease (EVD). Nonhuman primates (NHPs), including cynomolgus and rhesus macaques, are considered the gold standard animal model to interrogate mechanisms of EBOV pathogenesis. However, despite significant genetic similarity (>90%), NHP species display different clinical presentation following EBOV infection, notably a ∼1-2 days delay in disease progression. Consequently, evaluation of therapeutics is generally conducted in rhesus macaques, whereas cynomolgus macaques are utilized to determine efficacy of preventative treatments, notably vaccines. This observation is in line with reported differences in disease severity and host responses between these two NHP following infection with simian varicella virus, influenza A and SARS-CoV-2. However, the molecular underpinnings of these differential outcomes following viral infections remain poorly defined. In this study, we compared published transcriptional profiles obtained from cynomolgus and rhesus macaques infected with the EBOV-Makona Guinea C07 using bivariate and regression analyses to elucidate differences in host responses. We report the presence of a shared core of differentially expressed genes (DEGs) reflecting EVD pathology, including aberrant inflammation, lymphopenia, and coagulopathy. However, the magnitudes of change differed between the two macaque species. These findings suggest that the differential clinical presentation of EVD in these two species is mediated by altered transcriptional responses.


Subject(s)
Gene Expression Regulation/immunology , Hemorrhagic Fever, Ebola/veterinary , Macaca fascicularis , Macaca mulatta , Monkey Diseases/immunology , Transcription, Genetic/immunology , Animals , COVID-19 , Ebolavirus , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/immunology , Hemorrhagic Fever, Ebola/mortality , Humans , Immunity , Monkey Diseases/genetics , Monkey Diseases/mortality , RNA, Viral/metabolism , SARS-CoV-2 , Species Specificity
10.
Drug Dev Res ; 82(7): 873-879, 2021 11.
Article in English | MEDLINE | ID: covidwho-1263077

ABSTRACT

COVID-19 manifests as a mild disease in most people but can progress to severe disease in nearly 20% of individuals. Disease progression is likely driven by a cytokine storm, either directly stimulated by SARS-CoV-2 or by increased systemic inflammation in which the gut might play an integral role. SARS-CoV-2 replication in the gut may cause increased intestinal permeability, alterations to the fecal microbiome, and increased inflammatory cytokines. Each effect may lead to increased systemic inflammation and the transport of cytokines and inflammatory antigens from the gut to the lung. Few interventions are being studied to treat people with mild disease and prevent the cytokine storm. Serumderived bovine immunoglobulin/protein isolate (SBI) may prevent progression by (1) binding and neutralizing inflammatory antigens, (2) decreasing gut permeability, (3) interfering with ACE2 binding by viral proteins, and (4) improving the fecal microbiome. SBI is therefore a promising intervention to prevent disease progression in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Immunization, Passive/methods , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , Cattle , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Humans , Permeability
11.
EClinicalMedicine ; 36: 100926, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1261877

ABSTRACT

Background: Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most life-threatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. Methods: A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intention-to-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). Findings: Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54±13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087-1.272), arm II (RR, 0.5; 95% CI, 0.171-1.463), arm III (RR, 0.167; 95% CI, 0.024-1.145), and arm IV (RR, 0.667; 95% CI, 0.268-1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127-400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. Interpretation: Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. Funding: Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).

12.
Front Genet ; 12: 636441, 2021.
Article in English | MEDLINE | ID: covidwho-1259343

ABSTRACT

With the availability of COVID-19-related clinical data, healthcare researchers can now explore the potential of computational technologies such as artificial intelligence (AI) and machine learning (ML) to discover biomarkers for accurate detection, early diagnosis, and prognosis for the management of COVID-19. However, the identification of biomarkers associated with survival and deaths remains a major challenge for early prognosis. In the present study, we have evaluated and developed AI-based prediction algorithms for predicting a COVID-19 patient's survival or death based on a publicly available dataset consisting of clinical parameters and protein profile data of hospital-admitted COVID-19 patients. The best classification model based on clinical parameters achieved a maximum accuracy of 89.47% for predicting survival or death of COVID-19 patients, with a sensitivity and specificity of 85.71 and 92.45%, respectively. The classification model based on normalized protein expression values of 45 proteins achieved a maximum accuracy of 89.01% for predicting the survival or death, with a sensitivity and specificity of 92.68 and 86%, respectively. Interestingly, we identified 9 clinical and 45 protein-based putative biomarkers associated with the survival/death of COVID-19 patients. Based on our findings, few clinical features and proteins correlate significantly with the literature and reaffirm their role in the COVID-19 disease progression at the molecular level. The machine learning-based models developed in the present study have the potential to predict the survival chances of COVID-19 positive patients in the early stages of the disease or at the time of hospitalization. However, this has to be verified on a larger cohort of patients before it can be put to actual clinical practice. We have also developed a webserver CovidPrognosis, where clinical information can be uploaded to predict the survival chances of a COVID-19 patient. The webserver is available at http://14.139.62.220/covidprognosis/.

13.
World J Virol ; 10(3): 86-96, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1256931

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), enters affected cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in type II alveolar cells, enterocytes, and cholangiocytes. SARS-CoV-2 infection causes fever, dry cough, and breathing difficulty, which can progress to respiratory distress due to interstitial pneumonia, and hepatobiliary injury due to COVID-19 is increasingly recognized. The hepatobiliary injury may be evident at presentation of the disease or develop during the disease progression. The development of more severe clinical outcomes in patients with chronic liver diseases (CLD) with or without cirrhosis infected with SARS-CoV-2 has not been elucidated. Moreover, there is limited data related to common medications that affect the disease severity of COVID-19 patients. Additionally, ACE2 receptor expression of hepatobiliary tissue related to the disease severity also have not been clarified. This review summarized the current situation regarding the clinical outcomes of COVID-19 patients with chronic liver diseases who were treated with common medications. Furthermore, the association between ACE2 receptor expression and disease severity in these patients is discussed.

14.
Nutrients ; 13(6)2021 May 31.
Article in English | MEDLINE | ID: covidwho-1256620

ABSTRACT

The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R = 0.42, p < 0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/-SEM], Cu; 1475.9+/-22.7 vs. 1317.9+/-43.9 µg/L; p < 0.001, CP; 547.2.5 +/- 19.5 vs. 438.8+/-32.9 mg/L, p = 0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R = 0.23, p = 0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.


Subject(s)
COVID-19/blood , COVID-19/mortality , Copper/blood , SARS-CoV-2/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Cross-Sectional Studies , Disease-Free Survival , Female , Humans , Longitudinal Studies , Male , Middle Aged , Selenium/blood , Selenoprotein P/blood , Survival Rate
15.
Biomed Pharmacother ; 140: 111785, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1252500

ABSTRACT

Coronavirus disease 2019 (COVID-19) has caused significant devastation globally. Despite the development of several vaccines, with uncertainty around global uptake and vaccine efficacy, the need for effective therapeutic agents remains. Increased levels of cytokines including tumour necrosis factor are significant in the pathogenesis of COVID-19 and associated with poor outcomes including ventilator requirement and mortality. Repurposing tumour necrosis factor blocker therapy used in conditions such as rheumatoid arthritis and inflammatory bowel disease seems promising, with early feasibility data showing a reduction in circulation of pro-inflammatory cytokines and encouraging the evaluation of such interventions in preventing disease progression and clinical deterioration in patients with COVID-19. Here, we examine the biological activities of tumour necrosis factor inhibitors indicative of their potential in COVID-19 and briefly outline the randomised control trials assessing their benefit-risk profile in COVID-19 therapy.


Subject(s)
COVID-19/drug therapy , Inflammation/drug therapy , SARS-CoV-2/drug effects , Tumor Necrosis Factor Inhibitors/pharmacology , Animals , COVID-19/metabolism , Cytokines/metabolism , Humans , Inflammation/metabolism
16.
Front Immunol ; 12: 684142, 2021.
Article in English | MEDLINE | ID: covidwho-1247870

ABSTRACT

Background: Lung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course. Methods: 65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20). Results: The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 - 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 - 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 - 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 - 6.0, p <0.05). Conclusion: Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.


Subject(s)
Autoantibodies/blood , COVID-19/immunology , Receptor, Angiotensin, Type 1/immunology , Receptor, Endothelin A/immunology , Adult , Aged , Aged, 80 and over , COVID-19/blood , Female , Humans , Intensive Care Units , Male , Middle Aged , Netherlands , Receptor, Angiotensin, Type 1/blood , Receptor, Endothelin A/blood , Retrospective Studies , Risk Assessment , Severity of Illness Index
17.
Ann Med ; 53(1): 777-785, 2021 12.
Article in English | MEDLINE | ID: covidwho-1246573

ABSTRACT

The coronavirus SARS-CoV-2, the aetiological agent of COVID-19 disease, is representing a worldwide threat for the medical community and the society at large so that it is being defined as "the twenty-first-century disease". Often associated with a severe cytokine storm, leading to more severe cases, it is mandatory to block such occurrence early in the disease course, to prevent the patients from having more severe, sometimes fatal, outcomes. In this framework, early detection of "danger signals", possibly represented by alarmins, can represent one of the most promising strategies to effectively tailor the disease and to better understand the underlying mechanisms eventually leading to death or severe consequences. In light of such considerations, the present article aims at evaluating the role of alarmins in patients affected by COVID-19 disease and the relationship of such compounds with the most commonly reported comorbidities. The conducted researches demonstrated yet poor literature on this specific topic, however preliminarily confirming a role for danger signals in the amplification of the inflammatory reaction associated with SARS-CoV-2 infection. As such, a number of chronic conditions, including metabolic syndrome, gastrointestinal and respiratory diseases, in turn, associated with higher levels of alarmins, both foster the infection and predispose to a worse prognosis. According to these preliminary data, prompt detection of high levels of alarmins in patients with COVID-19 and co-morbidities could suggest an immediate intense anti-inflammatory treatment.Key messageAlarmins have a role in the amplification of the inflammatory reaction associated with SARS-CoV-2 infectiona prompt detection of high levels of alarmins in patients with COVID-19 could suggest an immediate intense anti-inflammatory treatment.


Subject(s)
Alarmins/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Animals , COVID-19/virology , Comorbidity , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Humans , Inflammation/immunology , Inflammation/virology , Prognosis , Severity of Illness Index
18.
Muscle Nerve ; 64(2): 215-219, 2021 08.
Article in English | MEDLINE | ID: covidwho-1245512

ABSTRACT

INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Cortical Excitability/drug effects , Motor Neurons/drug effects , Pyridones/administration & dosage , Receptors, AMPA/antagonists & inhibitors , Aged , Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/diagnosis , Cortical Excitability/physiology , Double-Blind Method , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Female , Humans , Male , Middle Aged , Motor Neurons/physiology , Nitriles , Pilot Projects , Pyridones/blood , Receptors, AMPA/physiology , Transcranial Magnetic Stimulation/methods
19.
Trials ; 22(1): 343, 2021 May 17.
Article in English | MEDLINE | ID: covidwho-1232435

ABSTRACT

OBJECTIVES: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression. TRIAL DESIGN: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested. PARTICIPANTS: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m2 Age > 65 years with at least one other risk factor (BMI > 35 kg/m2, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m2 with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety. MAIN OUTCOMES: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization. RANDOMIZATION: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center. BLINDING (MASKING): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate. TRIAL STATUS: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021. TRIAL REGISTRATION: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020). FULL PROTOCOL: The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
COVID-19 , Pharmaceutical Preparations , Pregnancy Complications, Infectious , Adolescent , Adult , Aged , Blood Component Transfusion , COVID-19/therapy , Child , Esters , Female , Germany , Guanidines , Humans , Immunization, Passive , Mesylates , Multicenter Studies as Topic , Plasma , Polymerase Chain Reaction , Pregnancy , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
20.
Cureus ; 13(4): e14574, 2021 Apr 20.
Article in English | MEDLINE | ID: covidwho-1229459

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), causing coronavirus disease-19 (COVID-19), has been responsible for approximately 75 million cases and 1.6 million deaths globally as of December 22, 2020. Currently, no treatment modalities or management options have been recommended by the National Institutes of Health (NIH) prior to patient hospitalization and supplemental oxygen requirement. This poses a unique challenge for outpatient primary care physicians, who are often tasked with initial care of patients early on in their disease course. During the pandemic, our family practice provided medical care to approximately 2,000 families located in the surrounding Brooklyn community. With only telemedicine at our disposal, our clinic was tasked with treating patients presenting remotely who may or may not have had COVID-19 - a large clinical diagnosis was made given the absence of in-person testing. Often co-administered, Azithromycin was considered a supportive agent that may or may not have increased the benefit of hydroxychloroquine. However, Azithromycin may perform well on its own for various reasons as it has been shown to have antiviral activity against other RNA viruses, anti-inflammatory properties, and antiviral effects within bronchial epithelial cells. Azithromycin has also shown efficacy as an add-on treatment for reducing asthma exacerbations - pertinent to the pro-inflammatory pulmonary conditions in COVID-19 progression - and may even prevent or treat bacterial co-infection in patients with SARS-COV-2. In order to investigate the association between Azithromycin and the COVID-19 disease process, our clinical study retrospectively identified patients who were prescribed Azithromycin (500 mg on day one + 250 mg on days two to five) during the peak months of the COVID-19 pandemic in New York City from March 2020 through May 2020. All patients prescribed Azithromycin with suspicion of COVID-19 infection were interviewed via telephone regarding their constellation of symptoms, compliance with the prescribed antibiotic for the intended course, symptom duration prior to and following antibiotic course initiation, as well as any further complications of their illness, if present. Ultimately, the majority of the patients who were interviewed over the phone concluded that a full course of Azithromycin helped improve their symptoms during their infection with COVID-19. Outcomes and complications in patients treated with Azithromycin were noteworthy in that there were no reports of pulmonary complications or deterioration of pulmonary function after treatment (e.g., no shortness of breath, wheezing, dyspnea, etc.), although some patients did experience residual coughing and nasal discharge post-treatment. We believe further study of this treatment in the setting of experimental, randomized controlled trials may reveal the benefits of Azithromycin in terms of reducing infection severity, length, and limiting the incidence of complications in patients with COVID-19.

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