Given the emergence of SARS-CoV-2 virus as a life-threatening pandemic, identification of immunodominant epitopes of the viral structural proteins, particularly the nucleocapsid (NP) protein and receptor binding domain (RBD) of spike protein, is important to determine targets for immunotherapy and diagnosis. In this study, epitope screening was performed using a panel of overlapping peptides spanning the entire sequences of the RBD and NP proteins of SARS-CoV-2 in the sera from 66 COVID-19 patients and 23 healthy subjects by enzyme-linked immunosorbent assay (ELISA). Also, three non-overlapping peptides belonging to the S2 domain of spike protein were assessed. Our results showed that while reactivity of patients’ sera with reduced recombinant RBD protein was significantly lower than the native form of RBD (p<0.001), no significant differences were observed for reactivity of patients’ sera with reduced and non-reduced NP protein. Pepscan analysis revealed weak to moderate reactivity towards different RBD peptide pools, which was more focused on peptides encompassing aa 181-223 of RBD. NP peptides, however, displayed strong reactivity with a single peptide covering aa 151-170. These findings were confirmed by peptide depletion experiments using both ELISA and Western blotting. Altogether, our data suggest the involvement of mostly conformational disulfide bond-dependent immunodominant epitopes in RBD-specific antibody response, while the IgG response to NP is dominated by linear epitopes. Identification of antigenic epitope in NP and RBD of SARS-CoV-2 could provide important advances for the development of passive and active immunotherapy as well as diagnostic tools for the control of COVID-19 infection.

We evaluated the increase in the risk of developing acute kidney and hepatic injury. Moreover, we investigate the association between kidney and liver biomarkers with poor prognosis and mortality rate. Methods: This was a prospective cohort study of 397 adult patients with an average age of 48.03 ± 14.09 were diagnosed with COVID-19 of whom, 46 (11.59%) died in hospital. The upper values of the kidney and liver biomarkers were obtained from the recovered patients during the disease period and are compared to the data for dead patients at admission (Baseline) and one day before death. Results: At admission to the hospital, the baseline S.Cr, BUN, and eGFR were not significantly varied between recovered and dead patients. Furthermore, the baseline values for AST, ALT, and ALP were not significantly differed between both groups. Whereas, baseline value of total serum bilirubin was higher in died compared to the recovered patients. For dead patients, the day before death, 52.17% of the patients had progressed to stage III and stage IV AKI. S.Cr and BUN were significantly higher, and eGFR was lower compared to the recovered patients. All of the kidney and liver function tests were abnormally increased from baseline to the day before death. The AST, ALT, and total bilirubin one day before death were significantly higher compared to their baseline value. Conclusions: COVID-19 patients have a high risk for the development of AKI and liver injury that can be progressed to a chronic stage and increase the mortality rate.

COVID-19 has caused devastation globally mostly affecting countries in colder climates. Therefore, vitamin D is thought to be one of the contributing factors towards causation and severity. Many guidelines do not recommend vitamin D for treatment or prevention. Hence, we set out to do a global survey to understand the use and prescribing habits of vitamin D amongst clinicians. Methods: Online anonymous questionnaire was sent to clinicians enquiring in their prescribing habits of vitamin D and personal use of vitamin D. Results: 4,440 practicing clinicians were included in the analysis with majority of those that responded were from Asia followed by Europe. 82.9% prescribed vitamin D before COVID-19, more commonly amongst general practitioners (GPs) and Asian clinicians more likely to prescribe vitamin D (p<0.005). GPs were also more likely to prescribe vitamin D prophylactically to prevent COVID-19 (OR 1.47, p<0.005). Majority would also prescribe vitamin D to treat COVID-19 (72.5%; OR:1.81, p<0.005), as well as Asian clinicians (OR 4.57, p<0.005). 80.4% of respondents were taking vitamin D, more so in the 45-54 and 65-74 age groups (OR2.15 and 2.40, respectively), many of whom did so before COVID-19 (72.1%). Conclusion: Clinicians from different countries have acknowledged the role of vitamin D during the COVID-19 pandemic. This survey has shown that many clinicians would prescribe vitamin D for the prevention and treatment of COVID-19. Majority also would recommend measuring vitamin D levels but not so in patients with COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic started over one year ago and produced almost 3.5 million deaths worldwide. We have been recently overwhelmed by a wide literature on how the immune system recognizes Severe Acute Respiratory Syndrome Coronavirus 2 and contributes to COVID-19 pathogenesis. Although originally considered a respiratory viral disease, COVID-19 is recognized as a far more complex, multi-organ-, immuno-mediated-, and mostly heterogeneous disorder. Though efficient innate and adaptive immunity may control infection, when the patient fails to mount an adequate immune response, a high innate-induced inflammation can lead to different clinical outcomes through heterogeneous compensatory mechanisms. The variability of viral load and persistence, the genetic alterations of virus-driven receptors/signaling pathways and the plasticity of innate and adaptive responses may all account for the extreme heterogeneity of pathogenesis and clinical patterns. As recently done for some inflammatory disorders as asthma, rhinosinusitis with polyposis and atopic dermatitis, herein we suggest to define different endo-types and the related phenotypes along COVID-19. Patients should be stratified for evolving symptoms and tightly monitored for surrogate biomarkers of innate and adaptive immunity. This would allow to preventively identify each endo-type (and its related phenotype) and to treat patients precisely with agents targeting pathogenic mechanisms.

A document by Isabella Annesi, written on Authorea.

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has milder presentation in children than adults, mostly requiring only supportive therapy. The immunopathogenic course of COVID-19 can be divided in two distinct but overlapping phases: the first triggered by the virus itself and the second one by the host immune response. Cytokine storm induces Acute Respiratory Distress Syndrome (ARDS) in 20-30% of adults while less than 1% of children develops severe pulmonary or systemic involvement as Multisystem Inflammatory Syndrome in Children (MIS-C), requiring intensive care. Less severe lung injury in children could be explained by qualitative and quantitative differences in age-related immune response. Evidence on the best therapeutic approach for COVID-19 lung disease in children is lacking. Currently, the approach is mainly conservative and based on supportive therapy. However, in hospitalized children with critical illness and worsening lung function, antiviral therapy with remdesivir and immunomodulant treatment with systemic steroids could be considered the “therapeutic pillars”. In addition, optimal disease control of allergic and asthmatic children and, in the near future, vaccinations are expected to be important as preventive strategies to reduce the COVID-19 burden.

ABSTRACT Young and middle-aged adults are the largest group of patients infected with SARS-CoV-2 and some of them develop severe disease. Objective: To investigate clinical manifestations in adults aged 18-65 years hospitalized for COVID-19 and identify predictors of poor outcome. Secondary objectives: to explore potential differences compared to the disease in elderly patients and the suitability of the commonly used community-acquired pneumonia prognostic scales in younger populations. Methods: Multicenter prospective registry of consecutive patients hospitalized for COVID-19 pneumonia aged 18-65 years between March and May 2020. We considered a composite outcome of “poor outcome” including intensive care unit admission and/or use of noninvasive ventilation, continuous positive airway pressure or high flow nasal cannula oxygen therapies and/or death. Results: We identified 513 patients <65 years of age, from a cohort of 993 patients. 102 had poor outcomes (19.8%) and 3.9% died. 78% and 55% of patients with poor outcomes were classified as low risk based on CURB and PSI scores respectively. A multivariate Cox regression model identified six independent factors associated with poor outcome: heart disease, chest pain, anosmia, low oxygen saturation, high LDH and lymphocyte count <800/mL. Conclusions: COVID-19 in younger patients carries significant morbidity and differs in some respects from this disease the elderly. Baseline heart disease is a relevant risk factor, while anosmia and pleuritic pain are more common and protective. Hypoxemia, LDH and lymphocyte count are predictors of poor outcome. We consider that CURB and PSI scores are not suitable criteria for deciding admission in this population.

Infections and pandemics will condition us in an increasingly predominant way regarding diagnostic, medical and surgical activities in all specialist areas; and this particularly in cardiovascular one. Nevertheless in the future the need to cohabit with pandemic events and to be able to continue an elective and not only emergency cardiac surgery program represents an imperative.

Allergic diseases include asthma, atopic-dermatitis, allergic-rhinitis, drug hypersensitivity and food-allergy. During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical-burden. A large fraction of allergic diseases is characterized by a type-2 immune response involving Th2 cells, type-2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network-based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point-of-care systems. Ideally, samples should be collected using quick, cost-efficient and non-invasive methods. In recent years, a plethora of research has been directed towards finding novel biomarkers of allergic diseases. Promising biomarkers of type-2 allergic diseases include sputum eosinophils, serum periostin and exhaled nitric-oxide. Several other biomarkers, such as pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, and microbiota changes are useful for diagnosis and monitoring of allergic diseases and can be quantified in serum, body-fluids and exhaled-air. Herein, we review recent studies on biomarkers for the diagnosis and treatment of asthma, chronic-urticaria, atopic-dermatitis, allergic-rhinitis, chronic-rhinosinusitis, food-allergies, anaphylaxis, drug hypersensitivity and allergen-immunotherapy. In addition, we discuss COVID-19 and allergic diseases within the perspective of biomarkers and recommendations on the management of allergic and asthmatic patients during the COVID-19 pandemic.

Objectives: To determine which risk factors contribute to worse COVID-19 outcome in children. Methods: Data sources: The review was conducted in Medline, CINAHL, Pubmed, Scopus, Web of Science, and LILACS. Study selection and data extraction: Articles published in the last year, written in Portuguese, English, and Spanish were included. Duplicates, editorials, letters to the editor, theses, dissertations, review articles, reports, case studies, and studies not addressing the theme were excluded. Controlled terms in Portuguese and English indexed in (DeCS) and (MeSH), and the Boolean operators “AND” and “OR” were used. Synthesis: The risk of bias was calculated using the R software, analysed by the GRADE system and using a funnel plot. All effects were analysed and calculated at a 95% confidence interval. The evidence level was analysed using Stillwell and collaborators’ proposal. Results: A total of 1,628 articles were found. All articles were written in English, one was published in 2019, and 10 in 2020. Six studies were descriptive, two were multicentric cohort studies, two were retrospective cohort studies, one was observational-retrospective, and most were evidence level VI. In essence, all studies pointed out that children with underlying diseases tend to develop more severe COVID-19 illnesses and more hospitalization than children without these diseases. Conclusion: The knowledge of the risk factors related to worse COVID-19 outcomes by professionals allow a better assessment of patients and make them able to act with greater precision in the promotion, prevention, and rehabilitation of these children.

Objectives The aim of the present study is to develop and validate the COVID-Q, a novel symptom questionnaire specific for COVID-19 patients, to provide a comprehensive and standard clinical evaluation. A secondary goal of the present study was to evaluate the performance of the COVID-Q in identifying subjects at higher risk of being tested positive for COVID-19. Material and methods 460 subjects (230 COVID-19 cases and 230 healthy controls), answered the COVID-Q. Parallel Analysis and Principal Component Analysis were used to identify clusters of items measuring the same dimension. The IRT-based analyses evaluated the functioning of item categories, the presence of clusters of local dependence among items, item fit within the model and model fit to the data. Results Parallel analysis suggested the extraction of six components, which corresponded to as many clinical presentation patterns: asthenia, influenza-like symptoms, ear and nose symptoms, breathing issues, throat symptoms, and anosmia/ageusia. The final IRT models retained 27 items as significant for symptom assessment. The total score on the questionnaire was significantly associated with positivity to the molecular SARS-CoV-2 test. Subjects with multiple symptoms were significantly more likely to be affected by COVID-19 (p < .001). Older age and male gender also represented risk factors. None of the examined comorbidities had a significant association with COVID-19 diagnosis. Conclusion The application of the novel COVID-Q to everyday clinical practice may help identifying subjects who are likely to be affected by COVID-19 and address them to a nasopharyngeal swab in order to achieve an early diagnosis.

Aims: Staying at home for a prolonged period and the stress experienced due to the COVID-19 quarantine may affect sleep quality and night eating behaviours of individuals. This study aimed to identify the relationship between night eating behaviour, sleep quality, and perceptions of health locus of control in women during the pandemic. Methods: A questionnaire form evaluating demographic information, nutritional habits, health information and anthropometric measurements was conducted along with the Night Eating Syndrome (NES) Scale, Pittsburgh Sleep Quality Index (PUKI), and Multidimensional Health Locus of Control (A) form. Results: With a mean age of 33.0 ± 8.0 years 529 women participated in the study. The mean night eating scale score was 14.44 ± 4.72 and the mean PUKI score was 6.44 ± 2.90. Higher night eating scores were observed in participants with a chance locus of control perception when compared to participants with internal health locus of control perception (p <.05). Obese participants have lower sleep quality compared to normal and overweight participants (p <.05). It was also found that night eating behaviours significantly predicted sleep quality (R = .364, R2 =.133; p <.01) and explained about 13.3 % of the total variance of sleep quality. Conclusion: In this study conducted during the quarantine period, we showed that night eating behaviours significantly predict sleep quality, and individuals with a high perception of chance locus of control had a higher night eating scores than individuals with high perception of internal health locus of control.

The present work analyses in detail the published data on ChAdOx1 nCoV-19 vaccine and provides arguments for the involvement of anti-vector immunity and of SARS-CoV-2 variants on the efficacy of ChAdOx1 nCoV-19 vaccine. First, it is suggested that anti-vector immunity takes place as the regimen of homologous vaccination with ChAdOx1 nCoV-19 vaccine is applied and interferes with efficacy of the vaccine when the interval between prime and boost doses is less than three months. Second, longitudinal studies suggest that ChAdOx1 nCoV-19 vaccine provides sub-optimal efficacy against UK variant of SARS-CoV-2, which appears to have an increased transmissibility over the ancestral SARS-CoV-2 among vaccinated people. At the moment, ChAdOx1 nCoV-19 vaccine is able to reduce the severity of symptoms and transmissibility; however, if the vaccinated individuals do not maintain everyday preventive actions, they could turn into potential spreaders, thus accelerating the process of generation of new viral variants due to the selective pressure of immune response. Prediction and possible consequences of the SARS-CoV-2 evolution and repeated anti-SARS-CoV-2 vaccinations are discussed. Since the impact of emerging SARS-CoV-2 variants suggests that vaccines are unlikely to be effective in quickly solving the pandemic crisis, it is highlighted the need to keep searching for new and more efficacious pharmacotherapy for COVID-19, such as those targeting ACE2 and ADAM17 zinc-metalloprotease activities.

Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity against SARS-CoV-2, has been rampant and unprecedented, leading to conditional emergency authorization of various vaccines. Despite progress on early multidrug therapy for COVID-19 patients, the current mandate is to immunize the world population as quickly as possible. The lack of thorough testing in animals prior to clinical trials, and authorization based on safety data generated during trials that lasted less than 3.5 months, raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate of occurrence of adverse effects that have been reported to date, as well as the potential for vaccine-driven disease enhancement, Th2-immunopathology, autoimmunity, and immune evasion, there is a need for a better understanding of the benefits and risks of mass vaccination, particularly in groups excluded from clinical trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been minimized or ignored by health organizations and government authorities. As for any investigational biomedical program, data safety monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not exist, then vaccination should be halted immediately, in particular for demographic groups at highest risk of vaccine-associated death or serious adverse effects, during such time as it takes to assemble these boards and commence critical and independent assessments. We urge for pluralistic dialogue in the context of health policies, emphasizing critical questions that require urgent answers, particularly if we wish to avoid a global erosion of public confidence in science and public health. 

This article assesses the role of recipient genetics to COVID-19 vaccine responses. Vaccines represent preventative interventions suitable to an immunogenetic perspective to predict how human variability will influence their safety and efficacy. The genetic polymorphism among individuals within any population can make possible that the immunity elicited by a vaccine is variable in length and strength. The same immune challenge (either virus or vaccine) could provoke partial, complete or even failed protection for some individuals treated under the same conditions. We review genetic variants and mechanistic relationships among chemokines, chemokine receptors, interleukins, interferons, interferon receptors, toll-like receptors, histocompatibility antigens, various immunoglobulins and major histocompatibility complex antigens. These are the targets for variation among macrophages, dendritic cells, Natural Killer cells, T- and B- lymphocytes, and complement. The acute nature of vaccine reactogenicity is reminiscent of the time course of adverse drug reaction mediated by the immune system. The variety of technology platforms (mRNA, viral vectors) utilized currently to produce vaccines against SARS-CoV-2 infections may each also trigger genetically distinct immune reactogenic profiles. With biobanking of recipient genomic DNA and serum immunoprofiling, global COVID-19 vaccinations could launch a new era of research and clinical translation in personalized health.

Objectives Possibility of reinfection with SARS-CoV-2 changes our view on herd immunity and vaccination, and can impact worldwide quarantine policies. We performed RT-PCR follow-up studies on recovered patients to assess possible development of reinfections and re-positivity. Method During a 6-month period, 202 PCR-confirmed recovering COVID-19 patients entered this study. Follow-up RT-PCR tests and symptoms assessment were performed one month after the initial Positive results. patients who tested negative were tested again one and three months later. The Serum IgG and IgM levels were measured in the last follow-up session. Results In the first two follow-up sessions, 82 patients continued their participation, of which four patients tasted positive. In the second follow-up 44 patients participated, three of whom tested positive. None of the patients who tested positive in the first and second follow-up session were symptomatic. In the last session, 32 patients were tested and four patients were positive, three of them were mildly symptomatic and all of them were positive for IgG. Conclusion A positive RT-PCR in a recovering patient may represent reinfection. While we did not have the resources to prove reinfection by genetic sequencing of the infective viruses, we believe presence of mild symptoms in the three patients who tested positive over 100 days after becoming asymptomatic, can be diagnosed as reinfection. The IgG may have abated the symptoms of the reinfection, without providing complete protection.

Since the start of the SARS-CoV-2 pandemic, it has been difficult to differentiate between SARS-CoV-2 re-infection and prolonged RNA shedding. In this report, we identified patients with positive rtPCR results for SARS-CoV-2 ≥70 days apart. Clinical and laboratory data were collected and criteria were applied to discern whether the presentation was consistent with SARS-CoV-2 re-infection or prolonged viral RNA shedding. Eleven individuals met the initial testing criteria, of which, seven met at least one criteria for re-infection and four were consistent with prolonged RNA shedding. These data demonstrate the need for criteria to differentiate SARS-CoV-2 re-infection from prolonged RNA shedding.

A 62-year-old man with rare blood type exhibited severe respiratory failure due to novel coronavirus. Extracorporeal membrane oxygenation was inapplicable, which requires numerous blood products with the same blood type. We thoroughly restricted fluid volumes by sacrificing renal function. He was discharged with complete recovery of respiratory and renal functions.

A document by Mina Kelleni, written on Authorea.

A document by Mina Kelleni, written on Authorea.

A document by Mina Kelleni, written on Authorea.

Aspirin has been recently suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19. However, we claim that the molecular interpretation of these important results was not scientifically valid, and we provide our academic interpretation that is also basing on our real-life practice using non-steroidal anti-inflammatory drugs in management of COVID-19 and we suggest that inhibition of COX-1 and/or COX-2 enzymes might play a lifesaving role in COVID-19 management, and we further discuss the potential of aspirin triggered lipoxins and resolivns in the same context.

A peer reviewed published version at Expert Review of Anti-Infective Therapy : https://doi.org/10.1080/14787210.2021.1939683IntroductionMediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Moreover, a weak, irregular, or inhibited early interferon response to SARS CoV-2 infection was shown to trigger an exaggerated inflammatory response leading to the COVID-19 associated mortality. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach.Areas coveredWe present a concise analysis and interpretations of selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the recent results that suggested a potential survival benefit of low dose aspirin and colchicine when used for COVID-19.Expert opinionNitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that were unfortunately almost globally avoided early in the COVID-19 era and still avoided in many developing ones or at best of second choice in the developed ones, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their ability to prevent, constrain or reverse COVID-19 associated dysregulated immune and hyper-inflammatory responses through mitigating the formation of several inflammatory cytokines and pathways including the interleukin-6 amplifier and its NF-kB component, as well as modulation of a described monocytic immunological dysrhythmia, which is also known to trigger the COVID-19 cytokine storm. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials as COVID-19 potential safe and economic cure might be available and unfortunately repeatedly ignored for one year.

We have previously suggested numerous immunomodulatory and anti-inflammatory benefits when NSAIDs are administered to manage COVID-19 and in this commentary, we add other potential benefits related to SARS CoV-2 ORF proteins dependent activation of caspases with subsequent mitochondrial dysfunction, endoplasmic reticulum stress and necroptosis that were described with complicated COVID-19 as NSAIDs are known to be caspase inhibitors. Moreover, NSAIDs might independently inhibit other COVID-19 associated downstream pathological signaling mechanisms. We also postulate that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in development of severe and critical COVID-19. We believe that it is very unfortunate that for more than one year of relentless struggle, our recommendation to adopt NSAIDs as first choice COVID-19 therapy has not adopted while lives are lost are succumbed every day.