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1.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333851

ABSTRACT

SARS-CoV-2 is a zoonotic agent capable of infecting humans and a wide range of animal species. Over the duration of the pandemic, mutations in the SARS-CoV-2 Spike protein (S) have arisen in circulating viral populations, culminating in the spread of several variants of concern (VOC) with varying degrees of altered virulence, transmissibility, and neutralizing antibody escape. In this study, we employed lentivirus-based pseudotyped viruses that express specific SARS-CoV-2 S protein substitutions and cell lines that stably express ACE2 from nine different animal species to gain insights into the effects of VOC mutations on viral entry and antibody neutralization capability. All animal ACE2 receptors tested, except mink, support viral cell entry for pseudoviruses expressing the parental (prototype Wuhan-1) S at levels comparable to human ACE2. Most single S substitutions (e.g., 452R, 478K, 501Y) did not significantly change virus entry, although 614G and 484K resulted in a decreased efficiency in viral entry. Conversely, combinatorial VOC substitutions in the S protein were associated with significantly increased entry capacity of pseudotyped viruses compared to that of the parental Wuhan-1 pseudotyped virus. Similarly, infection studies using live ancestral (USA-WA1/2020), Alpha, and Beta SARS-CoV-2 viruses in hamsters revealed a higher replication potential for the Beta variant compared to the ancestral prototype virus. Moreover, neutralizing titers in sera from various animal species, including humans, were significantly reduced by single substitutions of 484K or 452R, double substitutions of 501Y-484K, 452R-484K and 452R-478K and the triple substitution of 501Y-484K-417N, suggesting that 484K and 452R are particularly important for evading neutralizing antibodies in human, cat, and rabbit sera. Cumulatively, this study reveals important insights into the host range of SARS-CoV-2 and the effect of recently emergent S protein substitutions on viral entry, virus replication and antibody-mediated viral neutralization. AUTHOR SUMMARY: Cells stably expressing ACE2 from various animals and a lentivirus-based SARS-CoV-2 pseudotyped virus assay were established to study SARS-CoV-2 cell entry. The results demonstrated that ACE2 from a wide range of animal species facilitate S-mediated virus entry into cells, which is supported by in silico data as well as natural and experimental infection studies. Pseudotyped viruses containing mutations in the RBD of S representative of the Alpha, Gamma, and especially Beta, variants of concern demonstrated that certain mutations are associated with increased viral entry compared to the parental S. The Beta variant was also observed to have a replicative advantage in vitro and in vivo compared to the prototype virus. Pseudotyped viruses containing combinatorial substitutions of 501Y-484K-417K, 614G-501Y-484K and 614G-501Y-484K-417N increased viral entry via ACE2 across multiple species. The 501Y or 478K single substitution did not significantly affect neutralizing capacity of immune sera compared to the prototype strain, but the addition of 484K or 452R substitutions significantly reduced the neutralizing titers.

2.
Allergy: European Journal of Allergy and Clinical Immunology ; 76(SUPPL 110):539-540, 2021.
Article in English | EMBASE | ID: covidwho-1570426

ABSTRACT

Background: Oral food challenge (OFC) is the gold standard for the diagnosis of food allergy. OFC are traditionally performed in hospital, as a day ward procedure, with a high medical caregiver to patient ratio. This is likely to enhance communication and patient satisfaction. Despite the high incidence of adverse reactions, families generally report a positive experience . In Sep-Oct 2020 a novel, high throughput, OFC initiative was carried out by a cross-hospital, multidisciplinary Irish paediatric allergy team. Up to 25 OFCs were performed each day at an offsite, COVID-19 stepdown facility. The unique model was designed in response to the impact of the pandemic, on provision of ambulatory allergy services. It was essential to evaluate the patient experience of this unique, alternative OFC model, compounded by COVID related distancing. Method: An anonymised survey was conducted of randomised cross-section of patients attending. The survey was completed by the primary caregiver of the child attending for the OFC. 178 survey responses were collected from a total of 474 families and included for analysis. The survey was designed to assess patient satisfaction across a number of parameters. Results: 81% of respondents were highly satisfied with ease of use of a non-hospital facility. 81% reported that the site was “child friendly”. Patient experience was scored as “excellent” 82.9% of the time with a further 12.35% reporting it as above average. Communication was effective with 89% of carers reporting good understanding of the results of the OFC. 94.7% stated that their questions were answered by the Allergy Team present. Conclusion: Our results are remarkable for enhanced patient satisfaction despite a reduced medical caregiver to patient ratio. The patient's overall satisfaction was rated overwhelmingly as “excellent” despite almost 30% of patients experiencing allergic reactions. The pandemic has forced health services to seek new ways of doing things. This data reassures, that OFC models can be changed without sacrificing patient experience.

3.
Allergy: European Journal of Allergy and Clinical Immunology ; 76(SUPPL 110):570-571, 2021.
Article in English | EMBASE | ID: covidwho-1570363

ABSTRACT

Background: Internationally, the COVID-19 pandemic severely curtailed access to hospital facilities for those awaiting elective/semi elective procedures. For allergic children in Ireland, already waiting to 4yr for an elective oral food challenge (OFC), the restrictions signified indefinite delay. At the time of the initiative there were approx 900 children on the Chidren's Health Ireland (CHI) waiting list. In July 2020, a project was facilitated by short term (6wk) access to an empty COVID stepdown facility built, in a hotel conference centre, commandeered by the Health Service Executive Ireland (HSE). The aim was to the achieve rapid rollout of an off-site OFC service, delivering high throughput of long waiting patients, while aligning with hospital existing policies and quality standards, international allergy guidelines and national social distancing standards. Method: The working group engaged key stakeholders to rapidly develop an offsite OFC facility. Consultant Paediatric Allergists, Consultant Paediatricians, trainees and Allergy Clinical Nurse Specialists were seconded from other duties. The facility was already equipped with hospital beds, bedside monitors (BP, Pulse, Oxygen saturation) bedside oxygen. All medication and supplies had to be brought from the base hospital. Daily onsite consultant anaesthetic cover was resourced and a resuscitation room equipped. Standardised food challenge protocols were created. Access to onsite hotel chef facilitated food preparation. A risk register was established. Results: After 6wks planning, the remote centre became operational on 7/9/20, with the capacity of 27 OFC/day. 474 challenges were commenced, 465 (98%) were completed, 9(2%) were inconclusive. 135(29.03%) OFC were positive, 25(5%) causing anaphylaxis. No child required advanced airway intervention. 8 children were transferred to the base hospital. The CHI allergy waiting list was reduced by almost 60% in only 24 days. Conclusion: OFCs remain a vital tool in the care of allergic children, with their cost saving and quality of life benefits negatively affected by delay in their delivery. This project has shown it is possible to have huge impacts on a waiting list efficiently, effectively and safely with good planning and staff buy in -even in a pandemic. Adoption of new, flexible and efficient models of service delivery will be important for healthcare delivery in the post-COVID- 19 era.

4.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293261

ABSTRACT

SARS-CoV-2, a novel Betacoronavirus, was first reported circulating in human populations in December 2019 and has since become a global pandemic. Recent history involving SARS-like coronavirus outbreaks (SARS-CoV and MERS-CoV) have demonstrated the significant role of intermediate and reservoir hosts in viral maintenance and transmission cycles. Evidence of SARS-CoV-2 natural infection and experimental infections of a wide variety of animal species has been demonstrated, and in silico and in vitro studies have indicated that deer are susceptible to SARS-CoV-2 infection. White-tailed deer (Odocoileus virginianus) are amongst the most abundant, densely populated, and geographically widespread wild ruminant species in the United States. Human interaction with white-tailed deer has resulted in the occurrence of disease in human populations in the past. Recently, white-tailed deer fawns were shown to be susceptible to SARS-CoV-2. In the present study, we investigated the susceptibility and transmission of SARS-CoV-2 in adult white-tailed deer. In addition, we examined the competition of two SARS-CoV-2 isolates, representatives of the ancestral lineage A (SARS-CoV-2/human/USA/WA1/2020) and the alpha variant of concern (VOC) B.1.1.7 (SARS-CoV-2/human/USA/CA_CDC_5574/2020), through co-infection of white-tailed deer. Next-generation sequencing was used to determine the presence and transmission of each strain in the co-infected and contact sentinel animals. Our results demonstrate that adult white-tailed deer are highly susceptible to SARS-CoV-2 infection and can transmit the virus through direct contact as well as vertically from doe to fetus. Additionally, we determined that the alpha VOC B.1.1.7 isolate of SARS-CoV-2 outcompetes the ancestral lineage A isolate in white-tailed deer, as demonstrated by the genome of the virus shed from nasal and oral cavities from principal infected and contact animals, and from virus present in tissues of principal infected deer, fetuses and contact animals.

6.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-292925

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic that has had significant impacts on human health and economies worldwide. SARS-CoV-2 is highly transmissible and the cause of coronavirus disease 2019 (COVID-19) in humans. A wide range of animal species have also been shown to be susceptible to SARS-CoV-2 infection by experimental and/or natural infections. Domestic and large cats, mink, ferrets, hamsters, deer mice, white-tailed deer, and non-human primates have been shown to be highly susceptible, whereas other species such as mice, dogs, pigs, and cattle appear to be refractory to infection or have very limited susceptibility. Sheep (Ovis aries) are a commonly farmed domestic ruminant that have not previously been thoroughly investigated for their susceptibility to SARS-CoV-2. Therefore, we performed in vitro and in vivo studies which consisted of infection of ruminant-derived cell cultures and experimental challenge of sheep to investigate their susceptibility to SARS-CoV-2. Our results showed that sheep-derived cell cultures support SARS-CoV-2 replication. Furthermore, experimental challenge of sheep demonstrated limited infection with viral RNA shed in nasal and oral swabs primarily at 1-day post challenge (DPC), and also detected in the respiratory tract and lymphoid tissues at 4 and 8 DPC. Sero-reactivity was also observed in some of the principal infected sheep but not the contact sentinels, indicating that transmission to co-mingled naive sheep was not highly efficient;hovewer, viral RNA was detected in some of the respiratory tract tissues of sentinel animals at 21 DPC. Furthermore, we used challenge inoculum consisting of a mixture of two SARS-CoV-2 isolates, representatives of the ancestral lineage A and the B.1.1.7-like alpha variant of concern (VOC), to study competition of the two virus strains. Our results indicate that sheep show low susceptibility to SARS-CoV-2 infection, and that the alpha VOC outcompeted the ancestral lineage A strain.

7.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-292865

ABSTRACT

Patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme-2 (ACE-2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized COVID-19 patients developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or RBD, to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.

8.
Palliative Medicine ; 35(1 SUPPL):174-175, 2021.
Article in English | EMBASE | ID: covidwho-1477052

ABSTRACT

Background: Many studies have shown benefits of early Palliative Care(PC)in advanced lung cancer patients. There's increasing evidence about better symptom control and survival. A PC physician joined the multidisciplinary LCC last year. Despite the SARS-CoV2 pandemic,472 cases were presented to the LCC in 2020. 470 cases were presented in 2018, so his activity remains stable. Aims: To describe clinical profile of the patients presented to the LCC and early referred to PC. To compare patient's survival when referred from ambulatory setting or when they are admitted in hospital. Methods: Descriptive study.DATA:Age, Gender, Comorbilities, Cancer Histology Tobacco exposure, TNM, Oncology Therapy, Survival time, Barthel, Charlson, Time to first PC consultation. ANALYSIS:T test to compare means of continuous variables and Chi-squared to compare proportions of categorical variables. Kaplan-Meier curve for survival analysis. Results: 41patients of 472(9%) were referred to PC. Males(75%),Median Age 72,87 years old(DS 11,95) no age differences by gender. Current Smokers 25%,Former smokers 65%.Hypertension 70%,Diabetes 45%,Dyslipemia 60%,Heart Failure45%, Renal impairment 35%. Barthel:mean 63,6(DS:22,7) Charlson:mean 6,5(DS2,35) Cancer Histology: Squamous55%, Adenocarcinome35%, Small Cell 7,5%,Other Neuroendocrine2,5%, Disease Stage: StageIV 65%, StageIII 55%, Cancer therapy: Chemotherapy 44%,Radiotherapy 56%, Immunotherapy 30%.PC exclusive follow-up:24,4%, PC and shared follow-up:75,6%. Setting: Refered to Ambulatory PC: 44%, Refered to PC when admitted in an hospital ward: 56%. Time from LCC to PC visit: Ambulatory setting: mean 27,7 days, median 14. Admitted hospital ward: mean 63,14 days(p=0,036), Survival: Ambulatory: mean 142,12 days (DS 90,9), Admitted Hospital ward 59,68 days (DS 59,1)p=0,002. Conclusion: Patients referred from LCC to Ambulatory PC showed an early intervention and better survival profile. Collaboration between LCC and the PC team can improve the early PC support.

9.
Ikala ; 26(3):697-713, 2021.
Article in English, French, Spanish | Scopus | ID: covidwho-1444574

ABSTRACT

The crisis in the education system generated by the appearance of covid-19 revealed the multiple gaps that exist due to the diversity of contexts to which students and teachers belong. This article reports on a case study which explored the challenges English teacher educators (tes) at a public university in Neiva, Colombia faced during the pandemic due to the imposition of emergency remote teaching (ert), the pedagogical strategies they used to respond to these challenges, and the ones that remain. To do this, data were collected from a questionnaire and a focus group with tes and pre-service teachers (psts) from the language teacher education program. The main findings show that the transition from classroom teaching to ert brought some challenges for tes and their trainees related to the social realities existing in the context of the latter. To respond to these challenges, tes had to adjust their teaching strategies and learn to use some technologies such as videoconferencing software and educational apps. Still some challenges remain for the future, such as enhancing pst's motivation, autonomy and classroom interaction. The study suggests the need to continue training language tes on the use of ert technologies and to find more and better ways to promote autonomous learning processes to adapt teaching practices to current times. © 2021 Universidad de Antioquia. All Rights Reserved.

10.
Clinical Cancer Research ; 26(18 SUPPL), 2020.
Article in English | EMBASE | ID: covidwho-992086

ABSTRACT

Background: Morbidity and mortality due to coronavirus disease 2019 (COVID-19) may in part be due tointerleukin-6 (IL-6)-mediated hyperinflammation. The IL-6 receptor-targeted monoclonal antibody tocilizumab (TCZ)has been repurposed to treat COVID-19-related hyperinflammation, but prospective data are lacking. Given TCZ'srisks of secondary infection and potential blunting of the adaptive immune response and its finite supply, study of theefficacy, safety, and dose response of TCZ for the treatment of COVID-19-related hyperinflammation is needed. Methods: We conducted an adaptive phase 2 study of low-dose (LD) TCZ in hospitalized, non-mechanicallyventilated adult patients with COVID-19 pneumonitis and evidence of hyperinflammatory syndrome, with C-reactiveprotein (CRP) ≥ 40 micrograms per milliliter. Dose cohorts were determined by a trial Operations Committee, withthe initial doses of 80 or 200 milligrams, depending on the magnitude of CRP elevation and epidemiologic riskfactors. Doses were decreased to 40 mg and 120 mg after interim assessment. The primary objective was to assessthe relationship of dose to clinical improvement in temperature and oxygen requirement and biochemical responseby CRP. Results: 32 patients received LD TCZ. 25 of 32 (78%) patients receiving LD TCZ at any dose achieved feverresolution. In terms of dose-response, fever resolution in 24 hours was observed in 6 of 8 (75%) who received 200milligrams, 3 of 4 (75%) who received 120 milligrams, 11 of 15 (73%) who received 80 milligrams, and 5 of 5 (100%)who received 40 milligrams (p = 0.80 for response rate difference). Biochemical response consistent withinterleukin-6 pathway inhibition, corresponding to a ≥ 25% CRP decline, after a single dose of LD TCZ wasobserved in 5 of 8 (63%) who received 200 milligrams, 4 of 4 (100%) who received 120 milligrams, 10 of 15 (67%)who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.34 for response rate difference).100% of patients achieved CRP response within two doses of LD TCZ. Within the 28-day follow-up period, 5 (16%)patients died. For patients who recovered, median time to clinical recovery was 4 days (interquartile range, 2-5).Clinically presumed and/or cultured bacterial superinfections were reported in 4 (12.5%) patients. Correlativebiologic studies examining anti-SARS-CoV-2 antibody production across a range of TCZ doses are presentedseparately (abstract A-22514927). Conclusions: LD TCZ, in addition to standard of care, was associated with improvement of clinicalhyperinflammation parameters in hospitalized adult patients with COVID-19 pneumonitis. No relationship betweenTCZ dose and clinical or biochemical response relationship was identified. Results of the COVIDOSE trial provide arationale for a randomized, controlled trial of LD TCZ versus standard of care in those patients with COVID-19pneumonitis who have evidence of hyperinflammation. (COVIDOSE, ClinicalTrials.gov number, NCT04331795 .).

11.
Clinical Cancer Research ; 26(18 SUPPL), 2020.
Article in English | EMBASE | ID: covidwho-992084

ABSTRACT

Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor-blocking monoclonal antibody, is used to treat variousrheumatologic conditions and cytokine release syndrome in CAR-T cell therapy and has been repurposed to treatCOVID-19-related hyperinflammation. There are limited data available reporting how TCZ affects the immuneresponse in the context of COVID-19. To investigate this question, we recruited patients treated with TCZ as part ofa COVID-19 biobanking protocol (A-28063295) to study immune parameters that might be affected. We enrolled 19patients who were treated with a range of 40-200mg TCZ as part of a low-dose TCZ trial (COVIDOSE, reportedseparately as abstract A-94803796), and 11 patients who received 400mg TCZ on a standard-of-care expanded-access basis. As IL-6 acts as a stimulant of B-cell proliferation, plasma cell maturation, and antibody responses, weevaluated whether blocking the IL-6 receptor with TCZ therapy impairs antibody generation to SARS-CoV-2. Toevaluate antibody levels in these patients, we performed ELISAs against the SARS-CoV-2 spike glycoprotein and itsreceptor-binding domain (RBD). The spike glycoprotein, a structural protein of SARS-CoV-2, is a crucial componentin the recognition, attachment, and entry of the virus into host cells. Specifically, the RBD is responsible for bindingthe ACE2 receptor on human cells, and likely serves as a major target for neutralizing antibodies. To establish if theformation and persistence of antibodies was affected by TCZ treatment, we analyzed serum and plasma sampleslongitudinally from 29 patients treated with TCZ and 26 control patients. To account for potential variability betweenplates, the measured optical density (OD) values were normalized to the OD for COVID-19-negative control serumat 1:50 dilution, and the same negative control was tested on each plate. Titers were calculated as the linearinterpolation of the inverse dilution at which the normalized OD value crossed a threshold of 1, representing themaximum OD measured for the negative control. Anti-spike and anti-RBD antibodies increased significantly overtime in both TCZ-treated patients and controls (p < 0.005 for both). Increasing antibody titers throughout the diseasecourse followed a similar trajectory in TCZ-treated patients compared to control patients, suggesting that TCZtreatment does not impede the generation of antibodies to SARS-CoV-2. Additionally, TCZ-treated patients achievedcomparable maximal observed antibody titers to control patients (average maximal log10 (titer) of 5.42 and 4.96 forspike and of 4.39 and 4.44 for RBD, respectively). These data suggest that TCZ does not impair the induction ofanti-SARS-CoV-2 antibodies.

12.
Clinical Cancer Research ; 26(18 SUPPL), 2020.
Article in English | EMBASE | ID: covidwho-992050

ABSTRACT

The clinical spectrum of SARS-CoV-2 (COVID-19) infection ranges from asymptomatic infection to fatal pneumonia, but the determinants of outcome are not well understood. To characterize the immune response to COVID-19, weestablished a protocol to collect biologic specimens from patients with confirmed or suspected COVID-19. BetweenApril 9th and June 8th, 2020, we enrolled 146 inpatients and 169 outpatients at the University of Chicago. Wehypothesized that the complex interplay of viral, environmental, and host genetic factors may influence diseaseseverity in patients with COVID-19. To probe for genetic predispositions that may influence outcomes, we collectedgermline DNA from 140 patients spanning the breadth of clinical severity, which will be sequenced for SNPs ingenes previously implicated in immune responsiveness and ARDS. To determine whether a pattern of commensalbacteria correlates with disease severity, we will analyze the composition of airway microbiota from 226nasopharyngeal swabs, using viral quantification and 16S sequencing. Longitudinal serum samples from 156patients were obtained to probe for the presence of antibodies using an ELISA against the spike protein of SARS-CoV-2. In tandem, 36-color flow cytometry on PBMCs, from the same patients, will characterize immune cellphenotypes influenced by infection. We also hypothesized that by characterizing mechanisms of immune-hyperresponsiveness, we may elucidate key biologic pathways that inform the development of novel therapeutics.To determine if severity of disease and response to therapy correlates with soluble factors, we are performing 44-plex cytokine Luminex assays on serum samples. We will probe the adaptive immune response using an ELISAagainst the SARS-CoV-2 RBD domain, and by performing IFN-g ELISPOT analysis against peptide pools fromSARS-CoV-2 proteins. We developed a bioinformatic pipeline to integrate clinical data with the results from thediverse data types and will adopt a machine learning approach to identify parameters contributing to diseaseseverity, response to therapies, and outcomes. In establishing this protocol, there were significant biosafetyconsiderations. To limit potential exposure and virus transmission, research coordinators contacted inpatients byphone for an informed consent discussion, and patients completed the consent form electronically using REDCap(n=61). Inpatients who were unable to navigate the electronic consent were visited with a paper consent (n= 85).Samples were processed in a BSL2 laboratory with enhanced biosafety precautions. Where feasible, samples werecollected into reagents such as Zymo DNA/RNA shield to immediately inactivate the virus. Other safety measuresincluded heat inactivation of some samples and use of a laminar flow washer to minimize aerosolization duringFACS staining. In summary, we have established a biorepository of specimens from patients with COVID-19, including a subset with active cancer or a history of the disease (n=22).

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