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1.
American Journal of Respiratory and Critical Care Medicine ; 203(9):2, 2021.
Article in English | Web of Science | ID: covidwho-1407082
2.
HemaSphere ; 5(SUPPL 2):101, 2021.
Article in English | EMBASE | ID: covidwho-1393447

ABSTRACT

Background: The Pfizer/BioNTech BNT162b2 vaccine, employing mRNA technology, has been recently approved by both the FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a 94.6% protection rate in a phase 3 study. While this vaccine is recommended by the FDA, EBMT and ASH-ASTCT for immunosuppressed patients, data regarding protection efficacy and safety in patients undergoing immunologic cell therapy are scarce. Aims: We aimed to evaluate efficacy and toxicity of the BNT162b2 vaccine in patients that underwent hematopoietic cell transplantation and CAR-T therapy. Methods: All patients under active treatment at the long-term follow-up HCT clinic (n=124) at the Tel Aviv Sourasky Medical Center, were evaluated for immunologic recovery (CD19+, CD4+, and CD8+ cell blood levels) pre-vaccination and were recommended to receive the commercial vaccination based on the EBMT recommendations. Patients were prospectively followed for vaccination-safety profile (laboratory tests, GVHD monitoring, and symptom-based questionnaire). We evaluated the humoral immune response to vaccine, 7-14 days after the second vaccine dose, by in vitro quantitative determination of anti-SARSCoV- 2S antibodies using Elecsys. assay and cellular immune response by ELISpot, estimating IL-2 and IFN-gamma secretion in response to a pool of lyophilized SARS-COV-2 S and M peptides (PepTivator;Miltenyi). The trial was approved by the local Ethics Committee and was registered by the clinical trials network (NCT04724642). Results: From 23-Dec-2020 all sequential patients (allogeneic, n=101 and CAR-T, n=23) were assessed for eligibility based on the EBMT recommendations (Version 5.0, Feb 21, 2021). Of those, 100 patients were eligible and 79 patients (allogeneic, n=65 and CAR-T, n=14) were vaccinated per-protocol. Characteristics of patients are depicted in Table 1. Overall, the 2 vaccine doses were well tolerated. Adverse events were reported in 39% of allogeneic HCT recipients (4.6% grade ≥3) and 32% of CART recipients (7% grade ≥3). All events resolved within few days, with the exception of 1 secondary graft rejection which is still under investigation. Among the CAR-T group, 5 patients (36%) had humoral antibody response. Patients with CD19+ lymphocytes >0 had a higher likelihood to develop antibodies compared to those with B cell aplasia (67% vs. 12.5%, p=.036). Among the allogeneic HCT group - 47 patients (81%) had a humoral antibody response. Incidence of positive serology was lower in patients with concomitant high intensity immunosuppressive therapy (IST) compared to those with low intensity IST (69% vs. 94%, p=.016). Linear regressions identified that male sex (beta=-.380, p=.012) and high intensity IST (beta=-.497, p=.014) were associated with lower antibody titer, while age, months from HCT, intensity of conditioning, low CD19 cell count, and active GVHD did not predict response. Analysis of peptide induced cytokine release by ELISpot is ongoing and will be presented at the EHA meeting. Summary/Conclusion: Humoral response to the BNT162b2 mRNA COVID-19 vaccine in CAR-T patients with B cell aplasia is significantly impaired, while overall response in patients after allogeneic HCT is encouraging. Patients on concomitant high intensity IST had impaired humoral response to BNT162b2. Longer follow-up is mandatory to test persistence of antibodies, and general preventive practices should be continued until more data are available.

3.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277296

ABSTRACT

RATIONALE Multiple case reports and case series have described pneumothorax and pneumomediastinum as a complication of patients hospitalized with COVID-19, particularly among those receiving invasive mechanical ventilation. However, it is not known whether patients with COVID-19 have a uniquely higher incidence of these events compared to historical ARDS (non-COVID-19 ARDS) patients. METHODS We compared barotrauma rates in patients hospitalized with COVID-19 who received invasive mechanical ventilation between March-July 2020 to patients with non-COVID-19 ARDS who received mechanical ventilation in 2016-2018. We defined barotrauma as pneumothorax or pneumomediastinum during mechanical ventilation. RESULTS We analyzed 222 patients with COVID-19 who received invasive mechanical ventilation and 421 patients with ARDS. Barotrauma events occurred in 13.1% of patients with COVID-19 and 9.3% of historical ARDS patients (p = 0.136). Mean tidal volumes were 5.7 and 6.4 mL/kg of predicted body weight, plateau pressures were 25.6 and 23.6, PEEP was 11.2 and 8.8, and driving pressures were 14.4 and 14.8 cmH2O, respectively, in COVID-19 and non-COVID-19 ARDS. There were 42 pneumothoraces among COVID-19 patients and 50 among historical ARDS patients (p = 0.144). Incidence rates were 1.7 and 2.7 per 100 ventilator days in COVID-19 and historical ARDS respectively (p=0.808). There were 14 cases of pneumomediastinum among patients with COVID-19 compared to 16 among patients with ARDS (p = 0.152). Overall, pneumothoraces were identified within 24 hours of ipsilateral internal jugular or subclavian line placement in 5.4% (5/92) of events. In both groups, barotrauma was associated with fewer vent-free days at 28 days (3.0 vs 9.2 in COVID-19, p < 0.001 and 7.6 vs 11.5 in historical ARDS, p = 0.0214). Barotrauma was not associated with an increased mortality at discharge for either cohort. For COVID-19 patients only, mean plateau pressure and driving pressure were associated with barotrauma events (28 vs 25 cmH2O, p = 0.0015;16.7 vs 14.0 cmH2O, p ≤ 0.01). Administered tidal volume, PEEP, age, sex, tobacco use, obesity, number of comorbidities, and the presence of lung comorbidities were not associated with barotrauma in either cohort. CONCLUSIONS Both COVID-19 and non-COVID-19 ARDS patients who are mechanically ventilated are at high risk of barotrauma;this was not unique to patients with COVID-19. Barotrauma is associated with prolonged ventilation and fewer ventilator-free days. Despite advances in lung-protective ventilation, barotrauma continues to be a significant source of morbidity in patients mechanically ventilated for respiratory failure.

4.
J Pers Med ; 10(4)2020 Sep 23.
Article in English | MEDLINE | ID: covidwho-966396

ABSTRACT

(1) Background: The five rights of clinical decision support (CDS) are a well-known framework for planning the nuances of CDS, but recent advancements have given us more options to modify the format of the alert. One-size-fits-all assessments fail to capture the nuance of different BestPractice Advisory (BPA) formats. To demonstrate a tailored evaluation methodology, we assessed a BPA after implementation of Storyboard for changes in alert fatigue, behavior influence, and task completion; (2) Methods: Data from 19 weeks before and after implementation were used to evaluate differences in each domain. Individual clinics were evaluated for task completion and compared for changes pre- and post-redesign; (3) Results: The change in format was correlated with an increase in alert fatigue, a decrease in erroneous free text answers, and worsened task completion at a system level. At a local level, however, 14% of clinics had improved task completion; (4) Conclusions: While the change in BPA format was correlated with decreased performance, the changes may have been driven primarily by the COVID-19 pandemic. The framework and metrics proposed can be used in future studies to assess the impact of new CDS formats. Although the changes in this study seemed undesirable in aggregate, some positive changes were observed at the level of individual clinics. Personalized implementations of CDS tools based on local need should be considered.

5.
Virology ; 553: 35-45, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-922156

ABSTRACT

We report the generation of a full-length infectious cDNA clone for porcine deltacoronavirus strain USA/IL/2014/026. Similar to the parental strain, the infectious clone virus (icPDCoV) replicated efficiently in cell culture and caused mild clinical symptoms in piglets. To investigate putative viral interferon (IFN) antagonists, we generated two mutant viruses: a nonstructural protein 15 mutant virus that encodes a catalytically-inactive endoribonuclease (icEnUmut), and an accessory gene NS6-deletion virus in which the NS6 gene was replaced with the mNeonGreen sequence (icDelNS6/nG). By infecting PK1 cells with these recombinant PDCoVs, we found that icDelNS6/nG elicited similar levels of type I IFN responses as icPDCoV, however icEnUmut stimulated robust type I IFN responses, demonstrating that the deltacoronavirus endoribonuclease, but not NS6, functions as an IFN antagonist in PK1 cells. Collectively, the construction of a full-length infectious clone and the identification of an IFN-antagonistic endoribonuclease will aid in the development of live-attenuated deltacoronavirus vaccines.


Subject(s)
DNA, Complementary/isolation & purification , Deltacoronavirus/genetics , Swine/virology , Animals , Clone Cells , Coronavirus Infections/pathology , Deltacoronavirus/pathogenicity , Deltacoronavirus/physiology , Endoribonucleases/physiology , Interferons/antagonists & inhibitors , Virus Replication
6.
Journal of Personalized Medicine ; 10(4):142, 2020.
Article | MDPI | ID: covidwho-783847

ABSTRACT

(1) Background: The five rights of clinical decision support (CDS) are a well-known framework for planning the nuances of CDS, but recent advancements have given us more options to modify the format of the alert. One-size-fits-all assessments fail to capture the nuance of different BestPractice Advisory (BPA) formats. To demonstrate a tailored evaluation methodology, we assessed a BPA after implementation of Storyboard for changes in alert fatigue, behavior influence, and task completion;(2) Methods: Data from 19 weeks before and after implementation were used to evaluate differences in each domain. Individual clinics were evaluated for task completion and compared for changes pre- and post-redesign;(3) Results: The change in format was correlated with an increase in alert fatigue, a decrease in erroneous free text answers, and worsened task completion at a system level. At a local level, however, 14% of clinics had improved task completion;(4) Conclusions: While the change in BPA format was correlated with decreased performance, the changes may have been driven primarily by the COVID-19 pandemic. The framework and metrics proposed can be used in future studies to assess the impact of new CDS formats. Although the changes in this study seemed undesirable in aggregate, some positive changes were observed at the level of individual clinics. Personalized implementations of CDS tools based on local need should be considered.

7.
J Virol ; 94(17)2020 08 17.
Article in English | MEDLINE | ID: covidwho-601769

ABSTRACT

Coronaviruses (CoVs) have repeatedly emerged from wildlife hosts and infected humans and livestock animals to cause epidemics with significant morbidity and mortality. CoVs infect various organs, including respiratory and enteric systems, as exemplified by newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The constellation of viral factors that contribute to developing enteric disease remains elusive. Here, we investigated CoV interferon antagonists for their contribution to enteric pathogenesis. Using an infectious clone of an enteric CoV, porcine epidemic diarrhea virus (icPEDV), we generated viruses with inactive versions of interferon antagonist nonstructural protein 1 (nsp1), nsp15, and nsp16 individually or combined into one virus designated icPEDV-mut4. Interferon-responsive PK1 cells were infected with these viruses and produced higher levels of interferon responses than were seen with wild-type icPEDV infection. icPEDV-mut4 elicited robust interferon responses and was severely impaired for replication in PK1 cells. To evaluate viral pathogenesis, piglets were infected with either icPEDV or icPEDV-mut4. While the icPEDV-infected piglets exhibited clinical disease, the icPEDV-mut4-infected piglets showed no clinical symptoms and exhibited normal intestinal pathology at day 2 postinfection. icPEDV-mut4 replicated in the intestinal tract, as revealed by detection of viral RNA in fecal swabs, with sequence analysis documenting genetic stability of the input strain. Importantly, icPEDV-mut4 infection elicited IgG and neutralizing antibody responses to PEDV. These results identify nsp1, nsp15, and nsp16 as virulence factors that contribute to the development of PEDV-induced diarrhea in swine. Inactivation of these CoV interferon antagonists is a rational approach for generating candidate vaccines to prevent disease and spread of enteric CoVs, including SARS-CoV-2.IMPORTANCE Emerging coronaviruses, including SARS-CoV-2 and porcine CoVs, can infect enterocytes, cause diarrhea, and be shed in the feces. New approaches are needed to understand enteric pathogenesis and to develop vaccines and therapeutics to prevent the spread of these viruses. Here, we exploited a reverse genetic system for an enteric CoV, porcine epidemic diarrhea virus (PEDV), and outline an approach of genetically inactivating highly conserved viral factors known to limit the host innate immune response to infection. Our report reveals that generating PEDV with inactive versions of three viral interferon antagonists, nonstructural proteins 1, 15, and 16, results in a highly attenuated virus that does not cause diarrhea in animals and elicits a neutralizing antibody response in virus-infected animals. This strategy may be useful for generating live attenuated vaccine candidates that prevent disease and fecal spread of enteric CoVs, including SARS-CoV-2.


Subject(s)
Coronavirus Infections/immunology , Coronavirus/immunology , Interferons/immunology , Porcine epidemic diarrhea virus/immunology , Vaccines, Attenuated/immunology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Betacoronavirus/immunology , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/prevention & control , Diarrhea/pathology , Diarrhea/virology , Disease Models, Animal , Endoribonucleases/antagonists & inhibitors , Feces/virology , Ileum/pathology , Immunity, Innate , Jejunum/pathology , Pandemics , Pneumonia, Viral/immunology , Porcine epidemic diarrhea virus/genetics , RNA, Viral , RNA-Dependent RNA Polymerase , SARS-CoV-2 , Swine , Swine Diseases/virology , Vero Cells , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/immunology
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