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1.
Viruses ; 13(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572667

ABSTRACT

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.


Subject(s)
COVID-19 , Diet, High-Fat/adverse effects , Dietary Carbohydrates/adverse effects , Lipid Metabolism , Severity of Illness Index , Animals , COVID-19/pathology , Cricetinae , Cytokines/blood , Disease Models, Animal , Edema , Fibrin , Hemorrhage , Humans , Interleukin-10 , Interleukin-6 , Lipidomics , Lipids/blood , Liver/pathology , Lung/pathology , Male , Mesocricetus , Obesity , SARS-CoV-2 , Sugars , Vasculitis/pathology , Virus Shedding
2.
Emerg Microbes Infect ; 10(1): 2173-2182, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1493581

ABSTRACT

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, we compared African green monkeys infected intranasally with either the UK B.1.1.7 (Alpha) variant or its contemporary D614G progenitor. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.


Subject(s)
COVID-19/virology , Chlorocebus aethiops/virology , Respiratory System/virology , Virus Replication , Virus Shedding , Administration, Intranasal , Animals , COVID-19/epidemiology , Gastrointestinal Tract/virology , Host Specificity , Polymorphism, Single Nucleotide , RNA, Viral/isolation & purification , Random Allocation , Rectum/virology , United Kingdom/epidemiology , Vero Cells , Viral Load
3.
Sci Adv ; 7(43): eabj3627, 2021 Oct 22.
Article in English | MEDLINE | ID: covidwho-1483968

ABSTRACT

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors. Here, we compared variants of concern (VOC) B.1.1.7 and B.1.351 to a recent B.1 SARS-CoV-2 isolate containing the D614G spike substitution in the rhesus macaque model. B.1.1.7 behaved similarly to D614G with respect to clinical disease and replication in the respiratory tract. Inoculation with B.1.351 resulted in lower clinical scores, lower lung virus titers, and less severe lung lesions. In bronchoalveolar lavages, cytokines and chemokines were up-regulated on day 4 in animals inoculated with D614G and B.1.1.7 but not with B.1.351. In nasal samples, cytokines and chemokines were up-regulated only in the B.1.1.7-inoculated animals. Together, our study suggests that circulation under diverse evolutionary pressures favors transmissibility and immune evasion rather than increased pathogenicity.

4.
Respir Care ; 2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1481092

ABSTRACT

Background: Burnout is a major challenge in health care, but its prevalence has not been evaluated in practicing respiratory therapist (RTs). The purpose of this study was to identify RT burnout prevalence and factors associated with RT burnout.Methods: An online survey was administered to 26 centers in the United States and between January and March 2021. Validated, quantitative, cross-sectional surveys were used to measure burnout and leadership domains. The survey was sent to department directors and distributed by the department directors to staff. Data analysis was descriptive and logistic regression analysis was performed to evaluate risk factors, expressed as odds ratios (OR), for burnout.Results: The survey was distributed to 3,010 RTs, and the response rate was 37%. Seventy-nine percent of respondents reported burnout, 10% with severe, 32% with moderate, and 37% with mild burnout. Univariate analysis revealed those with burnout worked more hours per week, worked more hours per week in the ICU, primarily cared for adult patients, primarily delivered care via RT protocols, reported inadequate RT staffing, reported being unable to complete assigned work, were more frequently exposed to COVID-19, had a lower leadership score, and fewer had a positive view of leadership. Logistic regression revealed burnout climate (OR 9.38, p<0.001), inadequate RT staffing (OR 2.08 to 3.19, p=0.004 to 0.05), being unable to complete all work (OR 2.14 to 5.57, p=0.003 to 0.20), and missing work for any reason were associated with increased risk of burnout (OR 1.96, p=0.007). Not providing patient care (OR 0.18, p=0.02) and a positive leadership score (0.55, p=0.02) were associated with decreased risk of burnout.Conclusion: Burnout was common among RTs in the midst of the COVID-19 pandemic. Good leadership was protective against burnout while inadequate staffing, inability to complete work, and burnout climate were associated with burnout.

5.
Nat Commun ; 12(1): 5868, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462005

ABSTRACT

We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observe a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 do not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals do not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus can be detected in lungs of vaccinated animals. Histopathological evaluation shows extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Administration, Intranasal , Amino Acid Substitution , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Female , Lung/immunology , Lung/pathology , Lung/virology , Mesocricetus , Spike Glycoprotein, Coronavirus/immunology , Vaccination
6.
Viruses ; 13(8)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367918

ABSTRACT

Many different vaccine candidates against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, are currently approved and under development. Vaccine platforms vary from mRNA vaccines to viral-vectored vaccines, and several candidates have been shown to produce humoral and cellular responses in small animal models, non-human primates, and human volunteers. In this study, six non-human primates received a prime-boost intramuscular vaccination with 4 µg of mRNA vaccine candidate CV07050101, which encodes a pre-fusion stabilized spike (S) protein of SARS-CoV-2. Boost vaccination was performed 28 days post prime vaccination. As a control, six animals were similarly injected with PBS. Humoral and cellular immune responses were investigated at time of vaccination, and two weeks afterwards. No antibodies could be detected at two and four weeks after prime vaccination. Two weeks after boost vaccination, binding but no neutralizing antibodies were detected in four out of six non-human primates. SARS-CoV-2 S protein-specific T cell responses were detected in these four animals. In conclusion, prime-boost vaccination with 4 µg of vaccine candidate CV07050101 resulted in limited immune responses in four out of six non-human primates.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccines, Synthetic/immunology , Animals , Antibodies, Neutralizing/blood , COVID-19 Vaccines/administration & dosage , Immunity, Cellular , Immunization Schedule , Macaca mulatta , Male , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage
7.
Sci Transl Med ; 13(607)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1329033

ABSTRACT

ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swabs obtained from intranasally vaccinated hamsters were decreased compared to control hamsters, and no viral RNA or infectious virus was found in lung tissue after a direct challenge or after direct contact with infected hamsters. Intranasal vaccination of rhesus macaques resulted in reduced virus concentrations in nasal swabs and a reduction in viral loads in bronchoalveolar lavage and lower respiratory tract tissue. Intranasal vaccination with ChAdOx1 nCoV-19/AZD1222 reduced virus concentrations in nasal swabs in two different SARS-CoV-2 animal models, warranting further investigation as a potential vaccination route for COVID-19 vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19 Vaccines , Cricetinae , Macaca mulatta , Vaccination , Virus Shedding
8.
mBio ; 12(4): e0150321, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1327616

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) has been associated with T cell lymphopenia, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we studied rhesus macaques that were depleted of either CD4+, CD8+, or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to that in controls. The T cell-depleted groups developed virus-neutralizing antibody responses and class switched to IgG. When reinfected 6 weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads, and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+ nor CD8+ T cells appeared critical for immunoglobulin class switching, the development of immunological memory, or protection from a second infection. IMPORTANCE Patients with severe COVID-19 often have decreased numbers of T cells, a cell type important in fighting most viral infections. However, it is not known whether the loss of T cells contributes to severe COVID-19 or is a consequence of it. We studied rhesus macaques, which develop only mild COVID-19, similar to most humans. Experimental depletion of T cells slightly prolonged their clearance of virus, but there was no increase in disease severity. Furthermore, they were able to develop protection from a second infection and produced antibodies capable of neutralizing the virus. They also developed immunological memory, which allows a much stronger and more rapid response upon a second infection. These results suggest that T cells are not critical for recovery from acute SARS-CoV-2 infections in this model and point toward B cell responses and antibodies as the essential mediators of protection from re-exposure.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/pathology , Immunologic Memory/immunology , Lymphopenia/immunology , SARS-CoV-2/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Female , Lymphocyte Depletion/methods , Macaca mulatta/immunology , Male
9.
Respir Care ; 2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1317300

ABSTRACT

Background: Burnout is a major challenge in health care, but its prevalence has not been evaluated in practicing respiratory therapist (RTs). The purpose of this study was to identify RT burnout prevalence and factors associated with RT burnout.Methods: An online survey was administered to 26 centers in the United States and between January and March 2021. Validated, quantitative, cross-sectional surveys were used to measure burnout and leadership domains. The survey was sent to department directors and distributed by the department directors to staff. Data analysis was descriptive and logistic regression analysis was performed to evaluate risk factors, expressed as odds ratios (OR), for burnout.Results: The survey was distributed to 3,010 RTs, and the response rate was 37%. Seventy-nine percent of respondents reported burnout, 10% with severe, 32% with moderate, and 37% with mild burnout. Univariate analysis revealed those with burnout worked more hours per week, worked more hours per week in the ICU, primarily cared for adult patients, primarily delivered care via RT protocols, reported inadequate RT staffing, reported being unable to complete assigned work, were more frequently exposed to COVID-19, had a lower leadership score, and fewer had a positive view of leadership. Logistic regression revealed burnout climate (OR 9.38, p<0.001), inadequate RT staffing (OR 2.08 to 3.19, p=0.004 to 0.05), being unable to complete all work (OR 2.14 to 5.57, p=0.003 to 0.20), and missing work for any reason were associated with increased risk of burnout (OR 1.96, p=0.007). Not providing patient care (OR 0.18, p=0.02) and a positive leadership score (0.55, p=0.02) were associated with decreased risk of burnout.Conclusion: Burnout was common among RTs in the midst of the COVID-19 pandemic. Good leadership was protective against burnout while inadequate staffing, inability to complete work, and burnout climate were associated with burnout.

10.
Sci Transl Med ; 13(578)2021 01 27.
Article in English | MEDLINE | ID: covidwho-1024212

ABSTRACT

Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be highly stable, whereas subgenomic RNA, an indicator of viral replication, was found to degrade quickly. We combined this information with single-cell RNA sequencing of cells isolated from the lung and lung-draining mediastinal lymph nodes and developed new analysis methods for unbiased targeting of important cells in the host response to SARS-CoV-2 infection. Through detection of reads to the viral genome, we were able to determine that replication of the virus in the lungs appeared to occur mainly in pneumocytes, whereas macrophages drove the inflammatory response. Monocyte-derived macrophages recruited to the lungs, rather than tissue-resident alveolar macrophages, were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching during clearance of infection. Together, our dataset provides a detailed view of the dynamics of virus replication and host responses over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Lung/virology , SARS-CoV-2/physiology , Sequence Analysis, RNA , Single-Cell Analysis , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , Bronchoalveolar Lavage Fluid/virology , COVID-19/genetics , Chlorocebus aethiops , DNA, Viral/genetics , Female , Genome, Viral/genetics , Inflammation/pathology , Lung/pathology , Lymph Nodes/pathology , Macrophages/pathology , Macrophages/virology , Male , Mediastinum/pathology , Transcription, Genetic , Viral Load , Virus Replication
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