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1.
J Virol ; 95(9)2021 04 12.
Article in English | MEDLINE | ID: covidwho-1102152

ABSTRACT

Current influenza vaccines, live attenuated or inactivated, do not protect against antigenically novel influenza A viruses (IAVs) of pandemic potential, which has driven interest in the development of universal influenza vaccines. Universal influenza vaccine candidates targeting highly conserved antigens of IAV nucleoprotein (NP) are promising as vaccines that induce T cell immunity, but concerns have been raised about the safety of inducing robust CD8 T cell responses in the lungs. Using a mouse model, we systematically evaluated effects of recombinant adenovirus vectors (rAd) expressing IAV NP (A/NP-rAd) or influenza B virus (IBV) NP (B/NP-rAd) on pulmonary inflammation and function after vaccination and following live IAV challenge. After A/NP-rAd or B/NP-rAd vaccination, female mice exhibited robust systemic and pulmonary vaccine-specific B cell and T cell responses and experienced no morbidity (e.g., body mass loss). Both in vivo pulmonary function testing and lung histopathology scoring revealed minimal adverse effects of intranasal rAd vaccination compared with unvaccinated mice. After IAV challenge, A/NP-rAd-vaccinated mice experienced significantly less morbidity, had lower pulmonary virus titers, and developed less pulmonary inflammation than unvaccinated or B/NP-rAd-vaccinated mice. Based on analysis of pulmonary physiology using detailed testing not previously applied to the question of T cell damage, mice protected by vaccination also had better lung function than controls. Results provide evidence that, in this model, adenoviral universal influenza vaccine does not damage pulmonary tissue. In addition, adaptive immunity, in particular, T cell immunity in the lungs, does not cause damage when restimulated but instead mitigates pulmonary damage following IAV infection.IMPORTANCE Respiratory viruses can emerge and spread rapidly before vaccines are available. It would be a tremendous advance to use vaccines that protect against whole categories of viruses, such as universal influenza vaccines, without the need to predict which virus will emerge. The nucleoprotein (NP) of influenza virus provides a target conserved among strains and is a dominant T cell target. In animals, vaccination to NP generates powerful T cell immunity and long-lasting protection against diverse influenza strains. Concerns have been raised, but not evaluated experimentally, that potent local T cell responses might damage the lungs. We analyzed lung function in detail in the setting of such a vaccination. Despite CD8 T cell responses in the lungs, lungs were not damaged and functioned normally after vaccination alone and were protected upon subsequent infection. This precedent provides important support for vaccines based on T cell-mediated protection, currently being considered for both influenza and SARS-CoV-2 vaccines.


Subject(s)
Adenoviridae , Genetic Vectors , Influenza B virus , Influenza Vaccines , Lung , Orthomyxoviridae Infections , Adenoviridae/genetics , Adenoviridae/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Disease Models, Animal , Female , Genetic Vectors/genetics , Genetic Vectors/immunology , Immunity, Cellular , Influenza B virus/genetics , Influenza B virus/immunology , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Lung/immunology , Lung/pathology , Lung/virology , Mice , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/prevention & control , T-Lymphocytes/immunology , T-Lymphocytes/pathology
2.
Respir Res ; 22(1): 38, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1067230

ABSTRACT

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.


Subject(s)
COVID-19/metabolism , Extracellular Matrix/metabolism , Pulmonary Fibrosis/metabolism , Wound Healing/physiology , Animals , Biomarkers/metabolism , COVID-19/diagnosis , Humans , Lung/metabolism , Pulmonary Fibrosis/diagnosis
3.
Ann Intensive Care ; 10(1): 151, 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-992558

ABSTRACT

BACKGROUND: In COVID-19 patients with severe acute respiratory distress syndrome (ARDS), the relatively preserved respiratory system compliance despite severe hypoxemia, with specific pulmonary vascular dysfunction, suggests a possible hemodynamic mechanism for VA/Q mismatch, as hypoxic vasoconstriction alteration. This study aimed to evaluate the capacity of inhaled nitric oxide (iNO)-almitrine combination to restore oxygenation in severe COVID-19 ARDS (C-ARDS) patients. METHODS: We conducted a monocentric preliminary pilot study in intubated patients with severe C-ARDS. Respiratory mechanics was assessed after a prone session. Then, patients received iNO (10 ppm) alone and in association with almitrine (10 µg/kg/min) during 30 min in each step. Echocardiographic and blood gases measurements were performed at baseline, during iNO alone, and iNO-almitrine combination. The primary endpoint was the variation of oxygenation (PaO2/FiO2 ratio). RESULTS: Ten severe C-ARDS patients were assessed (7 males and 3 females), with a median age of 60 [52-72] years. Combination of iNO and almitrine outperformed iNO alone for oxygenation improvement. The median of PaO2/FiO2 ratio varied from 102 [89-134] mmHg at baseline, to 124 [108-146] mmHg after iNO (p = 0.13) and 180 [132-206] mmHg after iNO and almitrine (p < 0.01). We found no correlation between the increase in oxygenation caused by iNO-almitrine combination and that caused by proning. CONCLUSION: In this pilot study of severe C-ARDS patients, iNO-almitrine combination was associated with rapid and significant improvement of oxygenation. These findings highlight the role of pulmonary vascular function in COVID-19 pathophysiology.

4.
Int J Mol Sci ; 21(21)2020 Oct 29.
Article in English | MEDLINE | ID: covidwho-902541

ABSTRACT

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.


Subject(s)
Acute Lung Injury/pathology , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Vasoconstriction/physiology , Betacoronavirus , COVID-19 , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Kallikrein-Kinin System/physiology , Pandemics , Renin-Angiotensin System/physiology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Vasoconstriction/drug effects
5.
Int J Clin Pract ; 74(12): e13636, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-745705

ABSTRACT

BACKGROUND: The most common extra pulmonary organ dysfunction in acute respiratory distress syndrome is acute kidney injury. Current data so far indicate low incidence of AKI in Covid-19 disease. OBJECTIVE: In this retrospective study, we analysed the clinical features of patients diagnosed with Covid-19 and investigated the effect of Covid-19 on kidney function. METHODS: Ninety-six patients diagnosed with Covid-19 were included in our study. Demographic features (Age, gender, co-morbidities), symptoms, thorax CT findings, Covid-19 PCR results and laboratory findings were recorded. The clinical features of the patients were analysed and kidney function values before Covid-19 diagnosis were compared with kidney function values after Covid-19 diagnosis. RESULTS: Most presenting symptom was fever (51%). Most accompanying co-morbidity was hypertension (56%). According to laboratory findings; ferritin, D-dimer and C-reactive protein levels were statistically significantly higher in ARDS group than severe pneumonia and pneumonia group (P = .002, P = .001 and P < .001, respectively). Also lymphocyte levels were statistically significantly lower in ARDS group than severe pneumonia and pneumonia group (P = .042). According to KDIGO criteria 3 (3.1%) patients had AKI during the hospital stay. For all patients, there was statistically significant difference between basal, 1st, 5th and 10th day BUN and SCr levels (P = .024 and P = .018, respectively). For severe pneumonia group there was statistically significant difference between basal, 1st, 5th and 10th day SCr levels (P = .045). CONCLUSION: Our study demonstrated that Covid-19 can cause renal impairment both with pneumonia and ARDS. A large-scale prospective randomised studies are needed to reach final judgement about this topic.


Subject(s)
Acute Kidney Injury/virology , COVID-19/complications , Pneumonia, Viral/etiology , Respiratory Distress Syndrome/virology , Adult , Aged , Blood Urea Nitrogen , C-Reactive Protein/analysis , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Humans , Lymphocyte Count , Male , Middle Aged , Retrospective Studies
6.
Acad Radiol ; 27(10): 1449-1455, 2020 10.
Article in English | MEDLINE | ID: covidwho-679392

ABSTRACT

RATIONALE AND OBJECTIVES: Mounting evidence supports the role of pulmonary hemodynamic alternations in the pathogenesis of COVID-19. Previous studies have demonstrated that changes in pulmonary blood volumes measured on computed tomography (CT) are associated with histopathological markers of pulmonary vascular pruning, suggesting that quantitative CT analysis may eventually be useful in the assessment pulmonary vascular dysfunction more broadly. MATERIALS AND METHODS: Building upon previous work, automated quantitative CT measures of small blood vessel volume and pulmonary vascular density were developed. Scans from 103 COVID-19 patients and 107 healthy volunteers were analyzed and their results compared, with comparisons made both on lobar and global levels. RESULTS: Compared to healthy volunteers, COVID-19 patients showed significant reduction in BV5 (pulmonary blood volume contained in blood vessels of <5 mm2) expressed as BV5/(total pulmonary blood volume; p < 0.0001), and significant increases in BV5-10 and BV 10 (pulmonary blood volumes contained in vessels between 5 and 10 mm2 and above 10 mm2, respectively, p < 0.0001). These changes were consistent across lobes. CONCLUSION: COVID-19 patients display striking anomalies in the distribution of blood volume within the pulmonary vascular tree, consistent with increased pulmonary vasculature resistance in the pulmonary vessels below the resolution of CT.


Subject(s)
Betacoronavirus , Coronavirus Infections , Lung , Pandemics , Pneumonia, Viral , COVID-19 , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Tomography, X-Ray Computed
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