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      Characterization of the Inflammatory Response to Severe COVID-19 Illness

      research-article

      1 , 2 , 3 , 1 , 2 , 1 , 1 , 1 , 2 , 2 , 3 , 2 , 3 , 2 , 2 , 1 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 4 , 2 , 4 , 5 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 6 , , 2 , 3 , 1 , 2

      American Journal of Respiratory and Critical Care Medicine

      American Thoracic Society

      COVID-19, cytokines, neutrophils, alpha-1 antitrypsin, immunometabolism

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          Abstract

          Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.

          Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.

          Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID stable patients), patients with COVID-19 requiring ICU admission (COVID ICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP ICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.

          Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID ICU patients could be clearly differentiated from COVID stable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP ICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission ( P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution ( P < 0.0001).

          Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

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          Most cited references 31

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            COVID-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome

            To the Editor: In northern Italy, an overwhelming number of patients with coronavirus disease (COVID-19) pneumonia and acute respiratory failure have been admitted to our ICUs. Attention is primarily focused on increasing the number of beds, ventilators, and intensivists brought to bear on the problem, while the clinical approach to these patients is the one typically applied to severe acute respiratory distress syndrome (ARDS), namely, high positive end-expiratory pressure (PEEP) and prone positioning. However, the patients with COVID-19 pneumonia, despite meeting the Berlin definition of ARDS, present an atypical form of the syndrome. Indeed, the primary characteristic we are observing (and has been confirmed by colleagues in other hospitals) is a dissociation between their relatively well-preserved lung mechanics and the severity of hypoxemia. As shown in our first 16 patients (Figure 1), a respiratory system compliance of 50.2 ± 14.3 ml/cm H2O is associated with a shunt fraction of 0.50 ± 0.11. Such a wide discrepancy is virtually never seen in most forms of ARDS. Relatively high compliance indicates a well-preserved lung gas volume in this patient cohort, in sharp contrast to expectations for severe ARDS. Figure 1. (A) Distributions of the observations of the compliance values observed in our cohort of patients. (B) Distributions of the observations of the right-to-left shunt values observed in our cohort of patients. A possible explanation for such severe hypoxemia occurring in compliant lungs is a loss of lung perfusion regulation and hypoxic vasoconstriction. Actually, in ARDS, the ratio of the shunt fraction to the fraction of gasless tissue is highly variable, with a mean of 1.25 ± 0.80 (1). In eight of our patients with a computed tomography scan, however, we measured a ratio of 3.0 ± 2.1, suggesting a remarkable hyperperfusion of gasless tissue. If this is the case, the increases in oxygenation with high PEEP and/or prone positioning are not primarily due to recruitment, the usual mechanism in ARDS (2), but instead, in these patients with poorly recruitable lungs (3), result from the redistribution of perfusion in response to pressure and/or gravitational forces. We should consider that 1) in patients who are treated with continuous positive airway pressure or noninvasive ventilation and who present with clinical signs of excessive inspiratory efforts, intubation should be prioritized to avoid excessive intrathoracic negative pressures and self-inflicted lung injury (4); 2) high PEEP in a poorly recruitable lung tends to result in severe hemodynamic impairment and fluid retention; and 3) prone positioning of patients with relatively high compliance provides a modest benefit at the cost of a high demand for stressed human resources. Given the above considerations, the best we can do while ventilating these patients is to “buy time” while causing minimal additional damage, by maintaining the lowest possible PEEP and gentle ventilation. We need to be patient.
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              Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

              The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 September 2020
                15 September 2020
                15 September 2020
                15 September 2020
                : 202
                : 6
                : 812-821
                Affiliations
                [ 1 ]Department of Medicine
                [ 3 ]Department of Anaesthesia and Critical Care
                [ 4 ]Department of International Health and Tropical Medicine, and
                [ 5 ]Data Science Centre, Division of Biostatistics and Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
                [ 2 ]Beaumont Hospital, Dublin, Ireland; and
                [ 6 ]Department of Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland
                Author notes
                Correspondence and requests for reprints should be addressed to Gerard F. Curley, M.Sc., Ph.D., Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland D09YD60. E-mail: gercurley@ 123456rcsi.ie .
                [*]

                Joint senior authorship.

                Article
                202005-1583OC
                10.1164/rccm.202005-1583OC
                7491404
                9df3f151-14be-412e-8ae1-6d93744b8af4
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

                Page count
                Figures: 3, Tables: 2, Pages: 10
                Product
                Categories
                Original Articles
                COVID-19/Pulmonary Infections

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