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      COVID-19-associated cytokine storm syndrome and diagnostic principles: an old and new Issue

      review-article
      Emerging Microbes & Infections
      Taylor & Francis
      SARS-CoV-2, COVID-19, cytokine storm syndrome, familial/primary hemophagocytic lymphohistiocytosis, secondary hemophagocytic lymphohistiocytosis

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          ABSTRACT

          SARS-CoV-2 has claimed 2,137,908 lives in more than a year. Some COVID-19 patients experience sudden and rapid deterioration with the onset of fatal cytokine storm syndrome (CSS), which have increased interest in CSS’s mechanisms, diagnosis and therapy. Although the prototypic concept of CSS was first proposed 116 years ago, we have only begun to study and understand CSS for less than 30 years. Actually, diseases under CSS umbrella include familial/primary and secondary hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), infection-associated hemophagocytic syndrome, cytokine release syndrome (CRS), and cytokine storm (CS). Hematologic malignancies and autoimmune diseases that cause CSS are named malignancy-associated hemophagocytic syndrome (MAHS) and MAS, respectively. In-depth research on the pathogenesis of HLH/CSS has greatly increased the number of patients that were able to be definitively diagnosed with HLH/CSS. However, it should be emphasized that HLH/CSS diagnosis is difficult at the early stages due to the non-specific clinical signs and symptoms, which tends to result in missed and incorrect diagnoses. Therefore, clinicians should not only possess extensive clinical experience to ensure high sensitivity to the characteristics of HLH/CSS but must also be familiar with HLH-2004/2009 diagnostic criteria, and HScore methods. The paper concisely comment evolution of CSS classifications, cytokines associated with CSS, evolution of CSS diagnostic criteria and importance of the correct identification of hemophagocytes in diagnosing CSS, which is timely and may benefit clinicians familiar HLH-2004/2009 diagnostic criteria, and HScore methods. In addition, clinicians must also understand that there are some limitations to these diagnostic criteria.

          Abbreviations: aBMT: autologous bone marrow transplantation; CAR-T: chimeric antigen receptor-engineered T-cell; COVID-19: coronavirus disease 2019; CSS: cytokine storm syndrome; HLH: hemophagocytic lymphohistiocytosis; MAS: macrophage activation syndrome; CRS: cytokine release syndrome; CS: cytokine storm; MAHS: malignancy-associated hemophagocytic syndrome; IAHS: infection-associated hemophagocytic syndrome; fHLH/pHLH: familial/primary hemophagocytic lymphohistiocytosis; sHLH: secondary hemophagocytic lymphohistiocytosis; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TCR-T, T-cell receptor-engineered T-cell

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          Most cited references50

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          Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

          Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.
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            COVID-19: consider cytokine storm syndromes and immunosuppression

            As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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              Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

              Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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                Author and article information

                Journal
                Emerg Microbes Infect
                Emerg Microbes Infect
                Emerging Microbes & Infections
                Taylor & Francis
                2222-1751
                18 February 2021
                2021
                : 10
                : 1
                : 266-276
                Affiliations
                Department of Immunology and National Center for Biomedicine Analysis; Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China
                Author notes
                [CONTACT ] Yongzhi Xi xiyz@ 123456yahoo.com Department of Immunology and National Center for Biomedicine Analysis, Fifth Medical Center of Chinese PLA General Hospital , No. 8, Dongda Ave, Fengtai District, Beijing100071, People’s Republic of China
                Article
                1884503
                10.1080/22221751.2021.1884503
                7894425
                33522893
                eab45f9c-b4ad-43d6-a091-fb644c9c82b0
                © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 2, Tables: 5, Equations: 0, References: 50, Pages: 11
                Categories
                Review
                Review

                sars-cov-2,covid-19,cytokine storm syndrome,familial/primary hemophagocytic lymphohistiocytosis,secondary hemophagocytic lymphohistiocytosis

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