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      Defining the scourge of COVID-19 hyperinflammatory syndrome

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      a , b , c
      The Lancet Rheumatology
      Elsevier Ltd.

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          Abstract

          It is abundantly clear that a subset of patients admitted to hospital with COVID-19 develop hyperinflammatory complications of severe COVID-19 infection or cytokine storm syndrome,1, 2 which is frequently fatal. What is less clear is how to define the cytokine storm syndrome in the context of severe COVID-19 infection. In The Lancet Rheumatology, Webb and colleagues 3 propose a set of clinical criteria for COVID-19-associated hyperinflammatory syndrome (cHIS). Development of such criteria are critically important for clinical trial enrolment and for aiding clinicians in recognising patients who will benefit from therapy targeting the cytokine storm syndrome associated with COVID-19. One of the silver linings of the COVID-19 pandemic is the attention brought to cytokine storm syndromes in general. Cytokine storm syndrome refers to an umbrella of clinical states in which hyperinflammation and multi-organ disease arise from excessive cytokine release due to uncontrolled immune activation, and includes infectious, rheumatic, oncological, and immunotherapeutic aetiologies responsible for mortality in children and adults all over the world. Despite this, cytokine storm syndromes are frequently under-recognised, 4 and the evidence base for treatment is lacking. There are both broad cytokine storm syndrome criteria and disease-specific cytokine storm syndrome criteria (appendix), none of which is perfectly sensitive or specific, thus adding to the complexities and difficulties in defining and diagnosing cytokine storm syndrome. The cytokine storm syndrome associated with COVID-19 is relatively unique among infectious cytokine storm syndromes with a propensity for early lung involvement in the form of acute respiratory distress syndrome and a predilection for clotting, as well as increased but less marked elevations in serum ferritin and interleukin-6 (IL-6) concentrations compared with other cytokine storm syndromes. 5 To establish criteria specific to COVID-19, Webb and colleagues did a systematic review of clinical and laboratory parameters linked to cHIS and compared those with other disease-associated cytokine storm syndrome criteria, particularly the 2016 systemic juvenile idiopathic arthritis macrophage activation syndrome criteria (appendix). 6 This approach lends credence to the concept that various hyperinflammatory syndromes triggered by different aetiologies, although not identical, share similar features and can be usefully categorised under the umbrella term of cytokine storm syndrome. 5 Webb and colleagues report that meeting two or more cHIS criteria place patients with COVID-19 at increased risk of mortality and requiring invasive mechanical ventilation (odds ratio 1·6 [95% CI 1·2–2·1], p=0·0020, for mortality and 4·3 [3·0–6·0], p<0·0001, for mechanical ventilation). 3 The cHIS score also correlates with severity of oxygen requirement and risk for clinical deterioration of people with severe COVID-19. This finding is important for early recognition of patients with COVID-19 cytokine storm syndrome who might benefit from immunomodulatory or immunosuppressive approaches to treat the syndrome. 5 The rapidly changing approach to COVID-19 management, including the early initiation of glucocorticoids 7 during hospital admission, will probably modify components of the cHIS criteria, such as the presence of fever. This mirrors previous experience in children with systemic juvenile idiopathic arthritis in which IL-1 and IL-6 blocking biological treatments diminished the sensitivity of systemic juvenile idiopathic arthritis macrophage activation syndrome criteria. 8 As knowledge about COVID-19 grows, evidence from a full range of medical specialties will need to be assimilated to further define and categorise the role of hyperinflammation and cytokine storm syndrome in COVID-19 mortality and morbidity. One approach for diagnosing cytokine storm syndrome in general has been to simplify criteria for early recognition of cytokine storm syndrome in the setting of febrile individuals admitted to hospital based largely on hyperferritinaemia. 9 Indeed, algorithms in our own hospitals support obtaining ferritin on all patients admitted to hospital with COVID-19 to help identify signs of cytokine storm syndrome. Whether or not this reductionist methodology will be of value for COVID-19 cytokine storm syndrome remains to be seen. Moreover, there will probably need to be successive iterations of the cHIS criteria to best define those who will benefit from treatment that targets cytokine storm syndromes in the context of ongoing developments in standard of care. Currently, clinicians worldwide are reliant on a collaborative approach of colleagues in various subspecialties who recognise or diagnose and treat various cytokine storm syndromes. A multidisciplinary team of intensivists, pulmonologists, haemato-oncologists, infectious disease experts, and paediatric and adult rheumatologists, among others, can be beneficial for aiding people with COVID-19 hyperinflammation in particular and to build on cytokine storm syndrome expertise in general. Perhaps, geneticists will be valuable as well in the near future, as we learn the genetic predispositions for cytokine storm syndrome development in the setting of infections and other triggers of disease. 10 For now, Webb and colleagues are the first to report cytokine storm syndrome clinical criteria specific to COVID-19 in the form of cHIS. 3 Importantly, these criteria are relatively standard assessments that are readily available, timely, and not cost-prohibitive for most countries. These criteria will need validation, but for now, should help clinicians to recognise cytokine storm syndrome in the setting of COVID-19 for early initiation of potentially life-saving immunotherapy. © 2020 Fernando Da Cunha/SPL 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

          Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
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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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              On the Alert for Cytokine Storm: Immunopathology in COVID ‐19

              Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.
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                Author and article information

                Journal
                Lancet Rheumatol
                The Lancet Rheumatology
                Elsevier Ltd.
                2665-9913
                29 September 2020
                29 September 2020
                Affiliations
                [a ]Division of Rheumatology, Children's of Alabama and Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
                [b ]Division of Rheumatology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
                [c ]Sheffield Teaching Hospitals NHS Foundation Trust and Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
                Article
                S2665-9913(20)30335-0
                10.1016/S2665-9913(20)30335-0
                7524518
                a8d078aa-a528-4161-bff0-150dbfa5f5c5
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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