Brown, M

Manson, JJ

McAuley, DF

Mehta, P

Sanchez, E

Tattersall, RS

English

UCL Discovery

  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.  Correspondencewww.thelancet.com   Vol 395   March 28, 2020 1033Submissions should be made via our electronic submission system at http://ees.elsevier.com/thelancet/However, in hyperinflammation, immunosuppression is likely to be beneficial. Re-analysis of data from a phase 3 randomised controlled trial of IL-1 blockade (anakinra) in sepsis, showed significant survival benefit in patients with hyperinflammation, without increased adverse events.8 A multicentre, randomised con trolled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved in patients with COVID-19: consider cytokine storm syndromes and immunosuppressionAs of March 12, 2020, coronavirus disease 2019 (COVID-19) has been con firmed 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 syn-drome (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 infections3 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 chemo-attractant 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<0·001) and IL-6 (p<0·0001),2 sug-gesting that mortality might be due to virally driven hyperinflammation.As during previous pandemics (severe acute respiratory syndrome and Middle East respiratory syndrome), corticosteroids are not routinely recommended and might exacerbate COVID-19-associated lung injury.7 Number of pointsTemperature<38·4°C 038·4–39·4°C 33>39·4°C 49OrganomegalyNone 0Hepatomegaly or splenomegaly 23Hepatomegaly and splenomegaly 38Number of cytopenias*One lineage 0Two lineages 24Three lineages 34Triglycerides (mmol/L)<1·5 mmol/L 01·5–4·0 mmol/L 44>4·0 mmol/L 64Fibrinogen (g/L)>2·5 g/L 0≤2·5 g/L 30Ferritin ng/ml<2000 ng/ml 02000–6000 ng/ml 35>6000 ng/ml 50Serum aspartate aminotransferase<30 IU/L 0≥30 IU/L 19Haemophagocytosis on bone marrow aspirateNo 0Yes 35Known immunosuppression†No 0Yes 18The HScore11 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 long-term immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).Table: HScore for secondary HLH, by clinical parameterPublished Online March 13, 2020 https://doi.org/10.1016/S0140-6736(20)30628-0For the HScore calculator see http://saintantoine.aphp.fr/score/Correspondence1034 www.thelancet.com   Vol 395   March 28, 2020The first question is why there was reluctance to call the COVID-19 outbreak a pandemic, and the second question is whether the terminology is of any practical importance.In almost all good textbooks, an epidemic becomes a pandemic when there is widespread geographical distribution of the disease. For some weeks, the COVID-19 epidemic, which had spread to over 100 countries, seemed to fit the classical definition of a pandemic. One could reasonably ask whether the use of the term pandemic would change any of the actions necessary to control the spread of the virus.There are several situations in which it could be helpful to use well defined terminology to control the spread of an infectious disease. The resources for controlling a pandemic are both different, substantially larger, and generally much more far-reaching than for a localised outbreak or epidemic. Thus the terms used for the different situations could be restricted according to the control measures that are necessary. Perhaps unique to pandemics, these include considerable international coordination and collaboration in providing aid to affected countries, recruiting the necessary resources for promoting research on medications and vaccines, and developing complex risk communication. In particular, travel restrictions become a major issue and, although these are guided by the International Health Regulations, countries have the option to adopt unilaterally their own barriers to international travel. This was clearly the case for COVID-19. If the term pandemic is clearly defined, it can communicate much more clearly the seriousness of the situation and help justify the extreme measures instituted. It can also provide the international health community with a common term to enlist the cooperation of the general public and convey the necessary sense of urgency to decision makers. This should stimulate rapid 2 Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; published online March 3. DOI:10.1007/s00134-020-05991-x.3 Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet 2014; 383: 1503–16.4 Karakike E, Giamarellos-Bourboulis EJ. Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis. Front Immunol 2019; 10: 55.5 Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis. Chest 2016; 149: 1294–301.6 Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506.7 Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395: 473–75.8 Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase iii trial. Crit Care Med 2016; 44: 275–81.9 Chinese Clinical Trial Registry. A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). Feb 13, 2020. http://www.chictr.org.cn/showprojen.aspx?proj=49409 (accessed March 6, 2020).10 Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020; 395: e30–31.11 Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66: 2613–20.COVID-19 pneumonia and elevated IL-6 in China (ChiCTR2000029765).9 Janus kinase (JAK) inhibition could affect both inflammation and cellular viral entry in COVID-19.10All patients with severe COVID-19 should be screened for hyperinflam-mation using laboratory trends (eg, increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) and the HScore11 (table) to identify the subgroup of patients for whom immunosuppression could improve mortality. Therapeutic options include steroids, intravenous immuno globulin, selective cytokine blockade (eg, anakinra or tocilizumab) and JAK inhibition.PM is a clinical training fellow within the Experimental Medicine Initiative to Explore New Therapies network and receives project funding unrelated to this Correspondence. PM also receives co-funding by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. DFM chairs the NIHR and Medical Research Council funding committee for COVID-19 for therapeutics and vaccines. DFM reports personal fees from consultancy for ARDS for GlaxoSmithKline, Boehringer Ingelheim, and Bayer; in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, and others, all unrelated to this Correspondence. DFM also has a patent issued to his institution for a treatment for ARDS. DFM is a Director of Research for the Intensive Care Society and NIHR Efficacy and Mechanism Evaluation Programme Director. All other authors declare no competing interests.Puja Mehta, Daniel F McAuley, Michael Brown, Emilie Sanchez, Rachel S Tattersall, *Jessica J Manson, on behalf of the HLH Across Speciality Collaboration, UKjessica.manson@nhs.netCentre for Inflammation and Tissue Repair, UCL Respiratory, Division of Medicine, University College London, London, UK (PM); Department of Rheumatology (JJM), Hospital for Tropical Diseases (MB), and Department of Clinical Virology (ES), University College London Hospital, London NW1 2PG, UK; Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK (DFM); Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK (DFM); Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK (RST); and Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, UK (RST)1 WHO. Coronavirus disease 2019 (COVID-19)situation report – 52. March 12, 2020. https://www.who.int/docs/default-source/coronaviruse/20200312-sitrep-52-covid-19.pdf?sfvrsn=e2bfc9c0_2 (accessed March 13, 2020).Did the hesitancy in declaring COVID-19 a pandemic reflect a need to redefine the term?WHO’s declaration that the global spread of coronavirus disease 2019 (COVID-19) is a pandemic1 has contributed greatly to clearing up confusion in the terminology in the professional literature and the media. Discussions on when wide geographical spread of a disease becomes a pandemic tend to recur when the world is confronted with an emerging infectious disease.2,3 The debate around the terminology used for COVID-19 raises two important questions. Published Online March 12, 2020 https://doi.org/10.1016/ S0140-6736(20)30630-9For the International Health Regulations see https://www.who.int/ihr/en/

COVID-19: consider cytokine storm syndromes and immunosuppression

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COVID-19: consider cytokine storm syndromes and immunosuppression

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