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%,1WHOCoronavirus disease 2019 (COVID-19)situation report – 52.https://www.who.int/docs/default-source/coronaviruse/20200312-sitrep-52-covid-19.pdf?sfvrsn=e2bfc9c0_2Date: March 12, 2020Date accessed: March 13, 2020Google Scholar 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.2Ruan 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-xCrossref PubMed Scopus (3386) Google Scholar 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 infections3Ramos-Casals M Brito-Zeron P Lopez-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome.Lancet. 2014; 383: 1503-1516Summary Full Text Full Text PDF PubMed Scopus (874) Google Scholar and occurs in 3·7–4·3% of sepsis cases.4Karakike E Giamarellos-Bourboulis EJ Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis.Front Immunol. 2019; 10: 55Crossref PubMed Scopus (191) Google Scholar Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients.5Seguin A Galicier L Boutboul D Lemiale V Azoulay E Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis.Chest. 2016; 149: 1294-1301Summary Full Text Full Text PDF PubMed Scopus (117) Google Scholar 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.6Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Summary Full Text Full Text PDF PubMed Scopus (32861) Google Scholar 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),2Ruan 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-xCrossref PubMed Scopus (3386) Google Scholar suggesting 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.7Russell CD Millar JE Baillie JK Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395: 473-475Summary Full Text Full Text PDF PubMed Scopus (1530) Google Scholar 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.8Shakoory 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: 275-281Crossref PubMed Scopus (613) Google Scholar A multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China (ChiCTR2000029765).9Chinese Clinical Trial RegistryA multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19).http://www.chictr.org.cn/showprojen.aspx?proj=49409Date: Feb 13, 2020Date accessed: March 6, 2020Google Scholar Janus kinase (JAK) inhibition could affect both inflammation and cellular viral entry in COVID-19.10Richardson P Griffin I Tucker C et al.Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.Lancet. 2020; 395: e30-e31Summary Full Text Full Text PDF PubMed Scopus (1073) Google Scholar All patients with severe COVID-19 should be screened for hyperinflammation using laboratory trends (eg, increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) and the HScore11Fardet 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: 2613-2620Crossref PubMed Scopus (781) Google Scholar (table) to identify the subgroup of patients for whom immunosuppression could improve mortality. Therapeutic options include steroids, intravenous immunoglobulin, selective cytokine blockade (eg, anakinra or tocilizumab) and JAK inhibition.TableHScore for secondary HLH, by clinical parameterNumber of pointsTemperature<38·4°C038·4–39·4°C33>39·4°C49OrganomegalyNone0Hepatomegaly or splenomegaly23Hepatomegaly and splenomegaly38Number of cytopenias*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.One lineage0Two lineages24Three lineages34Triglycerides (mmol/L)<1·5 mmol/L01·5–4·0 mmol/L44>4·0 mmol/L64Fibrinogen (g/L)>2·5 g/L0≤2·5 g/L30Ferritin ng/ml<2000 ng/ml02000–6000 ng/ml35>6000 ng/ml50Serum aspartate aminotransferase<30 IU/L0≥30 IU/L19Haemophagocytosis on bone marrow aspirateNo0Yes35Known immunosuppression†HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).No0Yes18The Hscore11Fardet 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: 2613-2620Crossref PubMed Scopus (781) Google Scholar 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.11Fardet 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: 2613-2620Crossref PubMed Scopus (781) Google Scholar 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). Open table in a new tab The Hscore11Fardet 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: 2613-2620Crossref PubMed Scopus (781) Google Scholar 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.11Fardet 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: 2613-2620Crossref PubMed Scopus (781) Google Scholar HLH=haemophagocytic lymphohistiocytosis. 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. Incident systemic rheumatic disease following COVID-19Although viruses can induce rheumatic diseases, the impact of SARS-CoV-2, the virus behind COVID-19, on the development of systemic rheumatic disease is unclear. COVID-19 can cause a hyperinflammatory state,1 and multiple studies report the development of autoantibodies in patients with COVID-19.2,3 However, progression into clinical autoimmunity in adults has only been described in case reports. Full-Text PDF