COVID-19: consider cytokine storm syndromes and immunosuppression

Remoted remoted 2020. 3. 21. 20:20

Published:March 16, 2020DOI:



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%,


 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.


 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


 and occurs in 3·7–4·3% of sepsis cases.


 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients.


 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.


 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),


 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.


 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.


 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).


 Janus kinase (JAK) inhibition could affect both inflammation and cellular viral entry in COVID-19.


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 HScore


 (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 parameter

Number of points

<38·4°C 0
38·4–39·4°C 33
>39·4°C 49
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)
<1·5 mmol/L 0
1·5–4·0 mmol/L 44
>4·0 mmol/L 64
Fibrinogen (g/L)
>2·5 g/L 0
≤2·5 g/L 30
Ferritin ng/ml
<2000 ng/ml 0
2000–6000 ng/ml 35
>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


 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.


 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).

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.


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Published: March 16, 2020




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