Defining the scourge of COVID-19 hyperinflammatory syndrome
Authors: Randy Q Cron, Grant S Schulert, Rachel S Tattersall
Journal: The Lancet Rheumatology (2020)

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,1Cron RQ Chatham WW The rheumatologist's role in COVID-19.J Rheumatol. 2020; 47: 639-642Crossref PubMed Scopus (86) Google Scholar, 2Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Summary Full Text Full Text PDF PubMed Scopus (6770) Google Scholar 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 colleagues3Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; (published online Sept 29.)https://doi.org/10.1016/S2665-9913(20)30343-XSummary Full Text Full Text PDF PubMed Scopus (212) Google Scholar 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,4Crayne C Cron RQ Pediatric macrophage activation syndrome, recognizing the tip of the iceberg.Eur J Rheumatol. 2020; 7: S13-S20Crossref Google Scholar 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.5Henderson LA Canna SW Schulert GS et al.On the alert for cytokine storm: immunopathology in COVID-19.Arthritis Rheumatol. 2020; 72: 1059-1063Crossref PubMed Scopus (490) Google Scholar 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).6Hutchinson M Tattersall RS Manson JJ Haemophagocytic lymphohisticytosis-an underrecognized hyperinflammatory syndrome.Rheumatology. 2019; 58: vi23-vi30Crossref PubMed Scopus (25) Google Scholar 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.5Henderson LA Canna SW Schulert GS et al.On the alert for cytokine storm: immunopathology in COVID-19.Arthritis Rheumatol. 2020; 72: 1059-1063Crossref PubMed Scopus (490) Google Scholar 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).3Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; (published online Sept 29.)https://doi.org/10.1016/S2665-9913(20)30343-XSummary Full Text Full Text PDF PubMed Scopus (212) Google Scholar 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.5Henderson LA Canna SW Schulert GS et al.On the alert for cytokine storm: immunopathology in COVID-19.Arthritis Rheumatol. 2020; 72: 1059-1063Crossref PubMed Scopus (490) Google Scholar The rapidly changing approach to COVID-19 management, including the early initiation of glucocorticoids7Horby P Lim WS Enberson JR et al.Dexamethasone in hospitalized patients with Covid-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Google Scholar 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.8Schulert GS Minoia F Bohnsack J et al.Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis.Arthritis Care Res. 2018; 70: 409-419Crossref PubMed Scopus (88) Google Scholar 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.9Eloseily EMA Minoia F Crayne CB Beukelman T Ravelli A Cron RQ Ferritin to erythrocyte sedimentation rate ratio: simple measure to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis.ACR Open Rheumatol. 2019; 1: 345-349Crossref PubMed Scopus (37) Google Scholar 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.10Schulert GS Cron RQ The genetics of macrophage activation syndrome.Genes Immun. 2020; 21: 169-181Crossref PubMed Scopus (57) Google Scholar For now, Webb and colleagues are the first to report cytokine storm syndrome clinical criteria specific to COVID-19 in the form of cHIS.3Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; (published online Sept 29.)https://doi.org/10.1016/S2665-9913(20)30343-XSummary Full Text Full Text PDF PubMed Scopus (212) Google Scholar 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. RQC reports grants and personal fees from SOBI, and personal fees from Novartis and Pfizer during the conduct of the study. GSS reports personal fees from SOBI and Novartis. RST declares no competing interests. Download .pdf (.18 MB) Help with pdf files Supplementary appendix Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort studyWe proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. Full-Text PDF