COVID-19 cytokine storm syndrome: a threshold concept
Authors: Luke Y C Chen, Tien T T Quach
Journal: The Lancet Microbe (2021)

The COVID-19 pandemic has placed the practice of medicine at a threshold overlooking a new and different era,1Awdish RLA The liminal space.N Engl J Med. 2020; 383: e17Crossref PubMed Scopus (4) Google Scholar and has led to the evolving concept of COVID-19 cytokine storm syndrome (COVID-19-CSS). Early in the pandemic, high levels of inflammatory cytokines such as interleukin-6 (IL-6) were observed in patients with poor outcomes. Comparison with other cytokine storm syndromes, such as haemophagocytic lymphohistiocytosis (HLH), which are characterised by an excessive and deleterious immune response, led to the idea of a maladaptive immune response driving COVID-19-related morbidity and mortality. Simultaneously, support increased for testing and using immunosuppressive therapies such as cytokine blockade and JAK inhibition.2England JT Abdulla A Biggs CM et al.Weathering the COVID-19 storm: lessons from hematologic cytokine syndromes.Blood Rev. 2020; (published online May 15.)https://doi.org/10.1016/j.blre.2020.100707Crossref PubMed Scopus (123) Google Scholar However, the proposition that hypercytokinaemia is pathological has been met with scepticism—suppressing the immune response to a microbial pathogen runs counter to decades of medical teaching. Critics of COVID-19-CSS posit that hypercytokinaemia might be necessary for viral clearance and observe that median IL-6 levels are low in COVID-19 compared with other inflammatory conditions, such as acute respiratory distress syndrome (ARDS) and bacterial sepsis.3Leisman DE Ronner L Pinotti R et al.Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.Lancet Respir Med. 2020; 8: 1233-1244Summary Full Text Full Text PDF PubMed Scopus (544) Google Scholar Three lines of evidence have arisen to support the existence of COVID-19-CSS. First, several large studies have shown that IL-6 levels of more than 80 pg/mL are the best laboratory predictor of respiratory failure and death.4Chen LYC Hoiland RL Stukas S Wellington CL Sekhon MS Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome.Eur Respir J. 2020; 562003006Crossref PubMed Scopus (147) Google Scholar Inflammatory markers such as C-reactive protein and IL-6 are important components of prognostic models, such as the ISARIC 4C model and others.5Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; 2: e754-e763Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar In conditions for which IL-6 blockade is routinely used, such as rheumatoid arthritis and giant cell arteritis, IL-6 levels are often only modestly elevated, at less than 100 pg/mL. Second, a 2020 autopsy study6Schurink B Roos E Radonic T et al.Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.Lancet Microbe. 2020; 1: e290-e299Summary Full Text Full Text PDF PubMed Scopus (326) Google Scholar of 21 patients showed that many cases of lethal COVID-19 were associated with extensive multiorgan inflammation with only sporadic presence of virus. This finding suggests a maladaptive immune response, resulting in continuous neutrophil activation and organ damage. And finally, some patients with COVID-19 benefit from immunosuppression. The first medication shown to reduce mortality was dexamethasone, although the pleiotropic effects of corticosteroids and insufficiency of detailed inflammatory marker data from the RECOVERY trial limit the degree to which it substantiates the CSS concept.3Leisman DE Ronner L Pinotti R et al.Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.Lancet Respir Med. 2020; 8: 1233-1244Summary Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 7Gordon AC Interleukin-6 receptor antagonists in critically ill patients with COVID-19—preliminary report.medRxiv. 2021; (published online Jan 7.) (preprint)https://doi.org/10.1101/2021.01.07.21249390PubMed Google Scholar More recent studies showing benefit for tocilizumab in critically ill patients and baricitinib in hospitalised patients provide more substantial evidence that some patients with COVID-19 benefit from immunosuppressive therapies.7Gordon AC Interleukin-6 receptor antagonists in critically ill patients with COVID-19—preliminary report.medRxiv. 2021; (published online Jan 7.) (preprint)https://doi.org/10.1101/2021.01.07.21249390PubMed Google Scholar Cytokine storm from viral infection is well accepted in rare diseases such Epstein-Barr virus-associated HLH (EBV-HLH). The standard of care in EBV-HLH is etoposide-based chemotherapy. Extending the umbrella of cytokine storm from rare diseases, such as EBV-HLH, to apply to some patients suffering from a pandemic illness is a new threshold concept. In education, threshold concepts are not merely core concepts, but rather induce a transformed understanding without which the learner cannot progress.8Chen LYC Poole G Grappling with troublesome knowledge.Med Educ. 2018; 52: 584-586Crossref PubMed Scopus (4) Google Scholar, 9Meek SEM Neve H Wearn A Threshold concepts and troublesome knowledge.in: Nestel D Reedy G McKenna L Gough S Clinical education for the health professions: theory and practice. Springer Singapore, Singapore2020: 1-23Crossref Google Scholar Threshold concepts are typically applied to established principles; however, new concepts can also transform a discipline—eg, germ theory revolutionised medicine in the late 1800s, leading to aseptic technique, abandonment of ineffective concepts such as miasmas (poisoned air), and, ultimately, effective anti-microbial therapies and vaccines.10Karamanou M Panayiotakopoulos G Tsoucalas G Kousoulis AA Androutsos G From miasmas to germs: a historical approach to theories of infectious disease transmission.Infez Med. 2012; 20: 58-62PubMed Google Scholar We provide a comparison of how both germ theory and COVID-19-CSS can be viewed as threshold concepts (table).TableGerm theory and COVID-19-CSS as threshold concepts in medicineDescription of criterion for a threshold conceptGerm theoryCOVID-19-CSSTransformativeThe learner or practitioner's understanding of a subject is transformed; the threshold concept is a portal of entry into a new, previously inaccessible way of thinking about the subjectSpecific microbes cause specific diseases transformed the 19th century understanding of transmissible diseaseTreating the maladaptive host immune response in addition to the microbe is a transformative conceptTroublesomeInvolves knowledge that is often alien, confronting, or counterintuitive; drastically alters one's perception of how that piece of the world worksThat microscopic organisms are responsible for human diseaseImmunosuppression in acute infection is counterintuitive, and on the surface, contradicts traditional medical teachingIrreversibleOnce learned, a threshold concept cannot be unlearned. Subject experts might not recall their own difficulties in grasping a threshold concept and underestimate why it is problematic for novicesTheories such as miasmas (poisoned air) and abiogenesis (simple life arising from non-living material) recededOngoing work will refine the definition and treatment of COVID-19-CSSIntegrativeBrings together different aspects of the subject that previously did not seem (to the learner or practitioner) to be related. Connections between different subjects that were previously hidden are revealedKoch's postulates integrated findings from Ehrlich, Löeffler, and others to establish a causative relationship between a microbe and a particular diseaseIntegrates established concepts (eg, EBV-HLH) with current concepts (COVID-19-CSS or COVID-19 hyperinflammation)BoundedThe concept is limited by boundaries with other concepts and by disciplinary boundariesGerm theory was inaccurately applied to other diseases such as Hodgkin lymphomaNon-microbial CSSs (eg, GVHD, CART CRS) have limited applicability to COVID-19-CSSDiscursiveCrossing a conceptual threshold involves enhancement and extension of discipline-specific languageNumerous neologisms arose; microbiology, bacteriology, vaccinesCOVID-19 cytokine storm syndrome; COVID-19 hyperinflammation; pathological immune activationReconstitutiveThe learner or practitioner's understanding is reconfigured according to the new understandingHelped usher in the modern era of scientific medicineIdentifying maladaptive immune responses will probably apply to other microbial diseasesLiminalLearners occupy a transitional liminal space characterised by oscillation between old and new conceptual understandingsGerm theory was fiercely debated for many years before it was widely acceptedThe entire discipline of medicine has been in a liminal space during the current pandemic, with ongoing controversies surrounding the definition and significance of COVID-19-CSSCSS=cytokine storm syndrome. EBV-HLH=Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis. GVHD=graft-versus-host disease. CART CRS=chimeric antigen receptor associated cytokine release syndrome. Open table in a new tab CSS=cytokine storm syndrome. EBV-HLH=Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis. GVHD=graft-versus-host disease. CART CRS=chimeric antigen receptor associated cytokine release syndrome. The concept of pathological immune activation and its therapeutic corollary, immunosuppression for the treatment of an infection, is most certainly troublesome and transformative. CSS does not apply to all patients with COVID-19. Identifying patients with immune misfiring and the most appropriate immunomodulatory therapy will require ongoing clinical trials. Given that new pandemics are certain to arise, learning how to identify and modulate maladaptive immune responses in our current liminal space is an essential learning opportunity. We declare no competing interests.