COVID-19 cytokine storm syndrome: a threshold concept

The COVID-19 pandemic has placed the practice of medicine at a threshold overlooking a new and different era,¹ 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.²

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.³

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.⁴ Inflammatory markers such as C-reactive protein and IL-6 are important components of prognostic models, such as the ISARIC 4C model and others.⁵ 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 study⁶ 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.3, 7 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.⁷

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.8, 9 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.¹⁰ We provide a comparison of how both germ theory and COVID-19-CSS can be viewed as threshold concepts (table ).

Table.

Germ theory and COVID-19-CSS as threshold concepts in medicine

	Description of criterion for a threshold concept	Germ theory	COVID-19-CSS
Transformative	The 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 subject	Specific microbes cause specific diseases transformed the 19th century understanding of transmissible disease	Treating the maladaptive host immune response in addition to the microbe is a transformative concept
Troublesome	Involves knowledge that is often alien, confronting, or counterintuitive; drastically alters one's perception of how that piece of the world works	That microscopic organisms are responsible for human disease	Immunosuppression in acute infection is counterintuitive, and on the surface, contradicts traditional medical teaching
Irreversible	Once 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 novices	Theories such as miasmas (poisoned air) and abiogenesis (simple life arising from non-living material) receded	Ongoing work will refine the definition and treatment of COVID-19-CSS
Integrative	Brings 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 revealed	Koch's postulates integrated findings from Ehrlich, Löeffler, and others to establish a causative relationship between a microbe and a particular disease	Integrates established concepts (eg, EBV-HLH) with current concepts (COVID-19-CSS or COVID-19 hyperinflammation)
Bounded	The concept is limited by boundaries with other concepts and by disciplinary boundaries	Germ theory was inaccurately applied to other diseases such as Hodgkin lymphoma	Non-microbial CSSs (eg, GVHD, CART CRS) have limited applicability to COVID-19-CSS
Discursive	Crossing a conceptual threshold involves enhancement and extension of discipline-specific language	Numerous neologisms arose; microbiology, bacteriology, vaccines	COVID-19 cytokine storm syndrome; COVID-19 hyperinflammation; pathological immune activation
Reconstitutive	The learner or practitioner's understanding is reconfigured according to the new understanding	Helped usher in the modern era of scientific medicine	Identifying maladaptive immune responses will probably apply to other microbial diseases
Liminal	Learners occupy a transitional liminal space characterised by oscillation between old and new conceptual understandings	Germ theory was fiercely debated for many years before it was widely accepted	The 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-CSS

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.