Cytokine Drizzle—The Rationale for Abandoning “Cytokine Storm”

Abstract

Background: ''Cytokine storm'' has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a ''cytokine storm'' resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a ''cytokine storm'' has yet to be defined. Methods: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. Results: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 ¼ 34 pg/mL; Crohn's disease, IL-6 ¼ 5 pg/mL), yet respond dramatically to cytokine inhibitors. Conclusion: The misleading term ''cytokine storm'' implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term ''cytokine storm''. ''Cytokine storm'' should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.

Should We Interfere with the Interleukin-6 Receptor During COVID-19: What Do We Know So Far?

“…Therefore, the immunologic response develops mainly in the lungs, especially the alveoli, with cytokine concentrations observed in the circulation being only an approximative marker of the intensity of the proinflammatory response [ 24 ]. Numerous studies in patients with disease of varying severity have found consistent values of serum IL-6 levels from 5.0 to approximately 240 pg/mL (see Tables 1 and 2 ), partially depending on the degree of severity [ 11 , 25 , 39 , 42 , 43 , 47 – 58 ]. In mild and moderate COVID-19, requiring hospitalization but not intensive care or resuscitation, circulating IL-6 concentrations are particularly low, around 5 pg/mL [ 42 , 59 ].…”

“…For further information, we recommend that the readers refer to [ 20 – 23 ]. Among the considerable number of inflammatory mediators produced or secreted in the inflammatory response, interleukin-6 (IL-6) has been shown to play a significant role [ 24 ], which is likely due to its high levels of expression rather than to the singularity of its action, as all mediators produced are somewhat redundant in their actions [ 25 ]. Nonetheless, pro-inflammatory mediators, in particular IL-6, are extensively produced by lung epithelial cells during COVID-19 and notably infect type 2 pneumocytes [ 26 ].…”

Cytokine Storm—Definition, Causes, and Implications

“…Especially in patients with an unfavorable clinical course, the typical appearance is an exuberant immune response with hyperactivity of dendritic cells, lymphocytes, macrophages, and other immune cells, leading to a self-sustaining and self-amplifying pathophysiology. Usually, elevated levels of inflammatory markers such as IL-6, IL-8, IL-10, ferritin, and CRP are found in these patients; however, CS, sensu stricto, can only be detected in a minority of cases, and some authors claim that “the storm is rather a breeze” [ 134 , 135 , 136 , 137 ]. Yet, primary major compartmentalized CS in the context of COVID-19 occurs regularly in the lungs [ 138 , 139 ].…”

Revisiting Metchnikoff's work in light of the COVID-19 pandemic

“…The severity of COVID-19 is exacerbated in obese patients in whom a contribution of macrophages, in an activated state in adipose tissue, is suspected 24 . Many scientists have mentioned that a cytokine storm was characteristic of COVID-19, but within the peripheral blood, it is more of a small drizzle 25 - 27 . In contrast, in the most severe patients, this storm operates in their lungs where cytokines contribute to tissue damage and mortality 28 .…”