Randy Q. Cron, MD, PhD

Early during the coronavirus pandemic clinical reports suggested the presence of a cytokine storm syndrome in those most severely ill patients infected with SARS-CoV-2. More recently, there has been the suggestion based on lower levels of detectable serum cytokines, in comparison to sepsis and other conditions, that a cytokine storm may not be present in those with severe COVID-19. However, based on all the available data, the question is not a cytokine storm complicates a substantial portion of hospitalized COVID-19 patients, but rather what type of cytokine storm and how best to treat it.

Many of the patients who require hospitalization for SARS-CoV-2 infection are admitted for respiratory distress with an oxygen requirement that can quickly transition to acute respiratory distress syndrome (ARDS). The cytokine storm syndrome associated with COVID-19 is somewhat unique with ARDS presenting as an early finding whereas in other cytokine storm syndromes, like macrophage activation syndrome (MAS) complicating rheumatic diseases, lung involvement is typically a late finding. Cytokine storm syndrome is an umbrella term under which many related but somewhat distinct hyper-inflammatory conditions reside, including MAS, hemophagocytic lymphohistiocytosis (HLH) and cytokine release syndrome (CRS).

As noted in the terminology, elevated pro-inflammatory cytokines are associated with cytokine storm syndromes. Interleukin-18 (IL-18) tends to be high in MAS, interferon-gamma in HLH, and IL-6 in CRS. Serum IL-6 levels are often elevated in the blood of COVID-19 patients, particularly those with fever and ARDS; however, the relative level of IL-6 levels is generally much lower than seen in CRS for example. Some cytokines are difficult to measure in the blood, including IL-1 and interferon-gamma, but this does not indicate that they are not pathologically elevated nor does it imply that targeting these cytokines will not help treat the underlying cytokine storm syndrome. Moreover, although measuring serum levels of cytokines is more practical and facile, it does not necessarily represent what is occurring at the cellular level within various organ tissues. The diagnosis of a cytokine storm is also more complicated than simply measuring cytokine levels in the blood.

Cytokine storm syndromes frequently result in multi-organ system failure and can be manifested by liver failure, disseminated intravascular coagulopathy, pancytopenia, central nervous system (CNS) dysfunction, etc. Severe COVID-19 shares many of these features, including elevated liver enzymes, lymphopenia, clotting tendencies and CNS derangement. COVID-19 patients at risk of cytokine storm syndrome can often be recognized by some practical clinical and laboratory features such as fever, respiratory distress, lymphopenia, hyperferritinemia, and elevated serum levels of C-reactive protein, lactate dehydrogenase (LDH) and D-dimers.

Perhaps the most compelling evidence for a cytokine storm in the setting of severe COVID-19 is the response of patients to therapies utilized for other cytokine storm syndromes. To date, glucocorticoids have been the only treatment reported to reduce mortality in severe COVID-19. Glucocorticoids are standard or care in treating many forms of MAS and HLH. In addition, targeting cytokines, such as IL-1 and IL-6, has appeared promising in many historically controlled COVID-19 case series from across the globe. Patient selection (those with fevers, respiratory distress, and laboratory features of inflammation) and timing of administration of anti-cytokine approaches (after respiratory distress and hospitalization but prior to intensive care) will likely be crucial for demonstrating benefits in randomized clinical trials. While primary outcomes in randomized trials of some of the IL-6 blocking therapies have not been realized, there are numerous ongoing clinical trials targeting many aspects of the COVID-19 cytokine storm. In the end, perhaps broadly targeting of the COVID-19 cytokine storm with glucocorticoids will save the day for the planet as these drugs are effective, globally available, and relatively inexpensive.

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