"In short, cytokine storm involves an immune response that causes collateral damage, which may be greater than the immediate benefit of the immune response."
— Carl H. June, MD, and David C. Fajgenbaum, MD, December 2020
It is a now familiar story - following her third infusion for CAR T cell therapy to treat acute lymphoblastic leukemia, young Emily Whitehead developed pyrexia, respiratory failure, severe hypotension and shock. Shortly thereafter, an expedited blood test revealed a thousand-fold increase in the cytokine IL-6. Fortunately, an IL-6 inhibitor, the monoclonal antibody tocilizumab, had recently been FDA approved to treat systemic juvenile idiopathic rheumatoid arthritis. By luck, Emily's caregivers were aware of this fact because the daughter of team member Carl June, MD, had recently begun taking the drug.
Emily is administered tocilizumab, experiences a rapid and complete recovery and is alive today. (Emily's experience and the early history of CAR T therapy are superbly related by Dr. Lisa Rosenbaum in the New England Journal of Medicine).
Emily's symptoms were caused by what is now known as cytokine storm, an exaggerated immune response driven by the pro-inflammatory cytokines IL-6, IL-1 and TNF-alpha, among other contributors. In the absence of treatment, cytokine storm can lead to hemodynamic instability, multi-organ failure and mortality, particularly in high-risk patients.
Carl H. June, MD, and David C. Fajgenbaum, MD
The cytokines are small, secreted proteins produced by the leukocytes of the innate immune system, and are mutable, in that some are pro-inflammatory, others anti-inflammatory, and a few have both characteristics. All act as chemical messengers in the immune response. In the presence of microbial invaders, pro-inflammatory cytokines are released to draw immune cells to the site, encourage inflammation, stimulate antibody production and increase core body temperature. With other effects, pro-inflammatory cytokines have the capacity to initiate an ever greater cascade of cytokine production from the proliferation of immune system cells arising in the wake of infection. Normally cast as immunoregulators, the anti-inflammatory cytokines are overwhelmed, setting the stage for immune dysregulation and massive systemic inflammation.
Cytokine storm has a unique identification with research at Penn Medicine and the Abramson Cancer Center, where its association with CAR T therapy was discovered, and where it has been the focus of study for more a decade. In December 2020, to mark the 10th anniversary of the first published description of CAR T-derived cytokine storm (described above), Drs. David Fajgenbaum and Carl June reviewed cytokine storm in the New England Journal of Medicine.
At Penn, Dr. Fajgenbaum leads the Center for Cytokine Storm Treatment & Laboratory (CSTL). He is also the co-founder and President of the Castleman Disease Collaborative Network (CDCN), and an internationally recognized investigator of the signaling pathways linked to cytokine storm in idiopathic multicentric Castleman's.
Given the expertise of the authors, their article offers invaluable direction for the evaluation and management of the patient with cytokine storm (particularly with regard to root cause), as well as a comprehensive profile of the many clinical and laboratory anomalies observed and the grading systems used to predict and assess the severity of the condition.
The distinction between normal and dysregulated responses to severe infection in the context of cytokine activation has complicated the definition of cytokine storm. To clarify this issue, Drs. Fajgenbaum and June propose three criteria for identifying cytokine storm, which can be abridged as
- elevated circulating cytokine levels,
- acute systemic inflammatory symptoms and
- either secondary organ dysfunction or, in the absence of a pathogen, any cytokine-driven organ dysfunction.
Like much else in the discourse surrounding cytokine storm, these criteria are a source of ongoing discussion.
Cytokine storm and COVID-19
Soon after the onset of the COVID-19 pandemic, researchers and clinicians began reporting episodes of a condition resembling cytokine storm in certain high-risk patient subsets. Again, the pro-inflammatory cytokines were cited as leading culprits in an uncontrolled immune activation, and some of the effects of the condition were familiar. However, the character of the cytokine storm identified with COVID seemed unlike that found elsewhere, particularly with regard to lymphopenia and the activation of thrombotic pathways.
Moreover, the implications of therapy for cytokine storm identified with COVID are somewhat different than those for other disease states. The drugs used to treat cytokine storm (including Tocalizumab and the glucocorticoids), are immunosuppressants. On the face of it, inducing immune suppression in the presence of active viral infection, particularly for a virus for which no active treatment exists, seems counter-intuitive. Elaborating on these differences, Drs. Fajgenbaum and June note that cytokines may be both a cause of cytokine storm in COVID infection and of the antimicrobial response.
"Thus," the authors write, "blocking cytokine signaling may actually impair clearance of SARS-CoV-2, increase the risk of secondary infections, and lead to worse outcomes, as seen with influenza virus."
Regarding this point, the authors conclude that because cytokines are critical to both cytokine storm and a healthy response to SARS-CoV2, it is particularly important that the right subgroups of patients with Covid-19 be selected for treatment, and treated at the right time.
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