Massive release of TH2 cytokines induced a cytokine storm during a severe mast cell activation event in a patient with indolent systemic mastocytosis

Abstract

In subjects with systemic mastocytosis, the number of mast cells is elevated many fold. These patients frequently experience unpredictable and recurrent life-threatening mast cell activation (MCA) events. Our aim was to analyze the derangements of chemokine and cytokine concentrations during severe MCA attacks. Samples from a patient with indolent systemic mastocytosis were used for this study. Atotal of 41 chemokines and cytokines were simultaneously measured in triplicate and at multiple time points during 2 severe and 2 moderate MCA events. These were compared to 3 to 5 baseline samples, taken when clinical symptoms were not present. During the severe MCA event, which required 2 days of treatment in the intensive care unit, peak chemokine (C-C motif) ligand 3, IL-1ra, IL-5, IL-6, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor concentrations were statistically significantly elevated 29-, 99-, 44-, 280-, 93-, 7-, and 6-fold above baseline, respectively. Ahighly similar pattern was observed during the second severe MCA event. In the moderate MCA event with PCR-proven influenza Ainfection, the TH1-associated cytokines INF-α, INF-γ, and TNF-α were only statistically significantly elevated 5- to 7-fold above baseline. The correlation coefficients between highly elevated histamine and cytokine concentrations during the acute phase were >95%, indicating the same cellular origin, possibly activated mast cells. One of the severe MCA events led to life-threatening symptoms over several days. During this event, the massive release of TH2 cytokines induced a hyperinflammatory state, fulfilling published criteria for cytokine release syndrome. Administration of IL-6- and IL-5-inhibiting biologicals might significantly shorten the acute phase of severe MCA events, likely offering significant clinical benefits to mastocytosis patients.