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

Thomas Boehm; Robin Ristl; Jakob Mühlbacher; Peter Valent; Markus Wahrmann; Bernd Jilma

doi:10.1016/j.jaci.2022.04.023

Massive release of T_H2 cytokines induced a cytokine storm during a severe mast cell activation event in a patient with indolent systemic mastocytosis

J Allergy Clin Immunol. 2022 Aug;150(2):406-414.e16. doi: 10.1016/j.jaci.2022.04.023. Epub 2022 Apr 30.

Authors

Thomas Boehm¹, Robin Ristl², Jakob Mühlbacher³, Peter Valent⁴, Markus Wahrmann⁵, Bernd Jilma⁶

Affiliations

¹ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: thomas.boehm@meduniwien.ac.at.
² Section for Medical Statistics (IMS), Center of Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
³ Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria.
⁴ Department of Internal Medicine I, Division of Hematology & Hemostaseology and the Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
⁵ Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
⁶ Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

PMID: 35504498
DOI: 10.1016/j.jaci.2022.04.023

Abstract

Background: 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.

Objective: Our aim was to analyze the derangements of chemokine and cytokine concentrations during severe MCA attacks.

Methods: Samples from a patient with indolent systemic mastocytosis were used for this study. A total 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.

Results: 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. A highly similar pattern was observed during the second severe MCA event. In the moderate MCA event with PCR-proven influenza A infection, the T_H1-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.

Conclusions: One of the severe MCA events led to life-threatening symptoms over several days. During this event, the massive release of T_H2 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.

Keywords: Mast cell activation; T(H)2 cytokines; cytokine release syndrome; cytokine storm; mastocytosis.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Chemokines
Cytokine Release Syndrome*
Cytokines*
Humans
Interleukin-5
Interleukin-6
Mast Cells
Mastocytosis, Systemic*
Th2 Cells

Substances

Chemokines
Cytokines
Interleukin-5
Interleukin-6