Theoharides, Theoharis C, Tsilioni, Irene, Ren, Huali · Expert review of clinical immunology · 2019 · DOI
Mast cells are immune cells in your body that release chemical messengers (mediators) in response to many different triggers—not just allergies. When these cells release too many mediators, they can cause widespread symptoms affecting multiple body systems, including the brain and nervous system. This review suggests that doctors should look for elevated levels of these chemical messengers to help diagnose and treat these conditions, rather than waiting for the traditional markers (like histamine and tryptase) that don't always show up.
Many ME/CFS patients experience multi-system symptoms (neurological, immune, gastrointestinal) that overlap with mast cell mediator disease, yet remain undiagnosed under existing criteria. This framework may help clinicians recognize and validate mast cell dysfunction as a potential mechanism in ME/CFS and guide development of targeted treatments beyond antihistamines. Expanding diagnostic criteria to include neuropsychiatric symptoms and diverse mediator profiles could improve identification and management of ME/CFS patients with underlying mast cell pathology.
This review does not directly demonstrate that mast cell mediator disorders are a primary cause of ME/CFS, nor does it establish causation between specific mediators and individual symptoms. The proposed MCMD diagnostic criteria have not yet been prospectively validated in clinical trials, and the study does not compare prevalence of mast cell mediators in ME/CFS populations versus healthy controls. The literature-based methodology cannot establish which mediator panels are most clinically relevant for diagnosis or prognosis.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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Primary citation
Theoharides, Theoharis C, Tsilioni, Irene, & Ren, Huali (2019). Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders?. Expert review of clinical immunology. https://doi.org/10.1080/1744666X.2019.1596800
BibTeX
@article{mecfsatlas-theoharides-2019-recent-advances,
author = {Theoharides, Theoharis C and Tsilioni, Irene and Ren, Huali},
title = {Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders?},
journal = {Expert review of clinical immunology},
year = {2019},
doi = {10.1080/1744666X.2019.1596800},
note = {PubMed: 30884251},
url = {https://www.mecfsatlas.com/evidence/theoharides-2019-recent-advances},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-30. https://www.mecfsatlas.com/evidence/theoharides-2019-recent-advances
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