Mast cell activation disorders : a liaison between anaphylaxis and mastocytosis

The term mast cell activation disorders (MCAD) comprises a broad spectrum of heterogeneous conditions, such as mastocytosis, characterized by inappropriate mast cell activation/accumulation. The patients present with protean clinical manifestations and severity grade of symptoms may vary from case-to-case. The periodic or chronic symptoms that attributable to the local and systemic effects of mast cell mediators are common findings, where anaphylaxis appears to be one of the predominating clinical manifestations that generate a sensation of fear in most affected patients. The overall aim of this thesis was to provide data on the demographic, epidemiologic and clinical characteristic of patients with systemic mastocytosis, and to investigate the prevalence and features of mast cell mediatorinduced symptoms, in particular, anaphylaxis. In addition, the complex interaction between anaphylaxis and mast cell activation disorders was explored by identifying risk factors. In Paper I, the case presented highlighted the many faces of mastocytosis and proved also that there was a lack of recognition of mastocytosis symptoms among physician. In this particular case, a correct diagnosis required almost 20 years despite that the patient had consulted several doctors and underwent extensive medical investigations. The turning point for making right diagnosis was to confirm that this patient had an elevated level of baseline serum tryptase. In Paper II, three puzzling cases of hymenoptera venom-induced anaphylaxis (HVA) with elevated levels of baseline tryptase were discussed. Although all three patients presented with demographically and clinically similar data and received diagnosis of HVA using traditional allergy work-up, investigation of bone marrow mast cells led to changes in final diagnosis. This paper lends further support to the hypothesis of a clear-cut association between severe HVA and clonal mast cell disorders. In Paper III, we provided a comprehensive insight into patients with systemic mastocytosis (SM) with respect to allergological aspects of this disease. We reported the presence of mast cell mediator induced symptoms in 90% of SM patients, of these symptoms 63% were related to gastrointestinal symptoms. In addition, the prevalence of anaphylaxis in this cohort was found to be clearly increased (43%). Hymenoptera sting was the main elicitors (53%) followed by idiopathic anaphylaxis (39%). Anaphylaxis occurred more frequently in SM patients with atopic predisposition and patients without cutaneous engagement. Also, baseline tryptase levels were significantly lower in SM patients with anaphylaxis. In Paper IV, we presented comprehensive data on the characteristics of patients with unexplained anaphylaxis (UEA), by investigating these patients’ bone marrow mast cells. We found that 47% of patients had clonal markers of aberrant mast cells. Baseline serum tryptase levels were significantly higher (≥11.4 ng/ml) and conversely, total IgE levels were lower in patients with clonal mast cell disorders compared to patients with true idiopathic anaphylaxis. In Paper V, we sought to examine whether mast cells of patients with mast cell disorders express hyperreactivity in the skin and lower airways compared to control subjects. We also analyzed different mast cell mediators (serum tryptase and urinary histamine and prostaglandin D2 metabolites). Although we found elevated baseline levels of these mediators in patients with SM/MCAD, we found no evidence to support the hypothesis that a hyperreactive mast cell phenotype would exist in the skin or bronchial airways of these patients. In conclusion, the work presented in this thesis provides a better understanding of different phenotypes of patients with mast cell disorders. We observed a high prevalence of anaphylaxis in these patients. Our findings, thus, support that all patients with mast cell activation disorders should undergo comprehensive allergy work-up providing personal risk assessment before considering treatment and preventive measures. Our data also indicates that clonal mast cell disorders are present in a substantial subset of patients with UEA. LIST OF SCIENTIFIC PAPERS I. Gülen T, Hägglund H, Dahlen SE, Sander B, Dahlen B, Nilsson G. Flushing, fatigue, and recurrent anaphylaxis: a delayed diagnosis of mastocytosis. Lancet. 2014 May 3; 383(9928):1608. II. Gülen T, Dahlen B, Sander B, Hägglund H, Nilsson G. The significance of diagnosing associated clonal mast cell diseases in patients with venominduced anaphylaxis and the role of bone marrow investigation. Clinical and translational allergy. 2013;3(1):22. III. Gülen T, Hägglund H, Dahlen B, Nilsson G. High prevalence of anaphylaxis in patients with systemic mastocytosis a single-centre experience. Clin Exp Allergy. 2014 Jan;44(1):121-9. IV. Gülen T, Hägglund H, Sander B, Dahlen B, Nilsson G. The presence of mast cell clonality in patients with unexplained anaphylaxis. Clin Exp Allergy. 2014 Sep;44(9):1179-87. V. Gülen T, Möller-Westerberg C, Lyberg K, Kolmert J, Bood J, Öhd J, Dahlén S-E, Nilsson G, Dahlén B. In-vivo mast cell reactivity in patients with mastocytosis and related mast cell activation disorders. (Manuscript)