Cluster-Analytic Identification of Clinically Meaningful Subtypes in MCAS: The Relevance of Heat and Cold

Abstract

Background: Mast cell activation syndrome (MCAS) is a clinically heterogeneous disease with allergy-like symptoms and abdominal complaints. Its etiology is only partially understood and it is often overlooked.

Aims: The aim of this study was to identify subgroups of MCAS patients to facilitate diagnosis and allow a personalized therapy.

Methods: Based on data from 250 MCAS patients, hierarchical and two-step cluster analyses as well as association analyses were performed. The data used included data from a MCAS checklist asking about symptoms and triggers and a set of diagnostically relevant laboratory parameters.

Results: Using a two-step cluster analysis, MCAS patients could be divided into three clusters. Physical trigger factors were particularly decisive for the classification as they showed remarkable differences between the three clusters. Cluster 1, labeled high responders, showed high values for the triggers heat and cold, whereas cluster 2, labeled intermediate responders, presented with high values for the trigger heat and low values for cold. The third cluster, labeled low responders, did not react to thermal triggers. The first two clusters showed more divers clinical symptoms especially with regard to dermatological and cardiological complaints. Subsequent association analyses revealed relationships between triggers and clinical complaints: Abdominal discomfort is mainly triggered by histamine consumption, dermatological discomfort by exercise, and neurological symptoms are related to physical exertion and periods of starvation. The reasons for the occurrence of cardiological complaints are manifold and triggers for respiratory complaints still need better identification.

Conclusion: Our study identified three distinct clusters on the basis of physical triggers, which also differ significantly in their clinical symptoms. A trigger-related classification can be helpful in clinical practice for diagnosis and therapy. Longitudinal studies should be conducted to further understand the relationship between triggers and symptoms.

Keywords: Cluster analysis; Food intolerance; Histamine; IBS; MCAS; Mast cell activation syndrome; Multisystemic complaints; SM; Systemic mastocytosis.

Fig. 1

A The prevalence of the triggers in the study cohort is given as a percentage. B The prevalence of initial triggers is given as a percentage. C Result of two-step cluster analysis. A value of 1 means that 100 percent of the patients in the cluster reported this trigger, whereas a value of 0 indicates that none of the patients reported it. D Prevalence of the symptoms in the three clusters given as a percentage. p-values were calculated with chi-square test

Fig. 2

The respective prevalence of Abdominal (A), Respiratory (B), Neurological (C), Cardiological (D), and Dermatological (E) are given as percentage. In F, the prevalence are given for progressive course of the complaints

Fig. 3

A Predictor importance table created with SPSS two-step cluster analysis. The formation of the clusters should be limited to the most important factors [47]. In this example, these could be clearly identified as physical exertion, heat, and cold. B Chart created with SPSS two-step cluster analysis, BIC values against number of clusters. The largest change in BIC values marks the optimal number of clusters. The largest change in BIC values was seen in the step from a 1 cluster to a 2 cluster and in the change from a 2-cluster to a 3-cluster solution. C Silhouette measure of cohesion and separation for a 2-cluster solution, the larger the silhouette measure for cohesion and separation becomes, the better the cluster result. D Silhouette measure of cohesion and separation for a 3-cluster solution

Fig. 4

A to E Boxplots for the respective laboratory parameters were in the reference range. F Boxplots of NMH created separately for men and women. The difference in urine NMH concentration between men and women was statistically significant as indicated by the p-value calculated with Wilcoxon–Mann–Whitney Test. Laboratory chemistry revealed normal mean values and medians for tryptase, chromogranin A, neuron-specific enolase, and immunoglobulin E (A–E). N-methylhistamine (NMH) in urine was elevated (average of 9.7 μg/mmol/Cr/m² Body Surface Area versus the reference value of < 6.5). 75% of MCAS patients had median NMH levels above the reference value (F). The median NMH excretion was significantly higher in women than in men (F)