Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022

Abstract

Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual's baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.

Keywords: Mast cell activation syndrome (MCAS); Classification; Diagnostic MCAS criteria; IgE; Mast cells; Tryptase.

Fig. 1

Approach to patients with suspected MCAS. In a first step, patients are examined for typical symptoms of MCA. In some of these patients, the symptoms are compatible with the diagnosis of anaphylaxis which increases the likelihood that the patient has an MCAS. In other patients, criteria for anaphylaxis are not met but symptoms still suggest MCA. In both groups, criteria for MCAS are applied. When MCAS criteria are met, the diagnosis MCAS is established, and the type of MCAS is defined. When MCAS criteria are not fulfilled, the patient may still suffer from MCA or a MCAD, for example, local MCA or a less severe form of MCA. When symptoms of MCA are mild, only local, or no signs for MCA are found, it is important to ask for alternative etiologies. In these patients, no symptoms of anaphylaxis are found, and serum tryptase levels do not increase over baseline during symptoms. Thicker arrows indicate the main-lines in the algorithm. In a very few patients without evidence of MCAS, the physician may ask for signs and symptoms of other MCAD (dashed line).

Fig. 2

Figure classification of MCAS based on underlying etiologies and disorders. When MCAS criteria are fulfilled, patients are examined for the presence of clonal KIT-mutated MCs (usually KIT D816V by qPCR), for the presence of HαT (by droplet digital PCR), and for underlying comorbidities, the most prevalent and clinically important one being an IgE-dependent allergy. When no clonal MCs and no IgE-dependent allergy (or other underlying reactive/atopic disease) is detected, the patient is either suffering from idiopathic MCAS or from a pure HαT+ MCAS. When more than one family member in such a HαT+ family fulfill MCAS criteria, the term hereditary or familial MCAS is also appropriate. When KIT D816V+ MCs are detected, a primary (clonal) form of MCAS is diagnosed. This MCAS variant is also known as MMAS. In most of these patients, an underlying SM is found. In MCAS patients who are suffering from a documented IgE-dependent allergy (or another form of allergy/atopy or another reactive underlying process that can explain anaphylaxis and MCAS), a secondary MCAS will be diagnosed. In many patients with MCAS, a combined form of MCAS (mixed MCAS) is detected. These patients are at highest risk to develop life-threatening repeated episodes of anaphylaxis fulfilling all MCAS criteria. MCAS, mast cell activation syndrome; IgE, immunoglobulin E; MMAS, monoclonal mast cell activation syndrome. The dashed line divides patients' groups into those with or without a genetic predisposition.

Fig. 3

Therapeutic approach to patients with MCAS. In the acute phase of an MCAS event, emergency treatment is required, and the patient is treated for acute anaphylaxis regardless of the etiology of MCAS. Rather, in most cases, MCAS criteria can only be applied in the event-free interval (when data from baseline and event-related tryptase are available). At that time, the diagnosis of MCAS is established using MCAS criteria, and the type of MCAS is determined. Then, based on the etiology, identified triggers, patient-related factors (including the genetic state), and underlying comorbidities and conditions, a comprehensive management plan is established. In primary, secondary and mixed forms of MCAS, it is a straightforward approach to develop a treatment plan. This is not the case in patients with idiopathic MCAS. In fact, in the absence of any known etiologies or underlying conditions, it is notoriously difficult to recommend specific treatments, and the only way to proceed is to repeat all diagnostic tests and investigations and to offer symptomatic treatment and prophylactic anti-allergic drugs. Details about various treatment options (management) for patients with distinct form of MCAS are provided in the text and in Table 4 of this manuscript.