Approach

General principles

Patients with MCAS typically present with recurrent anaphylaxis (or occasionally with recurrent sudden-onset episodes of other severe systemic symptoms of mast cell activation that do not meet the clinical definition of anaphylaxis).

Only make a diagnosis of MCAS if all of the three following criteria are met (the 'Vienna consensus' criteria):[3]​​[5][18][28]

  • The symptoms associated with recurrent anaphylaxis/severe mast cell activation concurrently affect two or more of the following organ systems: skin; respiratory/naso-ocular; cardiovascular; gastrointestinal.[2][3]​​[5][18][29]

    AND

  • These acute and recurrent symptomatic episodes are accompanied by a transient increase in a validated mast cell mediator (typically serum tryptase) that returns to the patient’s individual baseline level after symptoms have resolved

    AND

  • Symptoms improve in response to treatment with a medication that targets a mast cell mediator (e.g., an antihistamine and/or H2 antagonist and/or a leukotriene receptor antagonist and/or sodium cromoglicate).

After making the diagnosis, it is important to determine whether the patient has primary, secondary, or idiopathic MCAS as this will inform the long-term management plan.[2][3]​​​​[5][18][28]

  • Primary MCAS is a rare disease in which clonal mast cells arising from a somatic KIT mutation (most often KIT D816V) are more prone to activation, either spontaneously or in response to an external trigger. Mastocytosis is the most common underlying cause of primary MCAS. Among patients with systemic mastocytosis, the lifetime incidence of anaphylaxis has been reported to be as high as 50% but there are scarce data on what proportion of that group have recurrent episodes and meet all three diagnostic criteria for MCAS.[19][20][21]​​

  • In secondary MCAS - by far the most common of the three forms - normal mast cells are activated by an external trigger, usually an allergen but sometimes a physical stimulus such as pressure or temperature. Severe forms of IgE-dependent allergy that result in recurrent episodes of systemic anaphylaxis are the most common underlying cause of MCAS.[5]​​

  • Idiopathic MCAS is diagnosed when no clonal mast cells can be detected and no allergic or other external trigger can be identified for symptomatic episodes.

The highest prevalence of MCAS is in patients who have both an IgE-dependent allergy and mastocytosis; this is known as mixed primary and secondary MCAS.[5] These patients typically meet the diagnostic criteria for systemic mastocytosis and also have a severe IgE-dependent allergy.[2][18]​​​​ They are at high risk of life-threatening hypotensive anaphylaxis, most often triggered by wasp or bee stings or sometimes unprovoked.[1][5]​​​​[18]​​​[30]​​ This scenario is most commonly seen in men aged 50 to 60 years.[22][23][24]

History

Consider the possibility of MCAS whenever a patient presents with recurrent episodes of anaphylaxis or other severe symptoms and signs of mast cell activation involving two or more organ systems.[2][3][5][18][28]​​​​​​[30]​​First evaluate the presenting complaint (which, in severe cases, may be a life-threatening episode of anaphylaxis) and initiate urgent management if required (see Anaphylaxis); then take a systematic history. Keep in mind that there are no point-of-care tests available to diagnose MCAS and use your clinical assessment to guide urgent management.

To consider a diagnosis of MCAS, the patient must have sudden-onset, rapidly progressing symptoms affecting two or more of the following organ systems:[2][3]​​​​[5][18][29]

  • Cardiovascular: patients typically present with tachycardia, dizziness, hypotension, palpitations, and sometimes syncope or near-syncope. Note that hypotensive syncope/pre-syncope raises the suspicion for a clonal primary MCAS, such as systemic mastocytosis.[2]

  • Skin: common dermatological symptoms include flushing (in the authors’ experience, the predominant skin symptom in acute MCAS), urticaria (hives), itching, and angio-oedema (particularly of the lips and tongue).

  • Respiratory/naso-ocular: symptoms might include wheezing, dyspnoea, cough, and inspiratory stridor (which in severe anaphylaxis can quickly lead to life-threatening laryngeal oedema/obstruction).[31]​ Common naso-ocular symptoms are conjunctival injection, nasal congestion, and sneezing. If the patient reports throat discomfort, ensure an urgent laryngeal examination takes place (preferably by an ENT specialist) to check for laryngeal oedema.[32]

  • Gastrointestinal: common symptoms include nausea, vomiting, abdominal cramps, and diarrhoea.

Some patients may have additional symptoms in other organ systems (e.g., neurological or musculoskeletal), but these are non-specific and of little help in suspecting the diagnosis, especially if occurring in isolation.[2][14]

Severity of acute episodes

In most cases, the acute episodes of MCAS will meet the clinical definition of anaphylaxis.[3]​​[5][18][28]​​​​ Occasionally an acute MCAS episode will present with severe symptoms of mast cell activation affecting two or more organ systems but without any cardiovascular or respiratory compromise or other life-threatening features that are typical of anaphylaxis.[5]

  • Examples of such MCAS episodes would be a patient who presents with severe acute-onset hives together with gastrointestinal cramping, or with an acute episode of severe flushing together with nasal congestion.

  • In the authors’ experience, such episodes with reduced symptom severity are more likely in patients who are taking antihistamines.

Allergic and other triggers for acute episodes

Ask about any triggers for the acute episodes.

  • Check whether the patient has any known allergies and/or hypersensitivities. Severe IgE-dependent allergy is the commonest underlying cause of MCAS.[5]​ Known or likely IgE-dependent triggers of allergic reactions include Hymenoptera venom, medications, and food allergens.[18]​ The patient may report a history of rhinitis, conjunctivitis, asthma, urticaria/angio-oedema, or anaphylaxis.

  • Note whether the patient consumed food or medication (including non-prescription drugs) or was exposed to possible insect stings or bites before the event.[4][33][34]​​​​ Medications that have been reported as triggers include some classes of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids.[35]

  • Other reported triggers include hot or cold temperatures, exercise, physical stimulus such as pressure or vibration, and medical procedures such as surgery or imaging with radiocontrast media.[3][33][34]

Previous episodes

It is essential to take detailed information about whether the patient has experienced any similar acute episodes in the past.

  • For a diagnosis of MCAS to be suspected, sudden-onset episodes affecting two or more organ systems must be recurrent. For example:

    • The patient may report previous episodes of flushing (with or without pruritus) together with severe abdominal cramping or diarrhoea, with or without a known trigger.[4]

    • A history of cardiac symptoms such as palpitations, dizziness, hypotension, and/or unexplained syncope could indicate previous anaphylaxis episodes, in particular if combined with flushing and/or gastrointestinal symptoms.[4]​​[19][36]​​

Physical examination

Perform a thorough clinical evaluation, remembering that signs and symptoms must be related to two or more organ systems for MCAS to be suspected. Physical examination findings and vital signs are most useful during an acute symptom flare as there may not be any findings when the patient is at baseline.[31]

Auscultate the lungs and heart. Measure oxygen saturation and blood pressure.

  • Inspiratory stridor, cough, dyspnoea, and bronchospasm/wheeze can be features of anaphylaxis (although they may point towards asthma if the patient has no concurrent symptoms affecting other organ systems).[31][37]

    • Isolated inspiratory stridor can be seen in vocal cord dysfunction and should be evaluated by laryngoscopy, if possible in the emergency department.

  • Signs of arrhythmia may indicate cardiac involvement and can be a feature of an anaphylactic reaction.[31][37][38]

  • Hypotension is almost always seen in MCAS episodes.[5]​ In severe cases, cardiovascular collapse may occur.​[31][37][38]

Examine the skin for any signs of erythema, eczematous rash, urticaria and/or angio-oedema.

  • This could indicate a primary skin disease or a drug, food, or insect-related reaction.

  • Urticaria pigmentosa (maculopapular cutaneous mastocytosis) points towards underlying cutaneous or systemic mastocytosis (primary MCAS). This skin feature is present in around 70% to 80% of patients with systemic mastocytosis.[39][40]

Abdominal pain, nausea, vomiting, and diarrhoea are common symptoms so it is important to palpate the abdomen.

  • Note any signs of splenomegaly, hepatomegaly, or epigastric tenderness as these may be signs of underlying mastocytosis (suggesting primary MCAS).

A neurological examination during the acute hypotensive event might find dizziness, visual disturbances, tremor, disorientation, or even seizures, due to brain hypoperfusion. These neurological manifestations may be accompanied by urinary and/or faecal incontinence.

An immediate laryngeal examination - preferably by an ENT specialist - is recommended for any patient who presents with throat discomfort, regardless of the presence or absence of external swelling of the face, tongue or lips.

  • Laryngeal oedema is important to identify so that any measures needed to protect the airway can be urgently prioritised.[18][32]

Initial investigations

Confirmation of mast cell activation during acute episodes

​To make a diagnosis of MCAS, evidence must be obtained to confirm that the acute symptomatic episodes are associated with a transient rise in a validated mast cell mediator.[3][2]​​​[5][28]

Tryptase

An acute tryptase elevation of 20% above baseline +2 ng/ml (1.2 x baseline +2) is the standard test for mast cell activation sufficient to diagnose MCAS (provided the other two diagnostic criteria are met).[2][3]​​​​[5][18][28]

  • For example, if the baseline serum tryptase is 5 ng/ml, the acute level must be >8 ng/ml for an MCAS diagnosis to be made

  • The rise in total serum tryptase during the acute episode correlates with cardiovascular symptoms, such as hypotension.

  • A transient elevation in serum tryptase is highly specific for systemic mast cell activation, although sensitivity varies according to the time of blood sampling, clinical severity of the episode, and the type of trigger.[2][3]​​[5]​ The tryptase level usually peaks around 1-2 hours after symptom onset.[18][30]

If the tryptase level remains elevated in the baseline serum sample, this may indicate mastocytosis or hereditary alpha-tryptasaemia.

  • A baseline tryptase >20 ng/ml is highly suggestive of systemic mastocytosis (SM), even if no signs of cutaneous mastocytosis are present, and should prompt further investigation.[2][3]​​[41]​​ But note that a proportion of patients with SM also have secondary MCAS, with wasp/bee stings a commonly reported trigger.[2] In these patients, the tryptase will rise above the patient’s elevated baseline level during acute episodes of mast cell activation, returning to the elevated baseline level after the acute symptoms have fully resolved.

  • Patients with hereditary alpha-tryptasaemia also have a high baseline tryptase (generally >8 ng/ml).[3] Other conditions associated with an elevated basal serum tryptase level include end-stage chronic kidney disease, myeloid leukaemia, and other myeloproliferative disorders such as chronic eosinophilic leukaemia.[1]

Urinary markers of mast cell activation

In addition to serum tryptase levels, collect a urine sample during the acute event to measure urinary metabolites of histamine and/or prostaglandin D2 and/or leukotriene C4 (LTC4) if these tests are available.[2][3]​​​​[5][18][42][43][44][45][46]

  • These are less specific, less sensitive markers of mast cell activation than tryptase as they can also be derived from other cells.[1][30]​​ Testing urine for their metabolites may be helpful to support a diagnosis of MCAS, particularly if tryptase levels are inconclusive or if no blood (but only urine) could be collected during the acute event. In this scenario, a substantial and transient rise in an alternative mast cell mediator during symptomatic episodes may be considered sufficient to suspect the diagnosis, particularly if the patient’s symptoms subsequently respond to mast cell-targeted therapy.[1][2][5]​​​ Results may also help guide long-term management; if one of these mediators is found to be raised during acute episodes, the choice of long-term medication can be targeted towards that mediator.[3][5][18][43][45]​​ However, this approach is limited by the fact these investigations are not yet available in some centres.

  • Event-related values should be compared to baseline levels (24-hour or spot urine can be used); however, the diagnostic thresholds for urine mediators have yet to be determined.[2][5][18] In addition, many laboratories cannot measure these metabolites, and the normal cutoff levels vary depending on the test used. Paediatric normal ranges for urine mediators have not been established.

Other initial investigations

A 12 lead-ECG may be indicated by the clinical presentation, particularly if the patient has cardiovascular symptoms.

  • It may indicate arrhythmias and/or potential ST changes, which could indicate myocardial ischaemia. However, it is important when interpreting the ECG reading to remember that transient ST-changes may occur post-adrenaline (epinephrine) administration, particularly after intravenous injections.

If this is the patient’s first episode of anaphylaxis with confirmed mast cell involvement, it may be beneficial to provide a letter for them to present to the emergency department in any subsequent episode, with a recommendation to check the acute serum tryptase level.

  • This is because MCAS cannot be formally diagnosed after a single acute episode (though a presumptive diagnosis may be made at this point).[2]​ Mast cell mediator release must be documented during at least two episodes of anaphylaxis (or other severe symptoms of mast cell activation affecting two or more organ systems). It is therefore essential to test serum tryptase during recurrent acute episodes.[18]

It is important to also note that an MCAS diagnosis can only be formally confirmed (according to the Vienna consensus criteria) after a successful trial of treatment with a mast cell mediator blocking agent (e.g., antihistamine, H2 antagonist, montelukast) or mast cell stabiliser (e.g., sodium cromoglicate or ketotifen).[2][3]​​​​​​[5][18][28]​​​​​ Such medication is expected to result in significant relief of symptoms and to decrease the frequency and severity of acute episodes.[18] A response to an anti-IgE therapy (e.g., omalizumab) can be considered an indirect sign of MCAS.​[1][18]

Other investigations

Once an MCAS diagnosis has been confirmed based on the three Vienna consensus diagnostic criteria being met, subsequent investigations can help to establish whether the patient has primary, secondary, or idiopathic MCAS.[5][18][30]

  • It is important to evaluate the underlying cause in any patient with MCAS. The two most common are severe allergy (secondary MCAS) and systemic mastocytosis accompanied by episodes of severe mast cell activation (primary MCAS).[5][18]

  • Note that a small sub-group of patients have concomitant primary (systemic mastocytosis) and secondary (usually IgE-dependent) MCAS. This is referred to as mixed or combined MCAS.[2][18]

Consider requesting an allergy work-up if the patient’s history suggests an IgE- or non-IgE mediated trigger for the acute episodes.[5] Different health systems have varied protocols for the number of episodes of anaphylaxis that should prompt allergy investigations; in some countries, an allergy work-up is routine for any patient who has a single presentation with anaphylaxis. Check local guidance.

Highly sensitive peripheral blood detection of KIT D816V mutation (such as allele-specific PCR or ddPCR with an allelic limit of detection of at least <0.1%) may be useful, where available, to look for evidence of clonal mast cell disease (mastocytosis).[5][47][48]

  • This investigation is indicated if there are any pointers towards primary MCAS, for example elevated baseline tryptase level (>10 ng/ml), hypotensive syncope/pre-syncope during acute episodes, or signs of urticaria pigmentosa (maculopapular cutaneous mastocytosis).[5] Note, however, that the majority of children with cutaneous mastocytosis will have a negative result for the KIT D816V mutation in peripheral blood.[49]

  • If a KIT mutation is detected, bone marrow investigation is indicated for confirmation of systemic mastocytosis (and thereby primary/clonal MCAS) according to the World Health Organization diagnostic criteria.[18][48][50]

​If the patient has normal tryptase and urinary mast cell markers during the acute episodes, rule out MCAS and consider alternative causes of symptoms. See Differentials.

  • For example, a patient with recurrent flushing who does not have elevated mast cell markers may benefit from an endocrinological or neurological workup to rule out carcinoid or autonomic dysfunction.[18]

  • A patient with multiple food intolerances with a negative workup for food allergy may benefit from a gastroenterology or dysautonomia evaluation.

Pitfalls that can lead to overdiagnosis of MCAS

Many patients who are referred with suspected MCAS are instead diagnosed with other diseases unrelated to mast cell activation (e.g., autoimmune, neoplastic, or infectious conditions) or are found to have mast cell-related disorders (e.g., allergies) that are not severe enough to fulfil the diagnostic criteria for MCAS.​[1][5]​​​​​ Both the American Academy of Allergy, Asthma and Immunology and a panel of US/European specialists have highlighted the potentially detrimental consequences for patients resulting from the publication of alternative proposed criteria for diagnosing MCAS that are much broader and less stringent than the widely accepted Vienna consensus criteria.[3][13][18][51][52]​​​​[53]​​​ Chronic fatigue, joint hypermobility, fibromyalgia, anxiety, irritable bowel syndrome, multiple food intolerances without an IgE-mediated cause, and food aversions with or without clinical malnutrition are among the non-specific symptoms and conditions that have been erroneously attributed to MCAS, causing confusion for patients and raising the risk of missing a treatable condition as a result of an inappropriate diagnosis of MCAS.[1][3][5][18]​​​

​It is important to bear in mind that symptoms of mast cell activation are extremely common in daily clinical practice but only a small number of patients who experience them will meet the Vienna criteria for diagnosing MCAS.​[1][5]​​ Many symptoms that occur in MCAS as a result of the release of mast cell mediators (e.g., abdominal pain, flushing, diarrhoea) do not support the diagnosis if they occur in isolation or if they are chronic rather than episodic (e.g., chronic urticaria or poorly controlled persistent asthma).[3] Likewise, less severe mast cell activation can result in non-specific local symptoms such as headache, nausea, and other gastrointestinal complaints but these alone do not meet the definition of systemic symptoms as required for a diagnosis of MCAS (although such symptoms may nonetheless respond to mast cell mediators or mast cell stabilising medications).[5]

  • If the symptoms are not severe and/or are not recurrent and/or do not involve two or more organ systems and/or tryptase levels do not increase from the patient’s baseline during the symptomatic episode, the patient may be suffering from mast cell activation but a diagnosis of MCAS cannot be made.[18] Patients with episodic symptoms of mast cell activation in one organ system (e.g., asthma) also do not fulfill the diagnostic criteria for MCAS.

  • Remember that allergic diseases are common in the general population and are mediated by mast cell activation as the final pathway. It is important to diagnose patients with chronic atopic symptoms with the specific allergic disorder (e.g., allergic rhinitis, atopic dermatitis, or asthma) rather than mast cell activation syndrome unless they meet the strict criteria for MCAS.

An elevated baseline tryptase level alone is not diagnostic of MCAS, and may indicate hereditary alpha tryptasemia (H𝜶T). This is a common genetic variant of uncertain clinical significance that is present in 5% to 7% of the general population (with a higher prevalence among patients with mastocytosis) and per se is not MCAS.[54][55][56]​​ Individuals with isolated H𝜶T typically have normal levels of other mast cell mediators and are usually asymptomatic.​​

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