History and exam
Key diagnostic factors
common
recurrent episodes of anaphylaxis
Consider the possibility of MCAS whenever a patient presents with a history of recurrent anaphylaxis (or other acute, severe symptoms of mast cell activation affecting at least two organ systems).[2][3][5][18][28] See Anaphylaxis.
The symptoms of MCAS result from systemic mast cell activation and acute episodes usually meet the clinical definition of anaphylaxis. For a formal diagnosis of MCAS to be made, at least two organ systems (most commonly skin, respiratory, cardiovascular, and gastrointestinal) must be affected by acute-onset, rapidly progressive symptoms and signs of mast cell activation.[2][3][5][18][28] Occasionally these symptoms may be less severe than anaphylaxis, particularly in people who are taking antihistamines.
The patient may not experience any symptoms between acute episodes.
acute-onset cardiovascular symptoms and signs of mast cell activation
Cardiovascular symptoms of mast cell activation are common during acute MCAS episodes, for example:[2][3][5][18][29]
Hypotension - present in the vast majority of patients who present with an acute MCAS episode[18]
Dizziness
Tachycardia
Syncope/pre-syncope
Palpitations.[35]
Suspect a primary (clonal) MCAS - most commonly mastocytosis - if your patient presents with hypotensive syncope or pre-syncope.[2]
Signs of arrhythmia may indicate cardiac involvement and may be a feature of anaphylactic reaction.[31][37][38] In extreme cases, cardiovascular collapse may occur.
Note that for a diagnosis of MCAS to be confirmed, at least one other organ system must also be concurrently affected by acute-onset symptoms associated with mast cell activation.
acute-onset skin symptoms and signs of mast cell activation
Skin symptoms of mast cell activation are common during acute MCAS episodes, for example:[2][3][5][18][29]
Flushing. In the authors’ experience, this is the predominant skin symptom in patients who present with an acute episode of MCAS.
Urticaria (hives) can also occur during symptomatic MCAS episodes but note that in patients with mastocytosis, urticaria pigmentosa (maculopapular cutaneous mastocytosis) may be seen. This skin feature is present in around 70% to 80% of patients with systemic mastocytosis and may flare during acute episodes.[39][40]
Itching (pruritus)
Angio-oedema (particularly of the lips and tongue). If associated with inspiratory stridor, this can be a sign of upper airway obstruction necessitating emergency intervention.[57] See Anaphylaxis.
The patient may also report a history of episodic flushing, with or without pruritus and with or without a known trigger. Concurrent abdominal pain and/or diarrhoea is common, in which case the first MCAS diagnostic criterion - symptoms of mast cell activation affecting at least two organ systems - is met.[4]
Note that for a diagnosis of MCAS to be confirmed, at least one other organ system in addition to the skin must also be concurrently affected by acute-onset symptoms associated with mast cell activation.
acute-onset respiratory/naso-ocular symptoms and signs of mast cell activation
Respiratory (including naso-ocular) symptoms of mast cell activation are common during acute MCAS episodes, for example:[2][3][5][18][29]
Wheezing
Dyspnoea
Cough
Inspiratory stridor
Conjunctival injection
Nasal congestion
Sneezing.
Note that inspiratory stridor is a sign of upper airway obstruction that can quickly lead to life-threatening laryngeal angio-oedema. Emergency intervention may be needed to protect the airway.[57] See Anaphylaxis.
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.[32]
Note that for a diagnosis of MCAS to be confirmed, at least one other organ system must also be concurrently affected by acute-onset symptoms associated with mast cell activation.
acute-onset gastrointestinal symptoms and signs of mast cell activation
Gastrointestinal symptoms of mast cell activation are common during acute MCAS episodes, for example:[2][3][5][18][29]
Abdominal cramps
Nausea
Vomiting
Diarrhoea.
Palpate the abdomen; a finding of splenomegaly and/or hepatomegaly and/or epigastric tenderness may indicate mastocytosis (the most common cause of primary MCAS).
Note that for a diagnosis of MCAS to be confirmed, at least one other organ system must also be concurrently affected by acute-onset symptoms associated with mast cell activation.
allergic or other trigger for acute onset of symptoms
Known or likely allergic triggers of an acute MCAS episode can include insect (Hymenoptera) stings or bites, drug or food allergies, and prescription or non-prescription medications.[4][18][33][34] Medications that have been reported as triggers include some classes of antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids.[35]
Other triggers may include physical stimuli such as heat, cold, pressure/vibration or exercise, and medical procedures such as surgery or imaging with radiocontrast media.[3][33][34]
positive response to mast cell mediator medication
For a diagnosis of MCAS to be confirmed, the patient must have a positive response to a medication that targets a mast cell mediator.[2][3][5][18][29]
Such agents include antihistamines (H1 antagonists), H2 antagonists, leukotriene receptor antagonists (e.g., montelukast), and sodium cromoglicate. A response to an anti-IgE therapy (e.g., omalizumab) can be considered an indirect sign of MCAS.[18]
uncommon
skin signs of mastocytosis
Mastocytosis is the most common underlying cause of primary MCAS.[5][18] Characteristic skin lesions are often present. Urticaria pigmentosa (maculopapular cutaneous mastocytosis) is present in around 70% to 80% of patients with systemic mastocytosis (SM).[39][40]
Note that only a proportion of patients with SM have recurrent acute episodes that meet the criteria for an MCAS diagnosis.
Other diagnostic factors
uncommon
neurological symptoms
Neurological symptoms of mast cell activation may sometimes be present during an acute episode and can be an additional pointer towards the diagnosis when they occur simultaneously with symptoms affecting other organ systems.[2]
Examples include dizziness, visual disturbance, tremor, disorientation, seizures, and urinary and/or faecal incontinence.
musculoskeletal symptoms
Musculoskeletal symptoms of mast cell activation may sometimes be present during acute MCAS episodes but these are non-specific and of little practical use as a pointer toward the diagnosis.[14]
Examples include muscle pain, bone pain, and migratory arthritis.
Risk factors
strong
mastocytosis
Patients with mastocytosis are prone to anaphylaxis and therefore have an increased risk of developing primary MCAS. The lifetime incidence of anaphylaxis in adults with systemic mastocytosis has been reported to be as high as 50%.[19][20][21] There are no reliable published data to show the proportion of patients with mastocytosis who have recurrent acute episodes that meet all three diagnostic criteria for concomitant MCAS.
Among patients with mastocytosis, life-threatening venom-induced anaphylaxis - which if recurrent would indicate mixed primary and secondary MCAS - is predominantly seen in men aged 50 to 60 years.[22][23][24]
atopic predisposition
IgE-dependent allergies are the most common underlying cause of secondary MCAS, which is by far the most prevalent subtype of the condition.[5]
Among patients with primary (clonal) MCAS, the presence of concomitant atopy, elevated total IgE levels, and a history of documented IgE-mediated food or drug allergy are factors associated with a higher risk of anaphylaxis - and of recurrent episodes that meet the criteria for mixed primary and secondary MCAS.[20]
history of unprovoked anaphylaxis
A history of recurrent, unprovoked anaphylaxis is associated with primary (clonal) or idiopathic MCAS. In one small case series, 47% of adults with a history of unexplained anaphylaxis were found to have a clonal mast cell disorder, suggesting that the pathogenic mechanism underlying unprovoked anaphylaxis could involve clonal mast cells.[22]
weak
hereditary alpha-tryptasaemia
Hereditary alpha-tryptasaemia (H𝜶T) is present in 5% to 7% of the general population. It appears to increase the severity of mast cell activation, although its clinical significance remains unclear. Among patients with systemic mastocytosis, the risk for life-threatening episodes of anaphylaxis that meet the diagnostic criteria for MCAS was reported to be higher among patients with H𝜶T.[18] H𝜶T has also been reported more frequently in patients with severe venom-, idiopathic- and mastocytosis-related anaphylaxis.[25][26][27] Some of these studies are complicated by referral bias and the findings need to be confirmed in larger unselected and prospective cohorts. It is important to note that, on its own, alpha-tryptasaemia does not qualify as a mast cell activation syndrome.
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