Mast cell activation syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

acute MCAS: anaphylaxis episode

1st line – epinephrine (adrenaline) plus supportive care

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1st line –

epinephrine (adrenaline) plus supportive care

If a patient presents with an acute MCAS episode that meets the clinical definition of anaphylaxis, immediate administration of epinephrine is of paramount importance.[63][64][65][66]

These reactions may be life-threatening.[63]
The range and severity of symptoms varies, with cardiovascular and respiratory symptoms and signs - such as hypotension and laryngeal angioedema - a matter for utmost concern. In the event of cardiac arrest, start cardiopulmonary resuscitation.
Treat the episode as per the standard protocol for management of anaphylaxis.[3] The key considerations are highlighted below; for more detail, see Anaphylaxis.

Intramuscular epinephrine is the first-line drug of choice, as it stabilizes the mast cells and reverses the inappropriate effects of the mast cell mediators produced during anaphylaxis.[3][67][68]

Remove the trigger if known and feasible but do not allow this to delay treatment.[63][66]
Lie the patient flat before administering intramuscular epinephrine into the anterolateral thigh. Repeat the dose if needed after 5-15 minutes (guidelines vary on the precise timing of repeat dose(s) so check your local protocol).[63][64][66]
Evidence suggests that treatment of systemic reactions with epinephrine prevents progression to more severe symptoms.[65]

Take an ABCDE approach and give high-flow supplemental oxygen and intravenous fluids (e.g., normal saline) if indicated.[63][65][66]

In refractory cases of severe hypotension that does not respond to repeated doses of intramuscular epinephrine, intravenous epinephrine should be given by a clinician with appropriate specialist skills, with continuous monitoring of cardiac response, blood pressure, and oxygen saturation.[64][66]

If the patient has persistent bronchospasm despite epinephrine, an inhaled beta-2 agonist (e.g., albuterol) is indicated.[3][63][65]

Ensure at least two self-injectable epinephrine devices are prescribed for all patients with MCAS.[3][63][65]

Limiting the severity of any subsequent acute episodes is a vital aspect of managing MCAS.
Advise the patient to carry their epinephrine auto-injectors at all times.
Ensure the patient and their family/caregivers receive adequate information and training on appropriate use.[4]

If the patient is already under the ongoing care of a specialist (usually an allergist), it is important to inform the specialist about any episodes of anaphylaxis and to provide details of the patient’s acute event-related tryptase level, so that ongoing maintenance therapy can be adjusted accordingly.

ONGOING

confirmed MCAS (all subtypes): long-term management

1st line – trigger identification and avoidance

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1st line –

trigger identification and avoidance

The ongoing management plan for any patient with MCAS aims to reduce the frequency and severity of acute episodes via a combination of trigger avoidance and maintenance pharmacotherapy.

Take steps to identify any triggers for the individual patient’s acute episodes so that a tailored plan for trigger avoidance can be formulated.[3][30][71]

Refer your patient with MCAS for a thorough allergy workup to assess for potential culprit agents, including tests for any known/potential triggers.[4]
Triggers vary widely between patients and can range from Hymenoptera venom (a particularly common trigger in adults with MCAS), to medications, foods and alcohol, environmental triggers (e.g., temperature extremes), or physical exertion.[3][19]
Avoid giving generalized advice for a patient to avoid all potential triggers for mast cell degranulation that takes no account of their specific individual sensitivities; advice on trigger avoidance should be tailored to the individual patient’s trigger profile.[4]

Plus – antihistamine (H1 antagonist)

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Plus –

antihistamine (H1 antagonist)

Treatment recommended for ALL patients in selected patient group

Select a second-generation nonsedating antihistamine (H1 antagonist) as the first step in long-term maintenance therapy for any patient with MCAS (e.g., fexofenadine, cetirizine, loratadine).

Adjust the dose to the individual (this is particularly important in children); US guidelines on MCAS recommend that doses up to 2-4 times higher than the standard approved dose can be used if needed in adults (as per the approach in patients with chronic urticaria).[3]
Despite antihistamines being the mainstay of first-line maintenance treatment for patients with MCAS - based on the rationale that they will relieve symptoms caused by secreted histamine - there remains a need for large, well-designed placebo-controlled randomized controlled trials (RCTs).[3][77]

The goal of the step-up approach to pharmacotherapy for MCAS is to establish the lowest effective combination and doses of medication.[3][71]

If the patient does not respond to an antihistamine, consider the addition of an H2 antagonist and/or step up therapy by adding one or more of the options set out below.[4][73][74][75]
There is no direct evidence to guide the appropriate timeframe for making an assessment of whether or not a treatment has been effective. In practice, it is usual to allow up to 3 months for a medication to take effect before concluding that it has not achieved the required symptom control and deciding to step up to the next level of add-on therapy.
Bear in mind that it may be necessary to intensify treatment after a shorter period if the patient continues to have frequent anaphylaxis episodes.

Note that ketotifen can be considered for any patient with persistent skin symptoms that have not responded to other antihistamines.[3][4][76]

Ketotifen has properties as both a sedating antihistamine and a mast cell stabilizer.
One case report in a patient with systemic mastocytosis has also suggested benefits for gastrointestinal and neuropsychiatric symptoms.[81]
Ketotifen is not available as a proprietary oral formulation in the US and oral tablets need to be compounded.

Primary options

fexofenadine: children and adults: consult specialist for guidance on dose

cetirizine: children and adults: consult specialist for guidance on dose

loratadine: children and adults: consult specialist for guidance on dose

Consider – H2 antagonist

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Consider –

H2 antagonist

Treatment recommended for SOME patients in selected patient group

Adding an H2 antagonist (e.g., cimetidine, famotidine) can be particularly useful for patients with gastrointestinal symptoms and/or those who do not respond to an antihistamine.[3][4]

As for antihistamines, most of the data to support the use of H2 antagonists in MCAS is limited to case reports and case series.[3]

Primary options

cimetidine: children: consult specialist for guidance on dose; adults: 300 mg orally four times daily initially, increase gradually according to response, maximum 2400 mg/day

famotidine: children: consult specialist for guidance on dose; adults: 20 mg orally four times daily initially, increase gradually according to response, maximum 640 mg/day

symptomatic despite antihistamine ± H2 antagonist

Consider – leukotriene receptor antagonist

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Consider –

leukotriene receptor antagonist

Treatment recommended for SOME patients in selected patient group

If treatment with an antihistamine with or without an H2 antagonist fails to resolve symptoms of mast cell activation, a leukotriene receptor antagonist (e.g., montelukast, zafirlukast) is usually added.

This is commonly required as part of combination therapy in patients with MCAS.
Studies in patients with systemic mastocytosis suggest leukotriene receptor antagonists may be particularly effective for dermatologic symptoms of mast cell activation that do not respond to antihistamines.[78][79]

Note that the Food and Drug Administration (FDA) has issued a warning over serious neuropsychiatric adverse events associated with montelukast, including suicidal thoughts or actions. The FDA stressed the importance of considering the risk-benefit balance of montelukast and of counseling all patients about the potential psychiatric adverse effects.[80] Similar issues have also been reported with zafirlukast.

Primary options

montelukast: children and adults: consult specialist for guidance on dose

zafirlukast: children and adults: consult specialist for guidance on dose

Consider – cromolyn

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Consider –

cromolyn

Treatment recommended for SOME patients in selected patient group

If symptoms of mast cell activation persist in spite of combination therapy, consider adding oral cromolyn.[3][4]

Cromolyn is a mast cell stabilizer that has limited absorption from the gastrointestinal tract.
It may be of particular benefit for gastrointestinal symptoms that are unresponsive to antihistamines and H2 antagonists.[3]

Primary options

cromolyn: children: consult specialist for guidance on dose; adults: 200 mg orally four times daily, maximum 40 mg/kg/day

Consider – oral corticosteroid

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Consider –

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

A short course of a corticosteroid may be indicated if symptoms and signs are refractory to the treatments outlined above, but adverse effects limit long-term use.[3][30]

Primary options

prednisone: children and adults: 0.5 mg/kg orally once daily initially, adjust dose according to response and gradually taper over 1-3 months

ongoing recurrent anaphylaxis refractory to oral treatment

Consider – omalizumab

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Consider –

omalizumab

Treatment recommended for SOME patients in selected patient group

If a patient with MCAS has ongoing recurrent anaphylaxis that is resistant to combination therapy with medications targeted at mast cell mediators (as outlined above), omalizumab can be used under specialist care.[3][4][30]

Omalizumab is started as an add-on therapy, alongside ongoing use of the maintenance drugs the patient is already taking. In practice, once a good response has been achieved and the patient is symptom-free, an allergy specialist may advise a gradual reduction in the doses of the other medications and to use antihistamines only on an as-needed basis, although this will vary from patient to patient.

Omalizumab is a humanized monoclonal antibody that acts as a mast cell stabilizer by binding specifically to free IgE. Anecdotal reports and case series show varying success in using it to reduce the frequency of anaphylactic episodes among patients with systemic mastocytosis or unexplained anaphylaxis.[22][82][83]
Evidence in this area remains scarce and further trials are required before the routine use of omalizumab can be recommended in people with MCAS.

Primary options

omalizumab: children and adults: consult specialist for guidance on dose

sensitivity to Hymenoptera venom

Plus – venom immunotherapy

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Plus –

venom immunotherapy

Treatment recommended for ALL patients in selected patient group

Lifelong venom immunotherapy is recommended for any patient with MCAS whose allergy workup confirms sensitivity to Hymenoptera venom.[3][30][35][72] [ ]

Wasp or bee stings are a common trigger for anaphylaxis in adult patients with MCAS.
There is a particularly high risk of life-threatening episodes triggered by Hymenoptera venom in the subgroup of patients who have mixed secondary and primary MCAS (and usually meet the diagnostic criteria for systemic mastocytosis).[2][18] This scenario is most commonly seen in men ages 50 to 60 years.

primary (clonal) MCAS

Consider – cytoreductive therapy

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Consider –

cytoreductive therapy

Treatment recommended for SOME patients in selected patient group

In rare, refractory adult cases of primary (clonal) MCAS associated with systemic mastocytosis, cytoreductive therapies may be used (under the care of highly specialized services).[86] This is especially appropriate when MCAS acute episodes are recurrent and resistant to all conventional approaches and the patient is suffering from smouldering or advanced systemic mastocytosis.[30]

The current first-line option for cytoreductive therapy is a tyrosine kinase inhibitor (TKI).[3] These drugs control mast cell activation by targeting the mast cell growth receptor KIT.[3][4]

Midostaurin is a broad-acting TKI that has been approved in the US and Europe for patients with advanced systemic mastocytosis. Studies have provided initial evidence that midostaurin improves mediator-related symptoms and quality of life in patients with advanced mastocytosis, in addition to reversing organ damage and reducing splenomegaly and bone marrow mast cell burden.[87][88][89] It is the first-choice TKI for patients with primary MCAS who require cytoreductive therapy.[3] Midostaurin is not approved for the treatment of nonadvanced (indolent) mastocytosis.
Avapritinib is a more selective inhibitor of KIT D816V.[90] Prompt resolution of recurrent anaphylaxis has been described in a patient with advanced mastocytosis after the addition of avapritinib to the patient’s usual combination of maintenance medications.[91] Avapritinib is approved in the US and Europe for the treatment of advanced systemic mastocytosis. It is also approved in the US for the treatment of indolent systemic mastocytosis.
The effects of TKIs on MCAS remain to be further explored.

They may be used on a compassionate use basis in carefully selected patients outside of their license.

Prior to the emergence of TKIs, the two most commonly used cytoreductive therapies in patients with advanced systemic mastocytosis were interferon alfa and cladribine.[92][93]

Primary options

midostaurin: adults: consult specialist for guidance on dose

avapritinib: adults: consult specialist for guidance on dose

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Mast cell activation syndrome

Treatment algorithm

acute MCAS: anaphylaxis episode

epinephrine (adrenaline) plus supportive care

confirmed MCAS (all subtypes): long-term management

trigger identification and avoidance

antihistamine (H1 antagonist)

Primary options

H2 antagonist

Primary options

leukotriene receptor antagonist

Primary options

cromolyn

Primary options

oral corticosteroid

Primary options

omalizumab

Primary options

venom immunotherapy

cytoreductive therapy

Primary options