Mast cell activation syndrome

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

The key goals in management of MCAS are to:

Ensure appropriate emergency treatment of acute episodes. Treat any patient who presents with an acute severe episode of MCAS that meets the clinical definition of anaphylaxis with immediate epinephrine (adrenaline), regardless of the MCAS subtype. Follow your local protocol for management of anaphylaxis.
Put an ongoing management plan in place aimed at decreasing the frequency and severity of acute episodes. This generally involves a combination of advice to avoid any known triggers plus long-term maintenance pharmacotherapy.

Management of acute episodes

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, regardless of the MCAS subtype.[3] The key considerations are highlighted below. For more detail, see Anaphylaxis.
Obtain a serum tryptase level, ideally 1 to 4 hours after the onset of the acute episode. An acute rise in serum tryptase is a diagnostic criterion for MCAS. For more detail, see Diagnosis.[2][3]

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][66][65]

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]

After stabilization of cardiovascular status and respiratory function with epinephrine and initial supportive care, second-line medications such as antihistamines (H1 antagonists) or H2 antagonists are usually recommended, particularly for cutaneous symptoms.[64][65]

Unlike epinephrine, antihistamines and H2 antagonists are ineffective for cardiovascular and respiratory symptoms such as hypotension and bronchospasm.[64]
Their use must never delay or replace the administration of intramuscular epinephrine, which has a much faster onset of action and wider effects.[64]

Do not use corticosteroids (orally or intravenously) in the emergency management of anaphylaxis. They may be considered as an adjunct to reduce symptoms such as urticaria, but only after stabilization of the patient with epinephrine and supportive care.[64][69]

Although corticosteroids are sometimes used as an adjunct to epinephrine in the acute management of anaphylaxis, their value is unclear; they have no effect for 4-6 hours and evidence is lacking to support their putative effect on the prevention of protracted or biphasic reactions.[64][70] Some evidence suggests epinephrine remains underused in the initial management of anaphylaxis in some centers, with corticosteroids erroneously used as first-line therapy despite the lack of evidence.[70]

Monitoring after an acute MCAS episode

Guidelines differ on the recommended period of observation after all signs and symptoms of anaphylaxis have fully resolved. Check and follow your local protocol.

4-12 hours is usually recommended if the patient was evaluated in an emergency department setting (or longer if the episode involved severe hypotension).
US and European guidelines recommend tailoring the period of observation to the severity and duration of the episode, the number of epinephrine doses required, and any risk factors for biphasic reactions.[35][63][64]
- The US guideline recommends 4-8 hours’ observation for moderate to severe anaphylaxis, or longer if more than one dose of epinephrine was required. The latest update to the guideline states that it may be reasonable to discharge patients without risk factors for a biphasic reaction after 1 hour of asymptomatic observation.[35][64]
- The European guideline recommends monitoring for 6-8 hours if the anaphylaxis episode involved respiratory compromise or for 12-24 hours if the patient was hypotensive.[63]

Ensure the patient is prescribed two self-injectable epinephrine devices, to be carried at all times.[3][63]

Limiting the severity of any subsequent acute episodes is a vital aspect of managing MCAS; it is therefore essential to prescribe at least two epinephrine auto-injectors to all patients with MCAS, regardless of the subtype.

Ensure the patient and their family and carers receive adequate information and training on appropriate use, as part of an action plan for management of any future acute episode.[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 acute episodes and to provide details of the patient’s acute event-related tryptase level, so that ongoing maintenance therapy can be adjusted accordingly.

For additional detail on recognition and management of anaphylaxis, including recommended observation periods. See Anaphylaxis.

Maintenance treatments for MCAS

The main goal of long-term maintenance treatment in patients with MCAS is to reduce the frequency and/or severity of any acute episodes. This is achieved through a combination of trigger avoidance and long-term pharmacotherapy. It is also important to establish the MCAS subtype (primary, secondary, idiopathic or mixed) as this will inform a personalized management approach suited to the individual patient.[30]

Identification and avoidance of triggers

It is important to 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] The allergist’s evaluation can be used to map out the patient’s trigger profile so they can be given an individualized trigger avoidance plan.
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]
- Lifelong venom immunotherapy is recommended for any patient with sting-associated anaphylaxis who is found to be sensitized to Hymenoptera venom, to reduce the risk of recurrent anaphylaxis.[3][30][35][72] [ ]
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. For example, it is not routinely recommended to advise all MCAS patients to eliminate histamine-rich foods from their diet or to avoid whole classes of drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]) that have been reported as potential triggers, unless the individual patient’s allergy work-up has identified a specific sensitivity or there is strong suspicion based on the history.[4]

Stepwise approach to pharmacotherapy

Use a stepwise approach to long-term maintenance medication for all MCAS patients, with the goal of controlling symptoms caused by the release of mast cell mediators and reducing the risk of acute episodes.[3]

The first step in maintenance therapy is a nonsedating antihistamine (H1 antagonist), with the addition of an H2 antagonist for selected patients. If the patient does not respond, step up therapy to add one or more of a leukotriene receptor antagonist, cromolyn, short-course corticosteroid, and omalizumab.[4][73][74][75][76]
The objective is to establish the lowest effective dose of medication, although many patients require combination therapy.[71]
The medication options available work by either reducing the production and release of mediators by activated mast cells, or by blocking released mediators.

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.

Antihistamines and H2 antagonists

Select a second-generation nonsedating antihistamine (H1 antagonist) as the first step in maintenance therapy. 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]

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

Despite antihistamines and H2 antagonists 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]

Step-up combination treatment

If antihistamine with or without H2 antagonist treatment fails to resolve symptoms of mast cell activation, step up combination therapy using one or more of the options below, adding in medications until symptoms become well controlled:[3][4]

Leukotriene receptor antagonist - commonly required as part of combination therapy in patients with MCAS. Studies in patients with systemic mastocytosis suggest they 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.
Ketotifen - has properties as both a sedating antihistamine and a mast cell stabilizer and can be considered as an alternative for patients with persistent skin symptoms that have not responded to other antihistamines.[3][4][76] One case report has suggested benefits for gastrointestinal and neuropsychiatric symptoms in a patient with systemic mastocytosis.[81]
Oral cromolyn - a mast cell stabilizer that has limited absorption from the gastrointestinal tract. It may be of particular benefit for gastrointestinal symptoms that fail to respond to antihistamines and H2 antagonists.[3]
Oral corticosteroid - a short course may be indicated if symptoms and signs are refractory, but adverse effects limit long-term use.[3][30]

Omalizumab: anti-IgE therapy

In a patient with MCAS and severe, 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 medications 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.[19][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. One randomized controlled trial in 19 patients with idiopathic anaphylaxis showed no statistically significant difference in rates of anaphylaxis between the omalizumab-treated versus placebo-treated groups, although there was a trend toward efficacy in the treatment group, particularly after 60 days.[84] Another RCT, in 16 patients with systemic mastocytosis, showed no difference in anaphylactic event rates between the groups treated with omalizumab versus placebo, although the trial was underpowered to show this outcome.[85] Both RCTs suffered from limited patient numbers and there remains a need for larger studies.

Cytoreductive therapy for adults with primary (clonal) MCAS

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

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.

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]

Emerging management concepts

Expert groups have highlighted the potential to tailor the choice of maintenance medication to an individual patient by targeting the specific mast cell mediators that are elevated during acute MCAS episodes.[3][5][44][46] For example, a leukotriene receptor antagonist would be selected first-line in the stepwise approach if urinary LTE4 levels were raised and it has been postulated that aspirin may be beneficial in patients whose urinary metabolites of prostaglandin are elevated during acute MCAS episodes.[35][46]

In practice, urinary tests for different mediators remain unavailable in most centers and so the generalized stepwise approach outlined above remains recommended for all MCAS patients.

Use of this content is subject to our disclaimer