Editor: V. Dimov, M.D., Allergist/Immunologist, Cleveland Clinic Florida, Clinical Associate Professor, FAU Charles E. Schmidt College of Medicine
Mast cell activation (MCA) and MCA syndrome (MCAS) are not the same.
Mast cell activation (MCA) is very common. Based on divers physiologic and pathologic processes. MCA is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient.
MCA syndrome (MCAS) is uncommon. Mastocytosis is extremely rare. Patients with mastocytosis may have MCA and MCAS. MCAS is severe and almost always presents with hypotension (and anaphylaxis).
Mast cell activation (MCA) and MCA syndrome (MCAS): They are not the same (click to enlarge the image).
3 criteria for MCAS:
Criterion A: Typical clinical signs of severe, recurrent (episodic) systemic MCA are present (often in form of anaphylaxis) (definition of systemic: involving at least 2 organ systems)
Criterion B: Involvement of mast cells is documented by biochemical studies: preferred marker: increase in serum tryptase level from the individual's baseline to plus 20% plus 2 ng/mL.
Criterion C: Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators. Example: histamine receptor blockers.
All 3 MCAS criteria (A + B + C) must be fulfilled to call a condition MCAS.
The MCA formula is: 20% baseline tryptase plus 2 ng/mL. Thus if the baseline tryptase level is 5 ng/mL in a given patient, a level of 8 ng/mL or greater within 4 hours of a suspected anaphylactic event confirms that mast cell activation.
Diagnosis of MCAS requires: 1. typical clinical symptoms, often with hypotension, 2. an event-related, substantial increase in serum tryptase levels, and 3. A response of clinical symptoms to MC-stabilizing drugs or drugs counteracting the effects of MC-derived mediators.
MCAS criteria: mnemonic ABC:
Blood tryptase elevated
Control of symptoms with antihistamine
3 criteria for mast cell activation syndrome (MCAS) (click to enlarge the image).
3 variants of MCAS:
Primary MCAS (clonal MCAS). The KIT D816V mutation is detected and mast cells carry CD25 in most cases. (a) with confirmed mastocytosis (cutaneous mastocytosis or systemic mastocytosis) , (b) with only 2 minor systemic mastocytosis criteria.
Secondary MCAS. IgE-mediated allergy, non-IgE-mediated hypersensitivity reaction, other immunologic disease.
Idiopathic MCAS. No cause is found.
3 variants of mast cell activation syndrome (MCAS) (click to enlarge the image).
Questions for patients
It may be helpful for patients who suspect that they may have MCAS to review the following questions:
1. Did my symptoms happen repeatedly, as severe attacks that require immediate medical intervention or ED visit/hospital stay?
2. Did my symptoms lead to an extremely low blood pressure and anaphylactic shock requiring ED visit or hospital stay?
3. Did my doctor measure serum tryptase levels before, during, and after my attacks?
4. Did my doctor tell me that my tryptase levels increased during my attacks?
5. Did my symptoms improve with daily treatment with antihistamines for at least 30 days?
6. Did the frequency of severe attacks decrease since I took antihistamines or steroids?
7. Did my doctor diagnose an IgE-dependent allergy (allergic rhinitis or food allergy)?
8. Did my attacks resolve or decrease in number after I started with omalizumab injections (if prescribed)?
Differential diagnoses to mast cell activation:
Cardiovascular: MI, endomyocarditis, aortic stenosis with syncope, pericardial effusion, PE
Endocrinologic: hypo/hyperthyroidism, hypoglycemia, adrenal insufficiency, hypopituitarism, estrogen or testosterone deficiency, carcinoid, pheochromocytoma, medullary thyroid tumor
GI: IBD, VIPoma, food intoxication, IBS, mesenteric ischemia, EoE or gastroenteritis, gastroparesis
Rheumatologic and immunologic disorders: erythema nodosum, SLE, vasculitis, capillary leak syndrome
ID: bacterial or viral infections, septic shock, GI infection with dehydration, encephalitis/meningitis, parasites (Chagas), Helicobacter pylori with gastritis and urticaria
Neurologic: epilepsy, CNS bleeding, intoxication, MS, dysautonomia, psychiatric conditions
Skin diseases: HAE/AAE, pemphigus vulgaris, SLE, toxic dermatoses, rosacea, idiopathic flushing, urticaria, drug exanthem
Hematologic: anemia and hypovolemic shock, GI, bleeding, hypermenorrhea, peripheral T-cell lymphoma with pruritus and rash
Differential diagnoses to mast cell activation (MCA) (click to enlarge the image).
Conditions associated with an elevated basal serum tryptase level:
Hematologic: Systemic mastocytosis, leukemia, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)
Nonhematologic reactive: chronic inflammatory diseases, chronic helminth infection (worms)
Allergic diseases, chronic urticaria, Mast cell activation (MCA) and MCA syndrome (MCAS)
Other causes: ESRD (renal failure), familial (hyper) (alpha) tryptasemia, false positive result, idiopathic
Conditions with elevated basal serum tryptase level (click to enlarge the image).
Prevention: avoid triggers of MCAS symptoms
Physical factors: changes in temperature - heat or cold, pressure, rubbing, some forms of exercise, emotions, stress, sleep deprivation
Diagnostic agents and medications: opiates, NSAIDs, succinylcholine, drugs with tetrahydroisoquinoline (THIQ) motifs such as atracuronium, rocuronium, quinolones that may activate mast cells via non-IgE receptors
Foods that contain or release histamine
Insect stings or bites: Hymenoptera venoms
High risk environment: surgery, invasive procedures, radiological use of contrast media, vaccinations, and dental procedures.
Premedications for MCAS patients: combination of anti-H1 and anti-H2 antihistamines for minor procedures, add montelukast, and 0.5 mg/kg of prednisone for major procedures.
Skin testing and challenges are indicated for foods, airborne allergens and medications to rule out IgE-mediated allergy.
Foods that contain or release histamine (click to enlarge the image).
Treatment of MCA and MCAS
Symptoms of MCAS and systemic mastocytosis can be managed by:
- blockade of mediator receptors with H1 and H2 antihistamines and leukotriene receptor blockade (montelukast)
- inhibition of mediator synthesis (aspirin, zileuton)
- inhibition of mediator release (sodium cromolyn)
- anti-IgE therapy
Acute systemic episodes of MCA require epinephrine. Prolonged episodes of MCA may need steroids.
Patients with clonal mast cell syndromes may need a reduction in the number of mast cells to prevent severe symptoms (anaphylaxis) and progression to aggressive diseases such as leukemia. Patients with clonal mast cell syndromes are typically treated by a hematologist/oncologist.
Treatment of mast cell activation syndrome (MCAS) (click to enlarge the image).
Treatments for systemic mastocytosis (click to enlarge the image).
Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome
Doctor, I Think I Am Suffering from MCAS: Differential Diagnosis and Separating Facts from Fiction
Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management