Mast cell activation syndromes

Mast cell activation disease (MCAD) refers to a heterogeneous group of diseases, ranging from primary systemic mast cell disease, systemic mastocytosis (SM) with several subtypes, primary mast cell activation syndrome and mast cell leukemia. Pathogenetically, MCAD refers to a group of polygenic mast cell disorders characterized by aberrant release of variable subsets of mast cell mediators and accumulation of morphologically altered or immunohistochemically identifiable mutant mast cells.

Several variable clinical symptoms due to the effect of the different mast cell mediators, in acute cases, however, up to organ failure.

Current provisional criteria for the definition of mast cell activation syndrome (MCAS)

Main criteria

• Constellation of clinical symptoms attributable to pathologically increased mast cell activity.

Minor criteria:

• 1. focal or disseminated increased number of mast cells in bone marrow and/or extracutaneous organ(s) (e.g. gastrointestinal biopsies; CD117-, tryptase- and CD25-stained)
• 2. abnormal spindle-shaped morphology in >25% of mast cells in the bone marrow or other extracutaneous organ(s)
• 3. abnormal mast cell expression of CD2 and/or CD25 (i.e. co-expression of CD117/CD25 or CD117/CD2)
• 4. detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an influence on the activity state of affected mast cells in the sense of increased activity has been demonstrated
• 5. detection (typically from body fluids such as whole blood, serum, plasma or urine) of abnormal levels of mast cell mediators, including: tryptase in the blood, histamine or its metabolites (e.g. N-methylhistamine) in urine, heparin in blood, chromogranin A in blood (potential confounders of cardiac or renal failure, neuroendocrine tumors or recent use of proton pump inhibitors were excluded), further relatively mast cell specific mediators (e.g. eicosanoids including prostaglandin PGD2, its metabolite 11-β-PGF2α or leukotriene E4)
• 6. symptomatic reaction to inhibitors of mast cell activation or mast cell mediator production or effect (e.g. histamine H1 and/or H2 receptor antagonists, cromoglycine)

To diagnose mast cell activation syndrome, at least the main criterion plus one of the secondary criteria or three secondary criteria must be present

Primary mast cell activation syndromes:

By definition, monoclonal mast cells are detectable in a primary mast cell activation syndrome.

Secondary mast cell activation syndromes:

The term "secondary mast cell activation syndrome" is used to describe clinical pictures with symptoms of mast cell activation in which clonal mast cell proliferation is not detectable. Underlying are IgE-mediated allergic diseases, chronic inflammatory autoimmunological or neoplastic diseases, physical forms of urticaria, hypersensitivity reactions e.g. to drugs.

Idiopathic mast cell activation syndromes:

An "idiopathic mast cell activation syndrome" is a diagnosis of exclusion in which neither allergies nor monoclonal mast cell proliferations are present. This term includes conditions such as idiopathic urticaria/angioedema, idiopathic anaphylaxis, and others.

Prevalence of MCAS in Germany up to 17 %, that of systemic mastocytoses in Europe: 0.3 and 13 per 100,000 population

The clinical symptoms are not uniform. Clear objective parameters are lacking. The patient reports whistling/breathing in the airways (pulmonary sidetone), recurrent swelling of the upper airways, urticaria, angioedema, headache, hypotension, diarrhea, fatigue.

Symptoms can occur in virtually all organs, possibly different symptoms in the identical patient at different times.

Mediator's credentials. Tryptase: a transient increase in tryptase by at least 20% of the base value is considered relevant.

Presence of a corresponding clinical symptomatology

Response to H1/H2 antihistamines

Avoidance of possible triggers, if ascertainable.

H1-/H2-antihistamines; mast cell stabilizers. e.g. cromoglicic acid (^Colimune®; ^Ketotifen®); also sustained release vitamin C (inhibition of mast cell degranulation; degradation of histamine).

Immunosuppression as second line therapy

Omalizumab (Xolair®)

There are also some studies with kinase inhibitors, interleukin 6 inhibitors, otherwise symptomatic depending on the symptoms in the foreground.

Symptom-oriented therapy .

The following medications should be avoided in MCAS (Molderings et al. 2016):

Intravenous narcotics:methohexital, phenobarbital, thiopental.

Muscle relaxants: atracurium, mivacurium, rocuronium

Antibiotics: cefuroxime, gyrase inhibitors, vancomycin

Selective dopamine and norepinephrine reuptake inhibitors: bupropion

all selective serotonin reuptake inhibitors

Anticonvulsants: carbamazepine, topiramate

Opioid analgesics: meperidine, morphine, codeine

Peripherally acting analgesics: acidic nonsteroidal anti-inflammatory drugs, ASA, ibuprofen

Local anesthetics: lidocaine, articaine, tetracaine, procaine

X-ray contrast media: iodine-containing contrast medium, gadolinium chelate

Plasma substitutes: hydroxyethyl starch, gelatin

Cardiovascular drugs: ACE inhibitors ß-adrenoceptor antagonists

Peptidergic drugs: icatibant, cetrorelix, sermorelin, octreotide, leuprolide

1. Brockow K (2013) Mast cell activation syndrome. Dermatologist 64: 102-106
2. Ravi A et al. (2014) Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11β-prostaglandin2α. J Allergy Clin Immunol Pract 2:775-778.
3. Molderings GJ et al. (2014) Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Dtsch Med Wochenschr 139: 1523-1534http://Dtsch Med Wochenschr 139: 1523-1534.
4. Molderings GJ et al: (2016) Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol- 389: 671-694.
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903110/#CR144