Mast cell activation syndrome.pdf

Mast cell activation
Syndrome
F1 Pongsawat Rodsaward
rom lapipette.labs

Topic
•Mast cell
•Mast cell activation syndrome (MCAS)
•Mastocytosis

Mast cell
•Timeline
•Development
•Classification
•Activation of mast cell and signaling
•Mast Cell Mediators

Clinical Reviews in Allergy & Immunology (2020) 58:342–365
Mast cell timeline

Mast cell development
Cellular and Molecular Immunology, 10th Edition
CD34+
Kit-positive (CD117 + )
Mast cells are derived from CD13+CD34+CD117+ (KIT) hematopoietic progenitors
in the bone marrow. Developing mast cells subsequently migrate to peripheral
tissues where they terminate their differentiation under the influence of factors in
microenvironment.
Stem cell factor (SCF, Kit ligand, Steel factor) is an obligate
human MC growth factor.
Middleton's Allergy: Principles and Practice, Ninth Edition

KIT
• is a single-chain receptor that has inherent protein-
tyrosine-kinase activity
SCF-mediated dimerization of KIT
• autophosphorylation at multiple tyrosine residues in the
cytoplasmic tail
• PI3K activation
• PLCγ activation (slower and of lower magnitude
than those elicited by FcεRI aggregation)
• MAPK-cascade
• JAKs-STATs
The signal-transduction molecules that
are recruited and/or activated by KIT
Nat Rev Immunol. 2006 Mar;6(3):218-30.

Mast cell
Wright-Giemsa–stained perivascular dermal mast cells
Characteristic Mast Cells
Major site of maturation Bone marrow precursors
mature in connective tissue
and mucosal tissues
Location of cells Connective tissue and
mucosal tissues
Life span Weeks to months
Major growth and
differentiation factor
(cytokines)
Stem cell factor
Expression of FcεRI High
Major granule contents Histamine, heparin and/or
chondroitin sulfate,
proteases

Mast cell classification
MCT MCTC
Distribution Predominant subtype in small intestinal
mucosa (98%) and alveoli (93%)
Predominant subtype in the skin (88%)
and small intestinal submucosa (87%)
Granule neutral protease Tryptase Tryptase, chymase, carboxypeptidase,
cathepsin G
Granule ultrastructure Cylindrical scrolls Crystals (lattices/gratings)
Primary role Host defense Tissue repair
Cytokine IL-4↓, IL-13↓, IL-5↑, IL-6↑ IL-4↑, IL-13↑
T cell dependence Yes No
Activated by substance P No Yes
Response to C5a No Yes
Response to PAF Yes No
Inhibited by sodium
cromoglycate
Yes (weak effect) No
Clinical Reviews in Allergy & Immunology (2020) 58:342–365

• Transmission electron micrograph showing a skin
mast cell containing many prominent electron-
dense granules.
(B) Scrolls
(C) gratings
(D) lattices
• (E) Anaphylactic mast cell degranulation with
fusion of mast cell granules.
• (F) Piecemeal mast cell degranulation in
asthmatic bronchial mucosa.
Middleton's Allergy : Principles and Practice, 9th edition

Mast cell receptor
Cellular and Molecular Immunology, 10th

stimuli on the release of
mediators by mast cells

The principle signaling
cascade in activated mast cells
PIP2
FcεRIα - binds IgE
immunoreceptor tyrosine-based activation motif (ITAM)

The complementary (amplification)
signaling cascade in activated
mast cells
PIP2

Mast cell degranulation
Compound exocytosis
• Sequential exocytosis
• the initial fusion of vesicles
with the plasma membrane.
• Next, the vesicles will fuse
with the first vesicle.
• Multivesicular exocytosis
• vesicles fusing together
prior to having interacted
with the cell membrane
Piecemeal degranulation
• gradual loss of contents of
cytoplasmic granules
without distinguishable
granule fusion
• poorly understood and
require further research
• predominantly in chronic
asthma
Clinic Rev Allerg Immunol (2020) 58:342–365

Mast cell mediators
Redegeld, F.A. (2016). Mast Cells. In: Vohr, HW. (eds) Encyclopedia of Immunotoxicology.
Springer, Berlin, Heidelberg.

Mast cell mediators (performed)
Mediator Function
Histamine Bronchoconstriction; tissue edema; ↑ vascular permeability; ↑ mucus secretion; ↑ fibroblast
proliferation; ↑ collagen synthesis; ↑ endothelial cell proliferation, dendritic cell differentiation
and activation
Heparin Anticoagulant; mediator storage matrix; sequesters growth factors; fibroblast activation;
endothelial cell migration
Tryptase Degrades respiratory allergens and cross-linked IgE; generates C3a and bradykinin; degrades
neuropeptides; TGF-β activation; increases basal heart rate and ASM contractility; ↑ fibroblast
proliferation and collagen synthesis; epithelial ICAM-1 expression and CXCL8 release; potentiation
of mast cell histamine release; neutrophil recruitment
Chymase ↑ Mucus secretion; ECM degradation, type I procollagen processing; converts angiotensin I to
angiotensin II; ↓ T cell adhesion to ASM; activates IL-1β, degrades IL-4, releases membrane-
bound SCF

Mast cell mediators (newly synthesized)
Mediator Function
PGD2 Bronchoconstriction; tissue edema; ↑ mucus secretion; dendritic cell activation; chemotaxis of
eosinophils, Th2 cells, and basophils via the CRTH2 receptor
LTC4 /LTD4 Bronchoconstriction; tissue edema; ↑ mucus secretion; enhances IL-13-dependent airway
smooth muscle proliferation; dendritic cell maturation and recruitment; eosinophil IL-4
secretion; mast cell IL-5, IL-8, and TNF-α secretion; tissue fibrosis

Mast cell mediators

Tryptase
• Tryptase is a protein expressed by mast cells and
basophils
• Pro-tryptases generated in mast cells undergo
sequential proteolytic cleavage to become mature
tetrameric tryptase, stabilized by heparin, and stored in
secretory granules (top) awaiting appropriate stimuli to
induce degranulation.
• Alternatively, pro-tryptases can be secreted
constitutively into serum as enzymatically inactive pro-
peptides (bottom).
the vast majority of measured basal serum
tryptase (BST) in healthy individuals
Immunol Allergy Clin N Am 38 (2018) 483–495

Tryptase
Ann Allergy Asthma Immunol . 2021 Oct;127(4):420-426.

Tryptase
Each of these isoforms is remarkably similar,
being at least 97% identical, making
detection of distinct tryptase isoforms
extremely difficult
Only TPSB2 and TPSAB1 encode the secreted
isoforms of tryptase that are measured and
reported as serum tryptase by clinical
laboratories
The tryptase locus contains 4 tryptase-encoding genes (TPSG1, TPSB2, TPSAB1, and TPSD1)
and is present on the distal portion of the short arm of chromosome 16 at position p13.3

Tryptase
Ann Allergy Asthma Immunol . 2021 Oct;127(4):420-426.
Estimated prevalence of elevated BST and associated
causes in Western populations.
Int Arch Allergy Immunol 2020;181:357–364

Ann Allergy Asthma Immunol. 2021 Jun;126(6):655-660.
• a retrospective evaluation of 101 patients who were
referred to the Brigham and Women’s Hospital (BWH)
Mastocytosis Center for evaluation of mast cell
activation related symptoms.
• 80% were female with average tryptase of 17.2
ng/mL.
• KIT D816V mutation was negative in all subjects
tested.
(range 6.2-51.3 ng/mL)
• HαT encompasses a broad range of baseline tryptase and
should be considered in patients with symptoms of mast
cell activation and tryptase levels greater than 6.2 ng/mL.
• Patients may present with complex symptomatology
including cutaneous, gastrointestinal, neurologic, and
psychiatric symptoms and anaphylaxis, some of which
respond to omalizumab.

• One hundred patients were recruited between November 2019 and July 2020 from
allergy and immunology clinic at the University of Michigan, with 50 having
mastocytosis or monoclonal mast cell activation syndrome (MCAS).
• HaT was identified in 7.5% of the random biorepository samples and in 18% of
patients with mastocytosis.
• There was no difference in the clinical symptomology or medical history of
individuals with HaT compared to controls.
• Average baseline serum tryptase was higher in individuals with HαT compared to
controls, but there was no difference in urinary mast cell activation products.
J Allergy Clin Immunol . 2022 Feb;149(2):728-735.

II. Mast cell activation
syndrome (MCAS)

Mast cell activation syndrome (MCAS)
•Clinical manifestation
•Diagnostic criteria and classification
•Differential diagnosis
•Investigation
•Treatment

Clinical manifestation
J Allergy Clin Immunol Pract . 2019 Apr;7(4):1125-1133.e1.
Clinical effects of mast cell mediators
produced and released during mast
cell activation

Clinical manifestation
Clinical symptoms typically associated
with local or systemic MCA

• Eighteen adult patients who had characteristic signs and
symptoms of MC mediator release were prospectively
identified from 2006 to 2009 in an allergy clinic at a tertiary
care center (Brigham and Women’s Hospital, Boston,
Mass).
• Patients were included in the study on the basis of 3
criteria
• (1) they had at least 4 of 6 clinical features (abdominal pain,
diarrhea, flushing, headache, memory and concentration
difficulties, and dermatographism),
• (2) symptoms responded to anti-MC mediator medications
• (3) they had laboratory evidence of MC mediator release.
• Patients with cutaneous, indolent, or systemic forms of
mastocytosis and idiopathic anaphylaxis (IA) were not
included in this study.
J Allergy Clin Immunol . 2011 Jul;128(1):147-152.e2.

J Allergy Clin Immunol . 2011 Jul;128(1):147-152.e2.

Am J Med Sci. 2017 Mar;353(3):207-215.
The full population of 413 patients at a single
center (the Medical University of South Carolina)
• 298 patient population examined
retrospectively (diagnoses made between
November 2008 and September 2012)
• 115 patient population examined
prospectively (diagnoses made between
April 2012 and October 2013)
All diagnoses met published criteria 2012
Demographic Data
• Sex: Female (69%)
• Race: White (75%) , African American(25%)
• Median age at onset: was 9 years (0-88)
• Median age at diagnosis :49 years (16-92)
• Median time from onset to diagnosis : 30 years (1-85)

Am J Med Sci. 2017 Mar;353(3):207-215.

MCAS diagnostic criteria
•Proposed diagnostic criteria 2010
•Vienna consensus criteria 2012
•Vienna consensus criteria 2019
•AAAAI Work Group Report 2019
•Collegium Internationale Allergologicum Update 2022

MCAS diagnostic criteria (2010)
1. Symptoms
2. Response to therapy
3. MC markers
4. Rule out primary and secondary causes of mast cell activation
J Allergy Clin Immunol 2010;126:1099-104

•Episodic symptoms consistent with mast cell mediator release affecting
>=2 organ systems
• Skin: urticaria, angioedema, flushing
• Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
• Cardiovascular: hypotensive syncope or near syncope, tachycardia
• Respiratory: wheezing
• Naso-ocular: conjunctival injection, pruritus, nasal stuffiness

•A decrease in the frequency or severity or resolution of symptoms with
antimediator therapy:
• H1- and H2-histamine receptor inverse agonists
• antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-
lipoxygenase inhibitor)
• mast cell stabilizers (cromolyn sodium)

• Evidence of an increase in a validated urinary or serum marker of mast cell
activation:
• documentation of an increase of the marker to greater than the patient’s baseline
value during a symptomatic period on >=2 occasions
OR
• if baseline tryptase levels are persistently >15 ng, documentation of an increase of the
tryptase level above baseline value on 1 occasion.
• Total serum tryptase level is recommended as the marker of choice
• less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or
its metabolite 11-b-prostaglandin F2.

•Rule out primary and secondary causes of mast cell activation
• Primary
• Mastocytosis
• Monoclonal mast cell activation syndrome (MMAS)
• Secondary
• Allergic disorders
• Mast cell activation associated with chronic inflammatory or neoplastic disorders
• Physical urticarias
• Chronic autoimmune urticaria

Vienna consensus criteria (2012)
•Criterion A: Symptoms
•Criterion B: MC markers
•Criterion C: Response to therapy
Int Arch Allergy Immunol . 2012;157(3):215-25.
(Working Conference on Mast Cell Disorders 2012)

• Two or more organ systems exhibit these
signs or symptoms in parallel, require
therapy and are recurrent or even
permanent

• increase in serum tryptase level from the individual’s baseline serum tryptase
plus 20% + 2 ng/ml; histamine, prostaglandins and leukotrienes and metabolites
in serum or urine are also indicated

• Response of clinical symptoms to histamine receptor1 blockers or ‘MC-targeting’
agents, e.g. cromolyn

• Response of clinical symptoms to histamine receptor1 blockers or ‘MC-targeting’
agents, e.g. cromolyn
Complete response to other drugs, such as glucocorticosteroids, cromolyn,
cyclooxygenase inhibitors, leukotriene receptor blockers, 5-lipoxygenase inhibitors, or
antagonists of certain cytokines, may also be regarded as indirect evidence of MCA.

• 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)

• preferred marker: increase in serum tryptase level from the individual’s baseline
to plus 20% + 2 ng/mL

MCAS classification (2012)
•Primary MCAS
• Mastocytosis
• (Mono)clonal MCAS
•Secondary MCAS
• Allergy
• Other underlying disorder (autoimmune diseases, certain bacterial infections and
some adverse drug reactions)
•Idiopathic MCAS

•According to organ involvement and severity
• Systemic MCA
• Mild or moderate systemic MCA (MCAS criteria not fulfilled)
• Severe systemic MCA = MCAS (MCAS criteria fulfilled) Local MCA (mild/moderate or
severe) (MCAS criteria not fulfilled)
•According to underlying condition
•According to frequency and symptom-free interval

•According to organ involvement and severity
•According to underlying condition
•According to frequency and symptom-free interval
• Episodic recurrent
• With a known trigger (eg, allergen)
• Without a known trigger
• Chronic persistent

MCAS diagnostic criteria
(AAAAI 2019)
•A primary clinical condition in which patients present with spontaneous
episodic signs and symptoms of systemic anaphylaxis concurrently
affecting at least 2 organ systems and resulting from secreted MC
mediators.
•Antihistamines and type 1 cysteinyl leukotriene receptor antagonists, and
decreases in production occur with inhibitors of COX for PGD2 or 5-
lipoxygenase for LTC4 or with MC stabilizers, such as omalizumab, which
diminish MC activatability.
AAAAI Work Group Report 2019

MCAS diagnostic criteria (AAAAI 2019)
Recurrent episodes of
systemic anaphylaxis
with concurrent
involvement of at least
2 of the 4 organ systems
AAAAI Work Group Report 2019

Collegium Internationale Allergologicum Update 2022

Disorder
Disorder related to mast cell
activation

Estimated percentage of patients with a specific disorder
(underlying condition) who experience events that meet the
diagnostic criteria of MCAS
J Allergy Clin Immunol. 2018 Sep;142(3):1008-1010.

Idiopathic mast cell activation syndrome is more often
suspected than diagnosed
• prospectively investigated
patients with suspected MCAS
referred to allergy department
from February 2019 to
November 2020, over the course
of 12 weeks.
• Comorbid depression and
anxiety were explored with the
Hospital Anxiety and Depression
Scale (HADS).
patient reported outcome measures (PROMs) Allergy. 2022;00:1–9.
Mast cell activation syndrome was
confirmed in only 2% of patients

Idiopathic mast cell activation syndrome is more often
suspected than diagnosed
Allergy. 2022;00:1–9.

Differential
diagnosis
J Allergy Clin Immunol Pract . 2020 Feb;8(2):498-506.

Investigation
•Diagnosis of MCAS
• Tryptase
• Histamine and its metabolites
• PGD2 and its metabolites
• LTC4 and its metabolites
•Differential diagnosis
•Classification of MCAS
• TPSAB1 genotype
• KIT816V
• Bone marrow biopsy
• Allergic work up

Tryptase
b. Patients with mastocytosis with mild clinical symptoms not
resembling MCAS (no MCAS – left panel) and those with severe
clinical symptoms resembling MCAS (MCAS-like – right panel) were
examined for their serum tryptase levels post or prior to the event
and at or shortly after the event
20% + 2 formula
• defines a minimal diagnostic increase in
tryptase over the individuals’ baseline that
qualifies as solid indication and thus as
criterion of severe systemic MC activation in
all cohorts of patients
• has been validated in patients with MC
disorders as well as in patients without
mastocytosis

Histamine and its metabolites
•Once released, histamine is metabolized rapidly (half-life, 1-2 minutes),
primarily to N-methylhistamine
• Demonstrated clear utility to aid in the evaluation and diagnosis of systemic
mastocytosis
• For investigating MCAS, measurement of urine N-methylhistamine levels has
demonstrated little clinical utility
J Allergy Clin Immunol . 2019 Oct;144(4):883-896.

PGD2 and its metabolites
• Large amounts of PGD2 can be rapidly
synthesized and secreted by MCs
activated when FcεRI is aggregated
• PGD2 is metabolized by an aldo-keto
reductase, principally AKR1C3, at the 11-
ketone position to an 11b-hydroxyl moiety
or 9a,11b-PGF2 (also called 11b-PGF2a)
Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:401-7.

LTC4 and its metabolites
• LTE4, the most stable cysteinyl
leukotriene, is used to monitor this
pathway in plasma or urine because its
precursors, LTC4 and especially LTD4,
are very transient.

J Allergy Clin Immunol Pract. Nov-Dec 2014;2(6):775-8.
• A retrospective study of 25 patients with MCAS at Mayo
Clinic Rochester from 2006 to 2012 was performed.
• All 25 patients had undergone bilateral bone marrow
biopsies, and results of the analyses were negative for SM.
• Measurement of 24-hour urine 11b-PGF2a and
serum tryptase levels can help avoid misdiagnosis
and overinterpretation of MCAS symptoms in
clinical practice.
• Measurement of f 24-hour urine N-MH may be less
helpful in diagnosing MCAS.

Clin Exp Allergy . 2009 Jan;39(1):72-80.
• Changes in urinary leukotriene E4 (LTE4) and 9a,11b-
prostaglandin F2 (9a,11b-PGF2) concentrations in anaphylactic
patients during provocation test.
• 9a-11b-PGF2 increased during the 0- to 3-hour period
• LTE4 increased maximum during the 3- to 6-hour period

J Allergy Clin Immunol Pract . 2020 Feb;8(2):498-506.

TPSAB1 genotype
J Allergy Clin Immunol Pract. 2022 May 18;S2213-2198(22)00489-5.

Treatment
•Exclude confounding disorders
•Avoid known and specific triggers
•Medications

Exclude confounding disorders
• Endocrine causes
• pheochromocytoma, thyrotoxicosis, medullary carcinoma of the thyroid, insulinoma, carcinoid syndrome
• Cardiovascular disorders
• labile hypertension, deconditioning, orthostatic hypotension, paroxysmal arrhythmias, baroreflex
dysfunction
• Psychologic diseases
• anxiety and panic attacks, somatization disorder, hyperventilation
• Pharmacologic changes
• withdrawal of adrenergic inhibitor, mono amino oxidase [MAO] treatment + tyramine, sympathomimetic
ingestion, illegal drug ingestion, chlorpropamide-alcohol flush, vancomycin-red-man syndrome
• Neurologic reasons
• postural orthostatic tachycardia syndrome, autonomic neuropathy, migraine headache, seizure disorders,
stroke, cerebrovascular insufficiency
J Allergy Clin Immunol Pract. 2019 Apr;7(4):1097-1106.

Avoid known and specific triggers
•Specific foods, medications (NSAIDs, vancomycin, quinolones)
environmental allergens
•General triggers (stress, lack of sleep, emotions)
•Physical triggers
• Exercise, rubbing, pressure
• Changes in temperature (heat, cold)
• Extreme temperatures
• Dryness of skin

Medications
•Antihistamines
•Cysteinyl leukotriene receptor blocking agents
•Aspirin
•Cromolyn
•Glucocorticosteroids
•Anti-IgE therapy
•Cytoreductive therapies

Medications
H1
blocker
H2
blocker
LRA ASA Cromolyn Ketotifen Steroid Others
Skin: pruritus, flushing, urticaria, angioedema,
dermatographism
✓ ✓ ✓ ✓ ✓
(tropical)
✓
Gastrointestinal: diarrhea, abdominal bloating,
cramping/ pain, nausea, vomiting, GER
✓ ✓ ✓ PPI
Neuro/psychiatric: headache, poor concentration,
short memory span, brain fog, anxiety,
depression
✓ ✓ ✓ ✓ ✓
Cardiovascular: presyncope, syncope,
tachycardia, hypotension, hypertension
✓ ✓ ✓
Pulmonary: wheezing, shortness of breath, throat
swelling
✓ ✓ ✓ Broncho-
dilator

H1R antihistamines
• Cyproheptadine
• sedating H1R blocker and a serotonin receptor antagonist
• has been used to treat diarrhea and nausea in the setting of MCAS
• Ketotifen
• sedating H1R blocker and mast cell stabilizer
• used to treat dermatologic, gastrointestinal, and neuropsychiatric symptoms
• Rupatadine
• H1R blocker that also blocks platelet-activating factor
• improved control of pruritus, flushing, tachycardia, and headache but not
gastrointestinal symptoms
J Allergy Clin Immunol 2019;144:883-96.

Aspirin
• Aspirin might reduce flushing and hypotension
in some patients, particularly those with
increased urinary 11b-PGF2a levels
• Generally, 80% to 90% of patients will tolerate
aspirin or other NSAIDs, and there have been no
deaths reported from aspirin administration to
patients with SM or MCAS

Cromolyn
•is used predominately for gastrointestinal symptoms
•its mechanism of action is not known
•onset of action can be delayed and should be taken for at least 1 month
before deciding whether it is helping.
•It should be introduced at the lowest dose, with the dose gradually
increased to 200 mg 4 times a day given before each meal and at bedtime.
J Allergy Clin Immunol 2019;144:883-96.

Omalizumab
• A 52-year-old man with MMAS with Hymenoptera anaphylaxis had anaphylaxis
within minutes after the first dose (0.01 mg) of VIT.
• He subsequently received 3 doses of omalizumab (300 mg, subcutaneously) 10
weeks, 6 weeks, and then 2 weeks before recommencing VIT.
the successful use of omalizumab during an ultrarush protocol
for venom immunotherapy in a patient with monoclonal mast
cell activation syndrome.

Omalizumab
Sex Age Symptoms Tryptase Other labs Treatment
Female 28 Monthly episodes of idiopathic
anaphylaxis (nausea, abdominal
cramping, generalized pruritus,
urticaria, hypotension/orthostasis; 2
episodes with respiratory distress).
One episode required epinephrine.
Baseline: <2
During episode:
4.4, 3.2 mcg/L
Elevated PGF2 Failed combination high dose
H1 antagonists, H2 antagonists,
and montelukast. Did not
tolerate cromolyn Controlled with
omalizumab
Male 56 Intermittent flushing, diarrhea,
abdominal pain, pruritic rash, dyspnea
and bone pain.
Baseline: 68.3
ug/L, 107 ug/L
Mast cell
infiltrate with
atypical
morphology,
+CD2/CD25
and +D816V
Failed combination high dose
H1 antagonists, H2 antagonists,
montelukast 10mg daily,
cromolyn 200mg QID and
hydroxyurea 1000mg daily.
Significant improvement with
omalizumab
Ann Allergy Asthma Immunol. 2018 July ; 121(1): 128–130.
omalizumab increasingly is finding use in the
treatment of MCAS and idiopathic anaphylaxis
resistant to conventional therapy.

Curr Opin Allergy Clin Immunol. 2021 Oct 1;21(5):426-434.

Mast cell and MCAS
•Mast cell
• Timeline
• Development
• Classification
• Activation of mast cell and signaling
• Mast Cell Mediators
•MCAS
• Clinical manifestation
• Diagnostic criteria and classification
• Differential diagnosis
• Investigation
• Treatment

Mast cell activation syndrome.pdf

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Mast cell activation syndrome.pdf

Similar to Mast cell activation syndrome.pdf (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Mast cell activation syndrome.pdf