The Provider Primer Series: Relevance of mast cells in common health scenarios (continued)

Reason for care Post op care
Role of mast cells Mast cells are inherently activated following surgery as they drive tissue remodeling, angiogenesis, and wound repair.[i]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Mechanical trauma or pressure, such as dressing a wound or palpating the area, can directly induce degranulation and mast cell activation[ii].

Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation and cannot be taken by some mast cell patients.[iv]

Codeine and derivatives can trigger mast cell degranulation[v].

Vancomycin, gyrase inhibitors and cefuroxime should be avoided where possible due to risk of mast cell activation.[vi]

Amide caine anesthetics are preferred over ester caines.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management.[vi]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

Adhesive allergy is not unusual and patients may require specific occlusive dressings, tapes, or wound glue.

Notes regarding mast cell treatment Antihistamines and mast cell stabilizers can be helpful in mitigating common post op symptoms such as opiate induced itching and nausea. COX inhibitors can help with pain management.[vii]
Special considerations for mast cell patients Mast cells are the largest reservoir of endogenous heparin. Patient should be monitored for coagulopathy.[viii]

Mast cells contribute significantly to post operative ileus.[ix]

Intestinal manipulation directly results in mast cell degranulation.[ix]

 

Reason for care Hypertension
Role of mast cells Mast cell mediators can impact blood pressure. Histamine acting on H2 receptor can promote hypertension.[xi]

Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II.[xi]

9a,11b-PGF2, the degradation product of prostaglandin D2, thromboxane A2, and leukotrienes increase blood pressure.[xi]

Impact of condition on mast cells Dysregulation of angiotensin II and renin levels can affect mast cell behavior.[x]
Notes regarding condition treatment ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]
Notes regarding mast cell treatment Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.
Special considerations for mast cell patients Mast cell patients taking β-adrenergic receptor antagonists (beta blockers) should carry a glucagon pen to increase efficacy of epinephrine in anaphylaxis.[xi]

As many as 31% of patients with mast cell disease demonstrate elevated arterial blood pressure secondary to mast cell activation. These elevations may be episodic or chronic.[xi]

Mast cell patients may also have hyperadrenergic postural orthostatic tachycardia syndrome (hyperPOTS), a condition that can cause hypertension.[xii]

 

Reason for care Heart disease
Role of mast cells Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II, contributing to evolution of arrhythmia.[xi]

Prostaglandin D2, VIP, PAF, IL-6 and nitric oxide are all vasodilating and can contribute to tachycardia.[xi]

Tryptase, histamine, PAF, IL-10, TNF, IL-4, IL-6, FGF, and TGFB can contribute to heart failure.[xi]

Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Impact of condition on mast cells Heart disease, especially heart failure, can disrupt release of catecholamines including norepinephrine.[xv] Norepinephrine dysregulation can impact mast cell behavior.

Dysregulation of angiotensin II and renin levels can affect mast cell behaviorx

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]

Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.

Epinephrine can provoke myocardial ischemia, prolong QT interval, and exacerbate coronary vasospasm and arrhythmia.[xiv]

Special considerations for mast cell patients Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

 

Reason for care Chest pain
Role of mast cells Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Mast cells participate in esophageal inflammation in several models, including from acid reflux.[xvi]

Mast cells contribute to GI dysmotility which can cause esophageal spasms.[xvii]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]
Special considerations for mast cell patients Mast cell patients may experience GI dysmotility which can cause esophageal spasms.[xviii]

Mast cell patients sometimes have eosinophilic esophagitis, causing esophageal spasms, food impaction, and pain.[xix]

Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients can present with Kounis Syndrome. Management of Kounis Syndrome relies upon addressing both cardiovascular aspects of the episode as well as allergic aspects.[xiv]

Costochondritis can occur in mast cell patients and may present as chest pain.

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

References:

[i] Douaiher J, et al. (2014). Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol, 122, 211-252.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1), 113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharma,ological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol, 4(10).

[viii] Carvalhosa AB, et al. (2015). A French national survey on clotting disorders in mastocytosis. Medicine (Baltimore), 94(40).

[ix] Peters EG, et al. (2015). The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil, 27(6), 743-749.

[x] Biscotte SM, et al. (2007). Angiotensin II mediated activation of cardiac mast cells. The FASEB Journal, 21(6).

[xi] Kolck UW, et al. (2016). Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x, 1-10.

[xii] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45, 385-390.

[xiii] Kennedy S, et al. (2013). Mast cells and vascular diseases. Pharmacology & Therapeutics, 138, 53-65.

[xiv] Kounis NG. (2016). Kounis Syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[xv] Florea VG, Cohn JN. (2014). The autonomic nervous system and heart failure. Circulation Research, 114, 1815-1826.

[xvi] Morganstern JA, et al. (2008). Direct evidence of mast cell participation in acute acid-induced inflammation in mice. J Pediatr Gastroenterol Nutr, 46(2), 134-138.

[xvii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xviii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xix] Nurko S, Rosen R. (2010). Esophageal dysmotility in patients with eosinophilic esophagitis. Gastrointest Endosc Clin N Am, 18(1), 73-ix.

The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

[x] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[xv] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.

 

The Provider Primer Series: Management of mast cell mediator symptoms and release

Mast cell disease is largely managed by treatment of symptoms induced by mast cell mediator release or by interfering with mediator release.

The following tables detail treatment recommendations described in literature by mast cell disease key opinion leaders. Please refer to source literature for future details on dosing, duration, and so on. These are not my personal recommendations and any and all treatment decisions must be made by a medical professional familiar with the patient.

Second and third generation H1 antihistamines are preferred to exclude neurologic symptoms accompanying use of first generation H1 antihistamines. However, first generation H1 antihistamines are sometimes used by mast cell patients and in the setting of anaphylaxis.

In advanced and aggressive forms of mast cell disease, use of cytoreductive agents, chemotherapy, and, very rarely, hematopoietic stem cell transplant may be considered.

Table 1: Primary treatment options (consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
H1 antihistamines (second or third generation preferred) H1 histamine receptor Promotes GI motility, vasodilatation and production of prostaglandins, leukotrienes and/or thromboxanes (via release of arachidonic acid) and nitric oxide  Hypotension, decreased chronotropy, flushing, angioedema, pruritis, diarrhea, headache, urticaria, pain, swelling and itching of eyes and nose, bronchoconstriction, cough, and airway impingement Valent 2007[i], Picard 2013[ii], Molderings 2016[iii], Hamilton 2011[iv]
H2 antihistamines H2 histamine receptor Release of gastric acid, vasodilation, smooth muscle relaxation, and modulates antibody production and release in various immune cells Increased chronotropy, increased cardiac contractility, hypertensioni, bronchodilation, increased presence of Th2 T cells, increasing IgE production Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011
Mast cell stabilizer (cromolyn) Unknown targets to modulate electrolyte trafficking across the membrane to deter mast cell degranulation 

 

 

 

Unclear. Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011

 

Table 2: Primary treatment options (non-consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
Leukotriene receptor antagonists Leukotriene receptor Smooth muscle contraction, immune cell infiltration, production of mucus Bronchoconstriction, airway impingement, overproduction of mucus, pruritis, sinus congestion, runny nose Hamilton 2011, Valent 2007
N/A; Vitamin C decreases histamine levels by accelerated degradation and by interfering with production Unknown targets to deter mast cell degranulation  Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Molderings 2016
H1 antihistamine; mast cell stabilizer Histamine H1 receptor and mast cell stabilizer (ketotifen) See above for function of targets for H1 antihistamines and mast cell stabilizer See above for symptoms targets for H1 antihistamines and mast cell stabilizer Molderings 2016

 

Table 3: Secondary options for mast cell mediator symptoms or release described in literature
Symptom Treatment Reference
Abdominal cramping H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Abdominal cramping H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Abdominal pain H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Angioedema H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Angioedema Medications used for hereditary angioedema, including antifibrinolytic such as tranexamic acid, bradykinin receptor antagonist Molderings 2016
Blistering Local H1 antihistamines, H1 antihistamines, H2 antihistamines, systemic glucocorticoids, topical cromolyn, dressing Valent 2007
Bone pain Analgesics, NSAIDS, opiates and radiation if severe Valent 2007
Bone pain Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Colitis Corticosteroids active in GI tract or systemic Molderings 2016
Conjunctival injection H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Conjunctivitis Preservative free eye drops with H1 antihistamine, cromolyn, ketotifen or glucocorticoid Molderings 2016
Dermatographism H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Diarrhea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Diarrhea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Diarrhea Bile acid sequestrants, nystatin, leukotriene receptor antagonists, 5-HT3 receptor inhibitors, aspirin Molderings 2016
Flushing H1 antihistamines, leukotriene receptor antagonists, H2 antihistamines, glucocorticoids, topical cromolyn Valent 2007
Flushing H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Gastric symptoms Proton pump inhibitors Molderings 2016
Headaches H1 antihistamines, H2 histamines, oral cromolyn Valent 2007
Headaches, poor concentration and memory, brain fog H1 antihistamines, H2 antihistamines, cromolyn, ketotifen Picard 2013
Interstitial cystitis Pentosan, amphetamines Molderings 2016
Joint pain COX-2 inhibitors Molderings 2016
Mastocytoma (if symptomatic, growing) Local immunosuppressants, PUVA, removal Valent 2007
Miscellaneous/ overall elevated symptom profile Disease modifying anti-rheumatoid drugs, antineoplastic drugs, kinase inhibitors with appropriate target, anti-IgE, continuous antihistamine infusion Molderings 2016
Nasal pruritis H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nasal stuffiness H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nausea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Nausea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Nausea Dimenhydrinate, benzodiazepines, 5-HT3 inhibitors, NK1 antagonists Molderings 2016
Neuropathic pain, paresthesia Alpha lipoic acid Molderings 2016
Non-cardiac chest pain H2 antihistamines, proton pump inhibitors Molderings 2016
Osteopenia, osteoporosis Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Peptic ulceration/bleeding H2 antihistamines, proton pump inhibitors, blood products as needed Valent 2007
Pre-syncope/syncope H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Pruritis H1 antihistamines, H2 antihistamines, topical cromolyn, PUVA treatment, leukotriene receptor antagonists, glucocorticoids Valent 2007
Pruritis H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Pruritis Topical cromolyn, topical palmitoylethanolamine containing preparations Molderings 2016
Recurrent hypotension H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Respiratory symptoms Leukotriene receptor antagonists, 5-lipoxygenase inhibitors, short-acting β-sympathomimetic Molderings 2016
Severe osteopenia or osteoporosis Oral bisphosphonates, IV bisphosphonates, interferon alpha Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Tachycardia AT1 receptor antagonists, agents that target funny current Molderings 2016
Throat swelling H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013
Urticaria H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Vomiting H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Vomiting H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Wheezing H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013

 

[i] Valent P, et al. (2007). Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37(6):435-453.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: Monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5):548-562.

[iii] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[iv] Hamilton MJ, et al. (2011). Mast cel activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1):147-152.e2

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

Systemic mastocytosis (SM) is a primary hematologic disorder marked by the excessive proliferation of mast cells.

Neoplastic nature of mastocytosis:

  • Mast cells produced in this disease are neoplastic and may have some or all of the following markers: presence of somatic gain-of-function mutation at codon 816 of CKIT (KIT), usually, but not always, the D816V mutation; expression of CD2 or CD25 on mast cell surface; atypical spindled morphology of mast cells[i].
  • Mastocytosis is a neoplastic condition that is not described exclusively by excessive population of mast cells. Mast cell hyperplasia can occur in response to a number of conditions including chronic urticaria[ii], irritable bowel syndrome[iii], and other hematologic neoplasia, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, and myeloproliferative conditions[iv].
  • To meet criteria for SM, mast cell infiltration must be dense with at least 15 mast cells per cluster. In many instances, there is not a validated range of mast cells/hpf in healthy controls[iv].
Table 1: Diagnostic criteria for systemic mastocytosis[v]

1 major and 1 minor criterion; or 3 minor criteria

Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Presence of dense infiltrates:

  • The hallmark sign of systemic mastocytosis is multifocal dense infiltration of an organ that is not the skin. Despite this fact, it is possible to biopsy negative while still having SM. A 2004 study reported the pathological findings of bilateral bone marrow biopsies for 23 patients. 83% of patients demonstrated positive biopsy for SM bilaterally while 17% of patients had only one positive biopsy[vi].
  • One study found that 20% of ISM patients did not have dense infiltration of mast cells in bone marrow[vii].

Tryptase level in systemic mastocytosis:

  • Tryptase ≥20 ng/mL is a minor criterion for SM. In order to meet this criterion, tryptase must be ≥20 ng/mL at baseline, not during or following a reactive or anaphylactic event. Per Phadia, producer of ImmunoCAP® Tryptase test, it can take up to fourteen days for tryptase to return to baseline[viii]. However, other sources recommend shorter time to baseline, as low as “24 hours after clinical signs and symptoms have completely subsided”[ix].
  • 20-30% of SM patients do not meet the minor criterion of tryptase level ≥20 ng/mL[xiii].

Detection of CKIT D816V mutation:

  • The CKIT D816V mutation may not be detected in peripheral blood in a positive patient. Bone marrow aspirate is the preferred sample type for reliable testing for this mutation[xii].
  • One study reported as few as 78% of ISM patients were positive for the CKIT D816V mutation in bone marrow[xiii].

Natural history of indolent systemic mastocytosis:

  • Indolent systemic mastocytosis (ISM) is SM that does not meet criteria for smoldering systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia.
  • ISM is largely described by mediator release symptoms and increased risk of anaphylaxis. Mast cell infiltration does not cause appreciable organ dysfunction in this variant[x].
  • Progression from ISM to SSM occurred in about 8% of patients in a cohort of 74. In this same cohort, 4% ISM patients progressed to ASM[xi]. The risk of leukemic transformation from ISM was 0.6% in a cohort of 159[xii].
  • Organomegaly can present without loss of function at any level of hematologic disease in SM. Organ swelling may be stable over long periods of time without progression to aggressive systemic mastocytosis (ASM)[x].
  • Lifespan for indolent systemic mastocytosis is normal[x].
Table 2: Diagnostic criteria for smoldering systemic mastocytosis

 (2 or 3 B findings in addition to meeting criteria for systemic mastocytosis)[i]

B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Natural history of smoldering systemic mastocytosis:

  • Smoldering systemic mastocytosis (SSM) is defined by increased systemic mast cell burden, presence of markers associated with progression toward ASM (B findings), and potential need for cytoreduction[xiii].
  • SSM can remain stable for many years, even decadesix. In a cohort of 22 patients with SSM, 1 transformed to acute leukemia and 3 progressed to ASM[xiv].
  • Lifespan may be shortened in SSM. A widely reported study found an average lifespan of 10 years but reported that death was often unrelated to mastocytosis and in some cases was of natural old age[xiii].
Table 3: Diagnostic criteria for aggressive systemic mastocytosis

(1 or more C finding in addition to meeting criteria for systemic mastocytosis)[i]

C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Natural history of aggressive systemic mastocytosis:

  • Aggressive systemic mastocytosis (ASM) is defined by significant organ damage and failure as a direct result of mast cell infiltrationxv. Lifespan is often significantly shortened and can be as short as three years[ix] .
  • ASM generally follows one of two paths: a slow progressing form that resembles SSM but has C findings; or a rapidly progressing form that resembles mast cell leukemia. In rapidly progressing ASM, the patient may lose the CKIT D816V mutation[ix] .
  • ASM is managed with cytoreduction but patient response is often short lived. Tyrosine kinase inhibitors and other kinase inhibitors are also used in this population[ix] .
  • In treatment resistant cases, hematopoietic stem cell transplant offers an experimental option. One study on HSCT in advanced systemic mastocytosis included seven ASM patients. 3 (43%) achieved complete remission; 3 (43%) demonstrated progression free survival at the three year mark[xv].

References:

[i] Arber DA, et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

[ii] Minnei F, et al. (2006). Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch, 448(3), 262-268.

[iii] Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut, 56, 203-209.

[iv] Hamilton MJ, et al. (2011). Mast cell activation syndrome a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol, 128, 147-152.

[v] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[vi] Butterfield JH, Li, CY. (2004). Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient? Hematopathology, Am J Clin Pathol, 121: 264-267.

[vii] Sanchez-Munoz L, et al. (2011). Evaluation of the WHO criteria for the classification of patients with mastocytosis. Mod Pathol, 24(9), 1157-1168.

[viii] Phadia AB. ImmunoCAP® Tryptase: Clinical utility of Total Tryptase. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_Clin_Util.pdf

[ix] Schwartz LB. (2006). Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunology and Allergy Clinics of North America, 26(3), 451-463.

[x] Valent P, et al. (2010). How I treat patients with advanced systemic mastocytosis. Blood, 116(26), 5812-5817.

[xi] Matito A, et al. (2013). Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. PLoS One, 8(10), e76116.

[xii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[xiii] Pardanini A. (2013). How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood, 121, 3085-3094.

[xiv] Pardanini A. (2010). WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood, 115, 150-151.

[xv] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

[xvi] Pardanini A. (2013). Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. American Journal of Hematology, 88(7, 612-624).

[xvii] Valent P, et al. (2003). Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res, 27(7), 635-641.

The Provider Primer Series: Diagnostic criteria of systemic mastocytosis and all subvariants

World Health Organization Classification

  • Mastocytosis was classified by the WHO as a myeloproliferative neoplasm for a number of years. In 2016, the WHO placed mastocytosis into its own category, separate from myeloproliferative neoplasms.
  • In a paper summarizing changes to WHO classification of myeloid neoplasms and acute leukemias, the author stated that “mastocytosis…is no longer considered a subgroup of the MPNs due to its unique clinical and pathologic features, ranging from indolent cutaneous disease to aggressive systemic disease, and is now a separate disease category in the classification[i].”
Table 1: WHO Classification of Mastocytosisi
Category Subtype
Cutaneous mastocytosis (CM) Cutaneous mastocytosis (CM), including maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa); solitary mastocytoma of the skin; diffuse cutaneous mastocytosis*Author’s note: Telangiectasia macularis eruptiva perstans (TMEP) is considered a variant of maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa)
Systemic mastocytosis (SM) Indolent systemic mastocytosis (ISM)
Smoldering systemic mastocytosis (SSM)
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
Aggressive systemic mastocytosis (ASM)
Mast cell leukemia (MCL)
Mast cell sarcoma (MCS) Mast cell sarcoma (MCS)

 

Diagnostic criteria for subvariants of systemic mastocytosis

Table 2: Diagnostic criteria for indolent systemic mastocytosis[ii] 1 major and 1 minor criterion; or 3 minor criteria
Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Table 3: Examples that meet minimum criteria for indolent systemic mastocytosis
Scenario 1:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 2:

major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 3:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ
Scenario 4:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25
Scenario 5:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 6:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 7:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 8:

3 minor criteria

Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is essentially treated as two separate condition: systemic mastocytosis and an associated hematologic neoplastic condition. Accordingly, the diagnostic criteria for the systemic mastocytosis aspect of this diagnosis is the same as described here.

Table 4: Diagnostic criteria for smoldering systemic mastocytosis (2 or 3 B findings)[ii]
B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 5: Examples that meet the criteria for smoldering systemic mastocytosis (2 or 3 B findings)
Scenario 1:

2 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN
Scenario 2:

2 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 3:

2 B findings

Meets criteria for systemic mastocytosis Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 4:

3 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 6: Diagnostic criteria for aggressive systemic mastocytosis (1 or more C finding)[ii]
C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Table 7: Examples that meet the minimum criteria for aggressive systemic mastocytosis (1 or more C finding) 
Scenario 1:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl)
Scenario 2:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Malabsorption evidenced by low albumin and weight loss
Scenario 3:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)
Scenario 4:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension
Scenario 5:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Splenomegaly with hypersplenism

 

Table 8: Diagnostic criteria for mast cell leukemia[iii]
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 9: Examples that meet the minimum criteria for mast cell leukemia
Scenario 1 Meets criteria for systemic mastocytosis B findings may be present but are not required C findings may be present but are not required Mast cells compromise 20% of all nucleated cells in blood smears

 

[i] Arber DA, et al. (2016). The 2016 revisioin to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

[ii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

The Provider Primer Series: Cutaneous mastocytosis/ Mastocytosis in the skin

Mast cell disease: Categories

  • Mast cell disease is the collective term given to several distinct conditions mediated by mast cell dysfunction.  Speaking broadly, mast cell disease has two forms: mastocytosis, a clonal disease marked by excessive proliferation and infiltration of mast cells; and mast cell activation syndrome (MCAS), a disease that presents similarly to mastocytosis but demonstrates no clear indication of excessive proliferation. In addition, monoclonal mast cell activation syndrome (MMAS) can be viewed as straddling the two groupings with markers of clonality but minimum evidence to suggest overproduction of mast cells[i].
  • Mastocytosis has two forms: cutaneous, in which excessive mast cell infiltration is confined to the skin; and systemic, in which an organ that is not skin that is affected by excessive mast cell infiltration. Patients with systemic mastocytosis (SM) often have cutaneous mastocytosis; in this instance, this is called systemic mastocytosis with mastocytosis in the skin[ii].

Mastocytosis in the skin

  • Cutaneous mastocytosis (CM) is a proliferative condition marked by increased mast cell infiltration of the skin.  There are three subvariants of cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), formerly known as urticarial pigmentosa (UP); diffuse cutaneous mastocytosis (DCM); and solitary mastocytoma of skin[ii].
  • Mast cell density in lesions is usually increased 4-8x above the density in healthy controls. However, some patients have mast cell density comparable to that in healthy controls[ii].
  • All forms of cutaneous mastocytosis can be found in children. Over 78% present by 13 months and some at birth[v]. Childhood onset CM often resolves by adolescence but not always[ii].
  • Most patients with mast cell lesions in childhood have CM rather than SM. Conversely, most patients who develop these macules in adulthood have systemic mastocytosis with mastocytosis in the skin[ii].
  • MPCM (UP) is overwhelmingly the dominant presentation of mastocytosis in the skin. Over 80% of all mastocytosis patients demonstrate the type of cutaneous involvement[ii].
  • In children, MPCM lesions are usually large and have variable morphology which may change over time. In adults, MPCM often occurs as small red/brown macules and may result in few lesions or cover the majority of the body[iii].
  • Telangiectasia macularis eruptive perstans (TMEP) is described as telangiectatic red macules generally found above the midtrunk. While previously thought to be a discrete entity, TMEP is now recognized as a form of MPCM[ii].
  • DCM is almost exclusively found in children with few adult onset cases. It does not present as discrete lesions but rather generalized erythema. Pachydermia may also be present, as well as darkening of the skin[ii].
  • DCM can be associated with formation of severe bullae from a variety of triggers, including rubbing the skin, infections and teething. Due to mast cell release of heparin, it is not unusual for skin wounds to bleed excessively[ii].
  • A mastocytoma is a low grade mast cell tumor most often found on the skin. It is frequently raised and yellow or brown in color. Touching the lesion usually evokes a strong wheal and flare reaction. Sweating may also occur. Blistering may be present[ii].

Diagnosis of mastocytosis in the skin

  • While a biopsy is the definitive diagnostic method, positive Darier’s sign is present in most children and many adults with mastocytosis in the skin. Use of antihistamines can suppress a positive Darier’s sign[ii].
  • Biopsies from lesional skin should be stained for mast cells using toluidine blue or Giemsa-Wright stain; evaluated for CD117, CD25 and CD2 using IHC; and evaluated for activating mutations in the CKIT gene using PCR or sequencing methods[i] .
Diagnostic criteria for cutaneous mastocytosis  (requires one major and one minor criterion)[iii]
Major Minor
Typical mast cell rash, usually maculopapular, or atypical rash with positive Darier’s sign Dense infiltration by tryptase positive mast cells, >15 mast cells/cluster or >20 mast cells/x40 magnification hpf if not clustered
Activating CKIT mutation detected in biopsy from skin lesion

 

Symptoms and treatment of mastocytosis in the skin

  • Common symptoms localized to the skin include flushing, itching, burning, hives and blistering[iv].
  • Mediator release symptoms can affect other organs regardless of whether or not they have systemic mastocytosis. Flushing, nausea, vomiting, diarrhea and low blood pressure have been reported among other symptoms. Wheezing, shortness of breath and rarely cyanosis may be present. Anaphylaxis can also occur[iii].
  • Treatment for cutaneous mastocytosis/mastocytosis in the skin relies upon histamine blockade with H1 inverse agonists and H2 antagonists; cromolyn sodium; leukotriene antagonists; and PUVA treatment in severe cases[v].
  • In treatment resistant cases, systemic glucocorticoids and topical cromolyn may be used.  In some instances, mastocytomas may be excisedi. Anaphylaxis should be treated with epinephrine per current guidelines[v].

[i] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol, 4(10), 10.1186/1756-8722-4-10

[ii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1), 35-45.

[iii] Valent P, et al. (2007). Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37, 435-453.

[iv] Carter MC, et al. (2014). Mastocytosis. Immunol Allergy Clin North Am, 34(1), 10.1016/j.iac.2013.09.001

[v] Castells M, et al. (2011). Guidelines for the diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol, 12(4), 259-270.

 

The Provider Primers Series: Medications that impact mast cell degranulation and anaphylaxis

A number of medications can induce mast cell degranulation and histamine release. Other medications increase the risk of anaphylaxis and can increase the severity of anaphylaxis.

Medication reaction profile is very individual and not all mast cell patients react to the medications listed below. Additionally, there may be a need for some mast cell patients to take  medications listed below if the benefit outweighs the risk.

Medications that are reported to induce mast cell degranulation and histamine release
Alcohol[i] Amphoterecin B[ii] Aspirin[i] Atracurium[iii]
Caine anesthetics (esters)[iv] Codeine[v] Colistin (polymyxin E)[vi] Dextran[iii]
Dextromethorphan[iii] Gelatine[iii] Iodine based radiographic dye[vii] Meperidine[viii]
Miconazole[ix] Mivacurium[iii] Morphine[iv] Nefopam[iii]
NSAIDs[x] Phentolamine[xi] Polymyxin B[v] Reserpine[xii]
Rocuronium[iv] Succinylcholine[iv][xiii] Thiopental[iv] Tolazoline[v]
Vancomycin[xiv] (especially when given intravenously)

 

Patients on beta blockers are more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. Beta blockers also impede treatment of anaphylaxis by interfering with the action of epinephrine[xvi]. Patients at risk for anaphylaxis who are on beta blockers should get a glucagon pen to use prior to epinephrine[xv].

Beta adrenergic blockers[xvi] (Note: List is not exhaustive)
Acebutolol Atenolol Betaxolol Bisoprolol
Bucindolol Butaxamine Cartelol Carvedilol
Celiprolol Esmolol Metoprolol Nadolol
Nebivolol Oxprenolol Penbutolol Pindolol
Propranolol Sotalol Timolol

 

Alpha blockers impede treatment of anaphylaxis by interfering with the action of epinephrine[xvii].

Alpha-1 adrenergic blockers[xvii] (Note: List is not exhaustive)
Alfuzosin Amitryptiline Amoxapine Atiprosin
Carvedilol Chlorpromazine Clomipramine Clozapine
Dapiprazole Dihydroergotamine Doxazosin Doxepin
Ergotamine Etoperidone Fluphenazine Hydroxyzine
Imipramine Labetalol Loxapine Mianserin
Nefazodone Olanzapine Phentolamine Prazosin
Quetiapine Risperidone Silodosin Tamsulosin
Thimipramine Thioridazine Trazodone

 

Alpha-2 adrenergic blockers[xvii] (Note: List is not exhaustive)
Buspirone Chlorpromazine Clozapine Esmirtazapine
Fluophenazine Idazoxan Loxapine Lurasidone
Mianserin Mirtazapine Olanzapine Phentolamine
Risperidone Thioridazine Yohimbe

Patients on angiotensin-converting enzyme (ACE) inhibitors are also more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. The exact reason for this is unclear but ACE inhibitors impede appropriate bradykinin metabolism which may contribute to anaphylaxis[xvi].

Angiotensin converting enzyme (ACE) inhibitors[xvi] (Note: List is not exhaustive)
Benazopril Captopril Enalapril Fosinopril
Lisinopril Moexipril Perindopril Quinapril
Ramipril Trandolopril

Special notes:

Aspirin use in mast cell patients to suppress prostaglandin production is becoming increasingly common[xviii]. In some situations, other NSAIDs are also used.

Fentanyl, sufentanil, remifentanil and alfentanil are the preferred opioids for mast cell patientsiv. Hydromorphone releases minimal histamine and is also used in mast cell patients.[xix]

References:

[i] Valent P. (2014). Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clinical & Experimental Allergy, 44, 914-920.

[ii] Lange M, et al. (2012). Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci, 8(3), 533-541.

[iii] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[iv] Eggleston ST, Lush LW. (1996). Understanding allergic reactions to local anesthetics. Ann Pharmacother, 30(7-8), 851-857.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Kwa A, et al. (2014). Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Review of Anti-infective Therapy, 5(5), 811-821.

[vii] Kun T, Jakubowski L. (2012). Pol J Radiol, 77(3), 19-24.

[viii] Blunk JA, et al. (2004). Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analq, 98(2), 364-370.

[ix] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[x] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xi] Powell JR, Shamel LB. (1979). Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors. J Cardiovasc Pharmacol, 1(6), 633-640.

[xii] Muroi N, et al. (1991). Effect of reserpine on histamine metabolism in the muse brain. J Pharmacol Exp Ther, 256(3), 967-972.

[xiii] Sadleir PH, et al. (2013). Anaphylaxis to neuromuscular blocking drugs : incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth, 110(6), 981-987.

[xiv] Sanchez-Borges M, et al. (2013). Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy. World Allergy Organization Journal, 6(18), doi:10.1186/1939-4551-6-18

[xv] Thomas M, Crawford I. (2005). Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J, 22(4), 272-273.

[xvi] Lieberman P, Simons FER. (2015). Anaphylaxis and cardiovascular disease: therapeutic dilemmas. Clinical & Experimental Allergy, 45, 1288-1295.

[xvii] Higuchi H, et al.(2014). Hemodynamic changes by drug interaction of adrenaline with chlorpromazine. Anesth Prog, 61(4), 150-154.

[xviii] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xix] Guedes AG, et al. (2007). Comparison of plasma histamine levels after intravenous administration of hydromorphone and morphine in dogs. J Vet Pharmacol Ther, 30(6), 516-522.

The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.