The MastAttack 107: The Layperson’s Guide to Mast Cell Diseases, Part 17

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

25. How do I know what I will react to?
There is no way to definitively know what things will make you react. It is difficult to predict. There are some general guidelines many of us use to figure out what may be a problem but the only way to really know is to try something.
• Please note that because mast cell reactions are not known to be triggered by the same mechanisms as traditional allergies, you cannot exclude an entire class of drugs because you react to one in the way that you do for traditional allergies. This is particularly worth noting for opiates: reaction to morphine, for example, does not exclude fentanyl or hydromorphone.
• Mast cell reactions are not inherently triggered by IgE the way that “true” allergies are. This means that blood tests for IgE allergies will not identify triggers accurately for most mast cell patients. (Although some mast cell patients do have some IgE allergies.)
• Additionally, skin testing is wildly inaccurate in mast cell patients because of how reactive our skin is.
Stopping antihistamines is dangerous for mast cell patients.
Allergy testing is not accurate for mast cell patients.
• There are several ways that various things can cause mast cell reactions. Generally, they do it in one of the following ways: they cause mast cells to empty the chemicals in their pockets into the body (degranulation); they cause mast cells to release chemicals in another way; they already contain significant amounts of histamine; or the interfere with the mechanisms for controlling mast cell activation.
There are a number of medications that can cause mast cell degranulation or histamine release. Please note that not all of these medications are problematic for every patient. Only a provider managing your case can determine if these are safe for you or not. The major medications that may cause degranulation or histamine are listed below. This list is not exhaustive.

-Alcohol: Widely used to sterilize body area, surfaces, or tools; also used when preparing many medications that are not soluble in water
-Amphoterecin: Antifungal
-Aspirin: NSAID, for pain, inflammation, to block prostaglandins, to prevent clot formation
-Atracurium, mivacurium, rocuronium: Muscle relaxant
-Caine anesthetics (esters): Anesthetics, to numb
-Codeine, morphine, meperidine: Opiates, for pain or cough
-Colistin: Antibiotic
-Dextran: Volume expander, used in surgical or emergency situations to improve blood pressure
-Dextromethorphan: Cough suppressant
-Miconazole: Antifungal
-Nefopam: For pain
-NSAIDs (non steroidal anti-inflammatory drugs): For pain, inflammation, blocking production of prostaglandin
-Polymyxin B: Antibiotic
-Radioopaque contrast: To visualize structures in medical scanning procedures
-Reserpine: High blood pressure medication and antipsychotic
-Succinylcholine: Paralytic used for surgical procedures
-Thiopental: Anesthesia induction for surgical procedures
-Vancomycin (especially IV): Antibiotic

• There are a number of medications that are known to interfere with the mechanisms for controlling mast cell activation. Adrenaline is naturally made by the body to help control mast cell activation and other activities. When you interfere with the ability of adrenaline to act, it can potentially trigger mast cell activation. Drug classes that do this include beta blockers and alpha adrenergic blockers. This is particularly an issue if there is a history of anaphylaxis because these medications can interfere with Epipens.
Many foods either contain histamine or can trigger mast cell release of histamine. As with medication, you cannot exclude an entire family of foods because you react to one in the way that you do for traditional allergies.
• There are many lists of foods to avoid. They often conflict with each other. There is not yet a definitive list available. Despite this, there are some general rules of thumb that are agreed upon on what to avoid.
• Products that are fermented, contain alcohol, are overly ripe or leftover from previous days (especially meats), or contain dyes or preservatives are generally excluded.
• Beyond this, recommendations vary a lot more. Many diets recommend excluding yeast, citrus fruits, and nightshade vegetables.
Many activities inherently activate mast cells. Being too hot, standing or sitting in direct sunlight, exercise, sexual activities, menstruation, infection, and any type of physical trauma, even minor, can trigger mast cell activation as part of normal mast cell function.
Premedication is recommended for any medical procedure, even minor, as they can trigger mast cell activation.
• Patients may find that premedication prior to other activating activities is helpful for suppressing reactions.
Ultimately, the only way to know what is activating is through trial and error. Patients should consult their care team about what to trial, when, and how to make it as safe as possible.

For more detailed reading, please visit these posts:

Food allergy series: Mast cell reactions and the low histamine diet

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Medications that impact degranulation and anaphylaxis

Beta blockers and epinephrine

Beta blockers (often styled β-blockers) are medications used primarily for their impact on blood pressure and heart rhythm. Given their low cost and relative safety, beta blockers are very commonly prescribed for a number of other conditions as well, including anxiety. They work by blocking beta adrenergic receptors found throughout the body and specifically interfere with the action of norepinephrine and epinephrine.

The use of beta blockers in patients with risk of anaphylaxis requires some special consideration. This is because beta blockers directly block many of the places where epinephrine works to mitigate anaphylaxis. This means that using epinephrine to treat the anaphylaxis may be ineffective. This particular topic has been heavily researched and has not always yielded uniform findings.

The largest and most robust study included over 5000 patients with a history of systemic allergic reactions. This study found that patient use of beta blockers increased the risk of severe anaphylaxis. Use of ACE inhibitors, another drug class that impacts blood pressure, also increased the risk of severe anaphylaxis but to a smaller extent.

However, the risk of severe anaphylaxis was most increased in patients who took both beta blockers and ACE inhibitors together. Both beta blockers and ACE inhibitors were found to both decrease the threshold for mast cell activation and to prime mast cells (make them more easily activated).

Ongoing treatment with beta blockers has been found to be a risk factor for fatal anaphylaxis in some studies. It has also been found to be a risk factor for biphasic anaphylaxis, a type of anaphylaxis in which you have a second anaphylactic episode in the hours that follow successfully treated anaphylaxis.

Patients who must take beta blockers may be given a glucagon autoinjector for use prior to using injectable epinephrine. The reason for this is glucagon is the antidote to beta blocker overdose. When epinephrine binds to the beta receptor, it results in the cells making a molecule called cAMP. cAMP is a very important molecule for cells and it sends signals within the cell to regulate bodily processes. When a patient takes beta blockers, epinephrine can’t tell the cell to make cAMP. Glucagon is able to tell the cell to make cAMP even if the beta receptor is blocked. This action effectively counteracts the beta blocker.

Mast cell patients are usually recommended to use other medications to manage blood pressure and arrhythmias, including calcium channel blockers or renin inhibitors.

 

References:

Simons FER, et al. (2015) 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal, 8(32).

Nassiri M, et al. (2015) Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol, 135: 491-499.

Shephard G. (2006) Treatment of poisoning caused by β-adrenergic and calcium-channel blockers. American Journal of Health-System Pharmacy, 63(19): 1828-1835.

Tole J, Lieberman P. (2007) Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin N Am, 27(2): 309-326.

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

Reitter M, et al. (2014) Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis. Allergy, 69: 954-959.

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.

The price of surviving anaphylaxis

Anaphylaxis is a severe, multisystem allergic event. It is a medical emergency and can be fatal. A 2015 WAO update stated that Americans have a 1.6% risk of anaphylaxis over the course of their lifetime. In the US, anaphylaxis was fatal in 186-225 patients annually, a frequency of 0.63-0.76 per million people. 30-43% of patients with a history of anaphylaxis will have a recurrence.

Epinephrine is the only drug known to decrease the incidence of death from anaphylaxis and should be administered as the first-line agent. Delay in administration of epinephrine has been shown to directly increase the risk of death from anaphylaxis. The use of epinephrine autoinjectors by patients at risk of anaphylaxis is critically important to managing patient safety. Despite this, many patients do not have or do not use their epinephrine autoinjectors.

The use of epinephrine autoinjectors in anaphylaxis has been very well studied. A 2014 paper by Wood and colleagues reported the findings from surveying 35,079 patients. They found that 60% of patients did not have an epinephrine autoinjector on their person when anaphylaxis recurred. Another study by Sanchez found 9-28% of patients carried autoinjectors.

Wood found that 52% of patients with a history of anaphylaxis were never prescribed an autoinjector. In a patient group of 261 with history of proven anaphylaxis, a mere 11% used the autoinjector for their most recent anaphylactic event. Not using epinephrine in the appropriate time frame can have grave consequences. In anaphylaxis patients who progressed to cardiac arrest, 67% did not receive epinephrine within an hour of onset. Among patients who died from anaphylaxis, none of them received epinephrine when the first symptoms presented. Only 14% of fatal anaphylaxis patients were administered epinephrine prior to cardiac arrest.

In many instances, economics is to blame for not carrying an epinephrine autoinjector. A truly stunning statistic is that 50% of anaphylaxis patients do not fill prescriptions for autoinjectors once the cost is over $300. In the previously mentioned 2014 Wood publication, 41% of anaphylaxis patients reported a household income of less than $50,000. Despite being uniformly accepted as a medication used to prevent death and severe complications resulting from anaphylaxis, epinephrine autoinjectors are often not classified by insurance companies as a preventative medication. An analysis of American insurance plans found that the two pack of Epipens was classified as a tier 1 or 2 medication in 67% plans; tier 3 or 4 in 6% plans; “approved” without any contribution to the cost of the drug in 5% of plans; and 22% plans did not cover Epipens at all.

A 2012 paper assessed how patient cost related to adherence to treatment recommended by their provider for a wide array of conditions. Eaddy reported that of the 66 studies evaluated 85% (56 studies) demonstrated that patients were less likely to adhere to the treatment plan when their costs increased.  High out-of-pocket costs were definitively shown to decrease patient use of preventative health care measures, resulting in poorer outcomes.  Increasing copays and deductibles impede access to life saving medication for anaphylaxis patients. If epinephrine autoinjectors were classified universally as preventative medications, insurance companies would be obligated to fully cover the associated costs. They would also be prevented from requiring patients to pay large out of pocket costs for autoinjectors as contribution to deductibles.

Kaplan reported that only 11% of patients with a history of anaphylaxis refill their epinephrine autoinjectors as needed. Instead, many patients rely on expired autoinjectors. Epinephrine is an inherently unstable molecule that degrades quickly when exposed to oxygen or light. A study in 2000 showed that while autoinjectors still functioned as intended up to 90 months after expiration, epinephrine concentration was significantly reduced. Still, expired epinephrine is still better than no epinephrine in the event of anaphylaxis as the benefit would outweigh the risk.

Epinephrine autoinjectors are designed to be stored at 20-25°C but tolerate occasional exposure to higher or lower temperatures in the range of 15-30°C. While heat is known to hasten degradation of epinephrine, freezing apparently is not. The 2015 WAO update mentioned that if autoinjectors are frozen, epinephrine concentration is not affected and that patients can use them as long as they are completely thawed. (I find this really wild, I had never heard of this before.)

Exorbitant costs prevent anaphylaxis patients from having ready access to epinephrine autoinjectors, the only first line medication for anaphylaxis. 50% of patients do not fill prescriptions for epinephrine autoinjectors when their cost is over $300. With the cost of autoinjectors well into the hundreds of dollars for many patients, millions of people in the US may be unable to afford this lifesaving medication for which is there is no alternative.

References:

Simons FER, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal 2015: 8(32).

Wood RA, et al. Anaphylaxis in America The prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol 2014: 133, 461-467.

Noimark L, et al. The use of adrenaline autoinjectors by children and teenagers. Clinical & Experimental Allergy 2012: 42(2), 284-292. Eaddy MT, et al. How patient cost-sharing trends affect adherence and outcomes. Pharmacy & Therapeutics 2012: 37(1), 45-55.

Simons FER, et al. Outdated EpiPen and EpiPen Jr autoinjectors: Past their prime? J Allergy Clin Immunol 2000: 105(5), 1025-1030.

Sanchez J. Anaphylaxis. How often patients carry epinephrine in real life? Rev Alerg Mex 2013: 60, 168-171.

Kaplan MS, et al. Epinephrine autoinjector refill history in an HMO. Curr Allergy Asthma Rep 2011: 11, 65-70.)

Kim JS, et al. Parental use of EpiPen for children with food allergies. J Allergy Clin Immunol 2005: 116(1), 164-168.

 

No, using the manual syringe/vial method is NOT the same as using an epinephrine autoinjector

I have a lot of inflammatory things to say about the current economic situation for patients who need epinephrine autoinjectors but for now, I’m going to stick to dispelling the most damaging myth I have seen spreading like wildfire.

No, manually drawing epinephrine from a vial or ampule into a syringe and then administering is NOT the same as using an autoinjector.

The American Academy of Allergy, Asthma & Immunology is a professional organization that regularly publishes updated practice parameters on the treatment of anaphylaxis. In their 2015 Anaphylaxis Practice Parameter Update, the AAAAI recommended that providers “prescribe two doses of auto-injectable epinephrine for patients who have experienced an anaphylactic reaction and for those at risk for severe anaphylaxis.”

This publication also addresses commonly disputed situations relating to anaphylaxis such as when and how to administer epinephrine to patients in special populations, like children under the weight range for Epipen Jr (33 pounds). The recommendation in the practice parameter was to use an Epipen Jr rather prescribe a syringe and vial of epinephrine for the parents to administer a smaller dose. The justification for this recommendation given in the 2015 Anaphylaxis Practice Parameter Update is that “…underdosing might not effectively treat anaphylaxis, giving a dose that is slightly above the ideal dose appears to be a better option than giving a dose that is below the recommended dose.”

A 2001 study by Simons et al. assessed how long it takes parents to manually draw up epinephrine from a vial. They also determined how long this took for resident physicians, general duty nurses and ER nurses. The results are in table 1 below.

Table 1: Mean time to draw up dose of epinephrine, range of time and variation in drug concentration
Group Mean time to draw up dose Range of time Variation in epinephrine content within group
Parents 142 ± 13 seconds 83-248 seconds Forty-fold variation
Resident physicians 52 ± 3 seconds 30-83 seconds 7 to 8-fold variation
General duty nurses 40 ± 2 seconds 26-71 seconds 2-fold variation
ER nurses 29 ± 0.09 seconds 27-33 seconds No variation

 

As you can see, the fastest parent drew it up in 83 seconds (about a minute and a half) while the slowest drew it up in 248 seconds (over four minutes). There was a 40-fold variation in the amount of epinephrine drawn up so both underdosing (which will not stop anaphylaxis) and overdosing (which can cause severe CV effects) would have occurred. Please note that this study does not assess how much longer it took to inject the medication for obvious reasons. It was also done in a controlled environment that assuredly was much less stressful and chaotic than one that would accompany a real life anaphylactic emergency.

Say it takes 15 seconds to find the vial and needle and open them and another 15 seconds to inject it. In a best case scenario, in which the parent is aware of anaphylaxis at the exact moment it begins, is in no way flustered, confused, or scared, and is in a situation where they can immediately respond (by which I mean, they are not driving, they are not swimming, they are not watching their child from 100 feet away), the fastest a parent would be able to draw it up and administer the med would be about two and a half minutes. Two and a half minutes with no oxygen if the child’s airway closes right away. If you are an anaphylaxis patient and are trying to do this for yourself, you would be expected to be able to function without oxygen for two and a half minutes.

About 30% of anaphylaxis patients require a redose of epinephrine to control anaphylaxis. So if you or your child is one of those people, you then have to do all of this again. If the first dose doesn’t do much, it could be another two and a half minutes.

The numbers were better for resident physicians and general duty nurses but you are still looking at 2-2.5 minutes for the slower members of these groups. There was a 7 to 8-fold difference in amount of medication drawn by resident physicians. ER nurses reliably drew up the dose in about 30 seconds and assuming that it takes 30 seconds to get the med and needle, and to inject it, they could draw and deliver in about a minute. That is the best you can hope for.

I realize that many mast cell parents and patients draw from vials/push meds/inject meds frequently and they may be practiced enough to draw the dose reliably and administer correctly. If we assume the most competent among them to be as competent as the ER nurses, it takes about a minute to administer the med. I just timed myself and it took eight seconds for me to get the epipens out of my purse, open the case, and remove the blue cap. (I used a trainer). It took less than one second to bring the injector to my leg. The entirety of the dose of epinephrine is delivered from an epipen in three seconds.  So 12 seconds for use of an epipen vs 60 seconds for the fastest, most reliable manual draw and inject.

There are currently two other autoinjectors available in the US: Adrenaclick and epinephrine autoinjector, a generic version. Both of those autoinjectors differ from epipens in two important ways: they are syringe based, whereas epipens are cartridge based; and their needles are shorter compared to epipens. In one specific comparison study by Ram et al., Epipens were found to more reliably deliver the most epinephrine (74.3% of intended dose) compared to syringe autoinjectors like Adrenaclick and epinephrine autoinjector (25.7% of intended dose). Auvi-Q was pulled off the market for similar delivery issues. (Author’s note: please note that this study did not include the specific generic epinephrine autoinjector, but its delivery mechanism is comparable to Adrenaclick).

A 2015 study reported by Umasunthar and colleagues compared how often mothers of food allergic children were able to correctly administer Anapen (a syringe based autoinjector not available in the US) vs Epipen in a simulation. Six weeks after they were shown how to use it, 42% correctly administered Anapen and 43% correctly administered Epipen. This means that over half of participants could not correctly administer epinephrine even with an autoinjector.

Alternative autoinjectors are not comparable to Epipens and neither is the manual syringe/vial method.  Delay in administration of epinephrine is a strong risk factor for poor outcome, including fatal anaphylaxis. Additionally, delay in administration of epinephrine or inadequate initial dosing is a risk factor for biphasic anaphylaxis.

Stay safe out there.

References:

Lieberman P, et al. Anaphylaxis – a practice parameter update 2015. Ann Allergy Asthma Immunol 2015: 115, 341-384.

Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005: 95, 217-228.

Ram FSF, et al. Epinephrine self-administration in anaphylactic emergencies: Comparison of commonly available autoinjectors. Journal of Asthma and Allergy Educators 2012: 3(4), 178-181.

Simons FER, et al. Epinephrine for the out-of-hospital (first-aid) treatment of anaphylaxis in infants: Is the ampule/syringe/needle method practical? Journal of Allergy and Clinical Immunology 2001: 108(6), 1040-1044.

Umasunthar T, et al. Patients’ ability to treat anaphylaxis using adrenaline autoinjectors: a randomized controlled trials. Allergy 2015: 70(7), 855-863.

Anaphylaxis and mast cell reactions

Author’s note: I am not a medical doctor. Anaphylaxis and use of epinephrine must be discussed with the managing provider to determine the best treatment plan for any individual patient.

 

Determination of mast cell reaction vs anaphylaxis

Anaphylaxis has a very complicated relationship with mast cell disease. Mast cell symptoms and reactions are inherent parts of mast cell disease.  All mast cell patients can reasonably expect to have some mast cell symptoms as part of their baseline.

Anaphylaxis is not an inherent part of mast cell disease. Anaphylaxis is a complication of mast cell disease.  Mast cell patients are at increased risk for anaphylaxis, but not all mast cell patients experience anaphylaxis.  In some studies, as many as 50% of mast cell patients had never experienced anaphylaxis.

The fact that anaphylaxis and mast cell reactions can have the same symptoms is probably the reason why it is difficult to separate the two. So for a minute, let’s stop talking about mast cell disease and consider a similar scenario that is better described.

  • Coronary artery disease (CAD) is the leading cause of death worldwide. It affects millions of people around the world. Everyone knows someone with coronary artery disease.  Probably multiple someones.
  • Patients with CAD have narrow arteries that interfere with blood flow to the heart. When they are diagnosed with CAD, their provider will tell them about symptoms they may experience daily as a normal part of their disease.  Their provider will also tell them about symptoms that they may experience that indicate the heart is not getting enough oxygen, like radiating chest pain, shortness of breath and nausea.  In these scenarios, the patient needs to take a med like nitroglycerin to try and stop the episode.  If that doesn’t work, the patient is at risk for a heart attack.
  • Radiating chest pain, shortness of breath and nausea are symptoms of CAD. Heart attack is not a symptom of CAD.  It is a complication of CAD.  It can also present with the same symptoms of radiating chest pain, shortness of breath and nausea.

Flushing, nausea, diarrhea and hives are symptoms of mast cell disease. (I’m just using these as examples, there are many others).  Anaphylaxis is not a symptom of mast cell disease.  It is a complication of mast cell disease.  It can also present with the same symptoms of flushing, nausea, diarrhea and hives.

These are the potential scenarios when a mast cell patient starts experiencing more severe symptoms than usual.

  1. The patient experiences flushing, nausea, diarrhea and hives. They don’t take rescue meds and the symptoms resolve. This is a mast cell reaction. This is not anaphylaxis.
  2. The patient experiences flushing, nausea, diarrhea and hives. They take rescue meds (not including epi here) and the symptoms resolve. This is a mast cell reaction. This is not anaphylaxis.
  3. The patient experiences flushing, nausea, diarrhea and hives. They may or may not take rescue meds (not including epi here). Either way, the symptoms do not resolve.   The amount of mast cell degranulation triggers a large scale reaction that initiates anaphylaxis. This is anaphylaxis and requires epinephrine. There are two possibilities here: it was anaphylaxis from the beginning, or it started as a mast cell reaction and became anaphylaxis. Either way, it requires epinephrine and other rescue meds.

It seems to me that when anaphylaxis occurs in mast cell patients as a sudden onset event that the symptoms seen are usually distinct from regular mast cell reaction symptoms. (This last sentence is based upon what I have experienced and what is reported to me by patients. There is no data on this.)

 

General notes on use of epinephrine

How do you know it is anaphylaxis? That’s the hard part. Mast cell experts feel differently about this. Most say to only use epi if you have trouble breathing or low blood pressure because then you know it is life threatening and thus anaphylaxis and not a mast cell reaction.

If you are having trouble breathing or low blood pressure (for adults, under 90 systolic), that is generally cited as the appropriate point to use epi. However, it is a conversation and decision that must be made with you and a doctor that knows you and your disease.

If you have had an episode before where you had severe symptoms and recovered without epinephrine, it is phenomenally unlikely that it was anaphylaxis.

If you think you may need epinephrine and are unsure, it is generally recommended to use your epipen. The reason for this is that epinephrine is pretty safe, despite how the movies depict it. The risk of using an epipen when you don’t need it is side effects of epinephrine use: rapid heartbeat, elevated blood pressure, anxiety, and generally not feeling great for a day or so. The risk of not using an epipen when you need it is death. People die from anaphylaxis with their epipens on them unused.

 

 

Meeting diagnostic criteria for anaphylaxis

As I reviewed in the previous post, there are many sets of diagnostic criteria for anaphylaxis. The one that is the most widely used in the WAO criteria published in 2006.  This set of criteria has been validated, meaning it was effective for correctly identifying patients experiencing anaphylaxis while excluding those who weren’t.  Even still, they note that about 5% of patients with anaphylaxis will not be covered by these criteria and to use discretion with this population.

The 2006 WAO criteria (shown below) are often used by emergency departments to determine whether or not epinephrine is needed. If the patient meets the criteria, epi is warranted.  This is one of the reasons why anaphylaxis is often considered synonymous with requirement of epinephrine.

 

2006 WAO Anaphylaxis Criteria

2006 WAO Anaphylaxis Criteria

Determining whether or not you have anaphylaxis when your blood pressure is not very low and you can breathe fine is not straightforward for mast cell patients. There are several charts that are often posted in mast cell groups that show four or five stages of anaphylaxis.  These charts are designed for people who do not have baseline allergic symptoms.  Mast cell patients have baseline allergic symptoms.

If you have mast cell disease and have flushing, nausea and hives regularly, that is not grade II anaphylaxis. That is mast cell disease.  Symptoms that are part of your normal baseline or reaction profile do not contribute to the overall assessment of anaphylaxis.  So let’s assume I have flushing, nausea and hives every day.  But then one day I also have diarrhea and tachycardia, which isn’t normal for me.  That is grade III anaphylaxis per the Ring and Messmer scale (shown below).  Whether or not you use epi at that point, assuming your blood pressure is not low and you can breathe okay, depends upon whether or not your doctor endorses the use of that scale.

 

Ring and Messmer Anaphylaxis Grading Scale

Ring and Messmer Anaphylaxis Grading Scale

 

Anaphylaxis vs anaphylactic shock

I often see people use anaphylaxis and anaphylactic shock interchangeably. They’re not the same thing.

Anaphylaxis is a severe, multisystem allergic reaction.

Shock is more properly called circulatory shock. It is a state arising from poor circulation such that tissues are not receiving sufficient blood supply.  Weak pulse, tachycardia, low heart rate, and mental status changes including loss of consciousness are all symptoms of shock.

Anaphylactic shock is circulatory shock caused by low blood pressure due to the vasodilation from large scale degranulation. By definition, it is blood pressure 30% below the patient’s baseline or below standard values (90 systolic for adults).  So if you aren’t experiencing circulatory shock, you aren’t having anaphylactic shock.

 

References:

Sampson HA, et al. 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 2006: 117(2), 391-397.

Brown, SGA. Clinical features and severity grading of anaphylaxis. Journal of Allergy and Clinical Immunology 2004: 114(2), 371-376.

Sampson HA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115(3), 584-591.

Ring J, et al. History and classification of Anaphylaxis. Chem Immunol Allergy 2010: 95, 1-11.

The definition of anaphylaxis

The term anaphylaxis is derived from Greek words for “against protection.” It was coined in over 100 years ago during some ill-fated experiments to immunize dogs to sea anemone venom. Instead of developing a tolerance, the dogs had progressively worsening reactions to the venom. This was the opposite of the intended protective effect and so anaphylaxis was named.  (Lieberman P, et al. Anaphylaxis –a practice parameter update 2015. Annals of Allergy, Asthma & Immunology 2015: 115(5), 341-384.)

 

The following were agreed upon a roundtable meeting for Anaphylaxis in Emergency Medicine, July 2011.

Working definition of anaphylaxis:

  • Anaphylaxis is a serious reaction that is rapid in onset and may cause death. It is usually due to an allergic reaction but can also be non-allergic.

Consensus statements:

  • The traditional mechanistic definition of anaphylaxis is not useful at the bedside.
  • Most acute episodes of anaphylaxis are managed by ED clinicians and not by allergists.
  • Anaphylaxis is underdiagnosed (and, hence, undertreated) in most pre-hospital care situations and EDs.
  • It is important for pre-hospital and emergency medicine providers to recognize that a patient can have anaphylaxis without shock.
  • Anaphylaxis causes significant morbidity and can be fatal.
  • Epinephrine should be the first-line treatment for all pre-hospital and ED patients with anaphylaxis.
  • There are no absolute contraindications to the use of epinephrine for anaphylaxis. Serious adverse effects are very rare when epinephrine is administered at the appropriate intramuscular doses for anaphylaxis.
  • Anaphylaxis is a long-term diagnosis, and management does not end with discharge from ED.
  • Outcomes data are needed.

Anaphylaxis has been defined several times with different criteria. I have selected definitions that I feel are demonstrative of the evolution of these criteria.  This list is not exhaustive.

The 2006 NIAID/FAAN criteria are the most frequently used to define patients to include in studies.  This data has also been validated with subsequent studies. (Sampson HA, et al. 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 2006: 117(2), 391-397.)

Definitions and criteria of anaphylaxis
Year Source Definitions and statements Diagnostic criteria
1945 Cooke RA. Allergy in theory and practice. Philadelphia, PA: W. B. Saunders Company; 1945:5. Defined anaphylaxis as “A special of particular immunologic type of induced protein (or hapten) sensitivity in man or experimental animals and may properly be considered as a subdivision of allergy.”
1970s Nonspecific; in text of book “Anaphylaxis and hypersensitivity reactions” edited by M Castells Defined anaphylaxis as “a systemic, immediate hypersensitivity reaction caused by IgE-mediated immunologic release of mediators from mast cells and basophils.”

Defined anaphylactoid reaction as “a similar reaction without evidence of IgE involvement.”

 

1998 Joint Task Force on Practice Parameters Defined anaphylaxis as “immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral basophils.”

Defined anaphylactoid reaction as “reaction that mimic signs and symptoms of anaphylaxis, but are caused by a non-IgE mediated release of potent mediators from mast cells and basophils.”

2003 World Allergy Organization (WAO) Expanded definition of anaphylaxis to include immunologic events (with or without IgE) and non-immunologic (contrast, vibration, temperature, etc).

Recommended term “anaphylactoid reaction” be abandoned and term “nonallergic anaphylaxis” used instead.

2004 Brown, SGA. Clinical features and severity grading of anaphylaxis. Journal of Allergy and Clinical Immunology 2004: 114(2), 371-376. Recommended grading system for generalized hypersensitivity reactions. Grade 1: Mild

Skin and subcutaneous tissues only

Generalized erythema (redness/flushing), urticaria (hives), periorbital edema (swelling around eyes), or angioedema (swelling).

Can also be subdivided as with or without angioedema.

Grade 2: Moderate

Features suggesting respiratory, cardiovascular, or gastrointestinal involvement

Dyspnea (difficulty breathing), stridor, wheeze, nausea, vomiting, presyncope (dizziness/about to pass out), diaphoresis (sweating), chest or throat tightness, or abdominal pain.
Grade 3: Severe

Hypoxia (low blood oxygenation), hypotension (low blood pressure), or neurologic compromise

Cyanosis (turning blue), pulse oxygenation less than 92%, systolic blood pressure below 90 mm Hg (for adults), confusion, collapse, loss of consciousness, incontinence
2005 Sampson HA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115(3), 584-591. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria are for classic anaphylaxis and may not cover non-immunologic anaphylaxis cases, such as exercise anaphylaxis.

Anaphylaxis is likely when any 1 of the 3 criteria are fulfilled.

1 Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)

Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and low blood pressure or associated symptoms (low muscle tone, fainting)

2 Onset of illness within minutes to hours with involvement of two or more of the following after exposure to known allergen for that patient:

History of severe allergic reaction

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue)

 

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)

Low blood pressure or associated symptoms (low muscle tone, fainting)

In suspected food allergy: gastrointestinal symptoms (crampy abdominal pain, vomiting)

3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more

 

 

2006 Sampson HA, et al. 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 2006: 117(2), 391-397. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria may only identify 95% of anaphylaxis cases.

 

Anaphylaxis is highly likely when any 1 of the 3 criteria are fulfilled.

These definitions have been used frequently to identify whether or not epinephrine is indicated to treat potential anaphylaxis.

 

These criteria have been validated, please refer to:

 

Campbell RL, et al. Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129, 748-752.

1 Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)

2 Onset of illness within minutes to several hours with involvement of two or more of the following after exposure to likely allergen for that patient:

 

History of severe allergic reaction

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula)

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

 

Low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)

Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)

3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

 

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more

2007 Kroigaard M, et al. Scandinavian clinical practice guidelines on the diagnosis, management and follow-up of anaphylaxis during anesthesia. Acta Anaesthesiol Scand 2007: 51, 655-670. Assign severity grades for anaphylaxis. Grade 1 Generalized skin symptoms: flushing, hives, possible angioedema
Grade 2 Moderate multiorgan involvement with skin symptoms, low blood pressure, tachycardia, airway reactivity (cough, difficulty breathing)
Grade 3 Severe life threatening multiorgan involvement that requires specific treatment: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm. Skin symptoms may not be present.
Grade 4 Circulatory or respiratory arrest
Grade 5 Death due to a lack of response to cardiorespiratory resuscitation
2007 Ruggeberg JU, et al. Anaphylaxis: Case definition and guidelines for data collection, anaphylaxis, and presentation of immunization safety data. Vaccine 2007: 25, 5675-5684. Both defined anaphylaxis and attached diagnostic algorithm for “level of diagnostic certainty”, a measure of how confident a provider could be that anaphylaxis was the correct diagnosis.

 

Anaphylaxis was defined as “a clinical syndrome characterized by sudden onset AND rapid progression of signs and symptoms AND involving multiple (2 or more) organ systems as follows.”

Level 1 of diagnostic certainty

 

Highest level of certainty

One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness)
One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
Level 2 of diagnostic certainty

 

Moderate level of certainty

One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 

One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)

 

One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (hives or flushing, local or generalized) angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)
Level 3 of diagnostic certainty

 

Low level of certainty

One or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 

One or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
2010 Ring J, et al. History and classification of Anaphylaxis. Chem Immunol Allergy 2010: 95, 1-11. Assigned severity grade based upon worst symptom Grade 1 Skin (itching, flushing, urticaria, angioedema)
Grade 2 Skin (itching, flushing, urticaria, angioedema may or may not be present

GI (nausea, cramps)

Respiratory (stuffy nose, hoarseness, difficulty breathing, arrhythmia) Cardiovascular (increase of over 20 bpm, systolic blood pressure decreased by at least 20 mm Hg)

Grade 3 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defecation)

Respiratory (swelling in airway, bronchospasm, turning blue)

 

Cardiovascular (shock)

Grade 4 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defection)

Respiratory (respiratory arrest)

Cardiovascular (circulatory arrest)

2013 Ito K. Diagnosis of food allergies: the impact of oral food challenge testing. Asia Pac Allergy 2013: 3(1): 59-69. Identified severity of anaphylaxis based upon grade of most severe symptom. Grade 1

Per primary source, grade 1 is NOT considered anaphylaxis.

Skin (local itching, rash, hives, angioedema)

GI (oral itchiness, discomfort, lip swelling)

Respiratory (throat itchiness, discomfort)

Grade 2 Skin (systemic itching, rash, hives, angioedema)

 

GI (nausea, vomiting, diarrhea, transient colic)

Respiratory (mild nasal congestion, sneezing, single coughing)

Neurologic (loss of activity)

Grade 3 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (severe nasal congestion, repeated sneezing, continuous coughing, throat itching)

Cardiovascular (heart rate increased by 15 bpm or more)

 

Neurologic (anxiety)

Grade 4 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (choking sensation, hoarse voice, barking cough, difficulty in swallowing, wheezing, trouble breathing, turning blue)

 

Cardiovascular (arrhythmia, decreased blood pressure)

Neurologic (irritability, sense of impending doom)

Grade 5 Skin (systemic itching, rash, hives, angioedema)

GI (repeated vomiting, diarrhea, persistent colic)

 

Respiratory (respiratory arrest)

 

Cardiovascular (severe bradycardia, severe hypotension, cardiac arrest)

Neurologic (loss of consciousness)

Kounis Syndrome: Stress (Part 4 of 4)

The phenomenon we now called Kounis Syndrome has previously been called by names like morphologic cardiac reactions, acute carditis and lesions with basic characteristics of rheumatic carditis. It is sometimes still referred to as allergic angina or allergic myocardial infarction/heart attack depending upon the presentation. Allergic angina, which affected patients as microvascular angina, was first noted to progress to allergic heart attack in 1991.

In a small study done at a hospital, 31 patients with anaphylaxis or non-anaphylactic severe allergic reactions had higher serum troponin I than healthy control patients.  Among those 31 patients, those that experienced anaphylaxis had the highest troponin I overall.  This report, and similar findings, indicates that cardiovascular damage may be a frequent component of anaphylaxis, well beyond what is reported.

Mast cell patients often struggle to identify which is the chicken and which is the egg in the many instances of comorbid conditions. There is no such confusion here – mast cell activation causes Kounis Syndrome.  Tryptase increases in peripheral blood during a spontaneous heart attack.  However, when coronary spasm is induced with medications, there is no such increase in tryptase.  In instances where Kounis Syndrome was caused by disruption of an atherosclerotic plaque, mast cells entered the lesion and released mediators prior to the initiation of the coronary event.

Stress is well known to induce mast cell degranulation.  It has been documented in dozens of papers from various disciplines in the last twenty years. Corticotropin releasing hormone (CRH) is a stress hormone that can bind to the CRHR-1 receptor on mast cells, inducing the manufacture of VEGF. At the same time as CRH is released, neurotensin can also be released.  Experimental work has shown that stress induced mast cell degranulation can be compromised if the neurotensin receptor is blocked.

Reactive oxygen species can activate mast cells and induce sensory nerves to release substance P.  Substance P is a potent mast cell degranulator, inducing secretion of histamine and release of VEGF and other inflammatory mediators. These multiple activation pathways triggered by stress result in mast cell mediator release, which can induce coronary hypersensitivity syndromes such as Kounis Syndrome.

References:

Kounis NG, et al. Kounis Syndrome (allergic angina and allergic myocardial infarction). In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med 2016

Kounis NG. Coronary hypersensitivity disorder: the Kounis Syndrome. Clinical Therapeutics 2013, 35 (5): 563-571.

Alevizos M, et al. Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol 2014; 112 (4): 309-315.

IgE-independent anaphylaxis; or, I haven’t been this excited on a Tuesday night in a long time

Mast cell patients are intimately familiar with the phenomenon of testing positive for allergies to things you know aren’t problems and negative for things that almost killed you.  If you ask any health care provider what the allergy antibody is, they will say it is IgE.  And for the most part, that is true.  But mast cell patients suffer reactions that do not demonstrate an IgE pathway to their allergies and anaphylaxis, and it is reason most of us suffer for years before being diagnosed correctly.

The idea that anaphylaxis is a function directly executed by IgE is a deeply ingrained part of western medicine.  In this model, IgE specific for an allergen binds to the allergen, and binds to the IgE receptor on mast cells and basophils, resulting in massive degranulation.

This is the classic model of anaphylaxis, with some creative license:

  1. You come into contact with something. Let’s say it’s Peanut, an anthropomorphic peanut.
  2. Immune cells called B cells think they once saw Peanut in a dark alley behind a bar. Peanut could have been waiting for a ride like any responsible peanut who has been drinking, but dark alley = shady = Peanut is trouble.
  3. The B cells make “Wanted!” posters with a picture of the peanut on it. Many, many posters.
  4. The B cells make lots of IgE to make sure every cell in the body sees the Wanted! posters. There will be nowhere for peanuts to hide. (I swear that as I was typing, I just heard the theme to the Good, the Bad and the Ugly.  I SWEAR.)
  5. Everyone knows that Peanut is a bad guy. They have seen the poster many times.  They do not need to see it again.  Do not show the poster again.  WE KNOW PEANUT IS BAD, IGE.  GO HOME, IGE, YOU’RE DRUNK.
  6. You guys know what happens next.  Peanut shows up.
  7. Someone remembers that IgE has been coming around the bar with the poster of Peanut. Peanut = bad guy.
  8. Everyone is hoping that if they tell IgE where Peanut is that IgE will leave them alone. No one really likes IgE but he is making such a big deal about Peanut and maybe Peanut is bad.  A little bad.  No one really knows but they know they do NOT want to deal with IgE if Peanut gets away.
  9. IgE and Peanut have a Western style gun duel at high noon. IgE captures Peanut by binding to him.
  10. While IgE is bound to Peanut, he also binds to a mast cell, which is like home base. IgE knows that Peanut is trouble and he is part of a Peanut gang and they are all bad, too.
  11. Mast cells deploy the tanks, duckboats, submarines, helicopters and fighter planes in the early allergy response to fight the Peanut gang. This causes massive inflammation with effects throughout the whole body.  Mediators released in the early response include histamine and tryptase.
  12. Mast cells start building more defenses and release them a little at a time later on in the late allergy response. Mediators released in the late response include prostaglandins and leukotrienes.

But we all know that it doesn’t always happen like this, because mast cell patients often have normal tryptase and IgE despite having a massive anaphylactic event, or even normal histamine or prostaglandins.

Last month, a comprehensive paper described alternative anaphylaxis pathways in mice that may be analogous to what is happening to mast cell patients having anaphylaxis that is not mediated by IgE.  That is to say, this pathway needs more research to know for sure if it is what is happening to us, but I have been watching the literature on this closely for a while and I100% think this is real.

There have now been multiple reports of the ability to induce anaphylaxis in mice while interfering with the IgE allergy pathway (either by not making IgE or the IgE receptor, or by treating the mice with anti-IgE, which blocks the IgE from binding to the receptor). Scientists found that by anaphylaxis could be mediated by IgG if the trigger was given intravenously. In particular, they were able to identify the murine IgG2b as the antibody subclass responsible.  In mice, IgG2b can cause anaphylaxis when IgE is not able to participate, at all.

The most important mediator in IgE anaphylaxis is histamine.  But the most important mediator in IgG anaphylaxis is platelet activating factor (PAF).  PAF levels have been linked with severity of anaphylaxis previously (I wrote a post about this around this time last year).  This could explain why many patients have normal tryptase, n-methylhistamine or histamine levels despite a very short amount of time elapsed from anaphylaxis. This is not a histamine show.  And maybe the reason so many mast cell patients cannot get complete relief despite taking huge doses of antihistamines is because histamine isn’t the PRIMARY issue.  (Author’s note: Please do not stop taking your antihistamines.  I love my antihistamines.  Just saying I think maybe there is something happening above histamine in these reactions.)

It’s also not just a mast cell show.  IgG can activate basophils, monocytes and macrophages, and neutrophils to release PAF.  Human neutrophils can mediate IgG dependent anaphylaxis when infused into mice.  So now we have a mechanism for anaphylaxis that is not IgE independent – it can also be mast cell independent.  Mind blowing. (Worth mentioning here that the phenomenon of mast cell independent anaphylaxis is not new or specific to IgG anaphylaxis – groups have found instances of mast cell independent anaphylaxis for almost thirty years.)

PAF levels are much higher in anaphylaxis patients than in control patients, and the enzyme that degrades PAF, called PAF acetylhydrolase, is much lower. It is important to note that binding at the IgE receptor can also produce PAF, but that also causes degranulation and release of histamine and tryptase, which seems to be absent in some patients.

To induce IgG mediated anaphylaxis, you need more allergen than for IgE anaphylaxis.  A lot more. 100-1000x more.  So in mice that have both IgE and IgG for peanut (not really peanut), doesn’t it seem like the IgE would react first to the peanut, and you would have IgE anaphylaxis?  But that’s not what happens.  What happens is that the IgG scoops up the peanut faster than the IgE can.  The IgG can block IgE anaphylaxis.  (WHAT UP MAST CELL PATIENTS DOING WAY BETTER ON IVIG?!?!)

IgG anaphylaxis in mice has been exclusively isolated to triggers administered intravenously.  The reason this fact matters is because of the frequency with which people (who don’t always have mast cell disease) have anaphylaxis to intravenous antibody treats, like IVIG, monoclonal antibodies for treating various diseases, or transfusions (which contain IgG antibodies). Treatments of this kind provide a huge influx of allergen. This pathway favors IgG anaphylaxis over IgE anaphylaxis because of how the IgG will scoop the allergen up (see previous paragraph).

As a final aside, there is also the curious fact that a group of patients with CVID (common variable immunodeficiency, a primary immunodeficiency disease) have a mutation that makes one of the IgG receptors found on cells like mast cells WAY more active.  The CVID patients with this mutation also have antibodies to IgA and experience anaphylaxis after IVIG.

I know I have gone on and on but this is the most exciting thing to happen to tryptase and histamine normal anaphylaxis patients in the last decade, at least.  There is SO much work that needs to be done.  Mouse and human mast cells are different.  Mouse and human IgG antibodies are different.  They could not induce food allergy in mice with an IgG dependent mechanism.  We need to pursue research on the role of PAF specifically in anaphylaxis patients with normal tryptase and histamine.

But now, when you tell your doctor that anaphylaxis is not always IgE dependent, you can give them a reference to a solid paper that fairly describes the findings, the caveats and the strengths of the current research on IgE independent anaphylaxis.  And it’s not just speculation. PEOPLE OUTSIDE OF MAST CELL DISEASE RESEARCH GROUPS ACKNOWLEDGE THAT THIS IS REAL.  IGE INDEPENDENT ANAPHYLAXIS IS REAL.

Boom.

Someone hold my Epipens while I make my dog dance with me.

Reference:

Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016.