anaphylaxis

The Devil’s Arithmetic

When I was in grad school, I took immunology. I still have my textbook and refer to it sometimes, my crowded notes in the margins. The chapter on allergy and anaphylaxis is highlighted in green, somehow aggressively bright after eleven years.

It’s kind of amusing to recall this time in my life, before every mast cell activation pathway had been hammered into my brain. There’s also some black humor in reading about how IgE activation is the allergy pathway. You know, THE allergy pathway. This book doesn’t cover any other pathways. As if you cannot possibly be allergic to something without IgE.

That’s the problem, of course. This is what most healthcare providers or science majors learn in school. They learn about allergy and anaphylaxis, but they learn about the textbook description which invariably refers to IgE mediated food anaphylaxis. They learn about peanut allergy.

I don’t have a peanut allergy. I literally don’t have a single food allergy that displays the hallmark swelling/closing airway that people expect. But I have major food allergies, some bad enough to require epinephrine, IV Benadryl, Pepcid, Solu Medrol, Zofran and IV fluids.

The problem is not just that I’m allergic to some foods. It’s that I’m not always allergic to the same foods as I was the day before. Or the same medications. Or the same environmental exposures. My reactions on a given day are the cumulative product of the amount of irritation my mast cells have experienced in the previous day or two. There is always a running tally in my mind.

There are a lot of analogies and models used to describe mast cell attacks both to patients and to people who don’t have them. I have always thought of it as a bank. You make deposits and you make withdrawals. Like this:

For the sake of simplicity, let’s assume you have $100 in a bank account. Any activity that can cause mast cell activation has to be paid for. The cost is proportionate to the amount of activation. Getting a splinter: $2. Being hot: $10. Being in direct sunlight: $10. Standing up for 20 minutes while being hot in direct sunlight: $35. Cardiovascular exercise: $40. Arguing with your spouse: $60. Moderate pain experienced in your day to day life: $50. A painful medical procedure: $70. Mild cold: $40.

Some things are too costly to ever attempt.  Undercooked egg whites: $9000.  Massive bleach exposure: $7500.

You can make deposits into the bank with medications and physical changes. Getting enough sleep: $30. Wearing loose, comfortable clothes: $15. Doing orthostatic manuevers before standing up: $10. Taking baseline mast cell medications on your normal schedule: $50. Eating food that is warm but not hot: $15. Monitoring your exercise and stopping for breaks: $15. Wearing a cooling vest on a hot day: $20. Oral Benadryl: $25. IV Benadryl: $50. Steroids: $50.

So you have this running tally in your head all day long. When you start getting close to $100, you get stressed. You know you can’t afford to spend more than $100. Things that you could have done four hours ago safely are no longer safe. Things you could eat on a day spent relaxing at home inside with comfortable ambient temperature cannot be eaten if your apartment is too hot or if you are in a lot of pain.

You are constantly trying to avoid running out of dollars before you can get home and go to bed. Part of this is because you don’t want to trigger a physical reaction. Part of it is that this phenomenon – allergies as a function of circulating histamine/mast cell activation rather than IgE – is hard to explain briefly to people who don’t have this disease. So people will see you on a super crappy day only being able to eat one thing at a party and then four months later, when your body is much less inflamed, will see you eat three things at a party. And then it’s a thing, because these people invariably think that you are faking/being overdramatic as if somehow it is worth the effort to “pretend to have allergies.” WHO FUCKING DOES THAT?

Cost for being around someone who gives you shit for not always having the same restrictions: $75.

So everyday, you get $100. Except this is the US and our banks hate us so we have overdraft. This means that you can spend more money than you have but then they charge a steep fee and so the next day, you don’t have $100. You have maybe $30 dollars. After overspending, it can take a few days to get back to baseline.

Sometimes it’s worth it. Sometimes you can sort of game your body into getting more than $100 out of a day. This is the purpose of premedication for procedures and surgery. This is the purpose of good sleep hygiene, eating safe foods, not getting stressed, taking medications appropriately and on a schedule. You can bank a little. Not as much as you can overdraft, but you can get ahead a little bit.

Today, I went to the supermarket to grab some things for lunch at work. They didn’t have organic apples that looked in decent shape. They had non-organic apples and my safe peanut butter/honey and my safe pretzel chips. I had to run through my entire day to determine how much physical activity and stress was likely to be in the rest of my day to figure out what I could (probably) safely eat for lunch.

It’s like this all day, every day. This math wouldn’t be hard except that it’s constant and unavoidable and controls my life.

The Sex Series – Part Three: Allergic reactions of the vagina and vulva

Most of what I said about kissing applies to genitally penetrating intercourse, too.  It is not uncommon for people to develop hives as a result of the vibration, pressure, heat and friction of intercourse. Swelling after sex, called postcoital edema, is also not unusual.  Sex is also a known trigger for asthma and rhinitis.  Several aspects of sex, including the heat and emotion, can activate the autonomic nervous system and cause release of mast cell mediators.  Importantly, studies have revealed that the allergic effects of sex are not due to the physical exertion (ie. exercise anaphylaxis).

While local reactions are more common, there is precedent for sex causing multisystem allergic response or anaphylaxis.  The person receiving the vaginal penetration is more likely to have anaphylaxis following sex, especially if they are strongly sensitized to food or medications.  Seminal fluid can contain food or drug allergens.  Aspirin and penicillin derivatives have been reported to cause allergic reactions from sex, called postcoital hypersensitivity. Transfer of pollens from the clothes or skin of the partner can also cause allergic reactions.

One product we have not yet discussed that can cause contact dermatitis and anaphylaxis is condoms. 25% of reactions to latex condoms cause hives over large portions of the body, angioedema and respiratory symptoms. There are latex alternative condoms, but many patients react to those as well.

Vaginally penetrating intercourse often causes microscopic tearing, mostly due to inadequate lubrication.  As a former sex educator, if you think you are using enough lubrication, you are not.  It is my personal experience that water based lubricants are better tolerated by most allergy patients for vaginal intercourse.  Silicone lubricant is popular because it’s not absorbed by the body and is therefore slicker, whereas water based lubricant often requires reapplication.  But that’s okay.  That’s why you get a whole bottle.

Contributing to the insufficient lubrication is the fact that most people don’t engage in long enough foreplay.  Foreplay provides a number of benefits: it increases naturally secreted vaginal lubrication, increases blood flow to the vagina and tells the cervix to get out of the way. 20 minutes of foreplay is often recommended as a rule of thumb in order to get the vagina in order before penetrating intercourse.

Moisture, friction and heat can cause the vulvar skin to break down. Estrogen plays a large role in keeping this tissue strong and undamaged.  Urine on the skin can cause contact dermatitis.  Malnutrition and history of genital infections can also contribute towards the reactivity of the tissue. It is also possible to be IgE positive for Candida albicans, a yeast that lives normally in the vagina.  Inflammation can upset the balance of the normal flora, resulting not only in vaginal infections but a literal allergy to Candida.

References:

Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin 2010: 28; 697-706.

Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000; 85: 253-267.

Chen WW, Baskin M. A 33-year-old woman with burning and blistering of perivaginal tissue following sexual intercourse. Annals of Allergy, Asthma & Immunology 2004; 93: 126-130.

Harlow BL, He W, Nguyen RHN. Allergic reactions and risk of vulvodynia. Ann Epidemiol 2009; 19: 771-777.

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

Effects of Platelet Activating Factor (PAF) in asthma and anaphylaxis

PAF is released by many different cells, including eosinophils, mast cells, neutrophils, monocytes, macrophages and endothelial cells. PAF receptors are expressed by platelets, monocytes, mast cells, neutrophils, and eosinophils. T and B cells do not express PAF receptors, but PAF can stimulate them to migration of these cells. PAF receptors are found to be increased in eosinophils of asthma patients. PAF receptors are also elevated in lungs of asthmatic patients. PAF can activate mast cells and basophils, causing histamine release. One study proposed the PAF activation of basophils may play a role in aspirin sensitivity in asthma patients.

PAF is most well known for its effects on the airway. It causes constriction of the airway and can affect the way oxygen is brought into the lungs. However, it also has many other effects in the body, many of which affect anaphylaxis and severity thereof.

PAF activates eosinophils and neutrophils to degranulate. It also causes leukotriene C4 production by activated eosinophils in asthma patients, but not in normal patients. A PAF inhibitor has been observed to prevent eosinophil migration and leukotriene C4. Another PAF inhibitor was able to inhibit eosinophil activation by PAF. In activated neutrophils in asthma patients, PAF causes an increase in secretion of leukotriene B4 and increased 5-lipoxygenase activity.

PAF is a powerful signal for eosinophils to migrate toward the cell releasing PAF, and may be involved in inflammation resulting in eosinophilic infiltration. PAF can cause eosinophilic movement across endothelium and into airway. This behavior is increased during asthma attacks and can be minimized with steroids.

PAF injected into the skin causes a biphasic reaction with immediate hiving, then a delayed redness and pain reaction that causes eosinophilic infiltration. PAF also increases IL-6 production by macrophages, activates IL-4 production by T cells, and enhances IL-6 production by mononuclear cells in peripheral blood.

PAF has been heavily linked to asthma. One study found higher levels of PAF as well as lower level of the enzyme that inactivates PAF in plasma of asthmatic adults both during attacks and the rest of the time. When exposed to allergens, PAF level in blood rapidly increases. The large increases in PAF level upon exposure were ameliorated upon successful allergen immunotherapy (also known in the US as “allergy shots”).

PAF induced bronchoconstriction does not affect histamine release and is not alleviated by H1 receptor antihistamines. Inhaling PAF does not change plasma histamine level in asthmatics. Leukotrienes may behave as secondary mediators of PAF action. Zileuton attenuated systemic and respiratory effects of PAF, including airway constriction and changes in neutrophil behavior.

PAF level, and the level of the enzyme that metabolizes it, PAF-acetylhydrolase, is directly correlated to severity of anaphylaxis. Patients with grade I anaphylaxis have 2.5x as much PAF as controls; grade II, 5x; and grade III, 10x. PAF blockers are being investigated for use in this context. Rupatadine is available in some countries, and has H1 antihistamine and PAF blocking activity.

The exact nature of PAF’s activity in anaphylaxis is unclear. It has been shown to cause mast cell degranulation and increased production and release of prostaglandin D2. It can also amplify the response to IgE, making the allergic reaction worse. However, these effects were not seen in skin mast cells for unknown reasons. The source of PAF that acts on mast cells in anaphylaxis is unknown, but is thought to be at least partially from mast cells themselves.

 

References:

Kasperska-Zajac, Z. Brzoza, and B. Rogala. Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma. Inflammation, Vol. 31, No. 2, April 2008.

Peter Vadas, M.D., Ph.D., Milton Gold, M.D., Boris Perelman, Ph.D., Gary M. Liss, M.D., Gideon Lack, M.D., Thomas Blyth, M.D., F. Estelle R. Simons, M.D., Keith J. Simons, Ph.D., Dan Cass, M.D., and Jupiter Yeung, Ph.D. Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis. N Engl J Med 2008; 358:28-35.

Vadas P, Gold M, Liss G, Smith C, Yeung J, Perelman B. PAF acetylhydrolase predisposes to fatal anaphylaxis. J Allergy Clin Immunol 2003;111: S206-S206.

Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y. Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010 May; 125(5): 1137-1145.

Mast cell mediators: Sphingosine-1-phosphate

Sphingosine-1-phosphate (S1P) is a lipid mediator involved in many processes, including development of vessels, vascular permeability, and immune function. It is found in the blood, often bound with proteins such as high density lipoprotein (HDL, “good cholesterol”). Receptors for S1P are found on many cell types.

Activation of the high affinity receptor for IgE causes production of S1P by mast cells. This may also affect the expression and activation of S1P receptors. Mast cells then secrete S1P into the surrounding space.  Mast cells also have receptors to bind S1P.

The S1P1 receptor helps to direct mast cells to sites of inflammation, but does not influence degranulation. The S1P2 receptor deters from localizing to sites of inflammation but enhances degranulation once they have migrated. S1P is known to increase during acute tissue inflammation, in airways following asthmatic challenge and in joints of rheumatic patients. S1P may be responsible for the accumulation of immune cells in such places, but the exact nature of this role is unclear.

S1P receptors regulate the vascular system, including heart rate and permeability.  S1P2 receptor makes vessels more permeable and regulates blood flow to various organs. S1P2 receptor is involved in counteracting the vasodilation effect of histamine (and thus low blood pressure). Histamine can stimulate S1P production.

S1P can also cause bradycardia and high blood pressure via the S1P3 receptor.  I am curious to know if S1P is involved in the high blood pressure type of anaphylaxis some people have.

In models where the genes for making S1P have been deleted, recovery from anaphylaxis is delayed, with severe hypotension. However, in mice with S1P2 receptors, injecting S1P could rescue mice from anaphylaxis. For this reason, molecules that can act on the S1P receptors are being investigated as possible drug targets to produce an alternative to epinephrine.

 

References:
Olivera A, Rivera J. An emerging role for the lipid mediator sphingosine-1-phosphate in mast cell effector function and allergic disease. Adv Exp Med Biol. 2011; 716: 123–142.

Allende ML, Proia RL. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta. 2002;1582:222–227.

Olivera A, Eisner C, Kitamura Y, et al. Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock. J Clin Invest. 2010 “in press”.

Diabetes, mast cells and allergic disease

Patients with either type I or II diabetes mellitus demonstrate unusual physiology pertaining to hypersensitivity and mast cell activation. This was first described in 1962, when a paper reported that diabetic animals do not experience anaphylactic shock.   Despite the amount of time that has passed, the reasons for this are still being unraveled.

The role of mast cells in type II diabetes mellitus is more straightforward. When mice are made obese through dietary manipulation, they normally develop glucose intolerance or insulin resistance. If the mice are mast cell deficient, they do not develop these conditions. Transfer of mast cells to mast cel deficient mice was shown to reverse this protection against these complications.

In mice without established type Ii diabetes that were given manipulated diets to induce obesity, treatment with mast cell stabilizers actually prevented the development of type II diabetes. In mice with pre-established type II diabetes, treatment with mast cell stabilizers cromolyn or ketotifen protected against glucose intolerance and insulin resistance. These findings have been replicated in at least one patient, a type II diabetic who had normalized plasma glucose and A1C after six months on cromolyn.

The relationship between mast cells and type I diabetes is far more intricate.   This is mostly understood through a diabetic rat model. It is possible to induce type I diabetes in rats by administering a chemical called alloxan. Triggering diabetes in this way causes a variety of mast cell changes in these animals. The same changes can be seen when causing diabetes via administration of another chemical, streptozotocin.

Diabetic rats have less vascular response to the action of histamine and reduced mast cell degranulation. These animals are resistant to both local and systemic allergic responses, including anaphylaxis.   Mast cell populations become depleted and less likely to activate. When exposed to antigen, diabetic rats have 50% less degranulated mast cells and histamine release compared to non-diabetic controls.

IgE production is also suppressed in diabetic rats, both antigen specific IgE and total IgE. If you transfer mast cells from the spleen and lymph nodes of non-diabetic rats to diabetic rats, IgE production is diminished. Likewise, if mast cells from diabetic rats are transferred into non-diabetic animals, IgE production is restored.

This protection from allergic processes is well established in animals, but also translates to humans. Children with type I diabetes, and their siblings, are less likely to develop asthma. The incidence of bronchial asthma, rhinitis, and atopic dermatitis is lower than predicted in patients with diabetes mellitus.   Risk of death due to anaphylactic shock is significantly reduced in diabetes. This has been attributed to both the depletion of mast cell populations in diabetics, but also to the overproduction of corticosteroids in the body.

 

References:

Carvalho V.F., Barreto E.O., Diaz B.L. et al. (2003) Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur. J. Pharmacol. 472, 221–227.

Carvalho V.F., Barreto E.O., Cordeiro R.S. et al. (2005) Mast cell changes in experimental diabetes: focus on attenuation of allergic events. Mem. Inst. Oswaldo Cruz 100(Suppl. 1), 121–125.

Foreman JC, Jordan CC, Piotrowski W. Interaction of neurotensin with the substance P receptor mediating histamine release from rat mast cells and the flare in human skin. Br J Pharmacol. 1982 Nov;77(3):531-9.

Meng, Fanyin, et al. Regulation of the Histamine/VEGF Axis by miR-125b during Cholestatic Liver Injury in Mice. The American Journal of Pathology, Volume 184, Issue 3, March 2014, Pages 662–673

Theoharides, T., et al. A probable case report of stress-induced anaphylaxis. Ann Allergy Asthma Immunol xxx (2013) 1e2

Kjaer A, et al. Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons. Endocrinology. 1993 May;132(5):2213-20.

Carvalho V.F, et al. Reduced expression of IL-3 mediates intestinal mast cell depletion in diabetic rats: role of insulin and glucocorticoid hormones. Int. J. Exp. Path. (2009), 90, 148–155.

Carvalho V.F, et al. Suppression of Allergic Inflammatory Response in the Skin of Alloxan-Diabetic Rats: Relationship with Reduced Local Mast Cell Numbers. Int Arch Allergy Immunol 2008;147:246–254.

Carvalho VF, Barreto EO, Diaz BL, Serra MF, Azevedo V, Cordeiro RS, et al: Systemic anaphylaxis is prevented in alloxan-diabetic rats by a mechanism dependent on glucocorticoids. Eur J Pharmacol 2003; 472: 221–227.

S.C. Cavalher-Machado, et al. Down-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin. Eur Respir J 2004; 24: 552–558.

 

Inconvenient: The reality of living with food allergies

Earlier this week, a video was circulating on the internet showing a school board meeting in Michigan. In it, school board members were discussing food allergies and the effect they have on foods being allowed in school.

“Well, you should just shoot them,” a school board member said. She threw her arms up and shrugged a little after she said it. She was clearly kidding. It was a joke to her. It is the sort of thing said when forced to discuss inconveniences at length. She said it because food allergies are inconvenient and she was tired of talking about inconvenient things.

Linda Grossman did not want to harm food allergic children. She was just tired of talking about food allergies.

I am also tired. I am tired of people saying things like this that are meant in jest but are insidious and disrespectful and deeply hurtful.

I am tired of people behaving like food allergies are a personality attribute, not a life threatening medical condition.

I am tired of people feeling like they have more of a right to convenience than food allergic people have to be alive.

As of 2010, an estimated 8.96% of adults and 6.53% of children in the US are food allergic. Averaged, this means that about 1/13 people in the US have food allergies. 1/13 means that on average, each classroom in the US can be expected to have 1-2 food allergic students. Among asthmatic children, the frequency of food allergy skyrockets to a whopping 24%. Childhood food allergies cost approximately 25 billion dollars a year in the US.

Frequency of food allergy rose 50% between 1997 and 2011, with peanut allergy alone tripling in that time. As many as 40% of food allergic children have previously had severe anaphylactic reactions that could have resulted in death. Severe reactions requiring hospitalization have increased sevenfold in the last ten years in Europe.

Food allergy is the most common cause of anaphylaxis outside of a hospital setting and results in 200,000 emergency department visits yearly. This equates to one person every three minutes. It is estimated that 100-200 people die from food allergies each year in the US, with numerous conflicting reports.

I am tired of food allergic people and families having to beg for steps to help prevent DEATH.

I am tired of people feeling that making practical changes to prevent people from DYING is inconvenient.

I am tired of people making jokes about a medical issue that KILLS people.

I am tired of food allergic people being excluded from everything because their LIFE THREATENING condition is INCONVENIENT for the other people there.

I am tired of living in a world that prioritizes convenience over the health and welfare of its people.

I am tired of people who should damn well know better spouting dangerously inaccurate facts about food allergy. So I’m putting all my other posts on hold and we’re going to talk about food allergies, FPIES, eosinophilic gastrointestinal disease, celiac disease, and a-gal allergy.

This is not a joke. Anaphylaxis is not a joke. Food allergic people are not jokes. It’s time to stop pretending comments like these aren’t damaging. It’s time for us to stand up and fight.

Epinephrine: Dosage and safety

How should epinephrine be used?

Epinephrine administered into the side of the thigh is the preferred route. 0.3mg (Epipen strength) – 0.5mg is recommended for adults. This can be repeated every 5-15 minutes as necessary. 16-35% of patients need a second dose of epinephrine to manage initial symptoms. Epipen Jr. contains 0.15mg epinephrine, which is usually recommended up to 66 lbs. Dosage for children is 0.01 mg/kg.

Aqueous epinephrine diluted 1:1000, 0.1-0.3ml in 10ml NS can be used intravenously over several minutes as needed. For potentially dying subjects, epinephrine diluted 1:1000, 0.1ml in 0.9ml of blood or normal saline (1:10000) intravenously. Give as necessary for response.

Aqueous epinephrine diluted 1:1000, 0.1-0.2mg, can be administered at reaction site (bee sting, etc.)

 

Statements on the use of epinephrine

Intramuscular adrenaline is the acknowledged first line therapy for anaphylaxis, in hospital and in the community, and should be given as soon as the condition is recognized. There are no absolute contraindications to administering adrenaline in children. Absolute indications for prescribing self-injectable adrenaline and prior cardiorespiratory reactions, exercise-induced anaphylaxis, idiopathic anaphylaxis and persistent asthma with food allergy. Relative indications include peanut or tree nut allergy, reactions to small quantities of a given food, food allergy in teenagers, and living far away from a medical facility.

Reference: Muraru A et al. Allergy 2007; 62:857-71.

 

Statement of the World Allergy Organization

The Committee strongly believes that epinephrine is current under-utilized and often dosed suboptimally to treat anaphylaxis, is under-prescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate IM doses.

Reference: Kemp SF, Lockey RF, Simons FER, et al. Allergy 2008; 63:1061-1070.

 

Epinephrine may cause pharmacologic adverse effects such as anxiety, fear, restlessness, headache, dizziness, palpitations, pallor, tremor. Rarely, especially after overdose, it may lead to ventricular arrhythmias, angina, MI, pulmonary edema, sudden sharp increase in BP, intracranial hemorrhage. There is, however, no absolute contraindication to epinephrine use in anaphylaxis.

Reference: Simons FER. J Allergy Clinical Immunol 2004;113:837-44.

How to recognize anaphylaxis

When is it anaphylaxis?

Anaphylaxis is highly likely when any ONE of the three following criteria are met:

  1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (generalized hives, itching or flushing, swollen lips/tongue/uvula AND AT LEAST ONE OF THE FOLLOWING:
  • Respiratory compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced PEF, low oxygenation of the blood)
  • Reduced blood pressure or associated symptoms of end organ dysfunction (low blood pressure, collapse, fainting, incontinence)

 

  1. Two or more of the following that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours)
  • Involvement of skin, mucosal tissue (hives, itching, flushing, swollen lips, tongue, uvula)
  • Respiratory compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced PEF, low oxygenation of the blood)
  • Reduced blood pressure or associated symptoms of end organ dysfunction (low blood pressure, collapse, fainting, incontinence)
  • Persistent GI symptoms (crampy abdominal pain, vomiting)

 

  1. Reduced BP after exposure to KNOWN allergen for that patient (minutes to several hours)
  • Infants and children: low systolic blood pressure (age dependent) or greater than 30% decreased in systolic BP
  • Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline

Note: low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.

“When a patient fulfills any of the three criteria of anaphylaxis outlined above, the patient should receive epinephrine immediately because epinephrine is the treatment of choice in anaphylaxis. There undoubtedly will be patients who present with symptoms not yet fulfilling the criteria of anaphylaxis yet in whom it would be appropriate to initiate therapy with epinephrine, such as a patient with a history of near-fatal anaphylaxis to peanut who ingested peanut and within minutes is experiencing urticaria and generalized flushing.”

Reference: Sampson HA et al. J Allergy Clin Immunol 2006; 117:391-7

 

How can I recognize anaphylaxis in someone else  (including children or non-verbal persons?)

Symptoms that can be recognized without self reporting:

Skin and mucus membranes: sudden onset hives, angioedema (swelling of the face, tongue, mouth and throat)

Respiratory: rapid onset of coughing, choking, stridor (high pitched breath sound), wheezing, difficulty breathing, cessation of breathing, turning blue

GI: sudden, profuse vomiting

Cardiovascular: weak pulse, irregular heartbeat, sweating, clamminess, paleness, fainting, loss of consciousness

Central nervous system: sudden unresponsiveness, low muscle tone, lethargy, seizures

Reference: Simons FER. J Allergy Clin Immunol 2007; 120: 537-40.

Treatment of anaphylaxis

Treatment of Anaphylaxis: ABC

Remember the mnemonic ABC.

A: Adrenalin (epinephrine)

Epinephrine is the recommended drug for treating anaphylaxis. It works by stimulating alpha- and beta-adrenergic receptors to inhibit mediator release by both mast cells and basophils. Use of epinephrine at onset of symptoms inhibits the release of PAF, which is largely response for the life-threatening manifestations of anaphylaxis.

B: Benadryl (diphenhydramine)

Antihistamines will NOT stop anaphylaxis. They help to manage the symptoms experienced subsequent to the reaction.

C: Corticosteroids (hydrocortisone, prednisone, etc)

Corticosteroids will NOT stop anaphylaxis. It can decrease risk of biphasic or protracted anaphylaxis.

 

Standard treatment for anaphylaxis

  • Epinephrine
  • Airway maintenance.
  • Oxygen, 6-8L/min.
  • IV hydration. 25-50 ml/kg of lactated Ringer’s solution or normal saline.

 

Treatment of anaphylaxis in mast cell patients

  • 0.3ml of 1:1000 diluted epinephrine, repeated 3x at five minute intervals if BP is less than 90 systolic (0.1ml for children under 12)
  • Diphenhydramine 25-50mg (12.5-25mg for children under 12) orally, intramuscularly or intravenously (slow push) every 2-4 hours; or hydroxyzine 25mg (12.5mg for children ages 2-12) orally every 2-4 hours
  • Methylprednisolone 120mg (40mg for children under twelve), intramuscularly or intravenously
  • 100% oxygen by mask or nasal cannula
  • Nebulized albuterol

Reference:

Emergency Room Response Plan. The Mastocytosis Society. Recommended by Dr. Mariana Castells.

 

Other treatment options

  • Diphenhydramine 50mg or more in divided doses, oral or IV. Maximum dose is reported as 300mg (5mg/kg) for kids and 400mg for adults (under supervision.)
  • Ranitidine 50mg in adults, 12.5-50 mg (1mg/kg for kids), administered by IV as 5% solution, total of 20ml, over five minutes.
  • Albuterol 2.5-5 mg nebulized in 3ml normal saline, or levalbuterol 0.63-1.25 mg nebulized in 3ml normal saline as needed.
  • Aminophylline, IV loading dose 5-6 mg/kg over 20 minutes, followed by IV infusion, 0.5-0.9 mg/kg/hr. Useful for persistent bronchospasm.
  • For persistently low blood pressure, consider dopamine 400mg in 500ml, intravenously at dose of 2-20 mcg/kg/min.
  • Glucagon 1-5mg (20-30mcg/kg, max of 1mg for kids) intravenously over five minutes, followed by IV infusion of 5-15 mcg/min.
  • Methylprednisolone 1-2 mg/kg/24 hours.
  • Sodium bicarbonate, 0.5-1 mEq/kg every five minutes as determined by arterial blood gases. Useful for persistent low blood pressure or acidemia.
  • Methoxamine 10mg has been reported as working following failure of epinephrine. Has been suggested as a next-line medication following failure of second dose of epinephrine; has not seen much use.

References:

Higgins DJ and P Gayatri. Methoxamine in the management of severe anaphylaxis. Anesthesia 1999: 54(11), 1126.

Neugut et al. Arch Int Med 2001

Yocum et al. J Allergy Clin Immunol 1999

Sampson H. N Engl J Med 2002

Sampson et al. J Allergy Clin Immunol 2006

Sheikh et al. BMJ 2006

Kemp SF and Lockey JACI 2002; 110:341-8

Biphasic anaphylaxis

Anaphylaxis has several described variants, including monophasic (one episode of symptoms), biphasic (a second episode after resolution of symptoms), late onset (occurring several hours after exposure to antigen) and protracted (in which symptoms took several hours to resolve despite treatment.) There have been multiple studies on the incidence of biphasic reactions which yielded differing results.

Stark and Sullivan described a 20% incidence of biphasic reactions in 25 patients. They found that patients experienced their second reaction 1-8 hours after the resolution of symptoms. Reactions were 2.8X more likely to be biphasic if the trigger was ingested or if the onset of symptoms was longer than 30 minutes after exposure. Laryngeal edema in the throat was also a risk factor. Severity of initial reaction or treatment administered did not correlate to whether or not the reaction was biphasic.

Douglas reported a 5.8% incidence rate of biphasic anaphylaxis. They found that higher doses of corticosteroids may have decreased the incidence of a second phase.

Lee and Greenes specifically investigated children. They found occurrence 1.3-28.4 hours after the resolution of initial symptoms. Most had wheezing and shortness of breath. Some had abdominal pain. Low blood pressure was rare. Importantly, they found that delay in administration of epinephrine was a predisposed patients to a second reaction. Patients who had only one reaction were administered epinephrine, on average, 48 minutes after exposure; those with two reactions, 190 minutes after. No other risk factors were identified.

18% of patients in the Brazil and MacNamara study were found to have biphasic anaphylaxis. Second phase occurred 4.5-29.5 hours later. They were unable to find clinical features that distinguished biphasic patients from uniphasic, but those with two phases did require more epinephrine to resolve initial symptoms.

Forest-Hay found that nine patients out of 91 had biphasic reactions. Eight of those had symptoms within six hours, a finding not seen in other studies.

A large study done by Smit on Hong Kong hospitals found a 5.3% incidence of biphasic reactions. They found that the time of treatment to onset of second phase averaged 7.6 hours. 12/15 biphasic patients had mild reactions. In particular, they found that biphasic reactors were less likely to have respiratory involvement (35% vs 77%.)

Ellis and Day found a 19.4% biphasic reaction rate. The second phase appeared 2-38 hours after the initial resolution. 40% of these patients had the second phase more than ten hours after the end of the first phase. The second phase could be milder than, similar to or more severe than the first. However, 40% had a lifethreatening second phase and 20% needed more treatment to resolve the second phase than the first. Biphasic patients had longer lasting initial reactions, were given less epinephrine and received less steroids. Late biphasic reactors (after 8 hours) took an average of 193 minutes to resolve their initial symptoms vs 112 minutes for uniphasic reactors. Importantly, no biphasic reaction was found in any patient who administered epinephrine and resolve symptoms within 30 minutes of onset. No biphasic if responded completed in less than 30 minutes. All patients received epi for treatment.

Delay in administration of epinephrine, inadequate dosing of epinephrine for first response, or need for large doses of epinephrine were found to suggest that biphasic anaphylaxis was more likely. Corticosteroid administration was not definitively found to prevent a second phase, but was generally considered to be beneficial. Previous cardiovascular history, older age, and use of beta blockers were risk factors for biphasic reactions. Oral ingestion of the trigger elevated the likelihood of a second stage, but it was also seen in parenteral and inhaled exposures. Hospital admission for 24 hours after resolution of symptoms is recommended.

Studies of mastocytosis patients have found that they are more likely to experience anaphylaxis, but true investigation of whether or not they are more likely to have biphasic reactions has been undertaken.

 

References:

Tole, John and Phil Lieberman. Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors, and Observation Recommendations. Immunol Allergy Clin N Am 27 (2007) 309-326.

Douglas DM, Sukenick E, Andrade WP, et al. Biphasic systemic anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol 1994; 93:977–85.

Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106: 762–6.

Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol 2007; 98(1):64–9.

Brazil E, MacNamara AF. ‘‘Not so immediate’’ hypersensitivity: the danger of biphasic anaphylactic reactions. J Accid Emerg Med 1998 ;15: 252–3.

Forrest-Hay A, Taylor C, Tolchard S. Biphasic anaphylaxis in aUKemergency department. Presented at Open Paper Presentations of the 2003 Scientific Symposium of the Resuscitation Council of the United Kingdom (abstract)

Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28(4): 381–8.