Anaphylaxis: Frequently asked questions
Original question: Recently my physician noticed that my vitamin D levels were dropping, and at the same time I'm having anaphylaxis more often. Is there medical information I can share with my doctors that shows that anaphylaxis is more frequent with low levels of Vitamin D?
Answer: In addition to regulating how our bodies process calcium and phosphorous and how minerals are used in building bone, "vitamin D also has widespread immunomodulatory effects." Reference [Taback SP, Simons FE. Anaphylaxis and vitamin D: A role for the sunshine hormone? J Allergy Clin Immunol. 2007;120(1):128-30].
The possibility of a role for vitamin D supplementation in the prevention or treatment of a number of immune-mediated diseases has been suggested. These include microbial diseases such as tuberculosis; cancers of the colon, breast, and prostate; cardiovascular diseases; some forms of arthritis; transplant rejection; and autoimmune diseases such as multiple sclerosis and type 1 diabetes. Reference [Taback SP, Simons FE. Anaphylaxis and vitamin D: A role for the sunshine hormone? J Allergy Clin Immunol. 2007;120(1):128-30].
While at this point, it is not clear exactly what role, if any, vitamin D may play in the prevention or treatment of allergic diseases, there is some fascinating evidence that suggests that it may possible for low levels of vitamin D to predispose people toward having anaphylaxis. The 2007 study [Camargo CA, Jr., Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D. J Allergy Clin Immunol. 2007;120(1):131-6] by Camargo, et al., looked at the number of EpiPen® [Epinephrine auto-injectors] prescriptions in all 50 states and Washington, DC, during 2004. They divided the US into nine regions and ran statistical analyses comparing the number of EpiPens dispensed in the different areas of the country.
Of the over one-and-a-half million epinephrine auto-injectors prescribed, there was a definite bias towards the north and northeast areas of the country. Massachusetts had the highest number of prescriptions while Hawaii had the fewest. Even when the researchers controlled for other factors, the statistical differences were significant.
The authors wonder if the demonstrated tendency for people living in northern latitudes, like New England, to have lower levels of vitamin D may help to explain why anaphylaxis is so much more prevalent in that region. As they [Camargo CA, Jr., Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D. J Allergy Clin Immunol. 2007;120(1):131-6] point out, "Ecologic studies are, by their very nature, exploratory, but they can yield important etiologic clues about disease." It will be interesting to see if subsequent research supports the vitamin D-anaphylaxis hypothesis.
And if a more recent study [Sheehan WJ, Graham D, et al. Higher incidence of pediatric anaphylaxis in northern areas of the United States. J Allergy Clin Immunol. 2009;124(4):850–852] is any indication, subsequent research — this time focusing on pediatric instances of anaphylaxis — is supporting the vitamin D-anaphylaxis hypothesis. The authors note: "…Our study also suggests higher rates of anaphylaxis in northern areas of the United States." (It may also be of interest to note that in this study of 6,457 instances of anaphylaxis, almost 15% were apparently idiopathic. In this large sample, the median age was just over four years old, and boys made up over 53% of the children having anaphylaxis.) ◊
Original question: “Although I have never had to use one, I carry two EpiPens® [Epinephrine auto-injectors] with me at all times because in the past I have gone into anaphylactic shock. I usually try to take meds when I am starting an attack because I would rather avoid the injection if I can. The main reason is that I am nervous about using an epinephrine auto-injector, even in an emergency. Could the epinephrine cause a more severe shocking attack? I tend to react to all sorts of medications, and so I get very apprehensive about trying anything new.”
Answer: Epinephrine, or adrenaline, is different from other medications because it is a hormone that our own body naturally produces in our adrenal glands. So, you are being exposed to at least small amounts of it already on a daily basis.
Roth and Shields raised concern in a 2004 article [Roth JV, Shields A. Letter: A dilemma: How does one treat anaphylaxis in the sulfite allergic patient since epinephrine contains sodium metabisulfite? Anesth Analg 2004; 98(5):1499.] about using epinephrine that is preserved with sodium metabisulfite [the preservative used in both the EpiPen and Twinject auto-injectors] to treat an allergic reaction in a patient who has an allergy to sulfites, but the consensus seems to be that the presence of sulfite should not deter someone from using an epinephrine auto-injector, even if the person has a known allergy or sensitivity to sulfites.
“Occasionally, epinephrine is not injected because of fear of adverse effects. Individuals at risk for anaphylaxis, or their caregivers, should be advised that the transient anxiety, pallor, tremor, and palpitations that commonly occur after epinephrine injection correlate with the beneficial pharmacologic effects of epinephrine and should not be a cause for concern.... Serious adverse effects, such as myocardial ischemia, arrhythmias, and pulmonary edema [inadequate blood flow to heart muscle, heartbeat irregularities, and fluid in lungs, respectively], are seldom attributable to use of epinephrine auto-injectors by individuals in the community. More commonly they are attributable to overdose of epinephrine in health care settings, such as intravenous administration of inappropriately high concentrations or an overly rapid rate of infusion. Moreover, there is increasing awareness that the heart, like the skin, airways, gastrointestinal tract, and vasculature, can be a target organ in anaphylaxis and that coronary artery spasm, myocardial injury, and cardiac arrhythmias can occur in individuals who have anaphylaxis episodes before they receive any epinephrine treatment....” [page 240]
Epinephrine is the only treatment that can really stop the process of anaphylaxis. Medications like Benadryl® [diphenhydramine HCL] or other antihistamines just clean up the effects of the anaphylaxis. Epinephrine stops it.
Note: This is a revised version of the answer I originally wrote for the TMS Web site anaphylaxis FAQ. ◊
Original question: “If epinephrine is the drug that can most help us, then why don't they make it in pill form?”
Answer: Good question! In his book [Goldstein DS. Adrenaline and the Inner World. Kindle edition. Baltimore, MD:Johns Hopkins Univ Pr; 2006] on adrenaline [another name for epinephrine] David Goldstein comments on “the extremely efficient metabolic breakdown of adrenaline in the gastrointestinal tract and liver.”
In a recent paper, Simons and Simons [Simons FE, Simons KJ. Epinephrine (adrenaline) in anaphylaxis. Chemical Immunol & Allergy. 2010; 95:211–22] provide a more specific explanation: “Epinephrine is administered by a variety of different routes in anaphylaxis, except for the oral route, which is not feasible because of rapid inactivation of epinephrine in the gastrointestinal tract by catechol-O-methyltransferase and monoamine oxidase....”
Next to using an EpiPen, the next best way to take epinephrine] (outside a hospital) is probably via inhalation, although that is not an entirely settled question. Reference [McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: What is the evidence? Br Med J. 2003; 327:1332–5].
Follow-up question: “They have pills these days that might do the delivery — pills [that] actually pass in the stool intact. ”
Answer: The problem is that a pill that would prevent the epinephrine from being inactivated by GI activity would also interfere with its contents being rapidly absorbed, and since time is of the essence when treating anaphylaxis, that would defeat the purpose of taking it in the first place! ◊
Original question: “What's the difference between epinephrine and adrenaline? I heard that it's the same thing — so why does it have two different names?”
Answer: Epinephrine and adrenaline are two names for the exact same substance. To understand why, you need a bit of history. In the 1890s, two British scientists discovered that extracts from the adrenal gland had unexpected and powerful effects on our physiology, and this discovery set off a mad race among researchers who wanted to be the first to purify and identify this substance.
One scientist at Johns Hopkins, John Jacob Abel, worked on this challenge for nearly a decade, and in 1897 he reported that he had succeeded in isolating the substance that he named epinephrine.
Unfortunately, what he'd isolated was not, quite, epinephrine. And so it was a researcher working for Parke, Davis (the pharmaceutical company) named Jokichi Takamine who actually isolated this substance in 1901, and he named it adrenaline. Takamine and Parke, Davis proceeded to patent and later market this substance under the brand name of "Adrenaline."
What is notable is that epinephrine — or adrenaline — was the very first hormone that was chemically identified. And in 1904, Friedrich Stolz succeeded in synthesizing the hormone chemically, which means that epinephrine was the very first hormone to be produced in a laboratory. Reference [Goldstein DS. Adrenaline and the Inner World. Baltimore, MD:The Johns Hopkins Univ. Pr.; 2006]. ◊
Original question: “Why would you need to get a tryptase level if you go to the ER for an attack? Even if it came back sky high, the only thing it would prove is that you are having an allergic reaction, whether due to mastocytosis or not. Or am I missing something?”
Answer: First of all, tryptase is present in the secretory granules of human mast cells but not in the granules contained in basophils. So when tryptase levels are significantly increased during an attack, we know that mast cell activation was somehow involved in the attack. Reference [Schwartz LB, Metcalfe DD, et al. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987; 316:1622–6].
To put it another way, in making a differential diagnosis, the doctor needs to know whether it's the mast cells going nuts or the basophils. Tryptase helps to make that distinction. Of course, if you have been diagnosed with a proliferative mast cell disease (like systemic mastocytosis), then it's most likely that your attack would be caused by mast cell degranulation. But if there's any question about what your diagnosis might be, having the tryptase level checked could be helpful.
Caveat (you cannot make any statement about mast cell- or basophil-related ailments without making some kind of cautionary note): It's important to remember, however, that not everyone displays increased tryptase levels. About 30% of people having anaphylaxis display markedly increased tryptase, and another 30% of people have significantly elevated carboxypeptidase (CPA3). Reference [See my article: "Another marker for anaphylaxis?"]. And when autopsies are done, for example, on people who die of food allergies, it's not unusual to find relatively normal tryptase levels. Reference [El-Shanawany T, Williams PE, Jolles S. Clinical immunology review series: an approach to the patient with anaphylaxis. Clin Exp Immunol. 2008; 153:1–9].
Thus, a person can have anaphylaxis without having a high tryptase level during the attack. Reference [Zhou X, Buckley MG, et al. Mast cell carboxypeptidase as a new clinical marker for anaphylaxis. J Allergy Clin Immunol. 2006; 117(2):S85]. So, if a doctor tells you that a "normal" tryptase level means that you did not have anaphylaxis, you are entitled to gently whack him with a blivet (my Irish aunts tell me that a "blivet" consists of "10 lbs of sh*t in a 5-lb bag"). To put that in a slightly more genteel way, Estelle Simons says that a diagnosis of anaphylaxis must be based on symptoms, not lab tests. Reference [Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010; 125:S161–81.]. At this point in time, the magical, perfect anaphylaxis blood test has yet to be invented.
Also, tryptase has been implicated in certain aspects of rheumatoid conditions. For example, mast cell tryptase activates "latent collagenase [an enzyme that destroys collagen] derived from" cells in the rheumatoid synovium [the lining of joints that may be affected by inflammatory arthritis]. Reference [Gruber BL, Schwartz LB, et al. Activation of latent rheumatoid synovial collagenase by human mast cell tryptase. J Immunol. 1988; 140:3936–42]. So, for example, if a doctor were worried about joint damage exacerbated by mast cell activation during anaphylaxis, it might be worth checking to see what the tryptase levels were.
Some mast cells contain only tryptase (for example, those in the lung), while others contain both chymase and tryptase (for example, those in the digestive tract). The amount of tryptase in at least some tryptase-chymase-bearing mast cells can be twice that of cells that do not also contain chymase. Reference [Schwartz LB, Metcalfe DD, et al. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987; 316:1622–6].
For years researchers talked about "mast cells and basophils," but basophils weren't studied as extensively because (1.) they're one of the most uncommon white blood cells in the human body, and (2.) they used to be extremely hard to culture. Now, that's changing. In a paper published last year, authors point out that "Basophils are dispensable for IgE-mediated systemic anaphylaxis unlike mast cells. Instead, basophils play the major role in IgG-mediated systemic anaphylaxis." Reference [Karasuyama H, Tsujimura Y, Obata K, Mukai K. Role for basophils in systemic anaphylaxis. Chem Immunol Allergy. 2010; 95:85-97].
So finding out whether it's your mast cells or your basophils that are going crazy helps to determine whether the cause of your attacks is more likely to be related to immunoglobulin E (IgE) — as, for example, in allergies, or conditions involving antibodies to IgE — or to immunoglobulin G (IgG). ◊
Original question: “In the table that lists the symptoms of anaphylaxis, it says a little bit about the eyes. How much can anaphylaxis affect our eyes?”
Answer: There are nearly 100 papers in the medical literature that reference ocular anaphylaxis, and the phenomenon has been studied in experimental animals, such as rats. One early paper by Allansmith, Bloch and Sinclair [Allansmith MR, Bloch KJ, Baird RS, Sinclair K. Ocular anaphylaxis: induction by local injection of antigen. Immunol. 1981; 44:623–7.] on ocular anaphylaxis induced in rats by the injection of allergens reported that within minutes the eyes reddened, swelled and that more serum albumin was retained in tissue around the eye. Most of these symptoms subsided within one to six hours, but the swelling in and around the eye took 24 hours to resolve completely.
This may sound a little grisly, but the researchers weighed the eyeballs and surrounding tissue of the rats and found that the weight increased by about one-third. That may not sound like a lot, but think about it. Your eyeballs are located inside bony sockets. There's not a lot of excess room there. Increasing the mass of the tissue by one-third easily explains the feelings of pain and pressure that many of us experience when we have eye involvement. Reference [Allansmith MR, Bloch KJ, Baird RS, Sinclair K. Ocular anaphylaxis: induction by local injection of antigen. Immunol. 1981; 44:625.]. ◊
Original question: “If I have anaphylaxis, and then when I am worked up I have a whole bunch of negative allergy skin prick tests, does that mean that my anaphylaxis was not caused by a specific allergen? Does that mean that it must be IA?”
Answer: I often wish that I could give cut-and-dried, yes-and-no answers to questions like these, but in the land of mast cell and basophil-related problems, there are few simplistic questions — or answers!
In my reading, I have come across a couple of studies that present cases in which a patient who had negative skin-prick test (SPT) results soon after anaphylaxis, later showed a positive reaction to the same substance. In cases like that, it would be possible for an allergist to identify a reaction as idiopathic anaphylaxis (IA), when in fact the test responses were, for whatever reason, “behind the curve” in comparison to the functional effect of the allergen.
In 2001, two Finnish researchers reported a case of a 58-year-old woman who had anaphylaxis during an intravaginal ultrasound examination. Since the ultrasound transducer had a natural rubber latex (NRL) cover, it was suspected that she might be sensitive to latex. However, tests run 12 days after her reaction showed negative reactions to a variety of NRL extracts. And yet three months later, the same woman had positive SPT reactions to several different NRL extracts. Reference [Aalto-Korte K, Makinen-Kiljunen S. False negative SPT after anaphylaxis. Allergy. 2001; 56:461–2. ].
In 2006, European researchers studying anaphylaxis as a response to the bite of the Eurpean pigeon tick (Argas reflexus) reported that “…Diagnosis through SPT [skin prick testing] and specific IgE is hampered by false-negative and irrelevant positive results, particularly in atopy [the tendency to develop traditional allergic diseases] .” Reference [Kleine-Tebbe J, Heinatz A, et al. Bites of the European pigeon tick (Argas reflexus): Risk of IgE-mediated sensitizations and anaphylactic reactions. J Allergy Clin Immunol. 2006; 117:190–5.].
If a person can have an apparently false negative skin prick test result to latex or tick bites soon after a serious, systemic reaction, then it is possible that this could happen with other allergens. An allergist who runs one battery of tests at a single point in time may miss a reaction that may only show up on later SPTs.
Perhaps the more fascinating aspect of this phenomenon is that a person could have a life-threatening, whole-body reaction to a substance that he or she does not (yet) show a reaction to. This is just one example of something that makes me think that our understanding of even IgE-mediated reactions may be, as yet, incomplete. ◊
Page last updated: July 3, 2011