idiopathic anaphylaxis information center

a resource for people with ia and other mast cell disorders

Anaphylaxis: What causes anaphylaxis?

What are the conditions that can cause anaphylaxis?

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When we think about what kinds of things can cause anaphylaxis, bee stings and food allergies come to mind. Allergists and immunologists classify the various causes of anaphylaxis as shown in the figure and table below.

Figure created by Candace Van Auken based on information from a 2010 article by F. Estelle R. Simons. The same information is shown in Table 1 on the second tab or section of this article.

Click on graphic to view at larger size. Use browser’s Back button to return.

Reference for figure above and table below: Simons [Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010; 125:S161–81].

Table: Categories of causes of anaphylaxis

IgE-dependent Foods, pollen, venoms, latex [substance derived from the sap of plants like milkweed or poinsettias] , drugs.
Independent of IgE Dextran [a sucrose derivative used as a plasma volume expander], OSCS [over-sulfated chondroitin sulfate] contaminants in heparin.
Physical Exercise (with or without food or medication as a factor), cold, heat, sunlight or UV [ultraviolet] radiation.
Other Ethanol [aka ethyl alcohol or grain alcohol], medications such as opioids.
Idiopathic anaphylaxis


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IgE-dependent causes of anaphylaxis

Diagram explaining how an IgE-mediated reaction occurs. Created by US Federal Government for 2003 NIH publication in the public domain. Source: Wikimedia Commons.

When doctors talk about "IgE-dependent" symptoms, they are referring to the symptoms caused by traditional allergies.

An allergy is essentially a case of a person's immune system mistaking a harmless substance for a dangerous one. When a small amount of a particular kind of protein, for example birch pollen or shellfish or milkweed sap, is encountered by the person's immune system, it is identified as being an antigen [any substance capable of binding with an antibody or causing an immune response], that is, a threat. And the next time that the immune system encounters the antigen, it is ready to churn out immunoglobulin E (IgE, an antibody [substance produced by B cells in response to a specific antigen]) that has been designed to detect and capture that particular protein. When an antigen is attached to two different molecules of IgE that are hooked into the FcεRI receptors on a person's mast cell, it unleashes the potent biochemicals stored inside. The release of those substances, along with others manufactured as part of the mast cell's degranulation, cause the symptoms that we typically think of as "allergic."

If a person's allergic reaction is both violent and systemic (involving multiple organ systems), it is identified as anaphylaxis. We can have allergic reactions to substances we inhale (like birch pollen), eat (like shellfish), or touch (like latex). We can also have IgE-mediated anaphylaxis in response to the venom of bites (like those from some spiders or snakes) or to medications that we use.

As Janet Kalesnikoff and Stephen J. Galli [Kalesnikoff J, Galli SJ. Anaphylaxis: Mechanisms of mast cell activation. Chem Immunol Allergy 2010; 95:45–66.] recently observed, anaphylaxis "represents arguably the most grotesque example of a pathological imbalance between the cost and benefit of an acquired immune response."

They go on to observe:

It is generally accepted... that mast cells (and basophils), IgE and FcεRI [the high-affinity IgE receptor] are involved in most cases of allergen-induced anaphylaxis in humans. However, it is difficult to define the exact roles and relative importance of mast cells, basophils, and other potential effector cells (e.g., monocytes/macrophages, dendritic cells) in either IgE-dependent or IgE-independent human anaphylaxis. Reference [Kalesnikoff J, Galli SJ. Anaphylaxis: Mechanisms of mast cell activation. Chem Immunol Allergy 2010; 95:47.].

Another distinguishing featuer of IgE-mediated reactions is that they are dependent on both the cytokine [proteins that regulate growth and function of white blood cells] interleukin-4 (IL-4) and its receptors. Reference [Kemp SF, Lockey RF. Pathophysiology and organ damage in anaphylaxis. In: Castells MC, ed. Anaphylaxis and Hypersensitivity Reactions. NY: Humana; 2011;33–46].

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Common causes of allergic anaphylaxis

Photograph of peanuts taken by (URL:

The most common foods that trigger anaphylaxis are:

The medications that most often trigger anaphylaxis include:

  • Antibiotics (especially β-lactam),
  • Aspirin, ibuprofen and other pain-relievers, and
  • Substances as seemingly benign as folic acid.

The biologic agents that seem to be most likely to trigger anaphylaxis include:

Finally, stings from insects (especially Hymenoptera), latex, and occupational allergens round out the list of the most common allergens. Reference [Simons FE. Anaphylaxis: Recent advances in assessment and treatment. J Allergy Clin Immunol 2009; 124:626.].

To get a sense of the range of allergens [substances that cause a hypersensitivity reaction], both common and unusual, check out the Allergens page.

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IgE-independent (but immunologic) causes of anaphylaxis

Diagram illustrating two different pathways of the complement cascade. Created by US Federal Government for 2003 NIH publication in the public domain. Source: Wikimedia Commons.

Everything discussed so far has been related to the first category of the illustration and table on the first tab. IgE-dependent reactions are those that we describe as "allergic reactions." But what about that second category, "Immunologic IgE-independent" reactions?

IgE-independent reactions are also believed to involve mast cells, basophils, and other effector cells, but generally speaking, we understand less about these kinds of reactions than we do about those driven by allergies. Reference [Kalesnikoff J, Galli SJ. Anaphylaxis: Mechanisms of mast cell activation. Chem Immunol Allergy. 2010; 95:45–66].

Complement-mediated reactions

Immunologic reactions that involve complement [a family of blood proteins that are immunologically active through a cascade of biochemical interactions] produce substances that can cause or encourage anaphylaxis. These substances, which include complement components C3a, C4a, and C5a [plasma-activated complements 3, 4 and 5] , are called anaphylatoxins and are often a by-product of what is called “the complement cascade.”

So if some condition or chronic infection is causing frequent activation of the complement cascade, the possibility that the by-products of this activation will bring about anaphylaxis increases. We do not know if there is some opposing process that is supposed to protect against complement-induced anaphylaxis. It may exist but be flawed in some people, or it may not exist at all.

When a person has anaphylaxis as a result of the administration of blood products — for example, IV [intravenous] immunglobulin or animal antiserum [serum containing antibodies to a particular antigen] — it is believed to be at least partly due to the effects of anaphylatoxins resulting from the complement cascade. Reference [Kemp SF, Palmer GW. Anaphylaxis. eMedicine. Medscape; 29 April 2009].


What is complement?
It took almost a half century to dope out what complement is and how it aids the immune system's antibodies in destroying microbes. The substance was called "complement" because its action seemed to complement [meaning to complete or perfect] that of antibodies. We know that not only is it a component of the older (in evolutionary as well as historical terms) innate immune system, but it existed billions of years before antibodies made their appearance. While complement is less efficient in identifying microbes than are antibodies, it can do this even in the absence of antibodies. What does complement do to microbes? The complement cascades can gouge a large hole in a microbe’s membrane — large enough to kill it. Reference [Clark WR. In Defense of Self: How the Immune System Really Works. New York, NY: Oxford Univ Pr; 2008].

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Anaphylaxis associated with systemic mastocytosis

People who have systemic mastocytosis (SM) do not necessarily have any allergies. But even someone with SM who is totally allergy-free may still experience episodes of anaphylaxis. Why? Well, in people who have so many more mast cells than a typical person, anything that sets off their mast cells can initiate a powerful cascade of reactions. These reactions are considered to be immunologic reactions, even if IgE is not involved in any way.

Also, people with SM “appear to be at increased risk for food and venom reactions. Alcohol, vancomycin, opioids, radiocontrast media (RCM), and other biologic agents that can degranulate mast cells directly are discouraged.” Reference [Kemp SF, Palmer GW. Anaphylaxis. eMedicine. Medscape; 29 April 2009].

There is not perfect agreement among researchers in this field in terms of how to categorize various kinds of anaphylaxis. For example, Kemp [Kemp SF, Palmer GW. Anaphylaxis. eMedicine. Medscape; 29 April 2009] includes exercise-induced anaphylaxis as an immunologic but non-IgE-mediated form of anaphylaxis, while Simons [Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010; 125:S161–81] categorizes it was being non-immunologic.

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Page last updated: July 20, 2011

All information contained in this site is one layperson's interpretation of medical journal articles, textbooks, seminars, presentations, and other materials. Nothing that is stated here should carry more weight than the informed and considered opinions of your own highly trained and qualified medical caregivers. The author of this site is not a doctor and has absolutely no authority to prescribe or diagnose.

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