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Hypersensitivity and anaphylaxis.


After reading this article and completing the accompanying online learning activities, you should be able to:

* Describe hypersensitivity reactions and their classifications.

* Outline the normal function of the immune system.

* Discuss the events occurring in development of type I hypersensitivity reactions.

* Explain the rationale for therapeutic interventions in anaphylaxis.



The immune system protects us against invading pathogens such as bacteria, viruses and parasites. At the same time, it patrols our tissues, removing dead or dying cells and even protecting against some types of cancer. All this occurs while allowing the normal function of our bodies to proceed with minimal disruption, and while ignoring the presence of non-pathogenic substances and beneficial bacteria that colonise our bodies. There are three lines of defence against invading pathogens: physical and chemical barriers, innate (or non-specific) immune activity and the adaptive immune responses.

Defects in this system can have devastating consequences for the host. Most dramatic of these is anaphylaxis where an acute, systemic reaction to the presence of an allergen or other stimulus can be life-threatening. Hypersensitivity reactions may be milder and more localised, and may also be chronic (eg hay fever and asthma). Not all hypersensitivity reactions occur acutely or by the same mechanisms, and not all anaphylaxis is due to immune system activation. However, the common scenario for severe allergic reactions are those mediated by the antibody IgE in conjunction with mast cells and basophils, following activation of both the innate and adaptive immune systems. People who display a tendency toward allergy (eg asthma, eczema, hay fever or food allergies) are referred to as atopic individuals. Atopy increases the risk for some forms of anaphylaxis.


Hypersensitivity reactions are classified according to their underlying immune mechanisms--whether the reaction is generated by antibodies or immune cells. This system describes four types of hypersensitivity: (1)

Type I reactions: These are mediated by IgE antibodies and are also known as immediate hypersensitivity reactions. They include anaphylaxis, traditional notions of "allergies" and atopic asthma.

Type II hypersensitivity: This involves IgG and IgM antibodies that bind to antigens on body cells and trigger immune reactions. An example of this is rheumatic heart disease. This is also called cytotoxic hypersensitivity.

Type III or immune-complex reactions: These occur when antibody-antigen complexes in the circulation deposit in capillary beds, triggering immune reactions and inflammation that damage the surrounding tissues (eg kidneys, skin and joints). Examples are post-streptococcal glomerulonephritis and systemic lupus erythematosis.

Type IV reactions: These are cell-mediated and occur where T-lymphocytes are activated in response to allergens, triggering on-going inflammation and tissue destruction. This is the mechanism underlying many autoimmune disorders, including type, diabetes, and also contact dermatitis.

Anaphylactoid reactions may occur in the absence of IgE, but with similar clinical outcomes.

These occur when a substance directly triggers mast cells to release their contents, eg following injection of X-ray contrast media.

While there is debate in the literature about definitions of anaphylaxis that include these anaphylactoid reactions, the commonest definition of anaphylaxis is one of an immediate hypersensitivity reaction mediated by IgE, involving release of mediators from mast cells, that induces systemic adverse outcomes. (2) Signs and symptoms associated with allergic reactions and anaphylaxis can be found in Table 1 (below). (3,4,5)


An understanding of normal immune function is necessary to comprehend the events leading to an anaphylactic reaction.

Barriers to the invasion of pathogens include the skin and mucous membranes lining all areas of our bodies exposed to the external environment. Additionally, specific defences, such as gastric acid, or cilia and mucus in the airways, provide further mechanical and chemical defences. If these barrier defences are breached, the innate immune system must provide an immediate response and signal adaptive mechanisms to prepare for "battle".

In recent years, researchers have become more aware of the essential role the innate immune system plays in directing the entire immune response. Because the adaptive immune system is so specific to individual antibodies, it relies on the innate system to provide signals that invaders are both foreign and dangerous--the responses of the innate system permit the adaptive system to begin ramping up. The innate system also directs the adaptive response by signalling which sort of cells need ramping up, and where the attack is taking place. (6)

Innate immune responses are both chemical (humoral) and cellular. Key players are the complement system and professional phagocytes.

The complement system

The complement system involves numerous molecules synthesised in the liver and distributed throughout the body. Once activated, a very rapid chemical cascade occurs, ending with the production of membrane attack complexes that puncture holes in the surface of pathogens, destroying them. At the same time, complement proteins coat the surface of pathogens, signalling and providing receptor binding sites for professional phagocytes to attach--a process called opsonisation. Fragments of complement proteins produced during the chemical cascade act as signals for further immune responses. These protein fragments (C3a and C5a) are potent inflammatory mediators and also act as anaphylatoxins, directly triggering mast cells. (7)

Professional phagocytes

Phagocyte literally means "big eater"--these cells devour invading pathogens, cellular debris and dying body cells. The two key phagocytes in the innate immune system are macrophages and neutrophils. Both these cells contribute to inflammation and prolongation of the immune response through secretion of "danger signals" in the form of cytokines and, in the case of neutrophils, proteolytic enzymes. (8)


Like the innate immune system, adaptive immunity relies on both cellular and humoral responses. Unlike the adaptive system however, the response is specific and modifiable, but much slower to be activated. Vaccination triggers initial activation of adaptive immune responses to speed up responses if the actual disease-causing pathogen is subsequently encountered.

Critical to adaptive immunity is the concept of antigen specificity. During development, individual lymphocytes are preprogrammed by cutting and pasting of their genes to respond to only one antigen. This process codes for up to 100 million individual antibodies and matching cell receptors--enough diversity to treat almost every organic molecule in existence as an antigen. (6)

Normally we think of antigens as pathogens, but they can be formed of any organic substance (usually a protein or polysaccharide), including allergens. Many drugs are too small to acts as allergens on their own but may trigger an allergic response after binding to proteins in the body making these proteins appear "foreign" to the immune system. (9)

B-lymphocytes are responsible for generating antibodies, while T-cells play key regulatory roles in the adaptive immune system. There are three types of T-cells: killer T-cells, helper T-cells and regulatory T-cells.


NaYve or virgin B-lymphocytes are activated when they encounter their specific antigen, and are stimulated by T-cells. Activated B-lymphocytes secrete antibodies. The type of antibody a B-cell secretes changes in response to cytokines secreted by T-cells. There are four main classes of antibodies (or immunoglobulin, Ig), each with a separate role: (6)

IgM: These appear early in the immune response and are the first antibodies activated B-cells secrete. IgM antibodies activate the complement cascade.

IgG: These antibodies opsonise pathogens and trigger phagocytosis by local macrophages and neutrophils. IgG (also called gamma globulin) may be administered to a person after exposure to a disease, providing passive immunity for long enough to allow their own immune system to mount a defence. IgG crosses the placenta, providing immune protection to infants until their immune systems mature sufficiently to start producing their own antibodies.

IgA: IgA antibodies are found at mucosal surfaces --the lining of the GI, and respiratory and urogenital tracts. They are transported into the tracts and provide a passive form of immunity by binding to pathogens and preventing them from attaching to the mucosa for entry into the body. IgA is secreted into breast milk to provide protection to the breastfed infant from ingested pathogens.

IgE: These antibodies are thought to have evolved as our main defence against parasites. They are found in abundance just beneath the skin and mucous membranes. IgE binds to local mast cells, triggering degranulation and release of histamine when their antigen is encountered. Lack of exposure to parasitic infestations in developed nations means the main role of IgE has become mediation of Type I hypersensitivity reactions.


Antigen presentation

A lymphocyte that has not encountered its specific antigen is naYve. To be activated, it must be presented with its antigen by a professional antigen presenting cell (APC). The main APCs are dendritic cells and macrophages.

APCs are distinguished by the presence of major histocompatibility complex II (MHC-II--also called human leukocyte antigen or HLA) on their membranes. APCs ingest pathogens and then present antigenic fragments on their MHC-II complexes to helper T-cells. They also secrete co-stimulatory factors that enhance activation, and regulate some T-cell development. (8) A naYve T-cell will not recognise an antigen unless it is formally presented by an APC. (6)

MHC complexes are unique to an individual and may not be as effective in some individuals at displaying antigens for presentation. This may affect a person's susceptibility to disease (whether they can mount a good immune response) or their response to immunisation--whether a vaccine will "take". In other people, the MHC-II complex may be very good at presenting some types of antigens--certain variants of MHC genes are more likely to be present in atopic individuals.

Dendritic cells

These cells are found in the epithelial tissues lining body cavities and the skin. They patrol the borders of the body, often inserting into the epithelial layers with their tips protruding into the airway or GI tract. Dendritic cells (DC) continuously sample their surroundings and are activated by cytokines signalling danger or directly by encountering an antigen. How DCs distinguish pathogens from non-pathogenic antigens is not fully understood. (10)

Once activated, DCs produce large numbers of MHC-II, all displaying the antigen, and migrate to the nearest lymphatic vessels. It takes about 24 hours for the DCs to travel to the nearest lymph node where naive helper T-cells are found in large numbers.

In the lymph node, the DC presents the antigen on its MHC-II complex to the appropriate naYve helper T-cell. DCs not only activate helper T-cells, they also secrete cytokines, providing information about the location of the attack and directing development of helper T-cells into subtypes. Th1 helper T-cells produce an array of cytokines that stimulate B-cells to switch to producing IgG. Th2 cells secrete a different set of cytokines that switch B-cells to secreting IgE--these are the helper T-cells that are involved in type 1 hypersensitivity reactions.

Th cells then begin to proliferate--producing many identical subtype cells that respond to the same antigen. Clonal selection like this also occurs in activated B-cells, resulting in large numbers of lymphocytes that are targeted at a single antigen. This is useful when the invader is a dangerous pathogen, but less helpful when the system has been activated against a normally harmless antigen such as pollen, mould spores or proteins in our food.

Th1 versus Th2

In atopic individuals, presentation of an antigen by DCs directs development of the Th cell towards the Th2 subtype, whereas in non-atopic people the Th1 subtype is more likely to occur.

While the exact mechanisms involved in this bias toward Th2 for atopic individuals is unknown, it may be initiated in utero. The foetus carries many paternal antigens that would normally trigger an immune attack from the mother on the placenta. The placenta secretes numerous cytokines that direct maternal Th cells away from the more aggressively phagocytic Th1 subtype (Th1 activates phagocytes and killer cells) and toward the Th2 type. These cytokines also influence foetal immune cells so babies are born with a bias toward Th2 cells. (11)

Early exposure to infectious agents and allergens redresses the balance toward Th1 cells as the immune system matures. In this scenario, exposure creates a Th1-mediated response to allergens that involves high numbers of IgG antibodies and very few IgE. The Th1 response becomes locked in. At the same time, regulatory T-cells are induced on exposure to allergens and these dampen the immune response (including DCs) to allergens, while directing helper T-cells toward the Th1 subtype. These are the physiological occurrences underlying the hygiene hypothesis --early exposure to allergens and pathogens reduces the risk of developing allergies later in life. (6)

Heredity also plays a significant role in the development of an atopy. The MHC-II genetic polymorphism has already been mentioned as being more efficient at presenting allergens to T-cells. Some people may also have a polymorphism of the genes for their IgE receptors on the mast cell, which causes greater than normal responses by mast cells to the binding of IgE. There are numerous other genes involved in the development of an allergic phenotype. Current understanding is that a person with a genetic susceptibility to allergies has increased risk when exposed to environmental factors described by the hygiene hypothesis.

B-cell activation

An activated Th2 cell acts on B-cells in the area to trigger their activation and "class switching" to secrete IgE. Activated B-cells also modify the shape of their antigen receptors to get a better "fit" and be able to bind to the antigen with increased affinity. This somatic hypermutation results in a highly responsive pool of B-cells that can be reactivated much more rapidly on the next encounter with their antigen.

Maturation of activated B-cells is complete when they differentiate into memory cells and antibody-producing (plasma) cells. Most plasma cells only survive a few days but some persist for longer. These long-lived plasma cells produce low levels of antibody, which enables a prolonged (even life-long) antigenic response. As these long-lived plasma cells die, replacements are generated from the pool of memory B-cells. (6)

The time it takes for the initial activation of T- and B-lymphocytes to occur (sensitisation) means first exposure to an allergen rarely causes a type I hypersensitivity reaction or anaphylaxis. Initial sensitisation involving presentation of the allergen and subsequent T-cell and B-cell activation--can take up to a week or more, although this time may be reduced with repeated or high-dose exposure, and in more atopic phenotypes. In addition, while a person may never have been knowingly exposed to an allergen, there be a history of subclinical or hidden exposure, or there may be cross-reactivity with another chemical or antigen.


Mast cells are found throughout the body, but particularly in tissues underlying the mucous membranes that form the barrier between our bodies and the outside world. The surface of a mast cell has a number of different receptors, including those for IgE antibodies and the complement fragments C3a and C5a--the anaphylotoxins (see Figure 1, p22). (12)

Within the cytoplasm of the mast cell are many packets (granules) of preformed cytokines and inflammatory mediators. Mast cells, along with basophils and eosinophils, are classed as granulocytes because they all contain these packets of preformed mediators.

When a B-cell produces IgE, these attach to local mast cells. The IgE receptor on the mast cell surface has a high affinity for IgE, so antibodies, once produced, will cluster in large numbers on mast cells once produced. These mast cells are now primed for any further encounter with the antigen that stimulated the production of IgE in the first place. If the antigen or allergen is encountered again, mast cells undergo a degranulation, releasing their mediators into the surrounding tissue and triggering the symptoms of a type 1 hypersensitivity reaction. (12) Mast cell mediators rapidly recruit basophils from the bloodstream. Basophils also contain granules with much the same mediators, enhancing the inflammatory response. Once degranulated, mast cells and basophils start to synthesise and secrete other mediators that prolong and enhance inflammation. (9)


Type 1 hypersensitivity reactions usually have an early and a late phase. The early phase is generated by mast cell and basophil mediators that also initiate the later phase events.


Histamine is the main component of granules and, once released, acts mainly via H1 receptors to trigger vasodilation and increased vascular permeability. H1 receptor activation also causes smooth muscle contraction in the airways, leading to bronchospasm, and in the GI tract causing nausea, vomiting, bloating abdominal cramps and diarrhoea. Vasodilation of skin vessels may induce urticaria. Vasodilation in the soft tissues in the throat and upper airways (angioedema) increases the risk of airway obstruction. Histamine stimulation of H1 receptors in local nerve endings causes pruritis and sometimes pain.

Other mediators

Prostaglandins (PG) and leukotriennes (LT) are even more potent vasodilators and bronchcoconstrictors than histamine. The combined vasodilator effects may be sufficient for loss of up to 35 per cent of circulating volume within 10 minutes. (4) PGs also increase mucus secretion, while LTs act as signals to recruit late-phase cells.

Late-phase responses (two to eight hours after the initial stimulus) are due to recruitment of other cells, especially eosinophils, neutrophils and lymphocytes. Eosinophils produce cytokines that promote further inflammation and also damage surrounding tissue. This ongoing damage may make epithelial tissues more vulnerable to allergens in future exposures, driving the development of chronic allergic states.

If mediator release is localised, signs and symptoms are confined to individual organ systems--sneezing, itching and nasal congestion etc, in allergic rhinitis, and bronchoconstriction and mucus production in asthma. Systemic release and the involvement of more than one body system cause anaphylaxis.

Death in anaphylaxis is either due to shock from loss of circulating blood volume or asphyxiation due to airway obstruction from angioedema, bronchoconstriction and excessive mucus. Median times to cardio-respiratory arrest in untreated anaphylaxis are five minutes following intravenous allergen, 15 minutes following insect sting and 30 minutes after food ingestion. (5)


Therapy depends on the severity of the reaction and the degree of systemic involvement. Key initial steps include withdrawal of the antigenic trigger, if possible (eg stop intravenous drug infusion), calling for help (ambulance in the community), assessment and securing of airway, and assessment of vital signs and level of consciousness.

Victims of anaphylaxis should be positioned lying flat with legs elevated to maintain central circulating volume. Maintaining an upright position is strongly associated with death in anaphylaxis. (3,5) If the victim is in respiratory distress, they should sit slightly elevated but with legs above the level of the heart. (5) Oxygen should be administered if available and intravenous fluid resuscitation started. However, the most immediate intervention, and top priority, is administration of adrenaline.

Adrenaline (epinephrine)

Adrenaline should be administered immediately, via intramuscular injection in the community (Epipen/Anapen) or intravenously, if possible. Adrenaline (epinephrine) is a sympathomimetic--it activates the sympathetic nervous system. Actions of adrenaline on apha-1 receptors causes systemic vasoconstriction, countering the effects of histamine and preventing or relieving hypotension, loss of circulating volume, and angioedema that might obstruct the airways.

Beta-1 adrenergic receptor binding increases heart rate and cardiac output to help manage shock. Although this adds to the risk of cardiac dysrhythmias and ischaemia, the benefits, including dilation of coronary arteries, outweigh the risks in anaphylaxis. (5) Beta-2 binding causes bronchodilation and also reduces the release of histamine from mast cells, although this effect is subject to tolerance mechanisms--increased use of Beta-2 agonists (eg salbutamol) reduces responses. (14)

People with anaphylaxis who are taking antihypertensive drugs have increased risk for adverse outcomes. Beta-blockers, ACE-inhibitors, diuretics and other drugs that interfere with the actions of adrenaline in maintaining blood pressure will reduce the efficacy of interventions in anaphylaxis. They are also believed to increase the risk of developing anaphylaxis because they reduce the body's ability to compensate for initial reactions to an allergen. (15)

The utility of second-line drug therapies in anaphylaxis is subject to considerable debate as the evidence supporting their use is poor. Most concern centres on the risk that second-line therapies might be used in place of adrenaline, thus delaying essential life-saving therapy. (5)

Histamine H1 receptor antagonists (antihistamines)

The older, sedating antihistamines (eg promethazine) are not recommended due to their sedating effects, which could mask worsening anaphylaxis; they also increase risk of hypotension and necrosis when administered via IM injection. (3)

Oral, non-sedating antihistamines have a relatively slow onset of action. Antihistamines can help to relieve urticaria, nasal and eye symptoms associated with type 1 hypersensitivity reactions, and may help to reduce angioedema. (5) Because these drugs act as competitive antagonists at the histamine receptors, they are not useful in anaphylaxis where the H1 receptors are already well occupied by histamine. They do not affect histamine release and have not been demonstrated to relieve many of the effects of histamine on smooth muscle. They are accompanied by risk of sedation, anticholinergic effects (eg dry mouth, urinary retention), and potential for cardiac dysrhythmias and tachycardia. (5,16)

Beta-2 agonists

Salbutamol helps relieve bronchoconstriction but is not helpful in anaphylaxis, compared with adrenaline, because it has little effect on vasodilation, angioedema and upper airway obstruction, or shock. (5)


Steroid drugs inhibit the synthesis of many inflammatory mediators and may help reduce the number of mast cells and overall responsiveness to allergens in atopic individuals. However, their use in relieving acute anaphylactic symptoms is not supported by evidence. Glucocorticoids take several hours to exert an effect so they may have an impact on late-phase responses. (4,5)

The risk of relapse after adrenaline has worn off, or of a biphasic reaction, mean that a patient should be observed for at least four hours after the last dose of adrenaline.


Food allergies are the most common cause of anaphylaxis, although not all allergic individuals experience anaphylaxis on exposure. Allergies to food can arise at any age. Common allergies include egg, cow's milk, peanuts (more common in children), tree nuts, fish and shellfish (more common in adults). (5)

Stings from wasps, honey bees, paper wasps and bumble bees are common in New Zealand, and the incidence of allergy may be about one per cent of the population. (19) Risk for developing hypersensitivity is increased by repeated frequent exposure, but not by the presence of atopy, or when localised reactions to stings occur. (4)

Allergic reactions to drugs are relatively rare--approximately one in 10,000 courses of penicillin and one in 250,000 doses of vaccines and not strongly associated with a history of atopy. (3) Drugs that carry the highest risk are antibiotics, nonsteroidal anti-inflammatory drugs (including aspirin--although reactions are not always IgE-mediated), vaccines, general and local anaesthetics, and X-ray contrast agents or dyes. Biological agents such as monoclonal antibodies are associated with increased risk of anaphylaxis, as are contaminants in medications, including herbal remedies. (5)


Immunotherapy can be used to reduce sensitivity to some allergens mainly insect stings--with up to 90 per cent success rates. This involves repeated exposure to increasing doses of the offending allergen over a period of weeks, with maintenance over years. The mechanism underlying the development of tolerance is not well understood but involves the generation of high amounts of IgG antibodies that appear to inhibit the action of IgE. Repeated exposure to the antigen possibly redirects the immune system from Th2 to Th1 helper cells. Desensitisation carries associated risks of anaphylaxis, and localised reactions.

Children with food allergies may outgrow them, developing tolerance as they get older. This is related to the number of foods to which the child is allergic, the type of allergic response generated, and the types of food involved. Children with severe allergies are less likely to develop tolerance, while those with nut and seafood allergies are also less likely to outgrow them. (17) Development of tolerance may occur by similar mechanisms, as described above in relation to desensitisation. Immaturity of the immune system appears to be significant because the Thlymphocyte response to the presence of allergens is not yet locked in. (18)

Monoclonal antibodies

Omalizunab is an antibody that reacts to IgE. Omalizunab binds to IgE and prevents it from attaching to its receptors on the mast cells and basophils, thus inhibiting activation of type 1 hypersensitivity. This is not a drug that can be used acutely in the treatment of anaphylaxis or hypersensitivity as, in these cases, the mast cells have already been activated. Used long-term as a prophylactic therapy in asthma, omalizunab reduces exacerbations in people with severe, IgE-mediated asthma that is unresponsive to corticosteroids. It takes several weeks to reach full therapeutic effect and is itself associated with a risk for anaphylaxis. (4)

Education, identification and intervention

Risk of death from anaphylaxis is increased by delayed administration of adrenaline, failure to lie the patient down and a history of asthma. Positive outcomes following acute hypersensitivity reactions rest on the ability of the victim and caregivers to identify the occurrence of the reaction and to intervene rapidly and appropriately. For this reason, education about anaphylaxis is a high priority. There are many websites that provide excellent resources for both heath professionals and patients about hypersensitivity and anaphylaxis, eg the Australasian Society of Clinical Immunology and Allergy (

* References for this article can be found at

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Table 1. Signs and symptoms of allergic reactions and anaphylaxis

* Swelling around lips, face and * Wheezing, hoarseness, cough
 * Shortness of breath/ difficulty
* Urticaria (hives) and breathing
 * Swollen tongue/ tight throat
* Tingling/itching of mouth,
palms, soles * Dizziness and fainting

* Abdominal pain and vomiting * Nausea and vomiting

* Rhinorrhoea, sneezing, nasal * Diarrhoea, abdominal pain
 * Feeling of impending doom

 * Chest pain

 * Tachycardia and hypotension

 * Faecal and urinary incontinence

 * Respiratory arrest

 * Cardiac arrest

Skin reactions and angioedema occur in up to 90% of cases, but these
may be transient or subtle and easily missed. Symptoms may appear
within minutes or up to several hours after exposure to the antigen.
Rapid development of symptoms is associated with increased severity.
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Title Annotation:CPD + nurses; Continuing Professional Development
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Report
Geographic Code:8NEWZ
Date:Oct 1, 2013
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