Allergy is a harmful response to an otherwise innocuous substance. Allergic reactions are immunologically mediated reactions to external substances, usually proteins. These are often, but not always, mediated by immunoglobulin E (IgE) antibody. Initial exposure to an allergen results in sensitization with the production of allergen-specific IgE antibodies. These antibodies circulate in the blood but are largely bound to high-affinity receptors on the surface of basophils and mast cells and low affinity receptors on eosinophils, macrophages, and platelets.
On further exposure, the allergen reacts with the IgE bound to mast cells and basophils, causing degranulation and release of preformed mediators such as histamine and tryptase. These mediators cause the immediate phase of the type I reaction, which occurs within a few minutes (immediate hypersensitivity). Other mediators and cytokines are released and eosinophils are attracted to the site of activity, precipitating the late phase of the type I reaction, which starts 4–6 h after exposure.
Immediate hypersensitivity reaction occurs in asthma, rhinitis, and anaphylaxis. In a sensitized asthmatic, early and late phase asthmatic reaction can be observed following bronchial allergen challenge. Repeated or continued exposure to allergen results in chronic airway inflammation, which is characteristic of asthma.
Systemic allergic reactions vary in severity from mild (such as generalized urticaria) to severe and life-threatening reactions with cardiovascular collapse and death. Anaphylaxis is the clinical syndrome that represents the life-threatening systemic allergic reaction. It results from the immunologically induced release of mast cell and basophil mediators after exposure to a specific antigen in previously sensitized individuals.
Clinically indistinguishable reactions, caused by non-IgE-mediated immune mechanisms, are termed anaphylactoid reactions. Common causes of anaphylaxis are foods, drugs, insect stings, latex, and allergen extracts used for immunotherapy. The symptoms of anaphylaxis occur within a few minutes of exposure and are generally related to the skin, gastrointestinal tract, respiratory tract, and cardiovascular systems. Common manifestations include generalized urticaria/angioedema, nausea, vomiting, stridor, wheezing, hypotension, and syncope.
Anaphylaxis requires immediate treatment with epinephrine, given intramuscularly. The dosage for adults is 0.3–0.5 ml, and for children is 0.01 ml kg1, of a 1:1000 solution. The dose can be repeated at 5–15 min intervals. Supportive treatment includes cardiopulmonary resuscitation (if required), intravenous fluids, oxygen, antihistamine, and corticosteroids. Following the first episode, an assessment by an allergist is essential to establish the cause and for appropriate advice on preventive measures including avoidance of the offending agent and self-injectable epinephrine.
Atopy is defined as the genetic predisposition to form immunoglobulin (IgE) antibodies on exposure to allergens. The production of IgE is central to the induction of allergic diseases. Allergens are proteins with the capability to react to the immune system through their antigenic determinants. Initial exposure to the antigen results in sensitization. Antigens enter the body through the respiratory and gastrointestinal mucosa and the skin. Allergenic proteins are engulfed by antigen-presenting cells (APCs) such as monocytes, macrophages, and dendritic cells inducing primary immune response. The antigen is broken down to reveal the specific part of the molecule called antigenic determinant or epitope. Once processed in this way, the antigen is bound to the MHC class II molecules on the surface of these cells and the complex is presented to the T lymphocyte cell receptor. Bacterial antigens favor the production of Th1 cells with the secretion of its profile of cytokines, particularly interferon gamma (IFN-g). In atopic individuals, and in the presence of co-stimulatory signals, naı¨ve T cells are converted to activated CD4þ T-helper-2 (Th2) cells.
T lymphocytes play a central role in orchestrating the allergic reaction. Th2 cells produce cytokines, such as interleukin-4 (IL-4) and IL-13. These cytokines cause proliferation and switching of B cells to IgE producing B and plasma cells, specific to the antigen (Figure 1). Some of these cells have a long life and are called memory cells. IL-4 is the most important pro-allergy cytokine. Apart from switching of B cells to IgE production, it also stimulates T cells and macrophages, and enhances the expression of low-affinity IgE receptor (FceR2) on B cells and adhesion molecules on endothelial cells. This latter action promotes the movement of cells out of the blood vessels. It also inhibits other types of immune reaction, such as antibody-dependent cell-mediated cytotoxicity. IL-13 has similar but weaker biological activity though it lasts longer than IL-4. IFN-g inhibits allergic responses and its effects are opposite to IL-4 and IL-13. Therefore, it is crucial in the regulation of IgE production. Other cytokines, which inhibit allergic responses, are IL10, IL-12, TGF-b, and IL-8.
The direction of immune response on exposure to allergen depends on the balance of Th1 and Th2 reactivity and ensuing cytokine milieu. In atopic individuals the balance is tilted towards the production of Th2 type cytokines (IL-4 and IL-13) as opposed to Th1 type, such as IFN-g. The Th2 differentiation and production of IgE is also suppressed by regulatory T cells (CD4þCD25þ). Thus, an inappropriately weak T regulatory mechanism would facilitate Th2 dominance and production of IgE and allergic disease. It is likely that allergen exposure in early childhood results in a lifelong T cell memory pool. In atopic individuals, the immunological memory is dominated by Th2 type cells leading to allergic reactivity, whereas in nonatopic subjects, Th1 cells dominate the memory pool. In addition to genetic predisposition, environmental factors (infections, diet, etc.) may also influence the outcome of these initial responses by altering the cellular and cytokine milieu within the lymph nodes.
In atopic subjects with their Th2 skew, IgE is formed specific to the antigenic protein following initial exposure (sensitization). The IgE circulates in the blood in small quantities but is mostly present in the tissues bound to high-affinity receptors (FceR1) on the surface of mast cells and basophils and FceR2 on eosinophils, macrophages, and platelets. This IgE can be detected in the serum by immune assays or in the skin by allergy skin tests. On further exposure, multivalent antigens bind and cross-link IgE bound to FceR1 on cell surface leading to the signaling cascade that causes rapid release of preformed mediators such as histamine, tryptase, and heparin (Figure 1). These mediators cause the immediate phase of the type I hypersensitivity reaction, which occurs within a few minutes (hence immediate hypersensitivity). There is also induction of rapid synthesis of arachidonic acid metabolites such as prostaglandins and leukotrienes and expression of cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, and tumor necrosis factor alpha (TNF-a)) and chemokines. Eosinophils are attracted to the site of activity, precipitating the late phase of the type I reaction, which starts 46 h after exposure (Figure 2).
Immediate hypersensitivity is central to all IgE mediated allergic reactions and occurs in asthma, rhinitis, and anaphylaxis. During acute allergic reactions, the process is acute with the release of huge quantities of histamine causing typical symptoms and signs, such as acute bronchospasm or anaphylaxis. However, the process may be subacute or chronic and localized to one site such as lung or nose. Repeated exposure to allergens leads to the induction of a more chronic inflammatory process with the influx of inflammatory cells including T lymphocytes and eosinophils. Cytokines, produced by a variety of inflammatory cells, including T cells, regulate the inflammatory process. Proliferation of Th2 subsets producing predominantly IL-4 and IL-5 results in differentiation and isotype switching of the naı¨ve B cells to IgE-producing plasma cells as well as activation and influx of inflammatory effector cells such as eosinophils. Eosinophils are potentially tissue damaging, particularly after priming with IL-5. Various cytokines upregulate adhesion molecules on endothelial and epithelial cells, thereby enhancing migration of eosinophils into the mucosa.
Allergic Reaction in the Lung
Allergic reaction in the lung results in airway inflammation. Exposure to allergen is recognized as important in initiating and maintaining allergic airway inflammation in atopic asthmatics. In the appropriate setting of repeated allergen exposure and Th2 type immune responses, a cytokine milieu is created with upregulation of adhesion molecules and continuous recruitment and activation of inflammatory cells from the bloodstream towards the bronchial mucosa. The release of cytokines and inflammatory mediators by activated cells causes amplification and persistence of the inflammatory process. However, structural cells such as epithelial cells and smooth muscle cells are not merely passive recipients of immune-related tissue damage but are active participants of the complex inflammatory cascade, which may well have initiated at the epithelial/ mesenchymal level within the airways. Nonatopics show similar inflammation in their airways and thus IgE-mediated allergy in not a prerequisite for airway inflammation in asthma or rhinitis.
Early Asthmatic Reaction
The effect of allergen exposure can be observed and studied in a controlled fashion during bronchial allergen challenge. In an atopic asthmatic, inhalation of allergen to which the patient is sensitized, results in an immediate hypersensitivity reaction with the release of mast cell mediators in the bronchial mucosa. These mediators enhance vascular dilatation, increase permeability of the venule, and increase mucus secretion, resulting in edema and congestion, typical of an acute phase reaction. Histamine and leukotrienes are potent bronchoconstrictors. Histamine stimulates local type c neurones leading to the release of several neuropeptides, including substance P, which further increase vascular permeability and cause stimulation of parasympathetic reflexes augmenting mucous secretion and bronchoconstriction. These changes manifest clinically in cough, wheeze, and dyspnea.
Late Asthmatic Response
Clinically, the effect of early asthmatic reaction diminishes after 30min (Figure 2). This is followed by a relatively asymptomatic period during which a plethora of cytokines and mediators draw leukocytes to the tissues. Events initiated during the early response result in vascular dilatation and increased permeability, edema formation, and the accumulation of cells. IL-5, secreted from mast cells, lymphocytes, and eosinophils is the most important cytokine for eosinophils. Besides attracting them to the site of inflammation, it also causes their proliferation, activation, and increased survival. Other eosinophilic cytokines are IL- 3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokines. Upon activation, eosinophils release mediators such as eosinophilic cationic proteins, major basic proteins, leukotrienes, and prostaglandins. These and other mediators enhance inflammation and cause epithelial damage. This results in bronchoconstriction clinically 4–12 h later and prolonged bronchial hyperresponsiveness, mucus secretion, and edema formation. Further secretion of a host of cytokines including IL-3, IL-4 and IL-5, contribute to an ongoing inflammation.
With continued or repeated exposure to allergen, a state of chronic inflammation develops with increased numbers of activated Th2 cells, expressing mRNA for the secretion of IL-3, IL-4, IL-5, and GMCSF. These cytokines are important in the continuation of inflammation and the attraction of mast cells and eosinophils. These cells cause further increase in histamine, prostaglandins, and eosinophilic toxic products, causing epithelial damage. There is upregulation of intercellular adhesion molecules in the blood vessels promoting stickiness of the endothelium to leukocytes and facilitating their passage across, into the tissues. Increased permeability and cellular infiltration causes mucosal edema. Even in patients with mild, intermittent asthma, a state of low-grade inflammation persists, in the absence of symptoms. It is hypothesized that almost continuous exposure to very small amounts of allergens, such as house dust-mite, or pollen during summer, contributes to this ongoing allergic reaction without causing symptoms. Under the influence of IL-4 from mast cells, more B cells are switched to the production of IgE antibodies, thus maintaining allergic reaction. Bronchoscopy studies reveal increased numbers of activated inflammatory cells and cytokines in the respiratory mucosa and secretions.
The clinical features of asthma are due to the airway narrowing causing obstruction to airflow. This airway obstruction has three elements:
Excessive bronchial smooth muscle contraction. Inflammatory mediators such as histamine, bradykinin, prostaglandins, and leukotrienes act directly on their specific receptors to cause bronchoconstriction. In asthma, the smooth muscles contract easily and excessively following exposure to inflammatory mediators perhaps due to heightened sensitivity of their receptors. On the other hand, b2-receptors may have a diminished response. This feature is called bronchial hyperresponsiveness.
Thickening of bronchial wall. Bronchial wall thickening is due to inflammatory and fibrotic changes. Increased capillary permeability allows plasma exudation into the mucosa causing edema and cellular infiltration. Proliferation of fibroblast and myofibroblast leads to thickening of the basement membrane with deposition of collagen and hypertrophy of bronchial smooth muscles (airway remodeling). This leads to irreversible airway obstruction in chronic asthma.
Excessive luminal secretions and cellular debris. There is excess mucus secretion due to glandular hyperplasia. The epithelium is fragile and damaged epithelial cells are found in the sputum. Impaired ciliary function encourages retention of thick mucus in the lumen. During severe exacerbation, the lumen of the airway is blocked by thick mucus, plasma proteins, and cell debris.
Allergic reactions in the nose follow a similar process with inflammation of the nasal mucosa, resulting in rhinorrhea, sneezing, and nasal blockage.
Systemic Allergic Reactions and Anaphylaxis
Allergic reactions vary widely in severity from mild pruritis and urticaria to circulatory collapse and death. An acute systemic allergic reaction with one or more life-threatening features, such as stridor or hypotension, is termed anaphylaxis. Allergic reactions with troublesome but not life-threatening reactions, such as generalized urticaria/angioedema and bronchospasm of mild to moderate severity, may be called severe allergic reactions. Traditionally, the term anaphylaxis is used for IgE-mediated reactions. Systemic reactions that clinically resemble anaphylaxis but are caused by non-IgE-mediated mediator release from mast cells and basophils are referred to as anaphylactoid reactions. Anaphylaxis occurs in 30/100 000 population/year with a mortality of 1–2%. Offending agents include foods, drugs, insect stings, and exercise but in 20% of cases no cause can be found (idiopathic).
Systemic allergic reaction occurs as a result of degranulation of mast cells and basophils. Mast cells in respiratory and gastrointestinal tract, skin, and perivascular tissues are involved in both IgE and non-IgEmediated allergic reaction. IgE-mediated release is caused by antigen-specific cross-linking of IgE molecules on the surface of tissue mast cells and peripheral blood basophils. Non-IgE-mediated release may be due to direct stimulation of mast cells. Mast cells produce both histamine and tryptase while basophils secrete histamine but not tryptase. Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion.
Anaphylaxis is a rapidly developing generalized reaction that involves respiratory, cardiovascular, cutaneous, and gastrointestinal systems. Clinical manifestations vary depending on the cause of anaphylaxis, route of entry, host factors (such as degree of sensitization, associated factors such as exercise, comorbidity, etc.) and the amount of allergen exposure. The initial symptoms, such as nasal congestion or pruritis, can quickly progress to collapse or death. Laryngeal edema, cardiovascular collapse, and severe bronchospasm are life-threatening features. In one large series of fatal anaphylactic reactions, 70% of the deaths were from respiratory causes, and 24% were from cardiovascular causes. In 10–20% of cases, skin may not be involved. Anaphylaxis can be confused with septic or other forms of shock, asthma, airway foreign body, and panic attacks (Table 1).
Symptoms commonly occur within a few seconds or minutes of exposure and death may occur within minutes. Speed of onset of symptoms is indicative of the severity. Occasionally, the onset of symptoms may be delayed for 2 h or more. In general, the later the symptoms begin after exposure to a causative agent, the less severe the reaction. Food allergens may have slower onset or slow progression and gastrointestinal symptoms are more common. Onset of anaphylaxis to insect stings or allergen injections is usually rapid: 70% begin in o20 min and 90% in o40min.
A quick initial assessment should determine the nature and progression of the clinical event (Table 2). Continuous monitoring is essential as progression from a mild to a severe episode may occur rapidly. Epinephrine injected intramuscularly into the thigh provides the most efficient absorption (Figure 3).
If there is no response to several doses of intramuscular epinephrine, intravenous administration may be needed, by using a formulation of 1:10 000 (0.1 mg ml1) at 1mgmin1, which can be increased to 2–10 mg min1. If the response is still inadequate, transfer the patient to an intensive care unit for close monitoring and endotracheal intubation, if required. Specific treatment for coexisting medical conditions (e.g., coronary artery disease) may be necessary. There may be complete resolution of the reaction. However, if there are concerns, continued monitoring for remaining or recurring symptoms is essential. A short course of corticosteroids may reduce the risk of recurring or protracted symptoms of a biphasic reaction but this is not proven. Patients receiving badrenergic blocking agents may not respond adequately to epinephrine. They require continued fluid replacement and may respond to glucagon. Patients receiving angiotensin-converting enzyme inhibitors may also be at increased risk of anaphylaxis and be more refractory to treatment with epinephrine.
If there is any doubt regarding the diagnosis, blood should be taken for plasma histamine or serum tryptase levels within the first 4 h after the onset of symptoms. Elevated serum levels of b-tryptase indicate mast cell activation and degranulation in both IgE-mediated (anaphylaxis) and non-IgE-mediated (anaphylactoid) reactions. b-tryptase is useful in differentiating anaphylaxis from other events having similar clinical manifestations, particularly if hypotension is present. Blood for plasma histamine needs to be processed immediately to avoid detecting artificially high levels due to spontaneous basophil histamine release. If this is not possible, urinary histamine (or metabolites) levels can be checked for up to 24 h.
After initial treatment of acute anaphylaxis, the patient should be followed-up closely for the possibility of recurrent episodes. For mild to moderate episodes and good response to treatment, further monitoring can be done at home. However, following a severe episode, in-patient monitoring may be required for late-phase reactions.
All individuals who have had a known or suspected anaphylactic episode require a careful allergy evaluation. The aims are to review the diagnosis of anaphylaxis and prevent or minimize the risk of future anaphylactic episodes by identifying the cause, educate the patient and/or family members regarding avoidance of the offending agent, education and training to deal with future inadvertent exposures, and consideration of desensitization, if appropriate. The level of confidence in the diagnosis of the original episode should be reviewed with details of the events before and during the episode. Results of any laboratory tests (e.g., serum tryptase or urine histamine) may be helpful in supporting the diagnosis of anaphylaxis and differentiating it from other entities. However, a careful and comprehensive history is the most useful part of the assessment. Information on any previous similar episodes, known food or drug allergy, and medication record should be sought. The history might suggest a specific cause such as insect sting or peanut consumption just before the episode. However, the cause may not be obvious from history and sometimes no cause can be found despite thorough searching (idiopathic anaphylaxis).
Skin prick tests (SPTs) or determination of specific IgE in serum (in vitro test) is helpful in identifying a specific cause of anaphylaxis in cases of food, insect, and some cases of drug (penicillin, insulin) allergy. An SPT is more sensitive than in vitro testing and is the diagnostic procedure of choice. When possible, standardized extracts should be used. If skin tests or in vitro tests do not provide a cause, then challenge to the suspected agent/agents should be considered. Challenge procedures are helpful in IgE-mediated allergic reaction where standardized test material is not available and in non-IgE anaphylactic reactions (such as to aspirin).
Once the offending agent has been identified (e.g., food, medication, or insect sting), patients should be educated regarding the specific exposures and be counseled on avoidance measures (Table 3). All those with a risk of future anaphylaxis outside the medical settings should carry and be educated in the use of self-injectable epinephrine and antihistamines. Self-injectable epinephrine is available in two different strengths (for adults, 0.3 ml of 1:1000 solution and for children, 0.3 ml of 1:2000 solution) in ready to- use syringes. Antihistamine (such as chlorpheniramine 4–8 mg orally) may be sufficient for a mild episode but epinephrine should not be held back if symptoms are severe from the outset or response to antihistamine is inadequate. Humanized, monoclonal anti-IgE antibody has shown protection against peanut-induced anaphylaxis.
Food allergic reactions are common in children and presents clinically with systemic involvement (as described above), although oral (itching, numbness and tingling of lips and mouth) and gastrointestinal symptoms may be more prominent. Although any food can cause a reaction, commonly implicated foods are milk, egg, peanuts, tree nuts, fish, and shellfish. Symptoms often occur within minutes of ingestion and certainly within 2 h. Assessment of specific IgE to suspected food, either by skin prick test or in vitro test, in the presence of a suggestive history, is sufficient to make a definitive diagnosis. However, food challenges (single or double blind) may be required. Strict avoidance of the offending food is essential. Patients should also carry, and be trained, in the use of epinephrine in an emergency following inadvertent exposure.
Allergic reaction to penicillin is the most common cause of anaphylaxis. Severe reactions are usually attributable to parenteral administration. Atopy and family history of penicillin allergy does not increase the risk of a reaction. A history of penicillin allergy is not reliable as nearly 80% of these individuals tolerate penicillin without ill effects. However, these subjects should have a skin test to major and minor determinants before penicillin is administered. The risk of a reaction following a negative test is less than 2%. Skin tests do not resensitize a patient to penicillin. A positive skin test in the presence of a history of reaction to penicillin indicates a more than 50% risk of an allergic reaction and penicillin should be avoided, or if penicillin is mandatory, desensitization should be considered. Cross-reactivity exists between cephalosporins and penicillins due to the common b-lactam ring structure.
Aspirin and Nonsteroidal Anti-Inflammatory Drugs
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can induce life-threatening systemic, non- IgE-mediated reaction causing rhinoconjunctivitis, bronchospasm, urticaria, and laryngeal edema. In vitro or skin tests are not available and oral challenges are required for confirmation. If the diagnosis is confirmed, aspirin and NSAIDs should be strictly avoided. Desensitization may be performed if these drugs are considered essential.
Stinging insects belong to the order Hymenoptera. Common stinging insects include honeybees, wasps, yellow jackets, hornets, and fire ants. The self-reported prevalence of insect sting allergy is approximately 1%. Insect venoms contain several well-characterized allergens that can trigger anaphylactic reactions. Localized reaction may occur at the site of the sting and a large local reaction may involve, for example, the whole limb. However, these do not predispose to systemic allergic reaction. Urticaria and angioedema are key features of systemic allergic reactions caused by insect sting.
Skin test is the preferred method of confirming allergy and identifying the responsible insect species. However, careful interpretation is needed, as falsepositive reactions are common. Following a systemic allergic reaction, only about half of the patients will react to a future sting. Patients should carry self-injectable epinephrine for early treatment of a sting, and allergen immunotherapy should be considered, where risk of future sting is substantial. The immunotherapy is >90% effective but optimal duration is not known.
Common agents responsible for intraoperative anaphylaxis are neuromuscular blocking agents, latex, antibiotics, anesthesia induction agents, radiocontrast material, and opioids. Neuromuscular blocking agents and thiopental are responsible for most anaphylactic reactions during general anesthesia. Both IgE-mediated (muscle relaxants, latex) and direct stimulation of mast cell (opioids, radiocontrast material) occurs. Clinical manifestations of intraoperative reactions differ from anaphylactic reactions due to other causes as cardiovascular collapse, airway obstruction, and flushing is prominent. It may be difficult to differentiate allergic reaction from the pharmacologic effects of a variety of medications administered during general anesthesia. Plasma tryptase is useful in differentiating allergic reaction (due to mast cell release of mediators) from pharmacologic or other causes. Skin testing is used for diagnosis where IgE-mediated mechanism is suspected. Otherwise, graded challenge may be required.
IgE-mediated allergic reactions to natural rubber latex became common during the 1990s due to a sudden increase in the use of rubber gloves. Risk factors for latex allergy include atopy and previous repeated exposure to latex (e.g., multiple surgical procedures, healthcare workers). Skin tests are indicated for investigation of latex allergy in those who have a history of possible latex allergic reaction and for screening those who are at high risk. However, in the last few years, the use of latex-free gloves and other products have been effective in reducing the occurrence of latex allergic reactions.
Allergic reactions may complicate 1–3% of blood transfusions. Most reactions are mild, are associated with cutaneous manifestations such as pruritis, maculopapular, or urticarial rash and flushing, and require no specific treatment except discontinuation of transfusion and perhaps antihistamine. However, severe or life-threatening reactions with hypotension and bronchoconstriction may occur occasionally. Most of these reactions are due to IgE or IgM antibodies to serum proteins (e.g., albumin, complement components, IgG, and IgA). Other mechanisms include transfusion of allergen, IgE antibodies, bacterial components or inflammatory substances such as cytokines, histamine, or bradykinin. Blood components containing large amounts of plasma, such as fresh frozen plasma, may be associated with more severe allergic reactions. Serum tryptase, measured soon after the reaction, may differentiate allergic from transfusion-related reaction.
Allergen extracts are injected during skin test and allergen- specific immunotherapy. The risk of allergic reaction is extremely low with skin prick test but not insignificant when these extracts are injected for treatment. In a survey between 1985 and 1989 in the US, there were 17 deaths from allergen immunotherapy but none from skin testing. Mild, localized reactions are relatively common and respond to antihistamine. Factors that increase the risk of an allergic reaction should be kept in mind by those involved in administration of allergen-specific immunotherapy (Table 4).
Exercise-induced anaphylaxis is a physical form of allergy that may occur in isolation or in combination with ingestion of food or drug, such as aspirin or NSAIDs. The episode resembles typical anaphylaxis and emergency treatment is the same as for anaphylaxis due to other causes. Patients should carry self-injectable epinephrine. Exercise may also cause urticaria or bronchospasm without anaphylaxis.
Cockcroft DW (1998) Airway responses to inhaled allergens. Canadian Respiratory Journal 5(supplement A): 14A–17A.
El Biaze M, Boniface S, Koscher V, et al. (2003) T cell activation, from atopy to asthma: more a paradox than a paradigm. Allergy 58(9): 844–853.
Gould HJ, Sutton BJ, Beavil AJ, et al. (2003) The biology of IgE and the basis of allergic disease. Annual Review of Immunology 21: 579–633.
Holgate ST, Davies DE, Puddicombe S, et al. (2003) Mechanisms of airway epithelial damage: epithelial–mesenchymal interactions in the pathogenesis of asthma. European Respiratory Journal 44(supplement): 24s–29s.
Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology (1998) The diagnosis and management of anaphylaxis. Journal of Allergy and Clinical Immunology 101(6 Pt 2): S465–S528.
Kemp SF and Lockey RF (2002) Anaphylaxis: a review of causes and mechanisms. Journal of Allergy and Clinical Immunology 110(3): 341–348.
Lieberman P (2002) Anaphylactic reactions during surgical and medical procedures. Journal of Allergy and Clinical Immunology 110(supplement 2): S64–S69.
Moffitt JE (2003) Allergic reactions to insect stings and bites. Southern Medical Journal 96(11): 1073–1079.
Moneret-Vautrin DA and Kanny G (2002) Anaphylaxis to muscle relaxants: rational for skin tests. Allergic Immunology (Paris) 34(7): 233–240.
Noone MC and Osguthorpe JD (2003) Anaphylaxis. Otolaryngologic Clinics of North America 36(5): 1009–1020.
Sampson HA (2003) Anaphylaxis and emergency treatment. Pediatrics 111(6): 1601–1608.
Sicherer SH and Leung D (2004) Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insect stings. Journal of Allergy and Clinical Immunology 114(1): 118–124.
Tang AW (2003) A practical guide to anaphylaxis. American Family Physician 68(7): 1325–1332.